The Process Development of Ravuconazole: An Efficient Multikilogram Scale Preparation of an Antifungal Agent

Abstract

The development of a safe, robust process for the preparation of ravuconazole (1), an antifungal agent, is described. The discovery and development of procedures enabling the efficient synthesis of multikilogram quantities of 1 and the process demonstration through plant scale preparations are presented. A controlled means to prepare a Grignard reagent and utilization of Fourier Transform Infrared spectroscopy (FTIR) monitoring to safely conduct the reaction is featured.

Comparative performance evaluation and systematic screening of solvents in a range of Grignard reactions

“…The Grignard complex was stirred at 0 °C for 30 min and then a solution of 2-butanone (3.24 g, 4.5 mmol in 8 mL of 2-MeTHF) was added slowly maintaining the temperature below 5 °C. The reaction mixture was stirred at room temperature for 4 h and then poured into a beaker containing 10 g of NH 4 Cl in 80 mL of ice water. The mixture was extracted with ether (3 × 30 mL) and the combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo.…”

“…In addition to the broad applications on a research scale, Grignard reactions have also been adapted to a large scale and are the pivotal steps in the manufacture of numerous complex molecules. From a pharmaceutical perspective, the Grignard reaction has been employed as a key step in numerous syntheses such as that of tramadol, 3 ravuconazole, 4 naproxen, 5 ibuprofen, 6 aprepitant, 7 droloxifene, 8 and tamoxifen 9 ( Fig. 1).…”

Development of a Practical Synthesis of a Pyrimidine Derivative with Fungicidal Activity

“…Potential safety hazards associated with o -fluoro Grignard reagents are well-documented in the literature . These reactive intermediates have been reported to form arynes via elimination, which can potentially result in a runaway reaction.…”

Improved Laboratory Synthesis of YC-071, a Potent Azole Antifungal Agent

“…The original medicinal chemistry route to YC-071 is based on a ring-opening reaction of epoxide 5 (Scheme 1) 8 by an amino fragment. This is the common synthetic method used for structurally similar triazole agents such as 6, 9 7, 10 and 8 11 (Fig.…”