5-氨基水杨酸的合成工艺改进
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摘要
采用简单易行的操作方法对现有的5-氨基水杨酸的合成工艺进行改进。以2-氯苯甲酸(Ⅰ)为起始原料通过n(质量分数98%硫酸)∶n(质量分数65%硝酸)=6∶1的混酸进行硝化反应,得到2-氯-5-硝基苯甲酸(Ⅱ),化合物Ⅱ再与质量分数为15%的氢氧化钠进行亲核取代反应得到中间体5-硝基水杨酸(Ⅲ),最后由铁粉/锌粉与浓盐酸作为还原剂与中间体Ⅲ进行还原反应,得到最终产物5-氨基水杨酸(Ⅳ),3步反应总收率为61%,并且中间体及产品的结构均经IR、~1HNMR和MS进行表征。
The synthesis process of the existing 5-aminosalicylic acid is improved by a simple and easy operation method. 2-Chloro-5-nitrobenzoic acid( Ⅱ) was prepared by a nitration reaction of 2-chlorobenzoic acid(Ⅰ) with mixed acids of n(mass fraction 98% sulfuric acid)∶n(mass fraction of 65% nitric acid)=6∶1. Subsequently, a nucleophilic substitution reaction between compound Ⅱ and 15%(mass fraction) sodium hydroxide led to 5-nitrosalicylic acid( Ⅲ). Finally, the targeted product5-aminosalicylic acid(Ⅳ) was obtained via a reduction of intermediate Ⅲ in the presence of a catalytic amount of iron powder/zinc powder and concentrated hydrochloric acid. The total yield of 5-aminosalicylic acid in the three-step synthesis method was 61%. The structures of intermediates and product were characterized by IR, ~1HNMR and MS.
The synthesis process of the existing 5-aminosalicylic acid is improved by a simple and easy operation method. 2-Chloro-5-nitrobenzoic acid( Ⅱ) was prepared by a nitration reaction of 2-chlorobenzoic acid(Ⅰ) with mixed acids of n(mass fraction 98% sulfuric acid)∶n(mass fraction of 65% nitric acid)=6∶1. Subsequently, a nucleophilic substitution reaction between compound Ⅱ and 15%(mass fraction) sodium hydroxide led to 5-nitrosalicylic acid( Ⅲ). Finally, the targeted product5-aminosalicylic acid(Ⅳ) was obtained via a reduction of intermediate Ⅲ in the presence of a catalytic amount of iron powder/zinc powder and concentrated hydrochloric acid. The total yield of 5-aminosalicylic acid in the three-step synthesis method was 61%. The structures of intermediates and product were characterized by IR, ~1HNMR and MS.
引文
[1]Meng Jiangping(孟江平),Zheng Xia(郑霞).Study on synthetic Improvement of anti-colitis drug mesalazine[J].Journal of Chongqing University of Arts and Science(重庆文理学院学报),2013,32(5):73-75.
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[5]Cui Xuegang(崔学刚),Ding Lixin(丁立新),Yang Lindong(杨林栋).Synthesis of mesalazine[J].Heilongjiang Medicine and Pharmacy(黑龙江医药),1999,22(5):79-80.
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[7]Li Chunyuan(李春圆),Bai Yinjuan(白银娟),Zhu Yingjun(朱英俊),et al.Nitrification of sodium bisulfate sodium nitrate substituted phenol in aqueous phase[J].Chinese Joumai of Synthetic Chemistry(合成化学),2007,15(3):347-349.
[8]Tan Zaiyou(谭载友),Liu Tianhui(刘天穗),Zou Gengxin(邹更新),et al.Improved acid synthesis to improve the synthesis of methacetizine[J].Guangzhou Chemical(广州化工),2003,33(1):37-39.
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[10]Srinivasan N,Lilakar J.Green approach for large scale process of mesalamine:an anti inflammatory agent[J].Rasayan J Chem,2009,2(3):688-690.
[11]Chen Bangyin(陈邦银),Zhang Hanping(张汉萍),Cao Lei(曹蕾),et al.Synthesis and structural identification of anti-colitis drug mesalazine[J].Journal of Huazhong University of Science and Technology(华中科技大学学报:医学版),2002,31(2):163-164.
[12]Zheng Yumei(郑玉梅),Jin Xiran(金锡然).Synthesis of mesalazine[J].Heilongjiang Medicine Journal(黑龙江医药),1999,12(4):204-206.
[13]He Xin(何鑫),Liu Xiujie(刘秀杰),Si Hongqiang(司红强).5-Synthesis of aminosalicylic acid[J].Journal of Tianjin University of Technology(天津理工大学学报),2009,25(3):64-66.
[14]Li Yunshan(李运山),Que Yuhua(邱玉华),Chen Bai(陈柏).Synthesis of mesalazine[J].China Pharmaceutical Industry Journal(中国医药工业杂志),2015,46(12):1280-1282.
[15]Jia Jianhong(贾建洪),Sheng Weijian(盛卫坚),Chen Bin(陈斌),et al.Study on new synthetic process of 5-nitrosalicylic acid[J].Journal of Zhejiang University of Technology(浙江工业大学学报),2005,33(1):96-99.
[2]Xiao Mengyuan(肖梦媛).Study on the synthesis method of mesalazine laboratory[J].Scientific and Technological Innovation(科教导刊)(上旬刊),2013,(12):158.
[3]Xu Zhiyong(徐勇智),Shi Teijun(史铁钧).Method for synthesizing5-aminosalicylic acid[J].Fine Chemical Intermediate(精细化工中间体),2005,35(3):60-62.
[4]Chen Fener(陈芬儿).Organic drug synthesis law(Volume I)First edition[M].Beijing:China Medical Science and Technology Press(中国医药科技出版社),1999:413-414.
[5]Cui Xuegang(崔学刚),Ding Lixin(丁立新),Yang Lindong(杨林栋).Synthesis of mesalazine[J].Heilongjiang Medicine and Pharmacy(黑龙江医药),1999,22(5):79-80.
[6]Xu Chongyao(许崇摇),Wei Guiyun(韦贵云),Huang Xingzhen(黄兴振).Improvement of the method for synthesizing mesalazine in medicinal chemistry experiment[J].Chinese Medical Science(中国医药科学),2014,4(16):42-43.
[7]Li Chunyuan(李春圆),Bai Yinjuan(白银娟),Zhu Yingjun(朱英俊),et al.Nitrification of sodium bisulfate sodium nitrate substituted phenol in aqueous phase[J].Chinese Joumai of Synthetic Chemistry(合成化学),2007,15(3):347-349.
[8]Tan Zaiyou(谭载友),Liu Tianhui(刘天穗),Zou Gengxin(邹更新),et al.Improved acid synthesis to improve the synthesis of methacetizine[J].Guangzhou Chemical(广州化工),2003,33(1):37-39.
[9]Fatima E,Agharbaou I,Ashiey C,et al.Computational and synthetic approaches for developing Lavendustin B derivatives as allosteric inhibitors of HIV-1 integrase[J].European Journal of Medicinal Chemistry,2016,12(3):673-683.
[10]Srinivasan N,Lilakar J.Green approach for large scale process of mesalamine:an anti inflammatory agent[J].Rasayan J Chem,2009,2(3):688-690.
[11]Chen Bangyin(陈邦银),Zhang Hanping(张汉萍),Cao Lei(曹蕾),et al.Synthesis and structural identification of anti-colitis drug mesalazine[J].Journal of Huazhong University of Science and Technology(华中科技大学学报:医学版),2002,31(2):163-164.
[12]Zheng Yumei(郑玉梅),Jin Xiran(金锡然).Synthesis of mesalazine[J].Heilongjiang Medicine Journal(黑龙江医药),1999,12(4):204-206.
[13]He Xin(何鑫),Liu Xiujie(刘秀杰),Si Hongqiang(司红强).5-Synthesis of aminosalicylic acid[J].Journal of Tianjin University of Technology(天津理工大学学报),2009,25(3):64-66.
[14]Li Yunshan(李运山),Que Yuhua(邱玉华),Chen Bai(陈柏).Synthesis of mesalazine[J].China Pharmaceutical Industry Journal(中国医药工业杂志),2015,46(12):1280-1282.
[15]Jia Jianhong(贾建洪),Sheng Weijian(盛卫坚),Chen Bin(陈斌),et al.Study on new synthetic process of 5-nitrosalicylic acid[J].Journal of Zhejiang University of Technology(浙江工业大学学报),2005,33(1):96-99.