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

HRID 642606Notes

Reaction equation

HRID 642606 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 Example 8, 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 6, 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.

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 4 h
  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-75b447f683dd4c4db4224b02c6b68c08
Source dataset
uspto-grants-2010_04
Patent number
US07696233B2

Reaction notes

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