【结 构 式】 |
【分子编号】65374 【品名】4-fluoro-5-hydroxy-2-methylindole; 2-Methyl-4-fluoro-5-hydroxyindole; 4-Fluoro-5-hydroxy-2-methyl-1H-indole 【CA登记号】288385-88-6 |
【 分 子 式 】C9H8FNO 【 分 子 量 】165.1670632 【元素组成】C 65.45% H 4.88% F 11.5% N 8.48% O 9.69% |
合成路线1
该中间体在本合成路线中的序号:(X)Vanillic acid (I) is condensed with 1-(3-chloropropyl)pyrrolidine (II) by means of K2CO3 and KI in hot DMF yielding 3-methoxy-4-[3-(1-pyrrolidinyl)propoxy]benzoic acid (III), which is nitrated with fuming HNO3 in TFA to afford the ortho-nitrobenzoic acid (IV). Subsequent chlorination of acid (IV) with SOCl2, followed by reaction with ammonia in THF/CH2Cl2, leads to the corresponding benzamide (V), which is reduced at the nitro group by means of Fe/HCl, providing the expected ortho-aminobenzoic acid (VI). The cyclization of (VI) with Gold’s reagent (VII) in dioxane gives the quinazolinone (VIII), which is converted to the 4-chloroquinazoline (IX) upon treatment with SOCl2 in the presence of a catalytic amount of DMF. Cediranib is finally obtained by condensation of chloroquinazoline (IX) with 4-fluoro-5-hydroxy-2-methylindole (X) in the presence of K2CO3 in hot DMF (1, 2). Scheme 1.
【1】 Hennequin, L.F., Ple, P., Stokes, E.S. et al. Structure-activity relationship, physicochemical and pharmacokinetic properties of AZD2171: A highly potent inhibitor of VEGF receptor tyrosine kinases. Proc Am Assoc Cancer Res (AACR) 2004, 45: Abst 4539. |
【2】 Hennequin, L.F.A., McKerrecher, D., Stokes, E.S.E., Ple, P. (AstraZeneca plc; AstraZeneca SA). Quinazoline derivatives as angiogenesis inhibitors. EP 1154774, EP 1553097, JP 2002536414, JP 2006273860, US 2006004017, US 7074800, WO 2000047212. |
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) | 17786 | 4-hydroxy-3-methoxybenzoic acid; Vanillic acid | 121-34-6 | C8H8O4 | 详情 | 详情 |
(II) | 65366 | 1-(3-Chloropropyl)pyrrolidine | 39743-20-9 | C7H14ClN | 详情 | 详情 |
(III) | 65367 | 3-methoxy-4-[3-(1-pyrrolidinyl)propoxy]benzoic acid | C15H21NO4 | 详情 | 详情 | |
(IV) | 65368 | 3-methoxy-6-nitro-4-[3-(1-pyrrolidinyl)propoxy]benzoic acid | C15H20N2O6 | 详情 | 详情 | |
(V) | 65369 | 3-methoxy-6-nitro-4-[3-(1-pyrrolidinyl)propoxy]benzamide | C15H21N3O5 | 详情 | 详情 | |
(VI) | 65370 | 6-amino-3-methoxy-4-[3-(1-pyrrolidinyl)propoxy]benzamide | C15H23N3O3 | 详情 | 详情 | |
(VII) | 65371 | Gold’s reagent | C6H14ClN2 | 详情 | 详情 | |
(VIII) | 65372 | C16H21N3O3 | 详情 | 详情 | ||
(IX) | 65373 | C16H21ClN3O2 | 详情 | 详情 | ||
(X) | 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 |
合成路线2
该中间体在本合成路线中的序号:(X)The intermediate 4-fluoro-5-hydroxy-2-methylindole (X) can be prepared by three alternative methods. The condensation of 2-fluoro-4-nitroanisole (XI) with 4-chlorophenoxyacetonitrile (XII) by means of potassium tert-butoxide produces a regioisomeric mixture of ortho-nitroarylacetonitriles (XIIIa) and (XIIIb) which, without separation, are reductively cyclized to indoles (XIVa) and (XIVb) by catalytic hydrogenation over Pd/C. After protection of indoles (XIV) as the respective N-Boc derivatives (XVa) and (XVb), metalation with tert-butyllithium followed by treatment with iodomethane yields the corresponding 1-Boc-2-methylindoles, which are further deprotected to (XVIa) and (XVIb) utilizing TFA. Demethylation of the mixture of methoxyindoles (XVI) with BBr3 in cold CH2Cl2 leads to the analogous hydroxyindoles, which are separated by column chromatography to provide the target 4-fluoro-5-hydroxy-2-methylindole (X) (2). In a different method, 2,3,4-trifluoronitrobenzene (XVII) is condensed with ethyl acetoacetate (XVIII) by means of NaH in THF followed by chromatographic separation of the resulting regioisomeric mixture to provide the 2-aryl acetoacetate (XIX). After acidic decarboxylation of (XIX), the obtained arylacetone derivative (XX) is protected as the dimethyl ketal (XXI) with trimethyl orthoformate and montmorillonite K10. Selective displacement of one fluoride group in (XXI) with sodium methoxide in methanol affords 1-(2-fluoro-3-methoxy-6-nitrophenyl)acetone dimethyl ketal (XXII), which is hydrolyzed to ketone (XXIII) under acidic conditions. The reductive cyclization of (XXIII) by means of TiCl3 and ammonium acetate provides 4-fluoro-5-methoxy-2-methylindole (XVIa), which is demethylated to (X) by using BBr3 as above (1, 2). Alternatively, the difluorophenyl ketal (XXI) is displaced with benzyl alcohol in the presence of NaH to give the benzyl ether (XXIV), which undergoes further ketal hydrolysis to the ketone (XXV) under acidic conditions. Finally, simultaneous cyclization and deprotection of (XXV) with H2 and Pd/C furnishes the desired 4-fluoro-5-hydroxy-2-methylindole (X) (2). Scheme 2.
【1】 Hennequin, L.F., Ple, P., Stokes, E.S. et al. Structure-activity relationship, physicochemical and pharmacokinetic properties of AZD2171: A highly potent inhibitor of VEGF receptor tyrosine kinases. Proc Am Assoc Cancer Res (AACR) 2004, 45: Abst 4539. |
【2】 Hennequin, L.F.A., McKerrecher, D., Stokes, E.S.E., Ple, P. (AstraZeneca plc; AstraZeneca SA). Quinazoline derivatives as angiogenesis inhibitors. EP 1154774, EP 1553097, JP 2002536414, JP 2006273860, US 2006004017, US 7074800, WO 2000047212. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XIIIa) | 65375 | (6-fluoro-5-methoxy-2-nitrophenyl)acetonitrile | C9H7FN2O3 | 详情 | 详情 | |
(XIIIb) | 65376 | (4-fluoro-5-methoxy-2-nitrophenyl)acetonitrile | C9H7FN2O3 | 详情 | 详情 | |
(XIVa) | 65377 | 4-fluoro-5-methoxy-1H-indole | 288385-89-7 | C9H8FNO | 详情 | 详情 |
(XIVb) | 65378 | 6-fluoro-5-methoxy-1H-indole | 63762-83-4 | C9H8FNO | 详情 | 详情 |
(Xva) | 65379 | 4-fluoro-5-methoxy-1-Boc-indole | C14H16FNO3 | 详情 | 详情 | |
(XVb) | 65380 | 6-fluoro-5-methoxy-1-Boc-indole | C14H16FNO3 | 详情 | 详情 | |
(XVIa) | 65381 | 4-fluoro-5-methoxy-2-methyl-1H-indole | 288385-93-3 | C10H10FNO | 详情 | 详情 |
(XVIb) | 65382 | 6-fluoro-5-methoxy-2-methyl-1H-indole | C10H10FNO | 详情 | 详情 | |
(X) | 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 |
(XI) | 62907 | 2-Fluoro-4-nitrophenyl methyl ether; 2-Fluoro-1-methoxy-4-nitrobenzene | 455-93-6 | C7H6FNO3 | 详情 | 详情 |
(XII) | 29601 | 2-(4-chlorophenoxy)acetonitrile | 3598-13-8 | C8H6ClNO | 详情 | 详情 |
(XVII) | 30677 | 1,2,3-trifluoro-4-nitrobenzene; 2,3,4-trifluoronitrobenzene | 771-69-7 | C6H2F3NO2 | 详情 | 详情 |
(XVIII) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate;Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
(XIX) | 65383 | ethyl 2-acetyl-2-[(2-nitro-5,6-difluoro)phenyl]acetate | C12H11F2NO5 | 详情 | 详情 | |
(XX) | 65384 | 1-(2,3-Difluoro-6-nitrophenyl)propan-2-one; 3-Acetylmethyl-1,2-difluoro-4-nitrobenzene | 121247-16-3 | C9H7F2NO3 | 详情 | 详情 |
(XXI) | 65385 | C11H13F2NO4 | 详情 | 详情 | ||
(XXII) | 65386 | C12H16FNO5 | 详情 | 详情 | ||
(XXIII) | 65387 | C10H10FNO3 | 详情 | 详情 | ||
(XXIV) | 65388 | C18H20FNO5 | 详情 | 详情 | ||
(XXV) | 65389 | C16H14FNO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(XV)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 |