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【结 构 式】

【分子编号】65373

【品名】 

【CA登记号】 

【 分 子 式 】C16H21ClN3O2

【 分 子 量 】322.81446

【元素组成】C 59.53% H 6.56% Cl 10.98% N 13.02% O 9.91%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(IX)

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
Extended Information