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【结 构 式】 
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【分子编号】30677 【品名】1,2,3-trifluoro-4-nitrobenzene; 2,3,4-trifluoronitrobenzene 【CA登记号】771-69-7 |
【 分 子 式 】C6H2F3NO2 【 分 子 量 】177.0826296 【元素组成】C 40.7% H 1.14% F 32.19% N 7.91% O 18.07% |
合成路线1
该中间体在本合成路线中的序号：(I)The partial hydrolysis ot 2,3,4-trifluoronitrobenzene (I) with KOH in DMSO gives 2,3-difluoro-6-nitrophenol (II), which by condensation with chloroacetone (III) by means of K2CO3 - KI in refluxing acetone yields 2-acetonyloxy-3,4-difluoronitrobenzene (IV). The reductive cyclization of (IV) with H2 over Raney-Ni in ethanol affords 7,8-difluoro-2,3-dihydro-3-methyl-4H-benzoxazine (V), which is condensed with diethyl ethoxymethylenemalonate (VI) by heating at 145 C giving the malonic derivative (VII). The cyclization of (VII) by heating at 145 C with ethyl polyphosphate (PPE) yields ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (VIII), which is hydrolyzed with HCl in refluxing acetic acid affording the corresponding free acid (IX). Finally, this compound is condensed with N-methylpiperazine (X) in DMSO at 110 C.
| 【1】 Hayakawa, I.; Hiramitsu, T.; Tanaka, Y. (Daiichi Pharmaceutical Co., Ltd.); Benzoxazine derivs.. EP 0047005; US 4382892 . |
| 【2】 Serradell, M.N.; Blancafort, P.; Castaner, J.; DL-8280. Drugs Fut 1983, 8, 5, 395. |
| 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) | 30677 | 1,2,3-trifluoro-4-nitrobenzene; 2,3,4-trifluoronitrobenzene | 771-69-7 | C6H2F3NO2 | 详情 | 详情 |
| (II) | 30678 | 2,3-difluoro-6-nitrophenol | 82419-26-9 | C6H3F2NO3 | 详情 | 详情 |
| (III) | 15288 | 1-Chloroacetone; Chloroacetone | 78-95-5 | C3H5ClO | 详情 | 详情 |
| (IV) | 30679 | 1-(2,3-difluoro-6-nitrophenoxy)acetone | C9H7F2NO4 | 详情 | 详情 | |
| (V) | 30680 | 7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine | C9H9F2NO | 详情 | 详情 | |
| (VI) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (VII) | 30681 | diethyl 2-[(7,8-difluoro-3-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methylene]malonate | C17H19F2NO5 | 详情 | 详情 | |
| (VIII) | 30682 | ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate | C15H13F2NO4 | 详情 | 详情 | |
| (IX) | 12058 | 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid; 8,9-Difluoro-3-me-6-oxo-2,3-dihydro-6h-1-oxa-3a-aza-phenalene-5-carboxylic acid | 82419-35-0 | C13H9F2NO4 | 详情 | 详情 |
| (X) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVII)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 |