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【结 构 式】 
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【分子编号】32388 【品名】5-Fluoroindole; 5-Fluoro-1H-indole 【CA登记号】399-52-0 |
【 分 子 式 】C8H6FN 【 分 子 量 】135.1407832 【元素组成】C 71.1% H 4.48% F 14.06% N 10.36% |
合成路线1
该中间体在本合成路线中的序号：(VIII)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2
该中间体在本合成路线中的序号：(I)Alkylation of 5-fluoroindole (I) with 4-fluorobenzyl chloride (II) provided the N-benzyl indole (III). Subsequent reaction of (III) with oxalyl chloride furnished the indolylglyoxylic acid chloride (IV). This was finally coupled with 4-amino-3,5-dichloropyridine (V) to afford the corresponding amide.
| 【1】 Egerland, U.; Kronbach, T.; Höfgen, N.; Poppe, H.; Küsters, S.; szelenyi, S.; AWD 12-343, a new orally active PDE 4 inhibitor - Synthesis and comparison with SB 207499, rolipram and AWD 12-281. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PA-79. |
| 【2】 Hofgen, N.; et al.; AWD 12-343, a new orally active PDE 4 inhibitor - Synthesis and comparison with SB 207499, rolipram and AWD 12-281. 27th Natl Med Chem Symp (June 13 2000, Kansas City) 2000, Abst B-19. |
| 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) | 32388 | 5-Fluoroindole; 5-Fluoro-1H-indole | 399-52-0 | C8H6FN | 详情 | 详情 |
| (II) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
| (III) | 44312 | 5-fluoro-1-(4-fluorobenzyl)-1H-indole | C15H11F2N | 详情 | 详情 | |
| (IV) | 44313 | 2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetyl chloride | C17H10ClF2NO2 | 详情 | 详情 | |
| (V) | 25135 | 3,5-dichloro-4-pyridinamine; 4-amino-3,5-dichloropyridine | 22889-78-7 | C5H4Cl2N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Maleimide (I) was brominated in the presence of benzoyl peroxide to give 3,4-dibromomaleimide (II). Alkylation of (II) with 4-(tert-butyl)benzyl bromide (III) in the presence of potassium carbonate afforded the N-(tert-butylbenzyl) derivative (IV). Coupling of the dibromomaleimide (IV) with the indolylmagnesium iodide resulting from 5-fluoroindole (V) and MeMgI furnished the bis-indolyl maleimide (VI). Oxidative cyclization of (VI) using dicyanodichlorobenzoquinone yielded the target indolopyrrolocarbazole system (VIII). Glycosylation of (VIII) with the protected fluoro glucose derivative (VIII) under Mitsunobu conditions afforded adduct (IX). The O-benzyl protecting groups were then removed by transfer hydrogenation with cyclohexene and Pd(OH)2 to give (X). The tert-butylbenzyl group was finally removed by basic hydrolysis followed by recyclization with fused ammonium acetate.
| 【1】 Saulnier, M.G.; Balasubramanian, N.; Frennesson, D.B.; St. Laurent, D.R.; Langley, D.R. (Bristol-Myers Squibb Co.); Cytotoxic amino sugar and related sugar derivs. of indolopyrrolocarbazoles. EP 0971717; JP 2000516250; WO 9807433 . |
| 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) | 19711 | 1H-pyrrole-2,5-dione | 541-59-3 | C4H3NO2 | 详情 | 详情 |
| (II) | 48178 | 3,4-dibromo-1H-pyrrole-2,5-dione | C4HBr2NO2 | 详情 | 详情 | |
| (III) | 20588 | 1-(bromomethyl)-4-(tert-butyl)benzene | 18880-00-7 | C11H15Br | 详情 | 详情 |
| (IV) | 48179 | 3,4-dibromo-1-[4-(tert-butyl)benzyl]-1H-pyrrole-2,5-dione | C15H15Br2NO2 | 详情 | 详情 | |
| (V) | 32388 | 5-Fluoroindole; 5-Fluoro-1H-indole | 399-52-0 | C8H6FN | 详情 | 详情 |
| (VI) | 48180 | 1-[4-(tert-butyl)benzyl]-3,4-bis(5-fluoro-1H-indol-3-yl)-1H-pyrrole-2,5-dione | C31H25F2N3O2 | 详情 | 详情 | |
| (VII) | 48181 | 6-[4-(tert-butyl)benzyl]-3,9-difluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione | C31H23F2N3O2 | 详情 | 详情 | |
| (VIII) | 48182 | (3R,4R,5S,6R)-3,4-bis(benzyloxy)-6-[(benzyloxy)methyl]-5-fluorotetrahydro-2H-pyran-2-ol | C27H29FO5 | 详情 | 详情 | |
| (IX) | 48183 | 12-[(2R,3R,4R,5S,6R)-3,4-bis(benzyloxy)-6-[(benzyloxy)methyl]-5-fluorotetrahydro-2H-pyran-2-yl]-6-[4-(tert-butyl)benzyl]-3,9-difluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione | C58H50F3N3O6 | 详情 | 详情 | |
| (X) | 48184 | 6-[4-(tert-butyl)benzyl]-3,9-difluoro-12-[(2R,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione | C37H32F3N3O6 | 详情 | 详情 |