Triethylamine → N-[4-[[2-(Aminocarbonyl)-4-pyridinyl]oxy]-2,5-difluorophenyl]-N′-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide

HRID 2265710Notes

Reaction equation

HRID 2265710 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.S(Cl)(Cl)=O.[NH2:28][C:29]1[C:44]([F:45])=[CH:43][C:32]([O:33][C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH2:42])=[O:41])[CH:35]=2)=[C:31]([F:46])[CH:30]=1>O1CCCC1>[NH2:42][C:40]([C:36]1[CH:35]=[C:34]([O:33][C:32]2[C:31]([F:46])=[CH:30][C:29]([NH:28][C:14]([C:11]3([C:9]([NH:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[O:10])[CH2:12][CH2:13]3)=[O:16])=[C:44]([F:45])[CH:43]=2)[CH:39]=[CH:38][N:37]=1)=[O:41]

Participants

6

Reactant 4

HCID 8471Triethylamine2×HCID 24386Thionyl ChlorideHCID 210815301-[(4-Fluorophenyl)carbamoyl]cyclopropanecarboxylic AcidHCID 247886284-(4-Amino-2,5-difluorophenoxy)pyridine-2-carboxamide

Product 1

HCID 59597002N-[4-[[2-(Aminocarbonyl)-4-pyridinyl]oxy]-2,5-difluorophenyl]-N′-(4-fluorophenyl)-1,1-cyclopropanedicarboxamideYield 21%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

1-(4-Fluorophenylaminocarbonyl)cyclopropanecarboxylic acid (1.35 g) was dissolved in tetrahydrofuran (25.0 ml) under a nitrogen atmosphere, and triethylamine (1.06 ml) was added dropwise while cooling in an ice water bath, followed by stirring for 15 min. Then thionyl chloride (0.439 ml) was added at the same temperature, followed by stirring for 1.5 hr. To the reaction mixture was added dropwise at the same temperature a mixture of 4-(4-amino-2,5-difluorophenoxy)pyridine-2-carboxamide (1.0 g), tetrahydrofuran (12 ml) and triethylamine (1.06 ml), followed by stirring at 0° C. for 24 hr and 45 min. The reaction mixture was partitioned between ethyl acetate (70 ml) and a 2N aqueous solution of sodium hydroxide (15 ml). The organic layer was washed with a 2N aqueous solution of sodium hydroxide (15 ml) twice, 1N hydrochloric acid (15 ml) three times and a saturated aqueous solution of sodium hydrogencarbonate (10 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, 1:2, then ethyl acetate), and fractions containing the target compound were concentrated under reduced pressure. The residue was dried under reduced pressure to provide the titled compound as a white solid (372.8 mg, 21%).

Workup

  1. temperaturewhile cooling in an ice water bath
  2. stirringby stirring for 1.5 hr
  3. additionTo the reaction mixture was added dropwise at the same temperature
  4. stirringby stirring at 0° C. for 24 hr and 45 min
  5. customThe reaction mixture was partitioned between ethyl acetate (70 ml)
  6. washThe organic layer was washed with a 2N aqueous solution of sodium hydroxide (15 ml) twice
  7. dry with material1N hydrochloric acid (15 ml) three times and a saturated aqueous solution of sodium hydrogencarbonate (10 ml) in this order, and dried over anhydrous sodium sulfate
  8. customThe solvent was removed under reduced pressure
  9. customThe resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent
  10. additionheptane:ethyl acetate=1:1, 1:2, then ethyl acetate), and fractions containing the target compound
  11. concentrationwere concentrated under reduced pressure
  12. customThe residue was dried under reduced pressure

Sources & evidence

ORD record
ord-0949a4658d6b40929d127c00acf0cbd9
Source dataset
uspto-grants-2010_12
Patent number
US07855290B2

Reaction notes

Loading…