2-Chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one

To a vessel was added 5-bromo-2-chloro-6-cyclopentylamino-pyridimidine (10.0 g, 1.0 equiv.) along with N-methylpyrrolidone (NMP) (50 mL, 5.0 vol.) at ambient temperature. To the reaction mixture was added crotonic acid (4.7 g, 1.5 equiv.) and triethylamine (20.2 mL, 4.0 equiv.). The vessel was degassed and purged three times with nitrogen. To the degassed reaction mixture was added Pd(OAc)Preparation of 2-Chloro-8-Cyclopentyl-5-methyl-8H-pyrido[2, 3-d]pyrimidin-7-one 41.5 g (0.15 mol) of δ-bromo^-chlorcMl-cyclopentylaminopyrimidine 3a and 32.3g (0.375 mol) of crotonic acid were mixed in 100L of THF and 105ml (1.6 mol) diisopropyl ethylamine under nitrogen. The slurry was stirred, evacuated and refilled with nitrogen three times, after which 860mg (0.0022 mol) palladium dichloride dibenzonitrile complex and 685mg(0.0022mol) tri-ortho-tolylphosphine were added and the resulting slurry degassed an additional three times. The mixture was then heated and stirred at 70Compound 2 (10.0 g, 36.2 mmol, 1.0 eq) was added at room temperature.N-methylpyrrolidone (NMP, 50 mL), Crotonic acid (4.7 g, 54.6 mmol, 1.5 eq) and triethylamine (14.7 g, 144.9 mol, 4.0 eq).The container is passed through three times of nitrogen, PdCl 2 (0.195 g, 1.10 mmol, 0.03 eq) was added to the exhausted reaction mixture.Three more nitrogen passes.After the raw materials are stirred and dissolved at room temperature, Rapidly warm up to 75 ° C, The stirring reaction was closed for 6 h, Sampling (diluted with ethyl acetate), TLC detection (DCM: MeOH = 12:1), The starting compound 1 is completely reacted, Add acetic anhydride to react 0.5h sampling point plate, The intermediate reaction is complete, The reaction mixture will be brought to 20 ° C, Add triethylamine hydrobromide solution (100 mL), Stir for 1h, Filtering, Water washing, Get a gray solid. Add ethyl acetate to dissolve, Add anhydrous magnesium sulfate to dry the mixture, Insoluble matter (salt and insoluble catalyst) is filtered out, Wash with ethyl acetate.Concentrate the filtrate to a low volume, Add n-hexane, Beating at 65 ° C for 30 min, Cool to 20 ° C and stir for 1 h.Filtering the solid, Vacuum drying, Obtained a brownish yellow solid, That is, Compound 1 (9.04 g, yield 94.8percent, purity 99.1percent).Step ii): synthesis of 2-Chloro-8-cyclopentyl-5-methyl-8H-pyrido[2, 3-d]pyrimidin- 7-one formula 15)Step ii): A 1 L 3-necked RBF was charged with 50.0 g of (5-Bromo-2-chloro-pyrimidin- 4-yl)-cyclopentyl-amine (0.181 mol, 1 .00 eq.), 39.0 g crotonic acid (0.452 mol, 2.5 eq.), 125 ml diisopropylethylamine (0.741 mol, 4.1 eq.) and 125 ml THF. The mixture was degassed by applying 3 vacuum/argon cycles then 1 .10 g of tri-o-tolyl-phosphine (3.62 mmol, 0.02 eq.) and 1 .39 g dichlorobis(benzonitrile)palladium(ll) (3.62 mmol, 0.02 eq.) were added. The mixture was degassed again by applying 3 vacuum/argon cycles then heated to 75°C and stirred under argon for 20 h. Then, 43.0 ml of acetic anhydride (0.452 mol, 2.5 eq.) were added and the mixture further stirred at 75^ for 2 h. The reaction was quenched with 250 ml water and the mixture allowed to cool down to RT. After 1 h stirring, 125 ml water was added while cooling to Ι δ'. The precipitated solid was collected by filtration, washed with water (125 ml), cold isopropanol (3 x 125 ml), dried in air for 10 min then at 50To a vessel was added 5-bromo-2-chloro-6-cyclopentylamino-pyridimidine (10.0 g, 1.0 equiv.) along with N-methylpyrrolidone (NMP) (50 mL, 5.0 vol.) at ambient temperature. To the reaction mixture was added crotonic acid (4.7 g, 1.5 equiv.) and triethylamine (20.2 mL, 4.0 equiv.). The vessel was degassed and purged three times with nitrogen. To the degassed reaction mixture was added Pd(OAc)Preparation of 2-Chloro-8-Cyclopentyl-5-methyl-8H-pyrido[2, 3-d]pyrimidin-7-one 41.5 g (0.15 mol) of δ-bromo^-chlorcMl-cyclopentylaminopyrimidine 3a and 32.3g (0.375 mol) of crotonic acid were mixed in 100L of THF and 105ml (1.6 mol) diisopropyl ethylamine under nitrogen. The slurry was stirred, evacuated and refilled with nitrogen three times, after which 860mg (0.0022 mol) palladium dichloride dibenzonitrile complex and 685mg(0.0022mol) tri-ortho-tolylphosphine were added and the resulting slurry degassed an additional three times. The mixture was then heated and stirred at 70Compound 2 (10.0 g, 36.2 mmol, 1.0 eq) was added at room temperature.N-methylpyrrolidone (NMP, 50 mL), Crotonic acid (4.7 g, 54.6 mmol, 1.5 eq) and triethylamine (14.7 g, 144.9 mol, 4.0 eq).The container is passed through three times of nitrogen, PdCl 2 (0.195 g, 1.10 mmol, 0.03 eq) was added to the exhausted reaction mixture.Three more nitrogen passes.After the raw materials are stirred and dissolved at room temperature, Rapidly warm up to 75 ° C, The stirring reaction was closed for 6 h, Sampling (diluted with ethyl acetate), TLC detection (DCM: MeOH = 12:1), The starting compound 1 is completely reacted, Add acetic anhydride to react 0.5h sampling point plate, The intermediate reaction is complete, The reaction mixture will be brought to 20 ° C, Add triethylamine hydrobromide solution (100 mL), Stir for 1h, Filtering, Water washing, Get a gray solid. Add ethyl acetate to dissolve, Add anhydrous magnesium sulfate to dry the mixture, Insoluble matter (salt and insoluble catalyst) is filtered out, Wash with ethyl acetate.Concentrate the filtrate to a low volume, Add n-hexane, Beating at 65 ° C for 30 min, Cool to 20 ° C and stir for 1 h.Filtering the solid, Vacuum drying, Obtained a brownish yellow solid, That is, Compound 1 (9.04 g, yield 94.8percent, purity 99.1percent).Step ii): synthesis of 2-Chloro-8-cyclopentyl-5-methyl-8H-pyrido[2, 3-d]pyrimidin- 7-one formula 15)Step ii): A 1 L 3-necked RBF was charged with 50.0 g of (5-Bromo-2-chloro-pyrimidin- 4-yl)-cyclopentyl-amine (0.181 mol, 1 .00 eq.), 39.0 g crotonic acid (0.452 mol, 2.5 eq.), 125 ml diisopropylethylamine (0.741 mol, 4.1 eq.) and 125 ml THF. The mixture was degassed by applying 3 vacuum/argon cycles then 1 .10 g of tri-o-tolyl-phosphine (3.62 mmol, 0.02 eq.) and 1 .39 g dichlorobis(benzonitrile)palladium(ll) (3.62 mmol, 0.02 eq.) were added. The mixture was degassed again by applying 3 vacuum/argon cycles then heated to 75°C and stirred under argon for 20 h. Then, 43.0 ml of acetic anhydride (0.452 mol, 2.5 eq.) were added and the mixture further stirred at 75^ for 2 h. The reaction was quenched with 250 ml water and the mixture allowed to cool down to RT. After 1 h stirring, 125 ml water was added while cooling to Ι δ'. The precipitated solid was collected by filtration, washed with water (125 ml), cold isopropanol (3 x 125 ml), dried in air for 10 min then at 50A 250 ml four-necked flask equipped with a thermometer and mechanical stirring was charged with 42.5 g (0.3 mol) of phosphorus oxychloride, 12.3 g (0.05 mol) of 2-hydroxy-5-methyl-8-cyclopentylpyridine [2, 3-d] pyrimidin-8-hydro-7-one, stirred at 120 C for 4 hours, recovered excess phosphorus oxychloride under reduced pressure, lowered the temperature to 60-65 C, and slowly poured the obtained viscous liquid into 300 g of ice water , Filtered, the filter cake was washed with 20 g of methyl tert-butyl ether, and dried to obtain 12.3 g of 2-chloro-5-methyl-8-cyclopentylpyridine [2, 3-d] pyrimidine-8-hydro-7-one, yield 93.2%, liquid phase purity 99.8%.In a 3L three-necked flask, Compound III (112 g, 0.4 mol) was added, Chlorobenzene (330g), Temperature control 45 C, A solution of solid phosgene (47.8 g, 0.16 mol) in chlorobenzene (220 g) was added dropwise.After about 1 hour, the mixture was heated to reflux for 3 hours, and the solvent was evaporated under reduced pressure. EtOAc (3 mL), EtOAc (EtOAc)The pale yellow solid had a yield of 75%, Add to dry and clean 2000ml reaction bottle8-cyclopentyl-5-methyl-2-chloro-8H-pyrido[2, 3-d]pyrimidinePyridin-7-one (Formula 7) 60g, dissolved in 600g of dichloromethane, Add 90 g of sodium acetate and add 6.0 g of acetic acid.Add 100.0 g of bromine at 0-20 , After the addition is completed, Stirring reaction for 5 hours, After TLC monitors the reaction of the raw materials, An aqueous solution of 15% sodium hydrogen sulfite in an amount of 800 g was added dropwise.Until the reddish brown bromine was completely destroyed, Stir, dispense, The organic layer is washed twice with water.Wash once again with saturated brine.Distilled under reduced pressure until no flow, Beating with ethanol-water (300g 300g) for 2h, Filtering, The target compound was obtained 65.7g, The yield is 84.28%.The purity of 99.5% of the compound of formula 9 is 0.07%.The compound of formula 10 is present in an amount of 0.01%.Add in dry and clean 1000L reactor7 compound 30kg, Add 300 kg of dichloromethane to dissolve, JoinSodium acetate 45kg, Add 3.0kg of acetic acid, Add 50.0 kg of bromine at 0-20 degrees, After the addition is completed, Stirring reaction for 12 hours, After TLC monitors the reaction of the raw materials, Adding 450 kg of an aqueous solution of 20% sodium hydrogen sulfite dropwise, Until the reddish brown bromine was completely destroyed, Stir, Liquid separation, The organic layer is washed twice with water.Wash once again with saturated brine.Distilled under reduced pressure until no flow, Beating with ethanol-water (150kg 150kg) for 2h, Filtering, The target compound was 31.9kg, The yield is 81.85%.Purity 99.52%, The compound content of formula 9 is 0.06%.The compound of formula 10 was not detected.13.2 g of 2-Chloro-8-cyclopentyl-5-methylpyrido[2, 3-d]pyrimidin-7(8H)-one (2.0 g, 7.6 mmol) was suspended in 50 mL of 1, 4-dioxane In the ring, Add p-phenylenediamine (1.6 g, 15.2 mmol), Pd(OAc) 2 (42.6 mg, 0.2 mmol), BINAP (236.0 mg, 0.4 mmol) andCs2CO3 (1.6 g, 11.4 mmol), The mixture was evacuated under vacuum for 3 times, and the mixture was heated to 100 C and stirred overnight.After cooling to room temperature, the reaction mixture was concentrated under reduced pressure.The crude silica gel column was chromatographed to give the desired product 1 g.Gray-yellow solid, yield: 39.3%;2-Chloro-8-cyclopentyl-5-methylpyrido[2, 3-d]pyrimidin-7(8H)-one (200 mg, 0.76 mmol) was suspended in 6 mL of 1, 4-dioxane In the ring, Add N-(4-aminophenyl)-N-phenylcyclopropane-1, 1-dimethylformamide (0.76 mmol), Pd(OAc) 2 (5 mg, 0.02 mmol), BINAP (28 mg, 0.04 mmol) and Cs2CO3 (370 mg, 1.14 mmol), The mixture was evacuated under vacuum for 3 times, and the mixture was heated to 100 C and stirred overnight.After cooling to room temperature, the reaction mixture was concentrated under reduced pressure.The crude product was purified by silica gel column chromatography.White solid, yield: 38%.

Molecular Weight:263.72
XLogP3:2.3
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:263.0825398
Monoisotopic Mass:263.0825398
Topological Polar Surface Area:46.1
Heavy Atom Count:18
Complexity:378
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes