kilomentor

It is the opinion of Kilomentor that the most significant presentation at the Scientific Update Process Development Conference held in Montreal from June 24-26^th of this year was that of Alex Tao, Vice President and Chief Scientific Officer of Bioverdant. Dr. Tao was a recipient of the 2006 IChemE-AstraZeneca award for Excellence in Green Chemistry and Engineering for his process for Pregabalin. What I hear Dr. Tao saying is that the state of scientific knowledge now calls for a paradigm shift in our perspective on organic chemical process development most particularly for pharmaceuticals.

According to the presentation, because of the availability now of so much genomic data, the number of enzymes available for conducting the equivalent of common API process steps has increased to the point that now such a broad substrate spectrum can be handled that a screen for potential enzymes to catalyze a reaction step is more likely than not to provide a usable hit. This means that for the first time in history, chemists can be optimistic that they will be able to identify an enzyme, available in commercial quantities, that will catalyze any one of a dozen very common chemical conversions.

Furthermore, even if the best wild-type enzyme discovered has only a poor enantiomeric selectivity for the substrate of interest, the science of site-directed mutagenesis has developed so quickly that a wild-type enzyme that only provides say 61.4% of the correct enantiomer can be used to create a new mutant enzyme with 99.5% ee in something like 3-6 months more work and this can be scaled up to provide production quantities.

This Dr. Tao confirmed to me would make it very likely that, if the innovating company has not already done so, a generic pharmaceutical company can expect to improve the route available to make drugs coming off patent using these biocatalytic methods. Moreover, this opportunity is more likely because the technology was not available in its present robust state when the innovator was developing its chemistry.

Using one biotransformation in a process usually removes the need for any resolution because only one enantiomer reacts. This also opens up the possibility of racemizing the wrong enantiomer and so recycling the 50% of the racemic intermediate that is usually not useful. Also prochiral intermediates give chiral products with enzymes; in one step resolving the intermediate and selecting one of two superficially identical groups.

The reactions that can be confidently replaced now are:

• Regio and enantioselective reduction of ketones to alcohol
• Regio and enatioselective hydrolysis of nitriles to acids
• Regio and enantioselective reduction of ketone to primary amines
• Regio and enantioselective conversion of aldehyde to the corresponding homologated α-hydroxyacid, 2-hydroxy-1-amine; α-hydroxyamide
• Regio and enantioselective reduction of αβ-unsaturated aldehydes/ketones/acids/nitrile/nitro.
• Regio and enantioselective conversion of nitrile to primary amide

In his presentation Dr. Tao provided examples of completed improvements for synthesizing levetiracetam, montelukast, pregabalin, (S)-dimethenamid (an agricultural product), synthetic pyrethroids (insecticides), moxifloxacin, paroxetine and atorvastatin.

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• In Process Controls and Forensic Samples in Chemical Process Development
• Making a Good Recrystallization Process Step Better.
• Common Ground for Generic and Innovator Pharmaceutical Companies
• Biocatalytic Methods of Enantioselective Synthesis in Pharmaceutical Process Development
• Separation by Substantial Differences in Chemical Reactivity of the Same Nominal Functional Group.
• Sulfate Pharmaceutical Salts (reprint to remove comments)
• Pamoates or Embonates: crystalline Pharmaceutical Salts or Derivatives for Isolation and Purification
• Symmetrical Bis-N,N-(3-nitrophenyl)urea: A Super Co-crystal Former that might have applications in Product Purification.
• The Importance of the Molecular Weight of a Salt Former in choosing a Pharmaceutical Salt
• Reiterating the Objective of the Kilomentor Blog
• The process vision: an integrating strategy in pharmaceutical process development
• Phosphate Pharmaceutical Salts : Chemical Process Development & Organic Synthesis
• Green /Recyclable Solvents: Low Vapour pressure compositions for storage and recycling of solvents that are highly volatile or gaseous at room temperature
• Making the Hydrochloride Pharmaceutical Salt of Basic Drug Substances
• Kilomentor weighs in as “Pharmaceutical Manufacturing Goes Green”.

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