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Preparation method of dihydropyridone derivatives

A technology of dihydropyridone and derivatives, which is applied in the field of medicine and can solve the problems affecting the purity of apixaban, toxic and side effects, etc.

Active Publication Date: 2020-05-08
北京鑫开元医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The presence of impurities in apixaban will not only affect the purity of apixaban, but may also cause toxic and side effects

Method used

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  • Preparation method of dihydropyridone derivatives
  • Preparation method of dihydropyridone derivatives
  • Preparation method of dihydropyridone derivatives

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preparation example Construction

[0038] The embodiment of the present invention provides a preparation method of dihydropyridone derivatives, comprising:

[0039] Step S10, under the condition of the first base, using 1-(4-aminophenyl)-3-morpholinyl-5,6-dihydropyridin-2(1H)-one as raw material, and the first reactant React in the first solvent to generate amide compound;

[0040] Step S20, under the condition of the second base, heating the amide compound to obtain an intermediate;

[0041] Step S30, reacting the intermediate with the second reactant in the second solvent at room temperature;

[0042] Step S40, after the reaction is completed, the second solvent is distilled off under reduced pressure;

[0043] In step S50, under ice-bath conditions, a third base is added, and a reaction takes place in a third solvent to obtain the target compound.

[0044] Further, in step S10, the first solvent is dichloromethane or N,N-dimethylformamide; preferably dichloromethane; the first base includes triethylamine,...

Embodiment 1

[0060] Step S101: In a 250ml round bottom flask, add 10.0g raw material 1-(4-aminophenyl)-3-morpholinyl-5,6-dihydropyridin-2(1H)-one, and then add 100ml dihydrogen Chloromethane and 4.1g triethylamine, after stirring for 5min, 6.2g 5-chlorovaleryl chloride was added dropwise, and the reaction was monitored by thin-layer chromatography;

[0061] Step S102: After the reaction of the raw material 1-(4-aminophenyl)-3-morpholinyl-5,6-dihydropyridin-2(1H)-one is complete, dichloromethane is distilled off the reaction solution under reduced pressure, Add 100ml N,N-dimethylformamide and 3.0g sodium hydroxide, heat to 80°C for 5h;

[0062] Step S103: After the above reaction is completed, distill off 2 / 3 of N,N-dimethylformamide under reduced pressure, pour into dichloromethane-water (200ml:100ml) for extraction and layering, and use 2×50ml water for the organic layer Washed twice, the organic layer was dried with anhydrous sodium sulfate, filtered, dichloromethane was distilled off u...

Embodiment 2

[0074] Step S201: In a 250ml round bottom flask, add 10.0g raw material 1-(4-aminophenyl)-3-morpholinyl-5,6-dihydropyridin-2(1H)-one, then add 100ml N , N-dimethylformamide and 5.2g diisopropylethylamine, after stirring for 5min, 6.2g 5-chlorovaleryl chloride was added dropwise, and the reaction was monitored by thin-layer chromatography;

[0075] Step S202: After the reaction of the raw material 1-(4-aminophenyl)-3-morpholinyl-5,6-dihydropyridin-2(1H)-one is complete, add 3.0 g of sodium hydroxide and heat to 60°C Reaction 5h;

[0076] Step S203: After the above reaction is completed, distill off 2 / 3 of N,N-dimethylformamide under reduced pressure, pour into dichloromethane-water (200ml:100ml) for extraction and layering, and use 2×50ml water for the organic layer Washed twice, the organic layer was dried with anhydrous sodium sulfate, filtered, dichloromethane was distilled off under reduced pressure to obtain the first crude product;

[0077] Step S204: crystallize the ab...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of dihydropyridone derivatives. The preparation method comprises the following steps: reacting 1-(4-aminophenyl)-3-morpholinyl-5,6-dihydropyridin-2(1H)-one serving as a raw material with a first reactant in a first solvent under the condition of a first alkali to generate an amide compound;under the condition of a second alkali, heating the amide compound to obtain an intermediate; reacting the intermediate with a second reactant in a second solvent at room temperature; after the reaction is finished, performing reduced-pressure distillation to obtain the second solvent; and under an ice bath condition, adding a third alkali, and carrying out a reaction in a third solvent to obtainthe dihydropyridone derivatives. According to the preparation method of the dihydropyridone derivatives provided by the invention, the preparation method of the dihydropyridone derivatives of 3-morpholinyl-1-(4-(2-oxopiperidine-1-yl)phenyl)pyridin-2(1H)-one is provided for the first time, and the preparation method has important significance for effective control of the quality of apixaban.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a preparation method of dihydropyridone derivatives. Background technique [0002] Apixaban impurity 3-morpholinyl-1-(4-(2-oxopiperidin-1-yl)phenyl)pyridin-2(1H)-one is one of dihydropyridinone derivatives kind. Apixaban (ELIQUIS) is an oral selective activated factor X inhibitor jointly developed by Pfizer and Bristol-Myers Squibb. It can prevent and treat blood clots, and the adverse reactions of bleeding are far less than that of previous similar drugs. Clinically, it is mainly used to prevent the formation of venous thrombosis (VTE) in adult patients undergoing elective hip or knee replacement surgery. The presence of impurities in apixaban will not only affect the purity of apixaban, but may also cause toxic and side effects. Therefore, in the actual drug production process, using clear and definite impurities for comparison is an indispensable link in drug ...

Claims

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Application Information

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IPC IPC(8): C07D401/10
CPCC07D401/10
Inventor 王永广郑生伟张佳琪苏小庭戴信敏
Owner 北京鑫开元医药科技有限公司
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