阅读说明：本技术 一种高光学纯度烟碱的制备方法 (Preparation method of high-optical-purity nicotine ) 是由 李家全 魏庚辉 孟宪强 于 2020-11-18 设计创作，主要内容包括：本发明提供一种高光学纯度烟碱的制备方法,采用一种具有改变手性功能的还原酶体系,创新性的使用了生物酶催化技术,实现了中间产物麦斯明的定向还原,可以将中间体麦司明还原加氢并转化成单一手性,然后经过甲基化反应得到高收率、高光学纯度的左旋烟碱。创新性的开发了人工合成手性烟碱天然产物的新技术,手性纯度达到99％,可直接用于下游产品的制备。所用酶催化技术中的酶,可以高效率的循环使用,大大降低成本。(The invention provides a preparation method of high-optical-purity nicotine, which adopts a reductase system with a function of changing chirality, innovatively uses a biological enzyme catalysis technology, realizes the directional reduction of an intermediate product, namely, mesmine, can reduce and hydrogenate the intermediate product, namely, mesmine, and convert the intermediate product into single chirality, and then obtains the high-yield high-optical-purity levo-nicotine through a methylation reaction. Creatively develops a new technology for artificially synthesizing a chiral nicotine natural product, has the chiral purity of 99 percent, and can be directly used for preparing downstream products. The enzyme in the enzyme catalysis technology can be recycled with high efficiency, and the cost is greatly reduced.)

1. A preparation method of high optical purity nicotine comprises the following steps:

(a) under the condition of strong alkaline substance, the nicotinate and the vinyl pyrrolidone are condensed to obtain 3-nicotinoyl-1-vinyl-4, 5-dihydro-1H-pyrrole-2-potassium alcoholate;

(b) refluxing and stirring 3-nicotinoyl-1-vinyl-4, 5-dihydro-1H-pyrrole-2-potassium alcoholate in an acidic compound with a dilute concentration, and carrying out a one-pot reaction to obtain the Mairamine;

(c) under the condition of biological enzyme system making catalytic reduction reaction on myosmine to obtain intermediate with high optical purity-nornicotine;

(d) the final product, levo-nicotine, is obtained by aminomethylation reaction on the pyrrole ring of the nornicotine.

2. The method of claim 1, wherein the nicotinic acid ester is methyl nicotinate, ethyl nicotinate or tert-butyl nicotinate.

3. The method according to claim 2, wherein the strongly basic substance is sodium hydroxide, potassium hydroxide, sodium hydrogen, sodium tert-butoxide, potassium tert-butoxide, or lithium tert-butoxide.

4. The method according to claim 2, wherein the acidic compound is one or a mixture of two or more of perchloric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, trifluoromethanesulfonic acid, chlorosulfonic acid, sulfamic acid, trifluoroacetic acid, trichloroacetic acid, benzenesulfonic acid, and picric acid.

5. The method according to claim 4, wherein the concentration of the hydrochloric acid is 3M to 6M.

6. The method of claim 4, wherein the one-pot reaction comprises ring opening, decarboxylation, and cyclization reactions.

7. The preparation method according to claim 6, wherein the back-flow stirring is performed to generate the myosmine, the myosmine is cooled, the pH value of the myosmine is adjusted to 9-14 by adding alkali, and the myosmine is obtained by extraction and concentration.

8. The method according to claim 7, wherein the bio-enzyme catalysis system is bio-enzyme cycle catalysis, and the reduction of the myosmine in the bio-enzyme cycle catalysis results in the nornicotine as an intermediate with high optical purity.

9. The method of claim 8, wherein the biological enzyme system comprises a glucose dehydrogenase and an imine reductase.

10. The method of claim 9, wherein the prepared levo-nicotine has an optical purity of 99% or more.

11. The preparation method according to claim 10, wherein the reaction temperature of the bio-enzyme catalysis system is 22-37 ℃.

12. The preparation method of claim 11, wherein the reaction time of the bio-enzyme catalysis system is 8-16 hours.

13. The preparation method according to claim 11, wherein after aminomethylation reaction occurs on the pyrrole ring of the nornicotine, the pH value is adjusted to 9-14, and the final product, levonicotine, is obtained by extraction with an extractant, concentration and distillation.

14. The method according to claim 7 or 13, wherein the extraction solvent used for extraction is one or a mixture of two or more of n-hexane, ethyl acetate, dichloromethane, chloroform and butyl acetate.

Technical Field

The invention relates to the technical field of nicotine preparation processes, in particular to a preparation method of high-optical-purity nicotine.

Background

Nicotine, also known as nicotine, is a naturally occurring liquid alkaloid having strong physiological activity. Nicotine is generally found mainly in natural tobacco and has important applications in agriculture, the field of pharmaceutical intermediates, and the like. In agriculture, nicotine is used as a compound component of an insecticide, a herbicide and a plant growth regulator, the application range of the original pesticide is expanded, and the pesticide is a high-efficiency, low-toxicity and broad-spectrum green pesticide and meets the requirement of green food production. In addition, the compounding of nicotine and fertilizer can increase the fertilizer efficiency and reduce the loss of ammonium nitrogen. In the prevention and treatment of diseases in animals, nicotine in the form of an aerosol can be used for disinfection of poultry houses.

In the pharmaceutical industry, nicotine is used as a raw material, and medicines such as nicotinic acid, nicotinamide, ketamine, isoniazid and the like can be prepared through multi-step reactions. A small amount of nicotine can stimulate the central nervous system of human body, and has the effects of calming the mind and resisting melancholy, and relieving tension and weakness of human body. Nicotinic acid synthesized with nicotine is effective in treating Alzheimer's disease, Parkinson's disease, antioxidation, pyoderma gangrenosum, ulcerative colitis, antiepileptic, attention deficit, schizophrenia, memory and learning disorders, pain, etc., and is also effective in anxiety and depression. The high-purity nicotine can also be used as raw materials of health cigarette, smoking cessation paste, external drugs for treating arthralgia and muscle spasm, and special raw materials for developing cardiovascular diseases, venomous snake, insect bite and other diseases. The nicotine is also used for producing high-grade edible or feeding tobacco protein, medical health-care functional protein, nicotinic acid inositol lipid and other traditional medical raw materials. Nicotinic acid synthesized by nicotine can also be used for producing nicotinamide, and is a traditional medicine raw material for producing nicotinic acid inositol lipid and the like, and nicotine is a good raw material for producing cosmetics and skin care products in daily chemical industry.

Nicotine is also an important chemical raw material. Nicotinic acid and its derivatives, nicotinamide, creatine nicotinate, hexocoline nicotinate, tocopherol nicotinate, etc. can be prepared by oxidation and alcoholization.

In addition, the role of nicotine in smoking cessation is becoming more and more appreciated. In the early 80 s of the last century, the american promoter developed a "nicotine replacement therapy" and subsequently developed a series of alternative products for cigarettes, such as nicotine chewing gum, nicotine patch, nicotine aerosol inhalant, nicotine lozenge, and nicotine nasal spray.

The levo-nicotine used in the market is mainly derived from plant extraction, so that the levo-nicotine is influenced by various factors such as raw materials, climate, period and the like, and the racemic nicotine can only be obtained by synthesis.

The document journal of Organic Chemistry,1990,55(6), 1736-; the synthesis of racemic nicotine from pyrrolidine via a four-step reaction is reported as follows:

the tert-butyl lithium involved in the document and the low temperature of-120 ℃ in the reaction increase the difficulty of industrial production, and the yield of the method is low.

The Journal of the Chemical Society, Perkin Transactions I, 2002(2), 143-; a four-step process for the preparation of racemic nicotine starting from nicotinic acid is reported, as follows:

the grignard reagents used in this document also limit their industrial application.

Document Synlett,2009(15), 2497-; the preparation of racemic nicotine starting from 3-pyridinecarboxaldehyde is reported as follows:

the method still cannot fundamentally overcome the problem that the racemic nicotine is difficult to industrially produce.

The Journal of Heterocyclic Chemistry,2009,46(6), 1252-; a reported method for preparing racemic nicotine is shown below:

the route uses butyl lithium to carry out metal exchange on 3-bromopyridine at low temperature, and also has the defect that the scale production cannot be realized.

The document CN 102617547a reports a method for preparing racemic nicotine, as follows:

this route is a great improvement over the above-described process, but the synthesis is still racemic nicotine, and differs considerably from naturally extracted nicotine.

Patent CN 110357853B states a synthesis method of (R, S) nicotine, which uses 3-bromopyridine and magnesium chips as raw materials to prepare grignard reagent of 3-bromopyridine; adding N-methyl pyrrolidone into the system, carrying out condensation and hydrolysis reactions, adjusting the pH value to be alkaline, concentrating, and distilling to obtain an enamine intermediate; then carrying out reduction reaction in the presence of metal reduction catalysts such as Pd/C, Pt/C, Raney nickel and the like to obtain a racemized product R, S-nicotine.

Patent CN111511726A reports a method for preparing racemic nicotine, specifically: obtaining 3-nicotinoyl-1-vinyl pyrrolidine-2-ketone by ethyl nicotinate and N-vinyl pyrrolidone in the presence of alcoholate base, and obtaining myosmine under the action of acid; reduction of mesmine to nornicotine with reductant and methylation reaction to obtain racemic nicotine. In addition, the patent also reports that resolution of the resulting racemic nicotine using dibenzoyltartaric acid yields levonicotine with an optical purity of greater than 99%.

The reagents used in the above routes are expensive, the steps are complicated, and the period is long; low-temperature reaction is often adopted, and the separation and purification of each step are complex and the treatment difficulty is high; meanwhile, the production cost is high, and the industrial production is difficult to realize. In addition, the nicotine prepared by the above routes is racemic nicotine, and the production technology of levo-nicotine is only rarely reported at present.

The preparation method adopted by the prior art mainly has the following three disadvantages:

the invention adopts biotechnology biological enzyme for catalytic reaction, adopts water as a reaction solvent, has less three wastes, low post-treatment cost, excellent catalytic cycle and recyclable enzyme.

The second disadvantage is that nicotine prepared by the prior art is racemic substance, and to obtain single chiral nicotine with high optical purity, chemical resolution method is needed for separation and purification, and the process is complicated. The invention adopts biological enzyme catalysis, can directly generate the levonicotine without splitting.

The preparation method has the advantages that the preparation route is long, and the total yield is low; the invention has short preparation route and high total yield.

Disclosure of Invention

The invention provides a reductase system with a function of changing chirality, innovatively uses a biological enzyme catalysis technology to realize the directional reduction of an intermediate product, namely, the mesmine can be reduced and hydrogenated and converted into single chirality, and levo-nicotine with high yield and high chiral purity is finally obtained through a methylation reaction, and the process comprises the following steps:

a preparation method of high optical purity nicotine comprises the following steps:

(a) under the condition of strong alkaline substance, the nicotinate and the vinyl pyrrolidone are condensed to obtain 3-nicotinoyl-1-vinyl-4, 5-dihydro-1H-pyrrole-2-potassium alcoholate;

(b) refluxing and stirring 3-nicotinoyl-1-vinyl-4, 5-dihydro-1H-pyrrole-2-potassium alcoholate in an acidic compound with a dilute concentration, and carrying out a one-pot reaction to obtain the Mairamine;

(c) under the condition of biological enzyme system making catalytic reduction reaction on myosmine to obtain intermediate with high optical purity-nornicotine;

(d) the final product, levo-nicotine, is obtained by aminomethylation reaction on the pyrrole ring of the nornicotine.

As shown in the chemical reaction formula, the nicotinate (1) and the vinyl pyrrolidone are condensed to obtain 3-nicotinoyl-1-vinyl-4, 5-dihydro-1H-pyrrole-2-potassium alcoholate (2); refluxing and stirring 3-nicotinoyl-1-vinyl-4, 5-dihydro-1H-pyrrole-2-potassium alcoholate in hydrochloric acid with dilute concentration, and reacting in one pot to obtain the Maistine (3); under the condition of biological enzyme system the intermediate-nornicotine (4) with high optical purity can be obtained by means of catalytic reduction of myosmine (3), and the final product-levonicotine (5) can be obtained by means of aminomethylation reaction directly on pyrrole ring of nornicotine (4) without treatment.

Further, the one-pot reaction comprises ring opening, decarboxylation and cyclization reactions.

Further, the nicotinic acid ester is preferably methyl nicotinate, ethyl nicotinate or tert-butyl nicotinate.

Further, the strong base is sodium hydroxide, potassium hydroxide, sodium hydrogen, sodium tert-butoxide, potassium tert-butoxide or lithium tert-butoxide. Preferably, methyl nicotinate, vinyl pyrrolidone and potassium tert-butoxide are added into dry n-hexane and stirred under reflux for 2-5 hours.

Further, the acidic compound is one or a mixture of more than two of perchloric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, trifluoromethanesulfonic acid, chlorosulfonic acid, sulfamic acid, trifluoroacetic acid, trichloroacetic acid, benzenesulfonic acid and picric acid. Wherein the concentration of the hydrochloric acid is 3M-6M.

Further, cooling the reaction product after refluxing and stirring to generate the myosmine, adding alkali to adjust the pH value to 9-14, and extracting and concentrating to obtain the myosmine.

Further, the biological enzyme catalysis system is biological enzyme cycle catalysis.

Further, the product prepared by the biological enzyme cycle catalysis is a single chiral product, namely levonicotine.

Further, the optical purity of the prepared levo-nicotine reaches more than 99%. The optical purity of the L-nicotine product is basically consistent with that of a natural extraction product, and the total yield of the process route for preparing the L-nicotine can reach 80 percent or more.

Further, the biological enzyme system comprises glucose dehydrogenase and imine reductase.

Further, the reaction temperature of the biological enzyme catalysis system is 22-37 ℃.

Further, the reaction time of the biological enzyme catalysis system is 8-16 hours.

Further, after aminomethylation reaction is carried out on the nornicotine pyrrole ring, the pH value is firstly adjusted to 9-14, and the final product, namely the levonicotine, is obtained through extraction, concentration and distillation.

Further, the extraction solvent used for extraction is one or a mixture of more than two of n-hexane, ethyl acetate, dichloromethane, chloroform and butyl acetate.

The invention has the beneficial effects that:

1. creatively develops a new technology for artificially synthesizing a chiral nicotine natural product, has the chiral purity of 99 percent, and can be directly used for preparing downstream products.

2. Adopts a one-pot method without separation to prepare the levo-nicotine by multi-step integration. Compared with other synthetic routes, the steps are short, the product purity is as high as 99.7%, and the product purity is far higher than that of like products in the current market.

3. In the traditional process, extremely flammable alkali metal organic compounds such as butyllithium, hexamethyldisilazane lithium amide and the like are used, and the defects of high danger, harsh reaction conditions, high toxicity and the like are caused. After the improvement of our company, the main reaction solvent is water, and the method can be recycled, and has less waste liquid and low environmental protection pressure. The yield of the intermediate, namely the myosmine, synthesized by adopting the system can reach 85 percent, which is higher than that reported in the literature (the highest yield is 77 percent), and the system has lower production cost and safe and controllable production.

4. Compared with the traditional catalytic hydrogenation technology, the fermentation cost of the biological enzyme catalysis technology is low, the reaction condition is mild, and the potential safety hazard is greatly reduced; the reaction system adopts water as a solvent, and is safe, green and environment-friendly.

5. The enzyme in the enzyme catalysis technology can be recycled with high efficiency, and the cost is greatly reduced.

Drawings

FIG. 1 chemical structure diagram of the present invention;

figure 2 is a route diagram for synthesis of levonicotine according to the invention.

Detailed Description

The invention is further described below with reference to the figures and examples.

Under the condition of strong alkaline substance, the nicotinate (1) and the vinyl pyrrolidone are condensed to obtain 3-nicotinoyl-1-vinyl-4, 5-dihydro-1H-pyrrole-2-potassium alcoholate (2); 3-nicotinoyl-1-vinyl-4, 5-dihydro-1H-pyrrole-2-potassium alcoholate (2) is refluxed and stirred in hydrochloric acid with dilute concentration, a one-pot reaction is carried out to obtain myosmine (3) through ring opening, decarboxylation and cyclization, then an intermediate with high optical purity, namely nornicotine (4) is obtained through catalytic reduction in a biological enzyme system, aminomethylation reaction is directly carried out on the pyrrole ring of the nornicotine without post-treatment, and the final product, namely levonicotine (5), is obtained through pH regulation, extraction, concentration and distillation.

Wherein, the one-pot reaction comprises ring opening, decarboxylation and cyclization reactions, and the specific chemical reaction formula is as follows:

example 1

300g of methyl nicotinate, 300g of vinylpyrrolidone and 340g of potassium tert-butoxide were added to dry n-hexane, and the mixture was stirred under reflux for 3 hours. After cooling to room temperature, filtration was carried out, and the filter cake was added to dilute hydrochloric acid and stirred under reflux for 9 hours. After cooling, the pH was adjusted to 10 with a base and extracted with ethyl acetate. Concentrating, performing catalytic reaction for 14 hours by an enzyme system, then performing methylation reaction, adjusting the pH to 10, extracting by ethyl acetate, concentrating and distilling to obtain 283.8g of levonicotine, wherein the total yield is 80.6%, the GC purity is 99.69%, and the optical purity is 99% e.e.

Example 2

150g of ethyl nicotinate, 132.4g of vinyl pyrrolidone and 35.8g of sodium hydride are added into dry n-hexane, refluxed and stirred for 5 hours, cooled to room temperature, filtered, and a filter cake is added into dilute hydrochloric acid and refluxed and stirred for 16 hours. After cooling, the pH was adjusted to 14 by adding a base, and then n-hexane was extracted. Concentrating, performing catalytic reaction for 8 hours by an enzyme system, performing methylation reaction, adjusting pH to 14, extracting by n-hexane, concentrating, and distilling to obtain 136.7g of L-nicotine with total yield of 85%, GC purity of 99.7% and optical purity of 99% e.e.

Example 3

Adding 300g of ethyl nicotinate, 280g of vinyl pyrrolidone and 300g of potassium tert-butoxide into dry n-hexane, refluxing and stirring for 3 hours, cooling to room temperature, filtering, adding a filter cake into dilute hydrochloric acid, and refluxing and stirring for 21 hours. After cooling, the pH was adjusted to 12 by adding a base and extracted with dichloromethane. Concentrating, performing catalytic reaction for 12 hours by an enzyme system, performing methylation reaction, adjusting pH to 12, extracting with dichloromethane, concentrating, and distilling to obtain 261g of L-nicotine with total yield of 81.1%, GC purity of 99.7%, and optical purity of 99% e.e.

Example 4

200g of nicotinic acid tert-butyl ester, 175g of vinyl pyrrolidone and 160.9g of sodium tert-butoxide are added into dry n-hexane, refluxed and stirred for 2 hours, cooled to room temperature, filtered, and a filter cake is added into dilute hydrochloric acid and refluxed and stirred for 30 hours. After cooling, the pH was adjusted to 9 with alkali and chloroform extraction was carried out. Concentrating, performing catalytic reaction for 16 hours by an enzyme system, then performing methylation reaction, adjusting the pH to 9, extracting with chloroform, concentrating, and distilling to obtain 143g of L-nicotine with yield of 79.1%, GC purity of 99.62%, and optical purity of 99% e.e.

Example 5

200g of methyl nicotinate, 190.7g of vinyl pyrrolidone and 120g of lithium tert-butoxide are added into dry n-hexane, refluxed and stirred for 5 hours, cooled to room temperature, filtered, and a filter cake is added into dilute hydrochloric acid and refluxed and stirred for 30 hours. After cooling, the pH was adjusted to 11 by adding a base, and then n-hexane was extracted. Concentrating, performing catalytic reaction for 8 hours by an enzyme system, performing methylation reaction, adjusting pH to 11, extracting by n-hexane, concentrating, and distilling to obtain 190g of levonicotine with yield of 80%, GC purity of 99.69% and optical purity of 99% e.e.

Example 6

300g of nicotinic acid tert-butyl ester, 242g of vinyl pyrrolidone and 288g of potassium tert-butoxide are added into dry toluene, refluxed and stirred for 5 hours, cooled to room temperature, filtered, and a filter cake is added into dilute hydrochloric acid and refluxed and stirred for 30 hours. After cooling, the pH was adjusted to 9 by adding a base and extracted with dichloromethane. Concentrating, performing catalytic reaction for 16 hours by an enzyme system, performing methylation reaction, adjusting pH to 9, extracting with dichloromethane, concentrating, and distilling to obtain levonicotine g with yield of 79.1%, GC purity of 99.62%, and optical purity of 99% e.e.

While the invention has been described in connection with specific preferred embodiments, it is to be understood that the invention is not limited to the disclosed embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.