Cesium fluoride → 2-Pyrazinecarbonitrile,4-[(1S)-1-cyclopropyl-2-methoxyethyl]-6-[[6-(difluoromethoxy)-2,5-dimethyl-3-pyridinyl]amino]-4,5-dihydro-5-oxo-

HRID 2079522Notes

Reaction equation

HRID 2079522 reaction equation
[CH:1]1([C@H:4]([N:8]2[C:13](=[O:14])[C:12]([NH:15][C:16]3[C:17]([CH3:24])=[N:18][C:19]([OH:23])=[C:20]([CH3:22])[CH:21]=3)=[N:11][C:10]([C:25]#[N:26])=[CH:9]2)[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1.[F-].[Cs+].[F:29][C:30]([F:42])(S(F)(=O)=O)C(O[Si](C)(C)C)=O>C(#N)C>[CH:1]1([C@H:4]([N:8]2[C:13](=[O:14])[C:12]([NH:15][C:16]3[C:17]([CH3:24])=[N:18][C:19]([O:23][CH:30]([F:42])[F:29])=[C:20]([CH3:22])[CH:21]=3)=[N:11][C:10]([C:25]#[N:26])=[CH:9]2)[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 25953Cesium fluorideHCID 2778022Trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetateHCID 178495711HCID 178495711, compound

Product 1

HCID 441602642-Pyrazinecarbonitrile,4-[(1S)-1-cyclopropyl-2-methoxyethyl]-6-[[6-(difluoromethoxy)-2,5-dimethyl-3-pyridinyl]amino]-4,5-dihydro-5-oxo-

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A mixture of pure (S)-4-(1-cyclopropyl-2-methoxyethyl)-6-(6-hydroxy-2,5-dimethylpyridin-3-ylamino)-5-oxo-4,5-dihydropyrazine-2-carbonitrile (2.3 g, 6.5 mmol) and CsF (395 mg, 2.6 mmol) was added to acetonitrile (65 mL). To the resulting suspension, trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3.82 mL, 19.4 mmol) was slowly added (use extreme caution! The reagent can cause dermatological damage and should always be handled in hood). LC-MS analysis after 1 h showed the reaction to be complete (89% conversion to required product), Volatiles were evaporated in vacuo and the residue was partitioned between EtOAc (3×120 mL) and H2O (˜100 mL). The organic layer was washed with water (2×50 mL) and brine (50 mL), and dried over Na2SO4. The ethyl acetate was evaporated in vacuo and the residue was dissolved in DMF (10 mL). The solution was applied to C18 silica gel column (14 cm×5 cm) equilibrated with MeCN:H2O (1:2). The column was eluted with 33% MeCN/H2O (500 mL), 45% MeCN/H2O (500 mL), 60% MeCN/H2O (1000 mL), 70% MeCN/H2O (500 mL). Individual fractions were analyzed by LC-MS (product comes out in between 60%-70% MeCN/H2O). Fractions containing pure product were combined and concentrated in vacuo to give pure (S)-4-(1-cyclopropyl-2-methoxyethyl)-6-(6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino)-5-oxo-4,5-dihydropyrazine-2-carbonitrile (2.28 g, 87% yield) as pale yellow solid: 1H NMR (CDCl3) δ 8.43 (s, 1H); 8.01 (s, 1H); 7.56 (s, 1H); 7.49 (t, JH-F=73.8 Hz, 1H); 4.15-4.18 (m, 1H); 3.76 (dd, JAB=10.4, JAX=5.2 Hz, 1H); 3.68 (dd, JBA=10.4, JBX=3.1 Hz, 1H); 3.37 (s, 3H); 2.46 (s, 3H); 2.30 (s, 3H); 1.35-1.42 (m, 1H); 0.82-0.88 (m, 1H); 0.64-0.69 (m, 1H); 0.53-0.58 (m, 1H); 0.31-0.36 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 153.0, 151.5, 147.8, 143.8, 133.3, 129.4, 125.6, 119.1, 117.2, 114.8 (t, J=256.1 Hz, 1C), 107.6, 72.7, 62.6, 59.6, 20.0, 15.5, 11.4, 6.4, 4.2; 19F NMR (CDCl3) δ-88.73 (d); LRMS (ESI) m/e 406 [(M+H)+, calcd for C19H22N5O3F2 406]; tR=2.7 min (Solvent A: MeOH:H2O:TFA=10:90:0.1; Solvent B: MeOH:H2O:TFA=90:10:0.1; 40% B in A to 100% B in A linear gradient in a 3 min run with 1 min hold time at the end, λ=280 nm).

Workup

  1. customthe reaction

Sources & evidence

ORD record
ord-09ce56ba4e964b2ebb700dbfab1b0a3d
Source dataset
uspto-grants-2011_04
Patent number
US07932256B2

Reaction notes

Loading…