Chiral beta 2-amino acid derivative and preparing method thereof

A technology for amino acids and derivatives, which is applied in the field of chiral β2-amino acid derivatives and their preparation, can solve the problems of general chiral control, structural diversity and limited derivatives, and achieve high e.r value and total yield. The effect of simple processing and readily available raw materials

Active Publication Date: 2017-01-11
中翌科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At this stage, some β-amino acids have been commercialized, but most of the reported methods are induced by chiral prosthetic groups, the chiral control is general, and the structural diversity and derivatives are limited (Chem. Commun. 2004, 2778; J . Org. Chem. 2008, 73, 3970.)

Method used

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  • Chiral beta 2-amino acid derivative and preparing method thereof
  • Chiral beta 2-amino acid derivative and preparing method thereof
  • Chiral beta 2-amino acid derivative and preparing method thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0033] 1) Preparation of mixed anhydride (Compound-I):

[0034] Compound-I is composed of acid (compound-V) and pivaloyl chloride, dichloromethane is used as the reaction solvent, the reaction concentration is 0.2-1M, triethylamine is added, and the reaction temperature is 0-30 o C, the mixed acid anhydride prepared in situ is directly used in the reaction without separation. In the preparation of compound-I, the molar ratio of compound-V, pivaloyl chloride and triethylamine is 1:1-3:1-3, preferably 1:1:1.2, and the preferred reaction temperature is 0 o C, the reaction concentration is 0.3M, and the reaction time is 2 hours.

[0035] 2) Preparation of protected benzylamine (compound-II):

[0036] Reference Angew. Chem. 1996, 108, 1059 prepared.

[0037] 3) Preparation of Compound-III:

[0038] Add azacarbene catalyst precursor (NHC-I) to the mixed anhydride (compound-I) prepared in situ to protect benzylamine (compound-II), and the reaction temperature is 0-40 o C. Stir u...

Embodiment 1

[0042] According to the following preparation route:

[0043]

[0044] 1) Add phenylpropionic acid (Compound-V-a) (3.6g, 24.0mmol) dissolved in dry dichloromethane (80ml) to a 250ml round bottom flask under nitrogen protection under ice-water bath, triethylamine ( 4.0ml, 28.8mmol), slowly added pivaloyl chloride (2.95ml, 24.0mmol) dropwise, and kept stirring at this temperature for 2 hours to prepare a mixed anhydride solution. The prepared mixed anhydride is directly used in the carbene catalyzed reaction.

[0045] 2) At room temperature, continue to add protected benzylamine (compound-II) (4.83g, 20mmol) and azacarbene catalyst precursor (NHC-I) (838mg, 2.0mmol), heating and maintaining the reaction temperature at 35 o C, the reaction time is 24 hours. The reaction solvent was spin-dried, followed by flash column chromatography (ethyl acetate:petroleum ether=1:10), and white solid compound-III-a was obtained, 5.22g, with a yield of 70%. 1 H NMR (400 MHz, CDCl 3 ) δ 7...

Embodiment 2

[0048] According to the method of Example 1, compound III-b was prepared:

[0049]

[0050] White solid, yield 70%. 1H NMR (400 MHz, CDCl 3 ) δ 7.29-7.22 (m, 10H), 7.03 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H), 3.66 (d, J = 13.6 Hz, 2H), 3.56(s, 3H), 3.42 (d, J = 13.6 Hz, 2H), 3.00-2.93 (m, 1H), 2.81 (dd, J 1 = 12.8Hz, J 2 = 9.2 Hz, 1H), 2.71 (d, J = 7.6 Hz, 2H), 2.51 (dd, J 1 = 12.8 Hz, J 2 =6.0 Hz, 1H), 2.29 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 175.0, 139.1, 136.1, 135.7, 129.1, 129.0, 128.5, 128.1, 126.9, 58.4, 55.8, 51.4, 46.9, 36.0, 21.0; HRMS (ESI, m / z): H calcd. for C26H29NO2 + 388.2277, found 388.2278. [α] 21 D = +21.4 (c = 1.0 in CHCl 3 ); HPLC analysis: 95:5er.

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Abstract

The invention belongs to the technical field of drug intermediate synthesis and particularly relates to a chiral beta 2-amino acid derivative and a preparing method thereof. The chiral beta2-amino acid derivative is represented with the following structural formula, wherein R is selected from C1-C16 linear chain or branched chain alkoxycarbonyl, and phenyl, oxole, thiophene, pyridine and naphthyl substituted with substitutes; the substituent is selected from any one of halogen, alkyl group, alkoxy, nitryl, ester group and amino group. In the method, mixed acid anhydride and protection benzylamine are regarded as starting materials; beta 2-amino acid methyl ester is prepared by catalyzing n-heterocyclic carbene and beta 2-amino acid methyl ester hydrochloride is prepared through hydrogenation and protection removal. The raw materials are easy to obtain and treat by the method, and the derivative has the high e.r value and overall yield and can provide important reference for industrial production.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, in particular to a chiral β 2 -Amino acid derivatives and methods for their preparation. Background technique [0002] Many unnatural amino acids have good physiological activity and are used as important intermediates, and are widely used in marketed drugs and a large number of new drugs under development, and are becoming more and more important in the field of medicine. However, the difficulty in synthesizing such molecules lies in chiral control. The existing methods include: 1. Chiral resolution, including crystallization, chemical resolution, and extraction resolution. The disadvantage of this method is that at least half of the raw materials are lost , most of the resolution efficiency is not high; 2, bio-enzyme resolution method, this method has poor stability and is not conducive to large-scale production (PCT Int. Appl., 2005085462); 3, chromatographic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/18C07C229/34C07D307/54C07D333/24C07D213/55
CPCC07C51/56C07C67/313C07C201/12C07C227/10C07C227/18C07D213/55C07D307/54C07D333/24C07C229/34C07C57/30C07C59/64C07C205/56C07C229/38C07C69/73C07C57/40
Inventor 池永贵黄轩
Owner 中翌科技有限公司
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