Triethylamine → HCID 71008715, compound

HRID 1626156Notes

Reaction equation

HRID 1626156 reaction equation
Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C@:13]3([CH3:22])[C:18]([F:20])([F:19])[CH2:17][O:16][C:15]([NH2:21])=[N:14]3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24].C(N(CC)CC)C>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:19][C:18]1([F:20])[CH2:17][O:16][C:15]([NH2:21])=[N:14][C@:13]1([CH3:22])[C:11]1[CH:10]=[N:9][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:3]=2)[CH:12]=1

Participants

8

Reactant 3

HCID 8471TriethylamineHCID 66111Trimethylsilylacetylene2×HCID 71008464HCID 71008464, compound

Product 1

HCID 71008715HCID 71008715, compoundYield 44.2%

Reagents, catalysts & solvents 4

HCID 11776TriphenylphosphineCatalystHCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalyst2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
70 °C

Procedure

A solution of (R)-4-(1-(3-bromophenyl)-1H-pyrazol-4-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine (227 mg, 612 μmol) (intermediate K7.1) in tetrahydrofuran (5 ml) was treated consecutively with ethynyltrimethylsilane (120 mg, 169 μl, 1.22 mmol), triphenylphosphine (4.81 mg, 18.3 μmol) and triethylamine (186 mg, 256 μl, 1.83 mmol). The mixture was degassed by bubbling argon through the solution, then copper(I) iodide (1.16 mg, 6.12 μmol) and bis(triphenylphosphine)palladium(II) chloride (21.5 mg, 30.6 μmol) were added. The reaction mixture was stirred at 70° C. in a sealed tube. In order to complete the reaction, ethynyltrimethylsilane (120 mg, 169 μl, 1.22 mmol) and bis(triphenylphosphine)palladium(II) chloride (21.5 mg, 30.6 μmol) were added again and stirring continued at 70° C. for 20 hours. Thereafter, the reaction mixture was evaporated and the residue purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent. The (R)-5,5-difluoro-4-methyl-4-[1-(3-trimethylsilanylethynyl-phenyl)-1H-pyrazol-4-yl]-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (105 mg, 44% yield) was obtained as a brown, amorphous material. MS (ISP): m/z=389.3 [M+H]+.

Workup

  1. customThe mixture was degassed
  2. customby bubbling argon through the solution
  3. additionwere added again
  4. stirringstirring
  5. customThereafter, the reaction mixture was evaporated
  6. customthe residue purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent

Sources & evidence

ORD record
ord-4b47d81b26e548f289d396d5620c6ee9
Source dataset
uspto-grants-2014_07
Patent number
US08785436B2

Reaction notes

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