Pyridine → 2-Ethyl-4-[2-(2-ethyl-6-methyl-4-pyridinyl)-[1,3,4]oxadiazol-5-yl]-6-methyl-pyridine

HRID 1908855Notes

Reaction equation

HRID 1908855 reaction equation
[CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:6](O)=[O:7])[CH3:2].[NH2:13][NH2:14].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17]C=1.F[C:22](F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:36]1[CH2:40]O[CH2:38][CH2:37]1>O=S(Cl)Cl.C(OCC)C.C(Cl)Cl>[CH2:37]([C:36]1[CH:40]=[C:18]([C:17]2[O:7][C:6]([C:5]3[CH:9]=[C:10]([CH3:12])[N:11]=[C:3]([CH2:1][CH3:2])[CH:4]=3)=[N:14][N:13]=2)[CH:19]=[C:20]([CH3:22])[N:15]=1)[CH3:38]

Participants

9

Reactant 5

HCID 1049Pyridine2×HCID 8028Tetrahydrofuran2×HCID 9321HydrazineHCID 67749Trifluoromethanesulfonic anhydride2×HCID 584180972-Ethyl-6-methylisonicotinic acid

Product 1

HCID 584180222-Ethyl-4-[2-(2-ethyl-6-methyl-4-pyridinyl)-[1,3,4]oxadiazol-5-yl]-6-methyl-pyridine

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent2×HCID 24386Thionyl ChlorideSolvent

Conditions

Temperature
65 °C

Procedure

A suspension of 2-ethyl-6-methyl-isonicotinic acid (80 mg, 0.397 mmol) in SOCl2 (2 mL) is stirred at 65° C. for 1 h. The now clear solution is concentrated and dried to provide crude 2-ethyl-6-methyl-isonicotinic acid chloride. This material is dissolved in THF (4.5 mL) and treated with 1 M hydrazine in THF (1.59 mL, 1.59 mmol). The mixture is stirred at rt for 15 h before it is diluted with diethyl ether, washed with 1 M aq. HCl followed by 33% aq. KOH solution, dried over MgSO4, filtered and concentrated to give crude 2-ethyl-6-methyl-isonicotinic acid N′-(2-ethyl-6-methyl-pyridine-4-carbonyl)-hydrazide (38 mg) as a white solid; LC-MS: tR=0.47 min, [M+1]+=327.41. This material is dissolved in DCM (5 mL) and pyridine (42 mg, 0.536 mmol) followed by trifluoromethanesulfonic anhydride (91 mg, 0.322 mmol) is added at 0° C. The mixture is stirred at 0° C. for 2 h before another portion of pyridine (42 mg, 0.536 mmol) and trifluoromethanesulfonic anhydride (61 mg, 0.214 mmol) is added. Stirring is continued for 2 h. The mixture is diluted with DCM, washed with water, dried over MgSO4, filtered and the solvent of the filtrate is evaporated. The crude product is purified by prep. TLC with heptane:EA 7:3 to give 2-ethyl-4-[2-(2-ethyl-6-methyl-4-pyridinyl)-[1,3,4]oxadiazol-5-yl]-6-methyl-pyridine (16 mg) as a colourless oil; LC-MS: tR=0.59 min, [M+1]+=309.13; 1H NMR (CDCl3): δ 1.39 (t, J=7.8 Hz, 6H), 2.68 (s, 6H), 2.94 (q, J=7.5 Hz, 4H), 7.70 (s, 4H).

Workup

  1. concentrationThe now clear solution is concentrated
  2. customdried
  3. customto provide crude 2-ethyl-6-methyl-isonicotinic acid chloride
  4. stirringThe mixture is stirred at rt for 15 h before it
  5. washwashed with 1 M aq. HCl
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto give crude 2-ethyl-6-methyl-isonicotinic acid N′-(2-ethyl-6-methyl-pyridine-4-carbonyl)-hydrazide (38 mg) as a white solid
  10. additionis added at 0° C
  11. additionis added
  12. stirringStirring
  13. waitis continued for 2 h
  14. washwashed with water
  15. dry with materialdried over MgSO4
  16. filtrationfiltered
  17. customthe solvent of the filtrate is evaporated
  18. customThe crude product is purified by prep

Sources & evidence

ORD record
ord-db96fe68221a41d4b45ed8fdb4d279b9
Source dataset
uspto-grants-2013_12
Patent number
US08598208B2

Reaction notes

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