反应详情

Trifluoroacetic acid (1.0 ml) was added to a dichloromethane (3.0 ml) solution of 5-(2-amino-6-{2-[4-(tert-butoxycarbonylmethylamino)butyrylamino]ethylsulfanyl}pyrimidin-4-yl)-2-methoxy-4-methylbenzoic acid methyl ester (95 mg, 0.17 mmol) obtained in Step 1 above. The reaction solution was stirred for 3 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 again concentrated under reduced pressure. After this treatment was repeated three times, the obtained colorless syrup-like material was dissolved in tetrahydrofuran (1.5 ml), methanol (1.5 ml), and water (1.0 ml). Lithium hydroxide (74 mg, 1.75 mmol) was added to the mixture. The reaction solution was stirred at room temperature for 12 hours, and then acidified by adding 4N hydrochloric acid-ethyl acetate solution (1.32 ml). The solvent was distilled off under reduced pressure. N,N-Dimethylformamide (44 ml) and tetrahydrofuran (44 ml) were added to the obtained white solid material. N-Hydroxybenzotriazole (118 mg, 0.87 mmol), diisopropylethylamine (0.38 ml, 1.7 mmol), and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (335 mg, 1.7 mmol) were sequentially added to the mixture. The resulting reaction solution was stirred at room temperature for 2.5 hours. The solution was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (100 ml), and then 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-15,20-dimethyl-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 10) (7 mg) as a white solid material.

1. temperaturewhile gradually warming from 0° C. to room temperature
2. concentrationThe reaction solution was concentrated under reduced pressure
3. additionbenzene (1.5 ml) was added to the resulting residue
4. concentrationThe solution was again concentrated under reduced pressure
5. dissolutionthe obtained colorless syrup-like material was dissolved in tetrahydrofuran (1.5 ml)
6. stirringThe reaction solution was stirred at room temperature for 12 hours
7. distillationThe solvent was distilled off under reduced pressure
8. additionN,N-Dimethylformamide (44 ml) and tetrahydrofuran (44 ml) were added to the obtained white solid material
9. customThe resulting reaction solution
10. stirringwas stirred at room temperature for 2.5 hours
11. concentrationThe solution was concentrated under reduced pressure
12. additionThe resulting residue was diluted with ethyl acetate (100 ml)
13. washsequentially washed twice with water (50 ml)
14. dry with materialThe washed ethyl acetate solution was dried over anhydrous sodium sulfate (10 g)
15. filtrationAfter filtration
16. concentrationthe filtrate was concentrated under reduced pressure
17. customThe 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)