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A kind of preparation method of the intermediate of apixaban

A technology for intermediates and compounds, applied in the field of preparation of intermediates, can solve problems such as low yield, and achieve the effects of high product yield, low cost and high purity

Inactive Publication Date: 2015-10-21
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The technical problem to be solved by the present invention is to provide a method for preparing an intermediate of apixaban in order to overcome the defect of low yield in the existing intermediate preparation method of apixaban

Method used

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  • A kind of preparation method of the intermediate of apixaban
  • A kind of preparation method of the intermediate of apixaban
  • A kind of preparation method of the intermediate of apixaban

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Example 1: 1-(4-methoxyphenyl)-7-carbonyl-6-[4-(2-carbonylpiperidinyl)phenyl]-4,5,6,7-tetrahydro-1H- Preparation of ethyl pyrazolo[3,4-c]pyridine-3-carboxylate

[0031] Dissolve compound 3 (11.4g, 0.03mol), compound 4 (12.6g, 0.045mol), triethylamine (13.2ml, 0.09mol) in dichloromethane (250ml), reflux for 9 hours, add 4mol / L hydrochloric acid (64ml, 0.25mol), stirred for 2 hours. Liquid separation, extraction with dichloromethane, washing with water, drying over anhydrous magnesium sulfate, evaporation of the solvent to give a reddish-brown solid, which was recrystallized from absolute ethanol to give 12.6 g of a white solid. Yield: 80%, HPLC: 99.7%. (instrument: Agilent1260 high performance liquid chromatography, chromatographic column: C18, column length: 25cm, mobile phase: (water: acetonitrile=50:50), flow rate: 1.0ml / min, wavelength: 254nm, column temperature: 30 ℃, Injection volume: 20 μL).

[0032] MS (ESI, m / z): 489.21[M+1], 506.24[M+NH 4 + ]

[0033] 1...

Embodiment 2

[0034] Example 2: 1-(4-methoxyphenyl)-7-carbonyl-6-[4-(2-carbonylpiperidinyl)phenyl]-4,5,6,7-tetrahydro-1H- Preparation of ethyl pyrazolo[3,4-c]pyridine-3-carboxylate

[0035] Dissolve compound 3 (3.8g, 0.01mol), compound 4 (4.2g, 0.015mol), triethylamine (4.4ml, 0.03mol) in dichloromethane (90ml), reflux for 12 hours, add 4mol / L hydrochloric acid (21ml, 0.08mol), stirred for 2 hours. Liquid separation, extraction with dichloromethane, washing with water, drying over anhydrous magnesium sulfate, evaporation of the solvent to give a reddish-brown solid, which was recrystallized from absolute ethanol to give 4.3 g of a white solid. Yield: 82%, HPLC: 99.6%.

Embodiment 3

[0036] Example 3: 1-(4-methoxyphenyl)-7-carbonyl-6-[4-(2-carbonylpiperidinyl)phenyl]-4,5,6,7-tetrahydro-1H- Preparation of ethyl pyrazolo[3,4-c]pyridine-3-carboxylate

[0037] Dissolve compound 3 (3.0g, 0.008mol), compound 4 (2.5g, 0.0088mol), triethylamine (3.4ml, 0.024mol) in dichloromethane (70ml), reflux for 12 hours, add 4mol / L hydrochloric acid (16ml, 0.06mol), stirred for 2 hours. Separation, extraction with dichloromethane, washing with water, drying over anhydrous magnesium sulfate, evaporation of the solvent to give a reddish-brown solid, which was recrystallized from acetonitrile to give 3.3 g of a white solid. Yield: 80%, HPLC: 99.6%.

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Abstract

The invention relates to a preparation method of an apixaban intermediate shown as the formula 2. The preparation method comprises steps of (1) reacting a compound 3 and a compound 4 under reflux conditions and under the action of an organic alkali, wherein dichloromethane is used as solvent; and (2) continuously reacting the reaction liquid obtained in the step (1) under the action of an inorganic acid, wherein the mole ratio of the compound 3 to the compound 4 is 1: 1.1-1:3. The preparation method is low in cost, high in product yield and high in purity, and is simple, convenient, and suitable for industrial production.

Description

technical field [0001] The present invention specifically relates to a preparation method of an intermediate of apixaban. Background technique [0002] Thrombosis is mainly divided into arterial thrombosis and venous thrombosis. Venous thromboembolism (VET) is induced by various reasons in venous blood vessels, and its main clinical manifestations are deep venous thrombosis (DVT) and pulmonary embolism (pulmonary embolism, PE), which is a serious hazard to human health. Pulmonary embolism is one of the common respiratory and cardiovascular diseases. Deep vein thrombosis mainly occurs after major orthopedic surgery. Taking anticoagulant drugs is the main method to prevent thrombosis, which can effectively reduce mortality and prevent recurrence. [0003] Apixaban (Apixaban, 1) is a new oral inhibitor of factor Xa. Factor Xa is a key regulator in the coagulation cascade, located at the upper end of thrombin, and the coagulation cascade is a process of gradual amplification ,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 霍韶伟郭晔堃钟静芬时惠麟
Owner SHANGHAI INST OF PHARMA IND CO LTD
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