A method for synthesizing 3,5-dibromo-4-methylpyridine

Abstract

The application discloses a synthesis method of 3,5-dibromo-4-methylpyridine and relates to the technical field of organic heterocyclic compound synthesis. The method takes 4-methylpyridine as a starting material, and 3,5-dibromo-4-methylpyridine is prepared through the following steps of complexing with boron trifluoride, double-boronization of 3,5-position carbon-hydrogen bond, decomplexing, oxidation deprotection of boronic acid pinacol ester and bromination and deboronization reaction. The method adjusts the reaction state of the pyridine ring through complexing, and carries out the double functionalization of 3,5-position and the bromination conversion in stages, so that the synthesis route is clear, the site selection is easy to control, and the product purity and process stability show a good trend.

Description

Technical Field

[0001] This invention relates to the field of organic heterocyclic compound synthesis technology, specifically to a method for synthesizing 3,5-dibromo-4-methylpyridine. Background Technology

[0002] 3,5-Dibromo-4-methylpyridine belongs to the halopyridine class of organic compounds with the molecular formula C6H5Br2N. Bromine atoms are attached to the 3 and 5 positions of the pyridine ring, respectively. These bromine atoms can serve as active sites for cross-coupling, nucleophilic substitution, and other functional group conversion reactions. Therefore, this compound can be used as a basic raw material for constructing intermediates for polysubstituted pyridine pharmaceuticals, pesticides, and functional materials. The crystal structure of 3,5-dibromo-4-methylpyridine has been reported in prior art DOI: 10.1107 / S2414314616008592, confirming the molecular structure of this compound and the Br···N and Br···Br interactions in its crystal.

[0003] In the prior art, US patent application US20110021467A1 and its authorized text US7842711B2 disclose a method for preparing 3,5-dibromo-4-methylpyridine. This method uses 3,5-dibromopyridine as a raw material. First, a strong base system of diisopropylamine and n-butyllithium is formed in anhydrous tetrahydrofuran. The 4-position of 3,5-dibromopyridine is metallized at -78°C, followed by methylation with iodomethane. After the reaction, the mixture is quenched with an aqueous ammonium chloride solution, and then 3,5-dibromo-4-methylpyridine is obtained by extraction and silica gel column chromatography. While this method can form the target compound, it requires the use of highly reactive and hazardous n-butyllithium, strict anhydrousity of the reactants and solvents, an inert atmosphere in the reaction system, and cryogenic conditions at -78°C for both metallization and methylation. Post-reaction purification by column chromatography is also required, which is not conducive to reducing equipment requirements or simplifying scale-up production. Furthermore, this method uses 3,5-dibromopyridine, which already has two bromine substituents, as a starting material, and does not solve the problem of selectively constructing 3,5-dibromine-substituted structures directly from 4-methylpyridine.

[0004] Chinese patent application CN104945314A discloses a method for preparing 3-bromo-4-methylpyridine. This method uses 4-methyl-3-nitropyridine as a raw material, which is catalytically hydrogenated to obtain 4-methyl-3-aminopyridine. The 4-methyl-3-aminopyridine is then reacted with liquid bromine and sodium nitrite in a hydrobromic acid medium, resulting in 3-bromo-4-methylpyridine through diazotization and bromination. This method demonstrates the feasibility of converting aminopyridine to bromopyridine via aminodiazotization and bromination. However, it involves the reduction of nitro compounds, the addition of liquid bromine, a strong acid medium, and low-temperature diazotization. When using this technical approach to prepare 3,5-dibromo-4-methylpyridine, it is necessary to introduce bromine atoms at another position on the pyridine ring and control the substitution positions and degrees of continuous bromination, thus increasing the number of steps, impurity control, and post-processing difficulty.

[0005] Furthermore, the pyridine cyclic nitrogen possesses strong coordination ability and significant electronic effects. When using transition metal catalysis systems for the direct C-H bond functionalization of 4-methylpyridine, the pyridine cyclic nitrogen may coordinate with the metal catalytic center, thus affecting catalyst activity, regioselectivity, and the degree of bifunctionalization. For 4-methylpyridine, while maintaining the 4-methyl group and the pyridine ring skeleton unchanged, simultaneously introducing the same functional groups at the 3 and 5 positions requires addressing issues such as monosubstituted byproducts, byproducts from substitutions at other positions, and interference from nitrogen-containing substrates on the catalytic system.

[0006] Therefore, the existing technology still needs to provide a method for synthesizing 3,5-dibromo-4-methylpyridine using 4-methylpyridine as the starting material, so that the 3- and 5-positions of the pyridine ring can be controlled to be bifunctionalized, and the bromine atom can be introduced under the condition of avoiding the use of cryogenic organolithium metallization system and liquid bromine-strong acid diazotization system, so as to improve the controllability of reaction sites, simplify the separation and processing of each reaction stage, and improve the stability and ease of implementation of the synthesis process. Summary of the Invention

[0007] The purpose of this invention is to address the problems in the synthesis of 3,5-dibromo-4-methylpyridine in the prior art, such as the high requirements for strong base low-temperature metallization, the complexity of controlling the liquid bromine and diazotization reaction processes, the cumbersome connection of reaction steps, and the difficulty in controlling the regioselectivity and degree of conversion of the pyridine ring at the 3 and 5 positions. This invention provides a method for synthesizing 3,5-dibromo-4-methylpyridine from 4-methylpyridine as the starting material, through boron trifluoride complexation, 3,5-C-H bond double boronization, decomplexation, oxidative deprotection, and bromination deboronization reactions to obtain the target product. This method has a clear reaction route, controllable site selection, and is easy to implement.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is: a method for synthesizing 3,5-dibromo-4-methylpyridine, wherein the method uses 4-methylpyridine as the starting material and proceeds sequentially through a boron trifluoride complexation reaction, a 3,5-carbon-hydrogen bond double boronization reaction, a decomplexation and boron borate pinacol ester oxidation deprotection reaction, and a bromination deboronization reaction to prepare 3,5-dibromo-4-methylpyridine.

[0009] Furthermore, the synthesis method includes the following steps: S1,4-methylpyridine reacts with boron trifluoride diethyl ether to give a 4-methylpyridine-boron trifluoride complex.

[0010] S2. The 4-methylpyridine-boron trifluoride complex undergoes a 3,5-carbon-hydrogen bond diboration reaction with bis(pinacolborate)pyridine-boron trifluoride complex to obtain 4-methyl-3,5-bis(pinacolborate)pyridine-boron trifluoride complex.

[0011] S3. The 4-methyl-3,5-bis(pinacolborate)pyridine-boron trifluoride complex is subjected to a decomplexing reaction to obtain 4-methyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine.

[0012] S4. The 4-methyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine undergoes an oxidative deprotection reaction of the borate pinacol ester group to obtain 4-methylpyridine-3,5-diboronic acid.

[0013] S5. The 4-methylpyridine-3,5-diboronic acid is reacted with a brominating agent to undergo a bromination-deboronization reaction to obtain 3,5-dibromo-4-methylpyridine.

[0014] Furthermore, the structure of the 4-methylpyridine-boron trifluoride complex is as follows: .

[0015] Furthermore, the structure of the 4-methyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)pyridine is as follows: .

[0016] Furthermore, the structure of the 4-methyl-3,5-bis(pinacolborate)pyridine-boron trifluoride complex is as follows: .

[0017] Furthermore, the structure of the 4-methylpyridine-3,5-diboronic acid is as follows: .

[0018] Furthermore, the synthetic route of S1 is as follows: .

[0019] Further, the operation method of S1 is as follows: under nitrogen protection, 4-methylpyridine is dissolved in anhydrous dichloromethane, boron trifluoride diethyl ether is added dropwise at -5-5℃, and after the addition is complete, the reaction is carried out at 0-25℃ for 0.5-3h. An alkane antisolvent is added to precipitate the solid, and after solid-liquid separation, washing and vacuum drying, the 4-methylpyridine-boron trifluoride complex is obtained.

[0020] Furthermore, the molar ratio of 4-methylpyridine to boron trifluoride diethyl ether is 1:(1.00-1.20).

[0021] Furthermore, the alkane antisolvent is selected from at least one of petroleum ether, n-hexane, and n-heptane, which have a boiling range.

[0022] Furthermore, the volume ratio of the alkane antisolvent to anhydrous dichloromethane is (1-5):1.

[0023] Furthermore, the synthetic route of S2 is as follows: .

[0024] Further, the operation method of S2 is as follows: under nitrogen protection, bis(1,5-cyclooctadiene)di-μ-methoxydiiridium (I) and 4,4′-di-tert-butyl-2,2′-bipyridine are added to anhydrous tetrahydrofuran, followed by the sequential addition of bis(pinacolborate) and pinacolborane. The mixture is stirred at 20-40°C for 10-30 min to obtain a catalytic reaction solution. A 4-methylpyridine-boron trifluoride complex is added to the catalytic reaction solution, and the mixture is reacted in a pressure-resistant sealed reaction vessel at 70-90°C for 16-48 h. After the reaction is completed, the mixture is cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure, and anhydrous n-hexane is added to the obtained concentrate to precipitate the solid. After solid-liquid separation, washing with anhydrous n-hexane, and vacuum drying, the 4-methyl-3,5-bis(pinacolborate)pyridine-boron trifluoride complex is obtained.

[0025] Furthermore, the molar ratio of the 4-methylpyridine-boron trifluoride complex to bispinacol borate is 1:(1.5-3.5).

[0026] Furthermore, the molar ratio of the 4-methylpyridine-boron trifluoride complex to pinacol borane is 1:(0.05-0.20).

[0027] Furthermore, the molar ratio of the 4-methylpyridine-boron trifluoride complex to bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) is 1:(0.01-0.03).

[0028] Furthermore, the molar ratio of 4,4′-di-tert-butyl-2,2′-bipyridine to bis(1,5-cyclooctadiene)di-μ-methoxydiiridium (I) is 2:1.

[0029] Furthermore, the synthetic route of S3 is as follows: .

[0030] Further, the operation method of S3 is as follows: under nitrogen protection, 4-methyl-3,5-bis(pinacolborate)pyridine-boron trifluoride complex is dissolved in tetrahydrofuran, the system temperature is lowered to 0-10℃, and sodium bicarbonate aqueous solution is added dropwise, controlling the pH of the reaction system to 7.5-8.5 during the dropwise addition; after the dropwise addition is completed, the reaction is carried out at 10-30℃ for 1-6 hours; after the reaction is completed, ethyl acetate is added, and the mixture is allowed to stand for separation. The aqueous phase is extracted with ethyl acetate, the organic phases are combined, and the mixture is washed successively with water and saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, the mixture is filtered and concentrated under reduced pressure. Ethyl acetate and n-hexane are added to the obtained concentrate for crystallization. The mixture is allowed to stand at 0-10℃ for 1-6 hours, and after solid-liquid separation, washing with n-hexane and vacuum drying, 4-methyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine is obtained.

[0031] Furthermore, the molar ratio of the 4-methyl-3,5-bis(pinacolborate)pyridine-boron trifluoride complex to sodium bicarbonate is 1:(3.0-6.0).

[0032] Furthermore, the sodium bicarbonate aqueous solution has a mass fraction of 5-10%.

[0033] Furthermore, the amount of tetrahydrofuran used, calculated as 1 mmol of the 4-methyl-3,5-bis(pinacolborate)pyridine-boron trifluoride complex, is 5-15 mL.

[0034] Furthermore, the volume ratio of ethyl acetate to n-hexane during the crystallization process is 1:(3-8).

[0035] Furthermore, the vacuum drying temperature is 30-45℃, and the vacuum drying time is 4-12h.

[0036] Furthermore, the synthesis route of S4 is as follows: .

[0037] Further, the operation method of S4 is as follows: under nitrogen protection, 4-methyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine is dispersed in acetone, ammonium acetate aqueous solution is added, the system temperature is lowered to 0-10℃, and sodium metaiodate is added in batches; after the addition is complete, the reaction is carried out at 15-30℃ for 12-48h; after the reaction is completed, insoluble substances are removed by filtration, acetone is removed under reduced pressure, the pH of the resulting aqueous phase is adjusted to 4.5-6.0 with hydrochloric acid aqueous solution, concentrated under reduced pressure to 20-40% of the original volume, and allowed to stand at 0-10℃ for crystallization for 2-12h. After solid-liquid separation, washing with cold water and vacuum drying, 4-methylpyridine-3,5-diboronic acid is obtained.

[0038] Furthermore, the molar ratio of 4-methyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine, sodium metaiodate, and ammonium acetate is 1:(6-10):(8-14).

[0039] Furthermore, the concentration of the 4-methyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine, based on the total volume of acetone and water, is 0.02-0.10 mol / L. Furthermore, the volume ratio of acetone to water is (1.5-3):1.

[0040] Furthermore, the concentration of the hydrochloric acid aqueous solution used to adjust the pH is 1-3 mol / L.

[0041] Furthermore, the vacuum drying temperature is 25-40℃, and the vacuum drying time is 6-18h.

[0042] Furthermore, the synthesis route of S5 is as follows: .

[0043] Further, the operation method of S5 is as follows: under nitrogen protection, 4-methylpyridine-3,5-diboronic acid is added to anhydrous acetonitrile, sodium methoxide methanol solution is added, the system temperature is lowered to 0-10℃, and 1,3-dibromo-5,5-dimethylhydantoin is added in batches; after the addition is complete, a bromination-deboronization reaction is carried out; after the reaction is completed, a 5-15% sodium thiosulfate aqueous solution is added to quench the remaining brominating agent, then ethyl acetate is added, the mixture is allowed to stand and separate into layers, the aqueous phase is extracted with ethyl acetate, the organic phases are combined, washed successively with water and saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure, ethyl acetate and n-hexane are added to the obtained concentrate for crystallization, and after solid-liquid separation, washing with n-hexane and vacuum drying, 3,5-dibromo-4-methylpyridine is obtained.

[0044] Furthermore, the molar ratio of 4-methylpyridine-3,5-diboronic acid to 1,3-dibromo-5,5-dimethylhydantoin is 1:(1.05-1.30).

[0045] Furthermore, the molar ratio of 4-methylpyridine-3,5-diboronic acid to sodium methoxide is 1:(0.10-0.20).

[0046] Furthermore, the mass fraction of the sodium methoxide methanol solution is 20-30%.

[0047] Furthermore, the amount of anhydrous acetonitrile used, calculated as 1 mmol of the 4-methylpyridine-3,5-diboronic acid, is 8-25 mL.

[0048] Furthermore, the temperature of the bromination deboronization reaction is 20-35℃, and the reaction time is 2-8h.

[0049] Furthermore, the volume ratio of ethyl acetate to n-hexane during the crystallization process is 1:(3-10).

[0050] Furthermore, the vacuum drying temperature is 30-50℃, and the vacuum drying time is 4-12h.

[0051] A 3,5-dibromo-4-methylpyridine can be used in the production of chemical pharmaceutical raw materials.

[0052] This invention uses 4-methylpyridine as the starting material and constructs 3,5-dibromo-4-methylpyridine through a series of steps including complexation, diboration, decomplexation, borate conversion, and deboronization. The cyclic nitrogen in 4-methylpyridine first forms an adduct with boron trifluoride, reducing the coordination interference of the cyclic nitrogen on the metal catalytic center and adjusting the electron distribution of the pyridine ring, so that subsequent C-H bond boration occurs mainly at the 3 and 5 positions, generating a dipinalyl borate intermediate. This intermediate undergoes alkaline hydrolysis to remove boron trifluoride, restoring the original structure of the pyridine ring nitrogen. The dipinalyl borate group is then converted to a diboronic acid group, providing a reaction site for deboronization. Under the action of a brominating agent, the diboronic acid intermediate undergoes C-boron bond cleavage and C-bromine bond formation, converting the two borate groups into bromine atoms, retaining the 4-methyl group and the pyridine ring skeleton. The entire route separates the difunctionalization at the 3 and 5 positions and the introduction of the bromine atom, allowing for the separation and processing of intermediates at each stage, facilitating control of the degree of disubstitution, reaction positions, and impurity sources. Compared to the routes of strong base low-temperature metallization or amino protection, diazotization and then bromination, the present invention reduces the dependence on the strong base low-temperature metallization, liquid bromine drop addition and strong acid diazotization steps, and the process connection is more direct.

[0053] Compared with the prior art, the beneficial effects of the present invention are: 1. This invention regulates the reaction state of the pyridine ring through boron trifluoride complexation, which is beneficial for controlling the site of double boronization at positions 3 and 5.

[0054] 2. This invention uses 4-methylpyridine as the starting material, and the route proceeds in the order of complexation, diboration and deboronization, with clear process connections.

[0055] 3. This invention introduces bifunctionalization and bromine atoms in stages, making the intermediates easier to separate and process, which is beneficial to product purity and batch stability. Attached Figure Description

[0056] Figure 1 The 4-methyl-3,5-bis(pinacolborate)pyridine-boron trifluoride complex prepared in Example 1 of this invention 1 HNMR spectrum.

[0057] Figure 2 The 4-methylpyridine-3,5-diboronic acid prepared in Example 1 of this invention 1 HNMR spectrum.

[0058] Figure 3 The 3,5-dibromo-4-methylpyridine prepared in Example 1 of this invention 1 HNMR spectrum.

[0059] Figure 4 This is an HPLC chromatogram of 3,5-dibromo-4-methylpyridine prepared in Example 1 of the present invention. Detailed Implementation

[0060] The technical solution of the present invention will now be clearly and completely described with reference to the accompanying drawings. Obviously, the described embodiments are merely some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0061] Example 1

[0062] Synthesis of a 3,5-dibromo-4-methylpyridine: Synthesis of S1,4-methylpyridine-boron trifluoride complex: ; A 500 mL three-necked flask, after being dried, was placed under nitrogen protection. 9.31 g of 4-methylpyridine and 100 mL of anhydrous dichloromethane were added, and the mixture was stirred until homogeneous. The reaction system was then cooled to 0–2 °C. While maintaining the system temperature at 0 °C, 14.90 g of boron trifluoride diethyl ether was added dropwise over 30 min. After the addition was complete, the reaction system was heated to 20 °C and stirred for 1.5 h to allow the cyclic nitrogen of 4-methylpyridine to form a complex with boron trifluoride. After the reaction was complete, the system was cooled to 0 °C, and 300 mL of n-hexane for crystallization was added over 20 min. After the addition was complete, the mixture was stirred for another 30 min and allowed to stand at 0 °C for 1 h to allow the solid to precipitate. Solid-liquid separation was performed by vacuum filtration. The resulting filter cake was washed twice with 30 mL of n-hexane each time and dried under vacuum at 35 °C for 8 h to obtain 14.80 g of the 4-methylpyridine-boron trifluoride complex.

[0063] The CAS number of the 4-methylpyridine is 108-89-4.

[0064] The CAS number of the boron trifluoride ether is 109-63-7.

[0065] The NMR spectrum of the 4-methylpyridine-boron trifluoride complex is as follows: 1 HNMR-CD3CN: δ8.70(d,2H),7.62(d,2H),2.51(s,3H).

[0066] Synthesis of S2,4-methyl-3,5-bis(pinacolborate)pyridine-boron trifluoride complex: ; A 1L pressure-resistant sealed reaction vessel, after being dried, was placed under nitrogen protection. 1.22g of bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I), 0.99g of 4,4′-di-tert-butyl-2,2′-bipyridine, and 300mL of anhydrous tetrahydrofuran were added sequentially, and the mixture was stirred until the materials were evenly dispersed. Then, 46.71g of bis-pinacol borane and 1.18g of pinacol borane were added sequentially, and the mixture was stirred at 30°C for 20 min to obtain the catalytic reaction solution. Separately, 14.80g of the 4-methylpyridine-boron trifluoride complex obtained in the previous reaction was dispersed in 100mL of anhydrous tetrahydrofuran and added to the catalytic reaction solution under nitrogen protection. After nitrogen purging, the reaction vessel was sealed, and the mixture was stirred at 80°C for 24 h. After the reaction was completed, the reaction system was cooled to 20°C, filtered through a diatomaceous earth-lined filter layer, and the filter layer was washed with 50 mL of anhydrous tetrahydrofuran. The filtrates were combined and concentrated under reduced pressure to approximately 80 mL at a temperature not exceeding 40°C. 300 mL of anhydrous n-hexane was slowly added to the concentrate, and the mixture was stirred for 30 min and then allowed to stand at 0°C for 2 h to allow the solid to precipitate. Solid-liquid separation was performed by vacuum filtration. The resulting filter cake was washed twice with 30 mL of anhydrous n-hexane each time and dried under vacuum at 35°C for 8 h to obtain 17.09 g of 4-methyl-3,5-bis(pinacolborate)pyridine-boron trifluoride complex.

[0067] The CAS number of the bis-pinacol boronic acid ester is 73183-34-3.

[0068] The CAS number of the pinacol borane is 25015-63-8.

[0069] The CAS number of the bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) is 12148-71-9.

[0070] The CAS number of the 4,4′-di-tert-butyl-2,2′-bipyridine is 72914-19-3.

[0071] NMR of the 4-methyl-3,5-bis(pinacolborate)pyridine-boron trifluoride complex: 1 HNMR-CDCl3: δ8.68(s,2H),2.57(s,3H),1.34(s,24H).

[0072] Synthesis of S3,4-methyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)pyridine: ; A 1L three-necked flask, dried beforehand, was placed under nitrogen protection. 17.09 g of the 4-methyl-3,5-bis(pinacolborate)pyridine-boron trifluoride complex prepared in the previous reaction and 250 mL of tetrahydrofuran were added. The mixture was stirred to disperse the compounds, and the reaction system was cooled to 5°C. 13.91 g of sodium bicarbonate was prepared as an 8.0% (w / w) aqueous solution and added dropwise to the reaction system over 60 min, maintaining the temperature at 5°C and the pH at 7.5 during the addition. After the addition was complete, the system was heated to 20°C and the reaction was continued with stirring for 3 h to allow the complex structure between the pyridine ring nitrogen and boron trifluoride to de-complex. After the reaction was complete, 300 mL of ethyl acetate was added, and the mixture was allowed to stand for separation. The aqueous phase was extracted twice with 150 mL of ethyl acetate each time. The organic phases were combined and washed successively with 100 mL of water and 100 mL of saturated sodium chloride aqueous solution. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at a temperature not exceeding 40°C. Add 50 mL of ethyl acetate to the obtained concentrate to dissolve it, then slowly add 250 mL of n-hexane, stir for 30 min, and let it stand at 5 °C for 3 h to crystallize. Separate the solid and liquid by vacuum filtration. Wash the obtained filter cake twice with 30 mL of n-hexane each time, and dry it under vacuum at 35 °C for 8 h to obtain 12.57 g of 4-methyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine.

[0073] The NMR spectra of 4-methyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)pyridine are as follows: 1 HNMR-CDCl3: δ8.55(s,2H),2.54(s,3H),1.34(s,24H).

[0074] Synthesis of S4,4-methylpyridine-3,5-diboronic acid: ; A 2L three-necked flask, after being dried, was placed under nitrogen protection. 12.57 g of 4-methyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine, prepared in the previous reaction, and 400 mL of acetone were added and stirred until uniformly dispersed. 28.08 g of ammonium acetate was dissolved in 200 mL of deionized water and added to the reaction system. The system temperature was lowered to 5°C. While maintaining the system temperature at 8°C, 62.33 g of sodium periodate was added in portions over 60 min. After the addition was complete, the system temperature was raised to 25°C, and the reaction was continued with stirring for 24 h to allow the two pinacol borate ester groups to undergo an oxidative deprotection reaction. After the reaction, insoluble substances were removed by filtration, and acetone was removed under reduced pressure at a temperature not exceeding 35°C. The pH of the resulting aqueous phase was adjusted to 5.2 using a 2.0 mol / L hydrochloric acid aqueous solution, and then concentrated under reduced pressure to approximately 30% of its original volume. Crystallization was then carried out at 5°C for 6 hours. Solid-liquid separation was performed by vacuum filtration. The resulting filter cake was washed twice with 15 mL of cold water at 5°C each time, and then vacuum dried at 30°C for 12 hours to obtain 5.18 g of 4-methylpyridine-3,5-diboronic acid.

[0075] NMR of 4-methylpyridine-3,5-diboronic acid: 1 HNMR-DMSO-D6: δ8.55(s,2H),8.18(brs,4H),2.43(s,3H).

[0076] Synthesis of S5,3,5-dibromo-4-methylpyridine: ; A 1L three-necked flask, after being dried, was placed under nitrogen protection. 5.18g of 4-methylpyridine-3,5-diboronic acid, prepared in the previous reaction, and 400mL of anhydrous acetonitrile were added and stirred until uniformly dispersed. Then, 0.93g of a 25% sodium methoxide methanol solution was added, and the system temperature was lowered to 5℃. While maintaining the system temperature at 5-8℃, 9.01g of 1,3-dibromo-5,5-dimethylhydantoin was added in portions over 60 minutes. After the addition was complete, the system temperature was raised to 25℃, and the reaction was continued with stirring for 4 hours to allow the 4-methylpyridine-3,5-diboronic acid to undergo a bromination-deboronization reaction. After the reaction was completed, 120 mL of a 10% sodium thiosulfate aqueous solution was added to the reaction system to quench the remaining brominating agent. Then, 250 mL of ethyl acetate was added, and the mixture was allowed to stand for separation. The aqueous phase was extracted twice with 150 mL of ethyl acetate each time. The organic phases were combined and washed successively with 150 mL of deionized water and 150 mL of saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated under reduced pressure to obtain the crude product. 40 mL of ethyl acetate was added to the crude product to dissolve it, and then 240 mL of n-hexane was added to induce crystallization. The mixture was allowed to stand at 5 °C for 4 h, and then the solid and liquid phases were separated by vacuum filtration. The resulting filter cake was washed twice with 30 mL of n-hexane each time and dried under vacuum at 40 °C for 8 h to obtain 5.62 g of 3,5-dibromo-4-methylpyridine.

[0077] The CAS number of the 1,3-dibromo-5,5-dimethylhydantoin is 77-48-5.

[0078] NMR of 3,5-dibromo-4-methylpyridine: 1 HNMR-CDCl3: δ8.55(s,2H),2.45(s,3H).

[0079] Example 2

[0080] The synthesis of 3,5-dibromo-4-methylpyridine follows the steps of Example 1, except that the alkane antisolvent used to precipitate the solid in the synthesis of the 4-methylpyridine-boron trifluoride complex in S1 is replaced by an equal volume of hexane with petroleum ether, while the rest remains the same as in Example 1.

[0081] Example 3

[0082] The synthesis of 3,5-dibromo-4-methylpyridine follows the steps of Example 1, except that the temperature of the 3,5-carbon-hydrogen bond double boronization reaction during the synthesis of the 4-methyl-3,5-bis(pinacolborate)pyridine-boron trifluoride complex in S2 is replaced with 70°C instead of 80°C, while the rest remains the same as in Example 1.

[0083] Example 4

[0084] The synthesis of 3,5-dibromo-4-methylpyridine follows the steps of Example 1, except that the reaction time for the deprotection reaction of the 4-methyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine in S4 with pinacol ester group was changed from 24 h to 48 h, while the rest remained the same as in Example 1.

[0085] Comparative Example 1 The synthesis of 3,5-dibromo-4-methylpyridine follows the steps of Example 1, except that the alkane antisolvent used to precipitate the solid during the synthesis of the 4-methylpyridine-boron trifluoride complex in S1 is replaced with toluene instead of hexane by an equal volume of boiling range. The rest remains the same as in Example 1.

[0086] Comparative Example 2 The synthesis of 3,5-dibromo-4-methylpyridine follows the steps of Example 1, except that the temperature of the 3,5-carbon-hydrogen bond double boronization reaction during the synthesis of the 4-methyl-3,5-bis(pinacolborate)pyridine-boron trifluoride complex in S2 is replaced with 55°C instead of 80°C, while the rest remains the same as in Example 1.

[0087] Comparative Example 3 The synthesis of 3,5-dibromo-4-methylpyridine was carried out according to the steps of Example 1, except that the pH of the reaction system was controlled at 9.0 during the addition of sodium bicarbonate aqueous solution in S3, and the rest was the same as in Example 1.

[0088] Comparative Example 4 The synthesis of 3,5-dibromo-4-methylpyridine follows the steps of Example 1, except that the reaction time for the borate pinacol ester oxidation deprotection reaction of 4-methyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine in S4 is changed from 24 h to 8 h, while the rest remains the same as in Example 1.

[0089] Performance testing: 1. Purity test of the target product: The HPLC purity of 3,5-dibromo-4-methylpyridine obtained in each example and comparative example was determined by high performance liquid chromatography. The data are shown in Table 1.

[0090] 2. Overall Yield Test: Using 4-methylpyridine as the initial stoichiometric standard, the mass of the dried target product obtained after reactions S1 to S4, crystallization, washing, and vacuum drying in each example and comparative example was recorded. The overall yield was calculated using the formula: "Overall yield = Amount of 3,5-dibromo-4-methylpyridine actually obtained / Amount of 4-methylpyridine initially added × 100%". Three batches of each sample were prepared in parallel, and the average value was taken. The drying endpoint was defined as a mass change of no more than 0.5% between two consecutive weighings. The data are shown in Table 1.

[0091] Table 1. Test data for both examples and comparative examples

[0092] The performance test results show that the samples obtained by the route of this invention exhibit a stable trend in terms of purity, impurity levels, and batch repeatability. 4-Methylpyridine first forms a complex with boron trifluoride, reducing the interference of the cyclic nitrogen on the catalytic system and concentrating the reaction sites for the 3- and 5-position C-H double boronization. Subsequent decomplexing, oxidative deprotection, and bromination deboronization proceed step-by-step according to the intermediate structure, with each step having a relatively clear conversion target, making the operation easier to track. The intermediates at each stage are crystallized, washed, and dried before proceeding to the next step, reducing the risk of residual boron reagents, oxidation byproducts, and excess brominating agents being introduced into subsequent reactions, and making it easier to identify and control the sources of impurities.

[0093] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing 3,5-dibromo-4-methylpyridine, characterized in that, Includes the following steps: S1. Under nitrogen protection, 4-methylpyridine is dissolved in anhydrous dichloromethane, and boron trifluoride diethyl ether is added at -5 to 5°C. After the addition is complete, a complexation reaction is carried out at 0 to 25°C for 0.5 to 3 hours to obtain a 4-methylpyridine-boron trifluoride complex; wherein the molar ratio of 4-methylpyridine to boron trifluoride diethyl ether is 1:(1.00-1.20). S2. Under nitrogen protection, bis(1,5-cyclooctadiene)di-μ-methoxydiiridium (I) and 4,4′-di-tert-butyl-2,2′-bipyridine were added to anhydrous tetrahydrofuran, followed by the addition of dipinacol boronic acid ester and pinacol borane. The mixture was stirred at 20-40°C for 10-30 min to obtain a catalytic reaction solution. The 4-methylpyridine-boron trifluoride complex obtained in step S1 was added to the catalytic reaction solution, and the 3,5-position C-H bond double boronization reaction was carried out in a pressure-resistant sealed reaction vessel at 70-90°C for 16-48 h to obtain... 4-Methyl-3,5-bis(pinacolborate)pyridine-boron trifluoride complex; wherein the molar ratio of the 4-methylpyridine-boron trifluoride complex, bispinacolborate, pinacolborane and bis(1,5-cyclooctadiene)di-μ-methoxydiiridium (I) is 1∶(1.5-3.5):(0.05-0.20):(0.01-0.03), and the molar ratio of 4,4′-di-tert-butyl-2,2′-bipyridine to bis(1,5-cyclooctadiene)di-μ-methoxydiiridium (I) is 2∶1; S3. Under nitrogen protection, the 4-methyl-3,5-bis(pinacolborate)pyridine-boron trifluoride complex obtained in step S2 is dissolved in tetrahydrofuran. The system temperature is lowered to 0-10℃, and a 5%-10% sodium bicarbonate aqueous solution is added. During the addition, the pH of the reaction system is controlled at 7.5-8.

5. After the addition is complete, a decomplexing reaction is carried out at 10-30℃ for 1-6 hours to obtain 4-methyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine; wherein the molar ratio of the 4-methyl-3,5-bis(pinacolborate)pyridine-boron trifluoride complex to sodium bicarbonate is 1:(3.0-6.0). S4. Under nitrogen protection, the 4-methyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine obtained in step S3 is dispersed in acetone, and an aqueous solution of ammonium acetate is added. The system temperature is lowered to 0-10℃, and sodium periodate is added while maintaining the system temperature at 0-10℃. After the addition is complete, the borate pinacol ester group is oxidized and deprotected at 15-30℃ for 12-48 h to obtain 4-methylpyridine-3,5-diboronic acid; wherein, the molar ratio of 4-methyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine, sodium periodate and ammonium acetate is 1∶(6-10)∶(8-14); S5. Under nitrogen protection, 4-methylpyridine-3,5-diboronic acid obtained in step S4 is added to anhydrous acetonitrile, followed by sodium methoxide methanol solution. The system temperature is lowered to 0-10℃. While maintaining the system temperature at 0-10℃, 1,3-dibromo-5,5-dimethylhydantoin is added. After the addition is complete, a bromination-deboronization reaction is carried out at 20-35℃ for 2-8 hours to obtain 3,5-dibromo-4-methylpyridine. The molar ratio of 4-methylpyridine-3,5-diboronic acid to 1,3-dibromo-5,5-dimethylhydantoin is 1:(1.05-1.30), and the molar ratio of 4-methylpyridine-3,5-diboronic acid to sodium methoxide is 1:(0.10-0.20).

2. The method for synthesizing 3,5-dibromo-4-methylpyridine according to claim 1, characterized in that, In step S1, after the complexation reaction is completed, an alkane-based antisolvent is added to precipitate the 4-methylpyridine-boron trifluoride complex in solid form. After solid-liquid separation, washing, and vacuum drying, the 4-methylpyridine-boron trifluoride complex is obtained.

3. The method for synthesizing 3,5-dibromo-4-methylpyridine according to claim 2, characterized in that, The alkane antisolvent is selected from at least one of petroleum ether, n-hexane, and n-heptane; The volume ratio of the alkane antisolvent to anhydrous dichloromethane is (1-5):

1.

4. The method for synthesizing 3,5-dibromo-4-methylpyridine according to claim 1, characterized in that, In step S2, after the 3,5-position C-H bond double boronization reaction is completed, the reaction system is cooled to room temperature, filtered through diatomaceous earth and concentrated under reduced pressure. Anhydrous n-hexane is added to the obtained concentrate to precipitate the solid. After solid-liquid separation, washing with anhydrous n-hexane and vacuum drying, the 4-methyl-3,5-bis(pinacol boronic acid ester)pyridine-boron trifluoride complex is obtained.

5. The method for synthesizing 3,5-dibromo-4-methylpyridine according to claim 4, characterized in that, In step S2, the mixing temperature of the catalytic reaction solution is 30°C and the mixing time is 20 min, while the temperature of the 3,5-position carbon-hydrogen bond double boronization reaction is 80°C and the reaction time is 24 h.

6. The method for synthesizing 3,5-dibromo-4-methylpyridine according to claim 1, characterized in that, In step S3, after the decomplexing reaction is completed, ethyl acetate is added, and the mixture is allowed to stand for separation. The aqueous phase is extracted with ethyl acetate, and the organic phases are combined and washed successively with water and saturated sodium chloride aqueous solution. The mixture is dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate and n-hexane are added to the obtained concentrate for crystallization. The mixture is allowed to stand at 0-10℃ for 1-6 h, and after solid-liquid separation, washing with n-hexane, and vacuum drying, the 4-methyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine is obtained.

7. The method for synthesizing 3,5-dibromo-4-methylpyridine according to claim 6, characterized in that, In step S3, the amount of tetrahydrofuran used is 5-15 mL based on 1 mmol of the 4-methyl-3,5-bis(pinacolborate)pyridine-boron trifluoride complex; the volume ratio of ethyl acetate to n-hexane during crystallization is 1:(3-8); the vacuum drying temperature is 30-45℃, and the vacuum drying time is 4-12 h.

8. The method for synthesizing 3,5-dibromo-4-methylpyridine according to claim 1, characterized in that, In step S4, after the oxidative deprotection reaction is completed, insoluble substances are removed by filtration, acetone is removed by vacuum, the pH of the resulting aqueous phase is adjusted to 4.5-6.0 using hydrochloric acid aqueous solution, and the volume is concentrated to 20%-40% of the original volume under vacuum. Crystallization is carried out at 0-10℃ for 2-12 hours, followed by solid-liquid separation, cold water washing, and vacuum drying to obtain the 4-methylpyridine-3,5-diboronic acid.

9. The method for synthesizing 3,5-dibromo-4-methylpyridine according to claim 8, characterized in that, In step S4, the concentration of 4-methyl-3,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine is 0.02-0.10 mol / L based on the total volume of acetone and water; the volume ratio of acetone to water is (1.5-3):1; the concentration of the hydrochloric acid aqueous solution is 1-3 mol / L; the vacuum drying temperature is 25-40℃, and the vacuum drying time is 6-18 h.

10. The method for synthesizing 3,5-dibromo-4-methylpyridine according to claim 1, characterized in that, In step S5, the mass fraction of the sodium methoxide methanol solution is 20%-30%, and the amount of anhydrous acetonitrile used is 8-25 mL based on 1 mmol of the 4-methylpyridine-3,5-diboronic acid. After the bromination and deboronization reaction is completed, a 5%-15% sodium thiosulfate aqueous solution is added to quench the remaining brominating agent, followed by the addition of ethyl acetate. The mixture is allowed to stand and separate into layers. The aqueous phase is extracted with ethyl acetate, and the organic phases are combined and washed successively with water and saturated sodium chloride aqueous solution. The mixture is then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate and n-hexane are added to the resulting concentrate for crystallization. The mixture is then subjected to solid-liquid separation, washing with n-hexane, and vacuum drying to obtain the 3,5-dibromo-4-methylpyridine. During the crystallization process, the volume ratio of ethyl acetate to n-hexane is 1:(3-10), the vacuum drying temperature is 30-50℃, and the vacuum drying time is 4-12 h.

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