(758d) Reaction Engineering for a Sulfonamide Intermediate

Reaction engineering of a sulfonamide synthesis from early through mid and late stage development is discussed, with emphasis on consideration of reaction pathways.  Reaction of sulfonyl chloride with ammonia in acetone solvent eliminates the use of aqueous ammonium hydroxide at extreme cryogenic temperatures (-60 °C), or for solid ammonium carbamate to achieve the amidation.  The order of addition in the semi-batch amidation reaction was chosen to minimize use of excess equivalents of amidation reagent. In the revised process, the ammonia / acetone solution is charged into a solution of sulfonyl chloride, maintained at sub-ambient temperature (NMT -10 °C).  Hence, both temperature and reagent equivalents are used to control aniline sulfonamide impurity levels. Formerly, the sulfonyl chloride was added to an excess of ammonium carbamate reagent at sub-ambient temperatures, and was promptly quenched to avoid over-reaction.  The revised process affords robustness in design space including less potential for over reaction to aniline impurity.