布地奈德的合成工艺改进

··[e-mail]王宝伟，张贵民，王洪刚(鲁南制药集团股份有限公司，山东临沂276006)布地奈德的合成路线和工艺主要有半生物合成法和化学合成法两种合成路线，本工艺路线以醋酸泼尼松为起始原料，把反应路线简化为五步，并通过对反应温度、反应溶剂、pH值的摸索找到最佳配比，大大提高了产品收率。特别是对中间体Ⅱ使用氧化剂过氧化氢，使收率由以前的使用高锰酸钾氧化时的60%稳步提高到80%。与欧洲专利EP0164636和美国专利US3929768中的方法比较，提高了收率，简化了合成步骤，降低了原料成本，本工艺路线适合工业化生产。布地奈德;合成工艺;改进TQ460．31A2095－5375201403－0184－003ThesynthesisprocessoptimizationofbudesonideWANGBao-weiZHANGGui-minWANGHong-gangLunanPharmaceuticalGroupCo．Ltd．Linyi276006ChinaAbstractThesynthesisrouteandprocessesofbudesonideweremainlycontainsemi－biosynthesisandchemicalsyn-thesismethodthestartingmaterialoftheprocessroutewasprednisoneacetatethereactionroutereducedtofive－stepandthroughthereactiontemperaturethereactionsolventpHvalueofexplorationtofindthebestratiogreatlyimprovingtheproductyield．EspeciallyforintermediateIIusinganoxidizingagenthydrogenperoxidesothattheyieldofaprevioususeofpotassiumpermanganateoxidationincreasedsteadilyfrom60%to80%．ComparingwiththemethodofEuropeanPatentEP0164636andU．S．patentUS3929768theyieldwasimprovingthesynthesisstepwassimplifyingandthecostofrawma-terialisreducing．Theprocessroutewassuitableforindustrialproduction.KeywordsBudesonideSynthesisOptimization19811～3。Crohn'sdisease、、4。5。ＲSＲS2～367。Ⅴ1。Ⅴ。US35365861。EP0164636US3929768·481··JournalofPharmaceuticalＲesearch2014Vol．33No．3DOI:10.13506/j.cnki.jpr.2014.03.020、、、、。、、。11.1。1．2JJ－1CL－2000SeaStarＲ205L8823A、P3000、HW－2000。1.32。21.41.4.1Ⅰ100g0.25mol、DMF100mL、200mL5－10g70～80℃6hpH6.0～7.050g100～105℃6～7h8L92gⅠ76g79.6%mp207～209℃。1.4.2ⅡI50g0.131mol、3000mL0℃80%H2O2100mL－10℃10hII44g80.8%。1.4.3ⅢⅡ100g500mL12g－5℃4h83g－1∶2400mLⅢ72g71.7%mp195～201℃。1.4.4ⅣⅢ100g0.228mol、1500mL10%500mL0℃2hpH6.5～7.51000mLⅣ81gⅣ66g72.6%mp223～229℃。1.4.5ⅤⅣ50g500mL20mL35℃7mL30～35℃5h10℃10%K2CO3100mL300mLⅤ54g98.4%。1.4.6ⅤⅤ40g－1∶4200mL28g70%mp222～232℃。2。“1.4.1”DMFpH6.0～7.0。“1.4.2”－10～0℃。“1.4.3”－1∶2。“1.4.4”。“1.4.5”30～35℃－1∶3。－1∶4。Ⅱ·581··JournalofPharmaceuticalＲesearch2014Vol．33No．360%80%。5、、pH。ＲSＲ50%～60%99.8%0.1%。1WickstromLI．Synthesisandstructureelucidationof6al-phahydroxylatedand6betahydroxylatedbudesonideandrelatedcorticosteroidsJ．ActaPharmSuec1984213145－162．2．J．200425135－37．3ThalenAEpimersofbudesonideandrelatedcorticoste-roids．III．Synthesisandstructureelucidationbycarbon－13andprotonnuclearmagneticresonancespectroscopyJ．ActaPharmSuec198724397－114．4FedorakＲNBistritzL．Targeteddeliverysafetyandeffi-cacyoforalenteric－coatedformulationsofBudesonildeJ．AdvDrugDelＲev2005572303－316．5O＇ConnellEJ．ＲeviewoftheuniquepropertiesofBudes-onideJ．ClinicalTherapeutics200325supplC42－C60．6HouSHindleMByronPＲ．AstabilityindicatingHPLCassaymethodforBudesonideJ．JPharmBiomedAnal200l24337l－380．7KrzekJ1CzekajJSＲzeszutkoWetal．Directsepara-tionidentificationandquantificationofepimers22Ｒand22SofbudesonidebycapillarygaschromatographyonashortanalyticalcolumnwithＲtx－5stationaryphaseJ．JChromatogrBAnalytTechnolBiomedLifeSci20048032191－200．(上接第183页)91.7%59.4%。1MossＲBMollTEI－KalayMetal．Th1/Th2cellsininflammatorydiseasestatestherapeuticimplicationsJ．ExpertOpinBiolTher20044121887－1896．2PulendranB．ModulatingTh1/Th2responseswithmi-crobesdendriticcellsandpathogenrecognitionreceptorsJ．ImmunolＲes2004291－3187－196．3KawakamiK．Promisingimmuno－therapieswithTh1－relatedcytokinesagainstinfectiousdiseasesJ．JInfectChemother200393201－209．4ShenHHZhangGSWangPL．Mycobacteriumbovis－BacillusCalemette－GuerinandasthmaJ．ChinMedJEngl200511811942－947．5．2003J．20043165．6．M．20011046－1049．7．M．2006164－168．8DasPKvandenWijngaardＲMWankowicz－KalinskaAetal．AsymbioticconceptofautoimmunityandtumorimmunitylessonsfromvitiligoJ．TrendsImmunol2001223130－136．·681··JournalofPharmaceuticalＲesearch2014Vol．33No．3