Pyridine → 2-(3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-6-chloro-8-methyl-4H-benzo[d][1,3]oxazin-4-one

Temperature

-5 °C

Methanesulfonyl chloride (1.0 mL, 1.5 g, 13 mmol) was dissolved in acetonitrile (10 mL), and the mixture was cooled to −5° C. A solution of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the pyrazolecarboxylic acid product of Step E) (3.02 g, 10 mmol) and pyridine (1.4 mL, 1.4 g, 17 mmol) in acetonitrile (10 mL) was added dropwise over five minutes at −5 to 0° C. A slurry formed during the addition. The mixture was stirred five minutes at this temperature, and then a mixture of 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product of Step A) (1.86 g, 10 mmol) and pyridine (2.8 mL, 2.7 g, 35 mmol) in acetonitrile (10 mL) was added, rinsing with more acetonitrile (5 mL). The mixture was stirred 15 minutes at −5 to 0° C., and then methanesulfonyl chloride (1.0 mL, 1.5 mL, 13 mmol) in acetonitrile (5 mL) was added dropwise over five minutes at a temperature of −5 to 0° C. The reaction mixture was stirred 15 minutes more at this temperature, then allowed to warm slowly to room temperature, and stirred 4 hours. Water (20 mL) was added dropwise, and the mixture was stirred 15 minutes. The mixture was filtered, and the solids were washed with 2:1 acetonitrile-water (3×3 mL), then with acetonitrile (2×3 mL), and dried under nitrogen to afford the title product as a light yellow powder, 4.07 g (90.2% crude yield), melting at 203-205° C. HPLC of the product using a Zorbax® RX-C8 chromatography column (reversed phase column manufactured by Agilent Technologies containing n-octyldimethylsilyl groups bonded to 5-mm porous silica microspheres with 80 Å pore size) (4.6 mm×25 cm, eluent 25-95% acetonitrile/pH 3 water) showed a major peak corresponding to the title compound and having 95.7% of total chromatogram peak area.

1. customA slurry formed during the addition
2. additionwas added
3. washrinsing with more acetonitrile (5 mL)
4. stirringThe mixture was stirred 15 minutes at −5 to 0° C.
5. stirringThe reaction mixture was stirred 15 minutes more at this temperature
6. temperatureto warm slowly to room temperature
7. stirringstirred 4 hours
8. stirringthe mixture was stirred 15 minutes
9. filtrationThe mixture was filtered
10. washthe solids were washed with 2:1 acetonitrile-water (3×3 mL)
11. dry with materialwith acetonitrile (2×3 mL), and dried under nitrogen

ORD record

ord-d6753e5257794e1b8e1b3ac9be7e4930

Source dataset

uspto-grants-2008_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07339057B2