4,6-DICHLORO-2-METHYL-NICOTINIC ACID ETHYL ESTER

As shown in step 9-i of Scheme 9, ethyl 4, 6-dihydroxy-2-methylpyridine-3- carboxylate (Accla Biochem Inc.) was suspended in 50 mL of POCI3 and heated to 90°C under a nitrogen atmosphere for 5 hours. The reaction mixture was cooled and concentrated under reduced pressure. Ice was added to the dark oil with stirring followed by the addition of ethyl acetate and water. The organics were washed with water, brine, and dried over sodium sulfate. After filtration, the volatiles were removed under reduced pressure and the crude product purified by silica gel chromatography to yield ethyl 4, 6-dichloro-2- methylnicotinate as a pale yellow oil (Compound 2030, 62percent yield): ESMS (Μ+Η)234/236/238; 1H NMR (CDC1A solution of 4, 6-dihydroxy-2-methyl nicotinic acid ethyl ester (31 g, 157 mmol) in phosphorus oxychloride (60 mL, 629 mmol) was stirred at reflux for 1.5 hours. The extra phosphorus oxychloride was removed using a rotary evaporator and the reaction mixture was purred into icy water. The solid was EPO A mixture of malonic acid (20 g, 192 mmol), 2, 4, 6-trichlorophenol (72 g, 365 mmol), and phosphorus oxychloride (38 mL, 403.2 mmol) was stirred at reflux for 12 h. The reaction mixture was cooled to 70° C. and poured into ice water. The solid was collected by filtration, washed with water, and air-dried to give malonic acid bis-(2, 4, 6-trichloro-phenyl) ester (85 g, 95percent). A solution of malonic acid bis-(2, 4, 6-trichloro-phenyl)ester (85 g, 183.6 mmol) and ethyl 3-aminocrotonate (26.1 g, 202 mmol) in bromobenzene (100 mL) was stirred at reflux for 50 min. The reaction mixture was cooled to 50° C. and diluted with EtOAc (260 mL). The solid was collected by filtration, washed with water, and air-dried, to give 4, 6-dihydroxy-2-methyl nicotinic acid ethyl ester (31 g, 86percent).A solution of 4, 6-dihydroxy-2-methyl nicotinic acid ethyl ester (31 g, 157 mmol) in phosphorus oxychloride (60 mL, 629 mmol) was stirred at reflux for 1.5 h. The extra phosphorus oxychloride was removed and the reaction mixture was poured into ice water. The solid was removed by filtration. The filtrate was extracted with dichloromethane (3.x.100 mL) and concentrated. The residue was further purified by column chromatography to yield 4, 6-dichloro-2-methyl nicotinic acid ethyl ester (16.9 g, 46percent). A solution the ester (16.9 g, 71.3 mmol) in MeOH (60 mL) was mixed with sodium methoxide (58 mL, 257 mmol) and stirred at reflux for 12 h. The reaction was quenched by adding AcOH (50 mL), diluted with water (200 mL), extracted with dichloromethane (3.x.100 mL), and concentrated. The residue was purified by column chromatography to yield 4, 6-dimethoxy-2-methyl nicotinic acid methyl ester (10 g, 67percent). A solution of the ester (2.6 g, 12.3 mmol), lithium hydroxide (1.06 g, 44.1 mmol) in water (40 mL), MeOH (30 mL) and THF (20 mL) was stirred at reflux for 4 h. The reaction mixture was concentrated to dryness. The residue was mixed with HCl (conc., 20 mL) and was concentrated to dryness to yield crude 4, 6-dimethoxy-2-methyl nicotinic acid (quantitative). To a solution of 4, 6-dimethoxy-2-methyl nicotinic acid (2.5 g, 12.0 mmol) in dichloromethane (50 mL) and THF (50 mL) at room temperature was added oxalyl chloride (2.57 mL, 29.4 mmol) and DMF (3 drops). The reaction mixture was stirred at room temperature for 0.5 h, concentrated to afford 4, 6-dimethoxy-2-methyl nicotinic acid chloride HCl salt (2.8 g). A solution of 4, 6-dimethoxy-2-methyl nicotinic acid chloride HCl salt (8.5 g, 33.73 mmol) in dichloromethane (20 mL) and THF (20 mL) at room temperature was mixed with methylamine in THF (50 mL, 98 mmol) and stirred at 20° C. for 1 h. The reaction mixture was diluted with water (100 mL), extracted with dichloromethane (3.x.100 mL), and concentrated to yield 4, 6-dimethoxy-2, N-dimethyl-nicotinamide (4.2 g, 66percent) as a light yellow solid. A solution of 4-hydroxy-3, 5-dimethylbenzonitrile (2 g, 13.6 mmol) in DMF (20 mL) at room temperature was mixed with sodium hydride (0.706 g, 17.6 mmol) and stirred for 0.5 h. Benzyl bromide (1.62 mL, 13.59 mmol) was then added and the reaction mixture was stirred at room temperature for 24 h. The reaction was quenched by adding water (200 mL), extracted with EtOAc (3.x.100 mL), and concentrated. The residue was purified by column chromatography to yield 4-benzyloxy-3, 5-dimethylbenzonitrile (3.25 g, 100percent), as a white solid. To a solution of 4, 6-dimethoxy-2, N-dimethyl-nicotinamide (0.54 g, 2.57 mmol) in THF (50 mL) at -20° C. was added n-BuLi (3.54 mL, 5.67 mmol). The reaction was stirred at -20° C. to 0° C. for 2 h and then was cooled to -78° C. 4-Benzyloxy-3, 5-dimethylbenzonitrile (0.49 g, 2.057 mmol) was added, the cooling bath was removed, and the reaction was allowed to warm to room temperature. After 14 h, the reaction was quenched by adding water (100 mL), extracted with dichloromethane (3.x.100 mL), and concentrated. The residue was purified by column chromatography to yield 7-(4-benzyloxy-3, 5-dimethyl-phenyl)-2, 4-dimethoxy-6H-[1, 6]naphthyridin-5-one (0.32 g, 37percent). A solution of 7-(4-benzyloxy-3, 5-dimethyl-phenyl)-2, 4-dimethoxy-6H-[1, 6]naphthyridin-5-one (0.25 g, 0.6 mmol) in dichloromethane (100 mL) was mixed with BBrA solution of 4, 6-dihydroxy-2-methyl nicotinic acid ethyl ester (31 g, 157 mmol) in phosphorus oxychloride (60 mL, 629 mmol) was stirred at reflux for 1.5 h. The extra phosphorus oxychloride was removed and the reaction mixture was poured into ice water. The solid was removed by filtration. The filtrate was extracted with dichloromethane (3×100 mL) and concentrated. The residue was further purified by column chromatography to yield 4, 6-dichloro-2-methyl nicotinic acid ethyl ester (16.9 g, 46percent).Malonate (20g, 192mmol), 2, 4, 6-trichloro-phenolmixture (72g, 365mmol) and phosphorus oxychloride(38mL, 403.2mmol) was stirred at reflux for 12 hours.The reaction mixture was cooled to 70 , poured into icewater. The solid was collected by filtration, washed with water and dried, to give malonicacid bis-(2, 4, 6-trichloro-phenyl)-acetate (85g, 95percent). The malonic acid bis - (2, 4, 6-trichloro-phenyl) -acetate (85g, 184mmol)and ethyl 3-aminocrotonate (26.08g, 201.9mmol)in bromobenzene (100 mL) was added in It wasstirred under reflux for 50 minutes. Thereaction mixture was cooled to 50 , with EtOAc(260mL) diluted. The solid was collected by filtration, washed with water anddried to give 4, 6-dihydroxy-2-methyl-nicotinic acidethyl ester (31g, 86percent). 4, 6-dihydroxy-2-methyl-nicotinic acid ethyl ester (31g, 157mmol) in phosphorus oxychloride (60mL, 629mmol) was stirred at reflux for 1.5 hours.Remove the excess phosphorus oxychloride, the reaction mixture was poured intoice-water. The solid was removed by filtration. The filtrate was extracted withdichloromethane (3 × 100mL) was extracted and concentrated. The residue wasfurther purified by column chromatography to give4, 6-dichloro-2-methyl-nicotinic acid ethyl ester (16.9g, 46percent).4, 6-dichloro-2-methyl-nicotinicacid ethyl ester (16.9g, 71.3mmol) and a solution of sodium methanolate (60mL)in MeOH (58mL, 256.68mmol) were mixed and stirred at reflux 12hour. Wasadded HOAc (50mL) and the reaction was quenched. The mixture was washed withwater (200 mL) was diluted, and extracted with dichloromethane (3 × 100mL), andconcentrated. The residue was purified by column chromatography (of SiO2, hexane / EtOAc = 6:1) to obtain 4, 6-dimethoxy-2-methyl-nicotinicacid methyl ester (10g, 67percent). 4, 6-dimethoxy-2-methyl-nicotinic acid methyl ester (2.6g, 12.3mmol), lithium hydroxide (1.06g, 44.08mmol) in water (40mL), MeOH (30mL) and THF (20mL ) was stirredunder reflux for 4 hours.The reaction mixture was concentrated to dryness. The residue was stirred withHCl (conc., 20 mL) were mixed under high vacuum concentrated again to drynessto give crude 4, 6-dimethoxy-2-methyl nicotinic acid (quantitativeyield). The 4, 6-dimethoxy-2-methyl nicotinicacid (2.5g, 12.0mmol) was added oxalyl chloride(2.57mL, 29.4mmol in dichloromethane(50mL) and THF(50mL) at room temperaturewas ) and DMF (3drops). At room temperature the reaction mixture was stirred for 0.5 hours, using a rotaryevaporator and concentrated to dryness to give crude 4, 6-dimethoxy-2-methyl-nicotinicacid chloride HCl salt (2.8 g of, quantitative). A mixture of 4, 6-dimethoxy-2-methylnicotinic acid chloride HCl salt (4.8g, 23.5mmol) in dichloromethane (100 mL)was poured into a solution of ammonium hydroxide(200 mL) in a beaker. The reaction mixture was stirred at room temperature for one hour, (3 × 100mL) and extracted with dichloromethane, and concentrated using a rotaryevaporator, to give a paleyellow solid 4, 6-dimethoxy-2-methyl -nicotinamide (2.4 g, 52percent). At room temperature the 4-hydroxy-3, 5-dimethyl-benzonitrile (2.00g, 13 . 59mmol) in DMF (20 ml) with a solution of sodium hydride(0.706g, 17 . 6mmol) mixing, stirring 0.5 hours. Was added benzylbromide (1.62mL, 13.59mmol), The reaction mixture was stirredat room temperature for 24hours. Water was added (200 mL) and the reaction was quenched andextracted with EtOAc (3 × 100mL), and concentrated. The residue was purified bycolumn chromatography to give a white solid of 4-benzyloxy-3, 5-dimethyl-benzonitrile(3.25g, 100percent). The 4, 6-dimethoxy-2-methyl-nicotinamideat -20 (1g, 5.1mmol) was added n-BuLi (9.6mL, 15.3mmol) in THF (120mL) in a solution. At -20-0 reaction wasstirred for 2.5 hours, then cooled to -78 . Was added 4-benzyloxy-3, 5-dimethyl-benzonitrile (1.21g, 5.1mmol), cooling bath was removed and the reaction was allowed to warm gradually to room temperature. Stirring at room temperature for 20 hours, water wasadded (100mL) and the reaction was quenched and extracted with dichloromethane(3 × 100mL), using a rotary evaporator. The residue was purified by column (SiO2, Hexanes / EtOAc / MeOH = 3:2:1) was further purified to give 7- (4-benzyloxy-3, 5-dimethyl - phenyl) -2, 4-dimethoxy - [1 , 6] naphthyridin-5-amine (0.4g, 19percent) and 7-(4-benzyloxy-3, 5-dimethyl - phenyl) -2, 4-dimethoxy -6H- [1, 6]naphthyridin-5-one (0.34g, 16percent). 7- (4-benzyloxy-3, 5-dimethyl - phenyl)-2, 4-dimethoxy -6H- [1, 6] naphthyridin-5-one (0.34g, 0.82mmol ) in DMF (100mL) and the MeOH (100 mL) and a solution of palladium / carbon (0.1g) are mixed and hydrogenated(50psi) 2 hours.The mixture was filtered through a pad of Celite. The filtrate was concentratedunder high vacuum to give 7- (4-hydroxy-3, 5-dimethyl -phenyl) -2, 4-dimethoxy -6H- [1, 6] naphthyridin-5-one (0.23g, 88percent).7- (4-hydroxy-3, 5-dimethyl - phenyl) -2, 4-dimethoxy -6H-[1, 6] naphthyridin-5-one (0.23g, 0.7mmol) in MeOH (20mL) and DCM (20mL) with a solution of HCl in ether (7mL, 7mmol) were mixed and stirred 0.5 hours. Using a rotaryevaporator, the reaction was concentrated to give a solid residue. The solidwas rinsed with DCM, collected by filtration, washed with DCM to give a pale yellow solid 7- (4-hydroxy-3, 5-dimethylphenyl) -2, 4-dimethoxy-1, 6 -naphthyridine -5 (6H) - one (0.15g, 59percent) of the HCl salt. Selected data:MS (ES) m / z: 327.06; MP> 324 , decomposition (HCl salt)A mixture of malonic acid (20 g, 192 mmol), 2, 4, 6-trichlorophenol (72 g, 365 mmol), and phosphorus oxychloride (38 mL, 403.2 mmol) was stirred at reflux for 12 h. The reaction mixture was cooled to 70°C and poured into ice water. The solid was collected by filtration, washed with water, and dried to give malonic acid bis-(2, 4, 6-trich.oro-phenyl) ester (85 g, 95percent). A solution of malonic acid bis-(2, 4, 6-trichloro-phenyl) ester (85 g, 184 mmol) and ethyl 3- aminocrotonatψ (26.08 g, 201.9 mmol) in bromobenzene (100 mL) was stirred at reflux for 50 min. The reaction mixture was cooled to 50°C and diluted with EtOAc (260 mL). The solid was collected by filtration, washed with water, and dried to give 4, 6-dihydroxy-2-methyl nicotinic acid ethyl ester (31 g, 86percent). A solution of 4, 6-dihydroxy-2-methyl nicotinic acid ethyl ester (31 g, 157 mmol) in phosphorus oxychloride (60 mL, 629 mmol) was stirred at reflux for 1.5 h. The extra phosphorus oxychloride was removed and the reaction mixture was poured into Malonate (20g, 192mmol), 2, 4, 6-trichloro-phenolmixture (72g, 365mmol) and phosphorus oxychloride(38mL, 403.2mmol) was stirred at reflux for 12 hours.The reaction mixture was cooled to 70 , poured into icewater. The solid was collected by filtration, washed with water and dried, to give malonicacid bis-(2, 4, 6-trichloro-phenyl)-acetate (85g, 95%). The malonic acid bis - (2, 4, 6-trichloro-phenyl) -acetate (85g, 184mmol)and ethyl 3-aminocrotonate (26.08g, 201.9mmol)in bromobenzene (100 mL) was added in It wasstirred under reflux for 50 minutes. Thereaction mixture was cooled to 50 , with EtOAc(260mL) diluted. The solid was collected by filtration, washed with water anddried to give 4, 6-dihydroxy-2-methyl-nicotinic acidethyl ester (31g, 86%). 4, 6-dihydroxy-2-methyl-nicotinic acid ethyl ester (31g, 157mmol) in phosphorus oxychloride (60mL, 629mmol) was stirred at reflux for 1.5 hours.Remove the excess phosphorus oxychloride, the reaction mixture was poured intoice-water. The solid was removed by filtration. The filtrate was extracted withdichloromethane (3 × 100mL) was extracted and concentrated. The residue wasfurther purified by column chromatography to giveStep 1: ethyl 4-chloro-6-methoxy-2-methylnicotinateInto a 500-mL round-bottom flask, was placed a mixture of Synthesis of compound 73.2. To a solution of compound 73.1 (0.1 g, 0.427mmol, 1.0 equiv) in 1, 4-dioxane: water (8:2) was added 2, 6-difluoro phenylboronic acid (0.135g, 0.854mmol, 2.0 equiv), and diisopropylethylamine (0.3mL, 1.70mmol, 4.0 equiv). Reaction mixture was degassed under argon gas for 5-10 min. and Pd(PPh3)4 (0.05g, 0.0427mmol, 0.1 equiv) was added. Mixture was degassed under argon for additional 5 minutes. Reaction mixture was heated at 120 C in a microwave for 8 hours. Upon completion of the reaction, mixture was poured into water and product was extracted with ethyl acetate. Organic layers were combined and dried over sodium sulphate and concentrated under reduced pressure to obtain crude material which was purified using column chromatography to obtain pure 73.2 (0.045 g, 59.85%). MS (ES): m/z 312.05 [M+H]+.

Molecular Weight:234.08
XLogP3:3.1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:233.0010339
Monoisotopic Mass:233.0010339
Topological Polar Surface Area:39.2
Heavy Atom Count:14
Complexity:213
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes