Читать книгу Routes to Essential Medicines - Peter J. Harrington - Страница 16

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.