Ripasudil的新合成工艺

中国医药工业杂志 Chinese Journal of pharmaceuticals2016,47(6)Ripasud的新合成工艺王小华,李志杰,李志,张留(武昌理工学院生物多肽糖尿病药物湖北省协同创新中心,湖北武汉430223)摘要:4-氟异喹啉-5-磺酰氯与(S)-2-氨基-N-(叔丁氧羰基)-N-(3-叔丁基二甲基硅烷氧基丙基)丙胺发生偶联反应,经TBAF脱去羟基保护后通过 Mitsunobu反应自身环合,最后脱氨基保护得到青光眼治疗药物 ripasudil,总收率31.3%。关键词: ripasudil;青光眼;合成中图分类号:R988文献标志码:A文章编号:1001-8255(201606-0679-03Dol:10.16522/ cnki. cjph2016.06.002A New Synthetic Process of RipasudilWANG Xiaohua, Li Zhijie LI Zhi, ZHANG Liu(Wuchang University of Technology, Synergy Innovation Center of Biological Peptide Antidiabetics of Hubei Province, Wuhan 430223)ABSTRACT: Ripasudil was synthesized from 4-fluoroisoquinoline-5-sulfonyl chloride by coupling reaction with(S)-2-amino-N-(tert-butoxycarbonyl)-N-(3-tert-butyldimethylsilyloxypropyl)propylamine, then subjected to hydroxydeprotection with TBAF and then Mitsunobu reaction, followed by Boc deprotection with an overall yield of about 31.3%Key Words: ripasudil; glaucoma; syntRipasudil(1),化学名为(S)-(4氟异丙胺(3)发生偶联反应,经TBAF脱去羟基保护后喹啉-5-基)磺酰基-2-甲基-1,4-二氮环庚烷,通过 Mitsunobu反应自身环合,最后脱氨基保护得2014年9月日本厚生劳动省批准用于治疗青光眼。到1(图2)。与原有方法比,此法可在温和的反应本品是一种Rho-蛋白激酶2抑制剂2,单用或与条件下实现二氮环庚烷的合成,操作简单,收率高。现有治疗青光眼和眼高压的药物联用,可降低原发实验部分性开角型青光眼和眼高压患者的眼内压的(S)-1-(4-氟异喹啉-5-亚磺酰胺基)-N-(叔丁1的合成方法主要有以下2条(图1)14:①氧羰基)-N-(3-叔丁基二甲基甲硅烷基氧基丙基)-在拼接之前先合成7元氮杂环,闭环方法多采用胺(4)NaH等强碱,放大生产时不易控制。②在氟异喹啉室温将3(自制6,2.3g,6.72mmol)溶入环上逐级串联,步骤较长,总收率较低。二氯甲烷(15m)中,冷却至-5~0℃,加入三乙本研究以上述文献为基础,以如下路线制得胺(0.74g,73mmo)和4-二甲胺基吡啶(0.15g)1:用4氟异喹啉-5-磺酰氯(2)与(S)-2-氨基№-搅拌下缓慢加入2(1.5g,6.lmo),在-5~0℃(叔丁氧羰基)-N-(3-叔丁基二甲基硅烷氧基丙基)反应45min后升至室温反应16h,反应液中加入水(10ml),用二氯甲烷(8ml×3)萃取,有机相合并,收稿日期:2016-02经无水硫酸钠干燥后过滤,滤液浓缩,剩余物经柱基金项目:湖北省教育厅201计划(鄂教科函[2012]56号)作者简介:王小华(1983-),男,高级研究员,从事制药工程研色谱[洗脱剂:正己烷:乙酸乙酯(81)]纯化,得油状物4(197g,58.2%)。HNMRTel:027-81652972E-mail:msnhm123@gmail.com(400MHz,DMSO-d6)8:939(s,IH),8.74(d,J通信联系人:张留(1960-),男,教授,从事药物研究4.9 Hz, IH)Tel:027-81652958YH中国煤化工94(t,781,E-mail:uslzhang@163.com1H),3.59CNMHG=6.0 Hz, 2H)中国医药工业杂志 Chinese Joumal of pharmaceuticals2016,47(6)NHCbzNHCbzHNHCbzBoc、NHCbzNHCbzcbzBocsOzSO2图11的文献合成路线Fig. I Literature Route of 16·C!一图21的合成路线Fig2 Synthetic Route of 1中国煤化工CNMHG中国医药工业杂志 Chinese Journal of pharmaceuticals2016,47(6)681·289~3.01(m,4H),1.66~177(m,2H),1.48(s,(7ml)中,用甲苯(12ml×2)提取,用20%氯化9H),1.08(d,J=6.6Hz,3H),0.91(s,9H),0.05(s,钠溶液洗涤,经无水硫酸钠干燥后过滤,滤液减压蒸除溶剂,得淡黄色无定形固体1(0.29g,78%)。(S)-1-(4-氟异喹啉-5-亚磺酰胺基)∽N-(叔丁HNMR(400MHz,DMSO-d)8:947(s,1H,Ar-H)氧羰基)-N-(3-羟丙基)丙胺(5)8.98(s,1H,Ar-H),8.51(d,J=7.9Hz,IH,Ar-H),室温将4(1.6g,2.88mmo)溶于无水THF826(d,J=7.9Hz,1H,ArH),791(t,J=7.9Hz,IH,(12m)中,加入1mol/L氟化四丁铵(4.03ml,Ar-H),437~452(m,IH,CH,359~368(m,2H,4.03mmo),搅拌反应22h,TLC显示反应完成后,CH2),346~349(m,IH,CH,3.18~3.28(m,2H,向反应液中加入饱和氯化铵溶液(5m),用二氯甲CH2),2.99~309(m,IH,CH),1.93~2.08(m,2H,烷(6m×3)萃取,有机层合并,用饱和氯化铵溶CH2),116(d,J=64Hz,3H,CH3)。纯度98%[HPLC液(8ml×3)洗涤,经无水硫酸钠干燥后过滤,滤归一化法:色谱柱 Inertsil ODV-3ⅴ柱(4.6mmx液浓缩,剩余物经柱色谱[洗脱剂:二氯甲烷∶甲150mm,5μm);流动相A:水,B:乙腈(0min,醇(30:1→25:1)]纯化,得油状物5(1.02g,A90;6min,A20;10min,A20);检测波长80.5%)。HNMR(400MHz,DMSO-d)6:9.37(s,20nm;柱温40℃;流速1.0mlm]。ee值999%IH),873(d,J4.9Hz,IH),8.5(d,J7.8Hz,2H),(HPLC法)。793(,J=78Hz,1H),3.57~368(m,1H),344(t,J=60Hz,2H,2.86~300(m,4H,1.64~1.75(m,参考文献:2H),145(s,9H),1.06(d,J=66Hz,3H)。[1]五味宣明,扇谷忠明,涩谷公幸,异喹啉衍生物或其盐的(S)-4-[(4氟异喹啉5-基)磺酰基]-3-甲基新制造方法:中国,103068818A[P].2013-04241,4-二氮环庚烷-1-羧酸叔丁酯(6)[2] Garnock-Jones KP Ripasudil: First global approval [J]2014,74(18):2211-2215氮气保护下将5(1g,2.26mmol)溶于无水[3] Tanihara H, Inoue T, Yamamoto T, et al. Intra-ocular pressure-THF(8ml)中,冷却至-5~0℃,缓慢加入三苯膦lowering effects of a rho kinase inhibitor, ripasudil (K-115)(0.89g,3.39mmo)和DIAD(069g,1.37mmo),over 24 hours in primary open-angle glaucoma and ocular搅拌30min,室温反应8~9h,反应液浓缩至干,ypertension: a randomized, open- label, crossover study [J]剩余物经柱色谱[洗脱剂:正己烷:丙酮(3:1→Acta Ophthalmologica, 2015, 93 (4): 254-2605:2)]纯化,得白色油状物6(0.82g,85.6%)。[4] Gomi N, Ohgiya T, Shibuya K, et al. A practical synthesis ofHNMR(400MHz, DMSO-d)6:9.36(s,1H),865(novel Rho-kinase inhibitor,(S)-4-fluoro-5-(2-methyl-1. 4diazepan-1-ylsulfonyl) isoquinoline []. Heterocycles, 2011J=24Hz,1H),8.53(d,J=8.3Hz,1H),847(d,J=83(8):1771-178176Hz,1H),791~796(m,1H),4.18~429(m[5]大岛武,日高弘义,白土正三,等.(S)-(-)-1-(4-氟异喹1H),3.61~3.78(m,3H),3.11~3.43(m,3H)啉-5-基)磺酰基-2-甲基-1,4高哌嗪盐酸盐-二水合物1.68~1.7(m,2H),1.47(s,9H),0.95(d,J=6.6Hz,中国,101068806A[P].2007-11073H)[6] Sumi K, Inoue Y, Nishio M, et al. IOP-lo wering effectripasudil (1)of isoquinoline-5-sulfonamide compounds in ocularnormotensive monkeys [J]. Bioorg Med Chem Lett, 2014将6(0.5g,1.2mmol)溶于乙酸乙酯(5ml)中,24(3):831—834冷却至-5~0℃,缓慢滴加4moL氯化氢的乙酸[7] Gomi N, Higashimurayama S, Ohgiya T, et al. Novel乙酯溶液(5m1),搅拌反应3~4h,过滤,滤饼production method for isoquinoline derivatives and salts用冷的乙酸乙酯(12ml)充分淋洗,在冰水冷却下thereof:Us,20130144054[P].2013-06-06.将所得的固体加入到3.6%~4.5%氢氧化钠溶液V中国煤化工CNMHG