6-Methoxy-3-pyridinylamine → N-(6-Methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(4-(methylsulfonyl)benzyl)pyridin-2-amine

HRID 1811892Notes

Reaction equation

HRID 1811892 reaction equation
[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[C:26]([C:27]2[N:35]=[C:34]([CH3:36])[N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][N:31]3[CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)=[CH:25][C:24]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([S:50]([CH3:53])(=[O:52])=[O:51])=[CH:46][CH:45]=2)=[CH:23][N:22]=1>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:21]2[C:26]([C:27]3[N:35]=[C:34]([CH3:36])[N:33]=[C:32]4[C:28]=3[N:29]=[CH:30][N:31]4[CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][O:38]3)=[CH:25][C:24]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([S:50]([CH3:53])(=[O:51])=[O:52])=[CH:46][CH:45]=3)=[CH:23][N:22]=2)=[CH:5][CH:4]=1

Participants

5

Reactant 3

HCID 811216-Methoxy-3-pyridinylamineHCID 2733832Lithium HexamethyldisilazideHCID 595482776-(2-fluoro-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

Product 1

HCID 59548324N-(6-Methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(4-(methylsulfonyl)benzyl)pyridin-2-amine

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

6-methoxy-3-aminopyridine (Aldrich) (214 μL, 2.00 mmol) was dissolved in THF (1.80 mL) and cooled in an ice bath. LiHMDS (2.00 mL, 1.0 M in THF, 2.0 mmol) was added dropwise over 5 min. The resulting dark brown solution was stirred for 30 min prior to use. A solution of 6-(2-fluoro-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (92.6 mg, 0.192 mmol) in THF (1.0 mL) was cooled in an ice bath and treated dropwise with 0.85 mL of the above anilide solution (0.425 mmol) over 15 min, resulting in a deep red solution. 85% Conversion to desired product was observed by LCMS (215 nm) 5 min after completion of addition in a clean reaction. The reaction was checked after another 30 min and appeared to have stalled, so an additional 0.20 mL of the anilide solution was added dropwise. The mixture was stirred for 10 min, and then quenched by the addition of water (0.2 mL). The product was extracted into EtOAc from saturated aqueous NaHCO3, dried (MgSO4), concentrated and purified by flash chromatography (50% to 60% to 70% EtOAc/hexane) to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(4-(methylsulfonyl)benzyl)pyridin-2-amine (94.5 mg, 0.161 mmol, 84% yield) as a dark yellow foam. 1H NMR (400 MHz, CDCl3) δ 12.44 (s, 1H); 9.61 (d, J=2.15 Hz, 1H); 8.41 (d, J=2.74 Hz, 1H); 8.25 (s, 1H); 8.19 (dd, J=8.80, 2.74 Hz, 1H); 8.14 (d, J=2.15 Hz, 1H); 7.86 (d, J=8.22 Hz, 2H); 7.47 (d, J=8.02 Hz, 2H); 6.77 (d, J=8.80 Hz, 1H); 5.86 (d, J=10.37 Hz, 1H); 4.20 (d, J=11.35 Hz, 1H); 4.10 (s, 2H); 3.95 (s, 3H); 3.77-3.85 (m, 1H); 3.01 (s, 3H); 2.89 (s, 3H); 1.97-2.23 (m, 3H); 1.62-1.91 (m, 3H). m/z (ESI, +ve ion) 586.1 (M+H)+.

Workup

  1. temperaturecooled in an ice bath
  2. customresulting in a deep red solution

Sources & evidence

ORD record
ord-15a550eb1c5049c4951c11be46e8676c
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

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