Ripasudil的新合成工藝

中國醫藥工業(yè)雜志 Chinese Journal of pharmaceuticals2016,47(6)Ripasud的新合成工藝王小華,李志杰,李志,張留(武昌理工學(xué)院生物多肽糖尿病藥物湖北省協(xié)同創(chuàng )新中心,湖北武漢430223)摘要:4-氟異喹啉-5-磺酰氯與(S)-2-氨基-N-(叔丁氧羰基)-N-(3-叔丁基二甲基硅烷氧基丙基)丙胺發(fā)生偶聯(lián)反應,經(jīng)TBAF脫去羥基保護后通過(guò) Mitsunobu反應自身環(huán)合,最后脫氨基保護得到青光眼治療藥物 ripasudil,總收率31.3%。關(guān)鍵詞: ripasudil;青光眼;合成中圖分類(lèi)號:R988文獻標志碼:A文章編號: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),化學(xué)名為(S)-(4氟異丙胺(3)發(fā)生偶聯(lián)反應,經(jīng)TBAF脫去羥基保護后喹啉-5-基)磺?；?2-甲基-1,4-二氮環(huán)庚烷,通過(guò) Mitsunobu反應自身環(huán)合,最后脫氨基保護得2014年9月日本厚生勞動(dòng)省批準用于治療青光眼。到1(圖2)。與原有方法比,此法可在溫和的反應本品是一種Rho-蛋白激酶2抑制劑2,單用或與條件下實(shí)現二氮環(huán)庚烷的合成,操作簡(jiǎn)單,收率高?，F有治療青光眼和眼高壓的藥物聯(lián)用,可降低原發(fā)實(shí)驗部分性開(kāi)角型青光眼和眼高壓患者的眼內壓的(S)-1-(4-氟異喹啉-5-亞磺酰胺基)-N-(叔丁1的合成方法主要有以下2條(圖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元氮雜環(huán),閉環(huán)方法多采用胺(4)NaH等強堿,放大生產(chǎn)時(shí)不易控制。②在氟異喹啉室溫將3(自制6,2.3g,6.72mmol)溶入環(huán)上逐級串聯(lián),步驟較長(cháng),總收率較低。二氯甲烷(15m)中,冷卻至-5~0℃,加入三乙本研究以上述文獻為基礎,以如下路線(xiàn)制得胺(0.74g,73mmo)和4-二甲胺基吡啶(0.15g)1:用4氟異喹啉-5-磺酰氯(2)與(S)-2-氨基№-攪拌下緩慢加入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)反應45min后升至室溫反應16h,反應液中加入水(10ml),用二氯甲烷(8ml×3)萃取,有機相合并,收稿日期:2016-02經(jīng)無(wú)水硫酸鈉干燥后過(guò)濾,濾液濃縮,剩余物經(jīng)柱基金項目:湖北省教育廳201計劃(鄂教科函[2012]56號)作者簡(jiǎn)介:王小華(1983-),男,高級研究員,從事制藥工程研色譜[洗脫劑:正己烷:乙酸乙酯(81)]純化,得油狀物4(197g,58.2%)。HNMRTel:027-81652972E-mail:msnhm123@gmail.com(400MHz,DMSO-d6)8:939(s,IH),8.74(d,J通信聯(lián)系人:張留(1960-),男,教授,從事藥物研究4.9 Hz, IH)Tel:027-81652958YH中國煤化工94(t,781,E-mail:uslzhang@163.com1H),3.59CNMHG=6.0 Hz, 2H)中國醫藥工業(yè)雜志 Chinese Joumal of pharmaceuticals2016,47(6)NHCbzNHCbzHNHCbzBoc、NHCbzNHCbzcbzBocsOzSO2圖11的文獻合成路線(xiàn)Fig. I Literature Route of 16·C!一圖21的合成路線(xiàn)Fig2 Synthetic Route of 1中國煤化工CNMHG中國醫藥工業(yè)雜志 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,鈉溶液洗滌,經(jīng)無(wú)水硫酸鈉干燥后過(guò)濾,濾液減壓蒸除溶劑,得淡黃色無(wú)定形固體1(0.29g,78%)。(S)-1-(4-氟異喹啉-5-亞磺酰胺基)∽N-(叔丁HNMR(400MHz,DMSO-d)8:947(s,1H,Ar-H)氧羰基)-N-(3-羥丙基)丙胺(5)8.98(s,1H,Ar-H),8.51(d,J=7.9Hz,IH,Ar-H),室溫將4(1.6g,2.88mmo)溶于無(wú)水THF826(d,J=7.9Hz,1H,ArH),791(t,J=7.9Hz,IH,(12m)中,加入1mol/L氟化四丁銨(4.03ml,Ar-H),437~452(m,IH,CH,359~368(m,2H,4.03mmo),攪拌反應22h,TLC顯示反應完成后,CH2),346~349(m,IH,CH,3.18~3.28(m,2H,向反應液中加入飽和氯化銨溶液(5m),用二氯甲CH2),2.99~309(m,IH,CH),1.93~2.08(m,2H,烷(6m×3)萃取,有機層合并,用飽和氯化銨溶CH2),116(d,J=64Hz,3H,CH3)。純度98%[HPLC液(8ml×3)洗滌,經(jīng)無(wú)水硫酸鈉干燥后過(guò)濾,濾歸一化法:色譜柱 Inertsil ODV-3ⅴ柱(4.6mmx液濃縮,剩余物經(jīng)柱色譜[洗脫劑:二氯甲烷∶甲150mm,5μm);流動(dòng)相A:水,B:乙腈(0min,醇(30:1→25:1)]純化,得油狀物5(1.02g,A90;6min,A20;10min,A20);檢測波長(cháng)80.5%)。HNMR(400MHz,DMSO-d)6:9.37(s,20nm;柱溫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,參考文獻:2H),145(s,9H),1.06(d,J=66Hz,3H)。[1]五味宣明,扇谷忠明,澀谷公幸,異喹啉衍生物或其鹽的(S)-4-[(4氟異喹啉5-基)磺?；鵠-3-甲基新制造方法:中國,103068818A[P].2013-04241,4-二氮環(huán)庚烷-1-羧酸叔丁酯(6)[2] Garnock-Jones KP Ripasudil: First global approval [J]2014,74(18):2211-2215氮氣保護下將5(1g,2.26mmol)溶于無(wú)水[3] Tanihara H, Inoue T, Yamamoto T, et al. Intra-ocular pressure-THF(8ml)中,冷卻至-5~0℃,緩慢加入三苯膦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攪拌30min,室溫反應8~9h,反應液濃縮至干,ypertension: a randomized, open- label, crossover study [J]剩余物經(jīng)柱色譜[洗脫劑:正己烷:丙酮(3:1→Acta Ophthalmologica, 2015, 93 (4): 254-2605:2)]純化,得白色油狀物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]大島武,日高弘義,白土正三,等.(S)-(-)-1-(4-氟異喹1H),3.61~3.78(m,3H),3.11~3.43(m,3H)啉-5-基)磺?；?2-甲基-1,4高哌嗪鹽酸鹽-二水合物1.68~1.7(m,2H),1.47(s,9H),0.95(d,J=6.6Hz,中國,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將6(0.5g,1.2mmol)溶于乙酸乙酯(5ml)中,24(3):831—834冷卻至-5~0℃,緩慢滴加4moL氯化氫的乙酸[7] Gomi N, Higashimurayama S, Ohgiya T, et al. Novel乙酯溶液(5m1),攪拌反應3~4h,過(guò)濾,濾餅production method for isoquinoline derivatives and salts用冷的乙酸乙酯(12ml)充分淋洗,在冰水冷卻下thereof:Us,20130144054[P].2013-06-06.將所得的固體加入到3.6%~4.5%氫氧化鈉溶液V中國煤化工CNMHG