Potassium Iodide → Benzyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine-1-carboxylate

HRID 1499771Notes

Reaction equation

HRID 1499771 reaction equation
[Cl:1][C:2]1[C:3]([CH3:28])=[C:4]([CH:14]2[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8](Cl)[CH3:9])[CH:7]=1.[CH3:29][C:30]1[C:38]2[C:33](=[N:34][CH:35]=[N:36][C:37]=2[NH2:39])[NH:32][N:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C)C=O.CCOCC>[NH2:39][C:37]1[N:36]=[CH:35][N:34]=[C:33]2[N:32]([CH:8]([C:6]3[C:5]([O:11][CH2:12][CH3:13])=[C:4]([CH:14]4[CH2:15][N:16]([C:18]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])[CH2:17]4)[C:3]([CH3:28])=[C:2]([Cl:1])[CH:7]=3)[CH3:9])[N:31]=[C:30]([CH3:29])[C:38]=12

Participants

7

Reactant 4

HCID 4875Potassium IodideHCID 10796Cesium carbonateHCID 86677655HCID 86677655, compoundHCID 178434474HCID 178434474, compound

Product 1

HCID 86677703Benzyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine-1-carboxylateYield 50.5%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
140 °C

Procedure

A mixture of benzyl 3-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-methylphenyl]azetidine-1-carboxylate (0.375 g, 0.888 mmol, from Example 35, Step 3), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.16 g, 1.1 mmol), cesium carbonate (0.43 g, 1.3 mmol) and potassium iodide (15 mg, 0.089 mmol) in N,N-dimethylformamide (2.8 mL) was heated at 140° C. for 1 h. The mixture was diluted with ether, and washed with water. The organic layers were concentrated and purified on silica gel (eluting with 0 to 100% EtOAc in hexanes) to give the desired product (0.24 g, 50%). LCMS calculated for C28H32ClN6O3 (M+H)+: m/z=535.2; Found: 535.0. The enantiomers were separated on a Phenomenex Lux Cellulose C-2 column (5 μM, 21.2×250 mm), eluting with 20% ethanol in hexanes, at flow rate of 18 mL/min, and column loading of ˜4.5 mg/injection to separate two enantiomers. First peak retention time: 21.2 min; second peak retention time: 24.6 min.

Workup

  1. washwashed with water
  2. concentrationThe organic layers were concentrated
  3. custompurified on silica gel (eluting with 0 to 100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-39167347ccff4ffb99749b9d66869575
Source dataset
uspto-grants-2015_12
Patent number
US09199982B2

Reaction notes

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