Water → 8-chloro-6-fluoro-5-(2-(6-(trifluoromethyl) pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole

HRID 509780Notes

Reaction equation

HRID 509780 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]2[NH:7][C:6]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]2[N:7]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:26][CH:25]=3)[C:6]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:5]=3[C:4]=2[CH:3]=1

Participants

6

Reactant 4

HCID 962WaterHCID 14797Potassium HydroxideHCID 574168485-Ethenyl-2-(trifluoromethyl)pyridineHCID 594550388-chloro-6-fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

Product 1

HCID 578762598-chloro-6-fluoro-5-(2-(6-(trifluoromethyl) pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indoleYield 2.9%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

To a solution of 8-chloro-6-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (300 mg, 1.26 mmol) in NMP (3.0 ml), powdered KOH (705 mg, 12.57 mmol) was added and stirred for 10 min at 25 deg C. After which 2-(trifluoromethyl)-5-vinylpyridine (435 mg, 2.5 mmol) was added slowly to the above solution and stirred for 24 h at 25 deg C. After completion of the reaction (monitored by LCMS), DM water was added to the crude and extracted with the ethylacetate. The organic layer was separated, dried and concentrated. The resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 15 mg of 8-chloro-6-fluoro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole as TFA salt.

Workup

  1. stirringstirred for 24 h at 25 deg C
  2. additionwas added to the crude
  3. extractionextracted with the ethylacetate
  4. customThe organic layer was separated
  5. customdried
  6. concentrationconcentrated
  7. customThe resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL)

Sources & evidence

ORD record
ord-07d3c2516a284fad9ec3c323988fed15
Source dataset
uspto-grants-2015_08
Patent number
US09096591B2

Reaction notes

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