Chiral drugs business in 2001 reached $100 billion, representing one-third of all drugs sales worldwide. The industry's continuing growth is partly because of the discoveries in fundamental biochemistry. Of the top 100 drugs marketed today, 50 are single isomers. Single isomer drugs sale reached $115 billion worldwide in 1999 (32% of the total drug market) and expected to reach $146 billion in 2003. All this activity on chiral drugs has led the fine chemical producers to develop new enantioselective technology to produce chiral intermediates.
Amgen leads in the biopharma industry with more than $3.3 billion in annual revenue and more than $1.7 billion in profit (Oct 2000). Amgen acquired Kinetix, which focuses on inhibition of protein Kinases, enzymes that are key regulators of internal and external cellular communications.
Lilly Research Lab changed its synthesis of anticonvulsant drug from the chemical route to a biocatalytic route, to eliminate 340 l of solvent and 3 kg of chromium waste produced by the former approach. The new synthesis involves biocatalytic reduction of an alcohol to an optically pure alcohol using the yeast zygosacharomyces rouxii. The reaction is carried out in an agitated vessel. The ketone is added to an aqueous phase containing a polymeric resin, buffer, and glucose. Most of the ketone gets absorbed onto the resin, and the yeast reacts with the equilibrium concentration of the ketone in the aqueous phase. The product once again gets absorbed on to the resin surface. This novel triphasic system helps product recovery and keeps the product concentration low in the aqueous phase, preventing enzyme deactivation based on product inhibition.
Monsanto's NSC Technology produces d-phenylalanine and d-tryro-sine (intermediates for a series of derivative products that have use in HIV treatment, oncology, and cardiovascular drugs) using d-amino acid transaminase enzymes.
Ajinomoto, a Japanese company, manufactures anti-HIV agent dideox-yinosine through a hybrid process that involves chemical synthesis of dideoxyadenosine from adenosine followed by enzymatic conversion to the desired product. l-Glutamic acid is produced annually at 300,000 t scale by the same company by fermentation.
BASF is producing vitamin B2 through fermentation. Diversia, a San Diego-based company has nitrilases useful for enantioselective one-carbon homologation of aldehydes, preparation of (R)-mandelic acid derivatives at enantiomeric excess (ee) of >99%, preparation of (S)-phenyl lactic acid at 99% ee, and enantioselective preparation of ethyl (R)-3-hydroxy-4-cyanobu-tyrate an intermediate in the synthesis of the cholesterol-lowering drug Lipitor.
Enzymatic resolution in the pharmaceutical intermediates business include DSM Andeno's (The Netherlands) production of intermediates for the heart drugs Diltiazem and Captopril, Chiro Techs' production of a single isomer form of the analgesic ibuprofen and (-) lactam for the HIV drug abacavir, BASF's production of optically active amines using lipase in organic solvents, and Lonza's conversion of 2.5-dimethyl pyrazine to 5-methyl-2-pyrazine carboxylic acid, an intermediate for the diabetic drug glipzide using a microorganism that grows on p-xylene.
Tanabe Pharma (Osaka, Japan) uses lipase for the production of intermediates for Diltiazem. The reactor consists of immobilized lipase on membrane material. The product is recovered from the solution in a crystal-lizer, in the form of pure solid. Tanabe Seiyaku and Kyowa Hakko Kogyo (Japan) manufacture. l-Aspartate from fumaric acid using aspartate ammonia lyase.
Daicel produces chiral alcohols, like (S)-2-butanol and agrochemicals intermediates, using biocatalytic route. Intermediates such as amino acids and carboxamides for pharmaceuticals, fine chemicals, food products, and cardiovascular drugs are also being produced using biocatalyst by companies such as Zeneca Specialities, Daicel, Mitsubishi, SmithKline Beecham, etc.
l-Amino acid is used in medicine, food, and animal feed. At present, fermentation and chemical synthetic methods are followed to produce lamino acid. The chemically synthesized amino acid is a racemic mixture of l and d, which needs to be optically resolved to obtain the pure l form through hydrolysis. Aminoacylase supported on DEAE-Sephadex ion-exchange resin through covalent bond was used for this purpose. A process scheme is shown in Fig. 14.9. The main issues in the manufacturing process are pressure drop across column and slight change in the pH of the native enzyme when supported on ion-exchange resin leading to decrease in its active life. The same technique is used in the manufacture of several d-amino acids.
d-Phenyl glycine and d-4-hydroxy phenyl glycine, the precursors for semisynthetic penicillins, namely, ampicillin and amoxicillin, are currently being produced at a scale of higher than 1000 t/annum using hydantoinase/ carbamoylase. NSC Technology has a process for multi-ton production of d-phenylalanine and d-tyrosine using d-transaminase. Kyowa Hakko Kogyo has a process for producing d-alanine using l-glutamate using glutamate racemase and l-glutamate decarboxylase by fermentation. Degussa (Hanau, Germany) has a process for resolving (S)-t-leucine using a leucine dehydrogenase with a turn over number above 10,000.
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