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Method for preparing apixaban

A technology of apixaban and a refining method, which is applied in the field of preparation of apixaban, can solve the problems of low yield and low purity, achieve the effects of less by-products, simple and convenient operation methods, and mild reaction conditions

Active Publication Date: 2015-05-20
SHANDONG NEWTIME PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] In order to overcome the common problems of low yield and low purity in the above-mentioned prior art, the first object of the present invention is to provide a synthetic method of apixaban, which specifically includes the following steps:

Method used

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  • Method for preparing apixaban
  • Method for preparing apixaban

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Compound (2) (4.9g) and 150mL of ethanol were sequentially added into a stainless steel autoclave, sealed, started to pass ammonia gas, heated to 60°C, kept the pressure at 0.3MPa, reacted for 8 hours, and stopped the reaction. After the reactor was cooled to room temperature, it was opened, filtered, and the filter cake was washed with ethanol. After drying, 4.32 g of white solid mp236-239°C was obtained. The yield was 94.02%, and the HPLC purity was 98.31%.

[0031] Ethanol refining: volume of ethanol: 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6, 7-Tetrahydro-1H-pyrazolo[3,4-C]pyridine-3-carboxamide Mass=30ML: 1G, stir and heat to reflux, the system is clear, filter the insoluble matter while it is hot, and stand for crystallization at 25°C After 12 hours, filter with suction and wash with ethanol to obtain a white solid, which is dried. Yield 92.04%, purity 99.23%.

[0032] Purification of isopropanol: volume of isopropanol: 1-(4-methoxyphenyl...

Embodiment 2

[0034] Compound (2) (4.9g) and 100mL of isopropanol were sequentially added into a stainless steel autoclave, sealed, started to pass ammonia gas, heated to 60°C, kept the pressure at 0.4MPa, reacted for 12 hours, and stopped the reaction. After the reactor was cooled to room temperature, it was opened, filtered, and the filter cake was washed with ethanol. After drying, 4.23 g of white solid mp236-239°C was obtained. The yield was 92.06%, and the HPLC purity was 97.15%.

[0035] Ethanol refining: volume of ethanol: 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6, 7-Tetrahydro-1H-pyrazolo[3,4-C]pyridine-3-carboxamide Mass=15ML: 1G, stir and heat to reflux, the system is clear, filter the insoluble matter while it is hot, and stand for crystallization at 25°C After 12 hours, filter with suction and wash with ethanol to obtain a white solid, which is dried. Yield 93.24%, purity 98.92%.

[0036] Purification of isopropanol: volume of isopropanol: 1-(4-methoxyp...

Embodiment 3

[0038] Compound (2) (4.9g) and 200mL of methanol were sequentially added into a stainless steel autoclave, sealed, started to pass ammonia gas, heated to 80°C, kept the pressure at 0.2MPa, reacted for 4 hours, and stopped the reaction. After the reactor was cooled to room temperature, it was opened, filtered, and the filter cake was washed with ethanol. After drying, 4.27 g of white solid mp236-239°C was obtained. The yield was 92.93%, and the HPLC purity was 97.51%.

[0039] Ethanol refining: volume of ethanol: 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6, 7-Tetrahydro-1H-pyrazolo[3,4-C]pyridine-3-carboxamide Mass=60ML: 1G, stir and heat to reflux, the system is clear, filter the insoluble matter while it is hot, and stand for crystallization at 25°C After 12 hours, filter with suction and wash with ethanol to obtain a white solid, which is dried. Yield 90.23%, purity 99.54%.

[0040] Purification of isopropanol: volume of isopropanol: 1-(4-methoxypheny...

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Abstract

The invention relates to the field of chemical pharmacy and particularly relates to a method for preparing apixaban. The method comprises the following steps: (1) synthetic method of apixaban crude product: performing ammonolysis by an ammonia-accessing method; (2) refining method of apixaban: the refining method includes ethyl alcohol refining and isopropanol refining. The purity of the compounded apixaban is more than 97%, the byproducts are few, the operation method is simple and the reaction process is easy to control, at the same time, the yield of the ammonolysis is more than 91%; after two refining processes, the purity of the apixaban is greatly increased to more than 99.6%, and the single impurity is less than 0.1% and the yield is more than 90%. The solvent used in the refining process is low in toxicity, high in safety, cheap and easy to obtain. The refining process is simple in operation, mild in reaction condition, low in cost and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of chemical pharmacy, in particular to a preparation method of apixaban. Background technique [0002] Apixaban (apixaban, trade name Eliquis), chemical name: 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl) Phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-C]pyridine-3-carboxamide; molecular formula: C25H25N5O4; molecular weight: 459.50; CAS registration number: 503612-47- 3. The chemical structure is: [0003] [0004] For the synthesis of apixaban, 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5 , 6,7-tetrahydro-1H-pyrazolo[3,4-C]pyridine-3-carboxylic acid ethyl ester was obtained by ammonolysis. [0005] [0006] In the literature [pinto D.J.P.et.J.Med.Chem.2007, 50(22):5339-5356] and patent WO2010030983, ammonolysis is carried out with ammonia in ethylene glycol solution. WO2010030983 but the total yield is only 1.3%. [0007] In patent WO2003049681, compound (2) is reacted with 10 times e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 张贵民张纪云董怀民马超翟立海
Owner SHANDONG NEWTIME PHARMA
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