Читать книгу Routes to Essential Medicines - Peter J. Harrington - Страница 81

Medicines Acting on the Respiratory Tract/Antiasthmatic and Medicines for Chronic Obstructive Pulmonary Disease

Ear, Nose, and Throat 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 16α,17α‐dihydroxy‐20‐one steroid is often formed by dihydroxylation of a 16‐ene‐20‐one.

Discussion. Budesonide is manufactured in five steps from 21‐acetoxypregna‐1,4,9(11),16‐tetraene‐3,20‐dione and in 10 steps from another essential medicine, prednisolone.

Budesonide is a mixture of the 22R‐ and 22S‐diastereomers. The acetal is formed in the final step by reaction of the 16α,17α‐diol with butanal. The C21 alcohol is released by hydrolysis of the acetate ester. The 9α‐hydrogen is introduced by reduction of the 9α‐bromide. The bromohydrin is formed from the 9(11)‐ene. The 16α,17α‐diol is formed by dihydroxylation of the 16‐alkene of 21‐acetoxypregna‐1,4,9(11),16‐tetraene‐3,20‐dione.

The 9(11)‐ene of the tetraene is formed by elimination of the C11β mesylate which is formed in situ. The 16‐alkene is formed by elimination of the 17α‐acetate of prednisolone 17α,21‐diacetate. Prednisolone 17α,21‐diacetate is formed by reaction of the 17α‐acetate with acetic anhydride. The 17α‐acetate is formed from prednisolone 17α,21‐ethyl orthoacetate. The orthoester is formed from prednisolone and triethyl orthoacetate.