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

HRID 419387노트

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HRID 419387 반응식
[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]

참가 물질

5

반응물 3

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

생성물 1

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

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

실험 절차

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.

후처리

  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

출처 및 근거

ORD 기록
ord-068dec096d9e428db9b760ff223b243d
출처 데이터셋
uspto-grants-2012_01
특허 번호
US08093239B2

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