Synthesis method of teneligliptin key intermediate

Abstract

The invention discloses a synthesis method of a teneligliptin key intermediate, and relates to the technical field of synthesis, in particular to a synthesis method of a teneligliptin key intermediate(2S)-4-oxo-2-(3-thiazolidinylcarbonyl)-1-pyrrolidinecarboxylic acid tert-butyl ester. According to the synthesis method, L-hydroxyproline is subjected to an esterification reaction to obtain a compound 1; the compound 1 is protected by t-butyloxycarboryl to obtain a compound 2; the compound 2 is subjected to an oxidation reaction to obtain a compound 3; the compound 3 and thiazolidine are subjected to an ammonia ester exchange reaction to obtain a compound 4. According to the method, a synthesis route suitable for industrial production is designed aiming at the teneligliptin key intermediate,the complexity of the operation is lowered, expensive dehydration reagents are also avoided, the yield is high, the cost is low, and the synthesis method is suitable for industrial application and popularization.

Description

technical field [0001] The present invention relates to the technical field of synthesis, in particular to a method for synthesizing a key intermediate of tiagliptin, in particular to the key intermediate (2S)-4-oxo-2-(3-thiazolidinylcarbonyl) of tiagliptin -The synthetic method of tert-butyl pyrrolidinecarboxylate. Background technique [0002] Teneligliptin, the chemical name is 3-[[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1-piper Azinyl]-2-pyrrolidinyl]formyl]thiazolidine is an oral DPP-IV inhibitor developed by Mitsubishi Tanabe Pharmaceutical Co., Ltd., which was first launched in Japan in September 2012. Clinical studies have shown that whether it is used alone or in combination with other hypoglycemic drugs, Teneliptin can efficiently and selectively inhibit the activity of DPP-Ⅳ, and can play a good role in regulating postprandial and fasting blood glucose , and the incidence of hypoglycemia is low, and has no effect on body weight. Therefore, the market p...

AI Technical Summary

Problems solved by technology

The WO2016 / 079699 route uses L-hydroxyproline as a raw material. After tert-butoxycarbonyl protection, the water solubility is still very large. After a large amount of solvent extraction, there are still products in the water, which affects the yield; when reacting with tetrahydrothiazole, use Condensing agent (DCC, DMAP), the cost is high, and the by-product DCU is not easy to remove, and the overall yield is low

In WO2014041560A2, the synthetic route uses L-hydroxyproline as a raw material. After tert-butoxycarbonyl protection, it is very water-soluble and difficult to extract; it uses expensive condensing agents (HOBT, EDCI) when reacting with tetrahydrothiazole. Higher cost; oxidation after condensation of amino acid, the sulfur atom on the thiazole ring is easily oxidized and called sulfur sulfone, which is not easy to remove

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