Trifluoroacetic acid → HCID 86760076, compound

Participants

Reaction Steps

(S)-2-tert-Butoxycarbonylamino-pentanedioic acid 1-methyl ester. A solution of (S)-2-tert-Butoxycarbonylamino-pentanedioic acid 5-benzyl ester 1-methyl ester 41-1 (4.32 g, 12.3 mmol) and palladium on carbon (10%, 0.432 g) in methanol (45 mL) were stirred under 1 atmosphere of hydrogen for 4 hours. The solution was then filtered through a pad of celite and concentrated in vacuo to give 2.86 g of the desired product. Rt=1.61, MH+=262. 41-3: (S)-2-tert-Butoxycarbonylamino-4-(6-fluoro-benzothiazol-2-ylcarbamoyl)-butyric acid methyl ester. To a stirring solution of 41-2 (0.50 g, 1.91 mmol), N,N-diisopropylethylamine (1.0 mL, 5.74 mmol), 6-Fluoro-benzothiazol-2-ylamine (0.293 g, 1.74 mmol) and benzotriazol-1-ol (0.259 g, 1.91 mmol) in dichloromethane (10 mL) at 0° C. was added 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.367 g, 1.91 mmol). The solution was allowed to warm to room temperature and stirred overnight. The solution was then concentrated in vacuo, and the residue was diluted with ethyl acetate and washed with 1N HCl twice, saturated aqueous sodium bicarbonate twice, then brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (30% ethyl acetate/hexanes) gave 0.234 g of the desired product. Rt=2.46, MH+=412. 41-4: (S)-2-Amino-4-(6-fluoro-benzothiazol-2-ylcarbamoyl)-butyric acid methyl ester. To a stirring solution of 41-3 (0.234 g, 0.569 mmol) in dichloromethane (7 mL) was added trifluoroacetic acid (3 mL). The reaction was stirred at room temperature for 3 hours, then concentrated in vacuo. The residue was diluted with ethyl acetate then washed with saturated aqueous sodium bicarbonate solution twice, then dried over Na2SO4, filtered, and concentrated in vacuo to give 0.161 g of the desired product. Rt=1.03, MH+=312. 41-5: (S,S)-2-[3-(6-Fluoro-benzothiazol-2-ylcarbamoyl)-1-methoxycarbonyl-propylamino]-4-methyl-pentanoic acid methyl ester. To a solution of (R)-4-Methyl-2-trifluoromethanesulfonyloxy-pentanoic acid methyl ester (0.187 g, 0.672 mmol) in dichloromethane (4 mL) at −70° C. was added N,N-diisopropylethylamine (0.18 mL, 1.03 mmol) followed by a solution of 41-4 (0.161 g, 0.517 mmol) in dichloromethane (3 mL) dropwise. The solution was allowed to slowly warm to room temperature, and stirred for 16 hours. The solvent was evaporated, and the residue was diluted with ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate twice, followed by brine. The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (10–30% ethyl acetate/hexanes) gave 0.075 g of the desired product. Rt=2.34, MH+=440. 41-6: (S,S)-2-[1-Carboxy-3-(6-fluoro-benzothiazol-2-ylcarbamoyl)-propylamino]-4-methyl-pentanoic acid (Compound OV). To a stirring solution of 41-5 (0.075 g, 0.171 mmol) in tetrahydrofuran (2.1 mL), methanol (0.7 mL), and water (0.7 mL) at 0° C. was added lithium hydroxide monohydrate (0.029 g, 0.682 mmol). The solution was allowed to warm to room temperature and stirred for 16 hours. After concentrating the organics in vacuo, the aqueous layer was acidified with 1N HCl until a white precipitate formed which was filtered and dried to give 0.043 g of the desired compound. Rt=1.62, MH+=412. NMR consistent with the assigned structure.

Provenance & Evidence