Hydrochloric Acid → (R)-tert-butyl 3-(6-(5-(2-chloro-6-fluorophenyl)-1H-indol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate

HRID 1529319Notes

Reaction equation

HRID 1529319 reaction equation
[H-].[Na+].[OH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30](S(C1C=CC(C)=CC=1)(=O)=O)[CH:29]=[C:28]2[C:44]1[CH:49]=[N:48][CH:47]=[C:46](Cl)[N:45]=1.Cl>CN(C=O)C.CCOC(C)=O.O>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:44]1[N:45]=[C:46]([O:3][C@@H:4]2[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2)[CH:47]=[N:48][CH:49]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 24758Sodium hydride2×HCID 1514398(R)-1-Boc-3-hydroxypiperidine2×HCID 867097705-(2-chloro-6-fluorophenyl)-3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indole

Product 1

HCID 67960707(R)-tert-butyl 3-(6-(5-(2-chloro-6-fluorophenyl)-1H-indol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylateYield 37.7%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a slurry of NaH 60% in mineral oil (0.047 g, 1.171 mmol) in 2 mL DMF at 0° C. was added (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (0.236 g, 1.171 mmol). The reaction was warmed to RT. After 10 min, solid 5-(2-chloro-6-fluorophenyl)-3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indole (0.200 g, 0.390 mmol) was added and the reaction became dark brown. After 30 min, the reaction was sealed and heated to 80° C. overnight. Additional NaH 60% in mineral oil (0.047 g, 1.171 mmol) and (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (0.236 g, 1.171 mmol) were added, the reaction was sealed, and heated to 120° C. for 1 h. The reaction was cooled and treated with ice, water, and EtOAc, and the aqueous layer was acidified with 1N aqueous HCl. The aqeuous layer was extracted 2×EtOAc, and the combined organics were washed 1× water, 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (40 g column) using 0-60% EtOAc/hexane. The product-containing fractions were concentrated to afford (R)-tert-butyl 3-(6-(5-(2-chloro-6-fluorophenyl)-1H-indol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (0.077 g, 0.147 mmol, 37.7% yield) as a light-yellow oil. MS (ESI, pos. ion) m/z: 523 (M+1).

Workup

  1. waitAfter 30 min
  2. customthe reaction was sealed
  3. temperatureheated to 80° C. overnight
  4. customthe reaction was sealed
  5. temperatureheated to 120° C. for 1 h
  6. temperatureThe reaction was cooled
  7. extractionThe aqeuous layer was extracted 2×EtOAc
  8. washthe combined organics were washed 1× water, 1× brine
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. additionThe material was treated with DCM
  13. custompurified by silica gel chromatography (40 g column)
  14. concentrationThe product-containing fractions were concentrated

Sources & evidence

ORD record
ord-64a898d63b604d8ba9af097aeff4a704
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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