3-甲基-4-丁酰氨基-5-氨基苯甲酸甲酯的合成
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摘要
以3-甲基-4-丁酰氨基苯甲酸甲酯为原料，经硝硫混酸硝化、铁粉还原，得到新型药物中间体3-甲基-4-丁酰氨基-5-氨基苯甲酸甲酯。并对硝化反应中的底酸用量、混酸配比、反应温度、反应时间、后处理等因素进行了研究；同时也对还原反应中的电解质选用、反应温度、反应时间、铁粉用量等方面进行了研究。初步确定了合成3-甲基-4-丁酰氨基-5-氨基苯甲酸甲酯可应用于工业化生产的工艺条件。
The starting material Methyl 4-butylamino-3-methylbenzoate was nitrated with mixing acid of sulfuric acid and nitric acid, then reduction in the presence of Fe powder to afford methyl 4-butylamino-3-methyl-5-aminobenzoate, which is a new pharmaceutical intermediate. Several factors in nitration were investigated, including the amount of substrate acid, the ratio of mixing acid, temperature, time and the final dealing methods. Meanwhile, factors in the reduction including the choice of electrolytes, temperature, time and the amount of Fe powder were studied. The conditions of the synthesis of methyl 4-butylamino-3-methyl-5-aminobenzoate were preliminarily determined, which is also applicable in industrialization.
The starting material Methyl 4-butylamino-3-methylbenzoate was nitrated with mixing acid of sulfuric acid and nitric acid, then reduction in the presence of Fe powder to afford methyl 4-butylamino-3-methyl-5-aminobenzoate, which is a new pharmaceutical intermediate. Several factors in nitration were investigated, including the amount of substrate acid, the ratio of mixing acid, temperature, time and the final dealing methods. Meanwhile, factors in the reduction including the choice of electrolytes, temperature, time and the amount of Fe powder were studied. The conditions of the synthesis of methyl 4-butylamino-3-methyl-5-aminobenzoate were preliminarily determined, which is also applicable in industrialization.
引文
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2. Inukai N, et al.Chemical Pharmaceutical Bulletin.1971, 19, 1696.
3. Puchmann S,Engelbom R,Pharmakologische untersuchungen des bromhexin metaboliten ambroxol,Arzneim Forech, 1978, 28(1): 889-935.
4. Gravert DJ, Jamda KD.Telmisartan antihypertensive angiotensin Ⅱ antagonist[J].Drugs Future, 1997, 22(10): 1112-1116.
5． 蔡霞，冯光玲，替米沙坦的合成工艺改进，中国医药工业杂志，2003，34(6)：262～264。
6．C．K．Lngold，J．Chem．Soc，2559，2576，2612(1950)．
7．E．ro奥洛娃，烈性炸药地化学与工艺学。
8．吕春绪，硝化通论，华东工学院，1972，5。
9．珲魁宏主编，有机化学，高教出版社，1990，4。
10．孙荣康，魏远洋，硝基化合物炸药化学与工艺学第一版．兵器工业出版社，1992。
11．吕春绪，硝化理论，江苏科学技术出版社，1993，10。
12. K.Schofield, Aromatic Nitration, Cambridge University Press, 1980.
13. Ricardo Tapia, Glenda Torres&Jaime A.Valderrarna, Nitric acid on silica gel: A useful nitrating reagent for activated aromatic compounds, Synthetic Communications, 16(6), 681-7 (1986).
14. Cook, et al, U.S.P3981933, 1976, 9, 21.
15. Schossler, U.S.P4600797, 1986, 7, 15.
16. Tomasz A.Modro & Jerzy Pioch, Can.J.Chem.54, 560(1976).
17. Kokai Tokkyo koho, JP 58 67,650[83 67,650]
18. Lothrop, J.Am.Chem.Soc.64, 1698 (1942).
19．吕春绪，硝酰阳离子反应，华东工学院，1990，5。
20. M.Barton, U.S.P 3957889 (1976)
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22．姚蒙正等，大连工学院学报，26，No．1，23(1987)。
23．孙权一，化学通报，[3]，148(1980)。
24. D.S.Wulfman, C.F.Cooper, Synthesis, 924(1978).
25. D.C.Owsley, J.J.Bloomfield, Synthesis, 118 (1977).
26．奈良，科学工业，51，No．8，304(1977)。