洛匹那韦的合成

●2026●安徽医药Anhui Medical and Pharmaceutical Journal 2013 Dec;17(12)<>药学研究<>洛匹那韦的合成蒋敏',何勇”,余三喜”,赵世杰? ,高永好,吴宗好’(1.国药集团国瑞药业有限公司,安徽淮南232001;2.合肥华方医药科技有限公司,安徽合肥230088)摘要:目的研究抗病毒药物洛匹那韦的合成。 方法以(2S,3S,5S)-5-(叔丁 氧羰基)氨基-2-氨基-3-羟基-1 ,6-1二苯基已烷为起始原料，与2,6-二甲基苯氧乙酸经肽键缩合、脱保护、最终与(2S)-( 1-四氢嘧啶2-酮)-3-甲基丁酸再经肽键缩合制备目标产物洛匹那韦。结果三步 合成了目标产物洛匹那韦,以BDC计,总收率为50.7% ,通过' H-NMR、MS确定了结构。结论该方法简单,后处理方便,副产物较少,适合工业化生产。关键词:抗病毒;洛匹那韦;化学合成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洛匹那韦( Lopinavir, LPV),化学名为(S)-N-[(1S,2S,制和免疫学应答,且在发展中国家为发生耐药初治失败HIV4S)-4-[[(2,6-二甲基苯氧基)乙酰]氨基]-3-羟基-5-苯基-1-患者的抗病毒治疗发挥重要作用[5s6]。有学者在进行药物相(苯基甲基)苯基]四氢-(1-甲基乙基)-2-氧代-1 (2H)-吡咯烷互作用研究时发现,洛匹那韦与环孢素联用,可使环孢素血药乙酰胺,是HIV-1和HIV-2蛋白酶抑制剂,能阻止Gag-Pol多浓度增加”]蛋白的分裂,产生未成熟的、无感染力的病毒颗粒,洛匹那韦本文以(2S,3S,5S)-5-(叔丁氧羰基)氨基-2-氨基-3-羟联合低剂量利托那韦(Ritonavir,RTV)能够改善其药代特性，基-1 ,6-二苯基已烷( BDC)为起始原料,与2,6-二甲基苯氧乙主要通过抑制洛匹那韦在人体的代谢,提高血浆药物浓度,增酸经肽键缩合制备LP-1、用浓盐酸一乙酸乙酯体系脱除Boc强其抗病毒作用14)。洛匹那韦联合低剂量利托那韦复合片保护基制备LP-2、最终与(2S)-( 1-四氢嘧啶-2-酮)-3-甲基丁剂(克立芝)于2000年被美国食品药品监督管理局批准上酸缩合,三步反应制备目标产物洛匹那韦,总收率为50. 7% ,市,其疗效可靠、副作用少、受食物影响小,目前作为抗人类免该方法简单,后处理方便,副产物较少,适合工业化生产。合疫缺陷病毒的一线或二线治疗药物,实现了良好的病毒学抑成路线见图1。5] Zhang Z,Sun L, Wang Y ,et al. Renprotetive role of the vitamin D re-12]刘雷,甘华,王辉,等.活性维生素D3对糖尿病大鼠肾脏ceptor in diabetic nephropathy [J]. Kidney Int ,2008 ,73(2):163 -171.TGF-B1和HGF表达的影响[J].重庆医科大学学报,2008 ,33[6] Ishimura E, Nishizawa Y , Inaba M,et al. 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Kidney Int ,2007 ,72(2):193 -201.(收稿8期:2013 -06 -20,修回日期:2013 -09-17)安徽医药Anhui Medical and Pharmaceutical Joural 2013 Dec;17(12). 2027 .和食盐水(50mLx3)洗涤,无水硫酸钠干燥,减压回收溶剂至干，乙酸乙酯-正庚烷重结晶,得白色固体产物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丽LP2m,CH) ,3.65(1H, m, CH) ,3. 02(2H, m, NCH2),2. 89 -2.93图1洛匹那韦的合成路线(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仪器与试剂xCH3),1.98 -2.04(1H, m, CH),1.43 -1.60(4H,m,2 xWRS-1B数字熔点仪(上海申光仪器仪表有限公司);CH2) ,0. 76(3H,d,J = 6.8 Hz, CH,),0.74(3H,d,J =6.8Bruker核磁共振仪(德国Bruker 公司,400 MHz); LCQ AD-Hz,CH3); ESI-MS m/z: 629[M +H]*。VANTAGEMAX液质连用质谱仪( FINNIGAN公司); (2S,3S,3结果与结论5S)-5-(叔丁氧羰基)氨基-2-氨基-3-羟基-1 ,6-二苯基已烷(自本研究参考相关文献9-]1合成肽键:用固体碳酸钾为碱，制)[8];(2S)-( 1-四氢嘧啶-2-酮)-3-甲基丁酸(厦门市华兴化亲脂性季铵盐氯化苄基三乙铵(TEBAC1)为相转移催化剂,用工有限公司,99. 3% ) ;2,6-二甲基苯氧乙酸(厦门市华兴化工羧基和对甲苯磺酰氯(TsCl)反应制得混酐,与相应胺基反应有限公司,99. 6% );其他试剂为分析纯。合成肽键,避免使用二环已基碳二亚胺( DCC)作缩合剂合成2实验部分2.1 化合物LP-1的合成将2,6-二甲基苯氧乙酸(3.6g,肽键,产生的副产物二环已基脲(DCU),需多次重结晶才能20 mmol)、对甲苯磺酰氯(3.8 g,20 mmol).二氯甲烷( 100除去,导致成本增加;该方法简单,后处理方便,副产物较少,mL)、无水碳酸钾(12 g,80 mmol)和氯化苄基三乙铵(1 g,4适合工业化生产。mmol)加至500 mL三颈瓶中,加热至50C搅拌反应5 h。加参考文献:人BDC (7. 6g ,20 mmol) ,室温反应3 h[TLC检测,展开剂: V[1] Hasson H, Galli L, Galotta G, et al. 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