●2026●安徽醫(yī)藥Anhui Medical and Pharmaceutical Journal 2013 Dec;17(12)<>藥學(xué)研究<>洛匹那韋的合成蔣敏',何勇”,余三喜”,趙世杰? ,高永好,吳宗好’(1.國(guó)藥集團(tuán)國(guó)瑞藥業(yè)有限公司,安徽淮南232001;2.合肥華方醫(yī)藥科技有限公司,安徽合肥230088)摘要:目的研究抗病毒藥物洛匹那韋的合成。 方法以(2S,3S,5S)-5-(叔丁 氧羰基)氨基-2-氨基-3-羥基-1 ,6-1二苯基已烷為起始原料，與2,6-二甲基苯氧乙酸經(jīng)肽鍵縮合、脫保護(hù)、最終與(2S)-( 1-四氫嘧啶2-酮)-3-甲基丁酸再經(jīng)肽鍵縮合制備目標(biāo)產(chǎn)物洛匹那韋。結(jié)果三步 合成了目標(biāo)產(chǎn)物洛匹那韋,以BDC計(jì),總收率為50.7% ,通過(guò)' H-NMR、MS確定了結(jié)構(gòu)。結(jié)論該方法簡(jiǎn)單,后處理方便,副產(chǎn)物較少,適合工業(yè)化生產(chǎn)。關(guān)鍵詞:抗病毒;洛匹那韋;化學(xué)合成Synthesis of lopinavirJIANG Min' ,HE Yong2 , YU San-xi2 ,et al(1. China National Medicines Guorui Pharmaceutical Co. Ltd , Huainan ,Anhui 232001 ,China;2. Hefei Huafang Pharmaceutical Science & Technology Co. ,Ltd. ,Hefei 230088 ，China)Abstract:Objective To prepare antiviral drugs lopinavir. Methods Lopinavir was synthesized from (2S ,3S ,5S )-5-tert-Butyloxycar-bonylamino-2-amino-3-hydroxy-1 ,6-diphenylhexane reaction with 2, 6-Dimethylphenoxyacetic acid by condensation deprotection , whichwas subjected to condensation with (2S)-( 1-Tetrahydropyramid-2-one ) -3-methybutanoic acid. Results The target product was synthe-sized via three -step procedure starting from BDC in a total yield of 50. 7% and its structure was confirmed by 'H-NMR , ESI-MS. Conclu-sions The method of preparation is much easier to perform, with simple work-up and fewer by-products. It is suitable for industrial pro-duction. .Key words : antiviral drugs ;lopinavir ;synthesis洛匹那韋( Lopinavir, LPV),化學(xué)名為(S)-N-[(1S,2S,制和免疫學(xué)應(yīng)答,且在發(fā)展中國(guó)家為發(fā)生耐藥初治失敗HIV4S)-4-[[(2,6-二甲基苯氧基)乙酰]氨基]-3-羥基-5-苯基-1-患者的抗病毒治療發(fā)揮重要作用[5s6]。有學(xué)者在進(jìn)行藥物相(苯基甲基)苯基]四氫-(1-甲基乙基)-2-氧代-1 (2H)-吡咯烷互作用研究時(shí)發(fā)現(xiàn),洛匹那韋與環(huán)孢素聯(lián)用,可使環(huán)孢素血藥乙酰胺,是HIV-1和HIV-2蛋白酶抑制劑,能阻止Gag-Pol多濃度增加”]蛋白的分裂,產(chǎn)生未成熟的、無(wú)感染力的病毒顆粒,洛匹那韋本文以(2S,3S,5S)-5-(叔丁氧羰基)氨基-2-氨基-3-羥聯(lián)合低劑量利托那韋(Ritonavir,RTV)能夠改善其藥代特性，基-1 ,6-二苯基已烷( BDC)為起始原料,與2,6-二甲基苯氧乙主要通過(guò)抑制洛匹那韋在人體的代謝,提高血漿藥物濃度,增酸經(jīng)肽鍵縮合制備LP-1、用濃鹽酸一乙酸乙酯體系脫除Boc強(qiáng)其抗病毒作用14)。洛匹那韋聯(lián)合低劑量利托那韋復(fù)合片保護(hù)基制備LP-2、最終與(2S)-( 1-四氫嘧啶-2-酮)-3-甲基丁劑(克立芝)于2000年被美國(guó)食品藥品監(jiān)督管理局批準(zhǔn)上酸縮合,三步反應(yīng)制備目標(biāo)產(chǎn)物洛匹那韋,總收率為50. 7% ,市,其療效可靠、副作用少、受食物影響小,目前作為抗人類免該方法簡(jiǎn)單,后處理方便,副產(chǎn)物較少,適合工業(yè)化生產(chǎn)。合疫缺陷病毒的一線或二線治療藥物,實(shí)現(xiàn)了良好的病毒學(xué)抑成路線見(jiàn)圖1。5] Zhang Z,Sun L, Wang Y ,et al. Renprotetive role of the vitamin D re-12]劉雷,甘華,王輝,等.活性維生素D3對(duì)糖尿病大鼠腎臟ceptor in diabetic nephropathy [J]. Kidney Int ,2008 ,73(2):163 -171.TGF-B1和HGF表達(dá)的影響[J].重慶醫(yī)科大學(xué)學(xué)報(bào),2008 ,33[6] Ishimura E, Nishizawa Y , Inaba M,et al. Serum level of 1 ,25-di-(9) :1058 - 1062.hydroxyvitamin D, 24 , 25-dihydroxyvitamin D, and 25-hydroxyvita-[13] Li Y ,Spataro BC, Yang J,et al. 1 ,25- diyroxyvitamnin D inhibits renalmin D in nondialyzed patients with chronie renal failure[J]. Kidneyinterstitial myofibroblast activation by inducing hepatocyte growth factorInt,1999 ,55(3):1019 - 1027.expression[J]. Kidney Int ,2005 ,68<4):1500- 1510.[7] Shoben AB, Rudser KD , de Boer IH,et al. Association of oral cealcit-[14]李瑾,李微,殷少軍,等,活性維生素D3抑制大鼠間質(zhì)成纖riol with improved survival in nondialyzed CKD[ J]. J Am Soc .維細(xì)胞激活作用的研究[J].同濟(jì)大學(xué)學(xué)報(bào):醫(yī)學(xué)版,2012,33Nephrol ,2008 , 19(8) :1613- 1619.(2):38 -42.[8] 孫晶,程勁,張金元慢性腎臟病患者血清1 ,25( OH)2D水[15] Bonakdaran S , Hami M. Hatefi A. The efets of calcitiol on albumi-平與蛋白尿及尿炎癥細(xì)胞因子相關(guān)性研究[J].中國(guó)中西醫(yī)結(jié)nuria in patients with type-2 diabetes mellitus[J]. Saudi J Kidney合腎病雜志,2011 ,12(4):311 -314.中國(guó)煤化工220.[9] Sanchez-Nino MD,Bozic M,Cordoba-Lands E,et al. Beyond proteinuri-[16]in,et al. Selective vitamin D ra:VDR activation reduces renal inflammation in experimental diabeticHC N M H G reduction of albuminuria in pa-nephropathy[J]. Am J Physiol Renal Physiol ,2012 ,302(6):647 -657.tents wnth type 2 dhabetes ( VIIAL study ) :a randomised controlled[10]馬麗娟，杜國(guó)利,趙琦英 ，等.活性維生素D3對(duì)大鼠早期糖尿病trial[ J]. Lancet ,2010 ,376(9752) :1543 - 1551.腎病相關(guān)炎性因子的影響[J].中華實(shí)用診斷與治療雜志，[17] Kim MJ, Frankel AH, Donaldson M,et al. Oral cholecaciferol de-2012 ,26(3):234 -237.creases albuminuria and urinary TGF-B1 in patients with type 2 dia-11] Zhang Z, Yuan W , Sun L,et al.1 ,25-Dihyroxyvitamin D3 targetingbetic nephropathy on established renin-angiotensin-aldosterone sys-of NF+4192數(shù)推presses high glucose-included MCP-1 expressiontem inhibition[ J]. Kidney Int ,2011 ,80(8) :851 - 860.in mesangdr植J]. Kidney Int ,2007 ,72(2):193 -201.(收稿8期:2013 -06 -20,修回日期:2013 -09-17)安徽醫(yī)藥Anhui Medical and Pharmaceutical Joural 2013 Dec;17(12). 2027 .和食鹽水(50mLx3)洗滌,無(wú)水硫酸鈉干燥,減壓回收溶劑至干，乙酸乙酯-正庚烷重結(jié)晶,得白色固體產(chǎn)物4.1g,收率oH65. 2% ,mp 123. 8- 125.6°C。' H-NMR( DMSO-d。400MHz) δ:7. 54(1H,s,NH),7. 46(1H,s,NH),7.16 - 7. 25 (7H,m,ArH) ,7. 14-7.10(3H, m, ArH),7. 01(2H,m,ArH),6.91 -6.95(1H,m, ArH), 6.28(1H,s, NH),5.03( 1H, Brs, 0H),4.31(2H,s,CH2) ,4.15 -4.24(1H,m,CH) ,4.03 -4.12(1H,C麗LP2m,CH) ,3.65(1H, m, CH) ,3. 02(2H, m, NCH2),2. 89 -2.93圖1洛匹那韋的合成路線(2H,m, NCH2),2.74 -2.84(2H, m, Ar-CH2),2. 63 -2.67.(1H,m, Ar-CH2) ,2.53 -2.58(1H, m,Ar-CH2) ,2.15(6H,s,21儀器與試劑xCH3),1.98 -2.04(1H, m, CH),1.43 -1.60(4H,m,2 xWRS-1B數(shù)字熔點(diǎn)儀(上海申光儀器儀表有限公司);CH2) ,0. 76(3H,d,J = 6.8 Hz, CH,),0.74(3H,d,J =6.8Bruker核磁共振儀(德國(guó)Bruker 公司,400 MHz); LCQ AD-Hz,CH3); ESI-MS m/z: 629[M +H]*。VANTAGEMAX液質(zhì)連用質(zhì)譜儀( FINNIGAN公司); (2S,3S,3結(jié)果與結(jié)論5S)-5-(叔丁氧羰基)氨基-2-氨基-3-羥基-1 ,6-二苯基已烷(自本研究參考相關(guān)文獻(xiàn)9-]1合成肽鍵:用固體碳酸鉀為堿，制)[8];(2S)-( 1-四氫嘧啶-2-酮)-3-甲基丁酸(廈門市華興化親脂性季銨鹽氯化芐基三乙銨(TEBAC1)為相轉(zhuǎn)移催化劑,用工有限公司,99. 3% ) ;2,6-二甲基苯氧乙酸(廈門市華興化工羧基和對(duì)甲苯磺酰氯(TsCl)反應(yīng)制得混酐,與相應(yīng)胺基反應(yīng)有限公司,99. 6% );其他試劑為分析純。合成肽鍵,避免使用二環(huán)已基碳二亞胺( DCC)作縮合劑合成2實(shí)驗(yàn)部分2.1 化合物L(fēng)P-1的合成將2,6-二甲基苯氧乙酸(3.6g,肽鍵,產(chǎn)生的副產(chǎn)物二環(huán)已基脲(DCU),需多次重結(jié)晶才能20 mmol)、對(duì)甲苯磺酰氯(3.8 g,20 mmol).二氯甲烷( 100除去,導(dǎo)致成本增加;該方法簡(jiǎn)單,后處理方便,副產(chǎn)物較少,mL)、無(wú)水碳酸鉀(12 g,80 mmol)和氯化芐基三乙銨(1 g,4適合工業(yè)化生產(chǎn)。mmol)加至500 mL三頸瓶中,加熱至50C攪拌反應(yīng)5 h。加參考文獻(xiàn):人BDC (7. 6g ,20 mmol) ,室溫反應(yīng)3 h[TLC檢測(cè),展開(kāi)劑: V[1] Hasson H, Galli L, Galotta G, et al. HAART simplification with(乙酸乙酯):V(石油醚609goc)= 2:1] ,反應(yīng)結(jié)束后,加入5%lopinavir/ ritonavir monotherapy in HIV/HCV co-infected patients碳酸鈉溶液(50 mL) ,分出有機(jī)相,水相用二氯甲烷(50 mLxstarting anti-HCV treatment: a randomised pilot study ( KaMon )2)萃取。合并有機(jī)相,依次用5%碳酸鉀溶液(50 mL x2)洗[J]. New Microbiol ,2012 ,35(4) :469 -474.滌,飽和食鹽水(50mLx3)洗滌,無(wú)水硫酸鈉干燥,乙酸乙酯[2] Cooper C,la-Porte C,Tossonian H,et al. A pilot , propecive , open-重結(jié)晶,得白色固體產(chǎn)物L(fēng)P-1(8. 5g) ,收率77. 9% ,mp 153. 1label simplification study to evaluate the safety , eficacy , and pha- 153.9C。' H-NMR( DMSO-d, 400MHz) 8:7. 43(1H,s,NH),macokinetics of once-daily lopinavir-itonavir monotherapy in HIV-HCV coinfected patients : the MON0C0 study[J]. HIV Clin Trials,7.11 -7. 26( 10H,m, ArH),6. 91 - 7. 02(3H, m, ArH) ,6.642012,13(4):179 - 188.(1H,s,NH) ,4.96(1H, Brs, 0H),4.27 -4.34(1H,m, CH)，[3] Lambert-Niclot S，Masquelier B , Cohen Codar I,et al. Impact of lopi-4. 04(2H,s,CH2),3. 82-3. 89(1H,m,CH) ,3.66-3.67(1H,navir/ ritonavir use on antiretroviral resistance in recent clinicalm,CH) ,2. 80 -2.84(2H,m,Ar-CH2) ,2.61 -2.63(2H,m,Ar-practice[ J]. J Antimicrob Chemother ,2012 ,67( 10) :2487 - 2493.CH2) ,2.14(6H,s,2xCH3),1.42- 1.57(2H,m,CH2),1.31[4]Josephson F ,Andersson MC, Flamhole L,et al. The relation betweentreatment outcome and efavirenz , atazanavir or lopinavir exposure in2.2化合物 LP-2的合成取 LP-1(5.4 g,10 mmo) ,加入到the NORTHIV trial of treatment-naive HIV-1 infected patients[ J].Eur J Clin Pharmacol ,2010 ,66(4) :349 -357.250 mL三口瓶中,加入50mL乙酸乙酯溶解,室溫下滴加55] 姚亞敏,沐 俊,孫驥,等.洛匹那韋藥代動(dòng)力學(xué)的研究進(jìn)展mL濃鹽酸,滴加完畢后,緩慢升溫至40~50C,保溫5h,[J].藥學(xué)實(shí)踐雜志,2012 ,30(5) :336 - 339.[TLC檢測(cè),展開(kāi)劑:V(乙酸乙酯):V(石油醚_oc)= 2:1]，6] 姚亞敏,孫建軍,陳 軍,等. LC-MS/ MS法同時(shí)測(cè)定洛匹那韋和冷卻至室溫,滴加10%碳酸鉀水溶液,調(diào)節(jié)pH至8~9,分取利托那韋的血漿濃度[J].藥學(xué)學(xué)報(bào),2010 ,45(2):279 - 282.有機(jī)相,水相用乙酸乙酯(50 mLx2)萃取,合并有機(jī)相,用飽[7]代 玉英,梅曉冬.洛匹那韋逆轉(zhuǎn)LLC/cM0AT細(xì)胞多藥耐藥的作和食鹽水洗滌一次,用無(wú)水硫酸鈉干燥，減壓回收溶劑,直接用[J].安徽醫(yī)藥,2010,14(11):1263 - 1265.用于下一步反應(yīng)。8]何勇,陳仕云,余三喜，等.利托那韋異構(gòu)體雜質(zhì)的合成研究2.3洛匹那 韋的合成將(2S)-(1-四氫嘧啶-2-酮)-3-甲 基及控制方法.中國(guó):102786494 [P]. 2012 -07 -26.丁酸(2.0g ,10 mmol)、對(duì)甲苯磺酰氯(1.8 g,10 mmol)二氯[9]中國(guó)煤化工嗪芳酸醚甘氨酸街生物合成醫(yī)藥,2011 ,15(8) :937 -940.甲烷(50 mL)、無(wú)水碳酸鉀(6 g,40 mmol )和氯化芐基三乙銨[10]MHCNMH(奈的合成[J].中國(guó)醫(yī)藥工業(yè)(1g,4mmol)加至500mL三頸瓶中,加熱至50°C攪拌反應(yīng)5雜志,2012 ,43(2) :84 - 86.h。加入上一步產(chǎn)物,室溫反應(yīng)4h[TLC檢測(cè),展開(kāi)劑:V(乙酸[1]李家明,何 勇,周 鵬，等.阿魏酰胍丁T胺類似物的設(shè)計(jì)、合成乙酯):V(石油醚_9or:)= 2:1],反應(yīng)結(jié)束后。加入5%碳酸及Na- */H~ +交換器-1抑制活性[J].藥學(xué)學(xué)報(bào),2011,46鉀溶液(50 mL) .分出有機(jī)相,水相用二二氯甲烷(50 mL x2)萃(8) :936 -941.取。合并有機(jī)相，很款用5%碳酸鉀溶液(50 mLx3)洗滌,飽(收稿日期:2012-12 -25,修回日期:2013 -08 -05)