Chiral 6-methylnicotine preparation method

Abstract

The present invention relates to the field of organic chemical synthesis, and specifically relates to a chiral 6-methylnicotine preparation method. The monochiral 6-methylnicotine synthesis method uses methyl 6-methylnicotinate (compound I) and N-vinylpyrrolidone (compound II) as starting materials, which sequentially undergo a condensation reaction, a hydrolysis reaction, a cyclization reaction, a chiral reduction reaction and an amine methylation reaction, to finally obtain the target product chiral 6-methylnicotine (R or S, compound VI). The product purity of the 6-methylnicotine in the R and S configurations respectively obtained by means of the synthetic route can reach 99.5% 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 chiral 6-methylnicotine Technical Field

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

[0002] Over the past three decades, the global aging population trend has intensified, and the number of people suffering from neurodegenerative diseases has increased year by year, becoming a significant public health issue. Acetylcholine receptors, due to their crucial role in neurological diseases and the cognitive decline and cardiovascular damage associated with them, have gradually emerged as a highly promising therapeutic target. Nicotinic acetylcholine receptors (nAChRs) are the primary receptors present in the mammalian brain, specifically the α4β2 and α7 subtypes. Among natural alkaloids, nicotine is the most common nAChR receptor agonist, showing potential alleviating and treating neurodegenerative diseases. However, its adverse effects, including addictive properties and cardiovascular and gastrointestinal effects, limit its clinical application. Since the late 20th century, research on various types of nAChR receptors has been reported. Six-substituted nicotine compounds generally exhibit good nAChR affinity, with 6-methylnicotine showing high α4β2 selectivity, thus demonstrating promising application prospects.

[0003] 6-Methylnicotine cannot be obtained through extraction and can only be prepared through chemical synthesis. An earlier synthetic method involved the methylation of nicotine, but this method requires excessive amounts of strong organic bases and ligands, and produces 2-methylnicotine as a byproduct, making subsequent separation difficult. Patents CN11443702B and CN114437031A report methods for synthesizing racemic 6-methylnicotine, but these methods cannot synthesize chiral 6-methylnicotine.

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

[0005] Given the numerous shortcomings of current methods for synthesizing chiral 6-methylnicotine, this invention discloses a method for synthesizing chiral 6-methylnicotine. This method uses a chiral reducing agent to prepare highly optically active 6-methylnicotine, resulting in a product with a defined chiral structure and methyl site selectivity. The yield is high, the operation is simple, and it can be used for industrial production.

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

[0007] Starting with methyl 6-methylnicotinate (compound I) and N-vinylpyrrolidone (compound II), the synthesis proceeded sequentially through condensation, hydrolysis, cyclization, chiral reduction, and aminomethylation to finally yield the target product, chiral 6-methylnicotinic acid (R or S compound VI). The synthetic route is shown in the figure below.

[0008] Furthermore, the synthesis of chiral 6-methylnicotine specifically includes the following steps:

[0009] S1, the condensation reaction, 6-methylnicotinic acid methyl ester (compound I) and N-vinylpyrrolidone (compound II) are dissolved in an organic solvent to obtain a mixed solution, and under low temperature and inert gas protection, a base is added to the mixed solution, and after reacting at a low temperature of -40 to 0°C, compound III is obtained;

[0010] S2, the hydrolysis and cyclization reaction, compound III is added to an acid solution to obtain a mixed solution, and then the mixed solution is heated to 70-100℃ to react; after the reaction is completed, the solution is restored to room temperature, and then the pH value of the solution is adjusted to alkaline with an alkali. After extraction with an organic solvent, compound IV can be obtained.

[0011] S3, the chiral reduction reaction, the freshly prepared chiral reducing agent is dissolved in an organic solvent to obtain a mixed solution, compound IV is added to the mixed solution under low temperature and inert gas protection, and then the mixture is heated to room temperature to react fully; the pH of the mixed solution is adjusted to acidic with an acid solution, the aqueous phase is separated and the pH of the aqueous phase is adjusted to alkaline with an alkali, and then the chiral compound V is obtained by extraction with an organic solvent;

[0012] S4, the aminomethylation reaction, involves mixing chiral compound V, formic acid, and an aqueous formaldehyde solution to obtain a mixed solution, which is then reacted completely under heating conditions to obtain a crude product of chiral 6-methylnicotinic acid (compound VI); the crude product is purified by vacuum distillation to obtain high-purity chiral 6-methylnicotinic acid.

[0013] This synthesis method is simple to operate, safe and reliable, with high yield and low cost. It also has excellent chemical selectivity, with product purity reaching over 99.5%, and excellent enantioselectivity, with optical purity reaching over 99.5%.

[0014] Optionally, the alkali used to adjust the pH of the solution is sodium hydroxide or potassium hydroxide.

[0015] Optionally, the acid used to adjust the pH of the solution is one or a mixture of two or more of hydrochloric acid, sulfuric acid, nitric acid, formic acid, or acetic acid.

[0016] Optionally, the organic solvent used in step S1 is dichloromethane or tetrahydrofuran; preferably, the organic solvent used in the reaction is tetrahydrofuran.

[0017] 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-butyllithium, and sodium bis(trimethylsilyl)amino; preferably, the base used in the reaction is sodium hydride or sodium bis(trimethylsilyl)amino.

[0018] Optionally, the reaction temperature in step S1 is -20°C.

[0019] 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.

[0020] Optionally, the heating temperature of the reaction in step S2 is 70-100℃; preferably, the heating temperature of the reaction is 100℃.

[0021] Optionally, the organic solvent used for extraction in step S2 is dichloromethane or ethyl acetate; preferably, the organic solvent used for extraction is dichloromethane.

[0022] 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 under low temperature and inert gas protection; and then the reaction is carried out at low temperature. After the reaction is completed, the solvent is removed by vacuum distillation to obtain the chiral reducing agent, which can be directly used in the chiral reduction reaction. Optionally, the chiral proline includes D-proline, L-proline, or their common derivatives (such as N-benzyloxycarbonyl-L-proline).

[0023] Optionally, in step S3, the molar ratio of the chiral reducing agent to compound IV is 1.0-3.0:1.

[0024] Optionally, the organic solvent used in step S3 is dichloromethane or tetrahydrofuran; preferably, the organic solvent used in the reaction is dichloromethane.

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

[0026] Optionally, in step S4, the addition ratio of compound V, formic acid, and formaldehyde aqueous solution is 1.0g:0.5-0.8g:0.6-1.0g.

[0027] Optionally, the heating temperature in step S4 is 60-90°C.

[0028] In summary, this application has the following beneficial effects:

[0029] The method for synthesizing chiral 6-methylnicotine disclosed in this application is simple to operate, safe and reliable, with high yield and low cost. By using a chiral reducing agent to effectively construct the chiral center, a single configuration of chiral 6-methylnicotine can be obtained with an optical purity of over 99.5%. Attached Figure Description

[0030] Figure 1 is a schematic diagram of the synthesis route of the preparation method of this application;

[0031] Figure 2 is the GC-MS spectrum of the final product obtained in Example 1 of this application;

[0032] Figure 3 is the 1H NMR spectrum of the final product obtained in Example 1 of this application. Detailed Implementation

[0033] 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.

[0034] Examples 1-28 provide a method for synthesizing chiral 6-methylnicotine, and the following description uses Example 1 as an example.

[0035] Example 1:

[0036] Step S1: In a 2L round-bottom flask, 50.0g of methyl 6-methylnicotinate (compound I), 36.7g of N-vinylpyrrolidone (compound II), and 1L of anhydrous tetrahydrofuran were added sequentially. The mixture was stirred at -20°C, and 165mL of sodium bis(trimethylsilyl)amino(2N) was slowly added dropwise. The reaction was allowed to proceed for 2 hours. After the reaction was complete as monitored by TLC, water was added to quench the reaction, and the organic phase was distilled under reduced pressure to remove the solvent, yielding compound III.

[0037] Step S2: Compound III obtained in step S1 was added to a 1L round-bottom flask, followed by 500mL of hydrochloric acid aqueous solution (5N). The mixture was heated for 6 hours. After the reaction was completed by TLC monitoring, the mixture was brought to room temperature, the pH was adjusted to 10 with 12N sodium hydroxide solution, and then extracted twice with dichloromethane. The organic phases were combined, and the solvent was removed by vacuum distillation to obtain 52.9g of compound IV.

[0038] Step S3: In a 2L round-bottom flask, 205.0g of N-benzyloxycarbonyl-L-proline and 500mL of anhydrous tetrahydrofuran were added to obtain a mixed solution. The mixture was stirred at -10℃, and 37.8g of sodium borohydride was added in portions. The mixture was then heated to room temperature and stirred for 2 hours. The organic solvent was removed by vacuum distillation to obtain a newly prepared chiral catalyst, which was used directly in the reaction. 1L of dichloromethane was added to the newly prepared chiral catalyst, and the mixture was stirred at 0℃. Then, 52.9g of compound IV obtained in step S2 was added, and the mixture was heated to room temperature and reacted for 8 hours. After the reaction was completed by TLC monitoring, 6N hydrochloric acid was added dropwise until the pH of the mixed solution was 1. The aqueous phase was separated, and then the pH of the aqueous phase was adjusted to 10 with 12N sodium hydroxide solution. The mixture was then extracted twice with dichloromethane, and the organic phases were combined. The solvent was removed by vacuum distillation to obtain 53.7g of compound V.

[0039] Step S4: 53.7 g of compound V obtained in step S3, 32.2 g of formic acid, and 43.0 g of formaldehyde aqueous solution (40%) were added to a 500 mL round-bottom flask to obtain a mixed solution. The mixture was reacted at 90 °C for 3 hours. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, adjusted to pH 3 with 6N hydrochloric acid solution, and then extracted with dichloromethane solution. The aqueous phase was retained and adjusted to pH 10 with 12N sodium hydroxide solution, followed by two extractions with dichloromethane. The organic phases were combined, and the solvent was removed by vacuum distillation to obtain 52.6 g of crude S-6-methylnicotine. The crude S-6-methylnicotine was then distilled under vacuum at 100 °C and 0.8 kPa, and the middle fraction was collected to obtain high-purity S-6-methylnicotine. The overall yield of the four steps was 56%, the purity was 99.7%, and the ee value was 99%.

[0040] The chiral 6-methylnicotine obtained in Example 1 was detected by GC-MS and NMR. The results are shown in Figures 2 and 3. The specific detection data are as follows:

[0041] GC-MS: M+ = 176.1, consistent with the theoretical value of 176.1.

[0042] 1 HNMR: 1¹H NMR (400MHz, DMSO-d⁶) δ 8.34 (d, J = 2.2Hz, 1H), 7.58 (dd, J = 7.9, 2.3Hz, 1H), 7.19 (d, J = 7.9Hz, 1H), 3.13 (ddd, J = 9.7, 8.0, 2.3Hz, 1H), 3.03 (dd, J = 9.0, 7.7Hz, 1H), 2.43 (s, 3H), 2.21 (q, J = 9.0Hz, 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). These values ​​are consistent with the theoretical values ​​for S-6-methylnicotine. Therefore, the finished product obtained according to the method of this application is S-6-methylnicotine.

[0043] 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.

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

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

[0046] The difference between Examples 4-6 and Example 1 is that the molar ratio of compound I, compound II and base in step S1 is different. The specific results are shown in Table 2.

[0047] Table 2 shows the effect of the molar ratio of compound I, compound II, and base in step S1 on the final product.

[0048] The difference between Examples 7 and 8 and Example 1 is that the type of proline reagent used in the synthesis of the chiral catalyst in step S3 is different. The specific results are shown in Table 3.

[0049] Table 3 shows the effect of different types of proline reagents on the final product in step S3.

[0050] 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.

[0051] Table 4 shows the effect of the molar ratio of chiral reducing agent to compound IV in step S3 on the final product.

[0052] 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.

[0053] Table 5 shows the effect of the addition ratio of compound V, formic acid, and formaldehyde aqueous solution on the final product in step S1.

[0054] 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.

[0055] The embodiments described above are merely explanations of this application and are not intended to limit it. Those skilled in the art can make modifications to these embodiments without contributing any inventive step after reading this specification, 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 chiral 6-methylnicotine, characterized in that, Starting with methyl 6-methylnicotinate (compound I) and N-vinylpyrrolidone (compound II), the reaction proceeds sequentially through condensation, hydrolysis, cyclization, chiral reduction, and aminomethylation to finally obtain the target product, chiral 6-methylnicotinate (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: The condensation reaction described in S1 involves dissolving methyl 6-methylnicotinate (compound I) and N-vinylpyrrolidone (compound II) in an organic solvent to obtain a mixed solution. Under low temperature and inert gas protection, an alkali is added to the mixed solution, and after reacting at a low temperature of -40 to 0°C, compound III is obtained. The hydrolysis and cyclization reaction described in S2 involves adding an acid solution to compound III to obtain a mixed solution, which is then heated to 70-100°C for reaction. After the reaction is complete, the solution is restored to room temperature, and the pH of the solution is adjusted to alkaline using an alkali. After extraction with an organic solvent, compound IV can be obtained. The chiral reduction reaction described in S3 involves dissolving a freshly prepared chiral reducing agent in an organic solvent to obtain a mixed solution. Compound IV is added to the mixed solution under low temperature and inert gas protection, and then the mixture is brought to room temperature for complete reaction. The pH of the mixed solution is adjusted to acidic using an acid solution. After separating the aqueous phase, the pH of the aqueous phase is adjusted to alkaline using an alkali, and then extracted with an organic solvent to obtain chiral compound V. The aminomethylation reaction described in S4 involves mixing chiral compound V, formic acid, and an aqueous formaldehyde solution to obtain a mixed solution, which is then reacted completely under heating conditions to obtain a crude product of chiral 6-methylnicotinic acid (compound VI). The crude product is purified by vacuum distillation to obtain high-purity chiral 6-methylnicotinic acid.

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

6. The method for synthesizing chiral 6-methylnicotine according to claim 2, characterized in that, The alkali used in step S1 may be one or a mixture of two or more of sodium hydride, sodium hydroxide, n-butyllithium, or sodium bis(trimethylsilyl)amino.

7. The method for synthesizing chiral 6-methylnicotine according to claim 2, characterized in that, In step S1, the molar ratio of compound I, compound II, and alkali 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 used for extraction 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 under low temperature and inert gas protection, and then the reaction is carried out at low temperature. After the reaction is completed, the solvent is removed by vacuum distillation to obtain the chiral reducing agent, which is directly used in the 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 can 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 S3 can be dichloromethane or ethyl acetate.

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

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

Images