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1-Brom-2-nitrobenzol, Glycerin, wssr.HCl (neben anderen Verb.);
2
[ 50488-36-3 ]
[ 16567-11-6 ]
Yield
Reaction Conditions
Operation in experiment
77%
Step 3 8-Bromo-6-chloroquinoline 8-Bromo-6-chloroquinoline is synthesised by the method described for Example 5, Step 5, where 6-chloro-quinolin-8-ylamine is used in place of 6-methoxy-quinolin-8-yl-amine. Yield: 77% yield of a tan solid. MS (ES) m/z 243 (MH)+.
Stage #1: 8-Bromo-6-chloroquinoline With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; bis(pinacol)diborane; catacxium A In N,N-dimethyl acetamide at 90℃; for 1h; Inert atmosphere;
Stage #2: bromobenzene With potassium carbonate In water; <i>N</i>,<i>N</i>-dimethyl-aniline Inert atmosphere;
With hydrogenchloride; copper(l) chloride; sodium nitrite In water at 0℃; for 0.85h;
3 Step 3.Preparation of 8-bromo-6-chloroquinoline
Step 3. Preparation of 8-bromo-6-chloroquinoline 8-Bromoquinolin-6-amine (300 mg, 1.34 mmol) was taken up in concentrated hydrochloric acid (8 ml) and cooled to 0° C. (ice bath). Sodium nitrite (1.86 gm, 26.9 mmol) was added in three equal portions over 10 minutes. The mixture was removed from the cooling bath and copper (I) chloride (3.33 g, 33.6 mmol) was added in 3 portions, over about 6 minutes. On stirring a green-black rising foam developed. Stirring was continued for 45 minutes and then the reaction mixture was cooled to 0° C. (ice bath). A mixture of ice water (75 ml) and ammonium hydroxide (75 ml) was added with vigorous stirring. Dichloromethane (150 ml) was added and the material was shaken in a reparatory funnel. The organic phase was collected and shaken with an equal volume of brine. The aqueous phases were back extracted with dichloromethane (2*120 ml). The organics were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative thin layer chromatography (2 plates), eluting first with 1% methanol/dichloromethane and then re-developing the plate with 25% ethyl acetate/hexane. The product band was collected, providing the desired product as a light yellow-white solid (287 mg). (M+H)+=242/244 m/e.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 90℃; for 14h; Inert atmosphere;
Step 4.Preparation of [6-(6-Chloro-quinolin-8-ylamino)-pyridin-3-yl]-morpholin-4-yl-methanone
Step 4. Preparation of [6-(6-Chloro-quinolin-8-ylamino)-pyridin-3-yl]-morpholin-4-yl-methanone A mixture of 8-bromo-6-chlorquinoline (140 mg, 0.56 mmol), (6-aminopyrdin-3-yl)(morpholino)methanone (92 mg, 0.44 mmol), xantphos (38.5 mg, 0.067 mmol) and cesium carbonate was taken up in dry dioxane (6.5 ml). The reaction flask is evacuated and back-filled with argon (repeated 5 times). Tris(dibenzylidenacetone)palladium (0) (31 mg, 0.033 mmol) was added and the flask was evacuated and back-filled with argon (repeated 3 times). The material was heated to 90° C. (oil bath) under argon for 14 hours. The reaction mixture was cooled to ambient temperature and filtered through a short plug of celite, rinsing well with dioxane. The solvent was removed and the resulting residue loaded onto 2 preparative thin layer chromatography plates. The plates were eluted with 75% ethyl acetate/hexane and the product band collected. This provided the desired product as a light brown viscous oil (180 mg). (M+H)+=369 m/e.
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