Frederick W. Hartner

Rapid synthesis of tetrahydro-4H-pyrazolo[1,5-a]diazepine-2-carboxylate

Hydrazines condense with dimethyl 2-pyrrolidino-4-oxo-2-pentenedioate in the presence of aq. HCl to form N-substituted pyrazole-3,5-dicarboxylates 2. Complex bicyclic derivatives, such as pyrazolo-oxazine 3a, pyrazolo-oxazepine 3b, pyrazolo-pyrazine 4a, and pyrazolo-diazepine 4b, were generated using 2-hydrazinoethanol, 3-hydrazinopropanol, 2-hydrazinoethylamine, and 3-hydrazinopropylamine.

HIV-1 protease inhibitory activity of L-694,746, a novel metabolite of L-689,502

L-689,502 is a potent inhibitor of HIV-1 protease activity in vitro. Microbial biotransformations of L-689,502 by cultures belonging to the genus Streptomyces sp. were performed. Extracts of culture broths were examined for the production of metabolites of L-689,502 that could inhibit HIV-1 protease activity. One culture, MA 6804 (Streptomyces lavendulae, ATCC 55095), produced L-694,746 that, while being structurally related to L-689,502, is a novel metabolite and a potent inhibitor of HIV-1 protease.

Process development for the production of the (S)-acid precursor of a novel elastase inhibitor (L-694,458) through the lipase-catalyzed kinetic resolution of a β-lactam benzyl ester

Abstract A limited screen of several commercially-available and internally-produced lipases and esterases identified the lipase PS-800 as a suitable biocatalyst for the resolution of a racemic β-lactam benzyl ester to the ( S )-acid. This β-lactam is a precursor to the elastase inhibitor L-694,458, an experimental drug targeted for the treatment of cystic fibrosis. Key to the development of a scalable process was the optimization of β-lactam and surfactant (Triton X-100) charges. These optimization studies yielded a 21-fold increase in the volumetric production of the ( S )-acid (from 0.38 g/ l to 8.0 g/ l ) and a 10-fold improvement in the initial bioconversion rate (from 17 mg/( l ·h) to 170 mg/( l ·h)). Additionally, these studies achieved the control of the ( S )-acid enantiomeric excess (e.e.) which was improved from less than 65% to greater than 90%. Keys to an economical and high yielding process, both the recycling of the lipase (at levels of 90%) and the use of re-racemized unreacted ( R )-benzyl ester in multiple reaction cycles were successfully demonstrated. This process was scaled up in 2.0- l reactors and afforded gram quantities of greater than 90% e.e ( S )-acid, which upon purification was successfully used to synthesize the elastase inhibitor L-694,458.

A direct transformation of bicyclic keto esters to N-formimidoyl thienamycin

Abstract A convenient direct transformation of p -nitrobenzyl 6-(1′-hydroxyethyl)-1-azabicyclo-(3.2.0)heptane-3,7-dione-2-carboxylate to N -formimidoyl thienamycin utilizing the silylated derivative of N -formimidoyl cysteamine is described.