Method for Producing Pyrrolidine Compounds

Abstract

JPEG2024522936000038.jpg38118 The present invention provides a method suitable for industrial production of a compound of formula (V), which comprises the steps of subjecting compound (IV) to an asymmetric reductive amination reaction in the presence of a metal complex containing a chiral ligand, and subjecting the resulting product to purification by salt formation with N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine.

Description

[Technical field]

[0001] The present invention relates to a method for producing a pyrrolidine compound. [Background technology]

[0002] 2. Background of the Invention Pyrrolidine compounds, such as (2S,3S)-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-amine having a protecting group at the pyrrolidine 1-position, are useful as intermediates in the production of pharmaceuticals, and a method suitable for their industrial production is desired.

[0003] In Patent Document 1, a compound (18) containing a 3-oxopyrrolidine ring is subjected to a reductive amination reaction using an iridium catalyst to obtain the corresponding cis compound (19) containing a 3-aminopyrrolidine ring (Scheme 4). The cis compound is subjected to a chiral column to obtain the corresponding (2S,3S) compound.

[0004] Patent Document 2 discloses a method for obtaining (2S,3S)3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine having a protecting group at the 1-position by subjecting 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidine having a protecting group at the 1-position to a reduction reaction using irconium(IV) chloride. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2019 / 027058 [Patent Document 2] International Publication No. 2021 / 100730 Summary of the Invention [Problem to be solved by the invention]

[0006] In the method described in Patent Document 1, the (2S,3S) isomer is obtained by optical resolution using a chiral column, so it is difficult to say that this method is suitable for industrial production. In the method described in Patent Document 2, the purity and yield of (2S,3S)3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine having a protecting group at the pyrrolidine 1-position are not sufficient for industrial production.

[0007] The object of the present invention is to provide a method suitable for the large-scale production of chiral (2S,3S)-2-benzyl-3-amino substituted heterocycles. In another aspect, the object of the present invention is to provide a method suitable for the industrial production of (2S,3S)-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-amine having a protecting group at the pyrrolidine 1-position. In another aspect, the object of the present invention is to provide a method suitable for the industrial large-scale production of N-{(2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide using the prepared (2S,3S)-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-amine having a protecting group at the pyrrolidine 1-position. [Means for solving the problem]

[0008] The present inventors have conducted intensive research to solve the above-mentioned problems, and have found that (2S,3S)-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-amine having a protecting group at the pyrrolidine 1-position can be obtained as a salt by subjecting 2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-one having a protecting group at the pyrrolidine 1-position to an asymmetric reductive amination reaction in the presence of a metal complex containing a chiral ligand, and then subjecting the resulting compound to purification utilizing salt formation with a specific chiral acid, and that the starting material, 2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-one having a protecting group at the pyrrolidine 1-position, can be obtained with higher purity, and the present invention has been completed based on these findings.

[0009] Thus, the present invention provides the following: [1] Formula (V):

[0010] [ka]

[0011] (In the formula, each R 1 is independently selected from a halogen atom and a trifluoromethanesulfonyl group; A is an optionally further substituted 4-7 membered N-containing monocyclic saturated heterocyclyl; and PG is a protecting group. A method for producing a compound of the formula: The method comprises reacting a compound of formula (IV):

[0012] [ka]

[0013] subjecting the compound of formula (I) to an asymmetric reductive amination reaction in the presence of a metal complex containing a chiral ligand, and subjecting the resulting product to purification by salt formation with N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine.

[0014] [2] To provide a compound of formula (IV), (a) Formula (II):

[0015] [ka]

[0016] (In the formula, R 1 is independently selected from a halogen atom and a trifluoromethanesulfonyl group; and X is a halogen atom. with a compound of formula (III):

[0017] [ka]

[0018] where PG is a protecting group; and A is an optionally further substituted 4-7 membered N-containing monocyclic saturated heterocyclyl. reacting with the anion of a compound of (b) deprotecting the product of step (a); (c) reacting the product of step (b) with a racemic organic acid; and (d) introducing a protecting group onto the product of step (c); The method according to [1] above, further comprising:

[0019] [3] The method according to the above-mentioned [1] or [2], wherein A is selected from pyrrolidine, piperidine, and azetidine, each of which may be further substituted. [4] The method according to any one of the above [1] to [3], wherein A is pyrrolidine. [5] Each R 1 The method according to any one of the above-mentioned [1] to [4], wherein is independently selected from Cl, Br, I, and a trifluoromethanesulfonyl group. [6] The method according to any one of the above-mentioned [2] to [5], wherein the organic acid is racemic tartaric acid (DL-tartaric acid).

[0020] [7] A method for producing N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of (2S,3S)-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-amine having a protecting group at the pyrrolidine 1-position (hereinafter also referred to as compound (5)), Step 3a: subjecting 2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-one having a protecting group at the pyrrolidine 1-position (hereinafter also referred to as compound (4)) to an asymmetric reductive amination reaction in the presence of a metal complex containing a chiral ligand; and Step 3b: Purifying the product of step 3a by salt formation with N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine. The method comprises the steps of:

[0021] [8] Step 1a: reacting 1-bromo-3-(bromomethyl)-2-fluorobenzene with pyrrolidin-3-one having a protecting group at the pyrrolidine 1-position; Step 1b: deprotecting the product of step 1a and reacting with DL-tartaric acid; and Step 2: Introducing a protecting group into the product of step 1b to provide 2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-one bearing a protecting group at the pyrrolidine 1-position. The method according to [7] above, further comprising:

[0022] [9] The method according to any one of the above-mentioned [1] to [8], wherein the chiral ligand in the metal complex is a BINAP ligand, a phosphine ligand, a ferrocene ligand, or a cyclophane ligand.

[10] The method according to any one of the above [1] to [8], wherein the metal in the metal complex is ruthenium, rhodium, or iridium.

[11] The method according to any one of the above [1] to [8], wherein the metal complex containing a chiral ligand is a ruthenium complex containing a chiral BINAP ligand or a ruthenium complex containing a chiral cyclophane ligand.

[0023]

[12] A metal complex containing a chiral ligand has the formula: Ru(OAc)2(Ligand) (Wherein, Ligand is (S)-binap, (R)-xylyl-Phanephos or (R)-xylyl-binap.) The method according to any one of the above [1] to [8], wherein the metal complex is represented by the following formula:

[13] The method according to any one of the above [1] to [8], wherein the metal complex containing a chiral ligand is Ru(OAc)2{(R)-xylyl-binap}.

[0024]

[14] The method according to any one of the above-mentioned [1] to

[13] , wherein the protecting group at the 1-position of pyrrolidine is selected from tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, trityl, benzyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and methoxymethyl.

[15] The method according to any one of the above-mentioned [1] to

[14] , wherein the protecting group at the 1-position of pyrrolidine is tert-butoxycarbonyl.

[16] The method according to any one of the above-mentioned [1] to

[15] , wherein the purification conditions include crystallization.

[0025]

[17] The method according to

[16] above, wherein the crystallization comprises salt formation with N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine in a solvent at a temperature of 60°C to 78°C, stirring at a temperature of 60°C to 78°C for about 0.5 hours, stirring at 15°C to 35°C for about 12 to about 48 hours, and filtering the resulting precipitate.

[18] The method according to

[17] above, further comprising recrystallizing the precipitate from a solvent selected from an alcohol, an ether, or an aromatic hydrocarbon.

[19] The method according to

[18] above, wherein the solvent is ethanol.

[0026]

[20] Step 4: subjecting the N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of (2S,3S)-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-amine having a protecting group at the pyrrolidine 1-position to desalting and reacting with a methanesulfonylating agent; Step 5: reacting the product of step 4 with (3,5-difluorophenyl)boronic acid; Step 6: subjecting the product of step 5 to deprotection conditions; and Step 7: subjecting the product of step 6 to a condensation reaction with 2-hydroxy-2-methylpropanoic acid to obtain N-{(2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3′,5′-trifluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide, or a hydrate or solvate thereof. The method according to [7] or [8] above, further comprising: [twenty one]

[0027] [ka]

[0028] A compound which is a racemic organic acid salt of. [twenty two] The compound according to

[21] above, which is a racemic tartrate salt. [twenty three]

[0029] [ka]

[0030] The compound according to the above

[21] ,

[0031] [twenty four] A method for producing 2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-one (hereinafter also referred to as compound (3)) hemitartrate, comprising the steps of: Step 1a: reacting 1-bromo-3-(bromomethyl)-2-fluorobenzene (hereinafter also referred to as compound (1)) with pyrrolidin-3-one having a protecting group at the pyrrolidine 1-position (hereinafter also referred to as compound (2)); and Step 1b: subjecting the product of step 1a to a deprotection reaction, followed by salt formation with tartaric acid. The method comprises the steps of:

[0032] [twenty five] A method for producing 2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-one having a protecting group at the pyrrolidine 1-position, comprising the steps of: Step 2: Introducing a protecting group into the pyrrolidine 1-position of 2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-one hemitartrate A method comprising:

[26] 2-[(3-Bromo-2-fluorophenyl)methyl]pyrrolidin-3-one hemitartrate.

[0033]

[27] A method for producing N-{(2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide, or a hydrate or solvate thereof, comprising the steps of: Step 1a: reacting 1-bromo-3-(bromomethyl)-2-fluorobenzene with pyrrolidin-3-one having a protecting group at the pyrrolidine 1-position; and Step 1b: The product of step 1a is subjected to a deprotection reaction, followed by salification with tartaric acid to obtain 2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-one hemitartrate. a process comprising: Step 2: introducing a protecting group into the pyrrolidine 1-position of 2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-one hemitartrate to obtain 2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-one having a protecting group at the pyrrolidine 1-position; Step 3a: subjecting 2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-one having a protecting group at the pyrrolidine 1-position to an asymmetric reductive amination reaction in the presence of a metal complex containing a chiral ligand; Step 3b: The product of step 3a is subjected to purification by salt formation with N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine, To obtain N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of (2S,3S)-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-amine having a protecting group at the pyrrolidine 1-position a process comprising: Step 4: a step of desalting the N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of (2S,3S)-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-amine having a protecting group at the pyrrolidine 1-position, and then reacting the resulting compound with a methanesulfonylating agent to obtain N-(2S,3S)-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-yl)methanesulfonamide having a protecting group at the pyrrolidine 1-position (hereinafter also referred to as compound (6)); Step 5: reacting N-(2S,3S)-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-yl)methanesulfonamide having a protecting group at the pyrrolidine 1-position with (3,5-difluorophenyl)boronic acid to obtain N-{(2S,3S)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide having a protecting group at the pyrrolidine 1-position (hereinafter also referred to as compound (7)); Step 6: subjecting N-{(2S,3S)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide having a protecting group at the pyrrolidine 1-position to a deprotection reaction to obtain N-{(2S,3S)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide (hereinafter also referred to as compound (8)) hydrochloride; and Step 7: A step of subjecting N-{(2S,3S)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide hydrochloride to a condensation reaction with 2-hydroxy-2-methylpropanoic acid to obtain N-{(2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide, or a hydrate or solvate thereof (hereinafter also referred to as compound (I)). A method comprising:

[0034]

[28] The method according to

[27] above, wherein the metal complex containing a chiral ligand in step 3a is Ru(OAc)2{(R)-xylyl-binap}.

[29] The method according to

[27] above, further comprising the step of isolating the 2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-one hemitartrate salt produced in step 1b.

[0035]

[30] The method according to

[27] above, wherein the protecting group at the 1-position of pyrrolidine is selected from tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, trityl, benzyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and methoxymethyl.

[31] The method according to any one of the above-mentioned

[27] to

[30] , wherein the protecting group at the 1-position of pyrrolidine is a tert-butoxycarbonyl group.

[0036]

[32] Formula (V):

[0037] [ka]

[0038] (In the formula, each R 1is independently selected from a halogen atom and a trifluoromethanesulfonyl group; A is an optionally further substituted 4-7 membered N-containing monocyclic saturated heterocyclyl; and PG is a protecting group. A compound of formula (IV):

[0039] [ka]

[0040] subjecting a compound of formula (I) to an asymmetric reductive amination reaction in the presence of a metal complex containing a chiral ligand, and subjecting the resulting product to purification by salt formation with N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine.

[0041]

[33] (2S,3S)-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidine-1-carboxylate tert-butyl N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt produced by subjecting tert-butyl 2-[(3-bromo-2-fluorophenyl)methyl]-3-oxopyrrolidine-1-carboxylate to an asymmetric reductive amination reaction in the presence of Ru(OAc)2{(R)-xylyl-binap}; and subjecting the resulting product to purification by salt formation with N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine. Effect of the Invention

[0042] According to the production method of the present invention, compound (5) can be obtained as N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt by a method suitable for industrial production. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] Detailed Description of the Invention The production method of the present invention will be described below.

[0044] The compound obtained in each step can be used for the next reaction as it is as a reaction mixture or as a crude product. Alternatively, the compound obtained in each step can be isolated and purified from the reaction mixture according to a separation means known per se, such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, column chromatography, etc. The terms "treat", "treated" or "treating" used in the production method of the present invention are synonymous with the terms "react", "reacted" or "reacting".

[0045] When the raw material compounds and reagents used in each step are commercially available, the commercially available products can be used as they are.

[0046] Unless otherwise specified, the reaction in each step is carried out without solvent or by dissolving or suspending the raw material compounds in a suitable solvent. Examples of solvents include those described in the examples and the following solvents: Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, 1-propanol, 2-propanol, etc.; Ethers: diethyl ether, diisopropyl ether, cyclopentyl methyl ether (CPME), diphenyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane, 1,4-dioxane, etc.; Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, hexane, etc.; Amides: N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.; Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Sulfoxides: dimethyl sulfoxide, etc.; Organic bases: pyridine, triethylamine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Inorganic acids: hydrochloric acid, sulfuric acid, etc.; Esters: ethyl acetate, isopropyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; water.

[0047] The above mentioned solvents can be used in a mixture of two or more of them in an appropriate ratio.

[0048] When a base is used in the reaction in each step, examples thereof include the following bases and those described in the examples. Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, potassium carbonate, sodium acetate, lithium hydroxide, tripotassium phosphate, etc.; Organic bases: triethylamine, diethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, pyrrolidine, etc.; Metal alkoxides: sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, lithium ethoxide, etc.; Alkali metal hydrides: sodium hydride, etc.; Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; Organolithium: n-butyllithium, etc.

[0049] In the present invention, as shown in Scheme 1, a compound of formula (V) can be prepared from a compound of formula (II), and a compound of formula (V) can be used in the preparation of a compound of formula (X) (hereinafter, a compound of formula (...) may be simply referred to as "compound (...)").

[0050] [ka]

[0051] Compound (II) (X is a halogen atom or a trifluoromethanesulfonate group) can be reacted with compound (III) (A is an optionally further substituted 4-7 membered nitrogen-containing monocyclic saturated heterocycle. Examples of A include pyrrolidine, piperidine, and azetidine, each of which may be further substituted. Preferred examples of A include pyrrolidine, piperidine, and azetidine, and a more preferred example of A is pyrrolidine) by nucleophilic displacement of group X by the carbanion of compound (III). Examples of bases used for generating the carbanion include organolithiums, metal alkoxides, inorganic bases, organic bases, and the like. In certain embodiments, the base can be an organic base. In some embodiments, the base can be a secondary amine. In some embodiments, the base can be pyrrolidine.

[0052] Removal of the protecting group using conditions appropriate for the selected protecting group, followed by reaction with an acid, gives compound (IVA) in the form of a salt. In addition to organic acids (including organic acid racemates), inorganic acids (i.e., HCl) may also be used for the purpose of crystallization of compound (IVA).

[0053] Examples of organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.

[0054] Examples of inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.

[0055] In certain embodiments, the compound of formula (IVA) is formed as a salt of a racemic organic acid, hi some embodiments, the organic salt is a racemic form of tartaric acid (DL-tartaric acid).

[0056] A compound of formula (IVA) can be protected with a suitable protecting group to give a compound of formula (IV).

[0057] As described further herein, compound (V) is obtained by asymmetric reductive amination in the presence of a metal complex containing a chiral ligand. Examples of metal catalysts used include Ru catalysts such as Ru(OAc)2{(R)-binap}, [RuCl2(benzene)]2 and Ru(OAc)2{(R}-xylyl-binap}), and Rh catalysts such as [RhCl(cod)]2 and [Rh(cod)2]OTf, examples of ligands used include (S)-binap, (R)-xylyl-phanephos and (R)-xylyl-binap, examples of hydrogen sources used include hydrogen gas, formic acid, ammonium formate, etc. In addition, a nitrogen source can be added to the reaction system, examples of which include ammonia and ammonium acetate, etc.

[0058] Compound (V) is reacted with an alkylsulfonylating agent (e.g., methanesulfonylating agent, ethanesulfonylating agent) to give compound (VI) (R 2 is C 1-2 This can be coupled with (VII) by Suzuki coupling (Suzuki-Miyaura coupling) to obtain compound (VIII). Examples of metal catalysts used in the coupling include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), and 1,1'-bis(diphenylphosphino)-ferrocenepalladium(II) chloride; nickel compounds such as tetrakis(triphenylphosphine)nickel(0); rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride; cobalt compounds; copper compounds such as copper oxide and copper iodide(I); and platinum compounds. Furthermore, a base can be added to the reaction system, examples of which include inorganic bases.

[0059] Compound (IX) in the form of a salt is obtained by deprotection of compound (VIII). Examples of salts include hydrochloride and tartaric acid, etc., and preferably the salt is hydrochloride. Compound (IX) can be reacted with 2-hydroxy-2-methylpropanoic acid to obtain compound (X) in the form of a hydrate, anhydride, or solvate. Hydrates include hemihydrate and sesquihydrate.

[0060] In various pyrrolidine compounds used as raw materials or products in the production method of the present invention, examples of the protecting group at the 1-position of pyrrolidine include tert-butoxycarbonyl group, benzyloxycarbonyl group, acetyl group, trityl group, etc., benzyl group, 9-fluorenylmethyloxycarbonyl group (Fmoc group), 2,2,2-trichloroethoxycarbonyl group (Troc group), methoxymethyl group (MOM group), etc., and from the viewpoint of easy deprotection, the tert-butoxycarbonyl group is preferable. In the present specification, examples of the "optionally further substituted 4- to 7-membered N-containing monocyclic saturated heterocyclyl" include a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated C group, a methyl ... 1-6 Alkoxy group, carboxy group, optionally halogenated C 1-6 Alkyl group, carbamoyl group, amino group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups, and C 3-10 The heterocyclyl group includes a heterocyclyl group which may have 1 to 3 substituents selected from a cycloalkyl group.

[0061] In the present invention, the N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5) can be produced by a process including the following steps 3a and 3b. Step 3a: subjecting compound (4) to an asymmetric reductive amination reaction in the presence of a metal complex containing a chiral ligand; and Step 3b: subjecting the product of step 3a to purification by salt formation with N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine.

[0062] Process 3a In this step, compound (4) is subjected to an asymmetric reductive amination reaction in the presence of a metal complex containing a chiral ligand.

[0063] The reaction is carried out by reacting compound (4) with an amine source in a solvent in the presence of a metal complex containing a chiral ligand under a hydrogen atmosphere.

[0064] Compound (4) is preferably tert-butyl 2-[(3-bromo-2-fluorophenyl)methyl]-3-oxopyrrolidine-1-carboxylate (compound (4a)). This compound can be produced by a method known per se. Alternatively, this compound can also be produced by a process including step 1a and step 1b, and step 2, as described below.

[0065] Examples of the amine source include ammonia, ammonium chloride, ammonium salts such as ammonium formate, ammonium acetate, ammonium salicylate, etc. Among them, the combination of ammonium chloride and ammonium acetate is preferred.

[0066] The amount of the amine source used is generally 2 to 8 mol, preferably 4 to 6 mol, per 1 mol of compound (4).

[0067] Examples of chiral ligands in the metal complexes containing chiral ligands include BINAP ligands such as (S)-BINAP, (R)-xylyl-BINAP, (R)-p-tol-BINAP, (S)-m-tol-BINAP, (S)-DMANYL-BINAP, (S)-DADMP-BINAP, (R)-H8-BINAP, (S)-PMP-BINAP, and (S)-BOP-BINAP; (R,R)-iPr-DUPHOS, (R)-SYNPHOS, (R)-SOLPHOS, (R)-Tyr-BINAP ... Phosphine ligands such as (R)-MeO-BIPHEP, (R)-ClMeO-BIPHEP, (R,R)-Skewphos, (R,R)-PTBP-Skewphos, (R)-MONOPHOS; ferrocene ligands such as (R)(S)-SL-J003, (R)(R)-SL-T001, (R)(R)-SL-W002, (R)(S)-JOSIPHOS; cyclophane ligands such as (R)-PHANEPHOS, (R)-xylyl-PHANEPHOS, and the like.

[0068] Among these, from the viewpoints of enantioselectivity, amine selectivity, and cis selectivity, preferred are BINAP ligands such as (S)-BINAP, (R)-xylyl-BINAP, (R)-p-tol-BINAP, (S)-m-tol-BINAP, (S)-DMANYL-BINAP, (S)-DADMP-BINAP, (R)-H8-BINAP, (S)-PMP-BINAP, and (S)-BOP-BINAP, or (R)-PHANEPHOS, (R Preferably, the ligand is a cyclophane ligand such as (S)-xylyl-PHANEPHOS, more preferably (S)-BINAP, (R)-p-tol-BINAP, (S)-m-tol-BINAP, (R)-xylyl-PHANEPHOS or (R)-xylyl-BINAP, still more preferably (S)-BINAP, (R)-xylyl-PHANEPHOS or (R)-xylyl-BINAP, and particularly preferably (R)-xylyl-BINAP.

[0069] From the viewpoint of enantioselectivity and cis selectivity, the metal in the metal complex containing a chiral ligand is preferably ruthenium, rhodium or iridium, and particularly preferably ruthenium.

[0070] Examples of such metal complexes containing chiral ligands include ruthenium complexes containing chiral BINAP ligands, and ruthenium complexes containing chiral cyclophane ligands.

[0071] Preferred examples thereof include metal complexes having a structure selected from the following formulas (Ia) to (Id).

[0072] [ka]

[0073] wherein Ar is phenyl, tolyl or xylyl.

[0074] The metal complex containing the chiral ligand is more preferably represented by the formula: Ru(OAc)2(Ligand) (wherein Ligand is (S)-binap, (R)-xylyl-Phanephos or (R)-xylyl-binap) is a metal complex represented by the formula:

[0075] The ligand is preferably (R)-xylyl-binap.

[0076] The metal complex containing a chiral ligand is particularly preferably Ru(OAc)2{(R)-xylyl-binap}.

[0077] The amount of the metal complex containing a chiral ligand used is generally 0.10 to 1.00 mol %, and preferably 0.40 to 0.60 mol %, per mol of compound (4).

[0078] The hydrogen pressure is generally 0.60 to 5.00 MPa (G), and preferably 0.80 to 1.00 MPa (G).

[0079] Examples of the solvent include alcohols, ethers, water, etc. Among them, methanol and a mixed solvent of methanol and water are preferable.

[0080] The reaction is generally carried out at 75 to 95° C., preferably 80 to 85° C. The reaction time is generally about 10 to about 72 hours, preferably about 16 to about 48 hours.

[0081] After the reaction is completed, the reaction mixture is subjected to usual post-treatment such as phase separation and concentration.

[0082] In the reaction, it is desirable that the conversion rate of compound (4) is 95% or more, particularly 99% or more.

[0083] In the reaction, 2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-ol having a protecting group at the pyrrolidine 1-position is also produced as a by-product. However, it is desirable to produce 2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-amine having a protecting group at the pyrrolidine 1-position (hereinafter also referred to as compound (5A)) with an amine selectivity of 80% or more, particularly 90% or more.

[0084] In the reaction, in addition to the cis isomers ((2S,3S) and (2R,3R)), the trans isomers ((2R,3S) and (2S,3R)) are also produced. However, it is desirable to produce the cis isomer of compound (5A) having a protecting group at the pyrrolidine 1-position in a yield of 50% or more, particularly 70% or more.

[0085] In the reaction, it is desirable to produce compound (5) with an enantiomeric excess of 25% or more, particularly 35% or more.

[0086] The compound (5) present in the product obtained in this step is obtained as N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt in the next step 3b.

[0087] Process 3b In this step, the product of step 3a is purified by salt formation with N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine to obtain the N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5).

[0088] Purification is carried out by mixing the product of step 3a with N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine in a solvent and then filtering off the precipitated crystals.

[0089] The amount of N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine used is generally 1.1 to 2.4 mol, preferably 1.2 to 2.2 mol, per mol of compound (5) contained in the product of step 3a. Furthermore, the amount of N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine used is generally 0.80 to 1.20 mol, preferably 0.90 to 1.10 mol, based on compound (4) which is the starting material of step 3a.

[0090] Examples of the solvent for mixing the product of step 3a with N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine include alcohols, ethers, aromatic hydrocarbons, etc. Among them, ethanol is preferred.

[0091] The mixing is carried out by adding (preferably dropwise) the solution of the product of step 3a to N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine under stirring. The mixing is also carried out by adding N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine to the solution of the product of step 3a under stirring. The addition temperature is generally 60 to 78°C, preferably 65 to 75°C. After the addition, the mixture is generally aged at 60 to 78°C, preferably 65 to 75°C, for about 0.5 hours, and then at 15 to 35°C, preferably 20 to 30°C, for about 12 hours to about 48 hours, preferably about 18 hours to about 24 hours, under stirring.

[0092] By the above operation, crystals of N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5) are precipitated. The precipitated crystals are collected by filtration, and then recrystallized from a solvent such as alcohol, ether, or aromatic hydrocarbon, if necessary. Among such solvents, ethanol is preferred.

[0093] In this manner, the N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5) can be obtained with high purity (for example, a purity of 98.5% or higher).

[0094] The purity of compound (4), which is the starting material in step 3a, greatly affects the purity of N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5). Therefore, in order to obtain N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5) having a higher purity, it is important to use compound (4) having a higher purity in step 3a.

[0095] When compound (4) is tert-butyl 2-[(3-bromo-2-fluorophenyl)methyl]-3-oxopyrrolidine-1-carboxylate (compound (4a)), this compound is difficult to crystallize, and therefore it is difficult to increase the purity.

[0096] The present inventors have succeeded in obtaining compound (4) having a higher purity by a process including the following steps 1a and 1b, as well as the following step 2. Step 1a: reacting compound (1) and compound (2); and Step 1b: The product of step 1a is subjected to a deprotection reaction, followed by salt formation with tartaric acid to obtain the hemitartrate salt of compound (3). a process comprising: Step 2: Introducing a protecting group into the pyrrolidine 1-position of the hemitartrate salt of compound (3) to obtain compound (4).

[0097] Process 1a In this step, compound (1) and compound (2) are reacted.

[0098] The reaction is carried out by reacting compound (1) with compound (2) in a solvent in the presence of a secondary amine. More specifically, the reaction is carried out by converting compound (2) into an activated form (enamine form) in a solvent in the presence of a secondary amine, and then reacting the activated form with compound (1).

[0099] Compound (1) may be commercially available.

[0100] Compound (2) is preferably tert-butyl 3-oxopyrrolidine-1-carboxylate compound (2a)), which may be a commercially available product.

[0101] The amount of compound (2) used is generally 1.5 to 2.5 mol, preferably 1.9 to 2.1 mol, per 1 mol of compound (1).

[0102] Examples of the secondary amine include cyclic amines, among which pyrrolidine is preferred.

[0103] The amount of the secondary amine used is generally 1.5 to 3.5 mol, preferably 2.0 to 3.0 mol, per 1 mol of compound (1).

[0104] If necessary, a phase transfer catalyst such as tetrabutylammonium iodide (TBAI) may be added to the reaction system in an amount of generally 0.01 to 0.20 mol, preferably 0.09 to 0.11 mol, per 1 mol of compound (1).

[0105] Examples of the solvent include aromatic hydrocarbons, nitriles, etc. Among them, a mixed solvent of toluene and acetonitrile is preferred.

[0106] The reaction is generally carried out at 20 to 55° C., preferably 35 to 45° C. The reaction time is generally about 30 minutes to about 12 hours, preferably about 1 hour to about 2 hours.

[0107] After the reaction is completed, the reaction mixture is subjected to usual post-treatment such as phase separation and concentration.

[0108] In the reaction, compound (4) is produced, which can be subjected to the next step 1b without being isolated from the reaction mixture.

[0109] Process 1b In this step, the product of step 1a is subjected to a deprotection reaction, followed by salt formation with tartaric acid to obtain the hemitartrate of compound (3).

[0110] The deprotection reaction depends on the type of the protecting group at the pyrrolidine 1-position. For example, when the protecting group is a tert-butoxycarbonyl group, the deprotection reaction is carried out by reacting with an acid in a solvent.

[0111] Examples of acids include hydrogen chloride, etc. Hydrogen chloride is preferably used as a solution in an organic solvent, particularly preferably as a solution of hydrogen chloride in 2-propanol.

[0112] Examples of the solvent include alcohols, esters, etc. Among them, 2-propanol, ethyl acetate, and a mixed solvent thereof are preferable, and 2-propanol is particularly preferable.

[0113] The reaction is generally carried out at 40 to 60° C., preferably 45 to 55° C. The reaction time is generally about 1 to about 6 hours, preferably about 2 to about 4 hours.

[0114] The reaction produces compound (3), which precipitates as a hydrochloride when the deprotection reaction is treated with hydrogen chloride. After completion of the reaction, the hydrochloride can be obtained by adding ethyl acetate at 45-55°C for crystallization, cooling to 0-10°C over 1 hour or more, and then washing with ethyl acetate. The obtained hydrochloride of compound (3) is converted to a free form by adding a base in a solvent, and is then used for the subsequent salt formation with tartaric acid.

[0115] The salt formation with tartaric acid is carried out by mixing compound (3) with tartaric acid in a solvent, and then filtering off the resulting precipitated crystals.

[0116] The amount of tartaric acid used is generally 0.3 to 1.0 mol, preferably 0.4 to 0.6 mol, per 1 mol of compound (1).

[0117] Examples of the solvent include alcohols, aromatic hydrocarbons, ketones, etc. Among them, a mixed solvent of methanol and toluene is preferable.

[0118] The mixing is carried out by adding (preferably dropwise) the solution of compound (3) to the solution of tartaric acid under stirring. The addition temperature is generally 15 to 35° C., preferably 20 to 30° C. After the addition, the mixture is aged under stirring generally at −5 to 15° C., preferably 0 to 10° C., for about 1 hour to about 24 hours.

[0119] The above procedure precipitates the crystals of the hemitartrate salt of compound (3), which can be obtained by filtering the precipitated crystals, washing them with a mixed solvent of methanol and toluene, and then drying them.

[0120] In order to obtain compound (4) used in step 3a with higher purity, it is important to increase the purity of the hemitartrate salt of compound (3). By the above crystallization, the hemitartrate salt of compound (3) can be obtained with a high purity (for example, a purity of 98.0% or more).

[0121] The hemitartrate of compound (3) thus obtained is a novel compound.

[0122] Process 2 In this step, a protecting group is introduced at the pyrrolidine 1-position of the hemitartrate of compound (3) to give compound (4).

[0123] The reaction depends on the type of the protecting group at the pyrrolidine 1-position. For example, when the protecting group is a tert-butoxycarbonyl group, the reaction is carried out by reacting the hemitartrate of compound (3) with a tert-butoxycarbonylating agent in a solvent in the presence of a base.

[0124] Examples of tert-butoxycarbonylating reagents include di-tert-butyl dicarbonate, tert-butoxycarbonyl chloride, and the like.

[0125] The amount of the tert-butoxycarbonylating reagent used is generally 0.8 to 2.0 mol, preferably 0.9 to 1.1 mol, per 1 mol of the hemitartrate of compound (3).

[0126] Examples of the base include organic bases, among which triethylamine is preferred.

[0127] The amount of the base used is generally 1.5 to 3.0 mol, preferably 2.1 to 2.3 mol, per mol of the hemitartrate of compound (3).

[0128] Examples of the solvent include nitriles, ethers, etc. Among them, acetonitrile is preferred.

[0129] The reaction is generally carried out at −5 to 35° C., preferably 0 to 10° C. The reaction time is generally about 30 minutes to about 12 hours, preferably about 1 hour to about 2 hours.

[0130] After the reaction is completed, 10% citric acid aqueous solution and ethyl acetate are added to the reaction mixture, the mixture is stirred at 20-30°C for 15 minutes or more, and then the aqueous layer is removed. The organic layer is then washed with 5% saline. The organic layer is treated with activated carbon, and then the solvent is replaced with ethanol by repeated vacuum concentration and addition of ethanol. Water is added to it at 20-30°C, the mixture is cooled to 0-10°C, and then seed crystals of compound (4) are added to it to precipitate crystals of compound (4). The mixture is stirred at 0-10°C for 3 hours or more, water is added dropwise to it, and the mixture is stirred for 2 hours or more. The precipitated crystals are washed with water-ethanol and dried to obtain crystals of compound (4).

[0131] Treatment with activated carbon includes adding activated carbon to the reactor, stirring and filtering the mixture or passing the reaction solution through a filter containing activated carbon; and then washing the insolubles with ethyl acetate.

[0132] In this manner, compound (4) can be obtained with high purity (for example, a purity of 98% or more).

[0133] The N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5) obtained in step 3b can be converted to medicamentously useful N-{(2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide) by the following steps 4 to 7. Step 4: a step of desalting the N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5) and then treating the resulting compound with a methanesulfonylating reagent to obtain compound (6); Step 5: reacting compound (6) with (3,5-difluorophenyl)boronic acid to obtain compound (7); Step 6: subjecting compound (7) to a deprotection reaction to obtain the hydrochloride salt of compound (8); and Step 7: A step of subjecting the hydrochloride of compound (8) to a condensation reaction with 2-hydroxy-2-methylpropanoic acid to obtain compound (I).

[0134] Process 4 In this step, the N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5) is subjected to desalting, and the resulting compound is then reacted with a methanesulfonylating agent to obtain compound (6).

[0135] The reaction is carried out by converting the N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5) into a free form by desalting with a base in a solvent, and then reacting the free form with a methanesulfonylation reagent in the presence of a base.

[0136] The N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5) is preferably (2S,3S)-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidine-1-carboxylate tert-butyl (compound (5a)) N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt.

[0137] Examples of the base used for the conversion to the free form include inorganic bases, among which sodium carbonate is preferred.

[0138] Examples of methanesulfonylating reagents include methanesulfonyl chloride, etc. The methanesulfonylating reagent may be commercially available.

[0139] The amount of the methanesulfonylation reagent used is generally 1.0 to 3.0 mol, preferably 1.3 to 1.5 mol, per 1 mol of the N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5).

[0140] Examples of the base include organic bases, among which triethylamine is preferred.

[0141] The amount of the base used is generally 1.5 to 4.0 mol, preferably 1.9 to 2.1 mol, per mol of the N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5).

[0142] Examples of the solvent include esters, aromatic hydrocarbons, amides, etc. Among them, a mixed solvent of ethyl acetate and toluene is preferable.

[0143] The reaction is generally carried out at −10 to 15° C., preferably −2 to 8° C. The reaction time is generally about 30 minutes to about 6 hours, preferably about 1 hour to about 2 hours.

[0144] After the reaction is completed, the usual post-treatment such as phase separation and concentration is carried out. Then, compound (6) is precipitated by adding a saturated hydrocarbon such as n-heptane. If necessary, compound (6) may be recrystallized from an aromatic hydrocarbon such as toluene and a saturated hydrocarbon such as n-heptane.

[0145] In this manner, crystals of compound (6) can be obtained.

[0146] Process 5 In this step, compound (6) is reacted with (3,5-difluorophenyl)boronic acid to give compound (7).

[0147] The reaction is carried out by reacting compound (6) with (3,5-difluorophenyl)boronic acid in a solvent in the presence of a palladium catalyst, a phosphine ligand and a base.

[0148] Compound (6) is preferably (2S,3S)-tert-butyl 2-[(3-bromo-2-fluorophenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (compound (6a)).

[0149] (3,5-difluorophenyl)boronic acid may be commercially available.

[0150] The amount of (3,5-difluorophenyl)boronic acid used is generally 1.0 to 3.0 mol, and preferably 1.1 to 1.3 mol, per 1 mol of compound (6).

[0151] Examples of the palladium catalyst include Pd carbon powder, di-tert-butyl(3-methyl-2-butenyl)phosphine (Pd(m-Crophos)Cl2), palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride, etc. The palladium catalyst is preferably di-tert-butyl(3-methyl-2-butenyl)phosphine (Pd(m-Crophos)Cl2) or Pd carbon powder, particularly preferably 10% Pd carbon powder (e.g., PE-TYPE, manufactured by NECHEMCAT).

[0152] The amount of the palladium catalyst used is a catalytic amount, specifically, generally 0.01 to 2.00 mol %, preferably 0.08 to 0.12 mol %, per mol of compound (6).

[0153] Examples of phosphine ligands include Xphos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), etc. The phosphine ligand is preferably Xphos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl).

[0154] The amount of the phosphine ligand used is a catalytic amount, specifically, generally 0.02 to 4.00 mol %, preferably 0.16 to 0.24 mol %, per mol of compound (6).

[0155] Examples of the base include organic bases and inorganic bases. The base is preferably N,N-diisopropylethylamine or sodium hydroxide, particularly preferably sodium hydroxide.

[0156] The amount of the base used is generally 1.0 to 3.0 mol, preferably 1.4 to 1.6 mol, per 1 mol of compound (6).

[0157] The solvent is preferably an ether or a mixture of an ether and water, more preferably a mixture of water and 1,2-dimethoxyethane.

[0158] The reaction is generally carried out at 70 to 83° C., preferably 75 to 81° C. The reaction time is generally about 1 to about 12 hours, preferably about 3 to about 6 hours.

[0159] After the reaction is completed, ethyl acetate and water are added to the reaction mixture, and then the insoluble matter is filtered off. The filtrate is treated with N-acetylcysteine ​​and NaCl, and the solvent is replaced with ethanol by concentration. Water is added thereto at 60-70°C, and the mixture is cooled to 20-30°C to precipitate crystals of compound (7). The precipitated crystals are washed with ethanol-water and dried. In this way, crystals of compound (7) can be obtained.

[0160] Process 6 In this step, compound (7) is subjected to a deprotection reaction to give the hydrochloride of compound (8).

[0161] Compound (7) is preferably (2S,3S)-3-[(methanesulfonyl)amino]-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-1-carboxylate tert-butyl (compound (7a)). In this case, the reaction is carried out by reacting compound (7) with an acid in a solvent.

[0162] Examples of acids include hydrogen chloride, etc. Hydrogen chloride is preferably used as a solution in an organic solvent, more preferably as a solution of hydrogen chloride in 2-propanol or ethyl acetate, particularly preferably as a solution of hydrogen chloride in 2-propanol.

[0163] Examples of the solvent include alcohols, esters, water, etc. The solvent is preferably an alcohol, an ester, or a mixed solvent thereof, more preferably ethanol, ethyl acetate, 2-propanol, or a mixed solvent thereof, particularly preferably 2-propanol.

[0164] The reaction is generally carried out at 40 to 80° C., preferably 50 to 70° C. The reaction time is generally about 1 to about 12 hours, preferably about 2 to about 8 hours.

[0165] After the reaction is completed, n-heptane is added to the reaction mixture at 40 to 80° C. to precipitate crystals, the mixture is cooled to 0 to 10° C. over 1 hour or more, and the crystals are washed with 2-propanol / n-heptane or ethanol / n-heptane, preferably 2-propanol / n-heptane. In this manner, crystals of the hydrochloride of compound (8) can be obtained.

[0166] Process 7 In this step, the hydrochloride of compound (8) is subjected to a condensation reaction with 2-hydroxy-2-methylpropanoic acid to obtain compound (I).

[0167] The condensation reaction is carried out by reacting the hydrochloride of compound (8) with 2-hydroxy-2-methylpropanoic acid in the presence of a condensation reagent and a base.

[0168] 2-Hydroxy-2-methylpropanoic acid can be commercially available.

[0169] The amount of 2-hydroxy-2-methylpropanoic acid used is generally 1.5 to 5.0 mol, preferably 2.4 to 2.6 mol, per mol of the hydrochloride of compound (8).

[0170] Examples of the base include organic bases and inorganic bases. The base is preferably triethylamine.

[0171] The amount of the base used is generally 1.5 to 7.5 mol, preferably 3.6 to 3.8 mol, per mol of the hydrochloride of compound (8).

[0172] Examples of condensation reagents include carbodiimide condensation reagents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine condensation reagents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate condensation reagents such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl haloformates such as chloroethyl formate; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphorate (HATU); sulfuric acid; combinations thereof, and the like. When using a carbodiimide condensation reagent, an additive such as 1-hydroxybenzotriazole (HOBt) monohydrate, N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), dimethylaminopyridine (DMAP) or the like may be added to the reaction system. The condensation reagent is preferably CDI or WSCD. The condensation reagent is particularly preferably CDI. The additive is preferably HOBt monohydrate or HONB. The additive is particularly preferably HONB.

[0173] The amount of the condensation reagent used is generally 1.5 to 5.0 mol, preferably 2.4 to 2.6 mol, per mol of the hydrochloride of compound (8).

[0174] The amount of the additive used is generally 1.5 to 5.0 mol, preferably 2.2 to 2.4 mol, per mol of the hydrochloride of compound (8).

[0175] The reaction is generally carried out in a solvent. Examples of the solvent include amides, etc. The solvent is preferably an amide, more preferably dimethylacetamide.

[0176] The reaction is generally carried out at 20 to 50° C., preferably 32 to 42° C. The reaction time is generally about 2 to 24 hours, preferably about 4 to 8 hours.

[0177] After the reaction is completed, water is added to the reaction mixture, the pH is adjusted to alkaline with sodium hydroxide, and the mixture is stirred under heating. Then, the pH is adjusted to neutral with hydrochloric acid at room temperature, and water is added thereto to precipitate crystals of compound (I). If necessary, seed crystals (e.g., sesquihydrate seed crystals) may be added thereto. For example, water is added to the mixture at 15-45°C, the pH is adjusted to 13.0-14.0 with sodium hydroxide, and the mixture is stirred at 40-60°C. Then, the mixture is cooled to 20-40°C, and the pH is adjusted to 7.5-8.5 with hydrochloric acid. Then, water is added dropwise thereto at 55-65°C, seed crystals are added thereto, and the mixture is stirred at 55-65°C. Then, water is added dropwise thereto at 55-65°C, and the mixture is cooled to 45-55°C over 0.5 hours or more, and then cooled to 30°C or less over 1.5 hours or more to precipitate crystals of compound (I). The precipitated crystals are washed with ethanol-water to obtain crystals of compound (I). If necessary, the crystals may be stirred in ethanol-water-triethylamine or recrystallized from ethanol-water. If necessary, the solution of compound (I) may be passed through a filter with activated carbon and then recrystallized from ethanol-water.

[0178] In this manner, crystals of Compound (I) can be obtained with high purity (for example, a purity of 99% or more).

[0179] Compound (I) may be a hydrate, a non-hydrate or a solvate. Compound (I) is preferably a hydrate (preferably a sesquihydrate). EXAMPLES

[0180] The present invention will be described in detail below by referring to examples. However, the examples do not limit the present invention, and the examples may be modified within the scope of the present invention.

[0181] In the following examples, "room temperature" generally refers to about 10° C. to about 35° C. Ratios of mixed solvents are volumetric mixture ratios unless otherwise specified, and % means weight % unless otherwise specified.

[0182] In the examples, elution by column chromatography was performed under observation by TLC (thin layer chromatography) unless otherwise specified. 254 was used as the TLC plate, the solvent used as the eluting solvent in column chromatography was used as the eluent, and a UV detector was used for detection. In silica gel column chromatography, the designation NH means the use of aminopropylsilane-bonded silica gel, and the designation DIOL means the use of 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. In preparative HPLC (high performance liquid chromatography), the designation C18 means the use of octadecyl-bonded silica gel. The ratio of the eluting solvent is a volume mixture ratio unless otherwise specified. The temperatures in the reactions and treatment operations described in the Reference Examples and Examples include variations in the range of ±5°C.

[0183] 1 1 H NMR was measured by Fourier transform NMR. 1 For the H NMR analysis, ACD / SpecManager (trade name) software etc. was used. Peaks of hydroxyl groups, amino groups etc. having broad proton peaks may not be recorded.

[0184] In the examples below, the following abbreviations are used: M: Molar concentration N: Regulation HPLC: High-performance liquid chromatography

[0185] Experimental Example 1 Chiral Ligand Screening Chiral ligands were screened to identify the most suitable metal complexes for the asymmetric reductive amination reaction of the present invention.

[0186] [RuCl2(benzene)]2 (0.0010 g), chiral ligand, and ammonium salicylate or ammonium acetate (5.0 equivalents) were charged into a reactor. Then, a solution of 2-[(3-bromo-2-fluorophenyl)methyl]-3-oxopyrrolidine-1-carboxylate tert-butyl (compound (4a)) (0.7445 g) in methanol (25 ml) was prepared, and 1 ml of the solution was added thereto. The mixture was stirred at 50° C. for about 1 hour under a nitrogen atmosphere, and then stirred at 80° C. for 16 hours under a hydrogen pressure of 5.0 MPa (G) to obtain a mixture containing the desired compound (2S,3S)-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidine-1-carboxylate tert-butyl (compound (5a)).

[0187] The mixture containing the obtained compound (5a) was subjected to chiral HPLC analysis under the following conditions, and the yield of the cis isomer (HPLC amine area%), amine selectivity and enantiomeric excess (cis%ee) were calculated. The results are shown in Table 4.

[0188] Abbreviations are as follows: (2S,3S)-form: (2S,3S)-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidine-1-carboxylate tert-butyl (compound (5a)) (2R,3R)-form: (2R,3R)-tert-butyl 3-amino-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidine-1-carboxylate Trans isomer: trans-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidine-1-carboxylate tert-butyl

[0189] (HPLC analysis conditions) Yield of cis isomer (HPLC amine area%) and amine selectivity Column: YMC-Pack C18 Pro RS, 5 μm, 4.6 × 150 mm Mobile phase: A solution) CH3CN B solution) 0.03M K2HPO4 Flow rate: 1.0mL / min Column temperature: 25℃ Detection: UV 220nm Injection: 10mL Analysis time: 30 minutes Gradient Program:

[0190] [Table 1]

[0191] Retention time: (2S,3S)-Body 15.02 minutes Trance Body 15.78 minutes

[0192] Enantiomeric excess (cis %ee) %ee of cis = {[HPLC area of ​​(2R,3R)-isomer - HPLC area of ​​(2S,3S)-isomer] / [HPLC area of ​​(2R,3R)-isomer + HPLC area of ​​(2S,3S)-isomer]} x 100

[0193] (R,R)-iPr-DUPHOS or (R)-PHANEPHOS Column: Chiralpak (Daicel), 5 μm, 4.6 × 150 mm Mobile phase: A solution) 0.01M K2HPO4 B solution) CH3CN Flow rate: 1.0mL / min Column temperature: 25℃ Detection: UV 220nm Injection: 10μL Analysis time: 20 minutes Gradient Program:

[0194] [Table 2]

[0195] Retention time: (2S,3S)-body 6.48 minutes (2R,3R)-body 15.77 minutes

[0196] For cases other than (R,R)-iPr-DUPHOS and (R)-PHANEPHOS Column: Chiralpak IE (Daicel), 5 μm, 4.6 × 250 mm Mobile phase: A solution) 0.01M K2HPO4 B solution) CH3CN Flow rate: 1.0mL / min Column temperature: 25℃ Detection: UV 220nm Injection: 10μL Analysis time: 30 minutes Gradient Program:

[0197] [Table 3]

[0198] Retention time: 2-[(3-bromo-2-fluorophenyl)methyl]-3-hydroxypyrrolidine-1-carboxylate tert-butyl (mixture of stereoisomers) 6.90 min (2S,3S)-Body 8.84 minutes (2R,3R)-body 9.95 minutes Compound (4a) 11.02 minutes

[0199] [Table 4]

[0200] Table 4 shows that, among these, BINAP, phosphine, ferrocene and cyclophane chiral ligands have good reaction efficiency and high enantioselectivity.

[0201] Experimental Example 2-1 Metal Catalyst Screening Metal catalysts were screened to identify the most suitable metal complexes for the asymmetric reductive amination reaction of the present invention.

[0202] A metal catalyst (0.0010 g) and a chiral ligand (1.1 equivalents) were charged into a reactor. Then, a solution of 2-[(3-bromo-2-fluorophenyl)methyl]-3-oxopyrrolidine-1-carboxylate tert-butyl (compound (4a)) (0.2978 g) / methanol (5 ml) was prepared, and 0.5 ml of the solution was added thereto. Then, a solution of NHOAc (0.0308 g) / methanol (5 ml) was prepared, and 0.5 ml of the solution was added thereto, and the mixture was stirred for 30 minutes. The mixture was stirred at 80° C. under a hydrogen pressure of 5.0 MPa (G) for 17 hours to obtain a mixture containing the desired compound (2S,3S)-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidine-1-carboxylate tert-butyl (compound (5a)).

[0203] The mixture containing the obtained compound (5a) was subjected to chiral HPLC analysis under the following conditions, and the yield of the cis isomer (HPLC amine area%) and the enantiomeric excess (cis%ee) were calculated. The results are shown in Table 7.

[0204] Abbreviations are as follows: (2S,3S)-form: (2S,3S)-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidine-1-carboxylate tert-butyl (=compound (5a)) (2R,3R)-form: (2R,3R)-tert-butyl 3-amino-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidine-1-carboxylate Trans isomer: trans-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidine-1-carboxylate tert-butyl

[0205] (HPLC analysis conditions) Yield of cis isomer (HPLC amine area%) Column: YMC-Pack C18 Pro RS, 5 μm, 4.6 × 150 mm Mobile phase: A solution) 0.03M K2HPO4 B solution) CH3CN Flow rate: 1.0mL / min Column temperature: 25℃ Detection: UV 220nm Injection: 10mL Analysis time: 30 minutes Gradient Program:

[0206] [Table 5]

[0207] Retention time: (2S,3S)-Body 15.02 minutes Trance Body 15.78 minutes

[0208] Enantiomeric excess (cis %ee) %ee of cis = {[HPLC area of ​​(2R,3R)-isomer - HPLC area of ​​(2S,3S)-isomer] / [HPLC area of ​​(2R,3R)-isomer + HPLC area of ​​(2S,3S)-isomer]} x 100 Column: Chiralpak IE (Daicel), 5 μm, 4.6 × 250 mm Mobile phase: A solution) 0.01M K2HPO4 B solution) CH3CN Flow rate: 1.0mL / min Column temperature: 25℃ Detection: UV 220nm Injection: 10μL Analysis time: 30 minutes Gradient Program:

[0209] [Table 6]

[0210] Retention time: 2-[(3-bromo-2-fluorophenyl)methyl]-3-hydroxypyrrolidine-1-carboxylate tert-butyl (mixture of stereoisomers) 6.90 min (2S,3S)-Body 8.84 minutes (2R,3R)-body 9.95 minutes Compound (4a) 11.02 minutes

[0211] [Table 7]

[0212] Table 7 shows that rhodium and iridium metal catalysts have good reaction efficiency and high enantioselectivity in combination with various chiral ligands.

[0213] Experimental Example 2-2 Metal Catalyst Screening Ruthenium metal catalysts were screened to identify the most suitable metal complexes for the asymmetric reductive amination reaction of the present invention.

[0214] [RuCl(p-cymene)((R)-xylyl-binap)]Cl and RuCl 2 ((R)-Xylyl-binap)(dmf)n The ruthenium complex was charged into a reactor, and then a solution of tert-butyl 2-[(3-bromo-2-fluorophenyl)methyl]-3-oxopyrrolidine-1-carboxylate (compound (4a), 1.1911 g) in methanol (10 ml) was prepared, and 0.5 ml of the solution was added to the reactor. Then, a solution of 1.2333 g of NHOAc in methanol (10 ml) was prepared, and 0.5 ml of the solution was added to the reactor. The mixture was stirred and then stirred at 80° C. under a hydrogen pressure of 5.0 MPa (G) for about 18 hours to obtain a mixture containing (2S,3S)-tert-butyl 3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate (compound (5a)).

[0215] (NH 2 Me 2 )[(RuCl((R)-xylyl-binap)) 2 (η-Cl) 3 ], Ru(TFA) 2 ((R)-Xylyl-binap) and Ru(OAc) 2 ((R)-Xylyl-binap) The ruthenium complex was charged into a reactor. Then, a solution of compound (4a) (0.5956 g) / methanol (5 ml) was prepared, and 0.5 ml of the solution was added thereto. Then, a solution of NHOAc (0.6166 g) / methanol (5 ml) was prepared, and 0.5 ml of the solution was added thereto. The mixture was stirred, and then stirred at 80° C. under a hydrogen pressure of 5.0 MPa (G) to obtain a mixture containing compound (5a).

[0216] The mixture containing the obtained compound (5a) was subjected to HPLC analysis under the following conditions, and the conversion rate of the reaction, the formation ratio of cis / trans isomers (cis / trans) and the enantiomeric excess (cis%ee) were calculated. The results are shown in Table 10.

[0217] Abbreviations are as follows: (2S,3S)-form: (2S,3S)-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidine-1-carboxylate tert-butyl (compound (5a)) (2R,3R)-form: (2R,3R)-tert-butyl 3-amino-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidine-1-carboxylate Trans isomer: trans-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidine-1-carboxylate tert-butyl

[0218] (HPLC analysis conditions) Conversion rate and cis / trans formation ratio (cis / trans) Cis / trans = (HPLC area of ​​cis isomer) / [(HPLC area of ​​cis isomer)+(HPLC area of ​​trans isomer)] x 100 Column: YMC-Pack C18 Pro RS, 5 μm, 4.6 × 150 mm Mobile phase: A solution) 0.03M K2HPO4 B solution) CH3CN Flow rate: 1.0mL / min Column temperature: 25℃ Detection: UV 220nm Injection: 10mL Analysis time: 30 minutes Gradient Program:

[0219] [Table 8]

[0220] Retention time: (2S,3S)-Body 15.02 minutes Trance Body 15.78 minutes

[0221] Enantiomeric excess (cis %ee) %ee of cis = {[HPLC area of ​​(2R,3R)-isomer - HPLC area of ​​(2S,3S)-isomer] / [HPLC area of ​​(2R,3R)-isomer + HPLC area of ​​(2S,3S)-isomer]} x 100 Column: Chiralpak IE (Daicel), 5 μm, 4.6 × 250 mm Mobile phase: A solution) 0.01M K2HPO4 B solution) CH3CN Flow rate: 1.0mL / min Column temperature: 25℃ Detection: UV 220nm Injection: 10μL Analysis time: 30 minutes Gradient Program:

[0222] [Table 9]

[0223] Retention time: (2S,3S)-2-[(3-bromo-2-fluorophenyl)methyl]-3-hydroxypyrrolidine-1-carboxylate tert-butyl 6.90 min (2S,3S)-body 8.44 minutes (2R,3R)-body 9.55 minutes Compound (4a) 10.89 minutes Trance Body 11.02 minutes

[0224] [Table 10]

[0225] Table 10 shows that various ruthenium metals have good reaction efficiency and high enantioselectivity.

[0226] Example 1 Synthesis of 2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-one hemitartrate (the hemitartrate of compound (3)) 3-Oxopyrrolidine-1-carboxylate tert-butyl (compound (2a), 6.91 g) and toluene (45 ml) were charged into a reactor, then pyrrolidine (3.32 g) was added dropwise thereto at below 40° C., and the mixture was stirred for 10 minutes. The reaction solution was concentrated to 25 ml, toluene (25 ml) was added to the concentrate, and the solution was concentrated to 25 ml. Again, toluene (25 ml) was added to the concentrate, and the solution was concentrated to 25 ml. Acetonitrile (40 ml) was added to the obtained concentrate, and then tetrabutylammonium iodide (0.689 g) was added thereto. The temperature of the mixture was maintained at about 30° C., and an acetonitrile solution (7.5 ml) of 1-bromo-3-(bromomethyl)-2-fluorobenzene (compound (1), 5.00 g) was added thereto dropwise. The dropping funnel used was washed with acetonitrile (2.5 ml), the washing liquid was added to it, and the mixture was stirred at 40°C for 1 hour. Then, the mixture was cooled to 15-25°C, and the pH was adjusted to 2.0-3.0 with 2M hydrochloric acid. Ethyl acetate (40 ml) was added to it, the mixture was allowed to stand, and the aqueous layer was removed by separation to obtain an organic layer. 10% aqueous sodium thiosulfate solution (35 ml) was added to the obtained organic layer, the mixture was allowed to stand, and the aqueous layer was removed by separation to obtain an organic layer. 10% saline solution (35 ml) was added to the obtained organic layer, and the mixture was allowed to stand. The aqueous layer was removed by separation, and the obtained organic layer was concentrated to 15 ml.

[0227] 2-propanol (40 ml) was added to the concentrated solution, and the mixture was concentrated to 15 ml. 2-propanol (40 ml) was added again to the concentrated solution, and the mixture was concentrated to 15 ml. The concentrated solution was heated to 50° C., and while maintaining the temperature, 5M hydrogen chloride / 2-propanol (15 ml) was added dropwise to it to precipitate crystals. The solution in which crystallization occurred was stirred at 50° C. for 1 hour. Ethyl acetate (50 ml) was slowly added to it at 50° C., and the mixture was stirred at 50° C. for 1 hour. The mixture was slowly cooled to 5° C. and stirred at 5° C. for 1 hour, and the crystals were collected by filtration and washed with ethyl acetate (15 ml). The wet crystals of the hydrochloride salt of compound (3) thus obtained and toluene (40 ml) were placed in a reactor, and the mixture was cooled to 5° C. Triethylamine (2.27 g) was added dropwise to it at 5° C. The mixture was stirred at 5° C. for 1 hour, the insoluble material was removed by filtration and washed with toluene (25 ml), and the washings were combined with the filtrate.

[0228] Methanol (50 ml) and DL-tartaric acid (1.40 g) were charged into a separate reactor, and the mixture was stirred at 25° C. for 30 minutes. The above filtrate was added dropwise to it at 25° C. over 2 hours to precipitate crystals. The dropping funnel used was washed with toluene (5 ml), and the washings were combined with the above mixture. The mixture was stirred at 25° C. for 1 hour, cooled slowly to 5° C. with stirring, and stirred at 5° C. for 3 hours or more. The precipitated crystals were collected by filtration, washed with a toluene-methanol=2:1 (15 ml) solution cooled to 5° C., and dried under reduced pressure to obtain the title compound (3) hemitartrate crystals (3.35 g) (98.0 HPLC area %).

[0229] (Compound NMR data) 1 H NMR (300MHz, DMSO-d6) δ=7.56(t, J=7.3Hz, 1H), 7.34(t, J=7.3Hz, 1H), 7.10(t, J=7.3Hz, 1H), 4.16(m, 1H), 3.38(dd, J= 4.3, 9.3Hz, 1H), 3.22(m, 1H), 3.12-2.99(m, 2H), 2.70(dd, J=9.3, 14.2Hz, 1H), 2.47-2.17(m, 2H)

[0230] (HPLC analysis conditions) Column: YMC-Pack Pro C18 (YMC Corporation), column size 4.6 × 150 mm, particle size 5 μm Column temperature: 40℃ Mobile phase: A solution) 0.02M K2HPO4(pH7.0):CH3CN=70:30 B solution) 0.02M K2HPO4(pH7.0):CH3CN=30:70 Gradient Program:

[0231] [Table 11]

[0232] Flow rate: 1.0ml / min Retention time: Compound (1) 15.7 minutes 2-[(3-bromo-2-fluorophenyl)methyl]-3-oxopyrrolidine-1-carboxylate tert-butyl (compound (4a)) 16.5 min Compound (3) 7.7 minutes DL-Tartaric acid 1.4 minutes

[0233] Example 2 Synthesis of tert-butyl 2-[(3-bromo-2-fluorophenyl)methyl]-3-oxopyrrolidine-1-carboxylate (compound (4a)) Compound (3) hemitartrate (10.0 g) and acetonitrile (60 ml) were charged in a reactor, and triethylamine (6.4 g) was added dropwise thereto while maintaining the temperature at 25° C. Boc2O (6.3 g) and acetonitrile (15 ml) were charged in another reactor, the mixture was stirred at 25° C., and added dropwise to the above solution of compound (3), the dropping funnel used was washed with acetonitrile (5 ml), and the washings were added to the reactor. The mixture thus obtained was stirred at 25° C. for 1 hour. 10% citric acid aqueous solution (50 ml) and ethyl acetate (80 ml) were added thereto, the mixture was allowed to stand at 25° C., and the aqueous layer was removed by separation. 5% saline (50 ml) was added to the obtained organic layer, the mixture was allowed to stand at 25° C., and the aqueous layer was removed by separation to obtain an organic layer. Activated carbon SHIRASAGI A (Osaka Gas Chemical) (1.0 g) was added to the obtained organic layer, and the mixture was stirred at 25° C. for 30 minutes or more. Insoluble matter was filtered off, washed with ethyl acetate (30 ml), and the washing liquid was combined with the filtrate. The filtrate was concentrated to a volume of 30 ml at 40° C. or less. Ethanol (100 ml) was added thereto, and the mixture was concentrated to 30 ml at 40° C. or less. Ethanol (100 ml) was added again to the concentrated solution, and the mixture was concentrated to 30 ml at 40° C. or less. Ethanol (20 ml) was added to the concentrated solution at 25° C., and water (20 ml) was added dropwise thereto at 25° C. The mixture was cooled to 5° C., and seed crystals (5 mg) of compound (4a) were added thereto at 5° C., and after confirmation of crystallization, the mixture was stirred at 5° C. for 6 hours or more. Water (50 ml) was added dropwise thereto, and the mixture was stirred at 5° C. for 1 hour or more. After stirring at 5° C. for an additional 2 hours, the crystals were collected by filtration and washed with ethanol-water (1:2) (30 ml) cooled to 3° C. The drained wet crystals were dried under reduced pressure at 25° C. or lower to obtain wet crystals (10.73 g) (99.5 HPLC area %) of the title compound (4a). As the seed crystals of compound (4a), crystals that spontaneously precipitated in the above reaction before the addition of the seed crystals were used.

[0234] (Compound NMR data) 1H NMR (300MHz, DMSO-d6) δ=7.58(t, J=7.0Hz, 1H), 7.20-7.04(m, 2H), 4.12(t, J=6.2Hz, 1H), 3.76( m, 1H), 3.35-3.05(m, 2H), 2.97(m, 1H), 2.61(m, 1H), 2.34(m, 1H), 1.29(br s, 9H)

[0235] (HPLC analysis conditions) Column: YMC-Pack Pro C18 (YMC Corporation), column size 4.6 × 150 mm, particle size 5 μm Column temperature: 40℃ Mobile phase: A solution) 0.02M K2HPO4(pH7.0):CH3CN=70:30 B solution) 0.02M K2HPO4(pH7.0):CH3CN=30:70 Gradient Program:

[0236] [Table 12]

[0237] Flow rate: 1.0ml / min Retention time: Compound (4a) 16.5 minutes Compound (3) 7.7 minutes DL-Tartaric acid 1.4 minutes

[0238] Example 3 Synthesis of (2S,3S)-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidine-1-carboxylate tert-butyl N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt (N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5a)) Ru(OAc)2{(R)-xylyl-binap} (0.298 g), compound (4a) (23.24 g), ammonium chloride (13.36 g) and ammonium acetate (4.81 g) were charged into an autoclave. The mixture was subjected to vacuum degassing and nitrogen restoration 7 times under stirring. Methanol (232 ml) and water (2.87 ml) were charged into another reactor, and the mixture was subjected to vacuum degassing and nitrogen restoration 5 times under stirring. The obtained degassed methanol-water solution was added to the pre-reaction mixture at 20°C. After stopping the stirring of the mixture, the mixture was subjected to hydrogen pressurization to 0.10 MPa (G) and depressurization 10 times at 20°C. After hydrogen pressurization to 0.32 MPa (G) at 20°C, stirring was resumed and the mixture was heated to 80-85°C. The hydrogen pressure was adjusted to 0.90±0.05 MPa (G) at 80-85°C, and the mixture was stirred for 24 hours. The reaction solution was concentrated to 116 ml at an external temperature of 50°C or less. The concentrated solution was cooled to 25°C, and 1M aqueous sodium hydroxide solution (116 ml) and ethyl acetate (116 ml) were added to it. The reaction solution was concentrated to 232 ml at an external temperature of 50°C or less. Ethyl acetate (116 ml) was added to it, and the mixture was concentrated to 232 ml at an external temperature of 50°C or less. Ethyl acetate (116 ml) was added to it again, and the mixture was concentrated to 232 ml at an external temperature of 50°C or less. Ethyl acetate (47 ml) was added to it, the mixture was allowed to stand at 25°C, and the aqueous layer was removed by separation. The obtained organic layer was concentrated to 70 ml at an external temperature of 50°C or less. Ethanol (116 ml) was added to it, and the organic layer was concentrated to 70 ml at an external temperature of 50°C or less. Ethanol (116 ml) was added to the concentrate again, and the organic layer was concentrated to 70 ml at an external temperature of less than 50° C. Ethanol (163 ml) was added to the obtained concentrate, and the mixture was heated to 70° C. N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine (19.94 g) was added to it at 70° C., the used reactor was washed with ethanol (23 ml), and the washings were added to it. The mixture was stirred at 70° C. for 30 minutes, slowly cooled to 25° C., and stirred at 25° C. for not less than 18 hours.The crystals obtained by these operations were collected by filtration, washed with ethanol (186 ml), and dried under reduced pressure at 50°C to obtain crystals of the title compound (5a) as N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt (31.00 g) (99.1 HPLC area%).

[0239] (Compound NMR data) 1 H NMR (500 MHz, DMSO-d6, observed as a mixture of rotamers) δ 7.63-7.45 (m, 3H), 7.30-6.94 (m, 9H), 4.07 (bs, 1H), 3.59 (t, J = 6.0 Hz, 1H), 3.54-3.40 (m, 1H), 3.01-2.72 (m, 3H), 2.48-2.42 (m, 1H), 2.34 (s, 3H), 2.15-2.02 (m, 1H), 1.96-1.78 (m, 1H), 1.20 (s, 9H), 0.99.

[0240] (HPLC analysis conditions) Column: YMC-Pack Pro C18 RS (YMC Co., Ltd.), column size 4.6 × 150 mm, particle size 5 μm Column temperature: 25℃ Mobile phase: A solution) 0.03M K2HPO4 aqueous solution Solution B) Acetonitrile Gradient Program:

[0241] [Table 13]

[0242] Flow rate: 1.0ml / min Retention time: N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine 9.77 min Compound (5a) 15.02 minutes

[0243] Example 4 Synthesis of (2S,3S)-2-[(3-bromo-2-fluorophenyl)methyl]-3-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate tert-butyl ester (compound (6a)) Toluene (600 ml) was added to the N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5a) (60.0 g), and the mixture was heated to 40-50°C. Aqueous sodium carbonate solution (900 ml) was added thereto, the mixture was stirred, and the pH of the solution was adjusted to 9 or more to dissolve the N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5a). The solution was allowed to stand, and water (600 ml) was added to the separated organic layer. The mixture was stirred and allowed to stand again, and the organic layer was separated. The obtained organic layer was concentrated under reduced pressure to about 180 ml at an external temperature of 50°C or less, toluene (300 ml) was added thereto, and the mixture was concentrated under reduced pressure to 180 ml. Ethyl acetate (420 ml) was added to the obtained concentrated solution at 20-30°C, and triethylamine (17.53 g) was added dropwise thereto at -2-8°C. The dropping funnel used was washed with ethyl acetate (30 ml), and the washing liquid was added to it. Methanesulfonyl chloride (13.89 g) was dropped to it at -2 to 8 ° C, the dropping funnel used was washed with ethyl acetate (30 ml), and the washing liquid was added to it. The mixture was stirred at -2 to 8 ° C for 1 hour, 0.5 M hydrochloric acid (600 ml) was dropped to it at 30 ° C or less, the mixture was stirred for 15 minutes or more, and allowed to stand. The organic layer was separated, 5% aqueous sodium hydrogen carbonate solution (600 ml) was added to it, and the mixture was stirred at 20 to 30 ° C for 15 minutes, and allowed to stand. The organic layer was separated, 5% aqueous sodium chloride solution (600 ml) was added to it at 20 to 30 ° C, and the mixture was stirred and allowed to stand as in the previous step. The organic layer was separated and concentrated under reduced pressure to about 240 ml at an external temperature of 50 ° C or less. The mixture was twice subjected to the operation of adding toluene (240 ml) to the obtained concentrate and concentrating under reduced pressure to about 240 ml. Toluene (120 ml) was added thereto at 45-55° C., and n-heptane (120 ml) was added thereto dropwise at 45-55° C. over 30 minutes.

[0244] After confirming the precipitation of crystals, the mixture was stirred at 45-55°C for 2 hours or more. n-Heptane (240ml) was added dropwise thereto over 30 minutes or more, and the mixture was stirred for 1 hour or more, then at 0-10°C for 1 hour or more. The precipitated crystals were collected by filtration and washed with a toluene / n-heptane (1:1) solution (120ml) cooled to 0-10°C and a n-heptane-ethanol (10:1) solution (120ml) cooled to 0-10°C. The crystals were dried under reduced pressure to obtain the title compound (6a) crystals (34.18g).

[0245] (Compound NMR data) 1 H NMR (300MHz, DMSO-d6) δ7.61-7.53(2H, m), 7.25-7.19(1H, m), 7.09-7.04(1H, m), 4.14-4.09(1H, m), 3.94-3.84(1H, m), 3.34-3.28( 2H, m), 3.01(3H, s), 3.00-2.96(1H, m), 2.44-2.36(1H, m), 2.22-2.13(1H, m), 2.03-1.89(1H, m), 1.00(9H, s).

[0246] (HPLC analysis conditions) Column: L-column2 ODS (CERI, Japan), column size 4.6 x 100 mm, particle size 3 μm Column temperature: constant temperature of approximately 25°C Mobile phase: Solution A) 0.1% phosphoric acid aqueous solution B solution) MeCN Gradient Program:

[0247] [Table 14]

[0248] Flow rate: 1.0ml / min Retention time: Compound (6a) about 10 minutes Compound (5a) about 5 minutes

[0249] Example 5 Synthesis of (2S,3S)-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidine-1-carboxylate tert-butyl N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt (N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5a)) 1) Synthesis of 2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-one hemitartrate (the hemitartrate of compound (3)) 3-Oxopyrrolidine-1-carboxylate tert-butyl (compound (2a), 830 g) and toluene (4.8 L) were charged into a reactor, pyrrolidine (398 g) was added dropwise thereto at 40° C. or less, and the mixture was stirred for 12 minutes. The reaction solution was concentrated to 3 L, toluene (3 L) was added to the concentrate, and the reaction solution was concentrated to 3 L. Again, toluene (3 L) was added to the concentrate, and the mixture was concentrated to 3 L. Acetonitrile (4.8 L) was added to the obtained concentrate, and tetrabutylammonium iodide (83 g) was added thereto. The temperature of the mixture was maintained at about 30° C., and an acetonitrile solution (0.9 L) of 1-bromo-3-(bromomethyl)-2-fluorobenzene (compound (1), 600 g) was added thereto dropwise. The dropping funnel used was washed with acetonitrile (0.3 L), the washing liquid was added to it, and the mixture was stirred at 35-43 ° C for 1 hour. Then, the mixture was cooled to 23 ° C, and the pH was adjusted to 2.8 with 2 M hydrochloric acid. Ethyl acetate (4.8 L) was added to it, the mixture was allowed to stand, and the aqueous layer was removed by separation to obtain an organic layer. 10% sodium thiosulfate aqueous solution (4.2 L) was added to the obtained organic layer, the mixture was allowed to stand, and the aqueous layer was removed by separation to obtain an organic layer. 10% saline solution (4.2 L) was added to the obtained organic layer, the mixture was allowed to stand, and the aqueous layer was removed by separation to obtain an organic layer.

[0250] 2-propanol (4.8 L) was added to the concentrated solution, and the mixture was concentrated to 1.8 L. Again, 2-propanol (4.8 L) was added to the concentrated solution, and the mixture was concentrated to 1.8 L. The concentrated solution was heated to 50°C, and while maintaining the temperature, 5M hydrogen chloride / 2-propanol (1663 g) was added dropwise to it to precipitate crystals. The mixture containing the precipitated crystals was stirred at 50°C for 6 hours. Ethyl acetate (6.0 L) was slowly added to it at 47-52°C, and the mixture was stirred at 52°C for 1 hour. The mixture was slowly cooled to 1°C, stirred at 1°C for 1 hour, and the crystals were filtered and washed with ethyl acetate (1.8 L). The wet crystals of the hydrochloride salt of compound (3) thus obtained and toluene (4.8 L) were charged into a reactor, and the mixture was cooled to 9°C. Triethylamine (272 g) was added dropwise to it at 9-10°C. The mixture was stirred at 5° C. for 1.5 hours, the insoluble material was removed by filtration, washed with toluene (3 L), and the washings were combined with the filtrate.

[0251] Methanol (6.0 L) and DL-tartaric acid (168 g) were charged into another reactor, and the mixture was stirred at 24° C. for 45 minutes. The above filtrate was added dropwise to it at 24° C. over 2 hours to precipitate crystals. The dropping funnel used was washed with toluene (0.6 L), and the washings were combined with the above mixture. The mixture was stirred at 25° C. for 1 hour, slowly cooled to 5° C. with stirring, and stirred at 0-5° C. for 12 hours. The precipitated crystals were collected by filtration, washed with a toluene-methanol=2:1 solution (1.8 L) cooled to 5° C., and dried under reduced pressure to obtain the hemitartrate crystals of the title compound (3) (425 g) (99.0 HPLC area%).

[0252] (Compound NMR data) 1 H NMR (300MHz, DMSO-d6) δ=7.56(t, J=7.3Hz, 1H), 7.34(t, J=7.3Hz, 1H), 7.10(t, J=7.3Hz, 1H), 4.16(m, 1H), 3.38(dd, J= 4.3, 9.3Hz, 1H), 3.22(m, 1H), 3.12-2.99(m, 2H), 2.70(dd, J=9.3, 14.2Hz, 1H), 2.47-2.17(m, 2H)

[0253] 2) Synthesis of tert-butyl 2-[(3-bromo-2-fluorophenyl)methyl]-3-oxopyrrolidine-1-carboxylate (compound (4a)) The hemitartrate salt (400 g) of compound (3) obtained in 1) and acetonitrile (2.4 L) were charged in a reactor, and triethylamine (257 g) was added dropwise thereto while maintaining the temperature at 20-21°C. Boc2O (251 g) and acetonitrile (0.6 L) were charged in another reactor, and the mixture was stirred at 25°C and added dropwise to the above solution of compound (3). The dropping funnel used was washed with acetonitrile (0.2 L) and the washings were added to the reactor. The mixture thus obtained was stirred at 23-28°C for 1 hour. 10% citric acid aqueous solution (2 L) and ethyl acetate (3.2 L) were added thereto, the mixture was stirred for 15 minutes, allowed to stand for 45 minutes, and the aqueous layer was removed by separation. 5% saline (2 L) was added to the obtained organic layer, the mixture was stirred for 15 minutes, allowed to stand for 24 minutes, and the aqueous layer was removed by separation to obtain an organic layer. The obtained organic layer was passed through a 3-linked Pall SUPRAcap 50 (Pall part number SC050XAK2), and the filter was washed with a portion of ethyl acetate (1.2 L). The insoluble matter was filtered off, washed with the remainder of ethyl acetate (1.2 L), and the washings were combined with the filtrate. The filtrate was concentrated at an external temperature of 55-60 ° C to adjust the volume to 1.2 L. Ethanol (4 L) was added thereto, and the mixture was concentrated to 1.2 L at an external temperature of 60 ° C. Ethanol (4 L) was added again to the concentrated solution, and the mixture was concentrated to 1.2 L at an external temperature of 60 ° C. Ethanol (0.8 L) was added to the concentrated solution at 25 ° C, and water (0.8 L) was added dropwise thereto at 26-27 ° C. The mixture was cooled to 8 ° C, and seed crystals (218 mg) of compound (4a) were added thereto at 8 ° C. After confirmation of crystallization, the mixture was stirred at 0-5 ° C for 7.5 hours. Water (2 L) was added dropwise thereto, and the mixture was stirred at 0-5°C for 12.5 hours. The crystals were collected by filtration and washed with ethanol-water=1:2 (1.2 L) cooled to 0-6°C. The drained wet crystals were dried under reduced pressure at 25°C or less to obtain crystals of the title compound (4a) (396 g) (99.2 HPLC area%). As the seed crystals of compound (4a), crystals naturally precipitated in the above reaction before the addition of the seed crystals were used.

[0254] (Compound NMR data) 1 H NMR (300MHz, DMSO-d6) δ=7.58(t, J=7.0Hz, 1H), 7.20-7.04(m, 2H), 4.12(t, J=6.2Hz, 1H), 3.76( m, 1H), 3.35-3.05(m, 2H), 2.97(m, 1H), 2.61(m, 1H), 2.34(m, 1H), 1.29(br s, 9H)

[0255] 3) Synthesis of (2S,3S)-3-amino-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidine-1-carboxylate tert-butyl N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt (N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5a)) Ru(OAc)2{(R)-xylyl-binap} (3.2 g), crystals of compound (4a) obtained in 2) (250 g), ammonium chloride (143.5 g), ammonium acetate (51.7 g), methanol (2.5 L) and water (125 ml) were charged into an autoclave, and the mixture was subjected to vacuum degassing and nitrogen restoration 7 times. After stirring of the mixture was stopped, the mixture was subjected to hydrogen pressurization to 0.12-0.13 MPa (G) and depressurization 10 times. After hydrogen pressurization to 0.32 MPa (G) at 20 °C, stirring was resumed and the mixture was heated to 80-85 °C. The hydrogen pressure was adjusted to 0.90 ± 0.05 MPa (G) at 80-85 °C, and the mixture was stirred for 40 hours. The reaction solution was concentrated to 1.25 L at an external temperature of 50 °C or less. The concentrate was cooled to 25°C, and 1M aqueous sodium hydroxide solution (1.25L) and ethyl acetate (1.25L) were added to it. The reaction solution was concentrated to 2.5L at an external temperature of 50°C or less. Ethyl acetate (1.25L) was added to the concentrate, and the mixture was concentrated to 2.5L at an external temperature of 50°C or less. Ethyl acetate (1.25L) was added to the obtained concentrate again, and the mixture was concentrated to 1.25L at an external temperature of 50°C or less. Ethyl acetate (0.5L) was added to it, and the mixture was stirred for 15 minutes, allowed to stand for 24 minutes, and the aqueous layer was removed by separation. The obtained organic layer was concentrated to 0.75L at an external temperature of 50°C or less. Ethanol (1.25L) was added to it, and the organic layer was concentrated to 0.75L at an external temperature of 50°C or less. Ethanol (1.25L) was added to the concentrate again, and the organic layer was concentrated to 0.75L at an external temperature of 50°C or less. Ethanol (1.75 L) was added to the obtained concentrate, and the mixture was heated to 68°C. N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine (214 g) was added thereto at 68-69°C, the reactor was washed with ethanol (0.25 L), and the washings were added to the mixture. The mixture was stirred at 75°C for 30 minutes, slowly cooled to 22°C, and stirred at 22°C for 18 hours. The crystals obtained by these operations were filtered, washed with ethanol (186 ml), and dried under reduced pressure at 50°C to obtain crystals of N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of the title compound (5a) (305 g) (99.6 HPLC area%).

[0256] (Compound NMR data) 1 H NMR (500 MHz, DMSO-d6, observed as mixture of rotamers) δ 7.63-7.45 (m, 3H), 7.30-6.94 (m, 9H), 4.07 (bs, 1H), 3.59 (t, J = 6.0 Hz, 1H), 3.54-3.40 (m, 1H), 3.38-3.17 (m, 1H), 3.01-2.72 (m, 3H), 2.48-2.42 (m, 1H), 2.34 (s, 3H), 2.15-2.02 (m, 1H), 1.96-1.78 (m, 1H), 1.20 (s, 9H), 0.99.

[0257] (HPLC analysis conditions) Column: YMC-Pack Pro C18 RS (YMC Co., Ltd.), column size 4.6 × 150 mm, particle size 5 μm Column temperature: 25℃ Mobile phase: A solution) 0.03M K2HPO4 aqueous solution Solution B) Acetonitrile Gradient Program:

[0258] [Table 15]

[0259] Flow rate: 1.0ml / min Retention time: N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine 9.77 min Compound (5a) 15.02 minutes

[0260] The yield of the N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of compound (5a) thus obtained was about 33.1% based on compound (1).

[0261] Reference example 1 Synthesis of (2S,3S)-3-[(methanesulfonyl)amino]-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-1-carboxylate tert-butyl ester (compound (7a)) In a reactor, 1,2-dimethoxyethane (225 ml), water (135 ml) and sodium hydroxide (3.99 g) were added with crystals of compound (6a) (30 g) and (3,5-difluorophenyl)boronic acid (12.6 g) at 25°C. 10% Pd carbon powder (PE-TYPE, manufactured by NECHEMCAT) (179.3 mg) and Xphos (63.4 mg) were added thereto, the mixture was subjected to vacuum degassing, and the vacuum was released with nitrogen. The resulting mixture was stirred at 73-83°C for more than 3 hours, and ethyl acetate (330 ml) and water (270 ml) were added at 45-55°C. Insoluble matter was filtered off at 25°C and washed with ethyl acetate (60 ml) and water (60 ml) in turn. N-acetylcysteine ​​(5.42 g) and NaCl (19.5 g) were added to the filtrate at 25°C, and the mixture was stirred at 20-30°C for more than 30 minutes. Ethanol (300 ml) was added to the separated organic layer at 20-30°C, and the mixture was concentrated under reduced pressure to about 450 ml at an external temperature of 60°C or less. The mixture was then subjected to two operations of adding ethanol (300 ml) while stirring at 40°C or less, and concentrating under reduced pressure to about 450 ml at an external temperature of 60°C or less. Ethanol (150 ml) was added to the obtained concentrated liquid at 40°C or less, and the mixture was heated to 60-65°C and stirred for more than 30 minutes. Water (600 ml) was added dropwise to it at 60-65°C, and the mixture was stirred for more than 30 minutes and stirred at 20-30°C for more than 1 hour to precipitate crystals. The precipitated crystals were separated, washed with a mixed solvent (150 ml) of ethanol / water (1:1), and dried under reduced pressure at an external temperature of 60° C. to obtain crystals of the title compound (7a) (31.40 g).

[0262] (Compound NMR data) 1 H NMR (300MHz, DMSO-d6) δ7.61-7.59(1H, m), 7.50-7.45(1H, m), 7.33-7.20(5H, m), 4.16-4.10(1H, m), 3.95-3.85(1H, m), 3.35-3.27( 2H, m), 3.01(3H, s), 3.03-2.97(1H, m), 2.50-2.44(1H, m), 2.22-2.14(1H, m), 2.05-1.91(1H, m), 0.96(9H, s).

[0263] (HPLC analysis conditions) Column: L-column2 ODS (CERI, Japan), column size 4.6 x 100 mm, particle size 3 μm Column temperature: constant temperature of approximately 25°C Mobile phase: Solution A) 0.1% phosphoric acid aqueous solution B solution) MeCN Gradient Program:

[0264] [Table 16]

[0265] Flow rate: 1.0ml / min Retention time: Compound (7a) about 10 minutes Compound (6a) about 9 minutes

[0266] Reference example 2 Synthesis of N-{(2S,3S)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide hydrochloride (hydrochloride of compound (8)) 2-propanol (55 ml) was added to the crystals of compound (7a) (5.00 g), and 5-6M hydrogen chloride / 2-propanol solution (6.2 ml) was added dropwise thereto while stirring at 15-35°C. The mixture was gradually heated to 65-75°C and stirred for 2 hours or more, and n-heptane (82.5 ml) was added dropwise thereto at 65-75°C. The mixture was gradually cooled to 5°C and stirred for 2 hours or more. The precipitated crystals were separated, washed with a mixed solvent (15 ml) of 2-propanol / n-heptane (1:2), and dried under reduced pressure at an external temperature of 50°C to obtain the hydrochloride crystals of the title compound (8) (4.15 g).

[0267] (Compound NMR data) 1H NMR (300MHz, DMSO-d6) δ9.38(2H, brs), 7.60-7.49(3H, m), 7.36-7.27(4H, m), 4.19-4.11(1H, m), 3.89-3.83(1H, m ), 3.47-3.37(1H, m), 3.24-3.09(3H, m), 3.01(3H, s), 2.38-2.25(1H, m), 2.10-2.00(1H, m).

[0268] (HPLC analysis conditions) Column: L-column2 ODS (CERI, Japan), column size 4.6 x 100 mm, particle size 3 μm Column temperature: constant temperature of approximately 25°C Mobile phase: Solution A) 0.1% phosphoric acid aqueous solution B solution) MeCN Gradient Program:

[0269] [Table 17]

[0270] Flow rate: 1.0ml / min Retention time: Compound (8) about 5 minutes Compound (7a) about 10 minutes

[0271] (HPLC analysis conditions) Column: YMC-Pack Pro Cl8 RS (YMC, Japan), column size 4.6 × 250 mm, particle size 5 μm Column temperature: constant temperature of approximately 25°C Mobile phase: Solution A) 0.1% phosphoric acid aqueous solution B solution) MeCN Gradient Program:

[0272] [Table 18]

[0273] Flow rate: 1.0ml / min Retention time: Compound (8) approximately 17 minutes

[0274] Reference example 3 Synthesis of N-{(2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide (compound (I)) sesquihydrate Under nitrogen atmosphere, dimethylacetamide (30 ml) was charged into the reactor, 2-hydroxy-2-methylpropanoic acid (3.09 g) and 1,1-carbonyldiimidazole (CDI) (4.82 g) were added thereto at -10 to 0°C, the reactor was washed with dimethylacetamide (1.35 ml) and the washings were added to the mixture. Then, under nitrogen atmosphere, N-hydroxy-5-norbornene-2,3-dicarboximide (4.90 g) was added thereto at -10 to 0°C, the reactor was washed with dimethylacetamide (1.35 ml) and the washings were added to the mixture, and the mixture was stirred for not less than 2 hours. The reactor was degassed under vacuum three times (the mixture was subjected to degassing under vacuum and the vacuum was released with nitrogen). Crystals of hydrochloride of compound (8) (5.00 g) were added to the mixture at -10 to 0°C under nitrogen atmosphere, the reactor was washed with dimethylacetamide (1.35 ml), and the washings were added to the mixture. Triethylamine (4.45 g) was added dropwise to it at -10 to 0°C under nitrogen atmosphere, the dropping funnel used was washed with dimethylacetamide (0.95 ml), and the washings were added to the mixture. The mixture was stirred at 30 to 40°C (target about 37°C) under nitrogen atmosphere for more than 4 hours, and water (35 ml) was added dropwise to it at 15 to 45°C. Sodium hydroxide was added to it at 15 to 45°C until the pH was 13.4 to 13.9, and the mixture was stirred at 40 to 60°C for more than 1 hour. The pH was adjusted to 7.5 to 8.5 with 6N hydrochloric acid at 20 to 40°C. The mixture was heated to 60°C, and water (total amount of DMAc used x 1.214 - amount of water used 2 vol - amount of 6N hydrochloric acid used - amount of NaOH aqueous solution and hydrochloric acid used for pH readjustment) was added dropwise to it. Seed crystals (2.5 mg) of sesquihydrate of compound (I) were added to it, and the mixture was stirred at 55-65°C for 1 hour or more. Water (10 ml) was added dropwise to it at 55-65°C, and the mixture was gradually cooled to 45-55°C over 30 minutes or more, stirred for 1 hour or more, cooled to 20-30°C over 1.5 hours, and stirred for 1 hour or more. The precipitated crystals were separated and washed twice with a mixed solvent of ethanol (5 ml) and water (15 ml) to obtain a pre-slurry of crude sesquihydrate of compound (I). Ethanol (12.5 ml), water (12.5 ml) and triethylamine (0.30 g) were charged into a reactor, and the pre-slurried form of the crude Compound (I) sesquihydrate obtained was added thereto.The mixture was stirred at 40-50°C for 30 minutes or more, and water (25 ml) was added dropwise thereto at 40-50°C over 20 minutes or more. The mixture was then stirred at 40-50°C for 1 hour or more, cooled to 20-30°C over 1 hour or more, and stirred for 1 hour or more. The crystals were washed twice with a mixed solvent of ethanol (5 ml) and water (15 ml), drained, and dried under reduced pressure at an external temperature of 50°C to obtain crude crystals (5.39 g) of the sesquihydrate of compound (I).

[0275] The crude crystals (5 g) of the sesquihydrate of compound (I) thus obtained, ethanol (40 ml) and purified water (5.0 ml) were charged into a reactor, and the mixture was stirred at 40° C. to obtain a solution. The solution was subjected to polish filtration, the filter was washed with ethanol (5.0 ml), and the washing liquid was added to the filtrate. Purified water (40 ml) was dropped into the filtrate at 43-53° C., and seed crystals (2.5 mg) of the sesquihydrate of compound (I) were added thereto. After confirmation of crystal precipitation, purified water (54 ml) was dropped thereto at 48-53° C. over 2 hours or more, the mixture was stirred at 43-53° C. for 1 hour or more, heated to 60-65° C., and stirred for 1 hour or more. The mixture was cooled to 25° C. over 2 hours or more, and stirred for 1 hour or more. The crystals were separated, washed with a mixed solvent of ethanol (10 ml) and purified water (30 ml), dried under reduced pressure at an external temperature of 50°C, and humidified to obtain sesquihydrate crystals of the title compound (I) (4.90 g) (purity 99.8%).

[0276] (Compound NMR data) 1 H NMR (400MHz, DMSO-d6) δ7.51-7.21(6H, m), 7.18-7.08(1H, m), 5.00(1H, s), 4.68-4.50(1H, m), 3.99-3.69(3H, m), 3.10-2.95( 1H, m), 2.95-2.85 (3H, m), 2.70-2.59 (1H, m), 2.23-2.11 (1H, m), 2.07-1.90 (1H, m), 1.19-1.04 (6H, m). .

[0277] (HPLC analysis conditions) Column: YMC-Pack Pro C18 (YMC Corporation), column size 4.6 × 150 mm, particle size 5 μm Column temperature: constant temperature of approximately 25°C Mobile phase: A solution) 0.01mol / L phosphate buffer (pH3.0):MeCN=7:3 B solution) MeCN:0.01mol / L phosphate buffer (pH3.0)=4:1 Gradient Program:

[0278] [Table 19]

[0279] Flow rate: 1.0ml / min Retention time: Compound (I) approximately 17 minutes Column: CHIRALPAK IE-3 (Daicel), column size 4.6 x 150 mm, particle size 3 μm Column temperature: constant temperature of approximately 35°C Mobile phase: A solution) 0.1% phosphoric acid aqueous solution:MeCN:THF=70:25:5 Gradient Program:

[0280] [Table 20]

[0281] Flow rate: 1.0ml / min Retention time: Compound (I) about 12 minutes N-{(2R,3R)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide (enantiomer of compound (I)) approx. 14 min [Industrial Applicability]

[0282] According to the production method of the present invention, compound (5) can be obtained as N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt by a method suitable for industrial production.

Claims

1. Formula (V): 【Chemistry 1】 (In the formula, each R １ is independently selected from a halogen atom and a trifluoromethanesulfonyl group; A is an optionally further substituted 4- to 7-membered N-containing monocyclic saturated heterocyclyl; and PG is a protecting group. A method for producing a compound of the formula: The method comprises reacting a compound represented by formula (IV): 【Chemistry 2】 subjecting the compound of formula (I) to an asymmetric reductive amination reaction in the presence of a metal complex containing a chiral ligand, and subjecting the resulting product to purification by salt formation with N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine.

2. To provide a compound of formula (IV), (a) Formula (II): 【Chemistry 3】 (In the formula, R １ is independently selected from a halogen atom and a trifluoromethanesulfonyl group; and X is a halogen atom. with a compound of formula (III): 【Chemistry 4】 where PG is a protecting group; and A is an optionally further substituted 4-7 membered N-containing monocyclic saturated heterocyclyl; (b) deprotecting the product of step (a); (c) reacting the product of step (b) with a racemic organic acid; and (d) introducing a protecting group onto the product of step (c); The method of claim 1 further comprising:

3. 2. The method of claim 1, wherein A is selected from pyrrolidine, piperidine, and azetidine, each of which may be further substituted.

4. Each R １ 2. The method of claim 1, wherein is independently selected from Cl, Br, I, and a trifluoromethanesulfonyl group.

5. The method of claim 2, wherein the organic acid is racemic tartaric acid (DL-tartaric acid).

6. 1. A method for producing N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of (2S,3S)-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-amine having a protecting group at the pyrrolidine 1-position, comprising the steps of: Step 3a: subjecting 2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-one having a protecting group at the pyrrolidine 1-position to an asymmetric reductive amination reaction in the presence of a metal complex containing a chiral ligand; and Step 3b: Purifying the product of step 3a by salt formation with N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine. The method comprises the steps of:

7. Step 1a: reacting 1-bromo-3-(bromomethyl)-2-fluorobenzene with pyrrolidin-3-one having a protecting group at the pyrrolidine 1-position; Step 1b: deprotecting the product of step 1a and reacting with DL-tartaric acid; and Step 2: introducing a protecting group into the product of step 1b to provide 2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-one bearing a protecting group at the pyrrolidine 1-position. The method of claim 6 further comprising:

8. The method according to any one of claims 1 to 7, wherein the chiral ligand in the metal complex is a BINAP ligand, a phosphine ligand, a ferrocene ligand, or a cyclophane ligand.

9. The method according to any one of claims 1 to 7, wherein the metal in the metal complex is ruthenium, rhodium, or iridium.

10. The method according to any one of claims 1 to 7, wherein the metal complex containing a chiral ligand is a ruthenium complex containing a chiral BINAP ligand or a ruthenium complex containing a chiral cyclophane ligand.

11. A metal complex containing a chiral ligand has the formula: Ru(OAc) ２ (Ligand) The method according to any one of claims 1 to 7, wherein Ligand is a metal complex represented by the formula: (wherein Ligand is (S)-binap, (R)-xylyl-Phanephos or (R)-xylyl-binap.

12. The metal complex containing the chiral ligand is Ru(OAc). ２ The method according to any one of claims 1 to 7, wherein the xylyl is {(R)-xylyl-binap}.

13. The method according to claim 1, 3, 6 or 7, wherein the protecting group at the pyrrolidine 1-position is selected from tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, trityl, benzyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and methoxymethyl.

14. The method according to claim 1, 3, 6 or 7, wherein the protecting group at the 1-position of the pyrrolidine is tert-butoxycarbonyl.

15. The method of claim 1 or 6, wherein the purification conditions include recrystallization.

16. 16. The method of claim 15, wherein the crystallization comprises salt formation with N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine in a solvent at a temperature of 60° C. to 78° C., stirring at a temperature of 60° C. to 78° C. for about 0.5 hours, stirring at 15° C. to 35° C. for about 12 to about 48 hours, and filtering the resulting precipitate.

17. 17. The method of claim 16, further comprising recrystallizing the precipitate from a solvent selected from an alcohol, an ether, or an aromatic hydrocarbon.

18. 18. The method of claim 17, wherein the solvent is ethanol.

19. Step 4: Desalting the N-(4-methylbenzene-1-sulfonyl)-L-phenylalanine salt of (2S,3S)-2-[(3-bromo-2-fluorophenyl)methyl]pyrrolidin-3-amine having a protecting group at the pyrrolidine 1-position, and reacting with a methanesulfonylating agent; Step 5: reacting the product of step 4 with (3,5-difluorophenyl)boronic acid; Step 6: subjecting the product of step 5 to deprotection conditions; and Step 7: The product of step 6 is subjected to a condensation reaction with 2-hydroxy-2-methylpropanoic acid to obtain N-{(2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3′,5′-trifluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide, or a hydrate or solvate thereof. The method of claim 6 or 7, further comprising:

20. 【Chemical 5】 A compound which is a racemic organic acid salt of.

21. 21. The compound of claim 20 which is a racemic tartrate salt.

22. 【Chemical 6】 21. The compound of claim 20,

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