6-bromonicotine preparation method
By using 6-hydroxymasmin as a raw material to prepare 6-bromonoxine through reduction, aminomethylation and bromination reactions, the problems of low temperature and precious metal catalysis in the existing technology have been solved, and high-purity, low-cost industrial production has been achieved.
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- Filing Date
- 2025-12-01
- Publication Date
- 2026-04-16
AI Technical Summary
Existing methods for synthesizing 6-bromonicotinic acid require low temperatures and precious metal catalysis, making them unsuitable for large-scale production and posing safety risks and high costs.
Using 6-hydroxymasmin as a starting material, high-purity 6-bromonicotinic acid is prepared through reduction, aminomethylation, and bromination reactions. The process is simple, safe, and reliable, and suitable for industrial production.
The synthesis of high-purity (over 99.0%) 6-bromonicotinic acid has been achieved. The operation is simple, safe, reliable, and low-cost, making it suitable for industrial production.
Smart Images
Figure CN2025138915_16042026_PF_FP_ABST
Abstract
Description
A method for preparing 6-bromonicotinic acid Technical Field
[0001] This invention relates to the field of organic chemical synthesis, specifically to a method for synthesizing 6-bromonicotinic acid. Background Technology
[0002] The treatment of central nervous system diseases has always been a hot topic in medical research, and the role of acetylcholine receptors in this field has attracted much attention. As an acetylcholine receptor agonist, nicotine has shown significant potential in the treatment of neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and Tourette's syndrome. However, its common side effects limit its widespread clinical use. To address this issue, scientists urgently need to find acetylcholine receptor ligands with higher selectivity and safety to open up new drug treatment pathways. Against this backdrop, research has discovered several nicotine derivatives, among which 6-substituted nicotine derivatives have shown good biological activity. Among these derivatives, 6-bromonicotine is particularly noteworthy. Compared with conventional nicotine, 6-bromonicotine not only binds effectively to acetylcholine receptors but also has lower toxicity. In addition, it exhibits extremely high selectivity, accurately targeting receptors associated with neurological diseases. More importantly, 6-bromonicotine can also be chemically converted into other compounds with potential therapeutic effects, thus providing a broader range of possibilities for the treatment of neurological diseases. Therefore, based on its favorable pharmacological properties and potential therapeutic effects, 6-bromonicotinic acid has significant research value and clinical prospects in the treatment of neurological diseases. It may become a key component in the development of novel treatment regimens, providing patients with these diseases with more effective and safer treatment options.
[0003] 6-Bromonic acid is not a naturally occurring substance and can only be prepared through chemical synthesis. Currently, there are three main known methods for synthesizing 6-bromonicotinic acid. The first method, as described in US2005131030, involves converting nicotine into a lithium reagent, followed by electrophilic substitution to synthesize 6-bromonicotinic acid. However, this reaction requires a strong base such as butyllithium and a low temperature of -70°C, making it unsuitable for large-scale production. The second method, as described in patent CN 104341390 B, involves converting 2,5-dibromopyridine into 6-bromomasmin via butyllithium and Boc removal, followed by noble metal-catalyzed hydrogenation to 6-bromonornicotinic acid, and finally aminomethylation to obtain 6-bromonicotinic acid. However, this route requires a low temperature of -78°C and the use of a strong base such as butyllithium. Furthermore, the noble metal-catalyzed hydrogenation equipment is expensive and demanding, making it unsuitable for large-scale production. The third method, referencing US20030187270 A1, involves first converting nicotine oxide into a quaternary ammonium salt, and then using hydrogen bromide gas for nucleophilic substitution to synthesize 6-bromonicotinic acid. However, this route requires the use of highly corrosive hydrogen bromide gas and a low-temperature environment of -25°C, making it unsuitable for large-scale production.
[0004] In summary, existing methods for synthesizing 6-bromonicotinic acid cannot meet the requirements for its synthesis, therefore, it is necessary to develop a synthetic route for 6-bromonicotinic acid. Summary of the Invention
[0005] Given the numerous shortcomings of current methods for synthesizing 6-bromonicotinic acid, this invention discloses a method for synthesizing 6-bromonicotinic acid using 6-hydroxymaxamine (CAS: 70969-38-9) as a raw material to prepare high-purity, active 6-bromonicotinic acid. This route first converts 6-hydroxymaxamine into compound I through a reduction reaction, followed by aminomethylation and bromination reactions to finally obtain the target product, 6-bromonicotinic acid. The final product has a defined structure and bromine substitution site selectivity, exhibits high yield, is simple to operate, and can be used for industrial production.
[0006] This invention provides a method for synthesizing 6-bromonicotinic acid, achieved through the following technical solution:
[0007] Starting with 6-hydroxymasmin, the synthesis proceeded sequentially through reduction, aminomethylation, and bromination to finally yield the target product, 6-bromonoxine. The synthetic route is shown in the figure below.
[0008] Furthermore, the synthesis of 6-bromonicotinic acid specifically includes the following steps:
[0009] S1,6-hydroxymasmin was dissolved in an organic solvent, and an additive was added to obtain a reaction solution. A reducing agent was added to the reaction solution at low temperature, and the reaction was allowed to proceed to completion at low temperature. After the mixed solution was brought to room temperature, an acidic aqueous solution was slowly added to quench the reaction, followed by extraction with an organic solvent to obtain compound I.
[0010] S2, compound I, formic acid, and an aqueous formaldehyde solution were mixed to obtain a mixed solution, and then the reaction was carried out under heating. After the mixed solution cooled to room temperature, an alkaline aqueous solution was slowly added to quench the reaction, and then the mixture was extracted with an organic solvent to obtain compound II.
[0011] S3, compound II, the brominating reagent, and an organic solvent were mixed to obtain a mixed solution, which was then reacted completely under heating. After the mixed solution cooled to room temperature, an alkaline aqueous solution was slowly added to quench the reaction, followed by extraction with an organic solvent to obtain crude 6-bromonicotinic acid. The crude product was purified by vacuum distillation to obtain high-purity 6-bromonicotinic acid.
[0012] This synthesis method is simple to operate, safe and reliable, with high yield, low cost, and product purity of up to 99.0% or more.
[0013] Optionally, the organic solvent used in step S1 is at least one of tetrahydrofuran, methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, and water; preferably, the organic solvent used in the reaction is methanol.
[0014] Optionally, the additive used in step S1 may be at least one of formic acid, acetic acid, propionic acid, calcium chloride, lithium chloride, and magnesium chloride; preferably, the additive used in the reaction is acetic acid.
[0015] Optionally, the reducing agent used in step S1 may be at least one of sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium cyanoborohydride, sodium triethylborohydride, and sodium triacetoxyborohydride; preferably, the reducing agent used in the reaction is sodium borohydride.
[0016] Optionally, the temperature of the low-temperature reaction in step S1 is -40 to 10°C; preferably, the temperature of the low-temperature reaction is 0°C.
[0017] Optionally, the molar ratio of 6-hydroxymasmin, additives and reducing agents added in step S1 is 1.0:0.1-30:1.0-2.5.
[0018] Optionally, the heating temperature in step S2 is 60-90℃.
[0019] Optionally, in step S2, the addition ratio of compound I, formic acid, and formaldehyde aqueous solution is 1.0g:0.5-0.8g:1.0-10.0g.
[0020] Optionally, the organic solvent used in step S3 may be at least one of acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, chlorobenzene, dichloromethane, and ethyl acetate; preferably, the organic solvent used in the reaction is acetonitrile.
[0021] Optionally, the brominating reagent used in step S3 is selected from at least one of phosphorus tribromooxyphosphine, N-bromosuccinimide, dibromotriphenylphosphine, phosphorus tribromide, and phosphorus pentabromide; preferably, the brominating reagent used in the reaction is phosphorus tribromooxyphosphine.
[0022] Optionally, the heating temperature in step S3 is 70–100°C; preferably, the heating temperature is 80°C.
[0023] Optionally, the molar ratio of compound II to brominating reagent added in step S3 is 1:1-30.
[0024] Optionally, the extraction solvent used in step S3 is dichloromethane and ethyl acetate; preferably, the organic solvent used in the reaction is dichloromethane.
[0025] In summary, this application has the following beneficial effects:
[0026] The method for synthesizing 6-bromonicotinic acid disclosed in this application is simple to operate, safe and reliable, with high yield and low cost; using 6-hydroxymasmin as a starting material, the purity of the 6-bromonicotinic acid obtained can reach over 99.0%. Attached Figure Description
[0027] Figure 1 is a schematic diagram of the synthesis route of the preparation method of this application;
[0028] Figure 2 is the LC-MS spectrum of the final product obtained in Example 1 of this application;
[0029] Figure 3 is the 1H NMR spectrum of the final product obtained in Example 1 of this application. Detailed Implementation
[0030] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.
[0031] Examples 1-6 provide a method for synthesizing 6-bromonicotinic acid, and the following description uses Example 1 as an example.
[0032] Example 1:
[0033] Step S1: In a 1L round-bottom flask, add 32.4g (0.2mol, 1.0eq) of 6-hydroxymaxamine, 3.0g of acetic acid (0.02mol, 0.1eq), and 400mL of anhydrous methanol to obtain a mixed solution. Then cool to 0℃, add 13.8g (0.22mol, 1.1eq) of sodium cyanoborohydride, and stir for 4 hours. After the reaction is completed by TLC monitoring, the mixed solution is restored to room temperature, the reaction is quenched with dilute hydrochloric acid (1.0M solution), extracted with 400mL of dichloromethane, and the organic phase is distilled under reduced pressure to remove the solvent, yielding compound I.
[0034] Step S2: Compound I obtained in step S1 was mixed with 40% aqueous formaldehyde solution (300.0 g) and formic acid (20.0 g), and heated to 80 °C for 4 hours. After the reaction was completed by TLC monitoring, the mixture was returned to room temperature, and the pH was adjusted to 8 by adding saturated sodium carbonate solution. The mixture was extracted with 400 mL of dichloromethane, and the solvent was removed by vacuum distillation of the organic phase to obtain compound II.
[0035] Step S3: Compound II obtained in Step S2 was added to a 500 mL round-bottom flask, followed by 200 mL of acetonitrile and phosphorus tribromooxyphosphate (0.6 mol, 3.0 eq) to obtain a mixed solution. The mixed solution was heated to 80 °C and stirred for 2 hours. After the reaction was complete as monitored by TLC, the mixed solution was returned to room temperature, the solvent was removed by vacuum distillation, the pH was adjusted to 8 with saturated sodium carbonate solution, and then extracted twice with 300 mL of dichloromethane. The organic phases were combined, and the solvent was removed by vacuum distillation to obtain crude 6-bromonicotinic acid. The crude 6-bromonicotinic acid was then distilled under vacuum at 120 °C and 0.1 kPa, and the middle fraction was collected to obtain 21.6 g of high-purity 6-bromonicotinic acid. The overall yield of the three steps was 32%, with a purity of 99.0%.
[0036] The 6-bromonicotinic acid obtained in Example 1 was detected by LC-MS and NMR. The results are shown in Figures 2 and 3. The specific detection data are as follows:
[0037] LC-MS: M+H + [241.03]:[243.03] = 1:1, consistent with the theoretical value.
[0038] 1¹H NMR (400MHz, CDCl₃) values were 8.27 (s, ¹H), 7.57 (d, J = 8.1Hz, ¹H), 7.43 (d, J = 8.1Hz, ¹H), 3.22 (t, J = 8.5Hz, ¹H), 3.06 (t, J = 8.3Hz, ¹H), 2.32 (q, J = 9.0Hz, ¹H), 2.26–2.17 (m, ¹H), 2.15 (s, ³H), 2.00–1.93 (m, ¹H), 1.87–1.77 (m, ¹H), and 1.71–1.61 (m, ¹H). These values are consistent with the theoretical values for 6-bromonicotinic acid. Therefore, the product obtained according to the method of this application is 6-bromonicotinic acid.
[0039] It is worth noting that the mass and specific molar amount of each item in the embodiments of this application can be selected according to the size of the container for industrial production, as long as the equivalence ratio between each reactant is kept consistent.
[0040] The difference between Examples 2-4 and Example 1 lies in the type and amount of brominating reagent used in step S3. The specific results are shown in Table 1.
[0041] Table 1. Effects of different types and amounts of brominating reagents on the final product in step S3.
[0042] The difference between Examples 5 and 6 and Example 1 is that the types of organic solvents used in step S3 are different. The specific results are shown in Table 4.
[0043] Table 4 shows the effect of different types of organic solvents on the final product in step S3.
[0044] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.
[0045] The embodiments described above are merely explanations of this application and are not intended to limit it. After reading this specification, those skilled in the art can make modifications to these embodiments without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.
Claims
1. A process for the preparation of 6-bromo nicotinic acid, characterized in that, It includes the following steps: With 6-hydroxymaysine As a starting material, the compound I is produced by sequentially subjecting S1 reduction reaction S2 aminomethylation reaction produces compound II The bromination reaction ultimately yields the target product, 6-bromonoxine.
2. The method for preparing 6-bromonicotinic acid according to claim 1, characterized in that, In step S1, 6-hydroxymasmin (CAS: 70969-38-9) is dissolved in an organic solvent, and an additive is added to obtain a reaction solution. A reducing agent is added to the reaction solution under low temperature conditions, and the reaction is completed under low temperature conditions. After the mixed solution is heated to room temperature, an acidic aqueous solution is slowly added to quench the reaction, and then an organic solvent is used for extraction to obtain compound I. In step S2, compound I, formic acid, and an aqueous formaldehyde solution are mixed to obtain a mixed solution, and then the reaction is carried out under heating conditions. After the mixed solution is cooled to room temperature, an alkaline aqueous solution is slowly added to quench the reaction, and then an organic solvent is used for extraction to obtain compound II. In step S3, compound II, the brominating reagent, and the organic solvent are mixed to obtain a mixed solution, and then the reaction is carried out under heating conditions. After the mixed solution is cooled to room temperature, an alkaline aqueous solution is slowly added to quench the reaction, and then the mixture is extracted with an organic solvent to obtain the crude product of 6-bromonicotinic acid.
3. The method for synthesizing 6-bromonicotinic acid according to claim 2, characterized in that, The organic solvent used in step S1 may be at least one of tetrahydrofuran, methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, or water.
4. The method for synthesizing 6-bromonicotinic acid according to claim 3, characterized in that, The additive used in step S1 can be at least one of formic acid, acetic acid, propionic acid, calcium chloride, lithium chloride, and magnesium chloride.
5. The method for synthesizing 6-bromonicotinic acid according to claim 4, characterized in that, The reducing agent used in step S1 can be at least one of sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium cyanoborohydride, sodium triethylborohydride, and sodium triacetoxyborohydride.
6. The method for synthesizing 6-bromonicotinic acid according to claim 5, characterized in that, The temperature of the low-temperature reaction in step S1 is -40 to 10°C.
7. The method for synthesizing 6-bromonicotinic acid according to any one of claims 2-6, characterized in that, In step S1, the molar ratio of 6-hydroxymaxamine, additives, and reducing agents is 1.0:0.1-30:1.0-2.
5.
8. The method for synthesizing 6-bromonicotinic acid according to claim 7, characterized in that, The heating temperature in step S2 is 60-90℃.
9. The method for synthesizing 6-bromonicotinic acid according to claim 8, characterized in that, In step S2, the addition ratio of compound I, formic acid, and formaldehyde aqueous solution is 1.0g:0.5-0.8g:1.0-10.0g.
10. The method for synthesizing 6-bromonicotinic acid according to claim 9, characterized in that, The organic solvent used in the reaction in step S3 is selected from at least one of acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, chlorobenzene, dichloromethane, and ethyl acetate.
11. The method for synthesizing 6-bromonicotinic acid according to claim 10, characterized in that, The brominating reagent used in step S3 is selected from at least one of phosphorus tribromooxyphosphine, N-bromosuccinimide, dibromotriphenylphosphine, phosphorus tribromide, and phosphorus pentabromide.
12. The method for synthesizing 6-bromonicotinic acid according to claim 11, characterized in that, The heating temperature in step S3 is 70–100°C.
13. The method for synthesizing 6-bromonicotinic acid according to claim 12, characterized in that, In step S3, the molar ratio of compound II to the brominating reagent is 1:1-30.
14. The method for synthesizing 6-bromonicotinic acid according to claim 13, characterized in that, The organic solvent used in the extraction step S3 can be at least one of dichloromethane or ethyl acetate.
15. The method for synthesizing 6-bromonicotinic acid according to any one of claims 8-14, characterized in that, The crude product was purified by vacuum distillation to obtain high-purity 6-bromonicotinic acid.
16. A 6-bromonicotinic acid, characterized in that, It is prepared by the method described in claims 1-15.