Preparation method of chiral 6-methyl nicotine

Abstract

The invention relates to the field of organic chemical synthesis, in particular to a preparation method of chiral 6-methyl nicotine. The invention provides a synthesis method of single chiral 6-methyl nicotine, which comprises the following steps: taking methyl 6-methyl nicotinate (compound I) and N-vinyl pyrrolidone (compound II) as initial raw materials, and sequentially carrying out condensation reaction, hydrolysis reaction, cyclization reaction, chiral reduction reaction and aminomethylation reaction to finally obtain the target product chiral 6-methyl nicotine (R or S compound VI). According to the synthetic route, the 6-methyl nicotine with two configurations of R and S can be prepared respectively, and the purity of the product 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 chiral 6-methylnicotine. Background Art

[0002] In the past three decades, the global population aging trend has intensified, and the number of patients with neurodegenerative diseases has increased year by year, which has become an important public health issue. Acetylcholine receptors have gradually become a very promising diagnostic and therapeutic target because they play an important role in diseases such as cognitive impairment and cardiovascular damage associated with neurological diseases and neurodegenerative diseases. Nicotinic acetylcholine receptors (nAChR) are mainly present in the mammalian brain, specifically two subtypes, α4β2 and α7. Among natural alkaloids, nicotine is the most common nAChR receptor agonist, which has potential to alleviate and treat neurodegenerative diseases. However, its adverse effects, including addiction and effects on the cardiovascular and gastrointestinal systems, limit the clinical application of nicotine. Since the end of the 20th century, studies on various types of nAChR receptors have been reported. The 6-substituted nicotinic compounds have good nAChR affinity as a whole, among which 6-methylnicotine has high α4β2 selectivity, so it has good application prospects.

[0003] 6-Methylnicotine cannot be obtained by extraction and can only be prepared by chemical synthesis. An earlier synthesis method is to obtain it by methylation of nicotine, but this method requires the consumption of excessive amounts of organic strong bases and ligands, and 2-methylnicotine will be generated as a byproduct during the reaction, making subsequent separation difficult. Patents CN11443702B and CN114437031A respectively report methods for synthesizing racemic 6-methylnicotine, but these methods cannot synthesize chiral 6-methylnicotine.

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

[0005] In view of the many shortcomings of the current methods for synthesizing chiral 6-methylnicotine, the present invention discloses a method for synthesizing chiral 6-methylnicotine, which uses a chiral reducing agent to prepare 6-methylnicotine with high optical activity. The obtained product has a definite chiral structure and methyl 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-methylnicotine, which is achieved by the following technical scheme:

[0007] Using 6-methylnicotinate (Compound I) and N-vinylpyrrolidone (Compound II) as starting materials, condensation reaction, hydrolysis reaction, cyclization reaction, chiral reduction reaction and aminomethylation reaction are carried out in sequence to finally obtain the target product chiral 6-methylnicotine (R or S compound VI). The synthetic route is shown in the following formula:

[0008]

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

[0010] S1, the condensation reaction, 6-methylnicotinate (compound I) and N-vinylpyrrolidone (compound II) are dissolved in an organic solvent to obtain a mixed solution, and a base is added to the mixed solution under low temperature and inert gas protection, and the mixture is reacted at a low temperature of -40 to 0°C to obtain compound III;

[0011] S2, the hydrolysis and cyclization reaction, adding an acid solution to compound III to obtain a mixed solution, and then heating the mixed solution to 70-100° C. for reaction; after the reaction is completed, returning to room temperature, and then adjusting the pH value of the solution to alkaline with a base, and then extracting with an organic solvent to obtain compound IV;

[0012] S3, the chiral reduction reaction, the newly prepared chiral reducing agent is dissolved in an organic solvent to obtain a mixed solution, compound IV is added to the mixed solution at low temperature and under the protection of an inert gas, and then the temperature is raised to room temperature for sufficient reaction; the pH value of the mixed solution is adjusted to acidic with an acid solution, the pH value of the aqueous phase is adjusted to alkaline with a base after the aqueous phase is separated, and then the chiral compound V is extracted with an organic solvent;

[0013] S4, the aminomethylation reaction, the chiral compound V, formic acid and formaldehyde aqueous solution are mixed to obtain a mixed solution, and then the mixture is reacted completely under heating conditions to obtain a crude product of chiral 6-methylnicotine (compound VI); the crude product is purified by a reduced pressure distillation method to obtain high-purity chiral 6-methylnicotine.

[0014] The synthetic method is simple to operate, safe and reliable, has a high yield, low cost, and has excellent chemical selectivity. The purity of the product can be as high as over 99.5%. It also has excellent enantioselectivity, and the optical purity can reach over 99.5%.

[0015] Optionally, the alkali used to adjust the pH value of the solution is sodium hydroxide or potassium hydroxide.

[0016] Optionally, the acid used to adjust the pH value of the solution is one or a mixture of two or more of hydrochloric acid, sulfuric acid, nitric acid, formic acid or acetic acid.

[0017] Optionally, the organic solvent used in the reaction in step S1 is dichloromethane or tetrahydrofuran; preferably, the organic solvent used in the reaction is tetrahydrofuran.

[0018] Optionally, the base used in the reaction in step S1 is one or a mixture of two or more of sodium hydride, sodium hydroxide, n-butyl lithium and sodium bis(trimethylsilyl)amide; preferably, the base used in the reaction is sodium hydride or sodium bis(trimethylsilyl)amide.

[0019] Optionally, the reaction temperature in step S1 is -20°C.

[0020] Optionally, the molar ratio of compound I, compound II and base added in step S1 is 1.0:0.8-1.5:1.0-1.5.

[0021] Optionally, the heating temperature of the reaction in step S2 is 70-100°C; preferably, the heating temperature of the reaction is 100°C.

[0022] Optionally, the organic solvent used for extraction in step S2 is dichloromethane or ethyl acetate; preferably, the organic solvent used for extraction is dichloromethane.

[0023] Preferably, the chiral reducing agent used in step S3 is prepared as follows: chiral proline is dissolved in tetrahydrofuran to obtain a mixed solution, sodium borohydride is added at low temperature and under the protection of an inert gas, and then reacted at low temperature. After the reaction is completed, the solvent is removed by distillation under reduced pressure to obtain a chiral reducing agent, which is directly used in a chiral reduction reaction. Optionally, the chiral proline includes D-proline, L-proline or their common derivatives (such as N-benzyloxycarbonyl-L-proline).

[0024] Optionally, in step S3, the molar ratio of the chiral reducing agent to compound IV is 1.0-3.0:1.

[0025] Optionally, the organic solvent used in step S3 is dichloromethane or tetrahydrofuran; preferably, the organic solvent used in the reaction is dichloromethane.

[0026] Optionally, the organic solvent used in the extraction step in step S3 is dichloromethane or ethyl acetate; preferably, the organic solvent used in the extraction is dichloromethane.

[0027] Optionally, in step S4, the addition ratio of compound V, formic acid and formaldehyde aqueous solution is 1.0 g: 0.5-0.8 g: 0.6-1.0 g.

[0028] Optionally, the temperature of the heating reaction in step S4 is 60-90°C.

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

[0030] The chiral 6-methylnicotine synthesis method involved in the present application is simple to operate, safe and reliable, with high yield and low cost; a chiral reducing agent is used to effectively construct a chiral center, and a single-configuration chiral 6-methylnicotine 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 GC-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] Embodiments 1-28 provide a method for synthesizing chiral 6-methylnicotine, which will be specifically described below using Embodiment 1 as an example.

[0036] Embodiment 1:

[0037] Step S1: 50.0 g of methyl 6-methylnicotinate (Compound I), 36.7 g of N-vinylpyrrolidone (Compound II) and 1 L of anhydrous tetrahydrofuran were added in sequence into a 2 L round-bottom flask. Stirring was performed at -20 °C, 165 mL of sodium bis(trimethylsilyl)amide (2N) was slowly added dropwise, and the reaction was allowed to proceed for 2 hours. After the reaction was completed by TLC monitoring, water was added to quench the reaction, and the organic phase was distilled under reduced pressure to remove the solvent to obtain Compound III.

[0038] Step S2: Add the compound III obtained in step S1 to a 1L round-bottom flask, then add 500mL of aqueous hydrochloric acid solution (5N), and heat to react for 6 hours. After the reaction is completed by TLC monitoring, return to room temperature, adjust the pH to 10 with 12N sodium hydroxide solution, and then extract twice with dichloromethane. Combine the organic phases, and remove the solvent by distillation under reduced pressure to obtain 52.9g of compound IV.

[0039] Step S3: Add 205.0g of N-benzyloxycarbonyl-L-proline and 500mL of anhydrous tetrahydrofuran to a 2L round-bottom flask to obtain a mixed solution, stir at -10°C, add 37.8g of sodium borohydride in batches, and then warm to room temperature and stir to react for 2 hours. Remove the organic solvent by distillation under reduced pressure to obtain a newly prepared chiral catalyst, which is directly used in the reaction. Add 1L of dichloromethane to the newly prepared chiral catalyst, stir at 0°C, then add 52.9g of compound IV obtained in step S2, warm to room temperature and react for 8 hours. After the reaction is completed by TLC monitoring, 6N hydrochloric acid is added dropwise to the pH of the mixed solution = 1, the aqueous phase is separated, and then the aqueous phase is adjusted to pH = 10 with 12N sodium hydroxide solution, and then extracted twice with dichloromethane, the organic phases are combined, and the solvent is removed by distillation under reduced pressure to obtain 53.7g of compound V.

[0040] Step S4: Add 53.7g of compound V obtained in step S3, 32.2g of formic acid and 43.0g of formaldehyde aqueous solution (40%) to a 500mL round-bottom flask to obtain a mixed solution, and react at 90°C for 3 hours. After the reaction is completed by TLC monitoring, cool to room temperature, adjust to pH=3 with 6N hydrochloric acid solution, and then add dichloromethane solution for extraction. Retain the aqueous phase, adjust the aqueous phase to pH=10 with 12N sodium hydroxide solution, and then extract twice with dichloromethane. Combine the organic phases, remove the solvent by vacuum distillation, and obtain 52.6g of crude S-6-methylnicotine. The crude S-6-methylnicotine is vacuum distilled at 100°C and 0.8kPa, and the intermediate fractions are collected to obtain high-purity S-6-methylnicotine, with a total yield of 56% in 4 steps, a purity of 99.7%, and an ee value of 99%.

[0041] The chiral 6-methylnicotine obtained in Example 1 was tested by GC-MS and NMR, and the results obtained were as follows: Figure 2 and Figure 3 The specific test data are as follows:

[0042] GC-MS: M+=176.1, consistent with the theoretical value of 176.1.

[0043] 1 HNMR: 1H NMR (400 MHz, DMSO-d6) δ8.34 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 7.9, 2.3 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 3.13 (ddd, J = 9.7, 8.0, 2.3 Hz, 1H), 3.03 (dd, J = 9.0, 7.7 Hz, 1H), 2.43 (s, 3H), 2.21 (q, J = 9.0 Hz, 1H), 2.16-2.09 (m, 1H), 2.04 (s, 3H), 1.89-1.79 (m, 1H), 1.79-1.67 (m, 1H), 1.61-1.51 (m, 1H). The above values ​​are consistent with the theoretical values ​​of S-6-methylnicotine. It can be concluded that the finished product obtained according to the method of the present application is S-6-methylnicotine.

[0044] 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.

[0045] The difference between Example 2-3 and Example 1 is that the types of bases used in step S1 are different. The specific results are shown in Table 1.

[0046] Table 1 Effects of different types of bases on the final product in step S1

[0047] serial number Alkali Total yield Product purity Example 2 Sodium hydride 52％ 99.1％ Example 3 n-Butyl lithium 49％ 99.3％

[0048] The difference between Example 4-6 and Example 1 is that the molar ratios of compound I, compound II and base in step S1 are different. The specific results are shown in Table 2.

[0049] Table 2 Effect of the molar ratio of compound I, compound II and base in step S1 on the final product

[0050] serial number Compound I Compound II Alkali Total yield Product purity Example 4 1.0 0.8 1.0 43％ 99.3％ Example 5 1.0 1.2 1.2 56％ 99.4％ Example 6 1.0 1.5 1.5 54％ 99.3％

[0051] The difference between Examples 7 and 8 and Example 1 is that the types of proline reagents used in the synthesis of the chiral catalyst in step S3 are different. The specific results are shown in Table 3.

[0052] Table 3 Effects of different types of proline reagents on the final product in step S3

[0053]

[0054]

[0055] The difference between Examples 9-11 and Example 1 is that the molar ratio of the chiral reducing agent to compound IV in step S3 is different. The specific results are shown in Table 4.

[0056] Table 4 Effect of the molar ratio of the chiral reducing agent to compound IV in step S3 on the final product

[0057] serial number Chiral Catalyst Compound IV Total yield ee value Example 9 1.0 1.0 43％ 99.5％ Example 10 1.0 1.5 54％ 99.5％ Embodiment 11 1.0 2.0 56％ 99.5％

[0058] The difference between Examples 12-14 and Example 1 is that the addition ratios of compound V, formic acid and formaldehyde aqueous solution (40%) in step S4 are different. The specific results are shown in Table 5.

[0059] Table 5 Effect of the addition ratio of compound V, formic acid and formaldehyde aqueous solution in step S1 on the final product

[0060] serial number Compound V Formic acid Formaldehyde aqueous solution Total yield Product purity Example 12 1.0 g 0.5g 0.6g 47％ 99.5％ Example 13 1.0g 0.6g 1.0g 56％ 99.5％ Embodiment 14 1.0g 0.7g 0.8g 55％ 99.5％

[0061] 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.

[0062] 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-methylnicotine, characterized in that: Using 6-methylnicotinate (compound I) and N-vinylpyrrolidone (compound II) as starting materials, condensation reaction, hydrolysis reaction, cyclization reaction, chiral reduction reaction and aminomethylation reaction are carried out in sequence to finally obtain the target product chiral 6-methylnicotine (R or S compound VI).

2. The method for preparing chiral 6-methylnicotine according to claim 1, characterized in that: It includes the following steps: In the condensation reaction described in S1, methyl 6-methylnicotinate (compound I) and N-vinylpyrrolidone (compound II) are dissolved in an organic solvent to obtain a mixed solution, and a base is added to the mixed solution under low temperature and inert gas protection, and the mixture reacts at a low temperature of -40 to 0°C to obtain compound III; In the hydrolysis and cyclization reaction described in S2, an acid solution is added to compound III to obtain a mixed solution, and then the mixed solution is heated to 70-100° C. for reaction; after the reaction is completed, the room temperature is restored, and the pH value of the solution is adjusted to alkaline with a base, and compound IV can be obtained after extraction with an organic solvent; S3 is a chiral reduction reaction, wherein the newly prepared chiral reducing agent is dissolved in an organic solvent to obtain a mixed solution, compound IV is added to the mixed solution at low temperature and under the protection of an inert gas, and then the mixture is heated to room temperature for sufficient reaction; the pH value of the mixed solution is adjusted to acidic with an acid solution, the pH value of the aqueous phase is adjusted to alkaline with a base after the aqueous phase is separated, and then the chiral compound V is extracted with an organic solvent; In the amine methylation reaction described in S4, the chiral compound V, formic acid and formaldehyde aqueous solution are mixed to obtain a mixed solution, and then the mixture is reacted completely under heating conditions to obtain a crude product of chiral 6-methylnicotine (compound VI); the crude product is purified by a reduced pressure distillation method to obtain high-purity chiral 6-methylnicotine.

3. The method for synthesizing chiral 6-methylnicotine according to claim 2, characterized in that: The alkali used to adjust the pH value of the solution can be sodium hydroxide or potassium hydroxide.

4. The method for synthesizing chiral 6-methylnicotine according to claim 2, characterized in that: The acid used to adjust the pH value of the solution may be one or a mixture of two or more of hydrochloric acid, sulfuric acid, nitric acid, formic acid or acetic acid.

5. The method for synthesizing chiral 6-methylnicotine according to claim 2, characterized in that: The organic solvent used in step S1 may be dichloromethane or tetrahydrofuran.

6. The method for synthesizing chiral 6-methylnicotine according to claim 2, characterized in that: The base used in step S1 can be selected from one or a mixture of two or more of sodium hydride, sodium hydroxide, n-butyl lithium or sodium bis(trimethylsilyl)amide.

7. The method for synthesizing chiral 6-methylnicotine according to claim 2, characterized in that: The molar ratio of compound I, compound II and base added in step S1 is 1.0:0.8-1.5:1.0-1.

5.

8. The method for synthesizing 6-methylnicotine according to claim 2, characterized in that: The organic solvent extracted in step S2 is dichloromethane or ethyl acetate.

9. The method for synthesizing chiral 6-methylnicotine according to claim 2, characterized in that: The chiral reducing agent used in step S3 is prepared as follows: chiral proline is dissolved in tetrahydrofuran to obtain a mixed solution, sodium borohydride is added at low temperature and under the protection of an inert gas, and then reacted at low temperature; after the reaction is completed, the solvent is removed by distillation under reduced pressure to obtain a chiral reducing agent, which is directly used in a chiral reduction reaction.

10. The method for synthesizing chiral 6-methylnicotine according to claim 9, characterized in that: The chiral proline includes D-proline, L-proline or N-benzyloxycarbonyl-L-proline.

11. The method for synthesizing 6-methylnicotine according to claim 2, characterized in that: In step S3, the molar ratio of the chiral reducing agent to compound IV is 1.5-3.0:

1.

12. The method for synthesizing 6-methylnicotine according to claim 2, characterized in that: The organic solvent used in step S3 may be dichloromethane or tetrahydrofuran.

13. The method for synthesizing 6-methylnicotine according to claim 2, characterized in that: The organic solvent used in the extraction step in step S3 may be dichloromethane or ethyl acetate.

14. The method for synthesizing 6-methylnicotine according to claim 2, wherein in step S4, the addition ratio of compound V, formic acid and formaldehyde aqueous solution is 1.0 g: 0.5-0.8 g: 0.6-1.0 g.

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

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