WO2015151190A1

WO2015151190A1 - Method for producing irsogladine maleate

Info

Publication number: WO2015151190A1
Application number: PCT/JP2014/059529
Authority: WO
Inventors: 正之服部
Original assignee: 日本新薬株式会社
Priority date: 2014-03-31
Filing date: 2014-03-31
Publication date: 2015-10-08
Also published as: CN104245682A; CN104245682B

Abstract

Provided is a method for producing high-purity irsogladine maleate with high yield while reducing the production of a by-product. 2,4-diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine is dissolved in an organic solvent while heating and stirring to prepare a solution, then maleic acid is added and dissolved in the solution, and then the resultant solution is cooled to room temperature. In this manner, crystals can be produced with high yield while preventing the coloration of the crystals.

Description

Method for producing irsogladine maleate

The present invention relates to a method for producing 2,4-diamino-6- (2,5-dichlorophenyl) -1,3,5-triazine maleate.

2,4-Diamino-6- (2,5-dichlorophenyl) -1,3,5-triazine (hereinafter referred to as irsogladine) is represented by the following formula (I), and irsogladine or a pharmaceutically acceptable salt thereof: Is useful as a therapeutic agent for mucosal protective gastritis / gastric ulcer (Patent Document 1). Among them, irsogladine maleate is already marketed as Gaslon N (registered trademark).

Irsogladine maleate can be produced by heating and dissolving in a polar solvent such as methyl cellosolve and cooling in the presence of irsogladine and maleic acid. In order to produce on a commercial scale, it is important to efficiently obtain a high-purity target with a high yield. On the other hand, in the production of irsogladine maleate, irsogladine has low solubility in a solvent and needs to be heated for a long time in order to dissolve it. Not only does the yield of ginmaleate decrease over time, but the coloration of the crystals becomes noticeable, so it is difficult to say that it is sufficiently satisfactory commercially, and the production of a better irsogladine maleate Development of a method was desired.

Patent No. 1249105

An object of the present invention is to provide a method for producing a high yield and high purity irsogladine maleate.

As a result of diligent research to solve the above problems, the present inventor once dissolved irsogladine while heating in a polar solvent such as methyl cellosolve, and then added maleic acid to the heated solution to obtain a homogeneous solution. Then, by cooling, it was found for the first time that the crystals could be obtained in good yield by suppressing the coloration of the crystals, that is, this method could be produced on a commercial scale, and the present invention was completed based on these findings. .

That is, the present invention can include the following inventions (I) to (IV).

(I) A process for producing maleate crystals of 2,4-diamino-6- (2,5-dichlorophenyl) -1,3,5-triazine, comprising the following (A), (B), and ( A production method including the step C):
(A) a step of once dissolving 2,4-diamino-6- (2,5-dichlorophenyl) -1,3,5-triazine in an organic solvent with heating and stirring;
(B) A step of adding maleic acid to the solution of (A) to make a uniform solution;
(C) A step of cooling the solution to room temperature and isolating the precipitated crystals.
(II) The production method according to (I) above, wherein the organic solvent used is methyl cellosolve.
(III) The maleic acid used is 0.8-fold to 5.0-fold molar equivalents relative to 2,4-diamino-6- (2,5-dichlorophenyl) -1,3,5-triazine. The manufacturing method as described in (I) or (II).
(IV) The production method according to any one of (I) to (III), wherein the temperature of heating and stirring in the solution of (A) is 50 ° C. to 100 ° C.
(V) The organic solvent used is methyl cellosolve, and the maleic acid used is 0.8-fold mol with respect to 2,4-diamino-6- (2,5-dichlorophenyl) -1,3,5-triazine. The production method according to (I), wherein the molar equivalent is ˜5.0 times, and the temperature during heating and stirring is 50 ° C. to 100 ° C. in the solution of (A).

According to the present invention, it is possible to obtain a highly pure irsogladine maleate with no coloration, while suppressing a decrease in irsogladine over time.

Irsogladine, which is a starting material used in the present invention, can be produced by the method described in Patent Document 1.

A method for practicing the present invention to produce irsogladine maleate is provided. This method is a method for producing crystals of 2,4-diamino-6- (2,5-dichlorophenyl) -1,3,5-triazine maleate, and includes the following (A), (B), and ( A production method including the step C):
(A) a step of dissolving 2,4-diamino-6- (2,5-dichlorophenyl) -1,3,5-triazine in an organic solvent under heating and stirring to form a uniform solution;
(B) A step of adding maleic acid to the solution of (A) to make a uniform solution;
(C) A step of cooling the solution to room temperature and isolating the precipitated crystals.

The solvent used in the present invention is not particularly limited as long as it dissolves the starting material and does not inhibit the reaction, and examples thereof include alcohol solvents such as methanol, ethanol, methyl cellosolve (also referred to as 2-methoxyethanol). it can. Of these, methyl cellosolve or ethanol is preferable, and methyl cellosolve is more preferable. The amount of the solvent used is usually preferably 5 mL to 50 mL, more preferably 5 mL to 15 mL, and most preferably 10 mL per 1 g of irsogladine as a raw material.

The temperature at which irsogladine and maleic acid are dissolved is preferably kept at 80 ° C. from the viewpoint of preventing the precipitation of irsogladine and improving the reaction efficiency.

The amount of maleic acid used in the present invention is usually preferably 0.8 mol to 5.0 mol, more preferably 1.0 mol to 1.4 mol, and more preferably 1.0 to 1.2 mol with respect to 1 mol of irsogladine. Is most preferred.

In the case of adding maleic acid, it may be added all at once, or may be added in several to tens of times.

In the case of crystallization, seed crystals may be added. In order to further improve the effect of addition of the seed crystal, the seed crystal is preferably added after the irsogladine is completely dissolved, and more preferably added at 80 ° C.

The amount of seed crystals added is preferably 0.1% by weight to 10% by weight with respect to irsogladine used in the step (1).

It is a figure showing the relationship between the heating time of the methyl cellosolve solution of maleic acid and irsogladine, and the production | generation yield of irsogladine maleate, A vertical axis | shaft represents a yield and a horizontal axis | shaft represents the time which heated and stirred the solution. The dotted line is the wavy line, the solid line is the yield of irsogladine maleic acid when using 1.0 molar equivalents of maleic acid (Reference Examples 1 and 2), and the broken line is the irsogladine maleic acid when using 1.2 molar equivalents of maleic acid Yield (Reference Examples 3 and 4), the solid line represents the yield when 1.2 molar equivalents of maleic acid were added after heating and dissolving irsogladine (Examples 1 and 2).

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Reference example 1
Methyl cellosolve (200 mL) was poured into the reaction vessel and heated to 80 ° C. Irsogladine (20.0 g, 78.1 mmol) and maleic acid (9.1 g, 78.1 mmol, molar ratio to irsogladine 1.0) were added thereto, and the mixture was stirred at 80 ° C. for 5 hours to completely dissolve the above mixture. I let you. A part of the reaction solution was collected, and irsogladine maleate was crystallized from the collected reaction solution, washed with methyl cellosolve, and dried to obtain irsogladine maleate (58%). .

Reference example 2
Methyl cellosolve (200 mL) was poured into the reaction vessel and heated to 80 ° C. Irsogladine (20.0 g, 78.1 mmol) and maleic acid (9.1 g, 78.1 mmol, molar ratio to irsogladine 1.0) were added thereto and stirred at 80 ° C. for 7 hours to completely dissolve the above mixture. I let you. A part of the reaction solution was collected, and irsogladine maleate was crystallized from the collected reaction solution, washed with methyl cellosolve, and dried to obtain irsogladine maleate (47%). .

Reference example 3
Methyl cellosolve (200 mL) was poured into the reaction vessel and heated to 80 ° C. Irsogladine (20.0 g, 78.1 mmol) and maleic acid (10.9 g, 93.7 mmol, molar ratio to irsogladine 1.2) were added thereto, and the mixture was stirred at 80 ° C. for 5 hours to completely dissolve the above mixture. I let you. A part of the reaction solution was collected, and irsogladine maleate was crystallized from the collected reaction solution, washed with methyl cellosolve, and dried to obtain irsogladine maleate (55%). .

Reference example 4
Methyl cellosolve (200 mL) was poured into the reaction vessel and heated to 80 ° C. Add irsogladine (20.0 g, 78.1 mmol) and maleic acid (10.9 g, 93.7 mmol, molar ratio to irsogladine 1.2) and stir at 80 ° C. for 7 hours to completely dissolve the above mixture. I let you. A part of the reaction solution was collected, and irsogladine maleate was crystallized from the collected reaction solution, washed with methyl cellosolve, and dried to obtain irsogladine maleate (48%). .

Example 1
Ilsogladine (2.0 g, 7.8 mmol) was heated to 80 ° C. with stirring in methyl cellosolve (20 ml) and stirred for 5 hours to completely dissolve the above mixture, and then maleic acid (1.1 g , 9.4 mmol), and stirred at 80 ° C. for 15 minutes. The reaction solution was allowed to stand at room temperature for 40 hours, and the resulting crystals were separated. After washing with methyl cellosolve and drying, irsogladine maleate (62%) was obtained.

Example 2
Ilsogladine (2.0 g, 7.8 mmol) was heated to 80 ° C. with stirring in methyl cellosolve (20 ml) and stirred for 7 hours to completely dissolve the above mixture, and then maleic acid (1.1 g , 9.4 mmol), and stirred at 80 ° C. for 15 minutes. The reaction solution was allowed to stand at room temperature for 40 hours, and the resulting crystals were separated. After washing with methyl cellosolve and drying, irsogladine maleate (64%) was obtained.

Table 1 below shows the amount of maleic acid used in Reference Examples 1 to 4 and Examples 1 and 2, heating and stirring time and yield, and coloration of crystals.

* Represents the molar equivalent of irsogladine used.

As shown in FIG. 1, compared to the case where a mixture of irsogladine and maleic acid is heated and dissolved in methyl cellosolve, if maleic acid is added after irsogladine is heated and dissolved in methyl cellosolve, the yield does not decrease over time. Crystals of irsogladine maleate can be obtained well.

Claims

A method for producing crystals of 2,4-diamino-6- (2,5-dichlorophenyl) -1,3,5-triazine maleate, which comprises the following steps (i) to (iii):
(I) a step of dissolving 2,4-diamino-6- (2,5-dichlorophenyl) -1,3,5-triazine in an organic solvent under heating and stirring to form a uniform solution;
(Ii) a step of adding maleic acid to the solution of (i) to make a uniform solution;
(Iii) cooling the solution to room temperature and isolating the precipitated crystals.
The manufacturing method of Claim 1 whose organic solvent to be used is methyl cellosolve.
2. The maleic acid to be used is 1.0-fold to 5.0-fold molar equivalent to 2,4-diamino-6- (2,5-dichlorophenyl) -1,3,5-triazine. Or the manufacturing method of Claim 2.
The production method according to any one of claims 1 to 3, wherein in the solution (i), the temperature at the time of heating and stirring is 50 ° C to 100 ° C.
The organic solvent to be used is methyl cellosolve, and the maleic acid to be used is 1.0 times mol to 5.times.5 with respect to 2,4-diamino-6- (2,5-dichlorophenyl) -1,3,5-triazine. The production method according to claim 1, wherein the molar amount is 0 times, and the temperature during heating and stirring is 50 to 100 ° C in the solution of (i).