4-(4-Piperidinylcarbonyl)Morpholine → 4-({1-[1-(Diphenylmethyl)azetidin-3-yl]piperidin-4-yl}carbonyl)morpholine

HRID 426091Notes

Reaction equation

HRID 426091 reaction equation
[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:8])[CH2:3][CH2:2]1.[C:15]1([CH:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:22]2[CH2:25][C:24](=O)[CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO.C(O)(=O)C>[C:15]1([CH:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:22]2[CH2:25][CH:24]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]([N:9]4[CH2:14][CH2:13][O:12][CH2:11][CH2:10]4)=[O:8])[CH2:3][CH2:2]3)[CH2:23]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1

Participants

5

Reactant 2

HCID 15202114-(4-Piperidinylcarbonyl)MorpholineHCID 37355581-(Diphenylmethyl)azetidin-3-one

Product 1

HCID 236589584-({1-[1-(Diphenylmethyl)azetidin-3-yl]piperidin-4-yl}carbonyl)morpholineYield 83.2%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 887MethanolSolvent

Conditions

Temperature
120 °C

Procedure

4-(Piperidin-4-ylcarbonyl)morpholine (0.30 g, 1.26 mmol) and 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, 0.30 g, 1.5 mmol) were dissolved in a mixture of methanol (5 mL) and acetic acid (0.1 mL). (Polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 0.38 g) was added and the reaction mixture was heated for 10 min at 120° C. using microwave single node heating. The mixture was filtered through a phase separator and the resin washed with methanol. The solvent was removed by evaporation and the residue was dissolved in methylene chloride. The solution washed twice with a saturated solution of NaHCO3. The organic phase was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by chromatography on silica gel (methanol/methylene chloride, 5% methanol). There was obtained 0.44 g (83%) of 4-({1-[1-(diphenylmethyl)azetidin-3-yl]piperidin-4-yl}carbonyl)morpholine as a colorless oil. 1H NMR (500 MHz, CDCl3): 1.6-1.7 (m, 2H), 1.7-1.9 (m, 4H), 2.2 (m, 1H), 2.7-2.8 (m, 2H), 2.8-3.0 (m, 4H), 3.3-3.5 (m, 3H), 3.5-3.7 (m, 6H), 4.4 (s, 1H), 7.1-7.2 (t, 2H), 7.2-7.3 (t, 4H), 7.4 (d, 4H); LCMS: m/z 420 (M+1)+.

Workup

  1. temperatureheating
  2. filtrationThe mixture was filtered through a phase separator
  3. washthe resin washed with methanol
  4. customThe solvent was removed by evaporation
  5. dissolutionthe residue was dissolved in methylene chloride
  6. washThe solution washed twice with a saturated solution of NaHCO3
  7. filtrationThe organic phase was filtered through a phase separator
  8. customthe solvent was removed by evaporation
  9. customThe product was purified by chromatography on silica gel (methanol/methylene chloride, 5% methanol)

Sources & evidence

ORD record
ord-3c5115a7d4cc40a0a366b6ccd7ae11ba
Source dataset
uspto-grants-2012_01
Patent number
US08106208B2

Reaction notes

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