Synthetic method of (2S,5S or 5R)-N-tert-butoxycarbonyl-5-hydroxy-2-piperidinecarboxylic acid ethyl ester

Abstract

The invention discloses a synthetic method of (2S,5S or 5R)-N-tert-butoxycarbonyl-5-hydroxy-2-piperidinecarboxylic acid ethyl ester. Existing methods for synthesizing (2S,5S or 5R)-N-tert-butoxycarbonyl-5-hydroxy-2-piperidinecarboxylic acid ethyl ester have obvious deficiencies and further have difficulty in the construction of cis-piperidine acid hexatomic rings. According to the synthetic method, (2S,5S)-N-tert-butoxycarbonyl-5-hydroxy-2-piperidinecarboxylic acid ethyl ester or / and (2S, 5R)-N-tert-butoxycarbonyl-5-hydroxy-2-piperidinecarboxylic acid ethyl ester is / are prepared from a starting raw material, namely 5-hydroxy-2-pyridine carboxylic acid through nine steps of esterification salinization, reduction, Boc treatment, oxygen, protection treatment, lipase chiral resolution, Boc treatment, deprotection and reductase reduction. The synthetic method has the beneficial effects that reaction conditions are mild and easily controlled, the operation is simple and convenient, adopted reaction reagents are cheap, the production cost is greatly lowered, reaction byproducts are relatively low in toxicity and environmentally friendly, and the method is beneficial to the large-scale production.

Description

Technical field [0001] The invention belongs to the field of synthesis of pharmaceutical intermediates, specifically a (2S,5S)-N-tert-butoxycarbonyl-5-hydroxy-2-piperidine ethyl carboxylate or / and (2S,5R)-N- Synthetic method of tert-butoxycarbonyl-5-hydroxy-2-piperidine ethyl carboxylate. Background technique [0002] Pipecolic acid and its derivatives are very important synthetic intermediates. The six-membered ring piperidine structure of this type of compound has two hand-shaped centers, which is very difficult to synthesize. Generally, it can be synthesized through very complicated synthetic steps. Used in the preparation of drugs such as Avibactam sodium and many biologically active substances. However, the current market price is very expensive, which not only limits its application in the pharmaceutical industry and the organic synthesis of complex natural products, but also greatly increases the cost of medicines that use it as a raw material. [0003] [0004] As an exis...

AI Technical Summary

Problems solved by technology

[0012] This synthetic method has a long synthetic route, expensive reagents used in the reaction, and the two chiral centers need to be split twice, resulting in a low yield and difficult to achieve large-scale production

[0013] In summary, the methods for the synthesis of (2S,5S)-N-tert-butoxycarbonyl-5-hydroxyl-2-piperidinecarboxylic acid ethyl esters reported in the above literature all have obvious deficiencies, and the difficulty lies in the cis-piperidine six-membered ring Therefore, there is an urgent need to develop a method for the preparation of (2S, 5S)-N-tert-butoxycarbonyl-5-hydroxyl-2-piperidinecarboxylate with environmental friendliness, good selectivity, good yield and low cost

Images