5-Chloro-2-fluoroaniline → HCID 58314469, compound

HRID 624825Notes

Reaction equation

HRID 624825 reaction equation
Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:16][CH:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH3:18])C(=O)OC(C)(C)C)[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([F:36])=[C:33]([CH:35]=1)[NH2:34].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([F:36])=[C:33]([NH:34][C:2]2[CH:7]=[C:6]([NH:8][CH2:16][CH:17]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[CH3:18])[N:5]3[N:25]=[CH:26][CH:27]=[C:4]3[N:3]=2)[CH:35]=1

Participants

6

Reactant 4

HCID 750155-Chloro-2-fluoroanilineHCID 2733832Lithium HexamethyldisilazideHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 86654660HCID 86654660, compound

Product 1

HCID 58314469HCID 58314469, compoundYield 21%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Procedure

To tert-butyl 5-chloropyrazolo[1,5-a]pyrimidin-7-yl(2-morpholinopropyl)carbamate (396 mg, 1 mmol), 5-chloro-2-fluoroaniline (145 uL, 1.2 mmol), and LiHMDS (2.2 mL, 2.2 mmol, 1M in THF) was added X-Phos (11 mg, 0.024 mmol) and tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.02 mmol). The mixture was sealed and irradiated at 65° C. for 60 min in the microwave. The reaction was quenched with 1N HCL (2 mL) and then neutralized with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude residue was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). After stirring at room temperature for 1 hour, the solution was concentrated under a stream of nitrogen. The crude material was neutralized with saturated sodium bicarbonate solution then purified by silica gel chromatography (75% ethyl acetate/hexanes) to yield the product, N5-(5-chloro-2-fluorophenyl)-N7-(2-morpholinopropyl)pyrazolo[1,5-a]pyrimidine-5,7-diamine (84 mg, 21% yield). LCMS (M+1=405)

Workup

  1. customThe mixture was sealed
  2. customirradiated at 65° C. for 60 min in the microwave
  3. customThe reaction was quenched with 1N HCL (2 mL)
  4. extractionThe mixture was extracted with ethyl acetate
  5. washwashed with saturated sodium chloride solution
  6. customThe organic layer was collected
  7. dry with materialdried over anhydrous sodium sulfate
  8. filtrationfiltered
  9. customevaporated to dryness
  10. dissolutionThe crude residue was dissolved in dichloromethane (2 mL)
  11. concentrationthe solution was concentrated under a stream of nitrogen
  12. customthen purified by silica gel chromatography (75% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-f0c97c3903fe4c6797d83887caa7e58e
Source dataset
uspto-grants-2016_04
Patent number
US09303033B2

Reaction notes

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