Trimethyl orthoformate → HCID 86646360, compound

HRID 883577Notes

Reaction equation

HRID 883577 reaction equation
[ClH:1].Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:40]([O-])=O)=[C:15]([NH:17][C:18]3[S:22][C:21]([C:23]([O:25][CH3:26])=[O:24])=[C:20]([O:27][C@@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH3:29])[CH:19]=3)[CH:16]=2)[CH2:6][CH2:5]1.[CH3:43]OC(OC)OC.C([O-])=O.[NH4+]>CO.[Pd]>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]3[N:40]=[CH:43][N:17]([C:18]4[S:22][C:21]([C:23]([O:25][CH3:26])=[O:24])=[C:20]([O:27][C@@H:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[C:36]([F:39])([F:38])[F:37])[CH3:29])[CH:19]=4)[C:15]=3[CH:16]=2)[CH2:6][CH2:5]1

Participants

7

Reactant 3

HCID 9005Trimethyl orthoformateHCID 2723923Ammonium formateHCID 68518393HCID 68518393, compound

Product 2

HCID 313Hydrochloric AcidHCID 86646360HCID 86646360, compoundYield 83%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Conditions

Temperature
35 °C

Procedure

Methyl 5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate dihydrochloride (50.0 g, 76.8 mmol) was suspended in MeOH (100 mL) and trimethylorthoformate (200 mL) and stirred for half an hour. Ammonium formate (30.0 g) and 10% Pd/C (25 g, 15.4 mol %) were added and the mixture was heated to 35° C. The temperature was increased to 60° C. over 6 hours and then held at 60° C. overnight before filtering through fibreglass paper, washing with EtOAc (300 mL). The filtrate was washed with aqueous sodium hydroxide (2 M, 250 mL) and then brine (2×150 mL). A solution of HCl (4 M) was prepared by dropwise addition of acetyl chloride (16.4 mL) to MeOH (41.3 mL), cooled with an ice-bath. This solution was warmed to room temperature and then added dropwise over half an hour to the reaction mixture at 45° C. The mixture was stirred for a further half an hour at 45° C., cooled to room temperature over 1 hour and then cooled in an ice-bath for a further hour, filtered, washing with EtOAc (150 mL) and then dried under reduced pressure to give the title compound (42.7 g, 83% th) as off-white crystalline solid.

Workup

  1. temperatureThe temperature was increased to 60° C. over 6 hours
  2. filtrationbefore filtering through fibreglass paper
  3. washwashing with EtOAc (300 mL)
  4. washThe filtrate was washed with aqueous sodium hydroxide (2 M, 250 mL)
  5. temperaturecooled with an ice-bath
  6. temperatureThis solution was warmed to room temperature
  7. additionadded dropwise over half an hour to the reaction mixture at 45° C
  8. temperaturecooled to room temperature over 1 hour
  9. temperaturecooled in an ice-bath for a further hour
  10. filtrationfiltered
  11. washwashing with EtOAc (150 mL)
  12. customdried under reduced pressure

Sources & evidence

ORD record
ord-3f712c6477624eba89f3299e487931bd
Source dataset
uspto-grants-2012_08
Patent number
US08236954B2

Reaction notes

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