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Decomposing method of N-protected allyl glycinate

A technology of allyl glycine ester and equation, applied in the field of splitting N-protected allyl glycine ester, can solve the problem of low yield and optical purity, expensive, inapplicable, economical, and large-scale synthesis of N-protected Allylglycine and other problems, to achieve the effect of short reaction time, high yield and high optical purity of the product

Active Publication Date: 2008-10-15
苏州国镝医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these processes involve many-step synthetic routes and often have low yields and optical purity
A document published by Schricker (Schricker, B. et al. Bioorg. Med. Chem. Lett. 1992, 2, 387) reported the use of α-chymotrypsin to prepare optically pure N-protected L-allylglycine, However, its yield and optical purity are very low
Moreover, α-chymotrypsin, an enzyme derived from animals, is itself very expensive and banned from use in pharmaceutical production
Therefore, none of these processes are suitable for the economical and large-scale synthesis of optically pure N-protected allylglycine

Method used

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  • Decomposing method of N-protected allyl glycinate
  • Decomposing method of N-protected allyl glycinate
  • Decomposing method of N-protected allyl glycinate

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Experimental program
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Effect test

Embodiment 1

[0020]

[0021] Take 50ml, 0.1M, PH=7.0 Na 2 h 2 PO 4 ·Na 2 HPO 4 The buffer solution was put into a 250 ml Erlenmeyer flask, and the phosphate buffer solution (0.67g subtilisin cross-linking enzyme crystals suspended in 60ml Na 2 h 2 PO 4 ·Na 2 HPO 4 buffer solution), stirred at 50°C for 5 hours, controlled the pH value between 7.5-8.0, and monitored the completion of the reaction with high performance liquid chromatography (HPLC). The filtered enzyme can be reused. 6M NaOH was added dropwise to adjust the pH value to 9, extracted twice with ethyl acetate, and the organic layer was dried and spin-dried to obtain 2.54 g of compound 2 (optical purity>98%, yield 89%). The aqueous phase was adjusted to 3 with 36% hydrochloric acid, extracted twice with ethyl acetate, and the organic layer was dried and spin-dried to obtain 2.32 g of compound 3 (optical purity>99%, yield 81%).

Embodiment 2

[0023]

[0024] Take 75ml, 0.1M, PH=7.0 Na 2 h 2 PO 4 ·Na 2 HPO 4 Buffer solution is put into 250 milliliters Erlenmeyer flask, the phosphate buffer solution (0.67g subtilisin cross-linking enzyme crystal is suspended in 60ml Na 2 h 2 PO 4 ·Na 2 HPO 4 buffer solution), stirred at 10°C for 18 hours, controlled the pH value between 7.8-8.0, and monitored the completion of the reaction with high performance liquid chromatography (HPLC). The filtered enzyme can be reused. Add saturated sodium carbonate solution dropwise to adjust the pH to 8, extract twice with ethyl acetate, and dry the organic layer to obtain 3.24 g of compound 5 (optical purity>98%, yield 85%). The aqueous phase was adjusted to 4 with cold 36% hydrochloric acid, extracted twice with ethyl acetate, and the organic layer was dried and spin-dried to obtain 3.47 g of compound 6 (optical purity>99%, yield 91%).

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Abstract

The invention discloses a method for resoluting N-protected allyl glycinate and is characterized in that: the reaction equation of the resolution process is as above. In the above equation, R1 is selected from acetyl, propionyl, butyryl, benzyloxycarbonyl or tert-butoxycarbonyl, R2 is selected from hydrogen, alkyl containing one to six carbons or aryl containing six to fifteen carbons. The main principle of the method is as follows: a compound with a bacillus subtilis proteinase cross-linked enzyme crystal formula I is used to be hydrolyzed and resoluted to obtain a compound II, namely N-protected L- allyl glycolate, and a compound III, namely N-protected L- allyl glycin. The method has high yield and short reaction time; the catalyst can be reclaimed; the product has high optical purity; and the method is more suitable for large-scale industrial application.

Description

technical field [0001] The invention relates to a resolution method of N-protected allyl glycine ester, capable of preparing N-protected optically pure allyl glycine, and belongs to the application field of enzymes in chiral synthesis. Background technique [0002] N-protected allylglycine and its esters are an important class of intermediates, widely used in the synthesis of many important protease inhibitors and other chiral drug intermediates. This type of compound can be represented by the following general formula, in the structural formula, R 1 is acetyl, propionyl, butyryl, benzyloxycarbonyl or tert-butoxycarbonyl, R 2 is hydrogen, an alkyl group containing 1 to 6 carbons, or an aryl group containing 6 to 15 carbons. [0003] [0004] Among them, the compound N-protected allyl L-glycine is a particularly important intermediate. It is widely used, especially for the preparation of optically active cyclic amino acids. [0005] Many patents and documents have repo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/20C07C233/46C07C269/08C07C271/22C07B57/00
CPCY02P20/584
Inventor 李锐姚亦明韩国霞袁方
Owner 苏州国镝医药科技有限公司