Trifluoroacetic acid → HCID 68417685, compound

Temperature

0 °C

5-[2-Amino-6-(2-tert-butoxycarbonylaminoethylsulfanyl)pyrimidin-4-yl]-2-methoxy-4-methylbenzoic acid methyl ester (88 mg, 0.20 mmol) obtained in Step 1 of Example 3-1 was dissolved with dichloromethane (2.5 ml) in a reaction vessel, and cooled to 0° C. Trifluoroacetic acid (0.7 ml) was added to the solution, and stirred for 2.5 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 again concentrated under reduced pressure. This treatment was repeated three times, and the obtained pale yellow oily material was dissolved in N,N-dimethylformamide (3.0 ml). 4-tert-Butoxycarbonylmethylaminobutanoic acid (65 mg, 0.3 mmol) and N-hydroxybenzotriazole (54 mg, 0.4 mmol) were added to the solution. Diisopropylethylamine (0.5 ml, 2.8 mmol) was added to the solution, and then 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.6 mmol) was added. The resulting mixture was stirred at room temperature for 13 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and extracted with ethyl acetate (100 ml). The ethyl acetate solution was sequentially washed with 1N hydrochloric acid (50 ml), water (50 ml), 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 (developing solvent: ethyl acetate to ethyl acetate:methanol=25:1) to yield 5-(2-amino-6-{2-[4-(tert-butoxycarbonylmethylamino)butyrylamino]ethylsulfanyl}pyrimidin-4-yl)-2-methoxy-4-methylbenzoic acid methyl ester (99 mg) as a colorless syrup-like 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 pale yellow oily material was dissolved in N,N-dimethylformamide (3.0 ml)
6. stirringThe resulting mixture was stirred at room temperature for 13 hours
7. extractionextracted with ethyl acetate (100 ml)
8. washThe ethyl acetate solution was sequentially washed with 1N hydrochloric acid (50 ml), water (50 ml)
9. dry with materialThe washed ethyl acetate solution was dried over anhydrous sodium sulfate (10 g)
10. filtrationAfter filtration
11. concentrationthe filtrate was concentrated under reduced pressure
12. customThe resulting crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate to ethyl acetate:methanol=25:1)

ORD record

ord-28cb7fc7488648229b599363dce014fd

Source dataset

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08362236B2