合成路线:Two new methods for the preparation of citalopram have been developed:1) The Grignard condensation of 5-bromoisobenzofuran-1(3H)-one (I) with 4-fluorophenylmagnesium bromide (II) in THF gives a nonisolated intermediate,which by a new Grignard condensation with 3-(dimethyiamino)propylmagnesium bromide (III) in THF yields N-[3-[5-bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]propyl-N,N-dimethylamine (IV).Finally,this compound is treated with Zn(CN) and Pd(PPh3)4 with or without NaCN in refluxing THF.2) The Grignard condensation of 5-hydroxyisobenzofuran-1(3H)-one (V) with 4-fluorophenylmagnesium bromide (II) in THF gives a nonisolated intermediate,which by a new Grignard condensation with 3-(dimethylamino)propylmagnesium bromide (III) in THF yields N-[3-[5-hydroxy-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]propyl-N,N-dimethylamine (VI).The sulfonation of the hydroxy group of (VI) with trifluromethanesulfonyl chloride affords the triflate (VII),which is finally treated with NaCN,Cul and Pd(PPh3)4 in refluxing acetonitrile.
参考文献标题:Method for the preparation of citalopram
文献作者:Rock,M.H.; Petersen,H.; Svane,H.(H.Lundbeck A/S)
参考来源:WO 0013648
合成路线:A new method for the preparation of citalopram has been developed: The chlorination of 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (I) with refluxing SOCl2 gives the acyl chloride (II),which is condensed with 2-amino-2-methyl-1-propanol (III) in THF yielding the corresponding amide (IV).The cyclization of (IV) by means of SOCl2 affords the oxazoline (V),which is treated with 4-fluorophenylmagnesium bromide (VI) in THF giving the benzophenone (VII).This compound (VII),without isolation,is treated with 3-(dimethylamino)propylmagnesium chloride (VIII) in the same solvent,providing the cabinol (IX),which is cyclized by means of methanesulfonyl chloride and Et3N in CH2Cl2 yielding the isobenzofuran (X).Finally,this compound is treated with POCl3 in refluxing pyridine to generate the 5-cyano substituent of citalopram.
合成路线:The chlorination of 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (XII) with refluxing SOCl2 gives the acyl chloride (XIII),which is condensed with 2-amino-2-methyl-1-propanol (XIV) in THF to yield the corresponding amide (XV).The cyclization of (XV) by means of SOCl2 affords the oxazoline (XVI),which is treated with 4-fluorophenylmagnesium bromide (XVII) in THF to give the benzophenone (XVIII).This compound (XVIII),without isolation,is treated with 3-(dimethylamino)propylmagnesium chloride (XIX) in the same solvent to provide the carbinol (XX),which is submitted to optical resolution with (+)- or (-)-tartaric acid,or (+)- or (-)-camphor-10-sulfonic acid (CSA) to give the desired (S)-enantiomer (XXI).Cyclization of (XXI) by means of methanesulfonyl chloride and TEA in dichloromethane yields the chiral isobenzofuran (XXII),which is finally treated with POCl3 in refluxing pyridine.
参考文献标题:Method for the preparation of citalopram
文献作者:Dall'asta,L.; Casazza,U.; Petersen,H.(H.Lundbeck A/S)
参考来源:WO 0023431
合成路线:The reaction of 5-bromophthalide (I) with 4-fluorophenylmagnesium bromide (II) in ether gives 4-bromo-4'-fluoro-2-(hydroxymethyl)benzophenone (III),which is reduced with LiAlH4 or NaBH4 in ether to afford 4-bromo-4'-fluoro-2-(hydroxymethyl)benzhydrol (IV).The cyclization of (IV) with 60% H3PO4 or TsOH or H2SO4 at 100 C yields 5-bromo-1-(4-fluoropheny)phthalan (V),which by reaction with cuprous cyanide in refluxing DMF is converted into 1-(4-fluorophenyl)-5-phtalancarbonitrile (VI).Finally,this compound is condensed with 3-(dimethylamino)propyl chloride (A) by means of NaH in hot DMSO.
参考文献标题:Anti-depressive substituted 1-dimethylaminopropyl-1-phenyl phthalans
文献作者:Bogeso,K.P.; Toft,A.S.(Kefalas A/S)
参考来源:DE 2657013; FR 2338271; GB 1526331; JP 52105162; US 4136193
合成路线:The Grignard reaction of 5-aminophthalide (I) with 4-fluorophenylmagnesium bromide (II) in THF gives the methanone (III),which is submitted to a new Grignard reaction with 3-(dimethylamino)propylmagnesium chloride (IV) in the same solvent to yield 1-[4-amino-2-(hydroxymethyl)phenyl]-4-(dimethylamino)-1-(4-fluorophenyl)-1-butanol (V).The cyclization of (V) by heating in H3PO4 affords the isobenzofuran derivative (VI),which is finally submitted to diazotation with NaNO2 and H2SO4 ,followed by reaction with NaCN.
参考文献标题:Method for the preparation of citalopram
文献作者:Bregnedal,P.; Petersen,H.; Bogeso,K.P.(H.Lundbeck A/S)
参考来源:US 6258842; WO 9819512
合成路线:The reaction of terephthalic acid (I) with trioxane and oleum at 140-150 C gives 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (II),which is treated with SOCl2 in refluxing toluene to yield the acyl chloride (III).The condensation of (III) with 2-hydroxy-1,1-dimethylethylamine (IV) in the same solvent affords the amide (V),which is cyclized by means of SOCl2 in dichloromethane to provide the oxazoline (VI).The Grignard condensation of (VI) with 4-fluorophenylmagnesium bromide (VII) in THF gives the benzophenone (VIII),which is submitted to a new Grignard condensation with 3-(dimethylamino)propylmagnesium bromide (IX) in the same solvent to yield the diol (X).Finally,this compound is treated with POCl3 or SOCl2 and POCl3 in hot pyridine to afford the target citalopram.Alternatively,the cleavage of the oxazoline ring of (X) with H2SO4 and then with NaOH gives the sodium carboxylate (XI),which is treated with SOCl2 in dichloromethane to yield the corresponding acyl chloride (XII).The reaction of (XII) with dry ammonia in the same solvent affords the carboxamide (XIII),which is finally dehydrated with POCl3 in refluxing acetonitrile to provide the target citalopram.
参考文献标题:Process for the preparation of citalopram
文献作者:Greenwood,A.K.; McHattie,D.; Rechka,J.A.; Hedger,P.C.M.; Gamble,M.P.(Resolution Chemicals Ltd.)
参考来源:WO 0166536
合成路线:The condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (I) with N-(2,3-epoxypropyl)-N,N-dimethylamine (II) by means of LDA in THF gives the addition compound (III),which is then reduced to the target citalopram by means of H2 over Pd/C,Pt/C or Rh/C.Alternatively,the condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (I) with 3-(dimethylamino)propionaldehyde (IV) by means of LDA in THF also gives the intermediate addition compound (III).
参考文献标题:Method for the preparation of citalopram
文献作者:Petersen,H.(H.Lundbeck A/S)
参考来源:WO 0168628
产品链接: CAS No. 59729-32-7›› 产品链接: CAS No.59729-33-8››