Definitive Screening Design Optimization of Chemoenzymatic Process for (R)‐3‐(Carbamoylmethyl)‐5‐methylhexanoicacid: A Key Intermediate of Pregabalin

Abstract

A practical scalable chemoenzymatic process was developed for the synthesis of (R)‐3‐(carbamoylmethyl)‐5‐methylhexanoic acid (2) (R‐CMHA) and achieved 98.5% ee and 99% HPLC purity at pilot scale. The systematic statistical design of experimentation (DOE) of esterification, enzymatic desymmetrization and CaCl2 assisted amidation led to the robust design space.

Understanding and Controlling the Formation of an N-Alkyl Impurity in Olmesartan Medoxomil: A Derivative via Michael-Type Addition between Tetrazole and Mesityl Oxide In Situ Generated from Acetone

“…However, since its invention, the use of a DSD in organic synthesis is sporadic, and only a few representative examples were found , in the literature. Therefore, this work intends to form an example of its use in the crucial factors screening for organic process quality control.…”

“…23 In addition, it helps to identify the causes of nonlinear effects by fielding each continuous factor at three levels, which contain second-order interactions and quadratic effects, 24 whereas in the classical screening design, continuous factors have only two levels, with some of the interactions confounded with each other. 25 However, since its invention, the use of a DSD in organic synthesis is sporadic, and only a few representative examples were found 26,27 in the literature. Therefore, this work intends to form an example of its use in the crucial factors screening for organic process quality control.…”