Preparation method of 6-chloronicotine

Abstract

The invention relates to the field of organic chemical synthesis, in particular to a synthesis method of 6-chloronicotine. The invention provides a synthesis method of 6-chloronicotine, which comprises the following steps: taking 6-hydroxysmin (CAS: 70969-38-9) as an initial raw material, and sequentially carrying out reduction reaction, aminomethylation reaction and chlorination reaction to finally obtain the target product 6-chloronicotine. Through the synthetic route, the 6-chloronicotine can be obtained, and the product purity can reach 99.5% 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-chloronicotinamide. Background Art

[0002] At present, the treatment of central nervous system diseases has aroused extensive research interest, among which the role of acetylcholine receptors in this field has attracted much attention. Nicotine, as an acetylcholine receptor agonist, 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, the common side effects of nicotine limit its widespread use in clinical applications. Therefore, it has become an urgent need to find acetylcholine receptor ligands with high selectivity and safety to open up new drug treatment pathways. Past studies have shown that some nicotine derivatives have certain acetylcholine binding ability, especially 6-substituted nicotine derivatives show good biological activity. Among them, 6-chloronicotine is a nicotine derivative worthy of attention, which can not only bind to acetylcholine receptors, but also be converted into other potentially therapeutic compounds through chemical reactions. Therefore, 6-chloronicotine has important research value and clinical prospects in the treatment of nervous system diseases.

[0003] 6-Chloronicotine is not a naturally occurring substance, so it can only be prepared through chemical synthesis. There are currently two main known methods for synthesizing 6-chloronicotine. The first method is to convert nicotine into a lithium reagent, and then synthesize 6-chloronicotine by electrophilic substitution. However, this reaction requires the use of strong bases such as butyl lithium and a low temperature environment of -70°C, which is not suitable for large-scale production. The second method is to first convert nicotine into 6-aminonicotine, and then synthesize 6-chloronicotine through a diazotization reaction. However, this reaction requires a high temperature of 130-170°C, and the diazotization reaction is highly dangerous and is not suitable for large-scale production.

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

[0005] In view of the many shortcomings of the current methods for synthesizing 6-chloronicotine, the present invention discloses a method for synthesizing 6-chloronicotine, using 6-hydroxymysmine (CAS: 70969-38-9) as a raw material to prepare high-purity active 6-chloronicotine. In this route, 6-hydroxymysmine is first converted into compound I through a reduction reaction, an amine methylation reaction and a chlorination reaction, and finally the target product 6-chloronicotine is obtained. The final product has a definite structure and chlorine 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-chloronicotinamide, which is achieved by the following technical scheme:

[0007] Using 6-hydroxymysamine as the starting material, the target product 6-chloronicotinamide is finally obtained through reduction reaction, aminomethylation reaction and chlorination reaction. The synthetic route is shown in the following formula:

[0008]

[0009] Further, the synthesis of 6-chloronicotinamide specifically comprises the following steps:

[0010] S1, 6-hydroxymycamine is dissolved in an organic solvent, an 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 warmed 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.

[0011] S2, compound I, 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 compound II.

[0012] S3, compound II, a chlorination agent and an organic solvent 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-chloronicotine. The crude product is purified by a reduced pressure distillation method to obtain high-purity 6-chloronicotine.

[0013] 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 99.5%.

[0014] Optionally, the organic solvent used in the reaction 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.

[0015] Optionally, 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; preferably, the additive used in the reaction is acetic acid.

[0016] Optionally, the reducing agent used in step S1 can be at least one of sodium borohydride, lithium borohydride, lithium aluminum tetrahydride, sodium cyanoborohydride, sodium triethylborohydride, and sodium triacetoxyborohydride; preferably, the reducing agent used in the reaction is sodium borohydride.

[0017] 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.

[0018] Optionally, the molar ratio of 6-hydroxymysamine, additive and reducing agent added in step S1 is 1.0:0.1-30:1.0-2.5.

[0019] Optionally, the temperature of the heating reaction in step S2 is 60-90°C.

[0020] Optionally, in step S2, the addition ratio of compound I, formic acid and formaldehyde aqueous solution is 1.0g:0.5-0.8g:0.6-1.0g.

[0021] Optionally, the organic solvent used in the reaction in step S3 can be selected from at least one of acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dichloroethane, chlorobenzene, dichloromethane, and ethyl acetate; preferably, the organic solvent used in the reaction is acetonitrile.

[0022] Optionally, the chlorination reagent used in the reaction in step S3 is selected from at least one of thionyl chloride, phosphorus oxychloride, carbon tetrachloride, sulfonyl chloride, N-chlorosuccinimide, and phosphorus pentachloride; preferably, the chlorination reagent used in the reaction is phosphorus oxychloride.

[0023] Optionally, the temperature of the heating reaction in step S3 is 70-100°C; preferably, the temperature of the heating reaction is 80°C.

[0024] Optionally, the molar ratio of compound II and chlorination reagent added in step S3 is 1:1-30.

[0025] Optionally, the extraction solvent used in the reaction in step S3 is dichloromethane and ethyl acetate; preferably, the organic solvent used in the reaction is dichloromethane.

[0026] In summary, this application has the following beneficial effects:

[0027] The 6-chloronicotinamide synthesis method involved in the present application is simple to operate, safe and reliable, with high yield and low cost; using 6-hydroxymysamine as a starting material, the 6-chloronicotinamide that can be obtained has a product purity of more than 99.5%. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 It is a schematic diagram of the synthetic route of the preparation method of the present application;

[0029] Figure 2 is the LC-MS spectrum of the final product obtained in Example 1 of the present application;

[0030] Figure 3 This is the H NMR spectrum of the final product obtained in Example 1 of the present application. DETAILED DESCRIPTION

[0031] 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.

[0032] Embodiments 1-10 provide a method for synthesizing 6-chloronicotinamide, which will be specifically described below using Embodiment 1 as an example.

[0033] Embodiment 1:

[0034] Step S1: Add 32.4 g (0.2 mol, 1.0 eq) of 6-hydroxymysamine, 3.0 g of acetic acid (0.02 mol, 0.1 eq) and 400 mL of anhydrous methanol to a 1 L round-bottom flask to obtain a mixed solution, then cool to 0°C, add 8.3 g (0.22 mol, 1.1 eq) of sodium borohydride, and stir for 2 hours. After the reaction is completed by TLC monitoring, the mixed solution is restored to room temperature, and dilute hydrochloric acid (1.0 M solution) is added to quench the reaction, and 300 mL of dichloromethane is used for extraction, and the organic phase is distilled under reduced pressure to remove the solvent to obtain compound I.

[0035] Step S2: Compound I obtained in step S1 was added with formaldehyde aqueous solution (40%, 26.0 g) and formic acid (20.0 g), mixed evenly, and heated to 80°C for 4 hours. After the reaction was completed by TLC monitoring, the mixed solution was returned to room temperature, saturated sodium carbonate solution was added to adjust the pH to 8, extracted with 300 mL of dichloromethane, and the organic phase was distilled under reduced pressure to remove the solvent to obtain compound II.

[0036] Step S3: Add compound II obtained in step S2 to a 500mL round-bottom flask, and then add 200mL acetonitrile and phosphorus oxychloride (0.6mol, 3.0eq) to obtain a mixed solution. After the mixed solution is heated to 80°C, stir and react for 2 hours. After the reaction is completed by TLC monitoring, the mixed solution returns to room temperature, the solvent is removed by vacuum distillation, the saturated sodium carbonate solution is adjusted to pH 8, and then extracted twice with 300mL dichloromethane. Combine the organic phases, remove the solvent by vacuum distillation, and obtain crude 6-chloronicotine. The crude 6-chloronicotine is vacuum distilled at 120°C and 0.1kPa, and the intermediate fractions are collected to obtain 21.6g of high-purity 6-chloronicotine, with a total yield of 54% and a purity of 99.5% in 3 steps.

[0037] The 6-chloronicotinamide obtained in Example 1 was subjected to LC-MS and NMR detection, and the results obtained were as follows: Figure 2 and Figure 3 The specific test data are as follows:

[0038] LC-MS: M+H + ,[197.08]:[199.07]=3:1, which is consistent with the theoretical value.

[0039] 1 H NMR (400MHz, CDCl3) δ8.30 (d, J = 2.0Hz, 1H), 7.68 (dd, J = 8.4, 2.2Hz, 1H), 7.29 (d, J = 2.0Hz, 1H), 3.23 (m, 1H), 3.09 (t, J = 8.0, 1H), 2.31 (m, 2H), 2.16 (s, 3H), 2.01-1.91 (m, 1H), 1.90-1.78 (m, 1H), 1.72-1.64 (m, 1H), the above values ​​are consistent with the theoretical values ​​of 6-chloronicotine. It can be obtained that the finished product prepared according to the method of this application is 6-chloronicotine.

[0040] 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.

[0041] The difference between Examples 2 and 3 and Example 1 is that the types of reducing agents used in step S1 are different. The specific results are shown in Table 1.

[0042] Table 1 Effects of different types of reducing agents on the final product in step S1

[0043] serial number reducing agent Total yield Example 2 Sodium cyanoborohydride 58％ Example 3 Lithium Aluminum Tetrahydrogen 48％

[0044] The difference between Examples 4 and 5 and Example 1 is that the types of additives used in step S1 are different. The specific results are shown in Table 2.

[0045] Table 2 Effects of different types of additives in step S1 on the final product

[0046] serial number additive Total yield Example 4 Propionic acid 54％ Example 5 Lithium chloride 38％

[0047] The difference between Examples 6-8 and Example 1 is the type and amount of the chlorination reagent in step S3. The specific results are shown in Table 3.

[0048] Table 3 Effects of different types and amounts of chlorination reagents on the final product in step S3

[0049] serial number Chlorination reagent Dosage (eq) Total yield Example 6 Phosphorus oxychloride 2.0 49％ Example 7 Phosphorus oxychloride 10.0 59％ Example 8 Phosphorus pentachloride 2.0 64％

[0050] The difference between Examples 9 and 10 and Example 1 is that the types of organic solvents used in step S3 are different. The specific results are shown in Table 4.

[0051] Table 4 Effects of different types of organic solvents on the final product in step S3

[0052] serial number Organic solvents Total yield Example 9 1,2-Dichloroethane 50％ Example 10 chlorobenzene 48％

[0053] 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.

[0054] 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-chloronicotinamide, characterized in that: It contains the following steps: 6-hydroxymysamine As the starting material, it is successively reduced by S1 to obtain (Compound I), S2 amine methylation reaction to obtain (Compound II), and S3 chlorination reaction to finally obtain the target product 6-chloronicotinamide 2. The method for preparing 6-chloronicotinamide according to claim 1, characterized in that: In step S1, 6-hydroxymycamine (CAS: 70969-38-9) is dissolved in an organic solvent, an 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 I; In step S2, compound I, 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 compound II; In step S3, compound II, a chlorination agent and an organic solvent 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-chloronicotinamide.

3. The method for synthesizing 6-chloronicotinamide according to claim 2, characterized in that: The organic solvent used in step S1 can be selected from at least one of tetrahydrofuran, methanol, ethanol, isopropanol, ethyl acetate, dichloromethane and water.

4. The method for synthesizing 6-chloronicotinamide according to claim 3, characterized in that: 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.

5. The method for synthesizing 6-chloronicotinamide according to claim 4, characterized in that: The reducing agent used in step S1 may be at least one of sodium borohydride, lithium borohydride, lithium aluminum tetrahydride, sodium cyanoborohydride, sodium triethylborohydride, and sodium triacetoxyborohydride.

6. The method for synthesizing 6-chloronicotinamide 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-chloronicotinamide according to claim 6, characterized in that: The molar ratio of 6-hydroxymysamine, additive and reducing agent added in step S1 is 1.0:0.1-30:1.0-2.

5.

8. The method for synthesizing 6-chloronicotinamide according to any one of claims 1 to 7, characterized in that: The temperature of the heating reaction in step S2 is 60-90°C.

9. The method for synthesizing 6-chloronicotinamide according to claim 8, characterized in that: In the step S2, the addition ratio of compound I, formic acid and formaldehyde aqueous solution is 1.0g:0.5-0.8g:0.6-1.0g.

10. The method for synthesizing 6-chloronicotinamide 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, 1,2-dichloroethane, chlorobenzene, dichloromethane and ethyl acetate.

11. The method for synthesizing 6-chloronicotinamide according to claim 10, characterized in that: The chlorination reagent used in the reaction in step S3 is selected from at least one of thionyl chloride, phosphorus oxychloride, carbon tetrachloride, sulfonyl chloride, N-chlorosuccinimide, and phosphorus pentachloride.

12. The method for synthesizing 6-chloronicotinamide according to claim 11, characterized in that: The temperature of the heating reaction in step S3 is 70-100°C.

13. The method for synthesizing 6-chloronicotinamide according to claim 12, characterized in that: In step S3, the molar ratio of compound II to the chlorination reagent is 1:1-30.

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

15. The method for preparing 6-chloronicotinamide according to any one of claims 9 to 14, characterized in that: The crude product is purified by a reduced pressure distillation method to obtain high-purity 6-chloronicotinamide.

16. A 6-chloronicotinamide, characterized in that The method is prepared by the method described in claims 1 to 15.

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