Hydrochloric Acid → HCID 10425975, compound

HRID 2390411Notes

Reaction equation

HRID 2390411 reaction equation
CS(Cl)(=O)=O.[N:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([CH2:22][CH2:23]O)[CH:16]=[CH:15]2.C(N(CC)CC)C.S([O-])(=O)(=O)C.[CH3:37][C@@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C1COCC1.C(#N)C.CO>[CH3:37][C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[CH2:23][CH2:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][N:6]=1)[CH:21]=[CH:20]2

Participants

11

Reactant 7

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 10796Cesium carbonateHCID 31297Methanesulfonyl chlorideHCID 85257MethanesulfonateHCID 641544(R)-2-MethylpyrrolidineHCID 67104100HCID 67104100, compound

Product 1

HCID 10425975HCID 10425975, compound

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolvent

Procedure

Methanesulfonyl chloride (0.005 mL, 0.067 mmol, 1.2 equiv.) was added dropwise via a syringe to a stirred, 0° C. solution of 2-(6-pyrazin-2-yl-naphthalen-2-yl)-ethanol (Example 83A, 14 mg, 0.056 mmol) in anhydrous THF (10 mL) under a dry nitrogen atmosphere. Triethylamine (0.023 mL, 0.167 mmol, 3 equiv.) was then added. After 18 hours at −20° C., the reaction mixture was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. This crude mesylate (˜18 mg, 0.056 mmol), (2R)-2-methylpyrrolidine (190 mg, 2.237 mmol, 40 equiv.), and cesium carbonate (182 mg, 0.559 mmol, 10 equiv.) in anhydrous acetonitrile (5 mL) were stirred in a sealed tube at 40° C. for 62 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous Na2CO3. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (97:3:trace dichloromethane/methanol/NH4OH). Fractions containing product were combined and concentrated under reduced pressure to provide the free base. This free base was dissolved in methanol and the solution was treated with HCl gas. The hydrochloride salt of the title compound was obtained on evaporation of solvent (4.5 mg, 23% yield). 1H NMR (CD3OD, 300 MHz) δ 9.29 (br s, 1H), 8.79-8.74 (m, 1H), 8.64 (br s, 1H), 8.58 (d, J=2 Hz, 1H), 8.24 (dd, J=2, 9 Hz, 1H), 8.03 (t, J=9 Hz, 2H), 7.90 (br s, 1H), 7.55 (dd, J=2, 9 Hz, 1H), 3.84-3.68 (m, 2H), 3.64-3.49 (m, 1H), 3.44-3.17 (m, 4H), 2.43-2.30 (m, 1H), 2.27-2.00 (m, 2H), 1.84-1.68 (m, 1H), 1.50 (d, J=7 Hz, 3H). MS (DCI-NH3) [M+H]+ at 318.

Workup

  1. dry with materialthe reaction mixture was dried (MgSO4)
  2. filtrationfiltered
  3. concentrationThe filtrate was concentrated under reduced pressure
  4. concentrationThe reaction mixture was concentrated under reduced pressure
  5. customThe residue was partitioned between ethyl acetate and saturated aqueous Na2CO3
  6. dry with materialThe organic layer was dried (MgSO4)
  7. filtrationfiltered
  8. concentrationThe filtrate was concentrated under reduced pressure
  9. customthe residue was purified by column chromatography (97:3:trace dichloromethane/methanol/NH4OH)
  10. additionFractions containing product
  11. concentrationconcentrated under reduced pressure
  12. customto provide the free base

Sources & evidence

ORD record
ord-0edd2a9dd4434b1f904a6b9f1a4992ed
Source dataset
uspto-grants-2012_09
Patent number
US08273767B2

Reaction notes

Loading…