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【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%

与该中间体有关的原料药合成路线共 3 条

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
Extended Information