|
【结 构 式】 
|
【分子编号】25432 【品名】ethyl 4,4,4-trifluoro-3-oxobutanoate 【CA登记号】372-31-6 |
【 分 子 式 】C6H7F3O3 【 分 子 量 】184.1149896 【元素组成】C 39.14% H 3.83% F 30.96% O 26.07% |
合成路线1
该中间体在本合成路线中的序号：(II)The PPA condensation of 2-trifluoromethylaniline (I) with ethyl 4,4,4-trifluoroacetoacetate (II) yields 2,8-bis(trifluoromethyl)-4-quinolone (III), which is converted into 2,8-bistrifluoromethyl-4-bromoquinoline (IV) with POBr3. The carboxylation of the quinoline (IV) with butyllithium and CO2 gives 2,8-bistrifluoromethylquinoline-4-carboxylic acid (V); this product is condensed with 2-pyridyllithium (A) giving 2,8-bis(trifluoromethyl)-4-quinolinyl-2-pyridyl ketone (VI). The last step is the reduction of ketone (VI) with H2 over Pt in ethanol.
| 【1】 Blackwell, J.T.; Carrol, F.I.; Optical isomers of aryl-2-piperidylmethanol antimalarial agents. Preparation, opticol purity and absolute stereochemistry. J Med Chem 1974, 17, 2, 210-219. |
| 【2】 Lutz, R.; et al.; Antimalarials 7-Bis-(trifluoromethyl)-(2-piperidyl)-4-quinoline methanols. J Med Chem 1971, 14, 10, 926-928. |
| 【3】 Castaner, J.; Playle, A.C.; Mefloquine. Drugs Fut 1976, 1, 6, 296. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 34016 | 2-pyridinyllithium | C5H4LiN | 详情 | 详情 | |
| (I) | 34012 | 2-(trifluoromethyl)-2,4-cyclohexadien-1-ylamine; 2-(trifluoromethyl)-2,4-cyclohexadien-1-amine | C7H8F3N | 详情 | 详情 | |
| (II) | 25432 | ethyl 4,4,4-trifluoro-3-oxobutanoate | 372-31-6 | C6H7F3O3 | 详情 | 详情 |
| (III) | 34013 | 2,8-bis(trifluoromethyl)-4(1H)-quinolinone | C11H5F6NO | 详情 | 详情 | |
| (IV) | 34014 | 4-bromo-2,8-bis(trifluoromethyl)quinoline | 35853-45-3 | C11H4BrF6N | 详情 | 详情 |
| (V) | 34015 | 2,8-bis(trifluoromethyl)-4-quinolinecarboxylic acid | C12H5F6NO2 | 详情 | 详情 | |
| (VI) | 34017 | [2,8-bis(trifluoromethyl)-4-quinolinyl](2-pyridinyl)methanone | C17H8F6N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)1) Synthesis of Butanol (I): 1a) The reduction of 4,4,4-trifluoro-2-oxobutyric acid ethyl ester (III) with NaBH4 in dichloromethane gives 4,4,4-trifluoro-2-hydroxybutyric acid ethyl ester (IV), which is hydrolyzed with NaOH in ethanol, yielding the corresponding acid (V). The optical resolution of (V) with 1(S)-phenylethylamine in hot ethanol affords the 3(R)-hydroxy enantiomer (VI) (1,3), which is reduced with NaBH4 and BF3 ethearate in THF to provide 4,4,4-trifluorobutane-1,3(R)-diol (VII). Finally, this compound is monotosylated by means of tosyl chloride and DMAP in pyridine to afford intermediate (I). 1b) The digestion of 4,4,4-trifluoro-3-hydroxybutyric acid ethyl ester (IV) with Novozym in a phosphate buffer gives the corresponding (R)-enantiomer (VIII), which is reduced with NaBH4 in ethanol, yielding 4,4,4-trifluorobutane-1,3(R)-diol (VII) (4). Finally, this compound is monotosylated by means of tosyl chloride as before to give butanol (I).
| 【1】 Castaner, J.; Sorbera, L.A.; Rabasseda, X.; Befloxatone. Drugs Fut 1999, 24, 10, 1057. |
| 【2】 Koenig, J.-J.; Schoofs, A.; Jarreau, F.-X.; Rovei, V. (Laboratoires Delalande); 3-Aryl oxazolidinones, process for their preparation and their therapeutical use. EP 0424243; EP 0424244; EP 0428421; JP 1992502333; JP 1992502334; JP 1992502335; US 5036090; US 5036091; US 5171747; US 5196543; WO 9105775 . |
| 【3】 Jarreau, F.-X.; Koenig, J.-J.; Rovei, V. (Laboratoires Delalande); 3-Aryl-oxazolidinone derivs., process for their preparation and their use in therapeutics. EP 0511031; FR 2675504; JP 1993112542; US 5264443 . |
| 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) | 28681 | (3R)-4,4,4-trifluoro-3-hydroxybutyl 4-methylbenzenesulfonate | C11H13F3O4S | 详情 | 详情 | |
| (III) | 25432 | ethyl 4,4,4-trifluoro-3-oxobutanoate | 372-31-6 | C6H7F3O3 | 详情 | 详情 |
| (IV) | 28683 | ethyl 4,4,4-trifluoro-3-hydroxybutanoate | 372-30-5 | C6H9F3O3 | 详情 | 详情 |
| (V) | 28684 | 4,4,4-trifluoro-3-hydroxybutyric acid | C4H5F3O3 | 详情 | 详情 | |
| (VI) | 28685 | (3R)-4,4,4-trifluoro-3-hydroxybutyric acid | C4H5F3O3 | 详情 | 详情 | |
| (VII) | 28686 | (3R)-4,4,4-trifluoro-1,3-butanediol | C4H7F3O2 | 详情 | 详情 | |
| (VIII) | 28687 | (3R)-4,4,4-Trifluoro-3-hydroxybutanoic acid ethyl ester | 85571-85-3 | C6H9F3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)The intermediate 4-ethyltetrahydroquinoline (VII) has been prepared by two procedures: 1.- Conjugate addition of acrylic acid (II) to aniline (I) gave 3-(phenylamino)propionic acid (III), which was cyclized with PPA at 100 C to afford quinolinone (IV). After protection of (IV) as the tert-butyl carbamate (V), addition of ethylmagnesium bromide provided carbinol (VI). Hydrogenolysis of the hydroxyl group of (VI), followed by deprotection with trifluoroacetic acid then furnished tetrahydroquinoline (VII). 2.- In an alternative procedure, side-chain alkylation of lepidine (VIII) with CH3I and LDA provided 4-ethylquinoline (IX). This was then reduced to the desired tetrahydroquinoline (VII) using NaBH4 and NiCl2. 3.- After nitration of (VII) with HNO3 and H2SO4, the resulting 7-nitroquinoline (X) was reduced to diamine (XI) by catalytic hydrogenation over Pd/C. Finally, Knorr cyclization of (XI) with ethyl 4,4,4-trifluoroacetylacetate (XII) and ZnCl2 produced the target pyridoquinoline.
| 【1】 Hamann, L.G.; Mani, N.S.; Davis, R.L.; Marschke, K.B.; Wang, X.-N.; Jones, T.K.; Discovery of a potent, orally active, nonsteroidal androgen receptor agonist: 4-Ethyl-1,2,3,4-tetrahydro-6-(trifluoromethyl)-8-pyridono[5,6-g]quinoline (LG121071). J Med Chem 1999, 42, 2, 210. |
| 【2】 Jones, T.K.; Goldman, M.E.; Pooley, C.L.F.; Winn, D.T.; Edwards, J.E.; West, S.J.; Tegley, C.M.; Zhi, L.; Hamann, L.G.; Farmer, L.J.; Davis, R.J. (Ligand Pharmaceuticals, Inc.); Steroid receptor modulator cpds. and methods. EP 0800519; JP 1998510840; US 5688808; US 5688810; US 5693646; US 5693647; US 5696127; US 5696130; US 5696133; WO 9619458 . |
| 【3】 Edwards, J.P.; Higuchi, R.; Jones, T. (Ligand Pharmaceuticals, Inc.); Androgen receptor modulator cpds. and methods. EP 0918774; US 6017924; WO 9749709 . |
| 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) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (III) | 25423 | 3-anilinopropionic acid | 5652-38-0 | C9H11NO2 | 详情 | 详情 |
| (IV) | 25424 | 2,3-dihydro-4(1H)-quinolinone | 4295-36-7 | C9H9NO | 详情 | 详情 |
| (V) | 25425 | tert-butyl 4-oxo-3,4-dihydro-1(2H)-quinolinecarboxylate | C14H17NO3 | 详情 | 详情 | |
| (VI) | 25426 | tert-butyl 4-ethyl-4-hydroxy-3,4-dihydro-1(2H)-quinolinecarboxylate | C16H23NO3 | 详情 | 详情 | |
| (VII) | 25427 | 4-ethyl-1,2,3,4-tetrahydroquinoline | C11H15N | 详情 | 详情 | |
| (VIII) | 25428 | 4-methylquinoline | 491-35-0 | C10H9N | 详情 | 详情 |
| (IX) | 25429 | 4-ethylquinoline | C11H11N | 详情 | 详情 | |
| (X) | 25430 | 4-ethyl-7-nitro-1,2,3,4-tetrahydroquinoline | C11H14N2O2 | 详情 | 详情 | |
| (XI) | 25431 | 4-ethyl-1,2,3,4-tetrahydro-7-quinolinamine; 4-ethyl-1,2,3,4-tetrahydro-7-quinolinylamine | C11H16N2 | 详情 | 详情 | |
| (XII) | 25432 | ethyl 4,4,4-trifluoro-3-oxobutanoate | 372-31-6 | C6H7F3O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)Conjugate addition of crotonic acid (I) to aniline (II) gave amino acid (III), which was cyclized to the quinolinone (IV) with polyphosphoric acid at 110 C. Protection of the amino group of (IV) with Boc2O gave carbamate (V), which was subsequenty alkylated with iodoethane in the presence of NaH to yield (VI) as a diastereomeric mixture. Acid deprotection of the Boc group of (VI) gave amine (VII). The ketone group was then reduced with triethylsilane and boron trifluoride to the tetrahydroquinoline (VIII). Nitration of (VIII), followed by hydrogenation of the resulting nitro derivative (IX) furnished the aminoquinoline (X). Further Knorr cyclization of (X) with ethyl 4,4,4-trifluoroacetoacetate (XI) by means of ZnCl2 in refluxing EtOH yielded the corresponding pyridoquinoline. The required trans isomer was finally isolated by preparative HPLC.
| 【1】 Zhi, L.; Marschke, K.B.; Jones, T.K.; Tegley, C.M.; Switching androgen receptor antagonists to agonists by modifying C-ring substituents on piperidino[3,2-g]quinolinone. Bioorg Med Chem Lett 1999, 9, 7, 1009. |
| 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) | 20599 | (E)-2-butenoic acid; crotonic acid | 3724-65-0 | C4H6O2 | 详情 | 详情 |
| (II) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (III) | 31314 | 3-anilinobutyric acid | 14676-01-8 | C10H13NO2 | 详情 | 详情 |
| (IV) | 31315 | 2-methyl-2,3-dihydro-4(1H)-quinolinone | C10H11NO | 详情 | 详情 | |
| (V) | 31316 | tert-butyl 2-methyl-4-oxo-3,4-dihydro-1(2H)-quinolinecarboxylate | C15H19NO3 | 详情 | 详情 | |
| (VI) | 31317 | tert-butyl 3-ethyl-2-methyl-4-oxo-3,4-dihydro-1(2H)-quinolinecarboxylate | C17H23NO3 | 详情 | 详情 | |
| (VII) | 31318 | 3-ethyl-2-methyl-2,3-dihydro-4(1H)-quinolinone | C12H15NO | 详情 | 详情 | |
| (VIII) | 31319 | 3-ethyl-2-methyl-1,2,3,4-tetrahydroquinoline | C12H17N | 详情 | 详情 | |
| (IX) | 31320 | 3-ethyl-2-methyl-7-nitro-1,2,3,4-tetrahydroquinoline | C12H16N2O2 | 详情 | 详情 | |
| (X) | 31321 | 3-ethyl-2-methyl-1,2,3,4-tetrahydro-7-quinolinylamine; 3-ethyl-2-methyl-1,2,3,4-tetrahydro-7-quinolinamine | C12H18N2 | 详情 | 详情 | |
| (XI) | 25432 | ethyl 4,4,4-trifluoro-3-oxobutanoate | 372-31-6 | C6H7F3O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XI)Conjugate addition of pentenoic acid (I) to aniline (II) gave amino acid (III), which was cyclized to the quinolinone (IV) with polyphosphoric acid at 110 C. Protection of the amino group of (IV) with Boc2O gave carbamate (V), which was subsequenty alkylated with iodoethane in the presence of NaH to yield (VI) as a diastereomeric mixture. Acid deprotection of the Boc group of (VI) gave amine (VII). The ketone group of (VII) was then reduced with triethylsilane and boron trifluoride to the tetrahydroquinoline (VIII). Nitration of (VIII), followed by hydrogenation of the resulting nitro derivative (IX) furnished the aminoquinoline (X). Further Knorr cyclization of (X) with ethyl 4,4,4-trifluoroacetoacetate (XI) by means of ZnCl2 in refluxing EtOH yielded the corresponding pyridoquinoline. The required trans isomer was finally isolated by preparative HPLC.
| 【1】 Zhi, L.; Marschke, K.B.; Jones, T.K.; Tegley, C.M.; Switching androgen receptor antagonists to agonists by modifying C-ring substituents on piperidino[3,2-g]quinolinone. Bioorg Med Chem Lett 1999, 9, 7, 1009. |
| 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) | 31305 | (E)-2-pentenoic acid | 13991-37-2 | C5H8O2 | 详情 | 详情 |
| (II) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (III) | 31306 | 3-anilinopentanoic acid | C11H15NO2 | 详情 | 详情 | |
| (IV) | 31307 | 2-ethyl-2,3-dihydro-4(1H)-quinolinone | C11H13NO | 详情 | 详情 | |
| (V) | 31308 | tert-butyl 2-ethyl-4-oxo-3,4-dihydro-1(2H)-quinolinecarboxylate | C16H21NO3 | 详情 | 详情 | |
| (VI) | 31309 | tert-butyl 2,3-diethyl-4-oxo-3,4-dihydro-1(2H)-quinolinecarboxylate | C18H25NO3 | 详情 | 详情 | |
| (VII) | 31310 | 2,3-diethyl-2,3-dihydro-4(1H)-quinolinone | C13H17NO | 详情 | 详情 | |
| (VIII) | 31311 | 2,3-diethyl-1,2,3,4-tetrahydroquinoline | C13H19N | 详情 | 详情 | |
| (IX) | 31313 | 2,3-diethyl-7-nitro-1,2,3,4-tetrahydroquinoline | C13H18N2O2 | 详情 | 详情 | |
| (X) | 31312 | 2,3-diethyl-1,2,3,4-tetrahydro-7-quinolinylamine; 2,3-diethyl-1,2,3,4-tetrahydro-7-quinolinamine | C13H20N2 | 详情 | 详情 | |
| (XI) | 25432 | ethyl 4,4,4-trifluoro-3-oxobutanoate | 372-31-6 | C6H7F3O3 | 详情 | 详情 |