Sulfamate derivative compounds for the treatment or alleviation of mental disorders - Patents.com

Abstract

The present invention relates to a pharmaceutical composition for treating or preventing a psychiatric disorder, which comprises a sulfamate derivative compound and / or a pharmaceutically acceptable salt thereof as an active ingredient. The present invention also relates to a pharmaceutical composition for inducing anti-stress, anti-anxiety and / or antidepressant activity, which comprises a sulfamate derivative compound and / or a pharmaceutically acceptable salt thereof as an active ingredient.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition for treating or alleviating a psychiatric disorder, which comprises a sulfamate derivative compound and / or a pharmaceutically acceptable salt thereof as an active ingredient. Furthermore, the present invention relates to a pharmaceutical composition for inducing anti-stress, anti-anxiety and / or antidepressant activity, which comprises a sulfamate derivative compound and / or a pharmaceutically acceptable salt thereof as an active ingredient. [Background technology]

[0002] Psychiatry is a medical specialty dedicated to the study, diagnosis, treatment, and prevention of mental illness. This includes a variety of emotional, behavioral, cognitive, and perceptual disorders. Many psychiatric syndromes are characterized by depressed mood as a primary symptom. Depression is a state of sluggish mood and aversion to activities that can affect a person's thoughts, behaviors, emotions, and sense of well-being. Depressed people may feel sad, anxious, empty, hopeless, worried, powerless, worthless, guilty, depressed, hurt, or anxious. Mood disorders are a group of disorders considered to be primarily disturbances of mood. This includes major depressive disorder (MDD, commonly referred to as major depressive disorder or clinical depression). This disorder is characterized by a depressed mood for at least two weeks or a loss of interest or pleasure in almost all activities, as well as dysthymia, i.e., a state of chronic depression where symptoms do not match the severity of major depressive symptoms.

[0003] Bipolar disorder, another mood disorder, is characterized by one or more symptoms of abnormally elevated mood, cognition, and energy levels, which may include one or more depressive symptoms. When the course of depressive symptoms follows a seasonal pattern, the disorder (e.g., major depressive disorder, bipolar disorder) can be described as a seasonal affective disorder. In addition to mood disorders, borderline personality disorder is commonly characterized by depressed mood. Adjustment disorder with depressed mood is a mood disorder that manifests as a psychological response to a identifiable event or stressor, and while the resulting emotional or behavioral symptoms are significant, they do not meet the criteria for major depressive disorder, post-traumatic stress disorder, or anxiety disorders. Sometimes symptoms following trauma are commonly accompanied by depressed mood. Bipolar disorder has long been known as a chronic mental illness, with a high relapse rate, mostly recurrent, and presumed neurobiological substrate.

[0004] Anxiety is a broad, extremely unpleasant or vaguely unsettling sensation, encompassing not only the associated physical symptoms but also the most basic response that occurs when a living organism attempts to adapt to an unfamiliar environment. This response includes both physical and behavioral symptoms. Anxiety stimulates the autonomic nervous system, a normal psychological response that serves as a defense mechanism for protecting the body. However, frequent anxiety can be exhausting, and repeated stress or overwork can overactivate the sympathetic nervous system, disrupting daily life and potentially leading to anxiety disorders. Anxiety disorders include post-traumatic depression, stress disorder, obsessive-compulsive disorder, social phobia, and generalized anxiety disorder. Anxiety can also be associated with other mental disorders, such as depression and substance abuse. Social phobia and generalized anxiety disorder, in particular, are not well known but cause distress to many people and are sometimes considered mental illnesses. Patients with anxiety disorders often experience depression and frequently turn to alcohol to reduce anxiety, potentially leading to addictions such as alcoholism.

[0005] Representative anti-anxiety drugs currently on the market include benzodiazepines, such as diazepam, oxazepam, prazepam, lorazepam, loprazelam, alprazolam, erazepam, and clonazepam, and these drugs are also used primarily for the purposes of sedation and sleep induction.

[0006] However, most anti-anxiety drugs have been criticized for their side effects. Benzodiazepines, which are the most commonly prescribed drugs in Korea due to their rapid onset of action, have been criticized for their various side effects. Benzodiazepines are highly addictive, and discontinuing their administration can lead to a recurrence of symptoms or the appearance of withdrawal symptoms. Side effects include drowsiness, ataxia, orthostatic hypotension, respiratory depression, headaches, chronic sleep disorders, and liver disease.

[0007] Among anxiety disorders, depressive disorder refers to a state in which a person's internal emotional state is abnormally depressed and low. Depressive disorder, or depression, is also defined as a disease that causes various cognitive and psychosomatic symptoms, with a loss of motivation and depression as its main symptoms, resulting in a decline in daily functioning.

[0008] It has also been reported that approximately 80% of patients with depression complain of sleep disorders, particularly symptoms such as not being able to sleep until morning, waking up early, and frequently waking up in the middle of the night. Many patients also experience a loss of appetite and weight loss, while some patients exhibit atypical symptoms such as increased appetite and prolonged sleep. Furthermore, it is known that approximately 90% of patients with depression also exhibit symptoms related to anxiety. Other symptoms include decreased libido and impaired concentration, which can lead to cognitive decline.

[0009] Although various treatments have been proposed for the treatment of depression, such as psychotherapeutic approaches, electroconvulsive therapy, and phototherapy, the current situation is that drug therapy has been the mainstay. However, various antidepressants proposed based on the neurotransmitter system generally require several days to several weeks to become effective, and the drug's effectiveness can only be confirmed after at least four to six weeks of administration, and various side effects have been reported.

[0010] Meanwhile, mental stress is not only a cause of mental disorders such as anxiety and depression, but is also considered to be a trigger for various illnesses, including tension headaches, migraines, pain, various neuroses, high blood pressure, diabetes, indigestion, digestive ulcers, decreased physiological and immune activity, weakened body resistance, emotional instability, menopausal disorders, and sexual dysfunction. In particular, mental stress is considered to be a major cause of disorders such as anxiety and depression, acting on the central nervous system, endocrine system, and various metabolic systems in the body.

[0011] In stress research, several methods have been proposed for inducing acute stress, and among these, the forced swimming stress method has been proposed as a method using experimental animals. The forced swimming stress method can simultaneously inflict both physical and mental stress, and it has been reported that this stress increases the secretion of adrenocorticotropic hormone, increasing blood corticosterone levels, which act on the autonomic nervous system to increase catecholamines and activate the sympathetic nervous system. Therefore, the improvement effects of the forced swimming stress method can be confirmed not only as a stress-relieving effect, but also as a treatment, improvement, or prevention effect for anxiety and depression.

[0012] WO 2001 / 02349 discloses phenylsulfamate derivatives that are effective in preventing or treating diseases involving steroids such as estrogen, such as breast cancer, uterine cancer, endometrial hyperplasia, infertility, endometriosis, and adenomyosis, but the structures and uses of the sulfamate derivative compounds of the present invention are different. Summary of the Invention [Problem to be solved by the invention]

[0013] Under this background, the present inventors have confirmed that sulfamate derivatives exhibit excellent anti-stress, anti-anxiety or anti-depressant activity in the forced swimming test, and have completed the present invention.

[0014] Therefore, an object of the present invention is to provide a pharmaceutical composition for preventing and / or treating a mental disorder and a method for preventing and / or treating a mental disorder using a sulfamate derivative.

[0015] Another object of the present invention is to provide a pharmaceutical composition having anti-stress, anti-anxiety and / or anti-depressant activity using a sulfamate derivative, and a method for inducing anti-stress, anti-anxiety and / or anti-depressant activity. [Means for solving the problem]

[0016] In order to solve the above problems, the present invention provides a pharmaceutical composition for preventing or treating a mental disorder, comprising, as an active ingredient, a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [ka] where R 1 and R 2 are each independently hydrogen, C1 to C5 alkyl, C2 to C5 alkenyl, and C6 to C 10 aryl, or R 1 and R 2 is bonded to carbon atoms to form C3-C 12 Form a cycloalkyl group or R 1 and R 2 is bonded to the oxygen atom to form a carbonyl group; A is optionally hydrogen, hydroxyl, C1-C5 alkoxy, C1-C5 alkyl, C2-C5 alkenyl, C6-C 10 an aryl residue or a heterocyclic group substituted with one or more substituents selected from the group consisting of aryl, C1-C5 alkoxycarbonyl, carboxyl, C2-C5 acyl, C1-C5 alkylthio, cyano, nitro, amine, C1-C5 alkylamine, and halogen; R 3 and R 4 are each independently hydrogen or C1-C3 alkyl; l and m are each independently an integer of 0 to 4.

[0017] The present invention also provides a method for preventing or treating a mental disorder, which comprises administering a pharmaceutically effective amount of the above-mentioned pharmaceutical composition to an individual in need thereof.

[0018] Furthermore, the present invention provides use of the above pharmaceutical composition in the manufacture of a medicament for the prevention or treatment of a mental disorder.

[0019] In another aspect, the present invention provides a pharmaceutical composition having anti-stress, anti-anxiety or anti-depressant activity, comprising, as an active ingredient, a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [ka] where R 1 and R 2 are each independently hydrogen, C1 to C5 alkyl, C2 to C5 alkenyl, and C6 to C 10 aryl, or R 1 and R 2 is bonded to carbon atoms to form C3-C 12 Form a cycloalkyl group or R 1 and R 2 is bonded to the oxygen atom to form a carbonyl group; A is optionally hydrogen, hydroxyl, C1-C5 alkoxy, C1-C5 alkyl, C2-C5 alkenyl, C6-C 10 an aryl residue or a heterocyclic group substituted with one or more substituents selected from the group consisting of aryl, C1-C5 alkoxycarbonyl, carboxyl, C2-C5 acyl, C1-C5 alkylthio, cyano, nitro, amine, C1-C5 alkylamine, and halogen; R 3 and R 4 are each independently hydrogen or C1-C3 alkyl; l and m are each independently an integer of 0 to 4.

[0020] The present invention also provides a method for inducing anti-stress, anti-anxiety or anti-depressant activity, comprising administering a pharmaceutically effective amount of the above-described pharmaceutical composition to an individual in need thereof.

[0021] Furthermore, the present invention provides the use of the above pharmaceutical composition in the manufacture of a medicament for inducing anti-stress, anti-anxiety or anti-depressant activity. [Effects of the Invention]

[0022] The sulfamate derivatives of Chemical Formula 1 of the present invention exhibit excellent anti-stress, anti-anxiety or anti-depressant activity, and are therefore effective in treating various mental disorders caused by stress, anxiety or depression.

[0023] The present invention will now be described in more detail. Unless otherwise defined, all technical terms used herein have the meaning commonly understood by those skilled in the art to which the invention pertains. Furthermore, although preferred methods or samples are described herein, similar or equivalent methods or samples are also within the scope of the present invention.

[0024] A first aspect of the present invention relates to a pharmaceutical composition for preventing or treating a mental disorder, which comprises, as an active ingredient, a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof, and a method for preventing or treating a mental disorder, which comprises administering a pharmaceutically effective amount of the composition to an individual in need thereof: [ka] where R 1 and R 2 are each independently hydrogen, C1 to C5 alkyl, C2 to C5 alkenyl, and C6 to C 10 aryl, or R 1 and R 2 is bonded to carbon atoms to form C3-C 12 Form a cycloalkyl group or R 1 and R 2 is bonded to the oxygen atom to form a carbonyl group; A is optionally hydrogen, hydroxyl, C1-C5 alkoxy, C1-C5 alkyl, C2-C5 alkenyl, C6-C 10an aryl residue or a heterocyclic group substituted with one or more substituents selected from the group consisting of aryl, C1-C5 alkoxycarbonyl, carboxyl, C2-C5 acyl, C1-C5 alkylthio, cyano, nitro, amine, C1-C5 alkylamine, and halogen; R 3 and R 4 are each independently hydrogen or C1-C3 alkyl; l and m are each independently an integer of 0 to 4.

[0025] According to a particular embodiment, R 1 and R 2 are each independently selected from the group consisting of hydrogen, C1-C3 alkyl and phenyl, or R 1 and R 2 bonds with a carbon atom to form a C3-C6 cycloalkyl group.

[0026] In a preferred embodiment of the present invention, the aryl group is C6-C 10 It is represented by an aryl group.

[0027] In a preferred embodiment of the present invention, the heterocyclic group is a C 10 It appears as a heterocyclic group.

[0028] In a preferred embodiment of the present invention, A is phenyl optionally substituted with at least one substituent selected from the group consisting of hydrogen, halogen, C1-C5 alkyl, nitro, amine and C1-C5 alkylamine, or optionally substituted with at least one substituent selected from the group consisting of hydrogen, halogen, C1-C5 alkyl and C6-C 10 C3-C substituted with at least one substituent selected from the group consisting of aryl 10 It is a heterocyclic group.

[0029] According to a particular embodiment, R 3 and R 4 are each independently hydrogen or methyl.

[0030] In a preferred embodiment of the present invention, l and m are each independently an integer of 0-2.

[0031] In a more preferred embodiment of the present invention, l and m are each independently an integer of 0-1.

[0032] Specific examples of the substituent represented by A in Chemical Formula 1 are as follows: [ka] wherein X is independently selected from the group consisting of halogen, nitro, amine, and C1-C5 alkyl; n is an integer of 0 to 5; and Z is selected from S, O, or NH.

[0033] In a preferred embodiment of the present invention, n is an integer of 0-2.

[0034] In a more preferred embodiment of the present invention, n is an integer of 0-1.

[0035] In a preferred embodiment according to the present invention, R 1 and R 2 are each independently selected from the group consisting of hydrogen and C1-C5 alkyl, or R 1 and R 2 is bonded to carbon atoms to form C3-C 12 is a cycloalkyl group, or R 1 and R 2 is bonded to the oxygen atom to form a carbonyl group; A is a C6-C alkyl group containing one or two sulfur atoms optionally substituted with one or more substituents selected from the group consisting of hydrogen, C1-C5 alkyl, nitro, amine, and halogen. 10 aryl, or a 5- or 6-membered heterocyclic group; R 3 and R 4 are each independently hydrogen or C1-C3 alkyl; l and m are each independently an integer of 0-1.

[0036] In a more preferred embodiment according to the present invention, R 1 and R 2 are each independently C1-C3 alkyl, or R 1 and R 2may bond with a carbon atom to form a C5-C6 cycloalkyl group, or R 1 and R 2 forms a carbonyl group with an oxygen atom; A is hydrogen, C 1 ~ C optionally substituted with one or more substituents selected from the group consisting of C alkyl, nitro, amine, and halogen 6~ C 10 aryl or a 5-membered heterocyclic group containing one sulfur atom optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen; R 3 and R 4 are each independently hydrogen or C1-C3 alkyl; l and m are each independently an integer of 0-1.

[0037] The term "alkyl" as used herein means a straight or branched chain saturated hydrocarbon group, such as methyl, ethyl, propyl, butyl, isobutyl, tertiary butyl, and pentyl. As used herein, a "C1-C5 alkyl group" means an alkyl group having 1 to 5 carbon atoms.

[0038] The term "alkenyl," as used herein, unless otherwise noted, includes alkyl moieties having at least one carbon-carbon double bond, where alkyl is as defined above.

[0039] The term "alkoxy", as used herein, unless otherwise indicated, includes the group O-alkyl, where alkyl is as defined above.

[0040] As used herein, unless otherwise indicated, the term "alkylthio" includes the group S-alkyl, where alkyl is as defined above.

[0041] The term "alkoxycarbonyl," as used herein, unless otherwise stated, includes the group --C(O)O-alkyl, where alkyl is defined above.

[0042] The term "acyl," as used herein, unless otherwise indicated, includes the group --C(O)-alkyl, where alkyl is as defined above.

[0043] As used herein, the term "aryl" or "aryl group" refers to a fully or partially unsaturated monocyclic or polycyclic carbocyclic ring having aromatic character. The aryl group of the present invention is preferably monoaryl or biaryl, e.g., phenyl or naphthyl. The aryl radical may optionally be substituted with one or more substituents, as defined herein, such as hydroxy, mercapto, halo, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl, and alkoxycarbonyl.

[0044] The term "cycloalkyl" or "cycloalkyl group" as used herein means a mono- or polycyclic saturated ring containing carbon and hydrogen atoms.

[0045] As used herein, the term "heterocycle" or "heterocyclic group," unless otherwise specified, refers to aromatic and non-aromatic heterocyclic groups (including saturated heterocyclic groups) containing one or more heteroatoms selected from O, S, and N, respectively, where each heterocyclic group ring has 4 to 10 atoms. Non-aromatic heterocyclic groups may contain rings with only four atoms, while aromatic heterocyclic groups must contain at least five atoms. Heterocyclic groups of the present invention, unless otherwise specified, can contain one ring or more than one ring, i.e., monocyclic or polycyclic, e.g., bicyclic (which may include non-aromatic and / or aromatic rings).

[0046] According to a more specific embodiment, the compound is (1) (5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (2) (5-(2-chlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; (3) (5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; (4) (3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; (5) (3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; (6) (5-(2-chlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; (7) (5-(2-fluorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (8) (5-(2-fluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; (9) (5-(2-fluorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; (10) (3-(2-fluorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; (11) (3-(2-fluorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; (12) (5-(2-fluorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; (13) (5-(2-iodophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (14) (5-(2-iodophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; (15) (5-(2-iodophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; (16) (3-(2-iodophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; (17) (3-(2-iodophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; (18) (5-(2-iodophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; (19) (5-(2,4-dichlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (20) (5-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; (21) (5-(2,4-dichlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; (22) (3-(2,4-dichlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; (23) (3-(2,4-dichlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; (24) (5-(2,4-dichlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; (25) (5-(2,6-dichlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (26) (5-(2,6-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; (27) (5-(2,6-dichlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; (28) (3-(2,6-dichlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; (29) (3-(2,6-dichlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; (30) (5-(2,6-dichlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; (31) (5-(2-aminophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (32) (5-(2-aminophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; (33) (5-(2-aminophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; (34) (3-(2-aminophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; (35) (3-(2-aminophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; (36) (5-(2-aminophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; (37) (5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (38) (5-(2-nitrophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; (39) (5-(2-nitrophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; (40) (3-(2-nitrophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; (41) (3-(2-nitrophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; (42) (5-(2-nitrophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; (43) (5-(2-nitrophenyl)-2-oxo-1,3-dioxolan-4-yl)methylsulfamate; (44) (5-(2-methylphenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (45) (5-(2-methylphenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; (46) (5-(2-methylphenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; (47) (3-(2-methylphenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; (48) (3-(2-methylphenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; (49) (5-(2-methylphenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; (50) (5-(2-methylaminophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl methylsulfamate; (51) (5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (52) (5-phenyl-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; (53) (3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; (54) (3-phenyl-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; (55) 2-(5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; (56) 2-(5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethylsulfamate; (57) 2-(3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; (58) 2-(3-benzyl-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate; (59) (5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (60) (5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; (61) (3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; (62) (3-benzyl-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; (63) (5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl sulfamate: (64) (5-phenyl-2,2-diethyl-1,3-dioxolan-4-yl)ethyl sulfamate; (65) (3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl sulfamate; (66) (3-phenyl-1,4-dioxaspiro[4,5]decan-2-yl)ethyl sulfamate; (67) 2-(5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; (68) 2-(5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolan-4-yl)ethylsulfamate; (69) 2-(3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; (70) 2-(3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate; (71) (5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (72) (5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; (73) (3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; (74) (3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; (75) (5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; (76) (5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)ethylsulfamate; (77) (3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; (78) (3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate; (79) (5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (80) (5-(2-chlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (81) (2,2-dimethyl-5-(4-methylthiazol-5-yl)-1,3-dioxolan-4-yl)methylsulfamate; (82) (2,2-dimethyl-5-(2-chloro-4-methylthiazol-5-yl)-1,3-dioxolan-4-yl)methylsulfamate; (83) (2,2-dimethyl-5-(thiophen-3-yl)-1,3-dioxolan-4-yl)methylsulfamate; (84) (2,2-dimethyl-5-(5-chlorothiophen-2-yl)-1,3-dioxolan-4-yl)methylsulfamate; (85) (5-(3-chloropyridin-4-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (86) (5-(4-chloropyridin-3-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (87) (2,2-dimethyl-5-(pyrimidin-5-yl)-1,3-dioxolan-4-yl)methylsulfamate; and (88) (2,2-dimethyl-5-(2-chloropyrimidin-5-yl)-1,3-dioxolan-4-yl)methylsulfamate;

[0047] According to more specific embodiments, the compound is selected from the group consisting of: (1) (5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (4) (3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; (19) (5-(2,4-dichlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (25) (5-(2,6-dichlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (34) (3-(2-aminophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; (43) (5-(2-nitrophenyl)-2-oxo-1,3-dioxolan-4-yl)methylsulfamate; (44) (5-(2-methylphenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (51) (5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (53) (3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; (55) 2-(5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; (57) 2-(3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; (59) (5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (61) (3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; (63) 2-(5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; (65) 2-(3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; (67) 2-(5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; (69) 2-(3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; (71) (5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (73) (3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; (75) 2-(5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; (77) 2-(3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; (79) (5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; and (80) (5-(2-chlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate.

[0048] According to certain embodiments, the compound is in the form of a racemate, an optical isomer, a partial stereoisomer, a mixture of optical isomers or a mixture of partial stereoisomers.

[0049] According to certain embodiments, the configuration of each chiral center of the compound is (S).

[0050] According to more specific embodiments, the compound is selected from the group consisting of: ((4R,5R)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; (5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate (SS and RR mixture); (5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate (SR&RS mixture); ((4R,5R)-5-(2-chlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-chlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((2R,3R)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2S,3S)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2R,3R)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; ((2S,3S)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; ((4R,5R)-5-(2-chlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-chlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-fluorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-fluorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-fluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-fluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-fluorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-fluorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((2R,3R)-3-(2-fluorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2S,3S)-3-(2-fluorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2R,3R)-3-(2-fluorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; ((2S,3S)-3-(2-fluorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; ((4R,5R)-5-(2-fluorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-fluorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-iodophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-iodophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-iodophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-iodophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-iodophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-iodophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((2R,3R)-3-(2-iodophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2S,3S)-3-(2-iodophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2R,3R)-3-(2-iodophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; ((2S,3S)-3-(2-iodophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; ((4R,5R)-5-(2-iodophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-iodophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2,4-dichlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2,4-dichlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2,4-dichlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2,4-dichlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((2R,3R)-3-(2,4-dichlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2S,3S)-3-(2,4-dichlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2R,3R)-3-(2,4-dichlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; ((2S,3S)-3-(2,4-dichlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; ((4R,5R)-5-(2,4-dichlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2,4-dichlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2,6-dichlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2,6-dichlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2,6-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2,6-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2,6-dichlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2,6-dichlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((2R,3R)-3-(2,6-dichlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2S,3S)-3-(2,6-dichlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2R,3R)-3-(2,6-dichlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; ((2S,3S)-3-(2,6-dichlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; ((4R,5R)-5-(2,6-dichlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2,6-dichlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-aminophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-aminophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-aminophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-aminophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-aminophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-aminophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((2R,3R)-3-(2-aminophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2S,3S)-3-(2-aminophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2R,3R)-3-(2-aminophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; ((2S,3S)-3-(2-aminophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; ((4R,5R)-5-(2-aminophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-aminophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-nitrophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-nitrophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-nitrophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-nitrophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((2R,3R)-3-(2-nitrophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2S,3S)-3-(2-nitrophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2R,3R)-3-(2-nitrophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; ((2S,3S)-3-(2-nitrophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; ((4R,5R)-5-(2-nitrophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-nitrophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-nitrophenyl)-2-oxo-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-nitrophenyl)-2-oxo-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-methylphenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-methylphenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-methylphenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-methylphenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-methylphenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-methylphenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((2R,3R)-3-(2-methylphenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2S,3S)-3-(2-methylphenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2R,3R)-3-(2-methylphenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; ((2S,3S)-3-(2-methylphenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; ((4R,5R)-5-(2-methylphenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-methylphenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-methylaminophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-methylaminophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-phenyl-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-phenyl-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((2R,3R)-3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2S,3S)-3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2R,3R)-3-phenyl-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; ((2S,3S)-3-phenyl-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; 2-((4S,5S)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((4R,5R)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((4S,5S)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((4R,5R)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((2S,3S)-3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; 2-((2R,3R)-3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; 2-((2S,3S)-3-benzyl-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate; 2-((2R,3R)-3-benzyl-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate; ((4S,5S)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; 2-((4R,5R)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((4S,5S)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((4R,5R)-5-phenyl-2,2-diethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((4S,5S)-5-phenyl-2,2-diethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((2R,3R)-3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; 2-((2S,3S)-3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; 2-((2R,3R)-3-phenyl-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate; 2-((2S,3S)-3-phenyl-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate; 2-((4S,5S)-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((4R,5R)-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((4S,5S)-5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((4R,5R)-5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((2S,3S)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; 2-((2R,3R)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; 2-((2S,3S)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate; 2-((2R,3R)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate; ((4S,5S)-5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5R)-5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate; ((2S,3S)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2R,3R)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((2S,3S)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; ((2R,3R)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate; 2-((4R,5R)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((4S,5S)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((4R,5R)-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((4S,5S)-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((2R,3R)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; 2-((2S,3S)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; 2-((2R,3R)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate; 2-((2S,3S)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate; ((4S,5R)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5S)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5S)-5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5R)-5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5S)-5-(2-chlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5R)-5-(2-chlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5S)-2,2-dimethyl-5-(4-methylthiazol-5-yl)-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5R)-2,2-dimethyl-5-(4-methylthiazol-5-yl)-1,3-dioxolan-4-yl)methylsulfamate; ((4R,5S)-2,2-dimethyl-5-(2-chloro-4-methylthiazol-5-yl)-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5R)-2,2-dimethyl-5-(2-chloro-4-methylthiazol-5-yl)-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-2,2-dimethyl-5-(thiophen-3-yl)-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5R)-2,2-dimethyl-5-(5-chlorothiophen-2-yl)-1,3-dioxolan-4-yl)methylsulfamate; Sodium (((4R,5R)-5-(2-aminophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfonyl)amide; sodium (((4S,5S)-5-(2-aminophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfonyl)amide; and Sodium (((4S,5S)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)sulfonyl)amide.

[0051] According to more specific embodiments, the compound is selected from the group consisting of: ((4S,5S)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((2S,3S)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((4S,5S)-5-(2,4-dichlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2,6-dichlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((2S,3S)-3-(2-aminophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((4S,5S)-5-(2-nitrophenyl)-2-oxo-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-(2-methylphenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((4S,5S)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((2S,3S)-3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; 2-((4S,5S)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((2S,3S)-3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; ((4S,5S)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((2S,3S)-3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; ((4S,5S)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((2S,3S)-3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; 2-((4S,5S)-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((2S,3S)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; ((4S,5S)-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; ((2S,3S)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate; 2-((4S,5S)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate; 2-((2S,3S)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate; ((4S,5R)-5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate; and ((4S,5R)-5-(2-chlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate.

[0052] As shown in the Examples, the present inventors have synthesized compounds with various stereochemical properties and investigated their anti-stress, anti-anxiety and / or anti-depressant activities through multifaceted experiments.

[0053] As used herein, the term "optical isomer" refers to one of two stereoisomers that are non-superimposable mirror images of each other due to the presence of one or more chiral carbons. According to specific embodiments, the optical isomers of the present invention have various stereo-configurations at the chiral carbons C4 and C5.

[0054] As used herein, the term "partial stereoisomer" means a stereoisomer that is not an optical isomer, and occurs when two or more stereoisomers of a compound have different structures at one or more (but not all) of the equivalent chiral centers, and therefore are not mirror images of each other.

[0055] According to certain embodiments, the configuration of each chiral center of the compound is (S).

[0056] As used herein, the term "racemate" means equal amounts of two optical isomers of different stereo-configuration and lacking optical activity.

[0057] It will be apparent to those skilled in the art from the following examples that the compounds of the present invention are not limited to a particular stereochemistry.

[0058] According to a specific embodiment, the pharmaceutically acceptable salt is formed by reacting the compound with an inorganic acid, an organic acid, an amino acid, a sulfonic acid, an alkali metal, or an ammonium ion.

[0059] Pharmaceutically acceptable salts of the present invention can be prepared by methods known in the art, for example, salts with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sodium bisulfate, phosphate, nitrate, and carbonate; salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gentisic acid, pumaric acid, lactobionic acid, salicylic acid, trifluoroacetic acid, and acetylsalicylic acid (aspirin); or salts with amino acids such as glycine, alanine, valine, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tylosin, and proline; salts with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid; These include, but are not limited to, metal salts by reaction with alkali metals such as sodium, lithium, and potassium; or salts with ammonium ions.

[0060] In another aspect of the present invention, there is provided a method for managing psychiatric disorders, comprising administering to an individual in need thereof a pharmaceutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0061] As used herein, the term "pharmaceutically effective amount" means an amount sufficient to demonstrate and achieve efficacy and effect for preventing, alleviating or treating a mental illness-related disorder.

[0062] The pharmaceutical compositions of the present invention contain not only the active ingredient compound but also a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers contained in the pharmaceutical compositions of the present invention are those commonly used in pharmaceutical formulations, including, but not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, potassium phosphate, alginate, gelatin, potassium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. The pharmaceutical compositions of the present invention may further contain lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, and preservatives. For details on suitable pharmaceutically acceptable carriers and dosage forms, see Remington's Pharmaceutical Sciences (19th ed., 1995).

[0063] The pharmaceutical composition according to the present invention can be administered orally or parenterally, specifically parenterally. Parenteral administration can be by intravenous, subcutaneous, intramuscular, intraperitoneal, transdermal, or intraarticular injection. More specifically, it can be administered by intramuscular or intraperitoneal injection.

[0064] The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on the drug formulation, administration method, age, weight, sex, pathological condition, menu, administration time, administration route, excretion rate, and sensitivity to the pharmaceutical composition used. Preferably, the pharmaceutical composition of the present invention can be administered at a daily dosage of 0.001-10,000 mg / kg (body weight).

[0065] According to conventional techniques known to those skilled in the art, the pharmaceutical compositions of the present invention can be formulated in a pharmaceutically acceptable carrier or vehicle as described above, and ultimately provided in a variety of forms, including unit dose forms and multi-dose forms, including, but not limited to, solutions, suspensions or emulsions in milk or aqueous media, elixirs, powders, granules, tablets, and capsules, which may further contain dispersing agents or stabilizers.

[0066] As used herein, the term "mental illness" is used interchangeably with "mental disorder" and refers to mental health-related conditions that affect mood, mood, and behavior, usually resulting from brain problems. These conditions are broadly divided into psychoses and neuroses. Examples of the former include schizophrenia and depression, while examples of the latter include conversion disorder and obsessive-compulsive disorder. These mental illnesses include anxiety disorders, including generalized anxiety disorder, phobias (specific phobias, social phobia, agoraphobia), panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD); mood disorders, including depressive disorder and bipolar disorder; somatoform disorders including somatization disorder, conversion disorder, pain disorder, hypochondriasis, and body dysmorphic disorder; dissociative disorders including dissociative amnesia and dissociative congestion disorder; schizophrenia including schizophrenia, schizophrenia-stasis disorder, and delusional disorder; personality disorders including schizoid personality disorder, borderline personality disorder, and obsessive-compulsive personality disorder; sexual and gender identity disorders; substance-related disorders involving addiction to addictive substances including alcohol, tobacco, or drugs; eating disorders including anorexia nervosa or bulimia nervosa; sleep disorders including sleep disorders and dyssomnias; impulse control disorders including intermittent explosive disorder, gambling disorder, pyromania, and trichotillomania; adjustment disorders.

[0067] According to a preferred embodiment of the present invention, said depressive disorders include, but are not limited to, major depressive disorder, dysthymic disorder, persistent depression, premenstrual dysphoric disorder or postpartum depression.

[0068] As used herein, the term "bipolar disorder" refers to a mental disorder involving episodes of elevated or agitated mood, known as mania, alternating with episodes of depression.

[0069] As used herein, the term "anxiety disorder" refers to a mental disorder characterized by excessive rumination, anxiety, fear, apprehension and worry about future uncertainties based on real or imagined events.

[0070] As used herein, the term "postpartum depression (PPD)" refers to a type of mood disorder associated with childbirth that can affect both men and women. Symptoms include extreme sadness, low energy, anxiety, crying, moodiness, and changes in sleep or eating patterns. Onset typically occurs between one week and one month after delivery. PPD can also have adverse effects on the newborn.

[0071] Preferably, the pharmaceutical composition of the present invention is used for the prevention or treatment of a mental disorder selected from the group consisting of anxiety disorder, depressive disorder, bipolar disorder, and schizophrenia, where the anxiety disorder includes generalized anxiety disorder, phobia, panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder, and the depression includes postpartum depression.

[0072] In the methods of the present invention, the term "subject" includes, but is not limited to, any animal (e.g., a human, horse, pig, rabbit, dog, sheep, goat, non-human primate, cow, cat, guinea pig, or rodent). These terms do not denote a particular age or sex. Thus, they are intended to include adult and newborn subjects, whether female or male, as well as fetuses.

[0073] In the method of the present invention, the effects of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, its administration route, administration frequency, dosage, etc. are the same as those described above, and therefore will not be described here.

[0074] The first aspect of the present invention also relates to the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of a psychiatric disorder.

[0075] In the use of the present invention, the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof and its effects are the same as those described above, so the description thereof will be omitted.

[0076] In the application of the present invention, the explanation of mental disorders is the same as above, and therefore the explanation is omitted.

[0077] A second aspect of the present invention relates to a pharmaceutical composition having anti-stress, anti-anxiety or anti-depressant activity, which comprises a compound of the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and a method for inducing anti-stress, anti-anxiety or anti-depressant activity, which comprises administering a pharmaceutically effective amount of the composition to a subject:

[0078] [ka] where R 1 and R 2 are each independently hydrogen, C1 to C5 alkyl, C2 to C5 alkenyl, and C6 to C 10 aryl, or R 1 and R 2 is bonded to carbon atoms to form C3-C 12 Form a cycloalkyl group or R 1 and R 2 is bonded to the oxygen atom to form a carbonyl group; A is optionally hydrogen, hydroxyl, C1-C5 alkoxy, C1-C5 alkyl, C2-C5 alkenyl, C6-C 10 an aryl residue or a heterocyclic residue substituted with one or more substituents selected from the group consisting of aryl, C1-C5 alkoxycarbonyl, carboxyl, C2-C5 acyl, C1-C5 alkylthio, cyano, nitro, amine, C1-C5 alkylamine, and halogen; R 3 and R 4 are each independently hydrogen or C1-C3 alkyl; l and m are each independently an integer of 0-4. A second aspect of the present invention also relates to the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inducing anti-stress, anti-anxiety or anti-depressant activity.

[0079] In the second aspect of the present invention, the description of the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof is the same as that in the first aspect, and therefore the description thereof will be omitted.

[0080] In the second aspect of the present invention, the term "pharmaceutically effective amount" as used herein means an amount sufficient to exhibit and achieve anti-stress, anti-anxiety and / or anti-depressant activity.

[0081] In the pharmaceutical composition of the second aspect of the present invention, the pharmaceutically acceptable carrier, administration route, appropriate dosage and formulation form are the same as those described in the first aspect, and therefore description thereof will be omitted.

[0082] Furthermore, in the method of the second aspect, the explanation of the term "individual" is the same as that described in the first aspect, and the explanations of the administration route, frequency of administration, dosage, etc. of the pharmaceutical composition containing the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof are also the same as those described in the first aspect, and therefore, the explanations thereof will be omitted.

[0083] The term "anti-stress" as used herein means alleviating excessive physical reactions due to internal or external stimuli or recovering from mental / physical fatigue, and specifically means relieving tension, anxiety, or improving concentration.

[0084] As used herein, the terms "anti-anxiety" and "antidepressant" refer to activities that are effective in the prevention or treatment of mental disorders such as anxiety disorders and mood disorders (such as depression and bipolar disorder). Because mental stress is a cause of mental disorders such as anxiety and depression, the sulfamate derivatives of the present invention, which exhibit excellent anti-stress, anti-anxiety, and / or antidepressant activity, are effective in the prevention or treatment of various mental disorders. The types of various mental disorders are the same as those described in the first aspect, and therefore will not be described here.

[0085] The sulfamate derivative compound of the present invention can be produced according to the following chemical reaction formula.

[0086] [Chemical Reaction Scheme 1] Synthesis of Dioxolane-Alcohol Compounds [ka] The dioxolane-alcohol compounds used in the synthesis of sulfamate compounds are synthesized by dihydroxylation, condensation and deprotection reactions.

[0087] [Chemical Reaction Scheme 2] Synthesis of Alcohol Compounds [ka] The alcohol compound of formula 3 can be synthesized from the carboxylic acid compound of formula 2 by reduction using a reducing agent in a basic environment, including, but not limited to, LiAlH4 (lithium aluminum hydride), NaBH4 (sodium borohydride), Zn(BH4)2 (zinc borohydride), NaH (sodium hydride), KH (potassium hydride), AlH3 (aluminum hydride), and NaOMe (sodium methoxide).

[0088] [Chemical Reaction Scheme 3] Synthesis of Protected Alcohol Compounds [ka] The OH of the alcohol compound of Formula 3 is protected by a protecting group in a basic environment for use in the subsequent reaction, including, but not limited to, TMS (trimethylsilyl), TES (triethylsilyl), TIPS (triisopropylsilyl), TBDMS (tert-butyldimethylsilyl), TBDPS (tert-butyldiphenylsilyl), Piv (pivaloyl), MOM (methoxymethyl), acetyl, benzoyl, and Tityl (triphenylmethyl).

[0089] [Chemical Reaction Scheme 4] Synthesis of diol compounds [ka] The asymmetric dihydroxylation catalyst may be one or more selected from the group consisting of chiral ligands (e.g., (DHQD)PHAL, (DHQ)PHAL, etc.), osmium catalysts (e.g., OsO, KOsO(OH), etc.), KCO, KFe(CN), N-methylmorpholine oxide (NMO), methanesulfonamide (CHSONH), etc. For example, the asymmetric dihydroxylation catalyst may be AD-mix-a (KOsO(OH)(cat), KCO, KFe(CN), (DHQ)PHAL(cat)) and methanesulfonamide (CHSONH), or OsO and N-methylmorpholine oxide (NMO), but is not limited thereto and may be selected appropriately depending on the intended purpose.

[0090] [Chemical Reaction Scheme 5] Synthesis of dioxolane-alcohol compounds [ka] The diol compound of formula 5 can be prepared in an acidic environment, e.g., p-TsOH (p-toluenesulfonic acid), H 2S In a solution containing an acid such as 04 (sulfuric acid) or HNO3 (nitric acid), the dioxolane-alcohol compound is reacted with a ketone compound (e.g., acetone, 3-pentanone, cyclopentanone, or cyclohexanone), an alkoxy compound (e.g., dimethoxymethane, dimethoxypropane, diethoxyethane, or methoxypropene, 3-methoxypent-2-ene, 1-methoxycyclopent-1-ene, 1-methoxycyclohex-1-ene), or an aldehyde compound (e.g., benzaldehyde, cyclopentanecarboxaldehyde, or cyclohexanecarboxaldehyde), followed by removal of the protecting group to provide the dioxolane-alcohol compound of Formula 6. Although various examples of the ketone compound, alkoxy compound, aldehyde compound, and acid for the above reaction are described, they are not limited thereto and may be selected appropriately depending on the intended purpose.

[0091] [Chemical Reaction Scheme 6] Synthesis of ester compounds [ka] Straight or branched chain C1-C 10 Alkyl or cyclic C3-C 10 The ester compound of formula 7, in which R is selected from the group consisting of alkyl, allyl, and benzyl, is synthesized from the carboxylic acid compound of formula 2 by esterification in an acidic environment.

[0092] [Chemical Reaction Scheme 7] Synthesis of Ester-Diol Compounds [ka] The asymmetric dihydroxylation catalyst can be one or more selected from the group consisting of chiral ligands (e.g., (DHQD)PHAL, (DHQ)PHAL, etc.), osmium catalysts (e.g., OsO, KOsO(OH)4, etc.), KCO, KFe(CN), N-methylmorpholine oxide (NMO), methanesulfonamide (CHSONH), etc.

[0093] For example, the asymmetric dihydroxylation catalyst may be AD-mix-a (K2OsO2(OH)4(cat), K2CO3, K3Fe(CN)6, (DHQ)2PHAL(cat)) and methanesulfonamide (CH3SO2NH2), or OsO4 and N-methylmorpholine oxide (NMO), but is not limited thereto and may be appropriately selected depending on the intended purpose.

[0094] [Chemical Reaction Scheme 8] Synthesis of Dioxolane-Ester Compounds [ka] The diol compound of Formula 8 reacts with a ketone compound (e.g., acetone, 3-pentanone, cyclopentanone, or cyclohexanone), an alkoxy compound (e.g., dimethoxymethane, dimethoxypropane, diethoxyethane, or methoxypropene, 3-methoxypent-2-ene, 1-methoxycyclopent-1-ene, 1-methoxycyclohex-1-ene), or an aldehyde compound (e.g., benzaldehyde, cyclopentanecarboxaldehyde, or cyclohexanecarboxaldehyde) in an acidic environment, for example, in a solution dissolved in an acid such as p-TsOH (p-toluenesulfonic acid), HSO (sulfuric acid), or HNO (nitric acid), to provide a dioxolane-alcohol compound of Formula 9. Although various examples of the ketone compound, alkoxy compound, aldehyde compound, and acid for the above reaction are described, they are not limited thereto and may be appropriately selected depending on the intended purpose.

[0095] [Chemical Reaction Scheme 9] Synthesis of dioxolane-alcohol compounds [ka] The dioxolane-alcohol compound of formula 6 can be synthesized from the dioxolane-ester compound of formula 9 by reduction using a reducing agent in a basic environment, including, but not limited to, LiAlH (lithium aluminum hydride), NaBH (sodium borohydride), Zn(BH) (zinc borohydride), NaH (sodium hydride), KH (potassium hydride), AlH (aluminum hydride), and NaOMe (sodium methoxide).

[0096] [Chemical Reaction Scheme 10] Synthesis of sulfamate compounds [ka] The dioxolane-alcohol compound of formula 6 can be reacted with sulfamide or sulfamoyl chloride in a basic environment using a base, including but not limited to pyridine, piperidine, and piperazine, to produce the sulfamate compound of formula 1.

[0097] The present invention will be described in more detail below with reference to examples. However, the present invention can be modified in various ways and can have various forms. The specific embodiments and explanations described below are intended to aid in understanding the present invention and are not intended to limit the present invention to the specific disclosed forms. The scope of the present invention should be understood to include all modifications, equivalents, and alternatives that fall within the spirit and technical scope of the present invention.

[0098] Example

[0099] Production Example 1: (E)-3-(2-chlorophenyl)prop-2-en-1-ol [ka] To a 100 ml round-bottom flask was added 2-chlorocinnamic acid (5 g, 7.3 mmol) and THF (20 ml), and the reaction mixture was cooled to 0° C. Triethylamine (4.2 ml, 30.1 mmol) and ethylchloroformate (2.88 ml, 30.1 mmol) were added. The reaction mixture was stirred to precipitate a white solid. After 2 hours, the reaction mixture was filtered with THF (white solid + yellow solution).

[0100] The yellow solution was added dropwise to sodium borohydride (2.68 g, 142.3 mmol) in H2O at 0 °C and stirred for 2 h. The reaction was then quenched with 1N HCl solution. The reaction mixture was extracted with EtOAc and washed with H2O. The combined organic extracts were dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated in vacuo. The crude compound was purified by silica gel column chromatography to yield the title compound (2.96 g, 60-70%).

[0101] 1 H NMR (400MHz,CDCl3): δ1.67(s,1H),4.39 (t,J=4.0,2H),6.37 (dt J=5.6,16.0,1H),7.03 (d,J=16.0,1H),7.18~7.38(m,4H)

[0102] Production Example 2: (E)-1-chloro-2-(3-(methoxymethoxy)prop-1-enyl)benzene [ka] A 250 ml round-bottom flask was charged with (E)-3-(2-chlorophenyl)prop-2-en-1-ol (2.96 g, 17.5 mmol, Preparation 1) and dichloromethane (17.5 ml), and the reaction mixture was cooled to 0°C. Diisopropylethylamine (6.1 ml, 35.1 mmol) was added and stirred at 0°C. Methyl chloromethyl ether (2.77 ml, 35.1 mmol) was added dropwise and stirred overnight. The reaction mixture was quenched with 1 N NaOH solution and extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate (MgSO), filtered, and concentrated under vacuum. The crude compound was purified using a silica gel column to yield the title compound (3.43 g, 85-95%).

[0103] 1 H NMR (400MHz,CDCl3):δ3.44(s,3H),4.30 (dd,J=8.0,1.6,1H),4.73 (s,2H),6.30 (1H,dt,J=6.0,16),7.04 (d,J=16.0,1H),7.20~7.57(m,4H)

[0104] Production Example 3: (1R,2R)-1-(2-chlorophenyl)-3-(methoxymethoxy)propane-1,2-diol [ka] A 250 mL round-bottom flask equipped with a magnetic stirrer was charged with 80 mL of tert-butyl alcohol, 80 mL of water, and KFe(CN) (15.93 g, 48.3 mmol), KCO (6.7 g, 48.3 mmol), (DHQD)-PHAL (0.12 g, 0.16 mmol), KOsO(OH) (11.8 mg, 0.03 mmol), and methanesulfonamide (1.53 g, 16.1 mmol). The mixture was stirred at 0°C. (E)-1-chloro-2-(3-(methoxymethoxy)prop-1-enyl)benzene (3.43 g, 16.1 mmol, Preparation 2) was added in one portion, and the mixture was stirred vigorously at 0°C overnight. While the mixture was stirring at 0°C, solid sodium sulfite (Na 2S 03 (24.4 g, 193.5 mmol) was added and the mixture was warmed to room temperature. Ethyl acetate was added to the reaction mixture, and after layer separation, the aqueous phase was further extracted with organic solvent. The combined organic layers were washed with 2NHCl. The combined organic extracts were dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated under vacuum. The crude compound was purified by silica gel column to yield the title compound (3.31 g, 75-90%).

[0105] 1 H NMR (400MHz, CDCl3): δ3.09(d,J=5.6,1H),3.27 (d,J=4.4,1H),3.41 (s,3H),3.69-3.77 (m,2H),3.96~3.99(m,1H),4.69 (s,2H),5.19 (t,J=4.4,1H),7.23-7.61 (m,1H)

[0106] Production Example 4: (1S,2S)-1-(2-chlorophenyl)-3-(methoxymethoxy)propane-1,2-diol [ka] The title compound (3.1 g, 75-90%) was obtained in substantially the same manner as in Preparation Example 3, except that (DHQ)2-PHAL was used instead of (DHQD)2-PHAL. 1H NMR (400MHz,CDCl3): δ3.09 (d,J=5.6,1H),3.27 (d,J=4.4.1H),3.41 (s,3H),3.69~3.77 (m,2H),3.96~3.99 (m,1H),4.69 (s,2H),5.19 (t,J=4.4,1H),7.23~7.61(m,4H)

[0107] Preparation Example 5: 1-(2-chlorophenyl)-3-(methoxymethoxy)propane-1,2-diol [ka] (E)-1-Chloro-2-(3-(methoxymethoxy)prop-1-enyl)benzene (9.1 g, Preparation 2) was dissolved in 45 mL of a mixture of acetone / t-BuOH / HO (5:1:1, V / V). N-methylmorpholine-N-oxide (7.51 g) and OsO (0.54 g) were added to the solution at room temperature and stirred for 2-3 hours. Upon completion of the reaction, the resulting product was washed with water and methylene chloride (MC). The organic layer was then dried over anhydrous magnesium sulfate (MgSO) and concentrated under reduced pressure. The crude compound was purified using a silica gel column to yield the title compound (7.42 g, 70-90%).

[0108] 1 H NMR (400MHz,CDCl3): δ3.09(d,J=5.6,1H),3.27 (d,J=4.4,1H),3.41 (s,3H),3.69~3.77 (m,2H),3.96~3.99 (m,1H),4.69(s,2H),5.19 (t,J=4.4,1H),7.23~7.61 (m,4H)

[0109] Production Example 6: ((4R,5R)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] Dichloromethane was added to (1R,2R)-1-(2-chlorophenyl)-3-(methoxymethoxy)propane-1,2-diol (3.31 g, 13.4 mmol, Preparation 3) and cooled to 0°C. 2,2-Dimethoxypropane (3.3 ml, 26.8 mmol) and p-toluenesulfonic acid (2 g, 10.7 mmol) were added and stirred at room temperature for 5 hours. The reaction mixture was quenched with H2O, extracted with DCM, and washed with H2O. The organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated. The crude compound was purified using a silica gel column to yield the title compound (1.05 g, 30-40%).

[0110] 1 H NMR (400MHz,CDCl3):δ1.57(s,3H),1.63 (s,3H),1.95-1.98 (m,1H),3.88~3.89 (m,1H),3.90~3.96(m,2H),5.41 (d,J=8.4,1H),7.25~7.66 (m,4H)

[0111] Preparation Example 7: ((4S,5S)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.1 g, 30-40%) was obtained in substantially the same manner as in Preparation 6, except that (1S,2S)-1-(2-chlorophenyl)-3-(methoxymethoxy)propane-1,2-diol (Preparation Example 4) was used instead of (1R,2R)-1-(2-chlorophenyl)-3-(methoxymethoxy)propane-1,2-diol (Preparation Example 3).

[0112] 1 H NMR (400MHz,CDCl3):δ1.57(s,3H),1.64 (s,3H),1.98 (m,1H),3.76~3.83 (m,1H),3.88~3.90(m,2H),5.41 (d,J=8.4,1H),7.25-7.66 (m,4H)

[0113] Preparation 8: (5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (2.1 g, 30-40%) was obtained in substantially the same manner as in Preparation 6, except that 1-(2-chlorophenyl)-3-(methoxymethoxy)propane-1,2-diol (Preparation Example 5) was used instead of (1R,2R)-1-(2-chlorophenyl)-3-(methoxymethoxy)propane-1,2-diol (Preparation Example 3).

[0114] 1 H NMR (400MHz,CDCl3):δ1.57(s,3H),1.63 (s,3H),1.95-1.98 (m,1H),3.88~3.89 (m,1H),3.90~3.96(m,2H),5.41 (d,J=8.4,1H),7.25~7.66 (m,4H)

[0115] Production Example 9: (E)-3-(2-fluorophenyl)-acrylic acid [ka] Piperidine (247 mg, 2.90 mmol) was added to a stirred solution of malonic acid (3.1 g, 29.00 mmol) and 2-fluoroaldehyde (3 g, 24.17 mmol) in pyridine at room temperature under N2 conditions. The solution was cooled to room temperature and then quenched with HCl solution. The residue was treated with EA and H2O. The organic layer was separated and the aqueous layer was further extracted with EA. The combined extracts were washed with brine. The organic layer was washed with Na 2S It was dried over O4, filtered and concentrated. The crude compound was purified by silica gel column to give the title compound (3.66 g, 70-90%).

[0116] 1H NMR (400MHz,CDCl3): δ6.60(d,J=16.0,1H),7.24~7.50 (m,3H),7.66 (d,J=16.0,1H),7.84 (t,J=8.0,1H)

[0117] Production Example 10: (E)-3-(2-fluorophenyl)-prop-2-en-1-ol [ka] The title compound (1.6 g, 30-40%) was obtained in substantially the same manner as in Preparation 1, except that (E)-3-(2-fluorophenyl)-acrylic acid (Preparation Example 9) was used instead of 2-chlorocinnamic acid.

[0118] 1 H NMR (400MHz,CDCl3):δ1.67(s,1H),4.39 (t,J=4.0,2H),6.34-6.41 (m,1H),7.00-7.38 (m,4H)

[0119] Production Example 11: (E)-1-Fluoro-2-(3-(methoxymethoxy)prop-1-enyl)benzene [ka] The title compound (2.23 g, 85-95%) was obtained in substantially the same manner as in Preparation 2, except that (E)-3-(2-fluorophenyl)-prop-2-en-1-ol (Preparation Example 10) was used instead of (E)-3-(2-chlorophenyl)-prop-2-en-1-ol (Preparation Example 1).

[0120] 1 H NMR (400MHz, CDCl3): δ3.44(s,3H),4.30 (dd,J=1.6,8.0,1H),4.73 (s,2H),6.27-6.37 (m,1H),7.02~7.57(m,4H)

[0121] Production Example 12: (1R,2R)-1-(2-fluorophenyl)-3-(methoxymethoxy)propane-1,2-diol [ka] The title compound (2.13 g, 75-90%) was obtained in substantially the same manner as in Preparation 3, except that (E)-1-fluoro-2-(3-(methoxymethoxy)prop-1-enyl)benzene (Preparation Example 11) was used instead of (E)-1-chloro-2-(3-(methoxymethoxy)prop-1-enyl)benzene (Preparation Example 2).

[0122] 1 H NMR (400MHz,CDCl3): δ3.09(d,J=5.6,1H),3.27 (d,J=4.4,1H),3.41 (s,3H),3.69~3.77 (m,2H),3.96~3.99 (m,1H),4.69(s,2H),5.19 (t,J=4.4,1H),7.23~7.61 (m,4H)

[0123] Preparation 13: ((4R,5R)-5-(2-fluorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.73 g, 30-40%) was obtained in substantially the same manner as in Preparation 6, except that (1R,2R)-1-(2-fluorophenyl)-3-(methoxymethoxy)propane-1,2-diol (Preparation Example 12) was used instead of (1R,2R)-1-(2-chlorophenyl)-3-(methoxymethoxy)propane-1,2-diol (Preparation Example 3).

[0124] 1 H NMR (400MHz,CDCl3):δ1.57(s,3H),1.63 (s,3H),1.95-1.98 (m,1H),3.88~3.89 (m,1H),3.90-3.96(m,2H),5.41 (d,J=8.4,1H),7.25~7.66 (m,4H)

[0125] Production Example 14: (1S,2S)-1-(2-fluorophenyl)-3-(methoxymethoxy)propane-1,2-diol [ka] The title compound (2.13 g, 75-90%) was obtained in substantially the same manner as in Preparation 4, except that (E)-1-fluoro-2-(3-(methoxymethoxy)prop-1-enyl)benzene (Preparation Example 11) was used instead of (E)-1-chloro-2-(3-(methoxymethoxy)prop-1-enyl)benzene (Preparation Example 2).

[0126] 1 H NMR (400MHz,CDCl3): δ3.09(d,J=5.6,1H),3.27 (d,J=4.4,1H),3.41 (s,3H),3.69~3.77 (m,2H),3.96~3.99 (m,1H),4.69(s,2H),5.19 (t,J=4.4,1H),7.23-7.61 (m,4H)

[0127] Preparation 15: ((4S,5S)-5-(2-fluorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.73 g, 30-40%) was obtained in substantially the same manner as in Preparation 6, except that (1S,2S)-1-(2-fluorophenyl)-3-(methoxymethoxy)propane-1,2-diol (Preparation Example 14) was used instead of (1R,2R)-1-(2-chlorophenyl)-3-(methoxymethoxy)propane-1,2-diol (Preparation Example 3).

[0128] 1H NMR (400MHz, CDCl3): δ1.57(s,3H),1.63 (s,3H),1.95~1.98 (m,1H) 3.88~3.89 (m,1H),3.90~3.96 (m,2H),5.41 (d,J=8.4,1H),7.25~7.66(m,4H)

[0129] Preparation Example 16: 2-Iodobenzenealdehyde [ka] 2-Iodobenzyl alcohol (4 g, 17.09 mmol) was dissolved in dichloromethane (MC, 85 mL) in a flask, and then manganese oxide (MnO, 14.86 g, 170.92 mmol) was added. The resulting reaction mixture was stirred under reflux. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, filtered through celite, and concentrated to yield the title compound (3.6 g, 75-90% yield).

[0130] 1 H NMR (400MHz, CDCl3): δ7.30~7.99(m,4H),10.10 (s,1H)

[0131] Production Example 17: (E)-3-(2-iodophenyl)-acrylic acid [ka] The title compound (2.06 g, 70-90%) was obtained in substantially the same manner as in Preparation 9, except that 2-iodobenzenealdehyde (Preparation Example 16) was used instead of 2-fluoroaldehyde.

[0132] 1 H NMR (400MHz,CDCl3): δ6.60(d,J=16.0,1H),7.24~7.50 (m,3H),7.66 (d,J=16.0,1H),7.84 (t,J=8.0,1H)

[0133] Production Example 18: (E)-3-(2-iodophenyl)-prop-2-en-1-ol [ka] The title compound (1.08 g, 30-40%) was obtained in substantially the same manner as in Preparation 1, except that (E)-3-(2-iodophenyl)-acrylic acid (Preparation Example 17) was used instead of 2-chlorocinnamic acid.

[0134] 1 H NMR (400MHz,CDCl3):δ1.67(s,1H),4.39 (t,J=4.0,2H),6.34-6.41 (m,1H),7.00-7.38 (m,4H)

[0135] Preparation 19: (E)-1-Iodo-2-(3-(methoxymethoxy)prop-1-enyl)benzene [ka] The title compound (1.37 g, 85-95%) was obtained in substantially the same manner as in Preparation 2, except that (E)-3-(2-iodophenyl)-prop-2-en-1-ol (Preparation Example 18) was used instead of (E)-3-(2-chlorophenyl)-prop-2-en-1-ol (Preparation Example 1).

[0136] 1 H NMR (400MHz, CDCl3): δ3.44(s,3H),4.30 (dd,J=8.0,1.6,1H),4.73 (s,2H),6.27~6.34(m,1H),7.02~7.57 (m,4H)

[0137] Production Example 20: (1R,2R)-1-(2-iodophenyl)-3-(methoxymethoxy)propane-1,2-diol [ka] The title compound (1.32 g, 75-90%) was obtained in substantially the same manner as in Preparation 3, except that (E)-1-iodo-2-(3-(methoxymethoxy)prop-1-enyl)benzene (Preparation Example 19) was used instead of (E)-1-chloro-2-(3-(methoxymethoxy)prop-1-enyl)benzene (Preparation Example 2).

[0138] 1 H NMR (400MHz,CDCl3): δ3.09(d,J=5.6,1H),3.27 (d,J=4.4,1H),3.41 (s,3H),3.69~3.77 (m,2H),3.96~3.99 (m,1H),4.69(s,2H),5.19 (t,J=4.4,1H),7.23-7.61 (m,4H)

[0139] Preparation 21: ((4R,5R)-5-(2-iodophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.33 g, 30-40%) was obtained in substantially the same manner as in Preparation 6, except that (1R,2R)-1-(2-iodophenyl)-3-(methoxymethoxy)propane-1,2-diol (Preparation Example 20) was used instead of (1R,2R)-1-(2-chlorophenyl)-3-(methoxymethoxy)propane-1,2-diol (Preparation Example 3).

[0140] 1 H NMR (400MHz,CDCl3): δ1.57(s,3H),1.63 (s,3H),1.95~1.98 (m,1H),3.88~3.89 (m,1H),3.90~3.96 (m,2H),5.41 (d,J=8.4,1H),7.25~7.66(m,4H)

[0141] Production Example 22: (1S,2S)-1-(2-iodophenyl)-3-(methoxymethoxy)propane-1,2-diol [ka] The title compound (1.32 g, 75-90%) was obtained in substantially the same manner as in Preparation 4, except that (E)-1-iodo-2-(3-(methoxymethoxy)prop-1-enyl)benzene (Preparation Example 19) was used instead of (E)-1-chloro-2-(3-(methoxymethoxy)prop-1-enyl)benzene (Preparation Example 2).

[0142] 1 H NMR (400MHz,CDCl3): δ3.09(d,J=5.6,1H),3.27 (d,J=4.4,1H),3.41 (s,3H),3.69~3.77 (m,2H),3.96~3.99 (m,1H),4.69(s,2H),5.19 (t,J=4.4,1H),7.23-7.61 (m,4H)

[0143] Preparation 23: ((4S,5S)-5-(2-iodophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.33 g, 30-40%) was obtained in substantially the same manner as in Preparation 6, except that (1S,2S)-1-(2-iodophenyl)-3-(methoxymethoxy)propane-1,2-diol (Preparation Example 22) was used instead of (1R,2R)-1-(2-chlorophenyl)-3-(methoxymethoxy)propane-1,2-diol (Preparation Example 3).

[0144] 1 H NMR (400MHz,CDCl3):δ1.57(s,3H),1.63 (s,3H),1.95-1.98 (m,1H),3.88~3.89 (m,1H),3.90~3.96(m,2H),5.41 (d,J=8.4,1H),7.25~7.66 (m,4H)

[0145] Production Example 24: (E)-Methyl-3-(2-chlorophenyl)acrylate [ka] To a 250 mL round-bottom flask was added 2-chlorocinnamic acid (25 g, 136.9 mmol) and MeOH (56 mL). POCl3 (1.27 mL, 13.6 mmol) was added dropwise. The reaction mixture was stirred under reflux for 3-4 hours. The reaction mixture was cooled to room temperature and quenched with 1N NaOH solution. The mixture was extracted with EtOAc and washed with H2O. The aqueous layer was further extracted with EtOAc. The combined organic layers were dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated in vacuo (26.98 g, 85-97%).

[0146] 1 H NMR (400MHz, CDCl3): δ3.84(s,3H),6.45 (d,J=16.0,1H),7.28-7.65 (m,4H),8.12 (d,J=16.0,1H)

[0147] Production Example 25: (2R,3S)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate [ka] A 1000 ml round-bottom flask equipped with a magnetic stirrer was charged with 362 ml of tert-butyl alcohol, 362 ml of water, KFe(CN) (135.53 g, 411.63 mmol), KCO (56.89 g, 411.63 mmol), (DHQ)PHAL (1.06 g, 1.37 mmol), KOsO(OH) (0.1 g, 0.27 mmol), and methanesulfonamide (13.05 g, 137.21 mmol) and stirred at 0 °C. (E)-Methyl-3-(2-chlorophenyl)acrylate (26.98 g, Preparation 24) was added in one portion, and the mixture was stirred vigorously at 0 °C overnight. While the mixture was stirring at 0 °C, solid sodium sulfite (Na 2S O3 (24.4 g, 193.5 mmol), EtOAc, and water were added, and the mixture was allowed to warm to room temperature and stirred. After layer separation, the aqueous layer was added to EtOAc, and the aqueous layer was separated. The combined organic layers were diluted with 0.3 M H 2S O4 / Na 2SO4 solution (H 2S O476ml, H2O 2L, Na 2S The crude compound was washed twice with HO (360 g). After separation of the organic layer, the organic layer was washed with HO. After separation of the layers, the organic layer was dried over anhydrous MgSO, filtered, and concentrated under vacuum. The crude compound was purified by silica gel column to yield the title compound (24.42 g, 70-90%).

[0148] 1 H NMR (400MHz,CDCl3): δ7.62~7.26(4H,m),5.51 (1H,dd,J=7.2,2.4),4.50 (1H,dd,J=5.6,2.4),3.86 (3H,s),3.13 (1H,d,J=6.0),2.79(1H,d,J=7.2)

[0149] Preparation Example 26: (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] Dichloromethane (DMC) was added to (2R,3S)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (24.4 g, Preparation 25) and cooled to 0°C. 2,2-Dimethoxypropane (26 mL, 211.77 mmol) and p-toluenesulfonic acid (2 g, 10.58 mmol) were added and stirred at room temperature. The reaction mixture was quenched with HO, extracted with DCM, washed with HO, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude compound was purified using a silica gel column to yield the title compound (23.6 g, 70-95%).

[0150] 1 H NMR (400MHz, CDCl3): δ1.63(s,3H),1.65 (s,3H),3.78 (s,3H),4.30 (d,J=7.6,1H),5.62 (d,J=7.6,1H),7.28~7.64(m,4H)

[0151] Preparation 27: ((4S,5S)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] A solution of LAH (LiAlH4 3.31 g, 87.25 mmol) in THF was added dropwise to a solution of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (23.6 g, Preparation 26) in THF at 0 °C, and the mixture was stirred at room temperature. The reaction mixture was quenched with HO at 0 °C, filtered through Celite with EtOAc, washed with EtOAc, dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated. The crude compound was purified using a silica gel column to yield the title compound (21.13 g, 70-95%).

[0152] 1 H NMR (400MHz, CDCl3): δ1.57(s,3H),1.64 (s,3H),1.98 (m,1H),3.76~3.83 (m,1H),3.88~3.90(m,2H),5.41 (d,J=8.4,1H),7.25~7.66 (m,4H)

[0153] Production Example 28: (E)-Methyl-3-(2,4-dichlorophenyl)acrylate [ka] The title compound (9.7 g, 70-90%) was obtained in substantially the same manner as in Preparation Example 24, except that 2,4-dichlorocinnamic acid was used instead of 2-chlorocinnamic acid.

[0154] 1 H NMR (400MHz,CDCl3): δ3.84(s,3H),6.44 (d,J=16,1H),7.28-7.33 (m,1H),7.41 (d,J=2.0,1H),7.55 (d,J=8.4,1H),8.04(d,J=16,1H)

[0155] Production Example 29: (2R,3S)-methyl-3-(2,4-dichlorophenyl)-2,3-dihydroxypropanoate [ka] The title compound (3.8 g, 60-80%) was obtained in substantially the same manner as in Preparation 25, except that (E)-methyl-3-(2,4-dichlorophenyl)acrylate (Preparation Example 28) was used instead of (E)-methyl-3-(2-chlorophenyl)acrylate (Preparation Example 24).

[0156] 1 H NMR (400MHz, CDCl3): δ3.11(s,1H),3.88 (s,3H),4.42 (d,J=2.4,1H),5.43 (d,J=2.0,1H),7.28~7.33(m,1H),7.41 (d,J=2.0,1H),7.55 (d,J=8.4,1H)

[0157] Preparation Example 30: (4R,5S)-methyl-5-(2,4-dichlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (3.5 g, 60-80%) was obtained in essentially the same manner as in Preparation 26, except that (2R,3S)-methyl-3-(2,4-dichlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 29) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 25).

[0158] 1 H NMR (400MHz,CDCl3): δ1.59(s,3H),1.63 (d,J=8.8,3H),3.78 (s,3H),4.25 (d,J=7.6,1H),5.56 (d,J=8.0,1H),7.28~7.33(m,1H),7.41 (d,J=2.0,1H),7.56 (d,J=8.4,1H)

[0159] Preparation 31: ((4S,5S)-5-(2,4-dichlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (3.2 g, 70-95%) was obtained in essentially the same manner as in Preparation 27, except that (4R,5S)-methyl-5-(2,4-dichlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 30) was used instead of (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0160] 1 H NMR (400MHz,CDCl3): δ1.56(s,3H),1.62 (d,J=4.8,6H),1.97 (dd,J=7.6,J=7.2,1H),3.75~3.80 (m,1H),3.82~3.86 (m,1H),3.89~3.94(m,1H),5.36 (d,J=8.4,1H),7.28~7.33 (m,1H),7.41 (d,J=2.0,1H),7.56 (d,J=8.4,1H)

[0161] Production Example 32: (E)-Ethyl-3-(2,6-dichlorophenyl)acrylate [ka] To a stirred solution of 2,6-dichlorobenzaldehyde (5.0 g, 28.56 mmol) in THF was added triethylphosphonoacetate (6.4 g, 28.56 mmol) at 0 °C. To the reaction mixture was added t-BuOK (3.2 g, 28.56 mmol) at room temperature. After stirring for 10 h, the resulting mixture was quenched with 1N HCl, diluted with ether, washed with water, dried over MgSO, and concentrated under reduced pressure. The crude product was purified by SiO gel column chromatography (4.3 g, 40-60%).

[0162] 1 H NMR (400MHz,CDCl3): δ1.36(t,J=3.6,3H),4.31 (q,J=3.7,2H),6.61 (d,J=16,1H),7.21 (t,J=4.2,1H),7.38 (d,J=5.2,1H),7.81(d,J=16,1H)

[0163] Production Example 33: (2R,3S)-ethyl-3-(2,6-dichlorophenyl)-2,3-dihydroxypropanoate [ka] The title compound (3.9 g, 60-80%) was obtained in substantially the same manner as in Preparation 25, except that (E)-ethyl-3-(2,6-dichlorophenyl)acrylate (Preparation Example 32) was used instead of (E)-methyl-3-(2-chlorophenyl)acrylate (Preparation Example 24).

[0164] 1 H NMR (400MHz, CDCl3): δ1.21(t,J=7.2,3H),3.22 (s,1H),3.69 (s,1H),4.20~4.28 (m,1H),4.70(d,J=5.2,1H),5.62 (d,J=5.6,1H),7.19~7.36 (m,3H)

[0165] Preparation 34: (4R,5S)-ethyl-5-(2,4-dichlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (4.1 g, 60-90%) was obtained in essentially the same manner as in Preparation 26, except that (2R,3S)-ethyl-3-(2,6-dichlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 29) was used instead of (2R,3S)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 25).

[0166] 1H NMR (400MHz, CDCl3): δ1.26(t,J=7.2,3H),1.58 (s,3H),1.70 (s,3H),3.77 (s,3H),4.24 (q,J=7.2,1H),4.95 (q,J=4.4,1H),5.95(q,J=3.0,1H),7.20-7.39 (m,3H)

[0167] Preparation 35: ((4S,5S)-5-(2,6-dichlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (3.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 27, except that (4R,5S)-ethyl-5-(2,6-dichlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 33) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0168] 1 H NMR (400MHz,CDCl3): δ1.55(s,3H),1.68 (s,3H),3.66 (q,J=5.5,1H),3.85 (q,J=5.1,1H),4.56~4.61 (m,1H),5.78 (d,J=9.2,1H),7.19~7.37(m,3H)

[0169] Production Example 36: (2S,3R)-methyl-3-(2,4-dichlorophenyl)-2,3-dihydroxypropanoate [ka] The title compound (2.4 g, 75-90%) was obtained in substantially the same manner as in Preparation 3, except that (E)-methyl-3-(2,4-dichlorophenyl)acrylate (Preparation Example 28) was used instead of (E)-1-chloro-2-(3-(methoxymethoxy)prop-1-enyl)benzene (Preparation Example 2).

[0170] 1 H NMR (400MHz, CDCl3): δ3.11(s,1H),3.88 (s,3H),4.42 (d,J=2.4,1H),5.43 (d,J=2.0,1H),7.28~7.33(m,1H),7.41 (d,J=2.0,1H),7.55 (d,J=8.4,1H)

[0171] Preparation Example 37: (4S,5R)-methyl-5-(2,4-dichlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (3.2 g, 60-80%) was obtained in essentially the same manner as in Preparation 26, except that (2S,3R)-methyl-3-(2,4-dichlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 36) was used instead of (2R,3S)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 25).

[0172] 1 H NMR (400MHz,CDCl3): δ1.59(s,3H),1.63 (d,J=8.8,3H),3.78 (s,3H),4.25 (d,J=7.6,H),5.56 (d,J=8.0,1H),7.28~7.33(m,1H),7.41 (d,J=2.0,1H),7.56 (d,J=8.4,1H)

[0173] Preparation 38: ((4R,5R)-5-(2,4-dichlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (3.5 g, 70-95%) was obtained in substantially the same manner as in Preparation 27, except that (4S,5R)-methyl-5-(2,4-dichlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 37) was used instead of (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0174] 1 H NMR (400MHz,CDCl3): δ1.56(s,3H),1.62 (d,J=4.8,6H),1.97 (dd,J=7.6,J=7.2,1H),3.75~3.80 (m,1H),3.82~3.86 (m,1H),3.89~3.94(m,1H),5.36 (d,J=8.4,1H),7.28~7.33 (m,1H),7.41 (d,J=2.0,1H),7.56 (d,J=8.4,1H)

[0175] Production Example 39: (2S,3R)-ethyl-3-(2,6-dichlorophenyl)-2,3-dihydroxypropanoate [ka] The title compound (2.8 g, 75-90%) was obtained in substantially the same manner as in Preparation 3, except that (E)-ethyl-3-(2,6-dichlorophenyl)acrylate (Preparation Example 32) was used instead of (E)-1-chloro-2-(3-(methoxymethoxy)prop-1-enyl)benzene (Preparation Example 2).

[0176] 1 H NMR (400MHz, CDCl3): δ3.11(s,1H),3.88 (s,3H),4.42 (d,J=2.4,1H),5.43 (d,J=2.0,1H),7.28~7.33(m,1H),7.41 (d,J=2.0,1H),7.55 (d,J=8.4,1H) 1H NMR (400MHz,CDCl3): δ=1.21(t,J=7.2,3H),3.22 (s,1H),3.69 (s,1H),4.20~4.28 (m,1H),4.70(d,J=5.2,1H),5.62 (d,J=5.6,1H),7.19~7.36 (m,3H)

[0177] Preparation Example 40: (4S,5R)-ethyl-5-(2,4-dichlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (4.1 g, 60-90%) was obtained in essentially the same manner as in Preparation 26, except that (2S,3R)-ethyl-3-(2,6-dichlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 39) was used instead of (2R,3S)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 25).

[0178] 1 H NMR (400MHz,CDCl3):δ1.26(t,J=7.2,3H),1.58 (s,3H),1.70 (s,3H),3.77 (s,3H),4,24 (q,J=7.2,1H),4.95 (q,J=4.4,1H),5.95(q,J=3.0,1H),7.20~7.39 (m,3H)

[0179] Preparation 41: ((4R,5R)-5-(2,6-dichlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (5.2 g, 70-95%) was obtained in essentially the same manner as in Preparation 27, except that (4S,5R)-ethyl-5-(2,6-dichlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 40) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0180] 1 H NMR (400MHz,CDCl3): δ1.55(s,3H),1.68 (s,3H),3.66 (q,J=5.5,1H),3.85 (q,J=5.1,1H),4.56~4.61 (m,1H),5.78 (d,J=9.2,1H),7.19~7.37(m,3H)

[0181] Preparation Example 42: (E)-3-(2-nitrophenyl)-acrylic acid [ka] The title compound (2.06 g, 70-90%) was obtained in substantially the same manner as in Preparation Example 9, except that 2-nitrobenzenealdehyde was used instead of 2-fluoroaldehyde.

[0182] 1 H NMR (400MHz,DMSO): δ6.52 (d,J=15.6,1H),7.65(t,J=8.1,1H),7.75 (t,J=7.4,1H),7.83 (d,J=15.8,1H),7.92 (dd,J=7.6,1.1,1H),8.05(dd,J=8.1,1.2,1H)

[0183] Production Example 43: (E)-Methyl-3-(2-nitrophenyl)acrylate [ka] The title compound (15.8 g, 70-90%) was obtained in substantially the same manner as in Preparation 24, except that (E)-3-(2-nitrophenyl)-acrylic acid (Preparation Example 42) was used instead of 2-chlorocinnamic acid.

[0184] 1 H NMR (400MHz,CDCl3): δ3.80(s,3H),6.34 (d,J=15.9Hz,1H),7.49-7.68 (m,4H),8.01 (d,J=7.9hz,1H),8.08 (d,J=15.9,1H)

[0185] Preparation Example 44: (2S,3R)-methyl-3-(2-nitrophenyl)dihydroxypropanoate [ka] The title compound (12.5 g, 75-90%) was obtained in substantially the same manner as in Preparation 3, except that (E)-methyl-3-(2-nitrophenyl)acrylate (Preparation Example 43) was used instead of (E)-1-chloro-2-(3-(methoxymethoxy)prop-1-enyl)benzene (Preparation Example 2).

[0186] 1 H NMR (400MHz, CDCl3): δ=4.31(s,3H),5.44 (m,4H),5.89 (s,1H),7.53~7.90 (m,4H)

[0187] Preparation Example 45: (4S,5R)-methyl-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (11 g, 60-80%) was obtained in essentially the same manner as in Preparation 26, except that (2S,3R)-methyl-3-(2-nitrophenyl)-2,3-dihydroxypropanoate (Preparation Example 44) was used instead of (2R,3S)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 25).

[0188] 1 H NMR (400MHz, CDCl3): δ1.38(s,3H),1.40 (s,3H),3.75 (s,3H),4.49 (d,J=7.4,1H),5.25 (d,J=7.4,1H),7.48~7.77(m,3H),8.08 (m,1H)

[0189] Preparation 46: ((4R,5R)-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (13.1 g, 70-95%) was obtained in substantially the same manner as in Preparation 27, except that (4S,5R)-methyl-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 45) was used instead of (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0190] 1 H NMR (400MHz,CDCl3):δ1.38(s,3H),1.40 (s,3H),3.89 (d,J=4.1,2H),4.26 (dt,J=7.0,4.1,1H),5.26 (d,J=7.0,1H),7.55-7.86(m,3H),8.08 (m,1H)

[0191] Preparation 47: ((4R,5R)-5-(2-aminophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] To a stirred solution of ((4R,5R)-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Preparation 46, 14 g) in EtOAc was added Pd(OH) (20 wt%, 2.8 g) under hydrogen gas (balloon). After stirring for 6 h, the resulting mixture was filtered through Celite and concentrated under reduced pressure. The crude product was purified by SiO gel column chromatography to yield the title compound (7.5 g, 65-85%).

[0192] 1 H NMR (400MHz, CDCl3): δ1.39(s,3H),1.40 (s,3H),3.88 (d,J=4.27,2H),3.99 (dt,J=7.02,J=4.30,1H),4.74 (d,J=7.02,1H),6.65-6.72(m,2H),6.98 (m,1H),7.25 (m,1H)

[0193] Production Example 48: (2R,3S)-methyl-3-(2-nitrophenyl)-2,3-dihydroxypropanoate [ka] The title compound (21.7 g, 60-80%) was obtained in substantially the same manner as in Preparation 25, except that (E)-methyl-3-(2-nitrophenyl)acrylate (Preparation Example 43) was used instead of (E)-methyl-3-(2-chlorophenyl)acrylate (Preparation Example 24).

[0194] 1 H NMR (400MHz,CDCl3):δ4.31(s,3H),5.44 (m,4H),5.89 (s,1H),7.53-7.90 (m,4H)

[0195] Preparation Example 49: (4R,5S)-methyl-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (21 g, 60-90%) was obtained in essentially the same manner as in Preparation 26, except that (2R,3S)-methyl-3-(2-nitrophenyl)-2,3-dihydroxypropanoate (Preparation Example 48) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 25).

[0196] 1 H NMR (400MHz, CDCl3): δ1.38(s,3H),1.40 (s,3H),3.75 (s,3H),4.49 (d,J=7.4,1H),5.25 (d,J=7.4,1H),7.48~7.77(m,3H),8.08 (m,1H)

[0197] Preparation 50: ((4S,5S)-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (14 g, 70-95%) was obtained in essentially the same manner as in Preparation 27, except that (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 48) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0198] 1 H NMR (400MHz,CDCl3):δ1.38(s,3H),1.40 (s,3H),3.89 (d,J=4.1,2H),4.26 (dt,J=7.0,4.1,1H),5.26 (d,J=7.0,1H),7.55~7.86(m,3H),8.08 (m,1H)

[0199] Preparation 51: ((4S,5S)-5-(2-aminophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (11 g, 70-95%) was obtained in essentially the same manner as in Preparation 47, except that (4S,5S)-methyl-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 50) was used instead of (4R,5R)-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Preparation Example 46).

[0200] 1 H NMR (400MHz,CDCl3):δ1.38(s,3H),1.40 (s,3H),3.89 (d,J=4.1,2H),4.26 (dt,J=7.0,4.1,1H),5.26 (d,J=7.0,1H),7.55~7.86(m,3H),8.08 (m,1H)

[0201] Production Example 52: (E)-3-o-Tolylacrylic acid [ka] The title compound (1.5 g, 70-90%) was obtained in substantially the same manner as in Preparation Example 9, except that 2-methylbenzenealdehyde was used instead of 2-fluoroaldehyde.

[0202] 1 H NMR (400MHz,CDCl3):δ2.48(s,3H),6.16 (d,J=15.1,1H),7.00-7.10 (m,1H),7.21~7.26(m,3H),8.04 (d,J=15.1,1H),11.0 (s,1H)

[0203] Production Example 53: (E)-Methyl-3-o-tolyl acrylate [ka] The title compound (1.5 g, 70-90%) was obtained in substantially the same manner as in Preparation 24, except that (E)-3-o-tolylacrylic acid (Preparation Example 52) was used instead of 2-chlorocinnamic acid.

[0204] 1 H NMR (400MHz,CDCl3):δ2.48(s,3H),3.77 (s,3H),6.14 (d,J=15.1,1H),7.00~7.10(m,1H),7.21~7.26 (m,3H),8.07 (d,J=15.1,1H)

[0205] Production Example 54: (2S,3R)-methyl-3-(2-methylphenyl)-2,3-dihydroxypropanoate [ka] The title compound (1.3 g, 75-90%) was obtained in substantially the same manner as in Preparation 3, except that (E)-methyl-3-o-tolyl acrylate (Preparation Example 53) was used instead of (E)-1-chloro-2-(3-(methoxymethoxy)prop-1-enyl)benzene (Preparation Example 2).

[0206] 1 H NMR (400MHz, CDCl3): δ2.34(s,3H),2.80 (s,1H),3.65 (s,1H),3.68 (s,3H),4.52 (d,J=7.0,1H),5.22 (d,J=7.0,1H),7.19~7.39(m,4H)

[0207] Preparation Example 55: (4S,5R)-methyl-5-(2-methylphenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.7 g, 60-80%) was obtained in essentially the same manner as in Preparation 26, except that (2S,3R)-methyl-3-(2-methylphenyl)-2,3-dihydroxypropanoate (Preparation Example 54) was used instead of (2R,3S)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 25).

[0208] 1H NMR (400MHz,CDCl3):δ1.27(s,6H),2.34 (s,3H),3.68 (s,3H),5.11 (d,J=7.0,1H),5.81 (d,J=7.0,H),7.19~7.26(m,3H),7.37~7.39 (m,1H)

[0209] Preparation 56: ((4R,5R)-5-(2-methylphenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.3 g, 70-95%) was obtained in essentially the same manner as in Preparation 27, except that (4S,5R)-methyl-5-(2-methylphenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 55) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0210] 1 H NMR (400MHz, CDCl3): δ1.27(s,6H),2.34 (s,3H),3.52~3.60 (m,2H),3.65 (s,1H),4.36 (dd,J=7.0,J=7.0,1H),5.17(d,J=7.0,1H),7.19~7.26 (m,3H),7.37-7.39 (m,1H)

[0211] Production Example 57: (2R,3S)-methyl-3-(2-methylphenyl)-2,3-dihydroxypropanoate [ka] The title compound (1.7 g, 60-80%) was obtained in substantially the same manner as in Preparation 25, except that (E)-methyl-3-o-tolyl acrylate (Preparation Example 53) was used instead of (E)-methyl-3-(2-chlorophenyl)acrylate (Preparation Example 24).

[0212] 1H NMR (400MHz, CDCl3): δ2.34(s,3H),2.80 (s,1H),3.65 (s,1H),3.68 (s,3H),4.52 (d,J=7.0,1H),5.22 (d,J=7.0,1H),7.19~7.39(m,4H)

[0213] Preparation Example 58: (4R,5S)-methyl-5-(2-methylphenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.9 g, 60-90%) was obtained in essentially the same manner as in Preparation 26, except that (2R,3S)-methyl-3-(2-methylphenyl)-2,3-dihydroxypropanoate (Preparation Example 57) was used instead of (2R,3S)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 25).

[0214] 1 H NMR (400MHz,CDCl3):δ1.27(s,6H),2.34 (s,3H),3.68 (s,3H),5.11 (d,J=7.0,1H),5.81 (d,J=7.0,1H),7.19~7.26(m,3H),7.37~7.39 (m,1H)

[0215] Preparation 59: ((4S,5S)-5-(2-methylphenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 27, except that (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 58) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0216] 1 H NMR (400MHz, CDCl3): δ1.27(s,6H),2.34 (s,3H),3.52~3.60 (m,2H),3.65 (s,1H),4.36 (dd,J=7.0,J=7.0,1H),5.17(d,J=7.0,1H),7.19~7.26 (m,3H),7.37-7.39 (m,1H)

[0217] Preparation 60: ((4S,5R)-methyl-5-(2-chlorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate [ka] Dichloromethane (MC) was added to (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 433) at room temperature. 1,1-Diethoxyethane (8 ml) and p-toluenesulfonic acid (0.27 g) were added and stirred at room temperature. The reaction mixture was quenched with HO, extracted with MC, washed with HO, dried over anhydrous magnesium sulfate (MgSO), filtered, and concentrated. The crude compound was purified using a silica gel column to yield the title compound (3.6 g, 70-95%).

[0218] 1 H NMR (400MHz,CDCl3): δ1.36(d,J=6.4,3H),3.78 (s,3H),4.30 (d,J=7.6,1H),5.07 (m,1H),5.62 (d,J=7.6,1H),7.28~7.64(m,4H)

[0219] Preparation 61: ((4R,5R)-5-(2-chlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (3.1 g, 70-95%) was obtained in essentially the same manner as in Preparation 27, except that (4S,5R)-methyl-5-(2-chlorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 60) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0220] 1 H NMR (400MHz, CDCl3): δ1.37(d,J=6.0,3H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.19~7.26(m,3H),7.37~7.39 (m,1H)

[0221] Preparation 62: ((4R,5S)-methyl-5-(2-chlorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.1 g, 70-95%) was obtained in substantially the same manner as in Preparation 60, except that (2R,3S)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 25) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 54).

[0222] 1 H NMR (400MHz,CDCl3): δ1.36(d,J=6.4,3H),3.78 (s,3H),4.30 (d,J=7.6,1H),5.07 (m,1H),5.62 (d,J=7.6,1H),7.28~7.64(m,4H)

[0223] Preparation 63: ((4S,5S)-5-(2-chlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (3.1 g, 70-95%) was obtained in essentially the same manner as in Preparation 27, except that (4R,5S)-methyl-5-(2-chlorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 62) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0224] 1 H NMR (400MHz, CDCl3): δ1.37(d,J=6.0,3H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.19-7.26(m,3H),7.37~7.39 (m,1H)

[0225] Preparation 64: (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate [ka] 3-Pentanone was added to (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation 433) at room temperature. 2S The reaction mixture was quenched with H2O, extracted with EA, washed with H2O, and anhydrous sodium sulfate (Na 2S The crude compound was purified by silica gel column to give the title compound (1.6 g, 60-85%).

[0226] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.59 (m,4H),3.67 (s,3H),5.11 (d,J=7.6,1H),5.81 (d,J=7.6,1H),7.22~7.60 (m,4H)

[0227] Preparation 65: ((4R,5R)-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (2.0 g, 70-95%) was obtained in essentially the same manner as in Preparation 27, except that (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 64) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0228] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.59 (m,4H),3.66 (d,J=8.0,2H),5.09 (d,J=7.6,1H),5.88 (d,J=7.6,1H),7.26~7.62(m,4H)

[0229] Preparation 66: (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.4 g, 70-95%) was obtained in essentially the same manner as in Preparation 64, except that (2R,3S)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 25) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 54).

[0230] 1 H NMR (400MHz, CDCl3): δ0.96(m,6H),1.59 (m,4H),3.67 (s,3H),5.11 (d,J=7.6. 1H),5.81 (d,J=7.6,1H),7.22~7.60(m,4H)

[0231] Preparation 67: ((4S,5S)-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (2.2 g, 70-95%) was obtained in essentially the same manner as in Preparation 65, except that (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 66) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 64).

[0232] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.59 (m,4H),3.66 (d,J=8.0,2H),5.09 (d,J=7.6,1H),5.88 (d,J=7.6,1H),7.26~7.62(m,4H)

[0233] Preparation 68: (2S,3R)-methyl-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (2.2 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 64, except that cyclopentanone was used instead of 3-pentanone.

[0234] 1 H NMR (400MHz,DMSO): δ1.69-1.71 (m,4H),1.82-1.86(m,1H),1.91-2.00 (m,3H),3.68 (s,3H),4.40 (d,J=7.2,1H),5.39 (d,J=7.2,1H),7.39~7.61(m,4H)

[0235] Preparation 69: ((2R,3R)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (1.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 65, except that (2S,3R)-methyl-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 68) was used instead of (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 64).

[0236] 1 H NMR (400MHz,DMSO): δ1.60~1.72 (m,4H),1.83-1.94(m,1H),3.52-3.65 (m,2H),3.82~3.86 (m,1H),4.90 (t,J=5.2,1H),5.12 (d,J=7.6,1H),7.34~7.58(m,4H)

[0237] Preparation Example 70: (2R,3S)-methyl-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (1.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 68, except that (2R,3S)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 25) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 433).

[0238] 1H NMR (400MHz,DMSO): δ1.69-1.71 (m,4H),1.82-1.86(m,1H),1.91-2.00 (m,3H),3.68 (s,3H),4.40 (d,J=7.2,1H),5.39 (d,J=7.2,1H),7.39~7.61(m,4H)

[0239] Preparation 71: ((2R,3R)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (1.8 g, 70-95%) was obtained in essentially the same manner as in Preparation 69, except that (2R,3S)-methyl-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 70) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 68).

[0240] 1 H NMR (400MHz,DMSO): δ1.60~1.72 (m,4H),1.83-1.94(m,1H),3.52-3.65 (m,2H),3.82~3.86 (m,1H),4.90 (t,J=5.2,1H),5.12 (d,J=7.6,1H),7.34~7.58(m,4H)

[0241] Preparation Example 72: (2S,3R)-methyl-3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (1.2 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 64, except that cyclohexanone was used instead of 3-pentanone.

[0242] 1H NMR (400MHz,DMSO):δ1.61-1.69(m,10H),3.79 (s,3H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.35~7.63(m,4H)

[0243] Preparation 73: ((2R,3R)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (1.8 g, 70-95%) was obtained in essentially the same manner as in Preparation 65, except that (2S,3R)-methyl-3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 72) was used instead of (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 64).

[0244] 1 H NMR (400MHz,DMSO): δ1.63~1.75 (m,10H),3.52-3.81(m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.48~7.87 (m,4H)

[0245] Preparation 74: (2R,3S)-methyl-3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (2.1 g, 70-95%) was obtained in essentially the same manner as in Preparation 72, except that (2R,3S)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 25) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 433).

[0246] 1H NMR (400MHz,DMSO):δ1.61-1.69(m,10H),3.79 (s,3H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.35~7.63(m,4H)

[0247] Preparation 75: ((2S,3S)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (1.6 g, 70-95%) was obtained in essentially the same manner as in Preparation 65, except that (2R,3S)-methyl-3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 74) was used instead of (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 64).

[0248] 1 H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),3.52~3.81(m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.48~7.87 (m,4H)

[0249] Preparation 76: (4S,5R)-methyl-5-(2-chlorophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.1 g, 50-70%) was obtained in substantially the same manner as in Preparation Example 64, except that benzaldehyde was used instead of 3-pentanone.

[0250] 1 H NMR (400MHz,DMSO):δ1.61-1.69(m,10H),3.79 (s,3H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.35~7.63(m,4H)

[0251] Preparation 77: ((4R,5R)-5-(2-chlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (0.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 65, except that (2S,3R)-methyl-3-(2-chlorophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 76) was used instead of (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 64).

[0252] 1 H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),3.52-3.81(m,2H),3.95(t,J=8.0,1H),5.43 (d,J=7.6,1H),7.48~7.87 (m,4H)

[0253] Preparation 78: (4R,5S)-methyl-5-(2-chlorophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.9 g, 50-70%) was obtained in substantially the same manner as in Preparation Example 66, except that benzaldehyde was used instead of 3-pentanone.

[0254] 1 H NMR (400MHz,DMSO):δ1.61-1.69(m,10H),3.79 (s,3H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.35-7.63 (m,4H)

[0255] Preparation 79: ((4S,5S)-5-(2-chlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.3 g, 70-95%) was obtained in essentially the same manner as in Preparation 65, except that (2R,5S)-methyl-3-(2-chlorophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 78) was used instead of (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 64).

[0256] 1 H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),3.52~3.81(m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.48~7.87 (m,4H)

[0257] Production Example 80: (E)-Methyl-3-(2-fluorophenyl)acrylate [ka] The title compound (6.98 g, 70-90%) was obtained in substantially the same manner as in Preparation 24, except that (E)-3-(2-fluorophenyl)-acrylic acid (Preparation Example 9) was used instead of 2-chlorocinnamic acid.

[0258] 1 H NMR (400MHz, CDCl3): δ3.84(s,3H),6.45 (d,J=16.0,1H),7.24~7.62 (m,4H),8.12(d,J=16.0,1H)

[0259] Preparation Example 81: (2S,3R)-methyl-3-(2-fluorophenyl)-2,3-dihydroxypropanoate [ka] The title compound (7.5 g, 75-90%) was obtained in substantially the same manner as in Preparation 3, except that (E)-methyl-3-(2-fluorophenyl)acrylate (Preparation Example 80) was used instead of (E)-1-chloro-2-(3-(methoxymethoxy)prop-1-enyl)benzene (Preparation Example 2).

[0260] 1 H NMR (400MHz, CDCl3): δ=4.31(s,3H),5.44 (m,4H),5.89 (s,1H),7.32~7.70 (m,4H)

[0261] Preparation Example 82: (2R,3S)-methyl-3-(2-fluorophenyl)-2,3-dihydroxypropanoate [ka] The title compound (7.2 g, 60-80%) was obtained in substantially the same manner as in Preparation 25, except that (E)-methyl-3-(2-fluorophenyl)acrylate (Preparation Example 80) was used instead of (E)-methyl-3-(2-chlorophenyl)acrylate (Preparation Example 24).

[0262] 1 H NMR (400MHz, CDCl3): δ=4.31(s,3H),5.44 (m,4H),5.89 (s,1H),7.32~7.70 (m,4H)

[0263] Preparation 83: ((4S,5R)-methyl-5-(2-fluorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate [ka] The title compound (3.1 g, 70-95%) was obtained in essentially the same manner as in Preparation 60, except that (2S,3R)-methyl-3-(2-fluorophenyl)-2,3-dihydroxypropanoate (Preparation Example 81) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 433).

[0264] 1 H NMR (400MHz, CDCl3): δ1.36(d,J=6.4,3H),3.78 (s,3H),4.30 (d,J=7.6. 1H),5.07 (m,1H),5.62 (d,J=7.6,1H),7.29~7.67(m,4H)

[0265] Preparation 84: ((4R,5R)-5-(2-fluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (3.3 g, 70-95%) was obtained in essentially the same manner as in Preparation 27, except that (4S,5R)-methyl-5-(2-fluorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 83) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0266] 1 H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.19~7.39(m,4H)

[0267] Preparation 85: ((4R,5S)-methyl-5-(2-fluorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.9 g, 70-95%) was obtained in essentially the same manner as in Preparation 60, except that (2R,3S)-methyl-3-(2-fluorophenyl)-2,3-dihydroxypropanoate (Preparation Example 82) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 433).

[0268] 1 H NMR (400MHz,CDCl3): δ1.36(d,J=6.4,3H),3.78 (s,3H),4.30 (d,J=7.6,1H),5.07 (m,1H),5.62 (d,J=7.6,1H),7.29~7.69(m,4H)

[0269] Preparation 86: ((4S,5S)-5-(2-fluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (3.8 g, 70-95%) was obtained in essentially the same manner as in Preparation 27, except that (4R,5S)-methyl-5-(2-fluorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 85) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0270] 1 H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.19-7.42(m,4H)

[0271] Preparation 87: (4S,5R)-methyl-5-(2-fluorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.1 g, 60-85%) was obtained in essentially the same manner as in Preparation 64, except that (2S,3R)-methyl-3-(2-fluorophenyl)-2,3-dihydroxypropanoate (Preparation Example 81) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 433).

[0272] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.59 (m,4H),3.67 (s,3H),5.11 (d,J=7.6,1H),5.81 (d,J=7.6,1H),7.20~7.61 (m,4H)

[0273] Preparation 88: ((4R,5R)-5-(2-fluorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (2.2 g, 70-95%) was obtained in essentially the same manner as in Preparation 27, except that (4S,5R)-methyl-5-(2-fluorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 87) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0274] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.59 (m,4H),3.66 (d,J=8.0,2H),5.09 (d,J=7.6,1H),5.88 (d,J=7.6,1H),7.23~7.60(m,4H)

[0275] Preparation 89: (4R,5S)-methyl-5-(2-fluorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.3 g, 70-95%) was obtained in substantially the same manner as in Preparation 87, except that (2R,3S)-methyl-3-(2-fluorophenyl)-2,3-dihydroxypropanoate (Preparation Example 82) was used instead of (2S,3R)-methyl-3-(2-fluorophenyl)-2,3-dihydroxypropanoate (Preparation Example 81).

[0276] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.59 (m,4H),3.67 (s,3H),5.11 (d,J=7.6,1H),5.81 (d,J=7.6,1H),7.20~7.61 (m,4H)

[0277] Preparation 90: ((4S,5S)-5-(2-fluorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (2.2 g, 70-95%) was obtained in essentially the same manner as in Preparation 88, except that (4R,5S)-methyl-5-(2-fluorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 89) was used instead of (4S,5R)-methyl-5-(2-fluorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 87).

[0278] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.59 (m,4H),3.66 (d,J=8.0,2H),5.09 (d,J=7.6,1H),5.88 (d,J=7.6,1H),7.23~7.62(m,4H)

[0279] Preparation Example 91: (2S,3R)-methyl-3-(2-fluorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (2.1 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 87, except that cyclopentanone was used instead of 3-pentanone.

[0280] 1 H NMR (400MHz,DMSO): δ1.69-1.71 (m,4H),1.82~1.86(m,1H),1.91-2.00 (m,3H),3.68 (s,3H),4.40 (d,J=7.2,1H),5.39 (d,J=7.2,1H),7.33~7.62(m,4H)

[0281] Preparation 92: ((2R,3R)-3-(2-fluorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (1.9 g, 70-95%) was obtained in essentially the same manner as in Preparation 65, except that (2S,3R)-methyl-3-(2-fluorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 91) was used instead of (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 64).

[0282] 1 H NMR (400MHz,DMSO): δ1.60-1.72 (m,4H),1.83-1.94(m,1H),3.52-3.65 (m,2H),3.82~3.86 (m,1H),4.90 (t,J=5.2,1H),5.12 (d,J=7.6,1H),7.32~7.57(m,4H)

[0283] Preparation Example 93: (2R,3S)-methyl-3-(2-fluorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (1.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 91, except that (2R,3S)-methyl-3-(2-fluorophenyl)-2,3-dihydroxypropanoate (Preparation Example 82) was used instead of (2S,3R)-methyl-3-(2-fluorophenyl)-2,3-dihydroxypropanoate (Preparation Example 81).

[0284] 1 H NMR (400MHz,DMSO): δ1.69-1.71 (m,4H),1.82~1.86(m,1H),1.91~2.00 (m,3H),3.68 (s,3H),4.40 (d,J=7.2,1H),5.39 (d,J=7.2,1H),7.39~7.61(m,4H)

[0285] Preparation 94: ((2R,3R)-3-(2-fluorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (1.2 g, 70-95%) was obtained in essentially the same manner as in Preparation 88, except that (2R,3S)-methyl-3-(2-fluorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 93) was used instead of (4S,5R)-methyl-5-(2-fluorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 87).

[0286] 1 H NMR (400MHz,DMSO): δ1.60-1.72 (m,4H),1.83~1.94(m,1H),3.52~3.65 (m,2H),3.82~3.86 (m,1H),4.90 (t,J=5.2,1H),5.12 (d,J=7.6,1H),7.38~7.63(m,4H)

[0287] Preparation 95: (2S,3R)-methyl-3-(2-fluorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (1.7 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 91, except that cyclohexanone was used instead of cyclopentanone.

[0288] 1 H NMR (400MHz,DMSO):δ1.61-1.69(m,10H),3.79 (s,3H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.37~7.63(m,4H)

[0289] Preparation 96: ((2R,3R)-3-(2-fluorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (1.4 g, 70-95%) was obtained in essentially the same manner as in Preparation 73, except that (2S,3R)-methyl-3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 72) was replaced with (2S,3R)-methyl-3-(2-fluorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 95).

[0290] 1 H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),3.52~3.81(m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.42~7.89 (m,4H)

[0291] Preparation 97: (2R,3S)-methyl-3-(2-fluorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (1.8 g, 70-95%) was obtained in essentially the same manner as in Preparation 95, except that (2R,3S)-methyl-3-(2-fluorophenyl)-2,3-dihydroxypropanoate (Preparation Example 82) was used instead of (2S,3R)-methyl-3-(2-fluorophenyl)-2,3-dihydroxypropanoate (Preparation Example 81).

[0292] 1 H NMR (400MHz,DMSO):δ1.61-1.69(m,10H),3.79 (s,3H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.32~7.64(m,4H)

[0293] Preparation 98: ((2S,3S)-3-(2-fluorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (1.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 96, except that (2R,3S)-methyl-3-(2-fluorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 97) was used instead of (2S,3R)-methyl-3-(2-fluorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 95).

[0294] 1 H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),3.52~3.81(m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.33~7.67 (m,4H)

[0295] Preparation 99: (4S,5R)-methyl-5-(2-fluorophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.6 g, 50-70%) was obtained in substantially the same manner as in Preparation Example 87, except that benzaldehyde was used instead of 3-pentanone.

[0296] 1 H NMR (400MHz,DMSO):δ1.61-1.69(m,10H),3.79 (s,3H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.33~7.64(m,4H)

[0297] Preparation 100: ((4R,5R)-5-(2-fluorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.3 g, 70-95%) was obtained in essentially the same manner as in Preparation 65, except that (2S,3R)-methyl-3-(2-fluorophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 99) was used instead of (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 64).

[0298] 1 H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),3.52-3.81(m,2H),3.95(t,J=8.0,1H),5.43 (d,J=7.6,1H),7.43~7.85 (m,4H)

[0299] Preparation Example 101: (4R,5S)-methyl-5-(2-fluorophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.7 g, 50-70%) was obtained in substantially the same manner as in Preparation Example 89, except that benzaldehyde was used instead of 3-pentanone.

[0300] 1 H NMR (400MHz,DMSO):δ1.61-1.69(m,10H),3.79 (s,3H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.33~7.64(m,4H)

[0301] Preparation 102: ((4S,5S)-5-(2-fluorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.1 g, 70-95%) was obtained in essentially the same manner as in Preparation 65, except that (2R,3S)-methyl-3-(2-fluorophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 101) was used instead of (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 64).

[0302] 1 H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),3.52~3.81(m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.43~7.85 (m,4H)

[0303] Production Example 103: (E)-Methyl-3-(2-iodophenyl)acrylate [ka] The title compound (3.2 g, 70-90%) was obtained in substantially the same manner as in Preparation 24, except that (E)-3-(2-iodophenyl)-acrylic acid (Preparation Example 17) was used instead of 2-chlorocinnamic acid.

[0304] 1H NMR (400MHz,CDCl3):δ3.84(s,3H),6.45 (d,J=16.0,1H),7.01-7.35 (m,4H),8.09 (d,J=16.0,1H)

[0305] Preparation Example 104: (2S,3R)-methyl-3-(2-iodophenyl)-2,3-dihydroxypropanoate [ka] The title compound (3.2 g, 75-90%) was obtained in substantially the same manner as in Preparation 3, except that (E)-methyl-3-(2-iodophenyl)acrylate (Preparation Example 103) was used instead of (E)-1-chloro-2-(3-(methoxymethoxy)prop-1-enyl)benzene (Preparation Example 2).

[0306] 1 H NMR (400MHz, CDCl3): δ=4.31(s,3H),5.44 (m,4H),5.89 (s,1H),7.30~7.71 (m,4H)

[0307] Preparation Example 105: (2R,3S)-methyl-3-(2-iodophenyl)-2,3-dihydroxypropanoate [ka] The title compound (3.1 g, 60-80%) was obtained in substantially the same manner as in Preparation 25, except that (E)-methyl-3-(2-iodophenyl)acrylate (Preparation Example 103) was used instead of (E)-methyl-3-(2-chlorophenyl)acrylate (Preparation Example 24).

[0308] 1 H NMR (400MHz, CDCl3): δ=4.31(s,3H),5.44 (m,4H),5.89 (s,1H),7.31~7.72 (m,4H)

[0309] Preparation 106: ((4S,5R)-methyl-5-(2-iodophenyl)-2-methyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 60, except that (2S,3R)-methyl-3-(2-iodophenyl)-2,3-dihydroxypropanoate (Preparation Example 104) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 433).

[0310] 1 H NMR (400MHz,CDCl3): δ1.36(d,J=6.4,3H),3.78 (s,3H),4.30 (d,J=7.6,1H),5.07 (m,1H),5.62 (d,J=7.6,1H),7.29-7.70(m,4H)

[0311] Preparation 107: ((4R,5R)-5-(2-iodophenyl)-2-methyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (2.3 g, 70-95%) was obtained in essentially the same manner as in Preparation 27, except that (4S,5R)-methyl-5-(2-iodophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 106) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0312] 1 H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.17-7.41(m,4H)

[0313] Preparation 108: ((4R,5S)-methyl-5-(2-iodophenyl)-2-methyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.4 g, 70-95%) was obtained in essentially the same manner as in Preparation 60, except that (2R,3S)-methyl-3-(2-iodophenyl)-2,3-dihydroxypropanoate (Preparation Example 104) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 433).

[0314] 1 H NMR (400MHz,CDCl3): δ1.36(d,J=6.4,3H),3.78 (s,3H),4.30 (d,J=7.6,1H),5.07 (m,1H),5.62 (d,J=7.6,1H),7.29-7.70(m,4H)

[0315] Preparation 109: ((4S,5S)-5-(2-iodophenyl)-2-methyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.9 g, 70-95%) was obtained in essentially the same manner as in Preparation 107, except that (4R,5S)-methyl-5-(2-iodophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 108) was used instead of (4S,5R)-methyl-5-(2-iodophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 106).

[0316] 1H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62-3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.17~7.41(m,4H)

[0317] Preparation 110: (4S,5R)-methyl-5-(2-iodophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.6 g, 60-85%) was obtained in essentially the same manner as in Preparation 64, except that (2R,3S)-methyl-3-(2-iodophenyl)-2,3-dihydroxypropanoate (Preparation Example 104) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 433).

[0318] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.59 (m,4H),3.67 (s,3H),5.11 (d,J=7.6,1H),5.81 (d,J=7.6,1H),7.23~7.65 (m,4H)

[0319] Preparation 111: ((4R,5R)-5-(2-iodophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (2.1 g, 70-95%) was obtained in essentially the same manner as in Preparation 107, except that (4S,5R)-methyl-5-(2-iodophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 110) was used instead of (4S,5R)-methyl-5-(2-iodophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 106).

[0320] 1 H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62-3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.17~7.41(m,4H)

[0321] Preparation Example 112: (4R,5S)-methyl-5-(2-iodophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.3 g, 60-85%) was obtained in substantially the same manner as in Preparation 110, except that (2R,3S)-methyl-3-(2-iodophenyl)-2,3-dihydroxypropanoate (Preparation Example 105) was used instead of (2S,3R)-methyl-3-(2-iodophenyl)-2,3-dihydroxypropanoate (Preparation Example 104).

[0322] 1 H NMR (400MHz,CDCl3):δ0.96(m,6H),1.59 (m,4H),3.67 (s,3H),5.11 (d,J=7.6,1H),5.81 (d,J=7.6,1H),7.20-7.61 (m,4H)

[0323] Preparation 113: ((4S,5S)-5-(2-iodophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.8 g, 70-95%) was obtained in essentially the same manner as in Preparation 107, except that (4R,5S)-methyl-5-(2-iodophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 112) was used instead of (4S,5R)-methyl-5-(2-iodophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 106).

[0324] 1 H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.17~7.41(m,4H)

[0325] Preparation 114: (2S,3R)-methyl-3-(2-iodophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (2.7 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 110, except that cyclopentanone was used instead of 3-pentanone.

[0326] 1 H NMR (400MHz,DMSO): δ1.69-1.71 (m,4H),1.82~1.86(m,1H),1.91~2.00 (m,3H),3.68 (s,3H),4.40 (d,J=7.2,1H),5.39 (d,J=7.2,1H),7.19~7.44(m,4H)

[0327] Preparation 115: ((2R,2R)-3-(2-iodophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (2.1 g, 70-95%) was obtained in essentially the same manner as in Preparation 107, except that (2S,3R)-methyl-3-(2-iodophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 114) was used instead of (4S,5R)-methyl-5-(2-iodophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 106).

[0328] 1 H NMR (400MHz,DMSO): δ1.60-1.72 (m,4H),1.83~1.94(m,1H),3.52~3.65 (m,2H),3.82~3.86 (m,1H),4.90 (t,J=5.2,1H),5.12 (d,J=7.6,1H),7.20~7.45(m,4H)

[0329] Preparation Example 116: (2R,3S)-methyl-3-(2-iodophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (2.9 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 112, except that cyclopentanone was used instead of 3-pentanone.

[0330] 1 H NMR (400MHz,DMSO): δ1.69-1.71 (m,4H),1.82-1.86(m,1H),1.91-2.00 (m,3H),3.68 (s,3H),4.40 (d,J=7.2,1H),5.39 (d,J=7.2,1H),7.19~7.44(m,4H)

[0331] Preparation 117: ((2S,2S)-3-(2-iodophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (1.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 107, except that (2R,3S)-methyl-3-(2-iodophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 116) was used instead of (4S,5R)-methyl-5-(2-iodophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 106).

[0332] 1H NMR (400MHz,DMSO): δ1.60-1.72 (m,4H),1.83-1.94(m,1H),3.52-3.65 (m,2H),3.82~3.86 (m,1H),4.90 (t,J=5.2,1H),5.12 (d,J=7.6,1H),7.20~7.45(m,4H)

[0333] Preparation 118: (2S,3R)-methyl-3-(2-iodophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (1.9 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 114, except that cyclohexanone was used instead of cyclopentanone.

[0334] 1 H NMR (400MHz,DMSO):δ1.61-1.69(m,10H),3.79 (s,3H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.17~7.43(m,4H)

[0335] Preparation 119: ((2R,3R)-3-(2-iodophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (1.3 g, 70-95%) was obtained in essentially the same manner as in Preparation 107, except that (2S,3R)-methyl-3-(2-iodophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 118) was used instead of (4S,5R)-methyl-5-(2-iodophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 106).

[0336] 1H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),3.52~3.81(m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.19~7.49 (m,4H)

[0337] Preparation Example 120: (2R,3S)-methyl-3-(2-iodophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (2.3 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 116, except that cyclohexanone was used instead of cyclopentanone.

[0338] 1 H NMR (400MHz,DMSO):δ1.61-1.69(m,10H),3.79 (s,3H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.17~7.43(m,4H)

[0339] Preparation 121: ((2S,3S)-3-(2-iodophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (1.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 107, except that (2R,3S)-methyl-3-(2-iodophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 120) was used instead of (4S,5R)-methyl-5-(2-iodophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 106).

[0340] 1H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),3.52~3.81(m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.19~7.49 (m,4H)

[0341] Preparation 122: (4S,5R)-methyl-5-(2-iodophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.9 g, 50-70%) was obtained in substantially the same manner as in Preparation Example 118, except that benzaldehyde was used instead of cyclohexanone. 1 H NMR (400MHz,DMSO): δ3.67(s,3H),5.11 (d,J=8.0,1H),5.81 (d,J=8.0,1H),6.18 (s,1H),6.96~7.57(m,9H)

[0342] Preparation 123: ((4R,5R)-5-(2-iodophenyl)-2-phenyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.4 g, 70-95%) was obtained in essentially the same manner as in Preparation 107, except that (4S,5R)-methyl-5-(2-iodophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 122) was used instead of (4S,5R)-methyl-5-(2-iodophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 106).

[0343] 1 H NMR (400MHz,DMSO):δ3.66(d,J=7.6,2H),4.36 (m,1H),5.17 (d,J=8.0,1H),6.18 (s,1H),6.94~7.59(m,9H)

[0344] Preparation 124: (4R,5S)-methyl-5-(2-iodophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.1 g, 50-70%) was obtained in substantially the same manner as in Preparation Example 120, except that benzaldehyde was used instead of cyclohexanone.

[0345] 1 H NMR (400MHz,DMSO):δ3.67(s,3H),5.11 (d,J=8.0,1H),5.81 (d,J=8.0,1H),6.18 (s,1H),6.96~7.57(m,9H)

[0346] Preparation 125: ((4S,5S)-5-(2-iodophenyl)-2-phenyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.3 g, 70-95%) was obtained in essentially the same manner as in Preparation 107, except that (4R,5S)-methyl-5-(2-iodophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 124) was used instead of (4S,5R)-methyl-5-(2-iodophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 106).

[0347] 1 H NMR (400MHz,DMSO):δ3.66(d,J=7.6,2H),4.36 (m,1H),5.17 (d,J=8.0,1H),6.18 (s,1H),6.94~7.59(m,9H)

[0348] Preparation 126: ((4S,5R)-methyl-5-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate [ka] The title compound (0.9 g, 70-95%) was obtained in essentially the same manner as in Preparation 60, except that (2S,3R)-methyl-3-(2,4-dichlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 36) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 433).

[0349] 1 H NMR (400MHz,CDCl3): δ1.36(d,J=6.4,3H),3.78 (s,3H),4.30 (d,J=7.6,1H),5.07 (m,1H),5.62 (d,J=7.6,1H),7.07~7.21(m,3H)

[0350] Preparation 127: ((4R,5R)-5-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (0.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 27, except that ((4S,5R)-methyl-5-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 126) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0351] 1 H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.08~7.39(m,3H)

[0352] Preparation 128: ((4R,5S)-methyl-5-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.9 g, 70-95%) was obtained in essentially the same manner as in Preparation 126, except that (2R,3S)-methyl-3-(2,4-dichlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 29) was used instead of (2S,3R)-methyl-3-(2,4-dichlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 36).

[0353] 1 H NMR (400MHz,CDCl3): δ1.36(d,J=6.4,3H),3.78 (s,3H),4.30 (d,J=7.6,1H),5.07 (m,1H),5.62 (d,J=7.6,1H),7.07~7.21(m,3H)

[0354] Preparation 129: ((4S,5S)-5-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 27, except that (4R,5S)-methyl-5-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 128) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0355] 1 H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.08-7.39(m,3H)

[0356] Preparation 130: (4S,5R)-methyl-5-(2,4-dichlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.2 g, 60-85%) was obtained in essentially the same manner as in Preparation 64, except that (2S,3R)-methyl-3-(2,4-dichlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 36) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 433).

[0357] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.59 (m,4H),3.67 (s,3H),5.11 (d,J=7.6,1H),5.81 (d,J=7.6,1H),7.12~7.37 (m,3H)

[0358] Preparation 131: ((4R,5R)-5-(2,4-dichlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.4 g, 70-95%) was obtained in essentially the same manner as in Preparation 27, except that (4S,5R)-methyl-5-(2,4-dichlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 130) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0359] 1 H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.03~7.39(m,3H)

[0360] Preparation 132: (4R,5S)-methyl-5-(2,4-chlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.1 g, 70-95%) was obtained in substantially the same manner as in Preparation 130, except that (2R,3R)-methyl-3-(2,4-dichlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 29) was used instead of (2S,3R)-methyl-3-(2,4-dichlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 36).

[0361] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.59 (m,4H),3.67 (s,3H),5.11 (d,J=7.6,1H),5.81 (d,J=7.6,1H),7.12~7.37 (m,3H)

[0362] Preparation 133: ((4S,5S)-5-(2,4-chlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.2 g, 70-95%) was obtained in essentially the same manner as in Preparation 131, except that (4R,5S)-methyl-5-(2,4-dichlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 132) was used instead of (4S,5R)-methyl-5-(2,4-dichlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 130).

[0363] 1H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62-3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.08~7.39(m,3H)

[0364] Preparation 134: (2S,3R)-methyl-3-(2,4-chlorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (2.5 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 131, except that cyclopentanone was used instead of 3-pentanone.

[0365] 1 H NMR (400MHz,DMSO): δ1.69-1.71 (m,4H),1.82-1.86(m,1H),1.91-2.00 (m,3H),3.68 (s,3H),4.40 (d,J=7.2,1H),5.39 (d,J=7.2,1H),7.03~7.36(m,3H)

[0366] Preparation 135: ((2R,3R)-3-(2,4-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (1.8 g, 70-95%) was obtained in essentially the same manner as in Preparation 65, except that (2S,3R)-methyl-3-(2,4-dichlorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 134) was used instead of (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 64).

[0367] 1H NMR (400MHz,DMSO): δ1.60-1.72 (m,4H),1.83-1.94(m,1H),3.52~3.65 (m,2H),3.82-3.86 (m,1H),4.90 (t,J=5.2,1H),5.12 (d,J=7.6,1H),7.02~7.37(m,3H)

[0368] Preparation 136: (2R,3S)-methyl-3-(2,4-chlorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (2.2 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 132, except that cyclopentanone was used instead of 3-pentanone.

[0369] 1 H NMR (400MHz,DMSO): δ1.69-1.71 (m,4H),1.82~1.86(m,1H),1.91-2.00 (m,3H),3.68 (s,3H),4.40 (d,J=7.2,1H),5.39 (d,J=7.2,.1H),7.03~7.36(m,3H)

[0370] Preparation 137: ((2S,3S)-3-(2,4-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (1.2 g, 70-95%) was obtained in essentially the same manner as in Preparation 135, except that (2R,3S)-methyl-3-(2,4-dichlorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 136) was used instead of (2S,3R)-methyl-3-(2,4-dichlorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 134).

[0371] 1H NMR (400MHz,DMSO): δ1.60-1.72 (m,4H),1.83-1.94(m,1H),3.52~3.65 (m,2H),3.82~3.86 (m,1H),4.90 (t,J=5.2,1H),5.12 (d,J=7.6,1H),7.02~7.37(m,3H)

[0372] Preparation 138: (2S,3R)-methyl-3-(2,4-chlorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (1.8 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 134, except that cyclohexanone was used instead of cyclopentanone.

[0373] 1 H NMR (400MHz,DMSO):δ1.61-1.69(m,10H),3.79 (s,3H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.07~7.41(m,3H)

[0374] Preparation 139: ((2R,3R)-3-(2,4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (1.3 g, 70-95%) was obtained in essentially the same manner as in Preparation 73, except that (2S,3R)-methyl-3-(2,4-dichlorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 72) was replaced with (2S,3R)-methyl-3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 138).

[0375] 1H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),3.52~3.81(m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.04~7.40 (m,3H)

[0376] Preparation 140: (2R,3S)-methyl-3-(2,4-chlorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (1.6 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 136, except that cyclohexanone was used instead of cyclopentanone.

[0377] 1 H NMR (400MHz,DMSO):δ1.61-1.69(m,10H),3.79 (s,3H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.07~7.41(m,3H)

[0378] Preparation 141: ((2S,3S)-3-(2,4-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (1.2 g, 70-95%) was obtained in essentially the same manner as in Preparation 139, except that (2R,3S)-methyl-3-(2,4-dichlorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 138) was replaced with (2R,3S)-methyl-3-(2,4-dichlorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 140).

[0379] 1H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),3.52-3.81(m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.04~7.40 (m,3H)

[0380] Preparation 142: (4S,5R)-methyl-5-(2,4-chlorophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.9 g, 50-70%) was obtained in substantially the same manner as in Preparation Example 138, except that benzaldehyde was used instead of cyclohexanone.

[0381] 1 H NMR (400MHz,DMSO):δ1.61-1.69(m,10H),3.79 (s,3H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.03~7.41(m,3H)

[0382] Preparation 143: ((4R,5R)-5-(2,4-chlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 65, except that (4S,5R)-methyl-5-(2,4-chlorophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 142) was used instead of (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 64).

[0383] 1H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),3.52~3.81(m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.04~7.42 (m,3H)

[0384] Preparation 144: (4R,5S)-methyl-5-(2,4-chlorophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.6 g, 50-70%) was obtained in substantially the same manner as in Preparation Example 140, except that benzaldehyde was used instead of cyclohexanone.

[0385] 1 H NMR (400MHz,DMSO):δ1.61-1.69(m,10H),3.79 (s,3H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.03~7.41(m,3H)

[0386] Preparation 145: ((4S,5S)-5-(2,4-chlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.2 g, 70-95%) was obtained in essentially the same manner as in Preparation 143, except that (4R,5S)-methyl-5-(2,4-chlorophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 144) was used instead of (2S,3R)-methyl-3-(2,4-chlorophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 142).

[0387] 1H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),3.52-3.81(m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.04~7.42 (m,3H)

[0388] Preparation 146: ((4S,5R)-ethyl-5-(2,6-dichlorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 60, except that (2S,3R)-ethyl-3-(2,6-dichlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 39) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 433).

[0389] 1 H NMR (400MHz,CDCl3): δ1.36(d,J=6.4,3H),3.78 (s,3H),4.15 (m,2H),4.30 (d,J=7.6,1H),5.07 (m,1H),5.62 (d,J=7.6,1H),7.17~7.36(m,3H)

[0390] Preparation 147: ((4R,5R)-5-(2,6-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.2 g, 70-95%) was obtained in essentially the same manner as in Preparation 27, except that (4S,5R)-ethyl-5-(2,6-dichlorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 146) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0391] 1 H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.18-7.39(m,3H)

[0392] Preparation 148: ((4R,5S)-ethyl-5-(2,6-dichlorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.8 g, 70-95%) was obtained in essentially the same manner as in Preparation 146, except that (2R,3S)-ethyl-3-(2,6-dichlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 33) was used instead of (2S,3R)-methyl-3-(2,4-dichlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 39).

[0393] 1 H NMR (400MHz,CDCl3): δ1.36(d,J=6.4,3H),3.78 (s,3H),4.15 (m,2H),4.30 (d,J=7.6,1H),5.07 (m,1H),5.62 (d,J=7.6,1H),7.17~7.36(m,3H)

[0394] Preparation 149: ((4S,5S)-5-(2,6-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.3 g, 70-95%) was obtained in essentially the same manner as in Preparation 147, except that ((4R,5S)-ethyl-5-(2,6-dichlorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 148) was used instead of ((4S,5R)-ethyl-5-(2,6-dichlorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 146).

[0395] 1 H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.18~7.39(m,3H)

[0396] Preparation 150: (4S,5R)-ethyl-5-(2,6-dichlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.8 g, 60-85%) was obtained in essentially the same manner as in Preparation 130, except that (2S,3R)-ethyl-3-(2,6-dichlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 39) was used instead of (2S,3R)-methyl-3-(2,6-dichlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 36).

[0397] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.30 (t,J=8.0,3H),1.59 (m,4H),4.12 (m,2H),5.11 (d,J=7.6,1H),5.81 (d,J=7.6,1H),7.08~7.26(m,3H)

[0398] Preparation 151: ((4R,5R)-5-(2,6-dichlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.2 g, 70-95%) was obtained in essentially the same manner as in Preparation 147, except that (4S,5R)-ethyl-5-(2,6-dichlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 150) was used instead of (4S,5R)-ethyl-5-(2,6-dichlorophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 146).

[0399] 1 H NMR (400MHz,CDCl3): δ1.37(d,J=6.0. 3H),3.62~3.70 (m,2H),4.36 (dd,J=7.0. J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.07~7.29(m,3H)

[0400] Preparation 152: (4R,5S)-ethyl-5-(2,6-chlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 150, except that (2R,3S)-ethyl-3-(2,6-dichlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 33) was used instead of (2S,3R)-ethyl-3-(2,6-dichlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 39).

[0401] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.30 (t,J=8.0,3H),1.59 (m,4.12 (m,2H),5.11 (d,J=7.6,1H),5.81 (d,J=7.6,1H),7.08-7.26(m,3H)

[0402] Preparation 153: ((4S,5S)-5-(2,6-chlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (2.1 g, 70-95%) was obtained in essentially the same manner as in Preparation 151, except that (4R,5S)-ethyl-5-(2,6-dichlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 152) was used instead of (4S,5R)-ethyl-5-(2,6-dichlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 150).

[0403] 1 H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.07~7.29(m,3H)

[0404] Preparation 154: (2S,3R)-ethyl-3-(2,6-chlorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (2.1 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 150, except that cyclopentanone was used instead of 3-pentanone.

[0405] 1 H NMR (400MHz,DMSO): δ1.30 (t,J=7.8hz,3H),1.69-1.71(m,4H),1.73~1.86 (m,4H),4.07-4.14 (m,2H),5.11 (d,J=7.2,1H),5.81 (d,J=7.2,1H),7.07~7.31(m,3H)

[0406] Preparation 155: ((2R,3R)-3-(2,6-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (1.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 151, except that (2S,3R)-ethyl-3-(2,6-dichlorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 154) was used instead of (4S,5R)-ethyl-5-(2,6-dichlorophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 150).

[0407] 1 H NMR (400MHz,DMSO): δ1.60-1.72 (m,4H),1.83~1.94(m,4H),3.52~3.65 (m,2H),4.90 (t,J=5.2,1H),5.12 (d,J=7.6,1H),7.08~7.32 (m,3H)

[0408] Preparation Example 156: (2R,3S)-ethyl-3-(2,6-chlorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (2.5 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 152, except that cyclopentanone was used instead of 3-pentanone.

[0409] 1 H NMR (400MHz,DMSO): δ1.30 (t,J=7.8hz,3H),1.69-1.71(m,4H),1.73-1.86 (m,4H),4.07-4.14 (m,2H),5.11 (d,J=7.2,1H),5.81 (d,J=7.2,1H),7.07~7.31(m,3H)

[0410] Preparation 157: ((2S,3S)-3-(2,6-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (2.0 g, 70-95%) was obtained in essentially the same manner as in Preparation 155, except that (2R,3S)-ethyl-3-(2,6-dichlorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 156) was used instead of (2S,3R)-ethyl-3-(2,6-dichlorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 154).

[0411] 1 H NMR (400MHz,DMSO): δ1.60-1.72 (m,4H),1.83-1.94(m,4H),3.52~3.65 (m,2H),4.90 (t,J=5.2,1H),5.12 (d,J=7.6,1H),7.08~7.32 (m,3H)

[0412] Preparation 158: (2S,3R)-ethyl-3-(2,6-chlorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (2.2 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 154, except that cyclohexanone was used instead of cyclopentanone.

[0413] 1 H NMR (400MHz,DMSO): δ1.30 (t,J=7.6,3H),1.61~1.69(m,10H),4.08-4.18 (d,2H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.07-7.31 (m,3H)

[0414] Preparation 159: ((2R,3R)-3-(2,6-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (1.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 155, except that (2S,3R)-ethyl-3-(2,6-dichlorophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 154) was replaced with (2S,3R)-ethyl-3-(2,6-dichlorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 158).

[0415] 1 H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),3.52-3.81(m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.05~7.30 (m,3H)

[0416] Preparation 160: (2R,3S)-ethyl-3-(2,6-chlorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (1.9 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 156, except that cyclohexanone was used instead of cyclopentanone.

[0417] 1 H NMR (400MHz,DMSO): δ1.30 (t,J=7.6,3H),1.61-1.69(m,10H),4.08-4.18 (d,2H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.07-7.31 (m,3H)

[0418] Preparation 161: ((2S,3S)-3-(2,6-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (1.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 159, except that (2R,3S)-ethyl-3-(2,6-dichlorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 160) was used instead of (2S,3R)-ethyl-3-(2,6-dichlorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 158).

[0419] 1 H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),3.52~3.81(m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.05~7.30 (m,3H)

[0420] Preparation 162: (4S,5R)-ethyl-5-(2,6-chlorophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.0 g, 50-70%) was obtained in substantially the same manner as in Preparation Example 158, except that benzaldehyde was used instead of cyclohexanone.

[0421] 1 H NMR (400MHz,DMSO): δ1.30 (t,J=7.6,3H),4.08-4.18(d,2H),5.13 (d,J=8.0,1H),5.85 (d,J=8.0,1H),6.18 (s,1H),7.03~7.22 (m,8H)

[0422] Preparation 163: ((4R,5R)-5-(2,6-chlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.6 g, 70-95%) was obtained in essentially the same manner as in Preparation 159, except that (4S,5R)-ethyl-5-(2,6-chlorophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 162) was used instead of (2S,3R)-ethyl-3-(2,6-dichlorophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 158).

[0423] 1 H NMR (400MHz,DMSO):δ3.50-3.79(m,2H),5.13 (d,J=8.0,1H),5.85 (d,J=8.0,1H),6.18 (s,1H),7.03~7.22(m,8H)

[0424] Preparation 164: (4R,5S)-ethyl-5-(2,6-chlorophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.8 g, 50-70%) was obtained in substantially the same manner as in Preparation Example 160, except that benzaldehyde was used instead of cyclohexanone.

[0425] 1 H NMR (400MHz,DMSO): δ1.30 (t,J=7.6,3H),4.08-4.18(d,2H),5.13 (d,J=8.0,1H),5.85 (d,J=8.0,1H),6.18 (s,1H),7.03~7.22 (m,8H)

[0426] Preparation 165: ((4S,5S)-5-(2,6-chlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.4 g, 70-95%) was obtained in essentially the same manner as in Preparation 163, except that (4R,5S)-ethyl-5-(2,6-chlorophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 164) was used instead of (2S,3R)-ethyl-3-(2,6-chlorophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 162).

[0427] 1 H NMR (400MHz,DMSO): δ3.50~3.79 (m,2H),5.13(d,J=8.0,1H),5.85 (d,J=8.0,1H),6.18 (s,1H),7.03~7.22 (m,8H)

[0428] Preparation 166: ((4S,5R)-methyl-5-(2-nitrophenyl)-2-methyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.3 g, 70-95%) was obtained in essentially the same manner as in Preparation 60, except that (2S,3R)-methyl-3-(2-nitrophenyl)-2,3-dihydroxypropanoate (Preparation Example 44) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 433).

[0429] 1 H NMR (400MHz,CDCl3): δ1.36(d,J=6.4,3H),3.78 (s,3H),4.30 (d,J=7.6,1H),5.07 (m,1H),5.62 (d,J=7.6,1H),7.45-8.12(m,4H)

[0430] Preparation 167: ((4R,5R)-5-(2-nitrophenyl)-2-methyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.9 g, 70-95%) was obtained in essentially the same manner as in Preparation 27, except that (4S,5R)-methyl-5-(2-nitrophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 166) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0431] 1 H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.47-8.11(m,4H)

[0432] Preparation 168: ((4R,5S)-methyl-5-(2-nitrophenyl)-2-methyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.0 g, 70-95%) was obtained in essentially the same manner as in Preparation 160, except that (2R,3S)-methyl-3-(2-nitrophenyl)-2,3-dihydroxypropanoate (Preparation Example 48) was used instead of (2S,3R)-methyl-3-(2-nitrophenyl)-2,3-dihydroxypropanoate (Preparation Example 44).

[0433] 1 H NMR (400MHz,CDCl3): δ1.36(d,J=6.4,3H),3.78 (s,3H),4.30 (d,J=7.6,1H),5.07 (m,1H),5.62 (d,J=7.6,1H),7.45-8.12(m,4H)

[0434] Preparation 169: ((4S,5S)-5-(2-nitrophenyl)-2-methyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.6 g, 70-95%) was obtained in essentially the same manner as in Preparation 167, except that (4R,5S)-methyl-5-(2-nitrophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 168) was used instead of (4S,5R)-methyl-5-(2-nitrophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 166).

[0435] 1 H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.47-8.11(m,4H)

[0436] Preparation 170: (4S,5R)-methyl-5-(2-nitrophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.4 g, 60-85%) was obtained in essentially the same manner as in Preparation 150, except that (2S,3R)-methyl-3-(2-nitrophenyl)-2,3-dihydroxypropanoate (Preparation Example 44) was used instead of (2S,3R)-ethyl-3-(2,6-dichlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 39).

[0437] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.59 (m,4H),3.67 (s,3H),5.11 (d,J=7.6,1H),5.81 (d,J=7.6,1H),7.43~8.10 (m,4H)

[0438] Preparation 171: ((4R,5R)-5-(2-nitrophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.9 g, 70-95%) was obtained in essentially the same manner as in Preparation 167, except that (4S,5R)-methyl-5-(2-nitrophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 170) was used instead of (4S,5R)-methyl-5-(2-nitrophenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 166).

[0439] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.59 (m,4H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0. 1H),5.17 (d,J=7.0,1H),7.37~8.09(m,4H)

[0440] Preparation 172: (4R,5S)-methyl-5-(2-nitrophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.5 g, 60-85%) was obtained in essentially the same manner as in Preparation 170, except that (2R,3S)-methyl-3-(2-nitrophenyl)-2,3-dihydroxypropanoate (Preparation Example 48) was used instead of (2S,3R)-methyl-3-(2-nitrophenyl)-2,3-dihydroxypropanoate (Preparation Example 44).

[0441] 1 H NMR (400MHz,CDCl3):δ0.96(m,6H),1.59 (m,4H),3.67 (s,3H),5.11 (d,J=7.6,1H),5.81 (d,J=7.6,1H),7.43-8.10 (m,4H)

[0442] Preparation 173: ((4S,5S)-5-(2-nitrophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (2.0 g, 70-95%) was obtained in essentially the same manner as in Preparation 171, except that (4R,5S)-methyl-5-(2-nitrophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 172) was used instead of (4S,5R)-methyl-5-(2-nitrophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 170).

[0443] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.59 (m,4H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.17 (d,J=7.0,1H),7.37-8.09(m,4H)

[0444] Preparation 174: (2S,3R)-methyl-3-(2-nitrophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (2.5 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 170, except that cyclopentanone was used instead of 3-pentanone.

[0445] 1 H NMR (400MHz,DMSO):δ1.69-1.71(m,4H),1.82-1.86 (m,4H),3.68 (s,3H),4.40 (d,J=7.2,1H),5.39 (d,J=7.2,1H),7.44~8.06(m,4H)

[0446] Preparation 175: ((2R,3R)-3-(2-nitrophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (2.1 g, 70-95%) was obtained in essentially the same manner as in Preparation 171, except that (2S,3R)-methyl-3-(2-nitrophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 174) was used instead of (4S,5R)-methyl-5-(2-nitrophenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 170).

[0447] 1 H NMR (400MHz,DMSO): δ1.60-1.72 (m,4H),1.83-1.94(m,4H),3.52~3.65 (m,2H),4.90 (t,J=5.2,1H),5.12 (d,J=7.6,1H),7.46~8.09 (m,4H)

[0448] Preparation Example 176: (2R,3S)-Methyl-3-(2-nitrophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (2.9 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 172, except that cyclopentanone was used instead of 3-pentanone.

[0449] 1 H NMR (400MHz,DMSO): δ1.69-1.71 (m,4H),1.82~1.86(m,4H),3.68 (s,3H),4.40 (d,J=7.2,1H),5.39 (d,J=7.2,1H),7.44~8.06 (m,4H)

[0450] Preparation 177: ((2S,3S)-3-(2-nitrophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (2.0 g, 70-95%) was obtained in essentially the same manner as in Preparation 175, except that (2R,3S)-methyl-3-(2-nitrophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 176) was used instead of (2S,3R)-methyl-3-(2-nitrophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 174).

[0451] 1 H NMR (400MHz,DMSO): δ1.60-1.72 (m,4H),1.83~1.94(m,4H),3.52~3.65 (m,2H),4.90 (t,J=5.2,1H),5.12 (d,J=7.6,1H),7.46~8.09 (m,4H)

[0452] Preparation 178: (2S,3R)-methyl-3-(2-nitrophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (1.7 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 174, except that cyclohexanone was used instead of cyclopentanone.

[0453] 1 H NMR (400MHz,DMSO):δ1.61-1.69(m,10H),3.79 (s,3H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.45-8.12 (m,4H)

[0454] Preparation 179: ((2R,3R)-3-(2-nitrophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (1.4 g, 70-95%) was obtained in essentially the same manner as in Preparation 175, except that (2S,3R)-methyl-3-(2-nitrophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 178) was used instead of (2S,3R)-methyl-3-(2-nitrophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 174).

[0455] 1 H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),3.52~3.81(m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.46~8.09 (m,4H)

[0456] Preparation 180: (2R,3S)-methyl-3-(2-nitrophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (2.2 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 176, except that cyclohexanone was used instead of cyclopentanone.

[0457] 1 H NMR (400MHz,DMSO):δ1.61-1.69(m,10H),3.79 (s,3H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.45~8.12(m,4H)

[0458] Preparation 181: ((2S,3S)-3-(2-nitrophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (1.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 179, except that (2R,3S)-methyl-3-(2-nitrophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 178) was replaced with (2R,3S)-methyl-3-(2-nitrophenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 180).

[0459] 1 H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),3.52-3.81(m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.19~7.49 (m,4H)

[0460] Preparation 182: (4S,5R)-methyl-5-(2-nitrophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.9 g, 50-70%) was obtained in substantially the same manner as in Preparation Example 178, except that benzaldehyde was used instead of cyclohexanone.

[0461] 1 H NMR (400MHz,DMSO):δ3.67(s,3H),5.11 (d,J=8.0,1H),5.81 (d,J=8.0,1H),6.18 (s,1H),6.96-8.12 (m,9H)

[0462] Preparation 183: ((4R,5R)-5-(2-nitrophenyl)-2-phenyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 179, except that (4S,5R)-methyl-5-(2-nitrophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 182) was used instead of (2S,3R)-methyl-3-(2-nitrophenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 174).

[0463] 1 H NMR (400MHz,DMSO):δ3.66(d,J=7.6,2H),4.36 (m,1H),5.17 (d,J=8.0,1H),6.18 (s,1H),7.06-8.14 (m,9H)

[0464] Preparation 184: (4R,5S)-methyl-5-(2-nitrophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.8 g, 50-70%) was obtained in substantially the same manner as in Preparation Example 180, except that benzaldehyde was used instead of cyclohexanone.

[0465] 1 H NMR (400MHz,DMSO):δ3.67(s,3H),5.11 (d,J=8.0,1H),5.81 (d,J=8.0,1H),6.18 (s,1H),6.96-8.12 (m,9H)

[0466] Preparation 185: ((4S,5S)-5-(2-nitrophenyl)-2-phenyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.3 g, 70-95%) was obtained in essentially the same manner as in Preparation 183, except that (4R,5S)-methyl-5-(2-nitrophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 184) was used instead of (2S,3R)-methyl-3-(2-nitrophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 182).

[0467] 1 H NMR (400MHz,DMSO):δ3.66(d,J=7.6,2H),4.36 (m,1H),5.17 (d,J=8.0,1H),6.18 (s,1H),7.06-8.14 (m,9H)

[0468] Preparation 186: (4S,5R)-methyl-5-(2-methylphenyl)-2-methyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.1 g, 70-95%) was obtained in essentially the same manner as in Preparation 60, except that (2S,3R)-methyl-3-(2-methylphenyl)-2,3-dihydroxypropanoate (Preparation Example 54) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 433).

[0469] 1 H NMR (400MHz,CDCl3):δ1.36(d,J=6.4,3H),2.35 (s,3H),3.68 (s,3H),5.07 (m,1H),5.11 (d,J=7.6,1H),5.82 (d,J=7.6,1H),7.19-7.39(m,4H)

[0470] Preparation 187: ((4R,5R)-5-(2-methylphenyl)-2-methyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 185, except that (4S,5R)-methyl-5-(2-methylphenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 186) was used instead of (2R,3S)-methyl-3-(2-nitrophenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 184).

[0471] 1 H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62-3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.17-7.41(m,4H)

[0472] Preparation Example 188: (4R,5S)-methyl-5-(2-methylphenyl)-2-methyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.8 g, 70-95%) was obtained in essentially the same manner as in Preparation 186, except that (2R,3S)-methyl-3-(2-methylphenyl)-2,3-dihydroxypropanoate (Preparation Example 57) was used instead of (2S,3R)-methyl-3-(2-methylphenyl)-2,3-dihydroxypropanoate (Preparation Example 54).

[0473] 1 H NMR (400MHz,CDCl3):δ1.36(d,J=6.4,3H),2.35 (s,3H),3.68 (s,3H),5.07 (m,1H),5.11 (d,J=7.6,1H),5.82 (d,J=7.6,1H),7.19-7.39(m,4H)

[0474] Preparation 189: ((4S,5S)-5-(2-methylphenyl)-2-methyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.6 g, 70-95%) was obtained in essentially the same manner as in Preparation 187, except that (4R,5S)-methyl-5-(2-methylphenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 188) was used instead of (4S,5R)-methyl-5-(2-methylphenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 186).

[0475] 1 H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62-3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.17-7.41(m,4H)

[0476] Preparation 190: (4S,5R)-methyl-5-(2-methylphenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.1 g, 60-85%) was obtained in essentially the same manner as in Preparation 170, except that (2S,3R)-methyl-3-(2-methylphenyl)-2,3-dihydroxypropanoate (Preparation Example 54) was used instead of (2S,3R)-methyl-3-(2-nitrophenyl)-2,3-dihydroxypropanoate (Preparation Example 44).

[0477] 1 H NMR (400MHz,CDCl3):δ0.96(m,6H),1.59 (m,4H),2.33 (s,1H),3.67 (s,3H),5.11 (d,J=7.6,1H),5.81 (d,J=7.6,1H),7.00-7.17(m,4H)

[0478] Preparation 191: ((4R,5R)-5-(2-methylphenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 187, except that (4S,5R)-methyl-5-(2-methylphenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 190) was used instead of (4S,5R)-methyl-5-(2-methylphenyl)-2-methyl-1,3-dioxolane-4-carboxylate (Preparation Example 186).

[0479] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.59 (m,4H),2.37 (s,3H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.17(d,J=7.0,1H),7.15~7.39 (m,4H)

[0480] Preparation Example 192: (4R,5S)-methyl-5-(2-methylphenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.2 g, 60-85%) was obtained in essentially the same manner as in Preparation 190, except that (2R,3S)-methyl-3-(2-methylphenyl)-2,3-dihydroxypropanoate (Preparation Example 57) was used instead of (2S,3R)-methyl-3-(2-methylphenyl)-2,3-dihydroxypropanoate (Preparation Example 54).

[0481] 1 H NMR (400MHz,CDCl3):δ0.96(m,6H),1.59 (m,4H),2.33 (s,1H),3.67 (s,3H),5.11 (d,J=7.6,1H),5.81 (d,J=7.6,1H),7.00-7.17(m,4H)

[0482] Preparation 193: ((4S,5S)-5-(2-methylphenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.8 g, 70-95%) was obtained in essentially the same manner as in Preparation 191, except that (4R,5S)-methyl-5-(2-methylphenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 192) was used instead of (4S,5R)-methyl-5-(2-methylphenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 190).

[0483] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.59 (m,4H),2.37 (s,3H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.17(d,J=7.0,1H),7.15-7.39 (m,4H)

[0484] Preparation 194: (2S,3R)-methyl-3-(2-methylphenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (2.1 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 190, except that cyclopentanone was used instead of 3-pentanone.

[0485] 1 H NMR (400MHz,DMSO):δ1.49-1.57(m,4H),1.72~1.81 (m,4H),2.35 (s,3H),3.68 (s,3H),5.14(d,J=7.2,1H),5.89 (d,J=7.2,1H),7.02~7.25 (m,4H)

[0486] Preparation 195: ((2R,3R)-3-(2-methylphenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (1.6 g, 70-95%) was obtained in essentially the same manner as in Preparation 191, except that (2S,3R)-methyl-3-(2-methylphenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 194) was used instead of (4S,5R)-methyl-5-(2-methylphenyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 190).

[0487] 1 H NMR (400MHz,DMSO): δ1.49-1.57 (m,4H),1.72-1.81(m,4H),2.35 (s,3H),3.52~3.65 (m,2H),4.90 (t,J=5.2,1H),5.12 (d,J=7.6,1H),7.02~7.25(m,4H)

[0488] Preparation Example 196: (2R,3S)-methyl-3-(2-methylphenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (2.5 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 192, except that cyclopentanone was used instead of 3-pentanone.

[0489] 1 H NMR (400MHz,DMSO):δ1.49-1.57(m,4H),1.72-1.81 (m,4H),2.35 (s,3H),3.68 (s,3H),5.14 (d,J=7.2,1H),5.89 (d,J=7.2,1H),7.02~7.25(m,4H)

[0490] Preparation 197: ((2S,3S)-3-(2-methylphenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (2.0 g, 70-95%) was obtained in essentially the same manner as in Preparation 195, except that (2R,3S)-methyl-3-(2-methylphenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 196) was used instead of (2S,3R)-methyl-3-(2-methylphenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 194).

[0491] 1 H NMR (400MHz,DMSO): δ1.49-1.57 (m,4H),1.72-1.81(m,4H),2.35 (s,3H),3.52~3.65 (m,2H),4.90 (t,J=5.2,1H),5.12 (d,J=7.6,1H),7.02~7.25(m,4H)

[0492] Preparation 198: (2S,3R)-methyl-3-(2-methylphenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (1.8 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 194, except that cyclohexanone was used instead of cyclopentanone.

[0493] 1 H NMR (400MHz,DMSO):δ1.61-1.69(m,10H),2.34 (s,3H),3.79 (s,3H) 4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H) 7.01~7.30(m,4H)

[0494] Preparation 199: ((2R,3R)-3-(2-methylphenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (1.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 195, except that (2S,3R)-methyl-3-(2-methylphenyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 194) was replaced with (2S,3R)-methyl-3-(2-methylphenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 198).

[0495] 1 H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),2.33(s,3H),3.52~3.81 (m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.02~7.28 (m,4H)

[0496] Preparation Example 200: (2R,3S)-methyl-3-(2-methylphenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (2.2 g, 70-95%) was obtained in substantially the same manner as in Preparation Example 196, except that cyclohexanone was used instead of cyclopentanone.

[0497] 1 H NMR (400MHz,DMSO):δ1.61-1.69(m,10H),2.34 (s,3H),3.79 (s,3H),4.33 (d,J=8.0,1H),5.85 (d,J=8.0,1H),7.01~7.30(m,4H)

[0498] Preparation 201: ((2S,3S)-3-(2-methylphenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (1.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 199, except that (2R,3S)-methyl-3-(2-methylphenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 200) was used instead of (2S,3R)-methyl-3-(2-methylphenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 198).

[0499] 1 H NMR (400MHz,DMSO): δ1.63-1.75 (m,10H),2.33(s,3H),3.52-3.81 (m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.02~7.28 (m,4H)

[0500] Preparation Example 202: (4S,5R)-methyl-5-(2-methylphenyl)-2-phenyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.2 g, 50-70%) was obtained in substantially the same manner as in Preparation Example 198, except that benzaldehyde was used instead of cyclohexanone.

[0501] 1 H NMR (400MHz,DMSO):δ2.33(s,3H),3.67 (s,3H),5.11 (d,J=8.0,1H),5.81 (d,J=8.0,1H),6.18 (s,1H),6.96-7.32 (m,9H)

[0502] Preparation 203: ((4R,5R)-5-(2-methylphenyl)-2-phenyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.6 g, 70-95%) was obtained in essentially the same manner as in Preparation 199, except that (4S,5R)-methyl-5-(2-methylphenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 202) was used instead of (2S,3R)-methyl-3-(2-methylphenyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 198).

[0503] 1 H NMR (400MHz,DMSO):52.32 (s,3H),3.66 (d,J=7.6,2H),4.36 (m,1H),5.17 (d,J=8.0,1H),6.18 (s,1H),6.99~7.33(m,9H)

[0504] Preparation Example 204: (4R,5S)-methyl-5-(2-methylphenyl)-2-phenyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.9 g, 50-70%) was obtained in substantially the same manner as in Preparation Example 200, except that benzaldehyde was used instead of cyclohexanone.

[0505] 1 H NMR (400MHz,DMSO):δ2.33(s,3H),3.67 (s,3H),5.11 (d,J=8.0,1H),5.81 (d,J=8.0,1H),6.18 (s,1H),6.96~7.32(m,9H)

[0506] Preparation 205: ((4S,5S)-5-(2-methylphenyl)-2-phenyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.3 g, 70-95%) was obtained in essentially the same manner as in Preparation 203, except that (4R,5S)-methyl-5-(2-methylphenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 204) was used instead of (4S,5R)-methyl-5-(2-methylphenyl)-2-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 202).

[0507] 1 H NMR (400MHz,DMSO):δ2.32(s,3H),3.66 (d,J=7.6,2H),4.36 (m,1H),5.17 (d,J=8.0,1H),6.18 (s,1H),6.99~7.33(m,9H)

[0508] Preparation 206: ((4R,5R)-5-(2-aminophenyl)-2-methyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.5 g, 65-85%) was obtained in essentially the same manner as in Preparation 47, except that ((4R,5R)-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Preparation Example 167) was used instead of ((4R,5R)-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Preparation Example 46).

[0509] 1 H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62-3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.57~8.08(m,4H)

[0510] Preparation 207: ((4S,5S)-5-(2-aminophenyl)-2-methyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.1 g, 65-85%) was obtained in essentially the same manner as in Preparation 47, except that ((4S,5S)-5-(2-nitrophenyl)-2-methyl-1,3-dioxolan-4-yl)methanol (Preparation Example 169) was used instead of ((4R,5R)-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Preparation Example 46).

[0511] 1 H NMR (400MHz,CDCl3): δ1.37(d,J=6.0,3H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.06 (m,1H),5.17 (d,J=7.0,1H),7.57~8.08(m,4H)

[0512] Preparation 208: ((4R,5R)-5-(2-aminophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.5 g, 65-85%) was obtained in essentially the same manner as in Preparation 47, except that ((4R,5R)-5-(2-nitrophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol (Preparation Example 171) was used instead of ((4R,5R)-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Preparation Example 46).

[0513] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.59 (m,4H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.17 (d,J=7.0,1H),7.55~8.09(m,4H)

[0514] Preparation 209: ((4S,5S)-5-(2-aminophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.4 g, 65-85%) was obtained in essentially the same manner as in Preparation 47, except that ((4S,5S)-5-(2-nitrophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol (Preparation Example 173) was used instead of ((4R,5R)-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Preparation Example 46).

[0515] 1 H NMR (400MHz,CDCl3): δ0.96(m,6H),1.59 (m,4H),3.62~3.70 (m,2H),4.36 (dd,J=7.0,J=7.0,1H),5.17 (d,J=7.0,1H),7.55~8.09(m,4H)

[0516] Preparation 210: ((2R,3R)-3-(2-aminophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (1.7 g, 65-85%) was obtained in essentially the same manner as in Preparation 47, except that ((4R,5R)-5-(2-nitrophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol (Preparation Example 175) was used instead of ((4R,5R)-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Preparation Example 46).

[0517] 1 H NMR (400MHz,DMSO): δ1.62-1.73 (m,4H),1.82~1.95(m,4H),3.52~3.65 (m,2H),4.90 (t,J=5.2,1H),5.12 (d,J=7.6,1H),7.56~8.11 (m,4H)

[0518] Preparation 211: ((2S,3S)-3-(2-aminophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (1.6 g, 65-85%) was obtained in essentially the same manner as in Preparation 47, except that ((4S,5S)-5-(2-nitrophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol (Preparation Example 177) was used instead of ((4R,5R)-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Preparation Example 46).

[0519] 1 H NMR (400MHz,DMSO): δ1.62-1.73 (m,4H),1.82~1.95(m,4H),3.52~3.65 (m,2H),4.90 (t,J=5.2,1H) 5.12 (d,J=7.6,1H),7.56-8.11 (m,4H)

[0520] Preparation 212: ((2R,3R)-3-(2-aminophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (1.1 g, 65-85%) was obtained in essentially the same manner as in Preparation 47, except that ((4R,5R)-5-(2-nitrophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol (Preparation Example 179) was used instead of ((4R,5R)-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Preparation Example 46).

[0521] 1 H NMR (400MHz,DMSO): δ1.61-1.75 (m,10H),3.52~3.81(m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.49~8.12 (m,4H)

[0522] Preparation 213: ((2S,3S)-3-(2-aminophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (1.0 g, 65-85%) was obtained in essentially the same manner as in Preparation 47, except that ((4S,5S)-5-(2-nitrophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol (Preparation Example 181) was used instead of ((4R,5R)-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Preparation Example 46).

[0523] 1 H NMR (400MHz,DMSO): δ1.61-1.75 (m,10H),3.52~3.81(m,2H),3.95 (t,J=8.0,1H),5.43 (d,J=7.6,1H),7.49-8.12 (m,4H)

[0524] Preparation 214: ((4R,5R)-5-(2-aminophenyl)-2-phenyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.2 g, 65-85%) was obtained in essentially the same manner as in Preparation 47, except that ((4R,5R)-5-(2-nitrophenyl)-2-phenyl-1,3-dioxolan-4-yl)methanol (Preparation Example 183) was used instead of ((4R,5R)-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Preparation Example 46).

[0525] 1 H NMR (400MHz,DMSO):δ3.66(d,J=7.6,2H),4.36 (m,1H),5.17 (d,J=8.0,1H),6.18 (s,1H),7.06-8.14 (m,9H)

[0526] Preparation 215: ((4S,5S)-5-(2-aminophenyl)-2-phenyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (0.9 g, 65-85%) was obtained in essentially the same manner as in Preparation 47, except that ((4S,5S)-5-(2-nitrophenyl)-2-phenyl-1,3-dioxolan-4-yl)methanol (Preparation Example 185) was used instead of ((4R,5R)-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Preparation Example 46).

[0527] 1 H NMR (400MHz,DMSO):δ3.66(d,J=7.6,2H),4.36 (m,1H),5.17 (d,J=8.0,1H),6.18 (s,1H),7.06-8.14 (m,9H)

[0528] Preparation 216: (E)-Methyl cinnamate [ka] To a round-bottom flask was added trans-cinnamic acid (7 g, 47.25 mmol) and MeOH (70 mL). POCl3 (0.43 mL, 4.73 mmol) was added dropwise. The reaction mixture was stirred under reflux for 3 hours. The reaction mixture was cooled to room temperature and quenched with 1N NaOH solution. The mixture was extracted with EtOAc and washed with H2O. The aqueous layer was further extracted with EtOAc. The combined organic layers were dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated in vacuo (7.1 g, 80-95%).

[0529] 1 H NMR (400MHz,CDCl3): δ3.81(s,3H),6.42 (d,J=15.9,1H),7.37~7.39 (m,3H),7.50~7.53 (m,2H),7.67 (d,J=15.9,1H)

[0530] Preparation Example 217: (2S,3R)-methyl-3-phenyl-2,3-dihydroxypropanoate [ka] The title compound (6.2 g, 70-95%) was obtained in essentially the same manner as in Preparation 36, except that (E)-methyl cinnamate (Preparation Example 216) was used instead of (E)-methyl-3-(2,4-dichlorophenyl)acrylate (Preparation Example 28).

[0531] 1 H NMR (400MHz,CDCl3): δ2.70(bs,1H),3.08 (bs,1H),3.82 (s,3H),4.38 (d,J=2.9,1H),5.03 (d,J=2.9,1H),7.30-7.42(m,5H)

[0532] Preparation 218: (4S,5R)-methyl-2,2-dimethyl-5-phenyl-1,3-dioxolane-4-carboxylate [ka] The title compound (5.6 g, 70-95%) was obtained in essentially the same manner as in Preparation 45, except that (2S,3R)-methyl-3-phenyl-2,3-dihydroxypropanoate (Preparation Example 217) was used instead of (2S,3R)-methyl-3-(2-nitrophenyl)-2,3-dihydroxypropanoate (Preparation Example 44).

[0533] 1 H NMR (400MHz, CDCl3): δ1.56(s,3H),1.61 (s,3H),3.79 (s,3H),4.36 (d,J=7.8,1H),5.17 (d,J=7.8,1H),7.31~7.40(m,5H)

[0534] Preparation 219: ((4R,5R)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (4.4 g, 70-95%) was obtained in essentially the same manner as in Preparation 46, except that (4S,5R)-methyl-2,2-dimethyl-5-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 218) was used instead of (4S,5R)-methyl-5-(2-nitrophenyl)-1,3-dioxolane-4-carboxylate (Preparation Example 45).

[0535] 1 H NMR (400MHz, CDCl3): δ1.41(s,3H),1.46 (s,3H),2.79 (bs,1H) 3.48~3.52 (m,1H),3.68~3.76(m,2H),4.76 (d,J=8.8,1H),7.18~7.28 (m,5H)

[0536] Preparation Example 220: (2R,3S)-methyl-3-phenyl-2,3-dihydroxypropanoate [ka] The title compound (8.6 g, 70-95%) was obtained in essentially the same manner as in Preparation 30, except that (E)-methyl cinnamate (Preparation Example 216) was used instead of (E)-methyl-3-(2,4-dichlorophenyl)acrylate (Preparation Example 28).

[0537] 1 H NMR (400MHz,CDCl3): δ2.70(bs,1H),3.08 (bs,1H),3.82 (s,3H),4.38 (d,J=2.9,1H),5.03 (d,J=2.9,1H),7.30-7.42(m,5H)

[0538] Preparation Example 221: (4R,5S)-methyl-2,2-dimethyl-5-phenyl-1,3-dioxolane-4-carboxylate [ka] The title compound (5.6 g, 70-95%) was obtained in essentially the same manner as in Preparation 45, except that (2S,3R)-methyl-3-phenyl-2,3-dihydroxypropanoate (Preparation Example 217) was used instead of (2S,3R)-methyl-3-(2-nitrophenyl)-2,3-dihydroxypropanoate (Preparation Example 44).

[0539] 1 H NMR (400MHz, CDCl3): δ1.56(s,3H),1.61 (s,3H),3.79 (s,3H),4.36 (d,J=7.8,1H),5.17 (d,J=7.8,1H),7.31~7.40(m,5H)

[0540] Preparation 222: ((4S,5S)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (6.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 46, except that (4R,5S)-methyl-2,2-dimethyl-5-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 221) was used instead of (4S,5R)-methyl-5-(2-nitrophenyl)-1,3-dioxolane-4-carboxylate (Preparation Example 45).

[0541] 1 H NMR (400MHz, CDCl3): δ1.41(s,3H),1.46 (s,3H),2.79 (bs,1H),3.48~3.52 (m,1H),3.68~3.76(m,2H),4.76 (d,J=8.8,1H),7.18~7.28 (m,5H)

[0542] Preparation 223: (4S,5R)-methyl-2,2-diethyl-5-phenyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.9 g, 70-95%) was obtained in essentially the same manner as in Preparation 190, except that (2S,3R)-methyl-3-phenyl-2,3-dihydroxypropanoate (Preparation Example 217) was used instead of (2S,3R)-methyl-3-(2-methylphenyl)-2,3-dihydroxypropanoate (Preparation Example 54).

[0543] 1 H NMR (400MHz,CDCl3): δ=1.01(t,J=7.4,1H),1.06 (t,J=7.6,3H),1.78~1.90 (m,4H),3.78 (s,3H),5.12 (d,J=8.4,1H),7.32~7.45(m,5H)

[0544] Preparation 224: ((4R,5R)-5-phenyl-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.3 g, 70-95%) was obtained in essentially the same manner as in Preparation 219, except that (4S,5R)-methyl-2,2-diethyl-5-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 223) was used instead of (4S,5R)-methyl-2,2-dimethyl-5-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 218).

[0545] 1 H NMR (400MHz,CDCl3): δ=1.00(t,J=7.6,1H),1.06 (t,J=7.4,1H),1.74~1.90 (m,4H),3.64 (ddd,J=3.4,8.4,12.1,1H),3.84~3.91(m,2H),4.89 (d,J=8.8,1H),7.30~7.43 (m,5H)

[0546] Preparation 225: (4R,5S)-methyl-2,2-diethyl-5-phenyl-1,3-dioxolane-4-carboxylate [ka] The title compound (5.6 g, 70-95%) was obtained in essentially the same manner as in Preparation 223, except that (2R,3S)-methyl-3-phenyl-2,3-dihydroxypropanoate (Preparation Example 220) was used instead of (2S,3R)-methyl-3-phenyl-2,3-dihydroxypropanoate (Preparation Example 217).

[0547] 1 H NMR (400MHz,CDCl3): δ=1.01(t,J=7.4,1H),1.06 (t,J=7.6,3H),1.78~1.90 (m,4H),3.78 (s,3H),5.12 (d,J=8.4,1H),7.32~7.45(m,5H)

[0548] Preparation 226: ((4S,5S)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (6.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 224, except that (4R,5S)-methyl-2,2-dimethyl-5-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 225) was used instead of (4S,5R)-methyl-2,2-dimethyl-5-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 218).

[0549] 1 H NMR (400MHz,CDCl3): δ=1.00(t,J=7.6,1H),1.06 (t,J=7.4,1H),1.74~1.90 (m,4H),3.64 (ddd,J=3.4,8.4,12.1,1H),3.84~3.91(m,2H),4.89 (d,J=8.8,1H),7.30~7.43 (m,5H)

[0550] Preparation Example 227: (2S,3R)-methyl-3-phenyl-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (0.9 g, 50-75%) was obtained in substantially the same manner as in Preparation Example 223, except that cyclopentanone was used instead of 3-pentanone.

[0551] 1 H NMR (400MHz,CDCl3): δ=1.71-1.80(m,4H),1.87~1.94 (m,1H),2.00-2.08 (m,3H),3.79 (s,3H),4.35 (d,J=7.2,1H),5.08 (d,J=7.2,1H),7.32~7.45(m,5H)

[0552] Preparation 228: ((2R,3R)-3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (0.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 224, except that (2S,3R)-methyl-3-phenyl-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 227) was used instead of (4S,5R)-methyl-2,2-diethyl-5-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 223).

[0553] 1 H NMR (400MHz,CDCl3): δ=1.69-1.82(m,4H),1.85~2.03 (m,4H),3.66 (ddd,J=3.7,8.1,12.1,1H),3.83~3.90 (m,2H),4.84 (d,J=8.4,1H),7.26~7.41(m,5H)

[0554] Preparation Example 229: (2R,3S)-Methyl-3-phenyl-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (0.8 g, 50-75%) was obtained in substantially the same manner as in Preparation Example 225, except that cyclopentanone was used instead of 3-pentanone.

[0555] 1 H NMR (400MHz,CDCl3): δ=1.71-1.80(m,4H),1.87~1.94 (m,1H) 2.00-2.08 (m,3H),3.79 (s,3H),4.35 (d,J=7.2,1H),5.08 (d,J=7.2,1H),7.32~7.45(m,5H)

[0556] Preparation 230: ((2S,3S)-3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (0.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 228, except that (2R,3S)-methyl-3-phenyl-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 229) was used instead of (2S,3R)-methyl-3-phenyl-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 227).

[0557] 1 H NMR (400MHz,CDCl3): δ=1.69-1.82(m,4H),1.85~2.03 (m,4H),3.66 (ddd,J=3.7,8.1,12.1,1H),3.83-3.90 (m,2H),4.84 (d,J=8.4,1H),7.26~7.41(m,5H)

[0558] Preparation 231: (2S,3R)-methyl-3-phenyl-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (1.4 g, 50-75%) was obtained in substantially the same manner as in Preparation Example 227, except that cyclohexanone was used instead of cyclopentanone.

[0559] 1 H NMR (400MHz,CDCl3): δ=1.41-1.49(m,2H),1.58-1.76 (m,4H),1.79~1.90 (m,4H),3.78 (s,3H),4.36 (d,J=7.6,1H),5.16 (d,J=7.2,1H),7.31~7.44(m,5H)

[0560] Preparation 232: ((2R,3R)-3-phenyl-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (1.0 g, 70-95%) was obtained in essentially the same manner as in Preparation 224, except that (2S,3R)-methyl-3-phenyl-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 231) was used instead of (4S,5R)-methyl-2,2-diethyl-5-phenyl-1,3-dioxolane-4-carboxylate (Preparation Example 223).

[0561] 1 H NMR (400MHz,CDCl3): δ=1.41-1.50(m,2H),1.61~1.89 (m,8H),3.60~3.66 (m,1H),3.85~3.90 (m,2H),4.91 (d,J=8.4,1H),7.30~7.42(m,5H)

[0562] Preparation Example 233: (2R,3S)-Methyl-3-phenyl-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (1.2 g, 50-75%) was obtained in substantially the same manner as in Preparation Example 229, except that cyclohexanone was used instead of cyclopentanone.

[0563] 1 H NMR (400MHz,CDCl3): δ=1.41-1.49(m,2H),1.58-1.76 (m,4H),1.79-1.90 (m,4H),3.78 (s,3H),4.36 (d,J=7.6,1H),5.16 (d,J=7.2,1H),7.31~7.44(m,5H)

[0564] Preparation 234: ((2S,3S)-3-phenyl-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (0.8 g, 70-95%) was obtained in essentially the same manner as in Preparation 232, except that (2R,3S)-methyl-3-phenyl-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 233) was used instead of (2S,3R)-methyl-3-phenyl-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 231).

[0565] 1 H NMR (400MHz,CDCl3): δ=1.41-1.50(m,2H),1.61~1.89 (m,8H),3.60~3.66 (m,1H),3.85~3.90 (m,2H),4.91 (d,J=8.4,1H),7.30~7.42(m,5H)

[0566] Preparation 235: (E)-5-Phenylpent-3-enoic acid [ka] A solution of malonic acid (17.06 g, 163.96 mmol) in DMSO (65 mL) was treated with a solution of AcOH (0.1 mL, 1.49 mmol) and piperidine (0.15 mL, 1.49 mmol) in DMSO (4 mL). The reaction solution was warmed to 65 °C, and hydrocinnamic aldehyde (10 g, 74.53 mmol) was added dropwise within 1.5 h. Upon completion of the reaction, the reaction mixture was stirred at 65 °C for an additional 2 h. The solution was cooled to room temperature, injected with HO, and extracted with EtO. The combined organic extracts were washed with 5% aqueous KHSO and brine, dried over MgSO, and evaporated. The crude compound was purified using a silica gel column to yield the title compound (10.4 g, 75-90%).

[0567] 1 H NMR (400MHz, CDCl3): δ=3.19(d,J=6.9,2H),3.46 (d,J=6.9,2H),5.69~5.78 (m,1H),5.83~5.91 (m,1H),7.01~7.56 (m,5H),11.79(s,1H)

[0568] Preparation 236: (E)-5-phenylpent-3-en-1-ol [ka] To a stirred solution of LAH (LiAlH, 3.3 g, 86.73 mmol) in THF (66 mL) was added dropwise a solution of (E)-5-phenylpent-3-enoic acid (Preparation Example 235, 11.0 g, 57.82 mmol) in THF (44 mL) at 0 °C, followed by stirring at room temperature for 1 h. The reaction mixture was quenched with HO at 0 °C, filtered through Celite, washed with EtOAc, dried over anhydrous magnesium sulfate (MgSO), filtered, and concentrated. The crude compound was purified by silica gel column to yield the title compound (7.2 g, 70-90%).

[0569] 1H NMR (400MHz,CDCl3): δ=1.40(bs,1H),2.31 (q,J=6.3,2H),3.37 (d,J=6.8,2H),3.66 (t,J=6.4,2H),5.49 (dt,J=4.9,11.0,1H),5.73(dt,J=4.8,10.9,1H),7.17~7.31 (m,5H)

[0570] Preparation Example 237: (E)-tert-butyldimethyl(5-phenylpent-3-enyloxy)silane [ka] To a stirred solution of (E)-5-phenylpent-3-en-1-ol (Preparation 236, 6.3 g, 38.83 mmol) in CHCl was added imidazole (3.4 g, 50.48 mmol) and TBDMS-Cl (7.6 g, 50.48 mmol) at 0 °C and then stirred at room temperature for 1 h. The resulting mixture was diluted with EtOAc, washed with water, dried over MgSO, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column to yield the title compound (10.6 g, 80-98%).

[0571] 1 H NMR (400MHz,CDCl3): δ=0.00(s,6H),0.84 (s,9H),2.21 (ddd,J=6.8,13.6,0.8,2H),3.29 (d,J=6.8,2H),3.59 (t,J=6.8,2H),5.41~5.49(m,1H),5.56~5.63 (m,1H),7.13~7.26 (m,5H)

[0572] Preparation Example 238: (E)-5-Phenylpent-3-enyl pivalate [ka] To a stirred solution of (E)-5-phenylpent-3-en-1-ol (Preparation 236, 3.8 g, 23.42 mmol) in CHCl (40 mL) was added pyridine (2.3 mL, 28.1 mmol) and pivaloyl chloride (3.5 mL, 28.1 mmol) at 0 °C under N. The mixture was stirred for 14 h. The resulting mixture was diluted with CHCl, washed with water, dried over MgSO, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column to yield the title compound (5.5 g, 80-95%).

[0573] 1 H NMR (400MHz, CDCl3): δ=1.17(s,9H),2.36 (q,J=6.7,2H),8.34 (d,J=6.8,2H),4.09 (t,J=6.8,2H),5.45~5.51 (m,1H),5.64~5.69(m,1H),7.16~7.21 (m,3H),7.26~7.30 (m,2H)

[0574] Preparation 239: (2S,3S)-5-(tert-butyldimethylsilyloxy)-1-phenylpentane-2,3-diol [ka] The title compound (8.7 g, 70-95%) was obtained in essentially the same manner as in Preparation Example 217, except that (E)-tert-butyldimethyl(5-phenylpent-3-enyloxy)silane (Preparation Example 237) was used instead of (E)-methyl cinnamate (Preparation Example 216).

[0575] 1 H NMR (400MHz,CDCl3): δ=0.00(s,6H),0.82 (s,9H),1.57-1.62 (m,1H) 1.73~1.80 (m,1H),2.51 (d,J=6.0,1H),2.77 (dq,J=6.9,14.9,2H),3.50(d,J=3.6,1H),3.59~3.62 (m,1H),3.66 (dq,J=3.1,5.4,1H),3.72~3.82 (m,2H),7.12~7.25(m,5H)

[0576] Preparation 240: (2-((4S,5S)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)(tert-butyl)dimethylsilane [ka] The title compound (9.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 218, except that (2S,3S)-5-(tert-butyldimethylsilyloxy)-1-phenylpentane-2,3-diol (Preparation Example 239) was used instead of (2R,3S)-methyl-3-phenyl-2,3-dihydroxypropanoate (Preparation Example 217).

[0577] 1 H NMR (400MHz, CDCl3): δ=0.00(s,6H),0.85 (s,9H),1.29 (s,3H),1.34 (s,3H),1.52~1.58(m,2H),2.87 (dq,J=5.5,14.2,2H),3.64~3.69 (m,2H),3.80-3.88(m,2H),7.18~7.27 (m,5H)

[0578] Preparation 241: 2-((4S,5S)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethanol [ka] To a stirred solution of (2-((4S,5S)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)(tert-butyl)dimethylsilane (Preparation 240, 11.5 g, 32.80 mmol) in THF (115 ml) was added tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 48.8 ml, 48.8 mmol) slowly at room temperature. The mixture was stirred for 5 hours. The resulting mixture was diluted with EtOAc, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude compound was purified by silica gel column to yield the title compound (7.3 g, 80-95%).

[0579] 1 H NMR (400MHz, CDCl3): δ=1.38(s,3H),1.40 (s,3H),1.50-1.63 (m,2H),2.29 (t,J=5.4,1H),2.82 (dd,J=5.8,13.8,1H),3.01(dd,J=6.4,14.0,1H),3.72 (q,J=5.5,2H),3.86 (dt,J=3.2,8.4,1H),3.92~3.97 (m,1H),7.22~7.32(m,5H)

[0580] Preparation Example 242: (2R,3R)-5-(tert-butyldimethylsilyloxy)-1-phenylpentane-2,3-diol [ka] The title compound (10.6 g, 70-95%) was obtained in essentially the same manner as in Preparation 220, except that (E)-tert-butyldimethyl(5-phenylpent-3-enyloxy)silane (Preparation Example 237) was used instead of (E)-methyl cinnamate (Preparation Example 216).

[0581] 1 H NMR (400MHz,CDCl3): δ=0.00(s,6H),0.82 (s,9H),1.57-1.62 (m,1H) 1.73~1.80 (m,1H),2.51 (d,J=6.0,1H),2.77 (dq,J=6.9,14.9,2H),3.50(d,J=3.6,1H),3.59~3.62 (m,1H),3.66 (dq,J=3.1,5.4,1H),3.72-3.82 (m,2H),7.12~7.25(m,5H)

[0582] Preparation 243: (2-((4R,5R)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)(tert-butyl)dimethylsilane [ka] The title compound (11.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 221, except that (2R,3R)-5-(tert-butyldimethylsilyloxy)-1-phenylpentane-2,3-diol (Preparation Example 242) was used instead of (2R,3S)-methyl-3-phenyl-2,3-dihydroxypropanoate (Preparation Example 217).

[0583] 1 H NMR (400MHz, CDCl3): δ=0.00(s,6H),0.85 (s,9H),1.29 (s,3H),1.34 (s,3H),1.52~1.58(m,2H),2.87 (dq,J=5.5,14.2,2H),3.64~3.69 (m,2H),3.80~3.88(m,2H),7.18~7.27 (m,5H)

[0584] Preparation 244: 2-((4R,5R)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethanol [ka] The title compound (7.4 g, 80-95%) was obtained in essentially the same manner as in Preparation 241, except that (2-((4S,5S)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)(tert-butyl)dimethylsilane (Preparation Example 240) was replaced with (2-((4R,5R)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)(tert-butyl)dimethylsilane (Preparation Example 243).

[0585] 1 H NMR (400MHz, CDCl3): δ=1.38(s,3H),1.40 (s,3H),1.50-1.63 (m,2H),2.29 (t,J=5.4,1H),2.82 (dd,J=5.8,13.8,1H),3.01(dd,J=6.4,14.0,1H),3.72 (q,J=5.5,2H),3.86 (dt,J=3.2,8.4,1H),3.92~3.97 (m,1H),7.22~7.32(m,5H)

[0586] Preparation Example 245: (3S,4S)-3,4-Dihydroxy-5-phenylpentyl pivalate [ka] The title compound (5.5 g, 70-95%) was obtained in essentially the same manner as in Preparation Example 239, except that (E)-5-phenylpent-3-enyl pivalate (Preparation Example 238) was used instead of (E)-tert-butyldimethyl(5-phenylpent-3-enyloxy)silane (Preparation Example 237).

[0587] 1 H NMR (400MHz,CDCl3): δ=1.16(s,9H),1.83-1.88 (m,2H),2.08 (d,J=4.8,H),2.67 (d,J=5.2,1H),2.80 (dd,J=8.0,13.6,1H),2.92(dd,J=5.2,13.6,1H),3.50~3.55 (m,1H),3.66~3.71 (m,1H),4.09-4.19 (m,1H),4.35~4.41(m,1H),7.22~7.25 (m,3H),7.29~7.33 (m,2H)

[0588] Preparation 246: (2-((4S,5S)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethyl pivalate [ka] The title compound (0.9 g, 70-95%) was obtained in essentially the same manner as in Preparation Example 223, except that (3S,4S)-3,4-dihydroxy-5-phenylpentyl pivalate (Preparation Example 245) was used instead of (2R,3S)-methyl-3-phenyl-2,3-dihydroxypropanoate (Preparation Example 217).

[0589] 1H NMR (400MHz, CDCl3): δ=1.15(s,9H),1.76 (q,J=7.6,2H),1.84-1.90 (m,2H),2.00~2.07 (m,2H),3.85 (dt,J=3.7,8.5,1H),4,14~4.27(m,2H),5.17 (d,J=8.4,1H),7.22~7.28 (m,1H),7.32~7.38 (m,2H),7.64 (dd,J=1.4,7.8,1H)

[0590] Preparation 247: 2-((4S,5S)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethanol [ka] To a stirred solution of (2-((4S,5S)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation 246, 1.0 g, 2.87 mmol) in MeOH (10 ml) was added NaOMe (0.47 g, 8.61 mmol) and warmed to 45° C. The mixture was stirred for 14 h. The resulting mixture was diluted with EtOAc, washed with water, dried over MgSO, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column to yield the title compound (0.7 g, 80-95%).

[0591] 1 H NMR (400MHz, CDCl3): δ=0.89(t,J=7.4,6H),1.44-1.50 (m,1H),1.54~1.66 (m,5H),2.37 (t,J=5.6. 1H),2.80 (dd,J=5.6,14.0,1H),3.03(dd,J=6.4,14.0,1H),3.72 (q,J=5.5,2H),3.80~3.85 (m,1H),3.89~3.94 (m,1H),7.21-7.24(m,3H),7.28~7.31 (m,2H)

[0592] Preparation Example 248: (3R,4R)-3,4-Dihydroxy-5-phenylpentyl pivalate [ka] The title compound (4.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 242, except that (E)-5-phenylpent-3-enyl pivalate (Preparation Example 238) was used instead of (E)-tert-butyldimethyl(5-phenylpent-3-enyloxy)silane (Preparation Example 237).

[0593] 1 H NMR (400MHz,CDCl3): δ=1.16(s,9H),1.83~1.88 (m,2H),2.08 (d,J=4.8,H),2.67 (d,5=5.2,1H),2.80 (dd,J=8.0,13.6,1H),2.92(dd,J=5.2,13.6,1H),3.50~3.55 (m,1H),3.66~3.71 (m,1H),4.09-4.19 (m,1H),4.35~4.41(m,1H),7.22~7.25 (m,3H),7.29~7.33 (m,2H)

[0594] Preparation 249: (2-((4R,5R)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethyl pivalate [ka] The title compound (1.1 g, 70-95%) was obtained in essentially the same manner as in Preparation 246, except that (3R,4R)-3,4-dihydroxy-5-phenylpentyl pivalate (Preparation Example 248) was used instead of (3S,4S)-3,4-dihydroxy-5-phenylpentyl pivalate (Preparation Example 245).

[0595] 1H NMR (400MHz, CDCl3): δ=1.15(s,9H),1.76 (q,J=7.6,2H),1.84~1.90 (m,2H),2.00~2.07 (m,2H),3.85 (dt,J=3.7,8.5,1H),4.14~4.27(m,2H),5.17 (d,J=8.4,1H),7.22~7.28 (m,1H),7.32~7.38 (m,2H),7.64 (dd,J=1.4,7.8,1H)

[0596] Preparation 250: 2-((4R,5R)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethanol [ka] The title compound (0.9 g, 80-95%) was obtained in essentially the same manner as in Preparation Example 247, except that (2-((4S,5S)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation Example 249) was used instead of (2-((4S,5S)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation Example 246).

[0597] 1 H NMR (400MHz, CDCl3): δ=0.89(t,J=7.4,6H),1.44-1.50 (m,1H),1.54~1.66 (m,5H),2.37 (t,J=5.6,1H),2.80 (dd,J=5.6,14.0,1H),3.03(dd,J=6.4,14.0,1H),3.72 (q,J=5.5,2H),3.80-3.85 (m,1H),3.89~3.94 (m,1H),7.21~7.24(m,3H),7.28~7.31 (m,2H)

[0598] Preparation 251: 2-((2S,3S)-3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate [ka] The title compound (1.2 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 246, except that cyclopentanone was used instead of 3-pentanone.

[0599] 1 H NMR (400MHz, CDCl3): δ=1.18(s,9H),1.53-1.80 (m,10H),2.81 (dd,13.6,1H),3.00 (dd,J=6.4,14.0,1H),3.75~3.80 (m,1H),3.84~3.89(m,4.05-4.16 (m,2H),7.20~7.24 (m,3H),7.27~7.31 (m,2H)

[0600] Preparation 252: 2-((2S,3S)-3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethanol [ka] The title compound (0.7 g, 80-95%) was obtained in essentially the same manner as in Preparation Example 247, except that 2-((2S,3S)-3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate (Preparation Example 251) was used instead of (2-((4S,5S)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation Example 246).

[0601] 1 H NMR (400MHz,CDCl3): δ=1.44-1.51(m,1H),1.56-1.60 (m,1H),1.63~1.70 (m,4H),1,72~1.81 (m,4H),2.26 (t,J=5.4,1H),2.80(dd,J=6.0,14.0,1H),3.03 (dd,J=6.4,14.0,1H),3.71 (q,J=5.5,2H),3.81~3.92 (m,2H),7.22~7.24(m,3H),7.28~7.32 (m,2H)

[0602] Preparation 253: 2-((2R,3R)-3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate [ka] The title compound (1.7 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 249, except that cyclopentanone was used instead of 3-pentanone.

[0603] 1 H NMR (400MHz,CDCl3): δ=1.18(s,9H),1.53-1.80 (m,10H),2.81 (dd,J=6.0,13.6,1H),3.00 (dd,J=6.4,14.0,1H),3.75~3.80(m,1H),3.84-3.89 (m,1H),4.05-4.16 (m,2H),7.20~7.24 (m,3H),7.27~7.31 (m,2H)

[0604] Preparation 254: 2-((2R,3R)-3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethanol [ka] The title compound (0.8 g, 80-95%) was obtained in essentially the same manner as in Preparation Example 252, except that 2-((2R,3R)-3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate (Preparation Example 253) was used instead of 2-((2S,3S)-3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate (Preparation Example 251).

[0605] 1H NMR (400MHz,CDCl3): δ=1.44-1.51(m,1H),1.56-1.60 (m,1H),1.63-1.70 (m,4H),1.72~1.81 (m,4H),2.26 (t,J=5.4,1H),2.80(dd,J=6.0,14.0,1H),3.03 (dd,J=6.4,14.0,1H),3.71 (q,J=5.5,2H),3.81~3.92 (m,2H),7.22~7.24(m,3H),7.28~7.32 (m,2H)

[0606] Preparation 255: 2-((2S,3S)-3-benzyl-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate [ka] The title compound (1.4 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 251, except that cyclohexanone was used instead of cyclopentanone.

[0607] 1 H NMR (400MHz, CDCl3): δ=1.18(s,9H),1.53-1.60 (m,10H),1.61-1.66 (m,2H),2.83 (dd,J=5.6,14.0,1H),2.98 (dd,J=6.0,14.0,1H),3.78(dt,J=3.5,1H),3.86~3.91 (m,1H),4.11-4.15 (m,2H),7.20~7.31 (m,5H)

[0608] Preparation 256: 2-((2S,3S)-3-benzyl-1,4-dioxaspiro[4,5]decan-2-yl)ethanol [ka] The title compound (1.0 g, 80-95%) was obtained in essentially the same manner as in Preparation 254, except that 2-((2S,3S)-3-benzyl-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate (Preparation Example 255) was used instead of 2-((2R,3R)-3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate (Preparation Example 253).

[0609] 1 H NMR (400MHz,CDCl3): δ=1.34-1.43(m,2H),1.48~1.61 (m,10H),2.42 (t,J=5.6,1H),2.81 (dd,J=5.6,14.0,1H),3.02 (dd,J=6.2,13.8,1H),3.72(q,J=5.5,2H),3.82~3.87 (m,1H),3.91~3.96 (m,1H),7.21~7.31 (m,5H)

[0610] Preparation 257: 2-((2R,3R)-3-benzyl-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate [ka] The title compound (1.6 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 253, except that cyclohexanone was used instead of cyclopentanone.

[0611] 1 H NMR (400MHz, CDCl3): δ=1.18(s,9H),1.53~1.60 (m,10H),1.61-1.66 (m,2H),2.83 (dd,J=5.6,14.0,1H),2.98 (dd,J=6.0,14.0,1H),3.78(dt,J=3.5,8.2,1H),3.86-3.91 (m,1H),4.11-4.15 (m,2H),7.20-7.31 (m,5H)

[0612] Preparation 258: 2-((2R,3R)-3-benzyl-1,4-dioxaspiro[4,5]decan-2-yl)ethanol [ka] The title compound (1.1 g, 80-95%) was obtained in essentially the same manner as in Preparation Example 256, except that 2-((2R,3R)-3-benzyl-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate (Preparation Example 257) was used instead of 2-((2S,3S)-3-benzyl-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate (Preparation Example 255).

[0613] 1 H NMR (400MHz,CDCl3): δ=1.34-1.43(m,2H),1.48-1.61 (m,10H),2.42 (t,J=5.6,1H),2.81 (dd,J=5.6,14.0,1H),3.02 (dd,J=6.2,13.8,1H),3.72(q,J=5.5,2H),3.82~3.87 (m,1H),3.91~3.96 (m,1H),7.21~7.31 (m,5H)

[0614] Preparation 259: (E)-Methyl-4-phenylbut-2-enoate [ka] To a solution of phenylacetaldehyde (5.0 g, 41.61 mmol) in toluene (500 ml) was added methyl (triphenylphosphoranylidene)acetate (13.9 g, 41.61 mmol). The reaction mixture was stirred under reflux for 3 h. The resulting mixture was diluted with EtOAc, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. Ether / hexane (1:1, v / v) was added to the crude product at 0 °C and stirred for 30 min. The filtrate was concentrated and purified by silica gel column chromatography to yield the title compound (5.9 g, 70-90%).

[0615] 1H NMR (400MHz, CDCl3): δ=3.47(d,J=6.8,2H),3.67 (s,3H),5.79 (d,J=15.4,1H),7.06 (dt,J=15.4. 6.8,1H),7.28-7.12(m,5H)

[0616] Preparation 260: (2R,3S)-methyl-2,3-dihydroxy-4-phenylbutanoate [ka] The title compound (3.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 245, except that (E)-methyl-4-phenylbut-2-enoate (Preparation Example 259) was used instead of (E)-5-phenylpent-3-enyl pivalate (Preparation Example 238).

[0617] 1 H NMR (400MHz,CDCl3): δ=2.96(ddd,J=7.3,13.5,17.1,2H),3.10 (d,J=5.2,1H),3.80 (s,3H),4.08 (dd,J=1.4,5.4,1H),7.23~7.34(m,5H)

[0618] Preparation 261: (4R,5S)-methyl-5-benzyl-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (3.1 g, 70-95%) was obtained in essentially the same manner as in Preparation 240, except that (2R,3S)-methyl-2,3-dihydroxy-4-phenylbutanoate (Preparation Example 260) was used instead of (2S,3S)-5-(tert-butyldimethylsilyloxy)-1-phenylpentane-2,3-diol (Preparation Example 239).

[0619] 1H NMR (400MHz,CDCl3):δ=1.42(s,3H),1.43 (s,3H),3.01 (dd,J=6.8,14.4,1H),3.12 (dd,J=4.4,14.4,1H),3.72 (s,3H),4.19(d,J=7.6,1H),4.40 (ddd,J=4.4,7.0,7.8,1H),7.22~7.33(m,5H)

[0620] Preparation 262: ((4S,5S)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (2.3 g, 70-95%) was obtained in essentially the same manner as in Preparation 234, except that (4R,5S)-methyl-5-benzyl-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 261) was used instead of (4S,5R)-methyl-3-phenyl-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 233).

[0621] 1 H NMR (400MHz,CDCl3): δ=1.41(s,6H),1.79 (q,J=4.3,1H),2.83 (dd,J=6.2,13.8,1H),3.07 (dd,J=6.4,14.0,1H),3.29(ddd,J=4.7,7.5,12.1,1H),3.54 (ddd,J=2.8,5.2,12.0,1H),3.83 (ddd,J=3.9,3.9,7.1,1H),4.15(q,J=7.1,1H),7.22~7.32 (m,5H)

[0622] Preparation 263: (4R,5S)-methyl-5-benzyl-2,2-diethyl-1,3-dioxolane-4-carboxylate [ka] To a stirred solution of (2R,3S)-methyl-2,3-dihydroxy-4-phenylbutanoate (Preparation 260, 2.0 g, 9.51 mmol) in 3-pentanone (5 ml, 47.55 mmol) was added H 2S A catalytic amount of O4 (0.051 ml, 0.951 mmol) was added at room temperature. The mixture was stirred for 20 hours. The resulting mixture was diluted with EtOAc, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give the title compound (1.2 g, 50-75%).

[0623] 1 H NMR (400MHz,CDCl3): δ=0.85(t,J=6.0,3H),0.92 (t,J=7.6,3H),1.66 (dq,J=7.6,14.7,4H),3.01 (dd,J=6.6,14.2,1H),3.10(dd,J=4.4,14.4,1H),3.71 (s,3H),4.17 (d,J=8.4,1H),4.32~4.37 (m,1H),7.23~7.32 (m,5H)

[0624] Preparation 264: ((4S,5S)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (0.8 g, 70-95%) was obtained in essentially the same manner as in Preparation 262, except that (4R,5S)-methyl-5-benzyl-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 263) was used instead of (4R,5S)-methyl-5-benzyl-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 261).

[0625] 1H NMR (400MHz, CDCl3): δ=0.91(dt,J=1.9,7.5,6H),1.61-1.68 (m,4H),1.77 (t,J=6.2,1H),2.81 (dd,J=6.4,14.0,1H),3.09(dd,J=6.2,13.8,1H),3.24~3.30 (m,1H),3.49~3.54 (m,1H),3.78~3.82 (m,1H),4.08-4.13(m,1H),7.21~7.32 (m,5H)

[0626] Preparation Example 265: (2R,3S)-Methyl-3-benzyl-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (1.3 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 263, except that cyclopentanone was used instead of 3-pentanone.

[0627] 1 H NMR (400MHz,CDCl3): δ=1.61-1.79(m,5H),1.85~1.92 (m,3H),3.00~3.11 (m,2H),3.70 (s,3H),4.17 (d,J=7.2,1H),4.32 (dt,J=4.9,7.0,1H),7.21~7.33(m,5H)

[0628] Preparation 266: ((2S,3S)-3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (0.8 g, 70-95%) was obtained in essentially the same manner as in Preparation 264, except that (2R,3S)-methyl-3-benzyl-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 265) was used instead of (4R,5S)-methyl-5-benzyl-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 263).

[0629] 1 H NMR (400MHz,CDCl3): δ=1.57-1.88(m,8H),2.82 (dd,J=6.6,13.8,1H),3.08 (dd,J=6.4,14.0,1H),3.27~3.33 (m,1H),3.47~3.52(m,1H),3.79~3.83 (m,1H),4.07 (q,J=6.8,1H),7.21~7.32 (m,5H)

[0630] Preparation Example 267: (2R,3S)-Methyl-3-benzyl-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (1.5 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 265, except that cyclohexanone was used instead of cyclopentanone.

[0631] 1 H NMR (400MHz,CDCl3): δ=1.54-1.74(m,10H),2.99-3.12 (m,2H),3.70 (s,3H),4.18 (d,J=7.6,1H),4.36~4.41 (m,1H),7.21~7.32(m,5H)

[0632] Preparation 268: ((2S,3S)-3-benzyl-1,4-dioxaspiro[4,4]decan-2-yl)methanol [ka] The title compound (0.8 g, 70-95%) was obtained in essentially the same manner as in Preparation 266, except that (2R,3S)-methyl-3-benzyl-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 267) was used instead of (2R,3S)-methyl-3-benzyl-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 265).

[0633] 1H NMR (400MHz,CDCl3): δ=1.53-1.65(m,10H),2.82 (dd,J=6.2,13.8,1H),3.07 (dd,J=6.4,13.6,1H),3.24~3.30 (m,1H),3.52~3.56(m,1H),3.80~3.84 (m,1H),4.10~4.15 (m,1H),7.21~7.31 (m,5H)

[0634] Preparation 269: (2S,3R)-methyl-2,3-dihydroxy-4-phenylbutanoate [ka] The title compound (3.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 242, except that (E)-methyl-4-phenylbut-2-enoate (Preparation Example 259) was used instead of (E)-tert-butyldimethyl(5-phenylpent-3-enyloxy)silane (Preparation Example 237).

[0635] 1 H NMR (400MHz,CDCl3): δ=2.96(ddd,J=7.3,13.5,17.1,2H),3.10 (d,J=5.2,1H),3.80 (s,3H),4.08 (dd,J=1.4,5.4,1H),7.23~7.34(m,5H)

[0636] Preparation 270: (4S,5R)-methyl-5-benzyl-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (3.4 g, 70-95%) was obtained in essentially the same manner as in Preparation 261, except that (2S,3R)-methyl-2,3-dihydroxy-4-phenylbutanoate (Preparation Example 269) was used instead of (2R,3S)-methyl-2,3-dihydroxy-4-phenylbutanoate (Preparation Example 260).

[0637] 1H NMR (400MHz,CDCl3): δ=1.41(s,6H),1.79 (q,J=4.3,1H),2.83 (dd,J=6.2,13.8,1H),3.07 (dd,J=6.4,14.0,1H),3.29(ddd,J=4.7,7.5,12.1,1H),3.54 (ddd,J=2.8,5.2,12.0,1H),3.83 (ddd,J=3.9,3.9,7.1,1H),4.15(q,J=7.1,1H),7.22~7.32 (m,5H)

[0638] Preparation 271: ((4R,5R)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (2.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 262, except that (4S,5R)-methyl-5-benzyl-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 270) was used instead of (4R,5S)-methyl-5-benzyl-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 261).

[0639] 1 H NMR (400MHz, CDCl3): δ=1.41(s,6H),1.79 (q,J=4.3,1H),2.83 (dd,J=6.2. 13.8,1H),3.07 (dd,J=6.4,14.0,1H),3.29(ddd,J=4.7,7.5,12.1,1H),3.54 (ddd,J=2.8,5.2,12.0,1H),3.83 (ddd,J=3.9,3.9,7.1,1H),4.15(q,J=7.1,1H),7.22~7.32 (m,5H)

[0640] Preparation 272: (4S,5R)-methyl-5-benzyl-2,2-diethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.5 g, 50-75%) was obtained in essentially the same manner as in Preparation 263, except that (2S,3R)-methyl-2,3-dihydroxy-4-phenylbutanoate (Preparation Example 269) was used instead of 2,3-dihydroxy-4-phenylbutanoate (Preparation Example 260).

[0641] 1 H NMR (400MHz,CDCl3): δ=0.85(t,J=6.0,3H),0.92 (t,J=7.6,3H),1.66 (dq,J=7.6. 14.7,4H),3.01(dd,J=6.6,14.2,1H),3.10 (dd,J=4.4,14.4,1H),3.71 (s,3H),4.17 (d,J=8.4,1H),4.32~4.37(m,1H),7.23~7.32 (m,5H)

[0642] Preparation 273: ((4R,5R)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.2 g, 70-95%) was obtained in essentially the same manner as in Preparation 264, except that (4S,5R)-methyl-5-benzyl-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 272) was used instead of (4R,5S)-methyl-5-benzyl-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 263).

[0643] 1 H NMR (400MHz, CDCl3): δ=0.91(dt,J=1.9,7.5,6H),1.61-1.68 (m,4H),1.77 (t,J=6.2,1H),2.81 (dd,J=6.4,14.0,1H),3.09(dd,J=6.2,13.8,1H),3.24~3.30 (m,1H),3.49~3.54 (m,1H),3.78-3.82 (m,1H),4.08-4.13(m,1H),7.21~7.32 (m,5H)

[0644] Preparation 274: (2S,3R)-methyl-3-benzyl-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (1.2 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 272, except that cyclopentanone was used instead of 3-pentanone.

[0645] 1 H NMR (400MHz,CDCl3): δ=1.61-1.79(m,5H),1.85~1.92 (m,3H),3.00-3.11 (m,2H),3.70 (s,3H),4.17 (d,J=7.2,1H),4.32 (dt,J=4.9,7.0,1H),7.21~7.33(m,5H)

[0646] Preparation 275: ((2R,3R)-3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (1.1 g, 70-95%) was obtained in essentially the same manner as in Preparation 266, except that (2S,3R)-methyl-3-benzyl-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 274) was used instead of (2R,3S)-methyl-3-benzyl-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 265).

[0647] 1 H NMR (400MHz,CDCl3): δ=1.57-1.88(m,8H),2.82 (dd,J=6.6,13.8,1H),3.08 (dd,J=6.4,14.0,1H),3.27~3.33 (m,1H),3.47~3.52(m,1H),3.79~3.83 (m,1H),4.07 (q,J=6.8,1H),7.21~7.32 (m,5H)

[0648] Preparation 276: (2S,3R)-Methyl-3-benzyl-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (1.4 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 274, except that cyclohexanone was used instead of cyclopentanone.

[0649] 1 H NMR (400MHz, CDCl3): δ=1.54~1.74(m,10H),2.99~3.12 (m,2H),3.70 (s,3H),4.18 (d,J=7.6,1H),4.36~4.41 (m,1H),7.21~7.32(m,5H)

[0650] Preparation 277: ((2R,3R)-3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (1.4 g, 70-95%) was obtained in essentially the same manner as in Preparation 268, except that (2S,3R)-methyl-3-benzyl-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 276) was used instead of (2R,3S)-methyl-3-benzyl-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 267).

[0651] 1 H NMR (400MHz,CDCl3): δ=1.53-1.65(m,10H),2.82 (dd,J=6.2,13.8,1H),3.07 (dd,J=6.4,13.6,1H) 3.24~3.30 (m,1H),3.52~3.56(m,1H),3.80~3.84 (m,1H),4.10~4.15 (m,1H),7.21~7.31 (m,5H)

[0652] Preparation 278: (E)-4-Phenylbut-3-enoic acid [ka] To a stirred solution of 2-phenylacetaldehyde (5.0 g, 32.3 mmol) and malonic acid (4.0 g, 38.8 mmol) in pyridine (25.0 mL) was added a catalytic amount of piperidine (0.64 mL, 6.46 mmol) and then heated to reflux. After 3 hours, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. 2N HCl was slowly added to the crude product. The white precipitate was filtered and dried under vacuum to yield the title compound (3.5 g, 55-80%).

[0653] 1 H NMR (400MHz,CDCl3): δ=3.39(d,J=8.8,2H),6.31 (td,J=7.9,14.8,1H),6.94 (d,J=16,1H),7.17~7.45 (m,3H),7.56~7.59(m,1H)

[0654] Preparation 279: (E)-4-phenylbut-3-en-1-ol [ka] To a stirred solution of Zn(BH) (40.0 mL, 20.0 mmol) in THF (40 mL) was added dropwise a solution of (E)-4-phenylbut-3-enoic acid (Preparation Example 278, 2.0 g, 10.0 mmol) in THF (5 mL) at 0 °C and then heated to reflux for 0.5 h. The reaction mixture was quenched with HO at 0 °C, filtered through Celite, washed with EtOAc, dried over anhydrous magnesium sulfate (MgSO), filtered, and concentrated. The crude compound was purified using a silica gel column to give the title compound (1.0 g, 50-75%).

[0655] 1H NMR (400MHz,CDCl3): δ=2.55(ddd,J=4.1,11.9,21.5,2H),3.82 (t,J=5.8,2H),6.24 (td,J=7.2,15.7,1H),6.87 (d,J=14.8,1H),7.12~7.25(m,3H),7.36 (dd,J=1.2,8.0,1H),7.52 (dd,J=1.6,9.2,1H)

[0656] Preparation Example 280: (E)-tert-butyldimethyl(4-phenylbut-3-enyloxy)silane [ka] The title compound (1.7 g, 80-98%) was obtained in essentially the same manner as in Preparation 237, except that (E)-4-phenylbut-3-en-1-ol (Preparation Example 279) was used instead of (E)-5-phenylpent-3-en-1-ol (Preparation Example 236).

[0657] 1 H NMR (400MHz,CDCl3): δ=0.07(s,3H),0.10 (s,3H),0.92 (d,J=6.4,9H),2.51 (q,J=4.5,2H),3.78 (t,J=6.6,2H),6.26(td,J=7.2,15.7,1H),6.84 (d,J=15.6,1H),7.13~7.24 (m,3H),7.36 (dd,J=5.6,12.4,1H),7.53(dd,J=1.4,7.8,1H)

[0658] Preparation Example 281: (E)-4-Phenylbut-3-enyl pivalate [ka] The title compound (10.8 g, 75-95%) was obtained in essentially the same manner as in Preparation 238, except that (E)-4-phenylbut-3-en-1-ol (Preparation Example 279) was used instead of (E)-5-phenylpent-3-en-1-ol (Preparation Example 236).

[0659] 1 H NMR (400MHz,CDCl3): δ=1.22(s,9H),2.57 (ddd,J=1.3,6.7,13.5,2H),4.22 (t,J=6.6,2H),6.19 (td,J=7.0,16.0,1H),6.49(d,J=16.0,1H),7.23~7.26 (m,1H),7.31~7.41 (m,4H)

[0660] Preparation 282: (1R,2R)-4-(tert-butyldimethylsilyloxy)-1-phenylbutane-1,2-diol [ka] The title compound (0.8 g, 70-95%) was obtained in essentially the same manner as in Preparation Example 239, except that (E)-tert-butyldimethyl(4-phenylbut-3-enyloxy)silane (Preparation Example 280) was used instead of (E)-tert-butyldimethyl(5-phenylpent-3-enyloxy)silane (Preparation Example 237).

[0661] 1 H NMR (400MHz,CDCl3): δ=0.10(s,3H),0.11 (s,3H),0.92 (s,9H),1.69~1.70 (m,1H),1.93-2.07 (m,1H),3.51 (d,J=4.8,1H),3.86(d,J=3.2,1H),3.87 (dd,J=3.2,9.2,1H),3.91~3.96 (m,1H),4.01~4.06 (m,1H),5.05 (t,J=4.6,1H),7.22~7.26(m,1H),7.31~7.37 (m,2H),7.59 (dd,J=1.2,7.6,1H)

[0662] Preparation Example 283: (3R,4R)-3,4-Dihydroxy-4-phenylbutyl pivalate [ka] The title compound (8.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 282, except that (E)-4-phenylbut-3-enyl pivalate (Preparation Example 281) was used instead of (E)-tert-butyldimethyl(4-phenylbut-3-enyloxy)silane (Preparation Example 280).

[0663] 1 H NMR (400MHz,CDCl3): δ=1.18(s,9H),1.65~1.74 (m,2H),2.83 (d,J=2.4,1H),2.96 (d,J=3.2,1H),3.74~3.79 (m,1H),4.10-4.17(m,1H),4.33 (ddd,J=4.0,7.2,12.6,1H),4.49 (d,J=5.6,1H),7.31~7.41 (m,5H)

[0664] Preparation 284: tert-butyl(2-((4R,5R)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)dimethylsilane [ka] The title compound (1.6 g, 70-95%) was obtained in essentially the same manner as in Preparation 218, except that (1R,2R)-4-(tert-butyldimethylsilyloxy)-1-phenylbutane-1,2-diol (Preparation Example 282) was used instead of (2R,3S)-methyl-3-phenyl-2,3-dihydroxypropanoate (Preparation Example 217).

[0665] 1 H NMR (400MHz,CDCl3):δ=0.02(s,3H),0.07 (s,3H),0.86 (s,9H),1.50 (s,3H),1.58 (s,3H),1.82-1.99 (m,2H),3.68~3.78(m,2H),3.95 (dt,J=3.3,8.7,1H),5.16 (d,J=8.4,1H),7.21~7.27(m,1H),7.31~7.38 (m,2H),7.60 (dd,J=1.6,7.6,1H)

[0666] Preparation 285: 2-((4R,5R)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethanol [ka] The title compound (1.4 g, 80-95%) was obtained in essentially the same manner as in Preparation 244, except that tert-butyl(2-((4R,5R)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)dimethylsilane (Preparation Example 284) was used instead of (2-((4R,5R)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)(tert-butyl)dimethylsilane (Preparation Example 243).

[0667] 1 H NMR (400MHz, CDCl3): δ=1.56(s,3H),1.62 (s,3H),1.92~2.04 (m,2H),2.26 (q,J=3.7,1H),3.75~3.90 (m,2H),3.94 (td,J=3.9,8.5,1H),5.23(d,J=15.6,1H),7.22~7.27 (m,1H),7.33~7.39 (m,2H),7.62 (dd,J=1.6,7.6,1H)

[0668] Preparation 286: (1S,2S)-4-(tert-butyldimethylsilyloxy)-1-phenylbutane-1,2-diol [ka] The title compound (0.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 242, except that (E)-tert-butyldimethyl(4-phenylbut-3-enyloxy)silane (Preparation Example 280) was used instead of (E)-tert-butyldimethyl(5-phenylpent-3-enyloxy)silane (Preparation Example 237).

[0669] 1H NMR (400MHz,CDCl3): δ=0.10(s,3H),0.11 (s,3H),0.92 (s,9H),1.69-1.70 (m,1H),1.93-2.07 (m,1H),3.51 (d,J=4.8,1H),3.86(d,J=3.2,1H),3.87 (dd,J=3.2,9.2,1H),3.91~3.96 (m,1H),4.01~4.06 (m,1H),5.05 (t,J=4.6,1H),7.22~7.26(m,1H),7.31-7.37 (m,2H),7.59 (dd,J=1.2,7.6,1H)

[0670] Preparation Example 287: (3S,4S)-3,4-Dihydroxy-4-phenylbutyl pivalate [ka] The title compound (10.4 g, 70-95%) was obtained in essentially the same manner as in Preparation 286, except that (E)-4-phenylbut-3-enyl pivalate (Preparation Example 281) was used instead of (E)-tert-butyldimethyl(4-phenylbut-3-enyloxy)silane (Preparation Example 280).

[0671] 1 H NMR (400MHz, CDCl3): δ=1.18(s,9H),1.65~1.74 (m,2H),2.83 (d,J=2.4,1H),2.96 (d,J=3.2,1H),3.74~3.79 (m,1H),4.10~4.17(m,1H),4.33 (ddd,J=4.0,7.2,12.6,1H),4.49 (d,J=5.6,1H),7.31~7.41 (m,5H)

[0672] Preparation Example 288: tert-butyl(2-((4S,5S)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)dimethylsilane [ka] The title compound (0.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 284, except that (1S,2S)-4-(tert-butyldimethylsilyloxy)-1-phenylbutane-1,2-diol (Preparation Example 286) was used instead of (1R,2R)-4-(tert-butyldimethylsilyloxy)-1-phenylbutane-1,2-diol (Preparation Example 282).

[0673] 1 H NMR (400MHz,CDCl3):δ=0.02(s,3H),0.07 (s,3H),0.86 (s,9H),1.50 (s,3H),1.58 (s,3H),1.82~1.99(m,2H),3.68~3.78 (m,2H),3.95 (dt,J=3.3,8.7,1H),5.16(d,J=8.4,1H),7.21~7.27 (m,1H),7.31~7.38(m,2H),7.60 (dd,J=1.6,7.6,1H)

[0674] Preparation 289: 2-((4S,5S)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethanol [ka] The title compound (0.4 g, 80-95%) was obtained in essentially the same manner as in Preparation 285, except that tert-butyl(2-((4R,5R)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)dimethylsilane (Preparation Example 284) was replaced with tert-butyl(2-((4S,5S)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)dimethylsilane (Preparation Example 288).

[0675] 1H NMR (400MHz,CDCl3): δ=1.56(s,3H),1.62 (s,3H),1.92-2.04 (m,2H),2.26 (q,J=3.7,1H),3.75~3.90 (m,2H),3.94 (td,J=3.9,8.5,1H),5.23(d,J=15.6,1H),7.22~7.27 (m,1H),7.33~7.39 (m,2H),7.62 (dd,J=1.6,7.6,1H)

[0676] Preparation 290: 2-((4R,5R)-2,2-diethyl-5-phenyl-1,3-dioxolan-4-yl)ethyl pivalate [ka] The title compound (1.8 g, 70-95%) was obtained in essentially the same manner as in Preparation 264, except that (3R,4R)-3,4-dihydroxy-4-phenylbutyl pivalate (Preparation Example 283) was used instead of (4R,5S)-methyl-5-benzyl-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 263).

[0677] 1 H NMR (400MHz,CDCl3): δ=1.00(t,J=7.4,3H),1.08 (t,J=7.6,3H),1.14 (s,9H),1.76 (q,J=7.5,2H),1.81-1.89 (m,2H),1.91-1.98(m,2H),3.87 (td,J=5.8,8.8,1H),4.13~4.18 (m,1H),4.22~4.28 (m,1H),4.58 (d,J=8.8,1H),7.31~7.43(m,5H)

[0678] Preparation 291: 2-((4R,5R)-2,2-diethyl-5-phenyl-1,3-dioxolan-4-yl)ethyl pivalate [ka] The title compound (0.9 g, 80-95%) was obtained in essentially the same manner as in Preparation 258, except that 2-((4R,5R)-2,2-diethyl-5-phenyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation Example 290) was used instead of 2-((2R,3R)-3-benzyl-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate (Preparation Example 257).

[0679] 1 H NMR (400MHz,CDCl3): δ=1.01(t,J=7.4,3H),1.07 (t,J=7.6,3H),1.79 (q,J=7.5,2H),1.83-1.90 (m,4H),2.38 (q,J=3.7,1H),3.75~3.87(m,2H),3.90-3.95 (m,1H),4.63 (d,J=8.8,1H),7.32~7.43 (m,5H)

[0680] Preparation 292: 2-((2R,3R)-3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate [ka] The title compound (1.8 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 290, except that cyclopentanone was used instead of 3-pentanone.

[0681] 1 H NMR (400MHz, CDCl3): δ=1.14(s,9H),1.67-1.83 (m,4H),1.88-2.07 (m,6H),3.84 (td,J=6.0,8.4,1H),4.13 (td,J=7.0,11.1,1H),4.24(td,J=6.4,11.2,1H),4.55 (d,J=8.4,1H),7.31~7.39 (m,5H)

[0682] Preparation 293: 2-((2R,3R)-3-phenyl-1,4-dioxaspiro-[4,4]nonan-2-yl)ethanol [ka] The title compound (0.9 g, 80-95%) was obtained in essentially the same manner as in Preparation 291, except that 2-((2R,3R)-3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate (Preparation Example 292) was used instead of 2-((4S,5S)-2,2-diethyl-5-phenyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation Example 290).

[0683] 1 H NMR (400MHz, CDCl3): δ=1.71-1.81(m,4H),1.87~2.07 (m,6H),2.27 (q,J=3.7,1H),3.79~3.85 (m,2H),3.89~3.92 (m,1H),4.59(d,J=8.4,1H),7.32~7.41 (m,5H)

[0684] Preparation 294: 2-((2R,3R)-3-phenyl-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate [ka] The title compound (2.0 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 292, except that cyclohexanone was used instead of cyclopentanone.

[0685] 1 H NMR (400MHz, CDCl3): δ=1.14(s,9H),1.67-1.83 (m,4H),1.88-2.07 (m,6H),3.84 (td,J=6.0,8.4,1H),4.10~4.17 (m,1H),4.21-4.27(m,1H),4.55 (d,J=8.4,1H),7.31~7.39 (m,5H)

[0686] Preparation 295: 2-((2R,3R)-3-phenyl-1,4-dioxaspiro[4,5]decan-2-yl)ethanol [ka] The title compound (1.2 g, 80-95%) was obtained in essentially the same manner as in Preparation 293, except that 2-((2R,3R)-3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate (Preparation Example 292) was replaced with 2-((2R,3R)-3-phenyl-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate (Preparation Example 294).

[0687] 1 H NMR (400MHz, CDCl3): δ=1.71-1.83(m,4H),1.87-2.05 (m,6H),2.27 (q,J=3.7,1H),3.79~3.85 (m,2H),3.86~3.91 (m,1H),4.59(d,J=8.4,1H),7.32~7.41 (m,5H)

[0688] Preparation 296: 2-((4S,5S)-2,2-diethyl-5-phenyl-1,3-dioxolan-4-yl)ethyl pivalate [ka] The title compound (2.2 g, 70-95%) was obtained in essentially the same manner as in Preparation 290, except that (3S,4S)-3,4-dihydroxy-4-phenylbutylpivalate (Preparation Example 287) was used instead of (3R,4R)-3,4-dihydroxy-4-phenylbutylpivalate (Preparation Example 283).

[0689] 1 H NMR (400MHz,CDCl3): δ=1.00(t,J=7.4,3H),1.08 (t,J=7.6,3H),1.14 (s,9H),1.76 (q,J=7.5,2H),1.81~1.89 (m,2H),1.91-1.98(m,2H),3.87 (td,J=5.8,8.8,1H),4.13~4.18 (m,1H),4.22~4.28 (m,1H),4.58 (d,J=8.8,H),7.31~7.43(m,5H)

[0690] Preparation 297: 2-((4S,5S)-2,2-diethyl-5-phenyl-1,3-dioxolan-4-yl)ethyl pivalate [ka] The title compound (0.7 g, 80-95%) was obtained in essentially the same manner as in Preparation 295, except that 2-((4S,5S)-2,2-diethyl-5-phenyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation Example 296) was used instead of 2-((2R,3R)-3-phenyl-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate (Preparation Example 294).

[0691] 1 H NMR (400MHz,CDCl3): δ=1.01(t,J=7.4,3H),1.07 (t,J=7.6,3H),1.79 (q,J=7.5,2H),1.83~1.90 (m,4H),2.38 (q,J=3.7,1H),3.75~3.87(m,2H),3.90~3.95 (m,1H),4.63 (d,J=8.8,1H),7.32~7.43 (m,5H)

[0692] Preparation 298: 2-((2S,3S)-3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate [ka] The title compound (2.4 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 296, except that cyclopentanone was used instead of 3-pentanone.

[0693] 1H NMR (400MHz, CDCl3): δ=1.14(s,9H),1.67~1.83 (m,4H),1.88-2.07 (m,6H),3.84 (td,J=6.0,8.4,1H),4.13 (td,J=7.0,11.1,1H),4.24(td,J=6.4,11.2,1H),4.55 (d,J=8.4,1H),7.31~7.39 (m,5H)

[0694] Preparation 299: 2-((2S,3S)-3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethanol [ka] The title compound (0.7 g, 80-95%) was obtained in essentially the same manner as in Preparation 297, except that 2-((2S,3S)-3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate (Preparation Example 298) was used instead of 2-((4S,5S)-2,2-diethyl-5-phenyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation Example 296).

[0695] 1 H NMR (400MHz, CDCl3): δ=1.71-1.81(m,4H),1.87~2.07 (m,6H),2.27 (q,J=3.7,1H),3.79~3.85 (m,2H),3.89~3.92 (m,1H),4.59(d,J=8.4,1H),7.32~7.41 (m,5H)

[0696] Preparation 300: 2-((2S,3S)-3-phenyl-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate [ka] The title compound (2.4 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 298, except that cyclohexanone was used instead of cyclopentanone.

[0697] 1H NMR (400MHz,CDCl3): δ=1.14(s,9H),1.67-1.83 (m,4H),1.88-2.07 (m,6H),3.84 (td,J=6.0,8.4,1H),4.10-4.17 (m,1H),4.21~4.27(m,1H),4.55 (d,J=8.4,1H),7.31~7.39 (m,5H)

[0698] Preparation 301: 2-((2S,3S)-3-phenyl-1,4-dioxaspiro[4,5]decan-2-yl)ethanol [ka] The title compound (1.2 g, 80-95%) was obtained in essentially the same manner as in Preparation 299, except that 2-((2S,3S)-3-phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate (Preparation Example 300) was used instead of 2-((2S,3S)-3-phenyl-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate (Preparation Example 298).

[0699] 1 H NMR (400MHz, CDCl3): δ=1.71-1.83(m,4H),1.87~2.05 (m,6H),2.27 (q,J=3.7,1H),3.79~3.85 (m,2H),3.86-3.91 (m,1H),4.59(d,J=8.4,1H),7.32~7.41 (m,5H)

[0700] Preparation 302: (E)-5-(2-chlorophenyl)pent-3-enoic acid [ka] The title compound (6.1 g, 70-90%) was obtained in substantially the same manner as in Preparation Example 235, except that 3-(2-chlorophenyl)propanal was used instead of hydrocinnamic aldehyde.

[0701] 1H NMR (400MHz, CDCl3): δ=3.15(dd,J=0.8,6.8,2H),3.53 (d,J=6.4,2H),5.61~5.69 (m,1H),5.75~5.82 (m,1H) 7.16~7.28(m,3H),7.36~7.38 (m,1H)

[0702] Preparation 303: (E)-5-(2-chlorophenyl)pent-3-en-1-ol [ka] The title compound (4.6 g, 70-90%) was obtained in essentially the same manner as in Preparation 236, except that (E)-5-(2-chlorophenyl)pent-3-enoic acid (Preparation Example 302) was used instead of (E)-5-phenylpent-3-enoic acid (Preparation Example 235).

[0703] 1 H NMR (400MHz,CDCl3): δ=2.33(dq,J=1.0,6.5,2H),3.50 (dd,J=1.8,5.0,2H),3.67 (q,J=6.0,2H),5.45~5.53 (m,1H),5.70~5.77(m,1H),7.15-7.37 (m,4H)

[0704] Preparation Example 304: (E)-tert-butyl(5-(2-chlorophenyl)pent-3-enyloxy)dimethylsilane [ka] The title compound (4.9 g, 75-95%) was obtained in essentially the same manner as in Preparation 237, except that (E)-5-(2-chlorophenyl)pent-3-en-1-ol (Preparation Example 303) was used instead of (E)-5-phenylpent-3-en-1-ol (Preparation Example 236).

[0705] 1H NMR (400MHz,CDCl3): δ=0.60(s,6H),0.90 (s,9H),2.28 (dq,J=1.0,6.7,2H),3.47 (d,J=6.4,2H),3.65 (t,J=6.8,2H),5.49~5.56(m,1H),5.62~5.70 (m,1H),7.14~7.36 (m,4H)

[0706] Preparation Example 305: (E)-5-(2-chlorophenyl)pent-3-enyl pivalate [ka] The title compound (7.2 g, 75-95%) was obtained in essentially the same manner as in Preparation 238, except that (E)-5-(2-chlorophenyl)pent-3-en-1-ol (Preparation Example 303) was used instead of (E)-5-phenylpent-3-en-1-ol (Preparation Example 236).

[0707] 1 H NMR (400MHz, CDCl3): δ=1.18(s,9H),2.36 (q,J=6.7,2H),3.45 (d,J=6.4,2H),4.08 (t,J=6.6,2H),5.43~5.50 (m,1H),5.63~5.70(m,1H),7.12~7.35 (m,4H)

[0708] Preparation Example 306: (2S,3S)-5-(tert-butyldimethylsilyloxy)-1-(2-chlorophenyl)pentane-2,3-diol [ka] The title compound (2.8 g, 90%) was obtained in essentially the same manner as in Preparation 239, except that (E)-tert-butyl(5-(2-chlorophenyl)pent-3-enyloxy)dimethylsilane (Preparation Example 304) was used instead of (E)-tert-butyldimethyl(5-phenylpent-3-enyloxy)silane (Preparation Example 237).

[0709] 1 H NMR (400MHz,CDCl3): δ=0.11(s,6H),0.92 (s,9H),1.68-1.77 (m,1H),1.87-1.96 (m,1H),2.64 (d,J=6.0,1H),2.93 (dd,J=8.2,13.4,1H),3.07(dd,J=4.8,13.6,1H),3.68 (d,J=3.2,1H),3.76~3.96 (m,4H),7.17~7.25 (m,2H),7.35-7.39(m,2H)

[0710] Preparation 307: (2-(4S,5S)-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)(tert-butyl)dimethylsilane [ka] The title compound (3.6 g, 75-90%) was obtained in essentially the same manner as in Preparation 240, except that (2S,3S)-5-(tert-butyldimethylsilyloxy)-1-(2-chlorophenyl)pentane-2,3-diol (Preparation Example 306) was used instead of (2S,3S)-5-(tert-butyldimethylsilyloxy)-1-phenylpentane-2,3-diol (Preparation Example 239).

[0711] 1 H NMR (400MHz,CDCl3):δ=0.06(s,6H),0.91 (s,9H),1.39 (s,3H),1.40 (s,3H),1.69 (q,J=6.5,2H),3.05 (dq,J=5.8,15.1,2H),3.70-3.80(m,2H),3.86-3.93 (m,1H),3.97~4.02 (m,1H),7.17~7.25(m,2H),7.36~7.38 (m,2H)

[0712] Preparation 308: 2-((4S,5S)-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethanol [ka] The title compound (3.2 g, 80-95%) was obtained in essentially the same manner as in Preparation 241, except that (2-(4S,5S)-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)(tert-butyl)dimethylsilane (Preparation Example 307) was used instead of (2-(4S,5S)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)(tert-butyl)dimethylsilane (Preparation Example 240).

[0713] 1 H NMR (400MHz, CDCl3): δ=1.38(s,3H),1.40 (s,3H),1.50-1.63 (m,2H),2.29 (t,J=5.4,1H),2.82 (dd,J=5.8,13.8,1H),3.01(dd,J=6.4,14.0,1H),3.72 (q,J=5.5,2H),3.86 (dt,J=3.2,8.4,1H),3.92-3.97 (m,1H),7.17-7.25(m,2H),7.36-7.38 (m,2H)

[0714] Preparation Example 309: (2R,3R)-5-(tert-butyldimethylsilyloxy)-1-(2-chlorophenyl)pentane-2,3-diol [ka] The title compound (4.4 g, 90%) was obtained in essentially the same manner as in Preparation 242, except that (E)-tert-butyl(5-(2-chlorophenyl)pent-3-enyloxy)dimethylsilane (Preparation Example 304) was used instead of (E)-tert-butyldimethyl(5-phenylpent-3-enyloxy)silane (Preparation Example 237).

[0715] 1H NMR (400MHz,CDCl3): δ=0. 11(s,6H),0.92 (s,9H),1.68-1.77 (m,1H),1.87~1.96 (m,1H),2.64(d,J=6.0,1H) 2.93 (dd,J=8.2,13.4,1H),3.07 (dd,J=4.8,13.6,1H),3.68 (d,J=3.2,1H),3.76~3.96(m,4H),7.17~7.25 (m,2H),7.35~7.39(m,2H)

[0716] Preparation 310: (2-(4R,5R)-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)(tert-butyl)dimethylsilane [ka] The title compound (4.6 g, 70-95%) was obtained in essentially the same manner as in Preparation 307, except that (2R,3R)-5-(tert-butyldimethylsilyloxy)-1-(2-chlorophenyl)pentane-2,3-diol (Preparation Example 309) was used instead of (2S,3S)-5-(tert-butyldimethylsilyloxy)-1-(2-chlorophenyl)pentane-2,3-diol (Preparation Example 306).

[0717] 1 H NMR (400MHz,CDCl3):δ=0.06(s,6H),0.91 (s,9H),1.39 (s,3H),1.40 (s,3H),1.69 (q,J=6.5,2H),3.05 (dq,J=5.8,15.1,2H),3.70~3.80(m,2H),3.86~3.93 (m,1H),8.97~4.02(m,1H) 7.17~7.25 (m,2H),7.36~7.38(m,2H)

[0718] Preparation 311: 2-((4R,5R)-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethanol [ka] The title compound (3.0 g, 80-95%) was obtained in essentially the same manner as in Preparation 241, except that (2-(4S,5S)-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)(tert-butyl)dimethylsilane (Preparation Example 307) was used instead of (2-(4S,5S)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)(tert-butyl)dimethylsilane (Preparation Example 240).

[0719] 1 H NMR (400MHz, CDCl3): δ=1.38(s,3H),1.40 (s,3H),1.50-1.63 (m,2H),2.29 (t,J=5.4,1H),2.82 (dd,J=5.8,13.8,1H),3.01(dd,J=6.4,14.0,1H),3.72 (q,J=5.5,2H),3.86 (dt,J=3.2,8.4,1H),3.92~3.97 (m,1H),7.17~7.25(m,2H),7.36-7.38 (m,2H)

[0720] Preparation Example 312: (3S,4S)-3,4-Dihydroxy-5-(2-chlorophenyl)pentyl pivalate [ka] The title compound (6.0 g, 70-95%) was obtained in essentially the same manner as in Preparation 306, except that (E)-5-(2-chlorophenyl)pent-3-enylpivalate (Preparation Example 305) was used instead of (E)-tert-butyl(5-(2-chlorophenyl)pent-3-enyloxy)dimethylsilane (Preparation Example 304).

[0721] 1H NMR (400MHz, CDCl3): δ=1.16(s,9H),1.85~1.91 (m,2H),2.17 (d,J=6.0,1H),2.73 (d,J=5.2,1H),2.91 (dd,J=8.4,13.6,1H),3.08(dd,J=5.6,13.6,1H),3.52~3.55 (m,1H),3.77~3.80 (m,1H),4.11~4.19 (m,1H),4.37~4.41(m,1H),7.18~7.23 (m,2H),7.31 (dd,J=2.2,7.0,1H),7.36 (dd,J=1.8,7.4,1H)

[0722] Preparation 313: 2-((4S,5S)-5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolan-4-yl)ethyl pivalate [ka] The title compound (1.7 g, 70-95%) was obtained in essentially the same manner as in Preparation Example 246, except that (3S,4S)-3,4-dihydroxy-5-(2-chlorophenyl)pentyl pivalate (Preparation Example 312) was used instead of (3S,4S)-3,4-dihydroxy-5-phenylpentyl pivalate (Preparation Example 245).

[0723] 1 H NMR (400MHz, CDCl3): δ=0.90(t,J=7.4,6H),1.21 (s,9H),1.58-1.66 (m,4H),1.70~1.77 (m,2H),3.06 (d,J=5.6,2H),3.81~3.86(m,1H),3.94~3.99 (m,H),4.15~4.25 (m,2H),7.18~7.24 (m,2H),7.36~7.38 (m,2H)

[0724] Preparation 314: 2-((4S,5S)-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethanol [ka] The title compound (0.9 g, 80-95%) was obtained in essentially the same manner as in Preparation Example 247, except that 2-((4S,5S)-5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation Example 313) was used instead of 2-((4S,5S)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation Example 246).

[0725] 1 H NMR (400MHz,CDCl3): δ=0.91(dt,J=2.5,7.5,6H),1.46-1.79 (m,6H),2.42 (t,J=5.6,1H),3.01-3.12 (m,2H),3.79 (q,J=5.6,2H),3.88-3.93(m,1H),3.98~4.06 (m,1H),7.18~7.25 (m,2H),7.35-7.39 (m,2H)

[0726] Preparation Example 315: (3R,4R)-3,4-dihydroxy-5-(2-chlorophenyl)pentyl pivalate [ka] The title compound (4.4 g, 70-95%) was obtained in essentially the same manner as in Preparation 309, except that (E)-5-(2-chlorophenyl)pent-3-enylpivalate (Preparation Example 305) was used instead of (E)-tert-butyl(5-(2-chlorophenyl)pent-3-enyloxy)dimethylsilane (Preparation Example 304).

[0727] 1 H NMR (400MHz, CDCl3): δ=0.11(s,6H),0.92 (s,9H),1.68-1.77 (m,1H),1.87-1.96 (m,1H),2.64 (d,J=6.0,1H),2.93 (dd,J=8.2,13.4,1H),3.07(dd,J=4.8,13.6,1H),3.68 (d,J=3.2. 1H),3.76~3.96 (m,4H),7.17-7.25 (m,2H),7.35-7.39(m,2H)

[0728] Preparation 316: 2-((4R,5R)-5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolan-4-yl)ethyl pivalate [ka] The title compound (1.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 313, except that (3R,4R)-3,4-dihydroxy-5-(2-chlorophenyl)pentyl pivalate (Preparation Example 315) was used instead of (3S,4S)-3,4-dihydroxy-5-(2-chlorophenyl)pentyl pivalate (Preparation Example 312).

[0729] 1 H NMR (400MHz, CDCl3): δ=0.90(t,J=7.4,6H),1.21 (s,9H),1.58-1.66 (m,4H),1.70~1.77 (m,2H),3.06 (d,J=5.6,2H),3.81-3.86(m,1H),3.94~3.99 (m,1H),4.15-4.25 (m,2H),7.18~7.24 (m,2H),7.36~7.38 (m,2H)

[0730] Preparation 317: 2-((4R,5R)-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethanol [ka] The title compound (0.9 g, 80-95%) was obtained in essentially the same manner as in Preparation 314, except that 2-((4R,5R)-5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation Example 316) was used instead of 2-((4S,5S)-5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation Example 313).

[0731] 1H NMR (400MHz,CDCl3): δ=0.91(dt,J=2.5,7.5,6H),1.46-1.79 (m,6H),2.42 (t,J=5.6,1H),3.01-3.12 (m,2H),3.79 (q,J=5.6,2H),3.88~3.93(m,1H),3.98~4.06 (m,1H),7.18-7.25 (m,2H),7.35~7.39 (m,2H)

[0732] Preparation 318: 2-((2S,3S)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate [ka] The title compound (1.2 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 313, except that cyclopentanone was used instead of 3-pentanone.

[0733] 1 H NMR (400MHz, CDCl3): δ=1.21(s,9H),1.64~1.74 (m,5H),1.75~1.88 (m,5H),3.03~3.11 (m,2H),3.81~3.86 (m,1H),3.97(q,J=6.5,1H),4.12-4.22 (m,2H),7.18~7.25 (m,2H),7.34~7.39 (m,2H)

[0734] Preparation 319: 2-((2S,3S)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethanol [ka] The title compound (0.7 g, 80-95%) was obtained in essentially the same manner as in Preparation 317, except that 2-((2S,3S)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate (Preparation Example 318) was used instead of 2-((4R,5R)-5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation Example 316).

[0735] 1 H NMR (400MHz,CDCl3): δ=1.62-1.74(m,6H),1.75-1.88 (m,4H),2.28 (t,J=5.6,1H),3.03-3.12 (m,2H),3.78 (q,J=5.6,1H),3.88-3.95(m,1H),3.97~4.06 (m,1H),7.18~7.26 (m,2H),7.34~7.39 (m,2H)

[0736] Preparation 320: 2-((2R,3R)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate [ka] The title compound (1.4 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 316, except that cyclopentanone was used instead of 3-pentanone.

[0737] 1 H NMR (400MHz, CDCl3): δ=1.21(s,9H),1.64~1.74 (m,5H),1.75-1.88 (m,5H),3.03~3.11 (m,2H),3.81~3.86 (m,1H),3.97(q,J=6.5,1H),4.12-4.22 (m,2H),7.18~7.25 (m,2H),7.34~7.39 (m,2H)

[0738] Preparation 321: 2-((2R,3R)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethanol [ka] The title compound (0.8 g, 80-95%) was obtained in essentially the same manner as in Preparation 319, except that 2-((2R,3R)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate (Preparation Example 318) was replaced with 2-((2S,3S)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate (Preparation Example 320).

[0739] 1 H NMR (400MHz,CDCl3): δ=1.62-1.74(m,6H),1.75-1.88 (m,4H),2.28 (t,J=5.6,1H),3.03-3.12 (m,2H),3.78 (q,J=5.6,1H),3.88~3.95(m,1H),3.97~4.06 (m,1H),7.18~7.26 (m,2H),7.34~7.39 (m,2H)

[0740] Preparation 322: 2-((2S,3S)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate [ka] The title compound (1.1 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 318, except that cyclohexanone was used instead of cyclopentanone.

[0741] 1 H NMR (400MHz, CDCl3): δ=1.21(s,9H),1.58-1.61 (m,8H),1.77 (q,J=6.8,2H),3.07 (d,J=6.0,2H),3.81~3.88 (m,1H),3.96~4.01(m,1H),4.16-4.22 (m,2H),7.17~7.25 (m,2H),7.36~7.39 (m,2H)

[0742] Preparation 323: 2-((2S,3S)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethanol [ka] The title compound (0.7 g, 80-95%) was obtained in essentially the same manner as in Preparation 321, except that 2-((2S,3S)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate (Preparation Example 322) was used instead of 2-((2R,3R)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate (Preparation Example 320).

[0743] 1 H NMR (400MHz,CDCl3): δ=1.51-1.64(m,8H),1.65~1.74 (m,2H),2.59~2.63 (m,1H),3.06 (d,J=6.0,2H),3.76-3.78 (m,2H),3.89~3.94(m,1H),3.99~4.04 (m,1H),7.16~7.24 (m,2H),7.35~7.38 (m,2H)

[0744] Preparation 324: 2-((2R,3R)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate [ka] The title compound (1.5 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 320, except that cyclohexanone was used instead of cyclopentanone.

[0745] 1H NMR (400MHz, CDCl3): δ=1.21(s,9H),1.58~1.61 (m,8H),1.77 (q,J=6.8,2H),3.07 (d,J=6.0,2H),3.81~3.88 (m,1H),3.96-4.01(m,1H),4.16~4.22 (m,2H),7.17-7.25 (m,2H),7.36~7.39 (m,2H)

[0746] Preparation 325: 2-((2R,3R)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethanol [ka] The title compound (0.9 g, 80-95%) was obtained in essentially the same manner as in Preparation 323, except that 2-((2S,3S)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate (Preparation Example 322) was replaced with 2-((2R,3R)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate (Preparation Example 324).

[0747] 1 H NMR (400MHz,CDCl3): δ=1.51-1.64(m,8H),1.65-1.74 (m,2H),2.59~2.63 (m,1H),3.06 (d,J=6.0,2H),3.76~3.78 (m,2H),3.89~3.94(m,1H),3.99~4.04 (m,1H),7.16~7.24 (m,2H),7.35~7,38 (m,2H)

[0748] Preparation 326: (E)-methyl-4-(2-chlorophenyl)but-2-enoate [ka] The title compound (5.0 g, 65-85%) was obtained in substantially the same manner as in Preparation Example 259, except that 2-chlorophenylacetaldehyde was used instead of phenylacetaldehyde.

[0749] 1 H NMR (400MHz, CDCl3): δ=3.47(d,J=6.8,2H),3.67 (s,3H),5.79 (d,J=15.4. 1H),7.06 (dt,J=15.4,6.8,1H),7.12~7.28(m,4H)

[0750] Preparation 327: (2R,3S)-methyl-4-(2-chlorophenyl)-2,3-dihydroxybutanoate [ka] The title compound (3.0 g, 70-95%) was obtained in essentially the same manner as in Preparation 260, except that (E)-methyl-4-(2-chlorophenyl)but-2-enoate (Preparation Example 326) was used instead of (E)-methyl-4-phenylbut-2-enoate (Preparation Example 259).

[0751] 1 H NMR (400MHz,CDCl3): δ=3.08-3.17(m,2H),3.84 (s,3H),4.12 (dd,J=1.6,5.2,1H),4.28~4.34 (m,1H),7.20~7.27 (m,2H),7.33-7.36(m,1H),7.39~7.41 (m,1H)

[0752] Preparation 328: (4R,5S)-methyl-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (0.6 g, 70-95%) was obtained in essentially the same manner as in Preparation 261, except that (2R,3S)-methyl-2,3-dihydroxy-4-phenylbutanoate (Preparation Example 260) was replaced with (2R,3S)-methyl-4-(2-chlorophenyl)-2,3-dihydroxybutanoate (Preparation Example 327).

[0753] 1 H NMR (400MHz,CDCl3): δ=1.45(s,3H),1.49 (s,3H),3.11 (dd,J=7.6,14.4,1H),3.35 (dd,J=4.4,14.4,1H),3.74 (s,3H),4.30(d,J=7.6,1H),4.50 (dt,J=4.0,7.6,1H),7.19~7.26 (m,2H),7.36~7.40 (m,2H)

[0754] Preparation 329: ((4S,5S)-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (0.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 262, except that (4R,5S)-methyl-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 328) was used instead of (4R,5S)-methyl-5-benzyl-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 261).

[0755] 1 H NMR (400MHz,CDCl3): δ=1.43(s,6H),1.83 (q,J=4.3,1H),3.06-3.17 (m,2H),3.45 (ddd,J=4.6,7.4,12.0,1H),3.68(ddd,J=3.2,5.2,12.0,1H),3.91 (ddd,J=3.3,4.7,8.0,1H),4.22-4.27 (m,1H),7.20~7.26(m,2H),7.35-7.40 (m,2H)

[0756] Preparation 330: (4R,5S)-methyl-5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (0.8 g, 50-75%) was obtained in essentially the same manner as in Preparation 263, except that (2R,3S)-methyl-2,3-dihydroxy-4-phenylbutanoate (Preparation Example 260) was replaced with (2R,3S)-methyl-4-(2-chlorophenyl)-2,3-dihydroxybutanoate (Preparation Example 327).

[0757] 1 H NMR (400MHz,CDCl3): δ=0.93(t,J=7.4,6H),1.67~1.74 (m,4H),3.10 (dd,J=8.0,14.4,1H),3.35 (dd,J=4.0,14.4,1H),3.73(s,3H),4.27 (d,J=8.4,1H),4.42~4.47 (m,1H),7.18~7.26 (m,2H),7.37~7.40 (m,2H)

[0758] Preparation 331: ((4S,5S)-5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (0.6 g, 70-95%) was obtained in essentially the same manner as in Preparation 329, except that (4R,5S)-methyl-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 330) was used instead of (4R,5S)-methyl-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 328).

[0759] 1H NMR (400MHz, CDCl3): δ=0.93(dt,J=2.1,7.5,6H),1.62-1.70 (m,4H),1.83 (q,J=4.3,1H),3.11 (ddd,J=6.0,14.2,28.0,2H),3.44(ddd,J=4.8,7.2,12.0,1H),3.64~3.69 (m,1H),3.88 (ddd,J=3.3,4.9,8.3,1H),4.18~4.24(m,1H),7.19~7.26 (m,2H),7.36~7.39 (m,2H)

[0760] Preparation 332: (2R,3S)-methyl-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (0.8 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 330, except that cyclopentanone was used instead of 3-pentanone.

[0761] 1 H NMR (400MHz, CDCl3): δ=1.65~1.80(m,5H),1.89-2.00 (m,3H),3.13 (dd,J=7.8,14.2,1H),3.32 (dd,J=4.6,14.2,1H),3.72 (s,3H),4.28(d,J=7.2,1H),4.41~4.46 (m,1H),7.19~7.26 (m,2H),7.35~7.40 (m,2H)

[0762] Preparation 333: ((2S,3S)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (0.6 g, 70-95%) was obtained in essentially the same manner as in Preparation 331, except that (2R,3S)-methyl-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 332) was used instead of (4R,5S)-methyl-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 330).

[0763] 1 H NMR (400MHz,CDCl3): δ=1.69-1.74(m,3H),1.77~1.85 (m,5H),3.11 (ddd,J=6.3,14.1,31.3,2H),3.42~3.48 (m,1H),3.61~3.66(m,1H),3.87~3.91 (m,1H),4.19 (q,J=6.8,1H),7.19~7.26 (m,2H),7.34~7.40 (m,2H)

[0764] Preparation 334: (2R,3S)-methyl-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (0.5 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 332, except that cyclohexanone was used instead of cyclopentanone.

[0765] 1 H NMR (400MHz,CDCl3): δ=1.54-1.77(m,10H),3.12 (dd,J=7.6,14.4,1H),3.32 (dd,J=4.4,14.4,1H),3.72 (s,3H),4.30 (d,J=7.6,1H),4.46~4.51(m,1H),7.18~7.26 (m,2H),7.37~7.39 (m,2H)

[0766] Preparation 335: ((2S,3S)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (0.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 333, except that (2R,3S)-methyl-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 332) was replaced with (2R,3S)-methyl-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 334).

[0767] 1 H NMR (400MHz, CDCl3): δ=1.38-1.45(m,2H),1.58~1.63 (m,8H),1.84 (q,J=4.3,1H),3.11(ddd,J=7.9,15.9,22.1,2H),3.43(ddd,J=4.6,7.6,12.1,1H),3.66~3.71 (m,1H),3.88~3.92 (m,1H),4.21~4.26 (m,1H),7.18~7.26(m,2H),7.37~7.39 (m,2H)

[0768] Preparation 336: (2S,3R)-methyl-4-(2-chlorophenyl)-2,3-dihydroxybutanoate [ka] The title compound (3.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 269, except that (E)-methyl-4-(2-chlorophenyl)but-2-enoate (Preparation Example 326) was used instead of (E)-methyl-4-phenylbut-2-enoate (Preparation Example 259).

[0769] 1 H NMR (400MHz,CDCl3): δ=3.08-3.17(m,2H),3.84 (s,3H),4.12 (dd,J=1.6,5.2,1H),4.28~4.34 (m,1H),7.20~7.27 (m,2H),7.33~7.36(m,1H),7.39~7.41 (m,1H)

[0770] Preparation 337: (4S,5R)-methyl-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (3.4 g, 70-95%) was obtained in essentially the same manner as in Preparation 328, except that (2S,3R)-methyl-4-(2-chlorophenyl)-2,3-dihydroxybutanoate (Preparation Example 336) was used instead of (2R,3S)-methyl-4-(2-chlorophenyl)-2,3-dihydroxybutanoate (Preparation Example 327).

[0771] 1 H NMR (400MHz,CDCl3): δ=1.41(s,6H),1.79 (q,J=4.3,1H),2.83 (dd,J=6.2,13.8,1H),3.07 (dd,J=6.4,14.0,1H),3.29(ddd,J=4.7,7.5,12.1,1H),3.54 (ddd,J=2.8,5.2,12.0,1H),3.83 (ddd,J=3.9,3.9,7.1,1H),4.15(q. J=7.1,1H),7.22~7.32 (m,5H)

[0772] Preparation 338: ((4R,5R)-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (2.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 335, except that (4S,5R)-methyl-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 337) was used instead of (2R,3S)-methyl-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 334).

[0773] 1H NMR (400MHz,CDCl3): δ=1.41(s,6H),1.79 (q,J=4.3,1H),2.83 (dd,J=6.2,13.8,1H),3.07 (dd,J=6.4,14.0,1H),3.29(ddd,J=4.7,7.5,12.1,1H),3.54 (ddd,J=2.8,5.2,12.0,1H),3.83 (ddd,J=3.9,3.9,7.1,1H),4.15(q,J=7.1,1H),7.22~7.32 (m,5H)

[0774] Preparation 339: (4S,5R)-methyl-5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (0.6 g, 50-75%) was obtained in essentially the same manner as in Preparation 330, except that (2S,3R)-methyl-2,3-dihydroxy-4-phenylbutanoate (Preparation Example 336) was used instead of (2R,3S)-methyl-4-(2-chlorophenyl)-2,3-dihydroxybutanoate (Preparation Example 327).

[0775] 1 H NMR (400MHz,CDCl3): δ=0.93(t,J=7.4,6H),1.67-1.74 (m,4H),3.10 (dd,J=8.0,14.4,1H),3.35 (dd,J=4.0,14.4,1H),3.73(s,3H),4.27 (d,J=8.4,1H),4.42~4.47 (m,1H),7.18~7.26 (m,2H),7.37~7.40 (m,2H)

[0776] Preparation 340: ((4R,5R)-5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (0.5 g, 70-95%) was obtained in essentially the same manner as in Preparation 338, except that (4S,5R)-methyl-5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 339) was used instead of (4S,5R)-methyl-5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 337).

[0777] 1 H NMR (400MHz, CDCl3): δ=0.93(dt,J=2.1,7.5,6H),1.62-1.70 (m,4H),1.83 (q,J=4.3,1H),3.11 (ddd,J=6.0,14.2,28.0,2H),3.44(ddd,J=4.8,7.2,12.0,1H),3.64~3.69 (m,1H),3.88 (ddd,J=3.3,4.9,8.3,1H),4.18~4.24(m,1H),7.19-7.26 (m,2H),7.36~7.39 (m,2H)

[0778] Preparation 341: (2S,3R)-methyl-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate [ka] The title compound (0.5 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 339, except that cyclopentanone was used instead of 3-pentanone.

[0779] 1 H NMR (400MHz,CDCl3): δ=1.65-1.80(m,5H),1.89-2.00 (m,3H),3.13 (dd,J=7.8,14.2,1H),3.32 (dd,J=4.6,14.2,1H),3.72 (s,3H),4.28(d,J=7.2,1H),4.41~4.46 (m,1H),7.19~7.26 (m,2H),7.35-7.40 (m,2H)

[0780] Preparation 342: ((2R,3R)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methanol [ka] The title compound (0.4 g, 70-95%) was obtained in essentially the same manner as in Preparation 340, except that (2S,3R)-methyl-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 341) was used instead of (4S,5R)-methyl-5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolane-4-carboxylate (Preparation Example 339).

[0781] 1 H NMR (400MHz, CDCl3): δ=1.69-1.74(m,3H),1.77-1.85 (m,5H),3.11 (ddd,J=6.3,14.1,31.3,2H),3.42~3.48 (m,1H),3.61~3.66(m,1H),3.87~3.91 (m,1H),4.19 (q,J=6.8,1H),7.19~7.26 (m,2H),7.34~7.40 (m,2H)

[0782] Preparation 343: (2S,3R)-methyl-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate [ka] The title compound (0.9 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 341, except that cyclohexanone was used instead of cyclopentanone.

[0783] 1H NMR (400MHz,CDCl3): δ=1.54-1.77(m,10H),3.12 (dd,J=7.6,14.4,1H),3.32 (dd,J=4.4,14.4,1H),3.72 (s,3H),4.30 (d,J=7.6,1H),4.46~4.51(m,1H),7.18-7.26 (m,2H),7.37~7.39 (m,2H)

[0784] Preparation 344: ((2R,3R)-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)methanol [ka] The title compound (0.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 342, except that (2S,3R)-methyl-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation Example 341) was replaced with (2S,3R)-methyl-3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation Example 343).

[0785] 1 H NMR (400MHz, CDCl3): δ=1.38-1.45(m,2H),1.58-1.63 (m,8H),1.84 (q,J=4.3,1H),3.11 (ddd,J=7.9,15.9,22.1,2H),3.43(ddd,J=4.6,7.6,12.1,1H),3.66~3.71 (m,1H),3.88~3.92 (m,1H),4.21-4.26 (m,1H),7.18-7.26(m,2H),7.37-7.39 (m,2H)

[0786] Preparation 345: (E)-4-(2-chlorophenyl)but-3-enoic acid [ka] The title compound (4.0 g, 55-80%) was obtained in substantially the same manner as in Preparation Example 278, except that 2-(2-chlorophenyl)acetaldehyde was used instead of phenylacetaldehyde.

[0787] 1 H NMR (400MHz,CDCl3): δ=3.39(d,J=8.8,2H),6.31 (td,J=7.9,14.8,1H),6.94 (d,J=16,1H),7.17~7.45 (m,3H),7.56~7.59(m,1H)

[0788] Preparation 346: (E)-4-(2-chlorophenyl)but-3-en-1-ol [ka] The title compound (1.2 g, 55-80%) was obtained in essentially the same manner as in Preparation Example 279, except that (E)-4-(2-chlorophenyl)but-3-enoic acid (Preparation Example 345) was used instead of (E)-4-phenylbut-3-enoic acid (Preparation Example 278).

[0789] 1 H NMR (400MHz,CDCl3): δ=2.55(ddd,J=4.1,11.9,21.5,2H),3.82 (t,J=5.8,2H),6.24 (td,J=7.2,15.7,1H),6.87 (d,J=14.8,1H),7.12~7.25(m,3H),7.36 (dd,J=1.2,8.0,1H),7.52 (dd,J=1.6,9.2,1H)

[0790] Preparation Example 347: (E)-tert-butyldimethyl(4-(2-chlorophenyl)but-3-enyloxy)silane [ka] The title compound (1.1 g, 80-98%) was obtained in essentially the same manner as in Preparation 280, except that (E)-4-(2-chlorophenyl)but-3-en-1-ol (Preparation Example 346) was used instead of (E)-4-phenylbut-3-en-1-ol (Preparation Example 279).

[0791] 1 H NMR (400MHz,CDCl3): δ=0.07(s,3H),0.10 (s,3H),0.92 (d,J=6.4,9H),2.51 (q,J=4.5,2H),3.78 (t,J=6.6,2H),6.26(td,J=7.2,15.7,1H),6.84 (d,J=15.6,1H),7.13~7.24 (m,3H),7.36 (dd,J=5.6,12.4,1H),7.53(dd,J=1.4,7.8,1H)

[0792] Preparation 348: (E)-4-(2-chlorophenyl)but-3-enyl pivalate [ka] The title compound (3.5 g, 75-95%) was obtained in essentially the same manner as in Preparation 281, except that (E)-4-(2-chlorophenyl)but-3-en-1-ol (Preparation Example 346) was used instead of (E)-4-phenylbut-3-en-1-ol (Preparation Example 279).

[0793] 1 H NMR (400MHz, CDCl3): δ=1.21(s,9H),2.55~2.64 (m,2H),4.24 (t,J=6.4,2H),6.18 (td,J=7.9,14.8,1H),6.86 (d,J=16.0,1H),7.22~7.26(m,2H),7.38 (dd,J=3.6,10.8,1H),7.51 (dd,J=1.6,7.6,1H)

[0794] Preparation 349: (1R,2R)-4-(tert-butyldimethylsilyloxy)-1-(2-chlorophenyl)butane-1,2-diol [ka] The title compound (0.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 282, except that (E)-tert-butyldimethyl-4-(2-chlorophenyl)but-3-enyloxy)silane (Preparation Example 347) was used instead of (E)-tert-butyldimethyl(5-phenylpent-3-enyloxy)silane (Preparation Example 237).

[0795] 1 H NMR (400MHz,CDCl3): δ=0.10(s,3H),0.11 (s,3H),0.92 (s,9H),1.69~1.70 (m,1H),1.93-2.07 (m,1H),3.51 (d,J=4.8,1H),3.86(d,J=3.2,1H),3.87 (dd,J=3.2,9.2,1H),3.91~3.96 (m,1H),4.01~4.06 (m,1H),5.05 (t,J=4.6,1H),7.22~7.26(m,1H),7.31~7.37 (m,2H),7.59 (dd,J=1.2,7.6,1H)

[0796] Preparation Example 350: (3R,4R)-3,4-dihydroxy-4-(2-chlorophenyl)butyl pivalate [ka] The title compound (3.2 g, 70-95%) was obtained in essentially the same manner as in Preparation 349, except that (E)-4-(2-chlorophenyl)but-3-enylpivalate (Preparation Example 348) was used instead of (E)-tert-butyldimethyl-4-(2-chlorophenyl)but-3-enyloxy)silane (Preparation Example 347).

[0797] 1H NMR (400MHz, CDCl3): δ=1.19(s,9H),1.76~1.84 (m,1H),1.90~1.98 (m,1H),2.70 (d,J=4.4,1H),2.86 (d,J=5.2,1H),3.84~3.90(m,1H),4.14~4.21 (m,1H),4.35~4.41 (m,1H),5.05 (t,J=5.0,1H),7.23~7.39 (m,3H),7.54(dd,J=1.6,7.6,1H)

[0798] Preparation Example 351: tert-butyl(2-((4R,5R)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)dimethylsilane [ka] The title compound (0.8 g, 70-95%) was obtained in essentially the same manner as in Preparation 284, except that (1R,2R)-4-(tert-butyldimethylsilyloxy)-1-(2-chlorophenyl)butane-1,2-diol (Preparation Example 349) was used instead of (1R,2R)-4-(tert-butyldimethylsilyloxy)-1-phenylbutane-1,2-diol (Preparation Example 282).

[0799] 1 H NMR (400MHz,CDCl3):δ=0.02(s,3H),0.07 (s,3H),0.86 (s,9H),1.50 (s,3H),1.58 (s,3H),1.82-1.99 (m,2H),3.68~3.78(m,2H),3.95 (dt,J=3.3,8.7,1H),5.16 (d,J=8.4,1H),7.21~7.27(m,1H),7.31~7.38 (m,2H),7.60 (dd,J=1.6,7.6,1H)

[0800] Preparation 352: 2-((4R,5R)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethanol [ka] The title compound (0.7 g, 80-95%) was obtained in essentially the same manner as in Preparation 285, except that tert-butyl(2-((4R,5R)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)dimethylsilane (Preparation Example 351) was used instead of tert-butyl(2-((4R,5R)-5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)dimethylsilane (Preparation Example 284).

[0801] 1 H NMR (400MHz,CDCl3): δ=1.56(s,3H),1.62 (s,3H),1.92-2.04 (m,2H),2.26 (q,J=3.7,1H),3.75~3.90 (m,2H),3.94 (td,J=3.9,8.5,1H),5.23(d,J=15.6,1H),7.22~7.27 (m,1H) 7.33~7.39 (m,2H),7.62 (dd,J=1.6,7.6,1H)

[0802] Preparation 353: (1S,2S)-4-(tert-butyldimethylsilyloxy)-1-(2-chlorophenyl)butane-1,2-diol [ka] The title compound (0.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 286, except that (E)-tert-butyldimethyl(4-(2-chlorophenyl)but-3-enyloxy)silane (Preparation Example 347) was used instead of (E)-tert-butyldimethyl(4-phenylbut-3-enyloxy)silane (Preparation Example 280).

[0803] 1H NMR (400MHz, CDCl3): δ=1.19(s,9H),1.76~1.84 (m,1H),1.90-1.98 (m,1H),2.70 (d,J=4.4,1H),2.86 (d,J=5.2,1H),3.84~3.90(m,1H),4.14~4.21 (m,1H),4.35~4.41 (m,1H),5.05 (t,J=5.0,1H),7.23~7.39 (m,3H),7.54(dd,J=1.6,7.6,1H)

[0804] Preparation Example 354: (3S,4S)-3,4-dihydroxy-4-(2-chlorophenyl)butyl pivalate [ka] The title compound (3.0 g, 70-95%) was obtained in essentially the same manner as in Preparation 353, except that (E)-4-(2-chlorophenyl)but-3-enylpivalate (Preparation Example 348) was used instead of ((E)-tert-butyldimethyl(4-(2-chlorophenyl)but-3-enyloxy)silane (Preparation Example 347).

[0805] 1 H NMR (400MHz, CDCl3): δ=1.19(s,9H),1.76-1.84 (m,1H),1.90-1.98 (m,1H),2.70 (d,J=4.4,1H),2.86 (d,J=5.2,1H),3.84~3.90(m,1H),4.14~4.21 (m,1H),4.35~4.41 (m,1H),5.05 (t,J=5.0,1H),7.23-7.39 (m,3H),7.54(dd,J=1.6,7.6,1H)

[0806] Preparation Example 355: tert-butyl(2-((4S,5S)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)dimethylsilane [ka] The title compound (0.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 351, except that (1S,2S)-4-(tert-butyldimethylsilyloxy)-1-(2-chlorophenyl)butane-1,2-diol (Preparation Example 353) was used instead of (1R,2R)-4-(tert-butyldimethylsilyloxy)-1-(2-chlorophenyl)butane-1,2-diol (Preparation Example 349).

[0807] 1 H NMR (400MHz,CDCl3):δ=0.02(s,3H),0.07 (s,3H),0.86 (s,9H),1.50 (s,3H),1.58 (s,3H),1.82~1.99(m,2H),3.68~3.78 (m,2H),3.95 (dt,J=3.3,8.7,1H),5.16(d,J=8.4,1H),7.21~7.27 (m,1H),7.31~7.38(m,2H),7.60 (dd,J=1.6,7.6,1H)

[0808] Preparation 356: 2-((4S,5S)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethanol [ka] The title compound (0.3 g, 80-95%) was obtained in essentially the same manner as in Preparation 352, except that tert-butyl(2-((4R,5R)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)dimethylsilane (Preparation Example 355) was used instead of tert-butyl(2-((4R,5R)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)dimethylsilane (Preparation Example 351).

[0809] 1H NMR (400MHz,CDCl3): δ=1.56(s,3H),1.62 (s,3H),1.92-2.04 (m,2H),2.26 (q,J=3.7,1H),3.75~3.90 (m,2H),3.94 (td,J=3.9,8.5,1H),5.23(d,J=15.6,1H),7.22~7.27 (m,1H),7.33~7.39 (m,2H),7.62 (dd,J=1.6,7.6,1H)

[0810] Preparation 357: 2-((4R,5R)-2,2-diethyl-5-(2-chlorophenyl)-1,3-dioxolan-4-yl)ethyl pivalate [ka] The title compound (0.8 g, 70-95%) was obtained in essentially the same manner as in Preparation 290, except that (3R,4R)-3,4-dihydroxy-4-(2-chlorophenyl)butyl pivalate (Preparation Example 350) was used instead of (3R,4R)-3,4-dihydroxy-4-phenylbutyl pivalate (Preparation Example 283).

[0811] 1 H NMR (400MHz, CDCl3): δ=1.15(s,9H),1.76 (q,J=7.6,2H),1.84~1.90 (m,2H),2.00~2.07 (m,2H),3.85 (dt,J=3.7,8.5,1H),4.14~4,27(m,2H),5.17 (d,J=8.4,1H),7.22~7.28 (m,1H),7.32~7.38 (m,2H),7.64 (dd,J=1.4,7.8,1H)

[0812] Preparation 358: 2-((4R,5R)-2,2-diethyl-5-(2-chlorophenyl)-1,3-dioxolan-4-yl)ethyl pivalate [ka] The title compound (0.6 g, 80-95%) was obtained in essentially the same manner as in Preparation Example 291, except that 2-((4R,5R)-2,2-diethyl-5-(2-chlorophenyl)-1,3-dioxolan-4-yl)ethyl pivalate (Preparation Example 357) was used instead of 2-((4R,5R)-2,2-diethyl-5-phenyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation Example 290).

[0813] 1 H NMR (400MHz,CDCl3): δ=1.02(t,J=7.4,3H),1.08 (t,J=7.4,3H),1.80 (q,J=7.5,2H),1.86-1.91 (m,2H),1.96-2.00 (m,2H),2.37(q,J=3.7,1H),3.76~8.95 (m,3H),5.23 (d,J=8.4. 1H),7.25~7.27 (m,1H),7.32~7.39 (m,2H),7.65(dd,J=1.8,7.8,1H)

[0814] Preparation 359: 2-((2R,3R)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate [ka] The title compound (0.8 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 357, except that cyclopentanone was used instead of 3-pentanone.

[0815] 1 H NMR (400MHz, CDCl3): δ=1.17(s,9H),1.58-2.02 (m,10H),3.86 (ddd,J=3.8,8.2,8.2,1H),4.11~4.28 (m,2H),5.13 (d,J=8.0,1H),7.20~7.39(m,3H),7.58 (dd,J=1.6,8.0,1H)

[0816] Preparation 360: 2-((2R,3R)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethanol [ka] The title compound (0.5 g, 80-95%) was obtained in essentially the same manner as in Preparation 358, except that 2-((2R,3R)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate (Preparation Example 359) was used instead of 2-((4R,5R)-2,2-diethyl-5-(2-chlorophenyl)-1,3-dioxolan-4-yl)ethyl pivalate (Preparation Example 357).

[0817] 1 H NMR (400MHz,CDCl3): δ=1.72-1.90(m,4H),1.93~1.98 (m,6H),2.28 (q,J=3.7,1H),3.76~3.93 (m,3H),5.18 (d,J=8.0,1H),7.24~7.29(m,1H),7.32~7.38 (m,2H),7.60 (dd,J=1.8,7.8,1H)

[0818] Preparation 361: 2-((2R,3R)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate [ka] The title compound (1.0 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 359, except that cyclohexanone was used instead of cyclopentanone.

[0819] 1H NMR (400MHz, CDCl3): δ=1.15(s,9H),1.70-1.94 (m,10H),2.06~2.09 (m,2H),3.86 (dt,J=3.5,8.5,1H),4,16-4.26 (m,2H),5.18(d,J=8.4,1H),7.22~7.28 (m,1H),7.32~7.38 (m,2H),7.61 (dd,J=1.4,7.8,1H)

[0820] Preparation 362: 2-((2R,3R)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethanol [ka] The title compound (0.6 g, 80-95%) was obtained in essentially the same manner as in Preparation 360, except that 2-((2R,3R)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate (Preparation Example 359) was replaced with 2-((2R,3R)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate (Preparation Example 361).

[0821] 1 H NMR (400MHz,CDCl3): δ=1.42~1.50(m,2H),1.63-1.77 (m,5H),1.82~1.89 (m,5H),2.41 (q,J=3.9,1H),3.78~3.96 (m,3H),5.25(d,J=8.4,1H) 7.21~7.28 (m,1H),7.32~7.38 (m,2H),7.63 (dd,J=1.4,7.8,1H)

[0822] Preparation 363: 2-((4S,5S)-2,2-diethyl-5-(2-chlorophenyl)-1,3-dioxolan-4-yl)ethyl pivalate [ka] The title compound (0.7 g, 70-95%) was obtained in essentially the same manner as in Preparation 357, except that (3S,4S)-3,4-dihydroxy-4-(2-chlorophenyl)butyl pivalate (Preparation Example 354) was used instead of (3R,4R)-3,4-dihydroxy-4-(2-chlorophenyl)butyl pivalate (Preparation Example 350).

[0823] 1 H NMR (400MHz, CDCl3): δ=1.15(s,9H),1.76 (q,J=7.6,2H),1.84~1.90 (m,2H),2.00~2.07 (m,2H),3.85 (dt,J=3.7,8.5,1H),4.14~4.27(m,2H),5.17 (d,J=8.4,1H),7.22~7.28 (m,1H),7.32~7.38 (m,2H),7.64 (dd,J=1.4,7.8,1H)

[0824] Preparation 364: 2-((4S,5S)-2,2-diethyl-5-(2-chlorophenyl-)-1,3-dioxolan-4-yl)ethanol [ka] The title compound (0.5 g, 80-95%) was obtained in essentially the same manner as in Preparation 358, except that 2-((4S,5S)-2,2-diethyl-5-(2-chlorophenyl)-1,3-dioxolan-4-yl)ethyl pivalate (Preparation Example 363) was used instead of 2-((4R,5R)-2,2-diethyl-5-(2-chlorophenyl)-1,3-dioxolan-4-yl)ethyl pivalate (Preparation Example 357).

[0825] 1H NMR (400MHz,CDCl3): δ=1.02(t,J=7.4,3H),1.08 (t,J=7.4,3H),1.80 (q,J=7.5,2H),1.86~1.91 (m,2H),1.96-2.00 (m,2H),2.37(q,J=3.7,1H),3.76~3.95 (m,3H),5.23 (d,J=8.4,1H),7.25~7.27 (m,1H),7.32~7.39 (m,2H),7.65(dd,J=1.8,7.8,1H)

[0826] Preparation 365: 2-((2S,3S)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate [ka] The title compound (0.6 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 363, except that cyclopentanone was used instead of 3-pentanone.

[0827] 1 H NMR (400MHz, CDCl3): δ=1.17(s,9H),1.58-2.02 (m,10H),3.86 (ddd,J=3.8. 8.2,8.2,1H),4.11~4.28(m,2H),5.13 (d,J=8.0,1H),7.20~7.39 (m,3H),7.58 (dd,J=1.6,8.0,1H)

[0828] Preparation 366: 2-((2S,3S)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethanol [ka] The title compound (0.4 g, 80-95%) was obtained in essentially the same manner as in Preparation 364, except that 2-((2S,3S)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate (Preparation Example 365) was used instead of 2-((4S,5S)-2,2-diethyl-5-(2-chlorophenyl)-1,3-dioxolan-4-yl)ethyl pivalate (Preparation Example 363).

[0829] 1 H NMR (400MHz,CDCl3): δ=1.72-1.90(m,4H),1.93~1.98 (m,6H),2.28 (q,J=3.7,1H),3.76-3.93 (m,3H),5.18 (d,J=8.0,1H),7.24~7.29(m,1H),7.32~7.38 (m,2H),7.60 (dd,J=1.8,7.8,1H)

[0830] Preparation 367: 2-((2S,3S)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate [ka] The title compound (0.7 g, 60-85%) was obtained in substantially the same manner as in Preparation Example 366, except that cyclohexanone was used instead of cyclopentanone.

[0831] 1 H NMR (400MHz, CDCl3): δ=1.15(s,9H),1.70~1.94 (m,10H),2.06~2.09 (m,2H),3.86 (dt,J=3.5,8.5,1H),4.16~4.26 (m,2H),5.18(d,J=8.4,1H),7.22~7.28 (m,1H),7.32~7.38 (m,2H),7.61 (dd,J=1.4,7.8,1H)

[0832] Preparation 368: 2-((2R,3R)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethanol [ka] The title compound (0.4 g, 80-95%) was obtained in essentially the same manner as in Preparation 366, except that 2-((2S,3S)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethyl pivalate (Preparation Example 365) was replaced with 2-((2S,3S)-3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethyl pivalate (Preparation Example 367).

[0833] 1 H NMR (400MHz, CDCl3): δ=1.42~1.50(m,2H),1.63-1.77 (m,5H),1.82~1.89 (m,5H),2.41 (q,J=3.9,1H),3.78~3.96 (m,3H),5.25(d,J=8.4,1H),7.21-7.28 (m,1H),7.32~7.38 (m,2H),7.63 (dd,J=1.4,7.8,1H)

[0834] Preparation 369: (E)-1-(3(benzyloxy)prop-1-enyl)-2-chlorobenzene [ka] To a solution of (E)-3-(2-chlorophenyl)prop-2-en-1-ol (Preparation Example 1, 5.3 g, 31.6 mmol) in THF, NaH (60% in mineral oil, 0.91 g, 37.7 mmol) and benzyl bromide (4.12 mL, 34.8 mmol) were added sequentially at 0°C. The reaction mixture was stirred at room temperature for 18 hours. TLC showed complete consumption of SM. The reaction mixture was quenched with H2O at 0°C and then extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layers were washed with H2O, dried over MgSO4, and evaporated under reduced pressure. The crude compound was purified using a silica gel column to yield the title compound (4.94 g, 70-90%).

[0835] 1H NMR (400MHz,CDCl3): δ7.57(dd,J=7.76,2,1H),7.42~7.13 (m,3H),7.05 (d,J=16Hz,1H),6.37-6.30 (m,1H),4.62 (s,2H),4.26(dd,J=6,1.6,2H)

[0836] Preparation 370: (±)-2-(benzyloxymethyl)-3-(2-chlorophenyl)oxirane [ka] To a solution of (E)-1-(3-(benzyloxy)prop-1-enyl)-2-chlorobenzene (Preparation 369, 4.94 g, 22 mmol) in CHCl (110 ml) was added 3-chloroperoxybenzoic acid (70-75%, 8 g, 33 mol) portionwise at 0 °C. The mixture was stirred at room temperature for 18 h. TLC showed complete consumption of SM. The reaction mixture was quenched with H2O at 0 °C and extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layers were washed with saturated NaHCO3 and H2O, then dried over MgSO4 and evaporated under reduced pressure. The crude compound was purified on a silica gel column to yield the title compound (4.3 g, 60-80%).

[0837] 1 H NMR (400MHz, CDCl3): δ7.42~7.24(m,9H),4.68 (d,J=14.8,2H),4.18 (d,J=2Hz,1H),3.96 (dd,J=11.6,2.8Hz,1H),3.69-3.64(m,1H),3.14 (qt,J=2.4Hz,1H)

[0838] Preparation 371: (±)-3-(benzyloxy)-1-(2-chlorophenyl)-2-hydroxypropyl & (±)-3-(benzyloxy)-1-(2-chlorophenyl)-1-hydroxypropan-2-yl acetate [ka] To a solution of (±)-2-(benzyloxymethyl)-3-(2-chlorophenyl)oxirane (Preparation 370, 4.3 g, 15.6 mmol) in acetic acid (78 ml) was added cerium ammonium nitrate (1.71 g, 3.1 mmol) at room temperature. The mixture was stirred for 18 hours at room temperature. TLC showed complete consumption of SM. The reaction mixture was quenched with saturated NaHCO3 at 0 °C to pH 7 and extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layers were washed with H2O, dried over MgSO4, and evaporated under reduced pressure. The crude compound was purified by silica gel column to give the title compounds (1) (1.2 g, 23%) and (2) (1.8 g, 34%).

[0839] (1) 1 H NMR (400MHz,CDCl3) δ7.55-7.22(m,9H),5.41 (t,J=5Hz,1H) 5.33-5.29 (m,1H),4.61-4.47 (m,2H),3.70-3.63 (m,2H,-OH),2.09(s,3H) (2) 1 H NMR (400MHz,CDCl3): δ7.46-7.24(m,9H),6.31 (d,J=5.6Hz,1H),4.55 (d,J=9.6Hz,2H),4.24~4.22 (m,1H),3.67-3.55 (m,2H),2.52(d,J=5.2Hz,-OH),2.10 (s,3H)

[0840] Preparation Example 372: (±)-3-(benzyloxy)-1-(2-chlorophenyl)propane-1,2-diol (anti mixture) [ka] To a solution of (±)-3-(benzyloxy)-1-(2-chlorophenyl)-2-hydroxypropyl and (±)-3-(benzyloxy)-1-(2-chlorophenyl)-1-hydroxypropan-2-yl acetate (Preparation 371, 3 g, 8.9 mmol) in MeOH (36 mL) and H₂O (4 mL) was added K₂CO₃ (3.69 g, 26.7 mmol) at 0°C. The mixture was stirred for 1.5 h at 0°C. TLC showed complete consumption of SM. The reaction mixture was quenched with H₂O at 0°C and extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layers were washed with H₂O, dried over MgSO₄, and evaporated under reduced pressure. The crude compound was purified using a silica gel column to yield the title compound (2.4 g, 80-95%).

[0841] 1 H NMR (400MHz,CDCl3): δ7.50(dd,J=7.6,1.2Hz,1H),7.35-7.19 (m,8H),5.28 (t,J=4.8Hz,1H),4.46 (d,J=6Hz,2H),4.18-4.13(m,1H),3.55-3.42 (m,3H,-OH),3.02 (d,J=5.2Hz,-OH)

[0842] Preparation 373: (±)-4-(benzyloxymethyl)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane [ka] To a solution of (±)-3-(benzyloxy)-1-(2-chlorophenyl)propane-1,2-diol (Preparation 372, 2.4 g, 8.2 mmol) in CHCl (40 mL) were added p-toluenesulfonyl chloride (15.2 g, 0.08 mmol) and 2,2-dimethoxypropane (8.4 mL, 9.84 mmol) sequentially at 0°C. The mixture was stirred at room temperature for 1.5 h. TLC showed complete consumption of sulfonyl methylcellulose. The reaction mixture was quenched with H₂O and extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layers were washed with H₂O, dried over MgSO₄, and evaporated under reduced pressure. The crude compound was purified on a silica gel column to yield the title compound (2.2 g, 75-90%).

[0843] 1 H NMR (400MHz,CDCl3): δ7.61(dd,J=7.4,1.6Hz,1H),7.35-7.16 (m,8H),5.63 (d,J=6.8,1H),4.88-4.78 (m,1H),4.26 (d,J=12Hz,2H),3.14-3.06(m,2H),1.66 (s,3H),1.53 (s,3H)

[0844] Preparation 374: 5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (SR&RS mixture) [ka] To (±)-4-(benzyloxymethyl)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane (Preparation 375, 2.2 g, 6.6 mmol) in EtOAc (33 mL) was added 10% Pd / C on carbon (0.11 g) at room temperature. The mixture was stirred at room temperature under H2 (g) for 1 hour. TLC showed complete consumption of SM. The reaction mixture was filtered through a pad of Celite and evaporated under reduced pressure. The crude compound was purified using a silica gel column to give the title compound (1.5 g, 80-95%).

[0845] 1H NMR (400MHz, CDCl3): δ7.61(dd,J=7.4,1.6,1H),7.35-7.16 (m,8H),5.63 (d,J=6.8Hz,1H),4.83-4.78 (m,1H),4.26 (d,J=12,2H),3.14-3.06(m,2H),1.66 (s,3H),1.53 (s,3H)

[0846] Preparation 375: (2R,3R)-2-(benzyloxymethyl)-3-(2-chlorophenyl)oxirane [ka] A solution of (E)-1-(3-(benzyloxy)prop-1-enyl)-2-chlorobenzene (Preparation Example 369, 4.16 g, 18.58 mmol) and 1,2;4,5-di-O-isopropylidene-β-D-erythro-2,3-hexodiulo-2,6-pyranose (5.76 g, 22.30 mmol) in ACN-DMM (3:1, v / v) (185 ml) was added to the buffer (4 × 10 -4 185 ml of 0.2 M K2CO3-AcOH in MEDTA aqueous solution (buffer pH = 8.0) and Bu4NHSO4 (0.26 g, 0.75 mmol) were added. The mixture was cooled to 0 °C and then diluted with 4 × 10 -4 A solution of oxone (15.76 g, 25.64 mmol) in aqueous MEDTA (100 mL) and a solution of KCO (13.6 g, 98.47 mmol) in HO (100 mL) were added dropwise via syringe pump for 3.5 h at 0 °C. The reaction mixture was stirred for 14 h at 0 °C. The reaction mixture was quenched with HO and extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layers were washed with HO, dried over MgSO, and evaporated under reduced pressure. The crude compound was purified using a silica gel column to yield the title compound (2.9 g, 50-65%).

[0847] 1H NMR (400MHz,CDCl3): δ3.14(qt,J=2.4Hz,1H) 3.69-3.64 (m,1H),3.96 (dd,J=11.6,2.8Hz,1H),4.18 (d,J=2Hz,1H),4.68(d,J=14.8,2H),7.42~7.24 (m,9H)

[0848] Preparation 376: (1S,2R)-3-(benzyloxy)-1-(2-chlorophenyl)-2-hydroxypropyl acetate [ka] To a solution of (2R,3R)-2-(benzyloxymethyl)-3-(2-chlorophenyl)oxirane (Preparation 375, 2.9 g, 10.55 mmol) in acetic acid (55 ml) was added cerium ammonium nitrate (1.15 g, 2.11 mmol) at room temperature. The mixture was stirred for 18 hours at room temperature. TLC showed complete consumption of SM. The reaction mixture was quenched with saturated NaHCO3 at 0 °C to pH 7 and extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layers were washed with H2O, dried over MgSO4, and evaporated under reduced pressure. The crude compound was purified on a silica gel column to yield the title compound (1.2 g, 30-50%).

[0849] 1 H NMR (400MHz,CDCl3): δ2.10(s,3H),2.52 (d,J=5.2Hz,-OH),3.67-3.55 (m,2H),4.24~4.22 (m,1H),4.55 (d,J=9.6Hz,2H),6.31(d,J=5.6Hz,1H),7.46-7.24 (m,9H)

[0850] Preparation 377: (1S,2R)-3-(benzyloxy)-1-(2-chlorophenyl)propane-1,2-diol [ka] To a solution of (1S,2R)-3-(benzyloxy)-1-(2-chlorophenyl)-2-hydroxypropyl acetate (Preparation 376, 1.2 g, 3.58 mmol) in MeOH (16.2 mL) and HO (1.8 mL) was added KCO (1.48 g, 10.74 mmol) at 0 °C. The mixture was stirred for 1.5 h at 0 °C. TLC showed complete consumption of SM. The reaction mixture was quenched with HO at 0 °C and extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layers were washed with HO, dried over MgSO, and evaporated under reduced pressure. The crude compound was purified on a silica gel column to yield the title compound (1.0 g, 80-100%).

[0851] 1 H NMR (400MHz,CDCl3): δ3.02(d,J=5.2Hz,1H),3.55-3.42 (m,3H,-OH),4.18-4.13 (m,1H),4.46 (d,J=6Hz,2H),5.28 (t,J=4.8Hz,1H),7.35-7.19(m,8H),7.50 (dd,J=7.6,1.2Hz,1H)

[0852] Preparation 378: (4R,5S)-4-(benzyloxymethyl)-5-(2-chlorophenyl)-1,3-dioxolane [ka] The title compound (0.77 g, 80-100%) was obtained in essentially the same manner as in Preparation 373, except that (1S,2R)-3-(benzyloxy)-1-(2-chlorophenyl)propane-1,2-diol (Preparation Example 377) was used instead of (±)-3-(benzyloxy)-1-(2-chlorophenyl)propane-1,2-diol (Preparation Example 372).

[0853] 1H NMR (400MHz,CDCl3): δ1.53(s,3H),1.66 (s,3H),3.14-3.06 (m,2H),4.26 (d,J=12Hz,2H),4.83-4.78 (m,1H),5.63 (d,J=6.8,1H),7.35-7.16(m,8H),7.61 (dd,J=7.4,1.6Hz,1H)

[0854] Preparation 379: ((4R,5S)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (0.58 g, 80-100%) was obtained in essentially the same manner as in Preparation 374, except that ((4R,5S)-4-(benzyloxymethyl)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane (Preparation Example 378) was used instead of (±)-4-(benzyloxymethyl)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane (Preparation Example 373).

[0855] 1 H NMR (400MHz,CDCl3): δ1.66(s,3H),1.53 (s,3H),3.14-3.06 (m,2H),4.26 (d,J=12,2H),4.83-4.78 (m,1H),5.63 (d,J=6.8Hz,1H),7.35-7.16(m,8H),7.61 (dd,J=7.4,1.6,1H)

[0856] Preparation 380: (E)-Ethyl-3-(2,4-dichlorothiazol-5-yl)acrylate [ka] To a stirred solution of 2,4-dichlorothiazole-5-carbaldehyde (5.0 g, 27.5 mmol) in THF (200 mL) was added triethylphosphonoacetic acid (6.6 mL, 32.9 mmol), lithium hydroxide (0.79 mL, 3.9 mmol), and 5 g of 4A molecular sieves at room temperature under N2. The mixture was stirred for 3 h. The resulting mixture was diluted with EtOAc, washed with water, dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to yield the title compound (6.1 g, 80-95%).

[0857] 1 H NMR (400MHz,DMSO): δ=1.22 (q,J=12.5,3H),4.23(q,J=7.0,2H),6.54 (d,J=16,1H),7.54 (d,J=16,1H)

[0858] Preparation 381: (2S,3S)-ethyl-3-(2,4-dichlorothiazol-5-yl)-2,3-dihydroxypropanoate [ka] The title compound (3.94 g, 50-70%) was obtained in substantially the same manner as in Preparation 3, except that (E)-ethyl-3-(2,4-dichlorothiazol-5-yl)acrylate (Preparation Example 380) was used instead of (E)-1-chloro-2-(3-(methoxymethoxy)prop-1-enylbenzene) (Preparation Example 2).

[0859] 1 H NMR (400MHz,DMSO): δ=1.22 (q,J=12.5,3H),4.18(q,J=7.0,2H),4.20 (dd,J=2.4,J=7.6,1H),5.19 (dd,J=2.6,J=5.8,1H),6.03 (d,J=7.6,1H),6.37(d,J=5.6,1H)

[0860] Preparation 382: (4S,5S)-ethyl-5-(2,4-dichlorothiazol-5-yl)-2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (0.13 g, 65-80%) was obtained in essentially the same manner as in Preparation 26, except that (2S,3S)-ethyl-3-(2,4-dichlorothiazol-5-yl)-2,3-dihydroxypropanoate (Preparation Example 381) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (Preparation Example 25).

[0861] 1 H NMR (400MHz,DMSO):δ=1.20(t,J=7.2,3H),1.42 (s,3H),1.49 (s,3H),4.18 (m,2H),4.66 (d,J=6.8,1H),5.44 (d,J=6.8,1H)

[0862] Preparation 383: ((4R,5S)-5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (0.05 g, 50-70%) was obtained in essentially the same manner as in Preparation 27, except that (4S,5S)-ethyl-5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 382) was used instead of (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 26).

[0863] 1H NMR (400MHz,DMSO): δ=1.42 (d,J=6.0,6H),3.59(m,1H),3.67 (m,1H),3.97 (m,1H),5.04 (t,J=5.4,1H),5.10 (d,J=8.4,1H)

[0864] Preparation 384: (2R,3R)-ethyl-3-(2,4-dichlorothiazol-5-yl)-2,3-dihydroxypropanoate [ka] The title compound (3.9 g, 50-70%) was obtained in substantially the same manner as in Preparation Example 381, except that (DHQ)2-PHAL was used instead of (DHQD)2-PHAL.

[0865] 1 H NMR (400MHz,DMSO): δ=1.22 (q,J=12.5,3H),4.18(q,J=7.0,2H),4.20 (dd,J=2.4,J=7.6,1H),5.19 (dd,J=2.6,J=5.8,1H),6.03 (d,J=7.6,1H),6.37(d,J=5.6,1H)

[0866] Preparation 385: (4R,5R)-ethyl-5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (0.13 g, 65-80%) was obtained in essentially the same manner as in Preparation 382, ​​except that (2R,3R)-ethyl-3-(2,4-dichlorothiazol-5-yl)-2,3-dihydroxypropanoate (Preparation Example 384) was used instead of (2S,3S)-ethyl-3-(2,4-dichlorothiazol-5-yl)-2,3-dihydroxypropanoate (Preparation Example 381).

[0867] 1H NMR (400MHz,DMSO):δ=1.20(t,J=7.2,3H),1.42 (s,3H),1.49 (s,3H),4.18 (m,2H),4.66 (d,J=6.8,1H),5.44 (d,J=6.8,1H)

[0868] Preparation 386: ((4S,5R)-5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (0.05 g, 50-70%) was obtained in essentially the same manner as in Preparation 383, except that (4R,5R)-ethyl-5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 385) was used instead of (4S,5S)-ethyl-5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 382).

[0869] 1 H NMR (400MHz,DMSO): δ=1.42 (d,J=6.0,6H),3.59(m,1H),3.67 (m,H),3.97 (m,1H),5.04 (t,J=5.4,1H),5.10 (d,J=8.4,1H)

[0870] Preparation 387: (E)-Ethyl-3-(2-chlorothiazol-5-yl)acrylate [ka] The title compound (4.7 g, 80-95%) was obtained in substantially the same manner as in Preparation Example 380, except that 2-chlorothiazole-5-carbaldehyde was used instead of 2,4-dichlorothiazole-5-carbaldehyde.

[0871] 1H NMR (400MHz,DMSO): δ=1.25 (t,J=7.0,3H),4.19(q,J=7.2,2H),6.40 (d,J=16,1H),7.81 (d,J=16,1H),8.11 (s,1H)

[0872] Preparation 388: (2S,3S)-ethyl-3-(2-chlorothiazol-5-yl)-2,3-dihydroxypropanoate [ka] The title compound (4.1 g, 50-70%) was obtained in essentially the same manner as in Preparation 381, except that (E)-ethyl-3-(2-chlorothiazol-5-yl)acrylate (Preparation Example 387) was used instead of (E)-ethyl-3-(2,4-dichlorothiazol-5-yl)acrylate (Preparation Example 380).

[0873] 1 H NMR (400MHz,DMSO):δ=1.20(t,J=7.0,3H),4.12 (q,J=7.2,2H),5.18 (d,J=1.6,1H),5.87 (s,1H),6.12 (s,1H),7.63(s,1H)

[0874] Preparation 389: (4S,5S)-ethyl-5-(2-chlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.0 g, 65-80%) was obtained in essentially the same manner as in Preparation 382, ​​except that (2S,3S)-ethyl-3-(2-chlorothiazol-5-yl)-2,3-dihydroxypropanoate (Preparation Example 388) was used instead of (2S,3S)-ethyl-3-(2,4-dichlorothiazol-5-yl)-2,3-dihydroxypropanoate (Preparation Example 381).

[0875] 1H NMR (400MHz,DMSO):δ=1.44(d,J=16.8,3H),4.18 (m,2H),4.62 (d,J=7.6,1H),5.50 (d,J=7.2,1H),7.74 (s,1H)

[0876] Preparation 390: (4R,5S)-5-(2-chlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (0.84 g, 70-90%) was obtained in essentially the same manner as in Preparation 386, except that (4S,5S)-ethyl-5-(2-chlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 389) was used instead of (4R,5R)-ethyl-5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 385).

[0877] 1 H NMR (400MHz,DMSO): δ=1.40 (d,J=2.0,6H),3.59(q,J=4.7,2H),3.94 (m,1H),5.06 (t,J=6.6,1H),5.09 (d,J=0.8,1H),7.69 (s,1H)

[0878] Preparation 391: (2R,3R)-ethyl-3-(2-chlorothiazol-5-yl)-2,3-dihydroxypropanoate [ka] The title compound (3.9 g, 50-70%) was obtained in essentially the same manner as in Preparation 384, except that (E)-ethyl-3-(2-chlorothiazol-5-yl)acrylate (Preparation Example 387) was used instead of (E)-ethyl-3-(2,4-dichlorothiazol-5-yl)acrylate (Preparation Example 380).

[0879] 1H NMR (400MHz,DMSO):δ=1.20(t,J=7.0,3H),4.12 (q,J=7.2,2H),5.18 (d,J=1.6,1H),5.87 (s,1H),6.12 (s,1H),7.63(s,1H)

[0880] Preparation 392: (4R,5R)-ethyl-5-(2-chlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (0.73 g, 65-80%) was obtained in essentially the same manner as in Preparation 382, ​​except that (2R,3R)-ethyl-3-(2-chlorothiazol-5-yl)-2,3-dihydroxypropanoate (Preparation Example 391) was used instead of (2S,3S)-ethyl-3-(2,4-dichlorothiazol-5-yl)-2,3-dihydroxypropanoate (Preparation Example 381).

[0881] 1 H NMR (400MHz,DMSO):δ=1.44(d,J=16.8,3H),4.18 (m,2H),4.62 (d,J=7.6,1H),5.50 (d,J=7.2,1H),7.74 (s,1H)

[0882] Preparation 393: (4S,5R)-5-(2-chlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (0.60 g, 70-90%) was obtained in essentially the same manner as in Preparation 386, except that (4R,5R)-ethyl-5-(2-chlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 392) was used instead of (4R,5R)-ethyl-5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 385).

[0883] 1 H NMR (400MHz,DMSO): δ=1.40 (d,J=2.0,6H),3.59(q,J=4.7,2H),3.94 (m,1H),5.06 (t,J=6.6,1H),5.09 (d,J=0.8,1H),7.69 (s,1H)

[0884] Preparation 394: (E)-Ethyl-3-(4-methylthiazol-5-yl)acrylate [ka] The title compound (15 g, 80-95%) was obtained in substantially the same manner as in Preparation Example 380, except that 4-methylthiazole-5-carbaldehyde was used instead of 2,4-dichlorothiazole-5-carbaldehyde.

[0885] 1 H NMR (400MHz,DMSO):δ=1.25(t,J=7.0,3H),1.45 (s,3H),4.19 (q,J=7.0,2H),6.12 (d,J=16,1H),7.77 (d,J=16,1H),9.09(s,1H)

[0886] Preparation 395: (2S,3S)-ethyl-3-(4-methylthiazol-5-yl)-2,3-dihydroxypropanoate [ka] The title compound (4.0 g, 50-70%) was obtained in essentially the same manner as in Preparation 2, except that (E)-ethyl-3-(4-methylthiazol-5-yl)acrylate (Preparation Example 394) was used instead of (E)-ethyl-3-(2,4-dichlorothiazol-5-yl)acrylate (Preparation Example 381).

[0887] 1H NMR (400MHz,DMSO):δ=1.11(t,J=7.0,3H),1.43 (s,3H),4.04 (m,2H),5.11 (t,J=3.8,1H),5.70 (d,J=20.7,1H),5.92(d,J=4.0,1H),6.81 (s,1H),8.86 (s,1H)

[0888] Preparation 396: (4S,5S)-ethyl-5-(4-methylthiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (2.6 g, 55-70%) was obtained in essentially the same manner as in Preparation 382, ​​except that (2S,3S)-ethyl-3-(2,4-dichlorothiazol-5-yl)-2,3-dihydroxypropanoate (Preparation Example 395) was used instead of (2S,3S)-ethyl-3-(2,4-dichlorothiazol-5-yl)-2,3-dihydroxypropanoate (Preparation Example 381).

[0889] 1 H NMR (400MHz,DMSO):δ=1.17(t,J=3.6,3H),1.43 (s,3H),1.49 (s,3H),2.34 (s,3H),4.17 (q,J=7.0 2H),4.40 (d,J=14.0,1H),5.53(d,J=7.2,1H),9.01 (s,1H)

[0890] Preparation 397: (4R,5S)-5-(4-methylthiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (1.7 g, 70-90%) was obtained in essentially the same manner as in Preparation 386, except that (4S,5S)-ethyl-5-(4-methylthiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 396) was used instead of (4R,5R)-ethyl-5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 385).

[0891] 1 H NMR (400MHz,DMSO):δ=1.42(d,J=7.6,6H),2.36 (s,3H),3.58 (m,2H),3.80 (d,J=3.2,1H),5.02 (t,J=5.4,1H),5.17(d,J=8.4,1H),8.98 (s,1H)

[0892] Preparation 398: (2R,3R)-ethyl-3-(4-methylthiazol-5-yl)-2,3-dihydroxypropanoate [ka] The title compound (6.0 g, 50-70%) was obtained in essentially the same manner as in Preparation 384, except that (E)-ethyl-3-(4-methylthiazol-5-yl)acrylate (Preparation Example 394) was used instead of (E)-ethyl-3-(2,4-dichlorothiazol-5-yl)acrylate (Preparation Example 380).

[0893] 1 H NMR (400MHz,DMSO):δ=1.11(t,J=7.0,3H),1.43 (s,3H),4.04 (m,2H),5.11 (t,J=3.8,1H),5.70 (d,J=20.7,1H),5.92(d,J=4,0,1H),6.81 (s,1H),8.86 (s,1H)

[0894] Preparation 399: (4R,5R)-ethyl-5-(4-methylthiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (5.0 g, 65-80%) was obtained in essentially the same manner as in Preparation 382, ​​except that (2R,3R)-ethyl-3-(4-methylthiazol-5-yl)-2,3-dihydroxypropanoate (Preparation Example 398) was used instead of (2S,3S)-ethyl-3-(2,4-dichlorothiazol-5-yl)-2,3-dihydroxypropanoate (Preparation Example 381).

[0895] 1 H NMR (400MHz,DMSO):δ=1.17(t,J=3.6,3H),1.43 (s,3H),1.49 (s,3H),2.34 (s,3H),4,17 (q,J=7.0,2H),4.40 (d,J=14.0,1H),5.53(d,J=7.2,1H),9.01 (s,1H)

[0896] Preparation 400: (4S,5R)-5-(4-methylthiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol [ka] The title compound (4.1 g, 70-90%) was obtained in essentially the same manner as in Preparation 386, except that (4R,5R)-ethyl-5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 399) was used instead of (4R,5R)-ethyl-5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 385).

[0897] 1 H NMR (400MHz,DMSO):δ=1.42(d,J=7.6,6H),2.36 (s,3H),3.58 (m,2H),3.80 (d,J=3.2,1H),5.02 (t,J=5.4,1H),5.17(d,J=8.4,1H),8.98 (s,1H)

[0898] Preparation Example 401: (4R,5S)-ethyl-5-(2-chloro-4-methylthiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] To a stirred solution of (4R,5S)-5-(4-methylthiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Preparation 397, 3.1 g, 14.3 mmol) in THF (20 mL) was added n-butyllithium (14.3 mL, 35.7 mmol) and CCl4 (4.1 mL, 42.8 mmol) at -78 °C. The mixture was stirred for 0.5 h. The resulting mixture was diluted with EtOAc, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column to yield the title compound (2.8 g, 70-90%).

[0899] 1 H NMR (400MHz,DMSO):δ=1.40(d,J=5.6,6H),2.28 (s,3H),3.58 (m,2H),3.80 (m,1H),5.06 (m,1H),5.13 (d,J=8.4,1H)

[0900] Preparation 402: (4S,5R)-ethyl-5-(2-chloro-4-methylthiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate [ka] The title compound (1.5 g, 70-90%) was obtained in essentially the same manner as in Preparation 401, except that (4S,5R)-5-(4-methylthiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Preparation Example 400) was used instead of (4R,5S)-5-(4-methylthiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol (Preparation Example 397).

[0901] 1H NMR (400MHz,DMSO):δ=1.40(d,J=5.6,6H),2.28 (s,3H),3.58 (m,2H),3.80 (m,1H),5.06 (m,1H),5.13 (d,J=8.4,1H)

[0902] Preparation Example 403: (E)-Ethyl-3-(thiophen-3-yl)acrylate [ka] To a stirred solution of triethylphosphonoacetic acid (5.36 ml, 26.7 mmol) in THF (40 ml), t-BuOK (2 g, 26.7 mmol) was added dropwise at room temperature and stirred at the same temperature for 30 minutes. Thiophene-3-carbaldehyde (8 g, 26.7 mmol) was then added and stirred at 90°C for 30 minutes. The product was quenched with 1 M HCl solution. The resulting mixture was extracted with water using ethyl acetate. The combined organic layers were dried and purified by filtration (NaCl). 2S O4), filtered and concentrated. The residue was purified by silica gel column to give the title compound (3.9 g, 70-90%).

[0903] 1 H NMR (400MHz,CDCl3): δ=1.34(t,J=7.2,3H),4.26 (q,J=7.2,2H),6.31 (d,J=15.6,1H),6.89 (d,J=4,1H),7.69 (s,1H),7.73(d,J=4,1H),7.80 (d,J=15.6,1H)

[0904] Preparation Example 404: (2R,3S)-ethyl-2,3-dihydroxy-3-(thiophen-3-yl)propanoate [ka] The title compound (6.0 g, 60-80%) was obtained in essentially the same manner as in Preparation 384, except that (E)-ethyl-3-(thiophen-3-yl)acrylate (Preparation Example 403) was used instead of (E)-ethyl-3-(2,4-dichlorothiazol-5-yl)acrylate (Preparation Example 380).

[0905] 1 H NMR (400MHz,CDCl3): δ=1.34(t,J=7.2,3H),4.26 (q,J=7.2,2H),4.65 (d,J=5.5,1H),5.13 (d,J=5.5,1H),6.93 (dd,J=6.09,J=1.32,1H),7.47(dd,J=6.09,J=1.73,1H),7.88 (dd,J=1.73,J=1.32,1H)

[0906] Preparation Example 405: (4R,5S)-Ethyl-2,2-dimethyl-5-(thiophen-3-yl)-1,3-dioxolane-4-carboxylate [ka] The title compound (3.0 g, 65-80%) was obtained in essentially the same manner as in Preparation 382, ​​except that (2R,3S)-ethyl-2,3-dihydroxy-3-(thiophen-3-yl)propanoate (Preparation Example 404) was used instead of (2S,3S)-ethyl-3-(2,4-dichlorothiazol-5-yl)-2,3-dihydroxypropanoate (Preparation Example 381).

[0907] 1 H NMR (400MHz,CDCl3): δ=1.18(t,J=7.1,3H),1.41 (s,3H),1.43 (s,3H),4.16 (q,J=7.1,2H),4.21 (d,J=7.0,1H),4.94(d,J=7.0,1H),6.95 (dd,J=6.0,J=1.3,1H),7.48 (dd,J=6.0,J=1.7,1H),7.90 (dd,J=1.7.J=1.3,1H)

[0908] Preparation 406: ((4S,5S)-2,2-dimethyl-5-(thiophen-3-yl)-1,3-dioxolan-4-yl)methanol [ka] The title compound (2.2 g, 70-90%) was obtained in essentially the same manner as in Preparation 386, except that (4R,5R)-ethyl-2,2-dimethyl-5-(thiophen-3-yl)-1,3-dioxolane-4-carboxylate (Preparation Example 405) was used instead of (4R,5R)-ethyl-5-(2,4-dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (Preparation Example 385).

[0909] 1 H NMR (400MHz,CDCl3): δ=1.39(s,3H),1.42 (s,3H),3.47-3.6 (m,2H),3.84~3.88 (m,1H),4.82 (d,J=7.0,1H),6.93 (dd,J=6.1,J=1.3,1H),7.47(dd,J=6.1,J=1.7,1H,),7.89 (dd,J=1.7,J=1.3,1H)

[0910] Preparation Example 407: (E)-Ethyl-3-(5-chlorothiophen-2-yl)acrylate [ka] The title compound (4.0 g, 70-90%) was obtained in substantially the same manner as in Preparation Example 403, except that 5-chlorothiophene-3-carbaldehyde was used instead of thiophene-3-carbaldehyde.

[0911] 1 H NMR (400MHz,CDCl3): δ=1.36(t,J=7.2,3H),4.20 (q,J=7.2,2H),6.13 (d,J=15.6,1H),6.89 (d,J=4,1H),7.65 (d,J=15.6,1H),7.83(d,J=4.2,1H)

[0912] Preparation Example 408: (2R,3S)-ethyl-2,3-dihydroxy-3-(5-chlorothiophen-2-yl)propanoate [ka] The title compound (2.8 g, 60-80%) was obtained in substantially the same manner as in Preparation 404, except that (E)-ethyl-3-(thiophen-3-yl)acrylate (Preparation Example 403) was replaced with (E)-ethyl-3-(5-chlorothiophen-2-yl)acrylate (Preparation Example 407).

[0913] 1 H NMR (400MHz,CDCl3): δ1.34(t,J=7.2,3H),2.76 (d,J=8.4,1H),3.32 (d,J=5.6,1H),4.33 (q,J=7.2,2H),4.4 (dd,J=2.4,J=5.2,1H),5.16(dd,J=2,J=8,1H),6.82 (d,J=4,1H),6.88 (dd,J=0.8 J=3.6,1H)

[0914] Preparation Example 409: (4R,5S)-Ethyl-2,2-dimethyl-5-(5-chlorothiophen-2-yl)-1,3-dioxolane-4-carboxylate [ka] The title compound (0.85 g, 65-80%) was obtained in essentially the same manner as in Preparation 405, except that (2R,3S)-ethyl-2,3-dihydroxy-3-(thiophen-3-yl)propanoate (Preparation Example 404) was replaced with (2R,3S)-ethyl-2,3-dihydroxy-3-(5-chlorothiophen-2-yl)propanoate (Preparation Example 408).

[0915] 1H NMR (400MHz,CDCl3): δ=1.31(t,J=7.2 3H),1.54 (s,3H),1.58 (s,3H),4.29-4,36 (m,2H),4.42 (d,J=7.2,1H),5.29 (d,J=7.2,1H),6.81(q,J=4,1H),6.88 (d,J=3.2,1H)

[0916] Preparation 410: ((4S,5S)-2,2-dimethyl-...

Claims

1. A pharmaceutical composition for preventing or treating anxiety disorder or depressive disorder, comprising a sulfamate derivative compound of the following chemical formula 1 or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 Here, R 1 and R 2 are independently hydrogen, C 1 ~C 5 Alkyl, C 2 ~C 5 Alkenyl and C 6 ~C 10 aryl; or R 1 and R 2 is bonded to a carbon atom to form C 3 ~C 12 Form a cycloalkyl group or R 1 and R 2 combines with an oxygen atom to form a carbonyl group; A is optionally hydrogen, hydroxyl, C 1 ~C 5 Alkoxy, C 1 ~C 5 Alkyl, C 2 ~C 5 Alkenyl, C 6 ~C 10 Aryl, C 1 ~C 5 Alkoxycarbonyl, carboxyl, C 2 ~C 5 Achill, C 1 ~C 5 Alkylthio, cyano, nitro, amine, C 1 ~C 5 an aryl residue or a heterocyclic group substituted with one or more substituents selected from the group consisting of alkylamines and halogens; R 3 and R 4 are each independently hydrogen or C 1 ~C 3 With alkyl; l and m are each independently an integer from 0 to 4; Here, the anxiety disorder refers to generalized anxiety disorder, pan-anxiety disorder, phobia, panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD). Depressive disorders include major depressive disorder, dysthymic disorder, persistent major depressive disorder, premenstrual dysphoric disorder, and postpartum depression.

2. A is C 6 ~C 10 The pharmaceutical composition according to claim 1, wherein the aryl group represented by aryl group is an aryl group.

3. A is C 3 ~C 10 The pharmaceutical composition according to claim 1, wherein the heterocyclic group is represented by the heterocyclic group.

4. A is optionally hydrogen, halogen, C 1 ~C 5 Alkyl, nitro, amine and C 1 ~C 5 phenyl substituted with at least one substituent selected from the group consisting of alkylamines, optionally hydrogen, halogen, C 1 ~C 5 Alkyl and C 6 ~C 10 C substituted with at least one substituent selected from the group consisting of aryl 3 ~C 10 The pharmaceutical composition of claim 1, wherein the heterocyclic group is a heterocyclic group.

5. A is, 【Chemistry 2】 Selected from the group consisting of; where X is independently halogen, nitro, amine, or C 1 ~C 5 5. The pharmaceutical composition of claim 4, wherein said compound is selected from the group consisting of alkyl, n is an integer from 0 to 5, and Z is selected from S, O, or NH.

6. 6. The pharmaceutical composition of claim 5, wherein n is an integer from 0 to 2.

7. R 3 and R 4 2. The pharmaceutical composition of claim 1, wherein each is independently hydrogen or methyl.

8. 2. The pharmaceutical composition according to claim 1, wherein l and m are each independently an integer of 0 to 2.

9. 2. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of: (1) (5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (2) (5-(2-chlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate. (3) (5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (4) (3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (5) (3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (6) (5-(2-chlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate. (7) (5-(2-fluorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (8) (5-(2-fluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate. (9) (5-(2-fluorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (10) (3-(2-fluorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (11) (3-(2-fluorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (12) (5-(2-fluorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate. (13) (5-(2-iodophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (14) (5-(2-iodophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate. (15) (5-(2-iodophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (16) (3-(2-iodophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (17) (3-(2-iodophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (18) (5-(2-iodophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate. (19) (5-(2,4-dichlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (20) (5-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate. (21) (5-(2,4-dichlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (22) (3-(2,4-dichlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (23) (3-(2,4-dichlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (24) (5-(2,4-dichlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate. (25) (5-(2,6-dichlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (26) (5-(2,6-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate. (27) (5-(2,6-dichlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (28) (3-(2,6-dichlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (29) (3-(2,6-dichlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (30) (5-(2,6-dichlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate. (31) (5-(2-aminophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (32) (5-(2-aminophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate. (33) (5-(2-aminophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (34) (3-(2-aminophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (35) (3-(2-aminophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (36) (5-(2-aminophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate. (37) (5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (38) (5-(2-nitrophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate. (39) (5-(2-nitrophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (40) (3-(2-nitrophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (41) (3-(2-nitrophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (42) (5-(2-nitrophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate. (43) (5-(2-nitrophenyl)-2-oxo-1,3-dioxolan-4-yl)methylsulfamate. (44) (5-(2-methylphenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (45) (5-(2-methylphenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate. (46) (5-(2-methylphenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (47) (3-(2-methylphenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (48) (3-(2-methylphenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (49) (5-(2-methylphenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate. (50) (5-(2-methylaminophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl methylsulfamate. (51) (5-Phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (52) (5-Phenyl-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (53) (3-Phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (54) (3-Phenyl-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (55) 2-(5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate. (56) 2-(5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethylsulfamate. (57) 2-(3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate. (58) 2-(3-benzyl-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate. (59) (5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (60) (5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (61) (3-Benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (62) (3-Benzyl-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (63) (5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate: (64) (5-Phenyl-2,2-diethyl-1,3-dioxolan-4-yl)ethyl sulfamate. (65) (3-Phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate. (66) (3-Phenyl-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate. (67) 2-(5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate. (68) 2-(5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolan-4-yl)ethylsulfamate. (69) 2-(3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate. (70) 2-(3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate. (71) (5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (72) (5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (73) (3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (74) (3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (75) (5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate. (76) (5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)ethylsulfamate. (77) (3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate. (78) (3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate. (79) (5-(2,4-Dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (80) (5-(2-chlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (81) (2,2-Dimethyl-5-(4-methylthiazol-5-yl)-1,3-dioxolan-4-yl)methylsulfamate. (82) (2,2-Dimethyl-5-(2-chloro-4-methylthiazol-5-yl)-1,3-dioxolan-4-yl)methylsulfamate. (83) (2,2-Dimethyl-5-(thiophen-3-yl)-1,3-dioxolan-4-yl)methylsulfamate. (84) (2,2-Dimethyl-5-(5-chlorothiophen-2-yl)-1,3-dioxolan-4-yl)methylsulfamate. (85) (5-(3-chloropyridin-4-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (86) (5-(4-chloropyridin-3-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (87) (2,2-Dimethyl-5-(pyrimidin-5-yl)-1,3-dioxolan-4-yl)methylsulfamate. and (88) (2,2-Dimethyl-5-(2-chloropyrimidin-5-yl)-1,3-dioxolan-4-yl)methylsulfamate.

10. 2. The pharmaceutical composition of claim 1, wherein the compound is in the form of a racemate, an optical isomer, a partial stereoisomer, a mixture of optical isomers, or a mixture of partial stereoisomers.

11. 2. The pharmaceutical composition of claim 1, wherein the pharma- ceutically acceptable salt is prepared by reacting the compound with an inorganic acid, an organic acid, an amino acid, a sulfonic acid, an alkali metal or an ammonium ion.

12. Use of a pharmaceutical composition in the manufacture of a medicament for inducing anti-stress, anti-anxiety or anti-depressant activity, comprising a compound of the following formula 1 or a pharma- ceutically acceptable salt thereof: 【Chemistry 3】 Here, R 1 and R 2 are independently hydrogen, C 1 ~C 5 Alkyl, C 2 ~C 5 Alkenyl and C 6 ~C 10 aryl; or R 1 and R 2 is bonded to a carbon atom to form C 3 ~C 12 Form a cycloalkyl group or R 1 and R 2 combines with an oxygen atom to form a carbonyl group; A is optionally hydrogen, hydroxyl, C 1 ~C 5 Alkoxy, C 1 ~C 5 Alkyl, C 2 ~C 5 Alkenyl, C 6 ~C 10 Aryl, C 1 ~C 5 Alkoxycarbonyl, carboxyl, C 2 ~C 5 Achill, C 1 ~C 5 Alkylthio, cyano, nitro, amine, C 1 ~C 5 an aryl residue or a heterocyclic group substituted with one or more substituents selected from the group consisting of alkylamines and halogens; R 3 and R 4 are each independently hydrogen or C 1 ~C 3 With alkyl; l and m each independently represent an integer of 0 to 4.

13. A is C 6 ~C 10 The use according to claim 12, wherein the aryl group is represented by aryl group.

14. A is C 3 ~C 10 The use according to claim 12, wherein the heterocyclic group is represented by the heterocyclic group.

15. A is optionally hydrogen, halogen, C 1 ~ C 5 Alkyl, nitro, amine and C 1 ~ C 5 phenyl substituted with at least one substituent selected from the group consisting of alkylamines, optionally hydrogen, halogen, C 1 ~ C 5 Alkyl and C 6 ~C 10 C substituted with at least one substituent selected from the group consisting of aryl 3 ~C 10 13. The use according to claim 12, which is a heterocyclic group.

16. A is, 【Chemistry 4】 Selected from the group consisting of; where X is independently halogen, nitro, amine, or C 1 ~C 5 16. The use according to claim 15, wherein said alkyl is selected from the group consisting of: alkyl; n is an integer from 0 to 5; and Z is selected from S, O or NH.

17. 17. The use according to claim 16, wherein n is an integer from 0 to 2.

18. R 3 and R 4 The use according to claim 12, wherein each is independently hydrogen or methyl.

19. The use according to claim 12, wherein l and m are each independently an integer from 0 to 2.

20. 13. The use according to claim 12, wherein the compound is a compound selected from the group consisting of: (1) (5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (2) (5-(2-chlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate. (3) (5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (4) (3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (5) (3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (6) (5-(2-chlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate. (7) (5-(2-fluorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (8) (5-(2-fluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate. (9) (5-(2-fluorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (10) (3-(2-fluorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (11) (3-(2-fluorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (12) (5-(2-fluorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate. (13) (5-(2-iodophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (14) (5-(2-iodophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate. (15) (5-(2-iodophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (16) (3-(2-iodophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (17) (3-(2-iodophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (18) (5-(2-iodophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate. (19) (5-(2,4-dichlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (20) (5-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate. (21) (5-(2,4-dichlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (22) (3-(2,4-dichlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (23) (3-(2,4-dichlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (24) (5-(2,4-dichlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate. (25) (5-(2,6-dichlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (26) (5-(2,6-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate. (27) (5-(2,6-dichlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (28) (3-(2,6-dichlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (29) (3-(2,6-dichlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (30) (5-(2,6-dichlorophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate. (31) (5-(2-aminophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (32) (5-(2-aminophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate. (33) (5-(2-aminophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (34) (3-(2-aminophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (35) (3-(2-aminophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (36) (5-(2-aminophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate. (37) (5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (38) (5-(2-nitrophenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate. (39) (5-(2-nitrophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (40) (3-(2-nitrophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (41) (3-(2-nitrophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (42) (5-(2-nitrophenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate. (43) (5-(2-nitrophenyl)-2-oxo-1,3-dioxolan-4-yl)methylsulfamate. (44) (5-(2-methylphenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (45) (5-(2-methylphenyl)-2-methyl-1,3-dioxolan-4-yl)methylsulfamate. (46) (5-(2-methylphenyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (47) (3-(2-methylphenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (48) (3-(2-methylphenyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (49) (5-(2-methylphenyl)-2-phenyl-1,3-dioxolan-4-yl)methylsulfamate. (50) (5-(2-methylaminophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl methylsulfamate. (51) (5-Phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (52) (5-Phenyl-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (53) (3-Phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (54) (3-Phenyl-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (55) 2-(5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate. (56) 2-(5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethylsulfamate. (57) 2-(3-benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate. (58) 2-(3-benzyl-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate. (59) (5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (60) (5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (61) (3-Benzyl-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (62) (3-Benzyl-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (63) (5-phenyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate: (64) (5-Phenyl-2,2-diethyl-1,3-dioxolan-4-yl)ethyl sulfamate. (65) (3-Phenyl-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate. (66) (3-Phenyl-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate. (67) 2-(5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate. (68) 2-(5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolan-4-yl)ethylsulfamate. (69) 2-(3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate. (70) 2-(3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate. (71) (5-(2-chlorobenzyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (72) (5-(2-chlorobenzyl)-2,2-diethyl-1,3-dioxolan-4-yl)methylsulfamate. (73) (3-(2-chlorobenzyl)-1,4-dioxaspiro[4,4]nonan-2-yl)methylsulfamate. (74) (3-(2-chlorobenzyl)-1,4-dioxaspiro[4,5]decan-2-yl)methylsulfamate. (75) (5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethylsulfamate. (76) (5-(2-chlorophenyl)-2,2-diethyl-1,3-dioxolan-4-yl)ethylsulfamate. (77) (3-(2-chlorophenyl)-1,4-dioxaspiro[4,4]nonan-2-yl)ethylsulfamate. (78) (3-(2-chlorophenyl)-1,4-dioxaspiro[4,5]decan-2-yl)ethylsulfamate. (79) (5-(2,4-Dichlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (80) (5-(2-chlorothiazol-5-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (81) (2,2-Dimethyl-5-(4-methylthiazol-5-yl)-1,3-dioxolan-4-yl)methylsulfamate. (82) (2,2-Dimethyl-5-(2-chloro-4-methylthiazol-5-yl)-1,3-dioxolan-4-yl)methylsulfamate. (83) (2,2-Dimethyl-5-(thiophen-3-yl)-1,3-dioxolan-4-yl)methylsulfamate. (84) (2,2-Dimethyl-5-(5-chlorothiophen-2-yl)-1,3-dioxolan-4-yl)methylsulfamate. (85) (5-(3-chloropyridin-4-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (86) (5-(4-chloropyridin-3-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)methylsulfamate. (87) (2,2-Dimethyl-5-(pyrimidin-5-yl)-1,3-dioxolan-4-yl)methylsulfamate. and (88) (2,2-Dimethyl-5-(2-chloropyrimidin-5-yl)-1,3-dioxolan-4-yl)methylsulfamate.

21. 13. The use according to claim 12, wherein the compound is in the form of a racemate, an optical isomer, a partial stereoisomer, a mixture of optical isomers or a mixture of partial stereoisomers.

22. 13. The use according to claim 12, wherein the pharma- ceutically acceptable salt is prepared by reacting the compound with an inorganic acid, an organic acid, an amino acid, a sulfonic acid, an alkali metal or an ammonium ion.

23. Use of a pharmaceutical composition according to any one of claims 1 to 11 in the manufacture of a medicament for the prevention or treatment of an anxiety or depressive disorder, comprising: Here, the anxiety disorder refers to generalized anxiety disorder, pan-anxiety disorder, phobia, panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD). Depressive disorders include major depressive disorder, dysthymic disorder, persistent major depressive disorder, premenstrual dysphoric disorder, and postpartum depression.

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