|
【结 构 式】 
|
【药物名称】Cediranib, AZD-2171, Recentin 【化学名称】4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline 【CA登记号】288383-20-0 【 分 子 式 】C25H27FN4O3 【 分 子 量 】450.5054 |
【开发单位】AstraZeneca (SE, UK, US). 【药理作用】VEGFR Inhibitor，Antiangiogenic Agent，Oncolytic |
合成路线1
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
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 |