A new method for the preparation of citalopram has been reported: The Grignard reaction of 1-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (I) with 4-fluorophenylmagnesium bromide (II) in THF gives the hydroxymethyl benzophenone (III), which is esterified with pivaloyl chloride in ethyl ether/THF to yield the ester (V). A new Grignard reaction of (V) with 3-(dimethylamino)propylmagnesium bromide in THF affords citalopram.
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.
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.
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.
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.
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.
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.
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).
The condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (I) with N,N-dimethyl-2-propenamide (II) by means of LDA in THF gives the addition compound (III), which is then reduced to the target citalopram by means of Red-Al in toluene.
The reduction of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (I) with LiAlH4 in THF/ethyl ether gives 5-(aminomethyl)-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (II), which is finally oxidized with Cu2Cl2 and oxygen in hot pyridine, or with K2S2O8 and NiSO4 in dichloromethane/water to yield the target compound.
The reaction of 5-carboxyphthalide (I) with 4-fluorophenylmagnesium bromide (II) in THF gives the lactol (III), which is treated with 3-(dimethylamino)propylmagnesium chloride in the same solvent to yield the dihydroxylated intermediate (V). The cyclization of (V) by means of conc. HCl affords the isobenzofuran derivative (VI), which is finally treated with sulfamide and thionyl chloride in sulfolane at 130 C in order to convert the carboxy group of (VI) into the target 5-cyano group of citalopram.
The reaction of 5-chloro-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (I) with NaCN catalyzed by NiCl2, PPh3 and Zn in refluxing acetonitrile gives the target citalopram.
The intermediate 1-(4-fluorophenyl)-1-(3-hydroxypropyl)-1,3-dihydroisobenzofuran-5-carbonitrile (IV) has been obtained by three related ways: 1. The condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (I) with 3-(tert-butyldimethylsilyloxy)propyl bromide (II) by means of LDA in THF gives 1-[3-(tert-butyldimethylsilyloxy)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (III), which is deprotected with HCl in methanol to yield the hydroxypropyl intermediate (IV). 2. The condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (I) with 3-(benzyloxy)propyl bromide (V) by means of LDA in THF gives 1-[3-(benzyloxy)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (VI), which is deprotected by treatment with 1,4-cyclohexadiene over Pd/C in ethanol to yield the hydroxypropyl intermediate (IV). 3. The condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (I) with 3-(tetrahydropyranyloxy)propyl bromide (VII) by means of LDA in THF gives 1-(4-fluorophenyl)-1-[3-(tetrahydropyranyloxy)propyl]-1,3-dihydroisobenzofuran-5-carbonitrile (VIII), which is deprotected with Ts-OH in methanol to yield the hydroxypropyl intermediate (IV). The reaction of the intermediate (IV) with Ts-Cl and TEA in toluene gives the corresponding tosylate (IX), which is finally treated with dimethylamine in hot DMF to afford the target citalopram. The reaction of the intermediate (IV) with Ms-Cl and TEA in THF gives the corresponding mesylate (X), which is finally treated with dimethylamine in hot ethanol/THF to afford the target citalopram. Alternatively, the reaction of mesylate (X) with NaN3 in hot DMF gives the corresponding azido compound (XI), which is hydrogenated with H2 over Pd/C in EtOH to yield the 3-aminopropyl derivative (XII). Finally, this compound is methylated by means of formaldehyde and NaCNBH3 in methanol to provide the target citalopram.
The reaction of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-5-iodo-1,3-dihydroisobenzofuran (I) with CuCN and pyridine in DMF at 140 C gives the target citalopram.
This compound has been obtained by several related ways. 1.- The condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5- carbonitrile (I) with 3-chloropropyl tosylate (II) by means of LDA in THF gives 1-(4-fluorophenyl)-1-(3-tosyloxypropyl)-1,3-dihydroisobenzofuran-5-carbonitrile (III), which is then condensed with dimethylamine in hot DMF to yield the target citalopram. 2.- The condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5- carbonitrile (I) with 3-chloropropyl mesylate (IV) by means of LDA in THF gives 1-(4-fluorophenyl)-1-(3-mesyloxypropyl)-1,3-dihydroisobenzofuran-5- carbonitrile (V), which is then condensed with sodium azide in hot DMF to yield the corresponding azido derivative (VI). The reduction of (VI) with H2 over Pd/C in ethanol affords the 3-aminopropyl derivative (VII), which is finally reductively methylated with formaldehyde and NaBH3CN in methanol to provide the target citalopram. 3.- The reaction of mesylate (V) with methylamine in THF gives the corresponding methylaminopropyl derivative (VIII), which is finally methylated by means of HCHO in refluxing HCOOH to yield the target citalopram. 4.- The direct condensation of mesylate (V) with dimethylamine in hot ethanol/THF also gives the target citalopram.