[生物医药论文精品a]高效液相色谱法研究头孢他啶中间体动力学

高效液相色谱法研究头孢他啶中间体动力学张静12，李志伟1，哈婧1，付德才11A1A2A0A3A4A5A6A8A6A7A9A10A11A12A6A13A15A2A0A16A14A17050018A192A1A2A0A8A11A18A10A20A21A4A22A6A13A9A10A11A12A24A23A25A26A27A28A29050026A30A31A31A32A32A33A34A33A34A33A34A32A32A35A36A37A38A39A40A41A42A43A44A45A46A47A48A49A50A51A52A44A53A54A557A56A57A58A59A603A43A44A61A60A50A514A62A63A64A61A65A66A67A68A69A70A71A72A73A74A75A76A77A78A72A79A80A81A82A83A84A85A64A86A87A72A73A88A89A90A91A74A92A93A93A32A32A94A95A86A87A45SN2A96A73A97A78A72A91A9525A98A9935A98A100A101A102A61A103A53A86A87A68A104A105A106A107A97A108A109A110A111A112A113A114A4576882KJA115MOL1A74A92A116A77A117A86A87A118A119A120A43A44A121A122A118A88A123A124A125A79A86A87A126A105A74A127A128A129A32GCLEA1307A56A57A58A59A603A43A44A61A60A50A514A62A63A64A61A65A66A67A130A48A49A130A69A70A71A131A132A133A134A135A133A134A136A137A138A139A140A141A137A138A139A140A136A137A142A143A135A142A143A136KINETICSOFTHECEFTAZIDIMEINTERMEDIABYHPLCZHANGJING12,LIZHIWEI1,HAJING1,FUDECAI11COLLEGEOFCHEMICALANDPHARMACEUTICALENGINEERING,HEBEIUNIVERSITYOFSCIENCEANDTECHNOLOGY,SHIJIAZHUANG050018,HEBEI,CHINA2DEPARTMENTOFPHARMACEUTICALENGINEERING,HEBEICHEMICALANDPHARMACEUTICALVOCATIONALTECHNOLOGYCOLLEGE,SHIJIAZHUANG050026,HEBEI,CHINAABSTRACTOBJECTIVETHEKINETICSSTUDYWASABOUTTHECEFTAZIDIMEINTERMEDIA7PHENYLACETAMIDO3PYRIDINIUMMETHYLCEPHEM4CARBOXYLICACIDPMETHOXYBENZYLESTER,WHICHWASPREPAREDBYREACTIONOFGCLEWITHPYRIDINEMETHODSTHEREACTIONPROCESSWASINSPECTEDBYHPLCRESULTITWASDETERMINEDTHATTHENUCLEOPHILICSUBSTITUTIONREACTIONWAS2NDORDERREACTIONBYDETERMININGTHERATECONSTANTSAT25A144AND35A144INTHEDICHLOROMETHANE,THEAPPARENTACTIVATIONENERGYWAS76882KJA145MOL1CONCLUSIONTHEYIELDCANBEENHANCEDBYINCREASINGPYRIDINEKEYWORDSGCLE7PHENYLACETAMIDO3PYRIDINIUMMETHYLCEPHEM4CARBOXYLICACIDPMETHOXYBENZYLESTERSYNTHESISKINETICSA146A147A148A149A148A149A136A150A151A152A153A154A155A156A157A158A159A160A161A162A163A148A149A152A153A154A155A156A157A158A159A161A162A16406547003D2A1651引言高效液相色谱法自问世以来，在分析化学领域应用很广。在物理化学领域，MORIYASU等人首先应用HPLC法测定了某些鳌合物配体交换反应的动力学数据，为HPLC法在物理化学应用上开辟了途径。7苯乙酰氨基3吡啶甲基头孢4羧酸对甲氧苄酯（化合物）是头孢他啶的重要中间体。该化合物可由GCLE经碘活化后，与吡啶反应制得，该过程为制备头孢他啶药物的关键过程。在由GCLE出发制备3位含有季氮离子的抗生素药物中，头孢他啶的合成方法具有G1207G15932G5627。G7424G7003G6518G16764G2656G1183G13473了应用HPLC法G11752G12362头孢G14752素G12879抗生素头孢他啶中间体的动力学过程，G11842定了反应G13435数，G16757G12651出反应的活化G14033，为G6518G13046反应G10317G9869G2656G16280G5471，G17839G980G8505G11752G12362G2334合成头孢G14752素G12879药物的生G1147G5049G14414G7477G1226具有G980定的G6363G4560G1328用。G21G4466G20576G18108分G21G17G20G1214G3132与药G2709HH数G7186G5670G9213G8712G9032G19161G727LCG16G20G19G36G55G17G57PG17LG44G52G56G44G39CHG53G50G48G36G55G50G42G53G36PHG30G54PG39G16G20G19G36G17G57PG17G56G57G16G57G44G54G39G40G55G40CG55G50G53G727CHA166CG79A166，色谱G13443G727G42CLG40，CG17P，G5049G1006G2709G727G7092G8712G49G68G44，G36G17G53，G3837G8953G5078G3835G14550化学G16809G2070G2390G727吡啶，G36G17G53，G3837G8953G5078G3835G14550化学G16809G2070G2390。G21G17G21G7643G1946G2709的制备G4570G42CLG40G28G17G28G22G74G11G19G17G19G21G80G82G79G12G2656G49G68G44G25G17G25G23G74G11G19G17G19G23G80G82G79G12G2164G2052G20G19G19G80LG1005G18242中G6617G6304G22G19G80G76G81，G4472G9213G18003G1821反应G24G75。G1955G2399G14988出G9354G2070，G2164G1849G20G19G19G80LCHA166CG79A166G2656G20G19G19G80LG8712，静G13634分液。有G7438G4630用G23G19G80LG20293G2656G49G68A166G54A166G50A167G9354液G8939G9080，分液，G5190G10169，过G9400，G1955G2399G8999G13565G14279G13434G23G19G80L。G19489G9213G14279G19G263，G2164G1849G22G17G20G25G74G11G19G17G19G23G80G82G79G12吡啶，在G19G16G24G263下G6617G6304反应G23G75，过G9400，固体转移G14279G21G19G19G80L乙酸乙酯G2656石油醚的混合G9354液（G57G57G20G20）中，G4472G9213G6617G6304G22G19G80G76G81，过G9400，真空G5190G10169，得G2052G1147G2709G20G21G178G74，G13443度G288G178、收率G28G25，熔G986988G28G19G263,A168HG16G49G48G53与G7003献报道G980致A169A170A171。NONHNHHSCLCOOPMBONHNHHSICOOPMBCH2CL2,CH3COCH3NAIONHNHHSCOOPMBNIOOOGCLEGIEA172A173A174IA175A176A177A178A179A180A181A178A182FIG1SYNTHESISOFCOMPOUNDA180G21G17G22液相色谱分析色谱柱CA168A183柱（依利G10317G50G39G54G21G24G80，G23G17G19G80G80G20G24G19G80G80）G727流动相乙腈G16G19G17G21G24G80G82G79LA184A168磷酸二氢铵G9354液G16G8712（G57G57G57G22G19G19G20G19G19G25G19G19）G727检测波长G21G248G81G80G727流速G19G178G80G79G80G76G81A184A168G727G17839样量G21G19L。G21G17G22G17G20检测波长的G11842定取G7643G1946G2709G13434G21G24G80G74，用流动相稀释G14279G24G19G80G79，在G21G19G19G23G19G19G81G80扫描测定，由图G20可见，该样G2709在G21G21G22G81G80G2656G21G24G23G81G80处有最G3835吸收。参照中国药典G21G19G19G24版，选择G21G24G23G81G80为测定波长。G21G17G22G17G21流动相的G11842定通过尝G16809中国药典G21G19G19G24年版头孢他啶的色谱G7477G1226，G11842定该中间体的色谱G7477G1226为乙腈G16G19G17G21G24G80G82G79LA184A168磷酸二氢铵G9354液G16G8712（G57G57G57G22G19G19G20G19G19G25G19G19）。G22动力学G11752G12362G2656G3835多数G11752G12362动力学的方法G980样，HPLC法也是通过测定反应体系中各组分G8999度随时间的变化，即由动力学CT数据求得速率常数、速率方程G2656G6518G16764反应G7438理。HPLC法G11752G12362动力学的通常过程是在不同的反应时刻T，从反应G3132中取出G980定体积的样G2709注G1849色谱G1214，由G8939脱液在色谱柱上分离，检测G3132给出信号响应，记录G1214绘出色谱图。由色谱图G11842定不同反应时刻各组分的G8999度。G22G17G20G7643G1946曲线的G11842定为了G1946G11842考察化合物在CH2CL2中的G8999度随时间变化的G16280G5471，取精制后化合物01G，配制1MG74ML1的二氯甲烷G9354液，分别G4570其稀释成不同G8999度，测定不同G8999度的化合物的峰面积。在000205MGML1范围内峰面积与G8999度呈良好的线G5627关系，以化合物的G8999度为横坐G7643，峰面积为纵坐G7643G1328图，见图2。化合物的G7643G1946曲线为Y4779138614423000X，R09996。00000200400600801005000100001500020000SA185A186A187A188A189A190A191A192A193A194BLINEARFITOFDATA1_B10152025303540455055744743742741740739738BLINEARFITOFDATA1_BLNCGIET/HA1952A196A197A198A199A1953LNCGIEA200TA198A199A195FIG2STANDARDCURVEFIG3THECURVEOFLNCGIEA200TG22G17G21碘G1207物GIE反应G13435数的G11842定通过碘G1207物GIE与G3835过量吡啶反应G11842定GIE的反应G13435数。配制0002528MOLL1GIE的CH2CL2G9354液G2656002528MOLL1吡啶的CH2CL2G9354液（CGIECPYRIDINE110），分G13634容量瓶中。放G1849G5670G9213G8712G9032G19161中G5670G921325G263后混合，在不同时间取样，测定不同时间化合物的峰面积，依据上述G7643G1946曲线G2656反应方程式对化合物G2656反应物GIEG17839行物质量的G8999度换G12651。由于反应物吡啶G3835过量，反应速率方程式可用下式G15932示。RDC/DTKCGIEM式中KKCPYRIDINEN如果对GIE的反应G13435数为1时，即M1,则速率方程为LNCGIE0LNCGIEKT,其中CGIE0为反应物的起始G8999度，CGIE为T时刻反应物G8999度，LNCGIEA201T呈G11464线关系A202A203A204。以时间为横坐G7643，LNCGIE为纵坐G7643G1328图，见图3。可以G11487出LNCGIEA201T呈G11464线关系，Y735500164X，R09941，G3252G8504该反应对GIE的反应G13435数是G980G13435。由图3的G7024率可以求出25G263时，反应的G15932G16278速率常数为4555106S1。G22G17G22吡啶反应G13435数的G11842定101520253035404550398399400401402403BLINEARFITOFDATA1_B1/CGIE/LA205OL1T/H000510152025111213141516171819201/CGIE/LA206OL1BLINEARFITOFDATA1_BT/HA20741/CGIEA208TA209A210A20751/CGIEA208TA209A210FIG4THECURVEOF1/CGIEA208TFIG5THECURVEOF1/CGIEA208TG6365上述的G6817G1328过程，用等物质量G8999度的GIEG2656吡啶在CH2CL2G9354液中反应。测定不同时间化合物的峰面积，依据G7643G1946曲线G2656反应方程式对化合物G2656反应物GIEG17839行物质量的G8999度换G12651。等G6717G4584的GIE与吡啶反应，则得G2052动力学方程如下RDC/DTKCGIECPYRIDINENKCGIEN1如果N1，对上式G17839行积分，得1/CGIE1/CGIE0KT，即1/CGIE0CA211A212A213A2141/CGIE0KT。其中CGIE0为反应物的起始G8999度，CGIE为T时刻反应物G8999度。1/CGIEA208T应呈G11464线关系A215A216A217。以时间为横坐G7643，1/CGIE为纵坐G7643G1328图，得图4，1/CGIET呈G11464线，Y3968701229X，R09921。G3252G8504该反应对吡啶也是G980G13435反应，由G8504G11842定速率常数K25A218为341104LMOL1S1。G22G17G23反应G15932G16278活化G14033的G11842定G636532的G6817G1328过程，测定35G263时等物质量的G8999度GIEG2656吡啶在二氯甲烷反应过程中，不同时间化合物G8999度变化。1/CGIETG1328图呈G11464线（见图5），Y4071103358X，R09895。由G8504求得该G9213度时的速率常数K35A218为933104LG22109MOL1G22109S1。G7693据G1016G1022反应G9213度（25G263，35G263）G15932G16278速率常数,K25A218341104LMOL1S1,K35A218933104LMOL1S1,依据ARRHENIUS方程A215A216A217KAEXPE/RTG6524出，LNK35A218/K25A218EA/R1/T25A2181/T35A218，求得EA76881756JG22109MOL176882KJG22109MOL1G23G13479G16782G321利用高效液相色谱法G6732G13046出了G17878合于7苯乙酰氨基3吡啶甲基3头孢G14752素4羧酸对甲氧苄酯的分离G7477G1226，G6226出了化合物与G8999度变化的线G5627范围，G1946G11842G3332G11429测了反应过程中生成物G8999度的变化。G322通过测定在G9354G2070CH2CL2中不同G9213度（25G263、35G263）的速率常数，由ARRHENIUS方程求得G15932G16278活化G14033为76882KJG22109MOL1，G11842定G8504反应对GIEG2656吡啶G3355为G980G13435反应，G6524测G1158G7692反应G2394程为SN2G2394程。GCLE与吡啶可在CH2CL2中有效的G17839行反应，G6984G1022反应过程G7094与GIE相关，G2460与吡啶相关，G3252G8504G3698G2164吡啶用量可G17839G980G8505G6564高反应收率。A219A220A221A222A221A222A221A222A223A2231A224A225A226A227A228A229A230A231A232A233A234A235A236A237A238A239A240A241A241GCLEJA227A242A243A244A245A2462002A246A2476A248A24936A25040A2272A251A252A246A253A254A255A246A119A0A1A227A234A235A238A239A240A4A2A3A5A230A34A6A7A8A9A10A125A11A12A227A128A13A244A245A238A239A240A246A130A14A14A15A246A15A15A247A133A248A249A133A15A208A133A16A2273A135A17A18A227A4A2A3A5A2A138A15A139A19A20A244A34A6A141A142A143A227A144A21A146A144A21A22A23A245A24A34A6A25A26A27A34A6A28A29A24A30A31A246A130A14A14A32A146A133A133A2274A157A33A246A224A99A35A246A161A36A227A32A138A37A38A138A163A138A247A133A39A40A138A63A41A42A38A138A32A138A166A43A138A130A138A168A41A38A248A138A44A45A230A232A233A46A47A48A49A34A6A125A11A12A227A170A50A51A49A49A52A174A245A111A53A246A130A14A14A40A246A130A54A247A15A248A249A130A130A14A250A130A130A130A2