Heating under High‐Frequency Inductive Conditions: Application to the Continuous Synthesis of the Neurolepticum Olanzapine (Zyprexa)

Continuous flow (micro-)reactors for heterogeneously catalyzed reactions: Main design and modelling issues

“…Comprehensive examples for the production of many drugs are discussed in [55]. One example is the synthesis of olanxapine, a drug for bipolar disorder and schizophrenia, which include 4 reactors, inline extraction and filtration [57] (Fig. 7).…”

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

“…During the Olanzapine synthesis, addition of methanol to the hitherto employed ethyl acetate was necessary to obtain high yields in the cyclization step leading to a thieno [1,5]-benzodiazepine intermediate. 28 On the contrary, the cosolvent had to be removed before the next step in the modular approach towards Pregabalin, Gabapentin and related drugs. The olefination step required small amounts of methanol in toluene to prevent precipitation of the intermediate phosphate salt, but methanol was not tolerated by the next Michael addition.…”

“…28 In the synthesis of Lidocaine and Diazepam, separate pumps were used for the neat reagent and the solvent to avoid decomposition on standing. 25 On the other hand, the preliminary deprotonation occurring in the premixed solution of the benzimidazole substrate and the base was found beneficial for reaching appropriate regio-and chemoselectivity in an alkylation leading to Telmisartan.…”

“…80 The robust nature of liquid-liquid phase separation allows removal of multiple impurities at the same time. 25,28,29,39,98 Insoluble gases cause irreproducible residence time (due to the expansion of bubbles) and potential side reactions in downstream steps. Excess of gaseous reagents or co-products can be removed conveniently by using gas-liquid phase separation units.…”

“…104 A similar concept was applied in the early steps towards Olanzapine. 28 The drawbacks of this method are the wide dispersion of reactants on the column 90 and the exhaustion of the resin by time, principally when the stoichiometric amounts of the immobilized reagent is consumed. These issues can be solved by engineering solutions, such as intelligent pumping 90 and switching between multiple columns.…”