Dimethylcarbamoyl Chloride → 2,3-Dihydro-4-fluoro-2-(4-pyridinylamino)-1H-isoindol-5-yl dimethylcarbamate hydrochloride

HRID 612486

Reaction equation

HRID 612486 reaction equation
Br.[F:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([NH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH2:7]2.C(N(CC)CC)C.[CH3:27][N:28]([CH3:32])[C:29]([Cl:31])=[O:30].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[ClH:31].[CH3:27][N:28]([CH3:32])[C:29](=[O:30])[O:12][C:11]1[C:3]([F:2])=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([NH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH2:5]2

Participants

6

Reactant 4

HCID 6598Dimethylcarbamoyl ChlorideHCID 8471TriethylamineHCID 516892Sodium BicarbonateHCID 195952012,3-dihydro-4-fluoro-2-(4-pyridinylamino)-1H-isoindol-5-ol hydrobromide

Product 1

HCID 195952022,3-Dihydro-4-fluoro-2-(4-pyridinylamino)-1H-isoindol-5-yl dimethylcarbamate hydrochlorideYield 69.3%

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent2×

Procedure

To a mixture of 2,3-dihydro-4-fluoro-2-(4-pyridinylamino)-1H-isoindol-5-ol hydrobromide (600 mg), triethylamine (614 mg), and chloroform (10 ml), dimethylcarbamyl chloride (237 mg) in chloroform (5 ml) was added dropwise, with stirring at ambient temperature, under nitrogen. The reaction mixture was stirred under reflux for 5 hrs, at ambient temperature overnight and poured into dilute sodium bicarbonate solution (100 ml). The layers were separated. The aqueous phase was extracted with chloroform, and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated in vacuo. The residue was flash chromatographed (silica), eluting with 7% methanol-dichloromethane followed by 185:14:1 dichloromethane-methanol-ammonium hydroxide. The appropriate fractions were collected and evaporated. The residue was dissolved in absolute ethanol and excess ethereal hydrogen chloride was added. Ether was added and the solution was cooled. The precipitate was collected to give 450 mg (69%) of product, mp 250-252° C. (dec).

Workup

  1. additionwas added dropwise
  2. stirringThe reaction mixture was stirred
  3. temperatureunder reflux for 5 hrs, at ambient temperature overnight
  4. customThe layers were separated
  5. extractionThe aqueous phase was extracted with chloroform
  6. dry with materialthe combined organic layers were dried over anhydrous magnesium sulfate
  7. filtrationfiltered
  8. customthe filtrate was evaporated in vacuo
  9. customchromatographed (silica)
  10. washeluting with 7% methanol-dichloromethane
  11. customThe appropriate fractions were collected
  12. customevaporated
  13. dissolutionThe residue was dissolved in absolute ethanol
  14. additionexcess ethereal hydrogen chloride was added
  15. additionEther was added
  16. temperaturethe solution was cooled
  17. customThe precipitate was collected

Sources & evidence

ORD record
ord-84bb95d4e2c54ec2a49bf346cd8dcd44
Source dataset
uspto-grants-1999_12
Patent number
US06004977

Linked notes

Loading…