David J. Mathre

Development of a pharmaceutical cocrystal of a monophosphate salt with phosphoric acid

We report the first case of a pharmaceutical cocrystal formed between an inorganic acid and an active pharmaceutical ingredient (API), which enabled us to develop a stable crystalline and bioavailable solid dosage form for pharmaceutical development where otherwise only unstable amorphous free form or salts could have been used.

Practical chemoenzymatic synthesis of a 3-pyridylethanolamino β3 adrenergic receptor agonist

Abstract A chemoenzymatic synthesis of β 3 agonist 1 suitable for large scale preparation is described. The key chiral 3-pyridylethanolamine intermediate ( R )- 7 was prepared via an improved Neber rearrangement and a yeast-mediated asymmetric reduction. The tetrazolone fragment of the molecule was constructed via a dipolar cycloaddition between 1-(cyclopentyl)-3-propylazide and p -chlorosulfonyl phenylisocyanate. Sulfonamide coupling of these two intermediates under Shotten-Baumann conditions, followed by a borane reduction of the amide afforded 1 in 20–32% overall yield from 3-acetylpyridine.

Microplate evaluation of process adsorbents

A microplate-based assay to rapidly identify adsorbents suitable for removing process impurities is described. A solution containing both product and impurity is added to a number of wells, each containing a small amount of a candidate adsorbent. After equilibration, analysis of the supernatant solution allows one to determine the extent of adsorption of both product and impurity. Fast analysis techniques such as flow injection analysis LC-MS or the use of colorimetric indicators allows rapid identification of the most selective adsorbents for a given separation problem.

Asymmetric aza-Diels–Alder reactions of indole 2-carboxaldehydes

Abstract The aza-Diels–Alder reaction of substituted indole 2-carboxaldehydes with Danishefskys diene has been investigated. The reaction proceeds with a high degree of diastereoselectivity providing highly functionalized 2-(2-piperidyl)indoles which are further elaborated into novel polycyclic heterocycles.

New insights into the mechanism of molybdenum-catalyzed asymmetric alkylation

The major features of the catalytic cycle, including structures of key intermediates, have been determined for the molybdenum-catalyzed asymmetric alkylation. The crystal structure of the π-allyl intermediate exhibits 3-point binding of an anionic ligand. Based on NMR analysis, this species adopts in solution a structure consistent with that observed in the solid state. For the allylic alkylation, the crystal structure predicts the opposite stereochemistry vs. that observed experimentally, which suggests that either the reaction proceeds via a minor isomer (Curtin-Hammett conditions) or with retention of configuration. In addition, CO transfer, promoted by Mo(CO)6, has been found to play a key role in catalyst turnover.

Asymmetric Bioreduction of a β-Ketoester to (R)-β-Hydroxyester by the Fungus Mortierella alpina MF 5534

Abstract Two hundred and sixty strains of microorganisms, (60 strains of yeasts, 60 strains of bacteria and 140 strains of fungi), were evaluated for their ability to stereoselectively bioreduce a β-ketoester {[2 S -(2α,4β)]-1-[(1,1-dimethylethoxy)carbonyl]-4-hydroxy-β-oxo-2-pyrrolidinepropanoic acid 1,1-dimethylethyl ester} to the corresponding ( R )-β-hydroxyester {[2 S -(2α( S ∗ ),4β)]-β,4-dihydroxy-1-[(1,1-dimethylethoxy)carbonyl]-2-pyrrolidinepropanoic acid 1,1-dimethylethyl ester}, a precursor to the β-methyl carbapenem antibiotic BO 2727. Among all the microbes evaluated, only one fungal strain, Mortierella alpina MF 5534 (ATCC 8979) was found to catalyze the desired reaction. The scaled-up bioconversion process in laboratory bioreactor (23- l scale) supported ( R )-β-hydroxyester titers of 550 mg/ l during a 250-h cultivation cycle and allowed the timely production of gram quantities of diastereomerically pure materials (diastereomeric excess>98%).

Asymmetric bioreduction of cyclohexylphenyl ketone to its corresponding alcohol (+) cyclohexylphenyl alcohol by the yeast Candida magnoliae MY 1785

The screening of 129 fungal and yeasts strains yielded Candida magnoliae MY 1785 as a suitable biocatalyst for the asymmetric bioreduction of cyclohexylphenyl ketone to its corresponding alcohol. Preparative amounts of pure alcohol were prepared and purified. Polarimetry and chiral HPLC analyses indicated that C. magnoliae produced the (+) cyclohexylphenyl alcohol with an enantiomeric excess of 75%. A 55% bioconversion yield was achieved at the preparative scale.

Discovery of a stable molecular complex of an API with HCl: A long journey to a conventional salt

We report formation and characterization of the first pharmaceutically acceptable and stable molecular complex of a mono-HCl salt of Compound 1 with HCl. The novelty of this discovery is due to the fact that there is only one major basic site in the molecule. Thus this complex is reminiscent of other noncovalent crystalline forms including solvates, hydrates, cocrystals and others. To the best of our knowledge, the observed bis-HCl salt appears to be the first example of an active pharmaceutical ingredient in a form of a stable HCl complex. The paucity of stable complexes of APIs with HCl is likely due to the fact that HCl is a gas at ambient conditions and can easily evaporate compromising physical (and chemical) stability of a drug. The bis-HCl salt was chemically/physically stable at low humidity and the molecular HCl stays in the lattice until heated above 140 degrees C under nitrogen flow. Structure solution from powder diffraction using the Monte Carlo simulated annealing method as well as variable temperature ATR-FTIR suggest the possibility of weak hydrogen bonding between the molecular HCl and the nitrogen atom of the amide group. Two years later after the search for a suitable pharmaceutical salt began, the elusive conventional mono-HCl salt was obtained serendipitously concluding the lengthy quest for a regular salt. This work emphasizes the necessity to be open-minded during the salt selection process. It also highlights the difficult, lengthy and often serendipitous path of finding the most appropriate form of an API for pharmaceutical development.