4-Chlorophenol → (E)-5-[2-(4-chlorophenoxy)styryl]-8-fluoro-2,3-dihydro-1-methyl-1H-1,4-benzodiazepine dihydrochloride

HRID 48332Notes

Reaction equation

HRID 48332 reaction equation
F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])O.[Na+].C(OP([CH:31]=[C:32]1[NH:38][CH2:37][CH2:36][N:35]([CH3:39])[C:34]2[CH:40]=[C:41]([F:44])[CH:42]=[CH:43][C:33]1=2)(=O)OCC)C.[H-].[Na+]>CN(C)C=O>[ClH:10].[ClH:10].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[CH:31][C:32]2=[N:38][CH2:37][CH2:36][N:35]([CH3:39])[C:34]3[CH:40]=[C:41]([F:44])[CH:42]=[CH:43][C:33]2=3)=[CH:13][CH:12]=1

Participants

7

Reactant 5

HCID 46844-ChlorophenolHCID 24758Sodium hydrideHCID 67970o-FluorobenzaldehydeHCID 516892Sodium BicarbonateHCID 86585813(8-Fluoro-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester

Product 1

HCID 69893490(E)-5-[2-(4-chlorophenoxy)styryl]-8-fluoro-2,3-dihydro-1-methyl-1H-1,4-benzodiazepine dihydrochlorideYield 9.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
95 °C

Procedure

To a mixture of 56 mg (0.45 mmol) of 2-fluorobenzaldehyde and 64 mg (50 mmol) of 4-chlorophenol in 2.5 ml of dimethylformamide was added 75 mg (0.54 mmol) of sodium hydrogen carbonate. The mixture was heated at 95° C. for 18 hours. To the mixture at ambient temperature was added 118 mg (0.36 mmol) of (8-fluoro-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester followed by 25 mg (0.63 mmol) of sodium hydride (60% dispersion in mineral oil). The mixture was stirred for 2 hours. The mixture was partitioned between 12 ml of water and 3×4 ml of dichloromethane. The combined organic portions were dried (magnesium sulphate), filtered and evaporated. The product was purified by column chromatography (20 g IST pre-packed column) eluting with ethyl acetate and treated with 0.15 ml of 4M hydrogen chloride in dioxan. The solvent was evaporated to leave a red gum which was recrystallised from acetone/ethyl acetate/diethyl ether to give 17 mg of (E)-5-[2-(4-chlorophenoxy)styryl]-8-fluoro-2,3-dihydro-1-methyl-1H-1,4-benzodiazepine dihydrochloride as a red solid; MS: m/e 452 (M+).

Workup

  1. customThe mixture was partitioned between 12 ml of water and 3×4 ml of dichloromethane
  2. dry with materialThe combined organic portions were dried (magnesium sulphate)
  3. filtrationfiltered
  4. customevaporated
  5. customThe product was purified by column chromatography (20 g IST pre-packed column)
  6. washeluting with ethyl acetate
  7. additiontreated with 0.15 ml of 4M hydrogen chloride in dioxan
  8. customThe solvent was evaporated
  9. customto leave a red gum which
  10. customwas recrystallised from acetone/ethyl acetate/diethyl ether

Sources & evidence

ORD record
ord-38230e1caae94cd4895788b5ea884686
Source dataset
uspto-grants-2004_03
Patent number
US06703387B2

Reaction notes

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