5-amino-3-phenoxyphenyl pyrazole synthesis

The active ingredient, 5-amino-3-phenoxyphenyl pyrazole, of the oncolitic drug ibrutinib was synthesized starting from 4-phenoxy benzoic acid. Enol ether 24 was synthesized via activation of the carbonyl carbon of 4-phenoxy benzoic acid with ethyl chloroformate followed by addition of malononitrile. The hydroxyl group of the enol ether 24 was treated with MsCl and transformed to the facile chloro leaving group in order to form the pyrazole. The synthesis of 5-amino-3-phenoxyphenyl pyrazole was achieved in 3 steps via the reaction of 86 with hydrazine hydrate. After optimization of the reaction conditions, the obtained crude product was carried on to the next step without purification to synthesize the targeted product 28. Furthermore, in this work the "one-pot" synthesis of 28 was achieved on a 2 gram scale.