Triphenylphosphine → methyl 3-fluoro-4-[(1E)-5-methoxy-4,4-dimethyl-5-oxopent-1-en-1-yl]benzoate

HRID 1785979Notes

Reaction equation

HRID 1785979 reaction equation
[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH2:5][C:6](Br)([F:10])[CH:7]=[CH:8][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[K+].[CH3:37][C:38]([CH3:46])([CH2:43][CH:44]=[CH2:45])[C:39]([O:41][CH3:42])=[O:40]>CN(C)C=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1/[CH:45]=[CH:44]/[CH2:43][C:38]([CH3:46])([CH3:37])[C:39]([O:41][CH3:42])=[O:40])[C:3]([O:2][CH3:1])=[O:12]

Participants

8

Reactant 4

HCID 11776TriphenylphosphineHCID 517044Potassium AcetateHCID 11768679Methyl 2,2-dimethylpent-4-enoateHCID 86601700Methyl-3-bromo-3-fluorobenzoate

Product 1

HCID 68918765methyl 3-fluoro-4-[(1E)-5-methoxy-4,4-dimethyl-5-oxopent-1-en-1-yl]benzoate

Reagents, catalysts & solvents 3

HCID 70681Tetrabutylammonium ChlorideCatalystHCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
130 °C

Procedure

Methyl 5-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydro1quinolin-1(2H)-yl]carbonyl}-2-fluorophenyl)-2,2-dimethylpentanoate was prepared following general procedure B, substituting methyl 5-[4-(chlorocarbonyl)-2-fluorophenyl]-2,2-dimethylpentanoate for 6-trifluoromethyl nicotinyl chloride. (Methyl 5-[4-(chlorocarbonyl)-2-fluorophenyl]-2,2-dimethylpentanoate was prepared in five steps from 4-bromo-3-fluorobenzoic acid. To a solution of 3-bromo-3-fluorobenzoic acid in toluene/methanol was added dropwise a 2M solution of trimethylsilyl diazomethane until slight yellow coloration persists indicating reaction had gone to completion. Reaction mixture was concentrated to give methyl-3-bromo-3-fluorobenzoate. To a solution of methyl-3-bromo-3-fluorobenzoate in dimethylformamide was added sequentially palladium acetate, triphenylphosphine, tetrabutylammonium chloride, potassium acetate and methyl 2,2-dimethylpent-4-enoate. Reaction mixture was heated under microwave irradiation at 130° C. for 10 m. to give methyl 3-fluoro-4-[(1E)-5-methoxy-4,4-dimethyl-5-oxopent-1-en-1-yl]benzoate. Hydrogenation of this diester gave methyl 3-fluoro-4-(5-methoxy-4,4-dimethyl-5-oxopentyl)benzoate which benzoic ester was selectively hydrolyzed using lithium hydroxide to give 3-fluoro-4-(5-methoxy-4,4-dimethyl-5-oxopentyl)benzoic acid. Subsequent treatment of this carboxylic acid with oxalyl chloride and catalytic DMF afforded methyl 5-[4-(chlorocarbonyl)-2-fluorophenyl]-2,2-dimethylpentanoate in decent yield). The rest of the procedures were followed as indicated in general procedure H to afford methyl 5-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-fluorophenyl)-2,2-dimethylpentanoate.

Workup

  1. customReaction mixture

Sources & evidence

ORD record
ord-3ec990318aa842b0a8aa7d128b64c51a
Source dataset
uspto-grants-2009_03
Patent number
US07504508B2

Reaction notes

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