西他列汀中间体的合成研究
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摘要
全球目前有2.85亿人患糖尿病,其中2型糖尿病患者占糖尿病病例的93.7%以上。随着糖尿病患者的增多,每年对治疗糖尿病药物的需求量也相当可观。近几年出现了一系列新型糖尿病治疗药物,其中二肽基肽酶-IV抑制剂的研究是治疗2型糖尿病的新策略。西他列汀是2006年10月由FDA批准的用于治疗2型糖尿病的新药,也是第一个用于治疗2型糖尿病的二肽基肽酶-IV抑制剂。本文主要对其手性中间体(R)-3-胺基-4-(2,4,5-三氟苯基)丁酸的合成路线进行系统研究。
论文设计了以1,2,4-三氟苯为起始原料,经2,4,5-三氟苯乙酸制备关键中间体4-(2,4,5-三氟苯基)乙酰乙酸甲酯。之后,经引入手性试剂,双键还原,氢解,水解酯基得到目标产物的合成路线。论文对中间体2,4,5-三氟苯乙酸设计了三条合成路线,分别进行实验研究,确定以1,2,4-三氟苯为起始原料,经酰化,碱性水解重排,羟基氯代,催化脱氯四步反应得到2,4,5-三氟苯乙酸。对工艺路线进行了优化,在2-(2,4,5-三氟苯基)-2-氯乙酸的合成中用二氯甲烷代替甲基叔丁基醚做萃取剂并且缩短反应时间;在2,4,5-三氟苯乙酸的合成中,将文献中10% Pd/C用量减少57.7%;并进行了实验室放大研究,四步总收率为35.8%。对中间体4-(2,4,5-三氟苯基)乙酰乙酸甲酯设计了三条合成路线,分别进行研究,确定以2,4,5-三氟苯乙酸为起始原料,经羰基活化,酰化,脱羧获得。对工艺参数进行优化同时进行了实验室放大,总收率为80.1%。在4-(2,4,5-三氟苯基)乙酰乙酸甲酯合成中,通过产品的重结晶,简化后处理过程。中间体及产品由红外光谱和核磁共振进行了结构确证。
285 million people are currently suffering from diabetes in the world, and the number of type 2 diabetes patients is upto 93.7%. The drugs for diabetes is considerable with the rising number of diabetes patients every year. A series of new diabetes drugs is on the market in recent years and among them DPP-IV inhibitors is new way to treat type 2 diabetes. Sitagliptin, the first DPP-IV inhibitor, is a new drug approved by the FDA in October 2006 for the treatment of type 2 diabetes. The purpose of this paper is on the research how to preparation of the chiral intermediate of Sitagliptin (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid.
In this paper, the key intermediate methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate was prepared from 2,4,5-trifluorophenylacetic acid which is obtained from 1,2,4-trifluorobenzene. The target molecule was synthesized through using chiral reagent, reduction of double bond, hydrogenolysis and hydrolysis of ester group. There are three synthetic routes for intermediate 2,4,5-trifluorophenylacetic acid and the best method is with 1,2,4-trifluorobenzene as the starting material, through acylation, hydrolysis and rearrangement in base environment, chlorination, hydrogenolysis to afford the target product. The reaction condition is optimized and the reaction was scaled up. In the workup, chloromethane was choosed to replace methyl tert-butyl ether as the extractant and the reaction time is shortened. In the synthesis of 2,4,5-trifluorophenylacetic acid, the amount of 10% Pd/C is decreased by 57.7%. The total yield of four steps is 35.8%. There are three synthetic routes for intermediate methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate in the paper. The conclusion is that the best synthetic route is with 2,4,5-trifluorophenylacetic acid as the starting material, through activation of carboxylgroup, acylation and decarboxylation to afford methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate. The total yield of three steps is 80.1% and the reaction condition is optimized and the reaction was scaled up. In the synthesis of methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate, the product was obtained through recrystallization. The structures were confirmed through IR and NMR.
论文设计了以1,2,4-三氟苯为起始原料,经2,4,5-三氟苯乙酸制备关键中间体4-(2,4,5-三氟苯基)乙酰乙酸甲酯。之后,经引入手性试剂,双键还原,氢解,水解酯基得到目标产物的合成路线。论文对中间体2,4,5-三氟苯乙酸设计了三条合成路线,分别进行实验研究,确定以1,2,4-三氟苯为起始原料,经酰化,碱性水解重排,羟基氯代,催化脱氯四步反应得到2,4,5-三氟苯乙酸。对工艺路线进行了优化,在2-(2,4,5-三氟苯基)-2-氯乙酸的合成中用二氯甲烷代替甲基叔丁基醚做萃取剂并且缩短反应时间;在2,4,5-三氟苯乙酸的合成中,将文献中10% Pd/C用量减少57.7%;并进行了实验室放大研究,四步总收率为35.8%。对中间体4-(2,4,5-三氟苯基)乙酰乙酸甲酯设计了三条合成路线,分别进行研究,确定以2,4,5-三氟苯乙酸为起始原料,经羰基活化,酰化,脱羧获得。对工艺参数进行优化同时进行了实验室放大,总收率为80.1%。在4-(2,4,5-三氟苯基)乙酰乙酸甲酯合成中,通过产品的重结晶,简化后处理过程。中间体及产品由红外光谱和核磁共振进行了结构确证。
285 million people are currently suffering from diabetes in the world, and the number of type 2 diabetes patients is upto 93.7%. The drugs for diabetes is considerable with the rising number of diabetes patients every year. A series of new diabetes drugs is on the market in recent years and among them DPP-IV inhibitors is new way to treat type 2 diabetes. Sitagliptin, the first DPP-IV inhibitor, is a new drug approved by the FDA in October 2006 for the treatment of type 2 diabetes. The purpose of this paper is on the research how to preparation of the chiral intermediate of Sitagliptin (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid.
In this paper, the key intermediate methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate was prepared from 2,4,5-trifluorophenylacetic acid which is obtained from 1,2,4-trifluorobenzene. The target molecule was synthesized through using chiral reagent, reduction of double bond, hydrogenolysis and hydrolysis of ester group. There are three synthetic routes for intermediate 2,4,5-trifluorophenylacetic acid and the best method is with 1,2,4-trifluorobenzene as the starting material, through acylation, hydrolysis and rearrangement in base environment, chlorination, hydrogenolysis to afford the target product. The reaction condition is optimized and the reaction was scaled up. In the workup, chloromethane was choosed to replace methyl tert-butyl ether as the extractant and the reaction time is shortened. In the synthesis of 2,4,5-trifluorophenylacetic acid, the amount of 10% Pd/C is decreased by 57.7%. The total yield of four steps is 35.8%. There are three synthetic routes for intermediate methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate in the paper. The conclusion is that the best synthetic route is with 2,4,5-trifluorophenylacetic acid as the starting material, through activation of carboxylgroup, acylation and decarboxylation to afford methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate. The total yield of three steps is 80.1% and the reaction condition is optimized and the reaction was scaled up. In the synthesis of methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate, the product was obtained through recrystallization. The structures were confirmed through IR and NMR.
引文
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[2]林小玲.糖尿病――危害人类健康的第三杀手. http://www.sz16.cn/2051/18714.html, 2008-09-07
[3]仉文升,李安良主编.药物化学.北京:高等教育出版社, 2004: 458
[4]徐进宜编著.药物化学.北京:化学工业出版社, 2006: 153
[5]杨华章,陈亮.糖尿病的现状与进展.实用医学杂志, 2004, 20(11): 1209-1201
[6] Zander M, Madsbad S, Mdsen JL, et al. Effect of 6 Week Course of Glucagons-like Peptide 1 on Glycogenic Control, Insulin Sensitivity, andβ-Cell Function in Type 2 Diabetes; A Parallel-Group Study. Lancet, 2002, 359(9309): 824-830
[7]付敏.二肽基肽酶-Ⅳ抑制剂西他列汀及其类似物的合成与表征. [南昌大学硕士论文]. 2008: 5-6
[8]夏玲红.治疗糖尿病的新药西他列汀.中国新药杂质. 2007, 16(12): 979-981
[9]张新毅,高乌恩.治疗2型糖尿病的新药——二肽基肽酶-Ⅳ抑制剂.中国药学杂志, 2007, 42(16): 1204-1207
[10]佚名. 2009世界糖尿病日. http://bjtnbxh.blog.sohu.com/136907233.html, 2009-11-16
[11]响石潭. 2009世界糖尿病日主题. http://chinadoctor.org/post/1136.html, 2009-11-04
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