Triethylamine → tert-butyl (1R,3S,4S)-3-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

To a solution (15 mL) of (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (0.894 g) and triethylamine (0.541 mL) in tetrahydrofuran was added with stirring isobutyl chloroformate (0.487 mL) under ice-cooling. After stirring at room temperature for 30 min, a solution of 3-amino-5-bromothiophene-2-carboxamide (0.78 g) produced in Example 1, step D, in tetrahydrofuran (3 mL) was added. The reaction system was stirred with heating at 60° C. for 40 hr. Water was poured into the reaction system, and the mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. 2M Aqueous sodium hydroxide solution (7.06 mL) and ethanol (14 mL) were added to the residue, and the mixture was stirred with heating at 70° C. for 5 hr. The reaction system was neutralized with 1M hydrochloric acid (4 mL) while stirring under ice-cooling. Insoluble material was removed by filtration. The mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.06 g) as a pale-yellow solid.

1. temperaturecooling
2. stirringThe reaction system was stirred
3. temperaturewith heating at 60° C. for 40 hr
4. extractionthe mixture was extracted with ethyl acetate
5. washwashed with brine
6. dry with materialdried over anhydrous sodium sulfate
7. customInsoluble material was removed by filtration
8. concentrationthe filtrate was concentrated under reduced pressure
9. addition2M Aqueous sodium hydroxide solution (7.06 mL) and ethanol (14 mL) were added to the residue
10. stirringthe mixture was stirred
11. temperaturewith heating at 70° C. for 5 hr
12. stirringwhile stirring under ice-
13. temperaturecooling
14. customInsoluble material was removed by filtration
15. extractionThe mixture was extracted with ethyl acetate
16. washwashed with brine
17. dry with materialdried over anhydrous sodium sulfate
18. customInsoluble material was removed by filtration
19. concentrationthe filtrate was concentrated under reduced pressure
20. customThe residue was purified by basic silica gel column chromatography (ethyl acetate/hexane)

ORD record

ord-13281e4589bc427d9d048244fef495be

Source dataset

uspto-grants-2016_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09388195B2