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【结 构 式】 
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【分子编号】65371 【品名】Gold’s reagent 【CA登记号】 |
【 分 子 式 】C6H14ClN2 【 分 子 量 】149.64334 【元素组成】C 48.16% H 9.43% Cl 23.69% N 18.72% |
合成路线1
该中间体在本合成路线中的序号：(VII)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 |