4-氨基-5-乙磺酰基-2-甲氧基苯甲酸的合成工艺改进
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摘要
以对氨基水杨酸为起始原料,经过甲基化、硫氰化、还原乙基化、氧化、水解得到4-氨基-5-乙磺酰基-2-甲氧基苯甲酸。探讨了甲基化反应和硫乙基引入方法问题,并对各步反应合成条件进行了优化。改进后工艺总收率达55%,目标化合物和各中间体经IR,1 H NMR和MS等确证结构。
4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid is synthesized from amino salicylic acid via methylation,thiocyanation,reduction and ethylation,oxidation and hydrolysis reactions.The methylation reaction and the introduction method of ethylthio group are investigated,and the reaction conditions of all steps are optimized.The total yield rate is 55%after optimization,and the product and its intermediates are confirmed by IR,1 H NMR and MS.
4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid is synthesized from amino salicylic acid via methylation,thiocyanation,reduction and ethylation,oxidation and hydrolysis reactions.The methylation reaction and the introduction method of ethylthio group are investigated,and the reaction conditions of all steps are optimized.The total yield rate is 55%after optimization,and the product and its intermediates are confirmed by IR,1 H NMR and MS.
引文
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[2]PERRAULT G H,DEPOORTERE R,MOREL E,et al.Psychopharmacological profile of amisulpride:An antipsychotic drug with presynaptic D2/D3dopamine receptor antagonist activity and limbic selectivity[J].The Journal of Pharmacology and Experimental Therapeutics,1997,280(1):73-82.
[3]MARCHESE G,RUIU S,CASTI P,et al.Effect of the amisulpride isomers on rat prolactinemia[J].European Journal of Pharmacology,2002,448(2/3):263-266.
[4]黄文武,王祖承,徐鹤定.氨磺必利:一种非典型抗精神病药[J].上海精神医学,2000,12(2):114-115.HUANG Wenwu,WANG Zucheng,XU Heding.Amisulpride:An atypical antipsychotic drug amisulpride[J].Shanghai Archives of Psychiatry,2000,12(2):114-115.
[5]HAMON-VILCOT B,CHAUFOUR S,DESCHAMPS C,et al.Safety and pharmacokinetics of a single oral dose of amisulpride in healthy elderly volunteers[J].European Journal of Clinical of Pharmacology,1998,54(5):405-409.
[6]张越,徐世霞,于奕峰.PEG前药的合成研究进展[J].河北科技大学学报,2013,34(4):355-364.ZHANG Yue,XU Shixia,YU Yifeng.Study progress on the synthesis of PEG prodrug[J].Journal of Hebei University of Science and Technology,2013,34(4):355-364.
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[8]张恺,薛娜,杜玉民,等.(S)-(-)-氨磺必利-D-(-)-酒石酸盐的合成[J].中国现代应用药学杂志,2009,26(8):635-637.ZHANG Kai,XUE Na,DU Yumin,et al.Synthesis of D-(-)tratrate of(S)-(-)-amisulpride[J].Chinese Journal of Modern Applied Pharmacy,2009,26(8):635-637.
[9]程玉红,康江鹏,陈蔚,等.氨磺必利的合成[J].中国医药工业杂志,2011,42(11):801-803.CHENG Yuhong,KANG Jiangpeng,CHEN Wei,et al.Synthesis of amisulpride[J].Chinese Journal of Pharmaceuticals,2011,42(11):801-803.
[10]李付刚,白雪松,葛晶,等.2-甲氧基-4-氨基-5-乙砜基苯甲酸的合成[J].精细与专用化学品,2008,16(13):16-17.LI Fugang,BAI Xuesong,GE Jing,et al.Synthesis of 2-methoxy-4-amino-5-ethylsufonylbenzoic acid[J].Fine and Specialty Chemicals,2008,16(13):16-17.
[11]PAGHDAR D,KOLEKAR M,DESHPANDE T,et al.An Improved Process for Preparation of Amisulpride[P].WO:2011/158084,2011-12-22.
[12]刘磊,杨艺虹,张珩,等.4-氨基-5-乙磺酰基-2-甲氧基苯甲酸的合成[J].精细化工中间体,2008,38(3):29-32.LIU Lei,YANG Yihong,ZHANG Heng,et al.Synthesis of 4-amino-5-ethylsufonyl-2-methoxybenzoic acid[J].Fine Chemical Intermediates,2008,38(3):29-32.
[13]朱占元,沙作良,杨国军.4-氨基-2-甲氧基-5-乙硫基苯甲酸的合成[J].淮阴工学院学报,2010,19(1):69-70.ZHU Zhanyuan,SHA Zuoliang,YANG Guojun.Synthesis of 4-amino-2-methoxy-5-ethylthio benzoic acid[J].Journal of Huaiyin Institute of Technology,2010,19(1):69-70.
[14]张瑞刚,王锦堂.对氨基水杨酸酚羟基甲醚化的研究[J].化工时刊,2003,17(5):24-26.ZHANG Ruigang,WANG Jintang.The study of amino salicylic acid phenol hydroxyl methyl etherification[J].Chemical Publication,2003,17(5):24-26.
[15]PARKER J S,MOSELEY J D.Kepner-tregoe decision analysis as a tool to aid route selection[J].Organic Process Research&Development,2008,12(6):1041-1043.
[16]朱水耕.阿苯达唑的合成[J].中国医药工业杂志,1990,21(5):197-198.ZHU Shuigeng.Synthesis of albendazole[J].Chinese Journal of Pharmaceuticals,1990,21(5):197-198.
[17]吕栓起,顾秀波,张明路,等.酸性离子液体[Emim]HSO4催化合成丁二酸二乙酯[J].河北工业科技,2013,30(3):138-142.LYU Shuanqi,GU Xiubo,ZHANG Minglu,et al.Synthesis of diethyl succinate with ionic liquids[Emim]HSO4as catalyst[J].Hebei Journal of Industrial Science and Technology,2013,30(3):138-142.
[18]AMBROGI V,GRANDOLINI G,PERIOLI L,et al.Convenient synthesis of 2-aminonaphthalene-1-thiol and 3-aminoquinoline-4-thiol and cyclocondensations to 1,4-thiazino and 1,4-thiazepino derivatives[J].Synthesis,1992(7):656-658.