Development of a Commercial Process for (S)-β-Phenylalanine

Abstract

The development of a commercial manufacturing route for (S)-β-phenylalanine 8, a key pharmaceutical building block, is described. The different approaches which were investigated, based on catalytic asymmetric hydrogenation of enamide intermediates and on biocatalysis using acylase and lipase hydrolyses, are compared. The lipase resolution route was chosen for scaleup, and the final two-step process, based on readily available raw materials, is shown to be robust at full manufacturing scale

A chiral analog of the bicyclic guanidine TBD: synthesis, structure and Brønsted base catalysis

“…It was determined at this stage to be better than 99%. The S -configuration was assigned to 13 in accord with published data [22–24]. Intermediate 14 was converted into amine 16 by mesylation (79%), reaction with NaN 3 (96%) and hydrogenation (84%).…”

“…In contrast, our approach used the racemic ester rac- 12 of β-phenylalanine, easily accessible in a Knoevenagel-type condensation of benzaldehyde 11 , ammonium acetate and malonic acid, followed by esterification (Scheme 1) [20–21]. A kinetic resolution of the enantiomers was achieved by enzymatic hydrolysis with Amano lipase PS from Burkholderia cepacia [22–23], a method already optimized for technical use [24]. The best results were obtained with methyl tert- butyl ether as a cosolvent [24].…”

“…A kinetic resolution of the enantiomers was achieved by enzymatic hydrolysis with Amano lipase PS from Burkholderia cepacia [22–23], a method already optimized for technical use [24]. The best results were obtained with methyl tert- butyl ether as a cosolvent [24]. By simple precipitation, batches larger than 15 g of the S- configurated acid 13 could be isolated in 90% yield (45% based on rac - 12 ).…”

Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

“…[137,144,145] The remaining elemento f384 was prepared from commercially available( S)-b-phenylalanine methyl ester (393), which was protected by using Boc anhydride, producing intermediate 406 in 90 %y ield (Scheme 52). [148] The methyl ester was partially reduced to aldehyde 407 by using DIBAL, with carefult emperaturec ontrol to avoid over-reduction to the alcohol. [137,144,145] Aldehyde 407 could be used to couple the phenylpropyl linker to triazole-tropane fragment 401.…”

Enantioconvergent and enantiodivergent catalytic hydrogenation of isomeric olefins

“…Different ligands were screened, the best level of selectivity was obtained with a diphosphine ligand based on camphor (Scheme 40). 53 In the early 2000s major breakthroughs in the development of monodentate phosphorus ligands, applied to asymmetric hydrogenations were achieved by different research groups. 54 In particular, Feringa and co-workers developed a new series of phosphoramidites which were successfully employed in the hydrogenation of b-(acylamino)-acrylates (Scheme 41).…”