Mechanistic Details and Process Implications of Azide Mediated Conversion Route of Carboxylic Acid to Isocyanate

Mechanistic Details and Process Implications of Azide Mediated Conversion Route of Carboxylic Acid to Isocyanate

Anuj A. Verma, Herbert Ogutu, Yuanyuan Li, Ann M. Czyzewski, Su Yu, & Xiu C. Wang

Process Research & Development, AbbVie Inc., North Chicago, IL

The conversion of a carboxylic acid to an isocyanate via the Curtius rearrangement is a commercially attractive route in the pharmaceutical and chemical industries. Traditionally, the carboxylic acid is converted to acyl azide at 20°C by using diphenyl phosphoryl azide (DPPA) as the azide source. The acyl azide is subsequently heated to enable Curtius rearrangement to form isocyanate. A safety concern is identified in handling a pot of acyl azide across scales of operation and it is desired to minimize the inventory of that azide. Herein, we describe a process which minimizes that inventory. The process synthesis was accomplished by developing a generalized azide chemistry/reaction engineering platform (attached to Curtius reactions) to critically evaluate and identify optimal processes which are inherently safe at different scales of operation. The platform involves a detailed mechanistic understanding of product formation along-with impurity generation, and represents a step above traditional kinetic modeling by elucidating optimal reagent selection rules in addition to traditional reaction engineering solutions to reduce impurity generation and increase the product formation rate.

AbbVie contributed to the design, research, and interpretation of data, writing, reviewing, and approving the publication.  Anuj A. Verma, Herbert Ogutu, Yuanyuan Li, Ann M. Czyzewski, Su Yu, and Xiu C. Wang are AbbVie employees who worked on this project.