1-(4-fluorophenyl)-5-phtalancarbonitrile; 1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile -Drug Synthesis Database

【结构式】

【分子编号】33233

【品名】1-(4-fluorophenyl)-5-phtalancarbonitrile; 1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile

【CA登记号】

【分子式】C₁₅H₁₀FNO

【分子量】239.2489432

【元素组成】C 75.3% H 4.21% F 7.94% N 5.85% O 6.69%

与该中间体有关的原料药合成路线共 5 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

该中间体在本合成路线中的序号：(VI)

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.

参考文献中间体

合成目标

【1】 Bigler, A.J.; et al.; Quantitative structure-activity relationships in a series of selective 5-HT uptake inhibitors. Eur J Med Chem - Chim Ther 1977, 12, 3, 289-295.
【2】 Bogeso, K.P.; Toft, A.S. (Kefalas A/S); Anti-depressive substituted 1-dimethylaminopropyl-1-phenyl phthalans. DE 2657013; FR 2338271; GB 1526331; JP 52105162; US 4136193 .
【3】 Muddasani, P.R.; Nannapaneni, W.C. (Natco Pharma Ltd.); Process for the preparation of high purity citalopram and its pharmaceutically acceptable salts. WO 0416602 .
【4】 Roberts, P.J.; Castaner, J.; Serradell, M.N.; Blancafort, P.; Citalopram. Drugs Fut 1979, 4, 6, 407.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	24581	3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine	5407-04-5	C₅H₁₂ClN	详情	详情
(I)	33229	5-bromophthalide; 5-bromo-2-benzofuran-1(3H)-one	64169-34-2	C₈H₅BrO₂	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)	33230	[4-Bromo-2-(hydroxymethyl)phenyl](4-fluorophenyl)methanone; 4-Bromo-4'-fluoro-2-(hydroxymethyl)benzophenone		C₁₄H₁₀BrFO₂	详情	详情
(IV)	33231	4-bromo-4'-fluoro-2-(hydroxymethyl)benzhydrol; [4-bromo-2-(hydroxymethyl)phenyl](4-fluorophenyl)methanol		C₁₄H₁₂BrFO₂	详情	详情
(V)	33232	5-bromo-1-(4-fluoropheny)phthalan; 5-bromo-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran		C₁₄H₁₀BrFO	详情	详情
(VI)	33233	1-(4-fluorophenyl)-5-phtalancarbonitrile; 1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile		C₁₅H₁₀FNO	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 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.

参考文献中间体

合成目标

【1】 Petersen, H. (H. Lundbeck A/S); Method for the preparation of citalopram. WO 0168630 .

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)	33233	1-(4-fluorophenyl)-5-phtalancarbonitrile; 1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile		C₁₅H₁₀FNO	详情	详情
(II)	11727	N,N-Dimethylacrylamide; N,N-Dimethyl-2-propenamide	2680-03-7	C₅H₉NO	详情	详情
(III)	55287	3-[5-cyano-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]-N,N-dimethylpropanamide		C₂₀H₁₉FN₂O₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

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).

参考文献中间体

合成目标

【1】 Petersen, H. (H. Lundbeck A/S); Method for the preparation of citalopram. WO 0168628 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	33233	1-(4-fluorophenyl)-5-phtalancarbonitrile; 1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile	C₁₅H₁₀FNO	详情	详情
(II)	55288	cyclopropyl-N,N-dimethylmethanamine; N-(cyclopropylmethyl)-N,N-dimethylamine	C₆H₁₃N	详情	详情
(III)	55290	1-[(E)-3-(dimethylamino)-1-propenyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile	C₂₀H₁₉FN₂O	详情	详情
(IV)	55289	3-(dimethylamino)propanal	C₅H₁₁NO	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

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.

参考文献中间体

合成目标

【1】 Petersen, H.; Rock, M.H.; Ahmadian, H. (H. Lundbeck A/S); Method for the preparation of citalopram. US 6420574 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	33233	1-(4-fluorophenyl)-5-phtalancarbonitrile; 1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile	C₁₅H₁₀FNO	详情	详情
(II)	30994	3-bromopropyl tert-butyl(dimethyl)silyl ether; (3-bromopropoxy)(tert-butyl)dimethylsilane	C₉H₂₁BrOSi	详情	详情
(III)	55297	1-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile	C₂₄H₃₀FNO₂Si	详情	详情
(IV)	55298	1-(4-fluorophenyl)-1-(3-hydroxypropyl)-1,3-dihydro-2-benzofuran-5-carbonitrile	C₁₈H₁₆FNO₂	详情	详情
(V)	28080	1-[(3-bromopropoxy)methyl]benzene	C₁₀H₁₃BrO	详情	详情
(VI)	55299	1-[3-(benzyloxy)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile	C₂₅H₂₂FNO₂	详情	详情
(VII)	42252	3-bromopropyl tetrahydro-2H-pyran-2-yl ether; 2-(3-bromopropoxy)tetrahydro-2H-pyran	C₈H₁₅BrO₂	详情	详情
(VIII)	55300	1-(4-fluorophenyl)-1-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-1,3-dihydro-2-benzofuran-5-carbonitrile	C₂₃H₂₄FNO₃	详情	详情
(IX)	55301	3-[5-cyano-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl 4-methylbenzenesulfonate	C₂₅H₂₂FNO₄S	详情	详情
(X)	55302	3-[5-cyano-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl methanesulfonate	C₁₉H₁₈FNO₄S	详情	详情
(XI)	55303	1-(3-azidopropyl)-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile	C₁₈H₁₅FN₄O	详情	详情
(XII)	55304	1-(3-aminopropyl)-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile	C₁₈H₁₇FN₂O	详情	详情

合成路线5

该中间体在本合成路线中的序号：(I)

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.

参考文献中间体

合成目标

【1】 Rock, M.H.; Ahmadian, H. (H. Lundbeck A/S); Method for the preparation of citalopram. CA 2401374; EP 1263750; FR 2805814; JP 2003519692; US 2003092761; WO 0151478 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	33233	1-(4-fluorophenyl)-5-phtalancarbonitrile; 1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile	C₁₅H₁₀FNO	详情	详情
(II)	55581	3-Chloropropyl-p-toluenesulfonate	C₁₀H₁₃ClO₃S	详情	详情
(III)	55301	3-[5-cyano-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl 4-methylbenzenesulfonate	C₂₅H₂₂FNO₄S	详情	详情
(IV)	64194	3-chloropropyl methanesulfonate	C₄H₉ClO₃S	详情	详情
(V)	55302	3-[5-cyano-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-1-yl]propyl methanesulfonate	C₁₉H₁₈FNO₄S	详情	详情
(VI)	55303	1-(3-azidopropyl)-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile	C₁₈H₁₅FN₄O	详情	详情
(VII)	55304	1-(3-aminopropyl)-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile	C₁₈H₁₇FN₂O	详情	详情
(VIII)	64195	1-(4-fluorophenyl)-1-[3-(methylamino)propyl]-1,3-dihydro-2-benzofuran-5-carbonitrile	C₁₉H₁₉FN₂O	详情	详情

Extended Information