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

HRID 1724206Notes

Reaction equation

HRID 1724206 reaction equation
ClC1C=CC([C@H]([N:17]2[CH2:20][CH:19]([C@@H:21]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[C:22]([F:25])([CH3:24])[CH3:23])[CH2:18]2)C2C=C(C=CC=2)C#N)=CC=1.ClC(OC(Cl)C)=O>C1COCC1>[F:32][C:30]1[CH:31]=[C:26]([C@H:21]([CH:19]2[CH2:18][NH:17][CH2:20]2)[C:22]([F:25])([CH3:24])[CH3:23])[CH:27]=[C:28]([F:33])[CH:29]=1

Participants

4

Reactant 2

HCID 5213051-Chloroethyl chloroformateHCID 11983634HCID 11983634, compound

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 mmole) of 3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]-1-(diphenylmethyl)azetidine (Step 2 of Example 76) 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 methanol 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 dichloromethane, with 10% methanol in dichloromethane and finally with 80:20:2 dichloromethane-methanol-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 methanol
  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-5a228131994c4fb589a61eee5cec2d64
Source dataset
uspto-grants-2009_02
Patent number
US07485732B2

Reaction notes

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