1H-1,2,4-Triazole → HCID 58808788, compound

HRID 1921342Notes

Reaction equation

HRID 1921342 reaction equation
Br[C:2]1[C:3]([CH3:12])=[N:4][C:5]([O:10]C)=[C:6]([CH2:8][CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>[Cu](I)I>[CH2:8]([C:6]1[C:5](=[O:10])[NH:4][C:3]([CH3:12])=[C:2]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH:7]=1)[CH3:9]

Participants

5

Reactant 3

HCID 92571H-1,2,4-TriazoleHCID 11430Potassium CarbonateHCID 116586693-Bromo-5-ethyl-6-methoxy-2-methylpyridine

Product 1

HCID 58808788HCID 58808788, compoundYield 19%

Reagents, catalysts & solvents 1

HCID 83717Copper iodideCatalyst

Conditions

Temperature
180 °C

Procedure

Into a microwave vial is added 3-bromo-5-ethyl-6-methoxy-2-methyl-pyridine (400 mg, 1.74 mmol), potassium carbonate (360 mg, 2.61 mmol), copper iodide (50 mg, 0.263 mmol) and 1,2,4-triazole (240 mg, 3.47 mmol). The vial is flushed with N2 before anhydrous dimethylformamide (5 mL) is added and then sealed. The reaction is heated in the CEM Discover microwave at 180° C. for 40 minutes. LC/MS shows the reaction is incomplete. Further 1,2,4-triazole (120 mg) and copper iodide (30 mg) are added, the reaction flushed with N2 and is re-microwaved to 180° C. Initially the pressure limit of 20 bar is reached and the process is aborted. The residual pressure is released and the reaction is re-microwaved to 180° C. for 40 min with a maximum pressure of 9-11 bar attained. LC/MS shows the reaction to be complete. The reaction is diluted and extracted with 11 portions of dichloromethane. The combined extracts are then dried over magnesium sulfate and evaporated to give a dark oil. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (19:1). Clean fractions containing the product are combined, the solvent evaporated, and the residue is further purified by flash chromatography on a 5-gram silica gel cartridge by elution with heptane:ethyl acetate (19:1) then dichloromethane:heptane (1:1, increasing to 1:0). Clean fractions containing the product are combined and evaporated to give an orange residue. The product is triturated with ether/heptane to give 3-ethyl-6-methyl-5-(1,2,4-triazol-1-yl)-1H-pyridin-2-one as an orange powder (67 mg, 19% yield). This material (57 mg) is suspended in dichloromethane (2 mL) and treated with ethereal hydrochloric acid (2.0 M, 0.444 mL). The mixture is stirred for 1.5 h and then evaporated to give 3-ethyl-6-methyl-5-1,2,4-triazol-1-yl-1H-pyridin-2-one hydrochloride (70 mg) as a cream-orange solid. LC/MS: RT: 1.79 min, MS: m/e=205 (M+H).

Workup

  1. customThe vial is flushed with N2 before anhydrous dimethylformamide (5 mL)
  2. additionis added
  3. customsealed
  4. additionFurther 1,2,4-triazole (120 mg) and copper iodide (30 mg) are added
  5. customthe reaction flushed with N2
  6. customis re-microwaved to 180° C
  7. customthe reaction is re-microwaved to 180° C. for 40 min with a maximum pressure of 9-11 bar
  8. customthe reaction
  9. additionThe reaction is diluted
  10. extractionextracted with 11 portions of dichloromethane
  11. dry with materialThe combined extracts are then dried over magnesium sulfate
  12. customevaporated
  13. customto give a dark oil
  14. customThe crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (19:1)
  15. additionClean fractions containing the product
  16. customthe solvent evaporated
  17. customthe residue is further purified by flash chromatography on a 5-gram silica gel cartridge by elution with heptane:ethyl acetate (19:1)
  18. additionClean fractions containing the product
  19. customevaporated
  20. customto give an orange residue
  21. customThe product is triturated with ether/heptane

Sources & evidence

ORD record
ord-4b11d280f9cc44d4a0bb4859dcc386aa
Source dataset
uspto-grants-2012_05
Patent number
US08173682B2

Reaction notes

Loading…