, SO 2 R, COOR, CN) on C3.
Discussion. A C─N bond is formed by displacement of a chloride at the quinoline 4‐position by nitrogen of the 4‐aminophenol.
4,7‐Dichloroquinoline is formed from 7‐chloro‐ 4‐hydroxyquinoline (7‐chloroquinolin‐4‐one). 7‐Chloro‐ 4‐hydroxyquinoline is formed by thermolysis/decarboxylation of the 4‐hydroxyquinoline‐3‐carboxylic acid. The carboxylic acid is formed by ester hydrolysis. The quinoline ring is formed by an intramolecular acylation at C6 of the 3‐chloroaniline. An enamine is formed by reaction of the enol ether of ethyl ethoxymethylenemalonate with 3‐chloroaniline (The four‐step sequence from 3‐chloroaniline to 7‐chloro‐4‐hydroxyquinoline is an example of the Gould–Jacobs Reaction).
The 4‐aminophenol is formed by hydrolysis of the acetanilide. Another essential medicine, 4‐acetamidophenol (para‐acetamol or acetaminophen) is alkylated by reaction with formaldehyde and N,N‐diethylamine (Betti Reaction).
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route from 3‐chloroaniline to 7‐chloro‐4‐hydroxyquinoline utilizing a Conrad–Limpach Reaction. Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical raw materials. List pros and cons for the two routes and select one route as the preferred route.
Amoxicillin
Anti‐Infective Medicines/Antibacterials/Beta‐Lactam Medicines
Penicillins are produced by fermentation or are semisynthetic. A semisynthetic penicillin is often formed by acylation of the amine of 6‐aminopenicillanic acid (6‐APA). 6‐APA is produced from penicillin G (benzylpenicillin) by enzyme‐mediated hydrolysis of the side‐chain amide.
Discussion. Amoxicillin is a semisynthetic penicillin. The final step is enzyme‐mediated formation of the side‐chain amide by reaction of an amine with an ester. The amine, 6‐aminopenicillanic acid (6‐APA), is formed by enzyme‐mediated hydrolysis of the side‐chain amide of penicillin G. Penicillin G (benzylpenicillin) is produced by the fungus Penicillium chrysogenum.
The ester is formed from the carboxylic acid (Fischer Esterification). The α‐amino acid, (R)‐α‐(4‐hydroxyphenyl)glycine, is formed by enzyme‐mediated hydrolysis of the N‐carbamoyl α‐amino acid. The (R)‐N‐carbamoyl α‐amino acid is formed by enzyme‐mediated hydrolysis of the (R)‐hydantoin in a mixture of the (R)‐ and (S)‐hydantoins. Since the (R)‐ and (S)‐hydantoins interconvert under the hydrolysis conditions, the (S)‐hydantoin is also converted to the (R)‐N‐carbamoyl α‐amino acid. The mixture of (R)‐ and (S)‐hydantoins is formed from phenol, glyoxylic acid, and urea.
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to amoxicillin from (R)‐α‐(4‐hydroxyphenyl)glycine and 6‐APA which does not utilize an enzyme to mediate the formation of the side‐chain amide bond.
Ampicillin
Anti‐Infective Medicines/Antibacterials/Beta‐Lactam Medicines
Penicillins are produced by fermentation or are semisynthetic. A semisynthetic penicillin is often formed by acylation of the amine of 6‐aminopenicillanic acid (6‐APA). 6‐APA is produced from penicillin G (benzylpenicillin) by enzyme‐mediated hydrolysis of the side‐chain amide.
Discussion. Ampicillin is a semisynthetic penicillin. The final step is release of the amine by hydrolysis of an enamine. The side‐chain amide is formed by enzyme‐mediated formation of the reaction of 6‐aminopenicillanic acid (6‐APA) with a mixed anhydride. 6‐Aminopenicillanic acid is formed by enzyme‐mediated hydrolysis of the side‐chain amide of penicillin G. Penicillin G (benzylpenicillin) is produced by the fungus P. chrysogenum.
The mixed anhydride is formed from the potassium carboxylate salt and pivaloyl chloride. The N‐protected potassium carboxylate salt of the amino acid (known as a Dane Salt) is formed from (R)‐α‐phenylglycine and ethyl acetoacetate.
Extended Discussion
Ampicillin is also manufactured from 6‐APA and the acid chloride, (R)‐α‐phenylglycine chloride hydrochloride. List the pros and cons for both routes and select one route as the preferred route.
Anastrozole
Antineoplastics and Immunosuppressives/Hormones and Antihormones
A phenylacetonitrile is often formed by displacement of a benzyl chloride or bromide by cyanide.
Discussion. Each substituent on the central ring of anastrozole has a functional group (cyanide or 1,2,4‐triazole) which is likely introduced as a nucleophile. These features suggest disconnection strategies which have statistical product distribution problems. In a preferred strategy, the most significant problem is addressed in the preparation of the starting material.
Bromide is displaced by 1,2,4‐triazole in the final step. The bromomethyl group is formed by bromination of the methyl group.
Four methyl groups are added by α‐alkylation of the nitriles with iodomethane. The nitriles are formed by bromide displacement by sodium cyanide. The dibromide is formed by bromination of mesitylene.
Extended Discussion
Final product purity is critical when manufacturing a drug substance. To ensure high purity of the product, no side products which are difficult to separate from the product