Formamide → GSK-461364

HRID 883578Notes

Reaction equation

HRID 883578 reaction equation
[CH:1]([NH2:3])=[O:2].C[O-].[Na+].CO.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[CH:23][N:22]([C:25]4[S:29][C:28](C(OC)=O)=[C:27]([O:34][C@@H:35]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]([F:46])([F:45])[F:44])[CH3:36])[CH:26]=4)[C:21]=3[CH:47]=2)[CH2:12][CH2:11]1>C1COCC1.C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[CH:23][N:22]([C:25]4[S:29][C:28]([C:1]([NH2:3])=[O:2])=[C:27]([O:34][C@@H:35]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]([F:45])([F:44])[F:46])[CH3:36])[CH:26]=4)[C:21]=3[CH:47]=2)[CH2:12][CH2:11]1

Participants

9

Reactant 4

HCID 713FormamideHCID 887MethanolHCID 10942334Sodium MethoxideHCID 44185549HCID 44185549, compound

Product 1

HCID 15983966GSK-461364

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
20 °C

Procedure

Formamide (1.08 mL, 26.5 mmol) followed by 25% w/w sodium methoxide in MeOH (1.82 mL, 7.6 mmol) are added to a solution of methyl 5-{6-[(4-methyl-1-piperazinyl)methyl]-1H-benzimidazol-1-yl}-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate (5.0 g, 8.95 mmol) in THF (50 mL) and toluene (10 mL) at room temperature. The reaction mixture is heated at ca 65° C. for about 18 h and then cooled to ca 30° C. The reaction mixture is diluted with EtOAc (25 mL) and H2O (25 mL) and then the biphasic mixture is separated. The organic phase is washed sequentially with H2O (25 ml), saturated aqueous Na2CO3 and finally H2O (2×25 mL). The organic phase is then concentrated by rotary evaporation and the concentrate diluted with EtOAc (30 mL) and then heated at ca 70° C. for about 1 h. The resulting suspension is then cooled to about 20° C. and stirred at this temperature for ca 18 h. The suspension is then stirred at 0-5° C. for 2 h and the product, isolated by filtration, washed with EtOAc (5 mL) and dried under vacuum at ca 25° C. to constant weight (2.93 g, 60.2%).

Workup

  1. temperatureThe reaction mixture is heated at ca 65° C. for about 18 h
  2. temperaturecooled to ca 30° C
  3. customthe biphasic mixture is separated
  4. washThe organic phase is washed sequentially with H2O (25 ml), saturated aqueous Na2CO3 and finally H2O (2×25 mL)
  5. concentrationThe organic phase is then concentrated by rotary evaporation
  6. additionthe concentrate diluted with EtOAc (30 mL)
  7. temperatureheated at ca 70° C. for about 1 h
  8. stirringThe suspension is then stirred at 0-5° C. for 2 h
  9. customthe product, isolated by filtration
  10. washwashed with EtOAc (5 mL)
  11. customdried under vacuum at ca 25° C. to constant weight (2.93 g, 60.2%)

Sources & evidence

ORD record
ord-940ceab7e9be4bd6a4b693b57dced28c
Source dataset
uspto-grants-2012_08
Patent number
US08236954B2

Reaction notes

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