Synthesis of a novel water soluble phthalimide derivative of acetaminophen as potential analgesic and antipyretic agent

691-693A short process for the preparation of water soluble, potential analgesic compound, N-[(4-hydroxy-phenylcarbamoyl)-methyl]-phthalamic acid 4 has been developed. Two synthetic routes (A and B) have been established for the preparation of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-(4-hydroxyphenyl)acetamide 3. In route A, 4-aminophenol 5 is reacted with chloroacetyl chloride 6 in solution of potassium acetate and acetic acid at 0-5°C to yield N-(4-hydroxyphenyl)-2-chloroacetamide 7<span style="mso-bidi-font-weight: bold">. The latter is reacted with potassium phthalimide 8 and KI in DMF at 130°C to give 3. Alternatively, in route B, reaction of phthalic anhydride 8 with glycine 9 at 150<span style="font-size:12.0pt; mso-ansi-language:EN" lang="EN">°C yields the acid intermediate (1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid 11, which on reaction with 4-aminophenol 6 in DMF and in the presence of dicyclo­hexylcarbodimide gives 3. The latter is hydrolysed in ethanolic KOH to afford 4.