Diisopropylethylamine → (6-Fluoroquinolin-3-yl)(4-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)-2,3'-bipyridin-6'-ylamino)piperidin-1-yl)methanone

HRID 2283499Notes

Reaction equation

[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([C:19]2[CH:20]=[N:21][C:22]([NH:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:23][CH:24]=2)[CH:3]=1.CCN(C(C)C)C(C)C.[F:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[N:48]=[CH:47][C:46]([C:52](O)=[O:53])=[CH:45]2.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>CN(C=O)C.CS(C)=O>[F:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[N:48]=[CH:47][C:46]([C:52]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:22]3[N:21]=[CH:20][C:19]([C:4]4[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([NH:8][C:9]5[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=5)[N:5]=4)=[CH:24][CH:23]=3)[CH2:27][CH2:28]1)=[O:53])=[CH:45]2

Participants

Conditions

Temperature: 40 °C

Procedure

4-Methyl-N6′-(piperidin-4-yl)-N6-(4-(trifluoromethyl)pyridin-2-yl)-2,3′-bipyridine-6,6′-diamine (30 mg, 0.07 mmol) was dissolved in DMF (500 μL). The solution was then treated with DIEA (24 μL, 0.14 mmol), 6-fluoroquinoline-3-carboxylic acid (20 mg. 0.11 mmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (42 μL, 0.07 mmol). The reaction was warmed to 40° C. and stirred for 16 hours. The reaction was allowed to cool to room temperature: The mixture was diluted with DMSO (1.0 mL) and purified by mass-triggered reverse phase high pressure liquid chromatography, eleuting with a 1% ammonium hydroxide buffered water/acetonitrile gradient over a Waters X-Bridge C-18 column, to afford (6-fluoroquinolin-3-yl)(4-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)-2,3′-bipyridin-6′-ylamino)piperidin-1-yl)methanone. MS ESI calcd. for C32H28F4N7O [M+H]+ 602. found 602. 1H NMR (600 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.87 (d, J=2.0 Hz, 1H), 8.66 (d, J=2.1 Hz, 1H), 8.60 (s, 1H), 8.44 (d, J=5.2 Hz, 1H), 8.42 (d, J=1.8 Hz, 1H), 8.11 (dd, J=5.4, 9.2 Hz, 1H), 8.00 (dd, J=2.4, 8.8 Hz, 1H), 7.86 (dd, J=2.9, 9.3 Hz, 1H), 7.73 (m, 1H), 7.20 (s, 1H), 7.14 (d, J=5.1 Hz, 1H), 7.07 (s, 1H), 6.87 (d, J=7.6 Hz, 1H), 6.56 (d, J=8.8 Hz, 1H), 4.37 (s, 1H), 4.06 (s, 1H), 3.32 (s, 1H), 2.47-2.45 (m, 1H), 2.27 (s, 3H), 2.04 (s, 1H), 1.90 (s, 1H), 1.49 (s, 1H), 1.42 (s, 2H). rhSyk IC50=8 nM.

Workup

temperatureto cool to room temperature
custompurified by mass-triggered reverse phase high pressure liquid chromatography

Sources & evidence

ORD record: ord-845a38aca2954679841df8c71fe23297
Source dataset: uspto-grants-2015_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09145391B2

Reaction notes

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