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【结 构 式】 
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【分子编号】33229 【品名】5-bromophthalide; 5-bromo-2-benzofuran-1(3H)-one 【CA登记号】64169-34-2 |
【 分 子 式 】C8H5BrO2 【 分 子 量 】213.0305 【元素组成】C 45.11% H 2.37% Br 37.51% O 15.02% |
合成路线1
该中间体在本合成路线中的序号：(I)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.
| 【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)Two new methods for the preparation of citalopram have been developed: 1) The Grignard condensation of 5-bromoisobenzofuran-1(3H)-one (I) with 4-fluorophenylmagnesium bromide (II) in THF gives a nonisolated intermediate, which by a new Grignard condensation with 3-(dimethyiamino)propylmagnesium bromide (III) in THF yields N-[3-[5-bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]propyl-N,N-dimethylamine (IV). Finally, this compound is treated with Zn(CN) and Pd(PPh3)4 with or without NaCN in refluxing THF. 2) The Grignard condensation of 5-hydroxyisobenzofuran-1(3H)-one (V) with 4-fluorophenylmagnesium bromide (II) in THF gives a nonisolated intermediate, which by a new Grignard condensation with 3-(dimethylamino)propylmagnesium bromide (III) in THF yields N-[3-[5-hydroxy-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]propyl-N,N-dimethylamine (VI). The sulfonation of the hydroxy group of (VI) with trifluromethanesulfonyl chloride affords the triflate (VII), which is finally treated with NaCN, Cul and Pd(PPh3)4 in refluxing acetonitrile.
| 【1】 Rock, M.H.; Petersen, H.; Svane, H. (H. Lundbeck A/S); Method for the preparation of citalopram. WO 0013648 . |
| 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) | 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) | 37604 | bromo[3-(dimethylamino)propyl]magnesium | 120615-47-6 | C5H12BrMgN | 详情 | 详情 |
| (IV) | 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 | |
| (V) | 37606 | 5-hydroxy-2-benzofuran-1(3H)-one | C8H6O3 | 详情 | 详情 | |
| (VI) | 37607 | 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-ol | C19H22FNO2 | 详情 | 详情 | |
| (VII) | 37608 | 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-yl trifluoromethanesulfonate | C20H21F4NO4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXIII)Condensation of 5-bromophthalide (XXIII) with phenol (XIII) by means of K2CO3, CuBr and acetylacetone in DMF gives 5-phenoxyphthalide (XXIV), which is submitted to lactone ring opening using SOCl2, Ph3PCl2, B(OMe)3 and K2CO3 in refluxing toluene to yield 2-(chloro-methyl)-4-phenoxybenzoyl chloride (XXV). Esterification of acid chloride (XXV) with MeOH at 50 °C provides the methyl ester (XXVI), which is then condensed with methyl N-tosylglycinate (XXVII) in the presence of K2CO3 and NaI in DMF at 50 °C to afford the N-substituted amino ester (XXVIII). Cyclization of diester (XXVIII) with NaOMe in MeOH leads to methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (XXIX), which is submitted to Mannich reaction with bis(dimethylamino)methane (XXX) by means of AcOH at 57 °C to provide the 1-(dimethylaminomethyl)isoquinoline derivative (XXXI). Treatment of compound (XXXI) with Ac2O at 103 °C, followed by selective hydrolysis of the phenolic acetate with morpholine leads to methyl 1-(acetoxymethyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (XXXII). Hydrogenolysis of benzylic acetate (XXXII) in the presence of Pd/C and Na2CO3 in EtOAc yields methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboylate (XX), which is finally condensed with glycine (II) by means of NaOMe in MeOH at 110 °C .
| 【1】 Thompson, M.D., Park, J.M., Arend, M.P. (FibroGen, Inc.). Process for making isoquinoline compounds. CN 103435546; WO 2014014834. |
| 【2】 Witschi, C., Park, J.M., Thompson, M.D., Martinelli, M.J., Yeowell, D.A.,Arend, M.P. (FibroGen, Inc.). Crystalline forms of a prolyl hydroxylase inhibitor. WO 2014014835, US 2014024675. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 20436 | glycine | 56-40-6 | C2H5NO2 | 详情 | 详情 |
| (XIII) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (XX) | 67882 | methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate | C18H15NO4 | 详情 | 详情 | |
| (XXIII) | 33229 | 5-bromophthalide; 5-bromo-2-benzofuran-1(3H)-one | 64169-34-2 | C8H5BrO2 | 详情 | 详情 |
| (XXIV) | 67885 | 5-phenoxyphthalide | 57830-14-5 | C14H10O3 | 详情 | 详情 |
| (XXV) | 67886 | 2-(chloromethyl)-4-phenoxybenzoyl chloride | C14H10Cl2O2 | 详情 | 详情 | |
| (XXVI) | 67887 | methyl 2-(chloromethyl)-4-phenoxybenzoate | C15H13ClO3 | 详情 | 详情 | |
| (XXVII) | 57744 | methyl 2-{[(4-methylphenyl)sulfonyl]amino}acetate | 2645-02-5 | C10H13NO4S | 详情 | 详情 |
| (XXVIII) | 67888 | methyl 2-((N-(2-methoxy-2-oxoethyl)-4-methylphenylsulfonamido)methyl)-4-phenoxybenzoate | C25H25NO7S | 详情 | 详情 | |
| (XXIX) | 67889 | methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate | C17H13NO4 | 详情 | 详情 | |
| (XXX) | 14349 | N,N,N,N-tetramethylmethanediamine; tetramethylmethylenediamine;bis(dimethylamino)methane; N-[(dimethylamino)methyl]-N,N-dimethylamine | 51-80-9 | C5H14N2 | 详情 | 详情 |
| (XXXI) | 67890 | methyl 1-((dimethylamino)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate | C20H20N2O4 | 详情 | 详情 | |
| (XXXII) | 67891 | methyl 1-(acetoxymethyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate | C20H17NO6 | 详情 | 详情 |