Mechanism of base-catalyzed autooxidation of corticosteroids containing 20-keto-21-hydroxyl side chain

Tetrahedron Letters

Volumn 50, Issue 32, 2009, Pages 4575-4581

  Li, Min ^a   Chen, Bin ^a   Monteiro, Stephanie ^a   Rustum, Abu M ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Betamethasone 17 acid; Betamethasone 17 formyloxy 17 acid; Betamethasone 21 aldehyde; Corticosteroids; Enolate; Oxidation

Indexed keywords

BASE; BETAMETHASONE; BETAMETHASONE 17 ACID; BETAMETHASONE 17 DIFORMYLANHYDRIDE; BETAMETHASONE 17 FORMYLOXY 17 ACID; BETAMETHASONE 17 KETONE; BETAMETHASONE 20 HYDROXY 21 ACID; BETAMETHASONE 21 ALDEHYDE; BETAMETHASONE 9,11 EPOXIDE; CORTICOSTEROID; DEXAMETHASONE; DEXAMETHASONE 9,11 EPOXIDE; DIHYDROXYACETONE; HYDROCORTISONE; HYDROXYL GROUP; OXYGEN 18; UNCLASSIFIED DRUG;

ALKALINITY; ARTICLE; AUTOOXIDATION; CATALYSIS; CHEMICAL REACTION; CONCENTRATION (PARAMETERS); CORRELATION ANALYSIS; DEGRADATION; LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; OXIDATION;

EID: 67449107257     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2009.05.074     Document Type: Article

References (22)

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8. All the reactions studied in this Letter were monitored by LC-MS and/or high-resolution LC-MS. The characterization of the degradants formed during all the forced degradation studies was done through one of the two ways: (1) For the majority of the degradants formed, comparative LC-MS analyses were performed against authentic reference compounds available in-house. (2) In cases where authentic compounds were not available, high-resolution LC-MS characterization was further confirmed by 1D and 2D NMR determination. All the compounds generated in this study were found to be within 3 ppm of their theoretical formulas by high-resolution LC-MS. The LC-MS analyses were performed under ESI positive mode either on a Thermo Electron Surveyor HPLC system coupled with a PDA detector and an MSQ Plus MS detector or on a Thermo Electron Surveyor HPLC system coupled with a PDA detector and an LTQ MS detector or a high-resolution Orbitrap MS detector, with the MS conditions similar to those published by our group previously: Li, M.; Chen, B.; Lin, M.; T.-M. Chan; Rustum, A. Tetrahedron Lett. 2007, 48, 3901-3905. The LC conditions of the LC-MS methods used are summarized as follows. (1) For the conditions used in Figure 2, the chromatographic elution was effected isocratically on a Supelco Supercosil ABZ-plus column (25 cm × 4.6 mm ID, 5 μm) with a mobile phase consisting of 55% of A (0.2% acetic acid) and 45% of B (acetonitrile) at a flow rate of 2.0 mL/min. (2) For the conditions used in Figure 3 and Table 1, the chromatographic elution was effected on a Supelco Supercosil ABZ-plus column (25 cm × 4.6 mm ID, 5 μm) with a gradient generated between mobile phase A (0.1% TFA in water) and B (0.1% TFA in acetonitrile) at a flow rate of 1.3 mL/min according to the following program: 0-10 min, 30-60%B; 10.1-15 min, 30%B. (3) The conditions used in Figure 4 were similar to those used in Figure 3 and Table 1, except that the flow rate was 2.0 mL/min and the gradient program was slightly different: 0-10 min, 30-75%B; 10.1-15 min, 30%B.
9. A different nomenclature has been used in the literature for the majority of the degradants mentioned in this Letter. We prefer to use a more descriptive and self-explanatory name such as betamethasone 21-aldehyde. All the compound names we used are listed below along with other conventional names (if available) and the IUPAC names: betamethasone (1), (11β,16β)-9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione; betamethasone 17-ketone (5): (11β,16β)-9-fluoro-11-hydroxy-16-methylandrosta-1,4-diene-3,17-dione; betamethasone 21-aldehyde (7), betamethasone glyoxal, 21-dehydrobetamethasone, (11β,16β)-9-fluoro-11,17-dihydroxy-16-methylpregna-1,4-diene-3,20-dione-21-al; betamethasone 20-hydroxy-21-acid (8), betamethasone glycolic acid, (11β,16β)-9-fluoro-3-oxo-11,17,20-trihydroxy-16-methylpregna-1,4-diene-21-oic acid; betamethasone 17-formyloxy-17-acid (10), (11β,16β,17α)-9-fluoro-17-(formyloxy)-11-hydroxy-3-oxo-16-methylandrosta-1,4-diene-17-carboxylic acid; betamethasone 17-acid (11), (11β,16β,17α)-9-fluoro-11,17-dihydroxy-3-oxo-16-methylandrosta-1,4-diene-17-carboxylic acid.
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22. We did not see any difference in our own studies either with or without laboratory lighting.