Hydrochloric Acid → 2-Hydroxy-3-{5-[(3-methylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile

HRID 748540Notes

Reaction equation

HRID 748540 reaction equation
[H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)#[N:4].Cl[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[CH2:24]2)=[CH:18][N+:17]=1[O-].Cl.P(Cl)(Cl)Cl>CN(C)C=O.C(OCC)(=O)C>[OH:14][C:9]1[NH:10][C:11]2[C:7]([C:8]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[CH2:24]3)=[CH:18][N:17]=1)=[CH:6][C:5]([C:3]#[N:4])=[CH:13][CH:12]=2

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 24387Phosphorus trichlorideHCID 24758Sodium hydrideHCID 27733462-Oxo-2,3-dihydro-1H-indole-5-carbonitrileHCID 858730592-Chloro-5-[(3-methylpiperidin-1-yl)methyl]pyridine 1-oxide

Product 1

HCID 1363421222-Hydroxy-3-{5-[(3-methylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrileYield 36.1%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a suspension of sodium hydride (60% in mineral oil, 45 mg, 1.12 mmol) in N,N-dimethylformamide (1 mL) was added 5-cyanooxindole (133 mg, 0.84 mmol), and the mixture was stirred at ambient temperature for 10 min. To the obtained brownish solution was added a solution of 2-chloro-5-[(3-methylpiperidin-1-yl)methyl]pyridine 1-oxide (0.56 mmol) in N,N-dimethylformamide (1.5 mL). The reaction mixture was heated at 130° C. for 30 min, and was then allowed to cool. To the residue was added 2 M HCl(aq) and the obtained suspension was washed with ethyl acetate. The aqueous layer was neutalized with 45% NaOH(aq) and alkalized to saturation with NaHCO3 (s), and extracted two times with ethyl acetate. The extracts were combined, dried (MgSO4) and the solvent was removed in vacuo affording 84 mg of the crude product. The material was dissolved in ethyl acetate (10 mL), and to the solution was added phosphorus trichloride (0.2 mL, 2.24 mmol). The obtained orange suspension was heated at reflux for 1 h and was then allowed to cool. The precipitate was filtered, washed with ethyl acetate, and dried in vacuo affording 70 mg of an orange residue. The material was was purified by preparative HPLC (column: Xterra, C8, 7 μm, 19×300 mm; eluent: 0.1 M NH4OAc buffer/acetonitrile, 8:2 to 4:6) affording 15 mg (8% yield) of the title compund as an orange solid: 1H NMR (aceton-d6, 400 MHz) δ 9.86 (br s, 1 H), 8.11 (s, 1 H), 7.91 (dd, J=9, 2 Hz, 1 H), 7.84 (d, J=9 Hz, 1 H), 7.82 (d, J=1 Hz, 1 H), 7.26 (dd, J=8, 2 Hz, 1 H), 7.11 (d, J=8 Hz, 1 H), 3.44 (s, 2 H), 2.00-1.50 (m, 6 H), 0.95-0.81 (m, 4 H); MS (ES) m/z 347 (M++1).

Workup

  1. temperatureThe reaction mixture was heated at 130° C. for 30 min
  2. temperatureto cool
  3. washthe obtained suspension was washed with ethyl acetate
  4. extractionextracted two times with ethyl acetate
  5. dry with materialdried (MgSO4)
  6. customthe solvent was removed in vacuo
  7. customaffording 84 mg of the crude product
  8. temperatureThe obtained orange suspension was heated
  9. temperatureat reflux for 1 h
  10. temperatureto cool
  11. filtrationThe precipitate was filtered
  12. washwashed with ethyl acetate
  13. customdried in vacuo

Sources & evidence

ORD record
ord-63613004ff114557953f550d631db3d2
Source dataset
uspto-grants-2008_07
Patent number
US07399780B2

Reaction notes

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