Method for preparing apixaban

A technology of apixaban and compounds, which is applied in the field of preparation of pharmaceutical compounds, can solve problems such as long routes, unsuitable for industrial production of raw materials, expensive metal catalysts, etc., achieve high reaction yield, facilitate industrial production, and facilitate simple operation Effect

Inactive Publication Date: 2019-07-12
JIANGXI GUOYAO PHARMA LLC
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0034] Based on the above routes, there are long routes in the process of preparing apixaban, and operations such as high-temperature reflux reactions, chlorination reactions, hydrogenation reactions, flammable and explosive reagents, and expensive metal catalysts are not suitable for industrialized production of raw materials

Method used

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  • Method for preparing apixaban
  • Method for preparing apixaban

Examples

Experimental program
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Effect test

Embodiment 1

[0062]

[0063] At -5°C to 0°C, add 80Kg of acetone, compound II (10.0Kg, 25.5mol), and 40% potassium carbonate aqueous solution (10Kg, 29.0mol) into the reaction kettle (300L). Stir to lower the temperature, control the temperature from -5°C to 0°C, and slowly add 5-chlorovaleryl chloride (4.7Kg, 30.3mol). The reaction was incubated for 30 minutes, and TLC detected that there was no residue of the raw material compound II. Add 120Kg of purified water, and control the temperature at -5°C to 0°C to stir and crystallize for 20min. centrifugal. Dry at 50°C to obtain 12.4Kg of compound IV.

[0064] Yield: 97.1%, HPLC: 99.71%.

Embodiment 2

[0066]

[0067] At 25°C to 30°C, add 133Kg of dichloromethane, compound IV (10.0Kg, 19.6mol), potassium carbonate (7.2Kg, 52.1mol), tetrabutylammonium fluoride (6.7Kg, 25.6 mol). Stir the reaction for 1 h, and TLC detects that there is no residue of the starting compound IV. Add 100kg of purified water, stir and let stand to separate layers, continue to wash the organic phase once with 100kg of water, and dry with 5kg of anhydrous sodium sulfate for 1 hour. After filtering, the filtrate was concentrated, and after no effluent was added, 70 kg of isopropyl acetate was added, stirred for 2 hours, and centrifuged. Dry at 50°C to obtain 7.5Kg of compound V.

[0068] Yield: 80.6%, HPLC: 99.45%.

Embodiment 3

[0070]

[0071] At -5°C to 5°C, add 27Kg of N,N-dimethylformamide, compound V (7.0Kg, 14.7mol) and formamide (6.7Kg, 148.8mol) into the reaction kettle (100L). Stir to lower the temperature, control the temperature at -5°C to 5°C, and slowly add 30% sodium methoxide methanol solution (3.7Kg, 20.6mol). The reaction was incubated for 1 h, and no residual compound V was detected by TLC. Continue to insulate and stir for 2h. centrifugal. The solid was transferred to a reaction kettle (100 L), and 50 kg of ethanol was added for beating for 1 hour, and centrifuged. Dry at 50°C to obtain 5.4Kg of compound I.

[0072] Yield: 79.9%, HPLC: 99.89%.

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Abstract

The invention discloses a method for preparing apixaban. The method comprises the following steps: 1) subjecting a compound represented by a formula II to a reaction with a compound represented by a formula III in a two-phase system of water and an organic solvent, so as to obtain a compound represented by a formula IV; 2) subjecting the compound represented by the formula IV to a cyclization reaction in the presence of alkali and a phase transfer catalyst, so as to obtain a compound represented by a formula V; and subjecting the compound represented by the formula V to an ammonolysis reaction, thereby obtaining the apixaban represented by a formula I. The method is simple in operation and low in cost and is applicable to large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical compound, in particular to a preparation method of Apixaban. Background technique [0002] The chemical name of Apixaban is: 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5 , the preparation method of 6,7-tetrahydro-1H-pyrazolo(3,4-c)pyridine-3-carboxamide, chemical abstract number: 503612-47-3, its structural formula is as follows: [0003] [0004] Apixaban (BMS-562247) is an anticoagulant drug jointly developed by Bristol-Myers Squibb and Pfizer. It was approved for marketing in the EU in May 2011 for the prevention of elective hip Venous thromboembolic events (VTE) in adult patients undergoing joint or knee replacement. In December 2012, Apixaban tablets were successively approved in the United States, Japan, and Canada for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation. In March 2014, the United States adde...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 孟周钧万义斌葛友群左飞鸿杨明余承祥柒伟超刘威杨建国姚文涛胡凯璇刘林华
Owner JIANGXI GUOYAO PHARMA LLC
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