Preparation method of 6-fluoronicotine

Abstract

The invention relates to the field of organic chemical synthesis, in particular to a synthesis method of 6-fluoronicotine. The invention provides a synthesis method of 6-fluoronicotine, which comprises the following steps: by taking a myomine substituent (compound I) as an initial raw material, sequentially carrying out fluorination reaction, reduction reaction and amine methylation reaction to finally obtain the target product 6-fluoronicotine. Through the synthetic route, the 6-fluoronicotine can be obtained, and the product purity can reach 99.0% or above. The synthesis method is simple in process, high in yield and suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention relates to the field of organic chemical synthesis, and in particular to a method for synthesizing 6-fluoronicotine. Background Art

[0002] At present, the treatment of central nervous system diseases has received extensive research attention, especially the role of acetylcholine receptors. Nicotine and its related alkaloids, as acetylcholine receptor agonists, have shown significant potential in the treatment of neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD) and Tourette's syndrome. However, the common high toxicity and addiction of nicotine limit its wide application in clinical practice. Therefore, it is urgent to develop highly active and low-toxic nicotine analogs to meet clinical needs. Past studies have shown that some nicotine derivatives have certain acetylcholine binding ability, especially 6-substituted nicotine derivatives show good biological activity. It is worth noting that the highly lipid-soluble 6-fluoronicotine not only has the ability to bind to acetylcholine receptors, but also can be converted into other compounds with potential therapeutic effects through chemical reactions. Therefore, 6-fluoronicotine has important research value and clinical application prospects in the treatment of nervous system diseases.

[0003] 6-Fluoronicotine is not a naturally occurring substance, so it can only be prepared by chemical synthesis. The main method for synthesizing 6-fluoronicotine known so far is to convert nicotine into 6-aminonicotine, and then synthesize 6-fluoronicotine through a diazotization reaction, referring to the European Journal of Medicinal Chemistry, 1996, 31, 875–888. However, this reaction requires a high temperature of 120-150°C, and the diazotization reaction is highly dangerous, making it unsuitable for large-scale production.

[0004] In summary, the existing 6-fluoronicotine synthesis method cannot meet the demand for 6-fluoronicotine synthesis, so it is necessary to develop a synthesis route for 6-fluoronicotine. Summary of the invention

[0005] In view of the many shortcomings of the current methods for synthesizing 6-fluoronicotine, the present invention discloses a method for synthesizing 6-fluoronicotine, using 6-chloromycamine or 6-bromomycamine as a raw material to prepare high-purity active 6-fluoronicotine. In this route, compound I is first converted into compound II through a fluorination reaction, a reduction reaction and an amine methylation reaction, and finally the target product 6-fluoronicotine is obtained. The final product has a definite structure and fluorine substitution site selectivity, a high yield, simple operation, and can be used for industrial production.

[0006] The present invention provides a method for synthesizing 6-fluoronicotine, which is achieved by the following technical scheme:

[0007] Using myosamine substitution (Compound I) as the starting material, fluorination reaction, reduction reaction and amine methylation reaction are carried out in sequence to finally obtain the target product 6-fluoronicotine. The synthetic route is shown in the following formula:

[0008]

[0009] Wherein X is chlorine or bromine.

[0010] Furthermore, the synthesis of 6-fluoronicotine specifically comprises the following steps:

[0011] S1, the myosmine substitute (compound I) is dissolved in an organic solvent, a first additive and a fluorination agent are added to obtain a mixed solution, and then the mixture is 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 compound II.

[0012] S2, dissolving compound II in an organic solvent, adding a second additive to obtain a reaction solution, adding a reducing agent to the reaction solution under low temperature conditions, and then reacting completely under low temperature conditions. After the mixed solution is warmed to room temperature, slowly adding an acidic aqueous solution to quench the reaction, and then extracting with an organic solvent to obtain compound III.

[0013] S3, compound III, formic acid, and formaldehyde aqueous solution are mixed to obtain a mixed solution, and then the mixture is 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 a crude product of 6-fluoronicotine.

[0014] Furthermore, the crude product is purified by vacuum distillation to obtain high-purity 6-fluoronicotine.

[0015] The synthesis method is simple to operate, safe and reliable, has a high yield and low cost, and the purity of the product can be as high as over 99.0%.

[0016] Optionally, the myosamine substitute (compound I) used in step S1 is selected from any one of 6-chloromyosamine (cas: 200428-13-3) and 6-bromomyosamine (cas: 1352489-08-7).

[0017] Optionally, the organic solvent used in step S1 can be selected from 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.

[0018] Optionally, the first additive used in step S1 may be tetramethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetraphenylphosphonium chloride, tetraphenylphosphonium bromide, 18-crown-6, or no additive is required; preferably, the first additive used in the reaction is tetraphenylphosphonium chloride.

[0019] Optionally, the fluorination agent used in step S1 can be at least one of potassium fluoride, cesium fluoride, tetrabutylammonium fluoride, and tetramethylammonium fluoride; preferably, the fluorination agent used in the reaction is potassium fluoride.

[0020] Optionally, the temperature of the heating reaction in step S1 is 80-180°C.

[0021] Optionally, the molar ratio of compound I, the first additive and the fluorination agent added in step S1 is 1.0:0.1-1.0:1.0-3.0.

[0022] 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.

[0023] Optionally, the reducing agent used in step S2 can be at least one of sodium borohydride, lithium borohydride, potassium borohydride, magnesium borohydride, calcium borohydride, lithium aluminum tetrahydride, sodium cyanoborohydride, sodium triethylborohydride, and sodium triacetoxyborohydride; preferably, the reducing agent used in the reaction is sodium borohydride.

[0024] Optionally, 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; preferably, the second additive used in the reaction is acetic acid.

[0025] 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.

[0026] 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.

[0027] Optionally, the temperature of the heating reaction in step S3 is 70-100°C; preferably, the temperature of the heating reaction is 80°C.

[0028] 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.

[0029] Optionally, the organic solvent used in the extraction step in step S3 may be at least one of dichloromethane and ethyl acetate.

[0030] In summary, this application has the following beneficial effects:

[0031] The 6-fluoronicotine synthesis method involved in the present application is simple to operate, safe and reliable, with high yield and low cost; using myosamine substitute (compound I) as a starting material, the 6-fluoronicotine that can be obtained can have a product purity of more than 99.0%. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 It is a schematic diagram of the synthetic route of the preparation method of the present application;

[0033] Figure 2 is the LC-MS spectrum of the final product obtained in Example 1 of the present application;

[0034] Figure 3 This is the H NMR spectrum of the final product obtained in Example 1 of the present application.

[0035] Figure 4 This is the NMR carbon spectrum of the final product obtained in Example 1 of the present application.

[0036] Figure 5 This is the NMR fluorine spectrum of the final product obtained in Example 1 of the present application. DETAILED DESCRIPTION

[0037] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0038] Embodiments 1-10 provide a method for synthesizing 6-fluoronicotine, which will be specifically described below using Embodiment 1 as an example.

[0039] Embodiment 1:

[0040] Step S1: 45.0 g (0.2 mol, 1.0 eq) of 6-bromomysamine, 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 were added to a 1 L round-bottom flask to obtain a mixed solution, which was heated to 150° C. for 24 hours. After the reaction was completed by TLC monitoring, the mixed solution was restored to room temperature, a saturated sodium carbonate solution was added to adjust the pH to 8, and 300 mL of difluoromethane was used for extraction. The organic phase was distilled under reduced pressure to remove the solvent to obtain 26.3 g of compound II.

[0041] Step S2: Compound II obtained in step S1, 9.6 g of acetic acid (0.16 mol, 0.1 eq) and 200 mL of anhydrous methanol were added to obtain a mixed solution, which was then cooled to 0°C, and 6.7 g (0.18 mol, 1.1 eq) of sodium borohydride was added and stirred for 2 hours. After the reaction was completed by TLC monitoring, the mixed solution was returned to room temperature, and dilute hydrochloric acid (1.0 M solution) was added to quench the reaction, and 300 mL of dichloromethane was used for extraction, and the organic phase was distilled under reduced pressure to remove the solvent to obtain 24.5 g of compound III.

[0042] Step S3: Compound III obtained in step S1 is added with formaldehyde aqueous solution (40%, 200 g) and formic acid (19.6 g) and mixed evenly, and then heated to 80°C for reaction for 4 hours. After the reaction is completed by TLC monitoring, the mixed solution is restored to room temperature, saturated sodium carbonate solution is added to adjust the pH to 8, 300 mL of dichloromethane is used for extraction, and the organic phase is distilled under reduced pressure to remove the solvent to obtain crude 6-fluoronicotine. The crude 6-fluoronicotine is distilled under reduced pressure at 120°C and 0.1 kPa, and the intermediate fractions are collected to obtain 21.6 g of high-purity 6-fluoronicotine, with a total yield of 66% in 3 steps and a purity of 99.0%.

[0043] The 6-fluoronicotine obtained in Example 1 was subjected to LC-MS and NMR detection, and the results obtained were as follows: Figure 2 , Figure 3 , Figure 4 and Figure 5 The specific test data are as follows:

[0044] LC-MS: [M+H] + The m / z is 181.11, which is consistent with the theoretical value of 181.23.

[0045] 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).

[0046] 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);

[0047] 19 F NMR (376MHz, d6-DMSO) δ-71.44 (s, 1F).

[0048] The above values ​​are consistent with the theoretical values ​​of 6-fluoronicotine. Therefore, it can be concluded that the finished product obtained according to the method of the present application is 6-fluoronicotine.

[0049] It is worth noting that the masses and specific molar amounts in the examples of the present application can be selected according to the size of the container for industrial production, and it is only necessary to keep the equivalent ratio between the reaction raw materials consistent.

[0050] The difference between Examples 2 and 3 and Example 1 is that the types of fluorination reagents used in step S1 are different. The specific results are shown in Table 1.

[0051] Table 1 Effects of different types of fluorination reagents on the final product in step S1

[0052] serial number reducing agent Total yield Example 2 Cesium fluoride 66％ Example 3 Tetramethylammonium fluoride 68％

[0053] Embodiments 4 and 5 are different from Embodiment 1 in that the types of the first additive used in step S1 are different. The specific results are shown in Table 2.

[0054] Table 2 Effects of different types of first additives in step S1 on the final product

[0055] serial number First Additive Total yield Example 4 Tetramethylammonium chloride 54％ Example 5 Tetrabutylammonium chloride 44％

[0056] 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.

[0057] Table 3 Effects of different types of organic solvents in step S1 on the final product

[0058] serial number Organic solvents Total yield Example 6 N,N-Dimethylformamide 60％ Example 7 Sulfolane 64％

[0059] The difference between Examples 8-10 and Example 1 is that the types of reducing agents used in step S2 are different. The specific results are shown in Table 4.

[0060] Table 4 Effects of different types of reducing agents on the final product in step S2

[0061] serial number Reducing reagent Total yield Example 8 Sodium cyanoborohydride 65％ Example 9 Lithium borohydride 64％ Example 10 Lithium Aluminum Tetrahydrogen 52％

[0062] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described 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.

[0063] The above-described embodiments are merely explanations of the present application and are not limitations of the present application. After reading this specification, those skilled in the art may make modifications to the embodiments without any creative contribution as needed. However, as long as they are within the scope of the claims of the present application, they are protected by the patent law.

Claims

1. A method for preparing 6-fluoronicotine, characterized in that: Its synthetic route is as follows: S1, said (compound I) The fluorination reagent is used to generate (compound II) S2, said (compound II) Reduction reaction generates (Compound III) pass; S3, said (compound III) Generation of 6-fluoronicotine by amine methylation Wherein, X is chlorine or bromine.

2. The method for preparing 6-fluoronicotine according to claim 1, characterized in that: The myosmine substitute (Compound I) in S1 is dissolved in an organic solvent, a fluorination agent and a first additive are added to obtain a mixed solution, and then the mixture is 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 Compound II; In S2, compound II is dissolved in an organic solvent, a second additive is added to obtain a reaction solution, a reducing agent is added to the reaction solution under low temperature conditions, and then 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 III; In S3, compound III, formic acid and formaldehyde aqueous solution are mixed to obtain a mixed solution, and then the mixture is 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 a crude product of 6-fluoronicotine.

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

4. The method for synthesizing 6-fluoronicotine according to claim 3, characterized in that: The first additive is added simultaneously with the fluorination reagent used in step S1, and the first additive can be selected from at least one of tetramethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetraphenylphosphonium chloride, tetraphenylphosphonium bromide, and 18-crown-6.

5. The method for synthesizing 6-fluoronicotine according to claim 4, characterized in that: The fluorination agent used in step S1 may be at least one of potassium fluoride, cesium fluoride, tetrabutylammonium fluoride and tetramethylammonium fluoride.

6. The method for synthesizing 6-fluoronicotine according to claim 5, characterized in that: The temperature of the heating reaction in step S1 is 80-180°C.

7. The method for synthesizing 6-fluoronicotine according to claim 6, characterized in that: The molar ratio of compound I, the first additive and the fluorination agent added in step S1 is 1.0:0.1-1.0:1.0-3.

0.

8. The method for synthesizing 6-fluoronicotine according to any one of claims 2 to 7, characterized in that: The organic solvent used in step S2 can be selected from at least one of tetrahydrofuran, methanol, ethanol, isopropanol, ethyl acetate, dichloromethane and water.

9. The method for synthesizing 6-fluoronicotine 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 tetrahydride, sodium cyanoborohydride, sodium triethylborohydride, and sodium triacetoxyborohydride.

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

11. The method for synthesizing 6-fluoronicotine 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-fluoronicotine according to claim 11, characterized in that: 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.

13. The method for synthesizing 6-fluoronicotine according to any one of claims 9 to 12, characterized in that: The temperature of the heating reaction in step S3 is 70-100°C.

14. The method for synthesizing 6-fluoronicotine according to claim 13, characterized in that: In the 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-fluoronicotine according to claim 14, characterized in that: The organic solvent used in the extraction step in step S3 may be at least one of dichloromethane and ethyl acetate.

16. The method for synthesizing 6-fluoronicotine according to claim 14 or 15, characterized in that: The crude product is purified by a reduced pressure distillation method to obtain high-purity 6-fluoronicotine.

17. A 6-fluoronicotine, characterized in that The method is prepared by the method described in claims 1 to 16.

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