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

HRID 1391839Notes

Reaction equation

HRID 1391839 reaction equation
CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1.N1C=CC=CC=1.[NH2:28][C:29]1[C:37]([CH3:38])=[CH:36][C:35]([Cl:39])=[CH:34][C:30]=1[C:31](O)=[O:32]>C(#N)C.O>[Cl:39][C:35]1[CH:36]=[C:37]([CH3:38])[C:29]2[N:28]=[C:12]([C:10]3[N:9]([C:15]4[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=4)[N:8]=[C:7]([Cl:6])[CH:11]=3)[O:14][C:31](=[O:32])[C:30]=2[CH:34]=1

Participants

7

Reactant 4

HCID 1049Pyridine2×HCID 31297Methanesulfonyl chloride2×HCID 116440442-Amino-5-chloro-3-methylbenzoic acid2×HCID 211073323-Chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid2×

Product 1

HCID 211133906-chloro-2-[3-chloro-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6342AcetonitrileSolvent4×

Conditions

Temperature
-5 °C

Procedure

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 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 five minutes at −5 to 0° C. A slurry formed during the addition. The mixture was stirred five 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 over five minutes 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 over five minutes 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 for 4 hours. 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.

Workup

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

Sources & evidence

ORD record
ord-860bbe6070e740b8899734637ca0ee36
Source dataset
uspto-grants-2008_03
Patent number
US07339057B2

Reaction notes

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