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

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.

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 concentrated under reduced pressure
5. dissolutionThe resulting colorless syrup-like material was dissolved in tetrahydrofuran (0.7 ml)
6. stirringthe resulting mixture was stirred at room temperature for 24 hours
7. distillationThe solvent was distilled off under reduced pressure
8. dissolutionThe obtained white solid material was dissolved
9. additionby adding N,N-dimethylformamide (10 ml) and tetrahydrofuran (33 ml)
10. stirringThe resulting mixture was stirred at room temperature for 2.5 hours
11. concentrationThe reaction 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)

ORDレコード

ord-9be521ca1d2b48b5987715e88da88fcd

出典データセット

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08362236B2