4-Methylmorpholine → 4-[4-(3-cyclohexylpropoxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

HRID 1184021Notes

Reaction equation

HRID 1184021 reaction equation
[CH:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:20](O)=[O:21])[C:13](=[O:28])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[O:42][NH2:43]>O>[CH:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:20]([NH:43][O:42][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][O:36]3)=[O:21])[C:13](=[O:28])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1

Participants

5

Reactant 3

HCID 79724-MethylmorpholineHCID 5142091O-(Tetrahydropyran-2-yl)hydroxylamineHCID 672616014-(4-(3-Cyclohexylpropoxy)-2-oxopyridin-1(2h)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid

Product 1

HCID 866719714-[4-(3-cyclohexylpropoxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamideYield 95.2%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

4-[4-(3-Cyclohexylpropoxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (190 mg, 0.451 mmol) and CDMT (95.6 mg, 0.539 mmol) were charged into a flask. The flask was flushed with nitrogen and 2-MeTHF (10 ml) was added, followed by NMM (64 uL, 0.581 mmol). The reaction mixture was stirred at RT for 1 hour. O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (64 mg, 0.539 mmol) was added to the reaction mixture and stirred for 16 hours at RT. Water (25 ml) was added, the layers were separated and the aqueous layer was extracted with EtOAc (3×50 ml). The organic layers were combined and dried over sodium sulfate, filtered and concentrated in vacuo. Crude material was purified by chromatography on silica gel (70% heptane:30% ethyl acetate to 100% ethyl acetate) to afford a white solid (220 mg, 79%). MS (LC/MS) m/z 511.1 (M−1) 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.93 (t, J=7.02 Hz, 3H) 1.12-1.42 (m, 9H) 1.49-1.99 (m, 10H) 2.25-2.43 (m, 1H) 2.45-2.64 (m, 1H) 3.12 (d, J=5.07 Hz, 3H) 3.51-3.68 (m, 2H) 3.82-4.03 (m, 4H) 4.08-4.26 (m, 2H) 5.03-5.14 (m, 1H) 5.94 (d, J=2.54 Hz, 1H) 6.07-6.21 (m, 1H) 7.45-7.60 (m, 1H).

Workup

  1. customThe flask was flushed with nitrogen and 2-MeTHF (10 ml)
  2. additionwas added
  3. stirringstirred for 16 hours at RT
  4. customthe layers were separated
  5. extractionthe aqueous layer was extracted with EtOAc (3×50 ml)
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customCrude material was purified by chromatography on silica gel (70% heptane:30% ethyl acetate to 100% ethyl acetate)

Sources & evidence

ORD record
ord-bbe8c1812bb946ada7d456aaa2ab06eb
Source dataset
uspto-grants-2014_03
Patent number
US08664401B2

Reaction notes

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