The Synthesis And Structure Confirmation Of Ramosetron Hydrochloride

Ramosetron hydrochloride, trade name:Nasea, and chemical name:(R)-5-[(1-methyl-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-benzimidazole hydrochloride was synthesized by Yamanouchi pharmaceutical Co., Ltd in 1989 and appeared on the market for the first time in Japana in 1996. Ramosetron hydrochloride is a new generation of efficient selective 5-HT3 receptor antagonists and inhibits cancer therapy-induced nausea, vomiting and other adverse reactions by mainly blocking the 5-HT3 receptors existing on gastrointestinal mucosa afferent vagal nerve endings. Because of its long half-life, taking fewer, less toxicity, ramosetron hydrochloride is favored by the patients and produces good economic benefits in the market!Compared with traditional antiemetic, ramosetron hydrochloride is greatly effective and high selectivity while compared with other 5-HT3 receptor antagonists such as ondansetron and granisetron, ramosetron hydrochloride with small dose (0.3mg), is convenient to use due to its once a day and have prolonged action. The mode of its administration is intravenous, which is characterized by a rapid onset, safety, and little side effects. However, the current synthetic process of ramosetron hydrochloride is cumbersome, having low yield and high cost. Currently there is no API manufacturers of ramosetron hydrochloride in China, and therefore, the construction of a simple and effective method for synthesizing high purity and low-cost ramosetron hydrochloride has important research significance and market value!In this thesis, a variety of methods on the synthesis and purification of ramosetron hydrochloride were tried to improve and simplify the reaction conditions, purification technology. Refering to synthetic routes of the United States Patent (US5344927) and Chinese patent (CN1045583A), their synthetic processes were found to be complex without sale of raw materials in the China. Thus inexpensive 3,4-aminobenzoic acid was selected as a starting material to simplify the process, reduce costs, and improve the yield.In the synthesis of benzimidazole-5-carboxylic acid, we mainly investigated the reaction temperature, reaction time and the reaction molar ratio of the two materials (3, 4-aminobenzoic acid and HCOOH) were systematically investigated based on the yield. After several tests, the optimum reaction conditions were confirmed that the molar ratio of 3,4-aminobenzoic acid and HCOOH was 1:27, the suitable reaction temperature was 100-105℃ and the optimum reaction time was 3 hours. The final reaction yield was 92.2%.In the synthesis of 4,5,6,7-tetrahydro-benzimidazol-5-carboxylic acid, the effects of different pressure and temperature on the degree of hydrogenation were mainly investigated. And the most optimal hydrogenation condition is 6.5 Mpa and 80℃, which led to 93.6% of the yield. Consequently, the improved the yield, shortened production cycle are lay foundation for the safety of production for medium-scale production in the future.In the synthesis of 4,5,6,7-tetrahydro-benzimidazole-5-carbonyl chloride, we mainly studied the reaction time and the molar ratio of two materials (4,5,6, 7-tetrahydro-benzimidazole-5-carboxylic acid and SOCl2) were mainly studied on the basis of yield. After many tests, optimal reaction conditions were found to be the molar ratio 1:16 of 4,5,6,7-tetrahydro-benzimidazole-5-carboxylic acid and SOCl2 was 1:16, and the optimum reaction time was found to be 3 hours. The final reaction yield was 93.2%.In the preparation process of ramosetron hydrochloride, the reaction time and the dropping speed of the solvent N-methyl indole were mainly studied according to the yield. As a result,10 minutes after the 4,5,6,7-tetrahydro-benzimidazole-5-carbonyl chloride was dissolved in the solvent CH2Cl2 was the best dropping time of dropping the solvent of N-methyl indole. In this dropping rate, the reaction was stirred at room temperature for three hours to achieve maximum yield.We used D-(+)-DBTA as Chiral resolution reagent in the DMF and water solution to separate the crude product.The refining process of ramosetron hydrochloride was as follows. At reflux, the crude product was dissolved in ethanol, and after adding active carbon, it was refluxed for 10 to 15 minutes. After filtered, the hot and the filtrate was allowed to cool and crystallize. The filter cake was dried under reduced pressure (60℃,-0.085MPa).Finally, white crystals with high purity and high yield was obtained (20.6% total yield). By elemental analysis of IR, UV,1H NMR,13C NMR and high resolution MS, the ramosetron hydrochloride’s structure were confirmed.Compared with previous techniques, this synthetic process only need four-steps reaction and The synthetic method was simple and mild reaction conditions. More importantly, the construction of this synthetic method Using cheap raw materials possessed greatly improved yield, reduced production costs, suitable for industrial production. After preliminary verification via pilot magnification, this synthetic method was convinced to be reliable and feasible.