Escitalopram oxalate, (+)-(S)-Citalopram oxalate, MLD-55, Lu-26-054-0, Gaudium, Lexapro, Cipralex, -Drug Synthesis Database

【结构式】

【药物名称】Escitalopram oxalate, (+)-(S)-Citalopram oxalate, MLD-55, Lu-26-054-0, Gaudium, Lexapro, Cipralex

【化学名称】(+)-1(S)-[3-(Dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile oxalate

【CA登记号】219861-08-2, 128196-01-0 (free base)

【分子式】C₂₂H₂₃FN₂O₅

【分子量】414.43741

【开发单位】Lundbeck (Originator), Janssen-Cilag (Marketer), Forest (Licensee), Mochida (Licensee), Recordati (Licensee), Abbott (Comarketer)

【药理作用】Antidepressants, Anxiolytics, Generalized Anxiety Disorder (GAD), Treatment of, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT Reuptake Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

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.

参考文献中间体

【1】 Sorbera, L.A.; Martin, L.; Revel, L.; Castaner, J.; Escitalopram oxalate. Drugs Fut 2001, 26, 2, 115.
【2】 Boegesoe, K.P.; Perregaard, J. (H. Lundbeck A/S); New enantiomers and their isolation. AU 8936295; EP 0347066; JP 1990036177; JP 1999292867; US 4943590 .
【3】 Bogeso, K.P. (H. Lundbeck A/S); Novel intermediate and method for its preparation. US 4650884 .
【4】 Petersen, H.; Dancer, R.; Nielsen, O.; Rock, M.H.; Humble, R.E.; Christensen, T.V. (H. Lundbeck A/S); Process for the preparation of racemic citalopram and/or S- or R-citalopram by separation of a mixture of R- and S-citalopram. WO 0300672 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	37601	1-oxo-1,3-dihydro-2-benzofuran-5-carbonitrile	82104-74-3	C₉H₅NO₂	详情	详情
(II)	13643	4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide	352-13-6	C₆H₄BrFMg	详情	详情
(III)	44329			C₁₅H₉BrFMgNO₂	详情	详情
(IV)	44330			C₁₅H₉BrFMgNO₂	详情	详情
(V)	12587	Chloro[3-(dimethylamino)propyl]magnesium		C₅H₁₂ClMgN	详情	详情
(VI)	44331			C₂₀H₂₁BrClFMg₂N₂O₂	详情	详情
(VII)	44332	4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile		C₂₀H₂₃FN₂O₂	详情	详情
(VIII)	44333	3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride		C₁₀H₈ClF₃O₂	详情	详情
(IX)	44334	5-cyano-2-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]benzyl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate		C₃₀H₃₀F₄N₂O₄	详情	详情
(X)	44335	5-cyano-2-[(1S)-4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]benzyl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate		C₃₀H₃₀F₄N₂O₄	详情	详情
(XI)	44336	4-[(1S)-4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)benzonitrile		C₂₀H₂₃FN₂O₂	详情	详情

合成路线2

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.

参考文献中间体

【1】 Sorbera, L.A.; Martin, L.; Revel, L.; Castaner, J.; Escitalopram oxalate. Drugs Fut 2001, 26, 2, 115.
【2】 Dall'asta, L.; Casazza, U.; Petersen, H. (H. Lundbeck A/S); Method for the preparation of citalopram. WO 0023431 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	37594	1-oxo-1,3-dihydro-2-benzofuran-5-carboxylic acid		C₉H₆O₄	详情	详情
(XIII)	37595	1-oxo-1,3-dihydro-2-benzofuran-5-carbonyl chloride		C₉H₅ClO₃	详情	详情
(XIV)	21513	2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol	124-68-5	C₄H₁₁NO	详情	详情
(XV)	37596	N-(2-hydroxy-1,1-dimethylethyl)-1-oxo-1,3-dihydro-2-benzofuran-5-carboxamide		C₁₃H₁₅NO₄	详情	详情
(XVI)	37597	5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-benzofuran-1(3H)-one		C₁₃H₁₃NO₃	详情	详情
(XVII)	13643	4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide	352-13-6	C₆H₄BrFMg	详情	详情
(XVIII)	37598	[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl](4-fluorophenyl)methanone		C₁₉H₁₈FNO₃	详情	详情
(XIX)	12587	Chloro[3-(dimethylamino)propyl]magnesium		C₅H₁₂ClMgN	详情	详情
(XX)	37599	4-(dimethylamino)-1-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl]-1-(4-fluorophenyl)-1-butanol		C₂₄H₃₁FN₂O₃	详情	详情
(XXI)	44337	(1S)-4-(dimethylamino)-1-[4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl]-1-(4-fluorophenyl)-1-butanol		C₂₄H₃₁FN₂O₃	详情	详情
(XXII)	44338	N-[3-[(1S)-5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl]-N,N-dimethylamine; 3-[(1S)-5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]-N,N-dimethyl-1-propanamine		C₂₄H₂₉FN₂O₂	详情	详情

合成路线3

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.

参考文献中间体

【1】 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); Method for the preparation of escitalopram. WO 0306449 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	37605	5-bromo-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran; N-[3-[5-bromo-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl]-N,N-dimethylamine; 3-[5-bromo-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]-N,N-dimethyl-1-propanamine		C₁₉H₂₁BrFNO	详情	详情
(II)	60650	3-[(1R)-5-bromo-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]-N,N-dimethyl-1-propanamine; N-{3-[(1R)-5-bromo-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl}-N,N-dimethylamine		C₁₉H₂₁BrFNO	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)