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【结 构 式】 
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【分子编号】22135 【品名】1-(4-fluorophenyl)hydrazine 【CA登记号】371-14-2 |
【 分 子 式 】C6H7FN2 【 分 子 量 】126.1334632 【元素组成】C 57.13% H 5.59% F 15.06% N 22.21% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of 4-fluorophenylhydrazine hydrochloride (I) with N-carbethoxy-4-piperidone (II) under Fisher's conditions affords N2-carbethoxy-8-fluoro-2,3,4,5-tetrahydro-1H-pyridol[4,3-b]indole (III). Treatment of (III) with Claisen's alkali affords the N-2 unsubstituted 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (IV), which is finally condensed with 3-pyridinylpropyl bromide hydrobromide (V) in DMF in the presence of triethyl amine (TEA). Compound (V) is obtained by refluxing 3-pyridinylpropanol with 48% hydrobromic acid.
| 【1】 Andree, T.H.; Webb, M.B.; Patel, U.R.; Muth, E.A.; Moyer, J.A.; Abou-Gharbia, M.; Antipsychotic activity of substituted gamma-carbol. J Med Chem 1987, 30, 1818. |
| 【2】 Andree, T.; Abou-Gharbia, M.; WY-47384. Drugs Fut 1988, 13, 6, 541. |
| 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) | 13486 | Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone | 29976-53-2 | C8H13NO3 | 详情 | 详情 |
| (I) | 22135 | 1-(4-fluorophenyl)hydrazine | 371-14-2 | C6H7FN2 | 详情 | 详情 |
| (III) | 22137 | ethyl 8-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate | C14H15FN2O2 | 详情 | 详情 | |
| (IV) | 14941 | 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole | 39876-39-6 | C11H11FN2 | 详情 | 详情 |
| (V) | 22139 | 3-(3-bromopropyl)pyridine | C8H10BrN | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)The intermediate 5-fluoro-3-[3-(1-piperazinyl)propyl]-1H-indole (V) has been obtained as follows: a) The condensation of 5-fluoro-1H-indole (VIII) with acrylic acid (IX) by means of acetic anhydride gives 3-(1H-indol-5-yl)propionic acid (X), which is reduced with LiAlH4 to 3-(1H-indol-5-yl)-1-propanol (XI). The tosylation of (XI) with tosyl chloride yields the tosylate (XII), which is condensed with 1-benzylpiperazine (XIII) in refluxing butyl acetate affording 3-[3-(4-benzylpiperazin-1-yl)propyl]-5-fluoro-1H-indole (XIV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C yielding the target intermediate (V). b) The tosylate intermediate (XII) can also be condensed with ethyl piperazine-1-carboxylate (XVII) in refluxing butyl acetate giving 4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazine-1-carboxylic acid ethyl ester (XVIII), which is then decarboxylated with NaOH to the target intermediate (V). The intermediate 3-(1H-indol-5-yl)-1-propanol (XI) can also be obtained by direct cyclization of 4-fluorophenylhydrazine (XV) with dihydropyran (XVI) in hot propyleneglycol.
| 【1】 Anderson, N.G.; et al.; Process development of 5-fluoro-3[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-1H-indole dihydrochloride. Org Process Res Dev 1997, 1, 4, 300. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 32385 | 5-fluoro-3-[3-(1-piperazinyl)propyl]-1H-indole | C15H20FN3 | 详情 | 详情 | |
| (VIII) | 32388 | 5-Fluoroindole; 5-Fluoro-1H-indole | 399-52-0 | C8H6FN | 详情 | 详情 |
| (IX) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (X) | 32389 | 3-(5-fluoro-1H-indol-3-yl)propionic acid | C11H10FNO2 | 详情 | 详情 | |
| (XI) | 32390 | 3-(5-fluoro-1H-indol-3-yl)-1-propanol | C11H12FNO | 详情 | 详情 | |
| (XII) | 32391 | 3-(5-fluoro-1H-indol-3-yl)propyl 4-methylbenzenesulfonate | C18H18FNO3S | 详情 | 详情 | |
| (XIII) | 28542 | N-Benzylpiperazine; 1-Benzylpiperazine | 2759-28-6 | C11H16N2 | 详情 | 详情 |
| (XIV) | 32392 | 3-[3-(4-benzyl-1-piperazinyl)propyl]-5-fluoro-1H-indole | C22H26FN3 | 详情 | 详情 | |
| (XV) | 22135 | 1-(4-fluorophenyl)hydrazine | 371-14-2 | C6H7FN2 | 详情 | 详情 |
| (XVI) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (XVII) | 24694 | N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine | 120-43-4 | C7H14N2O2 | 详情 | 详情 |
| (XVIII) | 32393 | ethyl 4-[3-(5-fluoro-1H-indol-3-yl)propyl]-1-piperazinecarboxylate | C18H24FN3O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Condensation between 4-fluorophenylhydrazine (I) and 2-ketoglutaric acid (II) produced the intermediate hydrazone (III), which was cyclized and esterified to the indole diester (IV) under Fischer synthesis conditions. Alkylation of the indole nitrogen with iodomethane and NaH produced the N-methyl indole (V). This was condensed with dimethylformamide-dimethylacetal in refluxing DMF to furnish the enamino ester (VI). Condensation of enamine (VI) with aniline (VII), followed by cyclization of the intermediate enamino ester under basic conditions, gave rise to the pyridoindole (VIII). The remaining ester group of (VIII) was then hydrolyzed with NaOH to the corresponding carboxylic acid (IX), which was finally coupled with pyrrolidine (X) via activation with carbonyldiimidazole.
| 【1】 Sevrin, M.; Maloizel, C.; Evanno, Y.; Legalloudec, O.; George, P. (Sanofi-Synthelabo); 1H-Pyrido[3,4-b]indole-4-carboxamide derivs., preparation and application thereof in therapeutics. FR 2754262; JP 2001508403; US 6075021; WO 9815552 . |
| 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) | 22135 | 1-(4-fluorophenyl)hydrazine | 371-14-2 | C6H7FN2 | 详情 | 详情 |
| (II) | 52267 | 2-Ketoglutaric acid; 2-Oxoglutaric acid; alpha-Ketoglutaric acid; 2-Oxopentanedioic acid | 328-50-7 | C5H6O5 | 详情 | 详情 |
| (III) | 52268 | 2-[2-(4-fluorophenyl)hydrazono]pentanedioic acid | C11H11FN2O4 | 详情 | 详情 | |
| (IV) | 52269 | ethyl 3-[2-(ethyloxy)-2-oxoethyl]-5-fluoro-1H-indole-2-carboxylate | C15H16FNO4 | 详情 | 详情 | |
| (V) | 52270 | ethyl 3-[2-(ethyloxy)-2-oxoethyl]-5-fluoro-1-methyl-1H-indole-2-carboxylate | C16H18FNO4 | 详情 | 详情 | |
| (VI) | 52271 | ethyl 3-{2-(dimethylamino)-1-[(ethyloxy)carbonyl]ethenyl}-5-fluoro-1-methyl-1H-indole-2-carboxylate | C19H23FN2O4 | 详情 | 详情 | |
| (VII) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (VIII) | 52272 | ethyl 6-fluoro-9-methyl-1-oxo-2-phenyl-2,9-dihydro-1H-beta-carboline-4-carboxylate | C21H17FN2O3 | 详情 | 详情 | |
| (IX) | 52273 | 6-fluoro-9-methyl-1-oxo-2-phenyl-2,9-dihydro-1H-beta-carboline-4-carboxylic acid | C19H13FN2O3 | 详情 | 详情 | |
| (X) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 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 cyclization of p-fluorophenylhydrazine (I) with 1-carbethoxy-4-piperidinone (II) in refluxing ethanol gives 2-carbethoxy-8-fluoro-1,2,3,4-tetrahydro-gamma-carboline (III), which is arylated with p-fluorobromobenzene (IV), by means of Na2CO3 - Cu2Br2 in N-methyl-2-pyrrolidinone heated at 200 C to yield 2-carbethoxy-8-fluoro-5-(p-fluorophenyl)-1,2,3,4-tetrahydro-gamma-carboline (V). The hydrolytic decarboxylation of (V) with KOH in refluxing ethanol affords 8-fluoro-5-(p-fluorophenyl)-1,2,3,4-tetrahydro-gamma-carboline (VI), which is alkylated with p-fluoro-gamma-bromobutyrophenone (VII) by means of Na2CO3 in hot DMF to give 8-fluoro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-oxobutyl]-1,2,3,4-tetrahydro-gamma-carboline (VIII). Finally this compound is reduced with NaBH4 in ethanol - THF
| 【1】 Harbert, C.A.; et al.; Neuroleptic activity in 5-aryl-tetrahydro-gamma-carbolines. J Med Chem 1980, 23, Suppl. 3, 635. |
| 【2】 Plattner, J.J.; et al. (Pfizer Inc.); US 4001263 . |
| 【3】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Leeson, P.A.; Mealy, N.E.; Flutroline. Drugs Fut 1981, 6, 2, 84. |
| 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) | 22135 | 1-(4-fluorophenyl)hydrazine | 371-14-2 | C6H7FN2 | 详情 | 详情 |
| (II) | 13486 | Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone | 29976-53-2 | C8H13NO3 | 详情 | 详情 |
| (III) | 22137 | ethyl 8-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate | C14H15FN2O2 | 详情 | 详情 | |
| (IV) | 29012 | 1-bromo-4-fluorobenzene | 460-00-4 | C6H4BrF | 详情 | 详情 |
| (V) | 60777 | ethyl 8-fluoro-5-(4-fluorophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate | C20H18F2N2O2 | 详情 | 详情 | |
| (VI) | 60775 | 8-fluoro-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole | C17H14F2N2 | 详情 | 详情 | |
| (VII) | 60778 | 4-bromo-1-(4-fluorophenyl)-1-butanone | C10H10BrFO | 详情 | 详情 | |
| (VIII) | 60779 | 4-[8-fluoro-5-(4-fluorophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl]-1-(4-fluorophenyl)-1-butanone | C27H23F3N2O | 详情 | 详情 |