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Preparation method of (R)-2-(2,5-difluorophenyl)pyrrolidine or salt thereof

A kind of technology of difluorophenyl, pyrrolidine

Inactive Publication Date: 2019-04-09
SHANGHAI UNIV OF MEDICINE & HEALTH SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Aiming at the above-mentioned technical problems in the prior art, the present invention provides a preparation method of (R)-2-(2,5-difluorophenyl)pyrrolidine or a salt thereof, said (R)- The preparation method of 2-(2,5-difluorophenyl)pyrrolidine or its salt should solve the method for preparing (R)-2-(2,5-difluorophenyl)pyrrolidine or its salt in the prior art Complex process, harsh reaction conditions, and technical issues of safety and environmental protection

Method used

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  • Preparation method of (R)-2-(2,5-difluorophenyl)pyrrolidine or salt thereof
  • Preparation method of (R)-2-(2,5-difluorophenyl)pyrrolidine or salt thereof

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Embodiment 1

[0037] The preparation of embodiment 1 recombinant imine reductase

[0038] Inoculate a single colony of recombinant Escherichia coli containing the imine reductase gene from a glycerol tube or transformation plate into 4 mL of liquid LB medium containing (100 ug / mL) ampicillin resistance, and activate overnight at 37 ° C for 12 to 16 hours. The culture obtained after activation was transferred to 100mL liquid LB medium containing (100ug / mL) ampicillin resistance with 2% inoculum, and cultured with shaking at 37°C and 220rpm until the OD600 value reached about 0.6, and the inducer isotropic acid was added. Propyl-β-D-thiogalactoside was added to a final concentration of 0.8 mmol / L, and culture was continued overnight at 30°C. Collect the cells by centrifugation (4°C, 5000 rpm, 15 min), and suspend the cells with 10 mL of phosphate buffer (100 mM, pH 7.0). Place the cell suspension in an ice bath for 10 minutes, then centrifuge (4°C, 12000rpm, 15min), pre-freeze the supernatan...

Embodiment 2

[0039] Example 2 Synthesis of (R)-2-(2,5-difluorophenyl)pyrrolidine (compound 5 free base) 1 tert-butyl (4-(2,5-difluorophenyl) 4-carbonyl Synthesis of butyl) carbamate (compound 3)

[0040]

[0041] In a 250mL flask, under nitrogen protection, add N-Boc protected pyrrolidone (18.5g, 0.1mol), 50mL tetrahydrofuran, cool to below 25°C, add dropwise 2,5-difluorophenylmagnesium chloride lithium Grignard reagent ( 120mL, 0.12mol, 1M tetrahydrofuran solution, obtained by Grignard exchange of diisopropylmagnesium lithium chloride), after the dropwise addition was completed, the temperature was raised to 25°C, and the temperature was kept stirring for 5 hours, and the reaction was detected by TLC. Dilute hydrochloric acid was added dropwise to quench the reaction solution to pH 6-7, the mixture was extracted three times with dichloromethane, 60 mL each time, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a cr...

Embodiment 3

[0058] Example 3 Synthesis steps of (R)-2-(2,5-difluorophenyl)pyrrolidine (compound 5 bisulfate) 1 tert-butyl (4-(2,5-difluorophenyl) 4- Synthesis of Carbobutyl) Carbamate (Compound 3)

[0059]

[0060] In a 250mL flask, under nitrogen protection, add N-Boc-protected pyrrolidone (18.5g, 0.1mol), 2-methyltetrahydrofuran (40mL), cool to below 25°C, add dropwise 2,5-difluorophenylmagnesium chloride Lithium chloride Grignard reagent (140mL, 0.14mol, 1M 2-methyltetrahydrofuran solution, obtained by Grignard exchange of diisopropylmagnesium lithium chloride), after the dropwise addition was completed, the temperature was raised to 30°C, and the temperature was kept stirring for 4 hours. TLC detects that the reaction is complete. Add dilute sulfuric acid dropwise to quench the reaction solution to pH 6-7, the mixture is separated, the water layer is extracted twice with 2-methyltetrahydrofuran, 50 mL each time, the organic phase is combined, the temperature is lowered to below 10...

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Abstract

The invention provides a preparation method of (R)-2-(2,5-difluorophenyl)pyrrolidine or salt thereof. N-protected pyrrolidone and 1,4-difluoro-chlorobenzene are subjected to a Grignard reaction to obtain a compound shown in formula 3; the compound shown in the formula 3 is subjected to deportection and loop closing under an acid condition to obtain a compound shown in formula 4 or salt of the compound; the compound shown in the formula 4 or salt of the compound selectively reduce and synthesize an optical pure compound (R)-2-(2,5-difluorophenyl)pyrrolidine or salt thereof under catalysis ofenzyme, wherein enzyme is recombinant imine reductase and coenzyme circulation is performed by glucose and glucose dehydrogenase. The enzyme is used to replace a chemical chiral reagent, and the problem that chiral inducers are needed in the prior art is solved; compared with metal catalysis, the enzyme catalytic reaction has the characteristics that the cost is low, reaction selectivity is good,the conversion rate and optical purity of the product are high and the reaction process is simple to operate and environmentally friendly, and is applicable to mass industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a pyrrolidine, in particular to a preparation method of (R)-2-(2,5-difluorophenyl)pyrrolidine or a salt thereof. Background technique [0002] Among the novel inhibitors against tyrosine receptor kinase (TRK) discovered in recent years, many inhibitors have pyrazolo[1,5-a]pyridine (ZL20128006957.8, as tropomyosin receptor Substituted pyrazolo[1,5-a]pyridines) and pyrazolo[1,5-a]pyrimidines (US2016 / 0137654A1, (S)-N-(5-( -2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrrolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate The series structure of salt crystal form) is used for all tumor patients expressing tropomyosin receptor kinase (TRK), this inhibitor has strong selectivity for TRK, and inhibits the TRK signaling pathway , can inhibit tumor growth. It is effective against a variety of solid tumors in adults and children, including breast cancer, colorectal...

Claims

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Application Information

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IPC IPC(8): C12P17/10
CPCC12P17/10
Inventor 黄钢李斌
Owner SHANGHAI UNIV OF MEDICINE & HEALTH SCI
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