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 Grignard condensation of 5-cyanophthalide (I) with 4-fluorophenylmagnesium bromide (II) in THF gives 1-(4-fluorophenyl)-1-hydroxy-1,3-dihydroisobenzofuran-5-carbonitrile bromomagnesium salt (III),which slowly rearranges to the benzophenone (IV).A new Grignard condensation of (IV) with 3-(dimethylamino)propylmagnesium chloride (V) in THF affords the expected bis(magnesium) salt (VI),which is hydrolyzed with acetic acid to provide the diol (VII) as a racemic mixture.Selective esterification of the primary alcohol of (VII) with (+)-3,3,3-trifluoro-2-methoxy-2-phenylacetyl chloride (VIII) gives the monoester (IX) as a mixture of diastereomers.This mixture is separated by HPLC and the desired diastereomer (X) is treated with potassium tert-butoxide in toluene.
参考文献标题:Novel intermediate and method for its preparation
文献作者:Bogeso,K.P.(H.Lundbeck A/S)
参考来源:US 4650884
合成路线:The Grignard condensation of 5-cyanophthalide (I) with 4-fluorophenylmagnesium bromide (II) in THF gives 1-(4-fluorophenyl)-1-hydroxy-1,3-dihydroisobenzofuran-5-carbonitrile bromomagnesium salt (III),which slowly rearranges to the benzophenone (IV).A new Grignard condensation of (IV) with 3-(dimethylamino)propylmagnesium chloride (V) in THF affords the expected bis(magnesium) salt (VI),which is hydrolyzed with acetic acid to provide the diol (VII) as a racemic mixture.Selective esterification of the primary alcohol of (VII) with (+)-3,3,3-trifluoro-2-methoxy-2-phenylacetyl chloride (VIII) gives the monoester (IX) as a mixture of diastereomers.This mixture is separated by HPLC and the desired diastereomer (X) is treated with potassium tert-butoxide in toluene.
参考文献标题:Process for the preparation of racemic citalopram and/or S- or R-citalopram by separation of a mixture of R- and S-citalopram
文献作者:Petersen,H.; Dancer,R.; Nielsen,O.; Rock,M.H.; Humble,R.E.; Christensen,T.V.(H.Lundbeck A/S)
参考来源:WO 0300672
合成路线:Racemic 5-bromo-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (I) is submitted to optical resolution by chiral chromatography to give the corresponding (S)-isomer (II),which is treated with Zn(CN)2 and Pd(PPh3)4 to afford the target Escitalopram.
参考文献标题:Method for the preparation of escitalopram
文献作者:Pedersen,H.; Petersen,H.; Lee,J.; Bech Sommer,M.; Nielsen,O.; Ahmadian,H.; Broesen,P.; Geiser,F.; Cox,G.; Dapremont,O.; Suteu,C.; Assenza,S.P.; Hariharan,S.; Nair,U.(H.Lundbeck A/S)
参考来源:WO 0306449
合成路线:The esterification of racemic 1-[4-bromo-2-(hydroxymethyl)phenyl]-4-(dimethylamino)-1-(4-fluorophenyl)-1-butanol (I) with (S)-2-(6-methoxynaphth-2-yl)propionyl chloride (II) by means of TEA and DMAP in THF gives the corresponding ester (III) as a diastereomeric mixture that is separated by chiral chromatography over Daicel AD,the desired diastereomer (IV) is easily isolated.Finally,this ester is hydrolyzed and simultaneously cyclized by means of NaH in DMF to provide the target intermediate (V).Other acyl chlorides such as (S)-2-(4-isobutylphenyl)propionyl chloride,(S)-O-acetylmandeloyl chloride,(S)-benzyloxycarbonylprolyl chloride,(S)-2-phenylbutyryl chloride,(S)-2-methoxy-2-phenylacetyl chloride or (S)-N-acetylalanine can also be used in the preceding sequence.
参考文献标题:Method for the preparation of escitalopram
文献作者:Petersen,H.; Ahmadian,H.(H.Lundbeck A/S)
参考来源:WO 0351861
合成路线:The Grignard condensation of 5-cyanophthalide (I) with 4-fluorophenylmagnesium bromide (II) in THF gives 1-(4-fluorophenyl)-1-hydroxy-1,3-dihydroisobenzofuran-5-carbonitrile bromomagnesium salt (III),which slowly rearranges to the benzophenone (IV).A new Grignard condensation of (IV) with 3-(dimethylamino)propylmagnesium chloride (V) in THF affords the expected bis(magnesium) salt (VI),which is hydrolyzed with acetic acid to provide the diol (VII) as a racemic mixture.Selective esterification of the primary alcohol of (VII) with (+)-3,3,3-trifluoro-2-methoxy-2-phenylacetyl chloride (VIII) gives the monoester (IX) as a mixture of diastereomers.This mixture is separated by HPLC and the desired diastereomer (X) is treated with potassium tert-butoxide in toluene.
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:Escitalopram oxalate
文献作者:Sorbera,L.A.; Mart韓,L.; Revel,L.; Castar,J.
参考来源:Drugs Fut 2001,26(2),115
产品链接: CAS No. 219861-08-2›› 产品链接: CAS No.128196-01-0››