Method for preparing dabigatran amidated impurities

A technology of dabigatran etexilamide and dabi, which is applied in the field of preparing dabigatran etexilate amidation impurities, can solve the problems of complex operation and no impurity synthesis method, and achieve the effect of simple method and easy operation

Inactive Publication Date: 2016-05-11
BENGBU BBCA MEDICINE SCI DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, there are few research reports on this impurity. WO2012 / 152855A only mentions the impurity, analysis method and preparation technology of dabigatran etexilate that may be contained in dabigatran etexilate, but does not provide the synthesis method of this impurity. CN201410542553 Though provide a kind of method that dabigatran etexilate is destroyed and prepare this impurity, need chromatographic separation just can obtain this impurity high-purity product, complicated operation

Method used

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  • Method for preparing dabigatran amidated impurities
  • Method for preparing dabigatran amidated impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Embodiment 1 prepares compound (3)

[0025] Add 10g (33.36mmol) of compound (2) and 400g 0.1mol / L hydrochloric acid to a 1000mL reaction flask, heat to 60°C with stirring, keep at 60°C for 5h after dissolution, cool down and stir for crystallization. Suction filtration, washing with 20 mL of cold water, and vacuum drying at 45° C. for 4 hours gave 7.6 g of a yellow solid, yield 75.92%, HPLC: 98.72%.

Embodiment 2

[0026] Embodiment 2 prepares compound (3)

[0027] Add 10g (33.36mmol) of compound (2) and 400g of 0.1mol / L sulfuric acid to a 1000mL reaction flask, heat to 60°C under stirring, keep at 60°C for 5h after dissolution, cool down and stir for crystallization. Suction filtration, washing with 20 mL of cold water, and vacuum drying at 45°C for 4 hours gave 7.4 g of a yellow solid, yield 73.92%, HPLC: 98.54%.

Embodiment 3

[0028] Embodiment 3 prepares compound (3)

[0029] Add 10g (33.36mmol) of compound (2) and 300g 0.1mol / L hydrochloric acid to a 1000mL reaction flask, heat to 50°C with stirring, keep at 50°C for 5h after dissolution, cool down and stir for crystallization. Suction filtration, washing with 20 mL of cold water, and vacuum drying at 45°C for 4 hours gave 6.9 g of a yellow solid, yield 68.93%, HPLC: 97.36%.

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Abstract

The invention relates to the technical field of organic synthesis, in particular to a method for preparing dabigatran amidated impurities. The method includes subjecting a raw material, 4-aminobenzamidine-carbamic acid N-hexylester, to hydrolysis reaction to obtain a hydrolysate, and subjecting the hydrolysate and 3-[(3-amino-4-methyl amino benzoyl) pyridine-2-amino] ethyl propionate to condensation reaction under the action of a catalyst to obtain the dabigatran amidated impurities. The method has the advantages that final products, namely the dabigatran amidated impurities, can be obtained by the two-step method, the method is simple and easy to operate, high-purity composites can be obtained without chromatographic separation, and high-purity impurity comparison products can be provided for quality control of dabigatran drugs.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for preparing amidated impurities of dabigatran etexilate. Background technique [0002] Dabigatran (Dabigatran) was first disclosed in the patent WO98 / 37075, and later developed and marketed by Boehringer Ingelheim (Boehringer Ingelheim) in Germany. It is a new type of oral anticoagulant drug. The drug was first launched in Germany and the UK in April 2008, and was approved by the US FDA in October 2010 to reduce the risk of stroke and provincial embolism in patients with non-valvular atrial fibrillation. The drug has the characteristics of oral administration, strong potency, no need for special drug monitoring, and few drug interactions, so the market demand is relatively large. [0003] At present, the pharmaceutical research on dabigatran etexilate mesylate mainly focuses on the synthesis process of the finished drug and its intermediates. Patents US2010 / ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 李立标张瑾蔡雪燕陈昀郑爱李园魏珺璇
Owner BENGBU BBCA MEDICINE SCI DEV
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