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【结 构 式】 
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【分子编号】13619 【品名】Nicotinoyl azide 【CA登记号】 |
【 分 子 式 】C6H4N4O 【 分 子 量 】148.12412 【元素组成】C 48.65% H 2.72% N 37.82% O 10.8% |
合成路线1
该中间体在本合成路线中的序号：(I)Nicotinic acid azide (I) is mixed with a solution of gamma-aminobutyric acid (II) in 1 N NaOH (pH 8-9). The mixture is stirred for 24 hours, evaporated and the residue is washed with methanol. The resultant sodium salt of nicotinoyl-gamma-aminobutyric acid is then dried. It can be further converted to nicotinoyl-gamma-aminobutyric acid (III) by dissolving in a minimum amount of water and adjusting pH to 3.5.
| 【1】 Kopelevich, V.M.; Trubnikov, V.I.; Shmvilovich, L.M.; et al. (USSR Res. Inst. Vitamins); Process for the preparation of N-nicotinoyl-gamma-aminoaliphatic acids or its esters. SU 325232 . |
| 【2】 Rejholec, V.; PIKAMILONE. Drugs Fut 1990, 15, 2, 133. |
合成路线2
该中间体在本合成路线中的序号：(I)The heating of nicotinoyl azide (I) in refluxing toluene gives the corresponding isocyanate (II), which without isolation is condensed with 6-chloro-5-(methylsulfanyl)indoline (IV) to afford the target compound. Intermediate indoline (IV) is obtained by reduction of 6-chloro-5-(methylsulfanyl)indole (III) with NaBH3CN in HOAc.
| 【1】 Ham, P.; Jones, G.E.; Forbes, I.T. (SmithKline Beecham plc); Indoline derivs. as 5HT2C antagonists. EP 0707581; JP 1996512299; US 5834494; WO 9501976 . |
| 【2】 Davies, D.T.; Bromidge, S.M.; Dabbs, S.; et al.; Model studies on a synthetically facile series of N-substituted phenyl-N'-pyridin-3-yl ureas leading to 1-(3-pyridylcarbamoyl)indolines that are potent and selective 5-HT2C/2B receptor antagonists. Bioorg Med Chem 1999, 7, 12, 2767. |
| 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) | 13619 | Nicotinoyl azide | C6H4N4O | 详情 | 详情 | |
| (II) | 27045 | 3-isocyanatopyridine | 15268-31-2 | C6H4N2O | 详情 | 详情 |
| (III) | 43774 | 6-chloro-5-(methylsulfanyl)-1H-indole; 6-chloro-1H-indol-5-yl methyl sulfide | C9H8ClNS | 详情 | 详情 | |
| (IV) | 43775 | 6-chloro-5-(methylsulfanyl)indoline; 6-chloro-2,3-dihydro-1H-indol-5-yl methyl sulfide | C9H10ClNS | 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 reaction of 6-(trifluoromethyl)indoline (I) with potassium thiocyanate and Br2 in methanol gives 5-thiocyanato-6-(trifluoromethyl)indoline (II), which is treated with ammonia in hot dioxane/water yielding the disulfide (III). The acylation of (III) with acetic anhydride and triethylamine in dichloromethane affords the corresponding diacetyl derivative (IV), which is treated with triphenylphosphine and conc. HCl in refluxing dioxane to give 5-sulfanyl-6-(trifluoromethyl)-indoline (V). The methylation of (V) with methyl iodide and K2CO3 in hot DMF yields the methylsulfanyl compound (VI), which is deacetylated with NaOH in refluxing ethanol/water affording 5-(methylmsulfanyl)-6--(trifluoromethyl)-indoline (VII). Finally, this compound is condensed with 3-pyridyl isothiocyanate (VIII) in toluene. The indoline (VII) can also be obtained directly from indoline (I) by reaction of (I) with potassium thiocyanate and Br2 in methanol, followed by a treatment with methyl iodide and KOH. The 3-pyridyl isocyanate can be obtained by decomposition of pyridine-3-carboxylic acid azide (IX) in refluxing toluene.
| 【1】 Bromidge, S.M.; et al.; Novel and selective 5-HT2C/2B receptor antagonists as potential anxiolytic agents: Synthesis, quantitative structure-activity relationships, and molecular modeling of substituted 1-(3-pyridylcarbamoyl)indolines. J Med Chem 1998, 41, 10, 1598. |
| 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) | 27038 | 6-(trifluoromethyl)indoline | C9H8F3N | 详情 | 详情 | |
| (II) | 27039 | 6-(trifluoromethyl)-5-indolinesulfenyl cyanide | C10H7F3N2S | 详情 | 详情 | |
| (III) | 27040 | 6-(trifluoromethyl)-5-[[6-(trifluoromethyl)-2,3-dihydro-1H-indol-5-yl]disulfanyl]indoline | C18H14F6N2S2 | 详情 | 详情 | |
| (IV) | 27041 | 1-[5-[[1-acetyl-6-(trifluoromethyl)-2,3-dihydro-1H-indol-5-yl]disulfanyl]-6-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C22H18F6N2O2S2 | 详情 | 详情 | |
| (V) | 27042 | 1-[5-sulfanyl-6-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C11H10F3NOS | 详情 | 详情 | |
| (VI) | 27043 | 1-[5-(methylsulfanyl)-6-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C12H12F3NOS | 详情 | 详情 | |
| (VII) | 27044 | 5-(methylsulfanyl)-6-(trifluoromethyl)indoline | C10H10F3NS | 详情 | 详情 | |
| (VIII) | 27045 | 3-isocyanatopyridine | 15268-31-2 | C6H4N2O | 详情 | 详情 |
| (IX) | 13619 | Nicotinoyl azide | C6H4N4O | 详情 | 详情 |