Alkylated steroids. Part 3. The 21-alkylation of 20-oxopregnanes and synthesis of a novel anti-inflammatory 16α,17α,21-trimethyl steroid (Org 6216)

Abstract

The development of a 21 -alkylation reaction which proceeds via the lithium 20(21)-enolate is described and its scope demonstrated by the preparation of a variety of 21 -alkylpregnane derivatives. Application of this process to 1 l~-acetoxy-l6a,l7a-dimethyl-5ct-pregnane-3,2O-dione (28a) and its 5P-analogue (28b) led to the corresponding 16a,l7a,21 -trimethyl derivatives. Several routes from these saturated trimethylpregnane-3,2O-diones to 1 1 P-hydroxy-l6a,17a,21 -trimethylpregna-l,4-diene-3,20-dione (Org 621 6) were explored. The best method gave Org 621 6 in 75% yield. (61 000); vmSx. 1 707 cm-l (11-ketone) (Found, M+, 592.4262. C12Hb802 requires M , 592.4280) with zinc in acetic acid.

Improved Synthetic Route to Dexamethasone Acetate from Tigogenin

“…Many methods for introducing the 1,4-diene into the A-ring of steroids have been reported, for example, the use of selenium compounds, − DDQ (2,3-dichloro-5,6- dicyanobenzoquinone) as an oxidizing agent, , fermentation, − and bromination−dehydrobromination. − Among these, selenium compounds and DDQ are toxic and even gave the products in moderate yield. Fermentation needs a low substrate concentration and a very long reaction time, even though in the course of the production of corticosteroids, such as androstanedione and androstadienedione, from stigmasterol ( 6 ) and sitosterol ( 7 ), fermentation is the method for introducing alkenes into the A-ring.…”

Synthesis of the 16α,17α,21-Trimethyl Corticosteroid Rimexolone from Prednisolone

“…In principle, C-21 methylation could be performed on 5 or deferred until after vicinal C-16/C-17 methylation as in Scheme ( A → B ; note the concurrent methylation of the 11β-acetate). Either sequence had worked well in the absence of a second keto group . We perceived the former sequence to be more favorable here .…”

“…The previously published sapogenin-based synthesis of 1 is summarized in Scheme . The current shift toward utilization of soy-derived 17-oxo steroids as starting materials prompted consideration of alternative routes to 1 employing early construction of the D-ring ethyl enone (see 7 , Scheme ).…”

“…The current shift toward utilization of soy-derived 17-oxo steroids as starting materials prompted consideration of alternative routes to 1 employing early construction of the D-ring ethyl enone (see 7 , Scheme ). Complexities associated with the Δ 1 and 11β-OH functional group introductions would, however, remain. , In contrast, a synthesis of 1 from abundant, inexpensive ($1500/kg) prednisolone ( 2 ) would obviate these concerns. The key issue would then be the compatibility of anion-mediated methylations with the unprotected A-ring dienone.…”

“…Only the enolic silyl ether was cleaved. The mass spectrum of crude 9 showed only 0.2% polyalkylation, an important consideration in light of the difficulty of removing such materials from related intermediates …”