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Preparation method of apixaban

A technology for apixaban and its compounds, which is applied in the field of preparation of apixaban, and can solve problems such as cumbersome operation, large amount of waste water, and long steps

Active Publication Date: 2019-09-06
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] However, this route has long steps, cumbersome operation, and a large amount of waste water, which is not conducive to green industrial production

Method used

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  • Preparation method of apixaban
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  • Preparation method of apixaban

Examples

Experimental program
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Effect test

Embodiment 1

[0072] Embodiment 1: Preparation of 1-(4-nitrophenyl)piperidin-2-one-4-acetamide (III)

[0073] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, reflux condenser and dropping funnel, add 50 gram methanol, 60 gram toluene, 13.8 gram (0.1 mole) 4-nitroaniline, 4.5 gram sodium borohydride, 19.0 gram (0.1 mole) of 3-formylmethyl n-glutaric acid monomethyl ester monoamide (II), stirred and reacted at 60 to 65°C for 5 hours, and stirred at 95 to 100°C for 5 hours, while distilling and recovering methanol. Cool to 20 to 25°C, use 20wt% ammonium chloride aqueous solution to acidify the pH value of the system to 4.0-4.5, add 100 grams of dichloromethane, separate layers, extract the water layer with dichloromethane 3 times, 20 grams each time, and combine the organic phases , Dichloromethane and toluene were recovered by distillation to obtain 24.6 grams of 1-(4-nitrophenyl)piperidin-2-one-4-acetamide, the yield was 88.8%, and the liquid phase purit...

Embodiment 2

[0074] Example 2: Preparation of 1-(4-nitrophenyl)piperidin-2-one-4-acetamide (III)

[0075] In the 500 milliliter four-neck flask that is connected with stirring, thermometer, reflux condenser and dropping funnel, add 50 grams of tetrahydrofuran, 60 grams of toluene, 13.8 grams (0.1 moles) of 4-nitroaniline, 30.5 grams of triacetoxyboron Sodium hydride, 19.0 g (0.1 mole) of 3-formylmethyl n-glutaric acid monomethyl ester monoamide (II), stirred at 50 to 55°C for 6 hours, stirred at 95 to 100°C for 5 hours, and distilled and recovered tetrahydrofuran at the same time . Cool to 20 to 25°C, use 20wt% ammonium chloride aqueous solution to acidify the pH value of the system to 4.0-4.5, add 100 grams of dichloromethane, separate layers, extract the water layer with dichloromethane 3 times, 20 grams each time, and combine the organic phases , dichloromethane, tetrahydrofuran and toluene were recovered by distillation to obtain 24.9 g of 1-(4-nitrophenyl)piperidin-2-one-4-acetamide,...

Embodiment 3

[0076] Example 3: Preparation of 1-(4-nitrophenyl)piperidin-2-one-3,3-dichloro-4-dichloroacetamide (Ⅳ1)

[0077] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, reflux condenser and dropping funnel, add 220 grams of 1,2-dichloroethane, 13.9 grams (0.1 moles) of 1-(4- Nitrophenyl)piperidin-2-one-4-acetamide (III), 52.5 g of phosphorus pentachloride, stirred and reacted between 50 and 55° C. for 5 hours. Cool to 20 to 25°C, slowly add the resulting reaction mixture to 100 g of 1,2-dichloroethane and 300 g of crushed ice, and keep stirring, separate layers, and use 1,2-dichloroethane for the water layer Extract 3 times, 20 grams each time, combine the organic phases, and distill and recover 1,2-dichloroethane to obtain 21.2 grams of light brown viscous liquid 1-(4-nitrophenyl)piperidin-2-one-3 , 3-dichloro-4-dichloroacetamide was directly used in the next step (Example 5).

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Abstract

The invention provides a preparation method of apixaban. The method comprises the following steps: 3-formylmethyl-n-glutaric acid monoester monoamide (II) and 4-nitroaniline which are used as raw materials undergo reductive amination and intramolecular amidation reactions to produce 1-(4-nitrophenyl)piperidin-2-one-4-acetamide (III), the 1-(4-nitrophenyl)piperidin-2-one-4-acetamide (III) reacts with a halogenation reagent to obtain 1-(4-nitrophenyl)piperidin-2-one-3,3-dihalo-4-dihaloacetamide (IV), the 1-(4-nitrophenyl)piperidin-2-one-3,3-dihalo-4-dihaloacetamide (IV) and 4-methoxyphenylhydrazine hydrochloride are condensed to obtain 1-(4-methoxyphenyl)-7-oxo-6-(4-nitrophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (V), the 1-(4-methoxyphenyl)-7-oxo-6-(4-nitrophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide undergoes a hydrogenation reduction reaction, and the obtained reaction product and 5-oxo-n-pentanoate undergo reductive amination and intramolecular amidation reactions to form the apixaban (I). The method of the invention has the advantages of simplicity in operation, safety, greenness, low cost, high selectivity, and high yield and high purity of the product.

Description

technical field [0001] The invention relates to a preparation method of apixaban, which belongs to the technical field of medicinal chemistry. Background technique [0002] Apixaban (Apixaban, Ⅰ), the chemical name is l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, a novel direct factor Xa jointly developed by Bristol-Myers Squibb and Pfizer Inhibitors, which were approved by the European Union in March 2011 and approved by the US FDA on December 28, 2012, with a trade name of Eliquis, are used to prevent venous thromboembolism (VTE) in adult patients undergoing hip or knee replacement ) and atrial fibrillation. [0003] The chemical structural formula of apixaban is as follows: [0004] [0005] Patent documents WO2003049681 and WO2004083177 propose two routes for the preparation of apixaban, one of which is to use piperidin-2-one as a raw material and obtain 3,3-dichloropiperidin-2-one through ...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 戚聿新刘月盛张明峰周立山鞠立柱
Owner XINFA PHARMA
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