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Preparation method of apixaban and intermediates thereof

A technology for apixaban and its intermediates, applied in the field of preparation of apixaban and its intermediates, capable of solving problems such as high production costs, high requirements for production equipment, and unsuitability for industrialized production

Active Publication Date: 2018-04-24
SHANGHAI BOCIMED PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved by the present invention is to overcome the preparation method of apixaban in the prior art with long steps, high operational risk, serious environmental pollution, high requirements for production equipment, cumbersome post-treatment process, low yield and high production cost. , not suitable for industrialized production and other defects and provide a preparation method of apixaban and its intermediates

Method used

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  • Preparation method of apixaban and intermediates thereof
  • Preparation method of apixaban and intermediates thereof
  • Preparation method of apixaban and intermediates thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0082] Embodiment 1: Preparation of Apixaban Intermediate II

[0083]

[0084] Under nitrogen protection, 18.2 g of 5,6-dihydro-3-(4-morpholinyl)-2(1H)-pyridone and [(4-methoxyphenyl)hydrazine were added to 540 mL of ethyl acetate ] Ethyl chloroacetate 38.5g, add triethylamine 20.3g under stirring, heat the reaction to 75-85°C and stir for 16 hours. Cool to 15-25°C, filter and add 32 mL of trifluoroacetic acid dropwise, and stir at 15-25°C for 2 hours. Add 10% sodium bicarbonate aqueous solution to quench (the said mass percent refers to the percentage of the mass of sodium bicarbonate in the total mass of sodium bicarbonate aqueous solution), and then extract once with ethyl acetate. Organic phase is that 10% sodium bicarbonate aqueous solution and mass percentage are 15% salt water washings (described mass percentage is meant that the quality of sodium chloride accounts for the percentage of the total mass of saline solution) with mass percentage, without water and sodi...

Embodiment 2

[0085] Embodiment 2: Preparation of Apixaban Intermediate II

[0086]

[0087] Under nitrogen protection, 18.2 g of 5,6-dihydro-3-(4-morpholinyl)-2(1H)-pyridone and [(4-methoxyphenyl)hydrazine were added to 360 mL of ethyl acetate ] 30.8 g of ethyl chloroacetate, 19.4 g of diisopropylethylamine was added under stirring, and the reaction was heated to 85-95° C. and stirred for 20 hours. Cool to 15-25°C, filter and add 35 mL of trifluoroacetic acid dropwise, and stir at 15-25°C for 2 hours. Adding mass percentage composition is that 10% sodium bicarbonate aqueous solution is quenched (the described mass percentage composition refers to the percentage that the quality of sodium bicarbonate accounts for the total mass of sodium bicarbonate aqueous solution, the same below), then extracts with ethyl acetate for 1 Second-rate. Organic phase is that 10% sodium bicarbonate aqueous solution and mass percentage are 15% salt water washings (described mass percentage is meant that th...

Embodiment 3

[0089] Embodiment 3: Preparation of Apixaban Intermediate II

[0090]

[0091] Under nitrogen protection, 18.2 g of 5,6-dihydro-3-(4-morpholinyl)-2(1H)-pyridone and [(4-methoxyphenyl)hydrazino]chloride were added to 720 mL of toluene 64.1 g of ethyl acetate, 92.6 g of tri-n-butylamine was added under stirring, the reaction was heated to 95-105°C and stirred for 12 hours. Cool to 15-25°C, filter and add 50 mL of trifluoroacetic acid dropwise, and stir at 15-25°C for 2 hours. Adding mass percentage composition is that 10% sodium bicarbonate aqueous solution is quenched (the described mass percentage composition refers to the percentage that the quality of sodium bicarbonate accounts for the total mass of sodium bicarbonate aqueous solution, the same below), then extracts with ethyl acetate for 1 Second-rate. Organic phase is that 10% sodium bicarbonate aqueous solution and mass percentage are 15% salt water washings (described mass percentage is meant that the quality of so...

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Abstract

The invention discloses a preparation method of apixaban and intermediates thereof. The invention provides a preparation method of an apixaban intermediate I. The preparation method of the apixaban intermediate I comprises the step of performing nucleophilic substitution reaction on an apixaban intermediate II and p-fluoronitrobenzene in an organic solvent in the presence of an alkali to obtain the apixaban intermediate I. The preparation method has short steps, simple and safe operation, simple post-treatment steps, environmental friendliness and high total yield, and the obtained product hashigh purity, low production cost and high atomic utilization, and is suitable for industrial production. The formula is shown in the description.

Description

Technical field [0001] The present invention relates to a preparation method of apixaban and its intermediates. Background technique [0002] The new antibacterial drug apixaban (III) is an anticoagulant product jointly developed and sold by Bristol-Myers Squibb and Pfizer in a global strategic partnership. In 2011, it was the first in the 27 EU countries, Iceland and Norway to be approved for the prevention of venous thrombosis in adult patients undergoing elective hip or knee replacement surgery; in January 2013, it obtained the import drug license issued by the China State Food and Drug Administration. , used for adult patients undergoing elective hip or knee replacement to prevent venous thromboembolism events. It was officially launched in China in April 2013. [0003] [0004] Apixaban is a new oral anticoagulant drug. The recommended dose is 2.5 mg, taken orally twice a day. It can effectively prevent venous thromboembolism without increasing the risk of bleeding....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 陈健刘振峰应述欢
Owner SHANGHAI BOCIMED PHARMA CO LTD
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