- A novel and efficient route for synthesis of Taladegib
-
Taladegib (LY-2940680), a small molecule Hedgehog signalling pathway inhibitor, was obtained from N-benzyl-4-piperidone via Borch reductive amination, acylation with 4-fluoro-2-(trifluoromethyl)benzoyl chloride, debenzylation, substitution with 1,4-dichlorophthalazine and Suzuki cross-coupling reaction with 1-methyl-1H-pyrazole-5-boronic acid. The advantages of this synthesis route were the elimination of Boc protection and deprotection and the inexpensive starting materials. Furthermore, the debenzylation reaction was achieved with simplified operational procedure using ammonium formate as hydrogen source that provided high reaction yield. This synthetic procedure was suitable for large-scale production of the compound for biological evaluation and further study.
- Guo, Mingliang,Hong, Kwon Ho,Lv, Yongfeng,Ding, Yu,Li, Congcong,Xu, Hua,Qi, Wenxiu,Chen, Junqing,Ji, Min,Cai, Jin
-
-
Read Online
- Synthetic method of Taladegib
-
The invention discloses a synthetic method of Taladegib. The synthetic method is characterized by comprising the following steps that reductive amination is carried out on N-benzyl-4-piperidone to obtain a compound in formula VI; in the presence of an organic base, an acylation reaction is carried out on the compound in the formula VI and an acylation reagent to obtain a compound in the formula VIII; the acylation reagent is 4-fluoro-2-(trifluoromethyl)benzoyl chloride; in the presence of a hydrogen source and a palladium catalyst, debenzylation is carried out on the compound in formula VIII to obtain a compound in the formula IX; in the presence of an inorganic base, the compound in the formula IX is reacted with 1,4-dichloro phthalazine to obtain a compound in the formula X; in the presence of the inorganic base and the palladium catalyst, an SUZUKI coupling reaction is carried out on the compound in the formula X and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester to obtain Taladegib. According to the invention, the process route is improved, cheap N-benzyl-4-piperidone is taken as a starting material, the processes of Boc protection and deprotection are removed to reduce the synthesis steps and reduce the production cost.
- -
-
-
- DISUBSTITUTED PHTHALAZINE HEDGEHOG PATHWAY ANTAGONISTS
-
The present invention provides novel 1,4-disubstituted phthalazine hedgehog pathway antagonists useful in the treatment of cancer.
- -
-
Page/Page column 6
(2010/12/31)
-
