Lithium Hexamethyldisilazide → (3s)-Tert-butyl 4-((1r)-1-(6-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2h-pyran-2-yl)-9h-purin-6-yl)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate

HRID 1621857Notes

Reaction equation

HRID 1621857 reaction equation
F[C:2]1[N:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@@H:11]2[CH3:23])[CH3:9])=[CH:4][C:3]=1[C:24]1[N:32]=[C:31]([CH3:33])[N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1.[F:40][C:41]1[CH:42]=[C:43]([NH2:49])[CH:44]=[N:45][C:46]=1[O:47][CH3:48].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[F:40][C:41]1[CH:42]=[C:43]([NH:49][C:2]2[N:7]=[CH:6][C:5]([C@H:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][C@@H:11]3[CH3:23])[CH3:9])=[CH:4][C:3]=2[C:24]2[N:32]=[C:31]([CH3:33])[N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][N:28]3[CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[CH:44]=[N:45][C:46]=1[O:47][CH3:48]

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 454803515-Fluoro-6-methoxypyridin-3-amineHCID 68511317(3S)-tert-butyl 4-((1R)-1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate

Product 1

HCID 68516009(3s)-Tert-butyl 4-((1r)-1-(6-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2h-pyran-2-yl)-9h-purin-6-yl)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylateYield 39.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-20 °C

Procedure

A mixture of (3S)-tert-butyl 4-((1R)-1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (0.323 g, 0.599 mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.170 g, 1.197 mmol) in THF (15 mL) was chilled to −20° C. in a diluted dry ice/acetone bath, then lithium bis(trimethylsilyl)amide (1.0 M in THF, Aldrich; 1.796 mL, 1.796 mmol) was added slowly via syringe into the reaction mixture. After the addition, the ice bath was removed and the mixture was allowed to stir under inert atmosphere for 1 h. The mixture was diluted with chloroform (20 mL) and water (10 mL). The organic layer was extracted with chloroform (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was adsorbed onto silica gel and purified by chromatography through a silica-gel column (80 g) eluting with 100% EtOAc to give (3S)-tert-butyl 4-((1R)-1-(6-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (0.155 g, 0.234 mmol, 39.1% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 12.63 (s, 1H) 9.71 (d, J=2.15 Hz, 1H) 8.32 (dd, J=12.52, 2.15 Hz, 1H) 8.22 (s, 1H) 8.17 (d, J=2.35 Hz, 1H) 8.03 (d, J=2.15 Hz, 1H) 5.80 (dd, J=10.56, 2.15 Hz, 1H) 4.12 (s, 2H) 3.96 (s, 3H) 3.76 (d, J=2.54 Hz, 1H) 3.53 (m, 1H) 3.23 (m, 1H) 2.84 (s, 5H) 2.41 (m, 1H) 2.08 (s, 1H) 2.03 (s, 1H) 1.97 (s, 1H) 1.64 (s, 3H) 1.58 (s, 2H) 1.45 (d, J=6.85 Hz, 3H) 1.32 (s, 9H) 1.07 (d, J=5.87 Hz, 3H). m/z (ESI, +ve ion) 662.2 (M+H)+.

Workup

  1. additionAfter the addition
  2. customthe ice bath was removed
  3. additionThe mixture was diluted with chloroform (20 mL) and water (10 mL)
  4. extractionThe organic layer was extracted with chloroform (3×10 mL)
  5. dry with materialThe combined organic extracts were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. custompurified by chromatography through a silica-gel column (80 g)
  9. washeluting with 100% EtOAc

Sources & evidence

ORD record
ord-ead4a99661f64f459c298d4529f314af
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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