1,4-Dioxane → (R)-2-(3-chloro-phenyl)-morpholine hydrochloride

HRID 530594Notes

Reaction equation

HRID 530594 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCOCC1>Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[ClH:20].[Cl:20][C:16]1[CH:15]=[C:14]([C@H:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:19]=[CH:18][CH:17]=1

Participants

5

Reactant 2

HCID 312751,4-DioxaneHCID 117871442(R)-2-(3-chlorophenyl)-morpholine-4-carboxylic acid tert-butyl ester

Product 2

HCID 117869899(R)-2-(3-chloro-phenyl)-morpholine hydrochlorideYield 100.3%HCID 117871442(R)-2-(3-chlorophenyl)-morpholine-4-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 313Hydrochloric AcidSolvent

Conditions

Temperature
55 °C

Procedure

(R)-2-(3-Chlorophenyl)-morpholine-4-carboxylic acid tert-butyl ester was prepared using a similar procedure as that described in Example 4 (steps b-d). (R)-2-(3-Chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (2.7 g, 9.07 mmol) was dissolved in HCl in dioxane (4M, 11.3 mL, 45.3 mmol) and the resulting mixture was heated at 55° C. for 2 h and then stirred at room temperature overnight. The solvent was removed by concentration in vacuo. The crude product was purified by reverse phase column chromatography (5-80% acetonitrile containing 0.1% TFA in water containing 0.1% TFA). The desired fractions were pooled and concentrated in vacuo. The product was dissolved in acetonitrile and water and 0.1 mL of concentrated HCl was added. The resultant solution was lyophilized to afford (R)-2-(3-chlorophenyl)-morpholine hydrochloride (0.71 g), as a white solid. 1H NMR (400 MHz, DEUTERIUM OXIDE) δ ppm 3.18 (dd, J=12.80, 11.54 Hz, 1H) 3.30 (dd, J=12.17, 3.89 Hz, 1H) 3.34-3.51 (m, 2H) 3.99 (ddd, J=13.11, 12.11, 2.64 Hz, 1H) 4.22 (dd, J=13.18, 3.64 Hz, 1H) 4.82 (dd, J=11.42, 2.38 Hz, 1H) 7.26-7.33 (m, 1H) 7.34-7.42 (m, 2H) 7.44 (d, J=1.76 Hz, 1H).

Workup

  1. customThe solvent was removed by concentration in vacuo
  2. customThe crude product was purified by reverse phase column chromatography (5-80% acetonitrile containing 0.1% TFA in water containing 0.1% TFA)
  3. concentrationconcentrated in vacuo
  4. dissolutionThe product was dissolved in acetonitrile
  5. additionwater and 0.1 mL of concentrated HCl was added

Sources & evidence

ORD record
ord-18c23de87f3b4b538e8b29549afd6ef5
Source dataset
uspto-grants-2016_05
Patent number
US09353096B2

Reaction notes

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