调研报告格式阿立克仑调研报告
海风教育一对一价格该药由诺华公司研制的，已在美国等55个国家获得上市批准.专利与保护情况EP678503,US5559111，在中国同族专利CN1266118C，申请日1995.4.17，已授权，到期日2019.4.16国内外上市概况Rasilez已在55个国家获得上市批准.
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2019年3月,Tekturna（Rasilez在美国的商品名）在美国获得批准.2019年8月,Rasilez在欧盟获得批准.
miasmata2019年1月,TekturnaHCT，首个含有Tekturna的单片复方制剂在美国获得批准.在中国,Rasilez于2019-03-26年被SFDA批准.
Rasilez是由诺华公司研制，由诺华与Speedel公司合作开发.国内注册情况受理信息药品注册受理信息药品通用名阿利吉仑片(临床)英文名AliskirenTablets申请分类新药申请件数5首家受理日期2019-3-158:41:40备注申请阶段临床药品注册受理信息药品通用名阿利吉仑片(临床试验)英文名AliskirenTablets申请分类新药申请件数2首家受理日期2019-11-2513:56:20备注申请阶段临床试验批准信息\进口药品\的内容列表，共有2条记录1.阿利吉仑片(H20190221NovartisPharmaSchweizAG86978679001270)2.阿利吉仑片(H20190220NovartisPharmaSchweizAG86978679001263)进口药品注册证号H20190221产品名称（中文）阿利吉仑片产品名称（英文）AliskirenTablets 商品名（中文）锐思力商品名（英文）Rasilez剂型（中文）片剂规格（中文）150mg(以阿利吉仑计)包装规格（中文）7片\/盒生产厂商（英文）Novar
tisPharmaSteinAG发证日期2019-03-26有效期截止日2019-03-25进口药品注册证号H20190220产品名称（中文）阿利吉仑片产品名称（英文）AliskirenTablets商品名（中文）锐思力商品名（英文）Rasilez剂型（中文）片剂规格（中文）300mg(以阿利吉仑计)包装规格（中文）7片\/盒生产厂商（英文）NovartisPharmaSteinAG厂商国家（英文）Switzerland发证日期2019-03-26有效期截止日2019-03-25合成路线【记录号】267580【通用名】Aliskirenfumarate,CGP-60536(freeba),SPP-100B,SPP-100(freeba),CGP-60536B【化学名】(2S,4S,5S,7S)-5-Amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isop ropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamidehemi
adverbfumarate【CAS登记号】173334-58-2,173334-57-1(freeba),173399-03-6(monohydrochloride)【分子式】2-C30-H53-N3-O6.C4-H4-O4【分子量】1219.599【化学活性】CardiovascularDrugs,Hypertension,Treatmentof,RenalFailure,Agentsfor,R enal-UrologicDrugs,TreatmentofRenalDias,ReninInhibitors【开发阶段】PhaIII【研究机构】Novartis(Originator),Speedel(Licene)【药物名称】Aliskirenfumarate,CGP-60536(freeba),SPP-100B,SPP-100(freeba),CGP-60536B化学结构式(ChemicalStructure)：参考文献No.28958标题:Delta-amino-gamma-hydroxy-omega-arylalkanoicacidamideswithenzymees peciallyrenininhibitingactivities作者:G鰏chke,R.;Maibaum,J.K.;Schilling,W.;Stutz,S.;Rigollier,P.;Yama
guchi,Y.; Cohen,N.C.;Herold,P.(NovartisAG):EP0678500;EP0678503;JP1996053434;JP1 996081430;US5559111;US5627182;US5646143合成路线图解说明:Alkylationof3-hydroxy-4-methoxybenzylalcohol(I)with1-bromo-3-metho xypropane(II)givether(III).Subquentconversionofbenzylalcohol(III) intobromide(IV)iscarriedoutusingbromotrimetylsilane.Thechiralisovaler yloxazolidinone(V)isalkylatedwithbromide(IV)bymeansofLiHMDStoafford(V I),whichishydrolyzedtothe(S)-2-aryl-2-isopropylpropionicacid(VII)byme ansoflithiumperoxide.Thereductionofacid(VII)tothecorrespondingalcohol withNaBH4\/I2reagent,followedbytreatmentwithPPh3andNBS,providesbromid e(VIII).Alkylationofthechiraldimethoxydihydropyrazin(IX)withbromide(V III)produces(X).Furtherhydrolysisofthepyrazineringof(X)withHCl,follow edbyBocprotectionoftheresulting(S,S)-aminoester,yieldspound(XI).Reduc tionoftheestergroupof(XI)withDIBALgivesaldehyde(XII).Thispoundisconde ndwiththeGrignardreagent(XIII)toaffordthediastereomericmixtureofami noalcohols(XIV).Treatmentofmixture(XIV)with2,2-dimethoxypropane(XV)an dTsOHproducesamixtureofoxazolidines,fromwhichtherequired(S,S,S)-isome r(XVI)isisolatedbyflashchromatography.Hydrogenoliticdeprotectionofthe benzyletherof(XVI)givesalcohol(XVII).合成路线图解说
nevertheless
明:ThisalcoholisoxidizedtoaldehydewithNMMOandtetrapropylammoniumperru thenate(TPAP),andfurtheroxidizedtocarboxylicacid(XVIII)withKMnO4andte trabutylammoniumbromide(TBAB).Couplingof(XVIII)withaminoamide(XIX)bym eansofdiethylcyanophosphonateandTEAgives(XX).Finally,acidhydrolysisof theoxazolidineringandBocprotectinggroupsof(XX)furnishesthecorrespondi ngaminoalcohol,whichisfinallyconvertedtothehemifumaratesalt.参考文献No.47606标题:2-Alkyl-5-halogen-pent-4-enecarboxylicacidsandtheirproduction作者:Stutz,S.;Herold,P.(SpeedelPharmaInc.):WO0109079;WO0109083合成路线图解说明:Alternatively,thechiralazidointermediate(XXXIV)canalsobesynthesize dasfollows:Alkylationofoxazolidinone(V)with1-chloro-3-iodopropene(XLV III)bymeansofLiHMDSinTHFgivespound(XLIX),whichiscondendwiththemagne siumderivativeofthephenylpropylchloride(XXX)toyield,afterworkingup,am ide(L).Brominationof(L)withNBSandphosphoricacidaffordsthebromolactone (LI),whichbytreatmentwithNaN3intripropyleneglycol\/waterprovidestheaz idoderivative(XXXIV).参考文献No.58878标题:Preparationof(R)-2-alkyl-3-phenylpropionicacids作者:Herold,P.;Stutz,S.(SpeedelPharmaInc.):WO0202500合成路线图解说明:Thecondensationofbenzaldehyde(I)withethylisovalerate(II)bymeansofh exyllithiumandDIAinTHFgiorigen
vesthehydroxyester(III),whichisacylatedwithAc 2OandDMAPinTHFtoyieldtheacetoxyderivate(IV).Theeliminationreactionin( IV)bymeansoft-BuOKinTHFaffordstheunsaturatedester(V),whichishydrolyze dwithKOHinethanoltoprovidetheunsaturatedfreeacid(VI).Finally,thispoun dinantiolectivelyreducedwithH2oververalc.
初三家长会
departmentstorehiralRhcatalysts{[Rh(NBD)2BF4,[Rh(NBD)(OCOCF3)2],[Rh(NBD)Cl2],etc}tog ivethetargetintermediate2(R)-isopropyl-3-[4-methoxy-3-(3-methoxypropo xy)phenyl]propionicacid(VII).(escheme26758001a,intermediate(VII)).
致命译电英语教材下载参考文献No.58879标题:Processforthepreparationof(R)-2-alkyl-3-phenyl-1-propanols作者:Herold,P.;Stutz,S.;Spindler,F.(SpeedelPharmaInc.):WO0202487合成路线图解说明:Thecondensationofbenzaldehyde(I)withethylisovalerate(II)bymeansofh exyllithiumandDIAinTHFgivesthehydroxyester(III),whichisacylatedwithAc 2OandDMAPinTHFtoyieldtheacetoxyderivative(IV).Theeliminationreactioni n(IV)bymeansoft-BuOKinTHFaffordstheunsaturatedester(V),whichisreduced withdiisobutylaluminumhydrideintoluenetoprovidetheunsaturatedalcohol( VI).Finally,thispoundinantiolectivelyreducedwithH2overachiralbiph enylyldiphenylphosphinecatal
ystanda[Rh(norbornadiene)Cl]2catalystinto luenetogivethetargetintermediate2(R)-isopropyl-3-[4-methoxy-3-(3-meth oxypropoxy)phenyl]-1-propanol(VII).(escheme26758001d,intermediate(X XIX)).
