RU2803744C1 - Method of synthesis of (s)-nicotine - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: method for the synthesis of (S)-nicotine is proposed, in which, under the conditions of a coenzyme circulation system, including coenzyme, glucose and glucose dehydrogenase, using coenzyme as a hydrogen donor and imine reductase as a catalyst, myosmin is subjected to catalytic reduction to obtain (S)-nornicotine, and then (S)-nornicotine is methylated to give (S)-nicotine, where the coenzyme is a salt of NADP and/or a salt of NAD.

EFFECT: method for the synthesis of (S)-nicotine with high chemical purity and high optical purity.

9 cl, 3 tbl, 16 dwg, 11 ex

Description

Field of the present invention

The present application relates to the technical field of organic synthesis methods and, in particular, relates to the synthesis of (S)-nicotine, more particularly to a method for the synthesis of (S)-nicotine with high chemical purity and high optical purity.

BACKGROUND OF THE INVENTION

(S)-nicotine (nicotine) is an alkaloid present in the nightshade plant (Solatium) and is an important component of tobacco. Tobacco leaves contain between 1.5% and 3.5% (S)-nicotine. Currently, the most common method of obtaining nicotine is the extraction of nicotine from tobacco leaves. Chemical synthesis has been reported to be underdeveloped and significantly more expensive than the extraction method. Chemical synthesis methods that have been described so far are a chemical separation method, an asymmetric hydrogenation method, a chiral auxiliary method, etc.

US 20160326134 describes a process in which methyl nicotinate as a starting material is condensed with N-methylpyrrolidine (NMP) and subjected to intramolecular rearrangement, reduction and chiral resolution to produce (S)-nicotine. The synthesis route for (S)-nicotine is presented below.

The document (Jacob Peyton "Separation of (±)-5-bromonicotine. Synthesis of (R)- and (S)-nornicotine of high enantiomeric purity." The Journal of Organic Chemistry 1982, 4165-4167) describes a method for obtaining (S)-nornicotine with a chiral acid as the separating reagent through processes such as separation, reductive debromination, etc. (S)-nornicotine can be further methylated to conveniently produce (S)-nicotine. The corresponding synthesis route is presented below. However, the chemical separation method has the disadvantages of low yield and high cost.

The paper (Gui Guo, Dong-Wei Sun, Shuang Yang, et al. “Iridium-catalyzed asymmetric hydrogenation of 2-pyridylcyclic imines: a highly enantioselective approach to nicotine derivatives.” Journal of the American Chemical Society, 2015, 90-93) describes a synthesis method in process of asymmetric catalytic hydrogenation. The pathway for nicotine synthesis is presented below.

However, the asymmetric catalytic hydrogenation process requires the use of an expensive chiral metal catalyst and, therefore, the process is expensive, the reactions must be carried out under high pressure, a significant investment in equipment is required, and the use of hydrogen also poses a potential safety hazard. In addition, this document shows that only the hexasubstituted substrate participates in the catalytic reaction with relatively high performance, and there are no technical advances for the direct hydrogenation of myosmin.

In (Teck-Peng Loh, Jian-Rong Zhou, Xu-Ran Li, Keng-Yeow Sim "Novel reductive aminocyclization for the synthesis of chiral pyrrolidines: stereoselective synthesis of (S)-nornicotine and 2-(2'-pyrrolidyl)-pyridines" Tetrahedron Letters, 1999, 7847-7850) describes a method for the synthesis of (S)-nornicotine using galactosamine as a chiral auxiliary substance. (S)-nornicotine can be further reacted to produce (S)-nicotine. The corresponding synthesis route is presented below.

However, in this chiral auxiliary method, the chiral auxiliary must be present in a stoichiometric amount, which cannot be reused, resulting in high cost and lack of practical value.

Thus, each method for the chemical synthesis of (S)-nicotine described in the prior art literature has disadvantages, and there is a need to develop a more economical, efficient and safe synthesis method.

Brief Disclosure of the Present Invention

Due to the shortcomings of the prior art, the object of the present application is to provide a method for the synthesis of (S)-nicotine, in particular a method for the synthesis of (S)-nicotine with high chemical purity and high optical purity.

To achieve this goal, this application proposes technical solutions that are described below.

This application proposes a method for the synthesis of (S)-nicotine, in which, under the conditions of the coenzyme circulation system using coenzyme as a hydrogen donor and imine reductase as a catalyst, the catalytic reduction of myosmin is carried out to produce (S)-nornicotine and subsequent methylation of (S)-nornicotine to produce (S)-nicotine.

The synthesis method related to the present application can be represented by the following reaction scheme:

This synthetic route is easy to perform, safe and reliable, provides high yield, low cost, and provides very high chemical selectivity with product purity equal to or greater than 99.5% and excellent enantioselectivity with optical purity equal to or greater than 99.5 %.

The relevant IUPAC name for myosmin is 3-(3,4-dihydro-2H-pyrrol-5-yl)pyridine and the IUPAC name for (S)-nornicotine is ( S)-3-(pyrrolidin-2-yl)pyridine.

Preferably, coenzyme, glucose and glucose dehydrogenase are present in the coenzyme circulation system.

Preferably the coenzyme contains an NADP salt and/or an NAD salt, preferably an NADP salt.

Preferably, the glucose dehydrogenase is any glucose dehydrogenase or a combination of at least two glucose dehydrogenases from ES-GDH101-ES-GDH109. In particular, a glucose dehydrogenase is any glucose dehydrogenase or combination of at least two glucose dehydrogenases from ES-GDH101, ES-GDH102, ES-GDH103, ES-GDH104, ES-GDH105, ES-GDH106, ES-GDH107, ES-GDH108 or ES -GDH109. Glucose dehydrogenase ES-GDH109 (lot number: S20191121) is preferred. The above glucose dehydrogenases can be purchased from SyncoZymes (Shanghai) Co., Ltd.

Preferably, the imine reductase is any imine reductase or combination of at least two imine reductases from ES-IRED101-ES-IRED112, IRED1321104, IRED1321108, IRED1321110 or IRED1321114. In particular, an imine reductase is any imine reductase or combination of at least two imine reductases from ES-IRED101, ES-TRED102, ES-TRED103, ES-TRED104, ES-IRED105, ES-JRED106, ES-JRED107, ES-IRED108, ES- IRED109, ES-IRED110, ES-IRED111, ES-IRED112, IRED1321104, IRED1321108, IRED1321111 or I4RED13. Imin reductase ES-TRED103 (lot number: S20191121) or IRED1321110 is preferred. Imin reductases ES-IRED101-ES-IRED112 can be purchased from SyncoZymes (Shanghai) Co., Ltd., and imine reductases IRED1321104, IRED1321108, IRED1321110 or IRED1321114 can be independently obtained from the gene bank.

In particular, source IRED1321104 is bacteria of the species Streptomyces Kanamyceticus, source IRED 1321108 is bacteria of the species L2C084 mesorhizobium, source IRED1321110 is bacteria of the species Salinispora pacifica, and source IRED132 1114 are bacteria of the species mesorhibium ciceri (Mesorhizobium ciceri). The above selected imine reductase is sent to a gene synthesis company for synthesis, insertion into pET28(a) plasmids and introduction into Escherichia coli BL21 to construct a recombinant Escherichia coli strain. The above recombinant strain is inoculated under autoclave conditions in Luria-Bertani (LB) medium (10 g/L sodium chloride, 10 g/L tryptone and 5 g/L yeast powder) and cultured at 37°C and 220 rpm until until the optical density at 600 nm (OD600) is between 2 and 3. A solution of 0.1 M isopropylthiogalactoside (IPTG) is added for induction at 25°C for 16 hours. After centrifugation, the cells are collected, sonicated, and centrifuged to remove cell debris to obtain an enzyme solution. The enzyme solution is lyophilized to obtain home-made enzyme powder.

Preferably, the catalytic reduction is carried out at a temperature ranging from 15 to 45°C, for example 15°C, 20°C, 25°C, 30°C, 35°C, 40°C or 45°C, etc. Other specific point values within this range may be selected and the details are not described herein. A temperature of 25 to 30°C is preferred.

Preferably, the catalytic reduction is carried out for 8 to 72 hours, for example 8 hours, 10 hours, 12 hours, 16 hours, 24 hours, 30 hours, 48 hours, 56 hours, 60 hours or 72 hours, etc. Other specific point values within this range may be selected and the details are not described herein.

Preferably, the catalytic reduction is carried out under stirring conditions at a rotation speed of from 150 to 400 rpm, for example 150 rpm, 200 rpm, 250 rpm, 300 rpm, 350 rpm. min or 400 rpm, etc. Other specific point values within this range may be selected and the details are not described herein.

Preferably, the catalytic reduction is carried out in a buffer solution, the buffer solution being a phosphate buffer solution, a tris(hydroxymethyl)methylamine hydrochloride buffer solution or a triethanolamine hydrochloride buffer solution.

Preferably, the buffer solution has a pH value of from 5.0 to 9.0, for example pH=5.0, pH=5.5, pH=6.0, pH=6.5, pH=7.0, pH =7.5, pH=8.0, pH=8.5, or pH=9.0, etc. Other specific point values within this range may be selected and the details are not described herein. A pH value of 5.8 to 6.5 is preferred.

Preferably, methylation involves mixing and reacting (S)-nornicotine with formaldehyde and formic acid to produce (S)-nicotine.

Preferably, methylation is carried out at a temperature ranging from 55 to 80°C, for example, 55°C, 60°C, 65°C, 70°C, 75°C or 80°C, etc. Other specific point values within this range may be selected and the details are not described herein.

Preferably, methylation is carried out over a period of 8 to 48 hours, for example 9 hours, 12 hours, 18 hours, 26 hours, 32 hours, 38 hours, 46 hours or 48 hours, etc. Other specific point values within this range may be selected and the details are not described herein.

As a preferred technical solution of the present application, the method for synthesizing (S)-nicotine involves mixing myosmin, coenzyme, glucose, glucose dehydrogenase, buffer and imine reductase and reacting the mixture at 15-45°C for 8-72 hours to obtain (S)-nornicotine , and then mixing (S)-nornicotine with formaldehyde and formic acid and reacting the mixture at 55-80°C for 8-48 hours to obtain (S)-nicotine.

Preferably, the weight ratio of myosmin, coenzyme and imine reductase is 1:(0.001-0.05):(0.05-0.1).

Preferably, the weight ratio of coenzyme, glucose and glucose dehydrogenase is (0.001-0.05):(1.2-2.4):(0.01-0.05). At the above mass ratio, the production process provides improved chemical selectivity.

Compared with the prior art, the present application provides positive effects, which are described below.

The method for synthesizing (S)-nicotine according to the present application is simple to carry out, safe and reliable, provides high yield and low cost, and also exhibits very high chemical selectivity with product purity greater than or equal to 99.5%, as well as excellent enantioselectivity with an optical purity greater than or equal to 99.5%.

Brief description of the figures

In fig. 1 shows the characteristic proton nuclear magnetic resonance ( ^1H NMR) spectrum of the myosmin sample in example 1;

in fig. 2 is a liquid chromatogram illustrating the chemical purity of the myosmin sample in Example 1;

in fig. 3 is a characteristic ^1H NMR spectrum of the (S)-nornicotine sample in Example 2;

in fig. 4 is a liquid chromatogram illustrating the chemical purity of the (S)-nornicotine sample in Example 2;

in fig. Figure 5 shows a chiral chromatogram of a sample of nornicotine racemate;

in fig. Figure 6 shows a chiral chromatogram of a sample of (S)-nornicotine in example 2;

in fig. 7 is a liquid chromatogram illustrating the chemical purity of the (S)-nornicotine sample in Example 3;

in fig. Figure 8 shows a chiral chromatogram of the (S)-nornicotine sample in example 3;

in fig. 9 is a liquid chromatogram illustrating the chemical purity of the (S)-nornicotine sample in Example 6;

in fig. 10 shows a chiral chromatogram of a sample of (S)-nornicotine in example 6;

in fig. 11 is a characteristic ^1H NMR spectrum of the (S)-nicotine sample in Example 7;

in fig. 12 is a liquid chromatogram illustrating the chemical purity of the (S)-nornicotine sample in Example 7;

in fig. 13 shows a chiral chromatogram of a sample of nicotine racemate;

in fig. 14 shows a chiral chromatogram of the (S)-nicotine sample in example 7;

in fig. 15 is a liquid chromatogram illustrating the chemical purity of the (S)-nornicotine sample in Example 8; And

in fig. Figure 16 shows a chiral chromatogram of the (S)-nicotine sample in Example 8.

Detailed Disclosure of the Present Invention

The technical solutions of the present application are further described below with the presentation of specific examples. Those skilled in the art will understand that these examples are used to provide a better understanding of the present application and should not be construed as specifically limiting the present application.

Example 1

In this example, the compound myosmin was prepared. With regard to the method for the synthesis of myosmin, reference is made to the method in patent publication No. EP 2487172 A1. The resulting product was characterized by ¹ H NMR. FIG. 1 shows the characteristic NMR spectrum containing the following data: ¹ H NMR (400 MHz, CDCl ₃ ), δ (ppm): 8.97 (1H, d), 8.64 (1H, dd), 8.17 (1H, dt), 7.29-7.34 (m, 1H), 4.06 (2H), 2.91-2.96 (m, 2H), 2.01-2.09 (m, 2H ). It was shown that myosmin was successfully synthesized. The sample was analyzed and detected using high performance liquid chromatography. The purity of the sample was 99.3%. The chromatogram is shown in Fig. 2.

Example 2

This example provides a method for the synthesis of (S)-nornicotine. Its implementation is described below.

3 g of myosmin was placed in a 50 ml three-neck round-bottom flask, 10 ml of 0.1 M phosphate buffer solution was added, and the pH was adjusted to 6.0. Then 5.5 g of glucose was added to the reaction flask and stirred until completely dissolved. In another 50 ml flask, 0.2 g of imine reductase ES-IRED103, 0.04 g of glucose dehydrogenase ES-GDH109 and 0.008 g of NADP salt were added and stirred until completely dissolved. The solution from the second flask was then slowly added to the first flask, heated to 25°C, stirred at 300 rpm and reacted for 24 hours. The solution was filtered, the filtrate was extracted with chloroform, dried over anhydrous sodium sulfate and concentrated to obtain 2.2 g of (S)-nornicotine.

The resulting (S)-hophhkothh was characterized by ¹ H NMR. FIG. Figure 3 shows the characteristic NMR spectrum containing the following data: NMR ¹ H (400 MHz, CDCl ₃ ), 5 (ppm): 8.56 (1H, d), 8.44 (1H, dd), 7.68 (1H, dt), 7.19-7.22 (m, 1H), 4.12 (1H, t), 3.13-3.19 (1H, m), 2.98-3.00 (1H , m), 2.15-2.23 (1H, m), 2.02 (1H, s), 1.80-1.93 (2H, m), 1.58-1.67 (1H, m ). It was shown that (S)-nornicotine was successfully synthesized.

The chemical purity of the obtained (S)-nornicotine was determined using high-performance liquid chromatography. As shown in FIG. 4, purity is 93.6%. The optical purity of the sample was determined using a high-performance liquid chromatograph and a chiral chromatography column. In fig. Figure 5 shows the spectrum of the chiral resolution of the racemate of nornicotine, where the time of appearance of the (K)-nornicotine peak is 20.08 minutes, the time of appearance of the (S)-nornicotine peak is 21.79 minutes, and the area of these peaks is 49.9%. and 50.1% respectively; in fig. Figure 6 shows a chiral chromatogram of the product, in which (R)-nornicotine was not detected, but only the peak of (S)-nornicotine was detected with an appearance time of 21.6 minutes, that is, the optical purity of the sample approaches 100%.

Example 3

This example provides a method for the synthesis of (S)-nornicotine. Its implementation is described below.

3 g of myosmin was placed in a 50 ml three-neck round-bottom flask, 15 ml of 0.1 M phosphate buffer solution was added and the pH was adjusted to 5.8. 5.5 g of glucose was added to the reaction flask and stirred until completely dissolved. In another 50 ml flask, 0.3 g of imine reductase ES-IRED103, 0.04 g of glucose dehydrogenase ES-GDH102 and 0.01 g of NADP salt were added and stirred until completely dissolved. The solution from the second flask was then slowly added to the first flask, heated to 37°C and stirred for 24 hours. The solution was filtered, the filtrate was extracted with chloroform, dried over anhydrous sodium sulfate and concentrated to obtain 2.4 g of (S)-nornicotine.

The chemical purity and optical purity of the obtained (S)-nornicotine were determined separately using a high-performance liquid chromatograph. The specific operating method is the same as in Example 2. The chromatogram is shown in FIG. 7, where the calculated chemical purity is 97.2%; and the chiral chromatogram is shown in Fig. 8, where optical purity approaches 100%.

Example 4

This example provides a method for the synthesis of (S)-nornicotine. Its implementation is described below.

3 g of myosmin was placed in a 50 ml three-neck round-bottom flask, 15 ml of 0.1 M phosphate buffer solution was added and the pH level was adjusted to 5.8. 5.5 g of glucose was added to the reaction flask and stirred until completely dissolved. In another 50 ml flask, 0.3 g of imine reductase ES-IRED103, 0.03 g of glucose dehydrogenase ES-GDH109 and 0.01 g of NADP salt were added and stirred until completely dissolved. The solution from the second flask was then slowly added to the first flask, heated to 37°C and stirred for 24 hours. The solution was filtered, the filtrate was extracted with chloroform, dried over anhydrous sodium sulfate and concentrated to obtain 2.2 g of (S)-nornicotine. Optical purity is 99.5%.

Example 5

This example provides a method for the synthesis of (S)-nornicotine. Its implementation is described below.

3 g of myosmin was placed in a 50 ml three-neck round-bottom flask, 15 ml of 0.1 M phosphate buffer solution was added and the pH level was adjusted to 5.8. 5.5 g of glucose was added to the reaction flask and stirred until completely dissolved. In another 50 ml flask, 0.3 g of imine reductase IRED1321110, 0.03 g of glucose dehydrogenase ES-GDH102 and 0.01 g of NADP salt were added and stirred until completely dissolved. The solution from the second flask was then slowly added to the first flask, heated to 37°C and stirred for 24 hours. The solution was filtered, the filtrate was extracted with chloroform, dried over anhydrous sodium sulfate and concentrated to obtain 2.3 g of (S)-nornicotine. Optical purity is 99.5%.

Example 6

This example provides a method for the synthesis of (S)-nornicotine. Its implementation is described below.

100 g of myosmin was placed in a 1000 ml three-neck round-bottom flask, 650 ml of 0.1 M phosphate buffer solution was added, and the pH was adjusted to 6.2. 180 g of glucose was added to the reaction flask and stirred until the solution became clear. 100 g of ES-TRED103 imine reductase solution with a concentration of 10%, 50 g of ES-GDH102 glucose dehydrogenase solution with a concentration of 10% and 5 g of NADP salt were added to a 500 ml flask and stirred until a clear solution was obtained. The solution from the flask was slowly added to a 1000 ml three-neck round bottom flask, heated to 37°C and stirred for 36 hours. The solution was filtered, the filtrate was extracted with chloroform, dried over anhydrous sodium sulfate and concentrated to obtain 75 g of (S)-nornicotine.

The chemical purity and optical purity of the obtained (S)-nornicotine were determined separately using a high-performance liquid chromatograph.

The specific operating method is the same as in Example 2. The chromatogram is shown in FIG. 9, where the calculated chemical purity is 95.9%; and the chiral chromatogram is shown in Fig. 10, where the optical purity is 99.9%. Example 7

This example provides a method for the synthesis of (S)-nicotine. Its implementation is described below.

40 g of (S)-nornicotine, 32 g of 37% formaldehyde solution and 25 g of 85% formic acid solution were placed in each of three three-neck flasks with a volume of 500 ml, heated to 60°C and reacted for 24 hours. After completion of the reaction, sodium hydroxide to adjust the pH to 12. The aqueous phases were extracted with methyl tert-butyl ether and the extracts were combined, concentrated and distilled under reduced pressure to obtain 29 g of (S)-nicotine as a colorless liquid.

The resulting product was characterized by ¹ H NMR. FIG. 1 shows the characteristic NMR spectrum containing the following data: NMR ¹ H (400 MHz, CDCl ₃ ), 5 (ppm): 8.54 (1H, d), 8.50 (1H, dd), 7.70 (1H, dt), 7.24-7.27 (1H, m), 3.22-3.27 (1H, m), 3.08 (1H, t), 2.27-2.34 (1H , m), 2.17-2.24 (1H, m), 2.16 (3H, m), 1.91-2.02 (1H, m), 1.79-1.87 (1H, m ), 1.68-1.76 (1H, m). It was shown that (S)-nicotine was successfully synthesized.

The chemical purity of the prepared (S)-nicotine sample was determined using a high performance liquid chromatograph. As shown in FIG. 12, the detected purity is 99.9%. The optical purity of the sample was determined using a high-performance liquid chromatograph and a chiral chromatography column. In fig. 13 shows a chiral chromatogram of the nicotine racemate, where the peak at 5.43 min corresponds to (S)-nicotine, the peak at 6.17 min corresponds to (R)-nicotine, and the areas of these peaks are 50.1% and 49.9%, respectively. In fig. 14 shows the chiral chromatogram of the sample, and from the detection chromatogram it can be seen that the peak area at 5.43 min is 99.65%, that is, the purity of (S)-nicotine is 99.65%.

Example 8

This example provides a method for the synthesis of (S)-nicotine. Its implementation is described below.

107 g of (S)-nornicotine and 80 g of a 37% formaldehyde solution were placed in each of three three-neck flasks with a volume of 500 ml and heated to 75°C. 60 g of an 85% formic acid solution were added dropwise. After addition, the solution reacted for 24 hours while maintaining temperature. After completion of the reaction, sodium hydroxide was added to adjust the pH to 12. The aqueous phases were extracted with methyl tert-butyl ether, the extracts were combined, concentrated and distilled under reduced pressure to obtain 80 g of (S)-nicotine as a colorless liquid.

The chemical purity and optical purity of the resulting (S)-nicotine were determined separately using a high-performance liquid chromatograph. The specific operations are the same as in example 5. The chromatogram is shown in Fig. 15, where the calculated chemical purity is 99.7%; and the chiral chromatogram is shown in Fig. 16, where the optical purity is 99.87%.

Example 9

This example discusses the preferred type of imine reductase. The implementation of the corresponding method is described below.

IRED enzyme powder was weighed and 10 mg was placed into each of the 2 ml reaction vessels. 9.2 mg of glucose, 1 mg of sodium salt NAD, 1 mg of sodium salt of NADP, 2 mg of glucose dehydrogenase ES-GDH105 and 900 μl of 0.1 M phosphate buffer solution (pH 7.0) were added to each vessel and shaken until until the solution became clear. 5 mg myosmin and 100 μL DMSO were then added to each vessel. The vessels were tightly sealed, placed in a shaking device at a constant temperature of 30°C and shaken overnight. Samples were analyzed by HPLC for conversion and chirality. The results are presented in Table 1.

As can be seen from the data in Table 1, ES-TRED103 and IRED1321110 are the more preferred types of imine reductase.

Example 10

This example discusses the preferred type of glucose dehydrogenase. The implementation of the corresponding method is described below.

The GDH enzyme powder was weighed and 2 mg was placed into each of the 2 ml reaction vessels. 9.2 mg glucose, 1 mg sodium NAD, 1 mg sodium NADP, 10 mg ES-IRED103 and 900 μl of 0.1 M phosphate buffer solution (pH 7.0) were added to each vessel and shaken until the solution did not become transparent. 150 mg of myosmin and 100 μl of DMSO were then added to each vessel. The vessels were tightly sealed, placed in a shaking device at a constant temperature of 30°C and shaken overnight. Samples were analyzed by HPLC to determine the degree of conversion. The results are presented in Table 2.

As can be seen from the data in Table 2, ES-GDH109 is the preferred type of glucose dehydrogenase.

Example 11

This example discusses the preferred type of coenzyme. The implementation of the corresponding method is described below.

Samples of 1 mg of NAD sodium salt and 1 mg of NADP sodium salt were placed in each of the 2 ml reaction vessels, respectively. 9.2 mg of glucose, 2 mg of ES-GDH109 enzyme powder, 10 mg of ES-IRED103 and 900 μl of 0.1 M phosphate buffer solution (pH 7.0) were added to each vessel and shaken until the solution became clear . 150 mg of myosmin and 100 μl of DMSO were then added to each vessel. The vessels were tightly sealed, placed in a shaking device at a constant temperature of 30°C and shaken overnight. Samples were analyzed by HPLC to determine the degree of conversion. The results are presented in Table 3.

As can be seen from the data in Table 3, the sodium salt of NADP is the more preferred type of coenzyme.

Applicant states that although the method for synthesizing (S)-nicotine in the present application is described by means of the examples that are presented above, the present application is not limited to the examples described above, and this means that the implementation of the present application does not necessarily depend on the examples described above. It will be apparent to those skilled in the art that any improvements made to this application, equivalent substitutions of product starting materials, additions of auxiliary ingredients, selection of specific methods, and other terms in this application are in all cases within the scope of the legal protection and scope of the disclosure of this application.

Although the preferred embodiments of the present application are described in detail above, the present application is not limited to the details of the embodiments as described above, and various simple modifications can be made to the technical solutions of the present application without deviating from the technical concept of the present application. All of these simple modifications are within the scope of the present application.

In addition, it should be noted that, unless conflicting, the specific technical features described in the embodiments presented above may be combined in any suitable manner. To avoid unnecessary repetition, the various possible combinations are not further described herein.

Claims (11)

1. A method for the synthesis of (S)-nicotine, in which, under the conditions of a coenzyme circulation system, including coenzyme, glucose and glucose dehydrogenase, using coenzyme as a hydrogen donor and imine reductase as a catalyst, myosmin is subjected to catalytic reduction with the following reactions to obtain (S) -nicotine: where the coenzyme is an NADP salt and/or a NAD salt. 2. The method for synthesizing (S)-nicotine according to claim 1, in which the coenzyme includes an NADP salt. 3. A method for synthesizing (S)-nicotine according to claim 1 or 2, wherein the glucose dehydrogenase is any glucose dehydrogenase or a combination of at least two glucose dehydrogenases from ES-GDH101, ES-GDH102 or ES-GDH109, preferably ES-GDH109. 4. Method of synthesis of (S)-nicotine according to any one of paragraphs. 1-3, wherein the imine reductase is any imine reductase or a combination of at least two imine reductases from ES-TRED101, ES-IRED103, ES-IRED104, ES-IRED107, IRED1321104, IRED1321108, IRED1321110 or IRED1321114, preferably ES-TRED103 or IRED1321110. 5. Method of synthesis of (S)-nicotine according to any one of paragraphs. 1-4, in which the catalytic reduction is carried out at a temperature ranging from 15 to 45°C and preferably from 25 to 30°C; preferably the catalytic reduction is carried out for 8 to 72 hours; preferably the catalytic reduction is carried out under stirring conditions at a rotation speed of 150 to 400 rpm. 6. Method of synthesis of (S)-nicotine according to any one of paragraphs. 1-5, in which the catalytic reduction is carried out in a buffer solution, the buffer solution being a phosphate buffer solution, a tris(hydroxymethyl)methylamine hydrochloride buffer solution, or a triethanolamine hydrochloride buffer solution; preferably the buffer solution has a pH value of from 5.0 to 9.0 and preferably from 5.8 to 6.5. 7. Method of synthesis of (S)-nicotine according to any one of paragraphs. 1-6, in which methylation involves mixing and reacting (S)-nornicotine with formaldehyde and formic acid to produce (S)-nicotine. 8. Method of synthesis of (S)-nicotine according to any one of paragraphs. 1-7, in which methylation is carried out at a temperature of from 55 to 80°C; preferably, methylation is carried out over a period of 8 to 48 hours. 9. Method of synthesis of (S)-nicotine according to any one of paragraphs. 1-8, including mixing myosmin, coenzyme, glucose, glucose dehydrogenase, buffer solution and imine reductase and reacting the mixture at a temperature of 15 to 45°C for 8 to 72 hours to obtain (S)-nornicotine, the mass ratio of myosmin, coenzyme and imine reductase is 1:(0.001-0.05):(0.05-0.1); and subsequent mixing of (S)-nornicotine with formaldehyde and formic acid and reacting the mixture at a temperature of 55 to 80°C for 8 to 48 hours to obtain (S)-nicotine.