Ethyl Acetate → 1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine

HRID 2186443Notes

Reaction equation

HRID 2186443 reaction equation
[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][N:18](CC3C=CC=CC=3)[C@H:17]2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH2:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(OCC)(=O)C.[H][H]>[Pd].C(O)C>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:13]([O:15][CH:16]2[C:17]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[N:18][CH:19]=[CH:20][O:21]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1

Participants

6

Reactant 3

HCID 8857Ethyl AcetateHCID 113529882alpha-[[1-[3,5-Bis(trifluoromethyl)phenyl]vinyl]oxy]3alpha-(4-fluorophenyl)-4-benzylmorpholine2×HCID 178418361HCID 178418361, compound2×

Product 1

HCID 881849821-[3,5-Bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazineYield 159.3%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 702EthanolSolvent

Procedure

A solution of (2R-cis)-2-[[1-[3.5-bis(trifluoromethyl)phenyl]-ethenyl]oxy]-3-(4-fluorophenyl)-4-(phenylmethyl)mopholine (1082 g, 94% pure, 1.94 moles) in 1:1 ethyl acetate:ethanol (13 L) was mixed with 10% palladium-on-carbon (165 g). The resulting slurry was treated with hydrogen (40 psi, 20-25° C.) for 12 hours. The reaction was monitored by hydrogen uptake and HPLC. The vessel was vented, and the catalyst was removed by filtration. After washing the catalyst with 1:1 ethyl acetate:ethanol (6 L) followed by ethyl acetate (2 L), the combined organic phases containing crude product were vacuum concentrated. A second batch, starting with 1078 g of (2R-cis)-2-[[1-[3.5-bis(trifluoromethyl)phenyl]ethenyl]oxy]-3-(4-fluorophenyl)-4-(phenylmethyl)mopholine (1.93 moles) was prepared. The resulting crude product was vacuum concentrated and combined with the first batch. The combined batches of crude product were flushed with methyl-t-butyl ether (2×3 L) in order to remove residual ethyl acetate and ethanol, then were dissolved in methyl-t-butyl ether (3 L). The solution was assayed to contain 1348 g (3.09 moles, 80% yield) of the title compound (as the free base). Alternatively, 60 g of the vinyl ether, 650 mL of methyl t-butyl ether (MTBE), and 18 g of 5% Pd on alumina were stirred under 40 psi hydrogen pressure at 40° for 12 H. Assay yield was 87%, with a 91:9 ratio of diastereomers. At the end of the reaction age, the catalyst was removed by filtration through Solka-Floc, then the filtrate was concentrated to 140 mL.

Workup

  1. customthe catalyst was removed by filtration
  2. washAfter washing the catalyst with 1:1 ethyl acetate
  3. additionthe combined organic phases containing crude product
  4. concentrationconcentrated
  5. customwas prepared
  6. concentrationconcentrated
  7. customThe combined batches of crude product were flushed with methyl-t-butyl ether (2×3 L) in order
  8. customto remove residual ethyl acetate and ethanol
  9. dissolutionwere dissolved in methyl-t-butyl ether (3 L)

Sources & evidence

ORD record
ord-b2279767f8ad43ec932fab067fc6560e
Source dataset
uspto-grants-2002_06
Patent number
US06403793B2

Reaction notes

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