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【结 构 式】 
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【分子编号】17153 【品名】1H-indole-3-carbonyl chloride 【CA登记号】 |
【 分 子 式 】C9H6ClNO 【 分 子 量 】179.60548 【元素组成】C 60.19% H 3.37% Cl 19.74% N 7.8% O 8.91% |
合成路线1
该中间体在本合成路线中的序号：(I)By condensation of indole 3-carbonyl chloride (I) with endo-8-methyl-8-azabicyclo[3.2.1]octan-3-ol (II) by means of butyllithium in THF, or Na2CO3 in the same solvent.
| 【1】 Donatsch, P.; Engel, G.; Stadler, P.; Richardson, B.P.; Hügi, B. (Novartis AG; Novartis Deutschland GmbH); Pharmaceutically useful heterocyclic and carbocyclic acid esters and amides of alkylene bridged piperidines. CH 669792; CH 669954; DE 3322574; GB 2166726; GB 2166727; GB 2166728; US 4789673 . |
| 【2】 Castaner, J.; Serradell, M.N.; ICS-205930. Drugs Fut 1986, 11, 2, 106. |
合成路线2
该中间体在本合成路线中的序号：(XIV)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3
该中间体在本合成路线中的序号：(V)Alkylation of isonipecotamide (I) with n-butyl bromide in the presence of potassium carbonate gives the amide (II), which is reduced with lithium aluminum hydride to afford 1-butyl-4-piperidinylmethylamine (III). Conversion of indole-3-carboxylic acid (IV) to the acid chloride (V) is carried out with oxalyl chloride in dichloromethane containing N,N-dimethylformamide (DMF). Coupling of the amine (III) with the acid chloride (V) in dichloromethane in the presence of triethylamine gives N-[(1-butyl-4-piperidinyl)methyl]indole-3-carboxamide (VI). N-[(1-butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]-oxazino[3,2-a] indole-10-carboxamide (VIII) is formed by treatment of the amide (VI) with N-chlorosuccinimide in chloroform followed by reaction with 3-bromopropanol and cyclization of the intermediate ether (VII) with potassium carbonate in acetone. Conversion to N-[(1-butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a] indole-10-carboxamide hydrochloride (SB-207266) is effected by treatment of (VIII) with anhydrous HCl in ethanol.
| 【1】 Gaster, L.M.; Sanger, G.J.; SB-204070: 5-HT4 receptor antagonists and their potential therapeutic utility. Drugs Fut 1994, 19, 109-21. |
| 【2】 Ford, A.P.D.W.; Clarke, D.E.; The 5-HT4 receptor. Med Res Rev 1993, 13, 633-62. |
| 【3】 Gaster, L.; SB-207266A. Drugs Fut 1997, 22, 12, 1325. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 | |
| (I) | 11762 | 4-Piperidinecarboxamide; Isonipecotamide | 39546-32-2 | C6H12N2O | 详情 | 详情 |
| (II) | 17150 | 1-butyl-4-piperidinecarboxamide | C10H20N2O | 详情 | 详情 | |
| (III) | 17151 | (1-butyl-4-piperidinyl)methanamine; (1-butyl-4-piperidinyl)methylamine | C10H22N2 | 详情 | 详情 | |
| (IV) | 17152 | 1H-Indole-3-carboxylic acid; Indole-3-Carboxylic acid; 3-Indolecarboxylic acid | 771-50-6 | C9H7NO2 | 详情 | 详情 |
| (V) | 17153 | 1H-indole-3-carbonyl chloride | C9H6ClNO | 详情 | 详情 | |
| (VI) | 17154 | N-[(1-butyl-4-piperidinyl)methyl]-1H-indole-3-carboxamide | C19H27N3O | 详情 | 详情 | |
| (VII) | 17155 | 2-(3-bromopropoxy)-N-[(1-butyl-4-piperidinyl)methyl]-1H-indole-3-carboxamide | C22H32BrN3O2 | 详情 | 详情 | |
| (VIII) | 17156 | N-[(1-butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide | C22H31N3O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)3-Indolylcarboxylic acid (I) was converted to acid chloride (II) with oxalyl chloride in refluxing CH2Cl2, and subsequently condensed with cis 1,2-cyclohexanediamine (III) to provide racemic amide (IV). Coupling of (4-methylphenyl)acetyl chloride (VI) with D-3-(2-naphthyl)alanine (V) was carried out via previous silylation of the amino acid with bis(trimethylsilyl)acetamide in THF. The resulting amide (VII) was N-alkylated with ICH3 in the presence of NaH to provide (VIII). Then, the chiral acyl amino acid (VIII) was coupled to racemic amine (IV) using 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide-HCl (EDC) and 7-aza-1-hydroxybenzotriazole (HOAt) to furnish the corresponding amide as a diastereomeric mixture, from which the desired isomer was isolated by reverse phase chromatography.
| 【1】 Potier, E.; Fincham, C.; Sisto, A.; Terracciano, R. (Menarini Industrie Farma Riunite srl); Pseudo-peptide cpds. as antagonists of neurokinines. WO 9845262 . |
| 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) | 17152 | 1H-Indole-3-carboxylic acid; Indole-3-Carboxylic acid; 3-Indolecarboxylic acid | 771-50-6 | C9H7NO2 | 详情 | 详情 |
| (II) | 17153 | 1H-indole-3-carbonyl chloride | C9H6ClNO | 详情 | 详情 | |
| (III) | 21014 | cis-1,2-Diaminocyclohexane; (1R,2S)-1,2-cyclohexanediamine; (1R,2S)-2-aminocyclohexylamine | 1436-59-5 | C6H14N2 | 详情 | 详情 |
| (IV) | 21015 | N-[(1S,2R)-2-aminocyclohexyl]-1H-indole-3-carboxamide | C15H19N3O | 详情 | 详情 | |
| (V) | 21016 | (2R)-2-amino-3-(2-naphthyl)propionic acid; D-3-(2-Naphthyl)alanine | 76985-09-6 | C13H13NO2 | 详情 | 详情 |
| (VI) | 21017 | 2-(4-methylphenyl)acetyl chloride | 35675-44-6 | C9H9ClO | 详情 | 详情 |
| (VII) | 21018 | (2R)-2-[[2-(4-methylphenyl)acetyl]amino]-3-(2-naphthyl)propionic acid | C22H21NO3 | 详情 | 详情 | |
| (VIII) | 21019 | (2R)-2-[methyl[2-(4-methylphenyl)acetyl]amino]-3-(2-naphthyl)propionic acid | C23H23NO3 | 详情 | 详情 |