Potassium Carbonate → 2-(2-Methoxyphenyl)-8-methyl-3-[(7H-purin-6-ylthio)methyl]quinoline

HRID 1948736Notes

Reaction equation

HRID 1948736 reaction equation
Cl[C:2]1[C:11]([CH2:12]O)=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].P(Br)(Br)Br.C([O-])([O-])=O.[K+].[K+].[SH:44][C:45]1[N:53]=[CH:52][N:51]=[C:50]2[C:46]=1[NH:47][CH:48]=[N:49]2>COCCOC.O.CCOC(C)=O.C(Cl)Cl.CN(C=O)C.C(Cl)Cl.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[C:11]([CH2:12][S:44][C:45]2[N:53]=[CH:52][N:51]=[C:50]3[C:46]=2[NH:47][CH:48]=[N:49]3)=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1

Participants

14

Reactant 6

HCID 11430Potassium CarbonateHCID 24614Phosphorus tribromideHCID 62657Potassium Phosphate, TribasicHCID 865104(2-Chloro-8-methylquinolin-3-yl)methanolHCID 27339582-Methoxyphenylboronic acidHCID 178527888HCID 178527888, compound

Product 1

HCID 671995282-(2-Methoxyphenyl)-8-methyl-3-[(7H-purin-6-ylthio)methyl]quinolineYield 42.3%

Reagents, catalysts & solvents 7

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent2×HCID 21881112Ethyl ether methylene chlorideSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of (2-chloro-8-methylquinolin-3-yl)methanol (250 mg, 1.20 mmol) in DME (4 mL) and water (1 mL) was added 2-methoxybenzeneboronic acid (200 mg, 1.32 mmol), potassium phosphate tribasic (306 mg, 1.44 mmol) and Pd(PPh3)4 (69 mg, 0.06 mmol). The reaction mixture was heated to 120° C. under microwave irradiation for 1 h. The product was diluted with EtOAc (40 mL) and washed with water (10 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil, which was purified by column chromatography (SiO2, 30% EtOAc in heptane) to give a yellow foam. To a solution of this product (200 mg) in DCM (10 mL) was added phosphorus tribromide (0.13 mL, 1.43 mmol) and the mixture was stirred at r.t. for 2 h. The mixture was partitioned between DCM (75 mL) and aqueous NaHCO3 solution (20 mL). The organic layer was washed with water (20 mL), separated, dried (MgSO4) and the solvent removed in vacuo to give a yellow oil. To a solution of this oil (200 mg) in DMF (10 mL) was added K2CO3 (89 mg, 0.64 mmol) and 6-mercaptopurine (109 mg, 0.64 mmol) and the reaction mixture was stirred at r.t. for 18 h. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (7×30 mL). The organic layer was separated, dried (MgSO4) and the solvent removed in vacuo to give a colourless oil. Trituration in DCM/diethyl ether gave the title compound (112 mg, 22%) as an off-white solid. δH (DMSO-d6) 13.50 (br s, 1H), 8.63 (s, 1H), 8.46 (s, 1H), 8.42 (s, 1H), 7.80 (d, J 9 Hz, 1H), 7.58-7.60 (m, 1H), 7.35-7.50 (m, 3H), 7.02-7.16 (m, 2H), 4.60-4.70 (m, 2H), 3.78 (s, 3H), 2.65 (s, 3H). LCMS (ES+) 414.2 (M+H)+, RT 3.40 minutes (Method 3).

Workup

  1. washwashed with water (10 mL)
  2. customThe organic layer was separated
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customto give a yellow oil, which
  7. customwas purified by column chromatography (SiO2, 30% EtOAc in heptane)
  8. customto give a yellow foam
  9. customThe mixture was partitioned between DCM (75 mL) and aqueous NaHCO3 solution (20 mL)
  10. washThe organic layer was washed with water (20 mL)
  11. customseparated
  12. dry with materialdried (MgSO4)
  13. customthe solvent removed in vacuo
  14. customto give a yellow oil
  15. stirringthe reaction mixture was stirred at r.t. for 18 h
  16. washwashed with water (7×30 mL)
  17. customThe organic layer was separated
  18. dry with materialdried (MgSO4)
  19. customthe solvent removed in vacuo
  20. customto give a colourless oil

Sources & evidence

ORD record
ord-3641ae4634d9426e8fb5a826cf013e4f
Source dataset
uspto-grants-2013_03
Patent number
US08399483B2

Reaction notes

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