Carboxylic acids pharmaceuticals, conversion

Lonza, for example, has commercialized processes for highly chemo- and regioselective microbial ring hydroxylation and side-chain oxidation of heteroaromatics (see Fig. 2.32 for examples) (Kiener, 1995, 1999). The pharmaceutical intermediate 5-methylpyrazine-2-carboxylic acid, for example, is manufactured by microbial oxidation of 2,5-dimethylpyrazine. Many conversions of the type shown in Fig. 2.32 would not be possible by conventional chemical means. 

Another interesting commercial nonstereoselective application represents the biocatalytic conversion of methyl groups into carboxylic acids. This new technology, also developed at Lonza, is already successfully applied on an industrial scale in the production of 5-methylpyrazine-2-carboxylic acid, a versatile building block for pharmaceuticals [85]. 

As an example of a more complicated case than the two step sequence, we will discuss the esterification of a carboxylic acid with an alcohol. This is a very old and well-known category of homogeneous liquid-phase reactions. The esters of carboxylic acids are of an enormous practical importance for example, millions of tons of polyesters are produced via the reaction of dicarboxylic acids with diols and a wide variety of mono- and di-esters are used in the production of fine and specialty chemicals, such as pharmaceuticals, herbicides, pesticides and fragrances. The esterification reaction is a homogenous liquid-phase process where the limiting conversion of the reactants is determined by equilibrium. Typically the equilibrium constants of esterification reactions have values of 1-10, which implies that considerable amounts of reactants exist in the equilibrium mixture. 

The new Monsanto process makes use of a copper catalyst, which is used to reduce diethanolamine to DSIDA, the intermediate to Roundup (see Fig. 9.27). This process totally eliminates the use of ammonia, hydrogen cyanide, and formaldehyde, is free of contaminants and byproducts, and hence does not require further purification steps. The stream can be recycled after filtration of catalyst. Monsanto s process can also be used in the production of other amino acids such as glycine through reduction and is a general method for conversion of primary alcohols to carboxylic acid salts. The development of this technology for processes pertaining to the agricultural, commodity, specialty, and pharmaceutical sectors would have a pronounced impact on the environment. 

This catalysis technology can also be used in the production of other amino acids, such as glycine. It is also a general method for conversion of primary alcohols to carboxylic acid salts, and is potentially applicable to the preparation of many other agricultural, commodity, specialty, and pharmaceutical chemicals. 

Figure 6.26. The conversion of gramine into tryptophan, 3-(hydroxymethyl)indole, and indole-3-carboxylic acid (Digenis et al., 1966). Courtesy of the J. Pharmaceutical Science.

Acrylic acid represents a 4.5 million metric ton per year global market with BASF, Dow, and Arkema being major manufacturers [15]. AcryUc acid is manufactured by the oxidation of propylene. The reaction is a two-step process with oxidation to acrolein followed by further oxidation of the aldehyde to the carboxylic acid. Acrolein is a raw material for cosmetics, flavors, and pharmaceuticals. The major use of acrylic acid is as a monomer to make acrylic acid polymers and conversion to acrylate esters which are also used to make polymers. 

An pFl-dependent coordination isomerism has been observed for the tumor targeting rhenium(V) 0x0 complex [ReO(DMSA)2] (DMSA = 2,3-mercaptosuccinate). In solution the crystallo-graphically characterized syn,endo-isomQx (87a) slowly isomerizes into the anti- (87b) and the iyn,exo-isomers (87c) which has consequences for the biodistribution of the potential pharmaceutical (Scheme 10). The conversion rate decreases with increasing pH suggesting an acid catalyzed reaction. The syn,exo-comy> ex is favored in alkaline solutions (pH > 8.4) which can be understood in terms of the repulsions between the deprotonated carboxylic groups and the 0x0 ligand. 

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