Lithium Hexamethyldisilazide → N-(5-((4-methoxybenzyloxy)methyl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine

HRID 1811855Notes

Reaction equation

HRID 1811855 reaction equation
F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:6][C:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:4][N:3]=1.[O:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[N:41]1[C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([NH2:50])[C:44]=2[CH:43]=[N:42]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][O:25][CH2:24][C:5]2[CH:6]=[C:7]([C:8]3[N:16]=[C:15]([CH3:17])[N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][N:12]4[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:2]([NH:50][C:45]3[C:44]4[CH:43]=[N:42][N:41]([CH:36]5[CH2:37][CH2:38][CH2:39][CH2:40][O:35]5)[C:49]=4[CH:48]=[CH:47][CH:46]=3)=[N:3][CH:4]=2)=[CH:28][CH:29]=1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 441182321-(Oxan-2-yl)-1H-indazol-4-amineHCID 595483946-(2-fluoro-5-((4-methoxybenzyloxy)methyl)pyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

Product 1

HCID 68511560N-(5-((4-methoxybenzyloxy)methyl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amineYield 77.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

6-(2-Fluoro-5-((4-methoxybenzyloxy)methyl)pyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (1.223 g, 2.634 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (0.596 g, 2.74 mmol) were dissolved in THF (23.5 mL) and the flask was cooled in an ice water bath under nitrogen. Then, LiHMDS (1.0 M in THF, 7.8 mL, 7.8 mmol) was added via syringe, and the reaction was stirred under nitrogen at 0° C. for 35 minutes. Then, the reaction was quenched with water (40 mL) and diluted with water (40 mL), and then extracted with DCM and with 10:1 DCM/MeOH. Brine was added to break up emulsions. The organic extracts were combined, concentrated, and purified on a silica gel filter (about 3 inches, 50:1 DCM/2 N ammonia in MeOH to 40:1 DCM/2 N ammonia in MeOH) to afford N-(5-((4-methoxybenzyloxy)methyl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (1.343 g, 54% purity, 43% yield). MS (ESI pos. ion) m/z 661 (M+H)+.

Workup

  1. temperaturethe flask was cooled in an ice water bath under nitrogen
  2. customThen, the reaction was quenched with water (40 mL)
  3. additiondiluted with water (40 mL)
  4. extractionextracted with DCM and with 10:1 DCM/MeOH
  5. additionBrine was added
  6. concentrationconcentrated
  7. custompurified on a silica gel
  8. filtrationfilter (about 3 inches, 50:1 DCM/2 N ammonia in MeOH to 40:1 DCM/2 N ammonia in MeOH)

Sources & evidence

ORD record
ord-89082ea66f4043d3a940fb0e45519c23
Source dataset
uspto-grants-2013_01
Patent number
US08362241B2

Reaction notes

Loading…