676629-90-6Relevant academic research and scientific papers
Process research and development and scale-up of a 4,4-difluoro-3,3- dimethylproline derivative
Rossi, Francesco,Corcella, Francesco,Caldarelli, Francesco Saverio,Heidempergher, Franco,Marchionni, Chiara,Auguadro, Miriam,Cattaneo, Marco,Ceriani, Lucio,Visentin, Giuseppina,Ventrella, Giambattista,Pinciroli, Vittorio,Ramella, Giuliano,Candiani, Ilaria,Bedeschi, Angelo,Tomasi, Attilio,Kline, Billie J.,Martinez, Carlos A.,Yazbeck, Daniel,Kucera, David J.
, p. 322 - 338 (2013/01/03)
The multikilogram production of the proline derivative 1, a key intermediate of a HIV protease inhibitor, required the design of a synthetic route able to be safely, effectively, and easily scaled up. Synthesis of the proline skeleton began with construction of racemic glycine derivative 4, via an ester enolate Claisen rearrangement of Boc-glycine 3-methyl-but-2-enyl ester (3) in the absence of a Lewis acid. After a classical resolution of 4 with (S)- phenylglycinol, (S)-4 was transformed into bromo-lactone 6b with NBS. The bromo-lactone was transformed to proline alcohol 8 via a base-promoted rearrangement involving lactone solvolysis. An NMR study suggested that a bicyclic lactone was initially formed, which subsequently opened by the methanol solvent to form 8. The requisite ketone for fluorination was prepared via oxidation of the enantiomerically pure 8, using NaClO and catalytic TEMPO. gem-Difluoro proline 1 was then prepared from the ketone via fluorination with Deoxo-Fluor. During this study it was discovered that SiO2 promoted fluorination by Deoxo-Fluor. This study allowed the production of 7.5 kg of 1 after 10 steps, in 4.5% molar yield and high purity (94-99% HPLC assay).
Efficient enzymatic process for the production of (2S)-4,4-difluoro-3,3- dimethyl-N-Boc-proline, a key intermediate in the synthesis of HIV protease inhibitors
Hu, Shanghui,Martinez, Carlos A.,Kline, Billie,Yazbeck, Daniel,Tao, Junhua,Kucera, David J.
, p. 650 - 654 (2012/12/22)
(2S)-4,4-Difluoro-3,3-dimethyl-N-Boc-proline (3) is a key intermediate for the synthesis of HIV protease inhibitors. Here, several approaches for the preparation of enantiopure 3 and its analogues are disclosed. Among these methods, one strategy relies on
METHODS FOR THE PREPARATION OF STEREOISOMERICALLY ENRICHED AMINES
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Page/Page column 46-47, (2008/06/13)
The present invention relates to methods of preparing a stereoisomerically enriched compound of formula (I), wherein R6 is hydrogen, comprising treating a compound of formula (I), wherein R6 is chosen from C1-C10/sub
HIV PROTEASE INHIBITORS, COMPOSITIONS CONTAINING THE SAME AND THEIR PHARMACEUTICAL USES
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Page/Page column 107, (2010/02/11)
This invention relates to a novel series of chemical compounds useful as Human immunodeficiency Virus (HIV) protease inhibitors and to the use of such compounds as antiviral agents. The invention further relates to pharmaceutical compositions containing s
