Sodium bis(trimethylsilyl)amide → 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)piperazine-1-carboxylate

HRID 1621860Notes

Reaction equation

HRID 1621860 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][CH2:11]2)[CH3:9])=[CH:4][C:3]=1[C:23]1[N:31]=[C:30]([CH3:32])[N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1.[F:39][C:40]1[CH:41]=[C:42]([NH2:48])[CH:43]=[N:44][C:45]=1[O:46][CH3:47].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:39][C:40]1[CH:41]=[C:42]([NH:48][C:2]2[N:7]=[CH:6][C:5]([C@H:8]([N:10]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15]3)[CH3:9])=[CH:4][C:3]=2[C:23]2[N:31]=[C:30]([CH3:32])[N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3[CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH:43]=[N:44][C:45]=1[O:46][CH3:47]

Participants

5

Reactant 3

HCID 2724254Sodium bis(trimethylsilyl)amideHCID 454803515-Fluoro-6-methoxypyridin-3-amineHCID 68518749tert-butyl 4-((1R)-1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)piperazine-1-carboxylate

Product 1

HCID 68515999Tert-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)piperazine-1-carboxylateYield 55.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-20 °C

Procedure

A mixture of tert-butyl 4-((1R)-1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)piperazine-1-carboxylate (0.673 g, 1.280 mmol) in THF (15 mL) under inert atmosphere was treated with a solution of 5-fluoro-6-methoxypyridin-3-amine (0.364 g, 2.56 mmol) in THF (10 mL) via syringe. The mixture was chilled to −20° C. in a diluted dry ice/acetone bath, then sodium bis(trimethylsilyl)amide (1.0 M in THF, Aldrich; 3.84 mL, 3.84 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 a plug of silica gel and purified by chromatography through a silica-gel column (80 g) eluting with 100% ethyl acetate to give 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)piperazine-1-carboxylate (0.459 g, 0.709 mmol, 55.3% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 12.61 (s, 1H) 9.65 (t, J=1.96 Hz, 1H) 8.31 (dd, J=12.52, 2.35 Hz, 1H) 8.18-8.23 (m, 2H) 8.03 (d, J=2.35 Hz, 1H) 5.80 (dd, J=10.47, 2.05 Hz, 1H) 3.96 (s, 3H) 3.76 (s, 1H) 3.55 (d, J=6.85 Hz, 1H) 3.36 (s, 4H) 2.85 (s, 3H) 2.40 (d, J=3.33 Hz, 4H) 2.07 (s, 1H) 2.02 (s, 1H) 1.97 (s, 1H) 1.54-1.81 (m, 2H) 1.41 (d, J=6.65 Hz, 3H) 1.36 (s, 9H) 1.19 (s, 1H) 0.90 (d, J=6.65 Hz, 1H). m/z (ESI, +ve ion) 648.2 (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% ethyl acetate

Sources & evidence

ORD record
ord-03c8c857f5a3485497801ccd3784cb7e
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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