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【结 构 式】

【分子编号】69468

【品名】2-(4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)propan-2-ol

【CA登记号】

【 分 子 式 】C19H19FN4O2

【 分 子 量 】354.384

【元素组成】C 64.40% H 5.40% F 5.36% N 15.81% O 9.03%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(VIII)

Deprotection of the 6-benzyloxypyrrolotriazine (I) by transfer hydrogenation with ammonium formate and Pd/C in DMF provides alcohol (II) , which is condensed with (R)-propylene oxide (III) in the presence of triethylamine , and optionally LiCl , in ethanol at 70 °C to give the hydroxypropyl derivative brivanib (IV) . Subsequent coupling of alcohol (IV) with N-Cbz-L-alanine (V) by means of HATU in the presence of DIEA and DMAP in DMF or THF gives the N-protected alanine ester (VI), which is finally deprotected by treatment with ammonium formate and Pd/C in DMF . Alcohol intermediate (II) is alternatively obtained by addition of methylmagnesium bromide to the 6-(ethoxycarbonyl)pyrrolotriazine derivative (VII) in THF to afford the tertiary alcohol (VIII), which undergoes oxidative cleavage to the key 6-hydroxypyrrolotriazine (II) in the presence of H2O2 and BF3·Et2O in dichloromethane .

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.
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) 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
(II) 69464 4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol C16H13FN4O2 详情 详情
(III) 62110 (R)-(+)-PROPYLENE OXIDE; 1,2-Epoxypropane; R(+)-Propylene oxide; R(+)-Methyloxirane; (R)-propylene oxide; [(R-(+)-1,2-EPOXYPROPANE]; (R)-(+)-1,2-Propylene oxide; (R)-(+)-1,2-Epoxypropane 15448-47-2 C3H6O 详情 详情
(IV) 69465 (R)-1-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)oxy)propan-2-ol C19H19FN4O3 详情 详情
(V) 10445 N-Carbobenzyloxy-L-alanine;N-Benzyloxycarbonyl-L-alanine;Carbobenzyloxy-L-alanine;Z-L-Alanine;Z-Ala-OH;BenzyloxycarbonylLalanine;N-Cbz-L-alanine 1142-20-7 C11H13NO4 详情 详情
(VI) 69466 (R)-(S)-1-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)oxy)propan-2-yl 2-(((benzyloxy)carbonyl)amino)propanoate C30H30FN5O6 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
(VIII) 69468 2-(4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl)propan-2-ol C19H19FN4O2 详情 详情
Extended Information