反应详情

To a stirred solution of 4.4 g of 2-amino-1-adamantanecarboxylic acid in 100 ml of dry methanol at -70° C. is added 3.21 ml of thionyl chloride. The reaction mixture is allowed to stand at room temperature overnight. Removal of the solvent under reduced pressure gives methyl-2-amino-1-adamantanecarboxylate hydrochloride which is represented by the formula ##STR46## The residue containing the methyl 2-amino-1-adamantanecarboxylate hydrochloride is dissolved in 150 ml of chloroform, filtered through Filter Cel, washed with 10 ml of 5 M potassium carbonate solution, separated and then combined with a second chloroform extract of the aqueous phase. The chloroform extract is dried over sodium sulfate, filtered through Filter Cel and concentrated en vacuo. The syrup-like residue is dissolved in 10 ml of tetrahydrofuran and dried over sieves for 30 minutes before used in the mixed anhydride reaction. A dry (sieves) solution of 6.37 g of Boc-L-phenylalanine and 2.66 ml of N-methylmorpholine is stirred under a nitrogen atmosphere at -60° C. To this solution is added 2.12 ml of isobutylchloroformate. The solution is allowed to warm to -10° C. then is cooled to -40° C. over a 10 minute time period, and the tetrahydrofuran solution of methyl 2-amino-1-adamantane-carboxylate from above is added. The reaction mixture is warmed to room temperature and stirred overnight. 150 ml of chloroform is added and the chloroform solution is washed twice with 10 ml of 2 M potassium carbonate solution and once with 20 ml of 1 M potassium bisulfate solution. The chloroform layer is collected, dried over sodium sulfate and concentrated under reduced pressure to give an oily residue. Thin layer chromatography using 2.5% methanol-chloroform as eluent and NMR (CDCl3, 60 MHz, tetramethylsilane internal standard) on the oily residue indicates two disastereoisomers, A and B, of methyl Boc-L-phenylalanyl-2-amino-1-adamantanecarboxylate. Isomer A (Rf=0.41, --CO2Me at 216 cps) is obtained from ether as a crystalline solid melting at 153°-158° C. Isomer B (Rf=0.46, --CO2Me at 212 cps) and additional Isomer A are obtained by chromatographic separation on silica gel using a hexanechloroform gradient.

1. customRemoval of the solvent under reduced pressure