Diisopropylethylamine → 5-(3-Methyl-[1,2,4]oxadiazol-5-yl)-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine

HRID 1897259Notes

Reaction equation

HRID 1897259 reaction equation
[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.C(N(C(C)C)C(C)C)C.O.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.OC[NH:68][C:69](=[NH:71])[CH3:70]>CN(C=O)C.O>[CH3:70][C:69]1[N:71]=[C:19]([C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[O:21][N:68]=1

Participants

8

Reactant 5

HCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 27960291-Hydroxybenzotriazole hydrateHCID 665992136-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acidHCID 178465631HCID 178465631, compound

Product 1

HCID 426300455-(3-Methyl-[1,2,4]oxadiazol-5-yl)-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridineYield 69.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
140 °C

Procedure

To a stirred solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (500 mg, 1.6 mmol), N-ethyldiisopropylamine (1.04 g, 2.0 mmol) and 1-hydroxybenzotriazole hydrate (40 mg, 0.3 mmol) in DMF (16 mL) at ambient temperature and under argon was added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (517 mg, 1.6 mmol) followed by N-hydroxymethylacetamidine (149 mg, 2.0 mmol). After 14 h the mixture was diluted with water (15 mL) and extracted with EtOAc (3×25 mL). The combined extracts were washed with 10% aqueous LiCl solution (2×10 mL) then dried over sodium sulfate, filtered and concentrated. The residue was then dissolved in DMF (16 mL) and heated at 140° C. for 3 h then cooled, diluted with EtOAc (60 mL), washed with 10% aqueous LiCl (3×100 mL), then dried over sodium sulfate, filtered and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate 8:2 to 0:1) afforded the title compound (385 mg, 69%) as a yellow solid. MS: m/e=349.4 [M+H]+.

Workup

  1. extractionextracted with EtOAc (3×25 mL)
  2. washThe combined extracts were washed with 10% aqueous LiCl solution (2×10 mL)
  3. dry with materialthen dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. dissolutionThe residue was then dissolved in DMF (16 mL)
  7. temperaturethen cooled
  8. additiondiluted with EtOAc (60 mL)
  9. washwashed with 10% aqueous LiCl (3×100 mL)
  10. dry with materialdried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customPurification by chromatography (SiO2, heptane:ethyl acetate 8:2 to 0:1)

Sources & evidence

ORD record
ord-76f1506031cc4c7faa1e896189e8b063
Source dataset
uspto-grants-2013_08
Patent number
US08518974B2

Reaction notes

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