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目的 改进成纤维细胞生长因子受体拮抗剂AZD4547(1)的合成方法.方法 以3,5-二甲氧基苯甲醛(2)为起始原料,经过羟醛缩合、催化氢化、酯化反应制备3-(3,5-二甲氧基苯基)丙酸乙酯(5),5通过分步法或者一锅法制得关键中间体5-(3,5-二甲氧基苯基乙基)-1H-吡唑-3-胺(7).7再与4-((3S,5R)-3,5-二甲基哌嗪基-1-基)苯甲酸乙酯(9)反应生成酰胺,最终合成目标物AZD4547(1).结果与结论 分步法和一锅法分别将化合物7的收率由文献中的42.0％提高到86.0％和54.0％(以5计).分步法显著地提高了化合物7的收率,一锅法操作更加简便,反应条件更加安全、温和.“,”Pyrazole compound AZD4547 N-(5-(3,5-dimethoxyphenethyl)-1H-pyrazol-5-yl)-4-((3R,5S)-3,5-dimethylpiperazin-yl) benzamide is a fibroblast growth factor receptor inhibitor,developed by AstraZeneca,for potential cancer oral therapy.In this paper,3-(3,5-dimethoxyphenyl) propionate was synthesized based on the reported route.In the presence of n-butyllithium,3-(3,5-dimethoxyphenyl) propionate reacted with acetonitrile to synthesize 5-(3,5-dimethoxybenzeneyl)-3-carbonyl-pentanenitrile,followed by cyclization with hydrazine hydrate to give 5-(3,5-dimethoxyphenyethyl)-1H-pyrazol-3-amine.At the same time,a new synthetic method by one-pot reaction to afford 5-(3,5-dimethoxyphenethyl)-1H-pyrazol-3-amine was found,in which potassium tert-butoxide was selected as the alkaline reagent.As a result,two-step method and one-pot reaction increased the yield from 42.0％ reported in the literature to 86.0％ and 54.0％,respectively.Combination of 4-((3S,5R)-3,5-dimethylpiperazin-1-yl) benzoate and 5-(3,5-dimethoxy-phenethyl)-1H-pyrazol-3-amine was promoted by Al(CH3)3,affording AZD4547.Finally,the total yield of AZD4547 was increased from 21.0％ reported in the literature to 54.0％ and 34.0％,respectively.The structures of the target compound and some important intermediates have been identified by 1H-NMR and MS.Moreover,the two-step method significantly improves the total yield of AZD4547,and the operation of one-pot reaction is simpler and the reaction conditions are more safe and gentle.