Structure and photochemistry of lumiprednisone and lumiprednisone acetate

Abstract

46) NOTE ADDEO IN PROOF, The relatively higher stability of Nmethylimidazole vs. imidazole complexes suggested in our preliminary communication (ref 23) has not been substantiated by further work. The present evidence suggests that both heterocycles have about the same affinity for magnesium in its complexes. In complexes of histidine and Nr-methylhistidine with magnesium phosphates in the enzyme active site pocket, the unmethylated histidine could give rise to a tighter binding than the Kmethyl derivative for purely steric reasons. Abstract:The photolysis o f prednisone acetate ( l b ) in dioxane yielded lumiprednisone acetate (Zb) and not the previously proposed structure 3. Further photoisomerization o f 2b in dioxane gave 2 1 -acetoxy-2, I7a-dihydroxy-I m e t h y l -19-norpregna-1,3,5( IO)-triene-I I ,20-dione (lob). Irradiation o f 2b in 45% aqueous acetic acid yielded 2 I -acetoxy-l I a, I7a-dihydroxy-Ip.1 Ifi-oxa-IOa-pregna-2,20-dione (14a), which has added a molecule o f water. Similar results were observed when prednisone was irradiated. Treatment o f 2b with acid afforded 17a,21 -dihydroxy-I ( I 0 -SP)-abeo-pregna-I ,9-diene-3, I 1,20-trione (15). The mechanism o f these photoisomerization reactions is discussed. The influence o f solvents and the I I -keto function on the photochemistry of the bicyclo[3. I .O]hex-3-en-2-one system is explained. ResultsA. Irradiations in Neutral Media. Irradiation of l a or l b in dry dioxane with 254-nm light afforded the "lumiprednisones" 2a and 2b, respectively, in 65% yield. The assignment of the structure and stereochemistry of 2a and 2b was by comparison of their spectral data with those of the lumiproducts, 9a and 9b, derived by photoisomerization of I7P-acetoxy-1 -dehydrotestosterones 8a4 and 8b,5 respectively, in dioxane with 254-nm light. The structure of the lumiproduct 9a was proven by chemical degradation4 and by circular dichroism mea-suremenk6 The UV of the lumiproduct 2b, A , , , 266 nm ( E 2500), is in close agreement with that of 9b, 268 nm ( e 2950).5The 'H NMR spectra of the A-ring protons in the lumipro-Abstract: Acid and alkaline phosphatase reacts with phosphoenolpyruvate (PEP) to generate enolpyruvate, but neither ketopyruvate nor the geminate diol of pyruvate. The adsorption spectrum for the phosphatase product was derived by kinetic correlation of the changing spectra. Its A, , , , (225 nm) and molar absorptivity, €225 9600 M-I cm-I, are appropriate for 2-hydroxyacrylic acid. Mass spectral analysis shows that the phosphatase product that accumulates transiently requires the addition of a proton to C-3 to give pyruvate. The protonation is slowed ca. sixfold in DrO compared to HzO. Enolpyruvate has sufficient stability ((112 = 3.6 min at 20 OC in DzO, pD 6.4) to be examined as a possible intermediate in enzymatic catalysis. It was predictably shown to lead to strong inhibition of lactate dehydrogenase in the presence of DPN+. Catalysis by pyruvate kinase of the ketonization of enolpyruvate, generated with phosphatase in situ, was shown to occu...

Identification of Phototransformation Products of Prednisone by Sunlight: Toxicity of the Drug and Its Derivatives on Aquatic Organisms

“…These data, compared with those reported by Williams et al [10], allowed the assignment of the bicyclo[5.3.0]decane structure to compound 2. These data, compared with those reported by Williams et al [10], allowed the assignment of the bicyclo[5.3.0]decane structure to compound 2.…”

Rapid structure elucidation of drug degradation products using mechanism-based stress studies in conjunction with LC–MSn and NMR spectroscopy: identification of a photodegradation product of betamethasone dipropionate

“…Similar to the finding in the current study, the stereochemistry of the C10 carbon center in dexamethasone is reversed as the result of the photo-induced isomerization. In addition, the same reversal of the C10 carbon center is also observed in the photo-induced isomeric degradant of prednisone, lumiprednisone [10]; the A-ring of prednisone in its steroid core is identical to that of betamethasone and dexamethasone. A plausible mechanism for the formation of lumibetamethasone dipropionate is thus proposed in Scheme 3, based on the photoisomerization mechanism of dexamethasone [9] and prednisone [10].…”

“…In addition, the same reversal of the C10 carbon center is also observed in the photo-induced isomeric degradant of prednisone, lumiprednisone [10]; the A-ring of prednisone in its steroid core is identical to that of betamethasone and dexamethasone. A plausible mechanism for the formation of lumibetamethasone dipropionate is thus proposed in Scheme 3, based on the photoisomerization mechanism of dexamethasone [9] and prednisone [10]. During this photo-isomerization process, a new bond is formed between C1 and C5 under UV irradiation, followed by the formation of the C4-C10 bond and concomitant cleavage of the C1-C10 bond, leading to the formation of lumibetamethasone dipropionate.…”

Isolation and Characterization of Photodegradation Impurity in Budesonide Drug Product Using LC-MS and NMR Spectroscopy

“…sible mechanism for the formation of lumibudesonide is thus proposed in Scheme 2, based on the photoisomerization mechanism of dexamethasone [17] and prednisone [18]. During this photo-isomerization process, a new bond is formed between C15 and C17 (Scheme 3) under UV irradiation, leading to the formation of lumibudesonide (Scheme 3).…”