Method for preparing chiral diphenyl pyrrolidone and intermediate compounds

A biphenylpyrrolidone and chirality technology is applied in the field of preparation of chiral biphenylpyrrolidone and achieves the effect of short route and high purity

Inactive Publication Date: 2017-06-09
SHANGHAI SHYNDEC PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The purpose of the present invention is to solve the above-mentioned technical problems, provide a kind of new preparation method of chiral biphenylpyrrolidone and new intermediate compound, the chiral biphenylpyrrolidone obtained by utilizing this new synthetic method and new intermediate not only has high purity, And the whole synthetic route has also improved the environmental pollution problem with respect to prior art

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  • Method for preparing chiral diphenyl pyrrolidone and intermediate compounds
  • Method for preparing chiral diphenyl pyrrolidone and intermediate compounds
  • Method for preparing chiral diphenyl pyrrolidone and intermediate compounds

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Embodiment 1

[0037] Embodiment 1: the synthesis of compound 2

[0038] Dissolve 31.9g (0.1mol) of Boc-L-benzyl pyroglutamate in dry tetrahydrofuran, cool to -80°C, add 110ml of 1N LiHMDS solution dropwise, stir for 30 minutes after dropping, then add 28.4 g (0.2 mol) of methyl iodide, after dropping, stirred for about 1 hour, then naturally warmed to room temperature, and stirred overnight. Under cooling in an ice bath, 200 ml of saturated ammonium chloride solution was added, extracted with ethyl acetate, and the organic layer was washed with water until neutral, dried and concentrated to dryness under reduced pressure. 600g of silica gel column chromatography, eluting with ethyl acetate: n-hexane = 1:4, gave 21.6g of intermediate. Yield 64.9%, m / z 356.15 (100%, M+Na+ peak), 234.11 (50%, off Boc peak). 1H-NMR: see appendix figure 1 .

Embodiment 2

[0039] Embodiment 2: the synthesis of compound 3

[0040] Dissolve 17.7g (0.05mol) of CBZ-L-benzyl pyroglutamate in dry tetrahydrofuran, cool to -80°C, add 75ml of 1N LiHMDS solution dropwise, stir for 30 minutes after dropping, then add dropwise 14.2 g (0.1 mol) of iodomethane was added after dropping, stirred for about 1 hour, warmed up to room temperature naturally, and stirred overnight. Under cooling in an ice bath, 100 ml of saturated ammonium chloride solution was added, extracted with ethyl acetate, and the organic layer was washed with water until neutral, dried and concentrated to dryness under reduced pressure. Mass spectrum showed m / z 390.16 (M+Na+ peak).

Embodiment 3

[0041] Embodiment 3: the synthesis of compound 4

[0042] Dissolve 40g (0.12mol) of intermediate 2 in dichloromethane, add 4.4ml of trifluoroacetic acid, stir at room temperature for 2 hours, and remove the solvent to dryness under reduced pressure. Add methanol, 1g of 10% palladium carbon, and hydrogenate in a 5Kg / cm2 hydrogenation reactor until the reaction is complete. Filter and concentrate to dryness under reduced pressure. Crystallization with ethyl acetate gave white solid 15.8g, yield 92.1%, m / z ES+144.06 (100% M+H+ peak), 166.03 (M+Na+ peak); ES-142.02 (M-H+ peak)

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Abstract

The invention relates to the technical field of chiral diphenyl pyrrolidone preparation methods. Compared with the prior art disclosed in the patent WO2008083967, a method for preparing chiral diphenyl pyrrolidone disclosed by the invention avoids the two steps of adding a protection group of the pivaloyl group and removing the protection group of the pivaloyl group and is short in route, and does not need pivaloyl chloride which may cause serious pollution. Meanwhile, the purity of the important intermediate compound chiral diphenyl pyrrolidone obtained by the method is high, and the follow-up reaction is facilitated. The invention further provides a plurality of novel intermediate compounds.

Description

technical field [0001] The invention belongs to the technical field of preparation methods of chiral biphenylpyrrolidone. Background technique [0002] The patent WO2008083967 discloses the preparation method of chiral biphenylpyrrolidone. In the preparation process of the intermediate, pivaloyl chloride is used. Pivalic acid has a bad smell, and the working environment is not friendly. It pollutes the environment and wastes a lot. At the same time, when the protective group of the pivaloyl group is removed in the route disclosed in this patent, there are by-products, and the important intermediate 1 of chiral biphenylpyrrolidone with better purity cannot be obtained, which also affects the yield. [0003] Contents of the invention [0004] The purpose of the present invention is to solve the above-mentioned technical problems, provide a kind of new preparation method of chiral biphenylpyrrolidone and new intermediate compound, the chiral biphenylpyrrolidone obtained by...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/267C07D207/28C07D207/26
CPCC07D207/267C07B2200/07C07D207/26C07D207/28
Inventor 黄文武单晓燕陈旭东胡二营张杰
Owner SHANGHAI SHYNDEC PHARMA CO LTD
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