3-Hydroxyisovaleric acid → HCID 66733825, compound

HRID 2047228Notes

Reaction equation

HRID 2047228 reaction equation
[OH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](O)=[O:5].CC[N:11]([CH:15]([CH3:17])C)[CH:12]([CH3:14])C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(O[C:41]([N:43]1C(C(OC(C)(C)C)=O)CCC(C(O)=O)C1)=O)(C)(C)C>C1COCC1>[NH2:43][CH:41]1[CH2:14][CH2:12][N:11]([C:4](=[O:5])[CH2:3][C:2]([OH:1])([CH3:8])[CH3:7])[CH2:15][CH2:17]1

Participants

6

Reactant 4

HCID 693623-Hydroxyisovaleric acidHCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 67494799HCID 67494799, compound

Product 1

HCID 66733825HCID 66733825, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

3-hydroxy-3-methyl butyric acid (1.20 equiv), DIPEA (2.00 equiv), and T3P (1.50 equiv) were added to a stirring solution of compound 1 (1.00 equiv) in THF (0.2M) at room temperature under nitrogen. TLC analysis after 2 hours showed almost complete conversion, so reaction was concentrated. Residue was dissolved in ethyl acetate then washed with water, dilute HCl, saturated NaHCO3, and brine. The phases were separated and the organics dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash column chromatography (SiO2, 12 g; 0% to 10% methanol in methylene chloride). The resulting material was dissolved in methylene chloride (0.97M) and TFA (0.97M) was added under nitrogen and the mixture was stirred at room temperature for 1 hour at which time HPLC analysis indicated the reaction was complete. Reaction was concentrated and the resulting residue was dissolved in 1N NaOH and stirred at room temperature for 30 minutes. The aqueous mixture was extracted with methylene chloride. The phases were separated and the organics dried over sodium sulfate, filtered, and concentrated affording the title compound, 1-(4-aminopiperidin-1-yl)-3-hydroxy-3-methylbutan-1-one. 1H NMR (300 MHz, CDCl3) δ 4.40 (d, 1H, JHz=13.9), 3.73 (d, 1H, JHz=12.1), 2.99-2.95 (m, 1H), 2.90 (m, 1H), 2.70-2.63 (m, 1H), 2.33 (s, 2H), 1.76 (m, 2H), 1.12 (s, 8H).

Workup

  1. customconversion, so reaction
  2. concentrationwas concentrated
  3. dissolutionResidue was dissolved in ethyl acetate
  4. washthen washed with water, dilute HCl, saturated NaHCO3, and brine
  5. customThe phases were separated
  6. dry with materialthe organics dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe resulting residue was purified by flash column chromatography (SiO2, 12 g; 0% to 10% methanol in methylene chloride)
  10. dissolutionThe resulting material was dissolved in methylene chloride (0.97M)
  11. additionTFA (0.97M) was added under nitrogen
  12. customReaction
  13. concentrationwas concentrated
  14. dissolutionthe resulting residue was dissolved in 1N NaOH
  15. stirringstirred at room temperature for 30 minutes
  16. extractionThe aqueous mixture was extracted with methylene chloride
  17. customThe phases were separated
  18. dry with materialthe organics dried over sodium sulfate
  19. filtrationfiltered
  20. concentrationconcentrated

Sources & evidence

ORD record
ord-044f67636149457f990943ffc31208ac
Source dataset
uspto-grants-2013_11
Patent number
US08591943B2

Reaction notes

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