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Preparation method for drug apixaban intermediate preventing venous thrombosis after hip and knee replacement surgeries

A technology of venous thrombosis and apixaban, which is applied in the field of medicine, can solve the problems of long route, low yield, and difficult purification, and achieve the effect of high product purity, high product yield, and simple preparation process

Inactive Publication Date: 2018-04-20
董丹丹
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] And the existing method route for preparing intermediate is all long, and yield is not high, and purification is difficult, and reaction condition is also extremely strict, therefore needs a kind of simple, the method for preparing its intermediate with high yield badly

Method used

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  • Preparation method for drug apixaban intermediate preventing venous thrombosis after hip and knee replacement surgeries
  • Preparation method for drug apixaban intermediate preventing venous thrombosis after hip and knee replacement surgeries
  • Preparation method for drug apixaban intermediate preventing venous thrombosis after hip and knee replacement surgeries

Examples

Experimental program
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Effect test

Embodiment 1

[0030] The preparation method of the drug apixaban intermediate for preventing venous thrombosis after hip and knee replacement surgery comprises the following process steps:

[0031] (1) Mix 2-hydroxypiperidine ① (5g, 1.6mol) with p-hydroxychlorobenzene ② (7g, 1.8mol), and add catalyst bisulfite in the presence of 85% concentrated sulfuric acid solution (30ml) of inorganic acid solution Sodium was thoroughly mixed and stirred, and an alkylation reaction occurred at 2.7MPa and 230°C to generate (2-hydroxypiperidin-1-yl)chlorobenzene③ (9.6g, 2.92mol);

[0032] (2) (2-hydroxypiperidin-1-yl) chlorobenzene ③ (9.6g, 2.92mol) generated in step (1) was added as catalyst ferric chloride, and dilute sulfuric acid (30ml) and water (40ml) Fully mixed and stirred in the presence of the mixed solution to generate (2-oxopiperidin-1-yl)chlorobenzene ④ (7.78g, 1.9mol);

[0033] (3) Dissolve ethyl 5-formamido-4-ethyl-pyrazole-3-carboxylate ⑤ (8g, 2.2mol) in the organic solvent carbon tetrachl...

Embodiment 2

[0040] The preparation method of the drug apixaban intermediate for preventing venous thrombosis after hip and knee replacement surgery comprises the following process steps:

[0041] (1) Mix 2-hydroxypiperidine ① (16.5g, 2.0mol) with p-hydroxychlorobenzene ② (15g, 1.8mol), and add catalyst sulfurous acid in the presence of 85% concentrated sulfuric acid solution (80ml) of inorganic acid Sodium hydrogen was thoroughly mixed and stirred, and an alkylation reaction occurred at 2.7MPa and 230°C to generate (2-hydroxypiperidin-1-yl)chlorobenzene③ (25.2g, 3.9mol);

[0042] (2) (2-hydroxypiperidin-1-yl) chlorobenzene ③ (25.2g, 3.9mol) generated in step (1) is added with catalyst iron trichloride, and dilute sulfuric acid (70ml) and water (100ml) Fully mixed and stirred in the presence of the mixed solution to generate (2-oxopiperidin-1-yl)chlorobenzene ④ (20.16g, 3.7mol);

[0043](3) Dissolve ethyl 5-formamido-4-ethyl-pyrazole-3-carboxylate ⑤ (20g, 2.57mol) in the organic solvent c...

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Abstract

The invention discloses a preparation method for a drug apixaban intermediate preventing venous thrombosis after hip and knee replacement surgeries. The chemical name of the drug apixaban intermediatepreventing venous thrombosis after hip and knee replacement surgeries is 7-oxo-6-[4-(2-oxopipperidine-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazole[3,4-c]pyridine-3-forma-mide, and a structural formulathereof is as shown in the description. The simple preparation method uses raw materials easy to obtain, is economical and environmentally friendly, has high yield and produces highly pure product, is suitable for industrial production, can advance the economic technology of active ingredients of the apixaban intermediate, and lowers the production cost. The explored new intermediate preparationmethod is significant for the economic technology of apixaban.

Description

Technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of an intermediate of apixaban, a drug for preventing venous thrombosis after hip and knee replacement operations. Background technique [0002] Apixaban is a new oral direct factor Xa inhibitor. It is an anticoagulant jointly developed by Bristol-Myers Squibb and Pfizer. ) and pulmonary embolism (pulmonary embolism, PE), approved for the prevention of thrombosis in patients who have undergone hip or knee replacement surgery, its structural formula is as follows: [0003] [0004] There are multiple synthetic methods for the preparation of apixaban at present, but most of them prepare apixaban through the preparation of intermediates. The structural formula of the intermediates is as follows: [0005] [0006] However, the existing methods for preparing intermediates have long routes, low yields, difficult purification, and extremely strict reaction c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 董丹丹
Owner 董丹丹
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