Ammonia → 5-Ethyl-6-methoxy-2-methyl-nicotinamide

HRID 1921356Notes

Reaction equation

HRID 1921356 reaction equation
[CH2:1]([C:3]1[C:4]([O:13][CH3:14])=[N:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8](O)=[O:9])[CH3:2].F[B-](F)(F)F.O=C1C=CC=C[N:22]1OC(N(C)C)=[N+](C)C.O.OC1C2N=NNC=2C=CC=1.N.O1CCOCC1.C(N(C(C)C)C(C)C)C>ClCCl.O>[CH2:1]([C:3]1[C:4]([O:13][CH3:14])=[N:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([NH2:22])=[O:9])[CH3:2]

Participants

9

Reactant 6

HCID 222Ammonia3×HCID 312751,4-Dioxane2×HCID 81531DiisopropylethylamineHCID 2733204O-(2-Oxo-1(2H)-pyridyl)-N,N,N',N'-tetramethyluronium TetrafluoroborateHCID 674920765-Ethyl-6-methoxy-2-methyl-nicotinic acidHCID 178526939HCID 178526939, compound

Product 1

HCID 674926225-Ethyl-6-methoxy-2-methyl-nicotinamideYield 122.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

A round bottom flask under a nitrogen atmosphere is charged with 5-ethyl-6-methoxy-2-methyl-nicotinic acid (1.00 g, 5.13 mmol) of Step 2, Example 14 dissolved in dichloromethane (50 mL). To this is added O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.676 g, 5.64 mmol) followed by hydroxybenzotriazole hydrate (785 mg, 5.13 mmol). The resulting mixture is stirred at rt for 30 min then treated with a solution of ammonia in 1,4-dioxane (0.5 M, 10.3 mL, 5.15 mmol) followed by N-ethyl-diisopropylamine (2.32 mL, 13.3 mmol) to give a suspension. After stirring at rt for 23 hr, LC/MS shows the reaction to be incomplete. A solution of ammonia in 1,4-dioxane (0.5 M, 10 mL, 5.00 mmol) is added and stirred for an additional period of 24 hr. LC/MS shows the reaction is still incomplete and so more ammonia (0.5 M, 5 mL, 2.5 mmol) is added and allowed to stir for 68 hr to give a solution. LC/MS shows the reaction to be complete. The reaction is diluted with water and the mixture is extracted with seven portions of dichloromethane. The combined extract is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (1:0, increasing to 1:2). Fractions containing the product are combined and re-purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (1:0, increasing to 1:2). Fractions containing the product are combined, the solvent evaporated and the residue triturated with ether to give 5-ethyl-6-methoxy-2-methyl-nicotinamide (1.22 g) as a fluffy, pink solid. MS: m/e=195 (M+H); 1H NMR (CDCl3, δ, ppm): 7.50 (1H, s), 5.77 (2H, s), 3.96 (3H, s), 2.61 (3H, s), 2.56 (2H, q), 1.18 (3H, t).

Workup

  1. customto give a suspension
  2. stirringAfter stirring at rt for 23 hr
  3. customthe reaction
  4. stirringstirred for an additional period of 24 hr
  5. stirringto stir for 68 hr
  6. customto give a solution
  7. customthe reaction
  8. extractionthe mixture is extracted with seven portions of dichloromethane
  9. extractionThe combined extract
  10. dry with materialis dried over magnesium sulfate
  11. filtrationfiltered
  12. customevaporated
  13. customThe crude product is purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (1:0, increasing to 1:2)
  14. additionFractions containing the product
  15. customre-purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (1:0, increasing to 1:2)
  16. additionFractions containing the product
  17. customthe solvent evaporated
  18. customthe residue triturated with ether

Sources & evidence

ORD record
ord-8d4f2ec93bc34e5fa247780ab7d9d2fc
Source dataset
uspto-grants-2012_05
Patent number
US08173682B2

Reaction notes

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