4-Chloro-2,5-difluoropyridine synthesis

Yield: 78%

Reaction Conditions:

Stage #1:2,5-difluoropyridine with n-butyllithium;diisopropylamine in tetrahydrofuran;hexane;tert-butyl methyl ether at -78; for 1 h;
Stage #2: with 1,1,2-Trichloro-1,2,2-trifluoroethane in tetrahydrofuran;hexane;tert-butyl methyl ether at -75; for 2 h;Heating;

Steps:

1.1; 2.1; 3.1 Synthesis of 4-chloro-2,5-difluoropyridine:
Diisopropylamine (53 g, 0.525 mol) was added to tetrahydrofuran (150 ml) / methyl tert-butyl ether (200 ml)Of the mixed solution,Replace nitrogen.Cooling to -60 - 40 ,A solution of n-butyllithium / n-hexane (191 ml, 2.5 M)The temperature was then slowly warmed to -20 ° C and stirred for 10 minutes.The reaction flask was cooled to -75 ° C,A solution of 2,5-difluoropyridine (50 g, 0.434 mol)After dripping for 1 hour.A solution of Freon-113 (89.4 g, 0.478 mol) was added dropwise at -75 ° C,Dripping finished insulation for 2 hours.Saturated ammonium chloride quenching reaction,Methyl tert-butyl ether extraction reaction solution.The organic phase was washed with 2N aqueous hydrochloric acid,And then washed with water,Saturated sodium bicarbonate wash,Saturated brine washing,The organic phase was separated and dried over anhydrous sodium sulfate,filter.The filtrate was distilled at 80 ° C to 120 ° C under normal pressure to remove the solvent,The residue was distilled at 120 ° C to 190 ° C under atmospheric pressure to give the product 4-chloro-2,5-difluoropyridine (50 g, yield 78%).

References:

Danuo Pharmaceutical (Suzhou) Co., Ltd.;Ding, Jun;He, Shijie;Zhuang, Zhijun;Ma, Zhenkun CN106432222, 2017, A Location in patent:Paragraph 0038; 0039; 0040-0042; 0060-0064; 0079-0083