Method for producing pyrrolidine compounds

Abstract

The present invention provides an industrially practicable method for producing a (2S, 3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine that has a protecting group at the 1-position.　The present invention is a method for producing an N-[(4-methylphenyl)sulfonyl]-L-phenylalanine salt of a (2S, 3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine that has a protecting group at the 1-position, said method comprising: a step 2 wherein a 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidine that has a protecting group at the 1-position is subjected to a reduction reaction; and a step 3 wherein the product in the step 2 is subjected to optical resolution that utilizes the salt formation with N-[(4-methylphenyl)sulfonyl]-L-phenylalanine.

Description

[Technical Field]

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

[0002] BACKGROUND OF THE INVENTION Pyrrolidine compounds, such as (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine having a protecting group at the 1-position, are useful as intermediates in the production of pharmaceuticals, and there is a need for a production method suitable for industrial production. Summary of the Invention [Problem to be solved by the invention]

[0003] An object of the present invention is to provide a method suitable for industrial production of (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine having a protecting group at the 1-position. [Means for solving the problem]

[0004] As a result of intensive investigations aimed at solving the above-mentioned problems, the present inventors have found that, starting from 2-(3-bromo-2-fluorobenzyl)-3-oxopyrrolidine having a protecting group at the 1-position as a starting material, 3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine having a protecting group at the 1-position can be obtained via a method of obtaining 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidine having a protecting group at the 1-position, and that further, by subjecting this to optical resolution utilizing salt formation with a specific chiral acid, (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine having a protecting group at the 1-position can be obtained as a salt, thereby completing the present invention.

[0005] That is, the present invention is as follows. [1] Step 2: subjecting 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidine having a protecting group at the 1-position to a reduction reaction; and Step 3: subjecting the product of Step 2 to optical resolution by salt formation with N-[(4-methylphenyl)sulfonyl]-L-phenylalanine; A method for producing N-[(4-methylphenyl)sulfonyl]-L-phenylalanine salt of (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine having a protecting group at the 1-position, comprising: [2] The method according to [1] above, wherein the reduction reaction is carried out in the presence of zirconium(IV) chloride. [3] tert-Butyl (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate·N-[(4-methylphenyl)sulfonyl]-L-phenylalanine salt. [4] Step 1: A method for producing 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidine having a protecting group at the 1-position, comprising the step of reacting 2-(3-bromo-2-fluorobenzyl)-3-oxopyrrolidine having a protecting group at the 1-position with O-methylhydroxylamine or a salt thereof. [5] tert-Butyl 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidine-1-carboxylate. [Effects of the Invention]

[0006] According to the production method of the present invention, (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine having a protecting group at the 1-position can be obtained as an N-[(4-methylphenyl)sulfonyl]-L-phenylalanine salt by a method suitable for industrial production.

[0007] (Detailed Description of the Invention) The production method of the present invention is explained below. The compound obtained in each step can be used in the next reaction either as a reaction solution or as a crude product, or the compound obtained in each step can be isolated and / or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc., according to a conventional method.

[0008] When the raw materials and reagent compounds for each step are commercially available, the commercially available products can be used as they are.

[0009] Unless otherwise specified, the reactions in each step are carried out without solvent or by dissolving or suspending in a suitable solvent. Specific examples of the solvent include those described in the Examples below, as well as the following: 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, cyclopentyl methyl ether, 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. The above solvents may be used by mixing two or more kinds in an appropriate ratio.

[0010] When a base is used in the reaction of each step, for example, the bases shown below or the bases described in the Examples below are used. 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, 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 compounds: n-butyllithium, etc.

[0011] In various pyrrolidine compounds used as starting materials or products in the production method of the present invention, examples of the protecting group at the 1-position of pyrrolidine include a tert-butoxycarbonyl group, a benzyloxycarbonyl group, an acetyl group, a trityl group, a benzyl group, a 9-fluorenylmethyloxycarbonyl group (Fmoc group), a 2,2,2-trichloroethoxycarbonyl group (Troc group), a methoxymethyl group (MOM group), and the like. Among these, a tert-butoxycarbonyl group is preferred from the viewpoint of ease of deprotection.

[0012] In the present invention, the method for producing N-[(4-methylphenyl)sulfonyl]-L-phenylalanine salt of (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine having a protecting group at the 1-position is as follows: Step 1: reacting 2-(3-bromo-2-fluorobenzyl)-3-oxopyrrolidine having a protecting group at the 1-position with O-methylhydroxylamine or a salt thereof to obtain 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidine having a protecting group at the 1-position; Step 2: subjecting 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidine having a protecting group at the 1-position to a reduction reaction; and Step 3: subjecting the product of Step 2 to optical resolution by salt formation with N-[(4-methylphenyl)sulfonyl]-L-phenylalanine; Includes:

[0013] Project 1 In this step, 2-(3-bromo-2-fluorobenzyl)-3-oxopyrrolidine having a protecting group at the 1-position is reacted with O-methylhydroxylamine or its salt to give 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidine having a protecting group at the 1-position.

[0014] The 2-(3-bromo-2-fluorobenzyl)-3-oxopyrrolidine having a protecting group at the 1-position is preferably tert-butyl 2-(3-bromo-2-fluorobenzyl)-3-oxopyrrolidine-1-carboxylate. This compound can be produced by a method known per se.

[0015] Examples of salts of O-methylhydroxylamine include O-methylhydroxylamine hydrochloride, etc. The amount of O-methylhydroxylamine or a salt thereof used is usually 1.4 to 2.0 mol, preferably 1.6 to 1.8 mol, and in another embodiment 1.2 to 1.6 mol, preferably 1.3 to 1.5 mol, per 1 mol of 2-(3-bromo-2-fluorobenzyl)-3-oxopyrrolidine having a protecting group at the 1-position. When a salt of O-methylhydroxylamine is used, the reaction is carried out in the presence of a base. Examples of the base include organic bases and inorganic bases. The amount of the base used is usually 1.0 to 1.3 mol, preferably 1.0 to 1.1 mol, per mol of the salt of O-methylhydroxylamine.

[0016] The reaction is usually carried out in a solvent. Examples of the solvent include alcohols, ethers, etc. The solvent is preferably ethanol. The reaction is usually carried out at 45 to 65° C., preferably 50 to 60° C. The reaction time is usually about 10 minutes to about 3 hours, preferably about 3 minutes to about 1 hour.

[0017] After completion of the reaction, ordinary post-treatments such as separation and concentration can be carried out to isolate 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidine having a protecting group at the 1-position from the reaction mixture.

[0018] Among the 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidines having a protecting group at the 1-position obtained in this step, tert-butyl 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidine-1-carboxylate is a novel compound.

[0019] Project 2 In this step, 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidine having a protecting group at the 1-position is subjected to a reduction reaction. The reaction is carried out by reacting 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidine having a protecting group at the 1-position with a reducing agent.

[0020] Examples of the reducing agent include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and lithium borohydride. The amount of the reducing agent used is usually 10.0 to 15.6 mol, preferably 12.0 to 13.6 mol, and in another embodiment, 7.0 to 10.9 mol, preferably 8.4 to 9.5 mol, relative to 1 mol of 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidine having a protecting group at the 1-position. The amount of the reducing agent used is 5.0 to 7.8 mol, preferably 6.0 to 6.8 mol, relative to 1 mol of 2-(3-bromo-2-fluorobenzyl)-3-oxopyrrolidine having a protecting group at the 1-position, which is the starting material in Step 1.

[0021] The reaction may be carried out in the presence of zirconium(IV) chloride to promote the reduction reaction. The amount of zirconium(IV) chloride used is usually 2.4 to 4.0 mol, preferably 3.0 to 3.4 mol, per mol of 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidine having a protecting group at the 1-position. The amount of zirconium(IV) chloride used is usually 1.2 to 2.0 mol, preferably 1.5 to 1.7 mol, based on 1 mol of 2-(3-bromo-2-fluorobenzyl)-3-oxopyrrolidine having a protecting group at the 1-position, which is the starting material for Step 1.

[0022] The reaction is usually carried out in a solvent. Examples of the solvent include ethers, alcohols, aromatic hydrocarbons, etc. The solvent is preferably a mixed solvent of tetrahydrofuran, chlorobenzene, and cyclopentyl methyl ether. The reaction is usually carried out at 15 to 35° C., preferably 20 to 30° C. The reaction time is usually about 10 minutes to about 3 hours, preferably about 30 minutes to about 1 hour.

[0023] After completion of the reaction, 3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine having a protecting group at the 1-position can be isolated from the reaction mixture by carrying out usual post-treatments such as separation and concentration.

[0024] In this reaction, 3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine having a protecting group at the 1-position is produced, but it is obtained as a mixture of cis isomers ((2S,3S) and (2R,3R)) and trans isomers ((2R,3S) and (2S,3R)) (molar ratio = 2.5 / 1 to 1.5 / 1).

[0025] Project 3 In this step, the product of step 2 is subjected to optical resolution using salt formation with N-[(4-methylphenyl)sulfonyl]-L-phenylalanine to obtain the N-[(4-methylphenyl)sulfonyl]-L-phenylalanine salt of (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine having a protecting group at the 1-position. The optical resolution is carried out by mixing the product of step 2 with N-[(4-methylphenyl)sulfonyl]-L-phenylalanine in a solvent and collecting the precipitated crystals by filtration.

[0026] The amount of N-[(4-methylphenyl)sulfonyl]-L-phenylalanine used is usually 1.12 to 1.68 mol, preferably 1.26 to 1.54 mol, and in another embodiment 1.0 to 1.6 mol, preferably 1.2 to 1.4 mol, relative to 1 mol of (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine having a protecting group at position 1, which is contained in the product of step 2. The amount of N-[(4-methylphenyl)sulfonyl]-L-phenylalanine used is usually 0.80 to 1.20 mol, preferably 0.90 to 1.10 mol, and in another embodiment 0.50 to 0.80 mol, preferably 0.60 to 0.70 mol, relative to 1 mol of 2-(3-bromo-2-fluorobenzyl)-3-oxopyrrolidine having a protecting group at position 1, which is the starting material of step 1. The solvent for mixing the product of step 2 with N-[(4-methylphenyl)sulfonyl]-L-phenylalanine includes alcohols, ethers, aromatic hydrocarbons, etc. The solvent is preferably ethanol. The mixing is carried out by adding (preferably dropwise) a solution of N-[(4-methylphenyl)sulfonyl]-L-phenylalanine to the solution of the product from step 2 under stirring. The addition temperature is usually 45 to 70°C, preferably 50 to 60°C. After the addition, the mixture is aged under stirring usually at 50 to 70°C, preferably 55 to 65°C, for about 12 to about 18 hours, and then at 15 to 35°C, preferably 20 to 30°C, for about 15 to about 35 hours, preferably about 18 to about 24 hours.

[0027] The above procedure precipitates crystals of N-[(4-methylphenyl)sulfonyl]-L-phenylalanine salt of (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine having a protecting group at position 1. The precipitated crystals are collected by filtration and, if necessary, may be recrystallized from a solvent such as alcohols, ethers, or aromatic hydrocarbons.

[0028] Among the N-[(4-methylphenyl)sulfonyl]-L-phenylalanine salts of (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine having a protecting group at the 1-position obtained in this step, tert-butyl (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate·N-[(4-methylphenyl)sulfonyl]-L-phenylalanine salt is a novel compound. [Example]

[0029] The present invention will be further illustrated by the following examples, which are not intended to limit the scope of the present invention and may be modified without departing from the scope of the present invention. In the following examples, "room temperature" generally refers to about 10°C to about 35°C. Ratios shown for mixed solvents are by volume unless otherwise specified. % means % by weight unless otherwise specified.

[0030] Unless otherwise specified, elution in column chromatography in the examples was carried out under observation by TLC (Thin Layer Chromatography). In the TLC observation, a 60 F TLC plate manufactured by Merck was used. 254 The solvent used in column chromatography was the same as the elution solvent used in column chromatography. A UV detector was used for detection. In silica gel column chromatography, NH indicates aminopropylsilane-bonded silica gel, and Diol indicates 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. In preparative HPLC (high-performance liquid chromatography), C18 indicates octadecyl-bonded silica gel. The ratios of elution solvents are by volume unless otherwise specified.

[0031] The following abbreviations are used in the following examples: M: Molar concentration N: Normality HPLC:high performance liquid chromatography

[0032] Reference example 1 tert-Butyl 2-(3-bromo-2-fluorobenzyl)-3-oxopyrrolidine-1-carboxylate (TBFO) tert-Butyl 3-oxopyrrolidine-1-carboxylate (TOPC) (21.3 g) and toluene (193 ml) were added to a reaction vessel, pyrrolidine (10.2 g) was added dropwise at 40 °C or lower, and the mixture was stirred for 10 minutes. The reaction solution was concentrated to 97 ml. After adding toluene (97 ml) to the concentrated solution, it was concentrated to 97 ml. After adding acetonitrile (77 ml) to the concentrated solution, tetrabutylammonium iodide (0.532 g) was added. A solution of 2-bromo-6-bromomethyl-1-fluorobenzene (BBFB) (19.3 g) in acetonitrile (19 ml) was added dropwise at 30 °C, and the mixture was stirred at 40 °C for 3 hours. Water (116 ml) and ethyl acetate (154 ml) were added at 5 - 30 °C. 2N-HCl was added dropwise at 25 °C to adjust the pH to 2.0. After liquid separation of the reaction solution, the aqueous layer was extracted twice with ethyl acetate (77 ml). The combined organic layers were washed with a 5% aqueous Na2S2O3 solution (135 ml) and a 5% aqueous NaCl solution (135 ml). The organic layer was concentrated to 58 ml, ethanol (97 ml) was added, and it was concentrated again to 58 ml. Ethanol (58 ml) was added to obtain an ethanol solution of TBFO.

[0033] <HPLC analysis conditions> Column: YMC-Pack Pro C18 (manufactured by YMC Co., Ltd., model number AS12S05-1546WT), column size 4.6 x 150 mm, particle size 5 μm, pore size 12 nm Column temperature: Constant temperature around 40 °C Mobile phase: Solution A) 0.1% H3PO4 Solution B) MeCN Gradient program

[0034]

Table 1

[0035] Flow rate: 1.0 ml / min Retention time: BBFB 15.6 minutes, TBFO 16.2 minutes

[0036] Example 1 tert-Butyl 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidine-1-carboxylate (TBFM) An ethanol solution (total amount) of TBFO obtained in Reference Example 1 was added to a reaction vessel, and water (9.7 ml), sodium acetate (8.28 g), and H2NOMe·HCl (8.42 g) were added at 20°C, followed by stirring at 55°C for 1 hour. Ethyl acetate (193 ml) and water (193 ml) were added to the reaction solution at 25°C, and after stirring, the layers were separated. The organic layer was washed with 0.5 M HCl (193 ml), 5% aqueous NaHCO3 solution (193 ml), and water (193 ml) at 25°C. The organic layer was concentrated to 57 ml. Cyclopentyl methyl ether (CPME) (193 ml) was added to the concentrated solution, and the solution was concentrated to 57 ml to obtain a CPME solution of TBFM.

[0037] <HPLC analysis conditions> Column: YMC-Pack Pro C18 (manufactured by YMC Co., Ltd., model number AS12S05-1546WT), column size 4.6 x 150 mm, particle size 5 μm, pore size 12 nm Column temperature: Constant temperature around 40°C Mobile phase: Solution A) 0.1% H3PO4 Solution B) MeCN Gradient program

[0038] [Table 2]

[0039] Flow rate: 1.0 ml / min Retention time: TBFO 14.3 minutes, TBFM 16.8 and 16.9 minutes

[0040] Example 2 tert-Butyl (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate·N-[(4-methylphenyl)sulfonyl]-L-phenylalanine salt ((2S,3S)-TABF·(S)-PPSP) ZrCl4 (26.92 g) and chlorobenzene (34.4 ml) were added to the reaction vessel and suspended. THF (232 ml) was added dropwise at 40 °C or lower, and the mixture was stirred at 50 °C for 1 hour or more. NaBH4 (17.48 g) was added portionwise at 25 °C, washed with THF (9 ml), and stirred at 25 °C for 2 hours or more. At 25 °C, the entire amount of the CPME solution of TBFM obtained in Example 1 was added dropwise, washed with CPME (17.2 ml), and stirred at 25 °C for 1 hour or more. 1N-HCl (344 ml) was added dropwise at -5 to 20 °C and washed with CPME (17.2 ml). The mixture was stirred at 5 °C for 1 hour or more. Rochelle salt ((+)-sodium potassium tartrate tetrahydrate) (130.41 g) was added at -5 to 10 °C and stirred at -5 to 10 °C. After stirring at 35 °C, liquid separation was performed. Ethyl acetate (172 ml) was added to the aqueous layer and liquid separation was performed. The organic layers were combined and washed with 5% aqueous NaHCO3 solution (172 ml) and 10% aqueous NaCl solution (172 ml). The organic layer was concentrated to 61 ml. Ethanol (86 ml) was added to the concentrated solution, and the solution was concentrated to 52 ml. Ethanol (86 ml) was added to the concentrated solution, concentrated to 52 ml, and ethanol (46 ml) was added. In a separate container, N-[(4-methylphenyl)sulfonyl]-L-phenylalanine ((S)-PPSP) (14.76 g) and ethanol (172 ml) were added, heated to 55 °C to dissolve, and added dropwise to the ethanol solution of TABF obtained above at 55 °C, and washed with ethanol (6 ml). (2S,3S)-TABF·(S)-PPSP seed crystals (25 mg) were added at 50 °C, and after stirring at 25 °C for 15 hours or more, the crystals were collected by filtration. After completion of drying under reduced pressure, crude (2S,3S)-TABF·(S)-PPSP was obtained. The seed crystals used were those crystallized naturally through the same production method as above.

[0041] <HPLC analysis conditions> Column: YMC-Pack Pro C18RS (manufactured by YMC Co., Ltd., model number RS08S05-1546WT), column size 4.6 x 150 mm, particle size 5 μm, pore size 8 nm Column temperature: Constant temperature around 25 °C Mobile phase: A solution) 0.03 mol / L aqueous dipotassium hydrogen phosphate solution Solution B) MeCN Gradient program

[0042]

Table 3

[0043] Flow rate: 1.0 ml / min Retention time: (S)-PPSP 9.7 minutes, TABF 15.5 minutes

[0044] Column: CHIRALPAK IG (Daicel Corporation, model number 87324), column size 4.6 x 150 mm, particle size 5 μm Column temperature: Constant temperature around 25°C Mobile phase: Solution A) 0.01 mol / L potassium hydrogen phosphate aqueous solution Solution B) MeCN Gradient program

[0045]

Table 4

[0046] Flow rate: 1.0 ml / min Retention time: (2S,3S)-TABF 7 minutes, (2R,3R)-TABF 15 minutes

[0047] Example 3 tert-Butyl (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate·N-[(4-methylphenyl)sulfonyl]-L-phenylalanine salt ((2S,3S)-TABF·(S)-PPSP) The crude (2S,3S)-TABF·(S)-PPSP (23 g) obtained in Example 2 was suspended in ethanol (345 ml), heated to 70°C or higher to dissolve, cooled to 25°C, and after stirring for 2 hours or more, the crystals were collected by filtration and dried under reduced pressure to obtain (2S,3S)-TABF·(S)-PPSP.

[0048] <HPLC analysis conditions> Column: YMC-Pack Pro C18RS (YMC Co., Ltd., Model RS08S05-1546WT), column size 4.6 x 150 mm, particle size 5 μm, pore size 8 nm Column temperature: constant temperature around 25℃ Mobile phase: Solution A) 0.03 mol / L dipotassium hydrogen phosphate aqueous solution B liquid) MeCN Gradient Program

[0049] [Table 5]

[0050] Flow rate: 1.0ml / min Retention time: (S)-PPSP 9.7 minutes, TABF 15.5 minutes

[0051] Column: CHIRALPAK IG (Daicel Corporation, Model No. 87324), column size 4.6 x 150 mm, particle size 5 μm Column temperature: constant temperature around 25℃ Mobile phase: Solution A) 0.01 mol / L dipotassium hydrogen phosphate aqueous solution B liquid) MeCN Gradient Program

[0052] [Table 6]

[0053] Flow rate: 1.0ml / min Retention time: (2S,3S)-TABF 7 minutes, (2R,3R)-TABF 15 minutes

[0054] Reference example 2 tert-Butyl 2-(3-bromo-2-fluorobenzyl)-3-oxopyrrolidine-1-carboxylate (TBFO) To a reaction vessel, tert-butyl 3-oxopyrrolidine-1-carboxylate (TOPC) (96.8 g) and toluene (630 ml) were added, and pyrrolidine (46.5 g) was added dropwise at 40°C or below, followed by stirring for 10 minutes. The reaction mixture was concentrated to 350 ml. To the concentrated mixture, toluene (350 ml) was added and the mixture was further concentrated to 350 ml. Acetonitrile (630 ml) was added to the concentrated mixture, followed by the addition of tetrabutylammonium iodide (9.7 g). A solution of 2-bromo-6-bromomethyl-1-fluorobenzene (BBFB) (70 g) in acetonitrile (70 ml) was added dropwise at 25°C, followed by stirring at 40°C for 1.5 hours. Water (420 ml) and ethyl acetate (560 ml) were added at 25°C, and the layers were separated. The organic layers were combined, water (350 ml) was added, and 2N HCl was added dropwise at 25°C to adjust the pH to 3.7. The reaction mixture was separated, and then washed with 10% aqueous NaSO (490 ml) and 10% aqueous NaCl (490 ml). The organic layer was concentrated to 210 ml, and ethanol (350 ml) was added, followed by further concentration to 210 ml. Ethanol (210 ml) was added to obtain an ethanol solution of TBFO.

[0055] Example 4 tert-Butyl 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidine-1-carboxylate (TBFM) The entire ethanol solution of TBFO obtained in Reference Example 2 was added to a reaction vessel, and water (35 ml), sodium acetate (38.6 g), and H2NOMe·HCl (39.3 g) were added at 20°C. The mixture was stirred at 55°C for 1 hour. Ethyl acetate (700 ml) and water (700 ml) were added to the reaction mixture at 25°C, and the mixture was stirred and separated. The organic layer was washed with 0.5 M HCl (700 ml), 5% aqueous NaHCO3 solution (700 ml), and water (700 ml) at 25°C. The organic layer was concentrated to 210 ml. Cyclopentyl methyl ether (CPME) (700 ml) was added to the concentrated solution, and the mixture was concentrated to 210 ml to obtain a solution of TBFM in CPME.

[0056] Example 5 tert-Butyl (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate·N-[(4-methylphenyl)sulfonyl]-L-phenylalanine salt ((2S,3S)-TABF·(S)-PPSP) ZrCl4 (97.4 g) and chlorobenzene (126 ml) were added to a reaction vessel and suspended. THF (840 ml) was added dropwise at 40°C or below, and the mixture was stirred at 50°C for at least 1 hour. NaBH4 (63.3 g) was added in portions at 25°C, washed with THF (35 ml), and stirred at 25°C for at least 2 hours. The CPME solution of TBFM (whole amount) obtained in Example 4 was added dropwise at 25°C, washed with CPME (63 ml), and stirred at 25°C for at least 1 hour. 1N HCl (1246 ml) was added dropwise at -5 to 20°C, and washed with CPME (63 ml). The mixture was stirred at 5°C for at least 1 hour. Rochelle salt (potassium sodium (+)-tartrate tetrahydrate) (472 g) was added at -5 to 10°C, and the mixture was stirred at 5 to 10°C. After stirring at 35°C, the mixture was separated into layers. Ethyl acetate (630 ml) was added to the aqueous layer, and the layers were separated. The combined organic layers were washed with 5% aqueous NaHCO3 solution (623 ml) and 10% aqueous NaCl solution (623 ml). The organic layers were concentrated to 224 ml. Ethanol (315 ml) was added to the concentrate, and the mixture was concentrated to 189 ml. Ethanol (315 ml) was added to the concentrate, and the mixture was concentrated to 189 ml, and ethanol (168 ml) was added. In a separate container, N-[(4-methylphenyl)sulfonyl]-L-phenylalanine ((S)-PPSP) (83.4 g) and ethanol (623 ml) were added, heated to 55°C to dissolve, and added dropwise to the ethanol solution of TABF obtained above at 55°C, and washed with ethanol (21 ml). (2S,3S)-TABF·(S)-PPSP seed crystals (91 mg) were added at 55°C, and the mixture was stirred at 25°C for at least 15 hours. The crystals were collected by filtration and dried under reduced pressure to obtain crude (2S,3S)-TABF·(S)-PPSP. The seed crystals used were those naturally crystallized via the same preparation method as above.

[0057] Example 6 tert-Butyl (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate·N-[(4-methylphenyl)sulfonyl]-L-phenylalanine salt ((2S,3S)-TABF·(S)-PPSP) The crude (2S,3S)-TABF·(S)-PPSP (80 g) obtained in Example 5 was suspended in ethanol (1600 ml) and dissolved by heating to 70°C or higher. The suspension was cooled to 25°C and stirred for 2 hours or more. The crystals were collected by filtration and dried under reduced pressure to obtain (2S,3S)-TABF·(S)-PPSP. [Industrial Applicability]

[0058] According to the production method of the present invention, (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine having a protecting group at the 1-position can be obtained as an N-[(4-methylphenyl)sulfonyl]-L-phenylalanine salt by a method suitable for industrial production.

[0059] This application is based on patent application No. 2019-209070 filed in Japan on November 19, 2019, the contents of which are incorporated in full herein.

Claims

1. Step 2: subjecting 2-(3-bromo-2-fluorobenzyl)-3-(methoxyimino)pyrrolidine having a protecting group at the 1-position to a reduction reaction; and Step 3: subjecting the product of Step 2 to optical resolution by salt formation with N-[(4-methylphenyl)sulfonyl]-L-phenylalanine; A method for producing an N-[(4-methylphenyl)sulfonyl]-L-phenylalanine salt of (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine having a protecting group at the 1-position, comprising: The protecting group is selected from the group consisting of a tert-butoxycarbonyl group, a benzyloxycarbonyl group, an acetyl group, a trityl group, a benzyl group, a 9-fluorenylmethyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, and a methoxymethyl group.

2. 2. The process of claim 1, wherein the reduction reaction is carried out in the presence of zirconium(IV) chloride.

3. tert-Butyl (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)pyrrolidine-1-carboxylate N-[(4-methylphenyl)sulfonyl]-L-phenylalanine salt.

4. The method of claim 1, further comprising the step of: Step 1: reacting 2-(3-bromo-2-fluorobenzyl)-3-oxopyrrolidine having a protecting group at the 1-position with O-methylhydroxylamine or a salt thereof.

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