Название | Routes to Essential Medicines |
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Автор произведения | Peter J. Harrington |
Жанр | Химия |
Серия | |
Издательство | Химия |
Год выпуска | 0 |
isbn | 9781119722830 |
(1S,4R)‐4‐Amino‐2‐cyclopentene‐1‐methanol and the (1R,4S)‐enantiomer are separated by resolution. The amino alcohols are formed by reduction of the amides (Vince Lactam). The amides are formed by displacement of methanesulfinate by hydroxide.
The 2‐azabicyclo[2.2.1]hepta‐2,5‐dienes are formed by [4 + 2]‐cycloaddition of cyclopentadiene with methanesulfonyl cyanide (Diels–Alder Cycloaddition). Methanesulfonyl cyanide is formed from sodium methanesulfinate and cyanogen chloride. Sodium methanesulfinate is formed by reduction of methanesulfonyl chloride.
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to abacavir using a disconnection of the C─N bond joining the purine ring to the cyclopentene ring. Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical raw materials.
Acetazolamide
Ophthalmological Preparations/Miotics and Antiglaucoma Medicines
A sulfonyl chloride attached to an aromatic ring may be formed by oxidation of the thiol.
Discussion. Acetazolamide is formed in just three steps from 5‐amino‐1,3,4‐thiadiazole‐2‐thiol. The sulfonamide is formed from the sulfonyl chloride in the final step. The sulfonyl chloride is formed by oxidation of the thiol. The amide is formed by acetylation of the amine using acetic anhydride.
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to the starting material 5‐amino‐1,3,4‐thiadiazole‐2‐thiol. List the pros for the route presented and the alternative route and select one route as the preferred route.
Acetylcysteine
Antidotes/Specific
A chiral carbon in a single‐enantiomer molecule is often delivered in a starting material.
Discussion. N‐Acetyl‐L‐cysteine is formed by acetylation of L‐cysteine with acetic anhydride. L‐Cysteine is produced by fermentation.
Acetylsalicylic Acid
Medicines for Pain and Palliative Care/Non‐Opioids and Non‐Steroidal Anti‐Inflammatory Medicines
Antimigraine Medicines/For Treatment of Acute Attack
Cardiovascular Medicines/Antithrombotic Medicines/Anti‐Platelet Medicines
Medicines for Diseases of Joints/Juvenile Joint Diseases
salicylic acid
Dermatological Medicines/Medicines Affecting Skin Differentiation and Proliferation
Discussion. Acetylsalicylic acid (aspirin) is formed from another essential medicine, salicylic acid, and acetic anhydride. Salicylic acid is formed from phenol and carbon dioxide (Kolbe–Schmitt Reaction).
Acyclovir
Anti‐Infective Medicines/Antiviral Medicines/Antiherpes Medicines
Ophthalmological Preparations/Anti‐Infective Agents
Guanine is often converted to an acylated or silylated derivative to increase solubility in organic solvents. These derivatives react with alkylating agents to form a mixture of N7‐alkylated (kinetic) product and N9‐alkylated (thermodynamic) product.
Discussion. The concepts and challenges common to the many routes to acyclovir are featured in a comparison of two preferred routes. In route A, the alcohol is released by O‐desilylation in the final step. Acyclovir O‐trimethylsilyl ether is formed by desilylation of persilyl acyclovir. A mixture of the N9‐alkylated persilyl acyclovir and the N7‐alkylated regioisomer is formed in situ by in the reaction of persilyl guanine with 1,3‐dioxolane (What is the highest ratio of persilyl acyclovir to the N7‐alkylated regioisomer? What reaction conditions are associated with the highest ratio? How is the N7‐alkylated side product separated from the N9‐alkylated product?). Persilyl guanine is a mixture of N7‐TMS and N9‐TMS regioisomers formed in situ by the reaction of guanine with excess hexamethyldisilazane (HMDS).
In route B, the alcohol and amino group are released by hydrolysis of the ester and amide in the final step. The alkylation of N2,9‐diacetylguanine with 2‐(acetoxyethoxy)methyl acetate affords a mixture of the N7‐ and N9‐regioisomers. (Draw the structure of the N7‐regioisomer. What is the highest N9:N7 ratio? What reaction conditions are associated with the highest ratio? How is the N7‐alkylated side product separated from N9‐alkylated product?) N2,9‐Diacetylguanine is formed by reaction of guanine with acetic anhydride.
2‐(Acetoxyethoxy)methyl acetate is formed from 1,3‐dioxolane, acetic acid, and acetic anhydride.
Extended Discussion
List the pros and cons for routes A and B and select one route as the preferred route.
Albendazole
Anti‐Infective Medicines/Anthelmintics/Antifilarials