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Anti‐Infective Medicines/Antiviral Medicines/Antiretrovirals/Protease Inhibitors

A β‐amino alcohol with a primary β‐C is often formed by ring‐opening of an epoxide by an amine.

Discussion. Two amides are formed with expensive N‐(methoxycarbonyl)‐L‐tertleucine (Moc‐L‐tertleucine) in the final step. The amine and hydrazine needed to form the amides are released by hydrolysis of tert‐butoxycarbonyl (Boc) protecting groups. A key C─N bond near the center of the molecule is formed by ring‐opening of an epoxide with a Boc‐protected hydrazine.

Moc‐L‐Tertleucine is formed from L‐tertleucine and methyl chloroformate. L‐Tertleucine is formed by an enzyme‐mediated reductive amination of trimethylpyruvic acid. The pyruvic acid is formed by oxidation of the α‐hydroxyacid. The α‐hydroxyacid is formed from 1,1‐dichloropinacolone by rearrangement and hydrolysis. 1,1‐Dichloropinacolone is formed by α–chlorination of pinacolone.

The epoxide is formed from the chlorohydrin by nucleophilic displacement of chloride by oxygen. The chlorohydrin is formed by reduction of the α‐chloroketone, N‐(tert‐butoxycarbonyl)‐3(S)‐amino‐1‐chloro‐4‐phenyl‐2‐butanone. The α‐chloroketone is formed by reduction of the α,α‐dichloroketone. The α,α‐dichloroketone is formed from N‐(tert‐butoxycarbonyl)‐L‐phenylalanine methyl ester and dichloromethane.

The Boc‐protected hydrazine is formed by reduction of the hydrazone. The hydrazone is formed by reaction of the aldehyde with Boc‐hydrazine. The aldehyde, 4‐(2‐pyridyl)benzaldehyde, is formed from 2‐bromopyridine and 4‐formylbenzeneboronic acid (Suzuki–Miyaura Coupling). The boronic acid is formed from 4‐chlorobenzaldehyde and trimethylborate via an acetal.