LITMIR.BIZ

       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).

      Extended Discussion

      Draw the structures of the retrosynthetic analysis of one alternative route to cisatracurium besylate. List the pros and cons for both routes. Is one route preferred?

Atropine

      Anesthetics, Preoperative Medicines and Medical Gases/Preoperative Medication and Sedation for Short‐Term Procedures

      Antidotes and Other Substances Used in Poisonings/Specific

      Ophthalmological Preparations/Mydriatics

       A rigid bicyclic structure is often used to direct the formation of a new chiral carbon.

      Discussion. Atropine, a 1 : 1 mixture of the tropane alkaloids (R)‐hyoscyamine and (S)‐hyoscyamine, is usually produced by extraction from the plants Atropa belladonna, Datura stramonium, or Duboisis myoporoides.

      Atropine can also be synthesized from tropic acid and tropinone. In the final step of the synthesis, the primary alcohol is released by acetate ester hydrolysis. The tropic acid ester is formed from the acid chloride and the alcohol, 3‐tropanol (tropine).

In a one‐pot procedure, the acetate ester is formed from acetyl chloride and the primary alcohol of tropic acid then the acid chloride is then formed from the carboxylic acid. Tropic acid is formed by hydrolysis of the ethyl ester. The α‐hydroxymethyl ester is formed by reduction of the α‐formyl ester. The α‐formyl ester is formed from ethyl phenylacetate and ethyl formate (mixed Claisen Condensation).

      The axial alcohol of tropine is formed by reduction of the ketone. Tropinone is efficiently assembled in a single step from methylamine, 2,5‐dimethoxytetrahydrofuran, and 1,3‐acetonedicarboxylic acid (Robinson–Schopf Reaction). 1,3‐Acetonedicarboxlic acid is formed by oxidative decarboxylation of citric acid. Citric acid is produced by fermentation.

      Extended Discussion

      The yield in the first one‐pot synthesis of tropinone, described by Robinson in 1917, was just 17%. After a century of process development, the yield for the one‐pot synthesis is now 90%! List the references for the available procedures, the process modification(s) made, and the tropinone yield. Which process modification had the greatest impact on the yield?

Azathioprine

      Antineoplastics and Immunosuppressives/Immunosuppressive Medicines

      Medicines for Diseases of Joints/Disease‐Modifying Agents Used in Rheumatoid Disorders

       An aromatic thioether is often formed by displacement of chloride or bromide by a thiol.

      Discussion. The thioether is formed in the final step by displacement of chloride from 5‐chloro‐1‐methyl‐4‐nitroimidazole by 6‐mercaptopurine. 5‐Chloro‐1‐methyl‐4‐nitroimidazole is formed by nitration of 5‐chloro‐1‐methylimidazole. 5‐Chloro‐1‐methylimidazole is formed from N,N′‐dimethyloxamide (Wallach Imidazole Synthesis). The oxamide is formed from diethyl oxalate and methylamine. 6‐Mercaptopurine is formed from hypoxanthine.

      Extended Discussion

      Draw the structures of a retrosynthetic analysis of one alternative route to the thioether by nucleophilic aromatic substitution of chloride from 6‐chloropurine. Compare the two routes and select one route as the preferred route.

Azithromycin

      Anti‐Infective Medicines/Antibacterials/Other Antibacterials

      Ophthalmological Medicines/Anti‐Infective Agents

       Macrolide antibiotics are produced by fermentation or are semisynthetic. The process for manufacture of a semisynthetic macrolide antibiotic often begins with conversion of the C9 ketone of erythromycin A to the oxime.

      Discussion. Azithromycin is semisynthetic. Azithromycin is formed from the essential medicine erythromycin A which is produced by fermentation.

      The

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