반응 #90238

반응 방정식

Methanesulfonyl chloride

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

carboxylic acid

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

pyridine

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

product

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

pyridine

methanesulfonyl chloride

→

title product

6-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-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.STIRRINGThe mixture was stirred 15 minutes at −5 to 0° C.
3. 3
   workup.STIRRINGThe reaction mixture was stirred 15 minutes at this temperature
4. 4
   온도to warm slowly to room temperature
5. 5
   workup.STIRRINGstirred 4 h
6. 6
   workup.STIRRINGthe mixture was stirred 15 minutes
7. 7
   여과Then the mixture was filtered
8. 8
   세척the solids were washed with 2:1 acetonitrile-water (3×3 mL)
9. 9
   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-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the carboxylic acid product of Example 3, Step D) (2.58 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 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product from Example 1, Step A) (1.86 g, 10 mmol) was added all at once. Then a solution of pyridine (2.8 mL, 2.7 g, 35 mmol) in acetonitrile (10 mL) was added dropwise in 5 min at −5 to 0° C. 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 in 5 min at −5 to 0° C. The reaction mixture was stirred 15 minutes at this temperature, then allowed to warm slowly to room temperature, and stirred 4 h. Water (15 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 pale yellow powder, 3.83 g (94.0% crude yield), melting at 199-201° C. HPLC of the product using a Zorbax® RX-C8 chromatography column (4.6 mm×25 cm, eluent 25-95% acetonitrile/pH 3 water) showed a major peak corresponding to the title compound and having 97.8% of total chromatogram peak area.

출처