Process for producing a proline amide compound

Abstract

To provide an industrially advantageous method for producing a prolinamide compound that is useful as a pharmaceutical and the like.SOLUTION: A method for producing a compound of formula (1) or salt thereof includes a step of condensing a compound of formula (3) or a salt thereof with a thiazolidine in the presence of pivaloyl chloride and N,N-diisopropylethylamine to produce a compound represented by formula (2).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) useful as a therapeutic agent for diabetes or 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 production method of teneligliptin or a salt thereof and a production method of 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 use as an industrial production method.

[0004] Also, as another method, a method for producing teneligliptin or a salt thereof via a proline amide compound produced by condensing (2S)-1-t-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid and thiazolidine using n-propylphosphonic anhydride (cyclic trimer) in the presence of a base has been reported (see Patent Document 3). Although this production method is a method that can be used on an industrial scale, n-propylphosphonic anhydride (cyclic trimer) is a designated substance under the Chemical Weapons Prohibition Law, and certain measures such as the obligation to notify and the obligation to accept inspections by inspectors of international organizations are required. Moreover, since it is expensive (4,200 yen / mol), it cannot necessarily be said to be a method suitable for mass production.

[0005] Furthermore, as yet another method, a method for producing teneligliptin or a salt thereof via a proline amide 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 stepwise fine adjustment in a short time and is carried out at low temperatures (specifically, -5°C to -10°C for 30 minutes, then -6°C to -2°C for 15 to 20 minutes, and then 0°C to 5°C for 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 or to finely adjust the temperature. Also, DCC has toxicity (skin inflammation) and is expensive (825 yen / mol (4000 yen / kg)), so it cannot be said to be a method suitable for mass production.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Patent Document 3

[0007] An object of the present invention is to provide an inexpensive, safe and efficient production method suitable for the industrial production of a proline amide compound useful as a pharmaceutical synthetic intermediate or the like. Another object is to provide an industrially advantageous production method of teneligliptin or a salt thereof useful as a therapeutic agent for diabetes using the said production method. [Means for Solving the Problems]

[0008] As described above, in the industrial production of a proline amide compound, by optimizing the amidation method, reaction conditions (charge amount, reaction solvent, reaction temperature, reaction time, etc.), post-treatment method, etc. used in the condensation step of the carboxy group of the proline derivative and the cyclic amino group of thiazolidine, a safe, low-cost and high-yield method is required. However, none of the conventional methods are satisfactory as industrial production methods, and it is usually extremely difficult technically to identify an optimal combination that can withstand the industrial production of a specific proline amide compound from among the combinations of options such as a huge number of amidation methods (amidation reagents (e.g., acid chlorides, condensing agents, mixed acid anhydride forming agents, etc.), bases, additives, etc.), reaction conditions, post-treatment methods, etc.

[0009] As a result of intensive studies, 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 proline amide compound can be suitably produced at low cost and in high yield with good reproducibility even in an industrial-scale reaction on the order of several hundred kg without using an excessive amount of reagents or substrates, and thus completed the present invention. That is, the present invention provides [1]: General formula (3):

[0010] [Chemical formula]

[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] [Chemical formula]

[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]: According to the production method described in [1], a compound represented by general formula (2):

[0014] [Chemical formula]

[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] [Chemical formula]

[0017] to obtain a compound represented by general formula (5):

[0018] [Chemical formula]

[0019] A method for producing a compound represented by the formula or a salt thereof, and then removing the protecting group R of the amino group of the compound represented by the general formula (5) or a salt thereof, the general formula (1):

[0020] [Chemical formula]

[0021] A method for producing a compound represented by the formula or a salt thereof, [3]: A method for producing a salt of a compound represented by the general formula (1), which comprises producing a compound represented by the general formula (1):

[0022] [Chemical formula]

[0023] by the production method according to [2] above, and then subjecting it to a salt formation treatment with an acid. [4]: The production method according to any one of [1] to [3] above, wherein R is a substituted or unsubstituted alkoxycarbonyl. [5]: The production method according to [4] above, wherein R is t-butoxycarbonyl. [6]: The production method according to any one of [2] to [5] above, wherein the compound represented by the general formula (1) or a salt thereof is the 2.5 hydrobromide 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. [7]: The production method according to any one of [2] to [5] above, wherein the compound represented by the general formula (1) or a salt thereof is the 2.5 hydrobromide monohydrate 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, and [8]: A method for producing a pharmaceutical composition, which comprises mixing a compound represented by the general formula (1) or a salt thereof produced by the production method according to any one of [2] to [7] above with a pharmaceutically acceptable additive.

Advantages of the Invention

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

Embodiments for Carrying Out the Invention

[0025] (Definition)

[0026] In the present invention, the "protecting group for an amino group" represents a substituent that replaces a hydrogen atom for protecting an amino group from its high reactivity, which is generally used in the technical field of organic chemistry. . Representative "protecting groups for an amino group" include, for example, those described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter G. M. Wuts, ed.) published by Wiley-Interscience in 2007. The protecting group for the amino group represented by R is anti- Any protecting group that does not interfere with the reaction may be used. Examples of protecting groups for such amino groups include alkoxycarbonyl groups (methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, t-butoxycarbonyl, etc.) and substituted alkoxycarbonyl groups (benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 9-fluorenylmethoxycarbonyl, etc.). Among these, an alkoxycarbonyl group is preferred as R, and t-butoxycarbonyl is particularly preferred.

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

[0028] The compounds disclosed in this specification may have one or more asymmetric carbons. In that case, the compounds disclosed in this specification may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers or a mixture of diastereomers. The compounds disclosed in this specification may simultaneously contain a plurality of structural features that give rise to the above isomers. Also, the compounds disclosed in this specification may contain the above isomers in any ratio.

[0029] A mixture of diastereomers can be separated into each diastereomer by conventional methods such as chromatography and crystallization. Also, each diastereomer can be prepared by using a stereochemically single starting material or by a synthetic method using a stereoselective reaction.

[0030] Separation of each single enantiomer from a mixture of enantiomers can be carried out by methods well known in the art. For example, from a mixture of enantiomers and a mixture of diastereomers formed by reacting with a compound known as a chiral auxiliary, which is a substantially pure enantiomer, by standard methods such as fractional crystallization or chromatography, an isomer ratio can be increased or a substantially pure single diastereomer can be separated. The separated diastereomer can be converted to the desired enantiomer by removing the added chiral auxiliary.

[0031] Also, a mixture of enantiomers of a compound can be directly separated by a chromatography method using a chiral stationary phase, which is well known in the art.

[0032] Alternatively, either enantiomer of a compound can also be obtained by using a substantially pure optically active starting material or by performing stereoselective synthesis (asymmetric induction) using a chiral auxiliary or an asymmetric catalyst on a prochiral intermediate.

[0033] The absolute configuration can be determined by X-ray crystal analysis of a crystalline product or intermediate. In that case, a crystalline product or intermediate derivatized with a reagent having an asymmetric center of known configuration may be used if necessary.

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

[0035] The starting compound can be easily obtained as a commercial product, or can be produced by the production methods shown below or methods known per se (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 can be produced according to methods analogous 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) as long as they do not interfere with the reactions.

[0037] Also, the compounds obtained in the following steps may be used in the next step without isolation from the reaction mixture or as a crude product. Alternatively, the compounds may be isolated from the reaction mixture according to commonly known methods and may be easily purified by ordinary separation means such as recrystallization, distillation, chromatography, etc. Further, the compounds may be isolated as salts with inorganic acids, organic acids, metal salts, or bases according to commonly known methods.

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

[0039] (Step 1)

[0040] [Chemical formula]

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

[0042] This step involves producing the compound represented by the general formula (2) or a salt thereof through a condensation reaction (amidation reaction) via a mixed acid anhydride using pivaloyl chloride in the presence of N,N-diisopropylethylamine (DIPEA), with a compound represented by the general formula (3) or a salt thereof and thiazolidine, according to a method known per se (e.g., International Publication No. 2002 / 014271 (Patent Document 1), International Publication No. 2015 / 019238 (Patent Document 4), etc.) or a method analogous thereto. 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 moles, preferably 1.0 mole, per mole of the compound represented by the general formula (3). The amount of pivaloyl chloride used is usually 1.0 to 1.2 moles, preferably 1.0 mole, per mole of the compound represented by the 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 the general formula (3).

[0043] This reaction is preferably carried out in a solvent that does not affect the reaction. Examples of the reaction solvent 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 mixed solvents thereof. Preferably, ethyl acetate can be used.

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

[0045] The post-treatment method of this reaction is not particularly limited. However, in the industrial production method (bulk synthesis) of the compound represented by the general formula (2) or a salt thereof, for example, the following post-treatment method by crystallization can be preferably used. That is, water is added to the reaction mixture of the condensation reaction to stop the reaction. After extraction with a reaction solvent, a part of the organic layer is concentrated, an antisolvent is added thereto, and the mixture is stirred to cause crystallization, and the crystals are collected by filtration to obtain the compound represented by the general formula (2) or a salt thereof. Further, if necessary, a small amount of a polar protic solvent may be added before adding the antisolvent, or the crystallization may be carried out under cooling. Such a post-treatment method is applicable even for an industrial-scale charge amount (several hundreds kg scale), and thereby the compound represented by the general formula (2) or a salt thereof can be obtained in high purity and high yield. Examples of the polar protic solvent used in the above post-treatment method include alcohols such as methanol, ethanol, 2-propanol, and butanol, and 2-propanol is preferred. Examples of the antisolvent used in the above post-treatment method include nonpolar aprotic solvents such as n-hexane, n-heptane, and toluene, and n-heptane is preferred. The temperature (heating condition) when adding the antisolvent may vary depending on the type of the solvent used, but is usually 40°C to 80°C, preferably 40°C to 50°C. The temperature (cooling condition) when precipitating the crystals is usually 10°C or lower, preferably 0°C or lower, and more preferably -5°C or lower.

[0046] (Steps 2) to (4)

[0047] [Chemical formula]

[0048] (R in the formula has the same meaning as described above)

[0049] The compound represented by the general formula (2) or a salt thereof obtained in the above Step 1 can be converted into the compound (teneligliptin) represented by the general formula (1) or a salt thereof by appropriately using a method known per se or a combination thereof. Specifically, the compound represented by the general formula (2) obtained in the above step 1 or a salt thereof is subjected to a reductive amination reaction with a carboxylate of a compound represented by the general formula (4) produced by a method known per se (for example, refer to Example 2 of International Publication No. 2012 / 165547 (Patent Document 3)) or a method analogous thereto, to produce a compound represented by the general formula (5) or a salt thereof (step 2). Subsequently, the protecting group R of the amino group of the compound represented by the general formula (5) or a salt thereof is removed to produce a compound represented by the general formula (1) (step 3). Further, if desired, this can be converted to its salt (acid addition salt) by subjecting it to a salt formation treatment with an acid. Hereinafter, (step 2) to (step 4) will be described.

[0050] (Step 2)

[0051] As the reductive amination reaction of the compound represented by the general formula (2) in the presence of the carboxylate of the compound represented by the general formula (4), generally known methods can be used. Specifically, it can be carried out by reacting the carboxylate of the compound represented by the general formula (4), the compound represented by the 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, or 2-picoline borane, and preferably sodium triacetoxyborohydride. The amount of the reducing agent used is generally 1.0 to 2.0 moles, preferably 1.1 to 1.5 moles, per mole of the compound represented by the general formula (2). The amount of the carboxylate of the compound represented by the general formula (4) used is generally 0.9 to 1.1 moles, preferably 1.0 mole, per mole of the compound represented by the general 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. Preferably, toluene can be used.

[0054] The reaction temperature can usually be arbitrarily selected 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 the general formula (5) or a salt thereof obtained in the above step 2, a known method suitable according to the protecting group used can be appropriately used.

[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, sulfuric acid, etc. Preferably, hydrogen bromide is mentioned. The concentration of the acid is 0.01 to 10 mol / L, preferably 0.1 to 4 mol / L, based on the reaction mixture.

[0058] This reaction is preferably carried out in a suitable reaction solvent. As the reaction solvent, for example, dichloromethane, chloroform, methanol, ethanol, 2-propanol, THF, 1,4-dioxane, acetonitrile, toluene, water, or a mixed solvent thereof can be used. Preferably, a mixed solvent 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 usually about 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 with a base in a suitable solvent or without a solvent. Examples of the base include lithium hydroxide, sodium hydroxide or potassium hydroxide, and preferably potassium hydroxide. The concentration of the base is 0.1 to 100 mol / L, preferably 1 to 10 mol / L, based on the reaction mixture.

[0061] This reaction is preferably carried out in a suitable reaction solvent. As the reaction solvent, for example, methanol, ethanol, 2-propanol, THF, acetonitrile or water, or a mixed solvent thereof can be used, and preferably a mixed solvent 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 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 a 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 a suitable 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 a suitable solvent or without a solvent.

[0066] (Step 4)

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

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

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

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

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

[0072] Compounds preferably produced by the production method of the present invention include teneligliptin (that 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), or a salt thereof.

[0073] As such a compound, more specifically, for example, the 2.5 hydrobromide 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 can be mentioned. Even more specifically, the 1-2 hydrates of the 2.5 hydrobromide 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 can be mentioned.

[0074] As specific features of the production method of the present invention, the following can be mentioned. (A) Since pivaloyl chloride, which is a mixed acid anhydride-forming agent with relatively low toxicity and low cost as an amidation reagent, is used, a safe and economical production method can be provided as compared with the conventional method. (B) By using DIPEA as a base, unlike the case of using other organic bases (e.g., triethylamine), the precipitation amount of poorly soluble salts is reduced, and the stirring efficiency is improved, so the amount of reaction solvent used can be reduced (that is, the charging amount per lot can be increased). (C) For the compound represented by the general formula (3) which is a raw material substrate, the reaction proceeds with good yield just by using equimolar amounts without using an excessive amount of thiazolidine, amidation reagent, and base. Therefore, the generation of analogous substances is suppressed, and unnecessary purification operations such as removal of excessive reagents are not required, and the experimental operation and post-treatment can also be easily performed. (D) The reaction conditions (reaction temperature: -10°C to 10°C) are also mild and can withstand scale-up (hundreds of kg scale). Therefore, it is suitable as an industrial production method of a specific proline amide compound or a salt thereof (that is, the compound represented by the general formula (2) or a salt thereof), and teneligliptin or a salt thereof using the same.

[0075] A pharmaceutical composition containing a compound represented by the 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 an appropriate amount with at least one or more pharmaceutically acceptable additives, etc.

[0076] The content of the compound represented by the 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 whole pharmaceutical composition.

[0077] Examples of pharmaceutically acceptable additives include various organic or inorganic carrier substances commonly used as formulation materials. Examples include excipients, lubricants, binders, fluidizing agents, disintegrants, solubilizing agents, etc. Preferably, they are excipients, binders, fluidizing agents, and disintegrants, and more preferably excipients.

[0078] Preferable examples of excipients include D-mannitol, sorbitol, xylitol, corn starch, potato starch, lactose, crystalline cellulose, calcium hydrogen phosphate, etc. Preferably, they are D-mannitol, xylitol, and corn starch. Preferable examples of lubricants include magnesium stearate, calcium stearate, talc, stearic acid, sucrose fatty acid ester, etc. Preferable examples of binders include hydroxypropyl cellulose, polyvinyl alcohol, povidone, hypromellose, sodium carboxymethyl cellulose, methyl cellulose, etc. Preferable examples of fluidizing agents include light anhydrous silicic acid, hydrated silicon dioxide, talc, etc. Preferable examples of disintegrants include low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, calcium carboxymethyl cellulose, crospovidone, etc. Preferable examples of solubilizing agents include sodium benzoate, ethylenediamine, potassium iodide, etc.

[0079] The pharmaceutical composition containing the compound represented by the 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 granular, granulous or massive.

[0080] In this specification, as for 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, respectively.

Example

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

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

[0083]

Chemical formula

[0084] (2S)-1-tert-Butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid (Compound 3a) (250.0 kg), N,N-diisopropylethylamine (DIPEA) (141 kg) in ethyl acetate (2242.5 kg) solution, pivaloyl chloride (131.5 kg) was added at 10 °C or lower, and then the reaction mixture was stirred at 10 °C or lower for 30 minutes. Thiazolidine (97.2 kg) was added to this reaction mixture at 10 °C or lower, and then 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 washed successively 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, the remaining amount was adjusted to 1250 L, then 2-propanol (976.3 kg) was added and then concentrated again, the remaining amount was adjusted to 1000 L, then n-heptane (1368 kg) was added at 40 - 45 °C, and the mixture was stirred at -5 °C or lower 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, then n-heptane (1521.9 kg) was added at 40 - 45 °C, and the mixture was stirred at -5 °C or lower for 1 hour. The precipitated crystals were collected by filtration, washed with n-heptane (769.8 kg), and then dried under reduced pressure to obtain 283.1 kg of 3-[(2S)-1-tert-butoxycarbonyl-4-oxopyrrolidin-2-ylcarbonyl]thiazolidine (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 of 2.5 hydrobromide 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 (Compound 1a)

[0086] [ka]

[0087] (In the formula, Y represents 1 to 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. After adding toluene (75 L) slurry at 8°C, 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 obtained toluene layer was washed with 5w% sodium bicarbonate water (158 kg) and water (150 L) in that order, then concentrated under reduced pressure and dried. 2-propanol (125 L) was added to the obtained residue, and the mixture was concentrated under reduced pressure and dried again. 2-propanol (375 L) was added to this residue, the temperature was raised, 48w% hydrobromic acid (42.14 kg) was added dropwise at 75-77°C, and the mixture was refluxed for 2.5 hours. The reaction mixture was cooled, and seed crystals prepared by sampling the reaction mixture were inoculated at 58°C, followed by crystallization at 58°C for 1 hour, then at 33-40°C for 1 hour, and then at 17-25°C for 1 hour, and the mixture was left to stand overnight. The precipitated crystals were collected by filtration and washed with 2-propanol (50 L). The obtained crystals were dried with hot air (40 to 47°C) for 18 hours to obtain {(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] To the crude product (24.0 kg), ethanol (144 L) was added. After heating and dissolving at 73 °C, filtration was carried out while hot, and it was washed with ethanol (24 L). The filtrate and the washing solution were combined, water (3.4 L) was added at 67 °C, and then crystallization was carried out 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 obtained crystals were dried under reduced pressure at 45 °C for 19 hours and then dried with warm air at 50 °C for 18 hours, whereby 20.9 kg of the 1 - 2 hydrate of the hydrobromide of {(2S,4S)-4-[4-(3 - methyl - 1 - phenyl - 1H - pyrazol - 5 - yl)piperazin - 1 - yl]pyrrolidin - 2 - yl}(1,3 - thiazolidin - 3 - yl)methane (Compound 1a) was obtained. (Yield 79%, the yield was calculated assuming it was the 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 In the presence of various amidation reagents and various bases or various additives, the results of examining the conversion reaction from (2S)-1-tert-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid (Compound 3a) to 3-[(2S)-1-tert-butoxycarbonyl-4-oxopyrrolidin-2-ylcarbonyl]thiazolidine (Compound 2a) with thiazolidine (1.1 mol relative to Compound 3a) are shown in Table 1 below.

[0091]

Table 1

[0092] As a result, when SOCl2 and (CO)2Cl2 were used as the amidation reagents, Compound 2a was not obtained at all (Comparative Examples 11 and 12). Further, according to Table 1, no influence of the reaction solvent on the yield was observed (Comparative Examples 2 and 3). Furthermore, when using pivaloyl chloride as the amidation reagent and using other organic bases other than DIPEA, the precipitation amount of the hydrochloride salt of the poorly soluble organic base (e.g., triethylamine hydrochloride (Comparative Example 5)) increases, making stirring difficult, the reaction unstable, and by-products likely to occur. Also, when using DMAP, a highly reactive organic base (Comparative Example 6), a large amount of by-products were generated, so it was found that it is difficult to obtain Compound 2a with high purity and high yield, and it is difficult to scale up.

[0093] From Example 1 and the results in Table 1 above, in the condensation reaction of Compound 3a and thiazolidine, when using pivaloyl chloride as the amidation reagent in the presence of DIPEA as the base, it was found that Compound 2a can be produced with high purity and high yield even when increasing the charged amount up to an industrial scale (hundreds of kg scale). In contrast, amidation reagents other than pivaloyl chloride are all much more expensive than pivaloyl chloride. Also, as described above, even when using pivaloyl chloride as the amidation reagent, when using other bases, the purity and yield of the obtained Compound 2a decrease. Therefore, it was found that none of the production methods in Comparative Examples 1 to 14 are suitable as an industrial production method for Compound 2a.

Industrial Applicability

[0094] According to the production method of the present invention, by using pivaloyl chloride, which has relatively low toxicity and is inexpensive, as an amidation reagent, and DIPEA as a base, without using an excessive amount of substrate (thiazolidine), amidation reagent, and base, the reaction proceeds with good yield simply by using an equimolar amount of each with respect to the raw material substrate (i.e., the compound represented by the general formula (3)), and a proline amide compound (i.e., the compound represented by the general formula (2)) or a salt thereof, which is useful as a pharmaceutical synthesis intermediate or the like, can be provided with high purity. Further, according to the production method of the present invention, in the production process of the proline amide compound, the reaction conditions are milder and the post-treatment is simpler compared to the conventional method, and it can withstand scale-up (hundreds of kg scale). Therefore, an industrially advantageous production method with excellent economy and safety for teneligliptin or a salt thereof, which exhibits DPP-IV inhibitory activity and is useful in the treatment or prevention of diabetes and the like, can be provided.

[0095] As described above, some specific embodiments of the present invention have been described in detail. However, 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. Therefore, all such modifications and changes are also included within the spirit and scope of the present invention claimed in the claims.

Claims

[Claim 1] (4R)-1-(t-butoxycarbonyl)-4-hydroxy-L-proline is oxidized with (2,2,6,6-tetramethylpiperidin-1-yl)oxyl in the presence of trichloroisocyanuric acid to obtain a compound represented by the general formula (3a): 【Chemistry 1】 or a salt thereof, and then, a compound represented by general formula (3a) or a salt thereof and thiazolidine are condensed using pivaloyl chloride in the presence of N,N-diisopropylethylamine to obtain a compound represented by general formula (2a): 【Chemistry 2】 or a salt thereof, and then reacting a compound represented by general formula (2a) or a salt thereof with a compound represented by general formula (4): 【Chemistry 3】 In the presence of a carboxylate of a compound represented by the general formula (5a): 【Chemistry 4】 or a salt thereof, and then reacting a compound represented by general formula (5a) or a salt thereof with an acid, 【Chemistry 5】 A method for producing a compound represented by the formula:

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