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A kind of synthetic method of α-hydroxyl-β-amino acid single stereoisomer

A technology of stereoisomers and synthetic methods, which is applied in the direction of organic chemical methods, chemical instruments and methods, and the preparation of organic compounds, and can solve the problems of using expensive chiral ligands or highly toxic raw materials, which are not suitable for industrial production, etc. Achieve the effect of short synthesis period, low cost of raw materials, and ordinary reaction conditions

Active Publication Date: 2020-08-14
KANGHUA SHANGHAI DRUG RES DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The purpose of the present invention is to provide a method for synthesizing a single stereoisomer of α-hydroxy-β-amino acid, which mainly solves the existing synthetic methods that use expensive chiral ligands or highly toxic raw materials, which are not suitable for industrial production. question

Method used

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  • A kind of synthetic method of α-hydroxyl-β-amino acid single stereoisomer
  • A kind of synthetic method of α-hydroxyl-β-amino acid single stereoisomer
  • A kind of synthetic method of α-hydroxyl-β-amino acid single stereoisomer

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Example 1: Preparation of (2S,3S)-3-amino-2-hydroxyhexanoic acid and (2R,3R)-3-amino-2-hydroxyhexanoic acid hydrochloride

[0022]

[0023] (1) Preparation of trans-epoxides

[0024] Add trans-2-hexenoate (90g, 0.70 mol) into a 1-liter three-necked flask, add dichloroethane (500mL), add m-chloroperoxybenzoic acid (85% by mass, 142g, 0.91 mol), heated at 50°C for 3 hours, the reaction was complete. After cooling, it was filtered, and the filtrate was washed successively with saturated sodium bicarbonate and saturated sodium sulfite, dried over anhydrous sodium sulfate, and the concentrated oil was obtained. The oil was distilled under reduced pressure to obtain trans-epoxide a (88 g, yield 88%);

[0025] (2) Preparation of oxazoline ring

[0026] Add trans-epoxide a (88 g, 0.61 mol), phenylacetonitrile (254 g, 2.38 mol) and dichloromethane (880 mL) into a 2-liter three-necked flask. Boron trifluoride diethyl ether (308 g, 2.38 mol) was added dropwise at 0°C. Afte...

Embodiment 2

[0033] Example 2: R 1 For ethyl, use 3N sodium hydroxide solution to adjust the pH to 7.5~8.5; penicillin G acylase is an aqueous solution of penicillin G acylase, and the filtrate is acidified to pH 1~2 with 6N hydrochloric acid, and the reaction temperature in step (4) is 20~ 25°C. Step (5) The amount of 6N hydrochloric acid used for hydrolysis is 8 times that of the phenylacetyl-protected α-hydroxy-β-amino acid in the (R,R) configuration; the reaction temperature is 110°C, and the rest are the same as in Example 1.

Embodiment 3

[0034] Example 3: R 1For benzyl, use 3N sodium carbonate solution to adjust the pH to 7.5~8.5; penicillin G acylase is immobilized penicillin G acylase, the filtrate is acidified to pH 1~2 with 6N hydrochloric acid, and the reaction temperature in step (4) is 30~ 35°C. Step (5) The amount of 6N hydrochloric acid used for hydrolysis is 10 times that of the phenylacetyl-protected α-hydroxy-β-amino acid in the (R,R) configuration; the reaction temperature is 108°C, and the rest are the same as in Example 1.

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Abstract

The invention relates to a synthesis method of an alpha-hydroxyl-beta-amino acid simplex stereoscopic isomer. The method mainly solves the technical problems that an existing synthesis method uses expensive chiral ligand or highly-toxic raw materials and is not suitable for industrial production. The method includes the steps of firstly, synthesizing substitutive alpha-hydroxyl-beta-amino acid despinner according to a literature method; secondly, stereoscopically and selectively synthesizing an alpha-hydroxyl-beta-amino acid simplex isomer of an (S,S) structure and an alpha-hydroxyl-beta-aminoacid simplex isomer of an (R,R) structure with penicillin G acylase. The method is suitable for preparing the alpha-hydroxyl-beta-amino acid simplex isomers efficiently at low cost.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a method for synthesizing a single stereoisomer of α-hydroxyl-β-amino acid. Background technique [0002] Single isomer α-hydroxy-β-amino acid is an important building block of some drugs, such as in the synthesis of paclitaxel and its analogues, ubenimex, and in the screening of polypeptide drugs are widely used. The synthesis technology of single isomer α-hydroxy-β-amino acid has been reported in the literature: such as (1) the method of hydroxylation of chiral amine reported in the literature Synth. Commun. 1998, 28, 4463: Sharpless et al. Hydroxylation of α, β-unsaturated amides with unsymmetrical amines catalyzed by the body, and then a single isomer α-hydroxy-β-amino acid was synthesized through several steps. (2) The cyanation method reported in the literature Tetrahedron: Asymmetry, 2001, 12, 347–353: Jose M. Andresl et al. used sodium cyanide to attack chiral amino ald...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C227/20C07C229/22C12P13/04
CPCC07B2200/07C07C227/20C12P13/04C07C229/22
Inventor 徐红岩胡国航袁伟芳
Owner KANGHUA SHANGHAI DRUG RES DEV CO LTD