CN114702474B - Preparation method of levo-nicotine - Google Patents

Preparation method of levo-nicotine Download PDF

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CN114702474B
CN114702474B CN202110431497.2A CN202110431497A CN114702474B CN 114702474 B CN114702474 B CN 114702474B CN 202110431497 A CN202110431497 A CN 202110431497A CN 114702474 B CN114702474 B CN 114702474B
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reaction
formula
compound
nicotine
levo
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CN114702474A (en
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申理滔
刘遥岫
冯丕明
涂志波
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Huanggang Zhongzhong Biotechnology Co ltd
Wuhan Zhongyou Pharmaceutical Co ltd
Wuhan QR Pharmaceuticals Co Ltd
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Wuhan Ruisheng Pharmaceutical Co ltd
Huanggang Zhongzhong Biotechnology Co ltd
Wuhan QR Pharmaceuticals Co Ltd
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Abstract

The invention provides a preparation method of levo-nicotine, which can obtain the levo-nicotine with the optical purity as high as 99.7%, the total synthesis yield reaches 60-70%, and the reaction materials in the whole preparation process are cheap and easy to obtain, simple to operate, environment-friendly and suitable for large-scale industrial production.

Description

Preparation method of levo-nicotine
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of levonicotine.
Background
Chemical name of nicotine: 3- (1-methylpyrrole-2-yl) pyridine, which has a common name of nicotine, is a naturally occurring liquid alkaloid and has strong physiological activity. Nicotine is generally found mainly in natural tobacco and has wide application in the fields of agriculture, medical intermediates and electronic cigarettes.
Currently, commercial nicotine is mainly extracted and purified from plants such as tobacco, natural nicotine is mainly levorotatory nicotine, and tobacco leaves contain various alkaloids which are not easy to separate from each other, so that the levorotatory nicotine prepared by an extraction method is low in purity, generally less than 95% in purity, contains a lot of other nicotine impurities which are unhealthy to human body systems and have proved to be carcinogenic. Meanwhile, the nicotine extracted and purified from plants such as tobacco and the like can be influenced by various factors such as raw materials, climate, land resources, period and the like, so that the method for directionally synthesizing the levorotatory nicotine by using a chemical method is a current research focus, and can avoid the defects of low product purity, large limitation of raw materials and the like in the traditional extraction process.
The documents Journal of laboratory Compounds and radiopharmaceuticals, 1977,9 (4), 461-469; a process for the preparation of nicotine starting from pyridine by reaction with trimethylsilyl-protected pyrrolidones is reported:
Figure BDA0003031543010000011
the method needs flammable organic lithium metal and needs to be operated at-78 ℃, and in the route, nitrogen atoms are protected by pyrrolidone by trimethyl silicon, so that the material cost is relatively high.
The document Organic Syntheses, [ J ],1998, 215-218 discloses a synthetic route using methyl nicotinate as starting material, a process for the preparation of racemic nicotine by a four-step reaction:
Figure BDA0003031543010000021
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the reaction yield of the synthesis of the myosmine in the first two steps of the patent route is about 40 percent, and a large amount of tar affects the purity and appearance of subsequent finished products.
Patents US2013030188A1, CN102633773B disclose a synthetic route using methyl nicotinate and N-butenylpyrrolidone as starting materials to prepare racemic nicotine via a four-step reaction:
Figure BDA0003031543010000022
the N-butylene pyrrolidone in the route needs to be prepared by self, the material cost is high, sodium hydride with high risk is used as alkali, a large amount of hydrogen can be generated in the reaction process, and the potential safety hazard is caused by amplification production.
The patent EP2484673, US0197022, WO121644 and CN1124093293 disclose the preparation of levonicotine by resolution with racemic nicotine as starting material by cheap chiral acid.
Figure BDA0003031543010000023
In the route, the racemic modification is resolved by using cheap chiral acid to obtain the levonicotine, and the single-step resolution yield is about 40 percent. The resolution process has high cost, and 60 percent of nicotine is lost in the resolution mother liquor; and acid and alkali are required to be poured twice for resolution, so that more three wastes are generated.
Patent CN112409327 discloses a preparation method of target levo-nicotine by using nicotinic acid ester as a starting material, generating beta-keto acid amide under the action of alkali, performing cyclization under an acidic condition to obtain myosmine, obtaining levo-nornicotine by a biological fermentation method, and finally adding methyl.
Figure BDA0003031543010000031
The method obtains the levo-nicotine through enzyme catalysis, the cost is 50% lower than that of resolution, but trace protein residue can be introduced in a fermentation process, and the method belongs to a biological product non-fully synthesized product.
Most of nicotine prepared in the prior art is racemic nicotine, and to obtain single chiral nicotine with high optical purity, a chemical resolution method is needed for separation and purification, so that the process is complicated; or the levonicotine is prepared by adopting biological enzyme catalysis, trace protein residue can be introduced by the method, and the detection and quantification of the residual protein are difficult.
Therefore, in order to meet the demand of the market for high-purity levo-nicotine without other harmful compound pollution, a method for artificially synthesizing levo-nicotine, which has higher efficiency and higher product purity and is suitable for large-scale industrial production, needs to be developed.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a preparation method of levo-nicotine, which adopts the following synthetic route:
Figure BDA0003031543010000041
the preparation method comprises the following steps:
(1) Reducing the compound of the formula I to obtain a compound of a formula II;
(2) Performing cyclization reaction on the compound in the formula II to obtain levorotatory nornicotine;
(3) Methylating the levo-nornicotine to obtain levo-nicotine;
in the compounds of the formula I and the formula II, R is H, formyl, acetyl, propionyl, tert-butyloxycarbonyl or benzyloxycarbonyl.
According to an embodiment of the present invention, in the step (1), the reduction is performed in the presence of a ligand and a metal catalyst; in some embodiments, the ligand and metal catalyst generate the chiral catalyst in situ. According to an embodiment of the invention, the in situ generation reaction temperature range is: 10 to 100 ℃, preferably 20 to 80 ℃, for example, selected from 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃.
According to an embodiment of the present invention, one or more of the following reagents are used as a reaction solvent in the step (1): toluene, tetrahydrofuran, ethanol, 2-methyltetrahydrofuran, methyl tert-butyl ether, dichloromethane, ethyl acetate;
according to an embodiment of the invention, in step (1), the metal catalyst is selected from: rh (COD) Cl 2 、Ir(COD)Cl 2 、Ru(COD)Cl 2 、PdCl(PPh 3 ) 3 、PdCl 2 (PPh3) 2 、Ni(acac) 2 、NiCl 2 、Ni(COD) 2 。
According to an embodiment of the invention, in step (1), the ligand is selected from the following structures:
Figure BDA0003031543010000051
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according to an embodiment of the present invention, in the step (1), the reaction temperature range is: 10 to 150 ℃, preferably 20 to 100 ℃, for example selected from 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃, 80 ℃,90 ℃, more preferably 30 to 40 ℃.
According to an embodiment of the invention, in step (1), the mass ratio of the reaction solvent to the compound of formula I fed is 20 to 3:1, preferably 10 to 1 to 3:1, for example 5:1.
According to an embodiment of the present invention, in the step (1), the feeding mass ratio of the ligand to the metal catalyst is 10 to 1:1, for example, 10.
According to an embodiment of the present invention, in the step (1), the reduction reaction is hydrogenation reduction, and hydrogen gas is introduced into the reaction at a pressure of 0.5 to 2.0Mpa, for example, 1.0Mpa and 1.5Mpa.
According to an embodiment of the present invention, the step (1) further comprises a post-treatment step, wherein the post-treatment step comprises concentration under reduced pressure, and an organic solvent selected from small polar solvents such as n-hexane, n-heptane and the like is added to the concentrated solution to precipitate the compound of formula II.
According to an embodiment of the invention, in step (1), ethyl acetate, the compound of formula I, is added to the autoclave at room temperature; meanwhile, ligand and metal catalyst are added into another container under the protection of nitrogen, the system is stirred for 0.5 to 1.5 hours at the temperature of between 20 and 40 ℃, and the in-situ generated catalyst is transferred into the high-pressure kettle by nitrogen. The high-pressure autoclave is replaced by nitrogen for 3 times, and then 0.9-1.2 Mpa hydrogen is pressed in, the system reacts for 4 hours at the temperature of 30-40 ℃, and the compound of the formula II is obtained after post-treatment reaction.
According to an embodiment of the present invention, in the step (2), one or more of the following reagents are used as a reaction solvent: ethyl acetate, dichloromethane, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, n-hexane, methyl tert-butyl ether.
According to an embodiment of the present invention, in the step (2), the compound of formula II is subjected to a ring-forming reaction under the action of a base; the alkali is selected from one or more of potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium ethoxide, potassium carbonate, sodium hydride and triethylamine.
According to an embodiment of the present invention, in the step (2), after adding the reaction solvent, the compound of formula II and the base to the reaction vessel, further adding a reagent I; the reagent I is selected from p-toluenesulfonyl chloride, methylsulfonyl chloride, trifluoromethanesulfonic anhydride and the like; preferably, acid is added dropwise after the steps to acidify, and then an alkaline reagent is added to adjust the pH value. The acid can be selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like; the alkaline reagent is selected from sodium hydroxide aqueous solution.
According to an embodiment of the present invention, in the step (2), the feeding mass ratio of the reaction solvent and the compound of formula II is 20 to 3:1, preferably 10 to 1 to 3:1, such as 5:1.
According to an embodiment of the invention, in step (2), the mass ratio of the base to the compound of formula II fed is 5:1-1:5, preferably 3:1-1:3, for example 1:1.
According to an embodiment of the invention, in the step (2), the feeding mass ratio of the reagent I to the compound of formula II is 5:1 to 1:5, preferably 3:1 to 1:3, for example 1, 1.
According to the embodiment of the invention, in the step (2), after the cyclization reaction, the levorotatory nor-nicotine is obtained through a post-treatment step; the post-treatment step is extraction and concentration;
according to the embodiment of the invention, in the step (2), the reaction solvent, the compound shown in the formula II and the alkali are added into a reaction container at room temperature, the reagent I is dropwise added, the Bi Ti system is dropwise added to react for 1-3 h at the temperature of 20-40 ℃, hydrochloric acid is dropwise added and stirred for 1-3 h, then the sodium hydroxide aqueous solution is added, the system reacts for 1-3 h at the temperature of 20-40 ℃, and the levo-nornicotine is obtained through post-treatment
According to the embodiment of the invention, in the step (3), the levorotatory nor-nicotine is reacted with a methylating agent, and the pH is adjusted by an alkaline agent to obtain the levorotatory nicotine; the alkaline reagent is selected from sodium hydroxide aqueous solution; the pH value is greater than or equal to 8, and can be selected from 9, 10, 11 and 12.
Further, the step (3) further comprises a post-treatment step, wherein the post-treatment step is to obtain a crude levorotatory nicotine product through extraction, and obtain a pure levorotatory nicotine product through reduced pressure distillation.
According to an embodiment of the present invention, in the step (3), one or more of the following reagents are used as a methylation reaction solvent: water, 1,4-dioxane, tetrahydrofuran, methanol, ethylene glycol dimethyl ether, ethanol, and the like.
According to an embodiment of the invention, in step (3), the methylating agent is selected from: one or more of formaldehyde (e.g., aqueous formaldehyde solution), paraformaldehyde, methyl iodide, and dimethyl sulfate.
According to an embodiment of the present invention, in the step (3), the reaction temperature range is: 40 to 120 ℃, preferably 50 to 100 ℃, for example, selected from 60 ℃, 70 ℃, 80 ℃,90 ℃.
According to an embodiment of the present invention, in the step (3), a methylating agent system is adopted, and the methylating agent system further comprises formic acid in addition to one or more of formaldehyde (e.g. aqueous formaldehyde solution), paraformaldehyde, methyl iodide and dimethyl sulfate; preferably, the methylating agent system used comprises paraformaldehyde and formic acid; more preferably, in the methylating agent system, the mass ratio of paraformaldehyde to formic acid is 0.8. According to an embodiment of the present invention, the extraction solvent (e.g. used for the work-up in step (2) or step (3)) in the reaction may be selected from one or more of the following reagents: ethyl acetate, methyl tert-ether, dichloromethane, and the like.
According to an embodiment of the present invention, in the step (3), the mass ratio of the methylating agent to the levonornicotine is 5:1-1:5, preferably 2:1-1:2, for example 1, 1; the feeding mass ratio of the reaction solvent to the levonornicotine is 2:1-1:5, and is, for example, 1.
According to the embodiment of the invention, in the step (3), the reaction solvent, the levo-nornicotine, the paraformaldehyde and the formic acid system are added into a reaction container at room temperature, reflux reaction is carried out for 3-6 h, the system is concentrated to remove the organic solvent, the pH value is adjusted to be 10-11 by using sodium hydroxide aqueous solution, and the levo-nicotine is obtained through post-treatment.
The present invention also provides a catalyst generated in situ from a ligand and a metal catalyst, wherein the metal catalyst is selected from the group consisting of: rh (COD) Cl 2 、Ir(COD)Cl 2 、Ru(COD)Cl 2 、PdCl(PPh 3 ) 3 、PdCl 2 (PPh3) 2 、Ni(acac) 2 、NiCl 2 、Ni(COD) 2 (ii) a The ligand is selected from the following structures:
Figure BDA0003031543010000081
the invention also provides the use of the catalyst in reduction reactions, preferably in carbonyl reduction reactions, more preferably in asymmetric carbonyl reduction reactions, for example, as hereinbefore described for step (1).
Advantageous effects
1) The synthesis process can finally obtain the levorotatory nicotine with the optical purity as high as 99.7 percent, the total synthesis yield reaches 60 to 70 percent, reaction materials in the whole preparation process are cheap and easy to obtain, the operation is simple, the environment is friendly, and the method is suitable for large-scale industrial production.
2) The invention adopts specific ligand and metal catalyst to carry out reduction reaction, which can obviously improve the reaction quality.
Drawings
FIG. 1 is a mass spectrum of levonicotine according to the present invention;
FIG. 2 is a nuclear magnetic image of L-nicotine according to the present invention;
FIG. 3 is a graph of the optical purity of levonicotine according to the present invention.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the techniques realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Optical detection apparatus and method: detection instrument a (ultraviolet detector); a chiral chromatographic column Dasuilu OD-H column is adopted, and the mobile phase is as follows: isopropanol/n-heptane =5/95, flow rate 0.9mL/min, sample size 10 microliters, detection wavelength 254nm, column temperature 25 ℃.
General reaction scheme:
Figure BDA0003031543010000091
example 1: preparation of intermediate compound of formula II
Adding 10kg of ethyl acetate and 2kg of a compound of formula I (R is tert-butyloxycarbonyl, i.e., (4-oxo-4- (pyridin-3-yl) butyl) carbamic acid tert-butyl ester) into a 20L autoclave at 20 ℃, and uniformly mixing the system; while adding 10g of ligand L3 and 5g of Ni (COD) into a 500mL three-necked flask under the protection of nitrogen 2 The system was stirred at 30 ℃ for 1h and the in situ formed catalyst was transferred with nitrogen to a 20L autoclave. Replacing the 20L autoclave with 0.2MPa nitrogen for 3 times, then pressing 1.0MPa hydrogen, reacting the system at 30-40 ℃ for 4h, and confirming the complete conversion of the raw materials by TLC. After the system is emptied, the nitrogen gas with 0.2MPa is used for replacing 2 times, then the reduced pressure concentration is carried out to remove 6kg of ethyl acetate, the temperature is reduced to 20 ℃, 5kg of n-hexane is dripped into the concentrated solution to precipitate 2kg of the target intermediate compound with the formula II (R is tert-butoxycarbonyl, namely (S) - (4-hydroxy-4- (pyridine-3-yl) butyl) carbamic acid tert-butyl ester). Liquid phase purity of 99.2%, optical purity of 99.5%. 1 HNMR(CDCl 3 ，400M)δ：8.71(d,J＝8.0Hz,1H)，8.52(d,J＝8.2Hz,1H)，7.41(d,J＝8.0Hz,1H)，7.37～7.30(m,1H)，6.87(s,1H)，4.51(t,J＝4.0Hz,1H)，3.01～2.93(m,1H)，3.06(t,J＝4.2hz,2H)，1.56～1.50(m,4H)，1.43(s,9H)；LC-MS Calc：266.34，Detec.M+1：267.3。
Example 2: preparation of levo-nornicotine
15kg of dichloromethane, 3kg of intermediate 3 and 3kg of triethylamine are added into a 50L three-necked flask at 25 ℃, the temperature of the system is controlled to be 20 ℃, 2.5kg of paratoluensulfonyl chloride is dropwise added, bi Ti is dropwise added, the system reacts for 2h at 30 ℃, TLC confirms that the intermediate 3 is completely consumed, 2kg of 6N hydrochloric acid is dropwise added and stirred for 2h, and then 4kg of 20% sodium hydroxide aqueous solution reaction solution is added. The system is reacted for 2h at 30 ℃, extracted with dichloromethane three times, 9kg each time, and the combined organic phases are concentrated to obtain 1.42kg of the target intermediate 2, namely the levorotatory nor-nicotine. The liquid phase purity was 98%, the optical purity was 99.5% e.e, the yield was 85.1%, and it was used directly in the next reaction. 1 HNMR(CDCl 3 ,400M)δ：8.58(d,J＝8.0Hz,1H)，8.47(d,J＝8.2Hz,1H)，7.70～7.66(m,1H)，7.24～7.20(m,1H)，4.12(t,J＝4.5Hz,1H)，3.21(m,1H)，3.06(t,J＝4.2hz,2H)，2.20～2.18(m,1H)，1.81～1.66(m,3H)；LC-MS Calc：148.24，Detec.M+1：149.2。
Example 3: preparation of levo-nicotine
5kg of methanol, 10kg of intermediate 2, 8kg of paraformaldehyde and 8kg of formic acid system are added into a 50L three-necked flask at 25 ℃, and reflux reaction is carried out for 5 hours at 90 ℃. Concentrating the system to remove the organic solvent, adjusting pH =11 with sodium hydroxide aqueous solution, extracting with ethyl acetate for three times, 10kg each time, combining the organic phases, concentrating to obtain a nicotine crude product, and distilling under reduced pressure to obtain a pure product of levonicotine, wherein the product is colorless transparent liquid, and the optical purity is 99.6 percent. The pure product had a weight of 9.29kg of distillate, a yield of 84.9% and a chemical purity of 99.7%. 1 HNMR(400MHz,CDCl 3 ) δ:8.47 to 8.44 (br, 2H), 7.61 (d, J =8.0hz, 1h), 7.20 to 7.16 (m, 1H), 3.18 (t, J =8.0hz, 1h), 3.11 (t, J =8.0hz, 1h), 2.25 to 2.19 (m, 1H), 2.13 to 2.09 (m, 1H), 2.08 (s, 3H), 1.89 to 1.87 (m, 1H), 1.76 to 1.66 (m, 2H). LC-MS Calc:162.24, detec. M +1:163.20. the pure levo-nicotine was detected optically (detector a,254 nm), and the results are shown in fig. 3 and the following table:
Figure BDA0003031543010000101
Figure BDA0003031543010000111
the embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made without departing from the spirit and principle of the present invention shall fall within the protection scope of the present invention.

Claims (8)

1. A preparation method of levo-nicotine adopts the following synthetic route:
Figure FDA0003943582520000011
the preparation method comprises the following steps:
(1) Reducing the compound of the formula I to obtain a compound of a formula II;
(2) Performing cyclization reaction on the compound in the formula II to obtain levorotatory nornicotine;
(3) Methylating the levo-nornicotine to obtain levo-nicotine;
in the compounds of the formula I and the formula II, R is H, formyl, acetyl, propionyl, tert-butyloxycarbonyl or benzyloxycarbonyl; in the step (1), reducing in the presence of a ligand and a metal catalyst; the metal catalyst is selected from Ni (COD) 2 (ii) a The ligand is selected from the following structures:
Figure FDA0003943582520000012
in the step (1), one or more of the following reagents are adopted as a reaction solvent: toluene, tetrahydrofuran, ethanol, 2-methyltetrahydrofuran, methyl tert-butyl ether, dichloromethane, ethyl acetate; in the step (1), the reaction temperature range is as follows: 10 to 150 ℃; in the step (1), the reduction reaction is hydrogenation reduction, hydrogen is introduced into the reaction, and the reaction pressure is 0.5-2.0 Mpa; in the step (2), after the reaction solvent, the compound of formula II and the base are added to the reaction vessel, further adding a reagent I; the reagent I is selected from p-toluenesulfonyl chloride, methylsulfonyl chloride and trifluoromethanesulfonic anhydride.
2. The method according to claim 1, wherein in the step (2), one or more of the following reagents are used as a reaction solvent: ethyl acetate, dichloromethane, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, n-hexane, methyl tert-butyl ether.
3. The method according to claim 1, wherein in the step (2), the compound of formula II is subjected to a ring-forming reaction under the action of a base; the alkali is selected from one or more of potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium ethoxide, potassium carbonate, sodium hydride and triethylamine; in the step (2), the feeding mass ratio of the reaction solvent to the compound of the formula II is 20-3:1; the feeding mass ratio of the alkali to the compound of the formula II is 5:1-1:5.
4. The preparation method according to claim 1, wherein the step (2) further comprises adding dropwise an acid for acidification, and then adding an alkaline reagent to adjust the pH value; the acid can be selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid; the alkaline agent is selected from sodium hydroxide aqueous solution.
5. The method of claim 1, wherein in step (3), the levonornicotine is reacted with a methylating agent to obtain levonicotine after adjusting pH with an alkaline agent.
6. The production method according to any one of claims 1 to 5, wherein in the step (3), one or more of the following reagents are used as a methylation reaction solvent: water, 1,4-dioxane, tetrahydrofuran, methanol, ethylene glycol dimethyl ether, and ethanol.
7. The method according to any one of claims 1 to 5, wherein in the step (3), the methylating agent is selected from the group consisting of: one or more of formaldehyde, paraformaldehyde, methyl iodide and dimethyl sulfate.
8. The method according to any one of claims 1 to 5, wherein a methylating agent system is used in the step (3), and the methylating agent system further comprises formic acid in addition to one or more of formaldehyde, paraformaldehyde, methyl iodide, and dimethyl sulfate.
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