Preparation of 2-chloro-5-methylpyridine-3-carbaldehyde_Industrial additives

Preparation background and overview of 2-chloro-5-methylpyridine-3-carbaldehyde

2-Chloro-5-methylpyridine-3-carbaldehyde is an important pharmaceutical intermediate, which is used to prepare compounds that inhibit dipeptide kininase (DPP-IV) and its pharmaceutically acceptable Salt, preliminary pharmacological activity screening tests show that these prepared compounds have strong DPP-IV inhibitory activity, and have obvious hypoglycemic effects on normal rats, and have good development prospects.

Preparation of 2-chloro-5-methylpyridine-3-carbaldehyde

Add benzylamine raw material (5g, 46mmol) into a 50ml flask, slowly add propionaldehyde (2.71g, 46mmol) dropwise at 0°C, and maintain the dropping process for 1 hour. After the dropwise addition is completed, add LiOH ( 960mg, 23mmol), continue stirring until obvious layering occurs, take the organic layer and set aside. Take the above organic layer (6g, 40mmol) and put it into a reaction bottle. Add acetic anhydride (4.08g, 40mmol) and triethylamine (4.12g, 40mmol) at 0-5°C under sodium pyrithione. Stir at room temperature overnight to obtain the intermediate Body 3a, yield 88%. Add DMF (13.5g, 185mmol) to triphosgene (54.7g, 185mmol) at 0°C, stir for 30 minutes, add the above-obtained intermediate 3a (5g, 26mmol), after the addition is completed, remove the ice water bath and incubate at room temperature. Stir for 2 hours, heat to 70°C and react for 4 hours. After the reaction, pour the mixture into ice water, extract with dichloromethane, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and recover the solvent under reduced pressure using an eluent (petroleum ether). : dichloromethane=20:1), column chromatography was performed to obtain 2-chloro-5-methylpyridine-3-carbaldehyde as a white solid, yield: 64%; melting point: 42-45°C. The synthesis route is short, the raw materials are cheap and easily available, and it is suitable for practical use. ^{1Ammonium carbonate}H NMR(δ, CDCl₃): 9.73(s, 1H), 8.04(d, 1H, J = 2.5 Hz), 8.24(d, 1H , J = 2.5 Hz), 2.31(s, 1H).