Water → 2-chloro-3-(1-cyanocyclopropyl)-N-[2-fluoro-5-({2-[(2-methylpropanoyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)phenyl]benzamide

HRID 1800572Notes

Reaction equation

HRID 1800572 reaction equation
[NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([F:33])=[C:16]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:28][CH2:27]4)[C:21]=3[Cl:31])[CH:17]=1)[N:5]=2.[CH3:34][CH:35]([CH3:39])[C:36](Cl)=[O:37].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:31][C:21]1[C:22]([C:26]2([C:29]#[N:30])[CH2:28][CH2:27]2)=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:16]1[CH:17]=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:36](=[O:37])[CH:35]([CH3:39])[CH3:34])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=[CH:14][C:15]=1[F:33])=[O:32]

Participants

6

Reactant 3

HCID 962WaterHCID 62325Isobutyryl chlorideHCID 57387326HCID 57387326, compound

Product 1

HCID 595069592-chloro-3-(1-cyanocyclopropyl)-N-[2-fluoro-5-({2-[(2-methylpropanoyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)phenyl]benzamideYield 63%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 1049PyridineSolvent

Procedure

To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-fluorophenyl}-2-chloro-3-(1-cyanocyclopropyl)benzamide (0.16 g, 0.33 mmol) produced in Example C71(iv) and N,N-dimethylpyridine-4-amine (0.12 g, 1.00 mmol) in pyridine (2 mL) was added dropwise 2-methylpropanoyl chloride (0.12 g, 1.00 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (5 mL), 8N aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (114 mg, 63%) as white crystals.

Workup

  1. temperaturecooling
  2. extractionthe mixture was extracted with ethyl acetate (50 mL×2)
  3. dry with materialdried over anhydrous magnesium sulfate
  4. filtrationThe insoluble material was filtered off
  5. concentrationthe filtrate was concentrated under reduced pressure
  6. dissolutionThe obtained residue was dissolved in methanol (5 mL)
  7. addition8N aqueous sodium hydroxide solution (1 mL) was added
  8. stirringthe mixture was stirred at room temperature for 1 hr
  9. additionThe reaction mixture was poured into water (50 mL)
  10. extractionthe mixture was extracted with ethyl acetate (50 mL×2)
  11. dry with materialdried over anhydrous sodium sulfate
  12. filtrationThe insoluble material was filtered off
  13. concentrationthe filtrate was concentrated under reduced pressure
  14. customThe obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0)
  15. customrecrystallized from methanol

Sources & evidence

ORD record
ord-a50f04e71878401eb216ada1caf912fe
Source dataset
uspto-grants-2013_01
Patent number
US08344135B2

Reaction notes

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