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【结 构 式】 
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【分子编号】40684 【品名】ethyl 4-chloro-4-oxobutanoate; Ethyl succinyl chloride 【CA登记号】14794-31-1 |
【 分 子 式 】C6H9ClO3 【 分 子 量 】164.58836 【元素组成】C 43.79% H 5.51% Cl 21.54% O 29.16% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of indolizine (I) with 4-chloro-4-oxobutyric acid ethyl ester (II) by means of AlCl3 in dichloromethane gives 4-(3-indolizinyl)-4-oxobutyric acid ethyl ester (III), which is reduced with borane in THF to yield 4-(3-indolizinyl)butyric acid ethyl ester (IV). The condensation of (IV) with 4-acetoxybenzoyl chloride (V) by means of AlCl3 in dichloromethane affords the 1-(4-acetoxybenzoyl)indolizine derivative (VI), which is demethylated with NaH in ethanol to provide the corresponding 4-hydroxybenzoyl derivative (VII). The condensation of (VII) with 1(R)-(4-isobutyl)phenyl-1-butanol under Mitsunobu conditions (DEAD, PPh3) gives the corresponding (S)-ether (XI), which is finally hydrolyzed to the target acid by means of NaOH in methanol/THF. The chiral intermediate alcohol (VIII) has been obtained as follows: The condensation of isobutylbenzene (X) with butyryl chloride (XI) by means of AlCl3 in dichloromethane gives the butyrophenone (XII), which is then enantioselectively reduced with (+)-B-chlorodiisopinocampheyl borane [(+)-DIP- chloride] in isopropanol.
| 【1】 Okada, S.; Kuroda, A.; Sawada, K.; Sawada, Y.; Watanabe, S.; Tanaka, H.; 4-(Benzoylindolizinyl)butyric acids; novel nonsteroidal inhibitors of steroid 5alpha-reductase. III. Chem Pharm Bull 2001, 49, 7, 779. |
| 【2】 Okada, S.; Sawada, K.; Kuroda, A.; Watanabe, S.; Tanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Indolizin derivs., process for their preparation and pharmaceutical compsn. containing them. EP 0519353; JP 1993178856; US 5334716 . |
| 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) | 49217 | Indolizine | C8H7N | 详情 | 详情 | |
| (II) | 40684 | ethyl 4-chloro-4-oxobutanoate; Ethyl succinyl chloride | 14794-31-1 | C6H9ClO3 | 详情 | 详情 |
| (III) | 49218 | ethyl 4-(3-indolizinyl)-4-oxobutanoate | C14H15NO3 | 详情 | 详情 | |
| (IV) | 49219 | ethyl 4-(3-indolizinyl)butanoate | C14H17NO2 | 详情 | 详情 | |
| (V) | 49220 | 4-(chlorocarbonyl)phenyl acetate | C9H7ClO3 | 详情 | 详情 | |
| (VI) | 49221 | ethyl 4-[1-[4-(acetoxy)benzoyl]-3-indolizinyl]butanoate | C23H23NO5 | 详情 | 详情 | |
| (VII) | 49222 | ethyl 4-[1-(4-hydroxybenzoyl)-3-indolizinyl]butanoate | C21H21NO4 | 详情 | 详情 | |
| (VIII) | 49223 | (1R)-1-(4-isobutylphenyl)-1-butanol | C14H22O | 详情 | 详情 | |
| (IX) | 49224 | ethyl 4-[1-(4-[[(1S)-1-(4-isobutylphenyl)butyl]oxy]benzoyl)-3-indolizinyl]butanoate | C35H41NO4 | 详情 | 详情 | |
| (X) | 49225 | 1-Phenylisobutane; Isobutylbenzene; 2-Methyl-1-phenylpropane | 538-93-2 | C10H14 | 详情 | 详情 |
| (XI) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (XII) | 49226 | 1-(4-isobutylphenyl)-1-butanone | C14H20O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)5-Iodoanthranilic acid (I) was converted to ethyl ester (II) (1), which was subsequently reacted with ethoxysuccinyl chloride (III) to furnish the amide (IV). Dieckmann cyclization of (IV) using KH produced ketoester (V), and further dealkoxycarbonylation by heating in wet DMSO gave rise to benzazepinedione (VI). After formation of the corresponding hydrazone (VIII) with 4-(trifluoromethyl)phenylhydrazine (VII), Fisher indole synthesis yielded the paulone system (IX). The Heck reaction of (IX) with acrylonitrile in the presence of palladium catalyst gave adduct (X). The target saturated analogue was finally prepared by refluxing the acrylonitrile derivative (X) with Mg in MeOH.
| 【1】 Kunick, C.; Jalluri, R.K.; Sausville, E.A.; Gussio, R.; Zaharevitz, D.W.; Meijer, L.; Lemdke, T.; schultz, C.; Leost, M.; 2-Substituted paullones: CDK1/cyclin B-inhibiting property and in vitro antiproliferative activity. Bioorg Med Chem Lett 2000, 10, 6, 567. |
| 【2】 Gussio, R.; Zaharevitz, D.W.; Sausville, E.A.; Jalluri, R.K. (US Department of Health & Human Services); Fused azepinone cyclin dependent kinase inhibitors. WO 9965910 . |
| 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) | 19964 | 5-Iodoanthranilic acid; 2-amino-5-iodobenzoic acid | 5326-47-6 | C7H6INO2 | 详情 | 详情 |
| (II) | 40683 | ethyl 2-amino-5-iodobenzoate | C9H10INO2 | 详情 | 详情 | |
| (III) | 40684 | ethyl 4-chloro-4-oxobutanoate; Ethyl succinyl chloride | 14794-31-1 | C6H9ClO3 | 详情 | 详情 |
| (IV) | 40685 | ethyl 2-[(4-ethoxy-4-oxobutanoyl)amino]-5-iodobenzoate | C15H18INO5 | 详情 | 详情 | |
| (V) | 40686 | ethyl 5-hydroxy-7-iodo-2-oxo-2,3-dihydro-1H-1-benzazepine-4-carboxylate | C13H12INO4 | 详情 | 详情 | |
| (VI) | 40687 | 7-iodo-3,4-dihydro-1H-1-benzazepine-2,5-dione | C10H8INO2 | 详情 | 详情 | |
| (VII) | 40688 | 1-[4-(trifluoromethyl)phenyl]hydrazine | 368-90-1 | C7H7F3N2 | 详情 | 详情 |
| (VIII) | 40689 | 7-iodo-3,4-dihydro-1H-1-benzazepine-2,5-dione 5-[N-[4-(trifluoromethyl)phenyl]hydrazone] | C17H13F3IN3O | 详情 | 详情 | |
| (IX) | 40690 | 2-iodo-9-(trifluoromethyl)-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one | C17H10F3IN2O | 详情 | 详情 | |
| (X) | 40691 | (E)-3-[6-oxo-9-(trifluoromethyl)-5,6,7,12-tetrahydroindolo[3,2-d][1]benzazepin-2-yl]-2-propenenitrile | C20H12F3N3O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Condensation of ethyl succinyl chloride (II) with 4-(1-cyclohexenyl)morpholine (I) in the presence of Et3N produced enamino ketoester (III). Cyclization of (III) with diethyl aminomalonate (IV) gave the tetrahydroindole (V). Hydrolysis of the ester functions of (V) with NaOH, followed by acidic decarboxylation, afforded the tetrahydroindolylpropionic acid (VI). Vilsmeier formylation of (VI) with DMF and POCl3 furnished aldehyde (VII). This was then condensed with 5-bromo-2-oxindole (IX) (obtained by treatment of (VIII) with N-bromosuccinimide), using either pyrrolidine or piperidine in refluxing EtOH to yield the title compound.
| 【2】 Miller, T.A.; Tang, P.C.; Sun, L.; Tran, N.M.; Liang, C.; Nguyen, A.T.; Nematalla, A. (Sugen, Inc.); 3-Methylidenyl-2-indolinone modulators of protein kinase. WO 0008202 . |
| 【1】 Liang, C.; Sun, L.; Tran, N.; et al.; Identification of substituted 3-[(4,5,6,7-tetrahydro-1H-indol-2-yl)methylene]-1,3-dihydroindol-2-ones as growth factor receptor inhibitors for VEGF-R2 (F1k-1/KDR), FGF-R1, and PDGF-Rbeta tyrosine kinases. J Med Chem 2000, 43, 14, 2655. |
| 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) | 44735 | 4-(1-cyclohexen-1-yl)morpholine | 670-80-4 | C10H17NO | 详情 | 详情 |
| (II) | 40684 | ethyl 4-chloro-4-oxobutanoate; Ethyl succinyl chloride | 14794-31-1 | C6H9ClO3 | 详情 | 详情 |
| (III) | 44737 | ethyl 4-[2-(4-morpholinyl)-1-cyclohexen-1-yl]-4-oxobutanoate | C16H25NO4 | 详情 | 详情 | |
| (IV) | 44738 | Diethyl aminomalonate; diethyl 2-aminomalonate | C7H13NO4 | 详情 | 详情 | |
| (V) | 44739 | ethyl 3-(3-ethoxy-3-oxopropyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate | C16H23NO4 | 详情 | 详情 | |
| (VI) | 44740 | 3-(4,5,6,7-tetrahydro-1H-indol-3-yl)propionic acid | C11H15NO2 | 详情 | 详情 | |
| (VII) | 44741 | 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)propionic acid | C12H15NO3 | 详情 | 详情 | |
| (VIII) | 18699 | 1,3-dihydro-2H-indol-2-one | 59-48-3 | C8H7NO | 详情 | 详情 |
| (IX) | 44743 | 5-bromo-1,3-dihydro-2H-indol-2-one | C8H6BrNO | 详情 | 详情 |