6-Methoxy-3-pyridinylamine → 5-chloro-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine

HRID 1621435Notes

Reaction equation

HRID 1621435 reaction equation
[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:20][C:21]1[CH:22]=[C:23]([C:28]2[N:36]=[C:35]([CH3:37])[N:34]=[C:33]3[C:29]=2[N:30]=[CH:31][N:32]3[CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)[C:24](F)=[N:25][CH:26]=1>C1COCC1.C(Cl)Cl.[Cl-].[Na+].O>[Cl:20][C:21]1[CH:22]=[C:23]([C:28]2[N:36]=[C:35]([CH3:37])[N:34]=[C:33]3[C:29]=2[N:30]=[CH:31][N:32]3[CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)[C:24]([NH:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:25][CH:26]=1

Participants

7

Reactant 3

HCID 811216-Methoxy-3-pyridinylamineHCID 2733832Lithium HexamethyldisilazideHCID 595482256-(5-chloro-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

Product 1

HCID 595484095-chloro-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amineYield 91%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

A solution of 6-methoxypyridin-3-amine (0.357 g, 2.88 mmol) (Source: Aldrich) in THF (10 mL) was treated with lithium bis(trimethylsilyl)amide (5.03 mL, 5.03 mmol) (Source: Aldrich) and the mixture was stirred under an inert atmosphere for 20 minutes. Then 6-(5-chloro-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.500 g, 1.438 mmol) was added to the mixture and the mixture was stirred overnight. The reaction mixture was diluted with DCM and brine solution. The organic layer was collected by extracting the aqueous layer with DCM (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by ISCO Silica-Gel Chromatography, Teledyne ISCO, Lincoln, Nebr., (120 gram column), using a gradient of 10-60% EtOAc/DCM over 37 minutes. The fractions with desired material were combined and concentrated to give 5-chloro-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (0.590 g, 1.306 mmol, 91% yield) as a yellow solid. m/z (ESI, +ve) 452 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H); 8.40 (s, 1H); 8.23 (s, 1H); 8.16 (s, 2H); 7.19 (s, 1H); 6.75 (d, J=8.80 Hz, 1H); 5.80 (d, 1H); 4.14 (d, 1H); 3.91 (s, 4H); 3.76 (t, 1H); 2.83 (s, 3H); 1.46-2.25 (m, 5H).

Workup

  1. stirringthe mixture was stirred overnight
  2. customThe organic layer was collected
  3. extractionby extracting the aqueous layer with DCM (3×20 mL)
  4. dry with materialThe combined organic layers were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe crude was purified by ISCO Silica-Gel Chromatography, Teledyne ISCO, Lincoln, Nebr
  8. customover 37 minutes
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-59e6f9170cd64cb1b7239e93bc9bd5e7
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

Loading…