Sodium hydride → (+/-)-9-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4-a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester

HRID 1890413Notes

Reaction equation

HRID 1890413 reaction equation
Cl.[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[C:11]([NH2:25])=[N:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[H-].[Na+].[N:28]1[CH:33]=[CH:32][C:31]([C:34](=O)[CH2:35][C:36](OCC)=[O:37])=[N:30][CH:29]=1>O1CCCC1.C1(C)C=CC=CC=1>[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH:12]([N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])[C:11]2=[N:25][C:34]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][N:30]=3)=[CH:35][C:36](=[O:37])[N:10]2[CH2:9][CH2:8]1)=[O:6])[CH3:3]

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 11961458Ethyl 3-oxo-3-(pyrimidin-4-yl)propanoateHCID 68735238(+/-)-5-Amino-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2,3,6,7-tetrahydro-[1,4]diazepine-1-carboxylic acid ethyl ester hydrochloride

Product 1

HCID 86651032(+/-)-9-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4-a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl esterYield 45%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a suspension of 33.00 g (89.97 mmol) of (+/−)-5-amino-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2,3,6,7-tetrahydro-[1,4]diazepine-1-carboxylic acid ethyl ester hydrochloride (1:1) in 300 mL of tetrahydrofuran was added 6.47 g (161.94 mmol) of sodium hydride (60% in oil), the reaction mixture was stirred at room temperature for 1 h and 17.47 g (89.97 mmol) of ethyl 3-(pyrimidin-4-yl)-3-oxopropionate dissolved in 300 mL of toluene was added. The resulting solution was evaporated to remove tetrahydrofuran, heated under reflux and 5.00 mL of glacial acetic acid was added. The reaction mixture was stirred under reflux for 12 h. The cooled solution was evaporated to remove solvent. The mixture was dissolved in dichloromethane, washed with a saturated aqueous solution of ammonium chloride, saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was triturated with diethyl ether and filtered to afford 18.60 g (45%) of the product as a brown powder. The compound was used as such in the next step.

Workup

  1. additionwas added
  2. customThe resulting solution was evaporated
  3. customto remove tetrahydrofuran
  4. temperatureheated
  5. temperatureunder reflux
  6. addition5.00 mL of glacial acetic acid was added
  7. stirringThe reaction mixture was stirred
  8. temperatureunder reflux for 12 h
  9. customThe cooled solution was evaporated
  10. customto remove solvent
  11. dissolutionThe mixture was dissolved in dichloromethane
  12. washwashed with a saturated aqueous solution of ammonium chloride, saturated aqueous sodium chloride
  13. dry with materialdried over sodium sulfate
  14. customevaporated to dryness
  15. customThe residue was triturated with diethyl ether
  16. filtrationfiltered

Sources & evidence

ORD record
ord-ffee746e7f4447a1861746c0cd021dca
Source dataset
uspto-grants-2013_08
Patent number
US08507476B2

Reaction notes

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