Acetic Acid → HCID 11270031, compound

Temperature

35 °C

To a solution of i-PrMgCl in THF (10 mL, 20 mmol) was added 2-bromopyridine (1.93 g, 20.2 mmol) at room temperature in one portion. The mixture was stirred at 35° C. for 0.5 h. To the deep-red solution was added ZnBr2 (2.477 g, 11 mmol) under argon and the resulting mixture was stirred at 70° C. for 0.5 h to brown-red solution. 1-Methyl-2-pyrrolidinone (20 mL) was added and the mixture was stirred at 70° C. for 10 minutes. Palladium acetate (11.2 mg, 0.05 mmol), triphenylphosphine (52.5 mg, 0.20 mmol) and 1-[(2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carbonyl)-amino]-cyclobutanecarboxylic acid (2.097 g, 5 mmol) were added. The mixture was stirred at 90° C. for 6 h. Saturated ammonium chloride (20 mL) and THF (20 mL) were added. The pH of the mixture was adjusted to 4-5 using 4 HCl (˜3 mL) and the mixture was stirred at 60° C. for 5 minutes. The aqueous layer was separated and extracted with isopropyl acetate (20 mL) at 60° C. The combined organic phases were combined and washed with a mixture of saturated ammonium chloride (10 mL) and water (10 mL) at 60° C. The organic layer was extracted with 4 N HCl (10 and 5 mL). To the combined extracts cooled in an ice-water bath was slowly added 50% NaOH (5.60 g, 70 mmol). The mixture was heated to reflux until the internal temperature reached 89-90° C. The mixture was cooled to 60° C. and n-propanol (10 mL) was added. While stirring, acetic acid (1.14 mL, 20 mmol) was added to adjust the pH to 5-6. The resulting white suspension was stirred at 60° C. for 1 h and allowed to cool to room temperature (@200° C.). The white precipitate was collected by filtration and the wet cake was rinsed with 2:1 water/n-propanol (15 mL) and water (50 mL). The solid was dried under vacuum to provide the title compound (1.65 g, 79%).

1. stirringthe resulting mixture was stirred at 70° C. for 0.5 h to brown-red solution
2. stirringthe mixture was stirred at 70° C. for 10 minutes
3. stirringThe mixture was stirred at 90° C. for 6 h
4. stirringthe mixture was stirred at 60° C. for 5 minutes
5. customThe aqueous layer was separated
6. extractionextracted with isopropyl acetate (20 mL) at 60° C
7. washwashed with a mixture of saturated ammonium chloride (10 mL) and water (10 mL) at 60° C
8. extractionThe organic layer was extracted with 4 N HCl (10 and 5 mL)
9. temperatureTo the combined extracts cooled in an ice-water bath
10. temperatureThe mixture was heated
11. temperatureto reflux until the internal temperature
12. customreached 89-90° C
13. temperatureThe mixture was cooled to 60° C.
14. stirringWhile stirring
15. stirringThe resulting white suspension was stirred at 60° C. for 1 h
16. temperatureto cool to room temperature (@200° C.)
17. filtrationThe white precipitate was collected by filtration
18. washthe wet cake was rinsed with 2:1 water/n-propanol (15 mL) and water (50 mL)
19. customThe solid was dried under vacuum

ORD record

ord-7c52efd0b37e48ea897e278ecd4d2419

Source dataset

uspto-grants-2008_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07332614B2