Application of Quaternary Ammonium Bases in the Preparation of Dextrorotatory Nicotine

Abstract

This invention relates to the application of quaternary ammonium bases in the preparation of dextrorotatory nicotine, wherein the structure of the quaternary ammonium base is shown in formula (I): [NR1R2R3R4] + OH ‑ (I) R1, R2, R3, and R4 are independently selected from C 1‑3 Alkyl groups, C3-C6 cycloalkyl groups. This invention uses a novel quaternary ammonium base as a catalyst. First, racemic nicotine is prepared simply and efficiently from natural, optically active S-nicotine as the initial raw material. Then, preparative liquid chromatography is used to resolve the racemic nicotine, finally yielding high-purity dextrorotatory nicotine (R-nicotine).

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of preparing dextro-nicotine, and particularly relates to application of a quaternary ammonium base in preparation of dextro-nicotine. BACKGROUND

[0002] Nicotine, also known as nicotiana, is one of the important components of tobacco. Relevant researches show that nicotine has strong physiological activity and has a regulating effect on the central nervous system, peripheral nervous system and paraganglia. Nicotine also has a wide range of uses in the fields of medicine and pesticide. In medicine, isoniazid, nicotinamide and nicotinic acid are synthesized from nicotine, and they have good curative effects on anti-tuberculosis, anti-depression, anti-bacteria, treatment of Parkinson's syndrome, anti-oxidation, memory and learning impairment, etc. In pesticide, nicotine can be used for disinfection of poultry living environment, and also used as a plant growth regulator and insecticide, etc.

[0003] There is a chiral center in the molecule of nicotine, so there are two enantiomers, i.e. (R)-(+)-nicotine (R-nicotine, or dextro-nicotine) and (S)-(-)-nicotine (S-nicotine, or levo-nicotine), as shown in the following figure. In nature, the nicotine contained in tobacco and tobacco products is mainly S-nicotine. The proportion of R-nicotine in traditional tobacco products, such as cigarettes and smokeless tobacco products, is generally below 1%, while in cigarette smoke, it can reach about 3%.

[0004]

[0005] A pair of enantiomers has many same physicochemical properties in a non-chiral environment, such as the same melting point, the same solubility, and the same type of chemical reaction, etc. However, there are also some physicochemical properties with relatively large differences, such as optical activity and odor, etc. In a chiral environment, due to the different effects of a pair of enantiomers, the physiological activities of racemic nicotine ((R,S)-nicotine), S-nicotine and R-nicotine often have large differences, such as toxicity, sensory characteristics, etc. Although the relevant research is not sufficient, but the limited research results show that the pharmacological effect of R-nicotine is lower or similar to that of S-nicotine, including toxicity, biological metabolism, and binding with acetylcholine receptor (AChR), etc. Therefore, how to obtain high-purity R-nicotine has attracted more and more attention. In 2000, Lebreton reported a synthetic route of R-nicotine, which was synthesized in 4 steps, and the ee value of the obtained R-nicotine was 94% and the total yield was 61% (Tetrahedron Lett. 2000, 41, 9245-9249.).

[0006]

[0007] However, the above preparation method is complicated, harsh conditions and high cost. The synthesis method of dextromethorphan is rarely reported. SUMMARY

[0008] In order to overcome the defects of the prior art, the application provides an application of quaternary ammonium base in the preparation of dextromethorphan. Under the catalysis of the quaternary ammonium base, racemic nicotine is synthesized by using cheap and easily available S-nicotine as raw material, and then high-purity R-nicotine is obtained by preparing liquid phase and splitting. The reaction steps are less, the raw material is easy to obtain, and the application is suitable for mass production of R-nicotine.

[0009] An object of the application is to provide an application of quaternary ammonium base in the preparation of dextromethorphan.

[0010] Another object of the application is to provide a quaternary ammonium base.

[0011] Still another object of the application is to provide a preparation method of the quaternary ammonium base.

[0012] Still another object of the application is to provide a method for preparing racemic nicotine by using the quaternary ammonium base.

[0013] Still another object of the application is to provide a method for preparing dextromethorphan by using the quaternary ammonium base.

[0014] The object of the application is achieved by adopting the following technical solutions.

[0015] On the one hand, the application provides an application of quaternary ammonium base in the preparation of dextromethorphan.

[0016] Preferably, the structure of the quaternary ammonium base is as shown in formula (I):

[0017] [NR1R2R3R4] + OH - (I)

[0018] R1, R2, R3 and R4 are independently selected from C 1-3 alkyl, C3-C6 cycloalkyl.

[0019] Preferably, R1, R2, R3 and R4 are the same and selected from methyl, ethyl or isopropyl.

[0020] Preferably, at least one of R1, R2, R3 and R4 is cycloalkyl, and preferably the cycloalkyl is cyclohexane.

[0021] Preferably, the structure of the quaternary ammonium base is selected from the following structures:

[0022]

[0023] The application adopts a quaternary ammonium base with a novel structure as a catalyst, first uses natural optical active S-nicotine as an initial raw material to simply and efficiently prepare racemic nicotine, then uses a preparative liquid chromatograph to split the racemic nicotine, and finally obtains high-purity dextro nicotine (R-nicotine).

[0024] In still another aspect, the application provides a preparation method of the above quaternary ammonium base, which comprises the following steps: using a quaternary ammonium iodine salt as a raw material, and performing a redox reaction with Ag2O to obtain the quaternary ammonium base; and a synthesis route thereof is as follows:

[0025]

[0026] In still another aspect, the application provides a method for preparing racemic nicotine by using the above quaternary ammonium base, wherein the quaternary ammonium base is a catalyst.

[0027] Preferably, the method comprises using S-nicotine as a raw material, and obtaining racemic nicotine through one-step reaction under catalysis of the quaternary ammonium base, and a synthesis route thereof is as follows:

[0028]

[0029] Preferably, the method comprises adding S-nicotine and the above quaternary ammonium base in one pot under protection of an inert gas to perform reaction in a solvent or an organic solvent, cooling after the reaction is completed, and purifying to obtain the racemic nicotine.

[0030] Preferably, the inert gas is selected from nitrogen, argon or helium.

[0031] Preferably, the organic solvent is selected from one or more of toluene, xylene, methanol, ethanol, dichloromethane, dichloroethane, chloroform, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide and dimethyl sulfoxide, and preferably is selected from one or more of xylene, tetrahydrofuran or dimethyl sulfoxide.

[0032] Preferably, the reaction temperature is 40-200℃, and preferably is 40-100℃.

[0033] Preferably, the reaction time is 10 minutes-12 hours, and preferably is 15 minutes-5 hours.

[0034] Preferably, the molar ratio of the S-nicotine to the quaternary ammonium base is 100:1-100:40.

[0035] The method for preparing racemic nicotine has few reaction steps, and raw materials are easy to obtain, and is suitable for large-scale production.

[0036] In another aspect, the present application provides a method for preparing R-nicotine using the above-mentioned quaternary ammonium base, which comprises preparing racemic nicotine by the method as described above, and then using preparative liquid chromatography to separate the racemic nicotine to obtain R-nicotine.

[0037] Preferably, the racemic nicotine is separated by preparative liquid chromatography, and the chromatographic column used is a chiral chromatographic column, and the model is selected from AD, AD-H, AS, AS-H, OD, OD-H, ID, ID-H, OJ, OJ-H, IA, IB and IC, preferably OD-H, ID-H, OJ-H, IA, IB and IC. Preferably, the racemic nicotine is separated by preparative liquid chromatography, and the solvent used is selected from n-hexane, isopropyl alcohol, methanol, ethanol, ethyl acetate, tetrahydrofuran, methyl tert-butyl ether or water.

[0038] Preferably, formic acid, acetic acid, triethylamine, isopropylamine or diethylamine is added to the above-mentioned solvent.

[0039] In a specific embodiment, the method for preparing R-nicotine of the present application is as follows:

[0040] First, racemic nicotine is prepared in the presence of a quaternary ammonium base as a catalyst: S-nicotine, a quaternary ammonium base and a solvent are heated in a reactor under anhydrous and anaerobic conditions for a certain period of time, and after cooling, purification treatment is performed

[0041]

[0042] Second, the racemic nicotine is separated under certain conditions using high-performance preparative liquid chromatography to obtain R-nicotine

[0043]

[0044] Compared with the prior art, the present application provides a new quaternary ammonium base, which is used as a catalyst for preparing racemic nicotine, and can be synthesized in one step. The method uses S-nicotine as a raw material, has the advantages of easy availability of raw materials, fewer reaction steps, fewer by-products, less introduction of other impurities, and easy mass production. After obtaining racemic nicotine, the present application separates it by high-performance liquid chromatography to obtain high-purity R-nicotine. BRIEF DESCRIPTION OF DRAWINGS

[0045] Figure 1 The liquid chromatogram of racemic nicotine prepared by the present application (the test method refers to YC / T561-2018);

[0046] Figure 2 The liquid chromatogram of R-nicotine prepared by the present application (the test method refers to YC / T561-2018). DETAILED DESCRIPTION

[0047] The application will be further described in connection with specific examples. It should be understood that these examples are only used to illustrate the application and not used to limit the scope of the application.

[0048] Preparation of the catalyst

[0049] Example 1: Preparation of cat-1

[0050]

[0051] The raw material tetramethylammonium iodide (1 mmol) was added to a 10 mL round-bottom flask, 2 mL of water was added to the flask, and the mixture was stirred uniformly with a magnetic stirrer. The system was placed in an ice water bath, and then Ag2O (4 mmol) was added to the system in batches. Subsequently, the reaction system was slowly returned to room temperature, and the reaction was carried out for about 5 hours. After treatment, the corresponding cat-1 was obtained.

[0052] NMR data of cat-1: 1 H NMR (DMSO-d6, 400 MHz); δ: 2.32 (s, 12H).

[0053] Example 2: Preparation of cat-2

[0054] The preparation method of cat-2 is referred to cat-1.

[0055] NMR data of cat-2: 1 H NMR (DMSO-d6, 400 MHz); δ: 1.05 (t, 12H), 2.45 (q, 8H).

[0056] Example 3: Preparation of cat-3

[0057] The preparation method of cat-3 is referred to cat-1.

[0058] NMR data of cat-3: 1 H NMR (DMSO-d6, 400 MHz); δ: 1.12 (d, 24H), 2.81-2.87 (m, 4H).

[0059] Example 4: Preparation of cat-4

[0060] The preparation method of cat-4 is referred to cat-1.

[0061] NMR data of cat-4: 1 H NMR (DMSO-d6, 400 MHz); δ: 1.11-1.85 (m, 10H), 2.25 (s, 9H), 2.52-2.57 (m, 1H).

[0062] Example 5: Preparation of cat-5

[0063] The preparation method of cat-5 refers to cat-1.

[0064] NMR data of cat-5: 1 H NMR (DMSO-d6, 400 MHz) δ: 0.98-1.57 (m, 16H), 2.25 (s, 3H), 2.40 (t, 4H), 2.57 (t, 1H).

[0065] Example 6: Preparation of cat-6

[0066] The preparation method of cat-6 refers to cat-1.

[0067] NMR data of cat-6: 1 H NMR (DMSO-d6, 400 MHz) δ: 1.06 (d, 12H), 1.07-1.57 (m, 10H), 2.27 (s, 3H), 2.55-2.57 (m, 1H), 2.78-2.85 (m, 2H).

[0068] Preparation of racemic nicotine

[0069] cat-1 to cat-6 used in the following examples are prepared from examples 1-6.

[0070] Example 7

[0071] Under anaerobic conditions, anhydrous tetrahydrofuran, cat-1 (molar ratio of 1%), S-nicotine and magnetic son were added to the reactor, and then the reflux condenser was installed, the nitrogen balloon was added, and then heated to 80°C. After 10 minutes, the reaction was completed. After the end, the reaction system was cooled to room temperature, and then a proper amount of saturated sodium chloride aqueous solution was added to the reaction system, and then the organic phase in the system was extracted with dichloromethane, and then the organic phase was combined and dried with magnesium sulfate for 30 minutes, and then filtered with diatomite. After the organic phase was concentrated, it was distilled under reduced pressure to obtain a colorless liquid. The liquid chromatogram of the prepared racemic nicotine is shown in Figure 1 , and the yield was 88%.

[0072] Example 8

[0073] Under the condition of no oxygen, the reactor was added with anhydrous dichloromethane, cat-2 (molar ratio of 2%), S-nicotine and magnet, then the reflux condenser, nitrogen balloon were installed, and heated to 40°C, and the reaction was completed after 30 minutes. After the end, the reaction system was cooled to room temperature, and an appropriate amount of saturated sodium chloride aqueous solution was added to the reaction system, and the organic phase in the system was extracted with dichloromethane, and the organic phase was combined and dried with magnesium sulfate for 30 minutes, and then filtered with diatomite. After the organic phase was concentrated, a colorless liquid was obtained by distillation under reduced pressure, and the yield was 90%.

[0074] Example 9

[0075] Under the condition of no oxygen, the reactor was added with anhydrous dichloromethane, cat-2 (molar ratio of 2%), S-nicotine and magnet, then the reflux condenser, nitrogen balloon were installed, and heated to 40°C, and the reaction was completed after 30 minutes. After the end, the reaction system was cooled to room temperature, and an appropriate amount of saturated sodium chloride aqueous solution was added to the reaction system, and the organic phase in the system was extracted with dichloromethane, and the organic phase was combined and dried with magnesium sulfate for 30 minutes, and then filtered with diatomite. After the organic phase was concentrated, a colorless liquid was obtained by distillation under reduced pressure, and the yield was 90%.

[0076] Example 10

[0077] Under the condition of no oxygen, the reactor was added with anhydrous dichloromethane, cat-2 (molar ratio of 2%), S-nicotine and magnet, then the reflux condenser, nitrogen balloon were installed, and heated to 40°C, and the reaction was completed after 30 minutes. After the end, the reaction system was cooled to room temperature, and an appropriate amount of saturated sodium chloride aqueous solution was added to the reaction system, and the organic phase in the system was extracted with dichloromethane, and the organic phase was combined and dried with magnesium sulfate for 30 minutes, and then filtered with diatomite. After the organic phase was concentrated, a colorless liquid was obtained by distillation under reduced pressure, and the yield was 90%.

[0078] Example 11

[0079] Under the condition of no oxygen, the reactor was added with anhydrous dichloromethane, cat-2 (molar ratio of 2%), S-nicotine and magnet, then the reflux condenser, nitrogen balloon were installed, and heated to 40°C, and the reaction was completed after 30 minutes. After the end, the reaction system was cooled to room temperature, and an appropriate amount of saturated sodium chloride aqueous solution was added to the reaction system, and the organic phase in the system was extracted with dichloromethane, and the organic phase was combined and dried with magnesium sulfate for 30 minutes, and then filtered with diatomite. After the organic phase was concentrated, a colorless liquid was obtained by distillation under reduced pressure, and the yield was 90%.

[0080] Example 12

[0081] Under the condition of no oxygen, anhydrous chloroform, cat-1 (mole ratio 25%), S-nicotine and magneton were added into the reactor, and then the reflux condenser, nitrogen balloon were installed, and heated to 90°C, and the reaction was completed after 8 hours. After the end, the reaction system was cooled to room temperature, and then a proper amount of saturated sodium chloride aqueous solution was added into the reaction system, and the organic phase in the system was extracted with chloroform, and then the organic phases were combined and dried with magnesium sulfate for 30 minutes, and then filtered with diatomite. After the organic phase was concentrated, colorless liquid was obtained by reduced pressure distillation, and the yield was 91%.

[0082] Example 13

[0083] Under the condition of no oxygen, anhydrous chloroform, cat-1 (mole ratio 25%), S-nicotine and magneton were added into the reactor, and then the reflux condenser, nitrogen balloon were installed, and heated to 90°C, and the reaction was completed after 8 hours. After the end, the reaction system was cooled to room temperature, and then a proper amount of saturated sodium chloride aqueous solution was added into the reaction system, and the organic phase in the system was extracted with chloroform, and then the organic phases were combined and dried with magnesium sulfate for 30 minutes, and then filtered with diatomite. After the organic phase was concentrated, colorless liquid was obtained by reduced pressure distillation, and the yield was 91%.

[0084] Example 14

[0085] Under the condition of no oxygen, anhydrous chloroform, cat-1 (mole ratio 25%), S-nicotine and magneton were added into the reactor, and then the reflux condenser, nitrogen balloon were installed, and heated to 90°C, and the reaction was completed after 8 hours. After the end, the reaction system was cooled to room temperature, and then a proper amount of saturated sodium chloride aqueous solution was added into the reaction system, and the organic phase in the system was extracted with chloroform, and then the organic phases were combined and dried with magnesium sulfate for 30 minutes, and then filtered with diatomite. After the organic phase was concentrated, colorless liquid was obtained by reduced pressure distillation, and the yield was 91%.

[0086] Example 15

[0087] Under the condition of no oxygen, anhydrous chloroform, cat-1 (mole ratio 25%), S-nicotine and magneton were added into the reactor, and then the reflux condenser, nitrogen balloon were installed, and heated to 90°C, and the reaction was completed after 8 hours. After the end, the reaction system was cooled to room temperature, and then a proper amount of saturated sodium chloride aqueous solution was added into the reaction system, and the organic phase in the system was extracted with chloroform, and then the organic phases were combined and dried with magnesium sulfate for 30 minutes, and then filtered with diatomite. After the organic phase was concentrated, colorless liquid was obtained by reduced pressure distillation, and the yield was 91%.

[0088] Example 16

[0089] Under anaerobic condition, cat-4 (molar ratio 35%), S-nicotine and magneton were added into the reactor, and then the reflux condenser, nitrogen balloon and heating to 140°C were installed. After 35 minutes, the reaction was completed. After the reaction, the reaction system was cooled to room temperature, and then a proper amount of saturated sodium chloride aqueous solution was added into the reaction system, and the organic phase was extracted by dichloromethane. The organic phase was combined and dried by magnesium sulfate for 30 minutes, and then filtered by diatomite. After the organic phase was concentrated, colorless liquid was obtained by distillation under reduced pressure, and the yield was 96%.

[0090] Preparation of dextro nicotine

[0091] The racemic nicotine in the following examples was from the above-mentioned example 7-16.

[0092] Example 17

[0093] 100 g of the racemic nicotine sample was weighed into a volumetric flask, and then a total volume of 500 mL of n-hexane and methanol mixed solution was added. After complete dissolution, 1 mL of formic acid was added, and then the mixture was uniformly mixed. The chiral chromatographic column AD-H was used in batches to separate the mixture, and then the dextro-rotatory nicotine was obtained. The liquid chromatogram of the prepared dextro-rotatory nicotine is shown in Figure 2 The liquid phase detector was an ultraviolet detector, and the wavelength was 260 nm.

[0094] Example 18

[0095] 100 g of the racemic nicotine sample was weighed into a volumetric flask, and then a total volume of 400 mL of n-hexane and isopropanol mixed solution was added. After complete dissolution, 1 mL of acetic acid was added, and then the mixture was uniformly mixed. The chiral chromatographic column OD-H was used in batches to separate the mixture, and then the dextro-rotatory nicotine was obtained. The liquid phase detector was an ultraviolet detector, and the wavelength was 260 nm.

[0096] Example 19

[0097] 100 g of the racemic nicotine sample was weighed into a volumetric flask, and then a total volume of 300 mL of water and methanol mixed solution was added. After complete dissolution, 2 mL of triethylamine was added, and then the mixture was uniformly mixed. The chiral chromatographic column ID-H was used in batches to separate the mixture, and then the dextro-rotatory nicotine was obtained. The liquid phase detector was an ultraviolet detector, and the wavelength was 260 nm.

[0098] Example 20

[0099] 100 g of the racemic nicotine sample was weighed into a volumetric flask, and then a total volume of 400 mL of isopropanol and methanol mixed solution was added. After complete dissolution, 3 mL of isopropylamine was added, and then the mixture was uniformly mixed. The chiral chromatographic column OJ-H was used in batches to separate the mixture, and then the dextro-rotatory nicotine was obtained. The liquid phase detector was an ultraviolet detector, and the wavelength was 260 nm.

[0100] Example 21

[0101] Take 100 g of racemic nicotine sample, put it in a volumetric flask, add a total volume of 350 mL of n-hexane and tetrahydrofuran mixed solution, completely dissolve, then add 1 mL of diethylamine, mix uniformly, then use the chiral chromatographic column AS-H to split it in batches, and the liquid phase detector is an ultraviolet detector with a wavelength of 260 nm.

Claims

1. Use of a quaternary ammonium base in the preparation of dextro nicotine, wherein, The structure of the quaternary ammonium base is shown in formula (I): [NR1R2R3R4] + OH - (I) R1, R2, R3, R4are independently selected from C 1-3 alkyl, C3-C6cycloalkyl.

2. The use according to claim 1, wherein, R1, R2, R3 and R4 are the same and selected from methyl, ethyl or isopropyl.

3. The use according to claim 1, wherein, At least one of R1, R2, R3 and R4 is a cycloalkyl group, and the cycloalkyl group is cyclohexane.

4. The use according to claim 1, wherein, The structure of the quaternary ammonium base is selected from the following structures: 。 5. A method for preparing racemic nicotine using the quaternary ammonium base in the application of any one of claims 1 to 4 as a catalyst. The method comprises using S-nicotine as a raw material and catalyzing by the quaternary ammonium base to obtain racemic nicotine through one-step reaction, and the synthesis route is as follows: 。 6. The method of claim 5, wherein, The method comprises adding S-nicotine and the quaternary ammonium base in one pot under inert gas protection in a solvent or an organic solvent, cooling after the reaction is completed, and purifying to obtain the product. The inert gas is selected from argon or helium.

7. The method of claim 6, wherein, The organic solvent is selected from one or more of toluene, xylene, methanol, ethanol, dichloromethane, dichloroethane, chloroform, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide and dimethyl sulfoxide.

8. The method of claim 6, wherein, The organic solvent is selected from one or more of xylene, tetrahydrofuran or dimethyl sulfoxide.

9. The method of any one of claims 5-8, wherein, The temperature of the reaction is 40-160°C.

10. The method of any one of claims 5 to 8, wherein, The temperature of the reaction is 40-100°C.

11. The method of any one of claims 5 to 8, wherein, The time of the reaction is 10 minutes-12 hours.

12. The method of any one of claims 5 to 8, wherein, The time of the reaction is 15 minutes-5 hours.

13. The method of any one of claims 5 to 8, wherein, The molar ratio of the S-nicotine to the quaternary ammonium base is 100:1-100:

40.

14. The method of any one of claims 5 to 8, wherein, The molar ratio of the S-nicotine to the quaternary ammonium base is 100:3-100:

20.

15. A method for preparing R-nicotine using the quaternary ammonium base in the application of any one of claims 1 to 4, which comprises preparing racemic nicotine by the method of any one of claims 5 to 14, and then using preparative liquid phase to resolve the racemic nicotine to obtain R-nicotine. The chromatographic column used for resolving the racemic nicotine by preparative liquid phase is a chiral chromatographic column, and the model is selected from AD, AD-H, AS, AS-H, OD, OD-H, ID, ID-H, OJ, OJ-H, IA, IB and IC. The solvent used for resolving the racemic nicotine by preparative liquid phase is selected from n-hexane, isopropyl alcohol, methanol, ethanol, ethyl acetate, tetrahydrofuran, methyl tert-butyl ether and water. Formic acid, acetic acid, triethylamine, isopropylamine or diethylamine is added to the solvent.

16. The method of claim 15, wherein, The chromatographic column used for resolving the racemic nicotine by preparative liquid phase is a chiral chromatographic column, and the model is selected from OD-H, ID-H, OJ-H, IA, IB and IC.

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