Hydrochloric Acid → HCID 71270773, compound

HRID 510441Notes

Reaction equation

HRID 510441 reaction equation
Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:22])[C:10]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)=[C:6]2[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1.[CH3:29][OH:30].[OH-:31].[Na+].Cl>CN(C)C=O.O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH3:22][C:9]1[C:10]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[C:6]2[N:5]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:3]=[C:2]([C:29]([OH:31])=[O:30])[N:7]2[N:8]=1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 887MethanolHCID 14798Sodium HydroxideHCID 71532471HCID 71532471, compound

Product 1

HCID 71270773HCID 71270773, compoundYield 24.4%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalyst2×HCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)Catalyst2×HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
70 °C

Procedure

To the solution of 7-chloro-2-methyl-5-(4-morpholinyl)-3-(1-naphthalenylmethyl)pyrazolo[1,5-a]pyrimidine (0.8 g, 2.036 mmol) in N,N-Dimethylformamide (25 mL) and methanol (8 mL, 198 mmol) was added PdCl2(PPh3)3 (0.143 g, 0.204 mmol). The mixture was purged with carbon monoxide for 5 min and then TEA (0.851 mL, 6.11 mmol) was added in. The reaction mixture was stirred at 70° C. under CO atmosphere for 14 h. Very little product was detected. To the reaction mixture was added additional palladium(II) acetate (0.078 g, 0.346 mmol) and DPPF (0.192 g, 0.346 mmol). The mixture was purged with carbon monoxide for 5 min and then TEA (0.851 mL, 6.11 mmol) was added in. The reaction mixture was stirred at 70° C. under CO atmosphere for 6 h. Palladium(II) acetate (0.078 g, 0.346 mmol) and DPPF (0.192 g, 0.346 mmol) was added in. The mixture was purged with carbon monoxide for 5 min and then TEA (0.851 mL, 6.11 mmol) was added in. The reaction mixture was stirred at 70° C. under CO atmosphere for 14 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated. To the solution of the residue in Tetrahydrofuran (THF) (25 ml) was added sodium hydroxide (8.14 mL, 8.14 mmol). The reaction mixture was stirred at rt for 2 h. The reaction was acidified with 1 N HCl, then extracted with EtOAc (30 mL×2). The combined organic phases were dried and concentrated. The crude was purified on silica column (MeOH/DCM: 0˜10%) then reversed phase HPLC (27˜57% CH3CN (0.1% TFA)/Water (0.1% TFA)) to give the titled product (0.2 g, 23%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.24 (s, 3H) 3.67 (m, 8H) 4.35 (s, 2H) 7.01 (s, 1H) 7.24-7.57 (m, 4 H) 7.68-7.85 (m, 1H) 7.83-7.96 (m, 1H) 8.42 (m, 1H); LC/MS: MS (ES+) m/e 403.2 [M+H]+.

Workup

  1. customThe mixture was purged with carbon monoxide for 5 min
  2. customThe mixture was purged with carbon monoxide for 5 min
  3. stirringThe reaction mixture was stirred at 70° C. under CO atmosphere for 6 h
  4. customThe mixture was purged with carbon monoxide for 5 min
  5. stirringThe reaction mixture was stirred at 70° C. under CO atmosphere for 14 h
  6. filtrationThe reaction mixture was filtered through Celite
  7. concentrationthe filtrate was concentrated
  8. stirringThe reaction mixture was stirred at rt for 2 h
  9. extractionextracted with EtOAc (30 mL×2)
  10. customThe combined organic phases were dried
  11. concentrationconcentrated
  12. customThe crude was purified on silica column (MeOH/DCM: 0˜10%)

Sources & evidence

ORD record
ord-7ceccaa867c145bf91cdbb258f138b2c
Source dataset
uspto-grants-2015_08
Patent number
US09096605B2

Reaction notes

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