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【结 构 式】 
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【分子编号】48297 【品名】2-oxobutyric acid 【CA登记号】600-18-0 |
【 分 子 式 】C4H6O3 【 分 子 量 】102.08984 【元素组成】C 47.06% H 5.92% O 47.02% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of 2-pyrrolidone (I) with 2-oxobutyric acid (II) in refluxing toluene gives 2-(2-oxopyrrolidin-1-yl)-2-butenoic acid (III), which is treated with PCl5 in THF to yield the acyl chloride (IV). The reaction of (IV) with dry ammonia affords the corresponding amide (V), which is finally submitted to an asymmetric hydrogenation with H2 over a chiral Rh catalyst to provide the desired chiral butyramide.
| 【1】 Michel, P.; Differding, E.; Pasau, P.; Kenda, B.; Lallemand, B.; Matagne, A.; Talaga, P. (UCB SA); 2-Oxo-1-pyrrolidine derivs., processes for preparing them and their uses. WO 0162726; WO 0164637 . |
| 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) | 27397 | 2-Pyrrolidinone | 616-45-5 | C4H7NO | 详情 | 详情 |
| (II) | 48297 | 2-oxobutyric acid | 600-18-0 | C4H6O3 | 详情 | 详情 |
| (III) | 61959 | (Z)-2-(2-oxo-1-pyrrolidinyl)-2-butenoic acid | C8H11NO3 | 详情 | 详情 | |
| (IV) | 61960 | (Z)-2-(2-oxo-1-pyrrolidinyl)-2-butenoyl chloride | C8H10ClNO2 | 详情 | 详情 | |
| (V) | 61961 | (Z)-2-(2-oxo-1-pyrrolidinyl)-2-butenamide | C8H12N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Friedländer cyclization between 2-aminobenzophenone (I) and 2-oxobutyric acid (II) by means of NaOMe in MeOH gives carboxylic acid (III), which is then converted into the corresponding acid chloride (IV) by reaction with SOCl2 in CH2Cl2. Finally, the target product is obtained by reaction of (IV) with N-methylbenzylamine (V) by means of Et3N.
| 【1】 Anzini, M.; et al.; Synthesis of 2-substituted 2,3-dihydro-9-phenyl-1H-pyrrolo[3,4-b]quinolin-3-ones as potential peripheral benzodiazepine-receptor ligands. Heterocycles 1994, 38, 1, 103. |
| 【2】 Manzoni, C.; Anzini, M.; Cappelli, A.; Giorgi, G.; Menziani, M.C.; Vomero, S.; De Benedetti, P.G.; Mapping the peripheral benzodiazepine receptor binding site by conformationally restrained derivatives of 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195). J Med Chem 1997, 40, 18, 2910. |
| 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) | 21101 | (2-aminophenyl)(phenyl)methanone; 2-Aminobenzophenone | 2835-77-0 | C13H11NO | 详情 | 详情 |
| (II) | 48297 | 2-oxobutyric acid | 600-18-0 | C4H6O3 | 详情 | 详情 |
| (III) | 48298 | 3-methyl-4-phenyl-2-quinolinecarboxylic acid | C17H13NO2 | 详情 | 详情 | |
| (IV) | 48299 | 3-methyl-4-phenyl-2-quinolinecarbonyl chloride | C17H12ClNO | 详情 | 详情 | |
| (V) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The intermediates indolyloxy pyrrolotriazines (I) and (VII) can be prepared as follows. Cyclization of 2-oxobutyric acid (IX) with formamidine hydrochloride and hydrazine hydrate in the presence of AcOH in refluxing EtOH yields 6-ethyl-1,2,4-triazin-5-one (X). Subsequent condensation of triazinone (X) with 3-bromopyruvic acid (XI) in aqueous solution at 90 °C gives the pyrrolotriazine carboxylic acid (XII), which is esterified with refluxing EtOH/HCl to furnish ester (XIII) . Chlorination of hydroxypyrrolotriazine (XIII) with POCl3, optionally in the presence of DIEA, in refluxing toluene affords the 4-chloro derivative (XIV) , which is condensed with 4-fluoro-5-hydroxy-2-methylindole (XV) by means of K2CO3 in DMF to yield the indolyloxypyrrolotriazine adduct (VII) . Alternatively, displacement of chlorine in compound (XIV) with ethanolic NaOEt yields the 4-ethoxy derivative (XVI). Then, addition of methylmagnesium bromide to the ester group of (XVI) in THF leads to the tertiary alcohol (XVII), which undergoes oxidative cleavage to 4-ethoxy-6-hydroxy-5-methylpyrrolo[2,1-f]-1,2,4-triazine (XVIII) by treatment with H2O2 and BF3·Et2O in CH2Cl2. After protection of the hydroxyl group of (XVIII) with benzyl bromide and K2CO3 in DMF, selective cleavage of the O-ethyl group in the resulting diether (XIXa) by means of HCl in hot ethanol provides 6-benzyloxy-4-hydroxy-5-methylpyrrolo[2,1-f]-1,2,4-triazine (XXI) . Similarly, the 4-phenoxy analogue (XX) is protected as the corresponding benzyl ether (XIXb), which undergoes O-phenyl group cleavage to (XXI) upon heating with HCl . Reaction of alcohol (XXI) with POCl3 in refluxing toluene provides the 4-chloro derivative (XXII), which is then coupled with 4-fluoro-5-hydroxy-2-methylindole (XV) by means of NaH in DMF to provide intermediate (I) .
| 【1】 Bhide, R.S., Cai, Z.W., Zhang, Y.Z. et al. Discovery and preclinical studies of (R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor. J Med Chem 2006, 49(7): 2143-6. |
| 【2】 Cai, Z.-W., Qian, L., Bhide, R., Barbosa, A. (Bristol-Myers Squibb Co.).Novel inhibitors of kinases. EP 1434290, JP 2005538989, US 2004072832, US 6869952, WO 2004009784. |
| 【3】 Cai, Z.W., Zhang, Y.Z., Borzilleri, R.M. et al. Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl) 2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215). J Med Chem 2008, 51(6):1976-80. |
| 【4】 Chen, B.-C., Zhao, R., Sundeen, J.E., Leftheris, K., Hynes, J., Wrobleski,S.T. (Bristol-Myers Squibb Co.). Process for preparing pyrrolotriazine kinase inhibitors. JP 2006516653, US 2004157846, WO 2004072030. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIXa) | 69477 | 6-(benzyloxy)-4-ethoxy-5-methylpyrrolo[2,1-f][1,2,4]triazine | C16H17N3O2 | 详情 | 详情 | |
| (XIXb) | 69478 | 6-(benzyloxy)-5-methyl-4-phenoxypyrrolo[2,1-f][1,2,4]triazine | C20H17N3O2 | 详情 | 详情 | |
| (I) | 69463 | 6-(benzyloxy)-4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine | C23H19FN4O2 | 详情 | 详情 | |
| (VII) | 69467 | ethyl 4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate | C19H17FN4O3 | 详情 | 详情 | |
| (IX) | 48297 | 2-oxobutyric acid | 600-18-0 | C4H6O3 | 详情 | 详情 |
| (X) | 69469 | 6-ethyl-1,2,4-triazin-5(4H)-one | C5H7N3O | 详情 | 详情 | |
| (XI) | 69470 | 3-bromopyruvic acid;Bromopyruvic acid | 1113-59-3 | C3H3BrO3 | 详情 | 详情 |
| (XII) | 69471 | 4-hydroxy-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid | C8H7N3O3 | 详情 | 详情 | |
| (XIII) | 69472 | ethyl 4-hydroxy-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate | C10H11N3O3 | 详情 | 详情 | |
| (XIV) | 69473 | 4-Chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylicacid ethyl ester;ethyl 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate | 427878-41-9 | C10H10ClN3O2 | 详情 | 详情 |
| (XV) | 65374 | 4-fluoro-5-hydroxy-2-methylindole; 2-Methyl-4-fluoro-5-hydroxyindole; 4-Fluoro-5-hydroxy-2-methyl-1H-indole | 288385-88-6 | C9H8FNO | 详情 | 详情 |
| (XVI) | 69474 | ethyl 4-ethoxy-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate | C12H15N3O3 | 详情 | 详情 | |
| (XVII) | 69475 | 2-(4-ethoxy-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)propan-2-ol | C12H17N3O2 | 详情 | 详情 | |
| (XVIII) | 69476 | 4-ethoxy-6-hydroxy-5-methylpyrrolo[2,1-f]-1,2,4-triazine;4-ethoxy-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol | C9H11N3O2 | 详情 | 详情 | |
| (XX) | 69479 | 5-methyl-4-phenoxypyrrolo[2,1-f][1,2,4]triazin-6-ol | C13H11N3O2 | 详情 | 详情 | |
| (XXI) | 69480 | 6-(benzyloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-ol;6-benzyloxy-4-hydroxy-5-methylpyrrolo[2,1-f]-1,2,4-triazine | C14H13N3O2 | 详情 | 详情 | |
| (XXII) | 69481 | 6-(benzyloxy)-4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine | C14H12ClN3O | 详情 | 详情 |