Use of DOE for Rapid Development of a Red-Al Reduction Process for the Synthesis of 3,4-Isopropylidenedioxypyrrolidine Hydrotosylate

Abstract

Statistical design of experiments (DOE) was used to rapidly optimize Red-Al reduction of an imide to produce, after deprotection and salt formation, 3,4-isopropylidenedioxypyrrolidine hydrotosylate (1), an intermediate in the synthesis of Ingliforib. A Red-Al reduction process was successfully scaled to produce multikilogram quantities of 1, thus demonstrating a safer and more economical process. Further development resulted in an optimized procedure, which not only avoided borane reduction but also allowed the three-step procedure to be performed without isolation of the intermediates, solvent exchange, or distillation.

Statistical DoE Approach to the Removal of Palladium from Active Pharmaceutical Ingredients (APIs) by Functionalized Silica Adsorbents

“…An alternative approach is to use statistical DoE, a well-known and widely used method − to obtain the largest possible amount of information on a particular process from the minimum number of experiments. Furthermore, it also provides a clearer picture of how the studied parameters influence the variation in performance.…”

Process Safety Evaluation and Scale-up of a Lactam Reduction with NaBH4 and TFA

“…Lactam reduction proceeded when several reducing agents were employed. The amount of byproduct 3 could not be maintained within the desired range when Vitride (NaAlH 2 (OCH 2 CH 2 OCH 3 ) 2 ) was used (entry 2). Using BH 3 ·THF caused the lactam moiety to be reduced without forming byproduct 3 (entry 3).…”

“…Several reducing agents having reactivities similar to LiAlH 4 are available; however, some reagents cause difficulties when a reaction using them is scaled up. For example, BH 3 ·THF is a high-cost reagent and presents a storage hazard due to the risk of explosion. , Meanwhile, a combination of NaBH 4 and additives is equivalent to LiAlH 4 in terms of its reducing properties and is easy to handle in a manufacturing plant . Therefore, we focused on the reduction conditions during the conversion of 1 to 2 using NaBH 4 and additives.…”

Design of Experiments (DoE) and Process Optimization. A Review of Recent Publications

“…A Pfizer/DSM collaboration applied DoE to develop a scalable synthesis of pyrrolidine 106 , an intermediate in the synthesis of ingliforib, a candidate for treatment of diabetes (Scheme ). Reduction of imide 104 to amine 106 in toluene with BH 3 generated from NaBH 4 /BF 3 proceeded in good yield, but generated 3–5% of ether 107 .…”