Sodium Iodide → 3-[(3,5-Difluorophenyl)(methylsulfonyl)-methylene]azetidine

HRID 1058802Notes

Reaction equation

HRID 1058802 reaction equation
N1CCCC1.ClCC1C=CC([C@H](C2C=CC(Cl)=CC=2)[N:15]2[CH2:18][C:17](=[C:19]([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=3)[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:16]2)=CC=1.[I-].[Na+]>ClCCl>[F:31][C:26]1[CH:25]=[C:24]([C:19](=[C:17]2[CH2:18][NH:15][CH2:16]2)[S:20]([CH3:23])(=[O:22])=[O:21])[CH:29]=[C:28]([F:30])[CH:27]=1

Participants

5

Reactant 3

HCID 5238Sodium IodideHCID 31268Pyrrolidine3×HCID 685858541-{(R)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine

Product 1

HCID 865837463-[(3,5-Difluorophenyl)(methylsulfonyl)-methylene]azetidine

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
20 °C

Procedure

50 mm3 of pyrrolidine are added to a solution of 0.32 g of 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, and 5 mg of sodium iodide in 10 cm3 of dichloromethane. After stirring for 20 hours at 20° C., 50 mm3 of pyrrolidine are added to the mixture, stirred for 8 hours and then 50 mm3 of pyrrolidine are again added and the mixture is stirred for 20 hours at 20° C. The reaction mixture is washed with water and then the organic phase is dried over magnesium sulfate and concentrated to dryness under vacuum (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 1.2 cm, height 30 cm), at an argon pressure of 0.1 bar, eluting with dichloromethane and then with a dichloromethane and methanol mixture (97.5/2.5 by volume) and collecting 3 cm3 fractions. Fractions 12 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.18 g of 1-{(R*)-(4-chlorophenyl)[4-pyrrolidinylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [a]20365 nm=−22.5 +/−0.7 (c=0.5%; dichloromethane) [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 1.78 (mt, 4H), 2.51 (mt, 4H), 2.81 (s, 3H), 3.58 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

Workup

  1. stirringstirred for 8 hours
  2. stirringthe mixture is stirred for 20 hours at 20° C
  3. washThe reaction mixture is washed with water
  4. dry with materialthe organic phase is dried over magnesium sulfate
  5. concentrationconcentrated to dryness under vacuum (2.7 kPa)
  6. customThe residue obtained
  7. customis chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 1.2 cm, height 30 cm), at an argon pressure of 0.1 bar
  8. washeluting with dichloromethane
  9. customwith a dichloromethane and methanol mixture (97.5/2.5 by volume) and collecting 3 cm3 fractions
  10. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)

Sources & evidence

ORD record
ord-cdbad698da4d4e9089f054fd542305e0
Source dataset
uspto-grants-2003_02
Patent number
US06518264B2

Reaction notes

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