CN102924369A - Method for synthesizing 3,5-dibromo-4-iodopyridine by one step - Google Patents

Abstract

The invention discloses a synthesis method of halogenated pyridine 3,5-dibromo-4-iodopyridine. The synthesis method comprises the following steps: taking 3,5-dibromo-4-aminopyridine as an initial raw material to perform diazotization to obtain 3,5-dibromo-4-iodopyridine by one step. Compared with the disclosed prior art, the process provided by the invention is simple to operate, high in reaction yield (65-83%) and good in reaction in selectivity, industrial production can be easily implemented, and the product does not contain isomerides difficult to separate.

Description

Method for synthesizing 3,5-dibromo-4-iodopyridine in one step

technical field

The present invention relates to a synthetic method of halopyridine, especially a synthetic method of 3,5-dibromo-4-iodopyridine.

Background technique

Halopyridines are important fine chemical intermediates and are widely used in the fields of medicine and pesticides. Halogenated pyridines containing bromine and iodine are widely used in the fields of pesticides, medicines, and functional materials. 3,5-dibromo-4-iodopyridine is relatively difficult to synthesize, and there are few reports on the synthesis of 3,5-dibromo-4-iodopyridine at home and abroad, only literature ( Chemistry--A European Journal vol. 17; nb. 47; 2011; p. 13284 - 13297) disclosed its synthesis method: using 3,5-dibromopyridine as raw material, tetrahydrofuran and n-hexane as solvents, and n-butyllithium and tetramethyl Ethylenediamine zinc dichloride reacts to generate a lively carbanion intermediate, which reacts with iodine at room temperature to generate 3,5-dibromo-4-iodopyridine, and the reaction yield is only 8% (22% 3,5-dibromo-2-iodopyridine isomers are produced), and the isomer 3,5-dibromo-2-iodopyridine appears in the product, which makes separation and purification difficult. In this reaction, a large amount of expensive n-butyllithium (the molar ratio of n-butyllithium to 3,5-dibromopyridine is 1.5:1), makes the production cost high; at the same time, the use of n-butyllithium makes The anhydrous and oxygen-free operating conditions of the process are harsh, and engineering is difficult. To sum up, there are problems in the prior art that the yield is too low, a large number of isomers in the product make separation and purification difficult, the process operation conditions are harsh, and it is not easy to realize large-scale production. The literature reaction equation is as follows:

Contents of the invention

The object of the present invention is to provide a synthetic method of 3,5-dibromo-4-iodopyridine with short synthetic steps, high yield, good selectivity and simple operation.

The technical scheme adopted in the present invention is as follows:

A synthesis process of 3,5-dibromo-4-iodopyridine, the adopted starting material is 3,5-dibromo-4-aminopyridine.

The chemical reaction process of the present invention to synthesize 3,5-dibromo-4-iodopyridine is as follows:

The synthetic concrete process step of above-mentioned 3,5-dibromo-4-iodopyridine is:

Add 30-60% sulfuric acid into the three-necked flask, and add in batches at 15°C the reference literature ( Synthesis ; nb. 14; 2001; p. 2175 and Chemistry--A European Journal ; vol . 18; nb. 20; 2012 ; p. 6328, see Example 1) for the prepared 3,5-dibromo-4-aminopyridine, heated and stirred thoroughly to dissolve it, after the reaction bottle was cooled to room temperature, cooled with an ice-salt bath, slowly added nitrous acid dropwise Sodium aqueous solution, the temperature is controlled during the dropwise addition, after the dropwise addition, stir for 15 minutes, then add the diazotization iodide reagent dropwise into the reaction system, the temperature during the dropwise addition is controlled at 0-5°C, and after the dropwise addition, heat up rapidly to A certain temperature was maintained and stirred for 2 hours. Post-reaction treatment: After cooling the reaction liquid, pour it into ice water and stir it thoroughly, and the light yellow 3,5-dibromo-4-iodopyridine crude product is precipitated, and the obtained filtrate is filtered and neutralized to pH=6.0 with 10% sodium hydroxide aqueous solution. Extract with chloroform, separate the liquids, neutralize the organic phase with 5% aqueous sodium hydroxide solution to pH=7.5, separate the liquids, wash the organic phase once with saturated brine, separate the liquids, and dry the obtained organic layer with anhydrous sodium sulfate , filtered, and the solvent chloroform was removed by rotary evaporation to obtain a yellow crude product of 3,5-dibromo-4-iodopyridine. Filter the obtained filter cake, dry the water, combine two parts of the solid, and recrystallize with n-hexane to obtain pure white 3,5-dibromo-4-iodopyridine, with a yield of 65-83% and a liquid phase content of 95-99% .

In the reaction, the concentration of sulfuric acid is 20-60%, preferably 40%.

In the reaction, the molar ratio of 3,5-dibromo-4-aminopyridine to sodium nitrite is preferably 1:1-1.5.

In the reaction, the temperature for adding the sodium nitrite aqueous solution dropwise is -20 to 30°C, preferably 0 to 5°C.

In the described reaction, the diazotization iodide reagent is potassium iodide, sodium iodide, cesium iodide, cuprous iodide single component or any combination thereof, preferably potassium iodide and cuprous iodide, more preferably potassium iodide 2:1 mixture with cuprous iodide.

In the reaction, the molar ratio of 3,5-dibromo-4-aminopyridine to diazotization iodination reagent is preferably 1:1-3.

In the reaction, after the diazotization and iodination reagent is added dropwise, the temperature is raised to 20-130°C, preferably 80-100°C.

Compared with the prior art, the present invention has the following advantages:

1. Reagents such as n-butyllithium, which have harsh anhydrous and oxygen-free operating conditions and are difficult to engineer, are not used. The process of the present invention is simple to operate and easy to realize engineering.

2. The reaction yield is high (65-83%).

3. The reaction selectivity is good, and the impurities in the product are isomers that are difficult to separate.

Therefore, in summary, the present invention has good economic and social benefits.

Detailed ways

Example 1

Synthesis of 3,5-dibromo-4-aminopyridine: Add solvent carbon tetrachloride 900ml, 4-aminopyridine 94.11g (1.0mol), azobisisobutyronitrile (AIBN) in sequence in a 2000ml three-necked flask 0.82g, N-bromosuccinimide (NBS) 391.56g (2.2mol) was added in batches at 20°C, and reacted at room temperature for 24 hours. The raw material 4-aminopyridine and the intermediate 3- After all the bromo-4-aminopyridines were converted into the target product 3,5-dibromo-4-aminopyridine, the reaction was stopped. Post-reaction treatment: After stirring the reaction solution and cooling it to room temperature, pour it into 1000ml carbon tetrachloride, stir, filter, wash the filter cake twice with 2*200ml carbon tetrachloride, and wash the filtrate once with aqueous sodium bicarbonate solution. Wash once with saturated brine, remove the solvent carbon tetrachloride by rotary evaporation, obtain the crude product of 3,5-dibromo-4-aminopyridine, recrystallize with n-hexane to obtain white 3,5-dibromo-4-aminopyridine 225.6g, yield 89.6%, liquid phase content 97.8%, this product can be directly used in the next reaction.

Example 2

Add 40% sulfuric acid into a 1000ml three-neck flask, add 126.0g (0.50mol) of 3,5-dibromo-4-aminopyridine synthesized by the method in Example 1 above at 15°C, and heat to 45°C and stir thoroughly Make it dissolve, after the reaction bottle is cooled to room temperature, cool it with an ice-salt bath, slowly add a sodium nitrite solution containing 38.5g (0.56mol) sodium nitrite and 150g water dropwise, the dropping process is controlled at 0-3°C, dropwise After that, stir for 15 minutes, then add dropwise a saturated aqueous solution containing 83.0 g (0.5 mol, 1.0 eq) of potassium iodide and a 30% sulfuric acid solution containing 47.6 g (0.25 mol, 0.5 eq) of cuprous iodide simultaneously in the reaction system, During the dropwise addition, the temperature was controlled at 0-5°C. After the dropwise addition, the temperature was rapidly raised to an internal temperature of 80°C, and the temperature was maintained and stirred for 2 hours. Post-reaction treatment: After cooling the reaction solution, pour it into 2000ml of ice water, stir well, and precipitate light yellow crude 3,5-dibromo-4-iodopyridine, filter the obtained filtrate and neutralize it with 10% sodium hydroxide aqueous solution to pH=6.0 , extracted with chloroform, separated, the organic phase was neutralized with 5% aqueous sodium hydroxide solution to pH=7.5, separated, the organic phase was washed once with saturated brine, separated, and the obtained organic layer was washed with anhydrous sodium sulfate Dry, filter, and remove the solvent chloroform by rotary evaporation to obtain a yellow crude product of 3,5-dibromo-4-iodopyridine. Filter the obtained light yellow filter cake, dry the water, combine the two parts of the crude product, and recrystallize with n-hexane to obtain 141.3 g of light yellow pure product 3,5-dibromo-4-iodopyridine, with a yield of 78.0% and a liquid phase content of 98.8 %.

Example 3

In described reaction, initial sulfuric acid concentration is 30%, and other is with operation embodiment 2.

The operation was carried out according to Example 2, and 125.0 g of pure light yellow 3,5-dibromo-4-iodopyridine was obtained, with a yield of 69.0% and a content of 98.2%.

Example 4

In described reaction, initial sulfuric acid concentration is 50%, and other is with operation embodiment 2.

The operation was carried out according to Example 2, and 139.9 g of pure light yellow 3,5-dibromo-4-iodopyridine was obtained, with a yield of 77.2% and a content of 98.5%.

Example 5

In the reaction, the amount of sodium nitrite was 34.3g (0.50mol), and the others were the same as in Example 2, and the operation was carried out according to the example to obtain 133.9 grams of light yellow pure 3,5-dibromo-4-iodopyridine, with a content of 98.2 %, yield 73.9%.

Example 6

In the reaction, the diazotization and iodination reagent is a saturated aqueous solution containing 83.0 g (0.5 mol, 1.5 eq) of potassium iodide, and the others are the same as in Example 2. Operate according to the example to obtain light yellow 3,5-dibromo-4 - 121.7 grams of iodopyridine pure product, content 98.3%, yield 67.2%.

Example 7

In the reaction, the diazotization iodination reagent is a saturated aqueous solution containing 75.0g (0.5mol, 1.0eq) of sodium iodide and 47.6g (0.25mol, 0.5eq) of cuprous iodide, and the others are the same as in Example 2. According to the operation in the example, 117.9 g of pure light yellow 3,5-dibromo-4-iodopyridine was obtained, with a content of 97.6% and a yield of 65.1%.

Example 8

In the reaction, after the diazotization and iodination reagent is added dropwise, the reaction temperature is raised to 100°C, and the others are the same as in Example 2, and the operation is carried out according to the example to obtain light yellow 3,5-dibromo-4-iodopyridine pure Product 150.0 grams, content 99.3%, yield 82.8%.

Example 9

In the reaction, after the diazotization and iodination reagent is added dropwise, the reaction temperature is raised to 60° C., and the others are the same as in Example 2. Operate according to the example to obtain light yellow 3,5-dibromo-4-iodopyridine pure Product 129.1 grams, content 98.9%, yield 71.3%.

Claims (7)

1.3 the synthetic method of 5-two bromo-4-iodine pyridines is characterized in that with 3,5-, two bromo-4-aminopyridines be main starting raw material, through diazotization reaction, a step obtains target product, and chemical reaction process is as follows:

The concrete technology step is:

In three-necked bottle, add 30-60% sulfuric acid, under 15 ℃, add 3 of reference literature preparation, 5-two bromo-4-aminopyridines in batches, heating is fully stirred and is made its dissolving, after reaction flask is as cold as room temperature, bathes cooling with cryosel, slowly drip sodium nitrite in aqueous solution, drip the process control certain temperature, after dripping, stirred 15 minutes, then in reaction system, drip the diazotization iodination reagent, drip 0～5 ℃ of process temperature control, drip rear rapid heating and be warmed up to certain temperature, keep this temperature, stirred 2 hours; Post-reaction treatment: pour in the frozen water after the reaction solution cooling, fully stir, Precipitation light yellow 3,5-two bromo-4-iodine pyridine crude products, filter gained filtrate with the 10% aqueous sodium hydroxide solution pH=6.0 that neutralizes, use chloroform extraction, separatory, organic phase is again with the 5% aqueous sodium hydroxide solution pH=7.5 that neutralizes, separatory, organic phase is used the saturated common salt water washing once, separatory, gained organic layer anhydrous sodium sulfate drying, filter, revolve to steam and remove the solvent trichloromethane, obtain yellow 3,5-, two bromo-4-iodine pyridine crude products; Filter the gained filter cake, oven dry moisture merges two portions solid, uses the normal hexane recrystallization, obtains white 3,5-two bromo-4-iodine pyridine sterlings, yield 65～83%, liquid content 95～99%.

2. in the described reaction, sulfuric acid concentration is 20-60%, preferred 40%.

3. in the described reaction, 3,5-, two bromo-4-aminopyridines and Sodium Nitrite mol ratio are preferably 1:1～1.5.

4. in the described reaction, the temperature that drips sodium nitrite in aqueous solution is-20～30 ℃, is preferably 0～5 ℃.

5. in the described reaction, the diazotization iodination reagent is potassiumiodide, sodium iodide, cesium iodide, cuprous iodide one-component or its any both compositions, is preferably potassiumiodide and cuprous iodide, is preferably the 2:1 mixture of potassiumiodide and cuprous iodide again.

6. in the described reaction, 3,5-, two bromo-4-aminopyridines and diazotization iodination reagent mol ratio are preferably 1:1～3.

7. in the described reaction, drip the diazotization iodination reagent after, intensification is 20～130 ℃, is preferably 80～100 ℃.