Imidazole → 1-{(R)-(4-chlorophenyl) [4-(imidazol-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine

HRID 25203Notes

Reaction equation

HRID 25203 reaction equation
[NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=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)=[CH:10][CH:9]=1.[I-].[Na+]>ClCCl>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([C@@H:14]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:13][CH:12]=2)[N:15]2[CH2:18][C:17](=[C:19]([C:24]3[CH:25]=[C:26]([F:31])[CH:27]=[C:28]([F:30])[CH:29]=3)[S:20]([CH3:23])(=[O:21])=[O:22])[CH2:16]2)=[CH:37][CH:36]=1

Participants

5

Reactant 3

HCID 795ImidazoleHCID 5238Sodium IodideHCID 685858541-{(R)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine

Product 1

HCID 101196581-{(R)-(4-chlorophenyl) [4-(imidazol-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineYield 15.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
20 °C

Procedure

0.055 g of imidazole is added to solution of 0.24 g of 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, in 5 cm3 of dichloromethane. After heating for 3 hours under reflux, the mixture is supplemented with 5 mg of sodium iodide. After stirring for 20 hours under reflux, the reaction mixture is cooled to 20° C. and then chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 1.0 cm, height 20 cm), eluting with 120 cm3 of dichloromethane without fractionating, and then with a dichloromethane and methanol mixture (98/2 and then 96/4 by volume), collecting 4 cm3 fractions. Fractions 12 to 14 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.039 g of 1-{(R*)-(4-chlorophenyl)[4-(imidazol-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam.

Workup

  1. temperatureAfter heating for 3 hours
  2. temperatureunder reflux
  3. temperatureunder reflux
  4. customchromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 1.0 cm, height 20 cm)
  5. washeluting with 120 cm3 of dichloromethane without fractionating
  6. customwith a dichloromethane and methanol mixture (98/2 and then 96/4 by volume), collecting 4 cm3 fractions
  7. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)

Sources & evidence

ORD record
ord-52a14a4e2ebd419cb6d54733a445574c
Source dataset
uspto-grants-2005_02
Patent number
US06858603B2

Reaction notes

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