Hydrochloric Acid → (rac)-(R*,S*)-2-((2-hydroxy-(R)-1-methylethyl)amino)-1-(3,5-difluorophenyl)propanol

HRID 2357726Notes

Reaction equation

HRID 2357726 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C@:9]2([OH:17])[O:14][CH2:13][C@@H:12]([CH3:15])[NH:11][C@H:10]2[CH3:16])[CH:5]=[C:6]([F:8])[CH:7]=1.[BH4-].[Na+].Cl>C(O)C.O.O>[OH:14][CH2:13][C@H:12]([NH:11][C@@H:10]([CH3:16])[C@@H:9]([C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[OH:17])[CH3:15]

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 60829ManifaxineHCID 4311764Sodium borohydride

Product 1

HCID 68457326(rac)-(R*,S*)-2-((2-hydroxy-(R)-1-methylethyl)amino)-1-(3,5-difluorophenyl)propanol

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 19096565Water ethanolSolvent

Conditions

Temperature
0 °C

Procedure

The hydrobromide salt of (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (0.023 mole) (U.S. Pat. No. 5,104,870) is dissolved in a 50:50 mixture of ethanol/water (150 mL) and chilled to 0° C. while being stirred under a nitrogen atmosphere. A solution of sodium borohydride (0.093 mole) in water (25 mL) is added dropwise, and the solution is allowed to warm to room temperature while being stirred overnight. The solution is cooled to 0° C., and concentrated hydrochloric acid (25 mL) is carefully added dropwise. The mixture is concentrated under reduced pressure to remove ethanol and then diluted with water to dissolve the solids. This solution is cooled with an ice bath, made basic by treatment with 40% aqueous sodium hydroxide and extracted three times with diethyl ether. The combined ether extracts is washed with a saturated sodium chloride solution, dried over sodium sulfate and spin evaporated in vacuo to give the free base of (rac)-(R*,S*)-2-((2-hydroxy-(R)-1-methylethyl)amino)-1-(3,5-difluorophenyl)propanol (21). A sample of the free base is treated with ethereal hydrogen chloride to give a solid that may be recrystallized from ethanol/ether to give the hydrochloride salt of (rac)-(R*,S*)-2-((2-hydroxy-(R)-1-methylethyl)amino)-1-(3,5-difluorophenyl)propanol. See eg., Boswell et al., J. Heterocyclic Chem., (1996) 33:33.

Workup

  1. temperatureto warm to room temperature
  2. stirringwhile being stirred overnight
  3. temperatureThe solution is cooled to 0° C.
  4. concentrationThe mixture is concentrated under reduced pressure
  5. customto remove ethanol
  6. additiondiluted with water
  7. dissolutionto dissolve the solids
  8. temperatureThis solution is cooled with an ice bath
  9. extractionextracted three times with diethyl ether
  10. washThe combined ether extracts is washed with a saturated sodium chloride solution
  11. dry with materialdried over sodium sulfate
  12. customspin evaporated in vacuo

Sources & evidence

ORD record
ord-ddd5409b2d2648f0a6b070100883a001
Source dataset
uspto-grants-2010_07
Patent number
US07763612B2

Reaction notes

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