A novel oxidative degradation pathway of indomethacin under the stressing by hydrogen peroxide

Tetrahedron Letters

Volumn 46, Issue 20, 2005, Pages 3533-3536

  Li, Min ^a   Conrad, Beth ^a   Maus, Russell G ^a   Pitzenberger, Steven M ^a   Subramanian, Raju ^a   Fang, Xueguang ^a   Kinzer, Jeffery A ^a   Perpall, Holly J ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Decarboxylation; Degradation; Epoxide; Hydrogen peroxide; Indole; Indomethacin; Oxidation

Indexed keywords

HYDROGEN PEROXIDE; INDOMETACIN; INDOMETACIN DERIVATIVE; RRT 0 64; RRT 0 73; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL STRUCTURE; DEGRADATION; DRUG SYNTHESIS; OXIDATION; REACTION ANALYSIS; STRESS; STRUCTURE ANALYSIS;

EID: 17844364866     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2005.03.064     Document Type: Article

References (14)

1. M. O'Brien, J. McCauley, and E. Cohen Anal. Prof. Drugs Sub. 13 1984 211 238
2. A solution of 1.6 mg of indomethacin in 12 mL of a solvent mixture (methanol/acetonitrile/water, 1/2/3, v/v/v) was mixed with 1 mL of a 3% hydrogen peroxide solution. The resulting mixture was heated at 80 °C for 75 min. After cooling to room temperature, aliquots of the solution were injected into the HPLC system described in Ref. 3 for analysis
3. The HPLC analyses were performed on a Waters Alliance system consisting of a Model 2695 Separations Module and a Model 2996 photo diode array detector. The system was equipped with an Alltech Platinum EPS C8, 100 × 4.6 mm, 3 μm column. Elution was effected with a linear gradient generated between solution A (acetonitrile/methanol, 1/6, v/v) and solution B (0.1% formic acid in water): the percentage of solution A was increased from an initial 30% to 70% over a period of 15 min. The flow rate was 1.0 mL/min and the column was heated at 35 °C
4. The LC-MS analyses were carried out on a TSP HPLC system interfaced to a Finnegan LCQ mass spectrometer. Experiments were performed in electrospray ionization (ESI)-positive ion mode. A flow rate of 1.0 mL/min directly in source (no post-column split) was used. The temperature of the capillary was set to 200 °C. The LC gradient is the same as outlined in Ref. 3
5. RRT is 'relative retention time' of the peak relative to indomethacin which is defined as (retention time of the peak)/(retention time of indomethacin)
6. X. Zhang, and C.S. Foote J. Am. Chem. Soc. 115 1993 8867 8868
7. -1
8. 6 to which TMS was added as an internal chemical shift reference. Proton and carbon chemical shift assignments (Fig. 2) were made based on the results of proton 1D, HMQC, and gHMBC experiments performed at a sample temperature of 25 °C. The hydroxyl proton (6.55 ppm) exhibited a two-bond coupling to the 3-position carbon at 81.8 ppm and three-bond couplings to carbons at 133.2, 103.4, and 39.3 ppm. The methyl group protons were found coupled to the 2-position carbon at 103.4 (two-bond) and the 3-position carbon at 81.8 ppm (three-bond). The methylene protons (3.27 and 3.20 ppm) were nonequivalent due to the presence of stereocenters in the molecule. The methylene protons were found coupled to carbons at 171.5, 133.2, 103.4, and 81.8 ppm. The coupling from the 3.27 ppm proton to the 103.5 ppm carbon was stronger than the coupling to the coupling from the 3.20 ppm proton to the same carbon due to a more favorable dihedral angle. Irradiation of the 7.19 ppm proton in a difference NOE experiment produced a stronger enhancement in the 3.27 ppm proton than in the 3.20 ppm proton. Irradiation of the 1.68 ppm methyl group produced a strong enhancement in the hydroxyl proton (verified cis ring juncture) and an enhancement in the 3.20 ppm proton. The NOE results together with the heteronuclear couplings allowed their stereospecific assignment as shown in Figure 2
9. M. Komuro, T. Higuchi, and M. Hirobe J. Chem. Soc., Perkin Trans. 1 1996 2309 2313
10. M. Hirobe Pure Appl. Chem. 66 1994 729 736
11. The stressing condition is similar to what is described in Ref. 2 except that a more concentrated indomethacin solution was used (0.5 mg/mL in methanol/acetonitrile/water, 1/2/3, v/v/v) and final hydrogen peroxide concentration was 0.3%. Aliquots of the stressed solution were injected into a preparative Waters HPLC system consisting of a Model 600 pump and controller unit and a model 2996 photodiode array detector. The system was equipped with a Waters Xterra RP18, 19 mm × 100 mm, 5 μm column. Elution was effected with a linear gradient generated between solution A (acetonitrile/methanol, 1/6, v/v) and solution B (0.1% formic acid in water). The percentage of solution A was increased from an initial 40% to 90% over 15 min. The flow rate was 25 mL/min. and column was maintained at ambient temperature. The fractions corresponding to RRT 0.64 (compound 3) were collected and the pooled fractions were then dried by evaporation in vacuo
12. +], 330.0897. Found: 330.0978
13. J.P. Mario, S. Bogdan, and K. Kimura J. Am. Chem. Soc. 114 1992 5566 5572
14. C.H. van Dyck, P. Newhouse, W.E. Falk, and J.A. Mattes Arch. Gen. Psychiat. 57 2000 157 164