【结 构 式】 |
【分子编号】13476 【品名】Indole-3-glyoxylyl chloride; 2-(1H-Indol-3-yl)-2-oxoacetyl chloride 【CA登记号】22980-09-2 |
【 分 子 式 】C10H6ClNO2 【 分 子 量 】207.61588 【元素组成】C 57.85% H 2.91% Cl 17.08% N 6.75% O 15.41% |
合成路线1
该中间体在本合成路线中的序号:(XVII)The cyclization of diethyl malonate (I) with cis-1,4-dichloro-2-butene (II) by means of LiH in DMF gives 3-cyclopentene-1,1-dicarboxylic acid diethyl ester (III), which is monodecarboxylated by hydrolysis with NaOH in ethanol, followed by heating at 170-180 C to yield 3-cyclopentene-1-carboxylic acid (IV). The reaction of (IV) with SOCl2 affords the acyl chloride (V), which by reaction with ethanol provides the ethyl ester (VI). The oxidation of (VI) with OsO4 and N-methylmorpholine N-oxide (NMMO) in acetone/water gives the dihydroxy compound (VII), which is further oxidized with NaIO4 in THF to yield the dialdehyde (VIII). The cyclization of (VIII) by means of glycine ethyl ester and acetonedicarboxylic acid affords the 9-azabicyclo[3,3,1]nonan-3-one derivative (IX), which is reduced with NaBH4 in ethanol to provide the corresponding alcohol (X). The protection of the OH group of (X) with dihydropyran and methanesulfonic acid gives the tetrahydropyranyl ether (XI), which is cyclized by means of tBuO-K in hot toluene, yielding the tricyclic ketone (XII). The deprotection of (XII) with 5N HCl affords the alcohol (XIII), which is finally esterified with 1H-indole-3-carbonyl chloride (XIV) by means of tetrafluoroboric acid and silver tetrafluoroborate in nitroethane. Alternatively, 1H-indole (XV) is condensed with oxalyl chloride (XVI) to give 3-indolylglyoxylyl chloride (XVII), which is used to acylate the alcohol (XIII) by means of tetrafluoroboric acid and silver tetrafluoroborate as before. Simultaneous decarbonylation takes place in this acylation reaction.
【1】 Gittos, M.W. (Merrell Pharmaceuticals, Inc.); Esters of hexahydro-8-hydroxy-2, 6-methano-2H-quinolizin-3(4H)-one and related compds.. AU 8780596; EP 0266730; JP 1988258476 . |
【2】 Gittos, M.W.; Fatmi, M.; Potent 5-HT3 antagonists incorporating a novel bridged pseudopelletierine ring system. Actual Chim Ther 1989, 16, 187. |
【3】 Gittos, M.W.; Fatmi, M.; Galvan, M.; Dolasetron Mesylate. Drugs Fut 1993, 18, 6, 506. |
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) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
(II) | 50004 | cis-1,4-Dichloro-2-butene;(Z)-1,4-Dichlorobutene;(Z)-1,4-Dichloro-2-butene;(2Z)-1,4-Dichloro-2-butene;cis-1,2-Bis(chloromethyl)ethene | 1476-11-5 | C4H6Cl2 | 详情 | 详情 |
(III) | 50000 | diethyl 3-cyclopentene-1,1-dicarboxylate | C11H16O4 | 详情 | 详情 | |
(IV) | 50001 | 3-cyclopentene-1-carboxylic acid | C6H8O2 | 详情 | 详情 | |
(V) | 50002 | 3-Cyclopentenecarboxylic acid | 7686-77-3 | C6H7ClO | 详情 | 详情 |
(VI) | 13469 | ethyl 3-cyclopentene-1-carboxylate | C8H12O2 | 详情 | 详情 | |
(VII) | 13470 | ethyl 3,4-dihydroxycyclopentanecarboxylate | C8H14O4 | 详情 | 详情 | |
(VIII) | 13471 | ethyl 4-oxo-2-(2-oxoethyl)butanoate | C8H12O4 | 详情 | 详情 | |
(IX) | 13472 | ethyl 9-(2-ethoxy-2-oxoethyl)-7-oxo-9-azabicyclo[3.3.1]nonane-3-carboxylate | C15H23NO5 | 详情 | 详情 | |
(X) | 13473 | ethyl 9-(2-ethoxy-2-oxoethyl)-7-hydroxy-9-azabicyclo[3.3.1]nonane-3-carboxylate | C15H25NO5 | 详情 | 详情 | |
(XI) | 13474 | ethyl 9-(2-ethoxy-2-oxoethyl)-7-(tetrahydro-2H-pyran-2-yloxy)-9-azabicyclo[3.3.1]nonane-3-carboxylate | C20H33NO6 | 详情 | 详情 | |
(XII) | 50003 | 5-(tetrahydro-2H-pyran-2-yloxy)-8-azatricyclo[5.3.1.0(3,8)]undecan-10-one | C15H23NO3 | 详情 | 详情 | |
(XIII) | 13475 | 5-Hydroxy-8-azatricyclo[5.3.1.0(3,8)]undecan-10-one | C10H15NO2 | 详情 | 详情 | |
(XIV) | 17153 | 1H-indole-3-carbonyl chloride | C9H6ClNO | 详情 | 详情 | |
(XV) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
(XVI) | 29841 | Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride | 79-37-8 | C2Cl2O2 | 详情 | 详情 |
(XVII) | 13476 | Indole-3-glyoxylyl chloride; 2-(1H-Indol-3-yl)-2-oxoacetyl chloride | 22980-09-2 | C10H6ClNO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(VI)Reaction of indole (I) with chloroacetyl chloride (II) in the presence of pyridine in toluene afforded the chloro ketone (III). This was then treated with sodium azide in aqueous acetone to furnish the azido ketone (IV). Hydrogenation of (IV) over Pd/C in the presence of HCl gave the amino ketone (V). The intermediate 3-indolylglyoxylic chloride (VI) was obtained by acylation of indole (I) with oxalyl chloride in CH2Cl2. Subsequent condensation between acid chloride (VI) and amino ketone (V) produced amide (VII). This was finally cyclized to the desired bisindolyl pyrazinone by treatment with ammonia in a pressure vessel.
【1】 Jiang, B.; Gu, X.-H.; Syntheses and cytotoxicity evaluation of bis(indolyl)thiazole, bis(indolyl)pyrazinone and bis(indolyl)pyrazine: Analogues of cytotoxic marine bis(indole) alkaloid. Bioorg Med Chem 2000, 8, 2, 363. |
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) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
(II) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
(III) | 46764 | 2-chloro-1-(1H-indol-3-yl)-1-ethanone | C10H8ClNO | 详情 | 详情 | |
(IV) | 46765 | 2-azido-1-(1H-indol-3-yl)-1-ethanone | C10H8N4O | 详情 | 详情 | |
(V) | 46767 | 2-amino-1-(1H-indol-3-yl)-1-ethanone | C10H10N2O | 详情 | 详情 | |
(VI) | 13476 | Indole-3-glyoxylyl chloride; 2-(1H-Indol-3-yl)-2-oxoacetyl chloride | 22980-09-2 | C10H6ClNO2 | 详情 | 详情 |
(VII) | 46768 | 2-(1H-indol-3-yl)-N-[2-(1H-indol-3-yl)-2-oxoethyl]-2-oxoacetamide | C20H15N3O3 | 详情 | 详情 |