The scale-up of the synthesis of a very expensive key pharmaceutical intermediate requires a very accurate knowledge of the overall heat-transfer coefficient of the plant reactors. Those data allow the optimization of the safety, quality, and yield of the process. Starting from the accurate and reliable measurements determined by reaction calorimetry, the overall heat-transfer coefficient of the plant reactor can be evaluated, and the reaction performance can be simulated with a computer program. Here is reported an example of a reaction successfully scaled up to 1500-fold with excellent yield and high product quality.
A very efficient, cost-effective,
and easily scalable process for
the synthesis of lofexidine hydrochloride (1), an alpha
2-adrenergic receptor agonist used for treating opioid withdrawal
is presented. Process development allows the preparation of lofexidine
hydrochloride (1) through a one-pot amidation/imidazoline
ring formation reaction, starting from ethyl 2-(2,6-dichlorophenoxy)propionate
(13) and ethylenediamine (5) by the action
of titanium isopropoxide. The required intermediate ethyl 2-(2,6-dichlorophenoxy)propionate
(13) can efficiently be obtained through O-alkylation of 2,6-dichlorophenol (2) with ethyl 2-chloropropionate
(12) using potassium carbonate as an acid-scavenger agent.
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