Hydrochloric Acid → 1-{3-Cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionyl}-3-methyl-urea

HRID 2306396Notes

Reaction equation

HRID 2306396 reaction equation
[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:21]([CH3:22])=[N:20][N:19]=[N:18]3)=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:33][NH:34][C:35]([NH2:37])=[O:36].N1C=CC=CC=1.Cl>FC1C=CC=CC=1.CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:21]([CH3:22])=[N:20][N:19]=[N:18]3)=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=2)[C:8]([NH:37][C:35]([NH:34][CH3:33])=[O:36])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 1049PyridineHCID 11719MethylureaHCID 65578Oxalyl chlorideHCID 120196483-Cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionic acid

Product 1

HCID 102241761-{3-Cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionyl}-3-methyl-ureaYield 80%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 10008FluorobenzeneSolvent

Conditions

Temperature
25 °C

Procedure

A solution of 3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionic acid (368 mg, 1.0 mmol) in fluorobenzene (1.5 mL) and N,N-dimethylformamide (6 μL) at 25° C. was treated dropwise with oxalyl chloride (107.7 μL, 1.21 mmol) over 2-3 min. The clear solution was stirred for 1 h at 25° C. and then treated with methyl urea (322 mg, 2.0 mmol). The resulting suspension was heated at 70° C. (bath temperature) for 10 min and then treated with pyridine (162 μL, 2.0 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 (30 mL) and a 3N aqueous hydrochloric acid solution (30 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 40S, Silica, 1/1 to 1/2 hexanes/ethyl acetate) afforded 1-{3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionyl}-3-methyl-urea (338 mg, 80%) as an amorphous white solid: EI-HRMS m/e calcd for C19H23F3N6O2 (M+) 424.1834, found 424.1833.

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-781bb188257841be95a9d1ef749914cf
Source dataset
uspto-grants-2002_08
Patent number
US06441180B1

Reaction notes

Loading…