Triethylamine → 1-[4-(2-Carbamoylpyridin-4-yl)oxy-2-fluorophenylaminocarbonyl]cyclopropanecarboxylic acid

HRID 2066254Notes

Reaction equation

HRID 2066254 reaction equation
[C:1]1([C:7]([OH:9])=O)([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:37]=[CH:36][C:25]([O:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=2)=[CH:24][C:23]=1[F:38]>O1CCCC1>[C:33]([C:29]1[CH:28]=[C:27]([O:26][C:25]2[CH:36]=[CH:37][C:22]([NH:21][C:7]([C:1]3([C:4]([OH:6])=[O:5])[CH2:2][CH2:3]3)=[O:9])=[C:23]([F:38])[CH:24]=2)[CH:32]=[CH:31][N:30]=1)(=[O:34])[NH2:35]

Participants

6

Reactant 4

HCID 8471Triethylamine2×HCID 24386Thionyl ChlorideHCID 690171,1-Cyclopropanedicarboxylic acidHCID 231534864-(4-Amino-3-fluorophenoxy)pyridine-2-carboxamide

Product 1

HCID 686917891-[4-(2-Carbamoylpyridin-4-yl)oxy-2-fluorophenylaminocarbonyl]cyclopropanecarboxylic acidYield 44%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 1,1-cyclopropanedicarboxylic acid (3.12 g) in tetrahydrofuran (90 ml) was added dropwise triethylamine (2.43 g) while cooling in an ice water bath under a nitrogen atmosphere, followed by stirring for 1.5 hr. To the reaction mixture, was then added thionyl chloride (1.75 ml), followed by stirring at the same temperature for 30 min. To the reaction mixture were added 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxamide (2.97 g) and triethylamine (2.43 g) in this order while cooling in an ice water bath under a nitrogen atmosphere, followed by stirring for 70 min. The reaction mixture was partitioned after addition of tert-butyl methyl ether (30 ml) and a 1N aqueous solution of sodium hydroxide (90 ml). The aqueous layer was partitioned with tert-butyl methyl ether (30 ml) again, and the separated aqueous layer was treated with 1N hydrochloric acid to precipitate a solid. The solid was collected by suction filtration and washed with water (10 ml, four times). Drying under reduced pressure at 50° C. provided 1-[4-(2-carbamoylpyridin-4-yl)oxy-2-fluorophenylaminocarbonyl]cyclopropanecarboxylic acid as a pale purple solid (1.90 g, 44%). After the filtrate was stood overnight, further precipitated solid was collected by suction filtration and washed with water (10 ml, twice). Drying under reduced pressure provided additional 1-[4-(2-carbamoylpyridin-4-yl)oxy-2-fluorophenylaminocarbonyl]cyclopropanecarboxylic acid as a pale purple solid (758 mg, 18%).

Workup

  1. temperaturewhile cooling in an ice water bath under a nitrogen atmosphere
  2. stirringby stirring at the same temperature for 30 min
  3. temperaturewhile cooling in an ice water bath under a nitrogen atmosphere
  4. stirringby stirring for 70 min
  5. customThe reaction mixture was partitioned
  6. additionafter addition of tert-butyl methyl ether (30 ml)
  7. customThe aqueous layer was partitioned with tert-butyl methyl ether (30 ml) again
  8. additionthe separated aqueous layer was treated with 1N hydrochloric acid
  9. customto precipitate a solid
  10. filtrationThe solid was collected by suction filtration
  11. washwashed with water (10 ml, four times)
  12. customDrying under reduced pressure at 50° C.

Sources & evidence

ORD record
ord-65f75b844ca645989f06dd25ef10b491
Source dataset
uspto-grants-2012_10
Patent number
US08288538B2

Reaction notes

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