Hydrochloric Acid → (E)-1-[3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acryloyl]-3-methyl-urea

HRID 276240Notes

Reaction equation

HRID 276240 reaction equation
[CH:1]1(/[CH:7]=[C:8](\[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)/[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:32][NH:33][C:34]([NH2:36])=[O:35].N1C=CC=CC=1.Cl>FC1C=CC=CC=1.CN(C)C=O.C(OCC)(=O)C>[CH:1]1(/[CH:7]=[C:8](\[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[C:14]([C:22]([F:24])([F:25])[F:23])[CH:13]=2)/[C:9]([NH:36][C:34]([NH:33][CH3:32])=[O:35])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 1049PyridineHCID 11719MethylureaHCID 65578Oxalyl chlorideHCID 67483083(E)-3-cyclohexyl-2-(4-(methanesulfonyl)-3-(trifluoromethyl)-phenyl)-acrylic acid

Product 1

HCID 10296457(E)-1-[3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acryloyl]-3-methyl-ureaYield 32.1%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 10008FluorobenzeneSolvent

Conditions

Temperature
25 °C

Procedure

A solution of (E)-3-cyclohexyl-2-(4-(methanesulfonyl)-3-(trifluoromethyl)-phenyl)-acrylic acid (282 mg, 0.75 mmol) in fluorobenzene (1 mL) and N,N-dimethylformamide (3 μL) at 25° C. was treated dropwise with oxalyl chloride (81 μL, 0.9 mmol) over 2-3 min. The clear solution was stirred at 25° C. for 1 h and then treated with methyl urea (167 mg, 2.25 mmol). The resulting suspension was heated at 70° C. (bath temperature) for 10 min and then treated with pyridine (121 μL, 1.5 mmol). The reaction mixture was then stirred at 70° C. for 20 h. The reaction mixture was then cooled to 25° C. and diluted with ethyl acetate (50 mL) and a 3N aqueous hydrochloric acid solution (40 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×20 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate) afforded the (E)-1-[3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acryloyl]-3-methyl-urea (104 mg, 32%) as a white solid: mp 199-202° C. EI-HRMS m/e calcd for C19H23F3N2O4S (M+) 432.1331, found 432.1332.

Workup

  1. temperatureThe resulting suspension was heated at 70° C. (bath temperature) for 10 min
  2. stirringThe reaction mixture was then stirred at 70° C. for 20 h
  3. temperatureThe reaction mixture was then cooled to 25° C.
  4. customThe two layers were separated
  5. extractionthe aqueous layer was extracted with ethyl acetate (1×20 mL)
  6. washThe combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL)
  7. dry with materiala saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-e6554cdd1db540db84c10c9044781de8
Source dataset
uspto-grants-2002_03
Patent number
US06353111B1

Reaction notes

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