SCH-59884

Chemical Name: 4-(Phosphonooxy)butyric acid 2(S)-[4-[4-[4-[4-[5(R)-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3(R)-ylmethoxy]phenyl]piperazin-1-yl]phenyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-1(S)-methylbutyl ester
CAS No. 200346-83-4
项目整合开发状态: Preclinical
项目研究机构: Schering-Plough (Originator)
合成路线:2-Chloro-2',4'-difluoroacetophenone (I) was converted to acetate ester (II) by displacement of the chlorine with sodium acetate in the presence of NaI.Subsequent Wittig reaction of (II) with methylenetriphenylphosphorane produced the allyl ester (III),which was hydrolyzed to alcohol (IV) with KOH in aqueous dioxan.Asymmeytric Sharpless epoxidation of (IV) with tert-butyl hydroperoxide in the presence of L-(+)-diethyl tartrate and titanium tetraisopropoxide furnished the (S)-epoxide (V).Ring opening of (V) with the sodium salt of 1,2,4-triazole (VI) gave the triazolyl diol (VII).After conversion of the primary hydroxyl group to tosylate (VIII),ring closure in the presence of NaH generated epoxide (IX).Condensation of (IX) with diethyl malonate afforded a mixture of diastereomeric butyrolactones (Xa,Xb),which was converted to triol (XI) by reduction with lithium borohydride.Treatment of (XI) with p-toluenesulfonyl chloride produced ditosylate (XII).Ring closure of (XII) employing NaH in boiling toluene gave rise to a diastereomeric mixture of tetrahydrofurans,from which the required cis isomer (XIII) was isolated by column chromatography.

合成路线:Triol (XI) was enantioselectively acetylated to the (R)-monoacetate ester (XIV) employing EtOAc and porcine pancreatic lipase.Protection of the primary hydroxyl group of (XIV) with dihydropyran produced the tetrahydropyranyl ether (XV).After hydrolysis of the acetate ester of (XV) with KOH,tosylation of the resulting alcohol (XVI) furnished (XVII),which was subsequently cyclized to the cis tetrahydrofuran derivative (XVIII) in the presence of NaH.Acid deprotection of the tetrahydropyranyl ether of (XVIII) gave alcohol (XIX),which was then converted to tosylate (XIII).

合成路线:Coupling of tosylate (XIII) with the sodium salt of phenol (XX) produced ether (XXI).The nitro group of (XXI) was then reduced to amine (XXII) by hydrogenation over Pt/C.Subsequent condensation of (XXII) with phenyl chloroformate in pyridine afforded the phenyl carbamate (XXIII),which was reacted with hydrazine to yield the semicarbazide derivative (XXIV).Ring closure of (XXIV) with formamidine acetate then provided triazolone (XXV).

合成路线:Methyl (S)-lactate (XXVI) was protected as the benzyloxymethyl ether (XXVII) and subsequently reduced to aldehyde (XXVIII) with DIBAL in toluene at -78 C.Addition of ethylmagnesium bromide to this aldehyde (XXVIII) produced a diastereomeric mixture of carbinols.The required (2S,3R) isomer (XXIX) was isolated by column chromatography and then converted to brosylate ester (XXX) by reaction with 4-bromobenzenesulfonyl chloride.Nucleophilic displacement of the brosylate group of (XXX) by triazolone (XXV) produced the N-alkylated triazolone (XXXI).Then,acid cleavage of the benzyloxymethyl protec-ting group of (XXXI) provided alcohol (XXXII).

合成路线:In an alternative synthesis of compound (XXXII),methyl (S)-lactate (XXXIII) was converted to amide (XXXIV) by treatment with pyrrolidine,and then protected as the benzyl ether (XXXV).Reduction of (XXXV) by means of sodium bis(methoxyethoxy)aluminum hydride produced aldehyde (XXXVI).Condensation of (XXXVI) with formic hydrazide produced the formyl hydrazone (XXXVII),to which was added ethylmagnesium bromide affording a mixture of diastereoisomeric hydrazides.Separation by column chromatography provided the required (S,S) isomer (XXXVIII).Cyclization of (XXXVIII) with the phenyl carbamate (XXIII) in the presence of DBU furnished the triazolone (XXXIX).This was deprotected by hydrogenation in the presence of Pd/C and formic acid to produce compound (XXXII)