Triethylamine → HCID 57419171, compound

HRID 860887Notes

Reaction equation

HRID 860887 reaction equation
CS(Cl)(=O)=O.O[CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([N:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]1=[O:26])[CH:13]=[CH:12]2.C(N(CC)CC)C.S([O-])(=O)(=O)C.[CH3:39][C@@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.O1CCOCC1>C1COCC1.C(#N)C.CCOCC>[CH3:25][C:22]1[CH:23]=[CH:24][N:19]([C:14]2[CH:13]=[CH:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([CH2:8][CH2:7][N:41]4[CH2:42][CH2:43][CH2:44][C@H:40]4[CH3:39])[CH:10]=3)[CH:15]=2)[C:20](=[O:26])[CH:21]=1

Participants

11

Reactant 7

HCID 8471TriethylamineHCID 10796Cesium carbonateHCID 31297Methanesulfonyl chlorideHCID 85257MethanesulfonateHCID 641544(R)-2-MethylpyrrolidineHCID 204431481,4-Dioxane hydrochlorideHCID 67104649HCID 67104649, compound

Product 1

HCID 57419171HCID 57419171, compoundYield 17.2%

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Methanesulfonyl chloride (0.03 mL, 0.301 mmol, 1.2 equiv.) was added dropwise via a syringe to a stirred, 0° C. solution of 1-[6-(2-hydroxy-ethyl)-naphthalen-2-yl]4-methyl-1H-pyridin-2-one (Example 82A, 70 mg, 0.251 mmol) in anhydrous THF (10 mL) under a dry nitrogen atmosphere. Triethylamine (1.0 mL, 7.175 mmol, 28.6 equiv.) was then added. After two hours of stirring at 0° C., the reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous Na2CO3. The organic extract was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. This crude mesylate (˜89 mg, 0.249 mmol), (2R)-2-methylpyrrolidine (64 mg, 0.747 mmol, 3.0 equiv.), and cesium carbonate (81 mg, 0.249 mmol) in anhydrous acetonitrile (5 mL) were stirred in a sealed tube at 50° C. for 18 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 Et2O and the solution was treated with HCl-dioxane to precipitate the hydrochloride salt of the title compound (15 mg, 16% yield). 1H NMR (CD3OD, 300 MHz) δ 8.00 (d, J=9 Hz, 1H), 7.98 (d, J=9 Hz, 1H), 7.93–7.89 (m, 2H), 7.62 (d, J=7 Hz, 1H), 7.56 (dd, J=2, 9 Hz, 1H), 7.51 (dd, J=2, 9 Hz, 1H), 6.52 (br s, 1H), 6.45 (dd, J=2, 7 Hz, 1H), 3.83–3.68 (m, 2H), 3.61–3.49 (m, 1H), 3.43–3.17 (m, 4H), 2.43–2.30 (m, 1H), 2.33 (s, 3H), 2.24–1.99 (m, 2H), 1.83–1.69 (m, 1H), 1.49 (d, J=6 Hz, 3H). MS (DCI-NH3) [M+H]+ at 347.

Workup

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

Sources & evidence

ORD record
ord-c2c21283b7094546a593b01ac18287b0
Source dataset
uspto-grants-2006_12
Patent number
US07153889B2

Reaction notes

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