【结 构 式】 |
【分子编号】69481 【品名】6-(benzyloxy)-4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine 【CA登记号】 |
【 分 子 式 】C14H12ClN3O 【 分 子 量 】273.7216 【元素组成】C 61.43% H 4.42% Cl 12.95% N 15.35% O 5.85% |
合成路线1
该中间体在本合成路线中的序号:(XXII)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 |