Hydrochloric Acid → HCID 178479602, compound

HRID 2370314Notes

Reaction equation

HRID 2370314 reaction equation
[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C@H:9]1[C:18](=[O:19])[C:17]3[C:12]4=[C:13]([N:20](COCC[Si](C)(C)C)[N:21]=[C:11]4[CH2:10]1)[CH:14]=[N:15][CH:16]=3)[CH2:2]2.[ClH:30]>O1CCOCC1>[ClH:30].[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C@H:9]1[C:18](=[O:19])[C:17]3[C:12]4=[C:13]([NH:20][N:21]=[C:11]4[CH2:10]1)[CH:14]=[N:15][CH:16]=3)[CH2:2]2

Participants

4

Reactant 2

HCID 313Hydrochloric AcidHCID 66773152HCID 66773152, compound

Product 1

HCID 178479602HCID 178479602, compoundYield 18%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
115 °C

Procedure

To a sealed tube containing a solution of (S)-7-(quinuclidin-3-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-7,8-dihydropyrazolo[3,4,5-de]isoquinolin-6(2H)-one (0.71 g, 1.73 mmol) from Step D above in dioxane (10 mL) was added 6N HCl (20 mL). The reaction mixture was flushed with argon, sealed and heated to 115° C. for 30 min, cooled to ambient temperature and concentrated under reduced pressure. The residue was preabsorbed on silica gel and purified first by column chromatography (5 to 20% 6:3:1 dichloromethane/methanol/concentrated ammonium hydroxide in 9:1 dichloromethane/methanol) and subsequently by reverse phase semi-preparative HPLC (isocratic, 10% acetonitrile in water—both eluents contained 0.05% trifluoroacetic acid as modifier). The solvents were removed in vacuo and the desired product trifluoroacetate salt was dissolved in a solution 1.25 N HCl in methanol (4×5 mL) and the solvent removed (4×) to exchange the trifluoroacetate salt to the hydrochloride salt form. Recrystallization of the desired product hydrochloride salt from ethanol (10 mL), followed by lyophilization from acetonitrile/water (1:5, 6 mL) afforded (S)-7-(quinuclidin-3-yl)-7,8-dihydropyrazolo[3,4,5-de]isoquinolin-6(2H)-one, hydrochloride salt (85.9 mg, 18%) as an amorphous white solid: 1H NMR (500 MHz, d6-DMSO) δ 13.15 (s, 1H), 10.15 (s, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.75 (dd, J=7.0, 7.0 Hz, 1H), 7.45 (d, J=7.0 Hz, 1H), 5.32-5.14 (m, 2H), 4.79 (t, J=9.5 Hz, 1H), 3.78-3.47 (m, 4H), 3.32-3.16 (m, 3H), 2.26-2.18 (m, 1H), 2.03-1.80 (m, 3H), MS (ESI+) m/z 283 (M+H)+; HPLC 98.8% (AUC), tR 7.29 min.

Workup

  1. customThe reaction mixture was flushed with argon
  2. customsealed
  3. temperaturecooled to ambient temperature
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was preabsorbed on silica gel
  6. custompurified first by column chromatography (5 to 20% 6:3:1 dichloromethane/methanol/concentrated ammonium hydroxide in 9:1 dichloromethane/methanol) and subsequently by reverse phase semi-preparative HPLC (isocratic, 10% acetonitrile in water—both eluents
  7. customThe solvents were removed in vacuo
  8. dissolutionthe desired product trifluoroacetate salt was dissolved in a solution 1.25 N HCl in methanol (4×5 mL)
  9. customthe solvent removed (4×)
  10. customRecrystallization of the desired product hydrochloride salt from ethanol (10 mL)

Sources & evidence

ORD record
ord-f7fa7ed4fb6149bf8c37e8d160231abc
Source dataset
uspto-grants-2014_04
Patent number
US08710047B2

Reaction notes

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