Triphenylphosphine → N-(2-(5-cyano-2-(triethylsilyl)-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide

HRID 1918627Notes

Reaction equation

HRID 1918627 reaction equation
[N:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][C:7]=1[Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.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:76][C:77]1[CH:91]=[CH:90][C:89]([F:92])=[CH:88][C:78]=1[CH2:79][C:80]1[O:84][N:83]=[C:82]([C:85](O)=[O:86])[CH:81]=1>CO.CN(C=O)C>[C:15]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19])=[C:6]2[CH2:5][CH2:4][NH:1][C:85]([C:82]1[CH:81]=[C:80]([CH2:79][C:78]2[CH:88]=[C:89]([F:92])[CH:90]=[CH:91][C:77]=2[F:76])[O:84][N:83]=1)=[O:86])#[N:16]

Participants

8

Reactant 5

HCID 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 866638383-(2-azidoethyl)-2-(triethylsilyl)-1H-indole-5-carbonitrile

Product 1

HCID 66832142N-(2-(5-cyano-2-(triethylsilyl)-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamideYield 48%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of 3-(2-azidoethyl)-2-(triethylsilyl)-1H-indole-5-carbonitrile (0.400 g; 1.23 mmol) and triphenylphosphine (0.523 g; 2.00 mmol) in methanol (10 mL) was stirred at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude material was dissolved in a mixture of 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid intermediate 74 (0.318 g, 1.33 mmol), HATU (0.506 g; 1.33 mmol) and N,N diisopropylethylamine (0.614 mL; 3.33 mmol) in DMF (10 mL), was stirred at room temperature for 72 hours. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate; the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 60% ethyl acetate in heptane) to yield 0.338 g (48%) of N-(2-(5-cyano-2-(triethylsilyl)-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a solid.

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. stirringwas stirred at room temperature for 72 hours
  3. customThe reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate
  4. washthe organic layer was washed with sodium carbonate, brine
  5. customdried
  6. concentrationconcentrated under reduced pressure
  7. customThe crude mixture was purified by flash chromatography on silica (eluent 2 to 60% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-4f14b34901aa4b3eb9ab1cc5d46777bf
Source dataset
uspto-grants-2013_12
Patent number
US08618138B2

Reaction notes

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