Methyl isothiocyanate → tert-Butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-3-methyl-2-(methylthio)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate

Temperature

130 °C

Under a nitrogen atmosphere, methyl isothiocyanate (71 μl) and potassium carbonate (143 mg) were added to a solution (2.5 ml) of ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1-(2-chlorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate (260 mg) in pyridine, and the resulting mixture was stirred with heating at 130° C. for 3 hours. After the reaction solution was cooled to 25° C. and then concentrated under reduced pressure, toluene (5 ml) was added thereto and the resulting mixture was concentrated under reduced pressure. This procedure was repeated three times. To the resulting residue was added acetone (2.5 ml), and the resulting mixture was cooled to 0° C. Methyl iodide (65 μl) was added dropwise thereto and the resulting mixture was warmed to 25° C. and stirred for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1) to obtain the title compound (250 mg).

1. temperatureAfter the reaction solution was cooled to 25° C.
2. concentrationconcentrated under reduced pressure, toluene (5 ml)
3. additionwas added
4. concentrationthe resulting mixture was concentrated under reduced pressure
5. additionTo the resulting residue was added acetone (2.5 ml)
6. temperaturethe resulting mixture was cooled to 0° C
7. additionMethyl iodide (65 μl) was added dropwise
8. temperaturethe resulting mixture was warmed to 25° C.
9. stirringstirred for 4 hours
10. additionA saturated aqueous ammonium chloride solution was added to the reaction solution
11. extractionfollowed by extraction with ethyl acetate
12. dry with materialThe organic layer was dried over anhydrous sodium sulfate
13. filtrationfiltered
14. concentrationthe filtrate was concentrated under reduced pressure
15. customThe resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1)

ORD record

ord-90cfed8942bf47c9a617a3cb3dfef027

Source dataset

uspto-grants-2009_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07601728B2