Cesium carbonate → tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate

HRID 1499913Notes

Reaction equation

HRID 1499913 reaction equation
Cl[CH:2]([C:4]1[C:5]([O:24][CH3:25])=[C:6]([CH:13]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[C:7]([C:11]#[N:12])=[C:8]([CH3:10])[CH:9]=1)[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:32][C:33]1[C:41]2[C:36](=[N:37][CH:38]=[N:39][C:40]=2[NH2:42])[NH:35][N:34]=1>CN(C)C=O.C(OCC)(=O)C>[NH2:42][C:40]1[N:39]=[CH:38][N:37]=[C:36]2[N:35]([CH:2]([C:4]3[C:5]([O:24][CH3:25])=[C:6]([CH:13]4[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]4)[C:7]([C:11]#[N:12])=[C:8]([CH3:10])[CH:9]=3)[CH3:3])[N:34]=[C:33]([CH3:32])[C:41]=12

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 86677833Tert-butyl 3-[3-(1-chloroethyl)-6-cyano-2-methoxy-5-methylphenyl]azetidine-1-carboxylateHCID 178434474HCID 178434474, compound

Product 1

HCID 86677834tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylateYield 50%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

The tert-butyl 3-[3-(1-chloroethyl)-6-cyano-2-methoxy-5-methylphenyl]azetidine-1-carboxylate (2.3 g, 6.3 mmol) was dissolved in N,N-dimethylformamide (68 mL) with cesium carbonate (4.1 g, 13 mmol) and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.4 g, 9.4 mmol) and was heated in an oil bath to 80° C. The reaction was stirred for 18 hrs and allowed to cool to room temperature. The reaction mixture was taken up in ethyl acetate, filtered, washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product. The product was purified by FCC on silica gel eluting a (hexane: 10% ethanol ethyl acetate) gradient to give tert-butyl 3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate as a semisolid (1.5 g, 50%). LCMS calculated for C25H32N7O3(M+H)+: m/z=478.2; found: 478.2. The enantiomers were separated by Chiral column HPLC using: Phenomenex LUX Cellulose Column, 21.1×250 mm, 5 micron, 15% ethanol in hexane, 18 mL/min ˜5 mg/injection to give: First peak retention time: 2.1 minutes, tert-butyl 3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate; Second peak retention time: 3.9 minutes, tert-butyl 3-{3-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-methoxy-5-methylphenyl}azetidine-1-carboxylate.

Workup

  1. temperatureto cool to room temperature
  2. filtrationfiltered
  3. washwashed with water, brine
  4. dry with materialdried over magnesium sulfate
  5. concentrationconcentrated
  6. customto give the crude product
  7. customThe product was purified by FCC on silica gel eluting a (hexane: 10% ethanol ethyl acetate) gradient

Sources & evidence

ORD record
ord-7c9c1ce670784c5fbba4540fa0c49a7a
Source dataset
uspto-grants-2015_12
Patent number
US09199982B2

Reaction notes

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