diosgenin by acetylation, oxidation, and elimination is known as the Marker Degradation.
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to beclomethasone dipropionate via the 11β‐trifluoroacetate intermediate.
Bedaquiline
Anti‐infective Medicines/Antibacterials/Antituberculosis Medicines
A tertiary alcohol is often formed by addition of an organometallic reagent RLi or RMX (M = Mg, Zn, X = Cl, Br, I) to a ketone.
Discussion. Bedaquiline, the (1R,2S)‐enantiomer, is separated from a 1 : 1 mixture of (1R,2S)‐ and (1S,2R)‐enantiomers by resolution in the final step. (Draw the structures of the chiral acids used for the resolution. What is the yield of bedaquiline for the two‐step resolution process associated with each chiral acid?) The addition of an alkyllithium to a ketone results in a mixture of four stereoisomers. The undesired (1S,2S)‐ and (1R,2R)‐enantiomers are separated from the mixture by crystallization. The desired (1R,2S)‐ and (1S,2R)‐enantiomers are then isolated by crystallization. (What is the highest diastereoselectivity for the addition reaction? What reagents and reaction conditions are associated with the highest diastereoselectivity?) The alkyllithium is formed from 3‐benzyl‐6‐bromo‐2‐methoxyquinoline. The β–dimethylamino ketone is formed from 1‐acetonaphthone, formaldehyde, and dimethylamine (Mannich Reaction).
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).
Extended Discussion
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?)
Bendamustine
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.
Extended Discussion
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.
Benznidazole
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.
Extended Discussion
Why are anhydrous conditions preferred for the final two steps of the synthesis?
Benzoyl Peroxide
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.
Benzyl Benzoate