1-oxo-1,3-dihydro-2-benzofuran-5-carbonitrile -Drug Synthesis Database

【结构式】

【分子编号】37601

【品名】1-oxo-1,3-dihydro-2-benzofuran-5-carbonitrile

【CA登记号】82104-74-3

【分子式】C₉H₅NO₂

【分子量】159.14424

【元素组成】C 67.93% H 3.17% N 8.8% O 20.11%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

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.

参考文献中间体

合成目标

【1】 Ellegaard, P.; Petersen, H.; Rock, M.H. (H. Lundbeck A/S); Method for the preparation of citalopram. WO 0012044 .

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)	37602	4-(4-fluorobenzoyl)-3-(hydroxymethyl)benzonitrile		C₁₅H₁₀FNO₂	详情	详情
(IV)	13597	2,2-Dimethylpropanoyl chloride; Pivaloyl chloride	3282-30-2	C₅H₉ClO	详情	详情
(V)	37603	5-cyano-2-(4-fluorobenzoyl)benzyl pivalate		C₂₀H₁₈FNO₃	详情	详情
(VI)	37604	bromo[3-(dimethylamino)propyl]magnesium	120615-47-6	C₅H₁₂BrMgN	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

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

合成目标

【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

Extended Information