西格列汀中间体新合成方法
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摘要
L-门冬氨酸在氯化亚砜作用下选择性甲酯化生成L-门冬氨酸-4-甲酯盐酸盐,经二碳酸二叔丁酯保护氨基,再与N-甲基吗啉,氯甲酸叔丁酯低温下反应,加入硼氢化钠还原,得(3S)-3-(叔丁氧羰基氨基)-4-羟基丁酸甲酯,与对甲基苯磺酰氯反应后的产物继续与格式试剂(2,4,5-三氟苯基)溴化镁、溴化亚铜二甲硫醚反应,经氢氧化钠水解,调酸得化合物Boc-(R)-3-氨基-4-(2,4,5-三氟苯基)丁酸。
L-aspartic acid-4-methyl ester hydrochloride was obtained using L-aspartic acid as material by the action of thionyl chloride with selectively esterification.(3S)-3-(tert-butoxycarbonyl-amino)-4-hydroxyl methyl butyrate was got with follow reaction:the protecting amino using tert-butyl dicarbonate,then reacting with methyl N-morpholine,tert-butyl chloroformate under low temperature,reducing reaction using sodium borohydride.The compound Boc-(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid was obtained with follow reaction:by reaction using(3S)-3-(tert-butoxycarbonyl-amino)-4-hydroxyl methyl butyrate with p-toluenesulfonyl chloride,than continuting reaction with a Grignard reagent,at last by hydrolysis of lithium hydroxide.
L-aspartic acid-4-methyl ester hydrochloride was obtained using L-aspartic acid as material by the action of thionyl chloride with selectively esterification.(3S)-3-(tert-butoxycarbonyl-amino)-4-hydroxyl methyl butyrate was got with follow reaction:the protecting amino using tert-butyl dicarbonate,then reacting with methyl N-morpholine,tert-butyl chloroformate under low temperature,reducing reaction using sodium borohydride.The compound Boc-(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid was obtained with follow reaction:by reaction using(3S)-3-(tert-butoxycarbonyl-amino)-4-hydroxyl methyl butyrate with p-toluenesulfonyl chloride,than continuting reaction with a Grignard reagent,at last by hydrolysis of lithium hydroxide.
引文
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[2]孙桂芳,蔡正艳,周伟澄.西他列汀合成路线图解[J].中国医药工业杂志,2008,39(5):383-385.
[3]郭锦材,张拥军,张兴贤.(3S)-3-(叔丁氧羰基氨基)-4-氧代丁酸甲酯的合成[J].中国医药工业杂志,2012,43(3):172-174.
[4]Katritzky A R,Tao H,Jiang R,et al.Novel Syntheses of chiralβ-andγ-amino acid derivatives utilizing N-protected(aminoacyl)benzowiazoles from aspartic and ghtamic acids[J].J Org Chem,2007,72(2):407-414.
[5]Ramalingam K,Woodard R W.Synthesis of stereospecific deuterium-labeled homoscrines and homoscdne lactones[J].J Org Chem,1988,53(9):1900-1903.
[6]Markidis T,Kokotos G.A novel approach to the synthesis of chiral terminal 1,2-diamines[J].J 0rg Chem,2001,66(5):1919-1923.
[7]邢其毅,裴伟伟,徐瑞秋.基础有机化学(第三版)[M].北京:高等教育出版社.
[8]Anelli P L,Biffi C,Montanafi F,et al.Fast and selective oxidation of primary alcohols to aldehydes or to carboxylic acids and of secondary alcohols to ketones mediated by oxoammonium salts under two-phase conditions[J].J org Chem,1987,52(12):2559-2562.
[9]朱国良,张健,杨立军,等.西他列汀中间体及其制备方法和用途[P].WO 20110305725,2011-03-31.
[10]Robert A B,Dudley C S.Mechanism of the reaction between benzylmagnesium chloride and carbonyl compounds.A detailed study with formaldehyde[J].American Chemical Society,1982,47(7):1243-1249.
[11]Ahlfors J E,Mekouar K.Selective caspasc inhibitors and uses there of[P].WO 2009140765,2009-11-26.
[12]Alan J H,Shin M S,Jun M A,et al.Synthesis biological evaluation and structural determination ofβ-aminoacylcontaining cyclic hydrazine derivatives as dipeptidyl peptidase IV(DPP-N)inhibitors[J].Bioorg Med Chem Lett,2007,17(9):