A process for the preparation of 2-chloro-3-bromo-6-methylpyridine

Abstract

This invention discloses a method for preparing 2-chloro-3-bromo-6-methylpyridine, belonging to the field of pharmaceutical intermediate synthesis technology. This technical solution involves coupling 2,6-dichloropyridine with methylboronic acid to obtain 2-chloro-6-methylpyridine, followed by bromination to obtain 2-chloro-3-bromo-6-methylpyridine. It mainly addresses the technical problems of existing synthetic routes, such as safety concerns, high cost of raw materials, and limited applicability.

Description

Technical Field

[0001] This invention relates to a method for preparing 2-chloro-3-bromo-6-methylpyridine, belonging to the field of pharmaceutical intermediate synthesis technology. Background Technology

[0002] 2-Chloro-3-bromo-6-methylpyridine is widely used in pharmaceutical intermediates, pesticide intermediates, fragrances, surfactants, and many other fields. Using 2-chloro-3-bromo-6-methylpyridine as its core, the methyl group and halogen at the ortho-position of pyridine can react with other groups, thereby increasing functional groups and yielding a variety of pyridine compounds. Due to the good systemic properties of the pyridine ring, these compounds exhibit higher biological activity and lower toxicity. Patent US2011 / 70189,2011,A1 reports the use of 2-chloro-3-bromo-6-methylpyridine in the synthesis of hepatitis C virus NS5b polymerase inhibitors. Patent EP4019521,2022,A1 reports that compounds synthesized using 2-chloro-3-bromo-6-methylpyridine can be used to treat diseases related to the mechanism of action of EED protein and / or PRC2 protein complex.

[0003] Currently, the main reported methods for synthesizing 2-chloro-3-bromo-6-methylpyridine are as follows:

[0004] The first method, reported in the literature [Chemistry of Heterocyclic Compounds, 1996, vol. 32, #10, pp. 1173-1177], involves reducing the nitro group with 2-chloro-3-nitro-6-methylpyridine using hydrazine hydrate and Raney nickel, followed by diazotization to obtain 2-chloro-3-bromo-6-methylpyridine, with an overall yield of 48%. However, to avoid halogen substitution of the pyridine ring, more dangerous reactions are used: hydrazine hydrate, Raney nickel reduction, and diazotization. These are all hazardous reactions with limited safety and are unsuitable for large-scale production. The reaction equation is as follows:

[0005]

[0006] The second method, described in the Journal of the American Chemical Society (2022), involves the reaction of 2-chloro-6-methylnicotinic acid with tetra(acetonitrile)copper(I)tetrafluoroborate, 1-fluoro-2,4,6-trimethylpyridine boron tetrafluoride, and bromochloromethane in acetonitrile, achieving a yield of 67%. However, this method is not economically viable due to the high cost of the reagents used. The reaction equation is as follows:

[0007]

[0008] In view of the shortcomings of the above-mentioned synthesis methods, such as poor safety and expensive raw materials, this invention proposes an improved synthesis process for 2-chloro-3-bromo-6-methylpyridine, which reduces the price of raw materials, improves safety, and thus meets the growing market demand. Summary of the Invention

[0009] To overcome the aforementioned technical deficiencies, this invention discloses a method for preparing 2-chloro-3-bromo-6-methylpyridine. 2-chloro-6-methylpyridine is obtained by coupling 2,6-dichloropyridine with methylboronic acid, followed by bromination to yield 2-chloro-3-bromo-6-methylpyridine. This method primarily addresses the technical problems of existing synthetic routes, such as safety concerns, high cost of raw materials, and limited applicability.

[0010] This invention discloses a method for preparing 2-chloro-3-bromo-6-methylpyridine, the technical solution of which is represented by the following reaction equation:

[0011]

[0012] The method for preparing 2-chloro-3-bromo-6-methylpyridine according to the present invention includes the following steps:

[0013] Step 1: 2,6-Dichloropyridine, methylboronic acid, inorganic base, tetra(triphenylphosphine)palladium and organic solvent are mixed and coupled to obtain 2-chloro-6-methylpyridine;

[0014] Step 2: 2-Chloro-6-methylpyridine triphenylborane is mixed with an organic solvent, brominated with a brominating reagent, and then post-treated to obtain 2-chloro-3-bromo-6-methylpyridine.

[0015] Furthermore, in the above technical solution, the organic solvent mentioned in the first step is selected as 1,4-dioxane or acetonitrile.

[0016] Furthermore, in the above technical solution, the inorganic base mentioned in the first step is selected from potassium carbonate or potassium phosphate.

[0017] Furthermore, in the above technical solution, the molar ratio of 2,6-dichloropyridine, methylboric acid, inorganic base and tetrakis(triphenylphosphine)palladium in the first step is 1.0-1.2:1:1.5-3.0:0.006-0.01.

[0018] Furthermore, in the above technical solution, the organic solvent in the second step is selected from acetonitrile or dichloromethane.

[0019] Furthermore, in the above technical solution, the brominating reagent in the second step is selected from NBS or bromine.

[0020] Furthermore, in the above technical solution, the molar ratio of 2-chloro-6-methylpyridine and triphenylborane bromide reagent in the second step is 1:0.1-0.3:1.1-1.2.

[0021] Furthermore, in the above technical solution, the post-treatment in the second step involves quenching the reaction with an aqueous sodium thiosulfate solution after the reaction is complete. The product is then reacted with concentrated sulfuric acid in MTBE and dichloromethane to form a salt, which can increase the purity to over 99.0%. The 2-chloro-6-methylpyridine sulfate is dissociated with sodium hydroxide, extracted with n-heptane, and the solvent is evaporated under reduced pressure to obtain an oily substance, 2-chloro-6-methylpyridine. After standing for several days, it can become a solid, or after dissociation, it can be distilled under reduced pressure at 150-170℃ to obtain 2-chloro-6-methylpyridine (white solid) with a GC content of over 99.8%.

[0022] The technical solution of this invention has the following advantages: readily available raw materials, continuous operation, and enhanced safety; short reaction steps and high product purity; the use of triphenylborane catalyst for positioning, which can effectively bromine at the para position of methyl; and the use of sulfuric acid to form a salt with pyridine, which can greatly improve the purity of the product and obtain the product without distillation.

[0023] Instruction manual illustrations

[0024] Figure 1 The HNMR spectrum of 2-chloro-3-bromo-6-methylpyridine obtained in Example 5. Specific Implementation

[0025] The present invention will now be described in detail with reference to specific embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention.

[0026] Example 1

[0027]

[0028] Under nitrogen purging protection, 56.9 g (1.15 eq) of 2,6-dichloropyridine, 20 g (1 eq) of methylboric acid, 212.8 g (3.0 eq) of potassium phosphate, 2.3 g (0.006 eq) of tetrakis(triphenylphosphine)palladium, 800 mL of 1,4-dioxane, and 240 mL of water were mixed and heated to 104 °C for 6 hours. The mixture was then cooled, concentrated under reduced pressure to remove dioxane, and extracted with toluene at 50-60 °C. Anhydrous magnesium sulfate and a small amount of silica gel were added to the organic phase, and the mixture was stirred and filtered. The filtrate was concentrated to dryness to obtain 45 g of 2-chloro-6-methylpyridine. This was used directly in the next step; the HPLC external standard content was 86.9%, and the yield was 91.7%. 1 HNMR (400MHz, CDCl3): δ7.53(dd,1H),7.13(d,1H),7.07(d,1H),2.53(s,3H).

[0029] Example 2

[0030]

[0031] Under nitrogen purging protection, 56.9 g (1.15 eq) of 2,6-dichloropyridine, 20 g (1 eq) of methylboric acid, 97 g (2.1 eq) of potassium carbonate, 2.3 g (0.006 eq) of tetrakis(triphenylphosphine)palladium, 600 mL of acetonitrile, and 200 mL of water were mixed and heated to 85 °C for 14 hours. The mixture was then cooled, concentrated under reduced pressure to remove acetonitrile, and extracted with toluene at 50-60 °C. Anhydrous magnesium sulfate and a small amount of silica gel were added to the organic phase, and the mixture was stirred and filtered. The filtrate was concentrated to dryness to obtain 45.3 g of 2-chloro-6-methylpyridine. This was used directly in the next step, with an HPLC external standard content of 85.3% and a yield of 90.6%.

[0032] Example 3

[0033]

[0034] 40 g of 2-chloro-6-methylpyridine (external standard content 86.9%) and 13.2 g (0.2 eq) of triphenylborone were mixed with 400 mL of acetonitrile. The mixture was cooled to 15-20 °C, and 53.4 g (1.1 eq) of NBS was added in portions. The mixture was reacted at room temperature for 16 hours, concentrated under reduced pressure until it did not flow, and then added to an aqueous solution containing sodium thiosulfate. MTBE was then added. Extracted with 300 mL of sodium bicarbonate solution, washed with sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The filtrate was cooled to -5 to 0 °C, and 50 mL of dichloromethane was added. 27.2 g (1 eq) of 98% concentrated sulfuric acid was slowly added dropwise. The mixture was stirred at 0 °C for 2 hours, filtered, and the filter cake was washed with MTBE. The filter cake was returned to the reactor, and 100 mL of n-heptane was added. The pH was adjusted to 11.5-12.5 with 5% potassium hydroxide aqueous solution. The mixture was allowed to stand and separate into layers. The organic phase was concentrated under reduced pressure and evaporated to dryness to obtain 49.8 g of 2-chloro-3-bromo-6-methylpyridine, with a yield of 88.6% and an HPLC yield of 99.4%. 1 HNMR (400MHz, CDCl3): δ7.77(d,1H), 6.96(d,1H), 2.48(s,3H).

[0035] Example 4

[0036]

[0037] 40 g of 2-chloro-6-methylpyridine (external standard content 85.3%) and 16.2 g (0.25 eq) of triphenylborone were mixed with 500 mL of dichloromethane. The mixture was cooled to 0 °C, and 47.1 g (1.1 eq) of bromine was added dropwise. The mixture was then heated to room temperature and reacted for 4 hours. The mixture was then added to an aqueous solution containing sodium thiosulfate, washed with sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure to a final volume of 2V, and 300 mL of the solution was added. MTBE was added and cooled to -5 to 0°C. 50 mL of dichloromethane was added, and 26.7 g (1 eq) of 98% concentrated sulfuric acid was slowly added dropwise. The mixture was stirred at 0°C for 2 hours, filtered, and the filter cake was washed with MTBE. The filter cake was then returned to the reactor, and 100 mL of n-heptane was added. The pH was adjusted to 11.5-12.5 with 5% potassium hydroxide aqueous solution. The mixture was allowed to stand and separate into layers. The organic phase was concentrated under reduced pressure and evaporated to dryness to obtain 49.9 g of 2-chloro-3-bromo-6-methylpyridine, with a yield of 90.4% and an HPLC yield of 99.7%.

[0038] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing 2-chloro-3-bromo-6-methylpyridine, characterized in that, The reaction equation is as follows: ； Includes the following steps: Step 1: 2,6-Dichloropyridine, methylboronic acid, inorganic base, tetra(triphenylphosphine)palladium and organic solvent are mixed and coupled to obtain 2-chloro-6-methylpyridine; Step 2: 2-Chloro-6-methylpyridine, triphenylborane and organic solvent are mixed, brominated with a brominating reagent, and then post-treated to obtain 2-chloro-3-bromo-6-methylpyridine.

2. The method for preparing 2-chloro-3-bromo-6-methylpyridine according to claim 1, characterized in that: In the first step, the organic solvent is selected from 1,4-dioxane or acetonitrile.

3. The method for preparing 2-chloro-3-bromo-6-methylpyridine according to claim 1, characterized in that: In the first step, the inorganic base is selected from potassium carbonate or potassium phosphate.

4. The method for preparing 2-chloro-3-bromo-6-methylpyridine according to claim 1, characterized in that: In the first step, the molar ratio of 2,6-dichloropyridine, methylboric acid, inorganic base and tetrakis(triphenylphosphine)palladium is 1.0-1.2:1:1.5-3.0:0.006-0.

01.

5. The method for preparing 2-chloro-3-bromo-6-methylpyridine according to claim 1, characterized in that: In the second step, the organic solvent is selected from acetonitrile or dichloromethane.

6. The method for preparing 2-chloro-3-bromo-6-methylpyridine according to claim 1, characterized in that: In the second step, the brominating reagent is selected from NBS or bromine.

7. The method for preparing 2-chloro-3-bromo-6-methylpyridine according to claim 1, characterized in that: In the second step, the molar ratio of 2-chloro-6-methylpyridine, triphenylborane and the brominating reagent is 1:0.1-0.3:1.1-1.2.

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