Acetic Acid → 2-(3,4-Dichlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[h]quinoline-4-carboxylic Acid

HRID 2375560Notes

Reaction equation

HRID 2375560 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][C:8]3=2)[C:3](=O)[C:2]1=[O:15].C(OC[C:21](=O)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)(=O)C.[C:32]([OH:35])(=[O:34])C.Cl>C(O)C.[OH-].[Na+].O.C(#N)C>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[CH2:22][C:21]1[C:2]([OH:15])=[C:3]([C:32]([OH:35])=[O:34])[C:4]2[C:9](=[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]3=[CH:6][CH:5]=2)[N:1]=1

Participants

9

Reactant 4

HCID 176Acetic AcidHCID 313Hydrochloric AcidHCID 137804146,7,8,9-Tetrahydro-1H-benzo[g]indole-2,3-dioneHCID 161000723-(3,4-Dichlorophenyl)-2-oxopropyl Acetate

Product 1

HCID 114523902-(3,4-Dichlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[h]quinoline-4-carboxylic AcidYield 20%

Reagents, catalysts & solvents 4

HCID 702EthanolSolvent2×HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 14798Sodium HydroxideSolvent

Procedure

The Pfitzinger reaction was used. In a 2-necked 25 mL round-bottomed flask, 6,7,8,9-tetrahydrobenzo[g]indoline-2,3-dione (0.119 g, 0.590 mmol) was taken up in 1 mL ethanol and 3 mL 10 M NaOH, and the mixture heated to reflux temperature. A solution of 3-(3,4-dichlorophenyl)-2-oxopropyl acetate (0.200 g, 0.767 mmol) in 3 mL ethanol was added in small portions over the course of 1 hour, by syringe. Refluxing was continued for an additional hour after the addition was complete, and the reaction mixture was then cooled to room temperature and acidified with glacial acetic acid, and the yellow precipitate collected by filtration. This crude product was purified by preparative HPLC (acetonitrile/water/triethylamine), and the pure salt thus obtained was converted back to the free acid by acidification of a 5% acetonitrile in water solution with concentrated HCl. The bright yellow precipitate was collected by filtration and dried under vacuum (47.8 mg, 20% yield): 1H NMR (400 MHz, DMSO-d6) δ 1.73-1.86 (m, 4H) 2.81 (t, J=6.1 Hz, 2H) 3.12 (t, J=5.9 Hz, 2H) 4.30 (s, 2H) 7.28 (t, J=8.7 Hz, 2H) 7.53 (d, J=8.1 Hz, 1H) 7.59 (d, J=2.0 Hz, 1H) 8.19 (d, J=8.6 Hz, 1H); HRMS (ESI+) calcd for C21H18Cl2NO3 (MH+) 402.0658, found 402.0661.

Workup

  1. customThe Pfitzinger reaction
  2. temperatureto reflux temperature
  3. temperatureRefluxing
  4. waitwas continued for an additional hour
  5. additionafter the addition
  6. filtrationthe yellow precipitate collected by filtration
  7. customThis crude product was purified by preparative HPLC (acetonitrile/water/triethylamine)
  8. customthe pure salt thus obtained
  9. filtrationThe bright yellow precipitate was collected by filtration
  10. customdried under vacuum (47.8 mg, 20% yield)

Sources & evidence

ORD record
ord-f0e097254d46436ebd5a1e04d096291d
Source dataset
uspto-grants-2008_12
Patent number
US07465798B2

Reaction notes

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