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

HRID 1522753Notes

Reaction equation

HRID 1522753 reaction equation
CS(Cl)(=O)=O.[Br: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>[Br:6][C:7]1[CH:11]=[C:10]([C:12]2[O:14][C:31](=[O:32])[C:30]3[CH:34]=[C:35]([Cl:39])[CH:36]=[C:37]([CH3:38])[C:29]=3[N:28]=2)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1

Participants

7

Reactant 4

HCID 1049Pyridine2×HCID 31297Methanesulfonyl chloride2×HCID 115875353-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid2×HCID 116440442-Amino-5-chloro-3-methylbenzoic acid2×

Product 1

HCID 102533072-(3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-6-chloro-8-methyl-4H-benzo[d][1,3]oxazin-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-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the pyrazolecarboxylic acid product of Example 5, 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 1 Step A) (1.86 g, 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 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, 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.

Workup

  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 minutes more at this temperature
  6. temperatureto warm slowly to room temperature
  7. stirringstirred 4 h
  8. stirringthe mixture was stirred 15 minutes
  9. filtrationThen the 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

Sources & evidence

ORD record
ord-9cdd5c65bc8649b4a5eb29fe680927dd
Source dataset
uspto-grants-2015_07
Patent number
US09078437B2

Reaction notes

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