Synthesis of a pre-operative anesthetic Midazolam: Scale-up issues and challenges

ORGN 164

Madhup K. Dhaon, madhup.dhaon@abbott.com1, Deborah A. Davis, Deborah.Davis@abbott.com2, Grant Esser, Perry Labib, Ashok V. Bhatia, Ashok.bhatia@abbott.com3, Denton Langridge, Denton.langridge@abbott.com3, Gregory Brill, Gregory.brill@abbott.com4, and Daniel Chou, Daniel.Chou@abbott.com4. (1) Process R&D, GPRD, Abbott Laboratories, 1400 N. Sheridan Road, Bldg. R-13, North Chicago, IL 60064-6291, (2) GPRD Process Chemistry, Abbott Laboratories, 1400 N. Sheridan Road, North Chicago, IL 60064, (3) Process GPRD, D-R450, Abbott Laboratories, 1400 N. Sheridan Road, Bldg. R-13, North Chicago, IL 60064-6291, (4) Process Analytical R&D, GPRD, Abbott Laboratories, 1400 N. Sheridan Road, Bldg. R-13, North Chicago, IL 60064-6291
Midazolam, a benzodiazepine related pre-operative anesthetic is obtained by a three-step process from the starting material Desalkylflurazepam. Step 1 involves three individual steps: Desalkylflurazepam undergoes a Wittig reaction, a decarboxylation step, followed by an oximation reaction to produce the first isolated intermediate, Oxime. In the 2nd step the oxime is cyclized to a tricyclic ester, which upon hydrolysis and thermal decarboxylation gave midazolam. Various issues were encountered at all steps during the chemical scale-up of process from laboratory to manufacturing. The identification of these issues, the challenges to solve the problems in a short amount of time in the laboratory, and their implementation in the manufacturing will be presented.