Trifluoroacetic acid → {(1R,2R)-2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}methanol

HRID 1468852Notes

Reaction equation

HRID 1468852 reaction equation
[OH:1][CH2:2][C@@H:3]1[CH2:5][C@@H:4]1[CH:6]1[CH2:11][CH2:10][N:9]([C:12](OC(C)(C)C)=O)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].ClC1[N:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][N:34]=1>ClCCl>[CH2:39]([C:36]1[CH:35]=[N:34][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C@H:4]3[CH2:5][C@H:3]3[CH2:2][OH:1])[CH2:11][CH2:10]2)=[N:38][CH:37]=1)[CH3:40]

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 10796Cesium carbonateHCID 35727632-Chloro-5-ethylpyrimidineHCID 53393314HCID 53393314, compound2×

Product 1

HCID 71136253{(1R,2R)-2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}methanol

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To a cold (0° C.), stirred solution tert-butyl 4-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]piperidine-1-carboxylate (intermediate 4, 5.0 g, 19.58 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (100 mL) slowly over 10 minutes. After being stirred at 0° C. for 1 h, the mixture was concentrated under vacuum. Residual TFA was further removed by stripping twice from dichloromethane followed by drying in vacuum. The resulting residue was dissolved in DMF (40 ml) followed by the addition of cesium carbonate (35.09 g, 107.69 mmol) and 2-chloro-5-ethylpyrimidine (5.6 g, 39.15 mmol). The mixture was stirred at RT for 15 h before being quenched with H2O. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with H2O (2×), brine (1×), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by column chromatography on silica (elution with 2:1→1:1 hexane:ethyl acetate) to yield the title compound. H NMR (500 MHz, CDCl3) δ 8.18 (s, 2H), 4.74-4.65 (m, 2H), 3.74-3.67 (m, 2H), 2.89-2.81 (m, 2H), 2.47 (q, J 7.6 Hz, 2H), 1.91-1.82 (m, 2H), 1.46-1.34 (m, 2H), 1.23-1.16 (M, 4H), 1.16-1.07 (m 1H), 0.77-0.70 (m, 2H), 0.09-0.04 (m, 1H). MS (ESI) m/z 262 [M+H]+.

Workup

  1. concentrationthe mixture was concentrated under vacuum
  2. customResidual TFA was further removed
  3. customby drying in vacuum
  4. dissolutionThe resulting residue was dissolved in DMF (40 ml)
  5. stirringThe mixture was stirred at RT for 15 h
  6. custombefore being quenched with H2O
  7. extractionThe aqueous layer was extracted with EtOAc (2×)
  8. washThe combined organic layers were washed with H2O (2×), brine (1×)
  9. dry with materialdried over anhydrous MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated under vacuum
  12. customto leave a residue which
  13. customwas purified by column chromatography on silica (elution with 2:1→1:1 hexane:ethyl acetate)

Sources & evidence

ORD record
ord-28455d2f0d314ac0a00b89025ad81f2e
Source dataset
uspto-grants-2015_04
Patent number
US09006228B2

Reaction notes

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