2-BROMONICOTINIC ACID ETHYL ESTER

Ethyl cyanoacetate (59 mL, 0.5 mol) was added to the reactor, 1-dodecyl-3-methylimidazolium chloride50 mL, 3-dimethylaminopropenal 62 mL (0.5 mol) was homogeneously mixed, The oil bath was heated to 90 ° C and incubated for 4 hours. TLC detection (petroleum ether: methylene chloride 1: 2 expansion, sublimed iodine coloring) 3-dimethylaminophenaldehyde was complete, Cool to room temperature, organic solvent1, 2-dichloroethane 60mL extraction 3 times, residual phase ion water washing vacuum drying and reuse, The organic phase was passed through a dry HBr gas and the HPLC was followed by the reaction until the reaction was complete.Add the mass fraction of 20percent sodium carbonate solution to adjust the pH = 5-6, liquid, For water use1, 2-dichloroethane 20mL × 3 times extraction, the organic layer, combined with water, The molecular sieves were dried, filtered and the solvent was evaporated under reduced pressure1, 2-dichloroethane was recovered to give ethyl 2-bromonicotinate, 108.4 g of a light brown liquid in a yield of 94.0percent.In a 500 mL three-necked flask equipped with a thermometer, first, 2-dimethylaminoacrolein (62 mL, 0.5 mol) and pyridine (20 mL) were added, and then 65 mL (0.6 mol) of ethyl cyanoacetate was added to prepare the prepared device. Into the ultrasonic instrument. Ultrasonic radiation conditions were set, and the reaction was carried out at a temperature of 40 °C, an ultrasonic power of 150 W, and a frequency of 20KHz TLC test (petroleum ether:dichloromethane 1:2 development, sublimation iodine development) 3-dimethylaminopropylene Aldehyde reaction is complete. After that, HBr gas was introduced and the ultrasonic irradiation conditions were as above, and the reaction was followed by HPLC until the reaction was completed. After the reaction is completed, add 30percent sodium hydroxide solution to adjust ρΗ = 5-6, and separate the layers. The aqueous layer is extracted with dichloromethane 20 mL x 3 times. The organic layers are combined, and the deionized water is washed with 10 mL of water. The organic layer was dried over anhydrous Na2SO4 , filtered, and the solvent was evaporated under reduced pressure in the liquid phase to obtain ethyl 2-bromonicotinate as light brown liquid, 107.5 g, with a yield of 93.5percent.In a 500 mL three-necked flask equipped with a thermometer, First add 3-dimethylamino-acrolein 62 mL (0.5 mol) and Pyridin20 mL of pyridine, and then 65 mL (0.6 mol) of ethyl cyanoacetate, Place the prepared device in the microwave.Set microwave radiation conditions at a temperature of 40CThe microwave power is 150W and the frequency is 2450MHz.TLC test (petroleum ether: dichloromethane 1:2 developed, sublimation iodine developed) 3-dimethylaminoacrolein reaction was complete.After passing HBr gas, Microwave irradiation conditions were as above and HPLC followed the reaction until the reaction was complete.Then after the reaction is over, 30% sodium hydroxide solution was added to adjust the pH=5-6, the liquid was separated, and the aqueous layer was extracted with 20 mL×3 times of dichloromethane.Combine the organic layers, and after washing, separate the liquid.The organic layer was dried over anhydrous Na2SO4, filtered, and the liquid phase was depressurized to remove the solvent.Obtained ethyl 2-bromonicotinate, 106.3 g light brown liquid, The yield was 92.4%.61 mL (0.5 mol) of 3-diethylaminoacrolein, CuO 6.5 g, 12.0 g of tetraethylammonium hydroxide and 50 mL of deionized water were added to a hydrothermal reactor and 65 mL (0.6 mol) of ethyl cyanoacetate was added and the mixture was stirred at 100 C, 0.3MPa under the hydrothermal reaction 0.4h, after the end of the reaction filter, dichlorobenzene 181g extraction, the organic phase and then into the dry HBr gasThe reaction was followed by the reaction, TLC (ethyl acetate, UV lamp). The reaction was carried out until the reaction was completed.The amount of 40% monomethylamine to adjust the pH to neutral, the organic phase was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure(Recovered), 2-bromonicotinic acid ethyl ester, light brown liquid, 2-bromonicotinic acid ethyl ester content of 99.0%, the yield of 95.7%.Ethyl cyanoacetate (59 mL, 0.5 mol) was added to the reactor, 1-dodecyl-3-methylimidazolium chloride50 mL, 3-dimethylaminopropenal 62 mL (0.5 mol) was homogeneously mixed, The oil bath was heated to 90 C and incubated for 4 hours. TLC detection (petroleum ether: methylene chloride 1: 2 expansion, sublimed iodine coloring) 3-dimethylaminophenaldehyde was complete, Cool to room temperature, organic solvent1, 2-dichloroethane 60mL extraction 3 times, residual phase ion water washing vacuum drying and reuse, The organic phase was passed through a dry HBr gas and the HPLC was followed by the reaction until the reaction was complete.Add the mass fraction of 20% sodium carbonate solution to adjust the pH = 5-6, liquid, For water use1, 2-dichloroethane 20mL × 3 times extraction, the organic layer, combined with water, The molecular sieves were dried, filtered and the solvent was evaporated under reduced pressure1, 2-dichloroethane was recovered to give ethyl 2-bromonicotinate, 108.4 g of a light brown liquid in a yield of 94.0%.In a 500 mL three-necked flask equipped with a thermometer, first, 2-dimethylaminoacrolein (62 mL, 0.5 mol) and pyridine (20 mL) were added, and then 65 mL (0.6 mol) of ethyl cyanoacetate was added to prepare the prepared device. Into the ultrasonic instrument. Ultrasonic radiation conditions were set, and the reaction was carried out at a temperature of 40 C, an ultrasonic power of 150 W, and a frequency of 20KHz TLC test (petroleum ether:dichloromethane 1:2 development, sublimation iodine development) 3-dimethylaminopropylene Aldehyde reaction is complete. After that, HBr gas was introduced and the ultrasonic irradiation conditions were as above, and the reaction was followed by HPLC until the reaction was completed. After the reaction is completed, add 30% sodium hydroxide solution to adjust rhoEta = 5-6, and separate the layers. The aqueous layer is extracted with dichloromethane 20 mL x 3 times. The organic layers are combined, and the deionized water is washed with 10 mL of water. The organic layer was dried over anhydrous Na2SO4 , filtered, and the solvent was evaporated under reduced pressure in the liquid phase to obtain ethyl 2-bromonicotinate as light brown liquid, 107.5 g, with a yield of 93.5%.Example 4 2-(N-(3-(10, 11-Dihydro-5H-dibenz[b, f]azepin-5-yl)-1-propyl)-N-methylamino)nicotinic Acid STR7 To a solution of diisopropylamine (3.47 9, 0.034 mol) in tetrahydrofuran (100 ml) at -78 C., n-butyllithium (13 ml, 0.033 mol, 2.5M in hexane) was added. The reaction mixture was allowed to warm up to -30 C., and the mixture was then again cooled down to -78 C. Pre-cooled 2-bromopyridine (3.0 ml, 0.032 mol) was slowly added, and when addition was complete, the resulting mixture was stirred at -75 C. for 1 h. Ethyl chloroformate (5.0 ml, 0.052 mol) was added at once and the cooling bath was removed. At -10 C., saturated aqueous sodium bicarbonate (20 ml) was added followed by water (200 ml), and the mixture was extracted with ethyl acetate (3*100 ml). The combined organic extracts were washed with brine (2*100 ml), dried (MgSO4) and concentrated in vacuo. This afforded 9.18 g of an oil, containing crude EXAMPLE 4 2-(N-(3-(10, 11-Dihydro-5H-dibenz[b, f]azepin-5-yl)-1-propyl)-N-methyl-amino)nicotinic acid To a solution of diisopropylamine (3.47 g, 0.034 mol) in tetrahydrofuran (100 ml) at -78 C, n-butyllithium (13 ml, 0.033 mol, 2.5 M in hexane) was added. The reaction mixture was allowed to warm up to -30 C, and the mixture was then again cooled down to -78 C. Pre-cooled 2-bromopyridine (3.0 ml, 0.032 mol) was slowly added, and when addition was complete, the resulting mixture was stirred at -75 C for 1 h. Ethyl chloroformate (5.0 ml, 0.052 mol) was added at once and the cooling bath was removed. At -10 C, saturated aqueous sodium bicarbonate (20 ml) was added followed by water (200 ml), and the mixture was extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with brine (2 x 100 ml), dried (MgSO4) and concentratedin vacuo. This afforded 9.18 g of an oil, containing crude a Ethyl 2-(2-naphthylethen-1-yl)pyridine-3-carboxylate Hydrochloride 10 g (43.5 mmol) of

Molecular Weight:230.06
XLogP3:2.1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:228.97384
Monoisotopic Mass:228.97384
Topological Polar Surface Area:39.2
Heavy Atom Count:12
Complexity:163
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes