【药物名称】Escitalopram oxalate, (+)-(S)-Citalopram oxalate, MLD-55, Lu-26-054-0, Entact, Gaudium, Lexapro, Cipralex
化学结构式(Chemical Structure):
参考文献No.11683
标题:New enantiomers and their isolation
作者:Boegesoe, K.P.; Perregaard, J. (H. Lundbeck A/S)
来源:AU 8936295; EP 0347066; JP 1990036177; JP 1999292867; US 4943590
合成路线图解说明:

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No.43184
标题:Method for the preparation of citalopram
作者:Dall'asta, L.; Casazza, U.; Petersen, H. (H. Lundbeck A/S)
来源:WO 0023431
合成路线图解说明:

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.

合成路线图解说明:

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No.47461
标题:Novel intermediate and method for its preparation
作者:Bogeso, K.P. (H. Lundbeck A/S)
来源:US 4650884
合成路线图解说明:

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No.59812
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
作者:Petersen, H.; Dancer, R.; Nielsen, O.; Rock, M.H.; Humble, R.E.; Christensen, T.V. (H. Lundbeck A/S)
来源:WO 0300672
合成路线图解说明:

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No.60183
标题:Method for the preparation of escitalopram
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)
来源:WO 0306449
合成路线图解说明:

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No.63214
标题:Method for the preparation of escitalopram
作者:Petersen, H.; Ahmadian, H. (H. Lundbeck A/S)
来源:WO 0351861
合成路线图解说明:

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No.610572
标题:Escitalopram oxalate
作者:Sorbera, L.A.; Mart韓, L.; Revel, L.; Casta馿r, J.
来源:Drugs Fut 2001,26(2),115
合成路线图解说明:

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.

合成路线图解说明:

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.

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