MilliporeSigma
  • Home
  • Search Results
  • A qualitative method for prediction of amine oxidation in methanol and water.

A qualitative method for prediction of amine oxidation in methanol and water.

Journal of pharmaceutical sciences (2015-02-26)
Carina Bäcktorp, Eivor Örnskov, Emma Evertsson, Johan Remmelgas, Anders Broo
ABSTRACT

We have developed a predictive method, based on quantum chemical calculations, that qualitatively predicts N-oxidation by hydrogen peroxides in drug structures. The method uses linear correlations of two complementary approaches to estimate the activation barrier without calculating it explicitly. This method can therefore be automated as it avoids demanding transition state calculations. As such, it may be used by chemists without experience in molecular modeling and provide additional understanding to experimental findings. The predictive method gives relative rates for N,N-dimethylbenzylamine and N-methylmorpholine in good agreement with experiments. In water, the experimental rate constants show that N,N-dimethylbenzylamine is oxidized three times faster than N-methylmorpholine and in methanol it is two times faster. The method suggests it to be two and five times faster, respectively. The method was also used to correlate experimental with predicted activation barriers, linear free-energy relationships, for a test set of tertiary amines. A correlation coefficient R(2) = 0.74 was obtained, where internal diagnostics in the method itself allowed identification of outliers. The method was applied to four drugs: caffeine, azelastine, buspirone, and clomipramine, all possessing several nitrogens. Both overall susceptibility and selectivity of oxidation were predicted, and verified by experiments.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Acetonitrile solution, contains 10.0% acetone, 40.0% 2-propanol, 0.05% formic acid
Sigma-Aldrich
Methanol, NMR reference standard
Sigma-Aldrich
Acetonitrile solution, contains 0.05 % (v/v) trifluoroacetic acid
Sigma-Aldrich
Acetonitrile solution, contains 0.1 % (v/v) trifluoroacetic acid, suitable for HPLC
Sigma-Aldrich
Acetonitrile solution, contains 0.05 % (w/v) ammonium formate, 0.1 % (v/v) formic acid, 5 % (v/v) water, suitable for HPLC
Sigma-Aldrich
Acetonitrile solution, contains 0.1 % (v/v) formic acid, suitable for HPLC
Sigma-Aldrich
Azelastine hydrochloride, ≥98% (HPLC)
Sigma-Aldrich
Methanol, HPLC Plus, ≥99.9%, poly-coated bottles
Supelco
Hydrogen peroxide solution, 30 % (w/w), for ultratrace analysis
Sigma-Aldrich
Methanol, anhydrous, 99.8%
Sigma-Aldrich
Hydrogen peroxide solution, contains potassium stannate as inhibitor, 30-32 wt. % in water, semiconductor grade, 99.999% trace metals basis
Sigma-Aldrich
Methanol, suitable for HPLC, gradient grade, 99.93%
Sigma-Aldrich
Methanol, spectrophotometric grade, ≥99%
Sigma-Aldrich
Hydrogen peroxide solution, tested according to Ph. Eur.
Sigma-Aldrich
3-(Benzyldimethylammonio)propanesulfonate, BioXtra, ≥99.0% (HPCE)
Supelco
Methanol, analytical standard
Supelco
Hydrogen peroxide solution, ≥30%, for trace analysis
Sigma-Aldrich
Hydrogen peroxide solution, 34.5-36.5%
Millipore
Hydrogen peroxide solution, 3%, suitable for microbiology
Sigma-Aldrich
Hydrogen peroxide solution, 30 % (w/w) in H2O, contains stabilizer
Sigma-Aldrich
Methanol, suitable for HPLC, gradient grade, suitable as ACS-grade LC reagent, ≥99.9%
Sigma-Aldrich
Methanol, suitable for HPLC, ≥99.9%
Sigma-Aldrich
Methanol, suitable for HPLC, gradient grade, ≥99.9%
Sigma-Aldrich
Methanol, ACS reagent, ≥99.8%
Sigma-Aldrich
Methanol, Absolute - Acetone free
Sigma-Aldrich
Methanol, ACS spectrophotometric grade, ≥99.9%
Sigma-Aldrich
Methanol, Laboratory Reagent, ≥99.6%
Sigma-Aldrich
Hydrogen peroxide solution, contains inhibitor, 30 wt. % in H2O, ACS reagent
Sigma-Aldrich
Hydrogen peroxide solution, purum p.a., ≥35% (RT)
Sigma-Aldrich
Hydrogen peroxide solution, contains inhibitor, 30 wt. % in H2O, meets USP testing specifications