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 (4.50 g, 20 mmol) under argon and the resulting mixture was stirred at 70° C. for 0.5 h to obtain a thick off-white slurry. 1-Methyl-2-pyrrolidinone (20 mL) was added and followed by methyl benzoate (1.1 mL, 8.7 mmol). The mixture was stirred at 70° C. for 0.5 h and then cooled to room temperature. Palladium acetate (39.1 mg, 0.17 mmol), triphenylphosphine (182.6 mg, 0.70 mmol) and 1-[(2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carbonyl)-amino]-cyclobutanecarboxylic acid methyl ester (3.768 g, 8.70 mmol) were added. The mixture was stirred at 90° C. until no starting material was left (˜3 h) as monitored by HPLC. Saturated ammonium chloride (20 mL), isopropyl acetate (20 mL) and THF (10 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 and then transferred to a separatory funnel. The aqueous layer was separated and extracted with isopropyl acetate (20 mL) at 60° C. The combined organic phases were 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 (15 and 10 mL). To the combined extracts cooled in an ice-water bath was slowly added 50% NaOH (9.40 g, 117.5 mmol). The mixture was heated to reflux until the batch inside temperature reached 89-90° C. n-Propanol (10 mL) was added and the mixture was stirred at 90° C. for 1 h. After the mixture was cooled to 60° C., acetic acid (1.57 g, 26.1 mmol) was slowly 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 in 2 h. 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 until a constant weight (2.67 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.92 (s, 1H), 8.80 (d, J=4.0 Hz, 1H), 8.13 (s, 1H), 7.98 (dt, J=1.5, 7.5 Hz, 1H), 7.70 (d, J=8.5, 1H), 7.68-7.56 (m, 2H), 7.52-7.45 (m, 1H), 3.71 (s, 3H), 3.21-3.08 (m, 1H), 2.68-2.55 2H), 2.42-2.28 (m, 2H), 2.05-1.80 (m, 8H), 1.70-1.55 (m, 2H).

1. stirringthe resulting mixture was stirred at 70° C. for 0.5 h
2. customto obtain a thick off-white slurry
3. stirringThe mixture was stirred at 70° C. for 0.5 h
4. temperaturecooled to room temperature
5. stirringThe mixture was stirred at 90° C. until no starting material
6. waitwas left (˜3 h)
7. stirringthe mixture was stirred at 60° C. for 5 minutes
8. customtransferred to a separatory funnel
9. customThe aqueous layer was separated
10. extractionextracted with isopropyl acetate (20 mL) at 60° C
11. washThe combined organic phases were washed with a mixture of saturated ammonium chloride (10 mL) and water (10 mL) at 60° C
12. extractionThe organic layer was extracted with 4 N HCl (15 and 10 mL)
13. temperatureTo the combined extracts cooled in an ice-water bath
14. temperatureThe mixture was heated
15. temperatureto reflux until the batch inside temperature
16. customreached 89-90° C.
17. additionwas added
18. stirringthe mixture was stirred at 90° C. for 1 h
19. temperatureAfter the mixture was cooled to 60° C.
20. stirringThe resulting white suspension was stirred at 60° C. for 1 h
21. temperatureto cool to room temperature in 2 h
22. filtrationThe white precipitate was collected by filtration
23. washthe wet cake was rinsed with 2:1 water/n-propanol (15 mL) and water (50 mL)
24. customThe solid was dried under vacuum until a constant weight (2.67 g, 74%)

ORD record

ord-8525251bbd69423ea3e4d5ba6069a561

Source dataset

uspto-grants-2008_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07332614B2