Recently implementation of the mechano-chemistry approach for carrying out some of the steps in the synthesis of API’s, is considered an attractive and environment friendly approach as it permits solvent-free reactions or the use of activators for the reaction, making the process efficient and economical. In this study, we focused on the modification of some steps in the drug Ivacaftor, which is one of the most expensive drugs in the market. For the first time, a mechano-chemical approach was employed to replace some steps in the synthesis of Ivacaftor. One of the fragment 5-amino-2,4-di‑tert‑butyl‑phenol (5) required in the synthesis of Ivacaftor was prepared in two steps from commercially available 2, 4-bis(1,1-dimethylethyl)-5-nitrophenyl methyl carbonate (6) by mechano-chemistry approach in good yields. In the last step, fragment 5-amino-2,4-di‑tert‑butyl‑phenol (5) was coupled with 4-quinolone-3-carboxylic acid (4) using mechano-chemistry to obtain Ivacaftor (1) in good yields. The advantage of this methodology was it avoided the use of solvent in all three steps of ivacaftor synthesis, making the process efficient and economical.

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