Lithium Hydroxide → 4-Amino-18-methoxy-20-methyl-7-thia-3,5,10,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-11,16-dione

Participants

Reaction Steps

Trifluoroacetic acid (0.5 ml) was added to a dichloromethane (2.0 ml) solution of 5-{2-amino-6-[2-(4-tert-butoxycarbonylaminobutyrylamino)ethylsulfanyl]pyrimidin-4-yl}-2-methoxy-4-methylbenzoic acid methyl ester (45 mg, 0.08 mmol) obtained in Step 2 above. The reaction solution was stirred for 3.5 hours while gradually warming from 0° C. to room temperature. The reaction solution was concentrated under reduced pressure, and then benzene (1.5 ml) was added to the resulting residue. The solution was concentrated under reduced pressure. This treatment was repeated three times. The resulting colorless syrup-like material was dissolved in tetrahydrofuran (0.7 ml), methanol (0.7 ml), and water (0.5 ml). Lithium hydroxide (18 mg, 0.43 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 24 hours. The reaction solution was acidified by adding 4N hydrochloric acid-ethyl acetate solution (0.95 ml). The solvent was distilled off under reduced pressure. The obtained white solid material was dissolved by adding N,N-dimethylformamide (10 ml) and tetrahydrofuran (33 ml). N-Hydroxybenzotriazole (58 mg, 0.43 mmol), diisopropylethylamine (0.15 ml, 0.9 mmol), and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (165 mg, 0.9 mmol) were sequentially added to the solution. The resulting mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (100 ml), and sequentially washed twice with water (50 ml), and with a saturated aqueous sodium bicarbonate solution (50 ml), water (50 ml), and a saturated aqueous sodium chloride solution (50 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate (10 g). After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography with diol-silica gel (developing solvent: ethyl acetate to ethyl acetate:methanol=15:1) and amino-silica gel (developing solvent: ethyl acetate to ethyl acetate:methanol=15:1) to yield 4-amino-18-methoxy-20-methyl-7-thia-3,5,10,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-11,16-dione (Compound 9) (4 mg) as a white solid material.

Provenance & Evidence