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Synthesis process of crizotinib intermediate

A technology of crizotinib and synthesis process, which is applied in the field of synthesis technology of crizotinib intermediates, can solve the problems of long steps, low yield, low chiral purity of products, etc., and achieves low production cost and environmental protection. The effect of less pollution and shorter process cycle

Inactive Publication Date: 2018-04-13
ENANTIOTECH CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This kind of method steps is long, and yield is low, and the chiral purity of the product obtained is not high

Method used

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  • Synthesis process of crizotinib intermediate
  • Synthesis process of crizotinib intermediate
  • Synthesis process of crizotinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Get 0.01mol of 2,6-dichloro-3-fluoroacetophenone and dissolve it in 140ml of tetrahydrofuran, add 0.0001mol of catalyst β-BIMAH (S, S-4-1a), add 0.01mol of potassium tert-butoxide, pass Add 30 bar of hydrogen as a reducing agent, stir at 30°C for 16 hours, filter with suction, and remove the solvent by rotary evaporation to obtain the off-white solid of the product (R)-1-(2,6-dichloro-3-fluorophenyl)ethanol Powder, product purity 99.5%, yield 89.9%.

Embodiment 2

[0034] Take 0.01mol of 2,6-dichloro-3-fluoroacetophenone and dissolve it in 140ml of n-hexane, add 0.0001mol of catalyst β-BIMAH(S,S-4-1a), add 0.01mol of potassium carbonate, pass through 30 bar of hydrogen as a reducing agent, after stirring at 30 ° C for 16 hours, suction filtration, rotary evaporation to remove the solvent to obtain the off-white solid powder of the product (R)-1-(2,6-dichloro-3-fluorophenyl)ethanol , product purity 99.3%, yield 89%.

Embodiment 3

[0036] Take 0.01mol of 2,6-dichloro-3-fluoroacetophenone and dissolve it in a mixed solvent of 100ml of dichloromethane and 40ml of toluene, add 0.001mol of catalyst β-BIMAH (S, S-4-1a), add 0.01 mol of potassium hydroxide, feed 30bar of hydrogen as a reducing agent, stir at 30°C for 16h, filter with suction, and remove the solvent by rotary evaporation to obtain the product (R)-1-(2,6-dichloro-3-fluorobenzene Base) off-white solid powder of ethanol, product purity 99.6%, yield 93%.

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Abstract

The invention discloses a synthesis process of a crizotinib intermediate. The synthesis process comprises the following steps: with 2,6-dichloro-3-fluoroacetophenone as the raw material in an alkali and solvent environment and hydrogen as a reducing agent, reacting under the action of a chiral catalyst to obtain (R)-1-(2,6-dichloro-3-fluorophenyl)ethyl alcohol; the high-chiral-purity crizotinib intermediate is obtained at one step as the process adopts the reduction system, the complex chiral resolution process of the existing process is omitted, the period of the process is greatly shortened,the production cost is low, the reaction condition is mild, the process is stable, the conversion rate is high, the environment pollution caused by the reaction is small, and the synthesis process isfavorable for realizing the industrial production.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical and chemical intermediates, and mainly relates to a synthesis process of a crizotinib intermediate. Background technique [0002] Crizotinib (Crizotinib, English trade name Xalkori), chemical name: (R)-3-[1-(2,6-dichloro-3-fluoro-benzene)-ethoxy]-5-(1- Piperidine-4-alkyl-1hydro-pyrazole-4-alkyl)-pyrimidine-2-indan is an ATP-competitive multi-target protein kinase inhibitor developed by Pfizer that inhibits Met / ALK / ROS. It has been confirmed that crizotinib has a significant clinical effect on humans in tumor patients with abnormal activity of ALK, ROS and MET kinases. The structural formula of crizotinib is as follows: [0003] [0004] Crizotinib is one of the fastest drugs in the history of cancer drug development. It caused a sensation after it was launched in the United States in 2011. The inventor is Chinese scientist Dr. Cui Jingrong (US patent 7858643), who won the 38th US N...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C29/145C07C33/46B01J31/24
CPCB01J31/2414B01J2231/643B01J2531/821C07C29/145C07C33/46
Inventor 徐亮毛波李彦雄
Owner ENANTIOTECH CORP
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