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Preparation method of apixaban drug for preventing or treating joint replacement venous thrombosis

A technology of venous thrombosis and apixaban, which is applied in the field of drug synthesis, can solve the problems of cumbersome steps, harsh conditions, and high cost, and achieve the effects of simple process, increased yield, and reduced cost

Active Publication Date: 2018-02-02
张士伟 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The object of the present invention is to overcome the defects of low yield, harsh conditions, cumbersome steps and high cost in the existing method for preparing apixaban, and provide an antithrombotic drug with low cost, mild conditions, high yield and simple steps Preparation method of drug apixaban

Method used

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  • Preparation method of apixaban drug for preventing or treating joint replacement venous thrombosis
  • Preparation method of apixaban drug for preventing or treating joint replacement venous thrombosis
  • Preparation method of apixaban drug for preventing or treating joint replacement venous thrombosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] 1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl 3)phenyl]-4,5,6,7-tetrahydro- Preparation of 1H-pyrazole[3,4-c]pyridine-3-carboxylic acid ethyl ester

[0034] 1) Under the protection of nitrogen, mix 20.7g (150mmol) of p-methoxyphenylhydrazine, 10.2g (100mmol) of ethyl glyoxylate, 17g (piperidine), 10.2g of molecular sieve and 2.8g (20mmol) of cuprous bromide were added to the flask at 40°C to carry out the catalytic reaction. After the reaction, filter, and add borane dimethyl sulfide complex (2.0M in THF) to the filtrate at 20°C. , Containing borane dimethyl sulfide complex 12.2g) and the compound represented by formula I (DMF solution containing 28.4g of the compound represented by formula I), and then heated to 80°C for stirring and mixing reaction to the formula I The reaction of the compound shown is complete, and the reaction mixture L is obtained;

[0035] 2) The reaction mixture L obtained in step 1) was added to 100ml 4M HCl ice water and stirred for 2.5 hour...

Embodiment 2

[0037] 1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl 3)phenyl]-4,5,6,7-tetrahydro- Preparation of 1H-pyrazole[3,4-c]pyridine-3-carboxylic acid ethyl ester

[0038] 1) Under the protection of nitrogen, p-methoxyphenylhydrazine 19.3g (140mmol), ethyl glyoxylate 10.2g (100mmol), alkali 25.5g (piperidine), Molecular sieve 8.2g and cuprous bromide 1.4g (10mmol) were added to the flask at 35°C for catalytic reaction. After the reaction was completed, filtered, and added borane dimethyl sulfide complex (2.0M in THF) to the filtrate at 20°C. , Containing borane dimethyl sulfide complex 13.7g) and the compound represented by formula I (DMF solution containing 24.9g of the compound represented by formula I), and then heated to 60°C for stirring and mixing reaction to the formula I The reaction of the compound shown is complete, and the reaction mixture L is obtained;

[0039] 2) The reaction mixture L obtained in step 1) was added to 100ml 4M HCl ice water and stirred for 2.5 hours, ...

Embodiment 3

[0041] 1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl 3)phenyl]-4,5,6,7-tetrahydro- Preparation of 1H-pyrazole[3,4-c]pyridine-3-carboxylic acid ethyl ester

[0042] 1) Under the protection of nitrogen, 16.6g (120mmol) of p-methoxyphenylhydrazine, 10.2g (100mmol) of ethyl glyoxylate, 17.8g (tetrahydropyrrole), 13.3g of molecular sieve and 2.2g (15mmol) of cuprous bromide were added to the flask at 45°C to carry out the catalytic reaction. After the reaction was completed, it was filtered, and the borane dimethyl sulfide complex (2.0M in THF) was added to the filtrate at 25°C. , Containing borane dimethyl sulfide complex 11.4g) and the compound represented by formula I (DMF solution containing 31.9g of compound represented by formula I), and then heated to 70°C for stirring and mixing reaction to the formula I The reaction of the compound shown is complete, and the reaction mixture L is obtained;

[0043] 2) The reaction mixture L obtained in step 1) was added to 100ml 4M HCl ...

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Abstract

The invention discloses a method for preparing a drug Apixaban for preventing or treating venous thrombus after joint replacement. The method comprises the steps as follows: 1) p-tolylhydrazine and ethyl glyoxylate are subjected to a reaction by catalysis of cuprous bromide in the presence of an alkali and are filtered after the reaction is completed, a borane-methyl sulfide complex is added to a filtrate, a compound shown as the formula I is then added for stirred and mixed reaction, and a reaction mixture L is obtained; 2) the reaction mixture L obtained in the step 1) is stirred under the acidic condition; 3) 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidine-1-yl 3)phenyl]-4,5,6,7-tetrahydro-1H-pyrazole[3,4-c]pyridine-3-carboxylate in the step 1) is subjected to ammonolysis, and Apixaban with the formula shown in the specification is obtained. The method for preparing Apixaban has the advantages of mild condition and higher yield, a pyrazole ring product is generated with a one-pot method, the process is easier, the cost is greatly reduced, and the diazo-reaction widely adopted in the prior art is avoided.

Description

Technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to a preparation method of apixaban, a drug for preventing or treating joint replacement venous thrombosis Background technique [0002] Apixaban (Apixaban), the chemical name is 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl 3)phenyl]- 4,5,6,7-Tetrahydro-1H-pyrazole [3,4-c]pyridine-3-carboxamide is used to prevent and treat venous thromboembolism during hip or knee replacement surgery. Apixaban is a new type of direct inhibitor of factor Xa jointly developed by Bristol-Myers Squibb and Pfizer. The specific structure is as follows: [0003] [0004] At present, there are many reports on the synthesis methods of Apixaban, but there are still many problems in these methods. [0005] WO2010 / 030983 discloses a method for synthesizing apixaban. The method uses p-methoxyaniline as the starting material to undergo diazotization and then condense with ethyl chloroacetoacetate. The con...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 张士伟李玉国
Owner 张士伟
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