Investigating the continuous synthesis of a nicotinonitrile precursor to nevirapine.

2-Chloro-3-amino-4-picoline (CAPIC) is a strategic building block for the preparation of nevirapine, a widely-prescribed non-nucleosidic reverse transcriptase inhibitor for the treatment of HIV-infected patients. A continuous synthesis to the bromo derivative of a CAPIC intermediate, 2-bromo-4-methylnicotinonitrile, that terminates in a dead-end crystallization is described. The route uses inexpensive, acyclic commodity-based raw materials and has the potential to enable lower cost production of nevirapine as well as other value added structures that contain complex pyridines.

Continuous synthesis and use of N-heterocyclic carbene copper(I) complexes from insoluble Cu2O.

It is demonstrated that homogeneous N-heterocyclic carbene-copper(I)-chloride complexes can be prepared continuously by flowing NHC precursors through a packed bed of solid Cu(2)O suspended in molecular sieves. The method enables the synthesis of a wide range of complexes including those that are challenging to prepare using standard approaches. Our strategy enables both sustained output of complex production for long-term catalytic reactions (greater than 5 h) and for generation of gram quantities for storage (greater than 1 g of complex in ~16 min).

Continuous proline catalysis via leaching of solid proline.

Herein, we demonstrate that a homogeneous catalyst can be prepared continuously via reaction with a packed-bed of a catalyst precursor. Specifically, we perform continuous proline catalyzed α-aminoxylations using a packed-bed of L-proline. The system relies on a multistep sequence in which an aldehyde and thiourea additive are passed through a column of solid proline, presumably forming a soluble oxazolidinone intermediate.

Thiourea/proline derivative-catalyzed synthesis of tetrahydrofuran derivatives: a mechanistic view.

A thiourea/proline derivative-catalyzed synthesis of linear α-substituted tetrahydrofuran/pyran derivatives starting with lactol substrates is presented. This study demonstrates the utility and potential complications of using (thio)urea/proline cocatalysis as each of these catalysts is necessary to provide the observed reactivity, but a time-dependent decrease in enantioselectivity is observed. New mechanistic insights into (thio)urea/proline cocatalysis are presented.

Use of bifunctional ureas to increase the rate of proline-catalyzed alpha-aminoxylations.

The rate of the proline-catalyzed alpha-aminoxylation of aldehydes is significantly increased in the presence of a bifunctional urea. Structure-activity relationship data indicate that both an amine and a urea are crucial for rate enhancement. The evidence presented herein suggests that this rate enhancement originates from the hydrogen bonding interaction between the bifunctional urea and an oxazolidinone intermediate to increase the rate of enamine formation.