A preparation method of 4-bromo-6-chloronicotinic acid

Abstract

The invention discloses a preparation method of 4-bromo-6-chloronicotinic acid, which is characterized by comprising the following steps: dissolving 2-chloro-4-amino-5-methylpyridine in dilute acid, then adding a catalyst and a bromide, and dropwise adding a sodium nitrite aqueous solution to diazotize the bromine to obtain 2-chloro-4-bromo-5-methylpyridine, wherein the molar ratio of the 2-chloro-4-amino-5-methylpyridine, the catalyst, the bromide and the sodium nitrite is 1:(1-3):(2-5):(2-5); and (2) reacting the 2-chloro-4-bromo-5-methylpyridine with an oxidizing agent to obtain 4-bromo-6-chloronicotinic acid, wherein the molar ratio of the 2-chloro-4-bromo-5-methylpyridine to the oxidizing agent is 1:(1-3). The method has the advantages of simple process circuit, mild and safe reaction conditions, low production cost and high total yield.

Description

Technical Field

[0001] The present invention relates to the field of synthesis of pharmaceutical and pesticide intermediates, and in particular to a method for preparing 4-bromo-6-chloronicotinic acid. Background Art

[0002] 4-Bromo-6-chloronicotinic acid is an important pharmaceutical and pesticide intermediate. The original synthesis method uses 4-bromo-2-chloro-3-(trimethylsilyl)-pyridine as a raw material, uses carbon dioxide to form a carboxyl group under cryogenic conditions, and then removes trimethylsilane to obtain 4-bromo-6-chloronicotinic acid (WO2014074675A1). The disadvantages of this method are: the raw material source is difficult to obtain and the price is high; and it requires relatively harsh conditions such as anhydrous and oxygen-free conditions and ultra-low temperatures; due to the high raw material price, the two-step total yield is not high, only 60%, and the harsh operating conditions make this route impractical and difficult to achieve large-scale production. Its synthesis route is shown below:

[0003]

[0004] The above process has the problems of high industrialization cost and unsuitability for large-scale production due to the high price of starting raw materials and complex process operations. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a method for preparing 4-bromo-6-chloronicotinic acid with a simple process line, mild and safe reaction conditions, low production cost and high total yield.

[0006] The technical solution adopted by the present invention to solve the above technical problems is: a method for preparing 4-bromo-6-chloronicotinic acid, comprising the following steps:

[0007] (1) 2-chloro-4-amino-5-methylpyridine is dissolved in dilute acid, a catalyst and a bromide are then added, and a sodium nitrite aqueous solution is added dropwise to diazotize the bromine to obtain 2-chloro-4-bromo-5-methylpyridine;

[0008] (2) 2-chloro-4-bromo-5-methylpyridine is reacted with an oxidizing agent to obtain 4-bromo-6-chloronicotinic acid.

[0009] Furthermore, step (1) is specifically as follows: dissolving 2-chloro-4-amino-5-methylpyridine in dilute acid, stirring until dissolved, cooling to T1-30-100°C, adding a catalyst and a bromide, stirring for half an hour, cooling to T2-30-40°C, and then slowly adding a sodium nitrite aqueous solution dropwise, controlling the temperature not to be higher than T2. ​​After the addition is complete, maintaining the temperature at T2 and reacting for another hour; after the reaction is complete, extracting the reaction solution three times with methyl tert-butyl ether, combining the organic phases, washing with a saturated sodium bicarbonate aqueous solution, washing again with saturated brine, decolorizing with activated carbon, drying over anhydrous sodium sulfate, filtering, rinsing the filter cake twice with methyl tert-butyl ether, combining the organic phases, and concentrating to dryness to obtain a light yellow oily substance 2-chloro-4-bromo-5-methylpyridine.

[0010] Furthermore, the dilute acid is dilute sulfuric acid, dilute hydrobromic acid, dilute nitric acid or dilute phosphoric acid; the catalyst is copper sulfate, and the bromide is sodium bromide or potassium bromide.

[0011] Furthermore, the molar ratio of the 2-chloro-4-amino-5-methylpyridine, the catalyst, the bromide and the sodium nitrite is 1:(1-3):(2-5):(2-5).

[0012] Furthermore, the molar ratio of the 2-chloro-4-amino-5-methylpyridine, the catalyst, the bromide and the sodium nitrite is 1:2:2.5:3.

[0013] Furthermore, the temperature of T1 is 20°C; the temperature of T2 is -5°C-0°C.

[0014] Furthermore, step (2) is specifically as follows: adding 2-chloro-4-bromo-5-methylpyridine to a reaction flask containing a solvent, adding or introducing an oxidant at a temperature controlled at 10-180° C., and then controlling the temperature at 20-100° C. until the reaction is complete to obtain 4-bromo-6-chloronicotinic acid, wherein the molar ratio of the 2-chloro-4-bromo-5-methylpyridine to the oxidant is 1:(1-6).

[0015] Furthermore, the oxidant is oxygen, chlorine, sodium dichromate, potassium dichromate, potassium permanganate or nitric acid.

[0016] Furthermore, the solvent is selected according to different oxidants: if the oxidant is potassium permanganate, water is selected as the solvent; if the oxidant is oxygen, methanol, ethanol or isopropanol is selected as the solvent; if the oxidant is sodium dichromate or potassium dichromate, sulfuric acid is selected as the solvent.

[0017] When the oxidant is sodium dichromate or potassium dichromate, sulfuric acid is selected as the solvent; after the reaction of step (2) is complete, the obtained reaction solution is slowly poured into ice and stirred for half an hour. Solids are precipitated, filtered, and the filter cake is rinsed with water until neutral to obtain an off-white solid 4-bromo-6-chloronicotinic acid (sodium dichromate or potassium dichromate oxidation method);

[0018] When the oxidant is potassium permanganate, water is selected as the solvent; after the reaction of the above step (2) is completed, the reaction solution is cooled to 30°C, filtered, and the filter cake is rinsed with cold water to obtain a filtrate and an eluent, and the pH is adjusted to 3 with 6N hydrochloric acid to form a precipitate, which is filtered. The obtained solid is washed with water and dried to obtain an off-white solid 4-bromo-6-chloronicotinic acid (potassium permanganate oxidation method);

[0019] When the oxidant is oxygen, methanol, ethanol or isopropanol is selected as the solvent; after the reaction in step (2) is completed, the reaction mixture is filtered, and the solvent is evaporated under reduced pressure. The residue is added with cold water and stirred, and the pH is adjusted to 3 with 10wt% hydrochloric acid to precipitate a large amount of white solid. The solid is filtered, washed with water, and dried to obtain an off-white solid 4-bromo-6-chloronicotinic acid (air / oxygen oxidation method).

[0020] Compared with existing technologies, the present invention offers the following advantages: A method for preparing 4-bromo-6-chloronicotinic acid uses inexpensive 2-chloro-4-amino-5-methylpyridine (a key intermediate in the synthesis of omeprazole (see patent application publication number CN103193704A), which is already in large-scale production and widely available and low-cost) as a raw material. The target product is obtained through a two-step reaction of diazo bromination and methyl oxidation. This synthetic route utilizes widely available and inexpensive raw materials, a simple process, mild reaction conditions, and a total yield of up to 82%, making it suitable for large-scale production and promising for broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The nuclear magnetic resonance spectrum of 4-bromo-6-chloronicotinic acid prepared by the present invention. DETAILED DESCRIPTION

[0022] The present invention will be described in further detail below with reference to the accompanying drawings and embodiments. Specific embodiments

[0024] A method for preparing 4-bromo-6-chloronicotinic acid comprises the following steps:

[0025] 1. Dissolve 2-chloro-4-amino-5-methylpyridine in dilute acid, then add a catalyst and bromide, and dropwise add sodium nitrite aqueous solution to diazotize the bromine to obtain 2-chloro-4-bromo-5-methylpyridine;

[0026] 2. React 2-chloro-4-bromo-5-methylpyridine with an oxidizing agent to obtain 4-bromo-6-chloronicotinic acid. The synthetic route is as follows:

[0027]

[0028] The above step (1) is specifically as follows: dissolving 2-chloro-4-amino-5-methylpyridine in dilute acid, stirring until dissolved, cooling to T1-30-100°C, adding a catalyst and a bromide, stirring for half an hour, cooling to T2-30-40°C, and then slowly adding a sodium nitrite aqueous solution dropwise, controlling the temperature not to be higher than T2. ​​After the addition is complete, maintaining the temperature at T2 and reacting for another hour; after the reaction is complete, extracting the reaction solution three times with methyl tert-butyl ether, combining the organic phases, washing with a saturated sodium bicarbonate aqueous solution, washing again with saturated brine, decolorizing with activated carbon, drying over anhydrous sodium sulfate, filtering, rinsing the filter cake twice with methyl tert-butyl ether, combining the organic phases, and concentrating to dryness to obtain a light yellow oily substance 2-chloro-4-bromo-5-methylpyridine. The dilute acid is dilute sulfuric acid, dilute hydrobromic acid, dilute nitric acid or dilute phosphoric acid; the catalyst is copper sulfate; the bromide is sodium bromide or potassium bromide; the molar ratio of 2-chloro-4-amino-5-methylpyridine, the catalyst, the bromide and the sodium nitrite is 1:(1-3):(2-5):(2-5).

[0029] The above step (2) is specifically as follows: 2-chloro-4-bromo-5-methylpyridine is added to a reaction flask containing a solvent, an oxidant is added or introduced at a temperature of 10-180° C., and the temperature is controlled at 20-100° C. until the reaction is complete to obtain 4-bromo-6-chloronicotinic acid, wherein the molar ratio of 2-chloro-4-bromo-5-methylpyridine to the oxidant is 1:(1-3). The oxidant is oxygen, chlorine, sodium dichromate, potassium dichromate, potassium permanganate or nitric acid.

[0030] When the oxidant is sodium dichromate or potassium dichromate, sulfuric acid is selected as the solvent; after the reaction of step (2) is complete, the obtained reaction solution is slowly poured into ice and stirred for half an hour. Solids are precipitated, filtered, and the filter cake is rinsed with water until neutral to obtain an off-white solid 4-bromo-6-chloronicotinic acid (sodium dichromate or potassium dichromate oxidation method);

[0031] When the oxidant is potassium permanganate, water is selected as the solvent; after the reaction of the above step (2) is completed, the reaction solution is cooled to 30°C, filtered, and the filter cake is rinsed with cold water to obtain a filtrate and an eluent, and the pH is adjusted to 3 with 6N hydrochloric acid to form a precipitate, which is filtered. The obtained solid is washed with water and dried to obtain an off-white solid 4-bromo-6-chloronicotinic acid (potassium permanganate oxidation method);

[0032] When the oxidant is oxygen, methanol, ethanol or isopropanol is selected as the solvent; after the reaction in step (2) is completed, the reaction mixture is filtered, and the solvent is evaporated under reduced pressure. The residue is added with cold water and stirred, and the pH is adjusted to 3 with 10wt% hydrochloric acid to precipitate a large amount of white solid. The solid is filtered, washed with water, and dried to obtain an off-white solid 4-bromo-6-chloronicotinic acid (air / oxygen oxidation method).

[0033] Example 1

[0034] 1. Synthesis of 2-chloro-4-bromo-5-methylpyridine

[0035] Prepare a 10L three-necked flask, mechanical stirring, thermometer, and dropping funnel. First, prepare a sulfuric acid aqueous solution (548.8g, 5.6mol, 4L of water), then add it to a 10L reaction flask, start stirring, place in an ice-salt bath, add the raw material 2-chloro-4-amino-5-methylpyridine (290g, 2.0mol) and stir to dissolve. Then, when T1 < 20℃, add copper sulfate pentahydrate (1004g, 4mol) and sodium bromide (515g, 5mol), stir for half an hour, and when T2 < 0℃, add sodium nitrite aqueous solution (441.6g, 6.4mol, 1L of water) dropwise. Control T2 < 0℃. The system releases heat significantly, and slowly add dropwise for about two hours. After the dropwise addition is complete, keep the reaction warm for one hour. Take a sample by TLC (EA:PE=1:1). After the reaction is complete, the reaction solution is extracted three times with methyl tert-butyl ether (1.5L×3), the organic phases are combined, and the organic phase is washed once with a saturated sodium bicarbonate aqueous solution (1L×1), and once with saturated brine (1L×1). Decolorize with activated carbon, dry with anhydrous sodium sulfate, filter, and rinse the filter cake twice with methyl tert-butyl ether (500ml×2). The organic phases are combined and concentrated to dryness to obtain 380g of light yellow oil, y=92%, and purity of 97%.

[0036] The difference between Example 2-6 and Example 1 is that the amounts of 2-chloro-4-amino-5-methylpyridine, copper sulfate, sodium bromide, and sodium nitrite are not changed, only the reaction temperature is changed. The specific reaction conditions, yield, and purity of the prepared 2-chloro-4-bromo-5-methylpyridine are shown in Table 1 below.

[0037] Table 1 Effect of reaction temperature on yield and purity of product (2-chloro-4-bromo-5-methylpyridine)

[0038]

[0039] As can be seen from Table 1 above, the difference between Examples 3-6 and Example 1 is that, when other conditions remain unchanged, the yield and purity decrease as the reaction temperature increases. Increasing the temperature will produce more and more by-products such as 2-chloro-4-hydroxy-5-methylpyridine, 2,4-dibromo-5-methylpyridine and 2-bromo-4-chloro-5-methylpyridine, so the higher the temperature, the faster the product yield and purity will decrease.

[0040] Although the yield and purity of Example 2 are similar to those of Example 1, the reaction temperature of Example 1 is more economical and is the preferred reaction temperature for economic benefit. Therefore, the optimal temperature for T1 is 20°C; the optimal temperature for T2 is -5°C to 0°C.

[0041] Table 2 Effect of different molar ratios of reactants on the yield and purity of the product (2-chloro-4-bromo-5-methylpyridine)

[0042]

[0043]

[0044] As can be seen from Table 2, Examples 7-15 differ from Example 1 in that the equivalent ratios of copper sulfate and sodium bromide are different. When the reaction equivalents of copper sulfate and sodium bromide are increased from 1 eq to 3 eq, the yield increases from 40% to more than 90%, and the purity also increases from 55.7% to more than 95.4%. When the reaction equivalent of copper sulfate is increased to 5 eq, the yield and purity are not greatly affected, that is, the participation of an appropriate amount of catalyst (copper sulfate) in the reaction helps the reaction proceed in the forward direction. With the participation of an appropriate amount of catalyst, the reaction equivalent of sodium bromide is increased from 1 eq to 5 eq, and the yield increases from 40% to 94%. That is, a proper excess of brominating agent helps the reaction proceed in the forward direction. However, when the reaction equivalent exceeds 2.5 eq, the product purity decreases when the amount of sodium bromide is increased. It can be seen that while the excess brominating agent helps the reaction proceed in the forward direction, the increase in by-products is also significant. 2.5 eq is a balance point for optimal yield and purity.

[0045] 2. Synthesis of 4-bromo-6-chloronicotinic acid

[0046] Sodium dichromate oxidation

[0047] Prepare a 5L three-necked flask with mechanical stirring, a thermometer, and an ice-water bath. First, add 2L of concentrated sulfuric acid to the reaction flask. Start stirring, place in an ice-water bath, and keep the temperature below 5°C. Then, add the intermediate 2-chloro-4-bromo-5-methylpyridine (206.5g, 1mol) obtained in the previous step. Exotherm to 10°C, and the system will become a pale yellow clear liquid. Then, add sodium dichromate (447g, 1.5mol) in batches, controlling the temperature below 40°C, over approximately 3 hours. After the addition is complete, stir for one hour. Sample TLC (EA:PE = 1:3, UV) shows that the product has become much more polar. After sampling, add the sample to ice water for quenching and re-analyzing. After the reaction is complete, slowly pour the reaction solution into 8kg of ice and stir for half an hour. Solid precipitates, filter, and rinse the filter cake with water until neutral, yielding 210g of an off-white solid, 4-bromo-6-chloronicotinic acid, with y = 89%. Its NMR spectrum is as follows: Figure 1 shown.

[0048] Example 16

[0049] The same as Example 1, except that the synthesis of 4-bromo-6-chloronicotinic acid adopts potassium permanganate oxidation, and the specific steps are as follows: prepare a 5L three-necked flask, mechanical stirring, thermometer, and oil bath pot, first add 3L of cold water to the reaction flask, start stirring, add the intermediate 2-chloro-4-bromo-5-methylpyridine (150g, 0.73mol) obtained in the previous step, heat to 80°C, and after the temperature stabilizes, add potassium permanganate (500g, 3.2mol) in batches, control the temperature not to be higher than 95°C, and add it over about 3 hours. After the addition is completed, keep the reaction at 95°C overnight; the next day, cool to 30°C in an ice-water bath and filter, take the filtrate, wash the filter cake manganese dioxide with 500mL of cold water, mix the obtained filtrate and eluent, adjust the pH to 3 with 6N hydrochloric acid, form a precipitate, filter, wash the obtained solid with water, and dry to obtain 70g of off-white solid 4-bromo-6-chloronicotinic acid, y=40.6%.

[0050] Example 17

[0051] The same as Example 1, except that the synthesis of 4-bromo-6-chloronicotinic acid adopts oxygen oxidation, and the specific steps are as follows: 1.2L methanol and the intermediate 2-chloro-4-bromo-5-methylpyridine (150g, 0.73mol) obtained in the previous step, 0.02g of cobalt acetate, 0.02g of cobalt acetylacetonate, and 15g of cesium carbonate were added to a 2L autoclave. The air in the autoclave was replaced twice with nitrogen, and the mixture was stirred. Oxygen was introduced into the reaction mixture, and the reaction was carried out under a pressure of 0.5MPa and a temperature of 80°C for 20 hours. After completion of the reaction, the mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was added with 800mL of water, stirred, and the pH was adjusted to 3 with 10wt% hydrochloric acid to precipitate a large amount of white solid. The solid was filtered, washed with water, and dried to obtain 138g of 4-bromo-6-chloronicotinic acid as an off-white solid, with y=80%.

[0052] The above description is not intended to limit the present invention, and the present invention is not limited to the above examples. Any changes, modifications, additions or substitutions made by persons of ordinary skill in the art within the spirit and scope of the present invention shall also fall within the scope of protection of the present invention.

Claims

1. A method for preparing 4-bromo-6-chloronicotinic acid, characterized in that The following steps are involved: (1) dissolving 2-chloro-4-amino-5-methylpyridine in dilute acid, then adding a catalyst and a bromide, and dropping a sodium nitrite aqueous solution to diazotize the bromine to obtain 2-chloro-4-bromo-5-methylpyridine, specifically: dissolving 2-chloro-4-amino-5-methylpyridine in dilute acid, stirring until clear, cooling to T1-30-100°C, adding a catalyst and a bromide, stirring for half an hour, cooling to T2-30-40°C, and then slowly dropping a sodium nitrite aqueous solution, controlling the temperature not to be higher than T2, after the dropping is completed, maintaining the temperature at T2 and reacting for another hour; after the reaction is complete, the reaction solution is extracted three times with methyl tert-butyl ether, the organic phases are combined, washed with a saturated sodium bicarbonate aqueous solution, washed again with saturated brine, decolorized with activated carbon, dried over anhydrous sodium sulfate, filtered, the filter cake is rinsed twice with methyl tert-butyl ether, the organic phases are combined, and concentrated to dryness to obtain a light yellow oily substance 2-chloro-4-bromo-5-methylpyridine; (2) reacting 2-chloro-4-bromo-5-methylpyridine with an oxidizing agent to obtain 4-bromo-6-chloronicotinic acid, specifically: adding 2-chloro-4-bromo-5-methylpyridine to a reaction bottle containing a solvent, controlling the temperature at 10-180° C. to add or introduce an oxidizing agent, and then controlling the temperature at 20-100° C. until the reaction is complete to obtain 4-bromo-6-chloronicotinic acid, wherein the molar ratio of the 2-chloro-4-bromo-5-methylpyridine to the oxidizing agent is 1:(1-6).

2. The method for preparing 4-bromo-6-chloronicotinic acid according to claim 1, wherein: The dilute acid is dilute sulfuric acid, dilute hydrobromic acid, dilute nitric acid or dilute phosphoric acid; the catalyst is copper sulfate, and the bromide is sodium bromide or potassium bromide.

3. The method for preparing 4-bromo-6-chloronicotinic acid according to claim 1, wherein: The molar ratio of the 2-chloro-4-amino-5-methylpyridine, the catalyst, the bromide and the sodium nitrite is 1:(1-3):(2-5):(2-5).

4. The method for preparing 4-bromo-6-chloronicotinic acid according to claim 1, wherein: The molar ratio of the 2-chloro-4-amino-5-methylpyridine, the catalyst, the bromide and the sodium nitrite is 1:2:2.5:

3.

5. The method for preparing 4-bromo-6-chloronicotinic acid according to claim 1, wherein: The temperature of T1 is 20°C; the temperature of T2 is -5°C-0°C.

6. The method for preparing 4-bromo-6-chloronicotinic acid according to claim 1, wherein: The oxidant is oxygen, chlorine, sodium dichromate, potassium dichromate, potassium permanganate or nitric acid.

7. The method for preparing 4-bromo-6-chloronicotinic acid according to claim 6, characterized in that The solvent is selected according to different oxidants: if the oxidant is potassium permanganate, water is selected as the solvent; if the oxidant is oxygen, methanol, ethanol or isopropanol is selected as the solvent; if the oxidant is sodium dichromate or potassium dichromate, sulfuric acid is selected as the solvent.

8. The method for preparing 4-bromo-6-chloronicotinic acid according to claim 7, wherein: When the oxidant is sodium dichromate or potassium dichromate, sulfuric acid is selected as the solvent. After the reaction in step (2) is completed, the obtained reaction solution is slowly poured into ice and stirred for half an hour. Solids are precipitated, filtered, and the filter cake is rinsed with water until neutral to obtain an off-white solid 4-bromo-6-chloronicotinic acid. When the oxidant is potassium permanganate, water is selected as the solvent. After the reaction in step (2) is completed, the reaction solution is cooled to 30° C. and filtered. The filter cake is rinsed with cold water to obtain a filtrate and an eluent. The pH is adjusted to 3 with 6N hydrochloric acid to form a precipitate, which is filtered. The obtained solid is washed with water and dried to obtain an off-white solid 4-bromo-6-chloronicotinic acid. When the oxidant is oxygen, methanol, ethanol or isopropanol is selected as the solvent. After the reaction in step (2) is completed, the mixture is filtered and the solvent is evaporated under reduced pressure. The residue is added with cold water and stirred. The pH value is adjusted to 3 with 10 wt % hydrochloric acid to precipitate a large amount of white solid. The solid is filtered, washed with water, and dried to obtain an off-white solid 4-bromo-6-chloronicotinic acid.

Images