Synthesis method of 3,5-dibromopyridine_Industrial additives

Overview of the synthesis method of 3,5-dibromopyridine

3,5-Dibromopyridine is an important pharmaceutical intermediate and an important raw material for the prevention and treatment of central nervous system disorders TC-2559. Since the aromatic electrophilic reaction of pyridine occurs much slower than that of benzene, violent reaction conditions are often required, and only the 3-position substitution reaction is usually produced. Therefore, the reaction conditions for the synthesis of 3,5-dibromopyridine are very harsh. Using 4-aminopyridine as raw material, 3,5-dibromopyridine is produced by bromination, diazotization and Sandmeyer diazonium salt reduction method with sodium perborate tetrahydrate. The yield of the second step can reach 44.3%, and the total The yield can reach 36.8%, which is a good method for synthesizing 3,5-dibromopyridine.

Synthesis method of 3,5-dibromopyridineSynthesis method

Add 5.6 g (50 mmol) 80% sulfuric acid and 2.52 g (10 mmol) compound 4-aminopyridine into a 250 mL three-necked flask. After compound 4-aminopyridine is completely dissolved, heat it at 70 ~ 80 ℃ Add 0.69 g (10 mmol) sodium nitrite aqueous solution dropwise, and use the starch potassium iodide test paper to detect the reaction endpoint. When the reaction solution turns the starch potassium iodide test paper blue and does not fade away, stop the dropwise addition and react for 0.5 h. After adding 1.28 g (20 mmol) copper powder, add 20 mL ethanol mixed solution dropwise and reflux for 2 h. After cooling, use 50% NaOH solution to make it weakly alkaline, and then extract with ethyl acetate (20 mL×3) , dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized from ethanol to obtain 2.1 g of 3,5-dibromopyridine white solid, with a yield of 44.3%. m.p.112~113.℃. 1HNMR (MHz, CDCl3), δ: 8.622 1(d, 2H); 8.063 1(s, 1H). 13CHMR (MHz, CDC13), δ: 149.130, 140.895, 119.998.

Notes on the synthesis method of 3,5-dibromopyridine:

1. It is appropriate to control the diazotization reaction temperature between 70 and 80°C. Too high a reaction temperature will reduce the yield;

2. The concentration of sulfuric acid should be controlled at about 80%, and the amount of sulfuric acid used should be controlled at 4-amino-3,5-dibromopyridine:sulfuric acid = 1:2.5. If the amount of acid is insufficient, the generated diazonium salt will be The reacted raw materials produce coupling by-products.

3. The classic Sandmeyer diazotization reduction uses hypophosphorous acid as the protonation reagent after low-temperature diazotization. The reaction is generally performed at low temperature. However, the influence of the N atom in the pyridine ring on the aromatic ring is similar to the electron-withdrawing effect of the nitro group, and the electron-withdrawing effect of the two bromine atoms on the pyridine ring is not conducive to the synthesis of 3,5-dibromo-4-aminopyridine diazonium salt. generate. The acid concentration can be increased and the reaction temperature can be increased, and ethanol can be used as the protonation reagent instead of hypophosphorous acid.

Reference materials

[1] BENCHERIF M, BANE J, MILLER G H.TC-2559: a novel tetrahydrofuran titanium chloride o-rally active ligand selective at neuronal acetylcholine recep-tors[J]. Eur. J. Pharm., 2000 ,409:45-55.

[2] KATRIZKY A R,FAN W Q. Mechanisms and rates of the electrophillic substitution reactions of heterocycles[J]. Hete-rocycles, 1992,34(11):2 179-2 229.

[3] Hu Yadong, Yang Benmei. A synthesis method of 3,5-dibromopyridine