KR20130046213A - Improved process for preparing mitiglinide calcium salt - Google Patents

Abstract

PURPOSE: An improved method for preparing a mitiglinide calcium salt is provided to easily isolate and purify a core intermediate and to improve purity and yield of a final target material. CONSTITUTION: A method for preparing a mitiglinide calcium salt comprises: a step of introducing an imidazole group at C1 and C4 sites of 2-benzilsuccinic acid of chemical formula 11 and preparing 2-benzyl-1,4-di(1H-imidazole-1-yl)butane-1,4-dione of chemical formula 17; a step of reacting the compound of chemical formula 17 with cis-octahydro isoindole chloride to prepare 2-benzyl-1-imidazole-4-(octahydro-isoindole-2-yl)-butane-1,4-dione of chemical formula 19 as an intermediate compound; a step of reacting the compound of chemical formula 19 with a basic compound to prepare a mitiglinide alkali metal salt or amine salt of chemical formula 20; and a step of converting into a calcium salt. The steps are continuously performed without isolation and purification.

Description

Improved process for preparing Mitiglinide calcium salt

The present invention relates to an improved method for preparing mitiglinide calcium salt, and more particularly, 2-benzyl-1-imidazole-4- (octahydro-isoindole-) using 2-benzyl succinic acid as starting material. The synthesis of 2-yl) -butane-1,4-dione as a novel intermediate and the conversion of it to calcium salts in the presence of a base are carried out. The present invention relates to a method for efficiently preparing a calcium salt.

Mitiglinide (Mitiglinide) can be represented by the following formula (1), it is well known that a therapeutic drug for insulin-dependent diabetes mellitus (NIDDM) has a significant therapeutic effect in improving the postprandial blood sugar trend.

[Formula 1]

As a general method for preparing Mitiglinide, a method according to Scheme 1 is disclosed in US Patent Nos. 202,335 and 6,133,454.

[Reaction Scheme 1]

(In Reaction Scheme 1, R represents a hydrogen atom, an alkyl group, or an aryl group.)

Hereinafter, a method for preparing mitiglinide according to Scheme 1 will be described in detail. First, using a dialkyl succinate represented by the formula (2) as a starting material to react with benzaldehyde, cyclization reaction using acetic anhydride, and then alkylated with a cis-octahydroisoindole compound, A phenylacrylic acid represented by Formula 6 was prepared. The phenylacrylic acid thus prepared was reacted with a chiral derivative represented by Chemical Formula 7 to prepare a compound represented by Chemical Formula 8 having (S) -optical activity. Alternatively, the phenylacrylic acid represented by Chemical Formula 6 is reduced with a double bond using hydrogen and a palladium (Pd) catalyst to prepare a compound represented by Chemical Formula 9, and then reacted with a chiral derivative represented by Chemical Formula 7 ( The compound represented by Chemical Formula 10 having S) -optical activity was prepared. The compound represented by Formula 8 or 10 prepared as described above was reacted with calcium chloride (CaCl ₂ ) to prepare mitiglinide calcium salt.

However, the conventional manufacturing method according to the reaction formula 1, ① the manufacturing process is too long, the economy is insufficient, ② has the disadvantage of repeatedly using the expensive chiral derivative represented by the formula (7), ③ to synthesize the intermediate compound hydrogen gas Since the used hydrogenation reaction is carried out, there is a limit to apply industrially, such as the risk of fire.

The manufacturing method of Scheme 2 below has been developed as a method for producing mitiglinide, which is an improvement of the manufacturing method.

[Reaction Scheme 2]

(In Scheme 2, R represents an alkyl group.)

 In the preparation method according to Scheme 2, 2-benzyl succinic acid is used as a starting material, followed by esterification with an alkyl halide, and then sequentially treated with a chloroating agent, imidazole, and cis-octahydroisoindole. After synthesizing the 1-alkyl-2-benzyl-4- (octahydroisoindol-2-yl) succinate represented by the intermediate compound, it was converted to a calcium salt to prepare a mitiglinide calcium salt.

 However, the preparation method according to Scheme 2 also synthesizes the compound represented by Chemical Formula 12 as an intermediate by selectively monoalkylating the compound represented by Chemical Formula 11, so that the alkylation reaction is difficult to be selectively carried out in positionally. Undesired stereoisomers, represented by -1, are essentially produced. The stereoisomer represented by Chemical Formula 12-1 produced as a by-product has a critical disadvantage that it is difficult to remove.

As another method for preparing mitiglinide, a process according to Scheme 3 is disclosed in European Patent Publication No. 967,204.

Scheme 3

In the preparation method according to Scheme 3, after 1,2-dibenzyl-4- (octahydroisoindol-2-yl) succinate represented by Chemical Formula 15 is synthesized as an intermediate compound, it is converted to calcium salt and converted to mitigli Nade calcium salt was prepared.

 However, the preparation method according to Scheme 3 also has the disadvantage that ① the isomer represented by Formula 14-1 is produced as a by-product, as in Scheme 2, and ② a halide reagent such as benzyl bromide to introduce a benzyl group to the C1 position of succinic acid. Since benzyl bromide is the most acute substance that irritates eyes and skin, it can pose a significant risk to workers when used in industrial use in large quantities. ③ DCC coupling agent is used in alkylation reaction to introduce benzyl group to C1 position of succinic acid. The method used is a burden on the final cost of mitiglinide due to the high price of the DCC coupling agent, and ④ has the disadvantage that it is not easy to remove the isourea compound produced as a by-product of the use of DCC during the reaction.

As described above, it has been pointed out that the manufacturing method of mitiglinide or calcium salt thereof known to date is limited in industrial use due to the long manufacturing process and the use of reagents which are not suitable for industrial use.

The present invention is to provide an improved manufacturing method which is composed of a manufacturing process suitable for industrial use, and can be produced mitiglinide calcium salt represented by the formula (1) in high yield and high purity without the production of impurities The purpose is.

In order to solve the above problems, the present invention as shown in Scheme 4 below

By introducing an imidazole group at the C1 and C4 positions from 2-benzylsuccinic acid represented by the following formula (11), 2-benzyl-1,4-di (1H-imidazol-1-yl) represented by the following formula (17) A first step of preparing butane-1,4-dione;

The compound represented by the following formula (17) and cis-octahydroisoindole hydrochloride are reacted to form 2-benzyl-1-imidazol-4- (octahydro-isoindol-2-yl) -butane- represented by the following formula (19). A second step of preparing 1,4-dione as an intermediate compound; And

By reacting an intermediate compound represented by the formula (19) with a basic compound to prepare a mitiglinide alkali metal salt or an amine salt represented by the following formula (20), the conversion to calcium salts to perform a mitigli represented by the formula (1) A third step of preparing nit calcium salt;

Characterized in that the method for producing mitiglinide calcium salt comprising a.

[Reaction Scheme 4]

(In Reaction Formula 4, A represents an alkali metal (M), or NR ¹ R ² R ³ , R ¹ , R ² , and R ³ are each a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, Or may be combined with a substituent adjacent to each other to form a pentagonal to pentagonal heteroaliphatic ring or heteroaromatic ring containing 1 to 3 nitrogen atoms.)

The production method according to the present invention has the effect of simplifying the process and process improvement, such as being able to proceed to one-pot reation.

In addition, the core intermediate produced in the manufacturing process of the present invention is easy to separate and purify, there is an effect of improving the purity and yield of the final target.

In addition, the reaction reagent used in the production method of the present invention is relatively inconvenient to generate no toxic gas or handling, and the overall manufacturing process is environmentally friendly such that the reaction is completed within a short time under mild reaction conditions.

Therefore, the production method of the present invention is useful as a mass production method of mytiglinide calcium salt.

The preparation method of the present invention relates to a method for preparing the desired mitiglinide calcium salt in high purity and high yield using 2-benzylsuccinic acid represented by Chemical Formula 11 as a starting material. According to the preparation method of the present invention, even if a series of preparation processes are performed in one reactor without separating and purifying intermediate compounds, the desired mitiglinide calcium salt can be prepared in high purity and high yield.

The method for preparing mitiglinide calcium salt according to the present invention will be described in more detail by subdividing according to the preparation process as follows.

The first step is to introduce an imidazole group in the C1 and C4 positions of the 2-benzyl succinic acid represented by the formula (11), 2-benzyl-1,4-di (1H-imidazole represented by the formula (17) -1-yl) butane-1,4-dione.

The first process may be performed in a one step process using 1,1-carbonyldiimidazole (CDI) as a reaction reagent. In addition, the first process may be a two-step process consisting of a chlorolation reaction and imidazole introduction reaction in a one-pot reaction.

In the first process method using 1,1-carbonyldiimidazole (CDI) as the reaction reagent, it is possible to introduce imidazole groups directly at the C1 and C4 positions of the 2-benzylsuccinic acid. Specifically, the 2-benzyl succinic acid represented by the formula (11) and 1,1-carbonyldiimidazole (CDI) represented by Chemical Formula 11 in a conventional organic solvent are reacted under mild conditions of -20 ℃ to 30 ℃, C1 And directly preparing a compound represented by Chemical Formula 17 having an imidazole group introduced at the C4 position. At this time, the organic solvent used may be dichloromethane, chloroform, carbon tetrachloride, dimethylformamide and the like.

In addition, in the first process method consisting of a chlorolation reaction and an imidazole introduction reaction, a chloroating agent and an imidazole are used as reaction reagents. Specifically, the 2-benzyl succinic acid represented by the formula (11) in a conventional organic solvent as a chloroating agent, for example thioyl chloride (SOCl ₂ ), phosphorus pentachloride (PCl ₅ ), or ethyl chloroformate ( Reaction with ClC (O) OEt) at a temperature of 0 ° C. to 25 ° C., preferably at reflux, to introduce chloro atoms into the C1 and C4 positions of the succinic acid, followed by an ice bath (0 ° C. to 10 ° C.). Conditions react with imidazole to introduce an imidazole group at the C1 and C4 positions of the succinic acid. In this case, the reaction solvent used may be a single solvent or a mixed solvent selected from dichloromethane, ethyl acetate, acetone and the like.

The second step is to react the compound represented by the formula (17) with cis-octahydroisoindole hydrochloride, the intermediate compound represented by the formula (19) wherein the octahydroisoindole group is selectively introduced at the C4 position of the succinic acid Manufacturing process. In detail, the second process, by stirring the compound represented by the formula (17), cis-octahydroisoindole hydrochloride and amine base, the step of replacing the C4 position imidazole group of the succinic acid with octahydroisoindole to be. The amine used in the reaction is preferably an organic base such as ammonia, mono-, di-, tri (C _1-10 alkyl) amine, pyridine, and particularly preferably triethylamine base. The reaction temperature is maintained in the range of -20 ° C to 30 ° C, and the reaction proceeds smoothly even at room temperature. The organic solvent used may be a single solvent or a mixed solvent selected from dichloromethane, chloroform, carbon tetrachloride, dimethylformamide and the like.

In the third process, after the intermediate compound represented by Chemical Formula 19 is reacted with a basic compound to synthesize an alkali metal salt or an amine salt compound represented by Chemical Formula 20, a conversion reaction to calcium salt is performed to perform the desired Chemical Formula 1 It is a process for preparing mitiglinide calcium salt represented by.

The basic compound used in the third process may be an alkali metal compound or an amine compound of NR ¹ R ² R ³ . As the basic compound, the alkali metal compound may specifically include a hydroxide of an alkali metal selected from sodium, potassium, and lithium, a carboxylate having 2 to 6 carbon atoms, an alkyl alkanoate having 3 to 6 carbon atoms, and the like. Sodium acetate is used. As the basic compound, the amine compound may include mono (C _1-10 alkyl) amine, di (C _1-10 alkyl) amine, tri (C _1-10 alkyl) amine, pyridine, aniline, dimethylaniline, and the like. Preferable examples thereof include triethylamine, diethylamine, dicyclohexylamine, dipropylamine, pyridine, N, N-dimethylaniline, and the like, and dicyclohexylamine is particularly preferable. The reaction temperature with the basic compound is maintained in the range of -20 ° C to 30 ° C, and the reaction proceeds smoothly even at room temperature. The organic solvent used may be at least one single solvent or a mixed solvent selected from dichloromethane, ethyl acetate, acetone, tetrahydrofuran, acetonitrile, diformamide, isopropyl ether, and hexane.

The conversion reaction to the calcium salt performed in the third process is specifically carried out by dissolving the compound represented by Chemical Formula 20 in water or a polar organic solvent and then stirring the compound with the calcium compound. In this case, the calcium compound used may be calcium chloride (CaCl ₂ ), 0.5 to 1.0 equivalent. The reaction temperature is maintained in the range of -20 ° C to 30 ° C, and the reaction proceeds smoothly even at room temperature. As the polar organic solvent used as the reaction solvent, a single solvent or a mixed solvent selected from alcohols, acetones, nitriles, and the like of hydrocarbons 1 to 4 may be used. Specifically, methanol, acetone, acetonitrile, etc. may be used. have.

Intermediate compounds produced in the process of carrying out the preparation method according to the present invention may be separated into high purity compounds through a conventional separation and purification method, and may be used in the following preparation process, but these intermediate compounds are included without undergoing separate purification and purification process. Even if the reaction solution is used after the distillation and concentration in the following production process, the high purity compound desired by the present invention can be sufficiently obtained.

In addition, the compound represented by the formula (19) as a key intermediate produced during the process of the production method of the present invention is a novel compound not disclosed in the literature. None of the literature published so far discloses a method for synthesizing mitiglinide via synthesis of the compound represented by Formula 19 as an intermediate.

On the other hand, the manufacturing process consisting of the chlorolation reaction and imidazole introduction reaction as a first process according to the present invention is also shown in the conventional method of the reaction scheme 3. However, in the preparation method according to Scheme 3, the chlorolation reaction with thionyl chloride and imidazole introduction reaction are carried out step by step, and a work-up process for separation of the product is performed. Isomers represented by 14-1 are being produced as by-products. As a basis for this, even if the conventional method of the reaction scheme 3 is examined, the compound represented by the formula (14) is esterified to produce the compound represented by the formula (15), and then the resulting ester compound is hydrolyzed and represented by the formula (14). The conversion to the compound is performed again, wherein the esterification and hydrolysis reaction is determined to be a purification process for removing the isomer represented by Formula 14-1 produced as a by-product. Therefore, the conventional method of Scheme 3 further performs a cumbersome process for removing the isomeric compound represented by Chemical Formula 14-1 produced as a by-product.

However, the production method of the present invention was able to inhibit the formation of the isomer represented by Formula 14-1 by proceeding the chlorolation reaction and the imidazole reaction in a one-pot reaction, thereby to the formula (15). It was possible to omit the unnecessary process of conversion to the compound represented. Therefore, the manufacturing method of this invention has obtained the effect of simplifying a process.

In particular, in the case of using the 1,1-carbonyldiimidazole (CDI) as a first process according to the present invention, since the compound represented by the formula (17) is directly obtained, the process improvement effect is more excellent. In addition, the method using 1,1-carbonyldiimidazole (CDI) has a very high yield of 80% or more from the 2-benzylsuccinic acid represented by the above formula (11) to obtain the compound represented by the above formula (19). In addition, the purity is also higher than 98.5% (HPLC Area%) is the best method for commercial use.

The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.

[Example]

 Example 1 Synthesis of Mitiglinide Calcium Salts

1) Synthesis of 2-benzyl-1,4-di (1H-imidazol-1-yl) butane-1,4-dione

50 g (0.24 mol) of 2-benzyl succinic acid was added to the catalytic amount of pyridine (0.5 mL) and thiournyl chloride 37 mL (0.51 mol) while stirring and stirring in dichloromethane (350 mL), followed by stirring under reflux for 2 hours. It was. After the reaction solution was cooled to 0˜5 ° C., a solution of 70 g (1.03 mol) of imidazole in dichloromethane (457 mL) was added dropwise for 30 minutes, followed by stirring at the same temperature for 1 hour. After the reaction, the reaction proceeded to the next reaction without additional purification process.

2) Synthesis of 2-benzyl-1-imidazol-4- (octahydroisoindol-2-yl) -butane-1,4-dione

 2-Benzyl-1,4-di (1H-imidazol-1-yl) butane-1,4-dione obtained quantitatively in Example 1 was dissolved in dichloromethane (163 mL), followed by cis- 47 g (0.29 mol) of octahydroisoindole hydrochloride and 40 mL (0.29 mol) of triethylamine were added dropwise for 30 minutes, followed by stirring for 2 hours. Washed with 1N-HCl (850 mL) and water (850 mL), dried over magnesium sulfate, and concentrated under reduced pressure to obtain 82.3 g (93.8%) of the title compound.

¹ H-NMR (CDCl ₃ , 300 MHz, ppm) δ 8.23 (s, 1H), 7.46 (d, 1H), 7.1-7.2 (m, 6H), 3.1-3.3 (m, 4H), 2.7-2.9 ( m, 3H), 2.3-2.5 (m, 2H), 2.0-2.1 (m, 2H), 1.2-1.5 (m, 8H)

3) Synthesis of Mytiglinide Sodium Salt

80.0 g (0.21 mol) of 2-benzyl-1-imidazol-4- (octahydroisoindol-2-yl) -butane-1,4-dione was dissolved in acetone (200 mL) and then 39 g of sodium acetate 0.47 mol) was added, followed by stirring at room temperature for 1 hour. The resulting solid was filtered to give 69.2 g (yield 86.2%) of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz, ppm) δ 1.1-1.6 (8H, m), 2.1-2.3 (2H, m), 2.3-2.6 (2H, m), 2.6-3.5 (7H, m), 7.1-7.4 (5H, m)

4) Synthesis of Mitiglinide Calcium Salt

60 g (0.18 mol) of mitiglinide sodium salt was dissolved in water (1.2 L), and a solution of 11.8 g (0.11 mol) of calcium chloride in water (120 mL) was added dropwise at room temperature for 1 hour. Filtration after 1 h gave 65 g (96% yield) of the title compound as a white.

¹ H-NMR (CDCl ₃ , 300 MHz, ppm) δ 1.1-1.6 (16H, m), 2.1-2.3 (4H, m), 2.3-2.6 (4H, m), 2.6-3.5 (14H, m), 7.1-7.4 (10H, m)

Example 2 Synthesis of Mitiglinide Calcium Salts

50 g (0.24 mol) of 2-benzyl succinic acid was added to the catalytic amount of pyridine (0.5 mL) and thiournyl chloride 37 mL (0.51 mol) while stirring and stirring in dichloromethane (350 mL), followed by stirring under reflux for 2 hours. It was. After the reaction solution was cooled to 0˜5 ° C., a solution of 70 g (1.03 mol) of imidazole in dichloromethane (457 mL) was added dropwise for 30 minutes, followed by stirring at the same temperature for 1 hour. 47 g (0.29 mol) of cis-octahydroisoindole hydrochloride and 40 mL (0.29 mol) of triethylamine were added dropwise to the reaction solution in dichloromethane (163 mL) and stirred for 2 hours. . After washing with 1N-HCl (850 mL) and water (850 mL), dried over magnesium sulfate and concentrated. Acetone (200 mL) was added to the concentrate, followed by 39 g (0.29 mol) of sodium acetate, followed by stirring at room temperature for 1 hour, followed by filtration to obtain a white solid. The obtained white solid was dissolved in water (1.2 L), and then a solution of 11.8 g (0.11 mol) of calcium chloride in water (120 mL) was added dropwise at room temperature for 1 hour. After stirring for 1 hour, filtration gave 73.2 g (86.4%) of the title compound in white.

Example 3. Synthesis of 2-benzyl-1,4-di (1H-imidazol-1-yl) butane-1,4-dione

After 50 g (0.24 mol) of 2-benzylsuccinic acid were turbid in dichloromethane (350 mL), the reaction was cooled to 0-5 ° C. and then 46.7 g of 1,1-carbonyldiimidazole (CDI) 0.28 mol) was added slowly for 0.5 hour. The mixture was stirred for 30 minutes while maintaining the temperature, and after the reaction was completed, the product was used for the next reaction without further purification.

Example 4 Synthesis of Mytiglinide Sodium Salt

50 g (0.24 mol) of 2-benzyl succinic acid was added to the catalytic amount of pyridine (0.5 mL) and contaminated phosphorus 49.3 g (0.24 mol) with agitation of dichloromethane (350 mL), followed by stirring under reflux for 2 hours. . After the reaction solution was cooled to 0˜5 ° C., a solution of 70 g (1.03 mol) of imidazole in dichloromethane (457 mL) was added dropwise for 30 minutes, followed by stirring at the same temperature for 1 hour. 47 g (0.29 mol) of cis-octahydroisoindole hydrochloride and 40 mL (0.29 mol) of triethylamine were added dropwise to the reaction solution in dichloromethane (163 mL) and stirred for 2 hours. . After washing with 1N-HCl (850 mL) and water (850 mL), dried over magnesium sulfate and concentrated. Acetone (200 mL) was added to the concentrate, followed by 39 g (0.29 mol) of sodium acetate, followed by stirring at room temperature for 1 hour, followed by filtration to obtain 45.5 g (yield 56.3%) of the title compound as a white solid.

Example 5 Synthesis of Mitiglinide Dicyclohexylamine Salt

50 g (0.24 mol) of 2-benzyl succinic acid was added to the catalytic amount of pyridine (0.5 mL) and thiournyl chloride 37 mL (0.51 mol) while stirring and stirring in dichloromethane (350 mL), followed by stirring under reflux for 2 hours. It was. After cooling to 0˜5 ° C., a solution of 70 g (1.03 mol) of imidazole in dichloromethane (457 mL) was added dropwise for 30 minutes, followed by stirring at the same temperature for 1 hour. 47 g (0.29 mol) of cis-octahydroisoindole hydrochloride and 40 mL (0.29 mol) of triethylamine were added dropwise to dichloromethane (163 mL) for 30 minutes, followed by stirring for 2 hours. After washing with 1N-HCl (850 mL) and water (850 mL), dried over magnesium sulfate and concentrated. Acetone (200 mL) was added followed by 57 mL (0.29 mol) of dicyclohexylamine, followed by stirring at room temperature for 1 hour. The resulting solid was filtered to give 104 g (yield 85%) of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 300 MHz, ppm) δ 1.1-1.6 (28H, m), 2.1-2.4 (2H, m), 2.3-2.7 (4H, m), 2.8-3.3 (7H, m), 7.2-7.4 (5H, m)

Example 6 Synthesis of Mitiglinide Dicyclohexylamine Salt

After 50 g (0.24 mol) of 2-benzylsuccinic acid was turbid in dichloromethane (350 mL), 46.7 g (0.28 mol) of 1,1-carbonyldiimidazole (CDI) was slowly added for 0.5 hour. . The mixture was stirred for 30 minutes while maintaining the temperature, and the product was used for the next reaction immediately after completion of the reaction without performing any further purification. 47 g (0.29 mol) of cis-octahydroisoindole hydrochloride and 40 mL (0.29 mol) of triethylamine were added dropwise to the reaction solution in dichloromethane (163 mL) and stirred for 2 hours. . After washing with 1N-HCl (850 mL) and water (850 mL), dried over magnesium sulfate and concentrated. Acetone (200 mL) was added followed by 57 mL (0.29 mol) of dicyclohexylamine, followed by stirring at room temperature for 1 hour. The resulting solid was filtered to give 112.9 g (yield 92.3%) of the title compound as a white solid.

Example 7 Synthesis of Mitiglinide Calcium Salts

60 g (0.18 mol) of mitiglinide dicyclohexylamine salt was dissolved in water (1.2 L), and a solution of 11.8 g (0.11 mol) of calcium chloride in water (120 mL) was added dropwise at room temperature for 1 hour. After stirring for 1 hour, the title compound was quantitatively obtained by filtration.

 As described above, the method for preparing mytiglinide calcium salt according to the present invention is simple, and if necessary, it is possible to carry out a series of processes in one container without separating intermediate compounds, thereby producing mitigli with high yield and high purity. It is possible to prepare nit calcium salts.

Therefore, the production method of the present invention is particularly useful as a mass production method of mitiglinide calcium salt.

Claims (9)

By introducing an imidazole group at the C1 and C4 positions from 2-benzylsuccinic acid represented by the following formula (11), 2-benzyl-1,4-di (1H-imidazol-1-yl) represented by the following formula (17) A first step of preparing butane-1,4-dione;
The compound represented by the following formula (17) and cis-octahydroisoindole hydrochloride are reacted to form 2-benzyl-1-imidazol-4- (octahydro-isoindol-2-yl) -butane- represented by the following formula (19). A second step of preparing 1,4-dione as an intermediate compound; And
By reacting an intermediate compound represented by the formula (19) with a basic compound to prepare a mitiglinide alkali metal salt or an amine salt represented by the following formula (20), the conversion to calcium salts to perform a mitigli represented by the formula (1) A third step of preparing nit calcium salt;
Method for producing mitiglinide calcium salt comprising a.

(In the above scheme, A represents an alkali metal (M), or NR ¹ R ² R ³ , R ¹ , R ² , and R ³ are each a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, or May be combined with a substituent adjacent to each other to form a pentagonal to pentagonal heteroaliphatic ring or heteroaromatic ring containing 1 to 3 nitrogen atoms)
The method of claim 1,
The first process, the second process and the third process is a method for producing mitiglinide calcium salt, characterized in that carried out continuously without the separation and purification of the intermediate compound.
The method of claim 1,
In the first process, 1,1-carbonyldiimidazole (CDI) is used to introduce imidazole groups directly into the C1 and C4 positions of 2-benzyl succinic acid represented by Formula 11 Method for preparing glinide calcium salt.
The method of claim 1,
In the first step, the chlorolation reaction and imidazole introduction reaction are carried out continuously by a one-pot reaction to imidazole groups at positions C1 and C4 of the 2-benzylsuccinic acid represented by Formula 11 above. Method for producing mitiglinide calcium salt, characterized in that the introduction.
The method of claim 4, wherein
The chlorolation reaction is performed in the presence of a pyridine base using a chloroating agent selected from SOCl ₂ , PCl ₅ and ethyl chloroformate.
The method of claim 1,
The basic compound used in the third process is an alkali metal compound and an amine compound of NR ¹ R ² R ³ (wherein R ¹ , R ² , and R ³ are each a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, or It may be combined with a substituent adjacent to each other to form a pentagonal to pentagonal heteroaliphatic ring or heteroaromatic ring containing 1 to 3 nitrogen atoms), the method for producing a mitiglinide calcium salt, characterized in that.
The method according to claim 6,
The alkali metal compound as the basic compound is a metiglinide selected from a hydroxide of an alkali metal selected from sodium, potassium, and lithium, a carboxylate having 2 to 6 carbon atoms, and an alkyl alkanoate having 3 to 6 carbon atoms. Method for preparing calcium salt.
The method according to claim 6,
The amine compound as the basic compound is selected from mono (C _1-10 alkyl) amine, di (C _1-10 alkyl) amine, tri (C _1-10 alkyl) amine, pyridine, aniline, and dimethylaniline. Method for producing mitiglinide calcium salt.
2-Benzyl-1-imidazol-4- (octahydro-isoindol-2-yl) -butane-1,4-dione represented by the following formula (19).
[Chemical Formula 19]