摘要
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 AstraZen- eca, 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.
出处
《中国药物化学杂志》
CAS
CSCD
2017年第6期454-458,共5页
Chinese Journal of Medicinal Chemistry
