The S-oxidative degradation of a novel corticosteroid tipredane (INN) Part III. Detailed investigations into the disulphoxidation of tipredane.
The methyl- and ethylsulphoxide diastereoisomers (V and VI) of the corticosteroid tipredane (INN, I) have been shown to undergo further stereoselective S-oxidation to yield diastereoisomeric disulphoxides (II). Interactive computer optimisation software was employed to develop semi-preparative chromatography conditions for the isolation of the disulphoxide diastereoisomers (II) and to develop a multiselective gradient HPLC analysis of tipredane (I), the four monosulphoxide diastereoisomeric pairs (V, VI, IX and X), the four disulphoxide diastereoisomers (II), the vinyl methyl and ethyl derivatives (XI and XII) and the methylsulphone of tipredane (VII). The four diastereoisomeric disulphoxides (II) have been isolated by semi-preparative HPLC and their structures unambiguously confirmed by high resolution multinuclear NMR and mass spectrometry. The stereochemical assignment of the four disulphoxide diastereoisomers (II), the ethylsulphoxide diastereoisomeric pair (VI), and the vinyl methyl and ethylsulphoxide diastereoisomeric pairs (IX and X) was determined by degradation/synthesis and relation to the S/R-disulphoxide (II) whose stereochemistry was determined by X-ray crystallography. The monosulphoxides (V and VI) showed a high degree of site and stereoselectivity towards further S-oxidation. S-Oxidation on the C-17 beta-substituent of tipredane occurred at a rate approximately 50-fold faster than that on the alpha-substituent. The disulphoxides (II) have been shown to be susceptible to thermolysis yielding the vinyl methylsulphoxide diastereoisomers (IX) preferentially. The loss of the ethylsulphenic acid from the disulphoxide diastereoisomers (II) could be rationalised in terms of the preferred rotamers of the C-17 substituents.
Euerby
M R
MR
Pharmacuetical & Analytical Research & Development, Astra Charnwood, Leicestershire, UK.
Graham
J A
JA
Johnson
C M
CM
Lewis
R J
RJ
Wallace
D B
DB
D000287:Administration, Topical; D000730:Androstadienes / Q000737:chemistry*; D000893:Anti-Inflammatory Agents / Q000737:chemistry*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D005938:Glucocorticoids; D006863:Hydrogen-Ion Concentration; D010084:Oxidation-Reduction; D012996:Solutions; D013237:Stereoisomerism; D013454:Sulfoxides / Q000737:chemistry* / Q000302:isolation & purification
D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D012996:Solutions; D013454:Sulfoxides; C051756:tipredane