Preparation method for dabigatran etexilate intermediate cyclocompound

A technology of dabigatran etexilate and cyclization products, which is applied in the field of preparation of dabigatran etexilate intermediate cyclization products, can solve problems such as low purity, difficult operation, and difficulty in meeting the strict requirements of anhydrous water limit, and achieve purity High, high yield effect

Inactive Publication Date: 2015-08-19
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The first and second reactions of this patent use THF as a solvent. Since THF and water are miscible, the water limit in the product supplied by the product is difficult to meet the stringent requirements of this reaction for anhydrous. In addition, THF is easy to absorb moisture. This reaction uses Strict water removal operations are required before, and THF has an unpleasant smell and high price, which brings great difficulties to industrialization
[0005] The third reaction of this patent

Method used

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  • Preparation method for dabigatran etexilate intermediate cyclocompound
  • Preparation method for dabigatran etexilate intermediate cyclocompound

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Add 1.77g (10mmol) of compound (II), 1.42g (10mmol) of compound (III), and 10ml of toluene, and heat up to 50°C for the first reaction for 1 hour. Add 3.42g (10mmol) of compound (IV) and raise the temperature to 60°C for the second reaction for 3 hours. The temperature was raised to 100° C. for the third reaction for 3 hours. The toluene was evaporated, and 5ml of ethanol was added to re-purify to obtain 4.30g of off-white powder cyclized product. Yield 84.6%, content 95.0%.

Embodiment 2

[0034] Add 1.77g (10mmol) of compound (II), 1.70g (12mmol) of compound (III), and 40ml of toluene, and heat up to 50°C for the first reaction for 1 hour. Add 4.10 g (12 mmol) of compound (IV) and raise the temperature to 60° C. for the second reaction for 3 hours. The temperature was raised to 100° C. for the third reaction for 3 hours. Toluene was evaporated, and 20ml of ethanol was added to re-purify to obtain 4.20g of off-white powder cyclized product. Yield 82.4%, content 94.8%.

Embodiment 3

[0036] Add 1.77g (10mmol) of compound (II), 1.42g (10mmol) of compound (III), and 10ml of heptane, and heat up to 30°C for the first reaction for 3 hours. Add 3.42g (10mmol) of compound (IV) and raise the temperature to 40°C for the second reaction for 6 hours. The temperature was raised to 60° C. for the third reaction for 6 hours. The heptane was distilled off, and 5 ml of methanol was added to re-purify to obtain 4.20 g of off-white powder cyclized product. Yield 81.9%, content 94.1%.

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Abstract

The invention belongs to the technical field of medicinal chemistry and particularly relates to a preparation method for a dabigatran etexilate intermediate cyclocompound. The preparation method comprises the following steps: adding ((4-cyanophenyl) phenyl) glycine (II)), carbonyldimidazole (III) and a first solvent into a reaction bottle, and rising the temperature to T1 to perform first reaction for t1; then, adding 3-((3-amino-4-methylaminobenzoyl) pyridin-2-ylamino) propionic acid ethyl ester (IV),and rising the temperature to T2 to continuously perform second reaction for t2; rising the temperature to T3 to continuously perform third reaction for t3; and evaporating off the first solvent to obtain a cyclocompound crude product, and adding a second solvent to perform recrystallization and refining so as to obtain the dabigatran etexilate intermediate cyclocompound (I). The preparation method is stable in process, simple to operate, strong in operability and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of a cyclized product of a dabigatran etexilate intermediate. Background technique [0002] Dabigatran etexilate (trade name is Pradaxa) was first listed in Germany and the UK in April 2008 by Boehringer Ingelheim of Germany. Dabigatran etexilate is a direct thrombin inhibitor, which has the characteristics of oral administration, strong potency, no need for special drug monitoring, and few drug interactions. [0003] In the preparation method provided by WO2013 / 024384A1 (2013.2.21, Page13, Example3), tetrahydrofuran (hereinafter referred to as THF) is used as solvent reflux for the first and second reactions, and the second reaction is evaporated at low temperature and reduced pressure. THF, adding glacial acetic acid as solvent reflux for the third reaction. Then the glacial acetic acid was distilled off, and the residue was dissol...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 郑忠辉张代铭翟吉胜徐玲赵彬窦国华于磊
Owner SHANDONG XINHUA PHARMA CO LTD
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