阿法骨化醇合成的新方法-陈阳生

,　,(青岛海尔药业有限公司研发中心,青岛266103)　　[]　:合成阿法骨化醇。:以维生素D3为原料,经酯化、关环、氧化、开环、水解5步反应合成目标化合物。:本方法避开了光照反应,产物总收率为17.2%。:本方法提高了收率,操作安全,适合于工业化生产。　　[]　阿法骨化醇;药物合成;维生素D3[]R914.5;R977.24　　[]A　　[]1003-3734(2005)12-1441-03SynthesisofalfacalcidolCHENYang-sheng,RENLi,ZHAICui-yun(R&DCenter,HaierPharmaceuticalCo.,Ltd.,Qingdao266103,China)[Abstract]　Objective:Tosynthesizealfacalcidol.Methods:UsingVitaminD3asastartingmaterial,thealfacalcidolwassynthesizedvia5chainchemicalreactionsincludingesterifation,cyclization,oxidation,ringopeningreactionandhydrolysis.Results:Thetotalyieldofalfacalcidolwithoutaphotochemicalstepwas17.2%.Conclusion:Thisnovelsyntheticprocessmightbeusedforpharmaceuticalmanufacture.[Keywords]　alfacalcidol;synthesis;vitaminD3　　(alfacalcidol,1)9,10--5Z,7E,10(19)--1α,3β-,(BoneCareInternational),(1979)、(1979)、(1982)、(1985)。Leo,D。、、、D、。1997,()()2。[1,2],D3,、、、、5,1,10%～15%。[3～5],,,,,17.2%,1。1　—1441—　ChineseJournalofNewDrugs2005,Vol.14No.1220051412　X4,。Perkin-Elmer983。Shimadzu-265。VarianUnity500。VGZebSpec。1　D3(2)D310g(0.026mol)12g,50mL,(2～4℃)48h。20g100mL,15min。1500mL。3%(500mL×2),(500mL×1)(500mL×1),,。,2(13.5g,97.0%),。mp:99～103℃(),MS(EI)(mz):538(M+)。2　3,5-D3(3)3000mL2(13.0g,0.024mol)、30g2500mL,55℃8h。,1500mL。,,,,3(9.4g,97.5%),。MS(EI)(mz):398(M+)。3　1α-OH-3,5-D3(4)3000mL3(9.3g,0.023mol)、0.3g、15mL2500mL,50min,10%(200mL×2),(400mL×2),,,。[,-(1∶10)],4(4.2g,43.4%)。MS(EI)(mz):414(M+)。4　1α-OHD3-3-(5)250mL4(4.2g,0.010mol)120mL,55℃15min,,100mL4g[5],40℃8h,10%50mL,15min,,,,,,,[,-(1∶8)],5(2.4g,53.5%)。MS(EI)(mz):442(M+)。5　1α-OHD3(1)500mL5(2.4g,0.005mol),5%20mL200mL,3h,1500mL,,,,-(1∶3),,40℃2h1(1.7g,78.3%)。mp:138～139℃,UV:λmax=265(ε17469);211nm,λmin=227nm。IRυ(cm-1)∶3399,2869,1640,1058。MS(EI70EV)(mz):400(M+14.4),382(50.0),364(8.5),269(6.5),152(25.5),134(100.0)。1H-NMR(DMSO)δ:6.38(1H,d),6.02(1H,d),5.33(1H,s),5.01(1H,s),4.44(1H,m),4.23(1H,m),2.82(1H,m),2.60(1H,m),2.32(1H,m),0.92(3H,d),0.87(6H,m)。13C-NMR(DMSO)δ:70.77(1-C),42.81(2-C),66.81(3-C),45.21(4-C),132.75(5-C),124.96(6-C),116.90(7-C),143.29(8-C),29.09(9-C),147.56(10-C),22.82(11-C),40.46(12-C),45.90(13-C),56.56(14-C),23.60(15-C),27.62(16-C),56.34(17-C),11.99(18-C),111.73(19-C),36.10(20-C),18.83(21-C),36.10(22-C),23.83(23-C),39.48(24-C),28.00(25-C),22.28(26-C),22.56(27-C)。　　、,,,4,Diels-Alder,,。[]　陈阳生(1968-),男,副研究员,执业药师,主要从事新药研究开发工作。联系电话:[phone],E-mail:[e-mail]。[][1]　BaggioliniEG,IacobelliJA,HennessyBM.Stereocontrolledtotalsynthesisof1α,25-dihydroxycholecalciferoland1α,25-dihydroxycholecalciferol[J].OrgChem,1986,51(16)∶3098-3100[2]　JohnsonWS,ElliottJD,HansonGJ.Asymmetriesynthesisviaacetaltemplates.6.AstereoselectiveapproachtoakeyintermediateforthepreparationofvitaminDmetabolites[J].JAmChemSoc,1984,106∶1138-1139.—1442—　ChineseJournalofNewDrugs2005,Vol.14No.1220051412　[3]　PaarenHE,DelucaHF,SchnoesHK.DirectC(1)hydroxylationofvitaminD3andrelatedcompounds[J].OrgChem,1980,45(16)∶3253-3258.[4]　SatoT,YamauchiH,OgataY.Studieson1α-hydroxylderivativesofvitaminD3.I.synthesesof1α-hydroxyvitaminD3and1α,25-dihydroxyvitaminD3[J].ChemPharmBull,1978,25(10)∶2983-2940.[5]　DeLuca.Methodforpreparing1α-hydroxyvitaminDcompounds[P].US,4554106.1985-11-19.(接受日期:2005-08-02)1,　2,1,1(1沈阳药科大学制药工程学院药化教研室,沈阳110016;2东北制药总厂生产技术部,沈阳110026)　　[]　:合成非氨酯。:以2-苯基-1,3-丙二酸二乙酯为起始原料,经硼氢化钠还原后得到2-苯基-1,3-丙二醇,再与氯甲酸苯酯、氨水反应得到目标化合物非氨酯。:目标化合物经红外光谱、核磁共振氢谱、质谱确证其化学结构。非氨酯总收率达38.1%。:该法合成操作简便,适合于工业化生产。　　[]　非氨酯;药物合成;抗癫痫药[]R971.6;R914.5　　[]A　　[]1003-3734(2005)12-1443-02SynthesisoffelbamateZHAODong-mei1,LIUYao2,LJiu-an1,CHENGMao-sheng1(1DepartmentofMedicinalChemistry,ShenyangPharmaceuticalUniversity,Shenyang110016,China;2DepartmentofProductionandTechnology,NortheastGeneralPharmaceuticalFactory,Shenyang110026,China)[Abstract]　Objective:Tosynthesizefelbamate.Methods:Startingfromdiethylphenyl-malonate,felbamatewassynthesizedviaseveralchemicalreactionsincludingreduction,acylationandhydrolysis.Results:Thechemicalstructureofthetargetcompoundwasconfirmedby1H-NMRandMSanalysis.Thetotalyieldofthetargetcompoundwas38.1%.Conclusion:Aneasilymanipulatedsyntheticprocessoffelbamatewasattainable.[Keywords]　felbamate;synthesis;antiepilepticdrug　　(felbamate,1),2--1,3-,Carter-Wallace,19938,Schering-Plough,、、,。(L-G),。[1,2]2。1:2--1,3-(3),2--1,3-,,(1),,mp:151～152℃。2:12--1,3-,,(1)。1,,,;2。[3],2--1,3-(3),NaBH4(2),,(1),1。1　—1443—　ChineseJournalofNewDrugs2005,Vol.14No.1220051412