1-Chloroethyl chloroformate → 3-[(1S)-1-(3,5-Difluorophenyl)-2-fluoro-2-methylpropyl]azetidine

HRID 602978Notes

Reaction equation

HRID 602978 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.ClC(OC(Cl)C)=O>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]([CH:14]2[CH2:15][NH:16][CH2:17]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:3]=[C:2]([F:1])[CH:7]=1

Participants

4

Reactant 2

HCID 5213051-Chloroethyl chloroformateHCID 113273173-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]-1-(diphenylmethyl)azetidine

Product 1

HCID 670553593-[(1S)-1-(3,5-Difluorophenyl)-2-fluoro-2-methylpropyl]azetidine

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A sample of 2.25 g (5.5 mmol) of 3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]-1-(diphenylmethyl)azetidine(Step 2 of Preparation 14) was dissolved in 15 mL of THF and 1.1 mL (10 mmole) of 1-chloroethyl chloroformate was added. The solution was stirred at room temperature. After 2 h, the solution was concentrated under reduced pressure and the residue was dried under high vacuum for 1 h. The residue was dissolved in 20 mL of CH3OH and heated to reflux for 6 h. The solution was concentrated and the residue was partitioned between 100 mL ether and 50 mL of 1:1 saturated Na2CO3 solution-1M NaOH. The aqueous layer was washed with 3 portions of 100 mL ether, and the combined organic extracts were washed with NaHCO3, then brine, then concentrated. The oily residue was applied to a silica gel column packed in 20% ethyl acetate-hexane and the column was washed with 5 column volumes of 20% ethyl acetate-hexane, then with CH2Cl2, with 10% CH3OH in CH2Cl2 and finally with 80:20:2 CH2Cl2—CH3OH-ammonium hydroxide. Homogenous fractions were concentrated to afford the title compound, which was not further purified but was used directly in the next step; Mass Spectrum: m/e=244 (M+1).

Workup

  1. concentrationthe solution was concentrated under reduced pressure
  2. customthe residue was dried under high vacuum for 1 h
  3. dissolutionThe residue was dissolved in 20 mL of CH3OH
  4. temperatureheated
  5. temperatureto reflux for 6 h
  6. concentrationThe solution was concentrated
  7. customthe residue was partitioned between 100 mL ether and 50 mL of 1:1 saturated Na2CO3 solution-1M NaOH
  8. washThe aqueous layer was washed with 3 portions of 100 mL ether
  9. washthe combined organic extracts were washed with NaHCO3
  10. concentrationbrine, then concentrated
  11. washthe column was washed with 5 column volumes of 20% ethyl acetate-hexane
  12. concentrationHomogenous fractions were concentrated

Sources & evidence

ORD record
ord-d5fb1dec301849f89d883ee0edc9f01e
Source dataset
uspto-grants-2011_03
Patent number
US07906652B2

Reaction notes

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