氯法齐明的合成
|
摘要
2-氟硝基苯(2)与对氯苯胺在三乙胺作用下反应得N-(4-氯苯基)-2-硝基苯胺(4),收率95%。以连二亚硫酸钠代替铁粉/氯化铵还原4得N'-(4-氯苯基)苯基-1,2-二胺(5),避免了大量铁泥及氨氮废水的产生。以甲醇为溶剂,在三氯化铁存在下使5发生自身交叉偶联脱氢反应合成10-(对氯苯基)-2,10-二氢-3-(对氯苯胺基)-2-亚胺基吩嗪(6),并对催化剂三氯化铁进行回收套用,使生产过程更加绿色环保。最后用二(?)烷代替乙醇作溶剂,加入催化剂冰乙酸,使6与异丙胺反应得氯法齐明;后处理时采用混合溶剂(二氯甲烷和甲醇)打浆的方法进行纯化,纯度99.4%。改进后的工艺操作简捷、安全环保,总收率由45%提高至71%(以2计)。
The synthetic process of clofazimine was improved. 2-Fluoronitrobenzene(2) reacted with p-chloroaniline in the presence of triethylamine to give N-(4-chlorophenyl)-2-nitroaniline(4) in a yield of 95 %. Sodium dithionite was used instead of iron powder/ammonium chloride to reduce 4 in order to obtain N'-(4-chlorophenyl)-benzene-1,2-diamine(5), in which step the production of a large amount of iron sludge and ammonia nitrogen wastewater could be avoided. Then the latter was subjected to cross-coupling dehydrogenation in the presence of ferric chloride to produce 10-(4-chlorphenyl)-2,10-dihydro-3-(4-chloroanilino)-2-iminophenazine(6) in methanol. The catalyst ferric trichloride was recycled to make the production process more green and environmentally friendly. Finally,6 reacted with isopropylamine in dioxane with glacial acetic acid as the catalyst to prepare the target compound in a purity of 99.4% by pulping in dichloromethane and methanol. The improved process is simple, safe and environmentally friendly, and the total yield was increased from 45 % to 71 %(based on 2).
The synthetic process of clofazimine was improved. 2-Fluoronitrobenzene(2) reacted with p-chloroaniline in the presence of triethylamine to give N-(4-chlorophenyl)-2-nitroaniline(4) in a yield of 95 %. Sodium dithionite was used instead of iron powder/ammonium chloride to reduce 4 in order to obtain N'-(4-chlorophenyl)-benzene-1,2-diamine(5), in which step the production of a large amount of iron sludge and ammonia nitrogen wastewater could be avoided. Then the latter was subjected to cross-coupling dehydrogenation in the presence of ferric chloride to produce 10-(4-chlorphenyl)-2,10-dihydro-3-(4-chloroanilino)-2-iminophenazine(6) in methanol. The catalyst ferric trichloride was recycled to make the production process more green and environmentally friendly. Finally,6 reacted with isopropylamine in dioxane with glacial acetic acid as the catalyst to prepare the target compound in a purity of 99.4% by pulping in dichloromethane and methanol. The improved process is simple, safe and environmentally friendly, and the total yield was increased from 45 % to 71 %(based on 2).
引文
[1]王怀冲,徐颖颖,张相彩,等.联合氯法齐明方案治疗耐多药肺结核的临床研究[J].中国临床药理学与治疗学,2012.17(11):1268-1271.
[2]陆宇,郑梅琴.王彬,等.氯法齐明的抗结核作用研究[J].结核病与胸部肿瘤,2008,(3):183-187.
[3]国家药品监督管理局药品注册司.国家药品监督管理局药品注册司关于公布第二批化学药品说明书目录的通知[EB/OL].[2002.02.05].http://law. pharmnet. com.cn/laws/detail_817. html.
[4] CHAUHAN S M S, SINGH R, GEETANJALI. An improved synthesis of N-substituted-2-nitroanilines[J].Synth Commun,2003, 33(16):2899-2906.
[5] TAYLOR A M, VASWANI R G, GEHLING V S,et al.Discovery of benzotriazolo[4,3-d][1,4] diazepines as orally active inhibitors of BET bromodomains[J]. ACS Med Chem Lett, 2016, 7(2):145-150.
[6] KAMAL A, BABU A H, RAMANA A,et al. Synthesis ofphthalimido-and naphthalimido-linked phenazines as new prototype antitubercularagents[J]. Bioorg Med Chem Lett,2005, 15(7):1923-1926.
[7] BARRY V C, BELTON J G, O'SULLIVAN J F, et al. The oxidation of derivatives of o-phenylenediamine. Part V.N~3-substituted derivatives of anilinoaposafranine(riminocompounds)and related compounds[J].J Chem Soc,1958,859-863.
[8] LIU J, YANG D, YANG X, et al. Design, synthesis and biological evaluation of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydroquinoxaline moiety as c-Met kinase inhibitors[J].Bioorg Med Chem,2017,25(16):4475-4486.
[9] BABTHORPE D V, ANTHONY C. Mechanism of benzidine and semidine rearrangements. Part XX. Kinetics and products of the acid conversions of 2,2'-dichloro-, 4-chloro-,and 4,4'-dichloro-hydrazobenzene[J]. J ChemSoc B Phy Org,1968,618-623.
[10] GEETHA B, ASHWINI N. Clofazimine mesylate:a high solubility stable salt[J]. Cryst Growth Des, 2012, 12:6250-6259.
[2]陆宇,郑梅琴.王彬,等.氯法齐明的抗结核作用研究[J].结核病与胸部肿瘤,2008,(3):183-187.
[3]国家药品监督管理局药品注册司.国家药品监督管理局药品注册司关于公布第二批化学药品说明书目录的通知[EB/OL].[2002.02.05].http://law. pharmnet. com.cn/laws/detail_817. html.
[4] CHAUHAN S M S, SINGH R, GEETANJALI. An improved synthesis of N-substituted-2-nitroanilines[J].Synth Commun,2003, 33(16):2899-2906.
[5] TAYLOR A M, VASWANI R G, GEHLING V S,et al.Discovery of benzotriazolo[4,3-d][1,4] diazepines as orally active inhibitors of BET bromodomains[J]. ACS Med Chem Lett, 2016, 7(2):145-150.
[6] KAMAL A, BABU A H, RAMANA A,et al. Synthesis ofphthalimido-and naphthalimido-linked phenazines as new prototype antitubercularagents[J]. Bioorg Med Chem Lett,2005, 15(7):1923-1926.
[7] BARRY V C, BELTON J G, O'SULLIVAN J F, et al. The oxidation of derivatives of o-phenylenediamine. Part V.N~3-substituted derivatives of anilinoaposafranine(riminocompounds)and related compounds[J].J Chem Soc,1958,859-863.
[8] LIU J, YANG D, YANG X, et al. Design, synthesis and biological evaluation of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydroquinoxaline moiety as c-Met kinase inhibitors[J].Bioorg Med Chem,2017,25(16):4475-4486.
[9] BABTHORPE D V, ANTHONY C. Mechanism of benzidine and semidine rearrangements. Part XX. Kinetics and products of the acid conversions of 2,2'-dichloro-, 4-chloro-,and 4,4'-dichloro-hydrazobenzene[J]. J ChemSoc B Phy Org,1968,618-623.
[10] GEETHA B, ASHWINI N. Clofazimine mesylate:a high solubility stable salt[J]. Cryst Growth Des, 2012, 12:6250-6259.