The microreactor technology is an efficient tool for kilogramscale syntheses in continuous mode and is particularly effective for hazardous reactions that do not allow scale-up in conventional reactors. Applications to several classes of reactions including highly exothermic reactions, high-temperature reactions, reactions with unstable intermediates, and reactions involving hazardous reagents are described herein.

The standard method for preparing carboxylic acid hydrazides is hydrazinolysis of esters in alcoholic solutions. However, when applied to alpha,beta-unsaturated esters, the main product typically is the pyrazolidinone resulting from an undesired Michael-type cyclization. Other alternative methodologies reported for direct preparation of hydrazides from acids are inefficient. We developed an efficient and general process, involving preforming activated esters and/or amides followed by reaction with hydrazine, for the preparation of hydrazides including those of alpha,beta-unsaturated acids. This process gives the desired hydrazides in excellent yield and purity under mild conditions.

This report describes the development of a scaleable process to prepare 2,3-bis(chloromethyl)pyridine hydrochloride, 2, that is safe, economical, and environmentally acceptable. On a small scale this material is prepared using thionyl chloride as the solvent. However, this reaction is not readily scaleable because of environmental and disposal issues. Reaction calorimetry is used to evaluate a number of potentially viable chlorination procedures. In the course of this investigation potentially hazardous reagent/solvent incompatibilities were identified. The use of thionyl chloride in MTBE is particularly hazardous owing to solvent decomposition in the presence of HCl and subsequent outgassing of large amounts of isobutylene. Reaction conditions employing thionyl chloride and 1% v/v DMF in toluene were found to be safe for scale-up. As a result, an environmentally acceptable, safe process has been developed and scaled to produce multikilogram amounts of material.

This contribution describes the development of an improved scaleable process to prepare 1,3,4,12a-tetrahydro-11H-[1,4]-oxanio[3,4-c][1,4]benzodiazepine-6,12-dione, 2, in a safe and operationally simple procedure using iron powder in acetic acid. The original procedure being used to prepare initial quantities of this material also involves the use of iron with acetic acid. However, these original reaction conditions are not amenable to scale-up due to safety and operational issues. Reaction calorimetry is used to evaluate modifications to the original conditions that result in an improved procedure that has been developed and scaled to produce multikilogram amounts of material for initial development studies.

Preparation of methyl (S)-3-amino-3-(3′-pyridyl)propionate dihydrochloride in high enantiomeric purity by selective crystallization of a diastereomeric salt of a carboxylic acid precursor (N-BOC-protected) with (1R,2S)-(-)-ephedrine is described. Further demonstration of the usefulness of this procedure to resolve other 3-amino-3-[(substituted)pyridyl]propionic acids is also described.