Cesium carbonate → 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-pyrrolidin-1-ylbenzonitrile

HRID 1499923Notes

Reaction equation

[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([O:15][CH2:16][CH3:17])=[C:4]([CH:18](Cl)[CH3:19])[CH:3]=1.[CH3:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[N:28][C:29]=2[NH2:31])[NH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:31][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:24]([CH:18]([C:4]3[CH:3]=[C:2]([Cl:1])[C:7]([C:8]#[N:9])=[C:6]([N:10]4[CH2:14][CH2:13][CH2:12][CH2:11]4)[C:5]=3[O:15][CH2:16][CH3:17])[CH3:19])[N:23]=[C:22]([CH3:21])[C:30]=12

Participants

Conditions

Temperature: 85 °C

Procedure

The 6-chloro-4-(1-chloroethyl)-3-ethoxy-2-pyrrolidin-1-ylbenzonitrile (0.048 g, 0.15 mmol, racemic mixture) was combined with 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.034 g, 0.23 mmol) and cesium carbonate (0.10 g, 0.31 mmol) in N,N-dimethylformamide (3.0 mL) and heated in an oil bath to 85° C. After heating for 18 hrs the reaction was complete. The crude reaction was purified with out work up by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give the title compound as a white amorphous solid (0.012 g, 18%). The product was isolated as a racemic mixture. LCMS calculated for C21H25ClN7O (M+H)+: m/z=426.1; found 426.1. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 6.91 (s, 1H), 6.25 (q, J=7.1 Hz, 1H), 3.71 (dp, J=15.7, 8.1, 7.2 Hz, 4H), 3.49-3.35 (m, 2H), 2.55 (s, 3H), 2.00-1.76 (m, 4H), 1.70 (d, J=7.1 Hz, 3H), 1.34 (t, J=7.0 Hz, 3H).

Workup

temperatureAfter heating for 18 hrs the reaction
customThe crude reaction
customwas purified
washeluting water

Sources & evidence

ORD record: ord-97181ba0deac4c2189effa1578b65405
Source dataset: uspto-grants-2015_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09199982B2

Reaction notes

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