A kind of synthetic method of 3-bromo-2-hydroxy-6-methylpyridine

Abstract

The invention discloses a method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine. The method is characterized by comprising the following steps: 1) reacting 3-hydroxy-6-methylpyridine with a brominating agent to obtain 2-bromo-3-hydroxy-6-methylpyridine; 2) reacting 2-bromo-3-hydroxy-6-methylpyridine with a brominating agent to obtain 2,3-dibromo-6-methylpyridine; 3) reacting 2,3-dibromo-6-methylpyridine with sodium methoxide to obtain 3-bromo-2-methoxy-6-methylpyridine; and 4) reacting 3-bromo-2-methoxy-6-methylpyridine with an acid to remove the methyl group to obtain 3-bromo-2-hydroxy-6-methylpyridine. The method has the advantages of simple process line, mild reaction conditions, low production cost, high yield and suitability for large-scale production.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical chemistry, in particular to a method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine. Background Art

[0002] 3-Bromo-2-hydroxy-6-methylpyridine has a wide range of applications as a fine chemical raw material and pharmaceutical intermediate. For example, patent WO2015089192A1 reports that it can be used to synthesize lysine-specific demethylase-1 inhibitors for the treatment of cancers such as prostate cancer, breast cancer, bladder cancer, lung cancer, and melanoma. Patent WO2008101682A2 also reports that it can be used to synthesize new fungicides.

[0003] The currently reported synthesis process of 3-bromo-2-hydroxy-6-methylpyridine is to use 2-hydroxy-6-methylpyridine as raw material, first react with a bromination reagent to obtain 3,5-dibromo-6-methylpyridine-2-ol, with a yield of 88%, and then use n-butyl lithium to selectively remove a bromine atom under deep cold conditions (-60 to -90°C) to obtain a crude 3-bromo-2-hydroxy-6-methylpyridine. Due to the poor selective dehalogenation effect, the final product must be purified by column, with a yield of only 17%. (References: WO2015089192A1 and WO2016037005A1), and its synthesis route is shown in the following formula. This process is cumbersome and uses highly flammable n-butyl lithium, which is unsafe to operate. In addition, a large amount of by-products are produced during regioselective debromination, which makes post-processing of the final product difficult and it is difficult to obtain pure 3-bromo-2-hydroxy-6-methylpyridine. The overall yield is also low, less than 15%, resulting in high industrial costs. Therefore, this process is not suitable for large-scale production.

[0004]

[0005] In summary, the existing synthesis method of 3-bromo-2-hydroxy-6-methylpyridine has the problems of complex process operation, poor operation safety, low total yield, etc., which leads to high industrial cost and is not suitable for large-scale production. Summary of the invention

[0006] The technical problem to be solved by the present invention is to provide a method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine which has simple process line, mild reaction conditions, low production cost, high yield and is suitable for large-scale production.

[0007] The technical solution adopted by the present invention to solve the above technical problem is: a method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine, comprising the following steps:

[0008] (1) reacting 3-hydroxy-6-methylpyridine with a bromination reagent to obtain 2-bromo-3-hydroxy-6-methylpyridine;

[0009] (2) reacting 2-bromo-3-hydroxy-6-methylpyridine with a brominating agent to obtain 2,3-dibromo-6-methylpyridine;

[0010] (3) reacting 2,3-dibromo-6-methylpyridine with sodium methoxide to obtain 3-bromo-2-methoxy-6-methylpyridine;

[0011] (4) 3-bromo-2-methoxy-6-methylpyridine is reacted with an acid to remove the methyl group to obtain 3-bromo-2-hydroxy-6-methylpyridine.

[0012] Furthermore, the specific process of step (1) is as follows: 3-hydroxy-6-methylpyridine is added to the solvent pyridine, stirred to dissolve, and then slowly added with a bromination reagent at a temperature of -5°C ≤ T1 ≤ 50°C, and the temperature is controlled at T2, 10°C ≤ T2 ≤ 100°C. After the addition is completed, the reaction is continued at temperature T2 until the reaction is complete. After TLC detection shows that the reaction of the raw materials is complete, the reaction mixture is distilled under reduced pressure, and the residue is poured into ice water. After stirring at 0-5°C for 1 hour, a precipitate is formed, which is filtered, washed with water, and dried to obtain a light yellow solid 2-bromo-3-hydroxy-6-methylpyridine.

[0013] Furthermore, the bromination reagent described in step (1) is bromine, pyridinium tribromide, 1,3-dibromo-5,5-dimethylhydantoin, N-bromosuccinimide or 1,3,5-tribromo-1,3,5-thiazinane-2,4,6-trione; and the molar ratio of the 3-hydroxy-6-methylpyridine to the bromination reagent is 1:(1-3).

[0014] Furthermore, the specific process of step (2) is as follows: slowly add a brominating reagent to 2-bromo-3-hydroxy-6-methylpyridine in the presence of a solvent, and after the addition is completed, heat the mixture to T3, 20°C≤T3≤150°C, and react overnight. The next day, after TLC detection shows that the reaction is complete, cool the reaction solution to room temperature, pour it into ice water for destruction, stir for half an hour, adjust the pH to 7-8 with solid sodium bicarbonate, extract with an organic solvent for 3 times, combine the organic phases, wash the organic phases twice with saturated brine, dry with anhydrous sodium sulfate, and desolventize under reduced pressure to obtain a light yellow liquid 2,3-dibromo-6-methylpyridine.

[0015] Furthermore, the bromination reagent in step (2) is phosphorus oxybromide, phosphorus tribromide or trimethylsilyl bromide; the molar ratio of the 2-bromo-3-hydroxy-6-methylpyridine to the bromination reagent is 1:(1-8).

[0016] Furthermore, the solvent in step (2) is acetonitrile, toluene, dichloroethane or 1,4-dioxane; and the organic solvent for extraction is ethyl acetate, dichloroethane, dichloromethane, toluene or methyl tert-butyl ether.

[0017] Furthermore, the specific process of step (3) is as follows: sodium methoxide is added to an organic solvent, and then 2,3-dibromo-6-methylpyridine is added, and the reaction mixture is heated to T4, 20°C≤T4≤150°C, and the reaction is carried out overnight. The next day, after TLC detection shows that the reaction is complete, the reaction mixture is cooled to room temperature, and then the solvent is evaporated under reduced pressure, and the residue is poured into ice water. Then, the mixture is extracted with dichloromethane for 3 times, and the organic phases are combined, and the organic phases are washed twice with saturated brine, dried over anhydrous sodium sulfate, and desolventized under reduced pressure to obtain a colorless liquid 3-bromo-2-methoxy-6-methylpyridine.

[0018] Furthermore, the organic solvent described in step (3) is toluene, methanol, 1,4-dioxane or N,N-dimethylformamide; the molar ratio of the 2,3-dibromo-6-methylpyridine to the sodium methoxide is 1:(1-8).

[0019] Furthermore, the specific process of step (4) is as follows: 3-bromo-2-methoxy-6-methylpyridine is slowly added to the acid solution under stirring at room temperature. After the addition is completed, the reaction mixture is heated to T5, 40°C≤T5≤120°C for reaction. After TLC detection shows that the reaction is complete, the reaction mixture is cooled to room temperature, and then the solvent is evaporated under reduced pressure. The residue is poured into ice water, the pH is adjusted to 8 with solid potassium carbonate, and ethyl acetate is extracted 3 times. The organic phases are combined, and the organic phases are washed twice with saturated brine, dried over anhydrous sodium sulfate, and desolventized under reduced pressure to obtain an off-white solid 3-bromo-2-hydroxy-6-methylpyridine.

[0020] Furthermore, the acid solution in step (4) is hydrochloric acid, hydrobromic acid, hydrogen bromide acetic acid solution, dilute sulfuric acid or nitric acid.

[0021] Compared with the prior art, the invention has the advantages that: the invention discloses a method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine, and the synthetic route uses 3-hydroxy-6-methylpyridine as a raw material, and includes four steps of synthesizing 2-bromo-3-hydroxy-6-methylpyridine, synthesizing 2,3-dibromo-6-methylpyridine, synthesizing 3-bromo-2-methoxy-6-methylpyridine, and synthesizing 3-bromo-2-hydroxy-6-methylpyridine. The preparation method has cheap and easily available raw materials, a simple and easy-to-operate process, low cost, and a high yield and purity of the product, is suitable for large-scale production, and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The present invention provides a nuclear magnetic resonance spectrum of 3-bromo-2-hydroxy-6-methylpyridine synthesized by the present invention. DETAILED DESCRIPTION

[0023] The present invention is further described in detail below with reference to the accompanying drawings. Specific embodiments

[0025] A method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine comprises the following steps:

[0026] 1) reacting 3-hydroxy-6-methylpyridine with a bromination reagent to obtain 2-bromo-3-hydroxy-6-methylpyridine;

[0027] 2) reacting 2-bromo-3-hydroxy-6-methylpyridine with a brominating agent to obtain 2,3-dibromo-6-methylpyridine;

[0028] 3) reacting 2,3-dibromo-6-methylpyridine with sodium methoxide to obtain 3-bromo-2-methoxy-6-methylpyridine;

[0029] 4) 3-bromo-2-methoxy-6-methylpyridine is reacted with an acid to remove the methyl group to obtain 3-bromo-2-hydroxy-6-methylpyridine. The synthetic route is as follows:

[0030]

[0031] The specific process of the above step (1) is as follows: 3-hydroxy-6-methylpyridine is added to the solvent pyridine, stirred and dissolved, and then the bromination reagent is slowly added at a temperature of -5°C ≤ T1 ≤ 50°C, and the temperature is controlled at T2, 10°C ≤ T2 ≤ 100°C. After the addition is completed, the reaction is continued to react until it is complete at the temperature T2. After TLC detects that the raw material reaction is complete, the reaction mixture is distilled under reduced pressure, and the residue is poured into ice water. After stirring at 0-5°C for 1 hour, a precipitate is formed, filtered, the precipitate is washed with water, and dried to obtain a light yellow solid 2-bromo-3-hydroxy-6-methylpyridine. The bromination reagent is bromine, tribromide pyridine, 1,3-dibromo-5,5-dimethylhydantoin, N-bromosuccinimide or 1,3,5-tribromo-1,3,5-thiazinane-2,4,6-trione; the molar ratio of 3-hydroxy-6-methylpyridine to the bromination reagent can be 1: (1-3).

[0032] The specific process of the above step (2) is: slowly add the bromination reagent to 2-bromo-3-hydroxy-6-methylpyridine in the presence of a solvent, and after the addition, heat up to T3, 20°C≤T3≤150°C, react overnight, and the next day, after the reaction is complete by TLC, cool the reaction solution to room temperature, then pour it into ice water for destruction, stir for half an hour, adjust the pH to 7-8 with solid sodium bicarbonate, extract with an organic solvent for 3 times, combine the organic phases, wash the organic phases twice with saturated brine, dry with anhydrous sodium sulfate, and desolventize under reduced pressure to obtain a light yellow liquid 2,3-dibromo-6-methylpyridine. The bromination reagent can be phosphorus oxybromide, phosphorus tribromide or trimethylsilyl bromide; the molar ratio of 2-bromo-3-hydroxy-6-methylpyridine to the bromination reagent can be 1: (1-8). The solvent can be acetonitrile, toluene, dichloroethane or 1,4-dioxane; the organic solvent for extraction can be ethyl acetate, dichloroethane, dichloromethane, toluene or methyl tert-butyl ether.

[0033] The specific process of the above step (3) is: sodium methoxide is added to an organic solvent, and then 2,3-dibromo-6-methylpyridine is added, and the reaction mixture is heated to T4, 20°C≤T4≤150°C, and the reaction is carried out overnight. The next day, after the reaction is complete by TLC detection, the reaction mixture is cooled to room temperature, and then the solvent is evaporated under reduced pressure, and the residue is poured into ice water, and then extracted with dichloromethane for 3 times, the organic phases are combined, and the organic phases are washed twice with saturated salt water, dried over anhydrous sodium sulfate, and desolventized under reduced pressure to obtain colorless liquid 3-bromo-2-methoxy-6-methylpyridine. The organic solvent can be toluene, methanol, 1,4-dioxane or N,N-dimethylformamide; the molar ratio of 2,3-dibromo-6-methylpyridine to sodium methoxide can be 1: (1 to 8).

[0034] The specific process of the above step (4) is as follows: 3-bromo-2-methoxy-6-methylpyridine is slowly added to the acid solution under stirring at room temperature, after the addition is completed, the reaction mixture is heated to T5, 40°C≤T5≤120°C for reaction, after TLC detection of the reaction is complete, the reaction mixture is cooled to room temperature, then the solvent is evaporated under reduced pressure, the residue is poured into ice water, the pH is adjusted to 8 with potassium carbonate solid, ethyl acetate is extracted 3 times, the organic phases are combined, the organic phases are washed twice with saturated brine, dried over anhydrous sodium sulfate, and desolventized under reduced pressure to obtain an off-white solid 3-bromo-2-hydroxy-6-methylpyridine. The acid solution can be hydrochloric acid, hydrobromic acid, hydrogen bromide acetic acid solution, dilute sulfuric acid or nitric acid.

[0035] Example 1

[0036] 1. Synthesis of 2-bromo-3-hydroxy-6-methylpyridine

[0037] 1L four-necked bottle, add 400mL of pyridine, slowly add 100g (916mmol) of 3-hydroxy-6-methylpyridine under stirring, stir and dissolve, cool to 0℃ in ice-water bath, then slowly dropwise add 147g (916mmol) of bromine, control the temperature not higher than 10℃, stir and react at 0~10℃ for 1 hour, remove the ice-water bath, naturally warm to room temperature and react overnight. The next day, TLC detected that the raw material reacted completely, the reaction mixture was distilled under reduced pressure, the residue was poured into 800g of ice water, stirred at 0~5℃ for 1 hour, a precipitate was formed, filtered, washed with water, and dried to obtain 152g of 2-bromo-3-hydroxy-6-methylpyridine as a pale yellow solid, with a yield of 88%.

[0038] 2. Synthesis of 2,3-dibromo-6-methylpyridine

[0039] A 1L four-necked flask was added with acetonitrile (600ml), and 2-bromo-3-hydroxy-6-methylpyridine 188g (1000mmol) was added under stirring at room temperature, and then phosphorus oxybromide (373g, 1301mmol) was slowly added. After the addition, there was no obvious temperature rise. The temperature was raised to 50°C and the reaction was allowed to proceed overnight. The next day, TLC detected that the reaction was complete. The reaction solution was cooled to room temperature, and then poured into 2kg of ice water for destruction. The reaction solution was stirred for half an hour, and the pH was adjusted to 7-8 with solid sodium bicarbonate. The solution was extracted with ethyl acetate (1L*3), and the organic phases were combined. The organic phases were washed twice with saturated brine (1L×2), dried over anhydrous sodium sulfate, and desolventized under reduced pressure to obtain 234g of light yellow liquid 2,3-dibromo-6-methylpyridine with a yield of 93%.

[0040] 3. Synthesis of 3-bromo-2-methoxy-6-methylpyridine

[0041] A 2L four-necked flask was added with 1.2L of 1,4-dioxane, and 97g (1793mmol) of sodium methoxide was added under stirring at room temperature, and then 150g (598mmol) of 2,3-dibromo-6-methylpyridine was added. After the addition was completed, the reaction mixture was heated to 100°C and refluxed for reaction overnight. The next day, TLC detected that the reaction was complete. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was poured into 1.5kg of ice water, and then extracted with dichloromethane (1L*3). The organic phases were combined, washed twice with saturated brine (1L×2), dried over anhydrous sodium sulfate, and desolventized under reduced pressure to obtain 115g of colorless liquid 3-bromo-2-methoxy-6-methylpyridine with a yield of 95%.

[0042] 4. Synthesis of 3-bromo-2-hydroxy-6-methylpyridine

[0043] A 2L four-necked bottle was added with 1000mL of 30wt% hydrogen bromide acetic acid solution, and 101g (500mmol) of 3-bromo-2-methoxy-6-methylpyridine was slowly added under stirring at room temperature. After the addition, the reaction mixture was heated to 100°C and refluxed for 2 hours. The reaction was complete when detected by TLC. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was poured into 1.2kg of ice water, and the pH was adjusted to 8 with potassium carbonate solid. The mixture was extracted with ethyl acetate (1L*3), and the organic phases were combined. The organic phases were washed twice with saturated brine (1L×2), dried over anhydrous sodium sulfate, and desolventized under reduced pressure to obtain 88g of off-white solid 3-bromo-2-hydroxy-6-methylpyridine with a yield of 93%. The nuclear magnetic resonance spectrum of 3-bromo-2-hydroxy-6-methylpyridine is as follows Figure 1 As shown, 1H NMR (400 MHz, CDCI3): δ 2.35 (s, 3H), 5.97 (d, J = 7.2 Hz, 1H), 7.71 (d, J = 7.2 Hz, 1H), 12.36 (br. s, 1H).

[0044] Example 2

[0045] 1. Synthesis of 2-bromo-3-hydroxy-6-methylpyridine 23003-35-2

[0046] 1L four-necked flask, add 400mL of pyridine, slowly add 100g (916mmol) of 3-hydroxy-6-methylpyridine under stirring, stir to dissolve, cool to 10℃ in ice-water bath, then slowly add 147g (916mmol) of bromine dropwise, control the temperature not higher than 40℃, after dropping, react at 40℃ for 5 hours, TLC detection shows that the raw material reaction is complete, distill the reaction mixture under reduced pressure, pour the residue into 800g of ice water, stir at 0~5℃ for 1 hour, form a precipitate, filter, wash with water, and dry to obtain 131g of 2-bromo-3-hydroxy-6-methylpyridine as a light yellow solid with a yield of 76%.

[0047] 2. Synthesis of 2,3-dibromo-6-methylpyridine

[0048] A 1L four-necked flask was added with acetonitrile (600ml), and 2-bromo-3-hydroxy-6-methylpyridine 188g (1000mmol) was added under stirring at room temperature, and then phosphorus oxybromide (373g, 1301mmol) was slowly added. After the addition, there was no obvious temperature rise. The temperature was raised to 80°C and the reaction was allowed to proceed overnight. The next day, TLC detected that the reaction was complete. The reaction solution was cooled to room temperature, and then poured into 2kg of ice water for destruction. The mixture was stirred for half an hour, and the pH was adjusted to 7-8 with sodium bicarbonate solid. The mixture was extracted with ethyl acetate (1L*3), and the organic phases were combined. The organic phases were washed twice with saturated brine (1L×2), dried over anhydrous sodium sulfate, and desolventized under reduced pressure to obtain 223g of light yellow liquid 2,3-dibromo-6-methylpyridine with a yield of 89%.

[0049] 3. Synthesis of 3-bromo-2-methoxy-6-methylpyridine

[0050] 1.2 L of methanol was added to a 3 L four-necked flask. 97 g (1793 mmol) of sodium methoxide was added under an ice-water bath, and then 150 g (598 mmol) of 2,3-dibromo-6-methylpyridine was added. After the addition was completed, the reaction mixture was heated to 70 °C and refluxed for reaction overnight. The next day, TLC detected that the reaction was complete. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was poured into 1.5 kg of ice water, and then extracted with dichloromethane (1 L*3). The organic phases were combined, washed twice with saturated brine (1 L×2), dried over anhydrous sodium sulfate, and desolventized under reduced pressure to obtain 108 g of colorless liquid 3-bromo-2-methoxy-6-methylpyridine with a yield of 89%.

[0051] 4. Synthesis of 3-bromo-2-hydroxy-6-methylpyridine

[0052] A 2L four-necked flask was added with 1000mL of 30wt% aqueous hydrobromic acid solution, and 101g (500mmol) of 3-bromo-2-methoxy-6-methylpyridine was slowly added under stirring at room temperature. After the addition was completed, the reaction mixture was heated to 100°C and reacted for 5 hours. The reaction was completed by TLC detection. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was poured into 1.2kg of ice water, and the pH was adjusted to 8 with solid potassium carbonate. The mixture was extracted with ethyl acetate (1L*3), and the organic phases were combined. The organic phases were washed twice with saturated brine (1L×2), dried over anhydrous sodium sulfate, and desolventized under reduced pressure to obtain 83g of 3-bromo-2-hydroxy-6-methylpyridine as an off-white solid with a yield of 88%.

[0053] Example 3

[0054] 1. Synthesis of 2-bromo-3-hydroxy-6-methylpyridine

[0055] 1L four-necked bottle, add 400mL of pyridine, slowly add 100g (916mmol) of 3-hydroxy-6-methylpyridine under stirring, stir and dissolve, cool to 10℃ in ice-water bath, then slowly add 171g (960mmol) of N-bromosuccinimide, control the temperature not higher than 20℃, stir and react for 1 hour at 10~20℃, and react overnight at 50℃. The next day, TLC detected that the raw material reaction was complete, the reaction mixture was distilled under reduced pressure, the residue was poured into 800g of ice water, stirred for 1 hour at 0~5℃, a precipitate was formed, filtered, washed with water, and dried to obtain 117g of 2-bromo-3-hydroxy-6-methylpyridine as a pale yellow solid, with a yield of 68%.

[0056] 2. Synthesis of 2,3-dibromo-6-methylpyridine

[0057] In a 1L four-necked flask, add dichloroethane (600ml), add 2-bromo-3-hydroxy-6-methylpyridine 188g (1000mmol) under stirring at room temperature, then slowly add phosphorus oxybromide (287g, 1000mmol), after the addition, there is no obvious temperature rise, heat to 50℃, react overnight, the next day, TLC detection shows that the reaction is complete, cool the reaction solution to room temperature, then pour into 2kg ice water to destroy, stir for half an hour, adjust the pH to 7-8 with sodium bicarbonate solid, extract with dichloroethane (1L*3), combine the organic phases, wash the organic phases twice with saturated brine (1L×2), dry over anhydrous sodium sulfate, and desolventize under reduced pressure to obtain 196g of light yellow liquid 2,3-dibromo-6-methylpyridine with a yield of 78%.

[0058] 3. Synthesis of 3-bromo-2-methoxy-6-methylpyridine

[0059] 1.2 L of methanol was added to a 3 L four-necked flask. 65 g (1204 mmol) of sodium methoxide was added under an ice-water bath, and then 150 g (598 mmol) of 2,3-dibromo-6-methylpyridine was added. After the addition was completed, the reaction mixture was heated to 68 °C and refluxed for reaction overnight. The next day, TLC detected that the reaction was complete. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was poured into 1.5 kg of ice water, and then extracted with dichloromethane (1 L*3). The organic phases were combined, washed twice with saturated brine (1 L×2), dried over anhydrous sodium sulfate, and desolventized under reduced pressure to obtain 98 g of colorless liquid 3-bromo-2-methoxy-6-methylpyridine with a yield of 81%.

[0060] 4. Synthesis of 3-bromo-2-hydroxy-6-methylpyridine

[0061] To a 2L four-necked flask, 1000mL of 30wt% hydrochloric acid was added, and 101g (500mmol) of 3-bromo-2-methoxy-6-methylpyridine was slowly added under stirring at room temperature. After the addition was completed, the reaction mixture was heated to 110°C and reacted overnight. The next day, TLC detected that the reaction was complete. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was poured into 1.2kg of ice water, and the pH was adjusted to 8 with solid potassium carbonate. The mixture was extracted with ethyl acetate (1L*3), and the organic phases were combined. The organic phases were washed twice with saturated brine (1L×2), dried over anhydrous sodium sulfate, and desolventized under reduced pressure to obtain 76g of 3-bromo-2-hydroxy-6-methylpyridine as an off-white solid with a yield of 81%.

[0062] 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 a person skilled in the art within the spirit and scope of the present invention shall also fall within the protection scope of the present invention.

Claims

1. A method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine, characterized in that The following steps are involved: (1) reacting 3-hydroxy-6-methylpyridine with a bromination reagent to obtain 2-bromo-3-hydroxy-6-methylpyridine, wherein the specific process is as follows: adding 3-hydroxy-6-methylpyridine to a solvent pyridine, stirring to dissolve, slowly adding the bromination reagent at a temperature of -5°C ≤ T1 ≤ 50°C, controlling the temperature at T2, 10°C ≤ T2 ≤ 100°C, and continuing the reaction at T2 until the reaction is complete. After TLC detection shows that the reaction of the raw material is complete, the reaction mixture is distilled under reduced pressure, and the residue is poured into ice water. After stirring at 0-5°C for 1 hour, a precipitate is formed, which is filtered, washed with water, and dried to obtain a light yellow solid 2-bromo-3-hydroxy-6-methylpyridine; (2) reacting 2-bromo-3-hydroxy-6-methylpyridine with a brominating agent to obtain 2,3-dibromo-6-methylpyridine, wherein the specific process is as follows: slowly adding the brominating agent to 2-bromo-3-hydroxy-6-methylpyridine in the presence of a solvent, heating the mixture to T3, 20°C≤T3≤150°C, and reacting overnight. The next day, after the reaction is complete as detected by TLC, the reaction solution is cooled to room temperature, then poured into ice water for destruction, stirred for half an hour, and the pH value is adjusted to 7-8 with solid sodium bicarbonate, extracted three times with an organic solvent, combined the organic phases, washed the organic phases twice with saturated brine, dried over anhydrous sodium sulfate, and desolventized under reduced pressure to obtain a light yellow liquid 2,3-dibromo-6-methylpyridine; (3) reacting 2,3-dibromo-6-methylpyridine with sodium methoxide to obtain 3-bromo-2-methoxy-6-methylpyridine, wherein the specific process is as follows: adding sodium methoxide to an organic solvent, then adding 2,3-dibromo-6-methylpyridine, heating the reaction mixture to T4, 20°C≤T4≤150°C, reacting overnight, and the next day, after TLC detection of the reaction being complete, cooling the reaction mixture to room temperature, then evaporating the solvent under reduced pressure, pouring the residue into ice water, then extracting with dichloromethane three times, combining the organic phases, washing the organic phases twice with saturated brine, drying with anhydrous sodium sulfate, and desolventizing under reduced pressure to obtain a colorless liquid 3-bromo-2-methoxy-6-methylpyridine; (4) 3-bromo-2-methoxy-6-methylpyridine is reacted with an acid to remove the methyl group to obtain 3-bromo-2-hydroxy-6-methylpyridine. The specific process is as follows: 3-bromo-2-methoxy-6-methylpyridine is slowly added to the acid solution under stirring at room temperature. After the addition is completed, the reaction mixture is heated to T5 and reacted at 40°C≤T5≤120°C. After TLC detection shows that the reaction is complete, the reaction mixture is cooled to room temperature, and then the solvent is evaporated under reduced pressure. The residue is poured into ice water, and the pH is adjusted to 8 with solid potassium carbonate. The mixture is extracted with ethyl acetate for 3 times. The organic phases are combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and desolventized under reduced pressure to obtain 3-bromo-2-hydroxy-6-methylpyridine as an off-white solid.

2. A method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine according to claim 1, characterized in that: The bromination reagent described in step (1) is phosphorus oxybromide, phosphorus tribromide or trimethylsilyl bromide; the molar ratio of the 3-hydroxy-6-methylpyridine to the bromination reagent is 1:(1-3).

3. A method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine according to claim 1, characterized in that: The brominating agent described in step (2) is bromine, pyridinium tribromide, 1,3-dibromo-5,5-dimethylhydantoin, N-bromosuccinimide or 1,3,5-tribromo-1,3,5-thiazinane-2,4,6-trione; the molar ratio of the 2-bromo-3-hydroxy-6-methylpyridine to the brominating agent is 1:(1-8).

4. A method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine according to claim 1, characterized in that: The solvent described in step (2) is acetonitrile, toluene, dichloroethane or 1,4-dioxane; the organic solvent for extraction is ethyl acetate, dichloroethane, dichloromethane, toluene or methyl tert-butyl ether.

5. A method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine according to claim 1, characterized in that: The organic solvent described in step (3) is toluene, methanol, 1,4-dioxane or N,N-dimethylformamide; the molar ratio of the 2,3-dibromo-6-methylpyridine to the sodium methoxide is 1:(1-8).

6. A method for synthesizing 3-bromo-2-hydroxy-6-methylpyridine according to claim 1, characterized in that: The acid solution described in step (4) is hydrochloric acid, hydrobromic acid, hydrogen bromide acetic acid solution, dilute sulfuric acid or nitric acid.

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