2-chloro-5-cyanopyridine is a key compound in pharmaceutical and agrochemical synthesis. It is known for its reactivity and versatility, making it ideal for researchers in medicinal chemistry and crop protection. Here we will introduce several methods for synthesizing 2-chloro-5-cyanopyridine.

Synthesis from 6-Chloropyridine-3-carbonitrileOxalyl chloride

2-chloro-5-cyanopyridine Oxalyl chloride (40 mL) was added dropwise at 0 °C to a suspension of 6-chloropyridine-3- carboxylic acid (18 g, 114 mmol) in 300 mL of DCM with 3 mL of DMF. The mixture wasstirred at 25 °C for 2 hours and the clear solution was concentrated to dryness under reduced pressure. The residue was dissolved in 100 mL of anhydrous acetonitrile and then added to 500 mL of diluted aqueous NH3 .H2 0 at 0 °C. The mixture was stirred for 30 minutes then extracted with EtOAc twice. The combined EtOAc layers were washed with water and brine, dried over anhydrous Na2 S04 and concentrated. The residue was dissolved in 100 mL of DMF and cooled to 0 °C with ice/water bath. Cyanuric chloride (21.2 g, 114.9 mmol) was added and the mixture was stirred for 2 hours at 0 °C and then poured into ice/water. The resulting solid was collected by filtration, washed with water, dissolved in DCM, dried over anhydrous Na2S04 and concentrated to afford 2-chloro-5-cyanopyridine 6-(Prop-2-en-l-yl pyridine-3-carbonitrile: A mixture of 2-chloro-5-cyanopyridine (7.0 g, 50 mmol), allyl tri-n-butyltin (18.2 g, 55.0 mmol) and Pd(PPh3 )2 Cl2 (1 g) in 80 mL DMF was stirred at 90 °C for 3 hours. The mixture was cooled down and diluted with 1 L of EtOAc, washed with water (100 mL x 2) and brine (100 mL), then concentrated. The residue was purified by column chromatography (PE : EtOAc = 10 : 1) to afford the title compound.[1]

Synthesis from phenylacetic acid

Aromatic nitriles are important intermediates in organic synthesis and can be converted into a variety of other groups, including amino groups, amines, aldehydes and heterocyclic compounds, and are therefore widely used in the pharmaceutical industry, natural products and agrochemicals. Synthesis of drugs. However, the existing method for producing an aromatic nitrile compound does not require an explosive compound or a toxic cyanogen, that is, the reaction requires strong acidity. It is an object of the present invention to overcome the deficiencies of the prior art and to provide a process for the preparation of a 2-chloro-5-cyanopyridine. A preparation method of a 2-chloro-5-cyanopyridine, wherein a 2-chloro-5-cyanopyridine is prepared by using phenylacetic acid or a derivative thereof and urea as a raw material, a copper salt as a catalyst and oxygen as an oxidant, and the reaction mechanism is as follows:

General procedure: phenylacetic acid or its derivative (0.5mmol), Cu(TFA)2(20mmol%), urea (1.5 mmol) was added to the pressure sealed tube containing (0.75mL) of DMSO, after filling oxygen at 130 stirred for about 20h, the process by TLC and GC tracking (specifically the reaction time is determined by GC and TLC tracking results). After the raw material was observed by the GC and TLC the reaction has been completed the reaction, the reaction was removed, cooled to room temperature.To the reaction was added 20mL of ethyl acetate, washed with NaHCO3(20mL × 2), washed with saturated brine 20mL.The combined aqueous phases with ethyl acetate (20mL × 2) after stripping the combined organic phases with anhydrous sodium sulfate. The organic phase was dried by rotary evaporator spin solvent, product was purified by silica gel column, eluent ratio of ethyl acetate: petroleum ether = 50: 1. 2-chloro-5-cyanopyridine obtained in a yield of 84%.[2]

Synthesis from β-dimethylamino-acrylonitrile

13.2 g of β-dimethylamino-acrylonitrile were added dropwise at 30° C. to a solution of 22 g of DMF/HCl adduct in 100 ml of DMF. Following an after-reaction time of 2 h, this solution was added dropwise, while passing in HCl, to a solution, saturated at 50° C., of HCl gas in DMF. The temperature was maintained at 50° C. by cooling. After conventional work up (40 ml of water), 2-chloro-5-cyanopyridine was obtained in 77.7% of the theoretical yield, based on the C3 unit employed.[3]

References

[1] MERCK SHARP DOHME - WO2013/62892, 2013, A1

[2] HUAQIAO UNIVERSITY - CN103772236, 2016, B

[3] AYER CROPSCIENCE - US5459273, 1995, A