6-fluoronicotine preparation method

Abstract

The present invention relates to the field of organic chemical synthesis, and specifically relates to a 6-fluoronicotine synthesis method. The 6-fluoronicotine synthesis method uses a myosmine substitute (compound I) as a starting material, which sequentially undergoes a fluorination reaction, a reduction reaction and an amine methylation reaction, to finally obtain the target product 6-fluoronicotine. The product purity of the 6-fluoronicotine obtained by means of the synthetic route can reach 99.0% or more. The present synthesis method has a simple process and a high yield, and is suitable for industrial scale-up production.

Description

A method for preparing 6-fluoronicotinic acid Technical Field

[0001] This invention relates to the field of organic chemical synthesis, and specifically to a method for synthesizing 6-fluoronicotinic acid. Background Technology

[0002] Currently, the treatment of central nervous system diseases has received widespread research attention, especially the role of acetylcholine receptors. Nicotine and its related alkaloids, as acetylcholine receptor agonists, have shown significant potential in treating neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and Tourette's syndrome. However, the high toxicity and addictive nature of nicotine commonly limit its widespread clinical application. Therefore, there is an urgent need to develop highly active and low-toxicity nicotine analogs to meet clinical needs. Past studies have shown that some nicotine derivatives possess acetylcholine-binding capabilities, especially 6-substituted nicotine derivatives, which exhibit good biological activity. Of particular interest is the highly lipid-soluble 6-fluoronicotine, which not only possesses the ability to bind to acetylcholine receptors but can also be chemically converted into other compounds with potential therapeutic effects. Therefore, 6-fluoronicotine has significant research value and clinical application prospects in the treatment of nervous system diseases.

[0003] 6-Fluoronic acid is not a naturally occurring substance and can only be prepared through chemical synthesis. The currently known method for synthesizing 6-fluoronicotinic acid, as described in the European Journal of Medicinal Chemistry, 1996, 31, 875-888, involves converting nicotine to 6-aminonicotinic acid and then synthesizing 6-fluoronicotinic acid via a diazotization reaction. However, this reaction requires a high temperature of 120-150℃, and the diazotization reaction is highly hazardous, making it unsuitable for large-scale production.

[0004] In summary, existing methods for synthesizing 6-fluoronicotinic acid cannot meet the requirements for its synthesis, therefore, it is necessary to develop a synthetic route for 6-fluoronicotinic acid. Summary of the Invention

[0005] Given the numerous shortcomings of current methods for synthesizing 6-fluoronicotinic acid, this invention discloses a method for synthesizing 6-fluoronicotinic acid using 6-chloromasmin or 6-bromomasmin as raw materials to prepare high-purity, active 6-fluoronicotinic acid. This route first converts compound I to compound II via fluorination, followed by reduction and aminomethylation reactions, ultimately yielding the target product, 6-fluoronicotinic acid. The final product exhibits a defined structure and fluorine substitution site selectivity, with high yield, simple operation, and suitability for industrial production.

[0006] This invention provides a method for synthesizing 6-fluoronicotinic acid, achieved through the following technical solution:

[0007] Starting with a substituted styramine compound (compound I), the synthesis proceeded sequentially through fluorination, reduction, and aminomethylation to finally yield the target product, 6-fluoronicotinic acid. The synthetic route is shown in the figure below:

[0008] Where X represents chlorine or bromine.

[0009] Furthermore, the synthesis of 6-fluoronicotinic acid specifically includes the following steps:

[0010] S1, the substituted methyl methacrylate (compound I) was dissolved in an organic solvent, and a first additive and a fluorinating agent were added to obtain a mixed solution. The mixture was then heated to completion. 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 give compound II.

[0011] S2, compound II was dissolved in an organic solvent, and a second additive was added to obtain a reaction solution. A reducing agent was added to the reaction solution under low temperature conditions, and the reaction was allowed to proceed to completion under low temperature conditions. After the mixed solution was brought to room temperature, an acidic aqueous solution was slowly added to quench the reaction, and then the mixture was extracted with an organic solvent to obtain compound III.

[0012] S3, compound III, 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 the crude product of 6-fluoronicotinic acid.

[0013] Furthermore, the crude product can be purified by vacuum distillation to obtain high-purity 6-fluoronicotinic acid.

[0014] 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.

[0015] Optionally, the substituted strychnine (compound I) used in step S1 is selected from either 6-chlorostrychnine (CAS: 200428-13-3) or 6-bromostrychnine (CAS: 1352489-08-7).

[0016] Optionally, the organic solvent used in step S1 may be at least one of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, sulfolane, N-methylpyrrolidone, tetrahydrofuran, and acetonitrile; preferably, the organic solvent used in the reaction is dimethyl sulfoxide.

[0017] Optionally, the first additive used in step S1 may be tetramethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetraphenylphosphonium chloride, tetraphenylphosphonium bromide, 18-crown ether-6, or no additive is required; preferably, the first additive used in the reaction is tetraphenylphosphonium chloride.

[0018] Optionally, the fluorinating agent used in step S1 may be at least one of potassium fluoride, cesium fluoride, tetrabutylammonium fluoride, and tetramethylammonium fluoride; preferably, the fluorinating agent used in the reaction is potassium fluoride.

[0019] Optionally, the heating temperature in step S1 is 80-180℃.

[0020] Optionally, the molar ratio of compound I, the first additive, and the fluorinating reagent added in step S1 is 1.0:0.1-1.0:1.0-3.0.

[0021] Optionally, the organic solvent used in step S2 may be at least one of tetrahydrofuran, methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, and water; preferably, the organic solvent used in the reaction is methanol.

[0022] Optionally, the reducing agent used in step S2 may be at least one of sodium borohydride, lithium borohydride, potassium borohydride, magnesium borohydride, calcium borohydride, lithium aluminum hydride, sodium cyanoborohydride, sodium triethylborohydride, and sodium triacetoxyborohydride; preferably, the reducing agent used in the reaction is sodium borohydride.

[0023] Optionally, the second additive used in step S2 may be at least one of formic acid, acetic acid, propionic acid, calcium chloride, lithium chloride, and magnesium chloride; preferably, the second additive used in the reaction is acetic acid.

[0024] Optionally, the temperature of the low-temperature reaction in step S2 is -40 to 10°C; preferably, the temperature of the low-temperature reaction is 0°C.

[0025] Optionally, the molar ratio of compound II, the second additive, and the reducing agent added in step S2 is 1.0:1.2-30:1.0-2.5.

[0026] Optionally, the heating temperature in step S3 is 70-100℃; preferably, the heating temperature is 80℃.

[0027] Optionally, in step S3, the addition ratio of compound I, formic acid, and formaldehyde aqueous solution is 1.0g:0.5-0.8g:0.6-1.0g.

[0028] Optionally, the organic solvent used in the extraction step of step S3 may be at least one of dichloromethane or ethyl acetate.

[0029] In summary, this application has the following beneficial effects:

[0030] The method for synthesizing 6-fluoronicotinic acid disclosed in this application is simple to operate, safe and reliable, with high yield and low cost; using a substituted mascara (compound I) as the starting material, the purity of the 6-fluoronicotinic acid obtained can reach over 99.0%. Attached Figure Description

[0031] Figure 1 is a schematic diagram of the synthesis route of the preparation method of this application;

[0032] Figure 2 is the LC-MS spectrum of the final product obtained in Example 1 of this application;

[0033] Figure 3 is the 1H NMR spectrum of the final product obtained in Example 1 of this application.

[0034] Figure 4 is the carbon NMR spectrum of the final product obtained in Example 1 of this application.

[0035] Figure 5 is the NMR fluorine spectrum of the final product obtained in Example 1 of this application. Detailed Implementation

[0036] 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.

[0037] Examples 1-10 provide a method for synthesizing 6-fluoronicotinic acid, and the following description uses Example 1 as an example.

[0038] Example 1:

[0039] Step S1: In a 1L round-bottom flask, add 45.0 g (0.2 mol, 1.0 eq) of 6-bromomasmin, 0.5 g (0.02 mol, 0.1 eq) of tetraphenylphosphonium chloride, 23.2 g of potassium fluoride (0.4 mol, 2.0 eq), and 225 mL of dimethyl sulfoxide to obtain a mixed solution. Heat to 150 °C and react for 24 hours. After the reaction is completed by TLC monitoring, the mixed solution is returned to room temperature, and the pH is adjusted to 8 by adding saturated sodium carbonate solution. Extract with 300 mL of difluoromethane, and remove the solvent by vacuum distillation of the organic phase to obtain 26.3 g of compound II.

[0040] Step S2: Compound II obtained in step S1 was mixed with 9.6 g of acetic acid (0.16 mol, 0.1 eq) and 200 mL of anhydrous methanol to obtain a mixed solution. The solution was then cooled to 0 °C, and 6.7 g (0.18 mol, 1.1 eq) of sodium borohydride was added. The mixture was stirred for 2 hours. After the reaction was completed by TLC monitoring, the mixed solution was brought back to room temperature, and the reaction was quenched with dilute hydrochloric acid (1.0 M solution). The mixture was extracted with 300 mL of dichloromethane, and the organic phase was distilled under reduced pressure to remove the solvent, yielding 24.5 g of compound III.

[0041] Step S3: Compound III obtained in step S1 was mixed with 40% aqueous formaldehyde solution (200g) and formic acid (19.6g), and heated to 80℃ 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. Extraction was performed using 300mL of dichloromethane, and the solvent was removed by vacuum distillation of the organic phase to obtain crude 6-fluoronicotinic acid. The crude 6-fluoronicotinic acid was then subjected to vacuum distillation at 120℃ and 0.1kPa, and the middle fraction was collected to obtain 21.6g of high-purity 6-fluoronicotinic acid. The overall yield of the three steps was 66%, with a purity of 99.0%.

[0042] The 6-fluoronicotinic acid obtained in Example 1 was detected by LC-MS and NMR. The results are shown in Figures 2, 3, 4 and 5. The specific detection data are as follows:

[0043] LC-MS: [M+H] + The m / z value is 181.11, consistent with the theoretical value of 181.23.

[0044] 1 H NMR (400MHz, d6-DMSO) δ8.12 (d, H-6), 7.91 (m, H-4), 7.12 (dd, 3 J H-F =4.0Hz, H-3), 3.14 (m, 2H), 2.25 (t, J = 8.0, 1H), 2.18 (m, 1H), 2.04 (s, 3H), 1.81-1.78 (m, 1H), 1.77-1.67 (m, 1H), 1.60-1.51 (m, 1H).

[0045] 13 C NMR (100MHz, d6-DMSO) δ163.5(d, 1 J C-F =233Hz,C-2),109.5(d, 2 J C-F =37Hz,C-3),140.8(d, 2 J C-F=8Hz,C-4),130.7(d, 4 J C-F =5Hz,C-5),146.3(d, 3 J C-F =15Hz,C-6),66.9(CN),56.2(CN),39.8(CH3),34.9(CH2),22.1(CH2);

[0046] 19 F NMR (376MHz, d6-DMSO) δ-71.44 (s, 1F).

[0047] The above values ​​are consistent with the theoretical values ​​for 6-fluoronicotinic acid. Therefore, the finished product obtained according to the method of this application is 6-fluoronicotinic acid.

[0048] 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.

[0049] The difference between Examples 2 and 3 and Example 1 is that the type of fluorinating reagent used in step S1 is different. The specific results are shown in Table 1.

[0050] Table 1. Effects of different types of fluorinating agents on the final product in step S1.

[0051] The difference between Examples 4 and 5 and Example 1 is that the type of first additive used in step S1 is different. The specific results are shown in Table 2.

[0052] Table 2 shows the effect of different types of first additives on the final product in step S1.

[0053] The difference between Examples 6 and 7 and Example 1 is that the types of organic solvents used in step S1 are different. The specific results are shown in Table 3.

[0054] Table 3 shows the effect of different types of organic solvents on the final product in step S1.

[0055] The difference between Examples 8-10 and Example 1 is that the type of reducing reagent used in step S2 is different. The specific results are shown in Table 4.

[0056] Table 4. Effects of different types of reducing agents on the final product in step S2.

[0057] 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.

[0058] 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 method for preparing 6-fluoronicotinic acid, characterized in that, Its synthetic route is as follows: S1, the (compound I) Compound II is generated through a reaction with a fluorinating reagent. S2, the (compound II) Compound III is generated through a reducing agent reaction. pass; S3, the (compound III) 6-Fluoronic acid is generated via aminomethylation. Where X is chlorine or bromine.

2. The method for preparing 6-fluoronicotinic acid according to claim 1, characterized in that, In S1, the substituted mesmin (compound I) is dissolved in an organic solvent, and a fluorinating agent and a first additive are added to obtain a mixed solution. The mixture is then heated to complete the reaction. 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 compound II. In step S2, compound II is dissolved in an organic solvent, and a second 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 the mixture is extracted with an organic solvent to obtain compound III. In step S3, compound III, formic acid, and an aqueous formaldehyde solution are mixed to obtain a mixed solution, which is then reacted completely 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 the crude product of 6-fluoronicotinic acid.

3. The method for synthesizing 6-fluoronicotinic acid according to claim 2, characterized in that, The organic solvent used in step S1 may be at least one of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, sulfolane, N-methylpyrrolidone, tetrahydrofuran, and acetonitrile.

4. The method for synthesizing 6-fluoronicotinic acid according to claim 3, characterized in that, In step S1, a first additive is added simultaneously with the fluorinating agent. The first additive may be at least one of tetramethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetraphenylphosphonium chloride, tetraphenylphosphonium bromide, and 18-crown ether-6.

5. The method for synthesizing 6-fluoronicotinic acid according to claim 4, characterized in that, The fluorinating agent used in step S1 can be at least one of potassium fluoride, cesium fluoride, tetrabutylammonium fluoride, and tetramethylammonium fluoride.

6. The method for synthesizing 6-fluoronicotinic acid according to claim 5, characterized in that, The heating temperature in step S1 is 80-180℃.

7. The method for synthesizing 6-fluoronicotinic acid according to claim 6, characterized in that, In step S1, the molar ratio of compound I, the first additive, and the fluorinating reagent is 1.0:0.1-1.0:1.0-3.

0.

8. The method for synthesizing 6-fluoronicotinic acid according to any one of claims 2-7, characterized in that, The organic solvent used in step S2 may be at least one of tetrahydrofuran, methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, or water.

9. The method for synthesizing 6-fluoronicotinic acid according to claim 8, characterized in that, The reducing agent used in step S2 may be at least one of sodium borohydride, lithium borohydride, potassium borohydride, magnesium borohydride, calcium borohydride, lithium aluminum hydride, sodium cyanoborohydride, sodium triethylborohydride, and sodium triacetoxyborohydride.

10. The method for synthesizing 6-fluoronicotinic acid according to claim 9, characterized in that, The second additive used in step S2 can be at least one of formic acid, acetic acid, propionic acid, calcium chloride, lithium chloride, and magnesium chloride.

11. The method for synthesizing 6-fluoronicotinic acid according to claim 10, characterized in that, The temperature of the low-temperature reaction in step S2 is -40 to 10°C.

12. The method for synthesizing 6-fluoronicotinic acid according to claim 11, characterized in that, In step S2, the molar ratio of compound II, the second additive, and the reducing agent is 1.0:1.2-30:1.0-2.

5.

13. The method for synthesizing 6-fluoronicotinic acid according to any one of claims 9-12, characterized in that, The heating temperature in step S3 is 70-100℃.

14. The method for synthesizing 6-fluoronicotinic acid according to claim 13, characterized in that, In step S3, the addition ratio of compound I, formic acid, and formaldehyde aqueous solution is 1.0g:0.5-0.8g:0.6-1.0g.

15. The method for synthesizing 6-fluoronicotinic acid according to claim 14, characterized in that, The organic solvent used in the extraction step S3 can be at least one of dichloromethane or ethyl acetate.

16. The method for synthesizing 6-fluoronicotinic acid according to claim 14 or 15, characterized in that, The crude product was purified by vacuum distillation to obtain high-purity 6-fluoronicotinic acid.

17. A 6-fluoronicotinic acid, characterized in that, It is prepared by the method described in claims 1-16.

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