| Omeprazole(l) is a specific drug for the treatment of gastric ulcer. Based on the review of the literatures, a synthesis process of OmeprazoleQJ with an overall yield of 45.5%(assay^99.5%) from cheap and easily available 2,3,5-trimethylpyridine (5) has been studied and developed. The synthetic route comprises eight reaction steps: N-oxidation, nitration, methoxylation, acetoxylation rearrangement, hydrolysis, chloration, etherification and S-oxidation. The quality of the product conforms to USP 24.N-Oxidation of 2,3,5-trimethylpyridine(5) was carried out by using peracetic acid formed in situ with 30% hydrogen peroxide and acetic acid as the oxidizing agent. The effect of the reaction temperature and time on the conversion, selectivity and yield was studied. The experimental results showed that the yield of 2,3,5-trimethylpyridine-N-oxide(6) reached 98.0% with a purity greater than 98.0%. The optimum reaction conditions are as follows: 2,3,5-trimethylpyridine(5):30% hydrogen peroxide=l: 1.55-1.70, the dropwise addition time of 30% hydrogen peroxide ^6 h, the reaction temperature is 95-100 癈 and the reaction time is 10 h. The crude N-oxide was directly nitrated without the purification by high vacuum distillation.The nitration mechanism of 2,3,5-trimethylpyridine-N-oxide(6) was discussed and it was revealed that the activity of nitrating agent was the key factor affecting the orientation selectivity of nitration. By substituting 65% nitric acid for fuming nitric acid, the selectivity of 4-position nitration was increased and the formation of 6-NOa and 4,6-(NC>2)2 by-products was controlled. The optimum reaction temperature and time were found to be 80 癈 and 6 h respectively. The yield of crude 4-nitro-2,3,5-trimethylpyridine-N-oxide(7) was 98.5% with a purity greater than 98.0%.Nucleophilic substitution of the - NO: radical by the -OCH3 radical was carried out by sodium methoxide of technical grade. By using benzyltriethylammonium chloride as catalyst, the reaction temperature was decreased from reflux to 55"C under 5 h of reaction time. The yield of raw 4-methoxyl-2,3,5-trimethylpyridine-N-oxide(8) was enhanced up to 95% with a purity of 97.5% compared to the yield of 68.5% (purity of 89.0%) reported in the literature. Meanwhile, a novel method for the synthesis of 4-methoxyl-2,3,5-trimethylpyridine with an overall yield of 82.0% from 2,3,5-trimethylpyridine(5) was developed via N-oxidation, nitration, methoxylation and deoxygenation.Based on exploring the mechanism of the rearrangement reaction of 4-methoxyl-2,3,5-trimethylpyridine-N-oxide(8) with acetic anhydride, O-acylation and subsequent acetoxylation of the 2-position methyl group and acid hydrolysis of the aceloxyl group were studied. The results showed that the optimum rearrangement reaction temperature was 70-80癈, while the literature reported temperature was 90-130 癈 . The yield of 2-hydroxymethyl-3,5-dimethyl-4-methoxylpyridine hydrochloride(lO) was 75.0% with purity ^99.0%. Through study on each reaction, the by-products in each step were controlled effectively and the purity of each intermediate was enhanced. Therefore, the five-step reaction could be conducted in "one pot", thus simplifying the equipment and operation. The overall yield of 10 from 2,3,5-trimethylpyride(5) was as high as 70% with purity^99.0%, compared with an overall yield 41.7% in the literature.Nucleophilic substitution of -OH radical by the -Cl radical of 10 of thionyl chloride was carried out in methylene chloride as solvent under 25~30癈 and 3 h of reaction time. The yield of 2-chloromethyl-4methoxyl-3,5-dimethylpyridine hydrochloride(3) was 98.0% with purity^99.0%.A study has been made on etherification of 2-chloromethyl-4methoxyl-3,5-dimethylpyridine hydrochloride(3) and5-methoxy-2mercaptobenzimidazole(4) with NaOH to synthesize 5-methoxyl-2((3,5-dimethyl-4-methoxyl-2-pyridinyl)-methylthio)-benzimidazole (2).According to the method in the literature, the reaction was carried out in water/...
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