[生物医药论文精品a]脂质体辅料二硬脂酰磷脂酰乙醇胺的合成研究

脂质体辅料二硬脂酰磷脂酰乙醇胺的合成研究吴立红，张宏武，郑利刚，刘亚英A1A2A0A3A4A5A6A7A0A8A9A1A2A10A11A13A14A12A15A16A18A2A10A11050051A13A17A19A20A21A22A23A24A25A26A27A28A29A30A31A32A33A28A34A35A36A37A22A38A39A40A41A42A43A44A45A46A47A48A49A36A50A51A52A53A32A18A54A55A56A57A58A59A60A61A59A62A53A59A63A64A57A58A59A65A66A59A67A61A59A68A66A59A33A34A61A69A7A70A71A72A42A73A74A21A75A61A38A76A54A29A77A78A79A80A68A77A81A82A18A83A84A85A50232A42A73A86A71A87A88A53A32A39A71A89A18A90A91A92A93A18A94A38A40A95A61A96A97A42A98A99A100A100A20A28A29A30A31A32A101A33A28A34A35A36A37A101A38A39A102A103A104A105A106A104A105A107R914A108A109A110A111A112A110A111A113ASTUDIESONSYNTHESISOFLIPOSOMEEXCIPIENT1,2STEAROYLPHOSPHATIDYLETHANOLAMINEWULIHONG,ZHANGHONGWU,ZHENGLIGANG,LIUYAYINGCSPCZHONGQIPHARMACEUTICALTECHNOLOGYSJZCOLTD,SHIJIAZHUANG050051ABSTRACTA113OBJECTIVETOSTUDYANDIMPROVETHESYNTHESISOFLIPOSOMEEXCIPIENTPHOSPHATIDYLETHANOLAMINEA114METHODSPHOSPHATIDYLETHANOLAMINEWASPREPAREDFROMDMANNITOLBYISOPROPYLIDENDANDOXYGENATION,REDUCTION,FOLLOWEDBYBENZYLATION,HYDROLYSIS,ESTERIFICATION,HYDROGENOLYSISANDPHOSPHORYLATIONA114RESULTSTHESTRUCTUREOFTARGETCOMPOUNDWASIDENTIFIEDBYMSAND1HNMRA114THEOVERALLYIELDWAS232A115A114CONCLUSIONTHISCOSTSAVINGANDSIMPLIFIEDMETHODCANBEUSEDINTHEINDUSTRIALPREPARATIONA114KEYWORDSA113LIPOSOMEEXCIPIENTA116PHOSPHATIDYLETHANOLAMINEA116SYNTHESIS二硬脂酰磷脂酰乙醇胺（DSPE），化学名1,2二硬脂酰SN甘油醇3磷脂酰乙醇胺，属于合成磷脂，由于磷脂具有两亲性既有亲水性又有亲脂性，分散在水中可以形成双分子层结构，利用该性质发展了一种新技术脂质体。近年来脂质体作为靶向给药系统新剂型，在制剂新技术研究中受到广泛关注。由于天然磷脂具有易氧化、不稳定的缺点，使得合成磷脂在脂质体研究和应用中起着重要作用。合成磷脂中应用最多的是磷脂酰乙醇胺和磷脂酰胆碱，全世界只有G1972G4490可以G17839G15904G10995G1147，G11458G2081G3281G1881G4590G7422G4466G10628G17837G1135G2709种的G1147G1006化。G3G7003G10498A117A118A119A120A121G6265G17959的二硬脂酰磷脂酰乙醇胺的合成G17347G13459是以的D甘G19718醇为起G3999G2419G7021，G13475G17819G1005G2461G1457G6264、氧化G17836G2419、G14488G3534G1457G6264、水G16311、G18243化、G14085G14488、磷酰化G12573多G8505G2465G3G3G3G3G3G3G3G3G3G3G3G3G3G3G3G3G3G3G3A122A123A124A125A126A127A128A129A130A131A132A133A134A135A136A137A138A124A125A139A140A142应G10995成G11458G7643化合G10301，G6117G1216在G2454G13783G8504G7003G10498的G3534G11796G990，G4557G5049G14414G7477G1226G17839G15904了G1260化，G1866中在G14488G3534化G2465应中用G7092G7438碱G7379G1207了G5390碱，使G2530G3800G10714G7368为G12628G2345，G2528G7114G10995成的G1147G10301不G19668G12946G20323，可G11464G6521用于G991一G8505G727在G18243化G2465应中用G8614性G17751G4579的二G8707G11014G9931G6454G6493了G11458G2081G5062G13475G19492制使用的G14280G11296G9354剂G3247G8707化G11911，G8616G17751G17878合G5049G1006化G10995G1147G727在G8694化G2465应中，G6117G1216G17902G17819G6523制G9213G5242、G7114G19400G2462G2399G2159，G18003G1825了G5334构体的G10995成G727在磷酰化G2465应中，G6117G1216G17902G17819G1260化G5445G2721G3252G13044G4570G7003G10498A117A143A121中G989、G3247G8505G2465应G13565G11713为两G8505，G12628化了G8505G20600，G19489G1314了成G7424。G6925G17839G2530的G17347G13459G5049G14414稳定，G2419G7460G7021G2462G16809剂G5277G1227易得，G17878合G1147G1006化G10995G1147。具体合成G17347G13459G16277图1。G3G3CH2OHOOHOOHOHOHOHOHOHHHHHOOOHOHOOHHHHBNCLC17H33COOHPOCL3OHCH2CH2NH2NABH4HCLNAIO4OHHOC17H33OOC17H33OOHOC17H33OOC17H33OPOOONH3OHOHOHOHOC17H33OOC17H33OACETONEH2/PB257346G3A144A145A146A147A148A149A150A151A149A152A153A154FIG1SYNTHESISROUTEOFTITLECOMPOUND1G3仪器与G7460G7021G3G3G3X4型数字显微熔点测定仪，WZZ2A型自动旋光仪，AC300型核磁共振仪（G1881G7643TMS，G9354剂CDCI3），所用G16809剂均为G5049G1006级G32G3合成G17347G13459G321G31,2,5,6G5334亚G1005G3534D甘G19718醇（3）的合成500MLG1005酮中加入G8707化锌（100G，073MOL），回流30MIN，加入D甘G19718醇（50G，027MOL）G2465应2H，然G2530加200ML饱和G8707化钠G9354液，200MLG8707仿萃取2次，合并G2530加入5的氨水400ML洗涤，加G7092水硫酸镁干燥，G17819滤、浓G13565G2530得白色固体（49G，681。），MP1151170C（G7003G10498值1171190C）。22G5334亚G1005G3534甘油醇（4）的合成G3在2700ML水中加入高碘酸钠（899G，042MOL），G9354清G2530加G8694氧化锂调PH值到6，G45703（36G，014MOLG9354于160MLG11014醇，G4570G11014醇G9354液滴加至G990述水G9354液中，G9213G5242G6523制在00C，G2465应2H，再加入8100MLG11014醇，G17819滤，滤液中加硼G8694化钠423G，112MOL，00CG2465应50MIN，1500MLG8707仿萃取3次，G7092水硫酸镁干燥，G17819滤，减G2399蒸G20323浓G13565G2530得到G7092色液体（289G，803），BP10MM77790C（G7003G10498值77780C）。233G14488G3534甘油醇（5）的合成在400MLG11014G3534乙G3534亚砜G9354液中加入416G，012MOL、G8694氧化钾134G，024MOL、G8707化G14488（38G，03MOL），室G9213G2465应45，加160ML纯净水，加160MLG11014G3534叔丁G3534醚萃取，浓G13565G2530得到的液体加200MLG11014醇，3N的盐酸100ML加热回流05H，65ML石油醚萃取1次，65ML乙酸乙G18243萃取2次，G7092水硫酸镁干燥，浓G13565得到G7092色液体4（178G，809）,BP1MM1451470C（G7003G10498值1451460C）。243G14488G35341,2二硬脂酰甘油（6）的合成G45705（12G，006MOL）、硬脂酸（454G，016MOL、二环己G3534G11911二亚胺（152G，012MOL、4二G11014胺G3534吡啶（032G，0002MOLG9354于360ML二G8707G11014G9931中，G6523G9213300C搅拌15H，G17819滤，滤液浓G13565得白色固体，乙醇重结晶G2530得白色粉末5（312G，664），MP505050C（G7003G1049850510C）。251,2二硬脂酰甘油（7）的合成G3800MLG3247G8694呋喃中加入6（20G，003MOL，10钯G11911（2G），G2399G2159为25MPA,G6523G9213600CG2465应G7114G194008H，置G6454G2530，G17819滤钯G11911，滤液浓G13565得到白色粉末6，（168G，96）。MP747450C（G7003G10498745750C）。261,2二硬脂酰甘油磷脂酰乙醇胺（1）的合成150MLG3247G8694呋喃中加入7（10G，002MOL、G989G8707氧磷53G，003MOL、13MLG989乙胺，G6523G9213350C搅拌2H，G17819滤，滤液浓G13565G2530再加入80MLG3247G8694呋喃，乙醇胺245G，004MOL和10MLG989乙胺，G6523G9213G5242200C，G2465应15MIN，G17819滤，滤液浓G13565得白色固体。正己G9931重结晶得到白色粉末1（985G，823），MH7481，1HNMRCDCI3087T，6H，J67HZ，CH3，126M，56H，CH3CH214，157M，4H，CH3CH214CH2,，228M，4H，COCH2，336M，2H，CH2NH，394M，2H，CH2OP，417M，2H，GLYCEROL3CH2，439M，2H，GLYCEROL1CH2，520M，1H，GLYCEROL2CH，760（T，1H，NH）REFERENCESA155A156A157EIBLH,ANIMPROVEDMETHODFORTHEPREPARACTIONOF1,2ISOPROPYLIDENESNGLYCEROLJCHEMPHYSLIPIDS,1981,28A1581A15915A155A160A157EIBLH,WOOLLEYP,SYNTHESISOFENANTIOMERICALLYPUREGLYCERYLESTERSANDETHERSIMETHODSEMPLOYINGTHEPRECURSOR1,2ISOPROPYLIDENESNGLYCEROLJCHEM