Trifluoroacetic acid → N-[(4'R)-2''-amino-2',2'-dimethyldispiro[cyclopropane-1,3'-chromene-4',4''-[1,3]oxazol]-6'-yl]-5-me thoxypyrazine-2-carboxamide

HRID 594918Notes

Reaction equation

HRID 594918 reaction equation
C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][C@@:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([C:25]4[CH:30]=[N:29][C:28]([O:31][CH3:32])=[CH:27][N:26]=4)=[O:24])[CH:20]=3)[O:15][C:14]([CH3:34])([CH3:33])[C:13]32[CH2:36][CH2:35]3)[N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:7][C:8]1[O:9][CH2:10][C@@:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([C:25]4[CH:30]=[N:29][C:28]([O:31][CH3:32])=[CH:27][N:26]=4)=[O:24])[CH:20]=3)[O:15][C:14]([CH3:33])([CH3:34])[C:13]32[CH2:35][CH2:36]3)[N:12]=1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 86724285tert-butyl [(4'R)-6'-{[(5-methoxypyrazin-2-yl)carbonyl]amino}-2',2'-dimethyldispiro[cyclopropane-1,3'-chromene-4',4''-[1,3]oxazol]-2''-yl]carbamate

Product 1

HCID 86724317N-[(4'R)-2''-amino-2',2'-dimethyldispiro[cyclopropane-1,3'-chromene-4',4''-[1,3]oxazol]-6'-yl]-5-me thoxypyrazine-2-carboxamideYield 75.9%

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Procedure

To a solution of tert-butyl[(4′R)-6′-{[(5-methoxypyrazin-2-yl)carbonyl]amino}-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (13.75 g, 26.98 mmol) in chloroform (140 ml) was added trifluoroacetic acid (68 ml) in an ice-water bath, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (pre-column: NH-silica gel; main column: neutral silica gel, chloroform/methanol=100:0-10:1). To the purified product was added saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (pre-column: basic silica gel; main column: neutral silica gel, chloroform/methanol=100:0-10:1). The purified product was triturated with a mixture of hexane/ethyl acetate (4:1) (300 mL), and the mixture was stirred at 60° C. for 1 hour and room temperature for 4 days. The precipitate was collected, washed with mixture of hexane/ethyl acetate (4:1) (200 mL), and dried in vacuo at 50° C. to afford N-[(4′R)-2″-amino-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-6′-yl]-5-me thoxypyrazine-2-carboxamide (8.38 g) as a crystal.

Workup

  1. concentrationThe mixture was concentrated in vacuo
  2. customthe residue was purified by silica gel column chromatography (pre-column: NH-silica gel; main column: neutral silica gel, chloroform/methanol=100:0-10:1)
  3. additionTo the purified product was added saturated aqueous sodium hydrogen carbonate
  4. extractionextracted with chloroform
  5. washThe organic layer were washed with brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. customthe filtrate was evaporated in vacuo
  9. customThe residue was purified by silica gel column chromatography (pre-column: basic silica gel; main column: neutral silica gel, chloroform/methanol=100:0-10:1)
  10. customThe purified product was triturated with a mixture of hexane/ethyl acetate (4:1) (300 mL)
  11. stirringthe mixture was stirred at 60° C. for 1 hour and room temperature for 4 days
  12. customThe precipitate was collected
  13. washwashed with mixture of hexane/ethyl acetate (4:1) (200 mL)
  14. customdried in vacuo at 50° C.

Sources & evidence

ORD record
ord-4b79fb4f13aa4271bf0050960a6ee8ea
Source dataset
uspto-grants-2016_01
Patent number
US09242973B2

Reaction notes

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