Method for preparing ticagrelor intermediate

A technology for ticagrelor and intermediates, which is applied in the field of synthesis of chemical drug intermediates, can solve the problems of high cost, unfavorable industrialization, and high risk of difluorobenzaldehyde, and achieve fewer staff, stable product quality, and high selectivity Effect

Inactive Publication Date: 2018-02-13
XUCHANG HENGSHENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this route is short, the cost of 3,4-difluorobenzaldehyde is expensive, and both the ylide and Simmons-Smith cyclopropanation reactions have extremely high requirements for solvents, equipment and operations, and the risk is relatively high, and the yield is low, which is not conducive to industrialization

Method used

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  • Method for preparing ticagrelor intermediate
  • Method for preparing ticagrelor intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Put (114.1g, 1.0mol) o-difluorobenzene, (146.7g, 1.1mol) aluminum trichloride in a 1L three-neck flask, stir, cool down to 15°C, and dropwise add (113.0g, 1.0mol) chloroacetyl chloride Control the temperature not to exceed 40°C, keep the reaction at 40°C for 2 hours, cool down to 5°C, drop the reaction liquid into 10% hydrochloric acid, control the temperature at 20°C, extract with 228g of dichloromethane, distill off the dichloromethane to obtain 178.5g 2-Chloro-1-(3,4-difluorophenyl)ethanone, yield 93.7%.

[0022] Add (178.5g, 0.94mol) 2-chloro-1-(3,4-difluorophenyl)ethanone, 250g glucose, and 900g water into a 2L three-necked flask, stir and mix, and adjust the pH to 6.5, temperature 20°C, add 35.7g Candida parapsilosis enzyme, keep pH 6.5, temperature 20°C, react for 3 hours, add 357.0g toluene for extraction, and separate liquid to obtain (S)-2-chloro-1-( 3,4-difluorophenyl) ethane-1-ol toluene solution;

[0023] Add (S)-2-chloro-1-(3,4-difluorophenyl)ethan-1-ol ...

Embodiment 2

[0026] Put (114.1g, 1.0mol) o-difluorobenzene, (133.4g, 1.0mol) aluminum trichloride in a 1L three-neck flask, stir, cool down to 25°C, and dropwise add (124.3g, 1.1mol) chloroacetyl chloride Control the temperature not to exceed 40°C, keep the reaction at 35°C for 4 hours, cool down to 8°C, drop the reaction liquid into 10% hydrochloric acid, control the temperature at 20°C, extract with 228g of dichloromethane, distill off the dichloromethane to obtain 175.6g 2-Chloro-1-(3,4-difluorophenyl)ethanone, yield 92.2%.

[0027] Add (175.6g, 0.92mol) 2-chloro-1-(3,4-difluorophenyl)ethanone, 300g glucose, and 900g water into a 2L three-necked flask, stir and mix, and adjust the pH to 7.5, temperature 30°C, add 52.7g Candida parapsilosis enzyme, keep pH 7.5, temperature 30°C, react for 5 hours, add 351.2g toluene for extraction, and separate liquid to obtain (S)-2-chloro-1-( 3,4-difluorophenyl) ethane-1-ol toluene solution;

[0028] Add (S)-2-chloro-1-(3,4-difluorophenyl)ethan-1-ol ...

Embodiment 3

[0031] Put (114.1g, 1.0mol) o-difluorobenzene, (146.7g, 1.1mol) aluminum trichloride in a 1L three-necked flask, stir, cool down to 15°C, and dropwise add (124.3g, 1.1mol) chloroacetyl chloride Control the temperature not to exceed 40°C, keep the reaction at 35°C for 5 hours, lower the temperature to 5°C, drop the reaction liquid into 10% hydrochloric acid, control the temperature at 15°C, extract with 228g of dichloromethane, distill off the dichloromethane to obtain 182.1g 2-Chloro-1-(3,4-difluorophenyl)ethanone, yield 95.6%.

[0032] Add (182.1g, 0.96mol) 2-chloro-1-(3,4-difluorophenyl)ethanone, 350g glucose, and 900g water into a 2L three-necked flask, stir and mix, and adjust the pH to 7.0, temperature 30°C, add 35.7g Candida parapsilosis enzyme, keep pH 7.0, temperature 30°C, react for 6 hours, add 364g toluene for extraction, and separate liquid to obtain (S)-2-chloro-1-(3 , 4-difluorophenyl) ethane-1-ol toluene solution;

[0033] Add (S)-2-chloro-1-(3,4-difluoropheny...

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Abstract

The invention discloses a method for preparing a ticagrelor intermediate. The method comprises the following steps: taking o-difluorobenzene and chloroacetyl chloride as initial raw materials, carrying out an F-K reaction, a bio-enzyme fermentation technology asymmetric reduction reaction, a ring-closure reaction and a cyclopropanation reaction, so as to obtain the key intermediate (1R, 2R)-2-(3,4-difluorophenyl) cyanocyclopropane carboxylate of the ticagrelor at high yield, high enantioselectivity and high purity. The method can realize industrialized production. The method is low in energy consumption, less in pollution, green, clean, high in yield and high in purity, the cost is reduced, the product quality is stable, and the method is suitable for large-scale stable industrial production.

Description

technical field [0001] The invention belongs to the technical field of synthesis of chemical drug intermediates, in particular to a preparation method of ticagrelor intermediates. Background technique [0002] Ticagrelor, also known as ticagrelor, chemically named (1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-difluorobenzene Base) cyclopropyl] amino] -5-propylthiotriazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol . Ticagrelor is a new type of selective small molecule anticoagulant drug developed by AstraZeneca. The drug can reversibly act on the purine 2 receptor purinoceptor 2 on vascular smooth muscle cells (VSMC), P2 subtype P2Y12, has obvious inhibitory effect on platelet aggregation caused by ADP, and takes effect rapidly after oral administration, so it can Effectively improve the symptoms of patients with acute coronary heart disease. Since the antiplatelet effect of ticagrelor is reversible, it is especially suitable for patients who need anticoagu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/343C07C69/743
CPCC12P7/22C07C45/46C07C67/343C07D301/26C07D303/08C07B2200/07
Inventor 蚩晓娜郭培娄见通
Owner XUCHANG HENGSHENG PHARMA
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