Cesium carbonate → 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-ethoxy-5-methylphenyl}-N,N-dimethylpyridine-2-carboxamide

HRID 1499906Notes

Reaction equation

HRID 1499906 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[N:14][C:15]=2[NH2:17])[NH:10][N:9]=1.Cl[CH:19]([C:21]1[C:22]([O:41][CH2:42][CH3:43])=[C:23]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([N:38]([CH3:40])[CH3:39])=[O:37])=[N:34][CH:35]=2)[C:24]([C:28]#[N:29])=[C:25]([CH3:27])[CH:26]=1)[CH3:20]>CN(C)C=O.CCOC(C)=O>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:19]([C:21]3[C:22]([O:41][CH2:42][CH3:43])=[C:23]([C:30]4[CH:31]=[CH:32][C:33]([C:36]([N:38]([CH3:39])[CH3:40])=[O:37])=[N:34][CH:35]=4)[C:24]([C:28]#[N:29])=[C:25]([CH3:27])[CH:26]=3)[CH3:20])[N:9]=[C:8]([CH3:7])[C:16]=12

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 866778285-[3-(1-chloroethyl)-6-cyano-2-ethoxy-5-methylphenyl]-N,N-dimethylpyridine-2-carboxamideHCID 178434474HCID 178434474, compound

Product 1

HCID 866778295-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-ethoxy-5-methylphenyl}-N,N-dimethylpyridine-2-carboxamideYield 77.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

Cesium carbonate (4000 mg, 10 mmol) was added to a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1300 mg, 8.5 mmol) and 5-[3-(1-chloroethyl)-6-cyano-2-ethoxy-5-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (2.1 g, 5.6 mmol) in N,N-dimethylformamide (100 mL). The reaction was stirred at 80° C. for 3 hrs and monitored by LC/MS. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered and concentrated to give the crude product. The product was purified by FCC on silica gel eluting (hexane/10% EtOH in EtOAc, gradient 0-100%) gradient to give the title compound (2.1 g, 77%). LCMS calculated for C26H29N8O2(M+H)+: m/z=485.2; found: 485.2. 1H NMR (500 MHz, DMSO-d6) δ 8.70-8.63 (m, 1H), 8.10 (s, 1H), 8.06 (dd, J=8.0, 2.2 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.51 (s, 1H), 6.34 (q, J=7.0 Hz, 1H), 3.59-3.47 (m, 1H), 3.33 (m, 1H), 3.03 (s, 3H), 2.96 (s, 3H), 2.57 (s, 3H), 2.45 (s, 3H), 1.79 (d, J=7.1 Hz, 3H), 0.90 (t, J=7.0 Hz, 3H). The enantiomers were separated by Chiral column HPLC using: AD column 20×25 cm, eluting hexane; 30% ethanol @ 13 mL/min 5 mg/injection to give: First peak retention time: 1.63 minutes, 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-ethoxy-5-methylphenyl}-N,N-dimethylpyridine-2-carboxamide; Second peak retention time: 4.13 minutes, 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-ethoxy-5-methylphenyl}-N N-dimethylpyridine-2-carboxamide.

Workup

  1. washwashed with water, brine
  2. dry with materialdried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customto give the crude product
  6. customThe product was purified by FCC on silica gel eluting (hexane/10% EtOH in EtOAc, gradient 0-100%) gradient

Sources & evidence

ORD record
ord-eaa167c1498f4764bcbce05bbbb9b2ab
Source dataset
uspto-grants-2015_12
Patent number
US09199982B2

Reaction notes

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