本文關鍵詞：琥珀酸曲格列汀合成工藝及有關物質研究　出處：《上海醫(yī)藥工業(yè)研究院》2017年碩士論文　論文類型：學位論文

  更多相關文章： 琥珀酸曲格列汀 2型糖尿病 二肽基肽酶-4抑制劑 有關物質 合成工藝

【摘要】：琥珀酸曲格列汀是第一個上市的口服長效二肽基肽酶-4抑制劑,用于2型糖尿病的治療,患者依從性高。Ⅲ期臨床研究證明,與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,且安全性較好。本文以原研公司專利路線為基礎展開合成工藝研究,2-甲基-4-氟苯甲腈溴代生成溴芐5和二溴代物5’,其中5’再用亞磷酸二乙酯轉化成5,再與3-甲基-6-氯尿嘧啶反應生成關鍵中間體6,6與(R)-3-氨基哌啶取代得到曲格列汀粗品。該粗品直接與琥珀酸成鹽,異丙醇/水重結晶后五步總收率61%(以2-甲基-4-氟苯甲腈計),純度大于99.9%,未檢出光學異構體。在優(yōu)化6與(R)-3-氨基哌啶的取代反應前,先合成了可能的有關物質A~G,并建立了能有效分離各有關物質及曲格列汀的HPLC方法,此方法為該反應條件的篩選提供了指引。研究結果發(fā)現:醇溶劑優(yōu)于非質子性溶劑,空間位阻大的醇能避免雜質生成,碳酸氫鈉作為堿優(yōu)于碳酸鉀和二異丙基乙胺。優(yōu)化后的取代反應條件是以異丙醇為溶劑,碳酸氫鈉為堿,用該方法制得曲格列汀粗品純度94%以上,故可以省略專利報道的酸堿純化方法而與琥珀酸直接成鹽。由二溴代5’轉化成單溴代5的反應,亞磷酸二乙酯投料量降為文獻方法的1/4,二異丙基乙胺投料量降為1/5。整條路線中,專利共使用7種有機溶劑,包括1類溶劑1,2-二氯乙烷,而本研究割除1,2-二氯乙烷,僅用3種有機溶劑:二氯甲烷,四氫呋喃和異丙醇。本文共合成了A~J共10個曲格列汀的有關物質,其中有2個(D和G)未見文獻報道。10個化合物都經1H-NMR和MS確證結構,并與藥物在HPLC能良好分離,為藥物的質量研究提供基礎。
[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.
【學位授予單位】：上海醫(yī)藥工業(yè)研究院
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R914

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本文編號：1420989