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A preparation method of betrixaban and its hydrochloride, and their crystal forms

A technology of betrixaban hydrochloride and betrixaban hydrochloride is applied in the field of preparation of betrixaban and its hydrochloride, and can solve the problems of harsh reaction operating conditions, unsuitable for industrialized production, and single-heterogeneous products. , to achieve the effect of simple preparation method, convenient storage and simple operation

Active Publication Date: 2022-06-21
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] In summary, the prior art has the following defects in the process of preparing betrixaban: harsh reaction operating conditions, low yield, high purity of the product, cumbersome operation, difficult purification, unsuitable for industrial production, etc.
Therefore, there is also a demand for improving the preparation method of betrixaban, so as to improve the yield and purity of betrixaban, overcome the defects of complicated operation and difficult purification, and make it more suitable for industrial production

Method used

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  • A preparation method of betrixaban and its hydrochloride, and their crystal forms
  • A preparation method of betrixaban and its hydrochloride, and their crystal forms
  • A preparation method of betrixaban and its hydrochloride, and their crystal forms

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Example 1: Preparation of Betrixaban Hydrochloride

[0072] 10g compound III (43.7mmol), dichloromethane 80mL, 0.2mL N,N-dimethylformamide (2.6mmol), 6.3mL thionyl chloride (87.4mmol) were added to the 500mL there-necked flask, and the temperature was controlled to react at 30°C After 1 h, a solution of compound VIII was obtained, which was used for later use.

[0073] 14.6g of compound IV (52.6mmol), 160mL of dichloromethane, 18mL of triethylamine (0.13mol) were added to a 1000mL three-necked flask, the temperature was controlled at 15°C, the solution of the above-mentioned compound VIII was added dropwise, the addition was completed, the reaction was performed for 3h, and suction filtered. , washed with dichloromethane, and dried in vacuo to obtain 18.7 g of off-white solid with a yield of 87.5%, HPLC purity of 99.7%, and all single impurities below 0.1%.

[0074] The off-white betrixaban hydrochloride solid obtained from Example 1 has crystal form I. The measured p...

Embodiment 2

[0078] Example 2: Preparation of Betrixaban Hydrochloride

[0079] 10g compound III (43.7mmol), acetone 70mL, 0.2mL N,N-dimethylformamide (2.6mmol), 4.8mL thionyl chloride (66.2mmol) were added to a 500mL three-necked flask, and the temperature was controlled at 15°C to react for 2h, A solution of compound VIII is obtained, which is used for subsequent use.

[0080] 12.2g of compound IV (43.9mmol), 150mL of acetone, 9.2g of sodium bicarbonate (0.11mol) were added to a 1000mL three-necked flask, the temperature was controlled at 20°C, the solution of the above-mentioned compound VIII was added dropwise, the dropwise addition was completed, the reaction was performed for 2h, and suction filtered, Washed with acetone and dried in vacuo to obtain 18.6 g of off-white solid with a yield of 87.1%, HPLC purity of 99.7%, and all mono-impurities below 0.1%.

[0081] The off-white betrixaban hydrochloride solid obtained from Example 2 has crystal form II. The measured powder X-ray diff...

Embodiment 3

[0085] Example 3: Investigation of solvent and base 1 type

[0086] With reference to the preparation method of betrixaban hydrochloride in Example 1, the investigation of the reaction solvent and base 1 type of compound VIII and compound IV:

[0087] base 1 solvent Response time (h) Yield (%) purity(%) Crystal form sodium hydroxide Dichloromethane 3 84.9 99.6 I sodium hydroxide acetone 3 84.2 99.5 II Pyridine Dichloromethane 3 87.5 99.7 I Sodium carbonate Dichloromethane 3 86.6 99.7 I

[0088] As can be seen from the above table: when selecting strong alkali, medium strength alkali or weak alkali, the purity of the obtained betrixaban hydrochloride can reach more than 99.5% (including 99.5%); select medium strength alkali or weak alkali as acid binding The product yield of the agent is higher than the product yield of the strong base as the acid binding agent.

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Abstract

The invention provides a preparation method of betrixaban and its hydrochloride, and their crystal forms. The method of the present invention is: compound III or its hydrochloride is reacted with thionyl chloride to obtain compound VIII or its hydrochloride, and then compound VIII or its hydrochloride and compound IV are acylized under the action of base 1. chemical reaction to obtain betrixaban hydrochloride shown in formula II; gained betrixaban hydrochloride is further reacted with base 2 to obtain betrixaban shown in formula I. The preparation method of betrixaban and its hydrochloride of the present invention has mild reaction conditions, simple operation, and is economical and effective, and betrixaban hydrochloride can be obtained directly from the crystallization of the reaction system without further purification, and is suitable for industrial scale production. Production; the purity of the obtained betrixaban and its hydrochloride can reach more than 99.5%, and has a new crystal form, stable properties, and storage, which is beneficial to the preparation of subsequent products.

Description

technical field [0001] The invention relates to the fields of organic chemistry and pharmacy, in particular to a preparation method of betrixaban and its hydrochloride, and their crystal forms. Background technique [0002] Betrixaban (structural formula shown in formula I), chemical name is N-(5-chloropyridin-2-yl)-2-[[[4-(N,N-dimethylamidino)benzoyl] Amino]-5-methoxybenzamide is a new type of oral factor Xa inhibitor anticoagulant developed by Portola Pharmaceutical Company of the United States, and is currently undergoing phase III clinical research abroad. [0003] [0004] Patent documents WO2012031017, WO2001019788, WO2007056517, CN104693114 and other patents have successively disclosed the preparation methods of betrixaban. [0005] Patent document WO2012031017 discloses the following preparation method (see Scheme 1): [0006] [0007] As shown in Scheme 1, in this preparation method, compound III and compound IV are subjected to condensation reaction under t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/75
CPCC07D213/75C07B2200/13
Inventor 王洁龚登凰盖京华杨敏杨杰孙文姣杨春巧蒋明阳
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD