Publications

Organic Process Research & Development, 2007 (145.25 KB)
A scaleable process for the synthesis of two naturally occurring procyanidins, namely (-)-epicatechin-(4ß,8)-(+)-catechin (1) and (-)-epicatechin-3-O-galloyl-(4ß,8)-(-)-epicatechin-3-O-gallate (2), is described. The key steps were highlighted by improvements for the benzylation of (+)-catechin (3), stereoselective reduction of the C-3 keto group of (2R)-5,7,3',4'-tetrakis(benzyloxy)flavan-3-one (10), and coupling between 4-hydroxyethoxy-5,7,3',4'-tetra-O-benzyl-(-)-epicatechin (11) and 5,7,3',4'-tetra-O-benzyl-(+)-catechin (4) or 5,7,3',4'-tetra-O-benzyl-(-)-epicatechin (6), respectively. The debenzylation performed in a biphasic system resulted in an improved yield and purity of the target compounds. The chemistry was scaledup to produce multigram quantities of the title compounds (1 and 2) for various in Witro, ex WiWo, and in WiWo studies. Moreover, the scale-up process provided a detailed description for the preparation of multihundred to kilogram scale quantities of intermediates used in the synthesis of these two titled procyanidins.

Organic Process Research & Development, 2009 (167.25 KB)
A process for the multigram asymmetric synthesis of the chiral tetraazamacrocycle 2-(R)-2-(4,7,10-tris tert-butylcarboxymethyl- 1,4,7,10-tetraazacyclododec-1-yl)-pentanedioic acid, 1-tert-butyl ester ((R)-tert-Bu4-DOTAGA, 4) has been devised and demonstrated. The nine-step synthesis features an improved synthesis of 2-(S)-5-oxotetrahydrofuran-2-carboxylic acid, tert-butyl ester 8, the precursor to the novel alkylating agent (S)-5-benzyl 1-tert-butyl 2-(methylsulfonyloxy)pentanedioate 12, which was used to introduce an orthogonally protected chiral glutarate arm to the 1,4,7,10-tetraazacyclododecane (cyclen) nucleus in high optical purity. Cyclen derivative (R)-t-Bu4-DOTAGA, 4, a key intermediate for the manufacture of a magnetic resonance imaging (MRI) candidate, was produced with high chemical (g95%) and optical (ee g 97%) purity. The process developed was successfully applied to the kilogram-scale cGMP synthesis of (R)-t-Bu4-DOTAGA.