Mr. Nagler considers Degussa one of the few companies with the technology to make any kind of amino acid-natural or unnatural-in-house. DSM is another. Vincent Elferink, manager new business development, says that in the 1960s, DSM began producing amino acids for antibiotic applications via classical resolution processes. Each year, DSM still produces several thousand tons of D-phenylglycine in this manner for ampicillin and cephalexin.
"Over time, of course, you want to strengthen your technical position," says Mr. Elferink, "so we have developed and and introduced into large scale several alternatives for producing optically pure amino acids. We now have a portfolio of technologies that can be used to produce any amino acid you want." These include the use of hydantoinases to produce a variety of D-amino acids, including several thousand tons of D-p-hydroxyphenylglycine each year. In total, amino acids and their derivatives account for over $1 billion of DSM’s annual revenue.
According to Mr. Elferink, DSM’s bio-process technology is founded on three microorganisms and isolated enzymes. “We have identified the genes that code for the desired activity of each microorganism and transferred it into easily fermented host organisms, with which we overexpress the enzyme that we want. This way we can also suppress undesirable activities.”
Implicit to any resolution is the presence of the undesired isomer. “Sometimes you can racemize the unwanted isomer, and sometimes you can use it, as with D-, Lvaline,” observes Mr. Elferink. “But sometimes it must be discarded-alpha-substituted amino acids are particularly difficult to racemize.” Avoiding resolutions requires asymmetric syntheses, and DSM also has processes of this type for the production of amino acids, such as its aspartase technology for the production of L-aspartic acid. Cost, however, always determines which technology is appropriate.
A new asymmetric technology has brought custom manufacturer ChiRex onto the amino acid scene. The company licensed Eric Jacobsen’s asymmetric Strecker synthesis in April of this year. Dr. Jacobsen, a professor of chemistry at Harvard University, has developed a series of chiral catalysts that direct imine addition with a high degree of stereo-selectivity [see page 121. As Roger Pettman, vice president and general manager of the ChiRex Technology Center, points out, it is not a technology that will be competitive in high volume markets like that for methionine. “But in terms of novel amino acids or derivatives, we now have the ability to make almost any you can think of from the starting aldehyde. Not only can we make the smaller volume, higher priced amino acids but we can also offer new unnatural amino acids that have not been readily available before.”
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Because the process is catalytic, either isomer, L or B, can be made, says Mr. Pettman. In select cases, it offers advantages of speed and cost. Additionally, because it passes through the amino nitrile, the new process offers access to chiral diamines and amino ketones species not so readily accessible from the amino acid itself.
With demand for amino acid-based pharmaceutical intermediates expanding, manufacturers known primarily for the fermentative production of natural amino acids are also finding themselves well positioned to expand their services to the pharmaceutical industry Kyowa Hakko, for example, has built its reputation on a wide range of pure amino acids obtained by fermentation. The company is expanding its involvement in the production of pharmaceutical intermediates based on amino acids, natural or unnatural. Donald Blame, general manager for Kyowa Hakko USA, says, “That is one of our goals-to be more involved in the business of pharmaceutical intermediates based on amino acids, whether natural or unnatural.”