A Practical and Robust Process to Produce SB-214857, Lotrafiban, ((2S)-7-(4,4^‘-Bipiperidinylcarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1, 4-Benzodiazepine-2-acetic Acid) Utilising an Enzymic Resolution as the Final Step

Abstract

During the scale-up of a chemical process to produce phase II supplies of the chiral compound Lotrafiban, partial racemisation occurred to produce drug substance of unacceptable chiral purity. A new route capable of producing several hundred kilograms of Lotrafiban of high chiral purity had to be rapidly identified and scaled up. The strategy adopted was to employ an enzymic resolution as the final step, thus introducing the chirality under very mild conditions to prevent any racemisation. This was achieved using an immobilised form of the Candida antarctica B lipase in water at 30 °C. The biotransformation was demonstrated to be a robust, reliable, and an economic way to introduce the chirality into the Lotrafiban molecule.

Shortening Synthetic Routes to Small Molecule Active Pharmaceutical Ingredients Employing Biocatalytic Methods

“…In its synthesis, CALB immobilized on a macroporous resin (Chirazyme L-2, Boehringer) was used to catalyze the enantioselective hydrolysis of the corresponding methyl ester to yield lotrafiban. The immobilized enzyme could be reused multiple times. , …”

“…The immobilized enzyme could be reused multiple times. 55,500 Doxazosin (Cardura, Scheme 63A) is used for the treatment of hypertension and benign prostetic hyperplasia. Preclinical studies showed that the (S)-enantiomer causes less side effects and improved the efficacy.…”

Preparation of pharmaceutically important enantiomer components through lipase catalysed acylation and hydrolysis

“…In the original medicinal chemistry synthesis 29 (S)-aspartic acid was used as the source of chirality. Walsgrove et al 30 described the preparation of Lotrafiban using an immobilised form of CAL-B (Boehringer L-2) as catalyst in water (pH = 6.2) at 30 °C (Scheme 2). The separation of the unreacted ester (3) from the product was carried out with the use of Cbz chloride.…”