Preparation method of S-nicotine intermediate

Abstract

The invention provides a preparation method of an intermediate for preparing S-nicotine and a method for preparing S-nicotine by using the intermediate, and the chemical name of the intermediate is (4S)-4-((S)-1-phenylethyl) amino-4-(3-pyridyl)-1-butanol. The method for preparing nicotine by adopting the intermediate has the advantages that high-price reagents and synthons are not needed, the condition is mild, the work amount is small, the total synthesis of S-nicotine can be completed by introducing a chiral center through a key chiral reductive amination reaction, and the method is high in efficiency, low in cost, safe, reliable and capable of being applied to industrial production.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and particularly relates to an intermediate of S-nicotine and a preparation method thereof. Background Art

[0002] Nicotine, commonly known as nicotine, is an alkaloid mainly present in solanaceous plants, and its chemical name is 1-methyl-2-(3-pyridyl)pyrrolidine. At present, it has been confirmed that nicotine has a variety of biological activities and is widely used in fields such as medicine and agriculture.

[0003] The means of obtaining nicotine are generally divided into two methods: extraction method and artificial synthesis method. The extraction method usually refers to extracting nicotine from tobacco, but this method is restricted by the supply and quality of tobacco. Factors such as the origin of tobacco, the part of the tobacco raw material used, and the quality will have a certain impact on the product quality, and the extraction process also varies. The quality stability of nicotine obtained by the extraction method is slightly poor. The artificial synthesis method refers to preparing nicotine from chemical raw materials by chemical or biological methods. The artificial synthesis method can overcome the deficiencies of the extraction method and obtain a large number of nicotine products stably and efficiently. The chemical structural formula of nicotine is .

[0004] As can be seen from the above structural formula, nicotine has two isomers, R and S. Most of the nicotine present in natural tobacco is the S-isomer, that is, (S)-1-methyl-2-(3-pyridyl)pyrrolidine. At present, the methods for obtaining single-configuration nicotine enantiomers are mainly divided into two technical routes: resolution method and asymmetric synthesis. At present, the raw materials used in the resolution method are racemic nicotine or its derivatives or upstream intermediates, and the optical isomers are separated by a chiral resolving agent. Commonly used resolving agents include L-tartaric acid and a series of its derivatives. For example, the US patent document US2018 / 0030028 discloses a method for resolving nicotine using L-dibenzoyl tartaric acid, and relatively pure S-nicotine is obtained by recrystallization.

[0005] For the chemical synthesis of S-nicotine, a variety of route schemes have been reported in the currently published literature. A common route is to introduce a chiral center in the later stage of the synthesis route. For example, S-nicotine is obtained by the asymmetric reduction of N-methylmesembrine or demethylmesembrine. The timing of introducing the chiral center in this route is relatively late. The advantages are that there are fewer subsequent processes and the conditions are relatively mild, and racemization reactions are not likely to occur. However, it often requires the use of relatively special conditions or reagents such as enzyme reactions, with high costs and certain requirements for production conditions. For example, Chinese patent CN113373188A discloses a process for the enzymatic asymmetric reduction of mesembrine to (S)-nornicotine.

[0006] Another type of synthetic strategy is to introduce chiral centers at the early stage of total synthesis. A common route is to use pyridine derivatives as raw materials, perform asymmetric modification on the side chain, and then obtain the nicotine nucleus with chiral centers through ring closure. For example, in US Patent US20220089564A1, an asymmetric center on the side chain is obtained by reducing pyridyl butanone in the presence of a chiral transition metal catalyst. Similarly, Chinese Patent CN114702474A also discloses a similar method of using a metal catalyst to obtain chiral alcohol and using it to prepare levonictine; Chinese Patent CN113121496A uses (R)-(+)-2-methyl-CBS-oxazaborolidine for stereoselective reduction reaction to prepare chiral alcohol. It can be seen that the currently disclosed prior art can obtain S-nicotine through various routes, but most of them still require the use of various special chiral reagents or catalysts, with high costs, which to a certain extent limits their application. Summary of the Invention

[0007] The present invention provides a method for synthesizing an intermediate for S-nicotine and a method for synthesizing S-nicotine using this intermediate. Compared with the prior art, this solution does not require the use of expensive special reagents or special conditions, and can complete the construction of chiral centers in S-nicotine through reagents with simple structures and low prices, thereby further obtaining S-nicotine products with high enantiomeric purity in high yields.

[0008] The present invention provides a method for preparing an intermediate, which is prepared by the following route to obtain a compound with the structure of formula (IV): Step 1: Using methyl nicotinate of formula I, that is, methyl pyridine-3-carboxylate, as the starting material, condensing with butyrolactone under strong base conditions to obtain α-(3-pyridylcarbonyl)-butyrolactone of formula II;

[0009] Step 2: Heating the α-(3-pyridylcarbonyl)-butyrolactone of formula II obtained in Step 1 in an acidic aqueous solution for ring-opening reaction, followed by a concerted decarboxylation reaction to remove the carboxyl group, obtaining 1-(3-pyridyl)-4-hydroxy-1-butanone of formula III.

[0010]

[0011] Step 3: Reacting the 1-(3-pyridyl)-4-hydroxy-1-butanone of formula III obtained in Step 2 with (S)-1-phenylethylamine under the condition of a borohydride reagent to perform reductive amination reaction to obtain chiral N-substituted pyridyl amino alcohol.

[0012]

[0013] Further, the solvent used in step 1 is selected from one of tetrahydrofuran and toluene, the strong base is selected from organic bases or inorganic bases, the organic base is selected from one or more of potassium tert-butoxide, sodium ethoxide, and sodium methoxide, and the inorganic base is selected from one of sodium hydride and lithium hydride or a mixture thereof.

[0014] Further, the acidic aqueous solution in step 2 is selected from one of sulfuric acid and acetic acid.

[0015] Further, the solvent used in step 3 is dichloromethane or tetrahydrofuran, and the temperature is 10°C - 30°C. Through experimental research by the inventors, it is found that milder conditions are beneficial to the stereoselectivity of the reaction and improve the optical purity of the product.

[0016] Further, in step 3, the borohydride reagent is selected from one of sodium triacetoxyborohydride and sodium cyanoborohydride.

[0017] The present invention provides a method for preparing S-nicotine using a compound of formula IV, and the steps are as follows: Step 4: The compound IV undergoes an intramolecular cyclization reaction to obtain N-protected S-nornicotine. The reaction conditions are to dissolve the compound IV in dichloromethane, add diethyl azodicarboxylate and triphenylphosphine, and react at 20°C - 30°C to obtain formula V (2S)-1-((S)-1-phenylethyl)-2-(3-pyridyl)pyrrolidine;

[0018] Step 5: The formula V (2S)-1-((S)-1-phenylethyl)-2-(3-pyridyl)pyrrolidine obtained in step 4 undergoes a catalytic hydrogenation reaction in an alcohol solvent to remove 1-phenylethyl, obtaining (2S)-2-(3-pyridyl)pyrrolidine, and the hydrogen pressure is 0.1 - 0.3 MPa;

[0019] Step 6: The formula VI (2S)-2-(3-pyridyl)pyrrolidine obtained in step 5 undergoes a methylation reaction in acetone. The methylation reagent is selected from one or more of methyl iodide, dimethyl carbonate, and dimethyl sulfate, and the acid-binding agent is potassium carbonate, sodium carbonate, or potassium phosphate. After reacting at room temperature for 6 - 10 h, it is filtered and evaporated to dryness, and after salting and then free purification, pure S-nicotine is obtained.

[0020]

[0021] Further, the catalyst in the step 5 is selected from one or more of H2 / 20%Pd(OH)2-C, H2 / Pd-C, H2 / PdCl2, Pd / HCOOH or Pd-C / HCOOH, Pd-C / HCOONH4, Pd-C / NH2NH2 or Pd-C / cyclohexene for hydrogen source transfer hydrogenation, or CCl3CH2COCl / CH3CN, Li / MH3, Na / NH3, CAN and CH3CHClOCOCl.

[0022] Beneficial effects The present invention provides an intermediate of S-nicotine and a preparation method of the intermediate. The advantages of using this intermediate to prepare nicotine are that there is no need to use expensive reagents and synthons, the conditions are mild, the workload is small, and the chiral center can be introduced through the key chiral reductive amination reaction, so as to complete the total synthesis of S-nicotine, with high efficiency, low cost, safety and reliability, and it can be applied to industrial production. Specific embodiments

[0023] To make the objectives, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below. Those not specified in the embodiments are carried out according to conventional conditions or conditions recommended by the manufacturer. Those reagents or instruments not specified by the manufacturer can be obtained as conventional products through commercial purchase.

[0024] Example 1 Preparation of (4S)-4-((S)-1-phenylethyl)amino-4-(3-pyridyl)-1-butanol (Formula IV) 66 g of 1-(3-pyridyl)-4-hydroxy-1-butanone (Formula III) was dissolved in 600 ml of dichloromethane, 53 g of (S)-1-phenylethylamine and 102 g of sodium triacetoxyborohydride were added, and the mixture was stirred at 10 °C for 8 h. After the reaction was completed, an aqueous sodium carbonate solution was added, stirred, and separated. The aqueous phase was extracted with dichloromethane twice, and the dichloromethane phases were combined and the solvent was removed under vacuum to obtain 86.5 g of pure (4S)-4-((S)-1-phenylethyl)amino-4-(3-pyridyl)-1-butanol (Formula IV), with ee = 99.0% Example 2 Preparation of (4S)-4-((S)-1-phenylethyl)amino-4-(3-pyridyl)-1-butanol (Formula IV) Dissolve 66 g of 1-(3-pyridyl)-4-hydroxy-1-butanone (Formula III) in 600 ml of dichloromethane, add 53 g of (S)-1-phenylethylamine and 31 g of sodium cyanoborohydride, and stir and react at 20 °C for 6 h. After the reaction is completed, add an aqueous sodium carbonate solution, stir, separate the layers, extract the aqueous phase with dichloromethane twice, combine the dichloromethane phases, and remove the solvent under vacuum to obtain 81.1 g of pure (4S)-4-((S)-1-phenylethyl)amino-4-(3-pyridyl)-1-butanol (Formula IV), with ee = 96.9%.

[0025] Example 3 Preparation of S-nicotine Dissolve 81 g of (4S)-4-((S)-1-phenylethyl)amino-4-(3-pyridyl)-1-butanol (Formula IV) in 1000 ml of dichloromethane, add diethyl azodicarboxylate and triphenylphosphine, and react at 20 °C - 30 °C to obtain 78 g of (2S)-1-((S)-1-phenylethyl)-2-(3-pyridyl)pyrrolidine (Formula V).

[0026] Carry out a catalytic hydrogenation reaction on (2S)-1-((S)-1-phenylethyl)-2-(3-pyridyl)pyrrolidine (Formula V) in an ethanol solvent, with the catalyst being H2 / 20% Pd(OH)2-C and the hydrogen pressure being 0.1 - 0.3 MPa to remove the 1-phenylethyl group and obtain (2S)-2-(3-pyridyl)pyrrolidine.

[0027] Carry out a methylation reaction on (2S)-2-(3-pyridyl)pyrrolidine in an acetone solvent, add the methylation reagent methyl iodide and the acid-binding agent potassium carbonate, filter and evaporate to dryness after reacting at room temperature for 6 - 10 h, and obtain pure S-nicotine after salification and then free purification.

[0028] The above are only the preferred embodiments of the present application and are not used to limit the present application. For those skilled in the art, the present application can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included within the protection scope of the present application.

Claims

1. A preparation method for preparing Compound IV, characterized in that, The compound of formula (IV) is prepared by the following route: Step 1: Using methyl nicotinate of formula I, i.e., methyl 3-pyridinecarboxylate, as the starting material, it undergoes a condensation reaction with butyrolactone under strong base conditions to obtain α-(3-pyridylcarbonyl)-butyrolactone of formula II; ； Step 2: The α-(3-pyridylcarbonyl)-butyrolactone of formula II obtained in Step 1 is heated in an aqueous sulfuric acid solution for a ring-opening reaction, followed by a concerted decarboxylation reaction to remove the carboxyl group, obtaining 1-(3-pyridyl)-4-hydroxy-1-butanone of formula III; ； Step 3: The 1-(3-pyridyl)-4-hydroxy-1-butanone of formula III obtained in Step 2 undergoes a reductive amination reaction with (S)-1-phenylethylamine under the condition of a borohydride reagent to obtain a chiral N-substituted pyridine amino alcohol; 。 2. The preparation method according to claim 1, wherein The solvent used in Step 1 is selected from one of tetrahydrofuran and toluene, the strong base is selected from an organic base or an inorganic base, the organic base is selected from one or more of potassium tert-butoxide, sodium ethoxide, and sodium methoxide, and the inorganic base is selected from one of sodium hydride and lithium hydride or a mixture thereof.

3. The preparation method according to claim 1, characterized in that, The acidic aqueous solution in Step 2 is selected from one of sulfuric acid and acetic acid.

4. The preparation method according to claim 1, characterized in that, The solvent used in Step 3 is dichloromethane or tetrahydrofuran, and the temperature is 10°C - 30°C.

5. The preparation method according to any one of claims 1-4, characterized in that, In Step 3, the borohydride reagent is selected from one of sodium triacetoxyborohydride and sodium cyanoborohydride.

6. A method for preparing S-nicotine using the compound of formula IV according to claims 1-5, characterized in that, The steps are as follows: Step 4: The intramolecular Mitsunobu reaction of Compound IV is carried out for ring closure to obtain N-protected S-nornicotine. The reaction conditions are as follows: Compound IV is dissolved in dichloromethane, diethyl azodicarboxylate and triphenylphosphine are added, and the reaction is carried out at 20 °C - 30 °C to obtain (2S)-1-((S)-1-phenylethyl)-2-(pyridin-3-yl)pyrrolidine of Formula V ; Step 5: Catalytic hydrogenation of the formula V (2S)-1-((S)-1-phenylethyl)-2-(3-pyridyl)pyrrolidine obtained in Step 4 is carried out in an alcohol solvent to remove 1-phenylethyl, and (2S)-2-(3-pyridyl)pyrrolidine is obtained. A 10% Pd / C catalyst is used in the reaction, and the hydrogen pressure is 0.1 - 0.3 MPa ; Step 6: Methylate the (2S)-2-(3-pyridyl)pyrrolidine obtained in Step 5 in acetone. The methylation reagent is selected from one or more of methyl iodide, dimethyl carbonate, and dimethyl sulfate, and the acid-binding agent is potassium carbonate, sodium carbonate, or potassium phosphate. After reacting at room temperature for 6-10 h, filter and evaporate to dryness, and obtain pure (S)-nicotine after salification and then free purification 。

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