Betrixaban salt, preparation method and application thereof

A technology of betrixaban and malic acid, applied in the field of organic chemistry, can solve problems such as difficult control of polycrystals

Inactive Publication Date: 2015-11-25
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although betrixaban maleate has good crystallinity, stability and solubility, it has polymorphism, and polymorphism is difficult to control

Method used

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  • Betrixaban salt, preparation method and application thereof
  • Betrixaban salt, preparation method and application thereof
  • Betrixaban salt, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0260] Example 1: Preparation of semi-L-betrixaban malate and its crystal form A

[0261] Dissolve 6.0g (13.3mmol) of betrixaban and 1.1g (8.0mmol) of L-malic acid in a mixed solvent of 70mL of tetrahydrofuran / 7mL of water at 55-60°C, add 60mL of acetone while stirring, and cool to room temperature. Crystallization. Precipitate a solid, filter it, and dry the obtained solid under reduced pressure at 40-45°C to obtain half-L-betrixaban malate.

[0262] 1 HNMR(400MHz,MeOD)δ:2.355-2.419(dd,0.5H),2.735-2.781(dd,0.5H),3.226(s,6H),3.907(s,3H),4.302-4.326(dd,0.5H) ),7.195-7.224(dd,1H),7.448-7.455(d,1H),7.744-7.764(d,2H),7.821-7.849(dd,1H),8.145-8.165(d,2H),8.196-8.219 (d,1H),8.238-8.261(d,1H),8.323-8.329(d,1H).

[0263] the above 1 In the H-NMR results, δ: 3.907(s,3H) is attributed to the methyl CH in the betrixaban molecule 3 , 4.302-4.326 (dd, 0.5H) is attributed to the methine CH in the L-malic acid molecule. It can be judged that the molar composition ratio of betrixaban an...

Embodiment 2

[0268] Example 2: Preparation of L-betrixaban malate and its crystal form A

[0269] Dissolve 6.0g (13.3mmol) of betrixaban (13.3mmol) and 2.1g (16.0mmol) of L-malic acid in 48mL of tetrahydrofuran / 12mL of water mixed solvent at 55-60°C, add 80mL of acetone dropwise under stirring, and cool to room temperature. Stand still and crystallize. Precipitate a solid, filter it, and dry the obtained solid under reduced pressure at 45-50°C to obtain L-betrixaban malate.

[0270] 1 HNMR(400MHz,MeOD)δ:2.491-2.549(dd,1H),2.779-2.832(dd,1H),3.122(s,3H),3.350(s,3H),3.925(s,3H),4.267-4.300 (dd,1H),7.220-7.250(dd,1H),7.474-7.481(d,1H),7.755-7.776(d,2H),7.841-7.869(dd,1H),8.164-8.185(d,2H) ,8.207-8.230(d,1H),8.275-8.298(d,1H),8349-8.357(d,1H).

[0271] the above 1 In the H-NMR results, δ: 3.925(s,3H) is attributed to the methyl CH in the betrixaban molecule 3 , δ: 4.267-4.300 (dd, 1H) is attributed to the methine CH in the L-malic acid molecule. It can be judged that the molar compositio...

Embodiment 3

[0276] Example 3: Preparation of hemi-D-betrixaban malate and its crystal form A

[0277] Dissolve 6.0g (13.3mmol) of betrixaban (13.3mmol) and 1.1g (8.0mmol) of D-malic acid in a mixed solvent of 70mL of tetrahydrofuran / 7mL of water at 55-60°C, add 60mL of acetone dropwise under stirring, and cool to room temperature. Stand still and crystallize for 12h. Precipitate a solid, filter it, and dry the obtained solid under reduced pressure at 50-55°C to obtain betrixaban hemi-D-malate.

[0278] 1 HNMR(400MHz,MeOD)δ:2.492-2.540(dd,0.5H),2.763-2.771(dd,0.5H),3.321(s,3H),3.148(s,3H),3.927(s,3H),4.277 -4.301(dd,0.5H),7.223-7.253(dd,1H),7.474-7.481(d,1H),7.755-7.775(d,2H),7.843-7.871(dd,1H),8.163-8.183(d ,2H),8.207-8.2229(d,1H),8.268-8.290(d,1H),8.352-8.358(d,1H).

[0279] the above 1 In the H-NMR results, δ: 3.927(s,3H) is attributed to the methyl CH in the betrixaban molecule 3 , δ: 4.277-4.301 (dd, 0.5H) is attributed to the methine CH in the D-malic acid molecule. It can be j...

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Abstract

The present invention relates to betrixaban salts as shown by formula II, wherein the method for preparing these salts is simple, the crystal form is easy to control, the stability and solubility are good, and the salts are suitable for preparing a variety of preparations. The present invention also relates to the method for preparing these salts, pharmaceutical compositions comprising these salts, and the use of these salts in the preparation of medicaments for the prevention and treatment of diseases characterized by adverse thrombus formation in mammals.

Description

technical field [0001] The present invention relates to the fields of organic chemistry and pharmacy, in particular to salts of betrixaban and their preparation methods and the use of these solid forms in medicines for preventing or treating diseases characterized by adverse thrombosis in mammals. Background technique [0002] Betrixaban, chemical name: N-(5-chloro-2-pyridyl)-2-[[4-[(dimethylamino)iminomethyl]benzoyl]amino]-5 -Methoxy-benzamide, the structure is as shown in formula I: [0003] [0004] Betrixaban, an oral small molecule compound, direct factor Xa inhibitor, was first developed by Millennium and later transferred to Portola Pharmaceuticals in the United States. This product is mainly used for the prevention and treatment of deep vein thrombosis and pulmonary embolism after orthopedic surgery. It can also be used for the prevention of stroke caused by atrial fibrillation. In addition, it can also be used as a second-line preventive drug for myocardial infa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75A61K31/44A61P7/02A61P11/00A61P9/10
CPCC07B2200/13C07D213/75A61K31/44
Inventor 陈大峰惠帅程睿贾晓曼刘小凤闫树军罗杰向志祥
Owner SICHUAN HAISCO PHARMA CO LTD
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