合成路线:6) The reaction of 5-(4-fluorophenyl)-4-pentenoic acid (XXVI) with oxalyl chloride gives the acyl chloride (XXVII),which is condensed with the chiral oxazolidinone (XXI) by means of DMAP and DIEA in dichloromethane,yielding the acyloxazolidinone (XXVIII).Condensation of (XXVIII) with the benzylideneimine (II) by means of TiCl4 affords adduct (XXIX),which is cyclized to the chiral azetidinone (XXX).The oxidation of the double bond of (XXX) with benzoquinone and HClO4 catalyzed by Pd(OAc)2 in acetonitrile/water provides the previously reported trans-(3R,4S)-azetidinone (XX),which is worked up to give azetimibe as described before.
参考文献标题:Process for preparing 1-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(S)-(4-hydroxyphenyl)-2-azetidinone
文献作者:Shankar,B.B.(Schering Corp.)
参考来源:US 5856473; WO 9716424
合成路线:1) The cyclization of 4(S)-hydroxytetrahydrofuran-2-one (I) with the benzylideneimine derivative (II) by means of LDA gives the trans-azetidinone (III),which is separated from its cis-isomer by crystallization.The oxidation of (III) with NaIO4 in acetonitrile yields the carbaldehyde (IV),which is condensed with the silylated enol ether (V),prepared from 4'-fluoroacetophenone (VI),Li and TMSCl,to afford compound (VII).The dehydration of (VII) by means of TsOH gives the enone (VIII),which is hydrogenated and debenzylated with H2 over Pd/C in ethanol,providing the saturated ketone (IX).Finally,this compound is enantioselectively reduced with borane and the chiral catalyst (R)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (CBS).2) Alternatively,the reduction of enone (VIII) with H2 over RhCl(PPh3)3 in dichloromethane gives the benzylated saturated ketone (X),which is enantioselectively reduced with borane and CBS,yielding the benzylated alcohol (XI).Finally,this compound is debenzylated with H2 over Pd/C in ethanol.
参考文献标题:3-Hydroxy gamma-lactone based enantioselective synthesis of azetidinones
文献作者:Steinman,M.; Schumacher,D.P.; Chen,X.; Wu,G.-Z.; Wong,Y.-S.(Schering Corp.)
参考来源:WO 9745406
合成路线:4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII),which is cyclized with the benzylideneimine (II) by means of TiCl4,titanium isopropoxide and TBAF in dichloromethane,yielding trans-(3R,4S)-azetidinone (XXIII).This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analogue (XVI) but without optical resolution.5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column),microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV),the compound also obtained by hydrolysis of (XXIII) with LiOH.This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV),which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX).Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI).
参考文献标题:Resolution of trans-2-(alkoxycarbonylethyl)-lactams useful in the synthesis of 1-(4-fluoro-phenyl)-3(R)-[(S)-hydroxy-3-(4-fluorophenyl)-propyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone
文献作者:Homann,M.J.; Morgan,W.B.(Schering Corp.)
参考来源:US 5919672
合成路线:The activation of 5-(4-fluorophenyl)-5-oxopentanoic acid (I) with pivaloyl chloride (II) gives the mixed anhydride (III),which is condensed with the chiral oxazolidinone (IV) by means of DMAP to yield the acylated oxazolidine (V) (1).The asymmetric reduction of (V) by means of BH3/Me2S catalyzed by the chiral boron catalyst (VI) affords the chiral alcohol (VII) (1-3),which is condensed with the imine (VIII) by means of Tms-Cl,DIEA and TiCl4 to provide the adduct (IX).The cyclization of (IX) by means of bis(trimethylsilyl)acetamide and TBAF gives the protected azetidinone (X),which is finally desilylated by means of sulfuric acid in isopropanol
参考文献标题:Enantioselective synthesis of azetidinone intermediate cpds.
文献作者:Thiruvengadam,T.K.; Tann,C.-H.; Fu,X.; McAllister,T.L.(Schering Corp.)
参考来源:US 2002193607; WO 0279174
合成路线:Treatment of acid chloride (I) with tributylamine generated the corresponding ketene,which was cyclocondensed to imine (II) to produce the racemic trans b-lactam (III).Resolution of (III) into enantiomers was then achieved by preparative HPLC on a Chiralcel OD column.Subsequent saponification of the desired enantiomer with methanolic LiOH afforded acid (IV),which was converted to acid chloride (V) upon treatment with oxalyl chloride.Further Pd-mediated coupling of (V) with the arylzinc reagent (VI) provided ketone (VII).Then,carbonyl reduction with BH3-Me2S,followed by chromatographic separation of the isomers furnished alcohol (VIII),which was finally deprotected by hydrogenolysis over Pd/C to afford the target phenol.
合成路线:4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII),which is cyclized with the benzylideneimine (II) by means of TiCl4,titanium isopropoxide and TBAF in dichloromethane,yielding trans-(3R,4S)-azetidinone (XXIII).This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analogue (XVI) but without optical resolution.5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column),microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV),the compound also obtained by hydrolysis of (XXIII) with LiOH.This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV),which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX).Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI).
参考文献标题:Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed,potent,orally active inhibitor of cholesterol absorption
文献作者:Rosenblum,S.B.; Huynh,T.; Afonso,A.; Davis,H.R.Jr.; Yumibe,N.; Clader,J.W.; Burnett,D.A.
参考来源:J Med Chem 1998,41(6),973
合成路线:3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII),which is condensed with 4-fluoroaniline (XIV) in isopropanol,yielding the imine (II).Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI),which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII).The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII),which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX).The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI),which is finally debenzylated as before with H2 over Pd/C in ethanol.
参考文献标题:2-Azetidinone cholesterol absorption inhibitors: Increased potency by substitution of the C-4 phenyl ring
文献作者:Vaccaro,W.D.; Sher,R.; Davis,H.R.Jr.
参考来源:Bioorg Med Chem 1998,6(9),1429
产品链接: CAS No. 163222-33-1›› 产品链接: CAS No.163380-16-3››