N-(4-Chloro-3-cyano-7-ethoxy-6-quinolinyl)acetamide

yellow powder

6-Acetylamido-7-ethoxy-3-cyano-4-chloro-quinoline (a compound of formula A, W=Cl) The title compound of example 28 (23 g, 0.0857 mol) was added to diethylene glycol dimethyl ether (400 mL), and then POCl3 (24 mL, 0.257 mol) was added thereto and stirred at 85 C. for 4-4.5 h. The reaction mixture was slowly poured into two volumes of ice-water and stirred for 1 h to precipitate a yellow powder. The precipitate was filtered and washed with water and then washed with a small amount of diethylene glycol dimethyl ether, and dried at 40 C. to give 23 g of the title compound with a yield of 93.6%.To the reaction flask was added Compound VIII (0.47 mol)Dissolved in diethylene glycol dimethyl ether (1L)POCl3 (1.41 mol) was added to the system, Heated to 100 ~ 102 reaction 1h.After the reaction, Cooling to 80 ~ 85 , Celite (50g), Suction filtration, The filter cake was washed with diethylene glycol dimethyl ether (100 ml * 3).To the filtrate was added potassium carbonate solution (150 g)Control the temperature below 50 , Suction filtration, The filter cake is washed with water, The solid was vacuum dried at 50 C, Compound IX (0.43 mol) was obtained, Yield 91%.Preparation of 4-chloro-3-cyano-7-ethoxy-6-acetylamino quinoline; 3-cyano-7-ethoxy-4-hydroxy-6-acetylamino quinoline (150 g, 0.474 mol) was stirred with silica gel (60 g) in acetonitrile (1.35 L). The brown suspension was heated to 78-82 C. Phosphorus oxychloride (146 g, 0.949 mol) was added over 30-40 min. The mixture was stirred at 78-82 C. for 1-2 hrs then cooled to 40-45 C., filtered over a celite pad and washed with acetonitrile. The filtrates were quenched in a potassium carbonate solution (262 g, 1.9 mol) in water (1.8 L) at 0-5 C. over 45 min. The brownish suspension was stirred at 5-20 C. for at least 2 hours then filtered and washed with water. The brown/tan solid was dried in a vacuum oven at 50 C. to yield 105 g (76.5%). HPLC Strength 89.9% Tot imp.=4.87% Sing. imp.=1.28% GC(CH3CN)=0.83% Water-content data determined on the basis of weight decrease in a loss on drying (LOD) test or determined by the Karl-Fisher method (KF) KF=0.91% LOD=1.3%.EXAMPLE 6 4-Chloro-3-cyano-7-ethoxy-6-N-acetylquinoline A 2-L 4-necked flask with a water-cooled condenser, thermal probe connected to a temperature controller, heating mantle, nitrogen blanket, and overhead stirrer was charged with 80 g of 3-Cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline. The flask was charged with 1.6 L of diethylene glycol dimethyl ether or dioxane and stirred. The flask was charged with 96.0 mL of phosphorus oxychloride and warmed to 100+-2 C. and maintained for 45 minutes. HPLC was used to verify that <1% (relative area) 3-Cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline remained in the reaction mixture. The mixture was cooled to 80+-5 C. and 25 g celite was added. The reaction mixture was filtered and the flask and celite were washed with 3*100 mL and 1*50 mL diethylene glycol dimethyl ether. The volume of the filtrate was reduced using a vacuum. The concentrated filtrates were added to a stirred aqueous solution of 70 g of K2CO3 in water while maintaining a temperature of <50 C. The solid was collected by filtration and washed with warm water and toluene and vacuum dried to yield 4-Chloro-3-cyano-7-ethoxy-6-N-acetylquinoline (55.7 g). Yield 65%, strength 82%, mp 250 C., 1H NMR (DMSO-d6+CDCl3) delta1.45 (t, 3H), 2.20 (s, 3H), 4.30 (q, 2H), 7.10 (m, 1H), 7.15-7.40 (m, 3H), 8.50 (s, 1H), 8.85 (s, 1H), 9.20 (s, 1H), 9.60 (s, 1H)A stirred mixture of 300 g 3-cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline in 2.53 L of 1, 2-diethoxyethane was heated to 80-85 C. To this was added 224 ml of phosphorus oxychloride over 30-40 minutes. The mixture was stirred at 80-85 C. for 2-4 hours. The mixture was cooled, filtered over a celite pad and washed with 1, 2-diethoxyethane. The filtrates were added over 1.5 hours to a cooled (0-10 C.) potassium carbonate (537 g in 1.5 L water) solution. The resulting yellow mixture was stirred for a minimum of 12 hours. The mixture was filtered and washed with hot water. The solids were dried (50 C., 10 mm Hg, 24 h) to give the title compound in 30-50% yield. The material was used directly in the next step.1) in the reactor added the substrate 3-cyano-4-hydroxyl-6-acetamido-7-ethoxyquinoline (10mmol, 1.0eq), 4-dimethylaminopyridine (0.3mmol, 3%eq) and 100 ml chlorobenzene stir at room temperature for 3-5 min;2) once added phosphorus oxychloride (25mol, 2.5eq), and then maintain the system temperature at 0-10 C, and then again added 1-methyl-3-propylimidazolium iodide (0.6mmol, 6%eq), and stirring for 0.5-1 h;3) Increasing to 80-100 C at a ramp rate greater than 10 C / min, stirring for 1-12h; HPLC detection, the substrate 3-cyano-4-hydroxyl-6-acetamido-7-ethoxyquinoline was completely converted and the product 3-cyano-4-chloro-6-acetamido-7-ethoxyquinoline stop the reaction when it no longer increases, cool down at 0-5 C; 5) in the reaction solution excessive phosphorus oxychloride was quenched by adding 20 ml of 0-5 C cold water, naturally warmed at room temperature and stirred for 20-30 min; 6) add 100ml saturated aqueous solution of sodium bicarbonate and stir for 20-30min, after standing for 5-10 minutes, the liquid was separated, collecting the organic phase and obtain an alkaline washing organic phase; 7) add 100 ml of saturated brine to the alkaline organic phase and stir for 10-20 min, after standing for 3-5 minutes, the liquid is separated, collecting the organic phase to obtain a salt-washed organic phase; 8) the organic phase of the salt wash is decomposed to a viscous state under reduced pressure, and then slowly add the drops of 200 ml of n-heptane for crystallization, after the crystallization, the temperature was raised to reflux for 30 min, and then cool down at 20-30 C at a cooling rate of 2 C / min, after thermal crystallization for 0.5-1h, it was filtered and dried and then obtained crude3-cyano-4-chloro-6-acetamido-7-ethoxyquinoline 2.64g, yield is 91.5%, purity of HPLC was 96.2% based on the area percentage, amide containing hydrolysate 2.8%, polymer 1.8%, the rest are unknown impurities; the above 2.64 g of 3-cyano-4-chloro-6-acetamido-7-ethoxyquinoline was thermally dissolved in 20 ml of toluene, at 70-80 C added the drops of n-heptane for crystallization, when there is no crystals are precipitated in the system then cooled at room temperature at a cooling rate of 5 C / h, Insulation and crystallization for 0.3-1h and then obtained 3-cyano-4-chloro-6-acetamido-7-ethoxyquinoline pure product 2.45g, HPLC purity is 99.8%, the amide hydrolyzate is 0.04% and the polymer is 0.08%.To a dark-brown suspension of 0.80 g (2.96 mmol) of 27 in 16.0 ml of diethylene glycol dimethyl ether, 0.96 ml (10.4 mmol) of phosphorus oxychloride in one portion was added. The reaction mixture was stirred at 100-102 C for 45 min. The reaction mixture was cooled to 80-85 C, and 2.50 g of Celite was added. The reaction mixture was filtered through a Celite pad with diethylene glycol dimethyl ether. The filtrate was concentrated and stirred in an aqueous solution of 7.50 g of K2CO3 (maintaining temperature less than 50 C). The yellow solid was filtered, washed with warm H2O and toluene to give crude 28 (0.66 g) (Scheme 2).To a solution of 7V-(4-chloro-3-cyano-7-ethoxyquinoJin-6-yJ)acetamide (301 mg, 1.04 mmol) and 4~([ l, 2, 4]triazolo[ l , 5~ajpyridin~7~yloxy)-3~methylaniline (250 mg, 1.04 mmol) m 2-butanol (3.5 ml) was added trifluoroacetic acid (1.5 ml). After stirring at 80 C for 4 hr, 4 M HC1 in dioxane was added to the reaction mixture and stirred at 80 C for additional 2 hr. The resulting mixture was cooled to room temperature, poured into ether. The precipitate was collected by filtration which was carried onto next step without further purification (441 mg, 87 %)Add 200 grams of methanol to a 500 ml stainless steel autoclave, 16.3 g (0.05 mol) of a compound of formula IV2 (prepared from Example 11), 0.5 g of 5 wt% palladium carbon catalyst, 3.0 g of ammonium iodide, after three replacements with nitrogen, Hydrogen was introduced, the hydrogen pressure was maintained at 0.2-0.3 MPa, and the reaction was carried out at 30-35 C for 6 hours.Displaced three times with nitrogen, filtered to remove palladium carbon, and the filtrate was concentrated.Add 100 g of tetrahydrofuran, 9.0 g of acetic anhydride, and react at 50-55 C for 5 hours.Dihydrofuran and acetic acid were recovered by distillation under reduced pressure, and 30 g of isopropyl ether was added to the residue.filter, Drying 13.9 g of (Compound II) in a DMF solvent in the presence ofa trifluoromethanesulfonic acid catalyst: 1:1.0 And the m-aminophenylacetylene (compound III) was subjectedto a substitution reaction at 90 C for 10 h to obtain a compound IV; the target product (compound V)content was 99.207% by HPLC, and the compound IV was used as an impurity, and the content was 0.79%;

Molecular Weight:289.71
XLogP3:2.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:289.0618043
Monoisotopic Mass:289.0618043
Topological Polar Surface Area:75
Heavy Atom Count:20
Complexity:409
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes