Proton sponge → HCID 49805020, compound

HRID 576109Notes

Reaction equation

HRID 576109 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11](C)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]

Participants

5

Reactant 3

HCID 88675Proton spongeHCID 5213051-Chloroethyl chloroformateHCID 66789597HCID 66789597, compound

Product 1

HCID 49805020HCID 49805020, compoundYield 5%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To an ice-cold solution of 4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (282 mg, 0.73 mmol) and N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (313 mg, 1.46 mmol) in 1,2-dichloroethane (10 mL) was added 1-chlorethyl chloroformate (0.32 mL, 1.46 mmol) drop wise. The mixture was stirred for 15 minutes and then heated to reflux for 2 hours. The mixture was cooled to room temperature, concentrated, and filtered through a pad of silica gel (1:1:1 hexanes/ethyl acetate/dichloromethane). The filtrate was concentrated, the residue dissolved in methanol (10 mL), and heated to reflux for 1 hour. The mixture was cooled, concentrated, neutralized with aqueous saturated sodium bicarbonate and ethyl acetate, and then purified by column chromatography (methylene chloride to 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) to give 4-(3,4-dichlorophenyl)-6-fluoro-7-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline as yellow oil (13 mg, 5%): 1H NMR (CDCl3, 500 MHz) δ 8.72 (d, J=4.7 Hz, 1H), 7.77-7.75 (m, 3H), 7.39 (d, J=8.3 Hz, 1H), 7.27-7.24 (m, 2H), 6.99 (dd, J=8.3, 2.0 Hz, 1H), 6.68 (d, J=11.9 Hz, 1H), 4.21-4.07 (m, 3H), 3.41 (dd, J=12.9, 5.3 Hz, 1H), 3.05 (dd, J=12.9, 6.4 Hz, 1H); ESI MS m/z 373 [M+H]+.

Workup

  1. temperatureheated
  2. temperatureto reflux for 2 hours
  3. concentrationconcentrated
  4. filtrationfiltered through a pad of silica gel (1:1:1 hexanes/ethyl acetate/dichloromethane)
  5. concentrationThe filtrate was concentrated
  6. dissolutionthe residue dissolved in methanol (10 mL)
  7. temperatureheated
  8. temperatureto reflux for 1 hour
  9. temperatureThe mixture was cooled
  10. concentrationconcentrated
  11. custompurified by column chromatography (methylene chloride to 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide)

Sources & evidence

ORD record
ord-9c132354e6f44a3fb86d73f8cd1cb5ce
Source dataset
uspto-grants-2015_05
Patent number
US09034899B2

Reaction notes

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