Hydrochloric Acid → (E)-1-{3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acryloyl}-3-methyl-urea

HRID 2306464Notes

Reaction equation

HRID 2306464 reaction equation
[CH:1]1(/[CH:6]=[C: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]([F:23])[CH:12]=2)/[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:30][NH:31][C:32]([NH2:34])=[O:33].N1C=CC=CC=1.Cl>FC1C=CC=CC=1.CN(C)C=O.C(OCC)(=O)C>[CH:1]1(/[CH:6]=[C: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]([F:23])[CH:12]=2)/[C:8]([NH:34][C:32]([NH:31][CH3:30])=[O:33])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 1049PyridineHCID 11719MethylureaHCID 65578Oxalyl chlorideHCID 12019650(E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid

Product 1

HCID 10133857(E)-1-{3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acryloyl}-3-methyl-ureaYield 22%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 10008FluorobenzeneSolvent

Conditions

Temperature
25 °C

Procedure

A solution of (E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid (158 mg, 0.5 mmol) in fluorobenzene (1 mL) and N,N-dimethylformamide (2 μL) at 25° C. was treated dropwise with oxalyl chloride (54 μL, 0.6 mmol) over 2-3 min. The clear solution was stirred for 1 h at 25° C. and then treated with methyl urea (111 mg, 1.5 mmol). The resulting suspension was heated at 70° C. (bath temperature) for 10 min and then treated with pyridine (81 μL, 1 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 40M, Silica, 1/1 hexanes/ethyl acetate) afforded the (E)-1-{3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acryloyl}-3-methyl-urea (41 mg, 22%) as a white solid: mp 186-192° C.; EI-HRMS m/e calcd for C18H21FN6O2 (M+) 372.1710, found 372.1708.

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-6a09b53120a640f39e2796f4113f9876
Source dataset
uspto-grants-2002_08
Patent number
US06441180B1

Reaction notes

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