Diisopropylethylamine → 2-Ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol

HRID 2040814Notes

Reaction equation

HRID 2040814 reaction equation
Cl.[CH2:2]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:9]([OH:11])=O)[CH:3]([CH3:5])[CH3:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:47]([C:49]1[CH:50]=[C:51]([CH:56]=[C:57]([CH2:60]C)[C:58]=1[OH:59])[C:52]([NH:54]O)=[NH:53])[CH3:48]>C(Cl)Cl>[CH2:47]([C:49]1[CH:50]=[C:51]([C:52]2[N:54]=[C:9]([C:8]3[CH:12]=[C:13]([CH3:15])[N:14]=[C:6]([CH2:2][CH:3]([CH3:4])[CH3:5])[CH:7]=3)[O:11][N:53]=2)[CH:56]=[C:57]([CH3:60])[C:58]=1[OH:59])[CH3:48]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 67026961HCID 67026961, compoundHCID 178436633HCID 178436633, compound

Product 1

HCID 1359239042-Ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenolYield 58.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 2-isobutyl-6-methyl-isonicotinic acid hydrochloride (2.18 g, 9.53 mmol) and DIPEA (3.69 g, 28.6 mmol) in DCM (10 mL), TBTU (3.67 g, 11.44 mmol) is added. The mixture is stirred for 5 min before 3,5-diethyl-4,N-dihydroxy-benzamidine (1.85 g, 9.53 mmol) is added. The mixture is stirred at rt for 1 h. The mixture is diluted with DCM, washed with sat. aq. NaHCO3 solution, dried over MgSO4, filtered and concentrated. The crude 2-isobutyl-6-methyl-isonicotinic acid (3-ethyl-4,N-dihydroxy-5-methyl-benzamidine) ester (LC-MS: tR=0.79 min, [M+1]+=370.06) is dissolved in dioxane (50 mL) and heated to 100° C. for 4 h. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (1.97 g) as a colourless oil; LC-MS: tR=0.93 min; [M+1]+=352.16; 1H NMR (CDCl3): δ 7.85 (s, 2 H), 7.75 (s, 1 H), 7.70 (s, 1 H), 5.05 (s br, 1H), 2.78 (d, J=7.5 Hz, 2H), 2.74 (q, J=7.5 Hz, 2H), 2.69 (s, 3H), 2.37 8 s, 3H), 2.19 (hept, J=7.5 Hz, 1H), 1.34 (t, J=7.5 Hz, 3H), 1.00 (d, J=6.5 Hz, 6H).

Workup

  1. additionis added
  2. washwashed with sat. aq. NaHCO3 solution
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. dissolutionThe crude 2-isobutyl-6-methyl-isonicotinic acid (3-ethyl-4,N-dihydroxy-5-methyl-benzamidine) ester (LC-MS: tR=0.79 min, [M+1]+=370.06) is dissolved in dioxane (50 mL)
  7. temperatureheated to 100° C. for 4 h
  8. customThe solvent is evaporated
  9. customthe crude product is purified by CC on silica gel eluting with heptane:EA 9:1

Sources & evidence

ORD record
ord-0f8df69fe9f24509b792e0864bc890eb
Source dataset
uspto-grants-2013_11
Patent number
US08580824B2

Reaction notes

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