Hydrochloric Acid → HCID 178483016, compound

HRID 2173956Notes

Reaction equation

HRID 2173956 reaction equation
[C:1]([C:3]1[CH:44]=[CH:43][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][N:20]4[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(O)[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].[C:45](C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(O)C(F)(F)F)N(COCC[Si](C)(C)C)C=2C=1)#[N:46].Cl.CO.S(Cl)(Cl)=O.CCO>CN.CN(C=O)C>[C:1]([C:3]1[CH:44]=[CH:43][C:6]2[NH:7][C:8]([C:10]([C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][N:20]4[C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])([NH:46][CH3:45])[C:11]([F:14])([F:12])[F:13])=[N:9][C:5]=2[CH:4]=1)#[N:2]

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 702EthanolHCID 887MethanolHCID 24386Thionyl ChlorideHCID 86701501HCID 86701501, compoundHCID 86701502HCID 86701502, compound

Product 1

HCID 178483016HCID 178483016, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6329MethylamineSolvent

Conditions

Temperature
60 °C

Procedure

To a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 33-A) (1.27 g, 2.014 mmol) was added 1.25 M HCl in MeOH (16.11 mL, 20.14 mmol) and the mixture was stirred at 60° C. After 40 minutes the reaction was cooled to room temperature and concentrated. The mixture was dissolved in CHCl3 (40 mL), then was added thionyl chloride (1.47 mL, 20.14 mmol) and DMF (0.5 mL) and the mixture was heated at 70° C. After 10 minutes the reaction was cooled to room temperature and concentrated. At this point the reaction was dissolved in 33% methylamine in EtOH (25 mL, 201 mmol) and stirred at room temperature. After 5 minutes the mixture was concentrated and the resulting residue was purified directly by flash chromatography (0-100% EtOAc in heptanes) to provide (±)-tert-butyl 4-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(methylamino)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate. MS (ESI+) m/z 514.3 (M+H). In addition, (±)-tert-butyl 4-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-1-(dimethylamino)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate was also isolated. MS (ESI−) m/z 526.3 (M−H).

Workup

  1. temperatureAfter 40 minutes the reaction was cooled to room temperature
  2. concentrationconcentrated
  3. dissolutionThe mixture was dissolved in CHCl3 (40 mL)
  4. temperaturethe mixture was heated at 70° C
  5. temperatureAfter 10 minutes the reaction was cooled to room temperature
  6. concentrationconcentrated
  7. stirringstirred at room temperature
  8. concentrationAfter 5 minutes the mixture was concentrated
  9. customthe resulting residue was purified directly by flash chromatography (0-100% EtOAc in heptanes)

Sources & evidence

ORD record
ord-5af54244456a4a09aa7bed8903e29f1e
Source dataset
uspto-grants-2015_06
Patent number
US09056874B2

Reaction notes

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