Pharmaceutical industry acetylation

Carbon-carbon bond lyases, used in the reverse, synthetic direction have also enjoyed significant application in the pharmaceutical industry. For example 7/-acetyl-D-neuraminic acid (NANA), an intermediate in the chemoenzymatic synthesis of the influenza virus sialidase inhibitor zanamavir, may be synthesized using NANA aldolase. 

Acetylating and dehydrating agent used in the chemical and pharmaceutical industries for the manufacture of cellulose acetate, for textile sizing agents and cold bleaching activators, for polishing metals and for the production of brake fluids, dyes, explosives. 

Despite this setback, the pharmaceutical industry was encouraged to prepare literally hundreds of sulfonamides, of which May and Baker 693 (sul-fapyridine) proved to be the most potent and broad spectrum. It also achieved star status once it was revealed that it had been used to save the life of Winston Churchill when he contracted pneumonia during a visit to North Africa in December 1943. Other sulfonamides that have been widely prescribed are sulfadiazine, sulfadimidine (especially for urinary tract infections and meningitis caused by meningococcal infections) and sulfamethoxazole. One problem with many sulfonamides is their relative water insolubility and their tendency to crystallise in the kidney tubules. They are also metabolised via acetylation of the aniline nitrogen, and these metabolites are both inactive and less soluble. 

An alternative to extraction crystallization is used to obtain a desired enantiomer after asymmetric hydrolysis by Evonik Industries. In such a way, L-amino acids for infusion solutions or as intermediates for pharmaceuticals are prepared [35,36]. For example, non-proteinogenic amino acids like L-norvaline or L-norleucine are possible products. The racemic A-acteyl-amino acid is converted by acylase 1 from Aspergillus oryzae to yield the enantiopure L-amino acid, acetic acid and the unconverted substrate (Figure 4.7). The product recovery is achieved by crystallization, benefiting from the low solubility of the product. The product mixture is filtrated by an ultrafiltration membrane and the unconverted acetyl-amino acid is reracemized in a subsequent step. The product yield is 80% and the enantiomeric excess 99.5%. 

The acylase-catalyzed resolution of N-acetyl-D,L-amino acids to obtain enantiomerically pure i-amino acids (see Chapter 7, Section 7.2.1) has been scaled up to the multi-hundred ton level. For the immobilized-enzyme reactor (Takeda, 1969) as well as the enzyme membrane reactor technology (Degussa, 1980) the acylase process was the first to be scaled up to industrial levels. Commercially acylase has broad substrate specificity and sufficient stability during both storage and operation. The process is fully developed and allowed major market penetration for its products, mainly pharmaceutical-grade L-methionine and L-valine. 

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