Chiral synthesis of tertiary alcohols

Abstract

Disclosed herein are methods for preparing tertiary alcohols from optionally substituted phenyl ketones or optionally substituted pyridyl ketones, the methods comprising the use of chiral ligands and boron trifluoride etherate. The tertiary alcohols can be used to prepare synthetic forms of natural products and / or drugs.

Description

[0001] Incorporate any priority claim by reference

[0002] Any or all patent applications that identify a foreign or domestic priority claim against it in, for example, a patent application data sheet or request filed with this patent application are hereby incorporated by reference under 37 CFR 1.57 and Rules 4.18 and 20.6, including U.S. Provisional Patent Application No. 62 / 935,894, filed November 15, 2019, and No. 62 / 037,761, filed June 11, 2020. Background Technology Technical Field

[0003] This application relates to the fields of chemistry and medicine. More specifically, this document discloses methods for preparing tertiary alcohols. This document also discloses methods for using tertiary alcohols in the preparation of compounds that can be used as anticancer agents. Background Technology

[0005] Novel methods for preparing chiral compounds with high enantiomeric purity while minimizing undesirable byproducts are highly valuable. Chiral secondary and tertiary alcohols are commonly used to prepare synthetic forms of natural products and pharmaceuticals. Many methods exist for preparing chiral secondary alcohols. However, providing methods for chiral tertiary alcohols with high enantiomeric purity and high yields remains a challenge. Summary of the Invention

[0006] Some embodiments disclosed herein relate to a method for preparing a tertiary alcohol or a salt thereof, the method comprising mixing: an optionally substituted phenyl ketone or an optionally substituted pyridyl ketone or a salt of any of the foregoing, wherein when the phenyl ketone or pyridyl ketone is substituted, the phenyl ketone and pyridyl ketone are substituted by one or more substituents selected from the group consisting of: halogens, unsubstituted C 1-4 Alkyl and unsubstituted C 1-4 Alkyl group; zinc reagent selected from Et₂Zn, Me₂Zn, and Ph₂Zn; having the structure Chiral ligands, wherein each Ar can independently be an unsubstituted or substituted phenyl or an unsubstituted or substituted naphthyl group, wherein when Ar is a substituted phenyl or a substituted naphthyl group, the phenyl or naphthyl group can be substituted by one or more substituents independently selected from the group consisting of: halogens, unsubstituted C 1-4 Alkyl and unsubstituted C 1-4 Alkoxy groups; and BF3·OEt2.

[0007] Some embodiments disclosed herein relate to compounds of formula (G1-a) or salts thereof, having the following structures:

[0008]

[0009] Where X is Cl, Br, or I. In some embodiments, X is Cl. In some embodiments, X is Br. In some embodiments, X is I. Attached Figure Description

[0010] Figure 1 A representative X-ray powder diffraction (XRPD) pattern of form A of (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol is provided.

[0011] Figure 2 A representative X-ray powder diffraction (XRPD) pattern is provided for form B of (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol. Detailed Implementation

[0012] definition

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, publications, and other disclosures cited herein are incorporated herein by reference in their entirety unless otherwise stated. Where multiple definitions exist for terms herein, the definition in that section shall prevail unless otherwise stated.

[0014] As used herein, any “R” and “X” groups, such as but not limited to R 1a R 1b R 2a R 2b R 3a R 3b R 4b R 5b R 1g R 2g R 3g R 1h R 2h R 3h R 1j R 2j R 3j R 1k R 2k R 3k R 4k R 5k R 1l R 2l R 3l R 4l R 5l R 1m R 2m R 3m R4m R 5m X 1a X 2a X 3a X 4a X 1g X 1h X 1j X 2g X 3g X 4g X 2h X 3h X 4h X 2j X 3j and X 4j This indicates a substituent that can be attached to a specified atom. Such R and / or X groups may be generally referred to herein as "R" or "X" groups. If two "R" groups are described as "together," the R groups and the atoms to which they are attached can form cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclic compounds. For example, but not limited to, if NR a R b R of the group a and R b When indicated as "together," it means that they are covalently bonded to each other to form a ring:

[0015]

[0016] Furthermore, as an alternative, if two “R” groups are described as “joining together” with the atoms to which they are attached to form a ring, then the R groups are not limited to the previously defined variables or substituents.

[0017] As used in this article, where "a" and "b" are integers, "C" represents the integers. a To C b The term "C1 to C4 alkyl" refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclic group. That is, the ring of an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclic group may contain "a" to "b" (including the endpoints) of carbon atoms. Therefore, for example, "C1 to C4 alkyl" groups refer to all alkyl groups having 1 to 4 carbons, namely CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. If "a" and "b" are not specified for alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclic group, the widest range described in these definitions should be assumed.

[0018] As used herein, “alkyl” refers to a straight-chain or branched hydrocarbon chain containing a fully saturated (without double or triple bonds) hydrocarbon group. An alkyl group may have 1 to 20 carbon atoms (wherever it appears herein, numerical ranges such as “1 to 20” refer to every integer within a given range; for example, “1 to 20 carbon atoms” means that an alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but the definition of this invention also covers the term “alkyl” when no numerical range is specified). An alkyl group may also be a medium-sized alkyl group having 1 to 10 carbon atoms. An alkyl group may also be a lower alkyl group having 1 to 6 carbon atoms. The alkyl group of a compound may be named “C1-C4 alkyl” or similar designations. By way of example only, “C1-C4 alkyl” indicates the presence of one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted.

[0019] As used herein, "alkenyl" refers to an alkyl group that contains one or more double bonds in a straight-chain or branched hydrocarbon chain. Examples of alkenyl groups include allyl, vinylmethyl, and vinyl. Alkenyl groups can be unsubstituted or substituted.

[0020] As used herein, "alkynyl" refers to an alkyl group that contains one or more triple bonds in a straight-chain or branched hydrocarbon chain. Examples of alkynyl groups include ethynyl and propynyl. The alkynyl group can be unsubstituted or substituted.

[0021] As used herein, “cycloalkyl” refers to a fully saturated (without double or triple bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, these rings can be joined together in a fused form. As used herein, the term “fused” refers to two rings sharing two atoms and one bond. Cycloalkyl groups may contain 3 to 30 atoms in one or more rings, 3 to 20 atoms in one or more rings, 3 to 10 atoms in one or more rings, 3 to 8 atoms in one or more rings, or 3 to 6 atoms in one or more rings. Cycloalkyl groups may be unsubstituted or substituted. Typical monocyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthyl, dodecahydro-1H-phenanthryl, and tetradecylhydroanthrayl.

[0022] As used herein, “cycloalkenyl” refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring; however, if more than one double bond is present, the double bond cannot form a fully delocalized π-electron system throughout all rings (otherwise the group would be “aryl” as defined herein). Cycloalkynyl groups may contain 3 to 10 atoms in one or more rings, or 3 to 8 atoms in one or more rings. When composed of two or more rings, the rings may be fused together. Cycloalkenyl groups may be unsubstituted or substituted.

[0023] As used herein, "aryl" refers to a monocyclic or polycyclic aromatic ring system (including fused ring systems where two carbon rings share a chemical bond) with a fully delocalized π-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be C6 to C4. 14 aryl group, C6 to C 10 An aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group can be substituted or unsubstituted.

[0024] As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic ring system (a ring system with a fully delocalized π-electron system) containing one, two, three or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur). The number of atoms in the ring of a heteroaryl group can vary. For example, a heteroaryl group may contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Furthermore, the term “heteroaryl” includes fused ring systems in which two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, those described herein and the following: furan, furazon, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazolium, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cyclophosphine, and triazine. The heteroaryl group may be substituted or unsubstituted.

[0025] As used herein, “heterocyclic group” refers to a ternary, quaternary, pentaneary, hexanal, septaneary, octaneary, nonaneary, decanal, or up to 18-membered monocyclic, bicyclic, and tricyclic ring system, wherein a carbon atom, together with one to five heteroatoms, constitutes the ring system. The heterocycle may optionally contain one or more unsaturated bonds positioned in such a manner that a fully delocalized π-electron system does not occur throughout all rings. Heteroatoms are elements other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. The heterocycle may also contain one or more carbonyl or thiocarbonyl functional groups so that the definition includes oxo- and thio-systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be fused or helically joined together, as described herein with respect to “cycloalkyl”. Additionally, any nitrogen in the heterocyclic group may be quaternized. The heterocyclic or heteroalicyclic group may be unsubstituted or substituted. Examples of such "heterocyclic" groups include, but are not limited to, those described herein and the following: 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxopentane, 1,3-dioxopentane, 1,4-dioxopentane, 1,3-oxothiacyclohexane, 1,4-oxothiacyclohexadiene, 1,3,4-oxadiazol-2(3H)-one, 1,2,3-oxadiazol-5(2H)-one, 1,3-oxothiacyclopentane, 1,3-dithiacyclopentadiene, 1,3-dithiacyclopentane, 1,4-oxothiacyclohexane, tetrahydro-1,4-thiazine, 1,3-thiazine, 2H-1,2-oxazine, maleimide, succinyl Imines, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazoline, isoxazoline, isoxazoline, oxazoline, oxazoline, oxazolidinone, thiazoline, thiazoline, morpholine, ethylene oxide, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidone-dione, 4-piperidinone, pyrzoline, pyrazole, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiaran, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, and their benzo[a]-fused analogues (e.g., benzimidazolinone, tetrahydroquinoline, and 3,4-methylenedioxyphenyl).

[0026] As used herein, “cycloalkyl” means a cycloalkyl group that is a substituent connected via a lower alkylene group. The lower alkylene group and the cycloalkyl group of a cycloalkyl group may be substituted or unsubstituted. Examples include, but are not limited to, cyclohexyl(methyl), cyclopentyl(methyl), cyclohexyl(ethyl), and cyclopentyl(ethyl).

[0027] As used herein, “aryl(alkyl)” means an aryl group that is a substituent connected via a lower alkylene group. The lower alkylene group and the aryl group of an aryl(alkyl) can be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

[0028] As used herein, “heteroaryl(alkyl)” means a heteroaryl group that is a substituent connected via a lower alkylene group. The lower alkylene group and the heteroaryl group of a heteroaryl(alkyl) can be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furanylalkyl, thienylalkyl, pyrroliylalkyl, pyridylalkyl, isoxazolylalkyl, imidazolylalkyl, and their benzofused analogs.

[0029] "Heterocyclic (alkyl)" refers to a heterocyclic group that is substituent via a lower alkylene group. The lower alkylene group and the heterocyclic group of the heterocyclic (alkyl) group can be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl (methyl), piperidin-4-yl (ethyl), piperidin-4-yl (propyl), tetrahydro-2H-thiaran-4-yl (methyl), and 1,3-thiazin-4-yl (methyl).

[0030] A “lower alkylene group” is a straight-chain -CH2- group that forms a bond to connect a molecular segment via its terminal carbon atom. Examples include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). A lower alkylene group can be substituted by replacing one or more hydrogen atoms of the lower alkylene group with one or more substituents listed in accordance with the definition of “substituted”.

[0031] As used herein, “alkoxy” refers to the formula –OR, where R is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl) group as defined herein. A non-limiting list of alkoxy groups includes methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), cyclopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, phenoxy, and benzoyloxy. Alkoxy groups may be substituted or unsubstituted.

[0032] As used herein, "acyl" refers to an alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), and heterocyclic(alkyl) group that is substituent via a carbonyl group. Examples include acetyl, propionyl, benzoyl, and acryloyl. The acyl group may be substituted or unsubstituted.

[0033] As used herein, the term "halogen atom" or "halogen" refers to any of the radioactively stable atoms in column 7 of the periodic table, such as fluorine, chlorine, bromine, and iodine.

[0034] "Phenylacetone" refers to both monocyclic and bicyclic phenyl ketones. Monocyclic phenyl groups have a "-C(=O)R" group attached to the benzene ring. a1 "part, in which R a1 It can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). Bicyclic phenyl ketones have a phenyl group fused to a 4- to 8-membered monocyclic hydrocarbon ring having a carbonyl moiety attached to one of the ring carbons of the hydrocarbon ring, wherein one or two ring carbons of the hydrocarbon ring can be replaced independently by heteroatoms selected from oxygen (O) and sulfur (S).

[0035] "Pyridyl ketone" refers to both monocyclic and bicyclic pyridyl ketones. Monocyclic pyridyl groups have a "-C(=O)R" group attached to a benzene ring. b1 "part, in which R b1 It can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). Bicyclic pyridyl ketones have a pyridyl group fused to a 4- to 8-membered monocyclic hydrocarbon ring having a carbonyl moiety attached to one of the ring carbons of the hydrocarbon ring, wherein one or two ring carbons of the hydrocarbon ring can be replaced independently by heteroatoms selected from oxygen (O) and sulfur (S).

[0036] When the number of substituents is not specified (e.g., alkoxyphenyl), one or more substituents may be present. For example, "alkoxyphenyl" may include one or more alkoxy groups of the same or different alkoxy groups. As another example, "C1 to C3 alkoxyphenyl" may include one or more alkoxy groups of the same or different alkoxy groups containing one, two, or three atoms.

[0037] As used herein, unless otherwise specified, abbreviations for any protecting groups, amino acids and other compounds conform to their common usage, recognized abbreviations, or the IUPAC-IUB Biochemical Nomenclature Committee (see Biochem. 11:942-944 (1972)).

[0038] The term "pharmaceutically acceptable salt" refers to a salt of a compound that will not cause significant irritation to the organism to which it is applied and will not eliminate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting the compound with inorganic acids, such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can also be obtained by reacting the compound with organic acids such as aliphatic or aromatic carboxylic acids or sulfonic acids (e.g., formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or naphthalenesulfonic acid). Drug salts can also be obtained by reacting compounds with bases to form salts, such as ammonium salts, alkali metal salts (such as sodium or potassium salts), alkaline earth metal salts (such as calcium or magnesium salts), organic bases (such as dicyclohexylamine, N-methyl-D-glucosamine, tri(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine), and salts formed by reacting with amino acids (such as arginine and lysine).

[0039] Unless otherwise specified, the term “crystallization” and related terms used herein, when used to describe a substance, component, product, or form, mean that the substance, component, product, or form is substantially crystalline, for example, as determined by X-ray diffraction. (See, for example, Remington's Pharmaceutical Sciences, 20th edition, Lippincott Williams & Wilkins, Philadelphia Pa., 173 (2000); The United States Pharmacopeia, 37th edition, 503-509 (2014)).

[0040] As used herein, and unless otherwise specified, the terms “about” and “approximately” indicating a value or range of values ​​may deviate to a degree that would be reasonable to a person skilled in the art when used in conjunction with numerical values ​​or ranges of values ​​provided to characterize a particular solid form, while still describing the solid form, such as a particular temperature or temperature range (e.g., describing melting, dehydration, desolvation, or glass transition temperature); mass change (e.g., mass change as a function of temperature or humidity); solvent or water content (e.g., mass or percentage); or peak position (e.g., in analysis by, for example, IR or Raman spectroscopy or XRPD). Techniques used to characterize crystalline and amorphous forms include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, vibrational spectroscopy (e.g., infrared (IR) and Raman spectroscopy), solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies. In some embodiments, when used in this context, the terms "about" and "approximately" indicating numerical values ​​or ranges may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of said values ​​or ranges. In the context of molar ratios, the terms "about" and "approximately" indicating a numerical value or range can vary within 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of said value or range. It should be understood that the peak values ​​in an X-ray powder diffraction pattern can vary from machine to machine or from sample to sample, and therefore the values ​​cited should not be interpreted as absolute, but have permissible variability, such as ±0.2 degrees 2θ (°20) or greater. For example, in some embodiments, the values ​​of XRPD peak positions can vary by up to ±0.2 degrees 2θ while still describing a particular XRPD peak.

[0041] The terms and phrases and their variations used in this application, particularly in the appended claims, should be understood as open-ended rather than restrictive, unless otherwise expressly stated. For the foregoing examples, the term “comprising” should be understood as “including but not limited to,” “including but not limited to,” etc.; as used herein, the term “comprising” is synonymous with “including,” “containing,” or “characterized as” and is inclusive or open-ended, and does not exclude additional unlisted elements or method steps; the term “having” should be interpreted as “having at least”; the term “comprising” should be interpreted as “including but not limited to”; the term “example” is used to provide exemplary instances of the items under discussion, not an exhaustive or restrictive list thereof; and the use of terms such as “preferred,” “ideal,” “desired,” and “expected,” and words with similar semantic meanings, should not be construed as implying that certain features are critical, necessary, or even important to the structure or function, but are merely intended to highlight alternative or additional features that may or may not be used in a particular embodiment. Furthermore, the term “comprising” should be interpreted as synonymous with the phrase “having at least” or “containing at least.” When used in the context of a method, the term "comprising" means that the method includes at least the stated steps, but may include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the stated features or components, but may also include additional features or components.

[0042] For virtually any plural and / or singular term used herein, those skilled in the art can convert from plural to singular and / or from singular to plural, as appropriate to the context and / or application. For clarity, various singular / plural substitutions may be explicitly stated herein. The indefinite article “a” or “an” does not exclude multiple. The fact that certain measures are referred to in mutually different dependent claims does not indicate that a combination of these measures cannot be used to make the advantages more pronounced. Any reference numerals in the claims should not be construed as limiting their scope.

[0043] It should be understood that in any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly specified, each center may independently be an R configuration, an S configuration, or a mixture thereof. Therefore, the compounds presented herein may be enantiomerically pure, enantiomerically enriched racemic mixtures, or diastereomeric pure, diastereomeric enriched stereoisomer mixtures. Furthermore, it should be understood that in any compound described herein having one or more double bonds that generate geometric isomers that can be defined as E or Z, each double bond may independently be E or Z, or a mixture thereof.

[0044] Similarly, it should be understood that all tautomer forms are intended to be included in any of the compounds described.

[0045] It should be understood that in cases where the compounds disclosed herein have unfilled valences, they are filled with hydrogen or its isotopes (e.g., hydrogen-1 (protium) and hydrogen-2 (deuterium)).

[0046] It should be understood that the compounds described herein may be isotopically labeled. Substitution with an isotope such as deuterium can provide certain therapeutic advantages due to increased metabolic stability, such as, for example, an increased in vivo half-life or a reduced dose requirement. Each chemical element represented in the compound structure may contain any isotope of that element. For example, in the compound structure, it may be explicitly disclosed or understood that a hydrogen atom is present in the compound. At any position in the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, unless the context clearly specifies otherwise, the compounds mentioned herein encompass all possible isotopic forms.

[0047] Regarding the range values ​​provided, it should be understood that the upper and lower limits, as well as each intermediate value between the upper and lower limits of the range, are covered within the implementation scheme.

[0048] Compounds and preparation methods

[0049] Some embodiments described herein relate to a method for preparing tertiary alcohols or salts thereof, the method comprising mixing the following: optionally substituted phenyl ketones or optionally substituted pyridyl ketones, or salts of any of the foregoing; a zinc reagent selected from Et₂Zn, Me₂Zn, and Ph₂Zn; having a structure Chiral ligands, of which R 1 It can be -CH3, –CH2CH3, –CH(CH3)2 or –C(CH3)3; R 2 It can be H; or R 1 and R 2 Can be used with each R 1 and R 2 The attached carbon atoms are bonded together to form an unsubstituted cyclohexyl ring; each Ar can be independently an unsubstituted or substituted phenyl or an unsubstituted or substituted naphthyl group, wherein when Ar is a substituted phenyl or a substituted naphthyl group, the phenyl or the naphthyl group can be substituted by one or more substituents independently selected from the group consisting of: halogens, unsubstituted C atoms, and substituted carbon atoms. 1-4 Alkyl and unsubstituted C 1-4 Alkyl group; and b can be 1 or 2; and BF3·OEt2.

[0050] Some embodiments described herein relate to a method for preparing tertiary alcohols or salts thereof, the method comprising mixing the following: optionally substituted phenyl ketones or optionally substituted pyridyl ketones, or salts of any of the foregoing; a zinc reagent selected from Et₂Zn, Me₂Zn, and Ph₂Zn; having a structure Chiral ligands, wherein each Ar can independently be an unsubstituted or substituted phenyl or an unsubstituted or substituted naphthyl, wherein when Ar is a substituted phenyl or a substituted naphthyl, the phenyl or naphthyl can be substituted by one or more substituents independently selected from the group consisting of: halogens, unsubstituted C 1-4 Alkyl and unsubstituted C 1-4 Alkyl groups; and BF3·OEt2.

[0051] Optionally substituted phenyl ketones can have various structures. For example, an optionally substituted phenyl ketone can be bicyclic and have a carbonyl group attached to a cyclic carbon atom of a 4- to 8-membered monocyclic hydrocarbon ring, wherein the hydrocarbon ring is fused to the phenyl group, and wherein one or two carbons of the hydrocarbon ring can be independently substituted with heteroatoms selected from O (oxygen) and S (sulfur). As another example, an optionally substituted phenyl ketone can be monocyclic, wherein an acyl group can be attached to a phenyl group.

[0052] In some embodiments, the optionally substituted phenyl ketone may have a structure selected from compounds of formula (A) and compounds of formula (B):

[0053]

[0054] Where: m1 can be 0, 1, 2, 3, or 4; n1 can be 0, 1, 2, 3, 4, or 5; m2 can be 1 or 2; X 1a It can be –CH2–; X 2a It can be –CH2–, –CH(CH3)–, –C(CH3)2– or O (oxygen); each R 1a and each R 1b It can be independently selected from halogens and unsubstituted C. 1-4 Alkyl and unsubstituted C 1-4 alkoxy groups; and R 2b Can be unreplaced C 1-4 Alkyl groups. Non-limiting examples of optionally substituted ketones include the following:

[0055]

[0056]

[0057]

[0058] Various optionally substituted pyridinol ketones can also be used in the methods described herein. As described herein, optionally substituted pyridinol ketones can be monocyclic or bicyclic. When the optionally substituted pyridinol ketone is bicyclic, the carbonyl group can be attached to a cyclic carbon of a 4- to 8-membered monocyclic hydrocarbon ring, wherein the hydrocarbon ring can have 1 to 2 cyclic carbons substituted by heteroatoms independently selected from O (oxygen) and S (sulfur), and wherein the hydrocarbon ring is fused to the pyridyl group. When the optionally substituted pyridinol ketone is monocyclic, an acyl group can be attached to the pyridyl group.

[0059] In some embodiments, the optionally substituted pyridyl ketone may have a structure selected from compounds of formula (G), formula (H), formula (J), formula (K), formula (L), and formula (M):

[0060]

[0061] Where: t1, u1, and v1 can independently be 0, 1, 2, or 3; w1, x1, and y1 can independently be 0, 1, 2, 3, or 4; t2, u2, and v2 can independently be 1 or 2; X 1g X 1h and X 1j Each can be –CH2–; X 2g X 2h and X 2j It can be independently –CH2–, –CH(CH3)–, –C(CH3)2– or O; R 1g R 1h R 1j R 1k R 1l and R 1m It can be independently selected from halogens and unsubstituted C. 1-4 Alkyl and unsubstituted C 1-4 alkoxy groups; and R 2k R 2l and R 2m Can be independently of unsubstituted C 1-4 Alkyl groups. A non-limiting list of optionally substituted pyridyl ketones includes the following:

[0062]

[0063]

[0064]

[0065] As described herein, tertiary alcohols can be provided using optionally substituted phenyl ketones and / or optionally substituted pyridyl ketones. For example, optionally substituted phenyl ketones and / or optionally substituted pyridyl ketones can be used in the methods described herein to provide chiral tertiary alcohols in high yield and / or with high enantiomeric purity. Examples of tertiary alcohols obtainable by the methods described herein include, but are not limited to, compounds of formula (A1) and compounds of formula (B1):

[0066]

[0067] Where: m3 can be 0, 1, 2, 3, or 4; n2 can be 0, 1, 2, 3, 4, or 5; m4 can be 1 or 2; X 3a It can be –CH2–; X 4a It can be –CH2–, –CH(CH3)–, –C(CH3)2– or O (oxygen); each R 2a and each R 3b It can be independently selected from halogens and unsubstituted C. 1-4 Alkyl and unsubstituted C 1-4 Alkoxy; R 4b Can be unreplaced C 1-4 Alkyl; and R 3a and R 5b It can be independently –CH3, –CH2CH3, or -Ph. Additional examples of tertiary alcohols obtainable by the methods described herein include, but are not limited to, compounds having the structures selected from formula (G1), (H1), (J1), (K1), (L1), and (M1):

[0068]

[0069] Where: t3, u3, and v3 can independently be 0, 1, 2, or 3; w2, x2, and y2 can independently be 0, 1, 2, 3, or 4; t4, u4, and v4 can independently be 1 or 2; X 3g X 3h and X 3j Each can be –CH2–; X 4g X 4h and X 4j It can be independently –CH2–, –CH(CH3)–, –C(CH3)2– or O (oxygen); R 2g R 2h R 2j R 3k R 3l and R 3m It can be independently selected from halogens and unsubstituted C. 1-4 Alkyl and unsubstituted C 1-4 Alkoxy; R 4k R4l and R 4m Can be independently of unsubstituted C 1-4 Alkyl; and R 3g R 3h R 3j R 5k R 5l and R 5m It can be -CH3, –CH2CH3 or -Ph independently.

[0070] Various structures of tertiary alcohols obtainable by the methods described herein include, but are not limited to, the following:

[0071]

[0072]

[0073]

[0074]

[0075] This article describes R 3a R 3g R 3h R 3j R 5b R 5k R 5l and / or R 5m In some implementations, including those in this paragraph, R 3a R 3g R 3h R 3j R 5b R 5k R 5l and / or R 5m Can be unreplaced C 1-4 Alkyl group. In some embodiments, including those described in this paragraph, R 3a R 3g R 3h R 3j R 5b R 5k R 5l and / or R 5m It can be –CH2CH3.

[0076] Having structure Chiral ligands, of which R 1 It can be -CH3, –CH2CH3, –CH(CH3)2 or –C(CH3)3; R 2 It can be H; or R 1 and R2 Can be used with each R 1 and R 2 The attached carbon atoms are bonded together to form an unsubstituted cyclohexyl ring; each Ar can be independently an unsubstituted or substituted phenyl or an unsubstituted or substituted naphthyl group, wherein when Ar is a substituted phenyl or a substituted naphthyl group, the phenyl or the naphthyl group can be substituted by one or more substituents independently selected from the group consisting of: halogens, unsubstituted C atoms, and substituted carbon atoms. 1-4 Alkyl and unsubstituted C 1-4 Alkyl group; and b can be 1 or 2; can be used in the methods described herein. In some embodiments, the chiral ligand can be... Each Ar can be an unsubstituted phenyl group. In other embodiments, the chiral ligand has a structure Each Ar can be a substituted phenyl group substituted with one or more substituents independently selected from the group consisting of: halogen, unsubstituted C. 1-4 Alkyl and unsubstituted C 1-4 Alkyl group. In other embodiments, the chiral ligand has a structure Each Ar group may be an unsubstituted naphthyl group. In other embodiments, the chiral ligand has a structure Each Ar can be a substituted naphthyl group substituted by one or more substituents independently selected from the group consisting of: halogens, unsubstituted C. 1-4 Alkyl and unsubstituted C 1-4 Alkyl group.

[0077] Substituent R 1 It can be various saturated hydrocarbons, such as C 1-4 Alkyl group. C 1-4 The alkyl group can be straight-chain or branched. In some embodiments, R 1 It can be methyl (-CH3). In other embodiments, R 1 It can be ethyl (–CH2CH3). In other embodiments, R 1 It can be isopropyl (–CH(CH3)2). In other embodiments, R 1 It can be tert-butyl (–C(CH3)3). Other C 1-4 Alkyl groups include n-propyl, n-butyl, sec-butyl, and isobutyl. When R... 1 C 1-4 When alkyl, R 2 It can be hydrogen. A saturated carbide ring can be formed by making R... 1 and R 2 Can be used with each R 1 and R 2 The bonded carbon atoms combine to form the structure. In some implementations, R... 1 and R 2 Can be used with each R1 and R 2 The attached carbon atoms assemble to form an unsubstituted cyclohexyl ring. Those skilled in the art will understand that when R... 1 C 1-4 When alkyl, R 1 The attached carbon atom can be a chiral center. For example, chiral ligands can have a structure Similarly, when R 1 and R 2 With each R 1 and R 2 When the connected carbon atoms come together to form an unsubstituted cyclohexyl ring, R 1 and R 2 Each carbon atom connected to the ligand can be a chiral center. As an example, a chiral ligand can have a structure...

[0078] Suitable chiral ligands include, but are not limited to, the following:

[0079] In some implementations, the chiral ligand may have a structure

[0080] Obtaining tertiary alcohols in high yield and / or with high enantiomeric purity can be advantageous for the synthetic preparation of natural products and / or pharmaceutical compounds. In some embodiments, the methods described herein can be used to obtain tertiary alcohols with an enantiomeric purity of ≥30%. In some embodiments, the methods described herein can be used to obtain tertiary alcohols with an enantiomeric purity of ≥40%. In some embodiments, the methods described herein can be used to obtain tertiary alcohols with an enantiomeric purity of ≥50%. In some embodiments, the methods described herein can be used to obtain tertiary alcohols with an enantiomeric purity of ≥60%. In some embodiments, the methods described herein can be used to obtain tertiary alcohols with an enantiomeric purity of ≥70%. In some embodiments, the methods described herein can be used to obtain tertiary alcohols with an enantiomeric purity of ≥80%. In some embodiments, the methods described herein can be used to obtain tertiary alcohols with an enantiomeric purity of ≥90%. In some embodiments, the methods described herein can be used to obtain tertiary alcohols with an enantiomeric purity of ≥95%.

[0081] In some embodiments, including those mentioned in the foregoing paragraphs, the methods described herein can be used to obtain tertiary alcohols in ≥50% yield. In some embodiments, including those mentioned in the foregoing paragraphs, the methods described herein can be used to obtain tertiary alcohols in ≥60% yield. In some embodiments, including those mentioned in the foregoing paragraphs, the methods described herein can be used to obtain tertiary alcohols in ≥70% yield. In some embodiments, including those mentioned in the foregoing paragraphs, the methods described herein can be used to obtain tertiary alcohols in ≥80% yield. In some embodiments, including those mentioned in the foregoing paragraphs, the methods described herein can be used to obtain tertiary alcohols in ≥90% yield.

[0082] Various solvents may be used in the methods described herein. For example, solvents may be hexane, heptane, dichloromethane, toluene, and combinations thereof. Various temperatures may also be used in the methods described herein. In some embodiments, the methods described herein may be carried out at temperatures ranging from about -78°C to about 25°C. In some embodiments, the methods described herein may be carried out at temperatures ranging from about -50°C to about 25°C.

[0083] The methods described herein may utilize BF3·OEt2. BF3·OEt2 can be used as a Lewis acid. In some embodiments, the amount of BF3·OEt2 used in the methods described herein may be present in a catalytic amount. For example, the amount of BF3·OEt2 used in the methods described herein may be in the range of about 0.05 equivalents to about 1 equivalent relative to 1 equivalent of an optionally substituted phenyl ketone or optionally substituted pyridyl ketone (BF3·OEt2: optionally substituted phenyl ketone or BF3·OEt2: optionally substituted pyridyl ketone). In some embodiments, the amount of BF3·OEt2 used in the methods described herein may be in the range of about 0.08 equivalents to about 0.25 equivalents relative to 1 equivalent of an optionally substituted phenyl ketone or optionally substituted pyridyl ketone (BF3·OEt2: optionally substituted phenyl ketone or BF3·OEt2: optionally substituted pyridyl ketone). In some embodiments, the amount of BF3·OEt2 used in the methods described herein may be 0.1 equivalents relative to 1 equivalent of an optionally substituted phenyl ketone or optionally substituted pyridyl ketone.

[0084] Examples of tertiary alcohols that can be obtained by the methods described herein include, but are not limited to, the following:

[0085]

[0086] Additional examples of tertiary alcohols obtainable by the methods described herein include, but are not limited to, the structures of compounds having formula (G1-a):

[0087]

[0088] X can be Cl, Br, or I. In some embodiments, X can be Cl (chlorine). In some embodiments, X can be Br (bromine). In some embodiments, X can be I (iodine).

[0089] Compounds of formula (G1-a) (where X is Cl) can be obtained as various polymorphs, such as form A and form B. Various methods can be used to characterize polymorphs of compounds of formula (G1-a) (where X is Cl). In some embodiments, form A can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks can be selected from peaks in the range of about 15.7 degrees 2θ to about 16.7 degrees 2θ, about 20.5 degrees 2θ to about 21.5 degrees 2θ, about 23.7 degrees 2θ to about 24.7 degrees 2θ, and about 26.0 degrees 2θ to about 27.0 degrees 2θ. In some embodiments, form A can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks can be selected from about 16.2 degrees 2θ ± 0.2 degrees 2θ, about 21.0 degrees 2θ ± 0.2 degrees 2θ, about 24.2 degrees 2θ ± 0.2 degrees 2θ, and about 26.5 degrees 2θ ± 0.2 degrees 2θ. In some embodiments, form B can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks can be selected from peaks in the range of about 13.5 degrees 2θ to about 14.5 degrees 2θ, peaks in the range of about 17.1 degrees 2θ to about 18.1 degrees 2θ, peaks in the range of about 19.6 degrees 2θ to about 20.6 degrees 2θ, peaks in the range of about 24.3 degrees 2θ to about 25.3 degrees 2θ, and peaks in the range of about 25.0 degrees 2θ to about 26.0 degrees 2θ. In some embodiments, form B can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks can be selected from approximately 14.0° 2θ ± 0.2° 2θ, approximately 17.6° 2θ ± 0.2° 2θ, approximately 20.1° 2θ ± 0.2° 2θ, approximately 24.8° 2θ ± 0.2° 2θ, and approximately 25.5° 2θ ± 0.2° 2θ. In some embodiments, form A can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks can be selected from the peaks in Table 5. In some embodiments, form B can be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks can be selected from the peaks in Table 6. In some embodiments, form A can exhibit the following characteristics: Figure 1 The X-ray powder diffraction pattern is shown. In some embodiments, form B can exhibit the following characteristics: Figure 2The X-ray powder diffraction pattern shown is provided. All XRPD patterns provided herein are measured on a 2-θ (2θ) degree scale. It should be understood that the peak values ​​of an X-ray powder diffraction pattern can vary from machine to machine or from sample to sample, and therefore the values ​​cited should not be interpreted as absolute, but have permissible variability, such as ±0.5 degrees 2θ (2θ) or greater. For example, in some embodiments, the values ​​of XRPD peak positions can vary by up to ±0.2 degrees 2θ while still describing a particular XRPD peak.

[0090] The methods for preparing tertiary alcohols described herein may include those for preparing tertiary alcohols such as those described herein. The method described herein may include tertiary alcohols (including NaHSO3), wherein the use of NaHSO3 increases the ee% of the enantiomeric excess (ee%) compared to the enantiomeric excess (ee%) before the use of NaHSO3. The recrystallization of the tertiary alcohol can increase the ee% of the enantiomeric excess (ee%) compared to the pre-recrystallization enantiomeric excess (ee%). In some embodiments, hexane can be used for recrystallization. In other embodiments, heptane can be used for recrystallization.

[0091] Uses of compounds

[0092] Those skilled in the art will recognize that the compounds described herein can be used in various methods to prepare compounds of interest. In some embodiments, the compounds described herein can be used to prepare compounds that act as WEE1 inhibitors, since WEE1 has been found to be overexpressed in various cancer types. Examples of WEE1 inhibitors include those described in PCT Publication WO2019 / 173082, published September 12, 2019, the entire contents of which are incorporated herein by reference for all purposes. Those skilled in the art will recognize that certain compounds described herein can be used as intermediates in the synthesis of WEE1 inhibitors. In some embodiments, the compounds described herein, such as those of formula (G1-a), can be used as intermediates in the synthesis of enantiomerically pure or substantially enantiomerically pure WEE1 inhibitors.

[0093] Example

[0094] Additional embodiments are disclosed in more detail in the following examples, which are not intended to limit the scope of the claims in any way.

[0095] Example A

[0096] (R)-N-(3-methyl-1-(pyrrolidone-1-yl)but-2-yl)-P,P-diphenylphosphineamide (63.8 mg, 0.179 mmol) was added to a flame-dried 40 mL vial. The vial was sealed with a septum cap, evacuated, filled with N2 (3×), and cooled to -50 °C. Hexane containing 1 M diethylzinc (2.39 mL, 2.39 mmol) was added at -50 °C, and the mixture was stirred for 30 min. Lewis acid (0.1 equivalent, Table 1) was added, and the mixture was stirred at -50 °C for 30 min. DCM (2.5 mL) containing 2-chloro-5,6-dihydro-7H-cyclopentano[b]pyridin-7-one (100 mg, 0.597 mmol) was added over 30 min using a syringe pump (5 mL / h). The mixture was stirred at -50°C for 5 h, then heated to room temperature (RT) overnight. The mixture was cooled to 0°C, and the reaction was slowly quenched with saturated NH4Cl (5 mL). The mixture was poured into a mixture of EtOAc (25 mL) and saturated NH4Cl (25 mL) with stirring. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried (Na2SO4). The crude residue was purified by column chromatography (SiO2, EtOAc: hexane) to give the alcohols listed below as in Example 1. Enantiomeric purity was determined by chiral LCMS. As shown in Table 1, BF3·OEt2 showed the best yield and ee% compared to the other Lewis acids listed.

[0097]

[0098] Table 1

[0099] Lewis acid ee% Yield <![CDATA[BF3·OEt2]]> 95％ 77％ <![CDATA[B(OEt)3]]> 62％ 51％ <![CDATA[Ti(OiPr)4]]> 16％ 46％ <![CDATA[ZnCl2]]> 55％ 31％ <![CDATA[LiBF4]]> 53％ 28％ <![CDATA[TiCl4]]> 73％ 18％

[0100] Example B

[0101] (R)-N-(3-methyl-1-(pyrrolidone-1-yl)but-2-yl)-P,P-diphenylphosphineamide (63.8 mg, 0.179 mmol) was added to a flame-dried 40 mL vial. The vial was sealed with a septum cap, evacuated, filled with N2 (3×), and then cooled to -78 °C. Hexane containing 1 M diethylzinc (2.98 mL, 2.98 mmol) was added at -78 °C, and the mixture was stirred for 30 min. BF3·OEt2 (see Table 2) was added to the mixture via syringe, and the mixture was stirred at -78 °C for 30 min. DCM containing 2-chloro-5,6-dihydro-7H-cyclopentano[b]pyridin-7-one (100 mg, 0.597 mmol) was added over 30 min at -78 °C using a syringe pump (5 mL / h) in 2.5 mL. The mixture was stirred at -78°C for 2 h, slowly heated to room temperature, and then stirred for 20 h. The mixture was cooled to 0°C, and the reaction was quenched by slowly adding saturated NH4Cl (5 mL) with stirring. The reactants were poured into a mixture of EtOAc (20 mL) and saturated NH4Cl (20 mL) with stirring. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried (Na2SO4). The solvent was evaporated, and the crude residue was analyzed by chiral LCMS. As shown in Table 2, 0.1 equivalents of BF3·OEt2 provided the highest ee%.

[0102]

[0103] Table 2

[0104] entry <![CDATA[BF3·OEt2 (equivalent)]]> Remaining ketones ee% 1 1 4％ 20％ 2 0.8 2.5％ 42％ 3 0.6 2％ 46％ 4 0.4 2％ 70％ 5 0.2 1.5％ 80％ 6 0.1 8％ 94％ 7 0 47％ 40％

[0105] Example C

[0106] The ligand (0.3 equivalents, Table 3) was added to a flame-dried 40 mL vial. The vial was sealed with a septum cap, evacuated, filled with N2 (3×), and then cooled to -50 °C. Hexane containing 1 M diethylzinc (2.39 mL, 2.39 mmol) was added at -50 °C, and the mixture was stirred for 30 min. A BF3·OEt2 solution [100 μL, prepared by diluting 70 μL of BF3·OEt2 (0.007 mL, 0.060 mmol) in 930 μL of DCM] was added to the mixture, and the mixture was stirred at -50 °C for 30 min. DCM containing 2-chloro-5,6-dihydro-7H-cyclopentano[b]pyridin-7-one (100 mg, 0.597 mmol) was added over 30 min at -50 °C using a syringe pump (5 mL / h) in 2.5 mL. The mixture was stirred at -50°C for 5 h, slowly heated to room temperature, and then stirred for 20 h. The mixture was cooled to 0°C, and the reaction was quenched by slowly adding saturated NH4Cl (5 mL) with stirring. The reactants were poured into a mixture of EtOAc (20 mL) and saturated NH4Cl (20 mL) with stirring. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried (Na2SO4). The solvent was evaporated, and the crude residue was analyzed by chiral LCMS. Ligand 1 provided a high ee% and a residual ≤10% of the starting ketone. Ligands 4 and 5 provided a high ee% and a residual ≤20% of the starting ketone.

[0107]

[0108] Table 3

[0109]

[0110]

[0111] The solvent for each entry is DCM.

[0112] Enantiomer 1 has a structure Furthermore, enantiomer 2 has a structure

[0113] General procedures of Examples 1-21

[0114] (R)-N-(3-methyl-1-(pyrrolidone-1-yl)but-2-yl)-P,P-diphenylphosphineamide (0.160 g, 0.450 mmol) was added to a flame-dried 40 mL vial. The vial was sealed with a septum cap, evacuated, filled with N2 (3×), and then cooled to -50 °C. Hexane containing 1 M diethylzinc (6.00 mL, 6.00 mmol) was added, and the mixture was stirred for 30 min. A BF3·OEt2 solution [100 μL, prepared by diluting 190 μL of BF3·OEt2 (0.019 mL, 0.150 mmol) in 810 μL of DCM] was added to the reaction mixture, and the mixture was stirred at -50 °C for 30 min. DCM containing methyl ketone (1.5 mmol) (2.5 mL) was added over 30 min using a syringe pump. The mixture was stirred at -50°C for 5 h, then heated to room temperature overnight. The mixture was cooled to 0°C, and the reaction was slowly quenched with saturated NH4Cl (5 mL). The mixture was poured into a mixture of EtOAc (25 mL) and saturated NH4Cl (25 mL) with stirring. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (1 × 75 mL) and dried (Na2SO4). The crude residue was purified by column chromatography (SiO2, EtOAc: hexane) to give the desired alcohol. The enantiomeric purity was determined by chiral LCMS, HPLC, or chiral SFC. The absolute stereochemistry of Example 1 was determined by X-ray crystallography of the latter compound in the synthesis provided in WO 2019 / 173082. The absolute stereochemistry of Examples 2-21 is arbitrarily specified.

[0115] Example 1

[0116] (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol

[0117]

[0118] Example 1: 908 mg (77%), colorless oily substance. 1 H NMR (400MHz, CDCl3) δ7.50(d,J=7.9Hz,1H),7.17(d,J=8.1Hz,1H),2.99-2.90(m,1H),2.82-2.71(m,1H),2.33(ddd,J=4.3,8 .7,13.4Hz,1H),2.19(ddd,J=6.8,9.0,13.5Hz,1H),2.04-1.89(m,1H),1.81(qd,J=7.3,14.1Hz,1H),0.94(t,J=7.5Hz,3H). 13C NMR (101MHz, CDCl3) δ166.90,150.07,135.67,134.94,123.10,81.98,36.03,32.37,26.47,8.13. LCMS(APCI)m / z 198.1[M+H] + 97% ee; Chiral analysis was performed by LCMS on a Lux Cellulose-4 column (4.6 × 150), eluted with CH3CN / water and 0.1% formic acid at 1.2 mL / min. Under these conditions, Example 1 eluted as peak 1 (t1 = 8.16 min), and the enantiomer eluted as peak 2 (t1 = 8.54 min). As provided in WO2019 / 173082, the compound of Example 1 can be used to prepare compounds that have shown inhibition of WEE1 activity in cells, and thus are effective as anticancer agents.

[0119] Example 2

[0120] (R)-2-Bromo-7-ethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol

[0121]

[0122] Example 2: 235 mg (65%) of colorless oily substance. 1 H NMR (400MHz, CDCl3) δ7.41(d,J=7.9Hz,1H),7.32(d,J=7.9Hz,1H),2.98-2.89(m,1H),2.80-2.71(m,1 H), 2.36-2.29 (m, 2H), 2.22-2.21 (m, 1H), 2.02-1.92 (m, 1H), 1.86-1.76 (m, 1H), 0.95 (t, J = 7.5Hz, 3H). 13 C NMR (101MHz, CDCl3) δ167.65,140.74,135.51,135.27,126.89,82.02,35.95,32.49,26.56,8.16. LCMS(APCI)m / z 242.7[M+H] + 96.4% ee. Chiral analysis was performed by LCMS on a Lux Cellulose-4 column (4.6 × 150 mm), eluted with CH3CN / water and 0.1% formic acid at 1.2 mL / min. Under these conditions, Example 2 eluted as peak 1 (t1 = 8.73 min), and the enantiomer eluted as peak 2 (t1 = 9.17 min).

[0123] Example 3

[0124] (R)-7-Ethyl-2-iodo-6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol

[0125]

[0126] Example 3: 114 mg (32%), colorless oily substance. 1 H NMR (400MHz, CDCl3) δ7.54(d,J=7.8Hz,1H),7.20(d,J=7.8Hz,1H),2.96-2.87(m,1H),2.78-2.68(m,1H),2.42(br s,1H),2.29(ddd,J=4.2,8.7,13.3Hz,1H),2.15(ddd,J=7.0,9.0,13.5Hz,1H),2.04-1.87(m,1H),1.83-1.73(m,1H),0.94(t,J=7.5Hz,3H). 13 C NMR (101MHz, CDCl3) δ168.53, 135.66, 134.78, 133.50, 115.94, 81.93, 35.75, 32.38, 26.58, 8.13. LCMS(APCI)m / z 290.0[M+H] + 92% ee; Chiral analysis was performed by LCMS on a Lux Cellulose-4 column (4.6 × 150 mm), eluted with CH3CN / water and 0.1% formic acid at 1.2 mL / min. Under these conditions, Example 3 eluted as peak 1 (t1 = 9.63 min), and the enantiomer eluted as peak 2 (t2 = 10.09 min).

[0127] Example 4

[0128] (R)-7-Ethyl-2-methoxy-6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol

[0129]

[0130] Example 4: 80 mg (27%), colorless oily substance. 1 H NMR (400MHz, CDCl3) δ7.43 (d, J = 8.3Hz, 1H), 6.60 (d, J = 8.3Hz, 1H), 3.94 (s, 3H), 2.88 (ddd, J = 3.9, 9.0, 15.7Hz, 1H), 2.71 (td, J = 7. 7,15.5Hz,1H),2.33(ddd,J=4.0,8.3,13.4Hz,2H),2.23-2.10(m,1H),2.00-1.87(m,1H),1.84-1.74(m,1H),0.96(t,J=7.5Hz,3H).13 C NMR (101 MHz, CDCl3) δ 164.38, 162.83, 135.63, 127.84, 109.68, 82.16, 53.41, 36.64, 32.48, 26.31, 8.22. LCMS (APCI) m / z 194.0 [M+H]. 96.7% ee. Chiral analysis was performed by chiral SFC on a Chiralpak IG-3 column (4.6 × 150 mm) eluted at 30 °C with 10% methanol (containing 0.5% DEA) at 3 g / min. Under these conditions, the enantiomeric elution was peak 1 (t1 = 1.45 min), and in Example 4, peak elution was peak 2 (t1 = 1.83 min).

[0131] Example 5

[0132] (R)-7-Ethyl-2-methyl-6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol

[0133]

[0134] Example 5: 55 mg (23%), colorless oil. 1 H NMR (400MHz, CDCl3) δ7.42(d,J=7.8Hz,1H),6.99(d,J=7.8Hz,1H),2.92(ddd,J=3.8,9.1,16.1Hz,1H),2.81-2.69(m,1H),2.66(s,1H),2.56-2. 53(m,3H),2.33(ddd,J=3.9,8.3,13.4Hz,1H),2.15(ddd,J=7.3,9.0,13.4Hz,1H),2.05-1.89(m,1H),1.86-1.74(m,1H),0.95(t,J=7.5Hz,3H). 13 C NMR (101MHz, CDCl3) δ165.47,156.77,133.19,132.87,122.24,82.02,36.34,32.51,26.64,23.83,8.24. LCMS(APCI)m / z178.0[M+H] + 93.0% ee. Chiral analysis was performed by chiral SFC on a Chiralpak IF-3 column (4.6 × 150 mm), eluted at 30 °C with 15% methanol (containing 0.5% DEA) at 3 g / min. Under these conditions, the enantiomeric elution was peak 1 (t1 = 1.23 min), and Example 5 eluted peak 2 (t1 = 1.40 min).

[0135] Example 6

[0136] (R)-7-Ethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol

[0137]

[0138] Example 6: 47 mg (19%), colorless oil. 1 H NMR (400MHz, CDCl3) δ8.47-8.42(m,1H),7.55(dd,J=1.2,7.6Hz,1H),7.14(dd,J=4.9,7.6Hz,1H),3.04-2.93(m,1H) ,2.86-2.76(m,1H),2.37-2.30(m,1H),2.30-2.11(m,1H),2.05-1.91(m,1H),1.91-1.79(m,1H),0.99-0.93(m,3H). 13 C NMR (101MHz, CDCl3) δ166.14,147.96,136.21,133.14,122.64,82.04,36.10,32.55,27.03,8.30. LCMS(APCI)m / z 164.6[M+H] + Chiral analysis was performed by chiral SFC on a Chiralpak AD-3 column (4.6 × 150 mm) at 30 °C using 10% methanol (containing 0.5% DEA) at 3 g / min. Under these conditions, the enantiomeric elution was peak 1 (t1 = 1.71 min), and in Example 6 it was peak 2 (t1 = 2.44 min).

[0139] Example 7

[0140] (R)-2-chloro-7-ethyl-4-methyl-6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol

[0141]

[0142] Example 7: 219 mg (69%), colorless oil. 1 H NMR (400MHz, CDCl3) δ7.01 (s, 1H), 2.87 (ddd, J = 4.3, 9.1, 16.4Hz, 1H), 2.71-2.62 (m, 1H), 2.41-2.30 (m,1H),2.26(s,3H),2.24-2.13(m,1H),2.04-1.88(m,1H),1.85-1.71(m,1H),0.92(t,J=7.5Hz,3H). 13C NMR (101MHz, CDCl3) δ166.00,150.35,147.14,134.41,123.67,82.24,35.51,32.62,25.20,18.47,8.24. LCMS(APCI)m / z 212.7[M+H] + 92% ee; Chiral analysis was performed by LCMS on a Lux Cellulose-4 column (4.6 × 150 mm), eluted with CH3CN / water and 0.1% formic acid at 1.2 mL / min. Under these conditions, Example 7 eluted as peak 1 (t1 = 9.43 min), and the enantiomer eluted as peak 2 (t2 = 9.77 min).

[0143] Example 8

[0144] (R)-2-Bromo-7-ethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol

[0145]

[0146] Example 8: 175 mg (60%), colorless oily substance. 1 H NMR (400MHz, CDCl3) δ7.35(d,J=7.8Hz,1H),7.11(d,J=8.1Hz,1H),3.04(br s,1H),2.84-2.66(m,2H),2.12-1.96(m,1H),1.96-1.62(m,5H),0.93(t,J=7.5Hz,3H). 13 C NMR (101MHz, CDCl3) δ161.65,148.44,139.73,130.02,122.66,72.58,34.22,32.09,28.07,18.98,7.68. LCMS(APCI)m / z 212.1[M+H] + 88% ee; Chiral analysis was performed by LCMS on a Lux Cellulose-4 column (4.6 × 150 mm), eluted with CH3CN / water and 0.1% formic acid at 1.2 mL / min. Under these conditions, Example 8 eluted as peak 1 (t1 = 10.41 min), and the enantiomer eluted as peak 2 (t2 = 10.75 min).

[0147] Example 9

[0148] (R)-2-bromo-8-ethyl-5,6,7,8-tetrahydroquinoline-8-ol

[0149]

[0150] Example 9: 193 mg (50%), colorless oil. 1 H NMR (400MHz, CDCl3) δ7.26 (s, 2H), 3.06 (s, 1H), 2.81-2.67 (m, 2H), 2.13-2.03 (m, 1H), 1.95-1.75 (m, 5H), 0.94 (t, J = 7.5Hz, 3H). 13 CNMR(101MHz, CDCl3)δ=162.44,139.46,138.92,130.42,126.43,72.59,34.25,32.04,28.11,18.93,7.67. LCMS(APCI)m / z 256.7[M+H] + Chiral analysis was performed by LCMS on a LuxCellulose-4 column (4.6 × 150 mm) with 85% ee and 0.1% formic acid eluted at 1.2 mL / min. Under these conditions, Example 9 eluted as peak 1 (t1 = 10.9 min) and the enantiomer eluted as peak 2 (t1 = 11.3 min).

[0151] Example 10

[0152] (R)-8-Ethyl-2-iodo-5,6,7,8-tetrahydroquinoline-8-ol

[0153]

[0154] Example 10: 298 mg (66%), colorless oil. 1 H NMR (400MHz, CDCl3) δ7.52-7.46(m,1H),7.05-6.99(m,1H),3.15(s,1H),2.79-2.65(m,2H),2.17-1.71(m,6H),0.93(t,J=7.4Hz,3H). LCMS(APCI)m / z 304.0[M+H] + 71% ee; Chiral analysis was performed by LCMS on a Lux Cellulose-4 column (4.6 × 150 mm), eluted with CH3CN / water and 0.1% formic acid at 1.2 mL / min. Under these conditions, Example 10 eluted as peak 1 (t1 = 11.79 min), and the enantiomer eluted as peak 2 (t2 = 12.12 min).

[0155] Example 11

[0156] (R)-8-Ethyl-2-methyl-5,6,7,8-tetrahydroquinoline-8-ol

[0157]

[0158] Example 11: 117 mg (41%), colorless oil. 1 H NMR (400MHz, CDCl3) δ7.27(d,J=8.0Hz,1H),6.94(d,J=7.8Hz,1H),3.76(s,1H),2.81- 2.69(m,2H),2.49(s,3H),2.20-2.10(m,1H),1.93-1.73(m,5H),0.94(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ160.03,155.16,136.98,127.35,121.61,72.29,34.24,32.30,27.91,23.93,19.16,7.67. LCMS(APCI)m / z192.0[M+H] + 84.6% ee. Chiral analysis was performed by chiral SFC on a Chiralpak IG-3 column (4.6 × 150 mm), eluted at 30 °C with 10% methanol (containing 0.5% DEA) at 3 g / min. Under these conditions, the enantiomeric elution was peak 1 (t1 = 1.98 min), and Example 11 eluted peak 2 (t1 = 2.46 min).

[0159] Example 12

[0160] (R)-8-ethyl-2-methoxy-5,6,7,8-tetrahydroquinoline-8-ol

[0161]

[0162] Example 12: 150 mg (48%), colorless oil. 1 H NMR (400MHz, CDCl3) δ7.29(d,J=8.4Hz,1H),6.57(d,J=8.3Hz,1H),3.92(s,3H),3.28( s,1H),2.76-2.63(m,2H),2.14-2.04(m,1H),1.92-1.73(m,5H),0.94(t,J=7.5Hz,3H). 13 C NMR (101MHz, CDCl3) δ162.05,157.15,139.93,123.13,109.38,72.46,53.16,34.21,32.41,27.59,19.32,7.83. LCMS(APCI)m / z208.0[M+H] +Chiral analysis was performed by chiral SFC on a Chiralpak AD-3 column (4.6 × 150 mm) at 30 °C using 15% methanol (containing 0.5% DEA) at 3 g / min. Under these conditions, the enantiomeric elution was peak 1 (t1 = 1.31 min), and Example 12 eluted as peak 2 (t1 = 1.47 min).

[0163] Example 13

[0164] (R)-8-ethyl-5,6,7,8-tetrahydroquinoline-8-ol

[0165]

[0166] Example 13: 81 mg (30%), colorless oil. 1 H NMR (400MHz, CDCl3) δ8.40(d,J=4.8Hz,1H),7.40(d,J=7.7Hz,1H),7.10(dd,J=4.8,7.7Hz,1H) ,3.52(s,1H),2.87-2.74(m,2H),2.23-2.01(m,1H),1.99-1.75(m,5H),0.93(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ160.89,146.51,136.92,131.21,122.10,72.53,34.35,32.43,28.50,19.06,7.77. LCMS(APCI)m / z 178.7[M+H] + 74% ee; Chiral analysis was performed by chiral SFC on a CHIRALPAK IG-3 column (4.6 × 150 mm), eluted with 15% methanol (containing 0.5% DEA) at 3 g / min. Under these conditions, Example 13 eluted as peak 1 (t1 = 2.35 min), and the enantiomer eluted as peak 2 (t2 = 3.07 min).

[0167] Example 14

[0168] (R)-6-chloro-4-ethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-ol

[0169]

[0170] Example 14: 122 mg (38%) of colorless oil. 1H NMR (400MHz, CDCl3) δ7.11 (d, J = 1.5Hz, 2H), 4.31-4.20 (m, 2H), 2.52 (br s, 1H), 2.20-2.01 (m, 3H), 1.88 (qd, J = 7.4, 14.4Hz, 1H), 0.93 (t, J = 7.5Hz, 3H). LCMS(APCI)m / z 214.1[M+H] + 79% ee; Chiral analysis was performed by LCMS on a LuxCellulose-4 column (4.6 × 150 mm), eluted with CH3CN / water and 0.1% formic acid at 1.2 mL / min. Under these conditions, Example 14 eluted as peak 1 (t1 = 6.85 min), and the enantiomer eluted as peak 2 (t2 = 7.04 min).

[0171] Example 15

[0172] (S)-2-(6-chloropyridin-2-yl)but-2-ol

[0173]

[0174] Example 15: 218 mg (78%), colorless oil. 1 H NMR (400MHz, CDCl3) δ7.66(t,J=7.8Hz,1H),7.28-7.26(m,1H),7.22(dd,J=0.6,7.8Hz,1H),1.88-1.66(m,2H),1.52(s,3H),0.77(t,J=7.5Hz,3H). 13 C NMR (101MHz, CDCl3) δ166.60,149.83,139.42,122.22,117.76,74.35,35.90,28.49,8.03. LCMS(APCI)m / z 186.1[M+H] + 40% ee; Chiral analysis was performed by chiral SFC on a CHIRALPAK IG-3 (4.6 × 150 mm) column eluted with 15% methanol (containing 0.5% DEA) at 3 g / min. Under these conditions, Example 15 eluted as peak 1 (t1 = 1.25 min), and the enantiomeric form eluted as peak 2 (t2 = 1.51 min).

[0175] Example 16

[0176] (S)-2-(6-bromopyridin-2-yl)but-2-ol

[0177]

[0178] Example 16: 229 mg (66%), colorless oily substance. 1 H NMR (400MHz, CDCl3) δ7.59-7.53(m,1H),7.38(dd,J=0.7,7.8Hz,1H),7.31(dd,J=0.6,7 .7Hz,1H),4.19(s,1H),1.83(dq,J=1.5,7.4Hz,2H),1.51(s,3H),0.78(t,J=7.5Hz,3H). 13 C NMR (101MHz, CDCl3) δ167.09, 140.40, 139.08, 126.00, 118.08, 74.28, 35.86, 28.42, 7.99. LCMS(APCI)m / z 230.6[M+H] + 84% ee. Chiral analysis was performed by chiral SFC on a Chiralpak IG-3 column (4.6 × 150 mm), eluted at 30°C with 20% methanol (containing 0.5% DEA) at 3 g / min. Under these conditions, Example 16 eluted as peak 1 (t1 = 1.44 min), and the enantiomer eluted as peak 2 (t1 = 1.76 min).

[0179] Example 17

[0180] (S)-2-(6-Fluoropyridin-2-yl)but-2-ol

[0181]

[0182] Example 17: 111 mg (44%), colorless oil. 1 H NMR (400MHz, CDCl3) δ7.80 (q, J = 7.9Hz, 1H), 7.27-7.24 (m, 1H), 6.82 (dd, J = 2.7, 8.1Hz, 1H), 1.89-1.80 (m, 2H), 1.53 (s, 3H), 0.78 (t, J = 7.5Hz, 3H). 13 C NMR (101MHz, CDCl3) δ165.09 (d, J = 10.3Hz), 162.42 (d, J = 241.4Hz), 141.72 (d, J =7.3Hz), 116.40 (d, J = 4.4Hz), 107.06 (d, J = 35.9Hz), 74.38, 35.83, 28.31, 7.97. LCMS(APCI)m / z170.0[M+H] +Chiral analysis was performed by chiral SFC on a Chiralpak IF-3 column (4.6 × 150 mm) at 30 °C using 10% methanol at 3 g / min. Under these conditions, Example 17 eluted as peak 1 (t1 = 1.13 min) and the enantiomer eluted as peak 2 (t1 = 1.31 min).

[0183] Example 18

[0184] (S)-2-(pyridin-2-yl)but-2-ol

[0185]

[0186] Example 18: 116 mg (51%), colorless oil. 1 H NMR (400MHz, CDCl3) δ8.51(td,J=0.8,4.9Hz,1H),7.70(dt,J=1.7,7.7Hz,1H),7.31(d,J=7.9Hz,1H),7.19(ddd,J=1.0,4.9,7.5Hz,1H),5.17(br s,1H),1.90-1.55(m,2H),1.50(s,3H),0.73(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3) δ164.79,147.14,136.89,121.69,119.23,73.85,36.02,28.81,7.97. LCMS(APCI)m / z 152.6[M+H] + Chiral analysis was performed by chiral SFC on a CHIRALPAK AD-3 column (4.6 × 150 mm) eluted with 20% methanol (containing 0.5% DEA) at 3 g / min. Under these conditions, Example 18 eluted as peak 1 (t1 = 1.17 min) and the enantiomer eluted as peak 2 (t2 = 1.32 min).

[0187] Example 19

[0188] (S)-2-(2-chloropyridin-4-yl)but-2-ol

[0189]

[0190] Example 19: 139 mg (50%), colorless oil. 1H NMR(400MHz, CDCl3) δ8.33(d,J=5.3Hz,1H),7.41(d,J=1.6Hz,1H),7.26(s,1H),7 .24(dd,J=1.6,5.3Hz,1H),1.88-1.74(m,2H),1.53(s,3H),0.81(t,J=7.5Hz,3H). 13 C NMR (101MHz, CDCl3) δ160.52,151.68,149.26,120.97,119.20,74.19,36.18,29.34,7.89. LCMS(APCI)m / z 186.1[M+H] + 75% ee; Chiral analysis was performed by chiral HPLC on a CHIRALPAK IF column (4.6 × 250 mm) using ethanol and n-hexane as eluents at a rate of 1.0 mL / min. Under the stated conditions, Example 19 eluted as peak 1 (t1 = 9.78 min), and the enantiomer eluted as peak 2 (t2 = 10.28 min).

[0191] Example 20

[0192] (S)-2-(2-bromopyridin-4-yl)but-2-ol

[0193]

[0194] Example 20: 170 mg (49%), white solid. 1 H NMR (400MHz, CDCl3) δ8.31 (d, J = 5.3Hz, 1H), 7.58 (d, J = 1.6Hz, 1H), 7.28 (dd, J = 1.6, 5.3Hz, 1H), 1.87-1.76 (m, 2H), 1.53 (s, 3H), 0.82 (t, J = 7.5Hz, 3H). 13 C NMR (101MHz, CDCl3) δ160.06,149.82,142.52,124.74,119.54,74.19,36.21,29.42,7.91. LCMS(APCI)m / z 230.6[M+H] + Chiral analysis was performed by chiral HPLC on a Lux Cellulose-4 column (4.6 × 150 mm) with 80% ee and 0.1% formic acid eluted at 1.2 mL / min. Under these conditions, Example 20 eluted as peak 1 (t1 = 6.56 min) and the enantiomer eluted as peak 2 (t1 = 6.75 min).

[0195] Example 21

[0196] (R)-2-bromo-7-methyl-6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol

[0197]

[0198] Example 21: The reaction was carried out using 10% Me₂Zn instead of Et₂Zn according to the general procedure. 54 mg (16%), white solid. 1 H NMR (400MHz, CDCl3) δ7.42 (td, J = 0.9, 7.9Hz, 1H), 7.33 (d, J = 7.9Hz, 1H), 2.99-2.90 (m, 1H), 2.81-2.69 (m, 1H), 2.34-2.18 (m, 2H), 1.59 (s, 3H). 13 C NMR (101MHz, CDCl3) δ168.09,140.69,135.66,134.61,126.89,79.27,39.27,26.69,26.33. LCMS(APCI)m / z227.9[M+H] + Chiral analysis was performed by LCMS on a Lux Cellulose-4 column (4.6 × 150 mm) with 94% ee and 0.1% formic acid eluted at 1.2 mL / min. Under these conditions, Example 21 eluted as peak 1 (t1 = 7.49 min) and the enantiomer eluted as peak 2 (t1 = 7.78 min).

[0199] Table 4

[0200]

[0201]

[0202]

[0203] As shown in Table 4, the methods described herein can be used to prepare tertiary alcohols in high yield, with high enantiomeric purity, and / or both. Furthermore, as described herein, tertiary alcohols can be used to prepare synthetic forms of natural products and pharmaceuticals.

[0204] Example D

[0205] Scale-up synthesis of (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol

[0206]

[0207] Under N2 conditions, (R)-N-(3-methyl-1-(pyrrolidone-1-yl)but-2-yl)-P,P-diphenylphosphineamide (16.0 kg, 44.9 mol) was suspended in n-heptane (125 L, 5 V) in a 1000 L reactor. The suspension was cooled to an internal temperature of -65 °C. Hexane containing 2.0 M diethylzinc (265 kg, 597 mol) was added at an average rate of 100 L / h using a peristaltic pump. The total addition time was 3 h, with a target internal temperature of -60 °C ± 5 °C. The solution was then stirred at -65 °C for 45 min. BF3·OEt2 (2.13 kg, 14.9 mol) was added over 10 min, and the mixture was stirred at -65 °C for 60 min. DCM (250 L, 10 V) containing 2-chloro-5,6-dihydro-7H-cyclopentano[b]pyridin-7-one (25.0 kg, 149 mol) was added over 3 h using a peristaltic pump. The internal temperature was maintained at -65 °C ± 5 °C. The solution was stirred at -65 °C for 1 h. The temperature was slowly increased to 14 °C over 13 h. The mixture was transferred to another container containing saturated NH4Cl (20% w / w, 125 L, 5 V) initially cooled to 0 °C. The internal temperature was quenched and maintained between 10 °C and 25 °C. The mixture was filtered, and the residue was washed with MTBE. The aqueous phase was separated and extracted with MTBE (62.5 L, 2.5 V). 125 L of NaHSO3 (1% w / w, 5 V) was added to the combined organic layer. The mixture was stirred for 30 min and then separated. Silica gel (30 kg, 1.2 wt) and activated carbon (2.5 kg) were added to the organic layer. The mixture was stirred for 60 min and then filtered. The filter cake was washed with MTBE (200 L, 8 V). The filtrate was concentrated. Recrystallization was carried out as follows: (1) the residue was dissolved in n-heptane (100 L, 4 V), (2) the mixture was heated to 60 °C and then slowly cooled to 30 °C, (3) seed crystals of (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol (1 wt%) were added, and (4) the mixture was slowly cooled to 10 °C and stirred at that temperature for 1 h. The solid was collected by filtration and then ground with 125 L NaHSO3 (1% w / w, 5 V). The slurry was stirred for 1 h and then collected by filtration. The filter cake was washed with water (125 L, 5 V) and dried under N2 flow for 15 h to give a white solid (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol (22.4 kg, 76% yield, 97.3% ee). 1H NMR(400MHz,CDCl3)δ7.50(d,J=7.9Hz,1H),7.17(d,J=8.1Hz,1H),2.99-2.90(m,1H),2.82-2.71(m,1H),2.33(ddd,J=4.3,8.7,13.4Hz,1H),2.19(ddd,J=6.8,9.0,13.5Hz,1H),2.04-1.89(m,1H),1.81(qd,J=7.3,14.1Hz,1H),0.94(t,J=7.5Hz,3H); 13 C NMR(101MHz,CDCl3)δ=166.90,150.07,135.67,134.94,123.10,81.98,36.03,32.37,26.47,8.13。LCMS(APCI)198.1[M+H] + 。

[0208] Example E

[0209] (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol form A

[0210] Under N2 atmosphere, (R)-N-(3-methyl-1-(pyrrolidone-1-yl)but-2-yl)-P,P-diphenylphosphineamide (6.38 kg, 17.9 mol) was suspended in n-heptane (32 L, 3.2 V) in a reaction vessel. The suspension was cooled to an internal temperature of -65 °C. Heptane containing 1.0 M diethylzinc (238.7 L, 238.7 mol) was added over 2 h using a peristaltic pump. The internal temperature was maintained between -48 °C and -55 °C. The solution was then stirred at -65 °C for 45 min. BF3·OEt2 (847 g, 5.97 mol) was added over 15 min, and the mixture was stirred at -65 °C for 60 min. DCM (100 L, 10 V) containing 10 kg (59.7 mol) of 2-chloro-5,6-dihydro-7H-cyclopentano[b]pyridin-7-one was added over 2 h using a peristaltic pump. The internal temperature was maintained at -65 °C ± 5 °C. The solution was stirred at -65 °C for 4 h. The temperature was slowly increased to 20 °C over 24 h. The mixture was transferred to another container containing saturated NH4Cl (100 L, 10 V) initially cooled to -5 °C. The internal temperature was quenched and maintained between 10 °C and 25 °C. The mixture was stirred for 30 min and filtered. The residue was washed with DCM (25 L, 2.5 V), and the layers were separated. The organic phase was washed with water (50 L). The aqueous phase was extracted with DCM (50 L, 5 V). The combined organic layers were concentrated. The crude residue was purified by column chromatography (SiO2) using a petroleum ether:ethyl acetate gradient: (10:1, 200 L), (5:1, 800 L), (1.5:1, 200 L). The eluent was concentrated. The residue was diluted in heptane (10 L, 1 V) and the mixture was heated to 60 °C. The mixture was slowly cooled to 30 °C and seed crystals (1 wt%) were added. The slurry was cooled to 10 °C and stirred for 1 h. The solid was collected by filtration and dried under N2 to give form A (7 kg, 59% yield, 92.1% ee) of (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopentano[b]pyridin-7-ol. Figure 1 The XRPD plot of form A is provided in Table 5, and a table of some XRPD peaks is provided in Table 5.

[0211] Table 5

[0212] Number of spectral peaks 2θ 5 16.19 9 21.00 12 24.18 13 24.88 14 26.54

[0213] Example F

[0214] (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol form B

[0215] Under N2 atmosphere, (R)-N-(3-methyl-1-(pyrrolidone-1-yl)but-2-yl)-P,P-diphenylphosphineamide (9.57 kg, 26.9 mol) was suspended in hexane (75 L, 5 V). The suspension was cooled to an internal temperature of -65 °C. Hexane containing 1.0 M diethylzinc (358 L, 358 mol) was added over 2 h using a peristaltic pump. The internal temperature was maintained at -60 °C ± 5 °C. The solution was then stirred at -65 °C for 45 min. BF3·OEt2 (1.27 kg, 8.95 mol) was added over 30 min, and the mixture was stirred at -65 °C for 60 min. DCM (150 L, 10 V) containing 15.0 kg (89.5 mol) of 2-chloro-5,6-dihydro-7H-cyclopentano[b]pyridin-7-one was added over 3 h using a peristaltic pump. The internal temperature was maintained at -65 °C ± 5 °C. The solution was stirred at -65 °C for 1 h. The temperature was slowly increased to 20 °C over 17 h. The mixture was transferred to another container containing saturated NH4Cl (150 L, 10 V) initially cooled to 0 °C. The internal temperature was quenched and maintained between 10 °C and 25 °C. The mixture was filtered and the layers were separated. The aqueous phase was extracted with MTBE (100 L). 75 L of NaHSO3 (1% w / w, 5 V) was added to the combined organic layers. The mixture was stirred for 30 min and then separated. Silica gel (30 kg, 2 wt) and activated carbon (3 kg) were added to the organic layers. The mixture was stirred for 60 min and then filtered. The filter cake was washed with MTBE (120 L, 8 V). The filtrate was concentrated, and the residue was dissolved in n-heptane (30 L, 2 V). The mixture was heated to 60 °C and then slowly cooled to 30 °C. Seed crystals (1 wt%) were added. The mixture was slowly cooled to 10 °C and stirred at that temperature for 1 h. The solid was collected by filtration and then ground with 70 L NaHSO3 (1% w / w, 5 V). The slurry was stirred for 2 h and then collected by filtration. The grinding with 1% NaHSO3 was repeated four times. The filter cake was washed with water (45 L, 3 V) and dried under N2 flow for 3 days to give a white solid (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol form B (6.76 kg, 38% yield, 99.3% ee). Figure 2 The XRPD plot of form B is provided in Table 6, and a table of some XRPD peaks is provided in Table 6.

[0216] Table 6

[0217] Number of spectral peaks 2θ 2 14.02 4 17.60 5 20.06 7 24.84 8 25.48

[0218] Furthermore, although some detailed description has been provided for clarity and understanding purposes by way of illustration and example, those skilled in the art will understand that many and various modifications can be made without departing from the spirit of this disclosure. Therefore, it should be clearly understood that the forms disclosed herein are merely illustrative and are not intended to limit the scope of this disclosure, but rather to cover all modifications and alternatives consistent with the true scope and spirit of the invention.

Claims

1. A method for preparing a tertiary alcohol or a salt thereof, the method comprising mixing the following: Optionally substituted pyridinyl ketones or their salts, wherein the optionally substituted pyridinyl ketone has a structure selected from the group consisting of: (G) (K) and (M); in: t1 is either 0 or 1; w1 and y1 are independently 0 or 1; t2 is 1 or 2; X 1g For –CH2–; X 2g It can be –CH2– or O; R 1g R 1k and R 1m Independently selected from the group consisting of: halogens, methyl groups, and methoxy groups; and R 2k and R 2m Independently methyl; Zinc reagents selected from the group consisting of: Et₂Zn, Me₂Zn, and Ph₂Zn; Having structure Chiral ligands, of which: R 1 It can be –CH3, –CH2CH3, –CH(CH3)2 or –C(CH3)3; R 2 For H; Each Ar is independently an unsubstituted or substituted phenyl group, wherein when Ar is a substituted phenyl group, the phenyl group is substituted by one or more substituents independently selected from the group consisting of methyl and methoxy groups; and b is 1 or 2; and BF3•OEt2, wherein the amount of BF3•OEt2 is 0.1 equivalent or 0.2 equivalent relative to 1 equivalent of the pyridyl ketone.

2. The method of claim 1, wherein the optionally substituted pyridyl ketone is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

3. The method of claim 1, wherein the tertiary alcohol has a structure selected from the group consisting of: (G1)、 (K1) and (M1); in: t3 is either 0 or 1; w2 and y2 are independently 0 or 1; t4 is 1 or 2; X 3g For –CH2–; X 4g It can be –CH2– or O; R 2g R 3k and R 3m Choose independently from the group consisting of: halogens, methyl groups, and methoxy groups; R 4k and R 4m Independently methyl; and R 3g R 5k and R 5m It can be -CH3 or –CH2CH3 independently.

4. The method according to any one of claims 1 to 3, wherein the chiral ligand has a structure , where each Ar is an unsubstituted phenyl group.

5. The method according to claim 4, wherein b is 1.

6. The method of claim 5, wherein R 1 It is -CH3; and R 2 For H.

7. The method of claim 5, wherein R 1 It is –CH2CH3; and R 2 For H.

8. The method of claim 5, wherein R 1 It is –CH(CH3)2; and R 2 For H.

9. The method of claim 5, wherein R 1 It is –C(CH3)3; and R 2 For H.

10. The method of claim 4, wherein b is 2.

11. The method of claim 10, wherein R 1 It is -CH3; and R 2 For H.

12. The method of claim 10, wherein R 1 It is –CH2CH3; and R 2 For H.

13. The method of claim 10, wherein R 1 It is –CH(CH3)2; and R 2 For H.

14. The method of claim 10, wherein R 1 It is –C(CH3)3; and R 2 For H.

15. The method according to any one of claims 1 to 3, wherein the chiral ligand has a structure , wherein each Ar is a substituted phenyl: methyl and methoxy substituted by one or more substituents independently selected from the group consisting of the following.

16. The method of claim 15, wherein b is 1.

17. The method of claim 16, wherein R 1 It is -CH3; and R 2 For H.

18. The method of claim 16, wherein R 1 It is –CH2CH3; and R 2 For H.

19. The method of claim 16, wherein R 1 It is –CH(CH3)2; and R 2 For H.

20. The method of claim 16, wherein R 1 It is –C(CH3)3; and R 2 For H.

21. The method of claim 15, wherein b is 2.

22. The method of claim 21, wherein R 1 It is -CH3; and R 2 For H.

23. The method of claim 21, wherein R 1 It is –CH2CH3; and R 2 For H.

24. The method of claim 21, wherein R 1 It is –CH(CH3)2; and R 2 For H.

25. The method of claim 21, wherein R 1 It is –C(CH3)3; and R 2 For H.

26. The method of claim 4, wherein the chiral ligand has a structure .

27. The method of claim 15, wherein the chiral ligand has a structure .

28. The method of claim 15, wherein the chiral ligand has a structure .

29. The method of claim 4, wherein the chiral ligand has a structure .

30. The method of claim 4, wherein the chiral ligand has a structure .

31. The method of claim 4, wherein the chiral ligand has a structure .

32. The method of claim 4, wherein the chiral ligand has a structure .

33. The method of claim 3, wherein the tertiary alcohol is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

34. The method according to any one of claims 1 to 3, wherein the obtained tertiary alcohol is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , and .

35. The method of claim 1, wherein the optionally substituted pyridinyl ketone or a salt thereof is The tertiary alcohol or its salt is The method further includes... Using NaHSO3, the ee% increased compared to before using NaHSO3. Enantiomer excess (ee%).

36. The method of claim 35, wherein the method further comprises The recrystallization, wherein the recrystallization increases compared to the ee% before recrystallization. Enantiomer excess (ee%).

37. The method of claim 36, wherein the recrystallization utilizes hexane or heptane.

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