多尼培南一水合物合成工艺改进
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摘要
(2S,4S)-1-对硝基苄氧羰基-2-(N-叔丁氧羰基-N-氨基磺酰胺甲基)-4-乙酰硫基吡咯烷(2)经硫酸脱除叔丁氧羰基保护后,与1β-甲基碳青霉烯双环母核(MAP)经缩合反应得(4R,5S,6S)-3-[[(3S,5S)-1-对硝基苄氧羰基-5-(氨基磺酰胺甲基)-3-毗咯烷]硫]-6-[(1R)-1-羟乙基]-4-甲基-7-氧代-1-氮杂双环[3.2.0]庚-2-烯-2-羧酸对硝基苄酯(5),5再经催化氢化脱保护得多尼培南一水合物(1),总收率77%,纯度99.7%。最后一步中,本研究用乙酸乙酯-水代替THF-水作溶剂,避免了氯化镁的使用,解决了后处理抽滤难和成品灼残超标的问题;用钯炭代替雷尼镍和锌粉作催化剂,钯炭过滤后可循环套用,降低生产成本,且反应时间由6h缩短为3h。优化后的工艺反应条件更温和,操作简捷,更适合工业化生产。
An improved kilo-scale process of doripenem hydrate(1)was reported.(2 S,4 S)-1-(4-Nitrobenzyloxycarbonyl)-2-[N-(tert-butoxycarbonyl)-N-[[(sulfamoyl)amino]methyl]]-4-(acetylthio)pyrrolidine(2)was used as the starting material.After a deprotection of 2 with H_2 SO_4,the corresponding product reacted with MAP via condensation to give 4-nitrobenzyl(4 R,5 S,6 S)-3-[[(3 S,5 S)-1-[[(4-nitrobenzyl)oxy]carbonyl]-5-[[(sulfamoyl)amino]-methyl]pyrrolidin-3-yl]thio]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(5),which was followed by a deprotection via catalytic hydrogenation to afford the target compound in a total yield of 77%,and a purity of 99.2%.In the last step,ethyl acetate-water was used as the solvent instead of THF-water to avoid the use of magnesium chloride and to solve the difficulty of filtration and excessive inorganic residue of products.In addition,palladium-carbon was used instead of Raney nickel and zinc powder as the catalyst,which could be recycled after filtration,so that the production costs were reduced and the reaction time was shorted from 6 h to 3 h.
An improved kilo-scale process of doripenem hydrate(1)was reported.(2 S,4 S)-1-(4-Nitrobenzyloxycarbonyl)-2-[N-(tert-butoxycarbonyl)-N-[[(sulfamoyl)amino]methyl]]-4-(acetylthio)pyrrolidine(2)was used as the starting material.After a deprotection of 2 with H_2 SO_4,the corresponding product reacted with MAP via condensation to give 4-nitrobenzyl(4 R,5 S,6 S)-3-[[(3 S,5 S)-1-[[(4-nitrobenzyl)oxy]carbonyl]-5-[[(sulfamoyl)amino]-methyl]pyrrolidin-3-yl]thio]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(5),which was followed by a deprotection via catalytic hydrogenation to afford the target compound in a total yield of 77%,and a purity of 99.2%.In the last step,ethyl acetate-water was used as the solvent instead of THF-water to avoid the use of magnesium chloride and to solve the difficulty of filtration and excessive inorganic residue of products.In addition,palladium-carbon was used instead of Raney nickel and zinc powder as the catalyst,which could be recycled after filtration,so that the production costs were reduced and the reaction time was shorted from 6 h to 3 h.
引文
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[2]YUTAKA N,MAKOTO K,TANEYOSHI S,et al.Practical large-scale synthesis of doripenem:a novel1 p-methylcarbapenem antibiotic[J].Org Process Res Dev,2003,7(6):846-850.
[3]ISO Y,IRIE T,NISHINO Y,et al.A novel1β-methylcarbapenem antibiotic,S-4661 synthesis and structure-activity relationships of 2-(5-substitutedpyrrolidin-3-ylthio)-1β-methylcarbapenems[J].J Antibiot,1996,49(2):199-209.
[4]ISO Y,IRIE T,KII M,et al.Synthesis and modification of a novel 1β-methyl-carbapenem antibiotic,S-4661[J].J Antibiot, 1996,49(5):478-484.
[5]唐志军,张庆文,时惠麟.一种吡咯烷硫基碳青霉烯衍生物的制备方法及其中间体:中国,101007806[P].2007-08-01.
[6]张爱艳,朱雪焱,袁哲东.多尼培南的合成[J].中国医药工业杂志.2006.37(6):361-363.