4-Methylmorpholine → HCID 68690514, compound

HRID 2265711Notes

Reaction equation

HRID 2265711 reaction equation
[C:1]1([C:7]([OH:9])=O)([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.CN1CCOCC1.S(Cl)(Cl)=O.[NH2:21][C:22]1[C:37]([F:38])=[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)=[C:24]([F:39])[CH:23]=1>O1CCCC1>[C:33]([C:29]1[CH:28]=[C:27]([O:26][C:25]2[C:24]([F:39])=[CH:23][C:22]([NH:21][C:7]([C:1]3([C:4]([OH:6])=[O:5])[CH2:2][CH2:3]3)=[O:9])=[C:37]([F:38])[CH:36]=2)[CH:32]=[CH:31][N:30]=1)(=[O:34])[NH2:35]

Participants

6

Reactant 4

HCID 79724-Methylmorpholine2×HCID 24386Thionyl ChlorideHCID 690171,1-Cyclopropanedicarboxylic acidHCID 247886284-(4-Amino-2,5-difluorophenoxy)pyridine-2-carboxamide

Product 1

HCID 68690514HCID 68690514, compoundYield 95%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 1,1-cyclopropanedicarboxylic acid (492 mg) in tetrahydrofuran (15 ml) was added dropwise 4-methylmorpholine (0.416 ml) while cooling in an ice water bath under a nitrogen atmosphere, followed by stirring for 15 min. To the reaction mixture, was then added thionyl chloride (0.276 ml), followed by stirring at the same temperature for 30 min. To the reaction mixture were added 4-(4-amino-2,5-difluorophenoxy)pyridine-2-carboxamide (500 mg) and 4-methylmorpholine (0.416 ml) in this order while cooling in an ice water bath under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned after addition of a 1N aqueous solution of sodium hydroxide (15 ml) and tert-butyl methyl ether (30 ml). The separated aqueous layer was treated with 1N hydrochloric acid (15 ml) to precipitate a solid. The solid was collected by suction filtration and washed with water (10 ml, three times). Hot air drying at 60° C. provided 1-[4-(2-carbamoylpyridin-4-yl)oxy-2,5-difluorophenylaminocarbonyl]cyclopropanecarboxylic acid as a pale purple solid (674 mg, 95%).

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. stirringstirred overnight
  5. customThe reaction mixture was partitioned
  6. additionafter addition of a 1N aqueous solution of sodium hydroxide (15 ml) and tert-butyl methyl ether (30 ml)
  7. additionThe separated aqueous layer was treated with 1N hydrochloric acid (15 ml)
  8. customto precipitate a solid
  9. filtrationThe solid was collected by suction filtration
  10. washwashed with water (10 ml, three times)
  11. customHot air drying at 60° C.

Sources & evidence

ORD record
ord-99d997ab630147f2b0007fa2db96913c
Source dataset
uspto-grants-2010_12
Patent number
US07855290B2

Reaction notes

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