Method for producing proline amide compound

Abstract

To provide an industrially advantageous method for producing a proline amide compound useful as a medicine or the like.SOLUTION: There is provided a method for producing a compound of the formula (1) or a salt thereof, which comprises a step of producing a compound of the formula (2) by condensing a compound of the formula (3) or a salt thereof with thiazolidine in the presence of pivaloyl chloride and N,N-diisopropylethylamine (DIPEA).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a novel method for producing a prolinamide compound useful as a synthetic intermediate for pharmaceuticals, etc. The present invention also relates to a method for producing teneligliptin (chemical name: {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl}(1,3-thiazolidin-3-yl)methanone or a salt thereof, which is useful as a therapeutic agent for diabetes, etc., by utilizing the novel method for producing the compound. [Background technology]

[0002] It has been reported that teneligliptin or a salt thereof, which has a side chain containing a prolinamide moiety, exhibits DPP-IV inhibitory activity and is useful in the treatment or prevention of diabetes and the like (see Patent Documents 1 and 2).

[0003] Patent Document 1 discloses a method for producing teneligliptin or a salt thereof, and a method for producing a prolinamide compound, which is a synthetic intermediate thereof. This production method involves condensing Nt-butoxycarbonyl-L-trans-4-hydroxyproline and thiazolidine with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole, followed by oxidation with a pyridine sulfur trioxide complex in the presence of a base to produce a prolinamide compound, via which teneligliptin or a salt thereof is obtained. However, this production method provides an insufficient yield of the prolinamide compound, and further improvement is desired for use as an industrial production method.

[0004] Another method has been reported in which teneligliptin or a salt thereof is produced via a prolinamide compound produced by condensing (2S)-1-t-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid and thiazolidine with n-propylphosphonic anhydride (cyclic trimer) in the presence of a base (see Patent Document 3). Although this production method can be used on an industrial scale, n-propylphosphonic anhydride (cyclic trimer) is a designated substance under the Chemical Weapons Prohibition Act, and certain measures such as notification obligations and obligations to accept inspections (tests) by inspectors from international organizations are required. In addition, it is expensive (4,200 yen / mol), so it cannot necessarily be said to be a method suitable for mass production.

[0005] As another method, a method for producing teneligliptin or a salt thereof via a prolinamide compound produced by condensing (2S)-1-t-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid and thiazolidine using N,N'-dicyclohexylcarbodiimide (DCC) in the presence of 4-dimethylaminopyridine has been reported (see Example 3 of Patent Document 4). This production method requires fine adjustments in steps over a short period of time. The process is carried out at low temperatures (specifically, -5°C to -10°C (30 minutes), followed by -6°C to -2°C (15 to 20 minutes), and then 0°C to 5°C (60 minutes)). However, on an industrial scale, it is difficult to maintain a uniform temperature inside the reaction vessel in a short time or to fine-tune the temperature. Furthermore, DCC is toxic (causing skin irritation) and expensive (825 yen / mol (4,000 yen / kg)), so it is not a suitable method for mass production. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2002 / 014271 [Patent Document 2] International Publication No. 2006 / 088129 [Patent Document 3] International Publication No. 2012 / 165547 [Patent Document 4] International Publication No. 2015 / 019238 Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide an inexpensive, safe, and efficient method for producing prolinamide compounds useful as pharmaceutical synthetic intermediates, etc., which are suitable for industrial production. Another object of the present invention is to provide an industrially advantageous method for producing teneligliptin or a salt thereof, which is useful as a therapeutic drug for diabetes, etc., using the production method. [Means for solving the problem]

[0008] As described above, in the industrial production of prolinamide compounds, there is a demand for a safe, low-cost, high-yield method that is achieved by optimizing the amidation method used in the condensation step between the carboxy group of a proline derivative and the cyclic amino group of a thiazolidine, the reaction conditions (charge amount, reaction solvent, reaction temperature, reaction time, etc.), post-treatment method, etc. However, none of the conventional methods is satisfactory as an industrial production method, and further, from the vast number of available combinations of amidation methods (amidation reagents (e.g., acid chlorides, condensing agents, mixed acid anhydride-forming agents, etc.), bases, additives, etc.), reaction conditions, post-treatment method, etc., it is usually accompanied by great technical difficulty to identify an optimal combination that can withstand the industrial production of a specific prolinamide compound.

[0009] As a result of extensive research, the present inventors have found that by using pivaloyl chloride, which is a mixed acid anhydride-forming agent with relatively low toxicity and low cost, as an amidation reagent and N,N-diisopropylethylamine (hereinafter, sometimes referred to as "DIPEA") as a base, the target prolinamide compound can be suitably produced inexpensively, in high yield, with good reproducibility, even in industrial-scale reactions of several hundred kg without using excessive amounts of reagents or substrates, and have completed the present invention. That is, the present invention is [1]: General formula (3):

[0010] [ka]

[0011] (wherein R represents a protecting group for an amino group) or a salt thereof is condensed with thiazolidine using pivaloyl chloride in the presence of N,N-diisopropylethylamine (DIPEA), to produce a compound represented by the general formula (2):

[0012] [ka]

[0013] (wherein R is as defined above) or a salt thereof, [2]: The compound represented by the general formula (2):

[0014] [ka]

[0015] (wherein R has the same meaning as in claim 1) or a salt thereof, and the compound is reacted with a compound represented by the general formula (4):

[0016] [ka]

[0017] In the presence of a carboxylate of a compound represented by the general formula (5):

[0018] [ka]

[0019] or a salt thereof, and then removing the protecting group R of the amino group of the compound represented by general formula (5) or a salt thereof,

[0020] [ka]

[0021] A method for producing a compound represented by the formula (I) or a salt thereof: [3]: The compound represented by the general formula (1):

[0022] [ka]

[0023] and then subjecting the compound to a salt formation treatment with an acid. [4]: The production method according to any one of the above [1] to [3], wherein R is a substituted or unsubstituted alkoxycarbonyl. [5]: The production method according to the above [4], wherein R is t-butoxycarbonyl. [6]: The method according to any one of the above [2] to [5], wherein the compound represented by the general formula (1) or a salt thereof is {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl}(1,3-thiazolidin-3-yl)methanone dihydrobromide; [7]: The method according to any one of the above [2] to [5], wherein the compound represented by the general formula (1) or a salt thereof is {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl}(1,3-thiazolidin-3-yl)methanone dihydrobromide hydrate; and [8]: A method for producing a pharmaceutical composition, comprising mixing the compound represented by general formula (1) or a salt thereof produced by the production method described in any one of the above [2] to [7] with a pharmaceutically acceptable additive. [Effects of the Invention]

[0024] According to the present invention, a prolinamide compound or a salt thereof, which is useful as a pharmaceutical synthetic intermediate or the like, can be produced inexpensively, safely, and simply, even on an industrial scale of several hundred kg, with high purity and high yield, by using pivaloyl chloride (200 yen / mol), a relatively low-toxicity and inexpensive mixed acid anhydride-forming agent, as an amidating reagent and N,N-diisopropylethylamine (DIPEA) as a base. Furthermore, teneligliptin or a salt thereof, which is useful as a diabetes therapeutic drug or the like, can be produced industrially advantageously and efficiently by using the prolinamide compound or a salt thereof obtained by the production method of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0025] (definition)

[0026] In the present invention, the term "amino group-protecting group" refers to a substituent that replaces a hydrogen atom and is generally used in the technical field of organic chemistry to protect an amino group from its high reactivity. Representative "protective groups for amino groups" include those described in, for example, "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM, Wiley-Interscience, 2007). Examples of the protecting group for the amino group represented by R include the groups described in Any protecting group that does not interfere with the reaction may be used, and suitable examples of such protecting groups for amino groups include alkoxycarbonyl groups (methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, t-butoxycarbonyl, etc.) and substituted alkoxycarbonyl groups (benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 9-fluorenylmethoxycarbonyl, etc.). Of these, R is preferably an alkoxycarbonyl group, and particularly preferably t-butoxycarbonyl.

[0027] The "carboxylic acid" that forms the carboxylate of the compound represented by general formula (4) is an optionally substituted linear or branched carboxylic acid having 1 to 7 carbon atoms (C 1-7 ) carboxylic acids having 2 to 7 carbon atoms (C 2-7 ) alkyl carboxylic acids (acetic acid, propionic acid, butyric acid, isobutyric acid, etc.), carbon atoms of 2 to 7 (C 2-7 Among these, alkylcarboxylic acids are preferred, and acetic acid is particularly preferred.

[0028] The compounds disclosed herein may have one or more asymmetric carbon atoms. In some cases, the compounds disclosed herein may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers, or a mixture of diastereomers. The compounds disclosed herein may simultaneously contain structural features that give rise to the above isomers, and may contain the above isomers in any ratio.

[0029] Diastereomeric mixtures can be separated into individual diastereomers by conventional methods such as chromatography or crystallization, or the individual diastereomers can be prepared by synthetic methods using stereochemically pure starting materials or stereoselective reactions.

[0030] Separation of individual enantiomers from a mixture of enantiomers can be accomplished by methods well known in the art. For example, enriched or substantially pure single diastereomers can be separated from a diastereomeric mixture formed by reacting a mixture of enantiomers with a compound known as a chiral auxiliary, using standard techniques such as fractional crystallization or chromatography. The separated diastereomer can be converted to the desired enantiomer by removing the added chiral auxiliary.

[0031] The enantiomeric mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

[0032] Alternatively, either enantiomer of a compound can be obtained by using substantially pure optically active starting materials or by stereoselective synthesis (asymmetric induction) of prochiral intermediates using chiral auxiliaries or asymmetric catalysts.

[0033] Absolute configuration may be determined by X-ray crystallography of crystalline products or intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known configuration.

[0034] (Production method of the present invention) The production method of the present invention will be described in more detail below.

[0035] The starting compounds are readily available as commercially available products, or can be produced by the production methods shown below or methods known per se (see, for example, WO 2002 / 014271 (Patent Document 1), WO 2012 / 165547 (Patent Document 3), and WO 2015 / 019238 (Patent Document 4)), or can be produced according to methods similar thereto.

[0036] The compounds used in the following reactions may form inorganic acid salts (e.g., hydrochloride, hydrobromide, sulfate, nitrate, phosphate), organic acid salts (e.g., acetate, tartrate, citrate, fumarate, maleate, toluenesulfonate, methanesulfonate), metal salts (e.g., sodium salt, potassium salt, calcium salt, aluminum salt), or salts with bases (e.g., ethylamine salt, guanidine salt, ammonium salt, hydrazine salt, quinine salt, cinchonine salt) within the range that does not interfere with the reaction.

[0037] The compounds obtained in each of the following steps may be used in the next step as crude products or without isolation from the reaction mixture. Alternatively, the compounds may be isolated from the reaction mixture according to a commonly known method, or may be easily purified by a commonly known separation means such as recrystallization, distillation, or chromatography. Furthermore, the compounds may be isolated as inorganic acid salts, organic acid salts, metal salts, or salts with bases according to a commonly known method.

[0038] The compounds used in the present invention and the resulting compounds, or salts thereof, include solvates or hydrates thereof.

[0039] (Process 1)

[0040] [ka]

[0041] (In the formula, R has the same meaning as above.)

[0042] This step is a step of producing a compound represented by general formula (2) or a salt thereof by subjecting a compound represented by general formula (3) or a salt thereof, which is produced according to a method known per se (e.g., WO 2002 / 014271 (Patent Document 1), WO 2015 / 019238 (Patent Document 4), etc.) or a method equivalent thereto, and thiazolidine to a condensation reaction (amidation reaction) via a mixed acid anhydride using pivaloyl chloride in the presence of N,N-diisopropylethyamine (DIPEA). This step can be carried out in a solvent that does not affect the reaction. The amount of thiazolidine used is usually 1.0 to 1.2 mol, preferably 1.0 mol, per 1 mol of the compound represented by formula (3). The amount of pivaloyl chloride used is usually 1.0 to 1.2 mol, preferably 1.0 mol, per 1 mol of the compound represented by formula (3). The amount of DIPEA used is usually 1.0 to 1.2 mol, preferably 1.0 mol, per 1 mol of the compound represented by formula (3).

[0043] This reaction is preferably carried out in a solvent that does not affect the reaction. Examples of reaction solvents that can be used include ethyl acetate, isopropyl acetate, diethyl ether, tetrahydrofuran (hereinafter abbreviated as THF), 1,2-dimethoxyethane, methyl ethyl ketone, acetone, acetonitrile, N-methylpyrrolidone, dichloromethane, chloroform, toluene, and mixtures thereof, and preferably ethyl acetate.

[0044] The reaction temperature can usually be selected arbitrarily from -10°C to 30°C, and is preferably from -10°C to 10°C. The reaction time is usually about 10 minutes to 6 hours, and preferably 30 minutes to 2 hours.

[0045] The post-treatment method for this reaction is not particularly limited. In the industrial production method (mass synthesis) of the compound represented by general formula (2) or a salt thereof, for example, the following post-treatment method by crystallization can be suitably used. That is, water is added to the reaction mixture of the condensation reaction to terminate the reaction, followed by extraction with a reaction solvent. The organic layer is then partially concentrated, a poor solvent is added thereto, and the mixture is stirred to cause crystallization. The crystals are then filtered off, thereby obtaining a compound represented by general formula (2) or a salt thereof. If necessary, a small amount of a polar protic solvent may be added before the addition of the poor solvent, or crystallization may be performed under cooling. This post-treatment method is applicable even to industrial-scale feed amounts (several hundred kg), and allows the compound represented by general formula (2) or a salt thereof to be obtained in high purity and high yield. Examples of the polar protic solvent used in the post-treatment method include alcohols such as methanol, ethanol, 2-propanol, and butanol, with 2-propanol being preferred. Examples of the poor solvent used in the post-treatment method include non-polar aprotic solvents such as n-hexane, n-heptane, and toluene, and n-heptane is preferred. The temperature (heating conditions) when the poor solvent is added may vary depending on the type of solvent used, but is usually 40°C to 80°C, and preferably 40°C to 50°C. The temperature (cooling conditions) at which the crystals are precipitated is usually 10°C or lower, preferably 0°C or lower, and more preferably -5°C or lower.

[0046] (Process 2)~(Process 4)

[0047] [ka]

[0048] (wherein R has the same meaning as above)

[0049] The compound represented by general formula (2) or a salt thereof obtained in step 1 can be converted into a compound represented by general formula (1) (teneligliptin) or a salt thereof by a method known per se or a combination thereof, as appropriate. Specifically, the compound represented by general formula (2) or its salt obtained in step 1 is subjected to a reductive amination reaction with a carboxylic acid salt of a compound represented by general formula (4) prepared by a method known per se (see, for example, Example 2 of WO 2012 / 165547 (Patent Document 3)) or a method analogous thereto to produce a compound represented by general formula (5) or its salt (step 2). The protecting group R of the amino group in the compound represented by general formula (5) or its salt is then removed to produce a compound represented by general formula (1) (step 3). If desired, this can be further converted into a salt (acid addition salt) by subjecting the resulting product to a salt formation treatment with an acid. Steps 2 to 4 are described below.

[0050] (Process 2)

[0051] The reductive amination reaction of the compound represented by general formula (2) in the presence of the carboxylate of the compound represented by general formula (4) can be carried out by a known method, specifically by reacting the carboxylate of the compound represented by general formula (4), the compound represented by general formula (2), and a reducing agent in a suitable solvent.

[0052] Examples of the reducing agent include sodium borohydride, sodium triacetoxyborohydride, dimethylamine borane, triethylamine borane, trimethylamine borane, t-butylamine borane, N,N-diethylaniline borane, and 2-picoline borane, and preferably sodium triacetoxyborohydride. The amount of the reducing agent used is usually 1.0 to 2.0 mol, preferably 1.1 to 1.5 mol, per 1 mol of the compound represented by formula (2). The amount of the carboxylate of the compound represented by formula (4) used is usually 0.9 to 1.1 mol, preferably 1.0 mol, per 1 mol of the compound represented by formula (2).

[0053] The reaction solvent is not particularly limited as long as it does not affect the reaction. For example, dichloromethane, methanol, ethanol, 2-propanol, THF, acetonitrile, toluene, dimethylformamide, or a mixed solvent thereof can be used, and preferably toluene can be used.

[0054] The reaction temperature can usually be selected arbitrarily from -20 to 100°C, and the reaction time is usually about 10 minutes to 1 day.

[0055] (Step 3)

[0056] As a method for removing the protecting group R of the amino group of the compound represented by general formula (5) or a salt thereof obtained in the above step 2, a known method suitable for the protecting group used can be used as appropriate.

[0057] Specifically, for example, when t-butoxycarbonyl is used as the protecting group R, deprotection can be carried out by reacting with an acid in a suitable solvent or without a solvent. Examples of the acid include trifluoroacetic acid, hydrogen chloride, hydrogen bromide, and sulfuric acid, and hydrogen bromide is preferred. The concentration of the acid is 0.01 to 10 mol / L, preferably 0.1 to 4 mol / L, relative to the reaction mixture.

[0058] This reaction is preferably carried out in a suitable reaction solvent, such as dichloromethane, chloroform, methanol, ethanol, 2-propanol, THF, 1,4-dioxane, acetonitrile, toluene, water, or a mixture thereof, preferably a mixture of 2-propanol and water.

[0059] The reaction temperature can usually be selected arbitrarily from 0 to 100° C., and the reaction time is usually about 10 minutes to 2 days.

[0060] When methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, or the like is used as the protecting group R, deprotection can be carried out by reacting with a base in an appropriate solvent or without a solvent. Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like, and potassium hydroxide is preferred. The concentration of the base is 0.1 to 100 mol / L, preferably 1 to 10 mol / L, relative to the reaction mixture.

[0061] This reaction is preferably carried out in a suitable reaction solvent, such as methanol, ethanol, 2-propanol, THF, acetonitrile, water, or a mixture thereof, preferably a mixture of methanol and water.

[0062] The reaction temperature can usually be selected arbitrarily from 0 to 100° C., and the reaction time is usually about 10 minutes to 2 days.

[0063] When benzyloxycarbonyl is used as the protecting group R, deprotection can be carried out in a suitable solvent under a hydrogen atmosphere in the presence of a palladium carbon catalyst or palladium hydroxide carbon catalyst.

[0064] When 2,2,2-trichloroethoxycarbonyl is used as the protecting group R, deprotection can be carried out by reacting with zinc powder in an appropriate solvent.

[0065] When 9-fluorenylmethoxycarbonyl is used as the protecting group R, deprotection can be carried out by reacting with pyrrolidine, piperidine or morpholine in an appropriate solvent or without a solvent.

[0066] (Step 4)

[0067] The salt formation treatment of the compound represented by general formula (1) obtained in the above step 3 with an acid can be carried out by treating with the corresponding acid according to a commonly known method, for example, by treating the compound represented by general formula (1) with an acid in an appropriate solvent to form a salt.

[0068] Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, and nitric acid, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, besylic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, gallic acid, and camphorsulfonic acid, and hydrogen bromide is preferred. Specifically, a salt of the compound represented by general formula (1) can be produced by reacting 1 mole of the compound represented by general formula (1) with 1 to 10 moles, preferably 2 to 5 moles, of an acid.

[0069] Examples of the reaction solvent include dichloromethane, chloroform, methanol, ethanol, 2-propanol, THF, acetonitrile, toluene, water, or a mixture thereof. A solvent may be used, preferably a mixed solvent of 2-propanol and water.

[0070] The reaction temperature can usually be selected arbitrarily from 0 to 100° C., and the reaction time is usually about 10 minutes to 2 days.

[0071] In producing a salt of a compound represented by general formula (1) with an acid, it is more preferable to use a protecting group that can be removed with an acid, such as t-butoxycarbonyl, as the protecting group R of the amino group of a compound represented by general formula (5) or a salt thereof, since the removal reaction of the protecting group R and the subsequent salt formation treatment can be carried out simultaneously.

[0072] Compounds that are preferably produced by the production method of the present invention include teneligliptin (i.e., {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl}(1,3-thiazolidin-3-yl)methanone) or a salt thereof.

[0073] More specifically, examples of such compounds include {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl}(1,3-thiazolidin-3-yl)methanone 2.5 hydrobromide salt, and even more specifically, mono- to dihydrates of {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl}(1,3-thiazolidin-3-yl)methanone 2.5 hydrobromide salt.

[0074] Specific features of the production method of the present invention include the following. (A) Since pivaloyl chloride, which is a relatively low-toxicity and inexpensive mixed acid anhydride-forming agent, is used as the amidation reagent, a safer and more economical production method can be provided compared to conventional methods. (B) By using DIPEA as a base, unlike the case of using other organic bases (e.g., triethylamine), the amount of hardly soluble salt precipitated is reduced and stirring efficiency is improved, so that the amount of reaction solvent used can be reduced (i.e., the amount charged per lot can be increased). (C) The reaction proceeds in a good yield by using equimolar amounts of thiazolidine, amidating reagent, and base relative to the starting substrate, the compound represented by general formula (3), without using excessive amounts of the thiazolidine, amidating reagent, and base. This suppresses the production of related substances and eliminates the need for extra purification procedures such as removal of excess reagents, making experimental procedures and post-treatments easy to perform. (D) The reaction conditions (reaction temperature: -10°C to 10°C) are mild, and the process can be scaled up (to several hundred kg scale). Therefore, the process is suitable as an industrial production method for a specific prolinamide compound or a salt thereof (i.e., a compound represented by general formula (2) or a salt thereof) and teneligliptin or a salt thereof using the same.

[0075] A pharmaceutical composition containing the compound represented by general formula (1) or a salt thereof (e.g., teneligliptin or a salt thereof) produced by the production method of the present invention is produced by appropriately mixing with at least one or more pharmaceutically acceptable additives in appropriate amounts.

[0076] The content of the compound represented by general formula (1) or a salt thereof in the pharmaceutical composition is not particularly limited, but is usually 30 to 80% by weight, preferably 45 to 55% by weight, of the total pharmaceutical composition.

[0077] Pharmaceutically acceptable additives include various organic or inorganic carrier substances commonly used as pharmaceutical ingredients. Examples of the additives include excipients, lubricants, binders, fluidizing agents, disintegrants, solubilizing agents, etc. Preferred are excipients, binders, fluidizing agents, and disintegrants, and more preferred are excipients.

[0078] Suitable examples of excipients include D-mannitol, sorbitol, xylitol, corn starch, potato starch, lactose, crystalline cellulose, calcium hydrogen phosphate, etc., with D-mannitol, xylitol, and corn starch being preferred. Suitable examples of lubricants include magnesium stearate, calcium stearate, talc, stearic acid, sucrose fatty acid esters, and the like. Suitable examples of binders include hydroxypropyl cellulose, polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methyl cellulose, and the like. Suitable examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, and talc. Suitable examples of the disintegrant include low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, carmellose calcium, and crospovidone. Suitable examples of the solubilizing agent include sodium benzoate, ethylenediamine, potassium iodide, and the like.

[0079] The pharmaceutical composition containing the compound represented by general formula (1) or a salt thereof produced by the production method of the present invention is usually solid, and its shape is not particularly limited and may be any of granules, granules, and lumps.

[0080] In this specification, the following abbreviations are used: "Me" represents a methyl group, "Ph" represents a phenyl group, "Ac" represents an acetyl group, "t-Bu" represents a tertiary butyl group, "EDC" represents 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, "HOBt" represents 1-hydroxybenzotriazole hydrate, "NMM" represents N-methylmorpholine, "TEA" represents triethylamine, "DMAP" represents 4-dimethylaminopyridine, "CDI" represents N,N'-carbonyldiimidazole, "EEDQ" represents 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, and "DMC" represents 1,3-dimethyl-2-chloroimidazolinium chloride. [Example]

[0081] The present invention will be described in more detail below with reference to examples, but is not limited to these. In the examples, "w%" represents weight percent, and "room temperature" represents a temperature of 15 to 30°C unless otherwise specified.

[0082] Example 1 Preparation of 3-[(2S)-1-t-butoxycarbonyl-4-oxopyrrolidin-2-ylcarbonyl]thiazolidine (Compound 2a)

[0083] [ka]

[0084] To a solution of (2S)-1-t-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid (compound 3a) (250.0 kg) and N,N-diisopropylethylamine (DIPEA) (141 kg) in ethyl acetate (2242.5 kg), pivaloyl chloride (131.5 kg) was added at 10°C or below, and the reaction mixture was stirred at 10°C or below for 30 minutes. Thiazolidine (97.2 kg) was added to the reaction mixture at 10°C or below, and the reaction mixture was stirred at 0-10°C for 1 hour. Water (500.0 kg) was added to the reaction mixture, and the layers were separated. The ethyl acetate layer was washed sequentially with an aqueous solution of diammonium hydrogen phosphate (prepared from 144.0 kg of ammonium hydrogen phosphate and 750.0 kg of water) and brine (prepared from 75.0 kg of sodium chloride and 425.0 kg of water). The ethyl acetate layer was concentrated to a residual volume of 1250 L, and then 2-propanol (976.3 kg) was added. The mixture was concentrated again to a residual volume of 1000 L. After that, n-heptane (1368 kg) was added at 40-45°C, and the mixture was stirred at -5°C or below for 1 hour. The precipitated crystals were collected by filtration and washed with n-heptane (684.0 kg). 2-Propanol (429.6 kg) was added to the obtained crystals, and then n-heptane (1521.9 kg) was added at 40-45°C, and the mixture was stirred at -5°C or below for 1 hour. The precipitated crystals were collected by filtration, washed with n-heptane (769.8 kg), and dried under reduced pressure to obtain 283.1 kg of 3-[(2S)-1-t-butoxycarbonyl-4-oxopyrrolidin-2-ylcarbonyl]thiazolidine (Compound 2a). (86% yield) 1 H-NMR(500MHz,DMSO-d6)δ1.36,1.40(9H,s),2.36-2.45(1H,m),2.97-3.12(3H, m),3.62-3.71(2H,m),3.74-3.94(2H,m),4.33-4.80(2H,m),4.91-5.04(1H,m).

[0085] Example 2 Preparation of {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl}(1,3-thiazolidin-3-yl)methanone 2.5 hydrobromide mono- and dihydrates (Compound 1a)

[0086] [ka]

[0087] (wherein Y represents 1 or 2)

[0088] Toluene (425 L) was added to the acetate salt of 3-methyl-1-phenyl-5-(1-piperazinyl)pyrazole (compound 4a) (25.2 kg) and 3-[(2S)-1-t-butoxycarbonyl-4-oxopyrrolidin-2-ylcarbonyl]thiazolidine (compound 2a) (25.0 kg), and sodium triacetoxyborohydride (23.0 kg) was added. A toluene (75 L) slurry was added at 8°C, followed by stirring at 20-28°C for 3 hours. Water (150 L) was added to the reaction mixture, and the mixture was separated. The resulting toluene layer was washed with 5 wt% aqueous sodium bicarbonate (158 kg) and water (150 L), then concentrated under reduced pressure and dried. 2-Propanol (125 L) was added to the resulting residue, and the mixture was again concentrated under reduced pressure and dried. 2-Propanol (375 L) was added to the residue, the temperature was raised, and 48 wt% hydrobromic acid (42.14 kg) was added dropwise at 75-77°C, followed by reflux for 2.5 hours. The reaction mixture was cooled, and seed crystals prepared by sampling the reaction mixture were inoculated at 58°C. Crystallization was carried out at 58°C for 1 hour, then at 33-40°C for 1 hour, and then at 17-25°C for 1 hour, followed by standing overnight. The precipitated crystals were collected by filtration, washed with 2-propanol (50 L), and dried in hot air (40-47°C) for 18 hours to give {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl}(1,3-thiazolidin-3-yl)methanone hydrobromide (50.0 kg) as a crude product.

[0089] Ethanol (144 L) was added to the crude product (24.0 kg), and the mixture was dissolved by heating (73°C). The mixture was then filtered while hot and washed with ethanol (24 L). The filtrate and washings were combined, and water (3.4 L) was added at 67°C. The mixture was then crystallized at 49-55°C for 2 hours and then at 19-25°C for 1 hour. The precipitated crystals were collected by filtration and washed with ethanol (24 L). The resulting crystals were dried under reduced pressure at 45°C for 19 hours and then dried with hot air at 50°C for 18 hours to obtain 20.9 kg of the purified product, {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl}(1,3-thiazolidin-3-yl)methanone 2.5 hydrobromide mono- and dihydrate (Compound 1a). (79% yield, calculated assuming dihydrate) 1 H-NMR(400MHz,C5D5N)δ2.02-2.14(1H,m),2.33(3H,m),2.46-2.56(4H,m),2.87(4H,m),2.91-3.12(3H,m) ,3.45-3.51(1H,m),3.63-3.67(1H,m),3.80-3.90(1.4H,m),4.08(0.6H,m),4.11-4.16(1H,m),4.68(0.6H, d,J=10.1Hz),4.72(0.6H,d,J=10.1Hz),4.80(0.4H,d,J=8.8Hz),4.96(0.4H,d,J=8.8Hz),5.42(0.6H,dd,J =8.8,8.8Hz),5.52(0.4H,dd,J=8.8,8.8Hz),5.76(0.4H,s),5.77(0.6H,s),7.32(1H,t,J=7.8Hz),7.53(2H ,dd,J=8.8,7.8Hz),8.07(2H,d=8.8Hz).

[0090] Comparative Examples 1 to 14 The conversion reaction of (2S)-1-t-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid (compound 3a) and thiazolidine (1.1 moles per mole of compound 3a) to 3-[(2S)-1-t-butoxycarbonyl-4-oxopyrrolidin-2-ylcarbonyl]thiazolidine (compound 2a) was investigated in the presence of various amidation reagents, various bases, or various additives. The results are shown in Table 1 below.

[0091] [Table 1]

[0092] As a result, when SOCl2 and (CO)2Cl2 were used as the amidation reagent, no compound 2a was obtained at all (Comparative Examples 11 and 12). Furthermore, according to Table 1, no effect of the reaction solvent on the yield was observed (Comparative Examples 2 and 3). Furthermore, when pivaloyl chloride was used as the amidation reagent and an organic base other than DIPEA was used, the amount of precipitation of the hydrochloride salt of the poorly soluble organic base (e.g., triethylamine hydrochloride (Comparative Example 5)) increased, making stirring difficult, the reaction unstable, and the production of by-products. Furthermore, when DMAP, a highly reactive organic base, was used (Comparative Example 6), many by-products were produced, making it difficult to obtain compound 2a with high purity and high yield, and it was found that scaling up was difficult.

[0093] From the results of Example 1 and Table 1 above, it was found that in the condensation reaction of compound 3a with thiazolidine, when pivaloyl chloride was used as the amidating reagent in the presence of DIPEA as the base, compound 2a could be produced in high purity and high yield even when the charge amount was increased to an industrial scale (several hundred kg scale). In contrast, all amidating reagents other than pivaloyl chloride are far more expensive than pivaloyl chloride. Furthermore, as mentioned above, even when pivaloyl chloride was used as the amidating reagent, the purity and yield of the obtained compound 2a decreased when other bases were used. Therefore, it was found that none of the production methods of Comparative Examples 1 to 14 are suitable as industrial production methods for compound 2a. [Industrial Applicability]

[0094] According to the production method of the present invention, by using pivaloyl chloride, which is relatively low in toxicity and inexpensive, as the amidating reagent and DIPEA as the base, the reaction proceeds in good yield without using excessive amounts of the substrate (thiazolidine), the amidating reagent, and the base, simply by using equimolar amounts of each relative to the starting substrate (i.e., the compound represented by general formula (3)), and a prolinamide compound (i.e., the compound represented by general formula (2)) or a salt thereof, which is useful as a pharmaceutical synthetic intermediate, can be provided in high purity. Furthermore, according to the production method of the present invention, the reaction conditions in the production process of the prolinamide compound are milder than those of conventional methods, post-treatment is simple, and the method can be scaled up (to several hundred kg scale), so that an economical and safe industrial production method for teneligliptin or a salt thereof, which exhibits DPP-IV inhibitory activity and is useful in the treatment or prevention of diabetes, etc., can be provided.

[0095] Although some specific embodiments of the present invention have been described in detail above, it will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments shown without substantially departing from the teachings and advantages of the present invention, and therefore, all such modifications and variations are intended to be included within the spirit and scope of the present invention as claimed.

Claims

[Claim 1] The invention described herein.

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