JP7279134B2 - Method for producing prolinamide compound - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel method for producing prolinamide compounds useful as synthetic intermediates for pharmaceuticals and the like. The present invention also provides 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.

It has been reported that teneligliptin or a salt thereof having 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).

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. The production method uses Nt-butoxycarbonyl-L-trans-4-hydroxyproline and thiazolidine in the presence of 1-hydroxybenzotriazole with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. and then oxidized with a pyridine sulfur trioxide complex in the presence of a base to obtain teneligliptin or a salt thereof via a proline amide compound produced. However, the yield of the proline amide compound is insufficient in this production method, and further improvement has been desired for use as an industrial production method.

As another method, (2S)-1-t-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid and thiazolidine are treated with n-propylphosphonic anhydride (cyclic trimer) in the presence of a base. A method has been reported for producing teneligliptin or a salt thereof via a prolinamide compound produced by condensing with (see Patent Document 3). This manufacturing method can also be used on an industrial scale. It is not necessarily suitable for mass production because it is expensive (4,200 yen/mol) and requires a certain response, such as an obligation to accept inspections (inspections) by inspectors.

As yet another method, (2S)-1-t-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid and thiazolidine are treated with N,N'-dicyclohexylcarbodiimide (DCC) in the presence of 4-dimethylaminopyridine. A method has been reported for producing teneligliptin or a salt thereof via a prolinamide compound produced by condensing with (see Example 3 of Patent Document 4). The production method requires stepwise fine adjustment in a short time at a low temperature (specifically, -5 ° C. to -10 ° C. (30 minutes), followed by -6 ° C. to -2 ° C. (15 to 20 minutes ), and then at 0 ° C. to 5 ° C. (60 minutes)), but 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 finely adjust the temperature. , DCC is toxic (skin inflammation) and expensive (825 Yen/mol (4000 Yen/kg)), so it cannot be said to be a method suitable for mass production.

WO2002/014271 WO2006/088129 WO2012/165547 WO2015/019238

An object of the present invention is to provide an inexpensive, safe and efficient production method suitable for industrial production of prolinamide compounds useful as intermediates for the synthesis of pharmaceuticals. 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 agent for diabetes, etc., using the production method.

As described above, in the industrial production of a proline amide compound, the amidation method used in the condensation step between the carboxy group of the proline derivative and the cyclic amino group of the thiazolidine, the reaction conditions (amount charged, reaction solvent, reaction temperature, reaction time etc.), there is a demand for a safe, low-cost, high-yield method by optimizing post-treatment methods and the like. However, none of the conventional methods are satisfactory as industrial production methods, and a vast 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., to identify the optimum combination that can withstand industrial production of a specific proline amide compound, usually with great technical difficulty. Accompanied by

As a result of intensive research, the present inventors have found that pivaloyl chloride, which is a mixed acid anhydride-forming agent with relatively low toxicity and is inexpensive, is used as an amidation reagent, and N,N-diisopropylethylamine (hereinafter referred to as It is also called "DIPEA".), without using excessive amounts of reagents and substrates, even in an industrial-scale reaction of several hundred kg, the target prolinamide compound can be produced at a low cost and in high yield. The inventors have found that the production rate is high and the reproducibility is good, and the present invention has been completed.
That is, the present invention
[1]:
General formula (3):

(Wherein, R represents an amino-protecting group.) A compound represented by or a salt thereof and thiazolidine are treated with pivaloyl chloride in the presence of N,N-diisopropylethylamine (DIPEA). General formula (2), characterized by condensing:

(wherein R is as defined above) or a method for producing a salt thereof,
[2]:
General formula (2) by the production method described in [1] above:

(wherein R is the same as in claim 1) or a salt thereof is produced, and the compound is converted to the general formula (4):

In the presence of a carboxylate of a compound represented by the general formula (5) by subjecting it to a reductive amination reaction:

General formula (1), comprising producing a compound represented by 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:

A method for producing a compound represented by or a salt thereof,
[3]:
General formula (1) by the production method described in [2] above:

A method for producing a salt of a compound represented by general formula (1), which comprises producing a compound represented by and then subjecting it to a salt-forming 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 [4] above, wherein R is t-butoxycarbonyl,
[6]:
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] The production method according to any one of the above [2] to [5], which is pyrrolidin-2-yl}(1,3-thiazolidin-3-yl)methanone 2.5 hydrobromide,
[7]:
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] The production method according to any one of the above [2] to [5], which is pyrrolidin-2-yl}(1,3-thiazolidin-3-yl)methanone 2.5 hydrobromide hydrate, as well as
[8]:
A medicament comprising mixing a compound represented by general formula (1) or a salt thereof produced by the production method according to any one of the above [2] to [7] and a pharmaceutically acceptable additive. A method for producing a composition.

According to the present invention, pivaloyl chloride (200 yen/mol), which is an inexpensive mixed acid anhydride-forming agent with relatively low toxicity, is used as the amidation reagent, and N,N-diisopropylethylamine (DIPEA) is used as the base. By using, a prolinamide compound or a salt thereof, which is useful as an intermediate for the synthesis of pharmaceuticals, etc., can be produced inexpensively, safely and simply at a high purity and in a high yield even on an industrial scale of several hundred kg. can do. Moreover, by using the prolinamide compound or its salt obtained by the production method of the present invention, teneligliptin or its salt, which is useful as a therapeutic drug for diabetes, can be produced industrially advantageously and efficiently.

(definition)

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

As the “carboxylic acid” forming the carboxylate of the compound represented by the general formula (4), an optionally substituted linear or branched chain having 1 to 7 carbon atoms (C _1-7 ) Carboxylic acids are mentioned. Specifically, for example, formic acid, alkylcarboxylic acids having 2 to 7 carbon atoms (C _2-7 ) (acetic acid, propionic acid, butyric acid, isobutyric acid, etc.), substitutions having 2 to 7 carbon atoms (C _2-7 ) and alkyl carboxylic acids (such as trifluoroacetic acid). Among these, alkylcarboxylic acids are preferred, and acetic acid is particularly preferred.

The compounds disclosed herein may have one or more asymmetric carbon atoms. In that case, 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 more than one structural feature giving rise to the above isomers. The compounds disclosed herein may also contain the above isomers in any ratio.

Diastereomeric mixtures can be separated into their respective diastereomers by conventional methods such as chromatography and crystallization. The respective diastereomers can also be made by using stereochemically uniform starting materials or by synthetic methods employing stereoselective reactions.

Separation of individual single enantiomers from a mixture of enantiomers can be accomplished by methods well known in the art.
For example, diastereomeric mixtures formed by reacting a mixture of enantiomers with compounds known as substantially pure enantiomers and chiral auxiliaries can be purified using standard methods such as fractional crystallization or chromatography. The method can separate enriched or substantially pure single diastereomers. The separated diastereomers can be converted to the desired enantiomers by removing the attached chiral auxiliary.

Mixtures of the compound's enantiomers can also be separated directly by chromatographic methods using chiral stationary phases, which are well known in the art.

Alternatively, either enantiomer of the compound may be synthesized by stereoselective synthesis (asymmetric induction).

The absolute configuration may be determined by X-ray crystallography of crystalline products or intermediates. In that case, if necessary, a crystalline product or intermediate derivatized with a reagent having an asymmetric center whose configuration is known may be used.

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

The raw material compounds are readily available as commercial products, or can be produced by the following production methods or methods known per se (e.g., 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 a method equivalent thereto.

The compounds used in the following reactions are inorganic acid salts (e.g., hydrochlorides, hydrobromides, sulfates, nitrates, phosphates), organic acid salts ( acetate, tartrate, citrate, fumarate, maleate, toluenesulfonate, methanesulfonate), metal salts (e.g. sodium, potassium, calcium, aluminum salts), or A salt with a base (eg, ethylamine salt, guanidine salt, ammonium salt, hydrazine salt, quinine salt, cinchonine salt) may be formed.

In addition, the compound obtained in each step below may be used in the next step without isolation from the reaction mixture or as a crude product. Alternatively, the compound may be isolated from the reaction mixture according to commonly known methods, and may be easily purified by conventional separation means such as recrystallization, distillation, chromatography and the like. Furthermore, the compound may be isolated as an inorganic acid salt, an organic acid salt, a metal salt, or a salt with a base according to generally known methods.

The compounds used in the present invention, the compounds obtained, or salts thereof include solvates or hydrates thereof.

(Step 1)

(R in the formula is as defined above.)

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

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

The reaction temperature can generally 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.

The post-treatment method for this reaction is not particularly limited. can be preferably used.
That is, water is added to the reaction mixture of the condensation reaction to stop the reaction, and after extraction with the reaction solvent, the organic layer is partially concentrated, a poor solvent is added thereto, and the mixture is stirred to crystallize. The compound represented by the general formula (2) or a salt thereof can be obtained by filtrating the crystals. If necessary, a small amount of a polar protic solvent may be added before the addition of the poor solvent, or the crystallization may be carried out under cooling. Such a post-treatment method can be applied even with an industrial-scale charge (several hundred kg scale), whereby the compound represented by the general formula (2) or a salt thereof can be obtained with high purity and high yield. can be obtained with
The polar protic solvent used in the post-treatment method includes, for example, alcohols such as methanol, ethanol, 2-propanol and butanol, preferably 2-propanol.
Examples of the poor solvent used in the post-treatment method include non-polar aprotic solvents such as n-hexane, n-heptane and toluene, preferably n-heptane.
The temperature (heating condition) at which the poor solvent is added may vary depending on the type of solvent used, but is usually 40°C to 80°C, preferably 40°C to 50°C.
The temperature (cooling condition) for precipitating crystals is usually 10° C. or lower, preferably 0° C. or lower, and more preferably -5° C. or lower.

(Step 2) to (Step 4)

(R in the formula is as defined above)

The compound represented by the general formula (2) obtained in the step 1 or a salt thereof is obtained by a method known per se or a combination thereof, to obtain the compound represented by the general formula (1) (teneligliptin) or a salt thereof. can be converted to
Specifically, the compound represented by the general formula (2) obtained in the step 1 or a salt thereof is prepared by a method known per se (for example, see Example 2 of International Publication No. 2012/165547 (Patent Document 3) ) or by subjecting the compound represented by the general formula (4) to a reductive amination reaction with a carboxylate of the compound represented by the general formula (4) produced according to a method equivalent thereto to produce the compound represented by the general formula (5) or a salt thereof (Step 2), and then removing the protecting group R for the amino group of the compound represented by the general formula (5) or a salt thereof to produce the compound represented by the general formula (1) (Step 3 ). Further, if desired, it can be converted to its salt (acid addition salt) by subjecting it to a salt forming treatment with an acid. (Step 2) to (Step 4) will be described below.

(Step 2)

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 general formula (4), the compound represented by general formula (2) and a reducing agent in a suitable solvent.

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, preferably includes sodium triacetoxyborohydride.
The amount of the reducing agent to be used is generally 1.0-2.0 mol, preferably 1.1-1.5 mol, per 1 mol of the compound represented by formula (2).
The amount of the carboxylic acid salt of the compound represented by the general formula (4) to be used is usually 0.9 to 1.1 mol, preferably 1.0 mol, per 1 mol of the compound represented by the general formula (2). Mole.

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 or dimethylformamide, or a mixed solvent thereof is used. preferably toluene can be used.

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.

(Step 3)

As a method for removing the amino-protecting group R of the compound represented by the general formula (5) obtained in step 2 or a salt thereof, a known method suitable for the protecting group used is appropriately used. sell.

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 solvent. Examples of the acid include trifluoroacetic acid, hydrogen chloride, hydrogen bromide, sulfuric acid, and the like, preferably hydrogen bromide. The concentration of the acid is 0.01-10 mol/L, preferably 0.1-4 mol/L, relative to the reaction mixture.

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 or water, or a mixed solvent thereof can be used, preferably 2- A mixed solvent of propanol and water can be used.

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.

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 a suitable solvent or without solvent. Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like, preferably potassium hydroxide. The concentration of the base is 0.1-100 mol/L, preferably 1-10 mol/L, relative to the reaction mixture.

This reaction is preferably carried out in a suitable reaction solvent. As the reaction solvent, for example, methanol, ethanol, 2-propanol, THF, acetonitrile, water, or a mixed solvent thereof can be used, preferably a mixed solvent of methanol and water.

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.

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

When 2,2,2-trichloroethoxycarbonyl is used as the protecting group R, it can be deprotected by reacting it with zinc powder in an appropriate solvent.

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

(Step 4)

Salt formation treatment with an acid of the compound represented by the general formula (1) obtained in the step 3 can be carried out by treating with a 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 an acid to a salt-forming treatment in a suitable solvent.

Examples of acids include inorganic acids such as hydrogen chloride, hydrogen bromide, and nitric acid, or p-toluenesulfonic acid, methanesulfonic acid, besylic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, and gallic acid. Alternatively, an organic acid such as camphorsulfonic acid may be mentioned, preferably hydrogen bromide. Specifically, with respect to 1 mol of the compound represented by the general formula (1), 1 to 10 mol, preferably 2 to 5 mol of acid is reacted to obtain the compound represented by the general formula (1). Salts of compounds can be prepared.

As the reaction solvent, for example, dichloromethane, chloroform, methanol, ethanol, 2-propanol, THF, acetonitrile, toluene or water, or a mixed solvent thereof can be used, preferably a mixed solvent of 2-propanol and water. can be used.

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.

In the case of producing a salt of the compound represented by the general formula (1) with an acid, an acid such as t-butoxycarbonyl as the amino-protecting group R of the compound represented by the general formula (5) or a salt thereof It is more preferable to use a protecting group that can be removed by using R because the removal reaction of the protecting group R and the subsequent salt formation treatment can be carried out at the same time.

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)piperazine- 1-yl]pyrrolidin-2-yl}(1,3-thiazolidin-3-yl)methanone), or salts thereof.

More specifically, such compounds include {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidine-2- yl}(1,3-thiazolidin-3-yl)methanone 2.5 hydrobromide. More particularly {(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- or dihydrates.

Specific features of the manufacturing 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 an amidation reagent, it is possible to provide a safer and more economical production method than conventional methods. can.
(B) By using DIPEA as a base, unlike the case of using other organic bases (e.g., triethylamine), the amount of sparingly soluble salts precipitated is reduced, and the stirring efficiency is improved. can be reduced (ie, the charge per lot can be increased).
(C) The reaction proceeds with good yield by using equimolar amounts of the compound represented by the general formula (3), which is the raw material substrate, without using excessive amounts of thiazolidine, amidation reagent, and base. Therefore, the production of analogues is suppressed, extra purification procedures such as removal of excess reagents are not required, and experimental procedures and post-treatments can be easily performed.
(D) The reaction conditions (reaction temperature: −10° C. to 10° C.) are moderate and can withstand scale-up (several hundred kg scale). 2) or a salt thereof) and a method for industrially producing teneligliptin or a salt thereof using the same.

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 production method of the present invention contains at least one pharmaceutically acceptable additive etc., and the like, as appropriate, by mixing an appropriate amount.

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 entire pharmaceutical composition. be.

Examples of pharmaceutically acceptable additives include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, lubricants, binders, fluidizers, disintegrants, solubilizers, and the like. mentioned. Excipients, binders, fluidizers and disintegrants are preferred, and excipients are more preferred.

Suitable examples of excipients include D-mannitol, sorbitol, xylitol, corn starch, potato starch, lactose, crystalline cellulose, calcium hydrogen phosphate and the like, preferably D-mannitol, xylitol and corn starch. be.
Suitable examples of lubricants include magnesium stearate, calcium stearate, talc, stearic acid, sucrose fatty acid esters, and the like.
Suitable examples of binders include hydroxypropylcellulose, polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methylcellulose and the like.
Preferable fluidizing agents include light anhydrous silicic acid, hydrous silicon dioxide, talc and the like.
Preferable examples of disintegrants include low-substituted hydroxypropylcellulose, carboxymethyl starch sodium, carmellose calcium, crospovidone and the like.
Suitable examples of solubilizing agents include sodium benzoate, ethylenediamine, potassium iodide and the like.

A 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 is granular, granular or It may be in any lump form.

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

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

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

(2S)-1-t-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid (compound 3a) (250.0 kg), N,N-diisopropylethylamine (DIPEA) (141 kg) in ethyl acetate (2242.5 kg) After pivaloyl chloride (131.5 kg) was added to the solution at below 10°C, the reaction mixture was stirred at below 10°C for 30 minutes. Thiazolidine (97.2 kg) was added to the reaction mixture at below 10°C, 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, and the ethyl acetate layer was separated from an aqueous diammonium hydrogen phosphate solution (prepared from 144.0 kg of ammonium hydrogen phosphate and water (750.0 kg)) and brine (salt (75.0 kg) and water (425.0 kg)). After concentrating the ethyl acetate layer to a residual amount of 1250 L, 2-propanol (976.3 kg) was added and concentrated again to a residual amount of 1000 L. Then, n-heptane (1368 kg) was added to 40 to 45°C. was added and the mixture was stirred below -5°C for 1 hour. Precipitated crystals were collected by filtration and washed with n-heptane (684.0 kg). After adding 2-propanol (429.6 kg) to the obtained crystals, 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 are collected by filtration, washed with n-heptane (769.8 kg), and dried under reduced pressure to give 3-[(2S)-1-t-butoxycarbonyl-4-oxopyrrolidin-2-ylcarbonyl. ] 283.1 kg of thiazolidine (compound 2a) was obtained. (Yield 86%)
¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 1.36, 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).

Example 2
{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl}(1,3-thiazolidine-3- yl)methanone 2.5 hydrobromide mono-dihydrate preparation (compound 1a)

(In the formula, Y represents 1 to 2)

Acetate salt of 3-methyl-1-phenyl-5-(1-piperazinyl)pyrazole (compound 4a) (25.2 kg), 3-[(2S)-1-t-butoxycarbonyl-4-oxopyrrolidine-2- Toluene (425 L) was added to ylcarbonyl]thiazolidine (compound 2a) (25.0 kg), and a slurry of sodium triacetoxyborohydride (23.0 kg) in toluene (75 L) was added at 8°C, followed by addition at 20 to 28°C. and stirred for 3 hours. Water (150 L) was added to the reaction mixture and the layers were separated. The obtained toluene layer was washed with 5w% aqueous sodium bicarbonate solution (158 kg) and water (150 L) in that order, concentrated under reduced pressure and dried to dryness. Hardened. 2-Propanol (375 L) was added to this residue, the temperature was raised, 48 w% hydrobromic acid (42.14 kg) was added dropwise at 75 to 77°C, and the mixture was refluxed for 2.5 hours. The reaction mixture is cooled, seed crystals prepared by sampling the reaction mixture are inoculated at 58° C., crystallized at 58° C. for 1 hour, then at 33 to 40° C. for 1 hour, and further at 17 to 25° C. for 1 hour, Let stand overnight. Precipitated crystals were collected by filtration and washed with 2-propanol (50 L). The obtained crystals are dried with warm air (40 to 47° C.) for 18 hours to give {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine-1 -yl]pyrrolidin-2-yl}(1,3-thiazolidin-3-yl)methanone hydrobromide (50.0 kg) was obtained as a crude product.

Ethanol (144 L) was added to the crude product (24.0 kg), dissolved by heating (73° C.), 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 the mixture was crystallized at 49-55°C for 2 hours and then at 19-25°C for 1 hour. 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 to give a purified product 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- or dihydrate 20.9 kg of (compound 1a) was obtained. (Yield 79%, yield calculated assuming dihydrate)
¹ H-NMR (400 MHz, C ₅ D ₅ N) δ 2.02-2.14 (1 H, m), 2.33 (3 H, m), 2.46-2.56 (4 H, 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 (0.6 H, d, J = 10.1 Hz), 4.80 (0.4 H, d, J = 8.8 Hz), 4.96 (0.4 H, d, J = 8.8 Hz). 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, 7.8 Hz), 8.07 (2H, d=8.8 Hz).

Comparative Examples 1-14
(2S)-1-t-butoxycarbonyl-4-oxopyrrolidine-2-carboxylic acid (compound 3a) and thiazolidine (1. 1 mol) to 3-[(2S)-1-t-butoxycarbonyl-4-oxopyrrolidin-2-ylcarbonyl]thiazolidine (compound 2a), and the results are shown in Table 1 below.

As a result, no compound 2a was obtained when SOCl ₂ and (CO) ₂ Cl ₂ were used as amidation reagents (Comparative Examples 11 and 12). Moreover, according to Table 1, the reaction solvent did not affect the yield (Comparative Examples 2 and 3). Furthermore, when pivaloyl chloride is used as an amidation reagent and organic bases other than DIPEA are used, precipitation of hydrochlorides of sparingly soluble organic bases (e.g., triethylamine hydrochloride (Comparative Example 5)) As the amount increases, stirring becomes difficult, the reaction becomes unstable, and by-products tend to occur. In addition, when DMAP, which is 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 scale-up was difficult. found to be difficult.

From the results of Example 1 and Table 1 above, in the condensation reaction of compound 3a and thiazolidine, in the presence of DIPEA as a base and using pivaloyl chloride as an amidation reagent, the amount of charge was reduced to an industrial scale. It was found that compound 2a can be produced with high purity and high yield even if the production is increased to (several hundred kg scale). In contrast, all amidation reagents other than pivaloyl chloride are much more expensive than pivaloyl chloride, and as described above, even when pivaloyl chloride is used as the amidation reagent, other When the base is used, the purity and yield of the obtained compound 2a are lowered, so it was found that none of the production methods of Comparative Examples 1 to 14 is suitable as an industrial production method of compound 2a.

According to the production method of the present invention, pivaloyl chloride, which has relatively low toxicity and is inexpensive, is used as an amidation reagent, and DIPEA is used as a base. Without using a base, the reaction proceeds in good yield only by using an equimolar amount of each relative to the raw material substrate (that is, the compound represented by the general formula (3)), and it is useful as an intermediate for the synthesis of pharmaceuticals. A prolinamide compound (that is, a compound represented by general formula (2)) or a salt thereof can be provided with high purity. In addition, according to the production method of the present invention, in the production process of the proline amide compound, the reaction conditions are relaxed compared to the conventional method, the post-treatment is simple, and it can withstand scale-up (several hundred kg scale). Therefore, it is possible to provide an economical and safe industrial production method for teneligliptin or a salt thereof that exhibits DPP-IV inhibitory activity and is useful in the treatment or prevention of diabetes and the like.

Although several specific aspects of the invention have been described in detail above, various modifications to the specific aspects presented to those skilled in the art may be made without departing substantially from the teachings and advantages of the invention. It is possible to make changes with Accordingly, all such modifications and variations are intended to be included within the spirit and scope of the invention as claimed.

Claims (1)

(4R)-1-(t-butoxycarbonyl)-4-hydroxy-L-proline with (2,2,6,6-tetramethylpiperidin-1-yl)oxyl in the presence of trichloroisocyanuric acid By oxidation, the general formula (3 a ):

to produce a compound represented by or a salt thereof , and then condense the compound represented by the general formula (3a) or a salt thereof with thiazolidine in the presence of N,N-diisopropylethylamine using pivaloyl chloride. General formula (2 a ), characterized in that

A method for producing a compound represented by or a salt thereof.