Proton sponge → HCID 131732861, compound

HRID 576132Notes

Reaction equation

HRID 576132 reaction equation
[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10]3[CH:19]=[C:18]4[C:13]([CH:14]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=5)[CH2:15][N:16](C)[CH2:17]4)=[CH:12][C:11]=3[F:29])[CH:7]=[CH:6][C:5]=12.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.ClC(OC(Cl)C)=O.[C:53]([OH:62])(=[O:61])[C@@H:54]([C@H:56]([C:58]([OH:60])=[O:59])[OH:57])[OH:55]>ClCCCl.C(Cl)Cl.C(#N)C.O>[C:58]([C@@H:56]([C@H:54]([C:53]([OH:62])=[O:61])[OH:55])[OH:57])([OH:60])=[O:59].[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[C:8]([C:10]3[CH:19]=[C:18]4[C:13]([CH:14]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=5)[CH2:15][NH:16][CH2:17]4)=[CH:12][C:11]=3[F:29])[CH:7]=[CH:6][C:5]=12

Participants

9

Reactant 4

HCID 88675Proton spongeHCID 444305L-Tartaric acidHCID 5213051-Chloroethyl chloroformateHCID 66788878HCID 66788878, compound

Product 1

HCID 131732861HCID 131732861, compoundYield 140.5%

Reagents, catalysts & solvents 4

HCID 111,2-DichloroethaneSolventHCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

To (+)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline (160 mg, 0.37 mmol) and N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (160 mg, 0.37 mmol) in 1,2-dichloroethane (5 mL) was added 1-chlorethyl chloroformate (0.082 mL, 0.75 mmol) dropwise. The mixture was heated to reflux for 3 hours and then cooled to ambient temperature. The reaction mixture was diluted with methylene chloride and washed with 1N HCl, water, dried over sodium sulfate, filtered, and concentrated in vacuo. To the residue was added methanol (15 mL) and the mixture was heated to reflux. After 1 h, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was taken up in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL), brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) and preparative TLC (90:9:1 methylene chloride/methanol/ammonium hydroxide). To the obtained material (10 mg, 0.024 mmol) in acetonitrile (1.5 mL) was added L-tartaric acid (3.6 mg, 0.024 mmol) in water (2 mL). The resultant solution was lyophilized to give (+)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline, L-tartrate salt (19 mg, 9%, AUC HPLC>99%) as a white powder: 1H NMR (CD3OD, 500 MHz) 9.03 (s, 1H), 8.47 (s, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.87 (d, J=9.5 Hz, 1H), 7.60-7.56 (m, 2H), 7.50 (d, J=2.0 Hz, 1H), 7.24 (dd, J=8.0, 1.5 Hz, 1H), 6.80 (d, J=11.5 Hz, 1H), 4.56-4.46 (m, 3H), 4.43 (s, 2.3H), 3.78-3.73 (m, 1H), 3.41-3.38 (m, 1H); ESI MS m/z 413 [M+H]+; [ ]24D+21.2° (c 0.11, methanol).

Workup

  1. temperatureThe mixture was heated
  2. temperatureto reflux for 3 hours
  3. washwashed with 1N HCl, water
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. additionTo the residue was added methanol (15 mL)
  8. temperaturethe mixture was heated to reflux
  9. temperaturethe reaction mixture was cooled to ambient temperature
  10. concentrationconcentrated under reduced pressure
  11. washwashed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL), brine (10 mL)
  12. dry with materialdried over sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo
  15. customThe residue was purified by column chromatography (methylene chloride to 90:9:1 methylene chloride/methanol/ammonium hydroxide) and preparative TLC (90:9:1 methylene chloride/methanol/ammonium hydroxide)

Sources & evidence

ORD record
ord-e71e0e0d9a6d45c0a6fbc3628ed3f0f0
Source dataset
uspto-grants-2015_05
Patent number
US09034899B2

Reaction notes

Loading…