Preparation process of S-beflubutamide by removing 2-bromobutanoic acid

Abstract

A method for preparing compound S-1, comprising: reacting compound rac-2 with a compound of formula 3, wherein R 1 , R 4 , m and n are as defined in this disclosure). [Formula 1] TIFF2023513185000153.tif41170 [2] TIFF2023513185000154.tif34170 [3] TIFF2023513185000155.tif45170

Description

[Technical field]

[0001] The present invention relates to a method for preparing the S-enantiomer of beflubutamid. [Background technology]

[0002] US Patent No. 5,999,633 discloses N-benzyl-2-(4-fluoro-3-trifluoromethylphenoxy)-butanoic acid amide of formula 1 as a herbicidal compound, which has a single asymmetric center at the 2-carbon of the amide moiety and is therefore capable of being a chiral molecule. [ka]

[0003] This racemic compound is commercially available under the name beflubutamid as a soil herbicide for pre- and post-emergence control of dicotyledonous weeds in cereals. It inhibits the enzyme phytoene-desaturase involved in the biosynthesis of carotenoids. Reduction of carotenoids leads to photooxidation of chlorophyll and bleaching / chlorosis of affected weeds.

[0004] Also, US Pat. No. 5,999,463 discloses that the (-)-enantiomer is more herbicidally active than the racemic mixture. The more active enantiomer has been identified as having the S-configuration, designated compound S-1 (Non-Patent Documents 1 and 2). [ka] [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Pat. No. 4,929,273 [Non-patent literature]

[0006] [Non-Patent Document 1] Environ.Sci.Technol.2013,47,6806-6811 [Non-Patent Document 2] Environ.Sci.Technol.2013,47,6812-6818 Summary of the Invention [Problem to be solved by the invention]

[0007] Although the methods disclosed in the above references can provide the desired compound S-1, there is a continuing need for improvement, particularly in the development of methods to provide materials on a commercial scale. Thus, there is a continuing need for new methods that are less costly, more efficient, more flexible, or more conveniently performed. [Means for solving the problem]

[0008] Embodiment A. The present invention relates to compound S-1 [ka] Compound R-2 [ka] wherein compound R-2 is compound rac-2 [ka] Equation 3 [ka] (In the formula, Each R 1 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl, C1-C6 haloalkoxy, or up to two R 2 or Two adjacent R1 The substituents, together with the phenyl to which they are attached, may be up to three R 3 forming a naphthalenyl ring optionally substituted by Each R 2 and each R 3 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl or C1-C6 haloalkoxy; Each R 4 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl, C1-C6 haloalkoxy, or up to two R 5 is phenyl optionally substituted by Each R 5 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl or C1-C6 haloalkoxy; m is 0, 1, 2 or 3, and n is 0, 1, 2 or 3, formula 4 [ka] (In the formula, R 1 , R 4 , m and n are as defined for compounds of formula 3; selectively isolating the R,R-salt of formula 4; The R,R-salt of formula 4 is treated with a sodium base to give compound R-5. [ka] and Treating compound R-5 with an acid; The present invention provides a method for preparing a compound comprising the steps of:

[0009] Embodiment B. The present invention relates to compound S-1 [ka] A method for preparing Compound R-2 [ka] wherein compound R-2 is compound rac-2 [ka] Equation 3 [ka] (In the formula, Each R 1 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl, C1-C6 haloalkoxy, or up to two R 2 or Two adjacent R 1 The substituents, together with the phenyl to which they are attached, may be up to three R 3 forming a naphthalenyl ring optionally substituted by Each R 2 and each R 3 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl or C1-C6 haloalkoxy; Each R 4 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl, C1-C6 haloalkoxy, or up to two R 5 is phenyl optionally substituted by Each R 5are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl or C1-C6 haloalkoxy; m is 0, 1, 2 or 3, and n is 0, 1, 2 or 3, formula 4 [ka] (In the formula, R 1 , R 4 , m and n are as defined for compounds of formula 3; selectively isolating the R,R-salt of formula 4; The R,R-salt of formula 4 is treated with a sodium base to give compound R-5. [ka] and treating compound R-5 with an acid; Converting compound R-2 to compound S-1 and a method for preparing the same.

[0010] Embodiment C. The present invention relates to compound S-1 [ka] A method for preparing compound rac-2 [ka] Equation 3 [ka] (In the formula, Each R 1are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl, C1-C6 haloalkoxy, or up to two R 2 or Two adjacent R 1 The substituents, together with the phenyl to which they are attached, may be up to three R 3 forming a naphthalenyl ring optionally substituted by Each R 2 and each R 3 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl or C1-C6 haloalkoxy; Each R 4 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl, C1-C6 haloalkoxy, or up to two R 5 is phenyl optionally substituted by Each R 5 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl or C1-C6 haloalkoxy; m is 0, 1, 2 or 3, and n is 0, 1, 2 or 3, formula 4 [ka] (In the formula, R 1 , R 4 , m and n are as defined for compounds of formula 3; selectively isolating the R,R-salt of formula 4; The R,R-salt of formula 4 is treated with a sodium base to give compound R-5. [ka] and Compound R-5 is treated with an acid to obtain compound R-2 [ka] and preparing Converting compound R-2 to compound S-1; Also provided is a method comprising:

[0011] Embodiment D. The present invention relates to compound S-1 [ka] A method for preparing compound rac-2 [ka] Equation 3 [ka] (In the formula, Each R 1 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl, C1-C6 haloalkoxy, or up to two R 2 or Two adjacent R 1 The substituents, together with the phenyl to which they are attached, may be up to three R 3 forming a naphthalenyl ring optionally substituted by Each R 2 and each R 3 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl or C1-C6 haloalkoxy; Each R 4are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl, C1-C6 haloalkoxy, or up to two R 5 is phenyl optionally substituted by Each R 5 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl or C1-C6 haloalkoxy; m is 0, 1, 2 or 3, and n is 0, 1, 2 or 3, formula 4 [ka] (In the formula, R 1 , R 4 , m and n are as defined for compounds of formula 3; selectively isolating the R,R-salt of formula 4; The R,R-salt of formula 4 is treated with a sodium base to give compound R-5. [ka] and Compound R-5 is treated with an acid to obtain compound R-2 [ka] and preparing Compound R-2 is treated with a chlorinating agent to obtain compound R-10. [ka] and preparing Compound R-10 was converted to compound 9 (i.e., benzylamine). [ka] Compound R-11 [ka] and preparing Compound R-11 was reacted with compound 7 (i.e., 4-fluoro-3-(trifluoromethyl)phenol). [ka] Processing by Also provided is a method comprising:

[0012] Embodiment E. The present invention relates to compound R-2 [ka] A method for preparing compound rac-2 [ka] Equation 3 [ka] (In the formula, Each R 1 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl, C1-C6 haloalkoxy, or up to two R 2 or Two adjacent R 1 The substituents, together with the phenyl to which they are attached, may be up to three R 3 forming a naphthalenyl ring optionally substituted by Each R 2 and each R 3 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl or C1-C6 haloalkoxy; Each R 4are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl, C1-C6 haloalkoxy, or up to two R 5 is phenyl optionally substituted by Each R 5 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl or C1-C6 haloalkoxy; m is 0, 1, 2 or 3, and n is 0, 1, 2 or 3, formula 4 [ka] (In the formula, R 1 , R 4 , m and n are as defined for compounds of formula 3; selectively isolating the R,R-salt of formula 4; The R,R-salt of formula 4 is treated with a sodium base to give compound R-5. [ka] and Treating compound R-5 with an acid; Also provided is a method comprising:

[0013] Embodiment F. The present invention relates to the compound rac-2 [ka] A method for preparing formula scal-2 [ka] with hydrobromic acid or a quaternary ammonium bromide salt.

[0014] Embodiment G. The present invention relates to a compound of formula 4 [ka] (In the formula, Each R 1 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl, C1-C6 haloalkoxy, or up to two R 2 or Two adjacent R 1 The substituents, together with the phenyl to which they are attached, may be up to three R 3 forming a naphthalenyl ring optionally substituted by Each R 2 and each R 3 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl or C1-C6 haloalkoxy; Each R 4 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl, C1-C6 haloalkoxy, or up to two R 5 is phenyl optionally substituted by Each R 5 are independently halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkenyl or C1-C6 haloalkoxy; m is 0, 1, 2 or 3, and n is 0, 1, 2 or 3. Also provided is the R,R-salt of DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] As used herein, the terms "comprises," "comprising," "includes," "including," "contains," "containing," "has," "having," "characterized by," or any variation thereof, are intended to include a non-exclusive inclusion, subject to any limitations expressly indicated. For example, a composition, mixture, process, or method that includes any elements is not necessarily limited to only those elements, but may include other elements not expressly indicated or inherent in such composition, mixture, process, or method.

[0016] The transitional phrase "consisting of" excludes any unspecified element, step, or ingredient. In a patent claim, it is usually relevant if the claim is closed to include, apart from impurities, substances other than those recited. When the phrase "consisting of" appears in the body of a claim rather than immediately following the preamble, it limits only the elements recited in that claim; other elements are not excluded from the claim as a whole.

[0017] The transitional phrase "consisting essentially of" is used to define a composition, process, or method that includes materials, steps, features, ingredients, or elements in addition to those literally disclosed, provided that these additional materials, steps, features, ingredients, or elements do not materially affect the basic and novel characteristics of the invention being claimed. The term "consisting essentially of" occupies a position intermediate between "comprising" and "consisting of."

[0018] It should be readily understood that if an applicant defines an invention or a portion thereof in open-ended terms such as, for example, "comprising," the statement should (unless otherwise stated) be construed as also describing such inventions using the terms "consisting essentially of" or "consisting of."

[0019] Furthermore, unless expressly stated to the contrary, "or" refers to an inclusive "or" and not an exclusive "or." For example, the condition "A or B" is satisfied by any of the following: A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist).

[0020] Furthermore, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to be open ended with regard to the number of instances (i.e., occurrences) of that element or component. Thus, "a" and "an" should be read to include one, or at least one, and such singular forms of the element or component also include the plural, unless it is clear that the number is intended to be singular.

[0021] As used herein, the term "suitable" indicates that the entity or state so described is suitable for use in the indicated situation or environment. As used herein, the term "treatment" or "treating" refers to using a chemical or chemical process to change the current state of another material, chemical, or compound. The terms "convert," "converted," variations thereof, and related terms refer to causing an entity, such as a compound, to change in structure, form, characteristics, or function. For example, a compound of a first formula or structure, as defined above, is converted to a compound of a second formula or structure by a chemical process that includes one or more treatments. The term "selectively isolate" refers to obtaining only the desired enantiomer, regioisomer, or diastereoisomer by taking advantage of the unique physical properties of the enantiomer, regioisomer, or diastereoisomer (e.g., solubility in a particular solvent or solvent system). "Selectively isolating" a desired enantiomer, regioisomer or diastereoisomer typically further includes mechanical means (i.e., filtration) to separate the desired enantiomer, regioisomer or diastereoisomer from undesired enantiomers, regioisomers or diastereoisomers (or other impurities).

[0022] As used herein, the term "intermediate" refers to a compound or chemical entity in a chemical process that is prepared at a step after a starting material is provided and before a final product is prepared. In some instances, an intermediate is not isolated during a chemical process, but is converted in situ into a subsequent compound. For example, a compound may undergo successive chemical reactions in only one reactor.

[0023] In the above description, the term "alkyl" used alone or in compound terms such as "haloalkyl" includes linear or branched alkyl, such as methyl, ethyl, n-propyl, i-propyl, or the various butyl, pentyl, or hexyl isomers. "Alkenyl" includes linear or branched alkenes, such as ethenyl, 1-propenyl, 2-propenyl, and the various butenyl, pentenyl, and hexenyl isomers. "Alkenyl" further includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. Alternatively, the term "C1-C6 alkanol" refers to C1-C6 hydroxyalkyl. "Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, and the various butoxy, pentoxy, and hexyloxy isomers.

[0024] The term "halogen", when used alone or in compound terms such as "haloalkyl", or in descriptions such as "alkyl substituted with halogen", includes fluorine, chlorine, bromine, or iodine. Furthermore, when used in compound terms such as "haloalkyl" or "haloalkenyl", or in descriptions such as "alkyl substituted with halogen", said alkyl may be partially or fully substituted with halogen atoms, which may be the same or different. Examples of "haloalkyl" or "alkyl substituted with halogen" include F3C, ClCH2, CF3CH2, and CF3CCl2. Terms such as "haloalkoxy" are defined analogously to the term "haloalkyl". Examples of "haloalkoxy" include CF3O-, CCl3CHO-, HCF2CH2CH2O-, and CF3CHO-. "Cyano" refers to the -C≡N group. "Nitro" refers to the NO2 group.

[0025] As used herein, "alkali metal" refers to elements of Group 1 of the periodic table, including lithium, sodium, potassium and cesium, preferably sodium or potassium, or their cations when used in combination with an anionic counterion to define a compound.

[0026] The term "quaternary ammonium bromide salt" refers to a compound having the structure (R 7 )4N+Br- (In the formula, each R 7 are independent, C1~C 20 alkyl or C1-C6 haloalkyl; or, each optionally having up to two R 2 or is phenyl or benzyl substituted by Two adjacent R 7 The substituents, together with the nitrogen atom to which they are attached, form a 5- to 8-membered ring structure. It refers to the bromide salt of a quaternary ammonium cation having the formula:

[0027] Examples of quaternary ammonium bromide salts include tetrabutylammonium bromide, N-cetyl-N,N,N-trimethylammonium bromide, and benzyltriethylammonium bromide.

[0028] The total number of carbon atoms in the substituent is "C i ~C j " where i and j are numbers from 1 to 6. When a compound is substituted with a substituent bearing a subscript indicating that the number of substituents can be more than one, the substituents (if they exceed one) can be independently selected from a defined group of substituents, e.g., (R 1 )m, m is selected from 0, 1, 2 or 3. If a group contains a substituent that can be hydrogen, e.g. (m=0), and then this substituent is taken to be hydrogen, this is considered equivalent to the group being unsubstituted. When various groups are shown to be optionally attached at a position (e.g., m can be 0 (R1 )m) Hydrogen may be present at positions not listed in the definitions of the various groups. When one or more positions on a group are listed as "unsubstituted" or "unsubstituted," a hydrogen atom is bonded to occupy any free valence.

[0029] As used herein, "adjacent" means that two substituents are near each other but are not directly connected. For example, "adjacent R 1 The term "substituent" refers to R groups attached to adjacent carbon atoms, such as a phenyl group. 1 The adjacent R 7 The "substituents" are geminally linked to a single nitrogen atom.

[0030] The term "optional" as used herein means that an optional condition may or may not be present. For example, if a reaction is optionally carried out in the presence of a solvent, then the solvent may or may not be present.

[0031] The term "optionally substituted" refers to a group that is unsubstituted or has at least one non-hydrogen substituent that does not destroy the chemical or biological activity retained by the unsubstituted analog. As used herein, the following definitions shall apply unless otherwise specified. The term "optionally substituted with" is used interchangeably with the phrase "substituted or unsubstituted" or the term "(un)substituted". Unless otherwise specified, an optionally substituted group may have a substituent at each exchangeable position of the group, and each substitution is independent of each other.

[0032] The present invention also includes, for example, racemic mixtures that contain essentially equal amounts of the enantiomers of 2-bromobutanoic acid.In addition, the present invention includes compounds that are enantiomerically enriched compared to racemic mixtures, such as the enantiomers of compound S-1, or any intermediate of the process described herein for preparing compound S-1.Also included are essentially pure enantiomers of compound S-1, or any intermediate of the process described herein for preparing compound S-1.

[0033] In enantiomerically enriched systems, one enantiomer is present in greater amount than the other, and the degree of enrichment can be defined in terms of enantiomeric excess (ee), which is the ratio of the enantiomers (F maj -F min )*100%, where F maj is the mole fraction of the predominant enantiomer in the mixture, and F min is the mole fraction of the minor enantiomer in a mixture (e.g., an "ee" of 20% corresponds to a 60:40 enantiomer ratio).

[0034] As used herein, compounds having at least 80% enantiomeric excess of a particular isomer, preferably at least 90% enantiomeric excess, more preferably at least 94% enantiomeric excess, at least 96% enantiomeric excess, at least 98% enantiomeric excess are designated as R- or S-, depending on the predominant configuration at the asymmetric center. Essentially enantiomerically pure embodiments (>99% ee) of the predominant enantiomer are noted. As used herein, compounds having less than 80% enantiomeric excess are designated as scalemic.

[0035] The depictions of molecules drawn herein generally follow standard conventions for depicting stereochemistry. To depict the three-dimensional configuration, bonds rising out of the plane of the drawing toward the viewer are represented as solid wedges, with the wider end of the wedge attached to an atom rising out of the plane of the drawing toward the viewer, as shown below, with group B rising out of the plane of the drawing. Hydrogen atoms attached to asymmetric centers are generally not shown, unless otherwise indicated. [ka]

[0036] Bonds that move below the plane of the figure, away from the viewer, are represented as dotted wedges with the wider end of the wedge attached to the atom further away from the viewer, i.e., group B' is below the plane of the figure. [ka]

[0037] Lines of constant width indicate bonds having the opposite or neutral orientation relative to bonds shown as solid or dotted wedges, and lines of constant width further indicate bonds in molecules or portions of molecules that are not intended to define a configuration. As used specifically herein, lines of constant width attached to an asymmetric center also represent an equal amount of R- and S-configuration at that center, e.g., a compound having a single asymmetric center is racemic. When a racemic mixture is intended herein with respect to any particular compound, it is designated by the prefix "rac-". [ka]

[0038] The wavy line indicates a bond in a molecule or a portion of a molecule where a specific configuration is not intended to be defined. Thus, as used herein, a wavy line attached to an asymmetric center represents a state in which the center has unequal amounts of R- and S-configuration, but not of sufficiently high enantiomeric excess with respect to either the R- or S-configuration, e.g., a compound with a single asymmetric center is scalemic, as defined herein. When a scalemic mixture is intended for any particular compound herein, it is indicated by the prefix "scal-". [ka]

[0039] Embodiments of the present invention include the following.

[0040] The method of Embodiment A wherein m is 0, 1 or 2.

[0041] The method of embodiment A1 wherein m is 1 or 2.

[0042] Embodiment A3. Each R 1 are independently halogen, nitro, C1-C4 alkyl, C1-C4 haloalkyl, or phenyl; Two adjacent R 1 The substituents, together with the phenyl to which they are attached, may be up to two R 3 The method of any of Embodiment A, Embodiment A1, or Embodiment A2, wherein the naphthalenyl ring is optionally substituted by

[0043] Embodiment A4. Each R 1 The method of Embodiment A3 wherein is independently halogen, nitro, C1-C4 alkyl or C1-C4 haloalkyl.

[0044] Embodiment A5. Each R 1 The method of Embodiment A4, wherein is independently halogen or C1-C4 alkyl.

[0045] In the embodiment A6.m is 2 and two adjacent R 1 The method of Embodiment A3 wherein the substituents, together with the phenyl to which they are attached, form an unsubstituted naphthalenyl ring.

[0046] Embodiment A7. The method of any of Embodiments A through A6, wherein n is 0, 1, or 2.

[0047] The method of embodiment A7, wherein n is 1 or 2.

[0048] Embodiment A9. Each R 4 The method of Embodiment A8, wherein is independently halogen, nitro, C1-C4 alkyl or C1-C4 haloalkyl.

[0049] Embodiment A10. Each R 4 The method of Embodiment A9, wherein is independently halogen or C1-C4 alkyl.

[0050] The method of embodiment A7, wherein n is 0.

[0051] Embodiment A12. The compound of formula 3 is (αR)-α-Methyl-N-(phenylmethyl)-benzenemethanamine, N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine, 2,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 3,4-Dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,6-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,4,6-trimethyl-N-[(1R)-1-phenylethyl]-benzenemethanamine, 4-nitro-N-[(1R)-1-phenylethyl]-benzenemethanamine, and 2-Methyl-3-phenyl-N-[(1R)-1-phenylethyl]-benzenemethanamine The method of any of embodiments A-A11, wherein the compound is selected from the group consisting of:

[0052] In the embodiment A13.m is 2 and two adjacent R 1 The method of any of Embodiments A through A12, wherein the substituents, together with the phenyl to which they are attached, form an unsubstituted 1-naphthalenyl ring and n is 0, i.e., the compound of Formula 3 is compound 3A [N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine]. [ka]

[0053] Embodiment A14. Compound R-2 is Compound R-2 is treated with a C1-C6 alkanol to give compound R-6 [ka] (In the formula, R 6 is C1-C6 alkyl; Compound of formula R-6 is compound 7 [ka] Treated according to formula S-8 [ka] (In the formula, R 6 is C1-C6 alkyl; The compound of formula S-8 was mixed with compound 9 [ka] Processing by The method of any of embodiments A through A13, wherein compound S-1 is converted to compound S-1 by a process comprising:

[0054] Treatment of compound R-2 to prepare a compound of formula R-6 Compound R-2 is treated with a chlorinating agent to obtain compound R-10. [ka] and preparing Treating compound R-10 with a C1-C6 alkanol or a salt thereof; The method of embodiment A14, comprising:

[0055] Embodiment A16. The method of Embodiment A15 wherein the chlorinating agent is thionyl chloride.

[0056] Embodiment A17.R 6 The method of any of embodiments A14-A16, wherein is CH3.

[0057] Embodiment A18. Compound R-2 is prepared by treating compound R-2 with a chlorinating agent to give compound R-10. [ka] and preparing Compound R-10 to Compound 9 [ka] Compound R-11 [ka] and preparing Compound R-11 to compound 7 [ka] Processing by The method of any of embodiments A through A13, wherein compound S-1 is converted to compound S-1 by a process comprising:

[0058] Embodiment A19. The method of Embodiment A18 wherein the chlorinating agent is thionyl chloride.

[0059] The method of Embodiment B wherein m is 0, 1 or 2.

[0060] The method of embodiment B1 wherein embodiment B2.m is 1 or 2.

[0061] Embodiment B3. Each R 1 are independently halogen, nitro, C1-C4 alkyl, C1-C4 haloalkyl, or phenyl; Two adjacent R 1 The substituents, together with the phenyl to which they are attached, may be up to two R 3 The method of any of Embodiment B, Embodiment B1 or Embodiment B2, wherein the naphthalenyl ring is optionally substituted by

[0062] Embodiment B4. Each R 1 The method of Embodiment B3, wherein is independently halogen, nitro, C1-C4 alkyl or C1-C4 haloalkyl.

[0063] Embodiment B5. Each R 1 The method of Embodiment B4, wherein is independently halogen or C1-C4 alkyl.

[0064] In the embodiment B6.m is 2 and two adjacent R 1 The method of Embodiment B3 wherein the substituents, together with the phenyl to which they are attached, form an unsubstituted naphthalenyl ring.

[0065] The method of any of Embodiments B through B6, wherein n is 0, 1, or 2.

[0066] The method of embodiment B7, wherein n is 1 or 2.

[0067] Embodiment B9. Each R 4 The method of Embodiment B8, wherein is independently halogen, nitro, C1-C4 alkyl or C1-C4 haloalkyl.

[0068] Embodiment B10. Each R 4 The method of Embodiment B9, wherein is independently halogen or C1-C4 alkyl.

[0069] The method of embodiment B7, wherein n is 0.

[0070] Embodiment B12. A compound of formula 3: (αR)-α-Methyl-N-(phenylmethyl)-benzenemethanamine, N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine, 2,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 3,4-Dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,6-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,4,6-trimethyl-N-[(1R)-1-phenylethyl]-benzenemethanamine, 4-nitro-N-[(1R)-1-phenylethyl]-benzenemethanamine, and 2-Methyl-3-phenyl-N-[(1R)-1-phenylethyl]-benzenemethanamine The method of any of embodiments B-B11, wherein the compound is selected from the group consisting of:

[0071] In the embodiment B13.m is 2 and two adjacent R 1 The method of any of Embodiments B through B12, wherein the substituents, together with the phenyl to which they are attached, form an unsubstituted 1-naphthalenyl ring and n is 0, i.e., the compound of Formula 3 is compound 3A [N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine]. [ka]

[0072] Embodiment B14. Compound R-2 is Compound R-2 is treated to give a compound of formula R-6 [ka] (In the formula, R6 is C1-C6 alkyl; Compound of formula R-6 is compound 7 [ka] Treated according to formula S-8 [ka] (In the formula, R 6 is C1-C6 alkyl; Compound S-8 is treated as compound 9 [ka] Processing by The method of any of embodiments B through B13, wherein compound S-1 is converted to compound S-1 by a process comprising:

[0073] Embodiment B15. Treating compound R-2 to prepare a compound of formula R-6 Compound R-2 is treated with a chlorinating agent to obtain compound R-10. [ka] and preparing Treating compound R-10 with a C1-C6 alkanol or a salt thereof; The method of embodiment B14, comprising:

[0074] Embodiment B16. The method of Embodiment B15 wherein the chlorinating agent is thionyl chloride.

[0075] Embodiment B17.R 6 The method of any of embodiments B14-B16, wherein is CH3.

[0076] Embodiment B18. Converting compound R-2 to compound S-1 by Compound R-2 is treated with a chlorinating agent to obtain compound R-10. [ka] and preparing Compound R-10 to Compound 9 [ka] Compound R-11 [ka] and preparing Compound R-11 to compound 7 [ka] Processing by The method of any of embodiments B-B13, comprising:

[0077] Embodiment B19. The method of Embodiment B18 wherein the chlorinating agent is thionyl chloride.

[0078] The method of embodiment C, wherein m is 0, 1 or 2.

[0079] The method of embodiment C1, wherein m is 1 or 2.

[0080] Embodiment C3. Each R 1 are independently halogen, nitro, C1-C4 alkyl, C1-C4 haloalkyl, or phenyl; Two adjacent R 1 The substituents, together with the phenyl to which they are attached, may be up to two R 3 The method of any of Embodiment C, Embodiment C1 or Embodiment C2, wherein the naphthalenyl ring is optionally substituted by

[0081] Embodiment C4. Each R 1 The method of Embodiment C3, wherein is independently halogen, nitro, C1-C4 alkyl, or C1-C4 haloalkyl.

[0082] Embodiment C5. Each R 1The method of Embodiment C4, wherein is independently halogen or C1-C4 alkyl.

[0083] In the embodiment C6.m is 2 and two adjacent R 1 The method of Embodiment C3 wherein the substituents, together with the phenyl to which they are attached, form an unsubstituted naphthalenyl ring.

[0084] Embodiment C7. The method of any of Embodiments C through C6, wherein n is 0, 1 or 2.

[0085] The method of embodiment C7, wherein n is 1 or 2.

[0086] Embodiment C9. Each R 4 The method of Embodiment C8, wherein is independently halogen, nitro, C1-C4 alkyl, or C1-C4 haloalkyl.

[0087] Embodiment C10. Each R 4 The method of Embodiment C9, wherein is independently halogen or C1-C4 alkyl.

[0088] The method of embodiment C7, wherein n is 0.

[0089] Embodiment C12. A compound of formula 3 (αR)-α-Methyl-N-(phenylmethyl)-benzenemethanamine, N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine, 2,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 3,4-Dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,6-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,4,6-trimethyl-N-[(1R)-1-phenylethyl]-benzenemethanamine, 4-nitro-N-[(1R)-1-phenylethyl]-benzenemethanamine, and 2-Methyl-3-phenyl-N-[(1R)-1-phenylethyl]-benzenemethanamine The method of any of embodiments C-C11, wherein the compound is selected from the group consisting of:

[0090] In the embodiment C13.m is 2 and two adjacent R 1 The method of any of Embodiments C-C12, wherein the substituents, together with the phenyl to which they are attached, form an unsubstituted 1-naphthalenyl ring and n is 0, i.e., the compound of Formula 3 is compound 3A [N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine]. [ka]

[0091] Embodiment C14. Compound R-2 is Compound R-2 is treated to give a compound of formula R-6 [ka] (In the formula, R 6 is C1-C6 alkyl; Compound of formula R-6 is compound 7 [ka] Treated according to formula S-8 [ka] (In the formula, R 6 is C1-C6 alkyl; The compound of formula S-8 was mixed with compound 9 [ka] Processing by The method of any of embodiments C-C13, wherein compound S-1 is converted to compound S-1 by a process comprising:

[0092] Embodiment C15. Treating compound R-2 to prepare a compound of formula R-6 Compound R-2 is treated with a chlorinating agent to obtain compound R-10. [ka] and preparing Treating compound R-10 with a C1-C6 alkanol or a salt thereof; The method of embodiment C14, comprising:

[0093] Embodiment C16. The method of Embodiment C15 wherein the chlorinating agent is thionyl chloride.

[0094] Embodiment C17.R 6 The method of any of embodiments C14-C16, wherein is CH3.

[0095] Embodiment C18. Converting compound R-2 to compound S-1 by treating compound R-2 with a chlorinating agent to prepare a compound of formula R-10; Compound R-10 was treated with compound 9 to give compound R-11 [ka] and preparing Treating compound R-11 with compound 7 The method of any of embodiments C-C13, comprising:

[0096] Embodiment C19. The method of Embodiment C18 wherein the chlorinating agent is thionyl chloride.

[0097] The method of embodiment D, wherein m is 0, 1 or 2.

[0098] The method of embodiment D1 wherein m is 1 or 2.

[0099] Embodiment D3. Each R 1are independently halogen, nitro, C1-C4 alkyl, C1-C4 haloalkyl, or phenyl; Two adjacent R 1 The substituents, together with the phenyl to which they are attached, may be up to two R 3 forming a naphthalenyl ring optionally substituted by The method of any of embodiment D, embodiment D1 or embodiment D2.

[0100] Embodiment D4. Each R 1 The method of Embodiment D3 wherein is independently halogen, nitro, C1-C4 alkyl or C1-C4 haloalkyl.

[0101] Embodiment D5. Each R 1 The method of Embodiment D4, wherein is independently halogen or C1-C4 alkyl.

[0102] In embodiment D6.m is 2 and two adjacent R 1 The method of Embodiment D3 wherein the substituents, together with the phenyl to which they are attached, form an unsubstituted naphthalenyl ring.

[0103] The method of any of Embodiments D-D6, wherein n is 0, 1, or 2.

[0104] The method of embodiment D7, wherein n is 1 or 2.

[0105] Embodiment D9. Each R 4 The method of Embodiment D8, wherein is independently halogen, nitro, C1-C4 alkyl, or C1-C4 haloalkyl.

[0106] Embodiment D10. Each R 4 The method of Embodiment D9, wherein is independently halogen or C1-C4 alkyl.

[0107] The method of embodiment D7, wherein n is 0.

[0108] Embodiment D12. The compound of formula 3 is (αR)-α-Methyl-N-(phenylmethyl)-benzenemethanamine, N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine, 2,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 3,4-Dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,6-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,4,6-trimethyl-N-[(1R)-1-phenylethyl]-benzenemethanamine, 4-nitro-N-[(1R)-1-phenylethyl]-benzenemethanamine, and 2-Methyl-3-phenyl-N-[(1R)-1-phenylethyl]-benzenemethanamine The method of any of embodiments D-D11, wherein the compound is selected from the group consisting of:

[0109] In the embodiment D13.m is 2 and two adjacent R 1 The method of any of Embodiments D-D12, wherein the substituents, together with the phenyl to which they are attached, form an unsubstituted 1-naphthalenyl ring and n is 0, i.e., the compound of Formula 3 is compound 3A [N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine]. [ka]

[0110] Embodiment D14. The method of any of Embodiments D-D13 wherein the chlorinating agent is thionyl chloride.

[0111] The method of Embodiment E, wherein m is 0, 1 or 2.

[0112] The method of embodiment E1, wherein m is 1 or 2.

[0113] Embodiment E3. Each R 1 are independently halogen, nitro, C1-C4 alkyl, C1-C4 haloalkyl, or phenyl; Two adjacent R 1 The substituents, together with the phenyl to which they are attached, may be up to two R 3 forming a naphthalenyl ring optionally substituted by The method of any of embodiment E, embodiment E1, or embodiment E2.

[0114] Embodiment E4. Each R 1 The method of embodiment E3, wherein is independently halogen, nitro, C1-C4 alkyl, or C1-C4 haloalkyl.

[0115] Embodiment E5. Each R 1 The method of embodiment E4, wherein is independently halogen or C1-C4 alkyl.

[0116] In the embodiment E6.m is 2 and two adjacent R 1 The method of embodiment E3 wherein the substituents, together with the phenyl to which they are attached, form an unsubstituted naphthalenyl ring.

[0117] Embodiment E7. The method of any of Embodiments E-E6, wherein n is 0, 1, or 2.

[0118] The method of embodiment E7, wherein n is 1 or 2.

[0119] Embodiment E9. Each R 4 The method of embodiment E8, wherein is independently halogen, nitro, C1-C4 alkyl, or C1-C4 haloalkyl.

[0120] Embodiment E10. Each R 4 The method of embodiment E9, wherein is independently halogen or C1-C4 alkyl.

[0121] The method of embodiment E7, wherein n is 0.

[0122] Embodiment E12. The compound of formula 3 is (αR)-α-Methyl-N-(phenylmethyl)-benzenemethanamine, N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine, 2,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 3,4-Dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,6-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,4,6-trimethyl-N-[(1R)-1-phenylethyl]-benzenemethanamine, 4-nitro-N-[(1R)-1-phenylethyl]-benzenemethanamine, and 2-Methyl-3-phenyl-N-[(1R)-1-phenylethyl]-benzenemethanamine The method of any of embodiments E-E11, wherein the compound is selected from the group consisting of:

[0123] In the embodiment E13.m is 2 and two adjacent R 1 The method of embodiment E6, wherein the substituents together with the phenyl to which they are attached form an unsubstituted 1-naphthalenyl ring and n is 0, i.e., the compound of formula 3 is compound 3A [N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine]. [ka]

[0124] Embodiment F1. The method of embodiment F wherein compound scal-2 is predominantly (S)-2-bromobutanoic acid.

[0125] Embodiment F2. The method of Embodiment F or Embodiment F1 wherein compound scal-2 is treated with hydrobromic acid.

[0126] Embodiment F3. The method of Embodiment F or Embodiment F1 wherein compound scal-2 is treated with a quaternary ammonium bromide salt.

[0127] Embodiment F4. The method of embodiment F3 wherein the quaternary ammonium bromide salt is tetrabutylammonium bromide.

[0128] Embodiment G1. A salt of embodiment G wherein m is 0, 1 or 2.

[0129] Embodiment G2. A salt of Embodiment G1 wherein m is 1 or 2.

[0130] Embodiment G3. Each R 1 are independently halogen, nitro, C1-C4 alkyl, C1-C4 haloalkyl, or phenyl; Two adjacent R 1 The substituents, together with the phenyl to which they are attached, may be up to two R 3 forming a naphthalenyl ring optionally substituted by A salt of any of Embodiment G, Embodiment G1 or Embodiment G2.

[0131] Embodiment G4. Each R 1 The salt of embodiment G3, wherein is independently halogen, nitro, C1-C4 alkyl or C1-C4 haloalkyl.

[0132] Embodiment G5. Each R 1 The salt of embodiment G4, wherein is independently halogen or C1-C4 alkyl.

[0133] In the embodiment G6.m is 2 and two adjacent R 1 A salt of embodiment G3 wherein the substituents, together with the phenyl to which they are attached, form an unsubstituted naphthalenyl ring.

[0134] Embodiment G7. A salt of any of Embodiments G through G6, wherein n is 0, 1 or 2.

[0135] Embodiment G8. A salt of embodiment G7 wherein n is 1 or 2.

[0136] Embodiment G9. Each R 4 The salt of embodiment G8, wherein is independently halogen, nitro, C1-C4 alkyl or C1-C4 haloalkyl.

[0137] Embodiment G10. Each R 4 The salt of embodiment G9, wherein is independently halogen or C1-C4 alkyl.

[0138] Embodiment G11. A salt of embodiment G7 wherein n is 0.

[0139] Embodiment G12. The salt of formula 4 is (αR)-α-Methyl-N-(phenylmethyl)-benzenemethanamine, N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine, 2,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 3,4-Dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,6-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,4,6-trimethyl-N-[(1R)-1-phenylethyl]-benzenemethanamine, 4-nitro-N-[(1R)-1-phenylethyl]-benzenemethanamine, and 2-Methyl-3-phenyl-N-[(1R)-1-phenylethyl]-benzenemethanamine The salt of any of embodiments G through G11, which comprises an amine selected from the group consisting of:

[0140] In the embodiment G13.m is 2 and two adjacent R 1 A salt of embodiment G6 wherein the substituents together with the phenyl to which they are attached form an unsubstituted 1-naphthalenyl ring and n is 0, ie, a salt of formula 4A. [ka]

[0141] The embodiments of the invention, including the above embodiments A-A19, B-B19, C-C19, D-D14, E-E13, F-F4, and G-G13, as well as any other embodiments described herein (including embodiments P1-P10), may be combined in any manner, and the descriptions of variables in the embodiments pertain not only to compound S-1, but also to starting compounds and intermediate compounds of formulas 2-11 that are useful for preparing compound S-1.

[0142] Preferred embodiments include the following:

[0143] Embodiment P1. m is 1 or 2; n is 0, and Each R 1 are independently halogen, nitro, C1-C4 alkyl, C1-C4 haloalkyl, or phenyl; Two adjacent R 1 The method of any of the above embodiments A, B, C, D or E wherein the substituents taken together with the phenyl to which they are attached form an unsubstituted naphthalenyl ring.

[0144] Embodiment P2. The compound of formula 3 is (αR)-α-Methyl-N-(phenylmethyl)-benzenemethanamine, N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine, 2,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 3,4-Dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,6-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,4,6-trimethyl-N-[(1R)-1-phenylethyl]-benzenemethanamine, 4-nitro-N-[(1R)-1-phenylethyl]-benzenemethanamine, and 2-Methyl-3-phenyl-N-[(1R)-1-phenylethyl]-benzenemethanamine The method of any of the above embodiments A, B, C, D or E, selected from the group consisting of:

[0145] In the embodiment P3.m is 2 and two adjacent R 1 The method of any of the above embodiments A, B, C, D or E wherein the substituents taken together with the phenyl to which they are attached form an unsubstituted 1-naphthalenyl ring and n is 0.

[0146] Embodiment P4. Compound R-2 has the formula S-8 [ka] (In the formula, R 6 is C1-C6 alkyl; and The compound of formula S-8 is compound 9 [ka] The method of any of the above embodiments A, B, C, D or E, wherein

[0147] Embodiment P5. Compound R-2 is treated to form a compound of formula R-6 [ka] (In the formula, R 6 is C1-C6 alkyl; and compound R-2 is converted to a compound of formula S-8 by a process comprising preparing a compound of formula S-8; The compound of formula R-6 is compound 7 [ka] The method of any of the above embodiments A, B, C, D or E, wherein

[0148] Embodiment P6. Compound R-2 is treated with a chlorinating agent to give compound R-10 [ka] Prepare Compound R-10 to Compound 9 [ka] Compound R-11 was obtained by treating with [ka] Prepare Compound R-11 to compound 7 [ka] The method of any of embodiments A, B, C, D or E above, wherein

[0149] Embodiment P7. The method of Embodiment P6 wherein the chlorinating agent is thionyl chloride.

[0150] Embodiment P8. m is 1 or 2; n is 0, and Each R 1 are independently halogen, nitro, C1-C4 alkyl, C1-C4 haloalkyl, or phenyl; Two adjacent R 1 A salt of embodiment G wherein the substituents, together with the phenyl to which they are attached, form an unsubstituted naphthalenyl ring.

[0151] Embodiment P9. (αR)-α-Methyl-N-(phenylmethyl)-benzenemethanamine, N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine, 2,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 3,4-Dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,6-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,4,6-trimethyl-N-[(1R)-1-phenylethyl]-benzenemethanamine, 4-nitro-N-[(1R)-1-phenylethyl]-benzenemethanamine, and 2-Methyl-3-phenyl-N-[(1R)-1-phenylethyl]-benzenemethanamine The salts of embodiment P7 include salts of an amine selected from the group consisting of:

[0152] In the embodiment P10.m is 2 and two adjacent R 1 A salt of embodiment P7, wherein the substituents together with the phenyl to which they are attached form an unsubstituted 1-naphthalenyl ring, and n is 0.

[0153] In the following scheme, R in the compounds of the following formulae R3 to R11 1 , R 2 , R 3 , R 4 The definitions of and m are as defined in the Summary of the Invention and Description of the Preferred Embodiments above, unless otherwise specified.

[0154] The methods described herein provide an efficient and reliable synthesis of compound S-1.

[0155] As summarized in Scheme 1, compounds of formula S-1 can be prepared from compound R-2, which is obtained by isolation of compound rac-2, as described in more detail with reference to Scheme 2. Conversion of compound R-2 to compound S-1 can be achieved by any of several reaction sequences described hereinafter. [ka]

[0156] Obtaining an acid with high enantiomeric purity can be achieved in several ways, including catalytic asymmetric synthesis, chromatographic separation, extractive separation, membrane separation, enzymatic separation, and diastereomeric salt separation. Optical separation of racemic substrates by diastereomeric salt formation is one of the more practical and economical approaches for industrial-scale production. However, the efficiency of diastereomeric salt separation depends on the different solubility of the diastereomeric salts in at least one solvent. Finding the appropriate resolving agent / solvent combination for a given racemate is a time-consuming and labor-intensive process, mainly by trial and error. Obtaining a high enantiomeric excess may require multiple recrystallizations of the diastereomeric salts, which can be very detrimental to industrial processes.

[0157] Separation of 2-halo acids using optically active 1-(1-naphthyl)ethylamine has been disclosed (JP 61227549 A). Separation of 4-chloromandelic acid using (R)-(+)-benzyl-1-phenylethylamine has been disclosed (Molecules 2018, 23, 3354).

[0158] As shown in Scheme 2, separation of racemic 2-bromobutanoic acid (compound rac-2) can be achieved with high efficiency by treatment with a compound of formula 3 having an R-configuration at the asymmetric center. Treatment of rac-2 with a compound of formula 3 provides the R,R- and R,S-diastereomeric salts of the compound of formula 3 with R- or S-2-bromobutanoic acid, respectively. Suitable solvents include ketones such as acetone and methyl isobutyl ketone (MIBK), alcohols such as methanol, ethanol and isopropanol, optionally mixed with water, polar aprotic solvents such as acetonitrile and ethyl acetate, and hydrocarbons such as hexane, petroleum ether, heptane and toluene, and mixtures thereof. The R,R-diastereomeric salts of formula 4 are generally less soluble or more stable salts and can be selectively isolated by filtration. [ka]

[0159] The resulting solid salt of formula 4 is treated with an aqueous base, for example, sodium bicarbonate, to provide a water-soluble sodium salt of formula R-5. Extraction with an organic solvent, such as toluene, can recover the separating agent of formula 3 for use in subsequent separation. Treatment of compound R-5 with an acid provides compound R-2, which can be extracted from the aqueous phase with a suitable organic solvent, such as toluene.

[0160] As shown in Scheme 3, compounds of formula 3 can be prepared by treatment of an optionally substituted (R)-1-phenylethylamine (i.e., a compound of formula 13) with the desired benzyl halide or naphthalenylmethyl halide, typically in the presence of an additional base such as potassium carbonate, and optionally in a suitable solvent. Certain compounds of formula 3 are disclosed in JP2005023055A. Suitable additional bases for the reaction include alkali metal alkoxides, such as sodium isopropoxide and potassium tert-butoxide; or alkali metal hydroxides, such as potassium hydroxide and sodium hydroxide; or alkali metal carbonates and bicarbonates, such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, and cesium carbonate. A preferred base is potassium carbonate. Suitable solvents include acetonitrile, dichloromethane, dichloroethane, toluene, tetrahydrofuran, dimethylsulfoxide, or N,N-dimethylformamide. A preferred solvent includes N,N-dimethylformamide.

[0161] Preferred compounds of formula 3 include those in which n is 0 and / or each R 1 are independently halogen, nitro, C1-C4 alkyl or phenyl; or two adjacent R 1 Included are those substituents taken together with the phenyl to which they are attached that form an unsubstituted naphthalenyl ring. [ka]

[0162] Compound 3A is more preferred (see Scheme 4), most preferably when used with a solvent mixture of heptane and MIBK. Using the most preferred combination of compound 3A with a mixture of heptane and MIBK, compound R-2 was obtained in 38% yield (76% of the available R-enantiomer of rac-2) with 96% ee without the need for recrystallization of the compound of formula 4. [ka]

[0163] It can be appreciated that the procedure outlined in Scheme 2 can be used to obtain compound S-2, if desired, with equal efficiency as when the S-enantiomer of the compound of formula 3 is used. [ka]

[0164] R-2-halobutanoic acid can also be obtained by treating racemic 2-halobutanoic acid with a 2-halo acid dehalogenase or a haloalkane dehalogenase, which selectively reacts with the S-halo enantiomer to produce R-2-halobutanoic acid of high enantiomeric purity (JP 04325096 A; JP 02238895 A).

[0165] For industrial applications and avoidance of waste, it is preferred to recycle and reuse the undesired enantiomer in the separation to the racemic material to prepare the desired enantiomer. This can be achieved as summarized in Scheme 5. The mother liquor and washes obtained from the filtration of the solid product R,R-diastereomeric salt of formula 4 can be treated as described, with reference to Scheme 3, to obtain a scalemic mixture of compound scal-2, which is mainly S-2-bromobutanoic acid with an ee of about 70-80%, for example about 74-78%. Compound scal-2 can be treated with concentrated hydrobromic acid or a quaternary ammonium bromide salt to provide compound rac-2 with essentially 0% ee. A notable quaternary ammonium bromide salt is tetrabutylammonium bromide. [ka]

[0166] As shown in Scheme 6, compound R-2 can be converted to compound R-6 by treatment with a C1-C6 alkanol by acid-catalyzed esterification or by dehydration with a water-absorbing agent such as zeolite. Methyl or ethyl esters are preferred, with methyl esters being more preferred. Alternatively, compound R-10 can be prepared by treatment with a chlorinating agent, followed by conversion of compound R-2 to compound R-6 by treatment with a C1-C6 alkanol. Suitable chlorinating agents include POCl3, SOCl2, (COCl)2 or COCl2. Thionyl chloride (SOCl2) is a preferred chlorinating agent. Suitable solvents include acetonitrile, dichloroethane, toluene, tetrahydrofuran, dimethylsulfoxide or N,N-dimethylformamide. Preferred solvents include N,N-dimethylformamide, dichloroethane, toluene or acetonitrile, more preferably toluene. [ka]

[0167] Compounds of formula R-6 can also be prepared by kinetic resolution of compounds of formula rac-6 using lipase enzymes (CN105063120). [ka]

[0168] As shown in Scheme 7, a compound of formula R-6 can be treated with a compound of formula 7 in the presence of a base to provide a compound of formula S-8. Suitable solvents include acetonitrile, dichloroethane, toluene, isopropanol, tetrahydrofuran, dimethylsulfoxide, or N,N-dimethylformamide. Preferred solvents include dichloroethane, toluene, acetonitrile, or N,N-dimethylformamide, more preferably toluene. Additional bases suitable for the reaction include alkali metal hydrides such as sodium hydride; or alkali metal alkoxides such as sodium isopropoxide and potassium tert-butoxide; or alkali metal hydroxides such as potassium hydroxide and sodium hydroxide; or alkali metal carbonates and bicarbonates such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, and cesium carbonate; or bases such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and lithium diisopropylamide; or tertiary amines such as triethylamine and diisopropylethylamine. Preferred bases include sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate, preferably as an aqueous solution.

[0169] The compound of formula S-8 can be treated with compound 9 (i.e., benzylamine) to provide compound S-1. Preferably, the treatment comprises heating the compound of formula S-8 with about 2-5 molar equivalents, such as about 3 molar equivalents, of compound 9 at about 100-125° C., such as about 110-120° C. Optionally, a solvent such as toluene can be used. After removal of excess benzylamine, the resulting crude material can be recrystallized from a mixture of isopropanol and water to provide compound S-1. [ka]

[0170] Alternatively, as shown in scheme 8, compound R-10 prepared in scheme 6 can be treated with a compound of formula 9 in the presence of an additional base to prepare compound R-11. Suitable solvents include acetonitrile, dichloroethane, toluene, tetrahydrofuran, dimethylsulfoxide or N,N-dimethylformamide. Preferred solvents include N,N-dimethylformamide, dichloroethane, toluene or acetonitrile, more preferably toluene. Suitable additional bases for the reaction include alkali metal hydrides such as sodium hydride; or alkali metal alkoxides such as sodium isopropoxide and potassium tert-butoxide; or alkali metal hydroxides such as potassium hydroxide and sodium hydroxide; or alkali metal carbonates and bicarbonates such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate; or bases such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and lithium diisopropylamide; or tertiary amines such as triethylamine and diisopropylethylamine. Preferred bases include sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate, preferably as an aqueous solution.

[0171] Compound R-11 can be treated with compound 7 in the presence of additional base to prepare compound S-1. Suitable solvents include acetonitrile, dichloroethane, toluene, isopropanol, tetrahydrofuran, dimethylsulfoxide or N,N-dimethylformamide. Preferred solvents include N,N-dimethylformamide, dichloroethane, toluene or acetonitrile, more preferably toluene. Suitable additional bases for the reaction include alkali metal hydrides such as sodium hydride; or alkali metal alkoxides such as sodium isopropoxide and potassium tert-butoxide; or alkali metal hydroxides such as potassium hydroxide and sodium hydroxide; or alkali metal carbonates and bicarbonates such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate; or bases such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and lithium diisopropylamide; or tertiary amines such as triethylamine and diisopropylethylamine. Preferred bases include sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate, preferably as an aqueous solution. [ka]

[0172] In some embodiments, each of the compounds of formula R-2, R-6, R-10 and R-11 can be isolated after preparation and before being transported to the next step. Alternatively, two or more steps from compound R-2 to compound S-1 can be combined without isolating the intermediate compound. For example, if compound R-2 is extracted from the aqueous phase after acidification with toluene, it can be treated with a chlorinating agent to prepare compound R-10 without isolation. In other embodiments, the conversion of compound R-2 to compound R-6 or compound R-11 can be carried out without isolating compound R-10. In another embodiment, compound R-10 can be converted to compound S-1 without isolating compound R-11. In another embodiment, the conversion of compound R-2 to compound S-1 can be carried out without isolating compounds R-10 and R-11.

[0173] Compound R-11 can also be prepared by kinetic resolution of compound rac-11 using haloalkane dehalogenase (Adv. Synth. Catal. 2011, 353, 931-944). [ka]

[0174] It is recognized that some of the reagents and reaction conditions described above for the preparation of compounds of formulas 1-11 may not be compatible with certain functionalities present in the intermediates. In those cases, the synthesis may employ a sequence of protection / deprotection or functional group interconversion to obtain the desired reaction product. The use and selection of protecting groups will be apparent to those familiar with chemical synthesis (see, for example, Greene, TW; Wuts, PGM, Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). Those skilled in the art will recognize that in some cases, it may be necessary to carry out additional conventional synthetic steps, not detailed, after the introduction of a given reagent shown in any individual scheme, in order to complete the synthesis of compounds of formulas 1-11. Those skilled in the art will also recognize that it may be necessary to combine and carry out the steps described in the above schemes in a different order than the specific order presented to prepare compounds of formulas 1-11. Additionally, one of skill in the art will recognize that the compounds of Formulas 1-11 and intermediates described herein can also be subjected to a variety of electrophilic, nucleophilic, radical, organometallic, oxidative, and reductive reactions to add substituents or modify existing substituents.

[0175] It is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent without undue effort. The following embodiments are therefore to be construed as merely illustrative and are not to be construed as limiting the disclosure in any manner. The steps in the following examples are intended to describe the procedure for each step in the overall synthetic transformation, and the starting material for each step is not necessarily prepared by the particular preparation procedure whose procedure is described in another example or step. Percentages are by weight. The abbreviation "h" stands for "hours". The abbreviation "GCA" stands for "gas chromatography area". EXAMPLES

[0176] Synthesis Example 1 Step 1: Preparation of N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine A 3-liter round bottom flask equipped with stirrer, condenser and thermometer pocket was charged with N,N-dimethylformamide (1000 g), (R)-1-phenylethanamine (243.10 g, 2 mol) and potassium carbonate (423.10 g, 3.0 mol). To this mixture was slowly added 1-(chloromethyl)naphthalene (347 g, 1.959 mol) at 28° C. The resulting slurry was heated to 45-46° C. and maintained at that temperature for 13 hours. The reaction mass was cooled to 27-28° C. and the salts were removed by filtration, washing with N,N-dimethylformamide (250 g x 2). The combined N,N-dimethylformamide filtrate was concentrated by distillation under reduced pressure to give the title compound (535.0 g). The purity by GCA was 95.98% and the yield was 98.25%.

[0177] Synthesis Example 2 Isolation of racemic 2-bromobutanoic acid Step 1: Preparation of salts of N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine and (R) 2-bromobutanoic acid A 3-liter round bottom flask equipped with a stirrer, condenser and thermometer pocket was charged with racemic 2-bromobutanoic acid (338.0 g, 2.0 mol), heptane (308 g) and methyl isobutyl ketone (252 g). The mixture was heated to about 70° C. To this mixture was slowly added a solution of the title compound of Synthesis Example 1 (525.37 g, 2.0 mol) in heptane (132 g) and methyl isobutyl ketone (108 g) at 67-70° C. over 1 hour. The resulting slurry was maintained at that temperature for 4 hours. The reaction mass was cooled to 28-30° C. and maintained at that temperature for 30 minutes, then filtered. The filter cake was washed with methyl isobutyl ketone (3×200 g). The crude diastereomeric salt (384.2 g, 44.85% yield) was obtained as a solid. The crude product was dissolved in methyl isobutyl ketone (500 g), heated to 50° C. and maintained at that temperature for 1.5 hours. The slurry was cooled to 28-30° C. and filtered. The filter cake was washed with methyl isobutyl ketone (2×200 g). A solid diastereomeric salt (364.1 g, 42.5% yield) was obtained.

[0178] Step 2: Preparation of (R)-2-bromobutanoic acid A 2-liter round bottom flask equipped with a stirrer, condenser and thermometer pocket was charged with the title compound from Step 1 (362 g, 0.4225 mol), toluene (422.6 g), water (502.0 g) and sodium bicarbonate (90.60 g). The resulting mixture was heated to 38-40°C and maintained at that temperature for 2 hours. The organic layer was separated and the aqueous layer was extracted with 211 g of toluene. The aqueous layer was acidified with 34% HCl (124.0 g, 1.15 mol) at 25°C. Toluene (660 g) was added and the resulting mixture was stirred for 1 hour. The organic and aqueous layers were separated and the aqueous layer was extracted with toluene (4 times with 230 g). The combined organic phases were concentrated to dryness to give the title compound (128 g) in 99.16% purity (GCA) and 38% yield (76% available R-isomer). R: 98:2, ee 96%.

[0179] Synthesis Example 3 Step 1: Racemization of scalemic 2-bromobutanoic acid The combined mother liquor and washes obtained from filtration of the solid product of Synthesis Example 2, Step 1 were treated according to the procedure of Synthesis Example 2, Step 2 to recover 170.43 g of a scalemic mixture of 87% (S)-2-bromobutanoic acid and 13% (R)-2-bromobutanoic acid (74% ee).

[0180] A 3 L round bottom flask equipped with stirrer, condenser and thermometer pocket was charged with water (178.56 g), the scalemic mixture of 2-bromobutanoic acid obtained above (170.43 g, 1 mole) and 45% HBr solution (17.98 g, 0.1 mole). The resulting clear solution was heated to about 78-80 °C and maintained at that temperature for about 6 hours. The reaction mixture was cooled to 27-30 °C and extracted three times with heptane (one with 340 g and two with 170 g). The combined organic phases were concentrated under vacuum to give 142.0 g of racemic 2-bromobutanoic acid with 98% purity by GCA, about 0% ee and 85% yield.

[0181] Synthesis Example 4 Step 1: Preparation of (R)-2-bromobutanoyl chloride A 3-liter round bottom flask equipped with stirrer, condenser, thermometer pocket, dropping funnel, nitrogen inlet and scrubber was flushed with nitrogen and charged with a solution of R-2-bromobutanoic acid (210.73 g) in toluene (210 g) solution with stirring. The solution was heated to about 48-50°C. To this, thionyl chloride (126.3 g) was added through the dropping funnel at 48-50°C over 1.5-2 hours. Sulfur dioxide and hydrochloric acid gases evolved from the reaction were scrubbed into aqueous sodium hydroxide. The reactants were heated at 60°C until the reaction was complete and concentrated under reduced pressure. R-2-bromobutanoic acid chloride (439 g) in toluene solution was obtained. The purity by GCA was 99.31%, the ee was 95.1%, and the yield was 99% from R-2-bromobutanoic acid.

[0182] Step 2: Preparation of (R)-2-bromo-N-benzylbutanamide A 3 liter round bottom flask equipped with stirrer, condenser, thermometer pocket, dropping funnel and nitrogen inlet was charged with a solution of (R)-2-bromobutyric acid chloride (443.5 g) in toluene (744 g) with stirring. The solution was cooled to -2-3°C. To this solution, benzylamine (118.5 g) was added through the dropping funnel over 1-1.5 hours at -2-3°C. Aqueous sodium hydroxide solution (440 g) was then added dropwise over 1 hour at -2-3°C. The reactants were stirred at -2-3°C until completion of the reaction and then allowed to phase separate. The organic phase was separated. The aqueous phase was extracted with toluene and the organic phases were combined and washed with water. The combined organic phases were evaporated to dryness to give the title compound (256 g). The purity by GCA was 98.74%, the ee was 94% and the yield was 98.7%.

[0183] Step 3: Preparation of (2S)-N-benzyl-2-(4-fluoro-3-trifluoromethylphenoxy)-butanoic acid amide A 3-liter round bottom flask equipped with stirrer, condenser, thermometer pocket, vacuum outlet and azeotropic water removal was charged with 4-fluoro-3-(trifluoromethyl)phenol (253.5 g), sodium hydroxide (100 g) and toluene (500 g) with stirring. The reaction mixture was heated to 55-60°C and water was removed by azeotropic distillation under reduced pressure. A solution of R-2-bromo-N-benzylbutanamide (257 g) in toluene (500 g) was then added to the reaction mixture at 50-55°C. The reactants were heated at 85-100°C until the reaction was complete. The reaction mixture was washed with dilute NaOH solution and the organic phase was separated. The aqueous phase was extracted with toluene. The combined organic phase was washed with brine solution. For toluene recovery, the brine washed organic phase was treated to dryness under reduced pressure. The resulting crude product was purified in a mixture of isopropyl and water. The title compound was obtained as a solid (317.51 ​​g) with 99.6% purity, 98.9% ee and 88.5% yield.

Claims

【Request 1】 【Chemistry 1】 Compound R-2 【Chemistry 2】 wherein compound R-2 is compound rac-2 【Chemistry 3】 Formula 3 【Chemistry 4】 (In the formula, Each R 1 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl, C 1 ~C 6 haloalkoxy, or up to two R 2 or Two adjacent R 1 The substituents, together with the phenyl to which they are attached, can be up to three R 3 forming a naphthalenyl ring optionally substituted by Each R 2 And each R 3 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl or C 1 ~C 6 is haloalkoxy; Each R 4 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl, C 1 ~C 6 haloalkoxy, or up to two R 5 is phenyl optionally substituted by Each R 5 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl or C 1 ~C 6 is haloalkoxy; m is 0, 1, 2 or 3; and and n is 0, 1, 2 or 3, Formula 4 【Chemistry 5】 (In the formula, R 1 , R 4 , m and n are as defined for compounds of formula 3 above; selectively isolating the R,R-diastereomeric salt of formula 4; The R,R-diastereomeric salt of formula 4 is treated with a sodium base to give compound R-5 【Chemistry 6】 and Treating compound R-5 with an acid; The method of preparation according to the present invention.

2. m is 1 or 2; n is 0, and Each R 1 are independently halogen, nitro, C 1 ~C 4 Alkyl, C 1 ~C 4 haloalkyl or phenyl; or Two adjacent R 1 2. The method of claim 1, wherein the substituents, together with the phenyl to which they are attached, form an unsubstituted naphthalenyl ring.

3. The compound of formula 3 is (αR)-α-methyl-N-(phenylmethyl)-benzenemethanamine, N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine, 2,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 3,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,6-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,4,6-trimethyl-N-[(1R)-1-phenylethyl]-benzenemethanamine, 4-nitro-N-[(1R)-1-phenylethyl]-benzenemethanamine, and 2-Methyl-3-phenyl-N-[(1R)-1-phenylethyl]-benzenemethanamine The method of claim 1 , wherein the compound is selected from the group consisting of:

4. The method of claim 3, wherein the compound of formula 3 is N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine.

5. Compound R-2 is C 1 ~C 6 Treating with an alkanol of formula R-6 【Chemistry 7】 (In the formula, R 6 is C 1 ~C 6 wherein R is an alkyl group; and The compound of formula R-6 is compound 7 【Chemistry 8】 Treated according to formula S-8 【Chemistry 9】 (In the formula, R 6 is C 1 ~C 6 wherein R is an alkyl group; and The compound of formula S-8 is compound 9 【Chemistry 10】 Processing by 2. The method of claim 1, wherein compound R-2 is converted to compound S-1 by a process comprising:

6. R 6 CH 3 The method according to claim 5, wherein

7. Compound R-2 is treated with a chlorinating agent to obtain compound R-10. 【Chemistry 11】 and preparing Compound R-10 was replaced with Compound 9 【Chemistry 12】 To compound R-11, 【Chemistry 13】 and preparing Compound R-11 was replaced with Compound 7 【Chemistry 14】 Processing by 2. The method of claim 1, wherein compound R-2 is converted to compound S-1 by a process comprising:

8. Compound S-1 【Chemistry 15】 A method for preparing Compound R-2 【Chemistry 16】 wherein compound R-2 is compound rac-2 【Chemistry 17】 Formula 3 【Chemistry 18】 (In the formula, Each R 1 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy or up to two R 2 or Two adjacent R 1 The substituents, together with the phenyl to which they are attached, can be up to three R 3 forming a naphthalenyl ring optionally substituted by Each R 2 And each R 3 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl or C 1 ~C 6 is haloalkoxy; Each R 4 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl, C 1 ~C 6 haloalkoxy, or up to two R 5 is phenyl optionally substituted by Each R 5 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl or C 1 ~C 6 is haloalkoxy; m is 0, 1, 2 or 3; and and n is 0, 1, 2 or 3, Formula 4 【Chemistry 19】 (In the formula, R 1 , R 4 , m and n are as defined for compounds of formula 3 above; selectively isolating the R,R-diastereomeric salt of formula 4; The R,R-diastereomeric salt of formula 4 is treated with a sodium base to give compound R-5 【Chemistry 20】 and treating compound R-5 with an acid; Converting compound R-2 to compound S-1; A method for preparing the same.

9. m is 1 or 2; n is 0, and Each R 1 are independently halogen, nitro, C 1 ~C 4 Alkyl, C 1 ~C 4 haloalkyl or phenyl; or Two adjacent R 1 9. The method of claim 8, wherein the substituents, together with the phenyl to which they are attached, form an unsubstituted naphthalenyl ring.

10. The compound of formula 3 is (αR)-α-methyl-N-(phenylmethyl)-benzenemethanamine, N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine, 2,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 3,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,6-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,4,6-trimethyl-N-[(1R)-1-phenylethyl]-benzenemethanamine, 4-nitro-N-[(1R)-1-phenylethyl]-benzenemethanamine, and 2-Methyl-3-phenyl-N-[(1R)-1-phenylethyl]-benzenemethanamine The method of claim 8, wherein the compound is selected from the group consisting of:

11. 11. The method of claim 10, wherein the compound of formula 3 is N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine.

12. Compound R-2 is treated with a C1-C6 alkanol to give compound R-6 【Chemistry 21】 (In the formula, R 6 is C 1 ~C 6 wherein R is an alkyl group; and The compound of formula R-6 is compound 7 【Chemical 22】 Treated according to formula S-8 【Chemistry 23】 (In the formula, R 6 is C 1 ~C 6 wherein R is an alkyl group; and The compound of formula S-8 is compound 9 【Chemistry 24】 Processing by 9. The method of claim 8, wherein compound R-2 is converted to compound S-1 by a process comprising:

13. R 6 The method of claim 12 , wherein is methyl.

14. Compound R-2 is treated with a chlorinating agent to obtain compound R-10. 【Chemistry 25】 and preparing Compound R-10 was replaced with Compound 9 【Chemistry 26】 To compound R-11, 【Chemical 27】 and preparing Compound R-11 was replaced with Compound 7 【Chemistry 28】 Processing by 9. The method of claim 8, wherein compound R-2 is converted to compound S-1 by a process comprising:

15. Compound S-1 【Chemical 29】 A method for preparing compound rac-2 【Chemistry 30】 Formula 3 【Chemistry 31】 (In the formula, Each R 1 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl, C 1 ~C 6 haloalkoxy, or up to two R 2 or Two adjacent R 1 The substituents, together with the phenyl to which they are attached, can be up to three R 3 forming a naphthalenyl ring optionally substituted by Each R 2 And each R 3 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl or C 1 ~C 6 is haloalkoxy; Each R 4 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl, C 1 ~C 6 haloalkoxy, or up to two R 5 is phenyl optionally substituted by Each R 5 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl or C 1 ~C 6 is haloalkoxy; m is 0, 1, 2 or 3; and and n is 0, 1, 2 or 3, Formula 4 【Chemistry 32】 (In the formula, R 1 , R 4 , m and n are as defined for compounds of formula 3 above; selectively isolating the R,R-diastereomeric salt of formula 4; The R,R-diastereomeric salt of formula 4 is treated with a sodium base to give compound R-5 【Chemical 33】 and Compound R-5 is treated with an acid to obtain compound R-2 【Chemical 34】 and preparing Converting compound R-2 to compound S-1; The method includes:

16. m is 1 or 2; n is 0, and Each R 1 are independently halogen, nitro, C 1 ~C 4 Alkyl, C 1 ~C 4 haloalkyl or phenyl; or Two adjacent R 1 16. The method of claim 15, wherein the substituents, together with the phenyl to which they are attached, form an unsubstituted naphthalenyl ring.

17. The compound of formula 3 is (αR)-α-methyl-N-(phenylmethyl)-benzenemethanamine, N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine, 2,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 3,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,6-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,4,6-trimethyl-N-[(1R)-1-phenylethyl]-benzenemethanamine, 4-nitro-N-[(1R)-1-phenylethyl]-benzenemethanamine, and 2-Methyl-3-phenyl-N-[(1R)-1-phenylethyl]-benzenemethanamine 16. The method of claim 15, selected from the group consisting of:

18. 18. The method of claim 17, wherein the compound of formula 3 is N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine.

19. Compound R-2 is C 1 ~C 6 Treating with an alkanol of formula R-6 【Chemistry 35】 (In the formula, R 6 is C 1 ~C 6 wherein R is an alkyl group; and The compound of formula R-6 is converted into a compound of formula 7 【Chemical Formula 36】 Treated according to formula S-8 【Chemical 37】 (In the formula, R 6 is C 1 ~C 6 wherein R is an alkyl group; and The compound of formula S-8 is compound 9 【Chemical Formula 38】 Processing by The method of claim 15, wherein compound R-2 is converted to compound S-1 by a method comprising:

20. R 6 20. The method of claim 19, wherein is methyl.

21. Compound R-2 is treated with a chlorinating agent to obtain compound R-10. 【Chemical Formula 39】 and preparing Compound R-10 was replaced with Compound 9 【Chemistry 40】 To compound R-11, 【Chemistry 41】 and preparing Compound R-11 was replaced with Compound 7 【Chemistry 42】 Processing by The method of claim 15, wherein compound R-2 is converted to compound S-1 by a method comprising:

22. Compound S-1 【Chemistry 43】 A method for preparing compound rac-2 【Chemistry 44】 Formula 3 【Chemistry 45】 (In the formula, Each R 1 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl, C 1 ~C 6 haloalkoxy, or up to two R 2 or Two adjacent R 1 The substituents, together with the phenyl to which they are attached, can be up to three R 3 forming a naphthalenyl ring optionally substituted by Each R 2 And each R 3 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl or C 1 ~C 6 is haloalkoxy; Each R 4 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl, C 1 ~C 6 haloalkoxy, or up to two R 5 is phenyl optionally substituted by Each R 5 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl or C 1 ~C 6 is haloalkoxy; m is 0, 1, 2 or 3; and and n is 0, 1, 2 or 3, Formula 4 【Chemistry 46】 (In the formula, R 1 , R 4 , m and n are as defined for compounds of formula 3 above; selectively isolating the R,R-diastereomeric salt of formula 4; The R,R-diastereomeric salt of formula 4 is treated with a sodium base to give compound R-5 【Chemistry 47】 and Compound R-5 is treated with an acid to obtain compound R-2 【Chemistry 48】 and preparing Compound R-2 is treated with a chlorinating agent to obtain compound R-10. 【Chemistry 49】 and preparing Compound R-10 was replaced with Compound 9 【Chemistry 50】 To compound R-11, 【Chemistry 51】 and preparing Compound R-11 was replaced with Compound 7 【Chemistry 52】 Processing by The method includes:

23. m is 1 or 2; n is 0, and Each R 1 are independently halogen, nitro, C 1 ~C 4 Alkyl, C 1 ~C 4 haloalkyl or phenyl; or 23. The method of claim 22, wherein two adjacent R1 substituents, together with the phenyl to which they are attached, form an unsubstituted naphthalenyl ring.

24. The compound of formula 3 is (αR)-α-methyl-N-(phenylmethyl)-benzenemethanamine, N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine, 2,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 3,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,6-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,4,6-trimethyl-N-[(1R)-1-phenylethyl]-benzenemethanamine, 4-nitro-N-[(1R)-1-phenylethyl]-benzenemethanamine, and 2-Methyl-3-phenyl-N-[(1R)-1-phenylethyl]-benzenemethanamine 23. The method of claim 22, selected from the group consisting of:

25. 25. The method of claim 24, wherein the compound of formula 3 is N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine.

26. Compound R-2 【Chemistry 53】 A method for preparing compound rac-2 【Chemical 54】 Formula 3 【Chemistry 55】 (In the formula, Each R 1 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl, C 1 ~C 6 haloalkoxy, or up to two R 2 or Two adjacent R 1 The substituents, together with the phenyl to which they are attached, can be up to three R 3 forming a naphthalenyl ring optionally substituted by Each R 2 And each R 3 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl or C 1 ~C 6 is haloalkoxy; Each R4 is independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl, C 1 ~C 6 haloalkoxy, or up to two R 5 is phenyl optionally substituted by Each R 5 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl or C 1 ~C 6 is haloalkoxy; m is 0, 1, 2 or 3; and and n is 0, 1, 2 or 3, Formula 4 【Chemistry 56】 (In the formula, R 1 , R 4 , m and n are as defined for compounds of formula 3 above; selectively isolating the R,R-diastereomeric salt of formula 4; The R,R-diastereomeric salt of formula 4 is treated with a sodium base to give compound R-5 【Chemistry 57】 and Treating compound R-5 with an acid; The method includes:

27. m is 1 or 2; n is 0, and Each R 1 are independently halogen, nitro, C 1 ~C 4 Alkyl, C 1 ~C 4 haloalkyl or phenyl; or Two adjacent R 1 27. The method of claim 26, wherein the substituents, together with the phenyl to which they are attached, form an unsubstituted naphthalenyl ring.

28. The compound of formula 3 is (αR)-α-methyl-N-(phenylmethyl)-benzenemethanamine, N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine, 2,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 3,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,6-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,4,6-trimethyl-N-[(1R)-1-phenylethyl]-benzenemethanamine, 4-nitro-N-[(1R)-1-phenylethyl]-benzenemethanamine, and 2-Methyl-3-phenyl-N-[(1R)-1-phenylethyl]-benzenemethanamine 27. The method of claim 26, selected from the group consisting of:

29. The method of claim 1, 8, 15, 22, or 26, wherein compound rac-2 is formula scal-2 【Chemistry 58】 with hydrobromic acid or a quaternary ammonium bromide salt.

30. 30. The method of claim 29, wherein the compound scal-2 is predominantly (S)-2-bromobutanoic acid.

31. Formula 4 【Chemistry 59】 (In the formula, Each R 1 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl, C 1 ~C 6 haloalkoxy, or up to two R 2 or Two adjacent R 1 The substituents, together with the phenyl to which they are attached, can be up to three R 3 forming a naphthalenyl ring optionally substituted by Each R 2 And each R 3 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl or C 1 ~C 6 is haloalkoxy; Each R 4 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl, C 1 ~C 6 haloalkoxy, or up to two R 5 is phenyl optionally substituted by Each R 5 are independently halogen, nitro, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkenyl, C 1 ~C 6 Haloalkenyl or C 1 ~C 6 is haloalkoxy; m is 0, 1, 2 or 3; and n is 0, 1, 2 or 3. The R,R-diastereomeric salt of

32. m is 1 or 2; n is 0, and Each R 1 are independently halogen, nitro, C 1 ~C 4 Alkyl, C 1 ~C 4 haloalkyl or phenyl; or Two adjacent R 1 32. The R,R-diastereomeric salt of claim 31, wherein the substituents, together with the phenyl to which they are attached, form an unsubstituted naphthalenyl ring.

33. (αR)-α-methyl-N-(phenylmethyl)-benzenemethanamine, N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine, 2,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 3,4-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,6-dichloro-N-[(1R)-1-phenylethyl]-benzenemethanamine, 2,4,6-trimethyl-N-[(1R)-1-phenylethyl]-benzenemethanamine, 4-nitro-N-[(1R)-1-phenylethyl]-benzenemethanamine, and 2-Methyl-3-phenyl-N-[(1R)-1-phenylethyl]-benzenemethanamine 32. The R,R-diastereomeric salt of claim 31, comprising a salt of an amine selected from the group consisting of:

34. 34. The R,R-diastereomeric salt of claim 33, comprising a salt of N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine.

35. 28. The method of claim 27, wherein the compound of formula 3 is N-[(1R)-1-phenylethyl]-1-naphthalenemethanamine.

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