Hydrochloric Acid → (R)-4-benzyl-2-methylmorpholine hydrochloride

HRID 41221

Reaction equation

HRID 41221 reaction equation
[CH2:1]([N:8]([CH2:13][CH2:14][OH:15])[CH2:9][C@H:10](O)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].CC1C=CC(S([Cl:28])(=O)=O)=CC=1.Cl>O1CCOCC1.COCCOCCN(CCOCCOC)CCOCCOC>[ClH:28].[CH2:1]([N:8]1[CH2:13][CH2:14][O:15][C@H:10]([CH3:11])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 73974-Toluenesulfonyl chlorideHCID 14797Potassium HydroxideHCID 60013076(R)-1-(benzyl(2-hydroxyethyl)amino)propan-2-ol

Product 1

HCID 70872727(R)-4-benzyl-2-methylmorpholine hydrochlorideYield 33.4%

Reagents, catalysts & solvents 2

HCID 112414Ethanamine, 2-(2-methoxyethoxy)-N,N-bis[2-(2-methoxyethoxy)ethyl]-CatalystHCID 312751,4-DioxaneSolvent3×

Conditions

Temperature
0 °C

Procedure

To a stirred solution of (R)-1-(benzyl(2-hydroxyethyl)amino)propan-2-ol (110 g, 525.60 mmol) in dioxane (500 mL) under nitrogen, potassium hydroxide powder (88 g, 1576.80 mmol) and tris(2-(2-methoxyethoxy)ethyl)amine (1.681 mL, 5.26 mmol) were successively added. The mixture was cooled to 0° C. and a solution of 4-methylbenzene-1-sulfonyl chloride (105 g, 551.88 mmol) in dioxane (500 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 45 min then at room temperature for an additional 4 h. The mixture was filtered and filtrate evaporated. The residue was dissolved in DCM and purified on silica, eluting with 25% of EtAc in DCM. The solvents were evaporated to afford an oil which was diluted with EtAc (250 mL). A solution of 4N HCl in dioxane (0.066 L, 262.8 mmol) was then added dropwise under stirring. After 30 min, the formed solid was collected by filtration, washed with diethyl ether and dried to afford (R)-4-benzyl-2-methylmorpholine hydrochloride (40 g, 33%) as a white solid. Proton NMR Spectrum: (DMSO-d6): 1.09 (d, 3H), 2.67-2.77 (m, 1H), 2.93-3.04 (m, 1H), 3.14-3.23 (m, 2H), 3.83-4.00 (m, 3H), 4.29-4.34 (m, 2H), 7.43-7.49 (m, 3H), 7.60-7.68 (m, 2H), 11.62 (bs, 1H).

Workup

  1. waitat room temperature for an additional 4 h
  2. filtrationThe mixture was filtered
  3. customfiltrate evaporated
  4. dissolutionThe residue was dissolved in DCM
  5. custompurified on silica
  6. washeluting with 25% of EtAc in DCM
  7. customThe solvents were evaporated
  8. customto afford an oil which
  9. additionwas diluted with EtAc (250 mL)
  10. stirringunder stirring
  11. waitAfter 30 min
  12. filtrationthe formed solid was collected by filtration
  13. washwashed with diethyl ether
  14. customdried

Sources & evidence

ORD record
ord-cf6a78ed22374a51968fffbda444d0f6
Source dataset
uspto-grants-2013_09
Patent number
US08530470B2

Linked notes

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