Potassium Carbonate → 2-(ethylamino)-4-(4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1,7-naphthyridin-8yl)benzonitrile

HRID 1403089Notes

Reaction equation

ClC1N=CC=C2C=1NC=CC2=O.C(C1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1NCC)#N.Cl[C:34]1[C:43]2[C:38](=[C:39]([C:44]3[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[C:46]([NH:52][CH2:53][CH3:54])[CH:45]=3)[N:40]=[CH:41][CH:42]=2)[N:37]=[CH:36][CH:35]=1.Cl.[NH:56]1[CH:60]=[C:59]([C:61]2[CH:62]=[N:63][N:64]([CH3:66])[CH:65]=2)[N:58]=[CH:57]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]=O>[CH2:53]([NH:52][C:46]1[CH:45]=[C:44]([C:39]2[N:40]=[CH:41][CH:42]=[C:43]3[C:38]=2[N:37]=[CH:36][CH:35]=[C:34]3[N:56]2[CH:60]=[C:59]([C:61]3[CH:62]=[N:63][N:64]([CH3:66])[CH:65]=3)[N:58]=[CH:57]2)[CH:51]=[CH:50][C:47]=1[C:48]#[N:49])[CH3:54]

Participants

Conditions

Temperature: 125 °C

Procedure

A suspension of 3-amino-2-chloropyridine (17.6 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (25.5 g) in isopropanol (274 ml) was heated to reflux for 5 minutes. After cooling, the deposit was filtrated to obtain 5-((2-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (34.8 g). The obtained 5-((2-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-di one (8.2 g) was gradually added to Dowtherm heated to 220° C., and the mixture was heated at 220° C. for 30 minutes. After cooling, hexane (300 ml) was added to the reaction solution, and the deposit was filtrated to obtain 8-chloro-1,7-naphthyridin-4(1H)-one (2.02 g). 4-(4-Chloro-1,7-naphthyridin-8-yl)-2-(ethylamino)benzonitrile (0.107 g) was obtained according to Example 5(1) using the obtained 8-chloro-1,7-naphthyridin-4(1H)-one (0.295 g) instead of compound (3a) and 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester instead of 3-quinolineboronic acid. A suspension of the obtained 4-(4-chloro-1,7-naphthyridin-8-yl)-2-(ethylamino)benzonitrile (0.0491 g), 4-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole hydrochloride (0.035 g), copper(II) oxide nanoparticles (0.06 g), and potassium carbonate (0.0883 g) in DMF (1.5 ml) was stirred overnight at 125° C. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 2-(ethylamino)-4-(4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1,7-naphthyridin-8yl)benzonitrile. An aqueous sodium hydroxide solution (4 M, 0.093 mL) and a 30% aqueous hydrogen peroxide solution (0.045 mL) were added to a solution of the obtained 2-(ethylamino)-4-(4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1,7-naphthyridin-8yl)benzonitrile in DMSO (3 mL) at room temperature, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, and the deposit was collected by filtration, then washed with water and ether by sprinkling, and then dried under reduced pressure to obtain compound (72) (0.040 g, yield based on 6 steps: 4%) as a pale yellow solid.

Workup

customThe reaction solution was partitioned between ethyl acetate and water
washThe organic layer was washed with brine
washThe organic layer thus washed
dry with materialwas dried over anhydrous sodium sulfate
distillationThen, the solvent was distilled off
customthe residue was purified by neutral silica gel column chromatography (chloroform/methanol)

Sources & evidence

ORD record: ord-acf50530ba27462497dc7035da8f13ed
Source dataset: uspto-grants-2014_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08912181B2

Reaction notes

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