KR20150041280A - Method for the preparation of Mitiglinide Calcium Dihydrate - Google Patents

Abstract

The present invention provides a method for preparing mitiglinide calcium dehydrate. According to the preparation method of the present invention, the mitiglinide calcium dehydrate is prepared by comprising the steps of adding an (S)-benzyl succinyl chloride solution to an imidazole-containing solution in a dropwise manner; and directly reacting the resultant solution with cis-octahydroisoindole hydrochloride. Thus, the present invention can prepare mitiglinide calcium dehydrate at high purity and high yield and provide a mass-production method through a safe preparation procedure in a relatively mild condition.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a method for producing a dihydrate of a dihydric aldehyde,

The present invention relates to a process for the preparation of a miniglidide calcium dihydrate.

Methylglycidol calcium dihydrate is a meglitinide compound that promotes insulin secretion and has a blood glucose lowering effect in a short time and can minimize side effects of hypoglycemia.

A general method for preparing a dihydric dihydrate is disclosed in U.S. Patent No. 5,202,335. The method for producing the di-methylglycidized calcium dihydrate disclosed in U.S. Patent No. 5,202,335 will be described in detail as follows.

Benzyl succinic acid derivative was used as a starting material to react with cis-octahydroisoindole to synthesize a mitiglinide benzyl derivative, followed by removal of the benzyl group with 10% Pd / C to synthesize a mitiglynide. The thus prepared mitoglynide was reacted with ammonia water and calcium chloride to prepare a mitiglinide calcium dihydrate.

However, benzylsuccinic acid derivatives are difficult to obtain and expensive in the above-mentioned production methods, and Pd / C and hydrogen gases used for synthesizing intermediate compounds have limitations in industrial application.

Another process for the preparation of the microglynide calcium dihydrate is disclosed in European Patent Publication No. 0,967,204. Hereinafter, a method for preparing the dihydrate of the dihydroxy compound of the present invention will be described in detail.

(S) -2-benzylsuccinic acid as a starting material, imidazole and triethylamine were dissolved in ethyl acetate, thionyl chloride was slowly added dropwise while keeping the temperature at -15 ° C, and the temperature was raised from -15 ° C to 0 ° C And cis-octahydroisoindole was injected. The mixture was stirred at 0 占 폚 to room temperature overnight, and then work-up was carried out to prepare the mitiglidide. The methylglycidyl benzyl ester was crystallized by using benzyl bromide or benzyl alcohol, and then hydrolyzed again to prepare a methylglyide calcium dihydrate.

However, in the above production method, thionyl chloride must be gradually added dropwise at a low temperature of -15 ° C to -20 ° C, and the purity of the methylglynide due to (S) -benzylsuccinic acid and the isomer of the produced methylglynide Is lowered. In addition, since benzyl bromide used for purifying this is a reagent for stimulating eyes and skin, it is not suitable for mass production, and the DCC coupling agent used for introducing benzyl group is expensive, so that the manufacturing cost of the di-glycidized calcium dihydrate is high and 3 There is a disadvantage to react to work. In addition, there is also a drawback that it is difficult to remove the isourea compound produced as a by-product of the use of DCC. In addition, the production process of producing the methylglycidyl benzyl ester and hydrolyzing it to produce the methylglynide and then converting it to the methylglycidized calcium dihydrate is greatly reduced in purity and the overall yield is only about 51% to be.

Another method for producing a dihydric dihydrate is disclosed in Korean Patent Publication No. 10-2013-0046213. Korean Patent Laid-Open No. 10-2013-0046213 discloses that chlorination and imidazole reaction can be carried out by benzyl succinic acid as a starting material in one vessel reaction. However, in the reaction, many isomers are produced in the production of methylglynide due to the imidazole moiety in the reaction, and when diimidazole compound and cis-octahydroisoindole hydrochloride are reacted, triethylamine is treated to form cis-octahydroisoindole free form is difficult to apply to mass production.

As described above, the method of producing the diacylglycine dihydrate, which has been known up to now, is disadvantageous in that it is not industrially applicable because of a long manufacturing process and the use of a reagent which is not suitable for mass production.

Therefore, there is a demand for development of a method for industrially manufacturing a microglycidized calcium dihydrate at a high yield while maintaining a high purity through a small process step.

Korean Patent Laid-Open Publication No. 10-2013-0046213, 2013. 05. 07 U.S. Patent No. 5,202,335, Apr. 13, 1993 European Patent Publication No. 0,967,204, December 29, 1999

SUMMARY OF THE INVENTION The present invention is directed to a method for preparing a microglynide calcium dihydrate.

The present invention relates to a process for preparing a compound represented by the following formula (2) by dropwise adding a solution containing a compound represented by the following formula (1) to a solution containing imidazole: And

Reacting a compound represented by the formula (2) with a cis-octahydroisoindole hydrochloride to prepare a compound represented by the following formula (3).

[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

In Formula 1, X ₁ or X ₂ may each independently be chloro (Cl), bromo (Br) or iodo (I), preferably X ₁ and X ₂ may be chloro .

In the method of the present invention, the compound represented by Formula 2 may be prepared by adding dropwise a solution containing the compound represented by Formula 1 to a solution containing imidazole. As the solvent for the imidazole-containing solution, ethyl acetate, dichloromethane, chloroform and the like to which triethylamine, pyridine and the like are added are preferable, and the reaction is carried out at a temperature of about -10 캜 to 15 캜, . The solution of the compound represented by the formula (1) is added dropwise to the solution containing imidazole to greatly reduce the amount of the flexible substance produced in the production of the mitoglynide, thereby achieving high purity and yield.

Also, the compound represented by the formula (2) can be prepared by reacting the compound represented by the formula (2) with the cis-octahydroisoindole hydrochloride. The reaction is preferably carried out at a temperature of about -10 DEG C to 15 DEG C, preferably at 5 DEG C or lower, and then gradually elevated to room temperature. The direct reaction of the compound represented by the general formula (2) of the present invention with the cis-octahydroisoindole hydrochloride is greatly effective in reducing the generation of the flexible substance and reducing the number of steps of the preparation method compared with administration in a solution state after dissolving in a solvent or the like It is convenient for mass production.

According to the present invention, the preparation of the dihydric calcium dihydrate is carried out by reacting the compound represented by the formula (3) under an acidic condition to prepare a compound represented by the formula (5);

Reacting a compound represented by the following formula (5) with an amine compound to prepare a mitiglinide amine salt; And

And a step of reacting the methylglycidylamine salt with a calcium compound to prepare a microglycidized calcium dihydrate represented by the general formula (4), thereby preparing a microglynide calcium dihydrate.

[Chemical Formula 5]

According to the production process of the present invention, the compound represented by the general formula (3) can be prepared by reacting the compound represented by the general formula (3) under an acid condition. In the preparation of the compound represented by the general formula (5), there are no particular restrictions on the acid condition and kind, and inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid and the like can be used, and hydrochloric acid can be preferably used.

In addition, the compound represented by the general formula (5) is reacted with an amine compound to produce a methylglycine amine salt, thereby reducing the production of a flexible substance and obtaining a high purity methylglycine calcium dihydrate based on an excellent purification effect.

According to the preparation method of the present invention, the amine compound may preferably be cyclohexylamine, benzylamine, n-butylamine or t-butylamine.

The calcium compound may be calcium chloride, calcium bromide, calcium hydroxide and hydrates thereof, preferably calcium chloride and its hydrate. Calcium compounds can be dissolved in purified water in an aqueous solution.

In the step of reacting the compound represented by the general formula (5) with an amine compound to prepare a methylglycidylamine salt, the solvent may be ethyl acetate, acetone, acetonitrile, toluene, cyclohexane, xylene or tetrahydrofuran, Use ethyl acetate, acetone or acetonitrile.

In the above process, the step of reacting the compound represented by the general formula (5) with an amine compound to prepare a methylglycidylamine salt may be carried out at about 50 ° C to about 120 ° C, And reacting the resulting mixture to prepare the methylglycine calcium dihydrate represented by the formula (4) can be carried out at about 50 ° C to about 120 ° C. After the reaction, the reaction product is cooled to room temperature and filtered to obtain a solid. The solid phase may be in a crystalline form.

In the method of the present invention, the compound represented by Formula 1 may be prepared by halogenating a hydroxy group.

[Chemical Formula 6]

Bromination reaction and iodination reaction can be carried out in an organic solvent such as dichloromethane, chloroform, carbon tetrachloride or dimethylformamide. As the chlorinating agent, thionyl chloride, phosphorus pentachloride and the like can be used , It is possible to use a general halogenating agent. Thionyl chloride or phosphorus pentachloride can preferably be used in the chlorination reaction.

In the present invention, the method for producing the above-mentioned < RTI ID = 0.0 > mitiglinide < / RTI >

[Reaction Scheme 1]

In the above reaction formula, X ₁ and X ₂ are as defined in Chemical Formula (1).

The above method will be described stepwise. The hydroxy group of the compound represented by the formula (6) is halogenated to prepare a compound represented by the formula (1). The halogenation is carried out by carrying out a chlorination reaction, a bromination reaction and an iodination reaction in an organic solvent.

Next, a solution containing a compound represented by the formula (1) is added dropwise to a solution containing imidazole to prepare a compound represented by the formula (2). The imidazole solution preferably contains triethylamine or pyridine in an organic solvent such as ethyl acetate, dichloromethane or chloroform.

Next, a compound represented by the formula (2) is prepared by reacting the compound represented by the formula (2) with cis-octahydroisoindole hydrochloride.

Next, the compound represented by formula (5) is prepared from the compound represented by formula (3) under appropriate acid conditions.

Next, a compound represented by the general formula (5) is treated with an amine compound to prepare a mitiglinide amine salt, and a calcium compound is then treated to prepare a mitiglinide calcium dihydrate represented by the general formula (4).

More preferably, the method for preparing the di-methylglycine dihydrate can include the reaction represented by the following reaction formula (2).

[Reaction Scheme 2]

The above process will be described stepwise. (S) -BSCl is prepared using (S) -2-benzylsuccinic acid as a starting material. (S) -2-benzylsuccinic acid and thionyl chloride under an organic solvent such as dichloromethane, chloroform, carbon tetrachloride or dimethylformamide at a temperature of 0 ° C to 50 ° C, preferably under refluxing conditions S) -BSCl.

Next, (S) -BSDI is prepared from (S) -BSCl. (S) -BSDI is prepared by dropping the (S) -BSCl solution prepared in the solution in which the organic solvent and triethylamine are injected into the imidazole and cooled.

Next, (S) -BSHI is prepared from (S) -BSDI. (S) -BSHI is prepared by reacting the cooled (S) -BSDI solution with cis-octahydroisoindole hydrochloride.

Next, a solution of (S) -BSHI and an aqueous hydrochloric acid solution is reacted to prepare a mitiglidide.

Next, the mitiglidide amine salt is prepared as a crystal by reacting the mitiglynide with an organic solvent and an amine.

Finally, the mitiglidide amine salt is reacted with an aqueous solution of calcium chloride in an organic solvent to prepare the mitiglidide calcium dihydrate.

The present invention can produce a microglycaned calcium dihydrate in high purity and high yield by carrying out a reaction involving the step of converting the methylglyneide to the methylglycidized calcium dihydrate via the methylglycidylamine salt. Therefore, the manufacturing method of the present invention can be effectively used for mass production applications for industrialization.

Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, the following examples should not be construed as limiting the scope of the present invention, but should be construed to facilitate understanding of the present invention.

The reagents and solvents mentioned below were purchased from Sigma-Aldrich, unless otherwise noted, and HPLC analysis was performed under the following conditions.

≪ ¹ > H-NMR and data were measured with BRUKER AVANCE III 400.

EXAMPLES Synthesis of Methylglyide Calcium Dihydrate

1. Synthesis of (S) -benzylsuccinyl chloride ((S) -BSCl)

After the addition of 41.6 g (0.2 mol) of (S) -benzylsuccinic acid and 416 ml of dichloromethane to a round bottom flask, 50 g (0.42 mol) of thionyl chloride was added and refluxed and stirred at 35 to 42 ° C for 2 hours to complete the reaction After that, the temperature of the solution containing (S) -BSCl was cooled to 10 to 20 ° C.

_{^{1 H-NMR (CDCl 3,}} 400 MHz, ppm) δ2.6-2.8 (1H, m), 2.9-3.1 (2H, m), 3.2-3.3 (1H, m), 3.4-3.6 (1H, m) , 7.1-7.4 (5H, m)

2. Synthesis of (S) -2-benzylsuccinyl-1,4-diimidazole ((S) -BSDI)

28.6 g (0.42 mol) of imidazole and 490 ml of dichloromethane were placed in a round-bottomed flask, and 80.9 g (0.8 mol) of triethylamine was added thereto and cooled to 3 ° C or lower. The (S) -BSCl solution prepared in the above step 1 was slowly added dropwise to the cooled imidazole solution, followed by cooling and stirring for 1 hour to obtain a solution containing (S) -BSDI.

_{^{1 H-NMR (CDCl 3,}} 400 MHz, ppm) δ2.4-3.2 (5H, m), 7.1-7.4 (7H, m), 7.6-7.8 (2H, m), 8.2-8.3 (2H, d)

3. (S) -2-Benzylsuccinyl-1-imidazol-4-c-octahydroisoindole

((S) -BSHI) Synthesis of

(S) -BSDI solution prepared in the above step 2 was continuously cooled and stirred at 5 ° C or lower, 34.0 g (0.21 mol) of cis-octahydroisoindole hydrochloride was added, and the mixture was stirred overnight while gradually warming to room temperature. A solution containing BSHI was obtained.

_{^{1 H-NMR (CDCl 3,}} 400 MHz, ppm) δ1.2-1.7 (8H, m), 2.0-2.2 (2H, m), 2.3-2.6 (2H, m), 2.7-3.0 (3H, m) , 3.2-3.6 (4H, m), 7.1-7.3 (6H, m), 7.6-7.8 (1H, d), 8.2-8.3

4. Synthesis of mitiglnide

To the (S) -BSHI solution prepared in the above step (3), 500 ml of a 1N aqueous hydrochloric acid solution was poured, followed by stirring for 1 hour. The dichloromethane layer was separated, dried over anhydrous sodium sulfate, and concentrated to obtain 63 g (0.2 mol) of mitiglidide.

HPLC area%: 98.5%, Yield: 100.0%

_{^{1 H-NMR (CDCl 3,}} 400 MHz, ppm) δ1.2-1.7 (8H, m), 2.1-2.3 (2H, m), 2.4-2.5 (2H, m), 2.7-2.8 (1H, m) , 2.8-3.5 (6H, m), 7.1-7.4 (5H, m)

5. Mitiglinide. Synthesis of n-butylamine salt

63 g (0.2 mol) of the mitoglynide synthesized in the above step 4 was added to 315 ml of ethyl acetate, and 14.6 g (0.2 mol) of n-butylamine was added dropwise while stirring. After the temperature was raised to 70 ° C, crystals were formed by cooling slowly to room temperature, filtered, and washed with 150 ml of ethyl acetate to obtain 60.0 g (0.154 mol, 77.2%) of the desired methylglycide.n-butylamine salt.

HPLC area%: 99.55%

_{^{1 H-NMR (CDCl 3,}} 400 MHz, ppm) δ0.8-1.0 (3H, t), 1.2-1.7 (12H, m), 2.0-2.3 (3H, m), 2.5-3.5 (13H, m) , 6.8-7.1 (3H), 7.1-7.4 (5H, m)

6. Synthesis of mitiglinide calcium dihydrate

30 g (0.077 mol) of the mitiglidide.n-butylamine salt synthesized in the above 5. and 300 ml of anhydrous ethanol were placed in a round bottom flask. After the temperature was raised to 70 ° C, an aqueous solution obtained by dissolving 6.24 g (0.042 mol) of calcium chloride dihydrate in 100 ml of purified water was added dropwise. After refluxing and stirring for 1 hour, the mixture was slowly cooled to room temperature. The resulting crystals were filtered, washed with an ethanol / purified water mixed solvent, and dried to obtain 23.5 g (0.033 mol, 86.6%) of a dihydrate of dihydroxy compound.

To 23.0 g of the obtained mitoglyed calcium dihydrate, 350 ml of ethanol was charged, and the temperature was raised to 70 ° C. Then, 18 ml of purified water was poured into the solution and the solution was slowly cooled to room temperature. The crystals were filtered, washed with a mixed solvent of ethanol / purified water, and dried to obtain 22.0 g (95.6%) of the dihydrate of the dihydrate.

HPLC area%: 99.98%

^{1 H-NMR (MeOD, 400} MHz, ppm) δ1.1-1.6 (8H, m), 2.0-2.2 (2H, m), 2.2-2.4 (1H, m), 2.5-2.8 (2H, m), 2.8-3.4 (6H, m), 7.1-7.4 (5H, m)

≪ Experimental Example > The content of the methylglynide flexible substance according to the manufacturing method

1. Analysis of major softeners of mitoglynide

The structures of the main flexible substances were confirmed by ¹ H-NMR and HPLC methods, and the results are shown in Table 1.

[Table 1] Analysis of main flexible substances

2. Purity analysis of mitiglinide materials according to the (S) -BSDI preparation method

(S) -BSCl solution prepared in Example 2, imidazole was injected into an organic solvent and triethylamine, and the cooled solution was reacted to prepare a (S) -BSDI. Respectively. The experiment was carried out by changing only the dropping method in the same amount as in the manufacturing method of Example 2. [ That is, the addition of the (S) -BSCI solution to the imidazole solution and the addition of the imidazole solution to the (S) -BSCl solution were compared. The results are shown in Table 2.

[Table 2] Comparison of the purity of the flexible material in the manufacture of the methylglynide according to the (S) -BSDI preparation method

As shown in Table 2, it was confirmed that dropwise addition of the (S) -BSCI solution to the imidazole solution during the preparation of the mitiglnide exhibited higher purity than dropwise the imidazole solution into the (S) -BSCl solution.

3. Analysis of Purity of Substance by Mitiglidene Amine Salt Formation

The salt with the mitiglnide was formed while changing only the amine and the solvent of Example 5. The results of measuring the purity of the amine salt and the impurity contained in the solution finally obtained in Example 5 are shown in Table 3 .

In Table 3, the term "mtiglinalide" refers to the purity before the formation of the amine salt, and the terms "cyclohexylamine salt", "n-butylamine salt" and "t-butylamine salt" refer to the purity relative to the methylglycidylamine salt.

[Table 3] Comparison of Solvent and Amine Salt Conditions for Preparation of Methylglycidylamine Salt

As described above, it was confirmed that high purity and yield were obtained while producing a flexible material having less cyclohexylamine salt, t-butylamine salt, and n-butylamine salt in various solvents.

That is, the purity and yield of the compound can be increased by synthesizing the di-methylglycidate dihydrate through the methylglycine amine salt.

Claims (7)

Adding a solution containing a compound represented by the formula (1) to a solution containing imidazole to prepare a compound represented by the following formula (2); And
A process for producing a microglynide calcium dihydrate represented by the following formula (4), comprising the step of reacting a compound represented by the following formula (2) with a cis-octahydroisoindole hydrochloride to prepare a compound represented by the following formula
[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

In Formula 1, X ₁ or X ₂ is independently chloro (Cl), bromo (Br), or iodo (I). The process according to claim 1, wherein X ₁ and X ₂ are chloro (Cl). The method according to claim 1, wherein the compound represented by formula (3) is reacted under an acidic condition to produce a compound represented by formula (5).
Reacting a compound represented by the following formula (5) with an amine compound to prepare a mitiglinide amine salt; And
A process for preparing a microglynide calcium dihydrate, which comprises the step of reacting a methylglycidylamine salt with a calcium compound.
[Chemical Formula 5]

4. The method according to claim 3, wherein the amine compound is at least one selected from cyclohexylamine, benzylamine, n-butylamine or t-butylamine. 4. The method of claim 3, wherein the step of preparing the methylglycine amine salt comprises using at least one solvent selected from ethyl acetate, acetone or acetonitrile. 4. The method of claim 3, wherein the step of reacting the amine salt of the < RTI ID = 0.0 > mitiglinide < / RTI > with the calcium compound comprises the step of adding an aqueous solution of calcium dissolved in purified water to a solution comprising the ≫ The method according to claim 1, wherein the compound represented by the formula (1) is prepared by halogenating the hydroxy group represented by the formula (6).
[Chemical Formula 6]