Preparation method of chiral 6-aminonicotine

Abstract

The invention relates to the field of organic chemical synthesis, in particular to a preparation method of chiral 6-amino nicotine. The invention provides a synthesis method of single chiral 6-amino nicotine, which comprises the following steps: by taking natural nicotine as an initial raw material, sequentially carrying out silanization reaction, nitro substitution reaction and reduction reaction to finally obtain the target product chiral 6-amino nicotine. Through the synthetic route, S-6-amino nicotine with a single configuration can be obtained, the product purity can reach 99.7% or above, and the optical purity is 99.5%. 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 chiral 6-aminonicotinamide. Background Art

[0002] Acetylcholine receptors play an important role in central nervous system diseases and are the focus of current medical research. Nicotine, as a well-known acetylcholine receptor agonist, has been shown to have beneficial effects in the treatment of neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD) and Tourette's syndrome. However, the various side effects of nicotine limit its application in clinical treatment. In view of this, the development of acetylcholine receptor ligands with high selectivity and good safety is crucial to expand new avenues of drug treatment. Existing studies have shown that some derivatives of nicotine have certain acetylcholine binding ability, especially 6-substituted nicotine derivatives have better overall performance in physiological activity. 6-aminonicotine is a 6-amino product of nicotine, which has the ability to bind to acetylcholine receptors and can be further converted into other nicotine derivatives through chemical reactions. It has high research value and application prospects.

[0003] 6-aminonicotine is not a naturally occurring substance, so it can only be prepared by chemical synthesis. There are two main known methods for synthesizing 6-aminonicotine. The first method is to directly aminize nicotine, but this reaction requires a high temperature of 130-170°C, and the reaction yield and regioselectivity are poor, which is not suitable for large-scale production. The second method is to first convert nicotine into 6-chloronicotine, and then synthesize 6-aminonicotine through a palladium-catalyzed coupling reaction. This method has a longer reaction route, and requires the use of a strong base and a palladium catalyst, and the material cost is relatively high.

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

[0005] In view of the many shortcomings of the current methods for synthesizing chiral 6-aminonicotine, the present invention discloses a method for synthesizing chiral 6-aminonicotine, which uses natural nicotine as a raw material to prepare 6-aminonicotine with high optical activity. In this route, nicotine is first converted into 6-nitronicotine, and then 6-aminonicotine is obtained by a nitro reduction method. The final product has a determined chiral structure and amino site selectivity, has a high yield, is simple to operate, and can be used for industrial production.

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

[0007] Using natural nicotine as the starting material, the target product chiral 6-aminonicotine is finally obtained through silylation reaction, nitro substitution reaction and reduction reaction. The synthetic route is as follows:

[0008]

[0009] Furthermore, the synthesis of chiral 6-aminonicotinamide specifically comprises the following steps:

[0010] S1, natural nicotine is dissolved in an organic solvent to obtain a reaction solution, and a base is added to the reaction solution under low temperature and inert gas protection. After low temperature reaction for 1 to 24 hours, trimethylsilyl chloride is added, and the low temperature reaction is continued for 2 to 24 hours until the reaction is complete, thereby obtaining compound I.

[0011] S2, compound I, a catalyst and a nitrating agent are dissolved in an organic solvent to obtain a mixed solution, and then the mixture is reacted completely under heating conditions. After the mixed solution is cooled to room temperature, the insoluble matter is filtered out, and the organic solvent is removed by reduced pressure distillation to obtain compound II.

[0012] S3, dissolving compound II in an organic solvent 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, a dilute hydrochloric acid solution is slowly added to quench the reaction, and then an organic solvent is used for extraction to obtain a crude product of chiral 6-aminonicotine. The crude product is purified by a reduced pressure distillation method to obtain high-purity chiral 6-aminonicotine.

[0013] By adopting the above-mentioned synthesis method and using highly optically active natural nicotine as the starting material, the subsequent use of chiral reagents to construct the chiral center in nicotine can be avoided, thereby reducing production costs. The synthesis method is simple to operate, safe and reliable, has a high yield, and low cost. The purity of the product can be as high as 99.7% or more, and the optical purity can reach 99.5% or more.

[0014] Optionally, the organic solvent used in the reaction in step S1 is dichloromethane and tetrahydrofuran; preferably, the organic solvent used in the reaction is tetrahydrofuran.

[0015] Optionally, the base used in the reaction in step S1 is n-butyl lithium, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, sodium tert-butoxide and sodium hydroxide; preferably, the base used in the reaction is sodium tert-butoxide.

[0016] Optionally, the temperature of the low temperature reaction in step S1 is -78 to -20°C; preferably, the temperature of the low temperature reaction is in the range of -78 to -40°C, with the optimal temperature being -40°C.

[0017] Optionally, the molar ratio of nicotine, trimethylsilyl chloride and base added in step S1 is 1.0:1.2-1.5:1.0-1.5.

[0018] Optionally, the nitrating agent used in the reaction in step S2 is N-nitrosaccharin, N-nitrosuccinimide and N-nitrophthalimide; preferably, the nitrating agent used in the reaction is N-nitrosaccharin.

[0019] Optionally, the temperature of the heating reaction in step S2 is 70-100°C; preferably, the temperature of the heating reaction is in the range of 70-90°C, and optimally 80°C.

[0020] Optionally, the organic solvent used in the reaction in step S2 is tetrahydrofuran and acetonitrile; preferably, the organic solvent used in the reaction is acetonitrile.

[0021] Optionally, the catalyst used in the reaction in step S2 is magnesium chloride, magnesium perchlorate and magnesium trifluoromethanesulfonate; preferably, the catalyst used in the reaction is magnesium trifluoromethanesulfonate.

[0022] Optionally, the molar ratio of the nitrating agent, catalyst and compound I added in step S2 is 1.0-1.5:0.1-0.2:1.

[0023] Optionally, the organic solvent used in the reaction in step S3 is methanol, ethanol and tetrahydrofuran.

[0024] Optionally, the reducing agent used in the extraction step in step S3 may be sodium borohydride, lithium aluminum hydride and hydrogen; preferably, the reducing agent used in the reaction is sodium borohydride.

[0025] Optionally, the molar ratio of the reducing agent added in step S3 to compound II is 1.5-3.0:1.

[0026] Optionally, the temperature of the low temperature reaction in step S3 is -40 to 0°C; preferably, the temperature of the low temperature reaction is in the range of -20 to 0°C, with 0°C being the most preferred.

[0027] Optionally, the alkali used in step S3 is sodium hydroxide or potassium hydroxide solution, and the pH value is adjusted to be greater than 8, and the most preferred pH value is 10.

[0028] 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.

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

[0030] The chiral 6-aminonicotine synthesis method involved in the present application is simple to operate, safe and reliable, with high yield and low cost; using natural nicotine as a starting material, chiral 6-aminonicotine of a single configuration can be obtained, and the optical purity can reach more than 99.5%. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 It is a schematic diagram of the synthetic route of the preparation method of the present application;

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

[0033] Figure 3 This is the H NMR spectrum of the final product obtained in Example 1 of the present application. DETAILED DESCRIPTION

[0034] 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.

[0035] Examples 1-12 provide a method for synthesizing chiral 6-aminonicotinamide, which will be specifically described below using Example 1 as an example.

[0036] Embodiment 1:

[0037] Step S1: Add 32.4g (0.2mol, 1.0eq) natural nicotine and 400mL anhydrous tetrahydrofuran to a 1L round-bottom flask to obtain a mixed solution, and then fill the flask with nitrogen for protection. After the mixed solution is cooled to -20°C, 21.1g (0.22mol, 1.1eq) sodium tert-butoxide is added, and after stirring at -20°C for 1 hour, 26.1g (0.24mol, 1.2eq) trimethylsilyl chloride is added, and the reaction is continued at -20°C for 2 hours. After the reaction is completed by TLC monitoring, the mixed solution is returned to room temperature, water is added to quench the reaction, and the organic phase is distilled under reduced pressure to remove the solvent to obtain compound I.

[0038] Step S2: Compound I obtained in step S1 was added to a 1L round-bottom flask, followed by 400mL of acetonitrile, 3.5g (0.02mol, 0.1eq) of magnesium trifluoromethanesulfonate and 59.3g (0.26mol, 1.3eq) of N-nitrosaccharin to obtain a mixed solution, which was heated to 70°C for 20 hours. After the reaction was completed by TLC monitoring, the mixed solution was returned to room temperature, insoluble impurities were removed by filtration, and the solvent was removed by distillation under reduced pressure to obtain a crude compound II.

[0039] Step S3: Add compound II obtained in step S2 to a 500mL round-bottom flask, and then add 200mL of ethanol to obtain a mixed solution. After the mixed solution is cooled to 0°C, 3.8g (0.1mol, 0.5eq) of sodium borohydride is added, and the mixture is stirred at 0°C for 5 hours. After the reaction is completed by TLC monitoring, the mixed solution returns to room temperature, is adjusted to pH=3 with a 3mol / L aqueous hydrochloric acid solution, and then 300mL of dichloromethane solution is added for extraction. The aqueous phase is retained, and the aqueous phase is adjusted to pH=10 with a 12mol / L sodium hydroxide solution, and then extracted twice with 300mL of dichloromethane. The organic phases are combined, and the solvent is removed by vacuum distillation to obtain crude S-6-aminonicotine. The crude S-6-aminonicotine is vacuum distilled at 120°C and 0.1kPa, and the intermediate fractions are collected to obtain 21.6g of high-purity S-6-aminonicotine, with a total yield of 61% in 3 steps, a purity of 99.7%, and an ee value of 99%.

[0040] The chiral 6-aminonicotinamide 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:

[0041] GC-MS: M+H + =178.12, which is consistent with the theoretical value of 178.13.

[0042] 1 H NMR (400MHz, CDCl3) δ7.92 (d, J = 1.9Hz, 1H), 7.45 (dd, J = 8.5, 2.2Hz, 1H), 6.50-6.45 (m, 1H), 4.47 (s, 2H), 3.19 (ddd, J = 9.4, 7.9, 2.0Hz, 1H), 2.90 (dd, J = 9.2, 7.5Hz, 1H), 2.29-2.17 (m, 1H), 2.16-2.03 (m, 4H), 1.99-1.84 (m, 1H), 1.84-1.62 (m, 2H), the above values ​​are consistent with the theoretical values ​​of S-6-aminonicotine. It can be obtained that the finished product prepared according to the method of this application is S-6-aminonicotine.

[0043] 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.

[0044] The difference between Examples 2 and 3 and Example 1 is that the types of bases used in step S1 are different. The specific results are shown in Table 1.

[0045] Table 1 Effects of different types of bases on the final product in step S1

[0046] serial number Alkali Total yield Example 2 n-Butyl lithium 58％ Example 3 Sodium hydroxide 37％

[0047] The difference between Example 4-7 and Example 1 is the amount of nicotine, trimethylsilyl chloride and base used in step S1. The specific results are shown in Table 2.

[0048] Table 2 Effect of the amount of nicotine, trimethylsilyl chloride and base used in step S1 on the final product

[0049] serial number Nicotine (eq) Trimethylsilyl chloride (eq) Base (eq) Total yield Example 4 1.0 1.0 1.0 54％ Example 5 1.0 1.2 1.0 58％ Example 6 1.0 1.2 1.2 60％ Example 7 1.0 1.5 1.2 61％

[0050] The difference between Examples 8-10 and Example 1 is the type and amount of the catalyst in step S2. The specific results are shown in Table 3.

[0051] Table 3 Effects of different types and amounts of catalyst reagents on the final product in step S2

[0052] serial number catalyst Dosage (eq) Total yield Example 8 Magnesium trifluoromethanesulfonate 0.2 63％ Example 9 Magnesium Perchlorate 0.1 51％ Example 10 Magnesium chloride 0.1 43％

[0053] The difference between Examples 11 and 12 and Example 1 is the type of nitration reagent in step S2. The specific results are shown in Table 4.

[0054] Table 4 Effects of different types of nitration reagents on the final product in step S3

[0055] serial number Nitration reagents Total yield Embodiment 11 N-Nitrosuccinimide 58％ Example 12 N-Nitrophthalimide 57％

[0056] 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.

[0057] 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 chiral 6-aminonicotinamide, characterized in that: It includes the following steps: S1, natural nicotine is dissolved in an organic solvent to obtain a reaction solution, and a base is added to the reaction solution under low temperature and inert gas protection, and a first low temperature reaction is carried out at -78 to -20°C for 1 to 24 hours, and then trimethylsilyl chloride is added, and the first low temperature reaction is continued for 2 to 24 hours until the reaction is complete, to obtain compound I; S2, dissolving compound I, a catalyst and a nitrating agent in an organic solvent to obtain a mixed solution, and then heating at 70-100° C. to complete the reaction; after the mixed solution cools to room temperature, filtering to remove insoluble matter, and removing the organic solvent by distillation under reduced pressure to obtain compound II; S3, dissolving compound II in an organic solvent to obtain a reaction solution, adding a reducing agent to the reaction solution under a second low temperature condition of -40 to 0°C, and then completing the reaction under the second low temperature condition; after the mixed solution is heated to room temperature, slowly adding a dilute hydrochloric acid solution to quench the reaction, then extracting with an organic solvent, retaining the aqueous phase and adjusting the pH to greater than 8 with a base, and then extracting with an organic solvent to obtain a crude product of chiral 6-aminonicotine; the crude product is purified by a reduced pressure distillation method to obtain high-purity chiral 6-aminonicotine.

2. The method for synthesizing 6-aminonicotinamide according to claim 1, characterized in that: The organic solvent used in step S1 may be dichloromethane or / and tetrahydrofuran.

3. The method for synthesizing 6-aminonicotinamide according to claim 1, characterized in that: The base used in step S1 can be selected from one or a mixture of two or more of n-butyl lithium, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, sodium tert-butoxide or sodium hydroxide.

4. The method for synthesizing 6-aminonicotinamide according to claim 1, characterized in that: The first low-temperature reaction in step S1 preferably ranges from -78 to -40°C.

5. The method for synthesizing 6-aminonicotinamide according to any one of claims 1 to 4, characterized in that: The molar ratio of nicotine, trimethylsilyl chloride and base added in step S1 is 1.0:1.2-1.5:1.0-1.

5.

6. The method for synthesizing 6-aminonicotinamide according to claim 5, characterized in that: The nitrating agent used in the reaction in step S2 can be selected from one or a mixture of two or more of N-nitrosaccharin, N-nitrosuccinimide or N-nitrophthalimide.

7. The method for synthesizing 6-aminonicotinamide according to claim 1 or 6, characterized in that: The catalyst used in step S2 may be one or a mixture of two or more of magnesium chloride, magnesium perchlorate or magnesium trifluoromethanesulfonate.

8. The method for synthesizing 6-aminonicotinamide according to claim 1, characterized in that: In step S2, the molar ratio of the nitrating agent, the catalyst and the compound I is 1.0-1.5:0.1-0.2:

1.

9. The method for synthesizing 6-aminonicotinamide according to claim 8, characterized in that: The preferred range of the heating reaction temperature in step S2 is 70-90°C.

10. The method for synthesizing 6-aminonicotinamide according to claim 9, characterized in that: The organic solvent used in step S2 may be tetrahydrofuran or acetonitrile or a mixture of the two.

11. The method for synthesizing 6-aminonicotinamide according to claim 1 or 10, characterized in that: The organic solvent used in step S3 may be selected from methanol, ethanol or tetrahydrofuran, or a mixture of two or more thereof.

12. The method for synthesizing 6-aminonicotinamide according to claim 11, characterized in that: The reducing agent used in step S3 may be one or a mixture of two or more of sodium borohydride, lithium aluminum hydride or hydrogen.

13. The method for synthesizing 6-aminonicotinamide according to claim 12, characterized in that: In step S3, the molar ratio of the reducing agent to compound II is 1.5-3.0:

1.

14. The method for synthesizing 6-aminonicotinamide according to claim 1 or 13, characterized in that: The temperature of the second low-temperature reaction in step S3 is preferably in the range of -20 to 0°C.

15. The method for synthesizing 6-aminonicotinamide according to claim 14, characterized in that: The organic solvent used in the extraction step in step S3 can be selected from dichloromethane and ethyl acetate or a mixture of the two.

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

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