A method to synthesize anticancer drug N-（ 4- hydroxyphenyl） retinamide （4-HPR）on a large scale is described. It consists of the preferred steps of reacting all-trans retinoic acid with thionyl chloride to form retinoyl chloride and then reacting with triethylamine to generate retinoyl ammonium salt which in turn is reacted with p-aminophenol to eventually produce 4-HPR. This process can overcome many scale-up challenges that exist in the methods reported in the literature and provide an easy, mild and high yield route for large scale synthesis of 4-HPR. Moreover, the effects of the molar ratios of the reagents on the yield are examined. The best molar ratios are a 2.0 molar equivalence of thionyl chloride and a 3.0 molar equivalence of paminophenol to retinoic acid, and the total yield is 80. 7%.
In order to study the hydrolytic characterization of an anti-inflammatory prodrug （ RI-1 ） in vitro, an effective, accurate and reliable method for the simultaneous determination of the prodrug and its two hydrolytic active compounds is developed using reverse phase high-performance liquid chromatography （RP-HPLC）. The chromatographic separation is performed on an ODS-2 C18 column （250 mm × 4. 6 mm, 5.0 μm particle size） with a simple elution program. The mobile phase is V（ methanol） ： V（0. 1% phosphoric acid solution） =90：10 （adjust pH to 2. 3）. A wavelength of 225 nm and a mobile phase flow rate of 1.0 mL/min are utilized for the quantitative analysis. Excellent linear behaviors over the investigated concentration ranges are observed with values of R2 higher than 0. 999 for all the analytes. The validated method is successfully applied to the simultaneous determination of the prodrug and its active components can be used to detect hydrolytic characterization in vitro.
