Sodium hydride → HCID 117675493, compound

HRID 1526192Notes

Reaction equation

HRID 1526192 reaction equation
[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[N:18]=[C:19]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][CH:38]([N:41]4[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]4)[CH2:37][CH2:36]3)=[C:31]([CH3:48])[CH:30]=2)[C:20]([C:25]([NH2:27])=[O:26])=[N:21][C:22]=1[CH2:23][CH3:24]>CN(C)C=O>[C:25]([C:20]1[N:21]=[C:22]([CH2:23][CH3:24])[C:17]([O:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[N:18][C:19]=1[NH:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][CH:38]([N:41]3[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]3)[CH2:37][CH2:36]2)=[C:31]([CH3:48])[CH:30]=1)(=[O:26])[NH2:27]

Participants

5

Reactant 3

HCID 24758Sodium hydride3×HCID 6544479tert-Butyl (3R)-3-hydroxypyrrolidine-1-carboxylateHCID 88569548HCID 88569548, compound

Product 1

HCID 117675493HCID 117675493, compoundYield 21.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a mixture of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (860 mg) and N,N-dimethylformamide (30 mL) was added 55% oily sodium hydride (200 mg) under ice-cooling. After stirring for 30 minutes under ice-cooling, 5-chloro-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (1 g) was added thereto, followed by further stirring for 1 hour under ice-cooling. 55% oily sodium hydride (100 mg) was added thereto, followed by stirring at room temperature for 4 hours, and then 55% oily sodium hydride (100 mg) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1) to obtain tert-butyl (3R)-3-{[5-carbamoyl-3-ethyl-6-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]oxy}pyrrolidine-1-carboxylate (284 mg).

Workup

  1. temperaturecooling
  2. temperaturecooling
  3. stirringby further stirring for 1 hour under ice-
  4. temperaturecooling
  5. stirringby stirring at room temperature for 4 hours
  6. stirringby stirring at room temperature overnight
  7. extractionfollowed by extraction with ethyl acetate
  8. washThe organic phase was washed with saturated brine
  9. dry with materialdried over anhydrous magnesium sulfate
  10. customThe solvent was evaporated under reduced pressure
  11. customthe obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1)

Sources & evidence

ORD record
ord-067cd82a453843bf940f0b3d5bfc7a28
Source dataset
uspto-grants-2015_07
Patent number
US09085540B2

Reaction notes

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