WO2015151190A1 - イルソグラジンマレイン酸塩の製造方法 - Google Patents

イルソグラジンマレイン酸塩の製造方法 Download PDF

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Publication number
WO2015151190A1
WO2015151190A1 PCT/JP2014/059529 JP2014059529W WO2015151190A1 WO 2015151190 A1 WO2015151190 A1 WO 2015151190A1 JP 2014059529 W JP2014059529 W JP 2014059529W WO 2015151190 A1 WO2015151190 A1 WO 2015151190A1
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WO
WIPO (PCT)
Prior art keywords
irsogladine
solution
maleic acid
methyl cellosolve
dichlorophenyl
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Application number
PCT/JP2014/059529
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English (en)
French (fr)
Japanese (ja)
Inventor
正之 服部
Original Assignee
日本新薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by 日本新薬株式会社 filed Critical 日本新薬株式会社
Priority to CN201480000788.4A priority Critical patent/CN104245682B/zh
Priority to PCT/JP2014/059529 priority patent/WO2015151190A1/ja
Publication of WO2015151190A1 publication Critical patent/WO2015151190A1/ja

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines

Definitions

  • the present invention relates to a method for producing 2,4-diamino-6- (2,5-dichlorophenyl) -1,3,5-triazine maleate.
  • irsogladine 2,4-Diamino-6- (2,5-dichlorophenyl) -1,3,5-triazine
  • Is useful as a therapeutic agent for mucosal protective gastritis / gastric ulcer Patent Document 1.
  • 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.
  • An object of the present invention is to provide a method for producing a high yield and high purity irsogladine maleate.
  • 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. .
  • a polar solvent such as methyl cellosolve
  • 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.
  • 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.
  • 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.
  • maleic acid In the case of adding maleic acid, it may be added all at once, or may be added in several to tens of times.
  • seed crystals may be added.
  • 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).
  • 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)
  • 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).
  • 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 (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,
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
PCT/JP2014/059529 2014-03-31 2014-03-31 イルソグラジンマレイン酸塩の製造方法 WO2015151190A1 (ja)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201480000788.4A CN104245682B (zh) 2014-03-31 2014-03-31 马来酸伊索拉定的制造方法
PCT/JP2014/059529 WO2015151190A1 (ja) 2014-03-31 2014-03-31 イルソグラジンマレイン酸塩の製造方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP2014/059529 WO2015151190A1 (ja) 2014-03-31 2014-03-31 イルソグラジンマレイン酸塩の製造方法

Publications (1)

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WO2015151190A1 true WO2015151190A1 (ja) 2015-10-08

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CN (1) CN104245682B (zh)
WO (1) WO2015151190A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106187928B (zh) * 2016-08-02 2019-06-07 安徽省逸欣铭医药科技有限公司 一种马来酸伊索拉定的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5824514A (ja) * 1981-08-04 1983-02-14 Nippon Shinyaku Co Ltd 消化性潰瘍治療剤
JPS5855423A (ja) * 1981-09-25 1983-04-01 Nippon Shinyaku Co Ltd ベンゾグアナミン類を主成分としする医薬
JPH0770090A (ja) * 1993-09-01 1995-03-14 Taiyo Yakuhin Kogyo Kk イルソグラジンおよびその酸付加塩の製造法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5824514A (ja) * 1981-08-04 1983-02-14 Nippon Shinyaku Co Ltd 消化性潰瘍治療剤
JPS5855423A (ja) * 1981-09-25 1983-04-01 Nippon Shinyaku Co Ltd ベンゾグアナミン類を主成分としする医薬
JPH0770090A (ja) * 1993-09-01 1995-03-14 Taiyo Yakuhin Kogyo Kk イルソグラジンおよびその酸付加塩の製造法

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CN104245682A (zh) 2014-12-24
CN104245682B (zh) 2019-04-05

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