Diisopropylethylamine → 3-{2-Ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid tert-butyl ester

HRID 2037355Notes

Reaction equation

HRID 2037355 reaction equation
[CH2:1]([C:5]1[C:6]([CH3:14])=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:57]([O:61][C:62](=[O:78])[CH2:63][CH2:64][C:65]1[C:70]([CH3:71])=[CH:69][C:68]([C:72](=[NH:75])[NH:73]O)=[CH:67][C:66]=1[CH2:76][CH3:77])([CH3:60])([CH3:59])[CH3:58]>CN(C=O)C.O1CCOCC1>[C:57]([O:61][C:62](=[O:78])[CH2:63][CH2:64][C:65]1[C:70]([CH3:71])=[CH:69][C:68]([C:72]2[N:73]=[C:11]([C:8]3[CH:7]=[C:6]([CH3:14])[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:10][N:9]=3)[O:13][N:75]=2)=[CH:67][C:66]=1[CH2:76][CH3:77])([CH3:60])([CH3:59])[CH3:58]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 584180455-Isobutyl-4-methylpyridine-2-carboxylic acidHCID 178436624tert-butyl 3-[2-ethyl-4-[(Z)-N'-hydroxycarbamimidoyl]-6-methylphenyl]propanoate

Product 1

HCID 686310763-{2-Ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid tert-butyl esterYield 84.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Procedure

To a solution of 5-isobutyl-4-methyl-pyridine-2-carboxylic acid (246 mg, 1.07 mmol) and DIPEA (415 mg, 3.21 mmol) in DMF (4 mL), PyBOP (589 mg, 1.13 mmol) is added at 0° C. The mixture is stirred for 15 min at 0° C. before 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid tert-butyl ester (328 mg, 1.07 mmol) is added and stirring is continued for 1 h at 0° C. The reaction is quenched by adding water, the mixture is diluted with sat. aq. NaHCO3-solution and extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated to give the crude hydroxy-amidine ester intermediate; LC-MS: tR=1.10 min, [M+H]+=482.27. This material is dissolved in dioxane (10 mL) and the mixture is stirred at 80° C. for 15 h. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 3-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid tert-butyl ester (420 mg) as a colourless oil; LC-MS: tR=1.26 min, [M+H]+=464.34.

Workup

  1. additionis added
  2. customThe reaction is quenched
  3. additionby adding water
  4. additionthe mixture is diluted with sat. aq. NaHCO3-solution
  5. extractionextracted twice with EA
  6. dry with materialextracts are dried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto give the crude hydroxy-amidine ester intermediate
  10. stirringthe mixture is stirred at 80° C. for 15 h
  11. customThe solvent is evaporated
  12. customthe crude product is purified by CC on silica gel eluting with heptane:EA 7:3

Sources & evidence

ORD record
ord-347a5a780a134591897d02dc76204bff
Source dataset
uspto-grants-2013_11
Patent number
US08575200B2

Reaction notes

Loading…