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Method for preparing antithrombotic drug apixaban

An antithrombotic drug, apixaban technology, applied in the direction of organic chemistry, etc., can solve the problems that products are difficult to meet API standards, difficult to large-scale production, and limited industrial production, and achieve large-scale production, easy large-scale production, etc. Simple and convenient production and post-processing

Active Publication Date: 2014-07-16
PHARMA SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the total yield of this route has been improved to a certain extent, it still adopts a linear synthetic route, which is long and difficult to realize large-scale production; it also uses a large amount of 5-bromovaleryl chloride and phosphorus pentachloride, which are unstable and difficult to recover. The raw materials to be processed and the expensive palladium-carbon hydrogenation conditions all limit industrial production; the last step of ammonolysis uses N,N-dimethylformamide as a solvent, and the solvent is easy to remain and difficult to remove, making it difficult for the product to meet the API standard

Method used

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  • Method for preparing antithrombotic drug apixaban
  • Method for preparing antithrombotic drug apixaban
  • Method for preparing antithrombotic drug apixaban

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0046] About the preparation steps of compound A:

[0047]

[0048] Step 1: Dissolve p-methoxyaniline in tetrafluoroboric acid and water, cool down to -10°- -5° with an ice-salt bath, slowly add a solution of sodium nitrite dissolved in water, and keep the temperature at 0°- -5 °, after the dropwise addition, the reaction continued to stir for 20-50 minutes, preferably the stirring time was 30-40 minutes, then filtered, the filter cake was washed with cooled ether, and the filter cake was vacuum-dried at room temperature to obtain a gray solid product p-methoxy Aniline diazonium tetrafluoroborate, wherein the molar ratio of methoxyaniline, tetrafluoroboric acid, sodium nitrite and water is 1.0:1.0:1.0:10-1.0:5.0:5.0:50, which includes The numerical range of any subinterval of , non-limiting examples: 1.0: 1.5: 1.5: 15-1.0: 4.5: 4.5: 45, 1.0: 2.0: 2.0: 20 -1.0:4.0:4.0:40, 1.0:3.0:3.0:30-1.0:3.5:3.5:35, the preferred molar ratio is 1.0:1.5:1.5:30, Yield: 90-95%.

[0049] ...

Embodiment 2

[0052] About the preparation steps of compound B

[0053]

[0054] Dissolving 5,6-dihydro]pyran-2-one in an aprotic organic solvent, wherein the aprotic organic solvent includes one or more of toluene, dichloromethane, dichloroethane, and chloroform , preferably dichloromethane, keep the temperature at 25°-30°, slowly add a solution of bromine dissolved in dichloromethane dropwise, and stir the reaction for 2-5 hours, preferably 4-5 hours. After the reaction, the reaction system was cooled to 0°-5°, stirred for 0.5-1 hour, the system was diluted with water, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the combined organic phase was washed with saturated brine, and dried over sodium sulfate , concentrated and dried to obtain a colorless liquid product B， Among them, the molar ratio of 5,6-dihydro-pyran-2-one, liquid bromine and dichloromethane is 1.0:1.0:5.0-1.0:3.0:50, and this range includes the numerical range of any subrange the...

Embodiment 3

[0056] Preparation steps of compound Ⅰ

[0057]

[0058] Compound A and Compound B are dissolved in a non-polar organic solvent, wherein the non-polar organic solvent can be one or more of toluene, dioxane, tetrahydrofuran, dichloromethane, dichloroethane, and chloroform, Preferred is toluene, adds alkali, and alkali can be one or more in organic bases such as triethylamine, pyridine, also can be one or more in inorganic bases such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate. One, preferably triethylamine, warming up to 20°-100°, preferably 80°-100°, stirring for 1-10 hours, preferably 8-10 hours, then reducing the reaction system to 20°-30°, dilute the filtrate with water, separate layers, wash the organic phase with saturated brine, dry over sodium sulfate, and concentrate to obtain a residue, stir and beat the residue in ethyl acetate, filter, and dry in vacuo to obtain a light yellow solid product Ⅰ , wherein, the molar ratio of ...

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Abstract

The invention discloses a method for preparing an antithrombotic drug apixaban. The method is characterized in that a compound IV is used as a raw material to perform a hydrolysis reaction for 5-60 minutes at 10-100 DEG C in a polar organic solvent under an alkaline condition, and is transformed into a compound antithrombotic drug apixaban; the antithrombotic drug apixaban is prepared by re-crystallizing, sizing and column chromatography purification. The method has the advantage of high yield, is simple and convenient in the subsequent treatment due to extraction, drying, sizing, filtering, crystallizing, recrystallizing and other operation methods, and large-scale production is easily realized.

Description

technical field [0001] The invention relates to a synthesis method of an antithrombotic drug apixaban, which belongs to the technical field of drug synthesis. Background technique [0002] Apixaban (Apixaban, BMS-562247), chemical name 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)benzene Base]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, American Chemical Abstracts Registration Number CAS: 503612-47-3, the drug is produced by A new oral direct factor Xa inhibitor jointly developed by Bristol-Myers Squibb and Pfizer. The drug was approved for marketing in the European Union in March 2011 under the trade name Eliquis, which is clinically used to prevent venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement. Clinical study results show that enoxaparin (enoxaparin) 40 mg administered orally twice daily is more effective and does not increase VTE after knee and total hip arthroplasty compared with once-daily injection ...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D491/052C07D401/12
CPCC07D471/04
Inventor 吴嗣林彭少平
Owner PHARMA SHANGHAI
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