Methanol → HCID 59419922, compound

HRID 587972Notes

Reaction equation

HRID 587972 reaction equation
[C:1]([C:3]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)([CH:20]([CH3:22])[CH3:21])[CH2:4][CH2:5][CH2:6][N:7]([CH3:19])[CH2:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])#[N:2].[C:33](N1C=CN=C1)(N1C=CN=C1)=O.CO>C1COCC1>[C:1]([C:3]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)([CH:20]([CH3:22])[CH3:21])[CH2:4][CH2:5][CH2:6][N:7]([CH3:19])[CH2:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH3:33])=[O:13])#[N:2]

Participants

5

Reactant 3

HCID 887MethanolHCID 682631,1'-CarbonyldiimidazoleHCID 68476360HCID 68476360, compound

Product 1

HCID 59419922HCID 59419922, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
22 °C

Procedure

To 331 mg (0.839 mmol) of 2-(3,4-dimethoxyphenyl)-2-isopropyl-5-(methyl(phenethyl)amino)pentanenitrile in 8.3 mL of benzene was added 226 mg (1.01 mmol) of palladium(II)acetate and the mixture was stirred for 72 h at 22° C. under nitrogen. The solution was transferred into a pressure flask, 10 mL of methanol was added and the mixture was treated with carbon monoxide at 40 psi for 24 h. After addition of 175 μL (1.26 mmol) of triethylamine, the mixture was filtered through a pad of celite and evaporated to give a crude mixture of 3au and 2-(3,4-dimethoxyphenyl)-2-isopropyl-5-(methyl(phenethyl)amino)pentanenitrile. In order to afford purification, a solution of 57 mg of the crude product was dissolved in 1 mL of methanol and treated with 63 μL of 10 N NaOH. After stirring for 1 h at 22° C., an additional 1264 of 10 N NaOH and 2 mL of methanol was added. The solution was heated to 50° C. then cooled to 22° C., evaporated and partitioned between ether and 0.5 N NaOH. The aqueous layer was acidified to about pH 6 with 12 N HCl then extracted with ethyl acetate (3×). The combined organic layers were dried (Na2SO4) and evaporated to give 2-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoic acid. The carboxylic acid was esterified by treating with 44 mg (0.24 mmol) of carbonyldiimidazole in 1 mL of THF for 3 h at 22° C. followed by addition of 8 mL of methanol and continued stirring for about 16 hours at 22° C. The solvent was evaporated and the residue was purified by flash chromatography on silica gel, eluting first with dichloromethane and then gradually increasing to 3% methanol/dichloromethane to give 3au. MS found M+H=453. Substitution of the ester group in the indicated ortho-position of the phenyl ring was confirmed by 1H NMR analysis.

Workup

  1. customThe solvent was evaporated
  2. customthe residue was purified by flash chromatography on silica gel
  3. washeluting first with dichloromethane
  4. temperaturegradually increasing to 3% methanol/dichloromethane
  5. customto give 3au

Sources & evidence

ORD record
ord-0bb73fe6c95b4f429bf9682956e5f14f
Source dataset
uspto-grants-2016_01
Patent number
US09227918B2

Reaction notes

Loading…