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【结 构 式】 
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【分子编号】54025 【品名】1,4-Benzenedicarboxylic acid; Benzene-1,4-dicarboxylic acid; p-Benzenedicarboxylic acid; p-Phthalic acid; Terephthalic acid 【CA登记号】100-21-0 |
【 分 子 式 】C8H6O4 【 分 子 量 】166.13324 【元素组成】C 57.84% H 3.64% O 38.52% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of terephthalic acid (I) with trioxane and oleum at 140-150 C gives 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (II), which is treated with SOCl2 in refluxing toluene to yield the acyl chloride (III). The condensation of (III) with 2-hydroxy-1,1-dimethylethylamine (IV) in the same solvent affords the amide (V), which is cyclized by means of SOCl2 in dichloromethane to provide the oxazoline (VI). The Grignard condensation of (VI) with 4-fluorophenylmagnesium bromide (VII) in THF gives the benzophenone (VIII), which is submitted to a new Grignard condensation with 3-(dimethylamino)propylmagnesium bromide (IX) in the same solvent to yield the diol (X). Finally, this compound is treated with POCl3 or SOCl2 and POCl3 in hot pyridine to afford the target citalopram. Alternatively, the cleavage of the oxazoline ring of (X) with H2SO4 and then with NaOH gives the sodium carboxylate (XI), which is treated with SOCl2 in dichloromethane to yield the corresponding acyl chloride (XII). The reaction of (XII) with dry ammonia in the same solvent affords the carboxamide (XIII), which is finally dehydrated with POCl3 in refluxing acetonitrile to provide the target citalopram.
| 【1】 Greenwood, A.K.; McHattie, D.; Rechka, J.A.; Hedger, P.C.M.; Gamble, M.P. (Resolution Chemicals Ltd.); Process for the preparation of citalopram. WO 0166536 . |
| 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) | 54025 | 1,4-Benzenedicarboxylic acid; Benzene-1,4-dicarboxylic acid; p-Benzenedicarboxylic acid; p-Phthalic acid; Terephthalic acid | 100-21-0 | C8H6O4 | 详情 | 详情 |
| (II) | 37594 | 1-oxo-1,3-dihydro-2-benzofuran-5-carboxylic acid | C9H6O4 | 详情 | 详情 | |
| (III) | 37595 | 1-oxo-1,3-dihydro-2-benzofuran-5-carbonyl chloride | C9H5ClO3 | 详情 | 详情 | |
| (IV) | 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 |
| (V) | 37596 | N-(2-hydroxy-1,1-dimethylethyl)-1-oxo-1,3-dihydro-2-benzofuran-5-carboxamide | C13H15NO4 | 详情 | 详情 | |
| (VI) | 37597 | 5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-benzofuran-1(3H)-one | C13H13NO3 | 详情 | 详情 | |
| (VII) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (VIII) | 37598 | [4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-(hydroxymethyl)phenyl](4-fluorophenyl)methanone | C19H18FNO3 | 详情 | 详情 | |
| (IX) | 37604 | bromo[3-(dimethylamino)propyl]magnesium | 120615-47-6 | C5H12BrMgN | 详情 | 详情 |
| (X) | 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 | |
| (XI) | 55284 | sodium 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboxylate | C20H21FNNaO3 | 详情 | 详情 | |
| (XII) | 55285 | 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonyl chloride | C20H21ClFNO2 | 详情 | 详情 | |
| (XIII) | 55286 | 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboxamide | C20H23FN2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The Birch reduction of 4-butylbenzoic acid (I) with Li in dry ammonia gives 4-butyl-3,4-dihydrobenzoic acid (II), which is submitted to a new Birch reduction to yield 4-butyl-2-cyclohexenecarboxylic acid (III). The methylation of (III) with methanol in acidic medium or with diazomethane, affords the corresponding methyl ester (IV), which is reduced with H2 over PtO2 in ethyl acetate to provide 4-butylcyclohexanecarboxylic acid methyl ester (V). This compound is hydrolyzed with NaOMe in methanol to give the expected carboxylic acid (VI) as a cis/trans mixture. This mixture is dissolved in a minimum amount of methanol, then thiourea and methanol are added and heated until a homogeneous mixture is obtained. The solution is allowed to cool and finally cools at -20 C; the resulting crystalline inclusion complex is filtered and decomposed with aq. KOH to yield trans-4-butylcyclohexanecarboxylic acid (VII) (1). This compound is treated with SOCl2 in benzene to give the corresponding acyl chloride (VIII), which is finally condensed with 14C-labeled testosterone (IX) by means of pyridine in benzene to provide the target labeled testosterone ester.
| 【1】 Acosta, C.K.; et al.; Tritium labeled trans-4-N-butyl-2,3-3H-cyclohexanecarboxylic acid. Preparation of testosterone 17beta-trans-4-N-butyl-2,3-3H-cyclohexanecarboxylate and [4-14C]-testosterone 17beta-trans-4-N-butylcyclohexane carboxylate. J Label Compd Radiopharm 1990, 28, 10, 1201. |
| 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) | 54202 | 4-Butylbenzoic acid; 4-n-Butylbenzoic acid | 20651-71-2 | C11H14O2 | 详情 | 详情 |
| (II) | 54203 | 4-butyl-1,5-cyclohexadiene-1-carboxylic acid | n/a | C11H16O2 | 详情 | 详情 |
| (III) | 54204 | 4-butyl-2-cyclohexene-1-carboxylic acid | n/a | C11H18O2 | 详情 | 详情 |
| (IV) | 54025 | 1,4-Benzenedicarboxylic acid; Benzene-1,4-dicarboxylic acid; p-Benzenedicarboxylic acid; p-Phthalic acid; Terephthalic acid | 100-21-0 | C8H6O4 | 详情 | 详情 |
| (V) | 54206 | methyl 4-butylcyclohexanecarboxylate | n/a | C12H22O2 | 详情 | 详情 |
| (VI) | 54207 | 4-butylcyclohexanecarboxylic acid | n/a | C11H20O2 | 详情 | 详情 |
| (VII) | 54208 | trans-4-n-Butylcyclohexanecarboxylic acid | 38289-28-0 | C11H20O2 | 详情 | 详情 |
| (VIII) | 54209 | 4-butylcyclohexanecarbonyl chloride | n/a | C11H19ClO | 详情 | 详情 |
| (IX) | 54210 | 17beta-Hydroxyandrost-4-en-3-one; 4-Androsten-17-beta-ol-3-one; Android; Androlin; delta4-Androsten-17beta-ol-3-one; Halotensin; Oreton; Testex; Testoderm; Testosterone; Testred; Virilon | 58-22-0 | C19H28O2 | 详情 | 详情 |
| (IX) | 54245 | (8R,9S,10R,13S,14S,17S)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | n/a | C19H28O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The hydrolysis of the 1-isopentyl-4-nitro-1H-pyrrole-2-carboxylic acid ethyl ester (I) with NaOH in hot ethanol gives the carboxylic acid (II), which is treated with refluxing SOCl2 to yield the acyl chloride (III). The reaction of (III) with 3-aminopropionitrile (IV) in toluene affords the carboxamide (V), which is treated with propane-1,3-diamine (VI) and HCl in ethanol to provide the tetrahydropyrimidine derivative (VII). The reduction of the nitro group of (VII) with H2 over Pd/C in methanol gives the aminopyrrole (VIII), which is finally condensed with bis pentafluorophenyl terephthalate (XI) to afford the target terephthalamide. The activated ester bis pentafluorophenyl terephthalate (XI) has been obtained by esterification of terephthalic acid (IX) with pentafluorophenyl trifluoroacetate (X) by means of DIEA in DMF.
| 【1】 Roberts, C.D.; Keicher, J.D.; Dyatkina, N.B.; et al.; Minor groove DNA binders as antimicrobial agents. 1. Pyrrole tetraamides are potent antibacterials against vancomycin resistant Enteroccoci and methicillin resistant Staphylococcus aureus. J Med Chem 2002, 45, 4, 805. |
| 【2】 Nelson, P.H.; Muchowski, J.M.; Dyatkina, N.B.; Shi, D.-F.; Zhang, W.; Liehr, S.J.R.; Velligan, M.D.; Botyanszki, J.; Roberts, C.D.; Khorlin, A. (Genelabs Technologies, Inc.); Novel cpds. possessing antibacterial, antifungal or antitumor activity. WO 0200650 . |
| 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) | 54019 | ethyl 1-isopentyl-4-nitro-1H-pyrrole-2-carboxylate | C12H18N2O4 | 详情 | 详情 | |
| (II) | 54020 | 1-isopentyl-4-nitro-1H-pyrrole-2-carboxylic acid | C10H14N2O4 | 详情 | 详情 | |
| (III) | 54021 | 1-isopentyl-4-nitro-1H-pyrrole-2-carbonyl chloride | C10H13ClN2O3 | 详情 | 详情 | |
| (IV) | 38094 | 3-aminopropanenitrile | 151-18-8 | C3H6N2 | 详情 | 详情 |
| (V) | 54022 | N-(2-cyanoethyl)-1-isopentyl-4-nitro-1H-pyrrole-2-carboxamide | C13H18N4O3 | 详情 | 详情 | |
| (VI) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (VII) | 54023 | 1-isopentyl-4-nitro-N-[2-(1,4,5,6-tetrahydro-2-pyrimidinyl)ethyl]-1H-pyrrole-2-carboxamide | C16H25N5O3 | 详情 | 详情 | |
| (VIII) | 54024 | 4-amino-1-isopentyl-N-[2-(1,4,5,6-tetrahydro-2-pyrimidinyl)ethyl]-1H-pyrrole-2-carboxamide | C16H27N5O | 详情 | 详情 | |
| (IX) | 54025 | 1,4-Benzenedicarboxylic acid; Benzene-1,4-dicarboxylic acid; p-Benzenedicarboxylic acid; p-Phthalic acid; Terephthalic acid | 100-21-0 | C8H6O4 | 详情 | 详情 |
| (X) | 54026 | Trifluoroacetic acid pentafluorophenylester | 14533-84-7 | C8F8O2 | 详情 | 详情 |
| (XI) | 54027 | bis(2,3,4,5,6-pentafluorophenyl) terephthalate | C20H4F10O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)Treatment of terephthalic acid (X) with pentafluorophenyl trifluoroacetate gives rise to the bis-pentafluorophenyl ester (XI). Then, coupling of the active ester (XI) with aminopyrrole (IX) in hot DMF yields the title terephthalic diamide.
| 【1】 Roberts, C.D.; Keicher, J.D.; Dyatkina, N.B.; et al.; Minor groove DNA binders as antimicrobial agents. 1. Pyrrole tetraamides are potent antibacterials against vancomycin resistant Enteroccoci and methicillin resistant Staphylococcus aureus. J Med Chem 2002, 45, 4, 805. |
| 【2】 Dyatkina, N.; Hanson, E.; Liehr, S.; et al.; Synthesis, SAR and antimicrobial activity of pyrrole tetraamides. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 62. |
| 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) | 54026 | Trifluoroacetic acid pentafluorophenylester | 14533-84-7 | C8F8O2 | 详情 | 详情 |
| (IX) | 61000 | 4-amino-N-[3-imino-3-(methylamino)propyl]-1-isopentyl-1H-pyrrole-2-carboxamide | C14H25N5O | 详情 | 详情 | |
| (X) | 54025 | 1,4-Benzenedicarboxylic acid; Benzene-1,4-dicarboxylic acid; p-Benzenedicarboxylic acid; p-Phthalic acid; Terephthalic acid | 100-21-0 | C8H6O4 | 详情 | 详情 |
| (XI) | 54027 | bis(2,3,4,5,6-pentafluorophenyl) terephthalate | C20H4F10O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)The hydrolysis of the 1-isopentyl-4-nitro-1H-pyrrole-2-carboxylic acid ethyl ester (I) with NaOH in hot ethanol gives the carboxylic acid (II), which is treated with refluxing SOCl2 to yield the acyl chloride (III). The reaction of (III) with 3-aminopropionitrile (IV) in toluene affords the carboxamide (V), which is treated with ethylamine (VI) and HCl in ethanol to provide the N-ethylamidino derivative (VII). The reduction of the nitro group of (VII) with H2 over Pd/C in methanol gives the aminopyrrole (VIII), which is finally condensed with bis pentafluorophenyl terephthalate (XI) to afford the target terephthalamide. The activated ester bis pentafluorophenyl terephthalate (XI) has been obtained by esterification of terephthalic acid (IX) with pentafluorophenyl trifluoroacetate (X) by means of DIEA in DMF.
| 【1】 Roberts, C.D.; Keicher, J.D.; Dyatkina, N.B.; et al.; Minor groove DNA binders as antimicrobial agents. 1. Pyrrole tetraamides are potent antibacterials against vancomycin resistant Enteroccoci and methicillin resistant Staphylococcus aureus. J Med Chem 2002, 45, 4, 805. |
| 【2】 Nelson, P.H.; Muchowski, J.M.; Dyatkina, N.B.; Shi, D.-F.; Zhang, W.; Liehr, S.J.R.; Velligan, M.D.; Botyanszki, J.; Roberts, C.D.; Khorlin, A. (Genelabs Technologies, Inc.); Novel cpds. possessing antibacterial, antifungal or antitumor activity. WO 0200650 . |
| 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) | 54019 | ethyl 1-isopentyl-4-nitro-1H-pyrrole-2-carboxylate | C12H18N2O4 | 详情 | 详情 | |
| (II) | 54020 | 1-isopentyl-4-nitro-1H-pyrrole-2-carboxylic acid | C10H14N2O4 | 详情 | 详情 | |
| (III) | 54021 | 1-isopentyl-4-nitro-1H-pyrrole-2-carbonyl chloride | C10H13ClN2O3 | 详情 | 详情 | |
| (IV) | 38094 | 3-aminopropanenitrile | 151-18-8 | C3H6N2 | 详情 | 详情 |
| (V) | 54022 | N-(2-cyanoethyl)-1-isopentyl-4-nitro-1H-pyrrole-2-carboxamide | C13H18N4O3 | 详情 | 详情 | |
| (VI) | 10928 | Ethanamine | 75-04-7 | C2H7N | 详情 | 详情 |
| (VII) | 54028 | N-[3-(ethylamino)-3-iminopropyl]-1-isopentyl-4-nitro-1H-pyrrole-2-carboxamide | C15H25N5O3 | 详情 | 详情 | |
| (VIII) | 54029 | 4-amino-N-[3-(ethylamino)-3-iminopropyl]-1-isopentyl-1H-pyrrole-2-carboxamide | C15H27N5O | 详情 | 详情 | |
| (IX) | 54025 | 1,4-Benzenedicarboxylic acid; Benzene-1,4-dicarboxylic acid; p-Benzenedicarboxylic acid; p-Phthalic acid; Terephthalic acid | 100-21-0 | C8H6O4 | 详情 | 详情 |
| (X) | 54026 | Trifluoroacetic acid pentafluorophenylester | 14533-84-7 | C8F8O2 | 详情 | 详情 |
| (XI) | 54027 | bis(2,3,4,5,6-pentafluorophenyl) terephthalate | C20H4F10O4 | 详情 | 详情 |