Chiral drug intermediates synthesis

R. N. Patel, Synthesis of Chiral Drug Intermediates, in R. N. Patel (Ed.), Stereoselective Biocatalysis, Marcel Dekker, New York, Basel, 2000, pp. 87-130. 

Laumen, K., Brunella, A., Graf, M., Kittelmann, M., Walser, P., and Ghisalba, O., New Biocata-lytic Approaches for the Synthesis of Chiral Drugs, Intermediates, and Substrates. In Trends in Drug Research II, van der Goot, H. (ed.) Pharmacochemistry Library, Vol. 29. Elsevier Amsterdam, 1998, pp. 17-28. 

Patel, R.N. (1999) Microbial/Enzymatic Synthesis of Chiral Drug Intermediates, Adv. Appl. Microbiol. 43,91-140. 

Patel RN, Hanson RL, Baneijee A, Szarka LJ (1997) Biocatalytic synthesis of some chiral drug intermediates by oxidoredudases. J Am Oil Chem Soc 74 1345-1360... 

Chapters 5-8 are directed to emerging enzymes, which include oxynitrilases, aldolases, ketoreductases, oxidases, nitrile hydratases, and nitrilases, and their recent applications especially in synthesis of chiral drugs and intermediates. 

Patel, R.N. (2001) Biocatalytic synthesis of intermediates for the synthesis of chiral drug substances. Current Opinion in Biotechnology, 12 (6), 587-604. 

In a similar approach, Kasture and coworkers describe the use of neat substrate (ethyl acetate both as alcohol donor and as the reaction medium) in the preparation of chirally pure S-(-)-l,4-benzodioxan-2-carboxylate, an important drug intermediate used in the synthesis of doxazosin mesylate, from racemic l,4-benzodioxan-2-carboxylic acid [138]. Again, CaLB catalyzed the transesterification reaction with good enanhoselectivity (E = 160) and acceptable enantiomeric excess (>95%) and chemical yield (50%). 

Candida tropicalis PBR-2, a yeast strain isolated from soil, is capable of carrying out the enantioselective reduction of N,N-dimethyl-3-keto-3-(2-thienyl)-l-propanamine 58 to (S)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)-l-propanamine 59 (Fig. 18.18), a key intermediate in the synthesis of the chiral drug (S)-Duloxetine (Soni and Banerjee, 2005). The organism produced the enantiopure (S)-alcohol with a good yield (>80%) and almost absolute enan-tioselectivity, with an ee >99%. Parameters of the bioreduction reaction were optimized and the optimal temperature and pH for the reduction were found to be 30 °C and 7.0, respectively. The optimized substrate and the resting cell concentration were lg/1 and 250 g/1, respectively. The preparative-scale reaction using resting cells of C. tropicalis yielded the (S)-alcohol at 84-88% conversion and ee >99%. 

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