Diisopropylamine → HCID 67099268, compound

HRID 2076939Notes

Reaction equation

HRID 2076939 reaction equation
[Li]CCCC.C(NC(C)C)(C)C.[CH3:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1.[CH2:27]([O:34][CH2:35][C@@H:36]1[CH2:41][C:40]([F:43])([F:42])[CH2:39][CH2:38][C@H:37]1[CH:44]=[O:45])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[NH4+].[Cl-]>C1COCC1>[CH2:27]([O:34][CH2:35][CH:36]1[CH2:41][C:40]([F:43])([F:42])[CH2:39][CH2:38][CH:37]1[CH:44]([OH:45])[CH:21]([C:18]1[CH:17]=[CH:16][C:15]([S:14][CH3:13])=[CH:20][CH:19]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1

Participants

7

Reactant 5

HCID 7912DiisopropylamineHCID 25517Ammonium ChlorideHCID 10512649Ethyl [4-(methylsulfanyl)phenyl]acetateHCID 25130207HCID 25130207, compoundHCID 178418339Butyllithium

Product 1

HCID 67099268HCID 67099268, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

A 2.1 M solution of n-BuLi (11 mL, 23 mmol) in hexanes was added slowly to a 0° C. solution of diisopropylamine (4.0 mL, 28 mmol) in THF (10 mL). Stirring was continued at this temperature for an additional 10 min prior to cooling to −78° C. A solution of ethyl [4-(methylthio)phenyl]acetate (4.64 g, 18.9 mmol) in THF (15 mL) was then introduced and the mixture was stirred at −78° C. for 10 min, −40° C. for 10 min and finally at 0° C. for 5 min. The solution was recooled to −78° C. and a solution of (1R,2R)-2-[(benzyloxy)methyl]-4,4-difluorocyclohexanecarbaldehyde (4.64 g, 18.9 mmol) in THF (15 mL) was added down the flask wall over 5 min. Stirring was continued at −78° C. for 30 min then at −40° C. for 1 h. A saturated aqueous solution of NH4Cl was added and the reaction mixture was warmed to rt and partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous NaCl solution and dried over Na2SO4. Concentration in vacuo and flash chromatography on silica gel eluting with 3/7 ethyl acetate/hexanes gave ethyl 3-{2-[(benzyloxy)methyl]-4,4-difluorocyclohexyl}-3-hydroxy-2-[4-(methylthio)phenyl]propanoate as a faint-yellow, thick syrup. 1H NMR (400 MHz, d6-acetone) δ 7.43-7.33 (5H, m), 7.33-7.29 (2H, m), 7.15-7.11 (2H, m), 4.66 (1H, m), 4.57-4.49 (2H, m), 4.16-4.00 (2H, m), 3.74 (2H, d, J= 10.7 Hz), 3.45 (1H, dd, J=2.8, 9.5 Hz), 2.46 (3H, s), 1.84-1.75 (2H, m) 13.5 Hz), 1.73-1.63 (1H, m), 1.17 (3H, t, 7= 7.1 Hz).

Workup

  1. stirringthe mixture was stirred at −78° C. for 10 min, −40° C. for 10 min and finally at 0° C. for 5 min
  2. customwas recooled to −78° C.
  3. stirringStirring
  4. waitwas continued at −78° C. for 30 min
  5. waitat −40° C. for 1 h
  6. temperaturethe reaction mixture was warmed to rt
  7. custompartitioned between ethyl acetate and water
  8. washThe organic phase was washed with saturated aqueous NaCl solution
  9. dry with materialdried over Na2SO4
  10. concentrationConcentration in vacuo and flash chromatography on silica gel eluting with 3/7 ethyl acetate/hexanes

Sources & evidence

ORD record
ord-651bc216b05540c9b20294a4fcb58790
Source dataset
uspto-grants-2011_04
Patent number
US07928091B2

Reaction notes

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