Peter J. Harrington - Routes to Essential Medicines

The 2‐methoxyquinoline is formed from the 2‐chloroquinoline by chloride displacement. 3‐Benzyl‐6‐bromo‐2‐chloroquinoline is formed from N ‐(4‐bromophenyl)‐3‐phenylpropanamide, and N,N ‐dimethylformamide ( Vilsmeier–Haack Reaction). N ‐(4‐Bromophenyl)‐3‐phenylpropanamide is formed from 4‐bromoaniline and the acid chloride. The acid chloride is formed from 3‐phenylpropanoic acid (dihydrocinnamic acid).

Bedaquiline is converted to a 1 : 1 salt with fumaric acid in the final step of the manufacturing process. Calculate the overall yield of bedaquiline fumarate (1 : 1) from 4‐bromoaniline. (What percent of the 4‐bromoaniline starting material is lost to waste?)

Antineoplastics and Immunosuppressives/Cytotoxic and Adjuvant Medicines

A 2‐alkylbenzimidazole is often formed by the reaction of a 1,2‐phenylenediamine with an acid chloride, anhydride, ester or carboxylic acid.

Discussion.The carboxylic acid is formed by ester hydrolysis in the final step. The bis‐(2‐chloroethyl)amine is formed from the bis‐(2‐hydroxyethyl)amine. The bis‐(2‐hydroxyethyl)amine is formed by ring‐opening of ethylene oxide by the 5‐aminobenzimidazole.

The 5‐aminobenzimidazole is formed by reduction of the 5‐nitrobenzimidazole. The ester is formed from the carboxylic acid and ethanol ( Fischer Esterification). The benzimidazole ring and the carboxylic acid both form in the reaction of N1‐methyl‐4‐nitro‐1,2‐phenylenediamine with glutaric anhydride. The phenylenediamine is formed by a selective reduction of N ‐methyl‐2,4‐dinitroaniline. The dinitroaniline is formed by the displacement of chloride from 1‐chloro‐2,4‐dinitrobenzene by methylamine.

The selective reduction of one nitro group in a 2,4‐dinitroaniline is a key step in the synthesis of bendamustine. (How selective is this reduction?) Draw the structures of the retrosynthetic analysis of an alternative route to bendamustine which is based on reduction of both nitro groups of a dinitroaromatic in the same step. List the pros and cons for both routes and select one route as the preferred route.

Anti‐Infective Medicines/Antiprotozoal Medicines/Antitrypanosomal Medicines/American Trypanosomiasis

A 2‐nitroimidazole is often formed from a 2‐aminoimidazole via the diazonium salt.

Discussion. The amide is formed in the final step by reaction of the ethyl ester with benzylamine. Ethyl 2‐nitroimidazole‐1‐ylacetate is formed from ethyl bromoacetate by bromide displacement by 2‐nitroimidazole. 2‐Nitroimidazole is formed from 2‐aminoimidazole via the diazonium salt. 2‐Aminoimidazole is formed from O ‐methylisourea and 2,2‐dimethoxyethanamine. O ‐Methylisourea is formed from cyanamide and methanol.

Why are anhydrous conditions preferred for the final two steps of the synthesis?

Dermatological Medicines/Medicines Affecting Skin Differentiation and Proliferation

Discussion.Benzoyl peroxide is formed by reaction of benzoyl chloride with hydrogen peroxide.

Dry (98%) benzoyl peroxide is a very dangerous material!

Benzoyl peroxide is not purified by crystallization.

Benzoyl peroxide melts with decomposition and may explode at 106° C.

Benzoyl peroxide may explosively decompose on shock, friction, or concussion.

Benzoyl peroxide is a strong oxidant and reacts violently with combustible or reducing materials.

Benzoyl peroxide reacts violently with inorganic acids, organic acids, alcohols, and amines.

Benzoyl peroxide (75%, with 25% added water) has a better safety profile.

Dermatological Medicines/Scabicides and Pediculicides

When a target molecule is accessible by more than one efficient route, the preferred route is likely to have the lowest raw material costs.

Discussion.Disconnection of the C─O bond suggests benzyl benzoate is manufactured from benzyl alcohol and the acid chloride, anhydride, ester, or carboxylic acid. Methyl benzoate, a byproduct from the manufacture of polyethylene terephthalate (PET or PETE) is used in one manufacturing route. Benzaldehyde is converted to benzyl benzoate in an alternative manufacturing route ( Claisen–Tishchenko Reaction).

Estimate a lowest cost per mole for methyl benzoate, benzyl alcohol, and benzaldehyde. Explain the estimation process used. Use the estimates to calculate a raw material cost to produce 1 mol of benzyl benzoate by both manufacturing routes.

Dermatological Medicines/Anti‐Inflammatory and Antipruritic 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 steroid with 16β‐methyl and 17α‐hydroxy substituents is often formed by ring‐opening of a 16α,17‐epoxide with a methylmagnesium halide.