Research On Synthesis Of Acotiamide And Its Key Intermediates

Acotiamide is a novel, first-in-class gastroprokinetic agent, developed for the treatment of FD, and has been approved in Japan on June 2013. Most of synthesis methods have the disadvantaged of low yield and high cost at present. The development of low cost, yield and quality stability of synthesis process is of great significance. Based on the review of the literatures, a synthesis process of Acotiamide (Z-338) with an overall yield of 45.5%and purity of 99.5% from cheap and easily available 2,4,5-trimethoxybenzoic acid (2), and its key intermediates have been studied and developed. The synthetic rout of Acotiamide comprises three reactions steps:"one-pot" (including chlorination, amidation and demethylation), aminolysis, and salt formation. The quality of the product conforms to the requirement of JP.The synthesis of Acotiamide (Z-338)The key intermediate 2-[N-(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-car--boxylic acid ethyl ester acetate (5a) was prepared by a one-pot method from 2 via an acyl chloride and amide. The optimum molar ratio was compound 2:thionyl chloride:compound 3:pyridine hydrochloride= 1:1.5:0.95:4. The optimum acyl chloride reaction conditions were as follows:the reaction temperature and time were found to be 70-80℃ and 1.5 h respectively. The optimum amidation reaction conditions were as follows:the reaction temperature was reflux temperature and the reaetion time was 1.5 h, the solvent was dichloromethane, the catalyst was pyridine, and the optimum demethylating reaction conditions were the demethylation reagents was pyridine hydrochloride, the reaction temperature was reflux temperature and the reaetion time was 8 h. The experimental results showed that the yield reached 73.0% with purity greater than 95.2% by recrystallization with the mixed solvent of acetic acid and methanol. The yield was increased by 25% compared with an overall yield 41.7% in the lietrature. The one pot method not only simplified the operation process, reduced the by-products, but also increased the total yield significantly.Acotiamide was prepared by aminolysis and salt formation from compound 5a. The low active of 5b in the compound 5a was successfully aminated by compound 6 in the presence of coupling reagent. On this basis, reaction condition was optimized. The optimum molar ratio was as follows:DCC:5b= 2:1, and 5a:6=1:5. The reanction temperature and time were room temperature for 0.5 h and then at 120℃ for 0.5 h. The selectivity was increased due to reduced reaction time which partly inhibited the undesired nucleophilic substitution pathway.The isolated yield was 85% and the purity was 98% with the purification by adjusting pH. Isolated the crude product from the mixture and then carried forward to the next step of salt formation improved the quality of product.The pilot study was performed according to the process route determined by laboratory experiment, and the cost was calculated on the basis of the pilot study.The synthesis of 2,4,5-trimethoxybenzoic acid (2)The compound 2,4,5-trimethoxybenzoic acid (2) was obtained from the starting material p-benzoquinone via Thiele reaction, methylation, carbonylation and oxidization, and the reaction condition of each step was studied and optimized. The experimental results showed that (1) Thiele reaction was more sensitive to temperature. The reaction was too slow at low temperature, while high temperature decomposed product. The reaction temperature was found to be 40 to 50℃ by optimizing. (2) Methylation reaction was studied by orthogonal experiment, and the effect of the proportion of material, alkali, reaction temperature on conversion and yield were studied. The optimum amidation reaction conditions were as follows:the best ratio of material to 1,2,4-triacetoxybenzene:dimethyl sulfate= 1:4, alkali was mixed alkali of potassium hydroxide and potassium carbonate, reaction temperature was 60℃. (3) Carbonylation reaction was carried out with Vilsmeier reagent as the oxidizing agent generated in the reaction process. The Vilsmeier reagent was directly involved in the reaction to avoid the decomposition of Vilsmeier reagent. (4) The cheap and environmental 30% hydrogen peroxide was chose as oxidant. The best ratio of raw material for the 2,4,5-trimethoxybenzaldehyde (14) and 30% hydrogen peroxide was 1:5, the reaction time was 6 h, catalyst was silver nitrate.The synthesis of 2-aminothiazole-4-carboxylic acid ethyl ester (3)The process was chosed pyruvic acid as the starting material, through esterification, bromination, and cyclization to prepared 2-amino thiazole-4-carboxylic acid ethyl ester. In this paper, the reaction conditions of each step were optimized, and the determined reaction conditions were as follows:(1) Esterification reaction:the molar ratio of pyruvic acid and ethanol was 1:6, reaction temperature was reflux temperature, the reaction time was 5 h; (2) Bromination reaction:the molar ratio of bromine and ethyl pyruvate was 1:1.05, reaction temperature was reflux temperature, the bromine dripping speed was 3-4 s/drop, the reaction solvent was dichloromethane. (3) Cyclization reaction:the molar ratio of ethyl bromopyruvate and thiourea was 1:1.2, reaction temperature was reflux temperature in ethanol, and reaction time was 3.5 h. This process has the advantages of simple operation, high yield, high economic value, environment, etc.The structure of Acotiamide (Z-338) and its key intermediate compounds in this paper was charaeterized by IR speetra, MS and NMR.