4-Methylmorpholine → Benzyl 1-{[(4-{[2-(aminocarbonyl)pyridin-4-yl]oxy}-2,5-difluorophenyl)amino]carbonyl}cyclopropanecarboxylate

HRID 388518Notes

Reaction equation

HRID 388518 reaction equation
[CH2:1]([O:8][C:9]([C:11]1([C:14]([OH:16])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.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]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=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 79724-Methylmorpholine2×HCID 24386Thionyl ChlorideHCID 247886284-(4-Amino-2,5-difluorophenoxy)pyridine-2-carboxamideHCID 574708601-(Benzyloxycarbonyl)cyclopropanecarboxylic acid

Product 1

HCID 24788627Benzyl 1-{[(4-{[2-(aminocarbonyl)pyridin-4-yl]oxy}-2,5-difluorophenyl)amino]carbonyl}cyclopropanecarboxylateYield 93.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

1-[(Benzyloxy)carbonyl]cyclopropanecarboxylic acid (1.04 g) was dissolved in tetrahydrofuran (15 ml) under a nitrogen atmosphere. N-Methylmorpholine (0.520 ml) was added at 0° C., and the mixture was stirred for 15 minutes. Thionyl chloride (0.345 ml) was added to the mixture at 0° C., and the mixture was stirred at the same temperature for 30 minutes; 4-(4-Amino-2,5-difluorophenoxy)pyridine-2-carboxamide (500 mg) and N-methylmorpholine (0.520 ml) were added, and the mixture was stirred at room temperature for 2 hours and 50 minutes. The reaction mixture was partitioned after the addition of a 1N aqueous solution of sodium hydroxide (15 ml) and ethyl acetate (20 ml). The organic layer was washed with a 1N aqueous solution of sodium hydroxide (15 ml), water (15 ml) and brine (15 ml), and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, to 1:2). The fractions containing the target compound was concentrated under reduced pressure to give the title compound (822.7 mg, 93%) as white powder.

Workup

  1. stirringthe mixture was stirred at the same temperature for 30 minutes
  2. stirringthe mixture was stirred at room temperature for 2 hours and 50 minutes
  3. customThe reaction mixture was partitioned
  4. additionafter the addition of a 1N aqueous solution of sodium hydroxide (15 ml) and ethyl acetate (20 ml)
  5. washThe organic layer was washed with a 1N aqueous solution of sodium hydroxide (15 ml), water (15 ml) and brine (15 ml)
  6. dry with materialdried over anhydrous magnesium sulfate
  7. customThe desiccant was removed by filtration
  8. concentrationthe filtrate was concentrated under reduced pressure
  9. customThe resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, to 1:2)
  10. additionThe fractions containing the target compound
  11. concentrationwas concentrated under reduced pressure

Sources & evidence

ORD record
ord-1e83b602999640699d501e435eca2b5f
Source dataset
uspto-grants-2013_02
Patent number
US08377938B2

Reaction notes

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