Pharmacia Upjohn synthesis

In the scale-up synthesis of linezolid21 (Pharmacia/Upjohn), the inexpensive (S)-epichlorohydrin was used as the chiral source and was used to prepare key intermediate 34, a crystalline material (Scheme 4). Treatment of carbamate 33 with BuOLi in alcohol-DMF, followed by addition of chloride 34, gave linezolid 14 in 73% isolated yield. In contrast, the Bayer team applied a much simpler method for the formation of oxazolidinone by directly heating the mixture of amino alcohol 35 with N.N1-carbonyldiimidazole (CDI) in refluxing THF, using catalytic amounts of DMAP, to provide oxazolidinone 36 (or 21) in 87% isolated yield. 

The chiral ligand used is based on a phthalazine (PHAL) modified by two dihydroquinidine (DHQD) substituents. Other asymmetric dihydroxylation reactions for the synthesis of pharmaceuticals have been developed at Chirex and Pharmacia/Upjohn. 

Because most examples in category IV described in this monograph use biocatalysts, it could be inferred that chemical catalysis is not suitable for the synthesis of NCEs. Just to show that this is not correct but rather due to the choice of our authors, Tab. 7 shows an extensive list of examples illustrating this point. In addition to these production and pilot processes, there were further reports on 19 bench-scale processes using homogeneous catalysts by Roche (7), HoechstMarion-Roussel/Aventis (5), SmithKline Beecham (2), Sepracor (2), Pharmacia/Upjohn (1), Eli Lilly (1) and Merck (1) [1],... 

Pharmacia Upjohn developed a practical synthesis toward the anticancer agent Irinotecan (Camptosar, 24), which involved an enzymatic resolution step to provide the strategic intermediate 23 (Scheme 7) [65,66]. Lactone 23 could be produced by internal esterification of oxidized (S)-diol 21, which in turn was obtained by biocatalytic resolution of mc-21. An asymmetric acetylation was achieved with isopropenyl acetate catalyzed by Amano PS-30 Pseudomonas cepacia) lipase immobilized on Celite and could be driven to 60% conversion. (S)-21 was isolated in 38% yield and with 99% optical purity, whereas the unwanted (i )-stereoisomer 22 was recycled in a three-step procedure. Changing the support to Celite 521 significantly increased the reaction rate, as did rais-... 

C-16H20FN3O4 Anti-infective agent Protein synthesis inhibitor Oral suspension and tablet Injectable 165800-03-3 April 2000/ Pharmacia and Upjohn... 

The synthesis of unsymmetrical bispyrimidines thio-ethers was reported in 1999 by medicinal chemists from Pharmacia and Upjohn because of their antibacterial activ-... 

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