(1S,3S,5S)-2-叔丁氧羰基-2-氮杂双环[3.1.0]已烷-3-甲酰胺3个立体异构体的合成
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摘要
本研究设计合成了(1S,3S,5S)-2-叔丁氧羰基-2-氮杂双环[3.1.0]己烷-3-甲酰胺(沙格列汀的关键中间体)的3个异构体。以(1S,3S,5S)-2-叔丁氧羰基-2-氮杂双环[3.1.0]己烷-3-羧酸乙酯为起始原料,经氢氧化锂水解得(1S,3S,5S)-2-叔丁氧羰基-2-氮杂双环[3.1.0]己烷-3-羧酸,与羰基二咪唑反应后,在碳酸钾作用下消旋化,再经氯甲酸异丁酯活化、氨化后制得(1S,3R,5S)-2-叔丁氧羰基-2-氮杂双环[3.1.0]己烷-3-甲酰胺。按照相同的方法,可由(1R,3R,5R)-2-叔丁氧羰基-2-氮杂双环[3.1.0]己烷-3-羧酸乙酯制得(1R,3R,5R)-2-叔丁氧羰基-2-氮杂双环[3.1.0]己烷-3-甲酰胺和(1R,3S,5R)-2-叔丁氧羰基-2-氮杂双环[3.1.0]己烷-3-甲酰胺。这3个异构体的结构均经MS、~1H NMR确证,可作为合成沙格列汀的立体异构体的重要中间体。
In this study, three stereo-isomers of(1 S,3 S,5 S)-2-tert-butoxycarbonyl-2-azabicyclo[3.1.0]hexane-3-amide, the key intermediate of saxagliptin, were synthesized. Ethy1(1 S,3 S,5 S)-2-tert-biitoxycarbonyl-2-azabicyclo [3.1.0]-hexane-3-carboxylate reacted with lithium hydroxide to give(1 S,3 S,5 S)-2-tert-butoxycarbonyl-2-azabicyclo[3.1.0]-hexane-3-carboxylic acid. After reacting with carbonyldiimidazole, the corresponding compound was subjected to racemization by potassium carbonate, activation by isobutyl chloroformate and ammoniation to afford(1 S,3 R,5 S)-2-tert-butoxycarbony1-2-azabicyclo[3.1.0]hexane-3-amide with a total yield of 40.4%. According to the same method,(1 R,3 R,5 R)-2-tert-butoxycarbony1-2-azabicyclo [3.1.0]hexane-3-amide and(IR,3 S,5 R)-2-tert-butoxycarbonyl-2-azabicyclo [3.1.0] hexane-3-amide was obtained from ethyl(1 R,3 R,5 R)-2-tert-butoxycarbonyl-2-azabicyclo[3.1.0]-hexane-3-carboxylate in a total yield of 23.1% and 46.1%, respectively. These substances were confirmed by MS and~1 H NMR. They may be used as the key intermediates for synthesis of the stereo-isomers of saxagliptin.
In this study, three stereo-isomers of(1 S,3 S,5 S)-2-tert-butoxycarbonyl-2-azabicyclo[3.1.0]hexane-3-amide, the key intermediate of saxagliptin, were synthesized. Ethy1(1 S,3 S,5 S)-2-tert-biitoxycarbonyl-2-azabicyclo [3.1.0]-hexane-3-carboxylate reacted with lithium hydroxide to give(1 S,3 S,5 S)-2-tert-butoxycarbonyl-2-azabicyclo[3.1.0]-hexane-3-carboxylic acid. After reacting with carbonyldiimidazole, the corresponding compound was subjected to racemization by potassium carbonate, activation by isobutyl chloroformate and ammoniation to afford(1 S,3 R,5 S)-2-tert-butoxycarbony1-2-azabicyclo[3.1.0]hexane-3-amide with a total yield of 40.4%. According to the same method,(1 R,3 R,5 R)-2-tert-butoxycarbony1-2-azabicyclo [3.1.0]hexane-3-amide and(IR,3 S,5 R)-2-tert-butoxycarbonyl-2-azabicyclo [3.1.0] hexane-3-amide was obtained from ethyl(1 R,3 R,5 R)-2-tert-butoxycarbonyl-2-azabicyclo[3.1.0]-hexane-3-carboxylate in a total yield of 23.1% and 46.1%, respectively. These substances were confirmed by MS and~1 H NMR. They may be used as the key intermediates for synthesis of the stereo-isomers of saxagliptin.
引文
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[7] BELEMA M, GOOD A C, GOODRICH J,et al. Bi-1H-benzimidazoles as hepatitis C virus inhibitors:WO2010017401[P]. 2010-11-02.
[8] LIU F, DING D, PAN X H, et al. An cost-effective and safe process of L-cis-4,5-methanoproline amide, the key synthetic intermediate of saxagliptin,via an improved Simmons-Smith reaction[J]. Heterocycles, 2015, 91(4):719-725.
[9]陶志强,刘飞孟,宓鹏程,等.一种沙格列汀关键中间体的制备方法:中国,16554301[P]. 2015-09-30.
[2] DEACON C F, HOLST J J. Saxagliptin:a new dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes[J]. Adv Ther,2009, 26(5):488-499.
[3] DEFRONZO R A, HISSA M N, GARBER A J, et al. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2diabetes with metformin alone[J]. Diabetes Care,2009,32(9):1649-1655.
[4]谭玲.夏路风,孙春华.治疗2型糖尿病新药二肽基肽酶Ⅳ抑制剂沙克列汀[J].中国新药杂志,2010, 19(13):1099-1102.
[5] TRUC C V U, BRZOZOWSKI D B, FOX R, et al. Methods and compounds producing dipeptidyl peprtidase IV inhibitors and intermediates thereof:WO, 2004052850[P]. 2004-06-24.
[6]ROBL J A,SULSKY R B, AUGERI D J,et al. Cyclopropylfused pyrrolidine-based inhibitors of dipeptidyl peprtidase IV and method:WO, 2001068603[P]. 2001-09-20.
[7] BELEMA M, GOOD A C, GOODRICH J,et al. Bi-1H-benzimidazoles as hepatitis C virus inhibitors:WO2010017401[P]. 2010-11-02.
[8] LIU F, DING D, PAN X H, et al. An cost-effective and safe process of L-cis-4,5-methanoproline amide, the key synthetic intermediate of saxagliptin,via an improved Simmons-Smith reaction[J]. Heterocycles, 2015, 91(4):719-725.
[9]陶志强,刘飞孟,宓鹏程,等.一种沙格列汀关键中间体的制备方法:中国,16554301[P]. 2015-09-30.