Ethoxalyl chloride → ethyl oxo((phenylmethyl){[(3S)-4-(phenylmethyl)-3-morpholinyl]methyl}amino)acetate

HRID 419387Notes

Reaction equation

HRID 419387 reaction equation
[C:1]1([CH2:7][NH:8][CH2:9][C@H:10]2[CH2:15][O:14][CH2:13][CH2:12][N:11]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH2:32]([O:34][C:35](=[O:39])[C:36](Cl)=[O:37])[CH3:33]>C1COCC1>[O:37]=[C:36]([N:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:9][C@H:10]1[CH2:15][O:14][CH2:13][CH2:12][N:11]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:35]([O:34][CH2:32][CH3:33])=[O:39]

Participants

5

Reactant 3

HCID 20884Ethoxalyl chlorideHCID 81531DiisopropylethylamineHCID 594527491-phenyl-N-{[(3S)-4-(phenylmethyl)-3-morpholinyl]methyl}methanamine

Product 1

HCID 66649783ethyl oxo((phenylmethyl){[(3S)-4-(phenylmethyl)-3-morpholinyl]methyl}amino)acetateYield 100%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

1-Phenyl-N-{[(3S)-4-(phenylmethyl)-3-morpholinyl]methyl}methanamine (4.35 g, 14.7 mmol) and diisopropylethylamine (3.30 mL, 19.1 mmol) in THF (50 mL) cooled to 0° C. Ethylchlorooxo-acetate (1.80 mL, 16.2 mmol) was added dropwise via syringe. The ice bath was removed and the reaction was stirred at rt for 2 h. The reaction mixture was concentrated, taken up in EtOAc and washed with half saturated NaHCO3. The aqueous layer was back extracted with EtOAc, dried over MgSO4 and azeotroped in EtOH to provide ethyl oxo((phenylmethyl){[(3S)-4-(phenylmethyl)-3-morpholinyl]methyl}amino)acetate (5.83 g, 14.7 mmol, used without further purification). Ethyl oxo((phenylmethyl){[(3S)-4-(phenylmethyl)-3-morpholinyl]methyl}amino)acetate (5.83 g, 14.7 mmol) was hydrogenated (1 atm.) with Pd on carbon (1.18 g, 20% w/w with starting morpholine) for 13 days. The reaction was filtered through Celite® and washed thoroughly with MeOH. The solution was concentrated and subsequently triturated with EtOAc providing the title compound of step E (2.06 g, 7.9 mmol, 54% over two steps). 1H NMR (400 MHz, CDCl3) δ ppm 3.00 (ddd, J=13.9, 12.3, 4.2 Hz, 1H), 3.14-3.23 (m, 3H), 3.49 (td, J=12.1, 2.9 Hz, 1H), 3.72-3.82 (m, J=10.0, 10.0, 6.3, 4.0 Hz, 1H), 3.87 (dd, J=11.4, 3.7 Hz, 1H), 4.02 (dd, J=11.7, 4.4 Hz, 1H), 4.28 (dd, J=13.9, 2.2 Hz, 1H), 4.61-4.67 (m, 1H), 4.70-4.75 (m, 1H), 7.26-7.38 (m, 5H). Chiral HPLC analysis (Chiralpak AS-H, 4.6×150 mm, methanol (0.1% isopropyl amine), 1.0 mL/min, UV 254 nm, 25° C.) ee=99%, retention time, S=2.99 min. [α]D20° C.=−9.0:I=100 mm, c=0.975 in CHCl3.

Workup

  1. customThe ice bath was removed
  2. concentrationThe reaction mixture was concentrated
  3. washwashed with half saturated NaHCO3
  4. extractionThe aqueous layer was back extracted with EtOAc
  5. dry with materialdried over MgSO4
  6. customazeotroped in EtOH

Sources & evidence

ORD record
ord-068dec096d9e428db9b760ff223b243d
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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