Potassium Phosphate, Tribasic → 4-(3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-7-isoquinolinyl)benzonitrile

HRID 860873Notes

Reaction equation

HRID 860873 reaction equation
Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH3:19])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][N:14]1[CH2:13][CH2:12][C:7]1[N:8]=[CH:9][C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([C:25]1[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=1)[CH:11]=2

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27343264-Cyanophenylboronic acidHCID 671046927-bromo-3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}isoquinoline

Product 1

HCID 104500064-(3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-7-isoquinolinyl)benzonitrile

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 3776IsopropanolSolvent

Procedure

The product from Example 52G (0.2 g, 0.6 mmol), 4-cyanophenylboronic acid (0.22 g, 1.5 mmol), bis(triphenylphosphine)palladium dichloride (55 mg, 0.08 mmol), and potassium phosphate (7 mL, 0.2 M in water) were combined in isopropanol (7 mL) and heated at 60–65° C. for 7 hours in a sealed flask. The mixture was filtered through diatomaceous earth, the filtrate was concentrated in vacuo, and then partitioned between MTBE (10 mL) and water (10 mL). The organic layer was separated, washed with aqueous sodium bicarbonate solution (5%, 10 mL), and then extracted with a solution of 2M HCl (15 mL). The pH of the acidic aqueous layer was adjusted with base using potassium carbonate and extracted with isopropyl acetate (15 mL). The organic layer was evaporated in vacuo and the residue was chased with heptane (10 mL) to provide the title compound. 1H NMR (CDCl3) δ 1.12 (d, J=6.0 Hz, 3H); 1.37–1.50 (m, 1H); 1.64–1.85 (m, 2H); 1.85–1.98 (m, 1H); 2.26 (q, J=8.8. Hz, 1H); 2.32–2.43 (m, 1H); 2.50–2.60 (m, 1H), 3.09–3.34 (m, 4H); 7.56 (m, 1H); 7.73–7. 81 (m, 4H), 7.84–7.87 (m, 2H), 8.12 (m, 1H); 9.26 (s, 1H); HRMS Calcd. for [C23H23N3+H+]: 342.1970. Found: 342.1974.

Workup

  1. temperatureheated at 60–65° C. for 7 hours in a sealed flask
  2. filtrationThe mixture was filtered through diatomaceous earth
  3. concentrationthe filtrate was concentrated in vacuo
  4. custompartitioned between MTBE (10 mL) and water (10 mL)
  5. customThe organic layer was separated
  6. washwashed with aqueous sodium bicarbonate solution (5%, 10 mL)
  7. extractionextracted with a solution of 2M HCl (15 mL)
  8. extractionextracted with isopropyl acetate (15 mL)
  9. customThe organic layer was evaporated in vacuo

Sources & evidence

ORD record
ord-ca3bd95c393841b8bac4c4b60e90f536
Source dataset
uspto-grants-2006_12
Patent number
US07153889B2

Reaction notes

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