琥珀酸曲格列汀合成工艺及有关物质研究

发布时间：2018-01-13 23:16

本文关键词：琥珀酸曲格列汀合成工艺及有关物质研究　出处：《上海医药工业研究院》2017年硕士论文　论文类型：学位论文

【摘要】：琥珀酸曲格列汀是第一个上市的口服长效二肽基肽酶-4抑制剂,用于2型糖尿病的治疗,患者依从性高。Ⅲ期临床研究证明,与每天一次口服阿格列汀相比,每周一次口服曲格列汀具有非劣效性,且安全性较好。本文以原研公司专利路线为基础展开合成工艺研究,2-甲基-4-氟苯甲腈溴代生成溴苄5和二溴代物5’,其中5’再用亚磷酸二乙酯转化成5,再与3-甲基-6-氯尿嘧啶反应生成关键中间体6,6与(R)-3-氨基哌啶取代得到曲格列汀粗品。该粗品直接与琥珀酸成盐,异丙醇/水重结晶后五步总收率61%(以2-甲基-4-氟苯甲腈计),纯度大于99.9%,未检出光学异构体。在优化6与(R)-3-氨基哌啶的取代反应前,先合成了可能的有关物质A~G,并建立了能有效分离各有关物质及曲格列汀的HPLC方法,此方法为该反应条件的筛选提供了指引。研究结果发现:醇溶剂优于非质子性溶剂,空间位阻大的醇能避免杂质生成,碳酸氢钠作为碱优于碳酸钾和二异丙基乙胺。优化后的取代反应条件是以异丙醇为溶剂,碳酸氢钠为碱,用该方法制得曲格列汀粗品纯度94%以上,故可以省略专利报道的酸碱纯化方法而与琥珀酸直接成盐。由二溴代5’转化成单溴代5的反应,亚磷酸二乙酯投料量降为文献方法的1/4,二异丙基乙胺投料量降为1/5。整条路线中,专利共使用7种有机溶剂,包括1类溶剂1,2-二氯乙烷,而本研究割除1,2-二氯乙烷,仅用3种有机溶剂:二氯甲烷,四氢呋喃和异丙醇。本文共合成了A~J共10个曲格列汀的有关物质,其中有2个(D和G)未见文献报道。10个化合物都经1H-NMR和MS确证结构,并与药物在HPLC能良好分离,为药物的质量研究提供基础。
[Abstract]:Traglutin succinate is the first oral long-acting dipeptidyl peptidase-4 inhibitor to be used in the treatment of type 2 diabetes with high compliance. Oral traglutin once a week has a non-inferior effect and good safety. This paper is based on the patent route of the original research company to develop the synthesis process. 2-methyl-4-fluorobenzonitrile bromobenzyl 5 and dibromobenzyl 5 were formed. 5 '-diethyl phosphite was converted to 5 and then reacted with 3-methyl-6-chlorouracil to form the key intermediate 6. The crude product of triglutin was obtained by substitution with RPU-3- aminoperidol. The crude product was directly salted with succinic acid. The total yield of the crude product was 61% after recrystallization of isopropanol / water (based on 2-methyl-4-fluorobenzonitrile). The purity was greater than 99.9, and the optical isomer was not detected. Before the substitution reaction of 6 with RPG-3-aminoperidol was optimized, the possible related substance AfG was synthesized. A HPLC method for the effective separation of the related substances and trioglitine was established, which provided guidance for the screening of the reaction conditions. The results showed that the alcohol solvent was superior to the non-proton solvent. The alcohol with large steric hindrance can avoid the formation of impurity and sodium bicarbonate as base is superior to potassium carbonate and diisopropylethylamine. The optimized reaction conditions are as follows: isopropanol as solvent and sodium bicarbonate as base. The purity of the crude product of traglutin was over 94%, so the reaction of dibromo-5'to monobromo-5 'could be obtained by omitting the purification method of acid and base reported by patent and directly forming salt with succinic acid. The amount of diethyl phosphite was reduced to 1 / 4 of the method in the literature, and the amount of diisopropylethylamine was reduced to 1 / 5. In the whole route, seven organic solvents were used in the patent, including 1 / 2 dichloroethane, a kind of solvent. In this study, only three organic solvents, methylene dichloromethane, tetrahydrofuran and isopropanol, were used to separate 1 chloride-2-dichloroethane. Ten related substances of trioglentin were synthesized. The structures of 10 compounds were confirmed by 1H-NMR and MS, and they were well separated from the drug in HPLC, which provided the basis for the study of drug quality.
【学位授予单位】：上海医药工业研究院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914

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