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Synthetic method for Apixaban drug intermediate

A synthetic method, the technology of apixaban, applied in the field of synthesis, to achieve the effects of reducing the generation of impurities, avoiding reaction conditions, and improving reaction efficiency

Inactive Publication Date: 2015-08-19
SHANGHAI TWISUN BIO PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In view of the shortcomings of the reported synthetic methods, in actual industrial production, considering factors such as preparation technology, safety, and cost control, the synthetic route of apixaban in the prior art still needs further improvement

Method used

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  • Synthetic method for Apixaban drug intermediate
  • Synthetic method for Apixaban drug intermediate
  • Synthetic method for Apixaban drug intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Synthesis of 1-(4-nitrophenyl) piperidone:

[0058] P-nitroaniline (100g, 0.724mol) was added to tetrahydrofuran (500mL), triethylamine (146.5g, 1.448mol) was added, and the reaction flask was replaced with nitrogen for protection. Begin to cool down to the internal temperature of -5-0°C, add 5-chlorovaleryl chloride (140.3g, 0.905mol) in tetrahydrofuran (180mL) solution dropwise to the reaction solution, control the temperature at -5-5°C, add dropwise to 0- Incubate at 5°C for half an hour, then heat to 23-25°C, and stir for 2 hours. The internal temperature was lowered to -5-0°C, solid potassium tert-butoxide (223.4g, 1.991mol) was added in batches, the temperature was controlled at 0-25°C, the temperature was raised to 23-25°C after the addition, and the stirring was continued for 12 hours. The reaction solution was concentrated to dryness, 600 mL of dichloromethane was added, 800 mL of water was added, and the separation was carried out. The aqueous phase was extracte...

Embodiment 2

[0061] Synthesis of compound 2:

[0062] The dichloromethane solution obtained in Example 1 was added to the reaction flask, the internal temperature was controlled at 20-25° C., and solid phosphorus pentachloride (560 g, 2.69 mol) was added in batches. The reaction was violent, smoking and heating up. After the addition was completed, the reaction was heated to reflux, and the stirring was continued for 1 hour. The reaction solution was cooled to 20-25°C, and the reaction solution was slowly poured into stirring ice water (1.2L) for extraction. The layers were separated, the aqueous phase was extracted with 400 mL of dichloromethane, and the organic phases were combined. Wash with saturated sodium bicarbonate to pH 7-8, then wash with 500 mL of brine. The organic phase was concentrated to viscous, and 440 mL of methyl tert-butyl ether was added under mechanical stirring. A large amount of solids precipitated, filtered with suction, the filter cake was washed with (100 mL) met...

Embodiment 3

[0067] Synthesis of compound 6:

[0068] Sodium sulfide nonahydrate (76g, 0.32mol) was added to 500mL water, heated to 60-65°C and stirred to dissolve. Then the compound 2 (100 g, 0.33 mol) obtained in Example 2 was added. After the addition, the internal temperature of the reaction was raised to 75-80° C. and the reaction was stirred for 2 hours. Add sodium sulfide nonahydrate (40g, 0.167mol) and continue to stir for 2 hours. A total of 4 supplements of sodium sulfide nonahydrate, 40g each time, continue stirring for 2 hours after each supplement. After all four additions were completed, the reaction was continued with stirring at 75-80°C for 12 hours. Cool down to 45℃-50℃ and filter with suction. The filter cake was slurried with 500 mL of water for 1 hour, and then filtered with suction. The filter cake was slurried with 400 mL of ethanol for 1 hour, and then filtered with suction. The filter cake was vacuum dried at 50°C for 12 hours to obtain 83.9 g of compound 6 with a ...

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Abstract

The present invention provides a synthetic method for an Apixaban drug intermediate. According to the invention, the reduction reaction of nitro groups in a compound 2 is conducted by sodium sulphide and amino groups in the compound 2 are protected by 5-chloro-pentanoyl. Therefore, the synthesis of Apixaban can be realized more simply and more directly. A novel one-pot synthesis method is provided by the invention and the method is mild in reaction conditions, high in safety coefficient, strong in maneuverability, simple in process and easy to industrialize. Meanwhile, a high-purity intermediate compound 14-1 can be obtained, so that the Apixaban of high purity and super-low impurity content can be obtained more easily. At the same time, the invention provides an effective and novel synthetic method for the preparation of an Apixaban key intermediate. By means of the method, the reaction efficiency is improved, and the production cost is lowered. The adoption of expensive reagents and severe reaction conditions can be avoided.

Description

Technical field [0001] The invention relates to a synthetic method, in particular to a new method for synthesizing an anticoagulant apixaban intermediate. Background technique [0002] Apixaban (ELIQUIS) is an oral selective activated factor Xa inhibitor, a new generation of oral anticoagulant drug jointly developed by Bristol-Myers Squibb and Pfizer. As a new type of oral factor Xa inhibitor, it does not require routine blood clotting function monitoring, is easy to use, and can be used for adult patients undergoing elective hip or knee replacement surgery to prevent venous thromboembolism. Some experts believe that Apixaban is the best alternative to warfarin. Compared with warfarin that has been used for decades, apixaban has an anticoagulant effect that reduces the risk of stroke by 21%, major bleeding by 31%, and mortality by 11%, and its safety and effectiveness are superior to similar drugs . Therefore, it is generally believed that apixaban will occupy a leading positi...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCY02P20/55C07D471/04
Inventor 叶方国汪太亮
Owner SHANGHAI TWISUN BIO PHARM
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