Hydrochloric Acid → 4-chloro-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

HRID 80772Notes

Reaction equation

HRID 80772 reaction equation
C(O)C.[CH:4]([C:7]1[CH:8]=[CH:9][C:10]([CH3:45])=[C:11]([N:13]2[CH2:44][CH2:43][C:16]3[N:17]=[C:18]([C:23]4[CH:31]=[CH:30][CH:29]=[C:28]5[C:24]=4[C:25]([CH3:42])=[CH:26][N:27]5[S:32]([C:35]4[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=4)(=[O:34])=[O:33])[N:19]=[C:20](OC)[C:15]=3[CH2:14]2)[CH:12]=1)([CH3:6])[CH3:5].Cl.[Cl-].[Cl:48]C=[N+](C)C>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:48][C:20]1[C:15]2[CH2:14][N:13]([C:11]3[CH:12]=[C:7]([CH:4]([CH3:6])[CH3:5])[CH:8]=[CH:9][C:10]=3[CH3:45])[CH2:44][CH2:43][C:16]=2[N:17]=[C:18]([C:23]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:24]=2[C:25]([CH3:42])=[CH:26][N:27]3[S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:33])=[O:34])[N:19]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 702EthanolHCID 77311Chloro-N,N-dimethylformiminium chlorideHCID 71240555HCID 71240555, compound

Product 1

HCID 866902544-chloro-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 516892Sodium BicarbonateSolvent2×

Conditions

Temperature
68 °C

Procedure

Ethanol (4 mL) was added to 6-(5-isopropyl-2-methylphenyl)-4-methoxy-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.92 g, 1.58 mmol) and then 12 N aqueous HCl (2 mL, 24 mmol) was added and the mixture was heated to 68° C. for ca. 15 hours. The reaction was then cooled to room temperature, diluted with dichloromethane, and neutralized via the slow addition of saturated aqueous sodium bicarbonate. The resulting layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The resulting residue was then dissolved in dichloromethane (20 mL) and cooled to 0° C. and N-chloromethylene-N,N-dimethyl ammonium chloride (Vilsmeier reagent) (0.41 g, 3.21 mmol) was added. The reaction was then placed at room temperature for 25 minutes. The reaction was then diluted with dichloromethane and saturated aqueous sodium bicarbonate. The resulting layers were separated and the aqueous layer was extracted one additional time with dichloromethane. The organic layers were combined, dried over Na2SO4 filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (0-45% ethyl acetate/heptanes) to provide 4-chloro-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 585.2 (M+H)+.

Workup

  1. temperatureThe reaction was then cooled to room temperature
  2. customThe resulting layers were separated
  3. extractionthe aqueous layer was extracted two additional times with dichloromethane
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. dissolutionThe resulting residue was then dissolved in dichloromethane (20 mL)
  8. temperaturecooled to 0° C.
  9. customThe resulting layers were separated
  10. extractionthe aqueous layer was extracted one additional time with dichloromethane
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe resulting residue was purified by silica gel flash chromatography (0-45% ethyl acetate/heptanes)

Sources & evidence

ORD record
ord-dea8ed04e1e14a8a8371e8ab0cbb3895
Source dataset
uspto-grants-2014_09
Patent number
US08846656B2

Reaction notes

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