Hydrochloric Acid → Tert-butyl [3-fluoro-2-(2-oxopropyl)phenyl]carbamate

HRID 2278518Notes

Reaction equation

HRID 2278518 reaction equation
C([Li])(CC)C.[F:6][C:7]1[C:8]([CH3:21])=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:11][CH:12]=1.CON(C)[C:25](=[O:27])[CH3:26].Cl>O1CCCC1.C(OCC)C.C1CCCCC1.CCCCCC>[F:6][C:7]1[C:8]([CH2:21][C:25](=[O:27])[CH3:26])=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH:10]=[CH:11][CH:12]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 537505N-Methoxy-N-methylacetamideHCID 14710384tert-Butyl (3-fluoro-2-methylphenyl)carbamateHCID 178418400CID 53628100

Product 1

HCID 86699261Tert-butyl [3-fluoro-2-(2-oxopropyl)phenyl]carbamate

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent2×HCID 22494920Cyclohexane hexaneSolvent

Conditions

Temperature
-50 °C

Procedure

4.3 ml of a 1.3 M solution of sec-butyllithium in 98/2 v/v cyclohexane/hexane are added dropwise, while maintaining the temperature between −40° C. and −30° C., to a solution of 0.5 g of tert-butyl (3-fluoro-2-methylphenyl)carbamate in 10 ml of tetrahydrofuran under argon and cooled to −40° C. The reaction mixture is then cooled to −50° C., and then a solution of 0.27 ml of N-methoxy-N-methylacetamide in 4 ml of tetrahydrofuran is added dropwise while maintaining the temperature between −50° C. and −40° C. The mixture is then left to warm up to approximately −10° C., and then stirred at this temperature for 0.5 hour. It is then treated with 5.6 ml of a 1N hydrochloric acid solution and then diluted with 20 ml of diethyl ether and left to warm up to ambient temperature with stirring for 1 hour. After settling out, the organic phase is separated and the aqueous phase is extracted with 40 ml of diethyl ether. The organic phases are combined, washed with 3×40 ml of water, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 30 g cartridge of 15-40 μm silica, elution being carried out with a 90/10 v/v cyclohexane/ethyl acetate mixture, at a flow rate of 30 ml/min, and then on a 30 g cartridge of 15-40 μm silica, elution being carried out with pure dichloromethane, at a flow rate of 30 ml/min. 0.38 g of tert-butyl [3-fluoro-2-(2-oxopropyl)phenyl]carbamate is thus obtained, in the form of a white solid, the characteristics of which are the following:

Workup

  1. temperaturewhile maintaining the temperature between −40° C. and −30° C.
  2. temperaturewhile maintaining the temperature between −50° C. and −40° C
  3. waitThe mixture is then left
  4. temperatureto warm up to approximately −10° C.
  5. waitleft
  6. temperatureto warm up to ambient temperature
  7. stirringwith stirring for 1 hour
  8. customthe organic phase is separated
  9. extractionthe aqueous phase is extracted with 40 ml of diethyl ether
  10. washwashed with 3×40 ml of water
  11. dry with materialdried over magnesium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated to dryness under reduced pressure
  14. customThe residue is purified by chromatography on a 30 g cartridge of 15-40 μm silica, elution
  15. washon a 30 g cartridge of 15-40 μm silica, elution

Sources & evidence

ORD record
ord-2c0589e54f0143939710b397ad667e4c
Source dataset
uspto-grants-2015_09
Patent number
US09133168B2

Reaction notes

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