Acetonitrile → (5R)-3-(2,2-Difluoro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester

HRID 723908Notes

Reaction equation

HRID 723908 reaction equation
[F:1][C:2]1([F:15])[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:4]=2[O:3]1.[O:16](S(C(F)(F)F)(=O)=O)[Li].[CH3:25][O:26][C:27](=[O:31])[C@@H]1OC1.C1N=CN([C:37](N2C=NC=C2)=[O:38])C=1.[C:44](#N)[CH3:45]>Cl>[CH3:25][O:26][C:27]([C@@H:44]1[O:16][C:37](=[O:38])[N:14]([C:12]2[CH:11]=[CH:10][C:5]3[N:6]([CH3:9])[C:7](=[O:8])[C:2]([F:1])([F:15])[O:3][C:4]=3[CH:13]=2)[CH2:45]1)=[O:31]

Participants

7

Reactant 5

HCID 6342AcetonitrileHCID 682631,1'-CarbonyldiimidazoleHCID 9877347Methyl (2R)-2-oxiranecarboxylateHCID 218776332,2-difluoro-4-methyl-7-amino-4H-1,4-benzoxazin-3-oneHCID 178506959HCID 178506959, compound

Product 1

HCID 68487729(5R)-3-(2,2-Difluoro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl esterYield 77%

Reagents, catalysts & solvents 1

HCID 313Hydrochloric AcidSolvent

Conditions

Temperature
50 °C

Procedure

To a stirred solution 2,2-difluoro-7-amino-4-methyl-4H-1,4-benzoxazin-3-one (Step 2, 1.05 g, 4.90 mmol) in acetonitrile (25 mL) is added LiOTf (841 mg, 5.39 mmol) followed by methyl-(R)-glycidate (549 mg, 5.39 mmol). The resulting mixture is heated to 50° C. over night at which time HPLC indicates complete consumption of the starting material. The reaction is quenched by addition of water (50 mL), EtOAc (100 mL) and saline (50 mL). The organic phase is separated followed by further extraction of the aqueous phase with EtOAc (20 mL×3). The combined organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure, and the residue is passed through a short silica gel column (EtOAc) to remove the polar impurities from the amino alcohol intermediate (MS (m/z): 317.5 [M+H]+). This intermediate is dissolved in anhydrous acetonitrile (20 mL) followed by addition of CDI (1.58 g, 9.80 mmol, 2 eq. wrt aniline above) at room temperature. The resulting reaction mixture is stirred overnight at which time it is diluted with 0.1 N HCl (10 mL). The resulting pale yellow precipitate is filtered off, washed with additional 0.1 N HCl (25 mL) and water (100 mL) and dried under high vacuum to give the title compound (1.30 g, 77% for two steps), MS (m/z): 342.7 [M+H]+.

Workup

  1. customconsumption of the starting material
  2. customThe reaction is quenched by addition of water (50 mL), EtOAc (100 mL) and saline (50 mL)
  3. customThe organic phase is separated
  4. extractionfollowed by further extraction of the aqueous phase with EtOAc (20 mL×3)
  5. dry with materialThe combined organic phase is dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customto remove the polar impurities from the amino alcohol intermediate (MS (m/z): 317.5 [M+H]+)
  9. dissolutionThis intermediate is dissolved in anhydrous acetonitrile (20 mL)
  10. customThe resulting reaction mixture
  11. filtrationThe resulting pale yellow precipitate is filtered off
  12. washwashed with additional 0.1 N HCl (25 mL) and water (100 mL)
  13. customdried under high vacuum

Sources & evidence

ORD record
ord-050f0de6cbc64ac4aae7efa93f574ae9
Source dataset
uspto-grants-2006_11
Patent number
US07141588B2

Reaction notes

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