BMS-582664;Brivanib alaninate, -Drug Synthesis Database

【结构式】

【药物名称】BMS-582664;Brivanib alaninate

【化学名称】L-Alanine 2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1(R)-methylethyl ester

【CA登记号】649735-63-7

【分子式】C₂₂H₂₄FN₅O₄

【分子量】441.4555

【开发单位】Bristol-Myers Squibb Co. (US)

【药理作用】VEGFR/FGFR Inhibitor；Oncolytic

合成路线1 合成路线2

合成路线1

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 .

参考文献中间体

【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

合成路线2

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) .

参考文献中间体

【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

Extended Information

Drug NewChemical Entity Original Patent(1)