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Preparation method for ticagrelor intermediate and mandelate thereof

A technology for ticagrelor and intermediates, which is applied in the field of synthesis of ticagrelor intermediates-2-cyclopropylamine and its mandelic acid salts, can solve the problems of high production cost, poor optical purity, cumbersome operation, etc., and achieve Less by-products, less pollution, better optical purity

Pending Publication Date: 2017-06-30
LIAONING TIANHUA CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In the above synthetic routes, chemical methods are used for asymmetric reduction, and there are problems such as low yield, poor optical purity, cumbersome operation, high production cost and serious pollution.

Method used

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  • Preparation method for ticagrelor intermediate and mandelate thereof
  • Preparation method for ticagrelor intermediate and mandelate thereof
  • Preparation method for ticagrelor intermediate and mandelate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: the cultivation of carbonyl reductase thalline

[0052] Seed culture:

[0053] Medium formula: peptone 1.0%, yeast extract powder 0.5%, sodium chloride 0.5%, pH 7.0 before disinfection, volume before disinfection 100mL (1000mL shake flask), cool after sterilization, add 100uL to the seed bottle under sterile condition The concentration is 10mg / mL ampicillin and 0.1mL glycerol tube bacteria solution (Escherichia coli, E.Coli BL21), cultured on a shaker at 37°C with a rotation speed of 200rpm, and the culture time is 18-20 hours.

[0054] Fermentation culture:

[0055]Medium formula: peptone 2.0%, yeast extract powder 1.0%, sodium chloride 0.5%, foam enemy (defoamer) 0.02%, glycerol 0.2%. The pH before disinfection is 7.5, and the volume before disinfection is 5L (10L fermenter); after the medium is sterilized, it is inoculated into the cultivated seed culture solution for fermentation by flame inoculation, and the culture conditions are fermentation tempe...

Embodiment 2

[0056] Example 2: Preparation of 2-chloro-1-S-(3,4-difluorophenyl)ethanol (II)

[0057] Add 40g of 2-chloro-1-(3,4-difluorophenyl)ethanone, 200ml of water and 100ml of isopropanol in a mixed solvent in a stirred 500ml four-neck flask, start stirring, and add Example 1 20 g of the bacterium containing carbonyl reductase obtained in , the temperature was raised to 30 ° C to start the reaction, after 3 h, samples were taken every 0.5 h and the residue of 2-chloro-1-(3,4-difluorophenyl)ethanone was detected by HPLC. After the reaction was completed, the cells were removed by filtration, the filtrate was extracted with toluene, the toluene phase was dried with anhydrous magnesium sulfate, filtered, and concentrated to obtain 39.5 g of yellow oily compound (II), with a yield of 98.8%, HPLC purity of 98.5%, and ee value of 99.9%.

Embodiment 3

[0058] Example 3: Preparation of 2-chloro-1-S-(3,4-difluorophenyl)ethanol (II)

[0059] In a stirred 500ml four-neck flask, sequentially add 40g of 2-chloro-1-(3,4-difluorophenyl)ethanone, 200ml of water and 40ml of tetrahydrofuran in a mixed solvent, start stirring, and add the 12g of bacteria containing carbonyl reductase, the temperature was raised to 40°C to start the reaction, after 3h, samples were taken every 0.5h and the residue of 2-chloro-1-(3,4-difluorophenyl)ethanone was detected by HPLC. The bacteria were removed by filtration, the filtrate was extracted with EA, the EA phase was dried with anhydrous magnesium sulfate, filtered, and concentrated to obtain 39.1 g of yellow oily compound (II), with a yield of 96.7%, an HPLC purity of 98.6%, and an ee value of 99.8%.

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Abstract

The invention discloses a synthetic method for an intermediate compound (I) of ticagrelor and a mandelate compound(VI) thereof. Asymmetric reduction is carried out by the enzymic method; the synthetic method has the advantages of simple operation, mild reaction condition, little pollution, high yield of the product, good optical purity, thus the synthetic method is suitable for large-scale production; the energy consumption and the discharge of organic waste-water are greatly reduced, and requirements of large-scale industrial production are met well.

Description

technical field [0001] The invention relates to the fields of biological enzyme catalysis and organic synthesis, in particular to the synthesis of a ticagrelor intermediate (1R, 2S)-2-(3,4-difluorophenyl)cyclopropylamine and its mandelate salt. Background technique [0002] Ticagrelor is a new type of selective small-molecule anticoagulant drug developed by AstraZeneca, which belongs to the cyclopentyltriazole pyrimidine class of oral antiplatelet drugs and is a selective adenosine diphosphate Receptor antagonist, acting on the P2Y12ADP receptor to inhibit ADP-mediated platelet activation and aggregation, the drug was approved for marketing by the US FDA in July 2011, and approved for marketing in China in November 2012. [0003] (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine is the key intermediate for the preparation of ticagrelor, because it is inconvenient to store and use as an oil, it is usually made into mandelate or salt salt use. The synthetic method of (1R, 2S)-2...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P7/22C07C209/00C07C211/40C07C51/41C07C59/50
CPCC07C51/412C07C67/343C07C209/00C07C209/58C07C231/02C07D301/28C07D303/08C12P7/22C07C69/753C07C233/58C07C211/40C07C59/50
Inventor 王亚辉莫章桦王姝昕宋辉
Owner LIAONING TIANHUA CHEM
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