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

A difluorophenyl, difluorophenyl magnesium chloride Grignard technology, applied in the field of medicinal chemistry, can solve problems such as harsh reaction conditions, complicated processes, and achieve the effects of good stability, process safety, and simplified post-processing steps

Active 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

[0012] 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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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1 Preparation of recombinant imine reductase

[0041] Ligate the gene fragment (synthesized by Shanghai Jierui Biotechnology Co., Ltd.) containing the imine reductase gene (SEQ ID No.1-15) with the digested product of pET28a plasmid (purchased from Invitrogen) from the glycerol tube or transformation plate , into the competent E.coliBL21 (DE3) strain (purchased from Beijing Quanshijin Biotechnology Co., Ltd.), screened to obtain positive clones, and inoculated into 4mL liquid LB medium containing (100ug / mL) ampicillin resistance , activate overnight at 37°C for 12-16 hours, transfer the culture obtained after activation to 100mL liquid LB medium containing (100ug / mL) ampicillin resistance with a 2% inoculum, and culture at 37°C and 220rpm with shaking When the OD 600 value reached about 0.6, the inducer isopropyl-β-D-thiogalactopyranoside was added to a final concentration of 0.8 mmol / L, and the cultivation was continued overnight at 30°C. Collect the cells by ...

Embodiment 2

[0043] Step 1 Synthesis of tert-butyl (4-(2,5-difluorophenyl) 4-carbonylbutyl) carbamate (compound 3)

[0044]

[0045] In a 2000 ml four-neck flask with mechanical stirring, 30.0 g of magnesium bars and 80 mL of anhydrous 2-methyltetrahydrofuran were added under nitrogen protection, and 2,5-difluorochlorobenzene (148.54 g, 1 mol) and 300 mL of 2-methyl tetrahydrofuran were added. About 30 ml of the mixed solution composed of tetrahydrofuran was heated slowly, and 2-3 mL of 1,2-dibromoethane was added dropwise under stirring to initiate the reaction, and the remaining 2,5-difluorochlorobenzene (148.54 g, 1mol) and 300mL 2-methyltetrahydrofuran, add about 2 hours, dropwise, continue to reflux for 6 hours, sampling follow-up, after the sample is cooled to room temperature, add methanoly Grignard reagent, quantified by GC Analysis shows that the remaining amount of 2,5-difluorochlorobenzene is less than 0.5%, and that of p-difluorobenzene is higher than 99%. The reaction is stop...

Embodiment 3

[0061] Step 1 The synthesis of tert-butyl (4-(2,5-difluorophenyl) 4-carbonylbutyl) carbamate (compound 3) is the same as in Example 2, step 1;

[0062] Step 2 Synthesis of 5-(2,5-difluorobenzene)-3,4-dihydro-2H-pyrrole (compound 4 free base)

[0063] With embodiment 2, step 2;

[0064] Step 3 Synthesis of (R)-2-(2,5-difluorophenyl)pyrrolidine (compound 5 free base)

[0065]

[0066] In a 10mL reaction flask, add 4.75mL (weight about 4.75g) of 0.1mol / L, pH 5.0-10.0 phosphate or carbonate buffer solution, then add 0.25mL DMSO (weight about 0.27g), add 0.1g Sodium formate, add compound 4 free base 0.451g, add 2mg recombinant imine reductase dry powder (SEQ ID No.1), 0.8mg formate dehydrogenase, and 0.1mg nicotinamide adenine dinucleotide (NAD+), reaction temperature Keep at 25°C, stirring speed 1000rpm, react for 21 hours, HPLC detects conversion rate, pH 5.0 (phosphate) sample conversion rate is 36.6%, pH 6.0 (phosphate) sample conversion rate is 45.4%, pH 7.5 (phosphate) s...

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PUM

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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 a 2,5-fluorophenyl magnesium chloride Grignard reagent are subjectedto a Grignard reaction, and a compound represented as the formula 3 is obtained; the compound represented as the formula 3 is subjected to deprotection and ring closure under the acidic condition, anda compound represented as the formula 4 or salt of the compound is obtained; under enzyme catalysis, formic acid or formate is utilized as a hydrogen donor, a cofactor is adopted, cofactor cycle is realized, and the compound represented as the formula 4 or the salt of the compound is selectively reduced to synthesize an optically pure compound, namely, (R)-2-(2,5-difluorophenyl) pyrrolidine or the salt thereof; enzyme is a combination of recombinant imine reductase and formate dehydrogenase, and the cofactor is oxidized/reduced type nicotinamide adenine dinucleotide phosphate or oxidized/reduced type nicotinamide adenine dinucleotide. The method is safe in process and simple to operate, and yield and optical purity of a product are both higher.

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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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/10C12P41/00
CPCC12P17/10C12P41/002
Inventor 黄钢李斌
Owner SHANGHAI UNIV OF MEDICINE & HEALTH SCI
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