Synthesis method of cis-3-amino-2-arylpyrrolidine derivative

An arylpyrrolidine and a synthesis method technology, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of inability to scale production, harsh reaction conditions, low yield, etc., and achieve easy industrial operation, few reaction steps, total high yield effect

Active Publication Date: 2013-02-20
CHANGZHOU HEQUAN PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the problems of long synthetic route, low yield, high cost, low content of cis products, difficult post-processing operation, difficult purif

Method used

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  • Synthesis method of cis-3-amino-2-arylpyrrolidine derivative
  • Synthesis method of cis-3-amino-2-arylpyrrolidine derivative
  • Synthesis method of cis-3-amino-2-arylpyrrolidine derivative

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Experimental program
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Embodiment 1

[0025]

[0026] 1. Synthesis of methyl 3-(4-fluorophenyl)-3-oxopropionate

[0027]

[0028] Add anhydrous tetrahydrofuran (540 ml), dimethyl carbonate (235.2 g, 2.61 mol) and sodium hydrogen (130.5 g, 3.263 mol, 60%) into a dry reaction flask, then heat the mixture to reflux, and slowly add A solution of p-fluoroacetophenone (180.3 g, 1.305 mol) in anhydrous tetrahydrofuran (180 ml) was added dropwise within 4 hours. The reaction solution was further refluxed for 0.5 hours. TLC (ethyl acetate:petroleum ether volume ratio=1:6, R f =0.3 ) to monitor the completion of the reaction, the reaction solution was cooled to 0° C., and a mixed solution of 90 ml of methanol and 270 ml of tetrahydrofuran was added dropwise to quench excess sodium hydrogen. Pour the reaction solution into a mixture of saturated ammonium chloride and ice, adjust the pH = 3 with hydrochloric acid, wash with ethyl acetate, water and brine, dry, and concentrate under reduced pressure to obtain the cr...

Embodiment 2

[0056]

[0057] 1. Synthesis of methyl 2-(cyanomethyl)-3-phenyl-3-oxopropionate

[0058]

[0059] Add anhydrous tetrahydrofuran (200 ml), methyl 3-(4-phenyl)-3-oxopropionate (28.6 g, 0.161 mol) to a dry reaction flask, and carefully add sodium hydrogen (9.6 g , 0.24 mol, 60%) and continued to stir for 0.5 hours. Then bromoacetonitrile (21.2 g, 0.18 mol) and tetrahydrofuran (63 ml) were slowly added dropwise. After the addition was complete, the reaction solution was stirred overnight at room temperature. TLC (ethyl acetate:petroleum ether volume ratio=1:6, R f =0.2 ) to monitor the completion of the reaction. The reaction solution was poured into ice water, adjusted to pH = 3 with hydrochloric acid, extracted with ethyl acetate, washed with water and brine, dried, and concentrated under reduced pressure to obtain a crude product, which was obtained by column chromatography to obtain 2-(cyanomethyl)-3-( Pure methyl 4-phenyl)-3-oxopropionate (24.6 g. 70.4 %).

[006...

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Abstract

The invention relates to an industrial preparation method of a cis-3-amino-2-arylpyrrolidine derivative, which mainly solves the technical problems that the synthetic route is long, the yield is low, the cost is high, the obtained cis-product content is low, the post treatment operation is difficult, the intermediate compound is difficult to purify, the reaction conditions are severe and large-scale production can not be realized in the existing cis-3-amino-2-arylpyrrolidine compound synthesis. The preparation method comprises the following steps: under the action of sodium hydride, condensing conventional and readily accessible aryl methyl ketone used as an initial raw material and dimethyl carbonate in a tetrahydrofuran solution, and performing bromoacetonitrile alkylation, Raney nickel hydrogenated cyclization and enamine hydrogenated reduction to obtain (cis)-2-(substituted phenyl)-pyrrolidine-3-carboxylate; and then, adding protective groups, performing acid hydrolysis, rearranging, and removing Boc groups to obtain the target product cis-3-amino-2-arylpyrrolidine derivative. The process provided by the invention is simple, has the advantages of fewer reaction steps, high gross production rate and mild conditions, avoids the use of expensive and dangerous reagents, can realize scale-up production and is easy to realize industrial operation.

Description

technical field [0001] The invention relates to a synthesis method of cis-3-amino-2-arylpyrrolidine derivatives. Background technique [0002] Cis-3-amino-2-arylpyrrolidine derivatives are widely used pharmaceutical intermediates, and compounds containing such core structures have neurokinin receptor (NK-1) antagonist activity. Drug application mainly for the treatment and prevention of the following diseases: antidepressant and anti-anxiety effects, and has a good therapeutic effect on nausea and vomiting caused by chemotherapy; combined use with antiemetic drugs can better control delayed vomiting and surgery post-emesis; additionally substances active on the kinin receptor (NK-1) are useful in the treatment of diseases associated with this receptor, such as inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease Diseases, as well as mediating emetic and regulating central nervous system disorders, such as Parkinson's disea...

Claims

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Application Information

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IPC IPC(8): C07D207/14
CPCY02P20/55
Inventor 韩芙蓉李少军尹云星马汝建林寿忠
Owner CHANGZHOU HEQUAN PHARMA CO LTD
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