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Dabigatran etexilate mesylate and preparation method thereof

A technology for dabigatran etexilate mesylate and aminobenzamidine dihydrochloride is applied in the field of chemical and pharmaceutical preparation, and can solve the problem of high raw material prices, unfavorable market promotion, and production of dabigatran etexilate mesylate. Low production rate and other problems, to achieve the effect of reducing production cost and high yield

Inactive Publication Date: 2020-09-01
安徽鼎旺医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The dabigatran etexilate mesylate productive rate prepared by the existing dabigatran etexilate mesylate preparation process is lower, and the raw material price used for preparing dabigatran etexilate mesylate is higher, making The preparation cost of dabigatran etexilate mesylate is greatly improved, which is not conducive to market promotion

Method used

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  • Dabigatran etexilate mesylate and preparation method thereof
  • Dabigatran etexilate mesylate and preparation method thereof
  • Dabigatran etexilate mesylate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] A kind of dabigatran etexilate mesylate, is made by following steps:

[0040] Step S1: Add 4-aminobenzamidine dihydrochloride, toluene, triethylamine, and deionized water into the reaction kettle, stir for 10 minutes at a rotation speed of 200r / min and a temperature of 25°C, and then cool down At a temperature of 5°C, n-hexyl chloroformate was added dropwise at a rate of 0.1 L / h, and the reaction was carried out for 1 hour. At a temperature of 120°C, toluene and water were distilled off to obtain intermediate 1;

[0041] Step S2: Add ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-2-yl)benzamido)propionate, ethanol, tin powder and concentrated hydrochloric acid into the reaction kettle , at a rotation speed of 200r / min and a temperature of 95°C, reflux reaction was carried out for 30 minutes, cooled to a temperature of 25°C, and sodium hydroxide solution was added until the pH value was 8 to obtain intermediate 2;

[0042]Step S3: Add chloroacetic acid to ethyl acetate, st...

Embodiment 2

[0046] A kind of dabigatran etexilate mesylate, is made by following steps:

[0047] Step S1: Add 4-aminobenzamidine dihydrochloride, toluene, triethylamine, and deionized water into the reaction kettle, stir for 13 minutes at a rotation speed of 250r / min and a temperature of 28°C, and then cool down At a temperature of 8°C, n-hexyl chloroformate was added dropwise at a rate of 0.15 L / h, and the reaction was carried out for 1.5 hours. At a temperature of 125°C, toluene and water were distilled off to obtain intermediate 1;

[0048] Step S2: Add ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-2-yl)benzamido)propionate, ethanol, tin powder and concentrated hydrochloric acid into the reaction kettle , at a rotation speed of 250r / min and a temperature of 98°C, reflux reaction was carried out for 35 minutes, cooled to a temperature of 28°C, and sodium hydroxide solution was added until the pH value was 8 to obtain intermediate 2;

[0049] Step S3: Add chloroacetic acid to ethyl acetat...

Embodiment 3

[0053] A kind of dabigatran etexilate mesylate, is made by following steps:

[0054] Step S1: Add 4-aminobenzamidine dihydrochloride, toluene, triethylamine, and deionized water into the reaction kettle, stir for 15 minutes at a rotation speed of 300r / min and a temperature of 30°C, and then cool down When the temperature is at 10°C, add n-hexyl chloroformate dropwise at a rate of 0.2 L / h, react for 1-2 hours, and at a temperature of 130°C, carry out distillation to remove toluene and water to obtain intermediate 1 ;

[0055] Step S2: Add ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-2-yl)benzamido)propionate, ethanol, tin powder and concentrated hydrochloric acid into the reaction kettle , at a rotation speed of 300r / min and a temperature of 100°C, reflux reaction was carried out for 40 minutes, cooled to a temperature of 30°C, and sodium hydroxide solution was added until the pH value was 9 to obtain intermediate 2;

[0056] Step S3: Add chloroacetic acid to ethyl acetate, st...

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Abstract

The invention discloses a dabigatran etexilate mesylate and a preparation method thereof. The preparation method comprises the following steps: carrying out amide reaction on 4-aminobenzamidine dihydrochloride and n-hexyl chloroformate to prepare an intermediate 1; reducing 3-(4-(methylamino)-3-nitro-N-(pyridine-2-yl) benzoylamino) ethyl propionate by using tin powder and concentrated hydrochloricacid; reducing nitro groups to amino groups to prepare an intermediate 2, reacting the intermediate 2 with chloroacetic acid for cyclization to obtain an intermediate 3; condensing the intermediate 3with the intermediate 1 under the combined action of potassium iodide and potassium bicarbonate to prepare an intermediate 4, reacting the intermediate 4 with a methanesulfonic acid to form a salt, so that the dabigatran etexilate mesylate is prepared. The dabigatran etexilate mesylate prepared by the preparation method disclosed by the inventionis high in yield, and compared with the existing preparation method, most of the used raw materials are low-price raw materials, so that the production cost of the dabigatran etexilate mesylate is greatly reduced.

Description

technical field [0001] The invention belongs to the technical field of chemical and pharmaceutical preparation, and in particular relates to a dabigatran etexilate methanesulfonate and a preparation method thereof. Background technique [0002] Dabigatran etexilate is a new type of oral anticoagulant drug. It has good anticoagulant efficacy, low toxicity, good tolerance, and few adverse effects. Coagulation function testing is widely welcomed. Dabigatran etexilate mesylate is the prodrug of dabigatran etexilate, which can effectively improve the absorption of dabigatran etexilate in human body. [0003] The dabigatran etexilate mesylate productive rate prepared by the existing dabigatran etexilate mesylate preparation process is lower, and the raw material price used for preparing dabigatran etexilate mesylate is higher, making The preparation cost of dabigatran etexilate mesylate is greatly improved, which is not conducive to marketing. Contents of the invention [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D213/75C07C309/04C07C303/32C07C257/20
CPCC07C257/20C07C303/32C07C309/04C07D213/75C07D401/12
Inventor 孙学喜杨会来毛杰
Owner 安徽鼎旺医药有限公司
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