반응 #562655

반응 방정식

Methanesulfonyl chloride

3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid

pyrazolecarboxylic acid

3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid

pyridine

2-amino-3-methyl-5-chlorobenzoic acid

pyridine

methanesulfonyl chloride

→

title product

2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one

용매

acetonitrile

acetonitrile

acetonitrile

acetonitrile

Water

반응 조건

후처리

1. 1
   기타A slurry formed during the addition
2. 2
   workup.ADDITIONwas added
3. 3
   세척rinsing with more acetonitrile (5 mL)
4. 4
   workup.STIRRINGThe mixture was stirred 15 minutes at −5 to 0° C.
5. 5
   workup.STIRRINGThe reaction mixture was stirred 15 minutes more at this temperature
6. 6
   온도to warm slowly to room temperature
7. 7
   workup.STIRRINGstirred 4 h
8. 8
   workup.STIRRINGthe mixture was stirred 15 minutes
9. 9
   여과Then the mixture was filtered
10. 10
    세척the solids were washed with 2:1 acetonitrile-water (3×3 mL)
11. 11
    건조with acetonitrile (2×3 mL), and dried under nitrogen

실험 절차

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 Example 10, Step D) (3.02 g, 10 mmol) and pyridine (1.4 ml, 1.4 g. 17 mmol) in acetonitrile (10 mL) was added dropwise over 5 minutes at −5 to 0° C. A slurry formed during the addition. The mixture was stirred 5 minutes at this temperature, and then a mixture of 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product of Example 6 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 5 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 h. Water (20 mL) was added dropwise, and the mixture was stirred 15 minutes. Then 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 (4.6 mm×25 cm, element 25-95% acetonitrile/pH 3 water) showed a major peak corresponding to the title compound and having 95.7% of total chromatogram peak area.

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