Читать книгу Routes to Essential Medicines - Peter J. Harrington - Страница 73

Dermatological Medicines/Anti‐Inflammatory and Antipruritic Medicines

A single‐enantiomer molecule with multiple chiral carbons is often formed by modification of a natural product which has most or all of the chiral carbons already in place. A steroid with 16β‐methyl and 17α‐hydroxy substituents is often formed by ring‐opening of a 16α,17‐epoxide with a methylmagnesium halide.

Discussion. Betamethasone is manufactured in 9 steps from 16β‐methylpregnane‐3β,17α,21‐triol 21‐acetate, 16 steps from 16‐dehydropregnenolone acetate, and 19 steps from diosgenin. Diosgenin is a phytosteroid sapogenin isolated from the tubers of Dioscorea wild yam.

Fluorine is introduced at C9 on the α–face in the final step by ring‐opening of the 9β,11‐epoxide with hydrogen fluoride. The 9β,11‐epoxide is formed from the bromohydrin. The 11β‐alcohol of the bromohydrin is formed in situ by hydrolysis of the formate ester. The 21‐alcohol is also released by hydrolysis of the carbonate ester. The bromohydrin formate is formed from the 9(11)‐alkene. The 9(11)‐alkene is formed by dehydration of the 11α‐alcohol. The C21 alcohol is protected as a carbonate.

The 11α‐alcohol is formed by microbial oxidation. The acetate ester is hydrolyzed during the microbial oxidation. The 1,4‐diene‐3‐one is formed from the 2α,4α‐dibromo‐3‐one by double elimination. The 2α,4α‐dibromo‐3‐one is formed by α‐bromination of the C3 ketone. The C3 ketone is formed by oxidation of the C3 alcohol of 16β‐methylpregnane‐3β,17α,21‐triol 21‐acetate.

The acetate ester is formed by displacement of bromide by acetate. The α‐bromoketone is formed by bromination of the C20 ketone. The C20 ketone is released by acetal hydrolysis. The 16β‐methyl substituent is introduced by ring‐opening of the 16α,17‐epoxide with methylmagnesium bromide (Grignard Reaction). Methylmagnesium bromide is formed from bromomethane. The 5,6‐alkene is reduced by catalytic hydrogenation. (What is the stereochemistry of the new chiral carbon at C5? Add this stereochemical feature to the structures in the retrosynthetic analysis.) The C20 ketone is protected as an acetal by reaction with ethylene glycol. The 16α,17‐epoxide is formed by epoxidation of the 16‐alkene of 16‐dehydropregnenolone acetate. The acetate ester is hydrolyzed under the epoxidation conditions.

The 16‐alkene of 16‐dehydropregnenolone acetate is formed from diosone by β‐elimination. Diosone is formed by oxidation of the 20(22)‐alkene of pseudodiosgenin‐3,26‐diacetate. Pseudodiosgenin 3,26‐diacetate is formed by reaction of diosgenin with acetic anhydride. The three‐step synthesis of 16‐dehydropregnenolone acetate from diosgenin by acetylation, oxidation, and elimination is known as the Marker Degradation.