(507a) Continuous Flow Nitration: Research and Process Development

Bi-phasic nitration is commonly executed for making nitro intermediates in the pharmaceutical industry. Their scale-up, however, is generally problematic because of the following concerns: high exothermicity, need for proper mixing and liquid-liquid dispersion, and formation of energetic di-nitro by-products. A detailed understanding of these aspects is required to ensure proper scale-up of nitration.

In this talk we will present a case study of a scale-up of 1-methyl-4-(trifluoromethyl)benzene nitration using KNO₃/H₂SO₄ as the nitrating agent. To understand these aspects, targeted experiments were performed to prepare a mass transfer with chemical reaction model (using film theory) to quantify the relation between liquid-liquid dispersion with the conversion and di-nitro impurity levels. Model predictions showed that acceptable conversion required a Hatta number of at least 1.9, with 80% of reaction done in the film. To meet these requirements, a CSTR was chosen as the preferred contacting device, with proper heat transfer protocols in place to handle the exotherm.

The work presented here was sponsored by AbbVie. AbbVie contributed to the design, research, and interpretation of data, writing, reviewing, and approving the presentation. All authors are employees of AbbVie.