Enantiopure 4-substituted oxazolidinones are well-known chiral auxiliaries for asymmetric synthesis of carboxylic acid derivatives. The 4-(phenylmethyl)-substituted oxazolidinones derived from D-or L-phenylalanine are known to be particularly useful. We have conducted chemical development studies toward an efficient and scaleable "one-pot" process for production of (S)-4-(phenylmethyl)-2-oxazolidinone 2. The first step in the process employed a sodium borohydride reduction of phenylalanine mediated by an additive. The second step utilized triphosgene as a phosgene source to effect cyclization of the intermediate amino alcohol. Both chemical steps and workup procedures were screened and optimized utilizing statistical design of experiments (DoE) and parallel synthesis. The procedure was further characterized in an automated reactor system that provided heat flow measurements and modeled production at the plant scale. The efficiency of this process was compared to those of others previously reported on the basis of raw material cost, time requirements, safety, and hazardous waste generation.

Two fields that routinely perform reaction optimization studies are chemical development (prior to scale-up) and medicinal or combinatorial chemistry (prior to analogue synthesis or library production). To date, the use of statistical design of experiments (DoE) in conjunction with automated synthesizers has been applied in process research to a greater extent than in the medicinal or combinatorial laboratories. We have applied DoE in conjunction with an automated synthesizer to optimize the synthesis of amides employing resin-bound N-hydroxybenzotriazole (PS-HOBt) active esters as intermediates. This methodology allowed the rapid development of an improved protocol for the parallel synthesis of amides by conversion of carboxylic acids to PS-HOBt esters followed by treatment with appropriate amines. Product isolation involved only simple filtration and evaporation.

Amine libraries and their derivatives are important targets for high throughput synthesis because of their versatility as medicinal agents and agrochemicals. As a part of our efforts towards automated chemical library synthesis, a titanium(IV) isopropoxide mediated solution phase reductive amination protocol was successfully translated to automation on the Trident(TM) library synthesizer of Argonaut Technologies. An array of 24 secondary amines was prepared in high yield and purity from 4 primary amines and 6 carbonyl compounds. These secondary amines were further utilized in a split synthesis to generate libraries of ureas, amides and sulfonamides in solution phase on the Trident(TM). The automated runs included 192 reactions to synthesize 96 ureas in duplicate and 96 reactions to synthesize 48 amides and 48 sulfonamides. A number of polymer-assisted solution phase protocols were employed for parallel work-up and purification of the products in each step.

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