Uses
N-(tert-Butoxycarbonyl)-D-4-chlorophenylalanine, is one of the phenylalanine derivatives, that can be used for the synthesis of THIQ (C380165), which is a selective melanocortin 4 receptor.
Synthesis
The general procedure for the synthesis of (R)-2-((tert-butoxycarbonyl)amino)-3-(4-chlorophenyl)propanoic acid from D-4-chlorophenylalanine was as follows: the crude product of D-4-chlorophenylalanine (22.0 mg, 0.110 mmol) was dissolved in a mixed solvent of water (2 mL) and acetone (1.0 mL). To this solution was sequentially added a solution of acetone (0.5 mL) of di-tert-butyl dicarbonate (Boc)2O (40.4 mg, 0.185 mmol) and a solution of acetone (0.5 mL) of triethylamine (18.8 mg, 0.186 mmol). The reaction mixture was stirred at room temperature for 44 hours. Upon completion of the reaction, the mixture was concentrated to a volume of ≤ 2 mL, followed by the addition of toluene (5 mL). The pH of the aqueous layer was adjusted to 2-3 by slowly adding 4N hydrochloric acid under stirring. the organic layer was separated and washed with saturated saline (5 mL x 2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to remove the solvent to give Boc-D-4-chlorophenylalanine (28.7 mg, 87.3% yield, ee value 98.6%) as a white solid. The product was analyzed by HPLC under the following conditions: column: CHIRALPAK AD-RH (5 μm, 150×4.6 mm ID); mobile phase: A (0.1% aqueous phosphoric acid solution):B (0.1% phosphoric acid acetonitrile solution)=35:65; flow rate: 1.0 mL/min; column temperature: 35°C; detection wavelength: 254 nm. The analytical results showed that the target The retention time of the compound Boc-D-4-chlorophenylalanine was 14.16 min, the isomer ratio was 0.7:99.3, and the corresponding ee value was 98.6%.
