Stannanecarbonitrile, tributyl- → 3-Methyl-2-(4-methylpyridin-2-yl)-4-(5-morpholinopyridin-3-ylamino)-quinoline-8-carbonitrile

HRID 1431540Notes

Reaction equation

C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([Sn]([C:48]#[N:49])(CCCC)CCCC)CCC.Cl[C:51]1[CH:52]=[CH:53][CH:54]=[C:55]2[C:60]=1[N:59]=[C:58]([C:61]1[CH:66]=[C:65]([CH3:67])[CH:64]=[CH:63][N:62]=1)[C:57]([CH3:68])=[C:56]2[NH:69][C:70]1[CH:71]=[N:72][CH:73]=[C:74]([N:76]2[CH2:81][CH2:80][O:79][CH2:78][CH2:77]2)[CH:75]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:68][C:57]1[C:58]([C:61]2[CH:66]=[C:65]([CH3:67])[CH:64]=[CH:63][N:62]=2)=[N:59][C:60]2[C:55]([C:56]=1[NH:69][C:70]1[CH:71]=[N:72][CH:73]=[C:74]([N:76]3[CH2:81][CH2:80][O:79][CH2:78][CH2:77]3)[CH:75]=1)=[CH:54][CH:53]=[CH:52][C:51]=2[C:48]#[N:49]

Participants

Conditions

Temperature: 100 °C

Procedure

To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.025 g, 0.053 mmol), tri-n-butyltin cyanide (0.104 g, 0.33 mmol), 8-chloro-3-methyl-2-(4-methylpyridin-2-yl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine (0.15 g, 0.33 mmol) and Pd2dba3 (0.012 g, 0.013 mmol) in toluene (3.30 mL) was added sodium tert-butoxide (0.079 g, 0.82 mmol). The reaction mixture was heated to 100° C. for 66 h. After which, the reaction mixture was filtered through a plug of alumina eluting with (EtOAc), the filtrate was cond in vacuo. The crude product was purified by column chromatography on alumina (0 to 50% EtOAc in hexanes) to give the desired product. The desired product was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution, the solvent was removed under reduced pressure to yield pure product 3-methyl-2-(4-methylpyridin-2-yl)-4-(5-morpholinopyridin-3-ylamino)quinoline-8-carbonitrile. 1H NMR (400 MHz, CD2Cl2) δ ppm 8.59 (1H, d, J=5.5 Hz), 8.06 (2H, ddd, J=14.8, 7.9, 1.4 Hz), 7.86 (1H, d, J=2.5 Hz), 7.78-7.83 (1H, m), 7.67 (1H, d, J=2.3 Hz), 7.48 (1H, dd, J=8.5, 7.1 Hz), 7.27 (1H, m), 6.60 (1H, s), 6.43 (1H, t, J=2.3 Hz), 3.75 (4H, m), 3.05 (4H, m), 2.51 (3H, s), 2.36 (3H, s). Mass Spectrum (ESI) m/e=437.1 (M+1).

Workup

filtrationAfter which, the reaction mixture was filtered through a plug of alumina eluting with (EtOAc)
customThe crude product was purified by column chromatography on alumina (0 to 50% EtOAc in hexanes)

Sources & evidence

ORD record: ord-6336e1e2e41d4131b0a2f4382d33da76
Source dataset: uspto-grants-2015_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08940724B2

Reaction notes

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