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

HRID 1948739Notes

Reaction equation

HRID 1948739 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.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].F.[K].P(Br)(Br)Br.C([O-])([O-])=O.[K+].[K+].[SH:46][C:47]1[N:55]=[CH:54][N:53]=[C:52]2[C:48]=1[NH:49][CH:50]=[N:51]2>COCCOC.O.CCOC(C)=O.C(Cl)Cl.CN(C=O)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>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[C:2]1[C:11]([CH2:12][S:46][C:47]2[N:55]=[CH:54][N:53]=[C:52]3[C:48]=2[NH:49][CH:50]=[N:51]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 7

HCID 11430Potassium CarbonateHCID 24614Phosphorus tribromideHCID 62657Potassium Phosphate, TribasicHCID 865104(2-Chloro-8-methylquinolin-3-yl)methanolHCID 35493952-Chloro-6-fluorophenylboronic acidHCID 53443437Potassium fluoride, 99%, spray-driedHCID 178527888HCID 178527888, compound

Product 1

HCID 441264182-(2-Chloro-6-fluorophenyl)-8-methyl-3-[(7H-purin-6-ylthio)methyl]quinolineYield 45%

Reagents, catalysts & solvents 6

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

Conditions

Temperature
120 °C

Procedure

To a solution of (2-chloro-8-methylquinolin-3-yl)methanol (250 mg, 1.21 mmol) in DME (4 mL) and water (1 mL) was added 2-chloro-6-fluorophenylboronic acid (230 mg, 1.32 mmol), potassium phosphate tribasic (306 mg, 1.44 mmol), potassium hydrogenfluoride (188 mg, 2.4 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 (30 mL) and washed with water (10 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. Purification by column chromatography (SiO2, 0-50% EtOAc in heptane) followed by preparative HPLC (Method 1) gave a white solid. To a solution of this solid (150 mg) in DCM (7 mL) was added phosphorus tribromide (0.2 mL, 2.48 mmol). The mixture was stirred at r.t. for 3 h and partitioned between DCM (50 mL) and 10% aqueous K2CO3 solution (20 mL). The organic layer was separated, dried (MgSO4) and the solvent removed in vacuo to give a clear oil. To a solution of this oil in DMF (7 mL) was added K2CO3 (72 mg, 0.52 mmol) and 6-mercaptopurine (88 mg, 0.52 mmol) and the mixture stirred at r.t. for 18 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (7×30 mL). The organic layer was separated, dried (MgSO4) and the solvent was removed in vacuo to give the title compound (102 mg, 19%) as a white solid. δH (DMSO-d6) 13.46 (br s, 1H), 8.64 (s, 1H), 8.57 (s, 1H), 8.41 (s, 1H), 7.89 (d, J 6 Hz, 1H), 7.65 (d, J 6 Hz, 1H), 7.56 (t, J 6 Hz, 1H), 7.40-7.50 (m, 2H), 7.24-7.30 (m, 1H), 4.64-4.72 (m, 2H), 2.64 (s, 3H). LCMS (ES+) 436.2 (M+H)+, RT 3.77 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
  7. customPurification by column chromatography (SiO2, 0-50% EtOAc in heptane)
  8. customgave a white solid
  9. custompartitioned between DCM (50 mL) and 10% aqueous K2CO3 solution (20 mL)
  10. customThe organic layer was separated
  11. dry with materialdried (MgSO4)
  12. customthe solvent removed in vacuo
  13. customto give a clear oil
  14. stirringthe mixture stirred at r.t. for 18 h
  15. washwashed with water (7×30 mL)
  16. customThe organic layer was separated
  17. dry with materialdried (MgSO4)
  18. customthe solvent was removed in vacuo

Sources & evidence

ORD record
ord-f2eadee9202f4cb4877f63fa61d6ce62
Source dataset
uspto-grants-2013_03
Patent number
US08399483B2

Reaction notes

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