Synthesis method of cis 3-phenyl substituted s-proline derivative

Abstract

The invention provides an optical isomers pure cis 3-phenyl substituted s-proline derivative synthesis method. A route is as follows: taking the substituted cinnamaldehyde and nitroethyl alcohol as raw materials, taking (S)-diphenyl prolinol trimethyl silicyl oxide as an asymmetric catalyst, and obtaining the optical isomers pure cis 3-phenyl substituted s-proline derivative through asymmetric michael addition reaction, hydrogenation and boc protection reaction, and oxidation and deprotection reaction. The synthesis method has the advantages of high yield, good three-dimensional selectivity, mild reaction conditions, convenient post-treatment, no need of column chromatography purification, low cost and the like, and is a synthesis route with industrial prospect.

Description

technical field [0001] The invention relates to a synthesis method of amino acid derivatives, in particular to a synthesis method of 3-phenyl substituted proline derivatives, and the purity of the obtained products reaches optical isomerism purity. Background technique [0002] 3-Phenyl-substituted proline is a kind of unnatural α-amino acid, which is the core fragment of many active drug molecules. The cis-3-phenyl-substituted proline is a conformationally constrained α-amino acid, which has a variety of physiological activities, and the optically pure 3-phenyl-substituted proline derivatives have become a hot spot in medicinal chemistry research. Example: compound As a melanocortin-4 receptor (MC4R), its inhibitor has the effect of reducing body weight and food intake, and can be used to treat conditions such as cancer progression. Recent studies have shown that its inhibitors also have the effect of treating anxiety and depression (Bioorg. Med. Chem. Lett., 2008, 18, 1...

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Problems solved by technology

But this route also has some disadvantages, such as: 1. 3-4 and 3-4' need to be separated by column chromatography, which is not conducive to large-scale operation; 2. Catalytic hydrogenation is carried out at room temperature and normal pressure for hydrogenation reaction, and the reaction conversion rate is low. The reaction time is long; 3. The intermediate 3-5 needs to be separated by column chromatography, which is not conducive to large-scale operation; 4. From 3-5 to the aldehyde 3-6, and then to the carboxylic acid 3-7, the increase The reaction step reduces the reaction yield, which is not conducive to large-scale preparation

[0015] In summary, although there have been many reports on the synthesis of optically pure cis-3-phenyl-substituted proline in recent years, there are unfavorable factors that are difficult to industrialize

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