Methyl iodide → (11-Methyl-5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-[4-(3-methyl-pyrazol-1-yl)-2-trifluoromethyl-phenyl]methanone

HRID 636372Notes

Reaction equation

HRID 636372 reaction equation
[H-].[Na+].[CH3:3]C1C=CNN=1.[N:9]1[C:14]2[NH:15][C:16]3[CH:41]=[CH:40][CH:39]=[CH:38][C:17]=3[N:18]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][C:30]([CH3:33])=[N:29]4)=[CH:24][C:23]=3[C:34]([F:37])([F:36])[F:35])=[O:21])[CH2:19][C:13]=2[CH:12]=[CH:11][CH:10]=1.CI>CCCCCC>[CH3:3][N:15]1[C:16]2[CH:41]=[CH:40][CH:39]=[CH:38][C:17]=2[N:18]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][C:30]([CH3:33])=[N:29]3)=[CH:24][C:23]=2[C:34]([F:37])([F:36])[F:35])=[O:21])[CH2:19][C:13]2[CH:12]=[CH:11][CH:10]=[N:9][C:14]1=2

Participants

6

Reactant 4

HCID 6328Methyl iodideHCID 24758Sodium hydride2×HCID 9824954(5,11-Dihydro-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-[4-(3-methyl-pyrazol-1-yl)-2-trifluoromethyl-phenyl]-methanoneHCID 178428694HCID 178428694, compound

Product 1

HCID 9890579(11-Methyl-5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-[4-(3-methyl-pyrazol-1-yl)-2-trifluoromethyl-phenyl]methanoneYield 45.1%

Reagents, catalysts & solvents 1

HCID 8058HexaneSolvent

Procedure

Sodium hydride (60% suspension in oil, 0.12 g, 3.0 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (20 mL). Neat 3-methylpyrazole (0.13 mL, 1.61 mmol) was added dropwise at ambient temperature. Stirring was continued until the gas evolution subsided, and then the (5,11-dihydro-pyrido [2,3-b][1,5]benzodiazepin-6-yl)-(4-fluoro-2-trifluoromethyl-phenyl)methanone of Example 4, Step B (0.52 g, 1.34 mmol) was added in one portion to the clear solution. The mixture was placed in an oil bath (preheated at 130° C.) for 30 minutes. After cooling, sodium hydride (60% suspension in oil, 0.080 g, 2.0 mmol, washed with hexane) and methyl iodide (0.25 mL, 4.0 mmol) were added. The reaction mixture was stirred for an additional 15 minutes, and then partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate and evaporated to dryness. The residue was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 20% ethyl acetate in hexane provided the title product (0.28 g, 45.1%) as a foam which crystallized by sonication from ethanol-hexane as a white solid, m.p. 188-190° C.

Workup

  1. customdried under nitrogen
  2. customThe mixture was placed in an oil bath
  3. temperatureAfter cooling
  4. stirringThe reaction mixture was stirred for an additional 15 minutes
  5. custompartitioned between water and ethyl acetate
  6. dry with materialThe organic extracts were dried over sodium sulfate
  7. customevaporated to dryness
  8. dissolutionThe residue was dissolved in dichloromethane
  9. customabsorbed onto a silica Merck-60 flash column
  10. washElution with 20% ethyl acetate in hexane

Sources & evidence

ORD record
ord-0463338f96ce4a468612dfd5c412ac61
Source dataset
uspto-grants-2001_02
Patent number
US06194407B1

Reaction notes

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