Method for producing prolineamide compounds

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 proline amide compound useful as a pharmaceutical synthetic intermediate or the like. Further, the present invention 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 and the like, using the novel method for producing the compound.

Background Art

[0002] Teneligliptin or a salt thereof having a side chain containing a proline amide moiety has been reported to exhibit DPP-IV inhibitory activity and be 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 proline amide compound which is a synthetic intermediate thereof. In this production method, N-t-butoxycarbonyl-L-trans-4-hydroxyproline and thiazolidine are condensed using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole, and then oxidized using a pyridine sulfur trioxide complex in the presence of a base to obtain teneligliptin or a salt thereof via the produced proline amide compound. However, in this production method, the yield of the proline amide compound is insufficient, and further improvement has been desired for industrial use.

[0004] Another method has been reported for producing teneligliptin or its salts via a prolineamide compound prepared by condensing (2S)-1-t-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid and thiazolidinedione in the presence of a base using n-propylphosphonic anhydride (cyclic trimer) (see Patent Document 3). Although this production method is usable on an industrial scale, n-propylphosphonic anhydride (cyclic trimer) is a designated substance under the Chemical Weapons Prohibition Act, requiring certain measures such as notification obligations and the obligation to accept inspections (tests) by inspectors of international organizations, and is also expensive (4,200 yen / mol), so it cannot necessarily be said to be a suitable method for mass production.

[0005] Another method has been reported for producing teneligliptin or a salt thereof via a prolineamide compound prepared by condensing (2S)-1-t-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid and thiazolidinedione with N,N'-dicyclohexylcarbodiimide (DCC) in the presence of 4-dimethylaminopyridine (see Example 3 of Patent Document 4). This production method requires stepwise fine-tuning in a short amount of time. The reaction 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 control the temperature inside the reaction vessel to a uniform temperature in a short time and to fine-tune the temperature. Furthermore, DCC is toxic (causes skin inflammation) and expensive (825 yen / mol (4000 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 [Overview of the project] [Problems that the invention aims to solve]

[0007] The object of the present invention is to provide an inexpensive, safe, and efficient manufacturing method suitable for the industrial production of prolineamide compounds useful as pharmaceutical synthesis intermediates, etc. Furthermore, the object is to provide an industrially advantageous manufacturing method for teneligliptin or its salts, which are useful as antidiabetic drugs, etc., using this manufacturing method. [Means for solving the problem]

[0008] As mentioned above, in the industrial production of proline amide compounds, there is a need for a safe, low-cost, and high-yield method by optimizing the amidation method used in the condensation step between the carboxyl group of the proline derivative and the cyclic amino group of the thiazolidinedione, reaction conditions (amount of charge, reaction solvent, reaction temperature, reaction time, etc.), and workup methods. However, conventional methods are not satisfactory as industrial production methods, and identifying the optimal combination that can withstand the industrial production of a specific proline amide compound from a vast number of combinations of amidation methods (amidation reagents (e.g., acid chlorides, condensing agents, mixed acid anhydride forming agents, etc.), bases, additives, etc.), reaction conditions, and workup methods usually involves significant technical difficulties.

[0009] As a result of diligent research, the present inventors have discovered that by using pivaloyl chloride, a mixed acid anhydride forming agent with relatively low toxicity and low cost, as the amidation reagent, and N,N-diisopropylethylamine (hereinafter sometimes referred to as "DIPEA") as the base, the target prolineamide compound can be suitably produced inexpensively, in high yield, and reproducibly, even in industrial-scale reactions on a scale of several hundred kilograms, without using excess amounts of reagents or substrates. This has led to the completion of the present invention. In other words, the present invention is [1]: General formula (3):

[0010]

Chem.

[0011] (In the formula, R represents a protecting group for an amino group.) A compound represented by the formula or a salt thereof and thiazolidine are condensed using pivaloyl chloride in the presence of N,N - diisopropylethylamine (DIPEA), characterized by a method for producing a compound represented by general formula (2):

[0012]

Chem.

[0013] (In the formula, R has the same meaning as described above) A method for producing a compound represented by the formula or a salt thereof, [2]: A compound represented by general formula (2):

[0014]

Chem.

[0015] (In the formula, R has the same meaning as in claim 1) is produced, and the compound is subjected to a reductive amination reaction in the presence of a carboxylate of a compound represented by general formula (4):

[0016]

Chem.

[0017] [[ID=五四]] <五四]]

[0018] <五四]] <五四]]

Chem.

[0019] <五四]] ​The process involves producing a compound represented by or a salt thereof, and then removing the protecting group R from the amino group of the compound represented by general formula (5) or a salt thereof, for general formula (1):

[0020] [ka]

[0021] A method for producing a compound represented by or a salt thereof, [3]: The manufacturing method described in [2] above is for general formula (1):

[0022] [ka]

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

[0024] According to the present invention, by using pivaloyl chloride (200 yen / mol), a relatively low-toxicity and inexpensive mixed acid anhydride forming agent, as the amidation reagent, and N,N-diisopropylethylamine (DIPEA) as the base, prolineamide compounds or salts thereof, which are useful as pharmaceutical synthesis intermediates, can be produced inexpensively, safely, and simply, and with high purity and high yield, even on an industrial scale of several hundred kilograms. Furthermore, by using the prolineamide compounds or salts thereof obtained by the production method of the present invention, teneligliptin or salts thereof, which are useful as diabetes treatment drugs, can be produced industrially advantageously and efficiently. [Modes for carrying out the invention]

[0025] (definition)

[0026] In this invention, "amino group protecting group" refers to a substituent that replaces a hydrogen atom, commonly used in the field of organic chemistry to protect an amino group from its high reactivity. A typical example of an "amino group protecting group" is, for example, "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM), published by Wiley-Interscience in 2007. Examples of protecting groups for the amino group represented by R include those described in (Wuts, etc.) Any protecting group that does not interfere with the response is acceptable, and suitable protecting groups for such amino groups include, for example, alkoxycarbonyl groups (methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, t-butoxycarbonyl, etc.) and substituted alkoxycarbonyl groups (benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 9-fluorenylmethoxycarbonyl, etc.). Of these, alkoxycarbonyl groups are preferred as R, and t-butoxycarbonyl is particularly preferred.

[0027] The "carboxylic acid" that forms the carboxylate salt of the compound represented by general formula (4) may be a linear or branched chain having 1 to 7 carbon atoms (C) which may be substituted. 1-7 Examples include carboxylic acids with 2 to 7 carbon atoms. Specifically, for example, formic acid, 2-7 ) alkylcarboxylic acids (acetic acid, propionic acid, butyric acid or isobutyric acid, etc.), with 2 to 7 carbon atoms (C 2-7 Examples include alkylcarboxylic acids (such as trifluoroacetic acid) that have been substituted with ). Of these, alkylcarboxylic acids are preferred, and acetic acid is particularly preferred.

[0028] The compounds disclosed herein may have one or more chiral 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 possess multiple structural features that give rise to the above-mentioned isomers. Furthermore, the compounds disclosed herein may contain the above-mentioned isomers in any proportion.

[0029] Diastereomer mixtures can be separated into their individual diastereomers by conventional methods such as chromatography and crystallization. Alternatively, each diastereomer can be synthesized using stereochemically monolithic starting materials or through stereoselective reactions.

[0030] The separation of each individual enantiomer from a mixture of enantiomers can be carried out by methods well known in this art. For example, a mixture of enantiomers can be reacted with a substantially pure enantiomer known as a chiral auxiliary compound to form a diastereomer mixture. From this mixture, a single diastereomer with an increased isomer ratio or that is substantially pure can be separated using standard methods such as fractional crystallization or chromatography. The separated diastereomer can then be converted back to the desired enantiomer by removing the added chiral auxiliary compound.

[0031] Furthermore, mixtures of enantiomers of a compound can be directly separated using chromatography, a well-known method in this field that utilizes a chiral stationary phase.

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

[0033] The absolute configuration can be determined by X-ray crystallography of the crystalline product or intermediate. If necessary, a crystalline product or intermediate derived with a reagent having a known chiral center configuration may be used.

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

[0035] The raw material compounds can be readily available as commercial products, or can be manufactured by the manufacturing methods described below or by methods known to the public (see, for example, International Publication No. 2002 / 014271 (Patent Document 1), International Publication No. 2012 / 165547 (Patent Document 3), and International Publication No. 2015 / 019238 (Patent Document 4)), or by methods equivalent thereto.

[0036] The compounds used in each of the following reactions may form inorganic salts (e.g., hydrochloride salts, hydrobromide salts, sulfate salts, nitrates, phosphate salts), organic salts (e.g., acetate salts, tartrate salts, citrate salts, fumarate salts, maleate salts, toluenesulfonate salts, methanesulfonate salts), metal salts (e.g., sodium salts, potassium salts, calcium salts, aluminum salts), or salts with bases (e.g., ethylamine salts, guanidine salts, ammonium salts, hydrazine salts, quinine salts, cinchonine salts), to the extent that they do not interfere with the reaction.

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

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

[0039] (Process 1)

[0040] [ka]

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

[0042] This process involves producing a compound represented by general formula (2) or a salt thereof by a condensation reaction (amidation reaction) via a mixed acid anhydride using pivaloyl chloride in the presence of N,N-diisopropylethiamine (DIPEA) with a thiazolidinedione, using a compound represented by general formula (3) or a salt thereof produced by a method known in itself (for example, International Publication No. 2002 / 014271 (Patent Document 1), International Publication No. 2015 / 019238 (Patent Document 4), etc.) or a similar method. This process can be carried out in a solvent that does not affect the reaction. The amount of thiazolidinedion used is typically 1.0 to 1.2 moles, preferably 1.0 mole, per mole of the compound represented by general formula (3). The amount of pivaloyl chloride used is typically 1.0 to 1.2 moles, preferably 1.0 mole, per mole of the compound represented by general formula (3). The amount of DIPEA used is usually 1.0 to 1.2 moles, preferably 1.0 mole, per mole of the compound represented by general formula (3).

[0043] This reaction is preferably carried out in a solvent that does not affect the reaction. Suitable reaction solvents include, for example, 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. Ethyl acetate is preferably used.

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

[0045] The post-treatment method for this reaction is not particularly limited, but in the industrial production (large-scale synthesis) of the compound represented by general formula (2) or its salt, for example, the following crystallization post-treatment method can be suitably used. Specifically, by adding water to the reaction mixture from the condensation reaction to stop the reaction, extracting with the reaction solvent, concentrating a portion of the organic layer, adding a poor solvent, and stirring the mixture to crystallize it, the resulting crystals can be filtered to obtain the compound represented by general formula (2) or its salt. Furthermore, if necessary, a small amount of polar protic solvent can be added before adding the poor solvent, or crystallization can be carried out under cooling. This post-treatment method is applicable even to industrial-scale batches (hundreds of kilograms), and thereby the compound represented by general formula (2) or its salt can be obtained in high purity and high yield. Examples of polar protic solvents used in the above post-treatment method include alcohols such as methanol, ethanol, 2-propanol, and butanol, with 2-propanol being preferred. Examples of poor solvents used in the above post-treatment method include nonpolar aprotic solvents such as n-hexane, n-heptane, and toluene, with n-heptane being preferred. The temperature at which the poor solvent is added (heating conditions) 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) for crystal precipitation 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] (The R in the formula is equivalent to the one described above.)

[0049] The compound represented by general formula (2) or a salt thereof obtained in step 1 can be converted to the compound represented by general formula (1) (teneligliptin) or a salt thereof by appropriately known methods or combinations thereof. Specifically, the compound represented by general formula (2) or a salt thereof obtained in step 1 is subjected to a reductive amination reaction with a carboxylate salt of the compound represented by general formula (4), which is produced according to a known method (for example, see Example 2 of International Publication No. 2012 / 165547 (Patent Document 3)) or a similar method, thereby producing the compound represented by general formula (5) or a salt thereof (step 2). Subsequently, the protecting group R of the amino group of the compound represented by general formula (5) or a salt thereof is removed to produce the compound represented by general formula (1) (step 3). Furthermore, if desired, this can be converted into a salt (acid addition salt) by subjecting it to an acid salting treatment. Steps 2 to 4 are described below.

[0050] (Process 2)

[0051] For the reductive amination reaction of a compound represented by general formula (2) in the presence of a carboxylate salt of a compound represented by general formula (4), known methods can usually be used. Specifically, this can be carried out by reacting a carboxylate salt of a compound represented by general formula (4), a compound represented by general formula (2), and a reducing agent in a suitable solvent.

[0052] Examples of reducing agents include sodium borohydride, sodium triacetoxyborohydride, dimethylamine borane, triethylamine borane, trimethylamine borane, t-butylamine borane, N,N-diethylaniline borane, or 2-picolin borane, with sodium triacetoxyborohydride being preferred. The amount of reducing agent used is usually 1.0 to 2.0 moles, preferably 1.1 to 1.5 moles, per mole of the compound represented by general formula (2). The amount of carboxylate salt of the compound represented by general formula (4) used is usually 0.9 to 1.1 moles, preferably 1.0 mole, per mole of the compound represented by general formula (2).

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

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

[0055] (Step 3)

[0056] As a method for removing the protecting group R from the amino group of the compound represented by general formula (5) or its salt obtained in step 2, a known method suitable for the protecting group used may 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 it with an acid in a suitable solvent or without a solvent. Examples of acids include trifluoroacetic acid, hydrogen chloride, hydrogen bromide, or sulfuric acid, with hydrogen bromide being 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. Suitable reaction solvents include, for example, dichloromethane, chloroform, methanol, ethanol, 2-propanol, THF, 1,4-dioxane, acetonitrile, toluene, or water, or a mixture thereof. Preferably, a mixture of 2-propanol and water can be used.

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

[0060] When a protecting group R such as methoxycarbonyl, ethoxycarbonyl, or n-propoxycarbonyl is used, deprotection can be carried out by reacting it with a base in a suitable solvent or without a solvent. Examples of bases include lithium hydroxide, sodium hydroxide, or potassium hydroxide, with potassium hydroxide being 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. Suitable reaction solvents include, for example, methanol, ethanol, 2-propanol, THF, acetonitrile, or water, or a mixture thereof. Preferably, a mixture of methanol and water can be used.

[0062] The reaction temperature can usually be arbitrarily selected from 0 to 100°C, and the reaction time is typically around 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 a palladium hydroxide-carbon catalyst.

[0064] When 2,2,2-trichloroethoxycarbonyl is used as the protecting group R, deprotection can be performed by reacting it with zinc powder in a suitable solvent.

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

[0066] (Step 4)

[0067] The salt formation treatment of the compound represented by general formula (1) obtained in step 3 can be carried out by treating it with the corresponding acid according to commonly known methods. For example, it can be carried out by salt formation treatment of the compound represented by general formula (1) and an acid in a suitable solvent.

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

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

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

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

[0072] Compounds that can be suitably produced by the production method of the present invention include teneligliptin (i.e., {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine-1-yl]pyrrolidine-2-yl}(1,3-thiazolidined-3-yl)methanone) or a salt thereof.

[0073] More specifically, examples of such compounds include the 2,5-hydrobromide salt of {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine-1-yl]pyrrolidine-2-yl}(1,3-thiazolidined-3-yl)methanone. More specifically, examples include the 1-2 hydrates of the 2,5-hydrobromide salt of {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine-1-yl]pyrrolidine-2-yl}(1,3-thiazolidined-3-yl)methanone.

[0074] The specific features of the manufacturing method of the present invention are as follows: (A) Since pivaloyl chloride, a mixed acid anhydride forming agent with relatively low toxicity and low cost, is used as the amidation reagent, a safer and more economical manufacturing method can be provided compared to conventional methods. (B) By using DIPEA as the base, unlike when other organic bases (e.g., triethylamine) are used, the amount of poorly soluble salt precipitated is reduced and stirring efficiency is improved, so the amount of reaction solvent used can be reduced (i.e., the amount charged per lot can be increased). (C) The reaction proceeds in good yield simply by using equimolar amounts of the compound represented by general formula (3), which is the starting material substrate, without using excess amounts of thiazolidinedione, amidation reagent, and base. This suppresses the formation of related substances and eliminates the need for extra purification steps such as the removal of excess reagents, making experimental procedures and post-processing simpler. (D) The reaction conditions (reaction temperature: -10°C to 10°C) are also mild and can withstand scaling up (to several hundred kilograms), making it suitable as an industrial method for producing specific prolineamide compounds or their salts (i.e., compounds represented by general formula (2) or their salts), and teneligliptin or its salts using them.

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

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

[0077] As pharmaceutically acceptable additives, various organic or inorganic carrier substances commonly used as pharmaceutical ingredients are Examples include excipients, lubricants, binders, fluidizers, disintegrants, and solubilizers. Preferably, the excipients are excipients, binders, fluidizers, and disintegrants, and more preferably, 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, and sucrose fatty acid esters. Suitable examples of binders include hydroxypropyl cellulose, polyvinyl alcohol, povidone, hypromellose, carmellose sodium, and methylcellulose. Suitable examples of fluidizing agents include light anhydrous silicic acid, hydrated silicon dioxide, and talc. Suitable examples of disintegrants include low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, carmellose calcium, and crospovidone. Suitable examples of solubilizers include sodium benzoate, ethylenediamine, and potassium iodide.

[0079] A pharmaceutical composition containing a compound represented by general formula (1) or a salt thereof, manufactured by the manufacturing method of the present invention, is usually solid, and its shape is not particularly limited; it may be granular, solid, or in lump form.

[0080] In this specification, abbreviations, "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. [Examples]

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

[0082] Example 1 Preparation of 3-[(2S)-1-t-butoxycarbonyl-4-oxopyrrolidine-2-ylcarbonyl]thiazolidinate (compound 2a)

[0083] [ka]

[0084] (2S)-1-t-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid (compound 3a) (250.0 kg) and N,N-diisopropylethylamine (DIPEA) (141 kg) were dissolved in ethyl acetate (2242.5 kg). Pivaloyl chloride (131.5 kg) was added at a temperature below 10°C, and the reaction mixture was stirred at a temperature below 10°C for 30 minutes. Thiazolidine (97.2 kg) was added to this reaction mixture at a temperature below 10°C, and the reaction mixture was stirred at 0-10°C for 1 hour. Water (500.0 kg) was added to this reaction mixture and separated, and the ethyl acetate layer was sequentially washed with an aqueous solution of diammonium hydrogen phosphate (prepared from 144.0 kg of ammonium hydrogen phosphate and 750.0 kg of water) and saline solution (prepared from 75.0 kg of sodium chloride and 425.0 kg of water). The ethyl acetate layer was concentrated to a volume of 1250 L, then 2-propanol (976.3 kg) was added, and the mixture was concentrated again to a volume of 1000 L. Then 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 filtered and washed with n-heptane (684.0 kg). 2-propanol (429.6 kg) was added to the obtained crystals, 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 filtered and washed with n-heptane (769.8 kg), and then dried under reduced pressure to obtain 283.1 kg of 3-[(2S)-1-t-butoxycarbonyl-4-oxopyrrolidine-2-ylcarbonyl]thiazolidin (compound 2a). (Yield 86%) 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 1-2 hydrates (compound 1a) of 2,5 hydrobromide of {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine-1-yl]pyrrolidine-2-yl}(1,3-thiazolidined-3-yl)methanone

[0086] [ka]

[0087] (In the formula, Y represents 1 to 2)

[0088] To 3-methyl-1-phenyl-5-(1-piperazinyl)pyrazole acetate (compound 4a) (25.2 kg) and 3-[(2S)-1-t-butoxycarbonyl-4-oxopyrrolidine-2-ylcarbonyl]thiazolidinate (compound 2a) (25.0 kg), toluene (425 L) was added, and then sodium triacetoxyborohydride (23.0 kg) was added. Luene (75 L) slurry was added at 8°C, and the mixture was stirred at 20-28°C for 3 hours. Water (150 L) was added to this reaction mixture and the mixture was separated. The resulting toluene layer was washed with 5 wt% sodium bicarbonate solution (158 kg) and then water (150 L), concentrated under reduced pressure, and dried. 2-propanol (125 L) was added to the resulting residue, concentrated again under reduced pressure, and dried. 2-propanol (375 L) was added to this 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 filtered and washed with 2-propanol (50 L). The obtained crystals were dried with hot air for 18 hours (40-47°C) to obtain hydrobromide of {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine-1-yl]pyrrolidine-2-yl}(1,3-thiazolidined-3-yl)methanone (50.0 kg) as the crude product.

[0089] Ethanol (144 L) was added to the crude product (24.0 kg), and after heating and dissolving (73°C), the mixture was filtered while hot and washed with ethanol (24 L). The filtrate and washings were combined, water (3.4 L) was added at 67°C, and crystallization was carried out at 49-55°C for 2 hours, followed by 19-25°C for 1 hour. The precipitated crystals were collected by filtration and washed with ethanol (24 L). The obtained 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 1-2 hydrate of {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine-1-yl]pyrrolidine-2-yl}(1,3-thiazolidined-3-yl)methanone (compound 1a) as a purified product. (Yield 79%, calculated assuming the yield is a 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 1-14 Table 1 below shows the results of investigating the conversion reaction from (2S)-1-t-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid (compound 3a) and thiazolidinedine (1.1 mole relative to compound 3a) to 3-[(2S)-1-t-butoxycarbonyl-4-oxopyrrolidine-2-ylcarbonyl]thiazolidinedine (compound 2a) in the presence of various amidation reagents, various bases, or various additives.

[0091] [Table 1]

[0092] As a result, when SOCl2 and (CO)2Cl2 were used as the amidation reagent, compound 2a was not obtained at all (Comparative Examples 11 and 12). Furthermore, as shown in Table 1, no effect of the reaction solvent on the yield was observed (Comparative Examples 2 and 3). In addition, when pivaloyl chloride was used as the amidation reagent and other organic bases other than DIPEA were used, the amount of precipitated hydrochloride salts of poorly soluble organic bases (e.g., triethylamine hydrochloride (Comparative Example 5)) increased, making stirring difficult, the reaction unstable, and by-products more likely to be generated. Moreover, when DMAP, a highly reactive organic base, was used (Comparative Example 6), a large amount of by-products were generated, making it difficult to obtain compound 2a in high purity and high yield, and thus difficult to scale up.

[0093] From the results of Example 1 and Table 1 above, it was found that in the condensation reaction of compound 3a with thiazolidinedione, when DIPEA is used as the base and pivaloyl chloride is used as the amidating agent, compound 2a can be produced in high purity and high yield even when the amount of charge is increased to an industrial scale (several hundred kg scale). In contrast, all amidating agents other than pivaloyl chloride are far more expensive than pivaloyl chloride, and as mentioned above, even when pivaloyl chloride is used as the amidating agent, the purity and yield of the resulting compound 2a decrease when other bases are used. Therefore, it was found that the production methods of Comparative Examples 1 to 14 are all unsuitable as industrial production methods for compound 2a. [Industrial applicability]

[0094] According to the manufacturing method of the present invention, by using pivaloyl chloride, which has relatively low toxicity and is inexpensive, as the amidation reagent, and DIPEA as the base, the reaction proceeds in good yield by using equimolar amounts of each relative to the starting substrate (i.e., the compound represented by general formula (3)) without using excess amounts of substrate (thiazolidinedione), amidation reagent, and base, and can provide a prolineamide compound (i.e., the compound represented by general formula (2)) or its salt in high purity, which is useful as a synthetic intermediate for pharmaceuticals, etc. Furthermore, according to the manufacturing method of the present invention, the reaction conditions in the production process of the prolineamide compound are more relaxed compared to conventional methods, the post-processing is simpler, and it can withstand scale-up (hundreds of kilograms), thus providing an economical and safe industrial manufacturing method for teneligliptin or its salt, which exhibits DPP-IV inhibitory activity and is useful in the treatment or prevention of diabetes, etc.

[0095] Although several specific embodiments of the present invention have been described in detail above, those skilled in the art can make various modifications and changes to the specific embodiments shown, without substantially departing from the teachings and advantages of the present invention. Accordingly, all such modifications and changes are also included within the spirit and scope of the present invention as claimed in the claims.

Claims

[Claim 1] (4R)-1-(t-butoxycarbonyl)-4-hydroxy-L-proline is produced by reacting trans-4-hydroxy-L-proline with di-tert-butyl dicarbonate in the presence of sodium hydroxide, and then (4R)-1-(t-butoxycarbonyl)-4-hydroxy-L-proline is oxidized with (2,2,6,6-tetramethylpiperidine-1-yl)oxyl in the presence of trichloroisocyanuric acid to produce a product of general formula (3a): 【Chemistry 1】 A compound represented by or a salt thereof is produced, and then the compound represented by general formula (3a) or a salt thereof and thiazolidinedione are condensed using pivaloyl chloride in the presence of N,N-diisopropylethiamine to produce general formula (2a): 【Chemistry 2】 A compound represented by or a salt thereof is produced, and then a compound represented by general formula (2a) or a salt thereof is produced using general formula (4): 【Transformation 3】 The compound represented by general formula (5a) is subjected to a reductive amination reaction in the presence of a carboxylate salt of the compound represented by: 【Chemistry 4】 A method for producing a compound represented by or a salt thereof.

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