1,2-Dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile

SLIGHTLY YELLOW GRANULAR CRYSTALLINE POWDER

46.5 g of sodium methoxide in 950 ml of tetrahydrofuran (THF) was added in the reaction vessel, the ice bath was cooled to an internal temperature of 0 ~ 5 °C, and a solution of 46.5 g of acetone and 59.6 g of ethyl formate was added dropwise within 1 h, after the addition, the ice bath was withdrawn and slowly raised to room temperature within 1 h and concentrated under reduced pressure (not exceeding 50° C.). The concentrate was transferred to a reaction vessel, 67 g of cyanoacetamide in 400 ml of water and piperidine acetic acid (condensation catalyst) were added, refluxed for 2h, cooled to room temperature, adjusted ρΗ=about 5 with acetic acid, the reaction mixture was allowed to stand at room temperature overnight, cooled in an ice bath for 45 minutes, suction-filtered, washed with ice water three times, dried in vacuo overnight at 80 ° C, to obtain compound 2 as a yellow solid 65.5g (yield 61.0percent).General procedure: A substituted alkyl methyl ketone or cyclic ketone (1 equiv) and ethyl formate or ethyl acetic(1 equiv) was added dropwise to absolute ether solution of sodium metal (1 equiv) for 1 h whilemaintained below 20 C. After the addition, the reaction was allowed to stir in an ice bath untilthe sodium metal had disappeared. The precipitate was filtered, washed with absolute ether anddried to give the corresponding compound which was directly used for the next step without further purification. To a solution of previous product (1 equiv), and cyanoacetamide (1.05 equiv) in water was stirred6 min at room temperature. The mixture was added dropwise piperidine acetate solution (0.3 equiv), which was prepared from piperidine (1 equiv), acetic acid (1 equiv) and water (5 equiv). The solutionwas heated to reflux for 2 h. Then, the reactor was cooled to room temperature, and adjusted to pH 4 by 4 N hydrochloric acid. The resulting solid was filtered, respectively washed with water and ether, and dried to give the corresponding compound which was purified by recrystallizing using menthol as solvent.To stirred a mixture of sodium methoxide (46.5 g, 860 mmole) in diethyl ether (950 ML), cooled in an ice bath, was added a mixture of acetone (46.5 g, 800 mmole) and ethyl formate (59.6 g, 800 mmole) dropwise over 1 hour.. 40.0 g of compound v (0.303 mol), 28.0 g of cyanoacetamide (0.333 mol) and 17.5 g of piperidinium acetate were added to 160 ml of purified water, the solution was clarified, heated and stirred to reflux. The mixture was stirred for 24 hours and cooled to 10 ° C. The crystals were collected by stirring and filtered to give a pale red solid which was weighed to give 35.5 g of a yield of 87.4percent.A reaction vessel was charged with a solution of 26.2 g of compound 2 and 36.5 g of NBS in 250 ml of dichloroethane, mixture was heated to reflux for 18 h, cooled to room temperature and filtered, solid was beaten with 500 ml of water for 2 h, washed with water and dried in vacuo to give 38.4 g of compound 3 as a white solid (yield: 92.3%).(0909) [00323] A mixture of 6-methyl-2-oxo-l , 2-dihydropyridine-3-carbonitrile (4.00 g, 29.8 mmol) and NBS (11.2 g, 62.6 mmol) in DCE (150 rnL) was heated to reflux overnight. The reaction was cooled to RT and the resulting precipitate was collected via vacuum filtration. The precipitate was suspended in water (330 mL), stirred for 2 hours, and then collected via vacuum filtration. The filter cake was washed with water (50 rnL), collected, and dried in vacuo to afford 5-bromo-6-methyl-2-oxo-l, 2-dihydropyridine-3-carbonitrile as a white powder (5.3 g, 84%). NMR (300 MHz, OMSO-de) delta ppm 12.99 (br s, H I ). 8.36 (s, H i t. 2.35 (s, 31 )30.0 g of compound iv (0.224 mol) and 83.6 g of NBS (0.470 mol) were added to 600 ml of dichloroethane, heated to reflux, kept under reflux for 18 h. Cooled to room temperature and filtered to give a white solid which was added to 450 ml of purified water and stirred for 2 h, filtered to give the off-white solid, 5-bromo-3-cyano-6-methyl-2 (1H) -pyridone(Compound iii), dried and weighed to 36.8 g, and the yield was 77.5%.5-bromo-6-methyl-2-oxo-1, 2-dihydro-3-pyridinecarbonitrile A mixture of 6-methyl-2-oxo-1, 2-dihydro-3-pyridinecarbonitrile (26.23 g, 95.5 mmol) and N-bromosuccinimide (36.54 g, 205 mmol) in 1, 2-dichloroethane (500 mL) heated to reflux for 18 hours, cooled to room temperature, and filtered. The solid was treated with water (1 L), stirred for 2 hours, filtered, washed with water, and dried under vacuum to provide 36.85 g (88%) of the desired product of sufficient purity for subsequent use. MS (DCI/NH3) m/z 230 (M+NH4)+; 1H NMR (DMSO-d6) delta12.96 (br s, 1H), 8.34 (s, 1H), 2.36 (s, 3H).EXAMPLE 43A 5-bromo-6-methyl-2-oxo-1, 2-dihydro-3-pyridinecarbonitrile A mixture of 6-methyl-2-oxo-1, 2-dihydro-3-pyridinecarbonitrile (26.23 g, 95.5 mmol) and N-bromosuccinimide (36.54 g, 205 mmol) in 1, 2-dichloroethane (500 mL) heated to reflux for 18 hours, cooled to room temperature, and filtered. The solid was treated with water (1 L), stirred for 2 hours, filtered, washed with water, and dried under vacuum to provide 36.85 g (88%) of the desired product of sufficient purity for subsequent use. MS (DCI/NH3) m/z 230 (M+NH4)+; 1H NMR (DMSO-d6) delta 12.96 (br s, 1H), 8.34 (s, 1H), 2.36 (s, 3H).a) 3-Cyano-6-methylpyrid-2-one was prepared from 3-oxo-butyraldehyde-1-dimethylacetal and cyanoacetamide following the procedure of Binovi and Arlt (J. Org. Chem. 26 , 1656, 1961).

Molecular Weight:134.14
XLogP3:0.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:134.048012819
Monoisotopic Mass:134.048012819
Topological Polar Surface Area:52.9
Heavy Atom Count:10
Complexity:277
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes