Preparation method for chiral 6-aminonicotine
The preparation of chiral 6-aminonicotinic acid via silanization and reduction reactions solves the problems of high temperature and high cost in existing methods, achieving high-purity and high-yield synthesis, which is suitable for industrial production.
Patent Information
- Application Number
- PCT/CN2025/138929
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2024-10-11
- Filing Date
- 2025-12-01
- Publication Date
- 2026-04-16
AI Technical Summary
Existing methods for synthesizing 6-aminonicotinic acid suffer from problems such as high-temperature reactions, low yields, and high costs, making it difficult to meet the synthesis requirements of chiral 6-aminonicotinic acid.
Using natural nicotine as raw material, highly optically active 6-aminonicotine is prepared through silanization, nitro substitution, and reduction reactions, avoiding the use of chiral reagents and reducing production costs.
It is simple to operate, safe and reliable, with high yield, and the product purity and optical purity reach 99.7% and 99.5% or higher, respectively, making it suitable for industrial production.
Smart Images
Figure CN2025138929_16042026_PF_FP_ABST
Abstract
Description
A method for preparing chiral 6-aminonicotinic acid Technical Field
[0001] This invention relates to the field of organic chemical synthesis, and more specifically to a method for synthesizing chiral 6-aminonicotinic acid. Background Technology
[0002] Acetylcholine receptors play a crucial role in central nervous system diseases and are a current focus of medical research. Nicotine, a well-known acetylcholine receptor agonist, has been shown to have beneficial effects in treating neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and Tourette's syndrome. However, nicotine's various side effects limit its clinical application. Therefore, developing highly selective and safe acetylcholine receptor ligands is crucial for expanding new avenues for drug therapy. Existing research indicates that certain nicotine derivatives possess acetylcholine-binding capabilities, particularly 6-substituted nicotine derivatives, which generally exhibit better physiological activity. 6-Aminonicotine, the 6-aminosubstituted product of nicotine, has the ability to bind to acetylcholine receptors and can be further converted into other nicotine derivatives through chemical reactions, demonstrating high research value and application prospects.
[0003] 6-Aminonicotinic acid is not a naturally occurring substance and can only be prepared through chemical synthesis. Currently, there are two main known methods for synthesizing 6-aminonicotinic acid. The first method involves direct amination of nicotine, but this reaction requires high temperatures of 130-170°C and suffers from poor yield and regioselectivity, making it unsuitable for large-scale production. The second method involves first converting nicotine to 6-chloronicotinic acid, and then synthesizing 6-aminonicotinic acid via a palladium-catalyzed coupling reaction. This method has a longer reaction route and requires both a strong base and a palladium catalyst, resulting in higher material costs.
[0004] In summary, existing methods for synthesizing 6-aminonicotinic acid cannot meet the requirements for synthesizing chiral 6-aminonicotinic acid, therefore, it is necessary to develop a synthetic route for chiral 6-aminonicotinic acid. Summary of the Invention
[0005] Given the numerous shortcomings of current methods for synthesizing chiral 6-aminonicotinic acid, this invention discloses a method for synthesizing chiral 6-aminonicotinic acid using natural nicotine as a raw material to prepare highly optically active 6-aminonicotinic acid. This route first converts nicotine into 6-nitronicotinic acid, and then obtains 6-aminonicotinic acid through nitro reduction. The final product has a defined chiral structure and amino site selectivity, with high yield, simple operation, and suitability for industrial production.
[0006] This invention provides a method for synthesizing chiral 6-aminonicotinic acid, achieved through the following technical solution:
[0007] Starting with natural nicotine, the synthesis proceeded sequentially through silanization, nitro substitution, and reduction reactions to finally obtain the target product, chiral 6-aminonicotine. The synthetic route is shown in the figure below:
[0008] Furthermore, the synthesis of chiral 6-aminonicotinic acid specifically includes the following steps:
[0009] S1, natural nicotine is dissolved in an organic solvent to obtain a reaction solution. Under low temperature and inert gas protection, an alkali is added to the reaction solution. After reacting at low temperature for 1 to 24 hours, trimethylchlorosilane is added, and the reaction is continued at low temperature for 2 to 24 hours until the reaction is complete, to obtain compound I.
[0010] S2, compound I, the catalyst, and the nitrating agent were dissolved in an organic solvent to obtain a mixed solution, which was then reacted completely under heating conditions. After the mixed solution was cooled to room temperature, insoluble matter was removed by filtration, and the organic solvent was removed by vacuum distillation to obtain compound II.
[0011] S3, compound II was dissolved in an organic solvent to obtain a reaction solution. A reducing agent was added to the reaction solution at low temperature, and the reaction was allowed to proceed to completion at low temperature. After the mixed solution was brought to room temperature, the reaction was quenched by slowly adding dilute hydrochloric acid solution. Then, extraction with an organic solvent was performed to obtain crude chiral 6-aminonicotinic acid. The crude product was purified by vacuum distillation to obtain high-purity chiral 6-aminonicotinic acid.
[0012] By employing the above-described synthesis method and using highly optically active natural nicotine as the starting material, the need for subsequent chiral reagents to construct the chiral center in nicotine can be avoided, thus reducing production costs. This synthesis method is simple to operate, safe and reliable, with high yield, low cost, and product purity reaching over 99.7%, with optical purity exceeding 99.5%.
[0013] Optionally, the organic solvent used in step S1 is dichloromethane and tetrahydrofuran; preferably, the organic solvent used in the reaction is tetrahydrofuran.
[0014] Optionally, the base used in step S1 is n-butyllithium, diisopropylaminolithium, sodium di(trimethylsilyl)amino, sodium tert-butoxide, and sodium hydroxide; preferably, the base used in the reaction is sodium tert-butoxide.
[0015] 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 -40°C being optimal.
[0016] Optionally, the molar ratio of nicotine, trimethylchlorosilane and alkali added in step S1 is 1.0:1.2-1.5:1.0-1.5.
[0017] Optionally, the nitrating agent used in step S2 is N-nitrosaccharin, N-nitrosuccinimide, or N-nitrophthalimide; preferably, the nitrating agent used in the reaction is N-nitrosaccharin.
[0018] Optionally, the heating temperature in step S2 is 70-100℃; preferably, the heating temperature is in the range of 70-90℃, with 80℃ being the most suitable.
[0019] Optionally, the organic solvent used in step S2 is tetrahydrofuran and acetonitrile; preferably, the organic solvent used in the reaction is acetonitrile.
[0020] Optionally, the catalyst used in step S2 is magnesium chloride, magnesium perchlorate, and magnesium trifluoromethanesulfonate; preferably, the catalyst used in the reaction is magnesium trifluoromethanesulfonate.
[0021] Optionally, in step S2, the molar ratio of the nitrifying agent, catalyst, and compound I is 1.0-1.5:0.1-0.2:1.
[0022] Optionally, the organic solvent used in step S3 is methanol, ethanol, or tetrahydrofuran.
[0023] Optionally, the reducing agent used in the extraction step of step S3 may be sodium borohydride, lithium aluminum hydride, or hydrogen; preferably, the reducing agent used in the reaction is sodium borohydride.
[0024] Optionally, in step S3, the molar ratio of the reducing agent to compound II is 1.5-3.0:1.
[0025] 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 optimal temperature.
[0026] Optionally, the alkali used in step S3 is a sodium hydroxide or potassium hydroxide solution, and the pH value is adjusted to be greater than 8, with the most preferred pH value being 10.
[0027] Optionally, the extraction solvent used in step S3 is dichloromethane and ethyl acetate; preferably, the organic solvent used in the reaction is dichloromethane.
[0028] In summary, this application has the following beneficial effects:
[0029] The method for synthesizing chiral 6-aminonicotinic acid disclosed in this application is simple to operate, safe and reliable, with high yield and low cost. Using natural nicotine as the starting material, a single configuration of chiral 6-aminonicotinic acid 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 LC-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 1-12 provide a method for synthesizing chiral 6-aminonicotinic acid, and the following description uses Example 1 as an example.
[0035] Example 1:
[0036] Step S1: 32.4 g (0.2 mol, 1.0 eq) of natural nicotine and 400 mL of anhydrous tetrahydrofuran were added to a 1 L round-bottom flask to obtain a mixed solution. The flask was then purged with nitrogen for protection. After the mixed solution was cooled to -20 °C, 21.1 g (0.22 mol, 1.1 eq) of sodium tert-butoxide was added. The mixture was stirred at -20 °C for 1 hour, followed by the addition of 26.1 g (0.24 mol, 1.2 eq) of trimethylchlorosilane. The reaction was continued at -20 °C with stirring for another 2 hours. After the reaction was completed as monitored by TLC, the mixed solution was returned to room temperature, the reaction was quenched with water, and the organic phase was distilled under reduced pressure to remove the solvent, yielding compound I.
[0037] Step S2: Compound I obtained in step S1 was added to a 1L round-bottom flask, followed by 400mL acetonitrile, 3.5g (0.02mol, 0.1eq) magnesium trifluoromethanesulfonate, and 59.3g (0.26mol, 1.3eq) N-nitrosaccharin to obtain a mixed solution. The mixture was heated to 70°C and reacted for 20 hours. After the reaction was completed by TLC monitoring, the mixed solution was returned to room temperature, filtered to remove insoluble impurities, and the solvent was removed by vacuum distillation to obtain crude compound II.
[0038] Step S3: Compound II obtained in Step S2 was added to a 500 mL round-bottom flask, followed by 200 mL of ethanol to obtain a mixed solution. After the mixed solution was cooled to 0 °C, 3.8 g (0.1 mol, 0.5 eq) of sodium borohydride was added, and the mixture was stirred at 0 °C for 5 hours. After the reaction was completed by TLC monitoring, the mixed solution was returned to room temperature, adjusted to pH 3 with 3 mol / L hydrochloric acid aqueous solution, and then extracted with 300 mL of dichloromethane solution. The aqueous phase was retained, adjusted to pH 10 with 12 mol / L sodium hydroxide solution, and then extracted twice with 300 mL of dichloromethane. The organic phases were combined, and the solvent was removed by vacuum distillation to obtain crude S-6-aminonicotinic acid. The crude S-6-aminonicotinic acid was then distilled under reduced pressure at 120 °C and 0.1 kPa, and the middle fraction was collected to obtain 21.6 g of high-purity S-6-aminonicotinic acid. The overall yield of the three steps was 61%, the purity was 99.7%, and the ee value was 99%.
[0039] The chiral 6-aminonicotinic acid obtained in Example 1 was detected by LC-MS and NMR. The results are shown in Figures 2 and 3. The specific detection data are as follows:
[0040] GC-MS: M+H + =178.12, consistent with the theoretical value of 178.13.
[0041] 1 ¹H NMR (400MHz, CDCl₃) values were 7.92 (d, J = 1.9 Hz, 1H), 7.45 (dd, J = 8.5, 2.2 Hz, 1H), 6.50–6.45 (m, 1H), 4.47 (s, 2H), 3.19 (ddd, J = 9.4, 7.9, 2.0 Hz, 1H), 2.90 (dd, J = 9.2, 7.5 Hz, 1H), 2.29–2.17 (m, 1H), 2.16–2.03 (m, 4H), 1.99–1.84 (m, 1H), and 1.84–1.62 (m, 2H). These values are consistent with the theoretical values for S-6-aminonicotinic acid. Therefore, the product prepared according to the method of this application is S-6-aminonicotinic acid.
[0042] 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.
[0043] The difference between Examples 2 and 3 and Example 1 is that the type of alkali used in step S1 is different. The specific results are shown in Table 1.
[0044] Table 1. Effects of different types of alkali on the final product in step S1.
[0045] The difference between Examples 4-7 and Example 1 is the amount of nicotine, trimethylchlorosilane and alkali used in step S1. The specific results are shown in Table 2.
[0046] Table 2 shows the effect of the amounts of nicotine, trimethylchlorosilane, and alkali in step S1 on the final product.
[0047] The difference between Examples 8-10 and Example 1 lies in the type and amount of catalyst used in step S2. The specific results are shown in Table 3.
[0048] Table 3 shows the effect of different types and amounts of catalysts in step S2 on the final product.
[0049] The difference between Examples 11 and 12 and Example 1 lies in the type of nitrating agent used in step S2. The specific results are shown in Table 4.
[0050] Table 4 shows the effect of different types of nitrating agents on the final product in step S3.
[0051] 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.
[0052] 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-aminonicotinic acid, characterized in that, It includes the following steps: S1, natural nicotine is dissolved in an organic solvent to obtain a reaction solution. Under low temperature and inert gas protection, alkali is added to the reaction solution. After reacting at a first low temperature of -78 to -20°C for 1 to 24 hours, trimethylchlorosilane 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, compound I, catalyst and nitrating agent are dissolved in an organic solvent to obtain a mixed solution, and then the reaction is carried out at 70-100℃. After the mixed solution is cooled to room temperature, the insoluble matter is removed by filtration, and the organic solvent is removed by vacuum distillation to obtain compound II. S3, compound II was dissolved in an organic solvent to obtain a reaction solution. A reducing agent was added to the reaction solution under a second low temperature condition of -40 to 0°C, and the reaction was completed under the second low temperature condition. After the mixed solution was raised to room temperature, dilute hydrochloric acid solution was slowly added to quench the reaction, and then the solution was extracted with an organic solvent. The aqueous phase was retained and adjusted to pH greater than 8 with alkali, and then extracted with an organic solvent to obtain the crude product of chiral 6-aminonicotinic acid. The crude product was purified by vacuum distillation to obtain high-purity chiral 6-aminonicotinic acid.
2. The method for synthesizing 6-aminonicotinic acid 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-aminonicotinic acid according to claim 1, characterized in that, The alkali used in step S1 may be one or a mixture of two or more of the following: n-butyllithium, diisopropylaminolithium, sodium di(trimethylsilyl)amino, sodium tert-butoxide, or sodium hydroxide.
4. The method for synthesizing 6-aminonicotinic acid according to claim 1, characterized in that, The preferred temperature range for the first low-temperature reaction in step S1 is -78 to -40°C.
5. The method for synthesizing 6-aminonicotinic acid according to any one of claims 1-4, characterized in that, In step S1, the molar ratio of nicotine, trimethylchlorosilane, and alkali is 1.0:1.2-1.5:1.0-1.
5.
6. The method for synthesizing 6-aminonicotinic acid according to claim 5, characterized in that, The nitrating agent used in step S2 can be one or a mixture of two or more of N-nitrosaccharin, N-nitrosuccinimide, or N-nitrophthalimide.
7. The method for synthesizing 6-aminonicotinic acid 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-aminonicotinic acid according to claim 8, characterized in that, In step S2, the molar ratio of nitrifying agent, catalyst and compound I is 1.0-1.5:0.1-0.2:
1.
9. The method for synthesizing 6-aminonicotinic acid according to claim 8, characterized in that, The preferred temperature range for the heating reaction in step S2 is 70–90°C.
10. The method for synthesizing 6-aminonicotinic acid according to claim 9, characterized in that, The organic solvent used in step S2 can be one or a mixture of two of tetrahydrofuran or acetonitrile.
11. The method for synthesizing 6-aminonicotinic acid according to claim 1 or 10, characterized in that, The organic solvent used in step S3 may be one or a mixture of two or more of methanol, ethanol or tetrahydrofuran.
12. The method for synthesizing 6-aminonicotinic acid according to claim 11, characterized in that, The reducing agent used in step S3 can be one or a mixture of two or more of sodium borohydride, lithium aluminum hydride, or hydrogen.
13. The method for synthesizing 6-aminonicotinic acid 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-aminonicotinic acid according to claim 1 or 13, characterized in that, The preferred temperature range for the second low-temperature reaction in step S3 is -20 to 0°C.
15. The method for synthesizing 6-aminonicotinic acid according to claim 14, characterized in that, The organic solvent used in the extraction step S3 can be one or a mixture of two of dichloromethane and ethyl acetate.
16. A chiral 6-aminonicotinic acid, characterized in that, It is prepared by the method described in claims 1-15.