ETHYL PICOLINOYLACETATE

Clear straw-yellow to brown liquid

Stir a mixture of sodium ethoxide (360 g, 5.29 mol), toluene (4 L), ethanol (18 mL, 0.265 mol), and ethyl acetate (1.04 L, 10.6 mol) in a 22 L flask equipped with a reflux condenser, nitrogen inlet, and mechanical stirrer. Stir for 1 h as the mixture warms to 26 °C. Add pyridine-2-carboxylic acid ethyl ester (Fluka; 400 g, 2.65 mol) and heat the mixture to reflux (90 °C) for 18 h. Cool the mixture to room temperature, dilute with toluene (8 L), wash with water (6 L), and separate the layers. Acidify the aqueous layer to pH 5 with glacial acetic acid. Extract with ethyl acetate (2 x 4 L), dry the combined organic layers (sodium sulfate), filter, and concentrate in vacuo to yield 466 g (91percent) the subtitled compound as a dark oil in 93percent purity by HPLC analysis. MS ES+ m/e 194 (M+1).To 8 g of compound 130 in 30 mL of methanol. 11.8 ml of thionyl chloride was added slowly at 5° C. The mixture was allowed to stir for 30 min at room temperature, and was refluxed overnight. The reaction mixture was concentrated under high vacuum, then dissolve in sodium bicarbonate solution. Then compound was extracted into dichloromethane, then dried and concentrated to give a 70percent yield of compound 131. To 6 g of compound 131 in 100 mL benzene, 2.6 g of NaOMe was added. The reaction mass was heated to 80° C. and 5 ml of ethyl acetate was added to the reaction and further refluxed for an additional one hour. The reaction was neutralized with citric acid and extracted with dichloromethane. Removal of solvent afforded a 60percent yield of compound 132. To 4 g of compound 132 was added 40 mL of 20percent sulphuric acid, which was then refluxed for two hours. Then reaction mixture was neutralized with the sodium hydroxide, extracted into dichloromethane, and concentrated to give a yield of 60percent of desired compound 133. To a 1 liter round bottom flask with 150 mL of DMF was added compound 133 added at 0° C. To the reaction mixture was added hydrogen peroxide and ferrous sulphate heptahydrate simultaneously at 0° C. The reaction mixture was allowed to stir overnight. The reaction mixture was poured in the water, then extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated to afford 2percent of desired compound 134. To 1 g of compound 134 in 10 mL benzene was added 0.8 g of sodium methoxide. The reaction mixture was heated gently to reflux, and allowed to stir for two hours. The reaction mixture was neutralized with citric acid then extracted with ethyl acetate. The organic layer was dried and concentrated to give 80percent yield of the compound 135. To 200 mg of compound 135 in ethanol was added methyl hydrazine. The mixture was allowed to stir for six hours at room temperature. Then reaction mixture was neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic layer was then dried and concentrated to afford a 50percent yield of the final compound 136.6-1. Synthesis of Compound (15)1.35 g of sodium ethoxide, 8.7 g of ethyl acetate and 0.05 g of ethanol were suspended in 100 ml of toluene. After stirring at room temperature for 1 hour, a solution of 1.5 g of ethyl picolinate (14) in 10 ml of toluene was added and stirred at 90 ° C. for 14 hours. After completion of the reaction, the reaction mixture was poured into water and extracted twice with toluene. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give ethyl 3-oxo-3- (pyridin-2-yl) propionate (15)1.87 g was obtained.General procedure: To the solution of ethyl acetate (60 mol), aryl ester (10 mol) in dry THF (20 mL), LiHMDS (30 mol) was added quickly at -50 °C and stirred at this temperature for 30 min. The reaction was monitored by TLC and it was quenched with acetic acid (20 mol) and water (25 mL), basified with sat. solution of sodium bicarbonate (20 ml) and extracted with ethyl acetate (2 .x. 20 mL). The combined organic extract was washed with water (10 mL) and brine solution (10 mL) and dried over anhyd NaA. Preparation of 3-Oxo-3-(pyridin-2-yl)-propionic acid ethyl ester; Stir a mixture of sodium ethoxide (360 g, 5.29 mol), toluene (4 L), ethanol (18 mL, 0.265 mol), and ethyl acetate (1.04 L, 10.6 mol) in a 22 L flask equipped with a reflux condenser, nitrogen inlet, and mechanical stirrer. Stir for 1 h as the mixture warms to 26°C. Add pyridine-2-carboxylic acid ethyl ester (Fluka; 400 g, 2.65 mol) and heat the mixture to reflux (90 General procedure: To the solution of ester (10 mmol) in THF (20 mL) and ethyl acetate (70 mmol), LiHMDS (30 mmol) was added very quickly at -40 °C, and stirred at this temperature for 20 min. After completion of the reaction, reaction mixture was quenched with acetic acid (50 mmol) and then basified using 10percent NaHCOSodium hydride (2.9 g, 124 mmmol) was taken in dry THF (50 mL) in a 100 mL round bottom flask under N2 and cooled it down to 0 C. To it was added a solution of 1-(pyridin-2-yl)ethan-1-one (5.0 g, 41.3 mmol) in THF (5 mL). The reaction mixture was stirred at rt for 30 min followed by the addition of diethyl carbonate (20 mL, 165 mmol). The reaction mixture was then stirred at rt for 12 h. Ice-cooled water was added dropwise to quench the reaction. It was extracted with EtOAc (3 * 100 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was further triturated with diethyl ether which afforded 26 as a pale yellow semi-solid (4.0 g, 50%). LCMS(ESI) m/z 194.06 [M+H+]; 40% (purity).

Molecular Weight:193.20
XLogP3:1.3
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:5
Exact Mass:193.07389321
Monoisotopic Mass:193.07389321
Topological Polar Surface Area:56.3
Heavy Atom Count:14
Complexity:215
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes