Acetic Acid → ((1S,2S)-2-((S)-1-phenylethylamino)cyclohexyl)methanol

HRID 2065932Notes

Reaction equation

HRID 2065932 reaction equation
[BH4-].[Li+].[C:3]1([C@@H:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18](OCC)=[O:19])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.[OH-].[Na+]>O1CCCC1.O>[C:3]1([C@@H:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[CH2:18][OH:19])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 14798Sodium HydroxideHCID 4148881Lithium borohydrideHCID 11109723(1S,2S)-Ethyl 2-((S)-1-phenylethyl amino)cyclohexanecarboxylate

Product 1

HCID 53236025((1S,2S)-2-((S)-1-phenylethylamino)cyclohexyl)methanol

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
15 °C

Procedure

Tetrahydrofuran (1.9 L) was charged to a reactor and cooled to 15° C. and lithium borohydride (52.8 g) was added under nitrogen. A solution of (1S,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate (10, 237.9 g) in tetrahydrofuran (0.35 L) was added and the reaction mixture was heated to reflux for NLT 12 hours, under nitrogen. The mixture was cooled to below 10° C. and acetic acid (NLT 278 mL) was added, while maintaining the temperature between 5-15° C. in NLT 30 minutes. 25% aqueous sodium hydroxide solution (1.78 L) and water (˜2 L) were added to adjust pH to ˜8.7. The aqueous layer was separated and extracted with 2×0.75 L of heptanes, which was kept aside. The organic layer was concentrated to about 0.8 L volume and combined with the heptane extracts and additional water (0.75 L). The aqueous layer was separated and extracted with heptanes (0.75 L) and the combined organic extracts were washed with water (2×0.75 L), 3.5 M aqueous sodium chloride solution (0.75 L) and dried using anhydrous magnesium sulfate. The filtered solution was concentrated under vacuum and provided 184.1 g) of (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) as the major isomer.

Workup

  1. temperaturethe reaction mixture was heated
  2. temperatureto reflux for NLT 12 hours, under nitrogen
  3. temperatureThe mixture was cooled to below 10° C.
  4. temperaturewhile maintaining the temperature between 5-15° C. in NLT 30 minutes
  5. customThe aqueous layer was separated
  6. extractionextracted with 2×0.75 L of heptanes, which
  7. concentrationThe organic layer was concentrated to about 0.8 L volume
  8. customThe aqueous layer was separated
  9. extractionextracted with heptanes (0.75 L)
  10. washthe combined organic extracts were washed with water (2×0.75 L), 3.5 M aqueous sodium chloride solution (0.75 L)
  11. customdried
  12. concentrationThe filtered solution was concentrated under vacuum

Sources & evidence

ORD record
ord-2d4d6f5f197e485aafe7a21868e7eddf
Source dataset
uspto-grants-2012_10
Patent number
US08288565B2

Reaction notes

Loading…