N-methyl-2-pyrrolidone → (4S)-3-{(2S)-2-[(S)-[3,5-bis(trifluoromethyl)phenyl](hydroxy)methyl]but-3-enoyl}-4-phenyl-1,3-oxazolidin-2-one

HRID 540438Notes

Reaction equation

HRID 540438 reaction equation
[C:1]([N:6]1[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][O:8][C:7]1=[O:17])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].CCN(C(C)C)C(C)C.CN1C(=O)CCC1.[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH:39]=[O:40]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:34][C:35]([F:48])([F:49])[C:36]1[CH:37]=[C:38]([C@@H:39]([OH:40])[C@H:2]([CH:3]=[CH2:4])[C:1]([N:6]2[C@@H:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][O:8][C:7]2=[O:17])=[O:5])[CH:41]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:43]=1

Participants

7

Reactant 4

HCID 13387N-methyl-2-pyrrolidoneHCID 81531DiisopropylethylamineHCID 1362473,5-Bis(trifluoromethyl)benzaldehydeHCID 5469245(4S)-3-[(2E)-But-2-enoyl]-4-phenyl-1,3-oxazolidin-2-one

Product 1

HCID 86682258(4S)-3-{(2S)-2-[(S)-[3,5-bis(trifluoromethyl)phenyl](hydroxy)methyl]but-3-enoyl}-4-phenyl-1,3-oxazolidin-2-oneYield 70.9%

Reagents, catalysts & solvents 2

HCID 24193Titanium TetrachlorideCatalystHCID 6344DichloromethaneSolvent3×

Conditions

Temperature
-40 °C

Procedure

To (4S)-3-[(2E)-but-2-enoyl]-4-phenyl-1,3-oxazolidin-2-one (13.8 g, 59.7 mmol) in DCM (100 mL) was added TiCl4 (1M in DCM, 59.7 mL, 59.7 mmol) at −10° C. The resulting reaction solution was transferred by cannula to a flask containing DIPEA (11.26 mL, 64.5 mmol) and DCM (100 mL) at 10° C. NMP (11.49 mL, 119 mmol) was added via a syringe and the reaction mixture was aged for 1 hour before cooling to −40° C. 3,5-Bis(trifluoromethyl)benzaldehyde (17.3 g, 71.6 mmol) in DCM (25 mL) was added via a syringe and the reaction was allowed to warm to 0° C. over 1.5 hr. The reaction was quenched by addition of acetic acid (15 mL), saturated Rochelle's salt (50 mL) and HCl (1.0 M, 200 mL). The organic was separated and the aqueous was back extracted with DCM (50 mL). The organics were combined, washed with HCl (1.0 M, 100 mL), dried over sodium sulfate, filtered and concentrated. The resultant oil was purified by column chromatography to give (4S)-3-{(2S)-2-[(S)-[3,5-bis(trifluoromethyl)phenyl](hydroxy)methyl]but-3-enoyl}-4-phenyl-1,3-oxazolidin-2-one (20 g, 42.3 mmol) as crystalline solid. 1H NMR (500 MHz, CDCl3) δ7.86 (s, 2H), 7.83 (s, 1H), 7.4 (m, 5H), 5.7 (m, 1H), 5.4 (m, 1H), 5.31 (d, J=10.3 Hz, 1H), 5.28 (d, J=3.9 Hz, 1H), 5.10 (d, J=17.3 Hz, 1H), 4.8 (m, 1H), 4.7 (t, J=9.0 Hz, 1H), 4.3 (m, 1H).

Workup

  1. customThe resulting reaction solution
  2. customwas transferred by cannula to a flask
  3. temperatureto warm to 0° C. over 1.5 hr
  4. customThe reaction was quenched by addition of acetic acid (15 mL), saturated Rochelle's salt (50 mL) and HCl (1.0 M, 200 mL)
  5. customThe organic was separated
  6. extractionthe aqueous was back extracted with DCM (50 mL)
  7. washwashed with HCl (1.0 M, 100 mL)
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe resultant oil was purified by column chromatography

Sources & evidence

ORD record
ord-c021ab594ea244a3893628ac42f10424
Source dataset
uspto-grants-2014_10
Patent number
US08871738B2

Reaction notes

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