Sodium hydride → tert-Butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate

HRID 1499672Notes

Reaction equation

HRID 1499672 reaction equation
[H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[NH:6][N:5]=1.[Cl:14][C:15]1[C:16]([CH3:37])=[C:17]([CH:26]2[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]2)[C:18]([O:24][CH3:25])=[C:19]([CH:21](Cl)[CH3:22])[CH:20]=1>CN(C)C=O.O>[NH2:13][C:11]1[N:10]=[CH:9][N:8]=[C:7]2[N:6]([CH:21]([C:19]3[C:18]([O:24][CH3:25])=[C:17]([CH:26]4[CH2:27][N:28]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:29]4)[C:16]([CH3:37])=[C:15]([Cl:14])[CH:20]=3)[CH3:22])[N:5]=[C:4]([CH3:3])[C:12]=12

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 86677627tert-Butyl 3-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylateHCID 178434474HCID 178434474, compound

Product 1

HCID 86677628tert-Butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylateYield 59%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Procedure

At room temperature, sodium hydride (0.32 g, 8.0 mmol) was added to a suspension of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (from ChemBridge, 0.59 g, 4.0 mmol) in N,N-dimethylformamide (20 mL). The resulting mixture was stirred at room temperature for 25 minutes during which time the suspension became a nearly clear solution. To the resultant mixture was added a solution of tert-butyl 3-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate (1.35 g, 3.61 mmol, from Example 1, step 5) in N,N-dimethylformamide (10 mL). The mixture was stirred at 50° C. overnight. After cooling, the mixture was diluted with water and extracted with EtOAc (2×). The combined extracts were washed with water and brine, dried over MgSO4 and concentrated. The resulting residue was purified on silica gel, eluted with 0-10% MeOH in dichloromethane to give 1.03 g (59%) of the desired product as a yellow gum. The racemic products were applied on a Phenomenex Lux-Cellulose 2 column (21.1×250 mm, 5 micron particle size), eluting with 10% ethanol in hexanes at a flow rate of 18 mL/min, 4 mg/injection, to provide two enantiomers. The retention time of the first peak was 8.34 min and the retention time for the second peak was 10.92 min. Peak 1 (463 mg), LCMS calculated for C24H32ClN6O3 (M+H)+: m/z=487.2; Found: 487.1. 1H NMR (400 MHz, CDCl3): δ 8.21 (s, 1H), 7.37 (s, 1H), 6.30, (q, 1H), 5.40 (s, 2H), 4.23 (m, 2H), 4.17-4.00 (m, 3H), 3.57 (s, 3H), 2.58 (s, 3H), 2.16 (s, 3H), 1.76 (d, 3H), 1.37 (s, 9H) ppm.

Workup

  1. stirringThe mixture was stirred at 50° C. overnight
  2. temperatureAfter cooling
  3. extractionextracted with EtOAc (2×)
  4. washThe combined extracts were washed with water and brine
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated
  7. customThe resulting residue was purified on silica gel
  8. washeluted with 0-10% MeOH in dichloromethane

Sources & evidence

ORD record
ord-c315b5537f00479db62957f50ec85dc1
Source dataset
uspto-grants-2015_12
Patent number
US09199982B2

Reaction notes

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