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 2079522노트

반응식

HRID 2079522 반응식
[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

참가 물질

5

반응물 3

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

생성물 1

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

시약·촉매·용매 1

HCID 6342Acetonitrile용매

실험 절차

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).

후처리

  1. customthe reaction

출처 및 근거

ORD 기록
ord-09ce56ba4e964b2ebb700dbfab1b0a3d
출처 데이터셋
uspto-grants-2011_04
특허 번호
US07932256B2

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