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【结 构 式】 
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【分子编号】15536 【品名】methyl 3-oxopentanoate 【CA登记号】30414-53-0 |
【 分 子 式 】C6H10O3 【 分 子 量 】130.1436 【元素组成】C 55.37% H 7.74% O 36.88% |
合成路线1
该中间体在本合成路线中的序号：(V)This compound can be prepared by two related ways: 1) The condensation of isatin (I) with methyl 3-phenylpropionate (II) by means of lithium diisopropylamide (LDA) in THF gives methyl alpha-benzyl-3 hydroxy-2-oxo-2,3-dihydro-1H-indole-3-acetate (III), which is reduced with LiAlH4 in THF to afford beta-benzylindole-3-ethanol (IV). The cyclization of (IV) with methyl propionylacetate (V) by means of boron trifluoride ethearate to toluene yields methyl 4-benzyl-1-ethyl 1,3,4,9 tetrahydropyrano[3,4-b]indole-1-acetate (VI), which is finally hydrolyzed with NaOH in refluxing ethanol. 2) The alkylation of methyl indole-3-acetate (VII) with benzyl chloride (VIII) by means of LDA o THF gives methyl alpha-benzylindole-3-acetate (IX), which is reduced with LiAlH4 in THF to the alcohol (IV), already obtained.
| 【1】 Gavin, G.; Katz, A.H.; Conway, K.M.; Asselin, A.A.; Demerson, C.A.; Guinoso, C.; Shah, V.; Mobilio, D.; Noureldin, R.; Humber, L.G.; Chau, T.T.; Jensen, N.P.; Schimid, J.; Shaw, C.-C.; Weichman, B.M.; Van Engen, D.; Synthesis and analgesic activity of pemedolac (cis. J Med Chem 1988, 31, 6, 1244. |
| 【2】 Katz, A.H.; Demerson, C.A.; Humber, L.G. (American Home Products Corp.); Substd. 1,3,4,9-tetrahydropyrano[3,4-b]indole-1-ac. EP 0238226; JP 1987221688; US 4670462; US 4775690 . |
| 【3】 Castaner, J.; Prous, J.; Pemedolac. Drugs Fut 1988, 13, 9, 834. |
| 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) | 14098 | 2,3-Indolinedione; 1H-Indole-2,3-dione; Isatin | 91-56-5 | C8H5NO2 | 详情 | 详情 |
| (II) | 23523 | methyl 3-phenylpropanoate | 103-25-3 | C10H12O2 | 详情 | 详情 |
| (III) | 23524 | methyl 2-(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-3-phenylpropanoate | C18H17NO4 | 详情 | 详情 | |
| (IV) | 23525 | 2-(1H-indol-3-yl)-3-phenyl-1-propanol | C17H17NO | 详情 | 详情 | |
| (V) | 15536 | methyl 3-oxopentanoate | 30414-53-0 | C6H10O3 | 详情 | 详情 |
| (VI) | 23527 | methyl 2-(4-benzyl-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetate | C23H25NO3 | 详情 | 详情 | |
| (VII) | 23528 | 2-(1H-Indol-3-yl)acetic acid methyl ester | 1912-33-0 | C11H11NO2 | 详情 | 详情 |
| (VIII) | 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 |
| (IX) | 23529 | methyl 2-(1H-indol-3-yl)-3-phenylpropanoate | C18H17NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The fluorination of 3-oxopentanoic acid methyl ester with F2 gas gives 2-fluoro-3-oxopentanoic acid methyl ester (II), which is cyclized with formamidine (III) by means of NaOMe yielding 6-ethyl-5-fluoropyrimidin-4-ol (IV). Reaction of (IV) with POCl3 and TEA in dichloromethane affords 4-chloro-6-ethyl-5-fluoropyrimidine (V), which is brominated with NBS and AIBN in dichloromethane to provide 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine (VI). Compound (VI) is condensed with 1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)ethanone (VII) by means of I2 and Zn in THF furnishing a mixture of the diastereomeric racemates (2R*,3R*)- and (2R*,3S*)-3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (VIII) in a 1:10.3 molar ratio. The reductive dechlorination of (2R*,3S*)-(VIII) with H2 over Pd/C gives the (2R*,3S*)-racemate (IX), which is submitted to optical resolution by means of crystallization with (1R)-10-camphorsulfonic acid.
| 【1】 Butters, M.; et al.; Process development of voriconazole: A novel broad-spectrum triazole antifungal agent. Org Process Res Dev 2001, 5, 1, 28. |
| 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) | 15536 | methyl 3-oxopentanoate | 30414-53-0 | C6H10O3 | 详情 | 详情 |
| (II) | 45716 | (E)-3-amino-2-chloro-2-propenal | C3H4ClNO | 详情 | 详情 | |
| (III) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (IV) | 45720 | 6-ethyl-5-fluoro-4-pyrimidinol | C6H7FN2O | 详情 | 详情 | |
| (V) | 15371 | 4-chloro-6-ethyl-5-fluoropyrimidine | C6H6ClFN2 | 详情 | 详情 | |
| (VI) | 45721 | 4-(1-bromoethyl)-6-chloro-5-fluoropyrimidine | 188416-28-6 | C6H5BrClFN2 | 详情 | 详情 |
| (VII) | 15372 | 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-1-ethanone; 2,4-Difluoro-alpha-(1H-1,2,4-triazolyl)acetophenone | 863867-75-6 | C10H7F2N3O | 详情 | 详情 |
| (VIII) | 15373 | (2R,3S)-3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C16H13ClF3N5O | 详情 | 详情 | |
| (IX) | 15375 | (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C16H14F3N5O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)1) The cyclization of aniline (I) with propionylacetic acid methyl ester (II) by means of p-toluenesulfonic acid in refluxing cyclohexane gives 2-ethylquinolin-4(1H)-one (III), which is condensed with 5-[4'-(bromomethyl)biphenyl-2-yl]-2-(triphenylmethyl)tetrazole (IV) by means of NaH in DMF, yielding 2-ethyl-4-[2'-[1-(triphenylmethyl)tetrazol-5-yl]biphenyl-4-ylmethoxy] quinoline (V). Finally, this compound is deprotected with HCl in ethanol - methanol. 2) The condensation of 4-methylphenylboronic acid (VI) with 2-bromobenzonitrile (VII) by means of Na2CO3 and PdCl2 in toluene - methanol gives 2-(4-methylphenyl)benzonitrile (VIII), which is brominated with N-bromosuccinimide (NBS) and azobis(isobutyronitrile) (AIBN) in hot chlorobenzene, yielding the bromomethyl derivative (IX). The condensation of (IX) with quinolone (III) by means of K2CO3 in N-methylpyrrolidone affords 4-(2'-cyanobiphenyl-4-ylmethoxy)-2-ethylquinoline (X), which is treated with tributyltin hydrazide in refluxing toluene to afford 2-ethyl-4-[2'-[2-(tributyltin)tetrazol-5-yl]biphenyl-4-ylmethoxy] quinoline (XI). Finally, this compound is deprotected with NaNO2 and HCl in cool water.
| 【1】 Roberts, D.A.; Russell, S.T.; Pearce, R.J. (AstraZeneca plc); Quinoline derivs., process for their preparation and their use as medicaments. AU 9160955; EP 0412848; GB 2234748; JP 1991169863; US 5444071 . |
| 【2】 Prous, J.; Castaner, J.; Graul, A.; ICI-D8731. Drugs Fut 1993, 18, 5, 428. |
| 【3】 Bradbury, R.H.; Allott, C.P.; Dennis, M.; et al.; New nonpeptide angiotensin II receptor antagonists. 2. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)quinoline derivatives. J Med Chem 1992, 35, 22, 4027. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 15536 | methyl 3-oxopentanoate | 30414-53-0 | C6H10O3 | 详情 | 详情 |
| (III) | 15537 | 2-ethyl-4(1H)-quinolinone | C11H11NO | 详情 | 详情 | |
| (IV) | 15538 | 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-trityl-2H-1,2,3,4-tetraazole | 124750-51-2 | C33H25BrN4 | 详情 | 详情 |
| (V) | 15539 | 2-ethyl-4-quinolinyl [2'-(2-trityl-2H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl ether; 2-ethyl-4-[[2'-(2-trityl-2H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methoxy]quinoline | C44H35N5O | 详情 | 详情 | |
| (VI) | 15540 | 4-methylphenylboronic acid; p-Tolylboronic acid | 5720-05-8 | C7H9BO2 | 详情 | 详情 |
| (VII) | 15541 | o-bromobenzonitrile; 2-bromobenzonitrile | 2042-37-7 | C7H4BrN | 详情 | 详情 |
| (VIII) | 13929 | 2-Cyano-4'-methylbiphenyl; 4'-Methyl[1,1'-biphenyl]-2-carbonitrile | 114772-53-1 | C14H11N | 详情 | 详情 |
| (IX) | 15332 | 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile; 4'-bromomethyl-2-cyanobiphenyl | 114772-54-2 | C14H10BrN | 详情 | 详情 |
| (X) | 15544 | 4'-[[(2-ethyl-4-quinolinyl)oxy]methyl][1,1'-biphenyl]-2-carbonitrile | C25H20N2O | 详情 | 详情 | |
| (XI) | 15545 | 5-[4'-(2-Ethylquinolin-4-yloxymethyl)biphenyl-2-yl]-2-(tributylstannyl)-2H-tetrazole | C37H47N5OSn | 详情 | 详情 |