Lithium Hydroxide → 4-(4-(3-Cyclohexylpropoxy)-2-oxopyridin-1(2h)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid

HRID 1184020Notes

Reaction equation

HRID 1184020 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13]CC)=[O:12])[C:4](=[O:21])[CH:3]=1.[CH:22]1([CH2:28][CH2:29][CH2:30]O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Li+].[OH-]>C(OCC)(=O)C.O.C1COCC1>[CH:22]1([CH2:28][CH2:29][CH2:30][O:1][C:2]2[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]([CH3:20])([S:16]([CH3:19])(=[O:17])=[O:18])[C:11]([OH:13])=[O:12])[C:4](=[O:21])[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1

Participants

9

Reactant 5

HCID 3939Lithium HydroxideHCID 11776TriphenylphosphineHCID 707633-Cyclohexyl-1-propanolHCID 5363146Diisopropyl azodicarboxylateHCID 67248478Ethyl 4-(4-hydroxy-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate

Product 1

HCID 672616014-(4-(3-Cyclohexylpropoxy)-2-oxopyridin-1(2h)-yl)-2-methyl-2-(methylsulfonyl)butanoic acidYield 51.2%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

Ethyl 4-(4-hydroxy-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (285 mg, 0.898 mmol) was weighed into a 20 ml septa cap vial with THF (10 ml) added. To this was added 3-cyclohexyl-1-propanol (0.191 ml, 1.26 mmol), followed by triphenylphosphine (330 mg, 1.21 mmol). The reaction mixture was stirred at RT for 20 minutes and then DIAD (0.248 ml, 1.26 mmol) was added. The reaction mixture was stirred for 72 hours at RT, was then diluted with ethyl acetate (100 ml) and washed with saturated sodium bicarbonate (50 ml). The product was re-extracted with ethyl acetate (100 ml). The organic phases were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dioxane (6 ml) and ethanol (6 ml). To this was added a 2.0M aqueous solution of LiOH (2.6 ml, 5.3 mmol). The reaction mixture was stirred at RT overnight, then was diluted with 30 ml of water and washed with ethyl acetate (2×50 ml) to remove any TPPO. The aqueous phase was adjusted to pH-2 with 1N HCl (10 ml) and the product was extracted with ethyl acetate (3×50 ml). The organic phases were combined, dried over sodium sulfate, filtered and concentrated to provide the title compound as a white solid (190 mg, 51%). MS (LC/MS) m/z 414.1 (M+1) 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.81-1.08 (m, 2H) 1.16-1.44 (m, 6H) 1.72 (s, 9H) 2.01 (s, 1H) 2.29-2.47 (m, 1H) 2.48-2.68 (m, 1H) 3.18 (s, 3H) 4.04 (s, 2H) 4.07-4.17 (m, 1H) 4.22-4.37 (m, 1H) 5.97-6.12 (m, 1H) 6.25-6.36 (m, 1H) 7.57-7.73 (m, 1H)

Workup

  1. additionadded
  2. stirringThe reaction mixture was stirred for 72 hours at RT
  3. washwashed with saturated sodium bicarbonate (50 ml)
  4. extractionThe product was re-extracted with ethyl acetate (100 ml)
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. dissolutionThe residue was dissolved in dioxane (6 ml)
  9. stirringThe reaction mixture was stirred at RT overnight
  10. washwashed with ethyl acetate (2×50 ml)
  11. customto remove any TPPO
  12. extractionthe product was extracted with ethyl acetate (3×50 ml)
  13. dry with materialdried over sodium sulfate
  14. filtrationfiltered
  15. concentrationconcentrated

Sources & evidence

ORD record
ord-b98177d6842243668c7f95dc1ad42506
Source dataset
uspto-grants-2014_03
Patent number
US08664401B2

Reaction notes

Loading…