2-CYANO-4-PYRIDINE CARBOXYLIC ACID METHYL ESTER

Compound DD (17.4 g, 80.5 mmol) was dissolved in DMF (160 mE), followed by the addition of Zn(CN)2 (5.7 g, 48.53 mmol) in one portion. The mixture was degassed using nitrogen and then Pd(PPh3)4 (4.7 g) was added. The mixture was degassed again and then heated in an oil bath (120° C.). After 2.5 h, the reaction was cooled to ambient temperature and water (200 mE) was added. The mixture was stirred for 30 mm and then filtered through a frit. The solid collected was washed with water (2x1 00 mE) and then dried under vacuum to give compound EE in 84percent yield (11.0 g, 67.9 mmol). EC-MS: [M+H] 163.2 (C8H5N202+H, calc: 162.1). Compound EE was used directly without thrther purificationThe formula (5) compound methyl isobutyl niacin-N-oxide 1.53g (10mmol), b a carbamic chloride (0.11 ml, 11mmol), sodium cyanide (0.98g, 20mmol), cuprous iodide 0.19g (1mmol) dissolved in 50 ml of acetonitrile, mixtures in 90 °C reaction under 7 hours, detecting reaction TLC (hexane/ethyl acetate = 1 the [...] 1), after the reaction, cooling to room temperature, add 20 ml water to stir reaction 5-30 minutes, removed the organic layer, the aqueous layer extracted with ethyl acetate three times, each 50 ml, combined with the organic layer, anhydrous sodium sulfate for drying, distilling solvent under reduced pressure, to obtain crude products, crude product using normal hexane/ethyl acetate = 4 the [...] 1 column chromatography, to obtain strawcoloured solid 1.16g, yield 71.6percent.The formula (5) compound methyl isobutyl niacin-N-oxide 1.53g (10mmol), b a carbamic chloride (0.11 ml, 11mmol), zinc cyanide (1.40g, 12mmol), cuprous iodide 0.19g (1mmol) dissolved in 50 ml of acetonitrile, mixtures in 80 °C reaction under 5 hours, TLC detection reaction (hexane/ethyl acetate = 1 the [...] 1), after the reaction, cooling to room temperature, add 20 ml water to stir reaction 5-30 minutes, removed the organic layer, the aqueous layer extracted with ethyl acetate three times, each 50 ml, combined with the organic layer, anhydrous sodium sulfate for drying, distilling solvent under reduced pressure, to obtain crude products, crude product using normal hexane/ethyl acetate = 4 the [...] 1 column chromatography, to obtain strawcoloured solid 1.53g, yield 94percent, HPLC purity ( unitary method ): 97.7percent ; melting point: 107.5-108.7 °C.A mixture of 4-(methoxycarbonyl)pyridine 1-oxide (2 g, 13.06 mmol, 1.00 equiv), N, N-dimethylcarbamoyl chloride (6 g, 55.79 mmol, 4.27 equiv) and trimethylsilanecarbonitrile (6 g, 60.48 mmol, 4.63 equiv) in chloroform (60 g) was stirred overnight under nitrogen at 50 °C. The reaction mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether ( 1 :20) to give 1.2 g (57percent) of methyl 2-cyanopyridine-4-carboxylate as a light yellow solid. LC MS (Method F, ESI): RT= 1.22 min, m/z = 163.0 [M+H]Trimethylsilyl cyanide (3.8 g, 0.0386 mol) and dimethylcarbamyl chloride (5.0 g, 0.0483 mol) were added to a solution of methylisonicotinate N-oxide (5.0 g, 0.0322 mol) in dry CHThe compound of formula (5), methyl isonicotinic acid-N-oxide, 1. 53 g (10 mmol), dimethylcarbamoyl chloride (0.1 mmol, 11 mmol), potassium cyanide (1.3 g, 20 mmol) and cuprous iodide 0.19 g (1 mmol) were dissolved in 50 ml of acetonitrile and mixed The reaction was carried out at 90 ° C for 8 hours. The reaction was monitored by TLC (n-hexane / ethyl acetate = 1: 1). After completion of the reaction, The reaction was stirred for 5 - 30 minutes at room temperature, the organic layer was discarded and the aqueous layer was extracted three times with 50 mL each of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the crude product which was recrystallized from n-hexane / ethyl acetate = 4: 1 Column chromatography to give 1.15 g of a light yellow solid, yield 70.8A reaction mixture of 4-(methoxycarbonyl)pyridine-1-oxide42g of the compound of the formula (8), 400 mL of ethyl acetate, 30g of diisopropylethylamine was added to the 2L reaction bottle.51 g of trifluoroacetic anhydride was added dropwise at 28 ± 2 ° C.After the dropwise addition was completed, the reaction was completed for 4 hours, and the reaction was completed.Add 320 mL of water, stir for 1 h, then add potassium carbonate aqueous solution to prepare the pH to be neutral, separate the liquid, dry over sodium sulfate, concentrate, beat with 220 mL of petroleum ether for 2 h, suction filtration, Drying to obtain 32.2 g of product, That is, the compound of formula (7), 2'cyanopyridine'4'carboxylic acid methyl ester, Yield: 85.1percent, HPLC purity (normalization method): 99.54percent;A solution of tert-butyl acetate (2M in THF) was flowed into a cooled flow reactor at a rate of 0.2mL per minute and a stream of LDA (2M in THF) is introduced to the same flow reactor, also at a rate of 0.2mL per minute. During this process the temperature of the flow reactor is held at -30°C to allow formation of the anion. A solution of

Molecular Weight:162.15
XLogP3:0.8
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:162.042927438
Monoisotopic Mass:162.042927438
Topological Polar Surface Area:63
Heavy Atom Count:12
Complexity:218
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes