Synthetic method of D-cycloserine intermediate

Abstract

The invention relates to a synthetic method of a D-cycloserine intermediate. According to the method, 3-halo-D-alanine methyl ester or an acid salt of 3-halo-D-alanine methyl ester is prepared from D-serine methyl ester or an acid salt of D-serine methyl ester and a halogenating agent through reaction in an organic solvent, and is an important intermediate for preparing D-cycloserine. The synthetic method adopts a process simple and convenient to operate, is high in safety, mild in reaction condition, high in yield and low in cost, greatly reduces production of waste acid and is quite suitable for industrial production.

Description

Technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a method for synthesizing a D-cycloserine intermediate. Background technique [0002] As a second-line anti-tuberculosis drug, D-cycloserine (Cycloserine) has a relatively broad market prospect because its drug resistance occurs more slowly than other anti-tuberculosis drugs and has no cross-resistance with other anti-tuberculosis drugs. Chemical name: D-4-amino-3-tetrahydroisoxazolone; its structural formula is as follows: [0003] [0004] The synthesis methods of D-cycloserine currently reported in the literature generally use D-serine or D-serine methyl ester acid salt as starting materials, and both of them must undergo two steps of halogenation and cyclization to prepare D-cycloserine. 3-halo-D-alanine methyl ester or its acid salt is an important intermediate for the preparation of D-cycloserine, and the halogenation step is the difficulty in the whole process of pre...

AI Technical Summary

Problems solved by technology

The method takes D-serine methyl ester hydrochloride as raw material, generates D-2-amino-3-chloropropionic acid methyl ester hydrochloride in chloroform with phosphorus pentachloride generation chlorination reaction, and this technique has the following points Insufficient: First, the PCl used 5 It is a solid powder with high risk and is not easy to feed. The second is PCl 5 When used as a chlorination reagent, a large amount of waste acid (4eq of HCl and 1eq of H 3 PO 4 ), the third is to react at low temperature (-20 ~ -15 ℃), the energy consumption is large, and the product is not easy to filter

[0010] This patent document further points out, in order to be able to reach higher yield, this reaction preferably carries out under the existence of HCl gas, and the shortcoming of this method is: (1) raw material HCl is gas, is stored in compressed cylinder, uses (2) HCl gas will have a certain corrosive effect on equipment during the scale-up production process; (3) when the process wants to obtain a higher yield in the reaction process, the usage of HCl gas needs to be within the substrate More than 3 molar equivalents, a large amount of waste acid will eventually be formed

[0011] Hee-Kwon Kim etc. reported a kind of synthetic method for preparing 3-bromoalanine methyl ester hydrobromide in document Simple and efficient synthetic routes to D-cycloserine (Tetrahedron Letters 53 (2012) 1668-1670), the The process uses D-serine methyl ester hydrochloride as the starting material, cyclohexane as the reaction solvent, and thionyl bromide as the halogenation reagent to generate 3-bromoalanine methyl ester hydrobromic acid under the catalysis of DMF. Salt, the defect of this technique is: (1) the price of the halogenated reagent dibromoxide thionyl used in this technique is on the high side, and atom economy is lower compared with thionyl chloride; (2) the total yield of this technique is low ( 85%), many by-products

[0013] The above disclosed 3-halo-D-alanine methyl ester acid salts or their analogues have defects in the synthesis and cannot meet the needs of industrial production. Therefore, there is an urgent need for a method that is easy to operate, safe, mild in conditions, and low in cost. and environmentally friendly production process

Images