CN114437029A - Preparation method for asymmetric synthesis of chiral nicotine and chiral nicotine - Google Patents
Preparation method for asymmetric synthesis of chiral nicotine and chiral nicotine Download PDFInfo
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Abstract
The application relates to the technical field of nicotine synthesis, and particularly discloses chiral nicotine and a preparation method for asymmetrically synthesizing the chiral nicotine. The preparation method of asymmetric synthesis chiral nicotine takes 3-bromopyridine, 4-chlorobutyraldehyde and chiral tertiary butyl sulfenamide as raw materials, and the chiral nicotine is obtained by dehydration condensation, nucleophilic addition, cyclization and aminomethylation reaction. The chiral nicotine prepared by the method has high purity and high yield, and meets the market demand. The preparation method has the advantages of easiness in operation, low cost and suitability for industrial production.
Description
Technical Field
The application relates to the technical field of chiral nicotine synthesis, in particular to a preparation method for asymmetrically synthesizing chiral nicotine and the chiral nicotine.
Background
Nicotine is widely present in Solanaceae plants, is the main component of nitrogenous alkaloid in tobacco, has content of 3-4% in tobacco leaf, and can be used as natural pesticide and smoking stopping medicine.
At present, nicotine is mainly extracted from waste tobacco, and nicotine extracted and purified from plants such as tobacco and the like usually contains a plurality of other tobacco compounds which are unhealthy to human body systems and are proved to be carcinogenic; meanwhile, the nicotine extracted and purified from plants such as tobacco and the like is influenced by various factors such as raw materials, climate, land resources, period and the like.
The nicotine molecule has 1 chiral center, namely chiral nicotine comprises two configurations of R-nicotine and S-nicotine.
The artificial synthetic nicotine is not extracted from traditional tobacco, is directionally synthesized by chemical raw material medicines, and does not contain harmful impurities such as nitrosamine and the like. The most direct difference between them is: the natural nicotine contains nitrosamine and is levorotatory. The synthetic nicotine contains no nitrosamine, the artificial synthetic nicotine products on the market are divided into racemic products and levorotatory products, and 5mg of levorotatory nicotine can produce the effect of 10mg of racemic nicotine. In the existing artificial nicotine synthesis process, raceme is generally required to be obtained first, and the raceme is required to be further separated and purified into a levorotatory product. The existing artificial synthesis method is very complex, high in cost and not beneficial to commercial popularization.
The inventor considers that the existing artificial synthesis of nicotine has various problems, and a new method for synthesizing nicotine is urgently needed to avoid the defects existing in the prior art.
Disclosure of Invention
In order to overcome the defect of low purity of synthesized nicotine in the related technology, the application provides chiral nicotine and a preparation method for asymmetrically synthesizing the chiral nicotine.
In a first aspect, the present application provides a method for asymmetrically synthesizing chiral nicotine, which adopts the following technical scheme:
a method for preparing asymmetric synthetic chiral nicotine comprises the following steps:
preparation of intermediate product I: dissolving 4-chlorobutyraldehyde in an organic solvent, adding chiral tert-butyl sulfenamide and a dehydrating agent, heating for reaction to obtain a first mixture, and separating an intermediate product I from the first mixture; dissolving the intermediate product I in an ether reagent to obtain a mixed solution for later use;
nucleophilic addition reaction: under the protection of inert gas, adding 3-bromopyridine into an anhydrous solvent, cooling, preparing an organic metal reagent, fully stirring, adding a mixed solution to react to obtain a second mixture, and sequentially quenching, layering, extracting, washing, drying and distilling under reduced pressure to obtain an intermediate product II;
cyclization reaction: dissolving the intermediate product II obtained in the nucleophilic addition reaction step in an aprotic polar solvent, adding carbonate, heating to react to obtain a third mixture, extracting, layering, washing, drying, filtering, distilling under reduced pressure, and purifying to obtain an intermediate product III;
preparation of chiral demethylated nicotine: adding the intermediate product III obtained in the cyclization reaction into an organic solvent, then adding an organic acid and/or an inorganic acid, heating and stirring to fully react, and separating and extracting the chiral demethyl nicotine after the reaction is finished.
Amine methylation reaction: and adding an amine methylation reagent into the prepared chiral demethylated nicotine, heating for full reaction, and separating and purifying after the reaction is finished to obtain the chiral nicotine.
By adopting the technical scheme, firstly, 4-chlorobutyraldehyde and chiral tertiary butyl sulfenamide are taken as raw materials, and the 4-chlorobutyraldehyde and chiral tertiary butyl sulfenamide are subjected to dehydration condensation reaction under the action of a dehydrating agent and heating to obtain an intermediate product I; under the protection of nitrogen or argon, 3-bromopyridine and an organic metal reagent or magnesium form an organic lithium reagent or a Grignard reagent, and then the organic lithium reagent or the Grignard reagent and the intermediate product 1 undergo nucleophilic addition to generate an intermediate product II, wherein the purity of the intermediate product II generated by the reaction is high; then, chiral demethyl nicotine is constructed through cyclization, and finally, aminomethylation is carried out to obtain nicotine with single configuration. The preparation method provided by the application is simple to operate, and the synthesized chiral nicotine is high in purity, ee value and total yield.
Optionally, the step of preparing intermediate product I is specifically operated as follows: dissolving 4-chlorobutyraldehyde in a certain volume of 1, 2-dichloroethane, stirring, adding chiral tert-butyl sulfenamide in parts by weight, adding a dehydrating agent, heating to 75-85 ℃, and carrying out reflux reaction for 5-12 hours to obtain a first mixture; cooling the first mixture to room temperature, filtering, washing with clear water, repeating the washing operation once or more, separating a water layer and an organic layer, drying the organic layer, filtering, and concentrating the filtrate at 40-50 deg.C under reduced pressure until no distillation is produced to obtain intermediate product I.
Optionally, in the step of preparing the intermediate product I, the dehydrating agent includes anhydrous copper sulfate, anhydrous magnesium sulfate, anhydrous calcium chloride, and dehydrated molecular sieve, and the dehydrated molecular sieve includes, but is not limited to, zeolite molecular sieve.
Optionally, in the step of preparing the intermediate product I, the reaction temperature is 75-85 ℃, and the reaction time is 5-12 hours; preferably, the reaction temperature is 80 ℃;
optionally, the intermediate I is (S, E) -N- (4-chlorobutene) -2-methyl-2-propane sulfinamide or (R, E) -N- (4-chlorobutene) -2-methyl-2-propane sulfinamide; the separation step comprises filtering, washing, layering, drying the organic layer, filtering, and concentrating under reduced pressure.
Optionally, the nucleophilic addition reaction comprises the following specific steps: dissolving the intermediate product I in an ether solvent to obtain a mixed solution for later use; adding a nucleophilic reagent into an anhydrous solvent under the protection of nitrogen/argon, reducing the temperature to-10 ℃ to-70 ℃, then adding a mixed solution to react to obtain a second mixture, and carrying out quenching, layering, extraction, washing, drying and reduced pressure distillation on the second mixture to obtain an intermediate product II.
Alternatively, the ether reagent includes diethyl ether and tetrahydrofuran.
Optionally, intermediate II is (S) -N- ((S) -4-chloro-1- (3-pyridinyl) butyl) -2-methyl-2-propanesulfinamide or (R) -N- ((R) -4-chloro-1- (3-pyridinyl) butyl) -2-methyl-2-propanesulfinamide.
Optionally, the organometallic reagent comprises an organolithium reagent and a grignard reagent.
Optionally, the nucleophilic agent is preferably an organolithium reagent, and the organolithium reagent is RLi (R is alkyl, alkenyl, alkynyl, aryl, etc.); preferably, the organolithium reagent includes n-butyllithium, methyllithium, phenyllithium, and the like; most preferably, the organolithium reagent is n-butyllithium.
Optionally, the organometallic reagent reacts with 3-bromopyridine to produce pyridine, which undergoes a nucleophilic addition reaction with intermediate II to form intermediate III.
By adopting the technical scheme, the organic lithium reagent and the Grignard reagent are selected, the two reagents are cheap and easy to obtain, the reaction is quick, the purity of the produced intermediate product II is high, the next reaction can be carried out without purification, in addition, the organic lithium reagent has higher activity than the Grignard reagent, the nucleophilic addition reaction can be more thorough, and the yield of the obtained product is higher.
Optionally, the reaction solution for quenching the second mixture includes a saturated ammonium chloride aqueous solution-methyl tert-butyl ether mixed solution, and an ammonium chloride aqueous solution-petroleum ether mixed solution.
Optionally, the reagent used in the extraction operation in the nucleophilic addition reaction is one or more of methyl tert-butyl ether or ethyl acetate.
Alternatively, the reagent used for washing in the nucleophilic addition reaction is saturated saline, and is washed 2 times.
Optionally, the carbonate used in the cyclization reaction comprises a combination of one or more of sodium carbonate, potassium carbonate and cesium carbonate.
Optionally, the temperature of the heating reaction in the cyclization reaction is between 60 ℃ and 70 ℃, and the reaction temperature is preferably 60 ℃ in the application.
Optionally, the heating reaction time in the cyclization reaction is 4-8 hours.
Optionally, the extraction, layering, washing, drying, filtering, reduced pressure distillation and purification in the cyclization reaction specifically comprise: cooling, filtering, quenching the filtrate, layering, extracting the water layer with methyl tert-butyl ether or chloroform, repeating the extraction operation twice, combining the obtained organic layers, washing the organic layers, washing with clear water for more than one time, washing with saturated saline for more than one time, drying the organic layers, filtering, distilling under reduced pressure to remove the solvent, and then performing column chromatography to remove impurities to obtain an intermediate product III.
Optionally, the intermediate III is 3- ((S) -2- (1- (S) -tert-butylsulfinyl) pyrrolidinyl) pyridine or 3- ((R) -2- (1- (R) -tert-butylsulfinyl) pyrrolidinyl) pyridine.
Optionally, the step of separating and extracting in the step of preparing chiral demethylated nicotine specifically comprises: standing for layering, adjusting pH of the water layer to 11 with 4M sodium hydroxide, extracting with dichloromethane, repeating the extraction operation for 3 times, mixing the organic layers, drying, filtering, and concentrating to obtain chiral demethyl nicotine.
By adopting the technical scheme, the yield of the generated chiral demethylated nicotine reaches more than 91 percent.
Optionally, the amine methylation reagent for the amine methylation reaction is formaldehyde solution (40%) and formic acid.
Optionally, the reaction temperature in the aminomethylation reaction is between 75 ℃ and 85 ℃, and the optimal reaction temperature in the application is 80 ℃.
Optionally, the separation and purification step in the aminomethylation reaction specifically includes cooling to room temperature, adding hydrochloric acid, extracting with dichloromethane, adjusting the pH of the water layer to 11 with 8M sodium hydroxide, extracting with dichloromethane again, repeating the extraction for 3 times, combining the organic layers, drying, filtering, concentrating, and rectifying to obtain chiral nicotine.
The purpose of adding the hydrochloric acid in the application is to react a target product, namely chiral nicotine, to form salt, dissolve the salt in a water layer, extract other organic matters by using dichloromethane, adjust the pH value of the water layer to enable the salified chiral nicotine to be dissociated, and extract the salt to obtain the chiral nicotine.
By adopting the technical scheme, the yield of the generated chiral nicotine reaches over 85 percent, and the purity reaches 99.8 percent.
The drying agent used in the drying step includes, but is not limited to, anhydrous copper sulfate, anhydrous sodium sulfate, anhydrous calcium chloride, etc., and anhydrous sodium sulfate is preferred in the present application.
Optionally, when the chiral tert-butyl sulfenamide in the reaction for preparing the intermediate product I is S-tert-butyl sulfenamide, the finally prepared chiral nicotine is S-nicotine; when the chiral tert-butyl sulfinamide in the reaction for preparing the intermediate product I is R-tert-butyl sulfinamide, the finally prepared chiral nicotine is R-nicotine.
Optionally, the organic solvent is selected from one or more of 1, 2-dichloroethane, dichloromethane, chloroform, and toluene.
Optionally, the anhydrous solvent is one or more selected from anhydrous diethyl ether, anhydrous tetrahydrofuran and anhydrous 2-methyltetrahydrofuran.
Optionally, the aprotic polar solvent is selected from one or more of dimethylsulfoxide, N-dimethylformamide, tetrahydrofuran, and acetone.
Optionally, the inorganic acid comprises one or more of sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, hydrobromic acid, hydroiodic acid, perchloric acid, in combination.
Optionally, the organic acid comprises a combination of one or more of trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, citric acid, tartaric acid, and maleic acid.
Optionally, when the inorganic acid is phosphoric acid, water needs to be added for dilution due to high viscosity of the phosphoric acid.
Optionally, in the separation steps of the preparation of chiral demethylated nicotine and the aminomethylation reaction, an inorganic base is added to adjust the pH to be greater than 10.
By adopting the technical scheme, the chiral demethylated nicotine can generate salt under the acidic condition, so that the salt is dissolved in a reaction system, and when the pH value is greater than 10, the chiral demethylated nicotine can dissociate out of a water system, so that layering is realized, and the extraction and separation are facilitated.
Optionally, the inorganic base comprises sodium hydroxide, potassium hydroxide, calcium hydroxide.
Preferably, the inorganic base is sodium hydroxide.
In a second aspect, the present application provides a chiral nicotine.
Chiral nicotine prepared by the method of claims 1-7.
By adopting the technical scheme, the chiral nicotine generated by adopting the method has high purity and high yield, and can meet the market demand.
The structural formula of chiral nicotine is shown as follows, and comprises two configurations of R and S;
in summary, the present application has the following beneficial effects:
the preparation process is easy to operate, raw materials are easy to obtain and low in cost, the prepared chiral synthetic nicotine is high in purity, and compared with natural chiral nicotine, other harmful tobacco compounds are avoided.
Drawings
FIG. 1 is a schematic diagram of the synthetic route of the preparation process of the present application;
FIG. 2 is a GC-MS spectrum of the final product obtained in example 1 of the present application;
FIG. 3 is a nuclear magnetic hydrogen spectrum of a finished product obtained in example 1 of the present application;
FIG. 4 shows a nuclear magnetic carbon spectrum of a finished product obtained in example 1 of the present application.
Detailed Description
The present application will be described in further detail with reference to the following drawings and examples. The special description is as follows: the following examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer, and the starting materials used in the following examples were obtained from ordinary commercial sources unless otherwise specified.
Examples
Examples 1-20 provide a method for the asymmetric synthesis of chiral nicotine, wherein examples 1-4 are examples of the preparation of S-nicotine and examples 5-20 are examples of the preparation of R-nicotine. Referring to figure 1 a schematic diagram of the synthetic pathway for the preparation of chiral nicotine according to the present application.
Example 1
Preparation of intermediate I: dissolving 4-chlorobutyraldehyde 100g in 1, 2-dichloroethane 500ml, stirring, adding 125g S-tert-butyl sulfenamide and anhydrous copper sulfate 150g, and heating and refluxing for 5 hours to obtain a first mixture; cooling the first mixture to room temperature, filtering to obtain filtrate, washing the filtrate with 100ml of clear water, repeating the process for 3 times, drying the organic layer with anhydrous sodium sulfate after layering, filtering, and concentrating under reduced pressure at 40 ℃ until no distillation is produced, thus obtaining 188g of an intermediate product I, namely (S, E) -N- (4-chlorobutene) -2-methyl-2-propane sulfinamide;
nucleophilic addition reaction: dissolving 70g of intermediate product I in 70g of diethyl ether to prepare a mixed solution for later use; introducing nitrogen into a three-necked bottle for protection, inserting a thermometer, adding 200ml of anhydrous ether into the three-necked bottle, stirring, adding 50g of 3-bromopyridine, cooling to-50 ℃, dropwise adding 133ml of n-butyl lithium (2.5M), and stirring for 30min after the addition is finished; then adding the mixed solution, and stirring and reacting for 30 minutes after the addition is finished to obtain a second mixture. Pouring the second mixture into 200ml of saturated ammonium chloride aqueous solution-100 ml of methyl tert-butyl ether mixed solution for quenching, standing for layering, extracting an aqueous layer with 200ml of ethyl acetate for 2 times, combining organic layers, washing with 50ml of saturated saline for 2 times, drying the organic layer with anhydrous sodium sulfate, filtering, and then distilling under reduced pressure to remove the solvent to obtain 92g of an intermediate product II, namely (S) -N- ((S) -4-chloro-1- (3-pyridyl) butyl) -2-methyl-2-propane sulfinamide;
cyclization reaction: dissolving 90g of intermediate product II prepared in the nucleophilic addition reaction step in 300ml of DMF, stirring, adding 55g of anhydrous potassium carbonate, heating to 60 ℃ and reacting for 4h to obtain a third mixture; cooling the third mixture after the reaction is finished, filtering, pouring into water-chloroform (1000ml:1000ml), stirring for 10 minutes, standing for layering, extracting a water layer with 500ml of chloroform, and repeating for 2 times; the organic layers were combined, washed 2 times with 200ml of clear water and 1 time with 200ml of saturated saline; the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure, and then impurities such as isomers were removed by column chromatography to obtain 71g of intermediate product III, i.e., 3- ((S) -2- (1- (S) -tert-butylsulfinyl) pyrrolidinyl) pyridine, with an ee value of 99%, and a reaction yield of 90% in this step.
(S) -demethylated nicotine: 200ml of 1, 2-dichloroethane and 100ml of water are added into a three-necked flask, 60g of the intermediate product III prepared in the previous step is added after stirring, 40g of 85% phosphoric acid is added dropwise, and the temperature is raised to 45 ℃ after the addition and the stirring is carried out for 1 h. After completion of the reaction, the mixture was allowed to stand for separation, and the separated aqueous layer was adjusted to pH 11 with 4M sodium hydroxide. And then 300ml of dichloromethane is used for extraction, the extraction is repeated for 3 times, organic layers are combined, 80g of anhydrous sodium sulfate is used for drying, filtration and concentration, 33g of (S) -demethyl nicotine is obtained, and the reaction yield of the step reaches 94%.
Amine methylation reaction: 30g of (S) -demethylnicotine and 17g of formaldehyde solution (40%) were added to a three-necked flask, followed by stirring, addition of 17g of formic acid, and heating to 80 ℃ for reaction for 18 hours. After completion of the reaction, it was cooled to room temperature, 100ml of hydrochloric acid (2M) was added, and extracted once with 200ml of dichloromethane. Adjusting pH of water layer to 11 with 8M sodium hydroxide, extracting with 300ml dichloromethane, repeating for 3 times, mixing organic layers, drying with 80g anhydrous sodium sulfate, filtering, concentrating to obtain 35g nicotine, and rectifying to obtain 30g S-nicotine with purity of 99.8% and yield of 92%.
The mass spectrum, hydrogen spectrum and carbon spectrum of the finished product obtained in example 1 are measured by GC-MS and NMR methods and are shown in FIGS. 2-4, and are analyzed:
GCMS：M+162.1, consistent with theoretical 162.1;
1HNMR(400MHz，CDCl3)δ8.52(m，1H)，8.48(m，1H)，7.68(m，1H)，7.24(m，1H)，3.24(m，1H)，3.06(m，1H)，2.29(m，1H)，2.21-2.14(m，4H)，1.95(m，1H)，1.80(m，1H)，1.71(m，1H)；
13C NMR(400MHz，CDCl3)δ149.58(CH)，148.65(CH)，138.75(CH)，134.80(CH)，123.55(CH)，68.86(CH)，57.01(CH2)，40.38(CH3)，35.20(CH2)，22.60(CH2) The above values are in accordance with the nicotine theoretical values. Thus, the finished product, namely the nicotine, is prepared according to the method.
Example 2
This example differs from example 1 in the preparation of intermediate I, which was: dissolving 100g of 4-chlorobutyraldehyde in 500ml of toluene, stirring, and adding 125g S-tert-butyl sulfenamide and 150g of anhydrous copper sulfate; heating to 80 ℃ and reacting for 10h to obtain a first mixture; the first mixture was cooled to room temperature, the filtrate was taken by filtration, washed with 100ml of clear water, repeated 3 times, the organic layer was dried over anhydrous sodium sulfate after separation, filtered and concentrated at 50 ℃ under reduced pressure until no more distillate was obtained, yielding 193g of intermediate I, i.e. (S, E) -N- (4-chlorobutene) -2-methyl-2-propane sulfinamide.
Example 3
The difference between this example and example 1 is that the nucleophilic addition reaction step of this example is: 70g of intermediate product I is dissolved in 70g of ether to prepare a mixed solution for later use; introducing nitrogen into a three-necked bottle for protection, inserting a thermometer, adding 200ml of anhydrous tetrahydrofuran into the three-necked bottle, stirring, adding 9g of magnesium powder and 0.5ml of 1, 2-dibromoethane, heating to 60 ℃, stirring for 30 minutes, cooling to room temperature, slowly dropwise adding 50g of 3-bromopyridine, stirring for 1 hour after adding, and cooling to-10 ℃; then adding the mixed solution, stirring and reacting after the addition is finished, and obtaining a second mixture after 1 hour. The second mixture was quenched by pouring it into a mixed solution of 200ml of saturated aqueous ammonium chloride solution and 100ml of methyl t-butyl ether, allowed to stand for separation, the aqueous layer was extracted 2 times with 200ml of ethyl acetate, the organic layers were combined, washed 2 times with 50ml of saturated brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure to obtain 85g of intermediate II, i.e., (S) -N- ((S) -4-chloro-1- (3-pyridyl) butyl) -2-methyl-2-propanesulfinamide.
Example 4
This example differs from example 1 in that the procedure for the preparation of intermediate I and the nucleophilic addition reaction step differ, the procedure for the preparation of intermediate I in this example is the same as in example 2, and the procedure for the nucleophilic addition reaction is the same as in example 3.
The yields and purities of the S-nicotine obtained in examples 1 to 4 are shown in Table 1
TABLE 1 summary of S-nicotine yield for examples 1-4
Example 5
Preparation of intermediate I: dissolving 4-chlorobutyraldehyde 100g in dichloromethane 500ml, stirring, adding 125g R-tert-butyl sulfenamide and anhydrous copper sulfate 150g, heating and refluxing for 8h to obtain a first mixture; cooling the first mixture to room temperature, filtering to obtain filtrate, washing the filtrate with 100ml of clear water, repeating the process for 3 times, layering, drying the organic layer with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure at 40 ℃ until no distillation occurs, to obtain 189g of intermediate product I, namely (R, E) -N- (4-chlorobutene) -2-methyl-2-propane sulfinamide;
nucleophilic addition reaction: dissolving 140g of intermediate product I in 140g of diethyl ether to prepare a mixed solution for later use; introducing nitrogen into a three-neck flask for protection, inserting a thermometer, adding 400ml of anhydrous tetrahydrofuran into the three-neck flask, stirring, adding 100g of 3-bromopyridine, cooling to-70 ℃, dropwise adding 267ml of n-butyl lithium (2.5M) for 1 hour, and stirring for 30min after the dropwise addition; then adding the mixed solution, and stirring and reacting for 30 minutes after the addition is finished to obtain a second mixture. Pouring the second mixture into 500ml of saturated ammonium chloride aqueous solution-300 ml of methyl tert-butyl ether mixed solution for quenching, standing for layering, extracting an aqueous layer with 300ml of ethyl acetate for 2 times, combining organic layers, washing with 50ml of saturated saline for 2 times, drying the organic layer with anhydrous sodium sulfate, filtering, and then distilling under reduced pressure to remove the solvent to obtain 186g of a crude product of an intermediate product II, namely (R) -N- ((R) -4-chloro-1- (3-pyridyl) butyl) -2-methyl-2-propane sulfinamide;
cyclization reaction: dissolving 90g of the prepared intermediate product II in 400ml of DMF, stirring, adding 55g of anhydrous potassium carbonate, heating to 60 ℃, and reacting for 5 hours to obtain a third mixture; cooling the third mixture after the reaction is finished, filtering, pouring into water-methyl tert-butyl ether (1000ml:1000ml), stirring for 10 minutes, standing for layering, extracting the water layer with 500ml of methyl tert-butyl ether, and repeating for 2 times; the organic layers were combined, washed 2 times with 200ml of clear water and 1 time with 200ml of saturated saline; the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure, and then impurities such as isomers were removed by column chromatography to obtain 67g of intermediate product III, i.e., 3- ((R) -2- (1- (R) -tert-butylsulfinyl) pyrrolidinyl) pyridine, with an ee value of 99%, and the yield of the reaction in this step reached 84%.
Preparation of (R) -demethylnicotine: 200ml of methylene chloride are added to a three-necked flask, 60g of the intermediate product III are added thereto after stirring, 100ml of 6N hydrochloric acid are added dropwise, and after completion of the addition, the mixture is kept at room temperature and stirred for 1 hour. After completion of the reaction, the mixture was allowed to stand for separation, and the separated aqueous layer was adjusted to pH 11 with 4M sodium hydroxide. And extracting with 300ml dichloromethane, repeating the extraction for 3 times, combining organic layers, drying with 80g anhydrous sodium sulfate, filtering, and concentrating to obtain 32g of (R) -demethyl nicotine, wherein the reaction yield of the step reaches 92%.
Amine methylation reaction: 30g of (R) -demethylnicotine and 17g of formaldehyde solution (40%) were added to a three-necked flask, followed by stirring, addition of 17g of formic acid, and heating to 80 ℃ for reaction for 18 hours. After completion of the reaction, it was cooled to room temperature, 100ml of hydrochloric acid (2M) was added, and extracted once with 200ml of dichloromethane. Adjusting pH of water layer to 11 with 8M sodium hydroxide, extracting with 300ml dichloromethane, repeating for 3 times, combining organic layers, drying with 80g anhydrous sodium sulfate, filtering, concentrating to obtain 36g nicotine, and rectifying to obtain 31 gR-nicotine with purity of 99.8%, wherein the yield of the step is 93%.
Example 6
This example differs from example 5 in that the procedure for the preparation of intermediate I differs, and the procedure for the preparation of intermediate I in this example is: dissolving 100g of 4-chlorobutyraldehyde in 500ml of trichloromethane, stirring, adding 125g R-tert-butyl sulfenamide and 150g of anhydrous copper sulfate, and heating and refluxing for 12 hours to obtain a first mixture; the first mixture was cooled to room temperature, the filtrate was taken by filtration, washed with 100ml of clear water, repeated 3 times, the organic layer was dried over anhydrous sodium sulfate after separation, filtered and concentrated at 40 ℃ under reduced pressure until no more distillate was obtained, yielding 189g of intermediate I, i.e. (R, E) -N- (4-chlorobutene) -2-methyl-2-propane sulfinamide.
Example 7
This example is different from example 5 in that the nucleophilic addition reaction step is: 70g of intermediate product I was dissolved in 70g of diethyl ether to prepare a mixed solution for later use. Introducing nitrogen into a three-necked bottle for protection, inserting a thermometer, adding 200ml of 2-methyltetrahydrofuran into the three-necked bottle, stirring, adding 50g of 3-bromopyridine, cooling to-70 ℃, dropwise adding 133ml of n-butyllithium (2.5M), wherein the dropwise adding time is 1 hour, and stirring for 30min after the addition is finished; then adding the mixed solution, and stirring and reacting for 30 minutes after the addition is finished to obtain a second mixture. The second mixture was quenched by pouring into 200ml of a saturated aqueous ammonium chloride solution-100 ml of a petroleum ether mixture, allowed to stand for separation, the aqueous layer was extracted 2 times with 200ml of ethyl acetate, the organic layers were combined, washed 2 times with 50ml of saturated brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure to obtain 93g of a crude product of intermediate II, i.e., (R) -N- ((R) -4-chloro-1- (3-pyridyl) butyl) -2-methyl-2-propanesulfinamide.
Example 8
The present example is different from example 5 in that the cyclization reaction step is different, and the cyclization reaction step of the present example is: dissolving 90g of the prepared intermediate product II in 400ml of tetrahydrofuran, stirring, adding 55g of anhydrous cesium carbonate, heating to 60 ℃ and reacting for 8 hours to obtain a third mixture; cooling the third mixture after the reaction is finished, filtering, pouring into water-methyl tert-butyl ether (1000ml:1000ml), stirring for 10 minutes, standing for layering, extracting the water layer with 500ml of methyl tert-butyl ether, and repeating for 2 times; the organic layers were combined, washed 1 time with 200ml of clean water and 1 time with 200ml of saturated saline; the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure, and then impurities such as isomers were removed by column chromatography to obtain 71g of intermediate product III, i.e., 3- ((R) -2- (1- (R) -tert-butylsulfinyl) pyrrolidinyl) pyridine, with an ee% of 99%, and the yield of the reaction in this step reached 88%.
Example 9
This example differs from example 5 in that the (R) -demethylnicotine preparation procedure differs, in that it is: 200ml of chloroform was added to a three-necked flask, and after stirring, 60g of the intermediate III obtained in the cyclization reaction step was added, 100g of 40% sulfuric acid was added dropwise, and after completion of the addition, the mixture was kept at room temperature and stirred for 1 hour. After completion of the reaction, the mixture was allowed to stand for separation, and the separated aqueous layer was adjusted to pH 11 with 4M sodium hydroxide. Further extraction was performed with 300ml of dichloromethane, extraction was repeated 3 times, and organic layers were combined, dried over 80g of anhydrous sodium sulfate, filtered, and concentrated to obtain 33g of (R) -demethylnicotine, which was obtained in 94% yield.
Example 10
The difference from example 5 is that the cyclization reaction in this example is the same as in example 8, and the procedure for the preparation of (R) -demethyl nicotine is the same as in example 9.
Example 11
The difference from example 5 is that the nucleophilic addition reaction step in this example is the same as in example 7, and the preparation step of (R) -demethylnicotine is the same as in example 9.
Example 12
The difference from example 5 is that the nucleophilic addition reaction step in this example is the same as example 7 and the cyclization reaction step is the same as example 8.
Example 13
The difference from example 5 is that the nucleophilic addition reaction step in this example is the same as in example 7, the cyclization reaction step is the same as in example 8, and the preparation step of (R) -demethylnicotine is the same as in example 9.
Example 14
The difference from example 5 is that the procedure for the preparation of intermediate I in this example corresponds to example 6 and that of (R) -nornicotine corresponds to example 9.
Example 15
The difference from example 5 is that the procedure for the preparation of intermediate I in this example is identical to example 6 and the procedure for the cyclization reaction is identical to example 8.
Example 16
The difference from example 5 is that the procedure for the preparation of intermediate I in this example is identical to example 6, the procedure for the cyclization reaction is identical to example 8, and the procedure for the preparation of (R) -nornicotine is identical to example 9.
Example 17
The difference from example 5 is that the procedure for the preparation of intermediate I in this example corresponds to example 6 and the procedure for the nucleophilic addition reaction corresponds to example 7.
Example 18
The difference from example 5 is that the procedure for the preparation of intermediate I in this example corresponds to example 6, the procedure for the nucleophilic addition reaction corresponds to example 7, and the procedure for the preparation of (R) -nornicotine corresponds to example 9.
Example 19
The differences from example 5 are that the procedure for the preparation of intermediate I in this example corresponds to example 6, the procedure for the nucleophilic addition reaction corresponds to example 7, and the procedure for the cyclization reaction corresponds to example 8.
Example 20
The difference from example 19 is that the procedure for the preparation of R) -demethylnicotine in this example is identical to that of example 9.
The yields and purities of R-nicotine obtained in examples 5-20 are shown in Table 2.
TABLE 2 summary of R-nicotine yield and purity obtained in examples 5-20
Example 21, which differs from example 1 only in that: the yield of R-nicotine prepared by replacing S-tert-butyl sulfinamide with R-tert-butyl sulfinamide is 77%, the ee value is 99% and the purity is 99.8%.
Example 22, which differs from example 5 in that R-tert-butylsulfinamide is replaced by S-tert-butylsulfinamide, gives a yield of 72% S-nicotine, an ee of 99% and a purity of 99.8%.
In summary, the preparation method adopted in the embodiment of the present application has simple process and mild conditions, the yield of the prepared chiral nicotine is above 70%, the purity of the prepared chiral nicotine is above 99.8%, the ee value of the prepared chiral nicotine is above 99.8%, and particularly, the preparation method of the embodiment 1 is the best, the purity of the prepared S-nicotine reaches 99.8%, and the yield of the prepared S-nicotine is 77%.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (10)
1. A method for preparing asymmetric synthetic chiral nicotine is characterized by comprising the following steps:
preparation of intermediate product I: dissolving 4-chlorobutyraldehyde in an organic solvent, adding chiral tert-butyl sulfenamide and a dehydrating agent, heating for reaction to obtain a first mixture, and separating an intermediate product I from the first mixture;
nucleophilic addition reaction: dissolving the intermediate product I in an ether reagent to obtain a mixed solution for later use; under the protection of inert gas, adding 3-bromopyridine into an anhydrous solvent, cooling, preparing an organic metal reagent, fully stirring, adding a mixed solution to react to obtain a second mixture, and sequentially quenching, layering, extracting, washing, drying and distilling under reduced pressure on the second mixture to obtain an intermediate product II;
cyclization reaction: dissolving the intermediate product II obtained in the nucleophilic addition reaction step in an aprotic polar solvent, adding carbonate, heating to react to obtain a third mixture, extracting, layering, washing, drying, filtering, distilling under reduced pressure, and purifying to obtain an intermediate product III;
preparation of chiral demethyl nicotine: adding the intermediate product III obtained in the cyclization reaction into an organic solvent, then adding an organic acid and/or an inorganic acid, heating and stirring to fully react, and separating and extracting the chiral demethyl nicotine after the reaction is finished.
2. Amine methylation reaction: and adding an amine methylation reagent into the prepared chiral demethylated nicotine, heating for full reaction, and separating and purifying after the reaction is finished to obtain the chiral nicotine.
3. The method of claim 1, wherein the asymmetric synthesis of chiral nicotine comprises: when the chiral tert-butyl sulfinamide in the reaction for preparing the intermediate product I is S-tert-butyl sulfinamide, the finally prepared chiral nicotine is S-nicotine; when the chiral tert-butyl sulfinamide in the reaction for preparing the intermediate product I is R-tert-butyl sulfinamide, the finally prepared chiral nicotine is R-nicotine.
4. The method of claim 1, wherein the organic solvent comprises a combination of one or more of 1, 2-dichloroethane, dichloromethane, chloroform, and toluene.
5. The method of claim 1, wherein the organometallic reagent comprises an organolithium reagent or a grignard reagent.
6. The method of claim 1, wherein the anhydrous solvent is selected from the group consisting of anhydrous diethyl ether, anhydrous tetrahydrofuran, and anhydrous 2-methyltetrahydrofuran.
7. The method of claim 1, wherein the aprotic polar solvent is selected from one or more of dimethylsulfoxide, N-dimethylformamide, tetrahydrofuran, and acetone.
8. The method of claim 1, wherein the inorganic acid comprises one or more of sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, hydrobromic acid, hydroiodic acid, perchloric acid; the organic acid comprises one or more of trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, citric acid, tartaric acid and maleic acid in combination.
9. Chiral nicotine, characterized by being prepared by the method of claims 1-7.
10. The chiral nicotine of claim 8, comprising two R and S configurations, and having the following specific structural formula: s-nicotine structural formula:
r-nicotine structural formula:
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| CN113272289A (en) * | 2018-11-16 | 2021-08-17 | 扎诺普瑞玛生命科学有限公司 | Process for preparing (S) -nicotine from myosmine |
| CN113444070A (en) * | 2021-07-28 | 2021-09-28 | 深圳市真味生物科技有限公司 | Preparation method for synthesizing chiral nicotine from chiral tert-butyl sulfinamide |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113272289A (en) * | 2018-11-16 | 2021-08-17 | 扎诺普瑞玛生命科学有限公司 | Process for preparing (S) -nicotine from myosmine |
| CN113444070A (en) * | 2021-07-28 | 2021-09-28 | 深圳市真味生物科技有限公司 | Preparation method for synthesizing chiral nicotine from chiral tert-butyl sulfinamide |
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