Hydrochloric Acid → 5-(2,5-difluorobenzyl)-N-(4-(triethylsilyl)but-3-ynyl)isoxazole-3-carboxamide

HRID 58641Notes

Reaction equation

HRID 58641 reaction equation
[N:1]([CH2:4][CH2:5][C:6]#[C:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:68][C:69]1[CH:83]=[CH:82][C:81]([F:84])=[CH:80][C:70]=1[CH2:71][C:72]1[O:76][N:75]=[C:74]([C:77](O)=[O:78])[CH:73]=1>CO.O1CCOCC1.ClCCl>[F:68][C:69]1[CH:83]=[CH:82][C:81]([F:84])=[CH:80][C:70]=1[CH2:71][C:72]1[O:76][N:75]=[C:74]([C:77]([NH:1][CH2:4][CH2:5][C:6]#[C:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10])=[O:78])[CH:73]=1

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 11776TriphenylphosphineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 668320395-(2,5-Difluorobenzyl)isoxazole-3-carboxylic acidHCID 86663839(4-Azidobut-1-ynyl)triethylsilane

Product 1

HCID 668320895-(2,5-difluorobenzyl)-N-(4-(triethylsilyl)but-3-ynyl)isoxazole-3-carboxamideYield 47%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of (4-azidobut-1-ynyl)triethylsilane (1.00; 4.78 mmol) and triphenylphosphine (1.88 g; 7.16 mmol) in methanol (10 mL) was stirred at 60° C. for two hours. HCl (4N in dioxane was added to resulting solution and the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane. HATU (2.18 g; 5.73 mmol), N,N-diisopropylethylamine (2.06 mL; 4.78 mmol) and 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid intermediate 74 (1.26 g; 5.25 mmol) were added and the resulting mixture was stirred at room temperature overnight and diluted in dichloromethane, washed with sodium hydrogen sulphate, sodium carbonate and brine and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 1 to 60% ethyl acetate in heptane) to yield 0.901 g (47%) of 5-(2,5-difluorobenzyl)-N-(4-(triethylsilyl)but-3-ynyl)isoxazole-3-carboxamide as a yellow oil.

Workup

  1. customto resulting solution
  2. concentrationthe mixture was concentrated under reduced pressure
  3. dissolutionThe residue was dissolved in dichloromethane
  4. stirringthe resulting mixture was stirred at room temperature overnight
  5. washwashed with sodium hydrogen sulphate, sodium carbonate and brine
  6. concentrationconcentrated under reduced pressure
  7. customThe crude mixture was purified by flash chromatography on silica (eluent 1 to 60% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-72c4cab0fe2940d58d9d70f75ffcbb04
Source dataset
uspto-grants-2016_09
Patent number
US09434722B2

Reaction notes

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