CN114249711A - Method for preparing nicotine by resolution - Google Patents
Method for preparing nicotine by resolution Download PDFInfo
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- CN114249711A CN114249711A CN202210195318.4A CN202210195318A CN114249711A CN 114249711 A CN114249711 A CN 114249711A CN 202210195318 A CN202210195318 A CN 202210195318A CN 114249711 A CN114249711 A CN 114249711A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention relates to the technical field of nicotine preparation processes, and provides a method for preparing nicotine by splitting, which comprises the following steps: adding (R, S) -nicotine and resolving agent into resolving solvent, dissolving, stirring, and crystallizing to obtain S-nicotine salt or R-nicotine salt; the resolution solvent comprises ethanol and isopropanol, and the volume ratio of the ethanol to the isopropanol is not less than 2: 3; the S-nicotine or R-nicotine is prepared by dissociating, extracting and concentrating the nicotine salt. The method for preparing nicotine by resolution provided by the invention has the advantages of mild reaction conditions, low cost, high yield and purity, and less influence on the resolution result due to other solvent impurities mixed in the resolution solvent, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of nicotine preparation processes, in particular to a method for preparing nicotine by splitting.
Background
Nicotine, also known as nicotine, is widely present in solanaceae plants, is the main component of alkaloid contained in tobacco, and is 3-4% of the content in tobacco leaves. The nicotine can be used as natural pesticide, and can also be used in medicine, pesticide, electronic cigarette, smoking stopping medicine, etc. Natural nicotine is levorotatory nicotine (S-nicotine) and is currently mainly derived from tobacco plant extracts. The tobacco leaves contain various alkaloids, and the alkaloids are not easy to separate, so the S-nicotine extracted and prepared from the tobacco leaves has low purity. The nicotine synthesized by the existing chemical synthesis method is generally a racemate or a partial racemate, and the levorotatory nicotine (S-nicotine) or dextrorotatory nicotine (R-nicotine) is prepared by resolution.
The prior art discloses some nicotine resolution methods, but the methods have the problems of unsatisfactory yield and EE value, and can obtain products with qualified purity by adopting a plurality of crystallization processes, so the method has high production cost and is not beneficial to industrial mass production. Therefore, it is necessary to develop a nicotine separation method with ideal product yield and EE value.
Disclosure of Invention
The invention aims to provide a method for preparing nicotine by splitting, and aims to solve the technical problems of non-ideal product yield and EE value of the nicotine splitting method in the prior art.
In order to achieve the purpose, the invention adopts the technical scheme that:
the invention provides a method for preparing nicotine by resolution, which comprises the following steps:
adding (R, S) -nicotine and resolving agent into resolving solvent, dissolving, stirring, and crystallizing to obtain S-nicotine salt or R-nicotine salt; the resolution solvent comprises ethanol and isopropanol, and the volume ratio of the ethanol to the isopropanol is not less than 2: 3;
the S-nicotine or R-nicotine is prepared by dissociating, extracting and concentrating the nicotine salt.
Further, the volume ratio of the ethanol to the isopropanol is not less than 1: 1.
further preferably, the volume ratio of the ethanol to the isopropanol is (1-3): 1.
further, washing the S-nicotine salt or the R-nicotine salt with the same solvent as the resolution solvent.
Further, the resolving agent for preparing the S-nicotine is L-dibenzoyl tartrate; the resolving agent for preparing R-nicotine is D-dibenzoyl tartrate.
Further, the mass-to-volume ratio of the (R, S) -nicotine to the resolving solvent is 1: (9-14).
Further preferably, the mass-to-volume ratio of (R, S) -nicotine to the resolving solvent is 1: (10-14).
Further, the ethanol is absolute ethanol or 95% ethanol.
Further preferably, the ethanol is absolute ethanol.
Further, the molar ratio of the (R, S) -nicotine to the resolving agent is 1: (0.9-1.1).
Further, the nicotine salt is recrystallized before the nicotine salt is dissociated, and the solvent for recrystallization comprises ethanol and isopropanol, wherein the volume ratio of the ethanol to the isopropanol is not less than 2: 3.
further preferably, the volume ratio of ethanol to isopropanol is not less than 1: 1.
further, the step of adding the (R, S) -nicotine and the resolving agent into the resolving solvent, dissolving, stirring and crystallizing to obtain the S-nicotine salt or the R-nicotine salt comprises the following steps:
adding (R, S) -nicotine and resolving agent into resolving solvent, heating for dissolving, keeping the temperature for 5-20min, stopping heating, naturally cooling at room temperature, stirring, and crystallizing to obtain S-nicotine salt or R-nicotine salt.
Compared with the rapid cooling, the adoption of the natural slow cooling can lead the EE value of the prepared split product to be more ideal in the nicotine salt crystallization process of the method provided by the invention.
Further, the dissociating comprises: adding nicotine salt into mixed solvent of water and organic solvent, and sequentially acidifying and alkalizing.
More preferably, the organic solvent is at least one of ethyl acetate and chloroform.
The invention has the beneficial effects that:
the method for preparing nicotine by resolution provided by the invention has the advantages of mild reaction conditions, low cost, high yield and purity, and less influence on the resolution result due to other solvent impurities mixed in the resolution solvent, and is suitable for industrial production.
Drawings
Fig. 1 is a high performance liquid chromatogram of S-nicotine prepared in example 1.
Fig. 2 is a table of peaks of a high performance liquid chromatogram of S-nicotine prepared in example 1.
Figure 3 is a high performance liquid chromatogram of racemic nicotine.
Figure 4 is a peak table of a high performance liquid chromatogram of racemic nicotine.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more apparent, the present invention is further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present patent and do not limit the scope of the invention in any way.
The method for preparing nicotine by resolution comprises the following steps:
adding (R, S) -nicotine and resolving agent into resolving solvent, dissolving, stirring, and crystallizing to obtain S-nicotine salt or R-nicotine salt; the resolution solvent comprises ethanol and isopropanol, wherein the volume ratio of the ethanol to the isopropanol is not less than 2: 3;
the S-nicotine or R-nicotine is prepared by dissociating, extracting and concentrating the nicotine salt.
(R, S) -nicotine is a mixture of S-nicotine and R-nicotine and may be S-nicotine and R-nicotine in a ratio of 50: 50 in a ratio of racemic mixture; or a partial racemic mixture of S-nicotine and R-nicotine mixed in other proportions, for example, the mixing ratio may be 10: 90. 15: 85. 25: 75. 40: 60. 45, and (2) 45: 55. 60: 40. 70: 30. 80: 20. 85: 15. 95: 5, and the like.
Wherein L-dibenzoyl tartrate can be selected as resolving agent for preparing S-nicotine. D-dibenzoyl tartrate can be selected as a resolving agent for preparing R-nicotine. The yield and EE value of the products prepared by the two resolution processes are different.
Preferably, the volume ratio of ethanol to isopropanol is not less than 1: 1.
further preferably, the volume ratio of ethanol to isopropanol is (1-3): 1. the volume ratio of the ethanol to the isopropanol is (1-3): 1 can lead to higher nicotine yield and EE value.
Preferably, the S-nicotine salt or the R-nicotine salt is washed with the same solvent as the resolving solvent.
Preferably, the mass-to-volume ratio of (R, S) -nicotine to resolving solvent is 1: (9-14). For example, 1: 9. 1: 10. 1: 12. 1: 12.5, 1: 14, etc.
In the present invention, too little amount of the resolving solvent results in too low EE value of the nicotine salt and operation problems that the nicotine salt is difficult to pour out from the reaction vessel; too much amount of the resolving solvent causes waste of the solvent and increase of the production cost.
Preferably, the molar ratio of (R, S) -nicotine to resolving agent is 1: (0.9-1.1). For example, 1: 0.9, 1: 0.95, 1: 0.98, 1: 1. 1: 1.1, etc.
Preferably, the ethanol is absolute ethanol or 95% ethanol. Low ethanol concentrations can adversely affect both product yield and EE value.
Preferably, the nicotine salt is recrystallized before the nicotine salt is released, and the solvent for recrystallization comprises ethanol and isopropanol, wherein the volume ratio of the ethanol to the isopropanol is not less than 2: 3. the recrystallization step can effectively increase the EE value of the nicotine produced.
The invention is described in more detail by referring to a part of the tests, which are carried out in sequence, and the following detailed description is given by combining specific examples:
unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the raw materials, instruments, equipment and the like used in the following examples are either commercially available or available by existing methods; the dosage of the reagent is the dosage of the reagent in the conventional experiment operation if no special description exists; the experimental methods are conventional methods unless otherwise specified.
The HPLC chromatogram of racemic nicotine (S-nicotine: R-nicotine = 1: 1) used in each example and comparative example of the present invention is shown in FIG. 3.
Example 1
A method for preparing S-nicotine by resolution, comprising:
adding 30.0g (184.9 mmol) of racemic nicotine and 66.3g (185.0 mmol) of L-dibenzoyl tartaric acid into a resolution solvent consisting of 200mL of absolute ethyl alcohol and 100mL of isopropanol, heating to 75-85 ℃ until the solution is clear, preserving the temperature for 10min, stopping heating, naturally cooling, cooling to 60 ℃, adding 0.1g of seed crystal (S-nicotine-L-dibenzoyl tartrate), cooling to room temperature (20 +/-5 ℃), stirring overnight, filtering, leaching with 40mL of mixed solvent (absolute ethyl alcohol: isopropanol = 2: 1), and drying at 70 ℃ to constant weight to obtain 37.8g (72.6 mmol) of S-nicotine-L-dibenzoyl tartrate with the yield of 78.5%.
30.0g (57.6 mmol) of S-nicotine-L-dibenzoyl tartrate is taken, recrystallized by 150mL of mixed solvent (absolute ethyl alcohol: isopropanol = 2: 1), and dried to constant weight at 70 ℃ to obtain 25.4g (48.8 mmol) of recrystallized S-nicotine-L-dibenzoyl tartrate, with the yield of 84.7%.
Adding 30mL of water and 60mL of ethyl acetate into the recrystallized S-nicotine-L-dibenzoyl tartrate, cooling to 10 ℃, dropwise adding 6mL of industrial hydrochloric acid, stirring for 10 minutes, standing, layering, washing an ethyl acetate layer with 10mL of 10% diluted hydrochloric acid, combining water layers, extracting once with 20mL of ethyl acetate, combining ethyl acetate, and recovering L-dibenzoyl tartaric acid; the aqueous layer was basified with liquid alkali and extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and rectified to give 7.5g (46.2 mmol) of colorless liquid (S-nicotine) with a yield of 94.7%, GC =99.8%, and EE% of 99.6% by chiral HPLC (fig. 1 and 2).
Comparing fig. 1 and fig. 3, the peak position of S-nicotine obtained by resolution in example 1 is 9.6min, and the peak position is the same substance as that of racemic nicotine at 9.7 min. The peak at 10.6min of racemic nicotine spectrum (fig. 3 and fig. 4) is R-nicotine.
The HPLC method for detecting EE value is as follows:
a chromatographic column: xylonite IB N-3 type chiral column;
mobile phase: n-hexane: isopropyl alcohol: triethylamine = 96: 4: 0.1 (volume ratio);
flow rate: 0.9 mL/min;
temperature: 25 ℃;
wavelength: 262 nm.
Example 2
A method for preparing S-nicotine by resolution, comprising:
adding 30.0g (184.9 mmol) of racemic nicotine and 66.3g (185.0 mmol) of L-dibenzoyl tartaric acid into a resolution solvent consisting of 200mL of absolute ethyl alcohol and 100mL of isopropanol, heating to 75-85 ℃ until the solution is clear, preserving the temperature for 10min, stopping heating, naturally cooling, cooling to 60 ℃, adding 0.1g of seed crystal (S-nicotine-L-dibenzoyl tartrate), cooling to room temperature (20 +/-5 ℃), stirring overnight, filtering, leaching with 40mL of mixed solvent (absolute ethyl alcohol: isopropanol = 2: 1), drying at 70 ℃ to constant weight, and obtaining 38.5g (74.0 mmol) of S-nicotine-L-dibenzoyl tartrate with the yield of 80.0%.
Adding 30mL of water and 60mL of ethyl acetate into S-nicotine-L-dibenzoyl tartrate, cooling to 10 ℃, dropwise adding 9mL of industrial hydrochloric acid, stirring for 10 minutes, standing, layering, washing an ethyl acetate layer with 10mL of 10% diluted hydrochloric acid, combining water layers, extracting once with 20mL of ethyl acetate, combining ethyl acetate, and recovering L-dibenzoyl tartrate; the water layer is alkalized by liquid alkali and extracted by ethyl acetate, the ethyl acetate layer is dried by anhydrous sodium sulfate, after filtration, reduced pressure concentration and rectification, 11.4g (70.3 mmol) of colorless liquid (S-nicotine) is obtained, the yield is 95.0 percent, and the EE percent is 91.8 percent by chiral HPLC detection.
Example 3
A method for preparing S-nicotine by resolution, which differs from example 2 in that: the resolution solvent consisted of 150mL of absolute ethanol and 150mL of isopropanol.
The S-nicotine-L-dibenzoyltartrate salt obtained in this example was 39.4g (75.7 mmol) and the yield was 81.9%.
The S-nicotine prepared by dissociating and extracting the S-nicotine-L-dibenzoyl tartrate is 11.8g (72.7 mmol), the yield is 96.1 percent, and the EE percent is 86.4 percent.
Example 4
A method for preparing S-nicotine by resolution, which differs from example 2 in that: the resolution solvent consisted of 225mL of absolute ethanol and 75mL of isopropanol.
The S-nicotine-L-dibenzoyltartrate salt obtained in this example was 38.0g (73.0 mmol), and the yield was 79.0%.
The S-nicotine prepared by dissociating and extracting the S-nicotine-L-dibenzoyl tartrate is 11.4g (70.3 mmol), the yield is 96.3 percent, and the EE percent is 91.8 percent.
Example 5
A method for preparing S-nicotine by resolution, which differs from example 2 in that: the resolution solvent consisted of 270mL of absolute ethanol and 30mL of isopropanol.
The S-nicotine-L-dibenzoyltartrate salt obtained in this example was 35.2g (67.6 mmol) and the yield was 73.1%.
The S-nicotine prepared by dissociating and extracting the S-nicotine-L-dibenzoyl tartrate is 10.5g (64.7 mmol), the yield is 95.7 percent, and the EE percent is 92.6 percent.
Example 6
A method for preparing S-nicotine by resolution, which differs from example 2 in that: the resolution solvent consisted of 120mL of absolute ethanol and 180mL of isopropanol.
The S-nicotine-L-dibenzoyltartrate salt obtained in this example was 44.1g (84.7 mmol) and the yield was 91.6%.
The S-nicotine obtained by dissociating and extracting the S-nicotine-L-dibenzoyl tartrate is 13.0g (80.1 mmol), the yield is 94.6 percent, and the EE percent is 76.4 percent.
Example 7
A method for preparing S-nicotine by resolution, which differs from example 2 in that: after the temperature is kept for 10min, the temperature is reduced to room temperature (20 +/-5 ℃) by using ice water, and then the mixture is stirred for 2 h.
The S-nicotine-L-dibenzoyltartrate salt obtained in this example was 38.1g (73.2 mmol), and the yield was 79.2%.
The S-nicotine prepared by dissociating and extracting the S-nicotine-L-dibenzoyl tartrate is 11.4g (70.3 mmol), the yield is 96.0 percent, and the EE percent is 85.4 percent.
Example 8
A method for preparing S-nicotine by resolution, which differs from example 2 in that: the mass volume ratio of the racemic nicotine to the resolution solvent is 1: 14.
the S-nicotine-L-dibenzoyltartrate salt obtained in this example was 37.0g (71.1 mmol) and the yield was 76.9%.
The S-nicotine obtained by dissociating and extracting the S-nicotine-L-dibenzoyl tartrate is 11.0g (67.8 mmol), the yield is 95.4%, and the EE% is 93.2%.
Example 9
A method for preparing S-nicotine by resolution, which differs from example 2 in that: the mass volume ratio of the racemic nicotine to the resolution solvent is 1: 12.
the S-nicotine-L-dibenzoyltartrate salt obtained in this example was 37.4g (71.9 mmol) and the yield was 77.7%.
The S-nicotine-L-dibenzoyl tartrate was isolated and extracted to give 11.2g (69.0 mmol), with a yield of 96.1% and EE% of 93.0%.
Example 10
A method for preparing S-nicotine by resolution, which differs from example 2 in that: the mass volume ratio of the racemic nicotine to the resolution solvent is 1: 9.
the S-nicotine-L-dibenzoyltartrate salt obtained in this example was 38.5g (74.0 mmol), and the yield was 80.0%.
The S-nicotine prepared by dissociating and extracting the S-nicotine-L-dibenzoyl tartrate is 11.5g (70.9 mmol), the yield is 95.8 percent, and the EE percent is 88.6 percent.
Example 11
A method for preparing S-nicotine by resolution, which differs from example 2 in that: the mass volume ratio of the racemic nicotine to the resolution solvent is 1: 7.
the amount of S-nicotine-L-dibenzoyltartrate prepared in this example was 39.1g (75.1 mmol), 81.2% yield; and the use amount of the resolving solvent used in the present example is too small, which makes it difficult to pour out the S-nicotine-L-dibenzoyltartrate from the reaction vessel after crystallization, thus increasing the difficulty of the filtration operation.
The S-nicotine prepared by dissociating and extracting the S-nicotine-L-dibenzoyl tartrate is 11.7g (72.1 mmol), the yield is 96.0 percent, and the EE percent is 82.6 percent.
Example 12
A method for preparing S-nicotine by resolution, which differs from example 2 in that: the absolute ethyl alcohol in the resolving agent is replaced by 95 percent (mass concentration) ethyl alcohol.
The S-nicotine-L-dibenzoyltartrate salt obtained in this example was 33.7g (64.7 mmol) and the yield was 70.0%.
The S-nicotine prepared by dissociating and extracting the S-nicotine-L-dibenzoyl tartrate is 10.1g (62.3 mmol), the yield is 96.2 percent, and the EE percent is 87.8 percent.
Example 13
A method for preparing S-nicotine by resolution, which differs from example 2 in that: 66.3g (185.0 mmol) of L-dibenzoyltartaric acid were replaced by 71.4g (184.9 mmol) of D- (+) -di-p-methylbenzoyltartaric acid.
The yield of S-nicotine-D-di-p-methylbenzoyl tartrate prepared in this example was 63.7g (116.1 mmol) and 125.6%.
Adding 60mL of water and 120mL of ethyl acetate into S-nicotine-D-di-p-methylbenzoyl tartrate, cooling to 10 ℃, dropwise adding 18mL of industrial hydrochloric acid, stirring for 10 minutes, standing, layering, washing an ethyl acetate layer with 20mL of 10% diluted hydrochloric acid, combining water layers, extracting once with 40mL of ethyl acetate, combining ethyl acetate, and recovering D-di-p-methylbenzoyl tartrate; the water layer was alkalified with liquid alkali and extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and rectified to give 18.1g (111.6 mmol) of colorless liquid (S-nicotine) with a yield of 96.1% and EE% of 22.6% as detected.
Example 14
A method for preparing R-nicotine by resolution, comprising:
adding 30.0g (184.9 mmol) of racemic nicotine and 66.3g (185.0 mmol) of D-dibenzoyl tartaric acid into a resolution solvent consisting of 200mL of absolute ethyl alcohol and 100mL of isopropanol, heating to 75-85 ℃ until the solution is clear, preserving the heat for 10min, stopping heating, naturally cooling, cooling to 60 ℃, adding 0.1g of seed crystal (R-nicotine-D-dibenzoyl tartrate), cooling to 20 +/-5 ℃, stirring overnight, filtering, leaching with 40mL of mixed solvent (absolute ethyl alcohol: isopropanol = 2: 1), drying at 70 ℃ to constant weight to obtain 38.6g (74.2 mmol) of R-nicotine-D-dibenzoyl tartrate, wherein the yield is 80.2%.
30.0g (57.6 mmol) of R-nicotine-D-dibenzoyl tartrate was recrystallized from 150mL of a mixed solvent (absolute ethanol: isopropanol = 2: 1) to obtain 25.7g (49.4 mmol) of R-nicotine-D-dibenzoyl tartrate after recrystallization, and the yield was 85.7%.
Adding 30mL of water and 60mL of ethyl acetate into the R-nicotine-D-dibenzoyl tartrate after recrystallization, cooling to 10 ℃, dropwise adding 6mL of industrial hydrochloric acid, stirring for 10 minutes, standing, layering, washing an ethyl acetate layer with 10mL of 10% diluted hydrochloric acid, combining water layers, extracting once with 20mL of ethyl acetate, combining ethyl acetate, and recovering D-dibenzoyl tartaric acid; the water layer was alkalified with liquid alkali and extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and rectified to give 7.6g of colorless liquid (R-nicotine) with a yield of 94.9%. EE% by chiral HPLC was 99.8%.
Comparative example 1
A method for preparing S-nicotine by resolution, which differs from example 2 in that: the resolution solvent consisted of 200mL of methanol and 100mL of isopropanol.
The comparative example produced 26.3g (50.5 mmol) of S-nicotine-L-dibenzoyl tartrate in 54.7% yield.
The S-nicotine prepared by dissociating and extracting the S-nicotine-L-dibenzoyl tartrate is 7.9g (48.7 mmol), the yield is 96.4 percent, and the EE percent is 72.6 percent.
Comparative example 2
A method for preparing S-nicotine by resolution, which differs from example 2 in that: the resolution solvent was 300mL ethanol.
The comparative example produced 29.1g (55.9 mmol) of S-nicotine-L-dibenzoyl tartrate in 60.5% yield. The crystalline product EE value of the resolution solvent which adopts pure ethanol is high, and the defects are that the yield is low, the requirement on water is high, and the filtration is not easy.
The S-nicotine obtained by dissociating and extracting the S-nicotine-L-dibenzoyl tartrate is 8.7g (53.6 mmol), the yield is 95.9 percent, and the EE percent is 94.2 percent.
Comparative example 3
A method for preparing S-nicotine by resolution, which differs from example 2 in that: the resolution solvent was 300mL isopropanol.
The comparative example produced 69.0g (132.6 mmol) of S-nicotine-L-dibenzoyl tartrate in 143.4% yield.
Adding 70mL of water and 140mL of ethyl acetate into S-nicotine-L-dibenzoyl tartrate, cooling to 10 ℃, dropwise adding 20mL of industrial hydrochloric acid, stirring for 10 minutes, standing, layering, washing an ethyl acetate layer with 20mL of 10% diluted hydrochloric acid, combining water layers, extracting once with 40mL of ethyl acetate, combining ethyl acetate, and recovering L-dibenzoyl tartrate; the water layer was alkalified with liquid alkali and extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and rectified to give 20.7g (127.6 mmol) of colorless liquid (S-nicotine) with a yield of 96.3% and an EE% of 16.8% as detected.
Comparative example 4
A method for preparing S-nicotine by resolution, which differs from example 2 in that: the resolution solvent consisted of 100mL of absolute ethanol and 200mL of isopropanol.
The S-nicotine-L-dibenzoyltartrate salt obtained in this example was 48.2g (92.6 mmol) and the yield was 100.2%.
Adding 50mL of water and 120mL of ethyl acetate into S-nicotine-L-dibenzoyl tartrate, cooling to 10 ℃, dropwise adding 15mL of industrial hydrochloric acid, stirring for 10 minutes, standing, layering, washing an ethyl acetate layer with 20mL of 10% diluted hydrochloric acid, combining water layers, extracting once with 40mL of ethyl acetate, combining ethyl acetate, and recovering L-dibenzoyl tartrate; the water layer was alkalified with liquid alkali and extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and rectified to give 14.5g (89.4 mmol) of colorless liquid (S-nicotine) with a yield of 96.5% and an EE% of 15.6% according to detection.
Comparative example 5
A method for preparing S-nicotine by resolution, which differs from example 2 in that: the resolution solvent consisted of 60mL of absolute ethanol and 240mL of isopropanol.
The S-nicotine-L-dibenzoyltartrate salt obtained in this example was 52.3g (100.5 mmol) and the yield was 108.7%.
Adding 50mL of water and 120mL of ethyl acetate into S-nicotine-L-dibenzoyl tartrate, cooling to 10 ℃, dropwise adding 15mL of industrial hydrochloric acid, stirring for 10 minutes, standing, layering, washing an ethyl acetate layer with 20mL of 10% diluted hydrochloric acid, combining water layers, extracting once with 40mL of ethyl acetate, combining ethyl acetate, and recovering L-dibenzoyl tartrate; the water layer was alkalified with liquid alkali and extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and rectified to give 15.6g (96.2 mmol) of colorless liquid (S-nicotine) with a yield of 95.7% and an EE% of 15.2% detection.
The influence of a small amount of other solvents mixed in the resolution solvent on the resolution effect.
The method provided in example 2 was used to prepare S-nicotine, and 30mL of other solvents were added to the resolution solvent, respectively, and the total yield and EE value of S-nicotine were measured. The results are shown in the following table:
the method provided in comparative example 1 was used to prepare S-nicotine, and 30mL of other solvents were added to the resolving solvent, respectively, and the total yield and EE value of S-nicotine were measured. The results are shown in the following table:
the comparison shows that the method for preparing nicotine by resolution has stronger anti-interference performance, and the influence of a small amount of impurities in the resolution solvent on the resolution result is relatively small, so that the method is suitable for industrial production.
Analysis of influence of recrystallization step
The S-nicotine salt (or R-nicotine salt) obtained by single crystallization is directly dissociated, extracted and concentrated to obtain the S-nicotine (or R-nicotine) with relatively low chiral purity. Experiments show that the chiral purity EE% of S-nicotine (or R-nicotine) prepared by carrying out a recrystallization step on an S-nicotine salt (or R-nicotine salt) with an isomer of less than 10% (EE% > 80%) is more than 99.0%; the EE% of the S-nicotine (or R-nicotine) prepared by the S-nicotine salt (or R-nicotine) with isomer <5% (EE% > 90%) through one recrystallization step is more than 99.5%.
The specific test data are as follows:
1. effect of the recrystallization step on the resolution of S-nicotine
2. Effect of the recrystallization step on the resolution of R-nicotine
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. A method for preparing nicotine by resolution, which is characterized by comprising the following steps:
adding (R, S) -nicotine and resolving agent into resolving solvent, dissolving, stirring, and crystallizing to obtain S-nicotine salt or R-nicotine salt; the resolution solvent comprises ethanol and isopropanol, and the volume ratio of the ethanol to the isopropanol is not less than 2: 3;
the S-nicotine or R-nicotine is prepared by dissociating, extracting and concentrating the nicotine salt.
2. The method according to claim 1, wherein the volume ratio of ethanol to isopropanol is not less than 1: 1.
3. the process according to claim 2, wherein the volume ratio of ethanol to isopropanol is (1-3): 1.
4. the process according to any of claims 1-3, wherein the S-nicotine salt or R-nicotine salt is washed with the same solvent as the resolution solvent.
5. A process according to any of claims 1-3, characterized in that the resolving agent for preparing S-nicotine is L-dibenzoyltartrate; the resolving agent for preparing R-nicotine is D-dibenzoyl tartrate.
6. The process according to any one of claims 1-3, wherein the mass to volume ratio of (R, S) -nicotine to resolving solvent is 1: (9-14).
7. The method according to any one of claims 1 to 3, wherein the ethanol is absolute ethanol or 95% ethanol.
8. A process according to any of claims 1-3, wherein the molar ratio of (R, S) -nicotine to the resolving agent is 1: (0.9-1.1).
9. A method according to any of claims 1-3, wherein the nicotine salt is recrystallized before the nicotine salt is freed, and the solvent for recrystallization comprises ethanol and isopropanol, the volume ratio of ethanol to isopropanol being not less than 2: 3.
10. the method according to any one of claims 1 to 3, wherein the step of adding the (R, S) -nicotine and the resolving agent to the resolving solvent, dissolving, and stirring for crystallization to obtain the S-nicotine salt or the R-nicotine salt comprises:
adding (R, S) -nicotine and resolving agent into resolving solvent, heating for dissolving, keeping the temperature for 5-20min, stopping heating, naturally cooling at room temperature, stirring, and crystallizing to obtain S-nicotine salt or R-nicotine salt.
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