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A kind of synthetic method of the intermediate of Apixaban

A synthetic method, the technology of apixaban, applied in the field of intermediate synthesis, can solve the problems of unsuitability for industrial production, cumbersome post-treatment, and low reaction conversion rate

Active Publication Date: 2020-10-30
ZHEJIANG TIANYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] 1) the alkali used in the cyclization step is an inorganic alkali such as NaH, and the cost is high, so it is not suitable for industrial production;
[0014] 2) In the reaction, the organic base of triethylamine tertiary amine is first used for amidation reaction, and then the more alkaline sodium tert-butoxide, potassium tert-butoxide, and sodium hydride are used for cyclization reaction. The operation is cumbersome, and sodium hydride is dangerous. Reagents have great safety hazards, and the post-processing is cumbersome, and product quality control is also relatively difficult;
[0015] 3) Inorganic bases such as potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate and potassium bicarbonate have low solubility in inert organic solvents, resulting in low reaction efficiency and low reaction conversion

Method used

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  • A kind of synthetic method of the intermediate of Apixaban
  • A kind of synthetic method of the intermediate of Apixaban
  • A kind of synthetic method of the intermediate of Apixaban

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1: the preparation of compound 1

[0044] Compound 3 (27.3g, 0.1mol), 546mL of dichloroethane was added into a three-necked flask, cooled in an ice bath to 0°C, added tetraethylammonium hydroxide (103g, 0.7mol), stirred in an ice bath for 10min, and then added dropwise 5- Chlorvaleryl chloride (18.6g, 0.12mol), temperature controlled at 0-5°C. After dropping, remove the ice bath and raise it to reflux (80-85°C), react for 5 hours, monitor the disappearance of the reaction raw materials and intermediate states, lower the synthetic solution to room temperature, wash with 500 mL of water, dry the organic phase with anhydrous sodium sulfate, and concentrate to After drying, the residue was recrystallized from acetonitrile to obtain 31.6 g of compound 1 as a yellow solid, the yield: 89%.

Embodiment 2

[0045] Embodiment 2: the preparation of compound 1

[0046] Add compound 3 (27.3g, 0.1mol), 546mL of dichloroethane into a three-necked flask, cool to 0°C in an ice bath, add benzyltriethylammonium hydroxide (146.3g, 0.7mol), stir in an ice bath for 10min, then drop Add 5-chlorovaleryl chloride (18.6 g, 0.12 mol), and control the temperature at 0-5°C. After dropping, remove the ice bath and raise it to reflux (80-85°C), react for 5 hours, monitor the disappearance of the reaction raw materials and intermediate states, lower the synthetic solution to room temperature, wash with 500 mL of water, dry the organic phase with anhydrous sodium sulfate, and concentrate to After drying, the residue was recrystallized from acetonitrile to obtain 31.2 g of compound 1 as a yellow solid, the yield: 88%.

Embodiment 3

[0047] Embodiment 3: the preparation of compound 1

[0048]Compound 3 (27.3g, 0.1mol), 546mL of dichloroethane was added into a three-necked flask, cooled in an ice bath to 0°C, added tetraethylammonium hydroxide (132g, 0.9mol), stirred in an ice bath for 10min, and then added dropwise 5- Chlorvaleryl chloride (18.6g, 0.12mol), temperature controlled at 0-5°C. After dropping, remove the ice bath and raise it to reflux (80-85°C), react for 5 hours, monitor the disappearance of the reaction raw materials and intermediate states, lower the synthetic solution to room temperature, wash with 500 mL of water, dry the organic phase with anhydrous sodium sulfate, and concentrate to After drying, the residue was recrystallized with acetonitrile to obtain 30.9 g of compound 1 as a yellow solid, the yield: 87%.

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Abstract

The invention belongs to the technical field of synthesizing of medicine intermediates, and particularly relates to a synthesizing method of an intermediate of Apixaban. The method includes the step of making 4-R-aniline and 5-chlorovaleryl chloride make contact for reaction in an inert solvent in the presence of amine quarter alkali to obtain the intermediate, namely 1-(4-R-aniline)piperidine-2-ketone, of Apixaban, wherein the reaction formula is shown as the formula I (the formula I is seen in the description). By means of the synthesizing method, the reaction efficiency and conversion rateof the intermediate of Apixaban are improved, there is no need to add tertiary amine organic base or use expensive NaH cyclization reagents, and production cost is saved.

Description

technical field [0001] The invention belongs to the technical field of synthesizing pharmaceutical intermediates, in particular to a method for synthesizing an intermediate of apixaban. Background technique [0002] Apixaban, its English name is Apixaban (trade name: Eliquis), its chemical name is 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6 -[4-(2-oxo-1-piperidinyl)phenyl]-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, its chemical structure is as formula II: [0003] [0004] Apixaban is a new generation of antithrombotic drugs. It is a new type of direct factor Xa inhibitor jointly developed by Bristol-Myers Squibb and Pfizer. It was approved for marketing in the European Union in March 2011 and launched in 2012 In December, the FDA approved the drug to be launched in the United States. This product is currently clinically used to prevent venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement. [0005] Among them, 5,6-dihydro-3-(4-mo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/88C07D211/76
CPCC07D211/76C07D211/88
Inventor 柯春龙王臻朱国荣屠勇军
Owner ZHEJIANG TIANYU PHARMA
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