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Muscle Relaxants (Peripherally Acting) and Cholinesterase Inhibitors

A tertiary amine is often formed by alkylation of a secondary amine.

Discussion. Atracurium besylate is produced as a mixture of 10 stereoisomers (label the four chiral centers in atracurium besylate). The discussion will be limited to routes to one of the 10 stereoisomers, the (1R‐cis, 1′R‐cis)‐isomer known as cisatracurium besylate.

In one preferred route, the quaternary salts are formed in the final step by reaction of the tertiary amines with methyl benzenesulfonate (draw structures for two side products formed in this reaction. How is cisatracurium besylate separated from the side products?) The tertiary amines are formed by conjugate addition of (R)‐tetrahydropapaverine to the acrylate.

(R)‐Tetrahydropapaverine is formed by resolution of tetrahydropapaverine. Tetrahydropapaverine is formed by reduction of dihydropapaverine. The dihydroisoquinoline ring of dihydropapaverine is formed from the amide (Bischler–Napieralski Reaction). The amide is formed from 3,4‐dimethoxyphenylacetic acid and 3,4‐dimethoxyphenethylamine.

The acrylate is formed by elimination of hydrogen bromide. The diester is formed from 1,5‐pentanediol and 3‐bromopropanoic acid (Fischer Esterification).