Continuous flow aminolysis under high temperature and pressure

• Bryan Li¹
• Scott Bader^{1, 2}
• Steve M. Guinness¹
• Sally Gut Ruggeri¹
• Cheryl M. Hayward¹
• Steve Hoagland¹
• John Lucas^{1, 3}
• Ruizhi Li¹
• David Limburg¹
• J. Christopher McWilliams¹
• Jeffrey Raggo¹
• John Van Alsten^{1, 4}

• ¹Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT, 06340, USA
• ²Celgene Corporation, 556 Morris Ave, Summit, NJ, USA
• ³Rhodes Technologies, 498 Washington Street, Coventry, RI, USA
• ⁴Nitto Denko Avecia Inc, 155 Fortune Blvd., Milford, MA, USA

Under continuous processing conditions, C-N bond formation via SN2 and SNAr substitutions by amines can be an effective preparative method, especially when volatile amines are used under high pressure and temperature. We have demonstrated SN2 substitution of a 2° mesylate with ammonia and opening of an epoxide with benzylamine, and SNAr substitution of a heteroaryl chloride with aqueous ammonia on multi-kg scales. The homogeneous continuous processes offered better process control, higher efficiency, and comparable or superior reaction profiles and yields to batch conditions.

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