CN114105869B - Preparation method of 2-propyl-4-cyanopyridine - Google Patents
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Abstract
The invention relates to a preparation method of 2-propyl-4-cyanopyridine, which takes 2-propyl-4-piperidone as an initial raw material, generates carbanion with p-toluenesulfonylmethyl isocyanide in the presence of alkali to carry out nucleophilic addition reaction, then loses sulfonyl and formyl to prepare 2-propyl-4-cyanopyridine, and then obtains the 2-propyl-4-cyanopyridine by dehydroxylation. The invention has simple and convenient synthetic route, common compounds as raw and auxiliary materials, and recyclable solvent and catalyst; the product is a single compound, and compared with the traditional synthetic method, the product does not generate isomer 3-propyl-4-cyanopyridine, and has lower post-treatment requirement on the synthetic prothioconazole.
Description
Technical Field
The invention relates to a preparation method of 2-propyl-4-cyanopyridine, belonging to the technical field of compound synthesis.
Background
The ipratropium sulfide is yellow crystal or crystalline powder, and has a special odor. The prothiocypamine is one of important drugs for treating tuberculosis, is often combined with other antituberculosis drugs to treat various tuberculosis, and is mainly used for treating retreated cases which are not effectively treated by other antituberculosis drugs or patients who cannot tolerate the treatment of other antituberculosis drugs. The ipratropium pyrithiobac has an antibacterial effect on the mycobacterium tuberculosis; the oral preparation is easy to absorb and widely distributed in vivo, can permeate into body fluid (including cerebrospinal fluid) of the whole body, and is completely metabolized into ineffective substances in vivo; the curative effect on exudative and infiltrative cheese lesions is better; the composition is used alone or in combination with other antituberculosis drugs to enhance curative effect and prevent drug resistance of pathogenic bacteria.
In recent years, the proportion of drug-resistant tuberculosis patients is increased, and the reason for the occurrence of the patients can be summarized as the following two points: first, lack of infection control measures in the space where people gather, such as medical institutions and prisons, leads to the emergence of primary drug resistance; secondly, the treatment is not thorough, and particularly for patients with positive sputum smear, the acquired drug resistance of the patients is caused, and the phenomenon of multidrug resistance is increasingly serious. The resistance of antitubercular drugs is an important public health problem, threatening the successful implementation of DOTS (the recommended treatment method of the world health organization for the discovery and treatment of tuberculosis) and also threatening the global tuberculosis control. Clinical observation for many years shows that the prothioconazole can be used for treating the cases which are not effectively treated by other antitubercular drugs or patients who can not tolerate the treatment of other antitubercular drugs, and becomes one of effective drugs in a treatment scheme for treating multidrug-resistant tuberculosis.
2-propyl-4-cyanopyridine is an important intermediate for synthesizing prothiocononicotinamide, and a plurality of reports about the preparation method of the prothiocononicotinamide are provided in the literature. The most common methods are: 4-cyanopyridine and n-butyric acid are taken as raw materials, and are subjected to free radical reaction under the catalytic oxidation of silver nitrate and persulfate to obtain 2-propyl-4-cyanopyridine, however, the side reaction of the method can generate 3-propyl-4-cyanopyridine, and the by-product is relatively close to the 2-propyl-4-cyanopyridine in property, is not easy to separate, increases the difficulty in further purifying and synthesizing the propylthioisonicotinamine, and is not beneficial to industrial production.
Disclosure of Invention
The main purposes of the invention are: the preparation method of the 2-propyl-4-cyanopyridine is simple and convenient in synthetic route, common compounds are adopted as raw and auxiliary materials, a single compound is generated, and the product purity is high; the solvent and the catalyst can be recycled, and the method is economical and environment-friendly.
The technical scheme for solving the technical problems of the invention is as follows:
a preparation method of 2-propyl-4-cyanopyridine is characterized by comprising the following steps:
dissolving 2-propyl-4-piperidone in a first solvent, adding p-toluenesulfonylmethyl isocyanide, cooling, adding alkali under the protection of inert gas, and heating for reaction; after the reaction is finished, concentrating, adding water, extracting by using an extraction reagent, collecting an organic phase, drying, concentrating, and distilling under reduced pressure to obtain 2-propyl-4-cyanopiperidine; wherein the weight ratio of the first solvent to the 2-propyl-4-piperidone is 5.0-15.0: the equivalent ratio of the 1, 2-propyl-4-piperidone to the p-toluenesulfonylmethyl isocyanide is 1:1.0-4.0, the equivalent ratio of 2-propyl-4-piperidone to base is 1:2.0-5.0;
secondly, taking 2-propyl-4-cyano piperidine, adding a second solvent and a catalyst, and heating for reaction; after the reaction is finished, cooling, filtering, concentrating the filtrate, and distilling under reduced pressure to obtain 2-propyl-4-cyanopyridine; wherein the weight ratio of the second solvent to the 2-propyl-4-cyanopiperidine is 10.0-20.0:1, the weight ratio of the catalyst to the 2-propyl-4-cyanopiperidine is from 0.01 to 0.05:1.
adding solvent B and catalyst into the 2-propyl-4-cyanopiperidine, heating to 60-100 ℃, reacting for 10-20hr, cooling, filtering, desolventizing, and distilling under reduced pressure to obtain the 2-propyl-4-cyanopyridine.
The method takes 2-propyl-4-piperidone as a starting material, generates carbanions with p-toluenesulfonylmethyl isocyan (Tosmic) in the presence of alkali to perform nucleophilic addition reaction, then loses sulfonyl and formyl to prepare 2-propyl-4-cyanopiperidine, and obtains 2-propyl-4-cyanopyridine through dehydroxidation; the total yield is more than 80%, and the product purity is more than 99%.
The technical scheme of the invention is further perfected as follows:
preferably, in the first step, the temperature is reduced to-5 ℃ to 5 ℃ after the p-toluenesulfonylmethylisocyan is added; reacting at 30-70 ℃ for 10-24h during temperature rising reaction, and finishing the reaction when the content of 2-propyl-4-piperidone is less than 1.0% by HPLC (high performance liquid chromatography) detection; when water is added, the temperature is controlled not to exceed 35 ℃ by using ice water bath.
More preferably, in the first step, the temperature is raised to 20 ℃ to 30 ℃ before the reaction is carried out at 30 ℃ to 70 ℃.
More preferably, in the first step, the first solvent is one of ethylene glycol dimethyl ether, diethylene glycol monomethyl ether, propylene glycol dimethyl ether or any mixture thereof; the alkali is one of potassium tert-butoxide, sodium methoxide and sodium ethoxide or any mixture thereof.
More preferably, in the first step, the weight ratio of the first solvent to 2-propyl-4-piperidone is 10.0 ± 1.0: the equivalent ratio of 1, 2-propyl-4-piperidone to p-toluenesulfonylmethyl isocyanide is 1:1.5-2.5, the equivalent ratio of 2-propyl-4-piperidone to base is 1:3.5-4.5.
More preferably, in the first step, the inert gas is nitrogen; removing the solvent by distillation under normal pressure or reduced pressure during concentration; the extraction reagent is ethyl acetate, and is dried by adopting anhydrous sodium sulfate.
After the preferred scheme is adopted, the specific technical details of the first step can be further optimized.
Preferably, in the second step, the temperature reaction is carried out for 10 to 20 hours at 60 to 100 ℃, and the reaction is finished when the HPLC detects that the content of 2-propyl-4-cyanopiperidine is less than 0.5 percent; cooling to ambient temperature and filtering.
More preferably, in the second step, the second solvent is one of toluene, xylene, mesitylene, trifluorotoluene or any mixture thereof; the catalyst is Ru/Co 3 O 4 、Ru/Al 2 O 3 One or a mixture thereof.
More preferably, in the second step, the weight ratio of the second solvent to 2-propyl-4-cyanopiperidine is 16.0 ± 1.0:1, the weight ratio of the catalyst to the 2-propyl-4-cyanopiperidine is 0.025-0.035:1.
more preferably, in the second step, the solvent is removed by distillation under normal pressure or reduced pressure while concentrating the filtrate.
After the preferred scheme is adopted, the specific technical details of the second step can be further optimized.
Compared with the prior art, the 2-propyl-4-piperidone is used as the starting material, and generates carbanion with p-toluenesulfonyl methyl isocyano (Tosmic) in the presence of alkali to perform nucleophilic addition reaction, then loses sulfonyl and formyl to prepare 2-propyl-4-cyanopiperidine, and finally obtains the 2-propyl-4-cyanopyridine through dehydroxidation. The synthetic route is simple and convenient, raw and auxiliary materials are common compounds, and the solvent and the catalyst can be recycled; the product is a single compound, and compared with the traditional synthetic method, the product does not generate isomer 3-propyl-4-cyanopyridine, and has lower post-treatment requirement on the synthetic prothioconazole. The method is safe and simple to operate, environment-friendly, equipment is used for relaxing bowels, and the method is suitable for industrial production.
Drawings
FIG. 1 is a reaction scheme of the first step of the present invention for synthesizing 2-propyl-4-cyanopiperidine.
FIG. 2 is a reaction scheme of the second step of the synthesis of 2-propyl-4-cyanopyridine according to the present invention.
FIG. 3 is a schematic representation of 2-propyl-4-cyanopyridine in example 2 of the present invention 1 H NMR 90MHz CDCl 3 Drawing.
Detailed Description
In specific implementation, as shown in fig. 1 and fig. 2, the preparation method of 2-propyl-4-cyanopyridine of the present invention comprises the following steps:
dissolving 2-propyl-4-piperidone in a first solvent, adding p-toluenesulfonylmethylisocyan, cooling, adding alkali under the protection of inert gas, and heating for reaction; after the reaction is finished, concentrating, adding water, extracting by using an extraction reagent, collecting an organic phase, drying, concentrating, and distilling under reduced pressure to obtain 2-propyl-4-cyanopiperidine; wherein the weight ratio of the first solvent to the 2-propyl-4-piperidone is 5.0-15.0:1 (preferably 10.0 ± 1.0), the equivalent ratio of 2-propyl-4-piperidone to p-toluenesulfonylmethyl isocyan is 1:1.0-4.0 (preferably 1.5-2.5), the equivalent ratio of 2-propyl-4-piperidone to base is 1:2.0-5.0 (preferably 1.
Specifically, adding p-toluenesulfonylmethyl isocyanide, and cooling to-5 ℃; reacting at 30-70 ℃ for 10-24h during temperature rise reaction, preferably firstly raising the temperature to 20-30 ℃ and then reacting at 30-70 ℃; when HPLC detects that the content of 2-propyl-4-piperidone is less than 1.0 percent, the reaction is finished; when water is added, the temperature is controlled not to exceed 35 ℃ by using ice water bath. The first solvent is one of ethylene glycol dimethyl ether, diethylene glycol monomethyl ether and propylene glycol dimethyl ether or any mixture thereof; the base is one of potassium tert-butoxide, sodium methoxide and sodium ethoxide or any mixture thereof. The inert gas is nitrogen; removing the solvent by distillation under normal pressure or reduced pressure during concentration; the extraction reagent is ethyl acetate, and is dried by anhydrous sodium sulfate.
Secondly, taking 2-propyl-4-cyano piperidine, adding a second solvent and a catalyst, and heating for reaction; after the reaction is finished, cooling, filtering, concentrating the filtrate, and distilling under reduced pressure to obtain 2-propyl-4-cyanopyridine; wherein the weight ratio of the second solvent to the 2-propyl-4-cyanopiperidine is 10.0-20.0:1 (preferably 16.0 ± 1.0), the weight ratio of catalyst to 2-propyl-4-cyanopiperidine is from 0.01 to 0.05:1 (preferably 0.025-0.035).
Specifically, the reaction is carried out for 10 to 20 hours at 60 to 100 ℃ during the temperature rising reaction, and when HPLC (high performance liquid chromatography) detects 2-propyl-4-cyanopiperidine<The reaction is finished when the concentration is 0.5 percent; cooling to ambient temperature and filtering. The second solvent is one of toluene, xylene, mesitylene and benzotrifluoride or any mixture thereof; the catalyst is Ru/Co 3 O 4 、Ru/Al 2 O 3 One or a mixture thereof. The solvent is removed by distillation under normal pressure or reduced pressure when the filtrate is concentrated.
The present invention will be described in further detail with reference to examples. The invention is not limited to the examples given.
Example 1 Synthesis of 2-propyl-4-cyanopiperidine
56.4g (0.4 mol, 1eq) of 2-propyl-4-piperidone and 564g of ethylene glycol dimethyl ether were put into a 1000ml four-neck reaction flask, stirred, and then Tosmic:156.2g (0.8mol, 2eq), the reaction bottle is replaced and protected by nitrogen, the temperature is reduced to-5 ℃, 179.2g (1.6 mol, 4eq) of potassium tert-butoxide is added, after the addition, the temperature of the system is raised to 20-25 ℃, and then the system is heated to 50-60 ℃ for reaction for 18h (the detected raw material is less than 1.0%). Removing solvent by decompression and desolventizing, slowly dripping 200g of water into the residue under the protection of nitrogen, and controlling the temperature to be not more than 35 ℃ under ice water bath. After the dropwise addition, the mixture was stirred in an ice-water bath for 0.5h, extracted with ethyl acetate (200 g. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, desolventized, and 59.5g of the residue was subjected to distillation under reduced pressure to obtain 54.3g (theoretical amount: 60.8 g) of 2-propyl-4-cyanopiperidine having a purity of 99.5% by HPLC and a yield of 89.3%.
Note: tosmic is p-toluenesulfonylmethyl isocyanide.
The analytical data for 2-propyl-4-cyanopiperidine at different feed ratios according to the same procedure are shown in table 1.
Table 1: 2-propyl-4-cyanopiperidine analytical data at different feed ratios
Example 2 Synthesis of 2-propyl-4-cyanopyridine
This example is based on example 1.
40g of 2-propyl-4-cyanopiperidine, 640g of toluene and Ru/Co were placed in a 1000ml four-neck reaction flask 3 O 4 1.2g, starting stirring, heating to 100 ℃ and reacting for 12h (detecting raw materials)<0.5%). The temperature is reduced to room temperature, the filtrate is filtered, the filtrate is subjected to desolventizing concentration, and the concentrate is distilled under reduced pressure to obtain 35.5g (the theoretical amount is 38.4 g) of 2-propyl-4-cyanopyridine with the purity of 99.4 percent by HPLC and the yield of 92.4 percent. The overall yield of the two steps is 82.5%.
The analytical data of 2-propyl-4-cyanopyridine at different feed ratios according to the same procedure are shown in Table 2.
Table 2: 2-propyl-4-cyanopyridine analytical data under different feed ratios
FIG. 3 is a schematic representation of 2-propyl-4-cyanopyridine 1 H NMR 90MHz CDCl 3 . Specific resonance spectroscopy data are shown in table 3:
table 3: process for preparing 2-propyl-4-cyanopyridine 1 H-NMR spectroscopic data
And (3) analysis: in that 1 The H-NMR spectrum showed 6 sets of proton signals, and the integrated area ratio of the signals indicated that the sample contained 10 hydrogen atoms. Wherein delta 0.873 to 0.906 is attributed to hydrogen at position 1, delta 1.653 to 1.728 is attributed to hydrogen at position 2, delta 2.491 to 2.737 is attributed to hydrogen at position 3, delta 7.634 to 7.650 is attributed to hydrogen at position 4, delta 7.723ppm is attributed to hydrogen at position 5, and delta 8.712 to 8.724 belongs to hydrogen at position 6.
And (4) conclusion: the nuclear magnetic resonance hydrogen spectrum data of the test sample is consistent with the chemical structure of the 2-propyl-4-cyanopyridine.
Example 3 Synthesis of 2-propyl-4-cyanopiperidine
56.4g (0.4 mol, 1eq) of 2-propyl-4-piperidone and 564g of ethylene glycol dimethyl ether were put into a 1000ml four-neck reaction flask, stirred, and then Tosmic:156.2g (0.8mol, 2eq), the reaction bottle is replaced and protected by nitrogen, the temperature is reduced to 0 ℃, 179.2g (1.6 mol, 4eq) of potassium tert-butoxide is added, after the addition, the temperature of the system is raised to 25-30 ℃, and then the system is heated to 60-70 ℃ for reaction for 15h (the detected raw material is less than 1.0%). Removing solvent under reduced pressure, slowly adding 200g water under nitrogen protection, and controlling temperature to be not more than 35 deg.C under ice water bath. After the dropwise addition, the mixture was stirred in an ice-water bath for 0.5h, extracted with ethyl acetate (200 g. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, desolventized, and 59.1g of the residue was subjected to distillation under reduced pressure to obtain 53.8g (theoretical amount: 60.8 g) of 2-propyl-4-cyanopiperidine having a purity of 99.4% by HPLC and a yield of 88.5%.
Example 4 Synthesis of 2-propyl-4-cyanopyridine
This example is based on example 3.
40g of 2-propyl-4-cyanopiperidine, 640g of toluene and Ru/Co were placed in a 1000ml four-neck reaction flask 3 O 4 1.2g, starting stirring, heating to 80 ℃ and reacting for 15h (detecting raw materials)<0.5%). The temperature is reduced to room temperature, the filtrate is filtered, the filtrate is subjected to desolventizing concentration, and the concentrate is distilled under reduced pressure to obtain 35.2g (the theoretical amount is 38.4 g) of 2-propyl-4-cyanopyridine with the purity of 99.4 percent by HPLC and the yield of 91.7 percent. The total yield of the two steps is 81.1%.
Example 5 Synthesis of 2-propyl-4-cyanopiperidine
In a 3000ml four-necked reaction flask were charged 141g (1mol, 1eq) of 2-propyl-4-piperidone and 1410g of ethylene glycol dimethyl ether, stirring was started, and Tosmic:390g (2mol, 2eq), replacing and protecting a reaction bottle with nitrogen, cooling to-5 ℃, adding 448g (4 mol, 4eq) of potassium tert-butoxide, heating the system to 20-25 ℃ after the addition is finished, and then heating to 50-60 ℃ for reaction for 18h (detecting that the raw material is less than 1.0%). Removing solvent by decompression desolventizing, slowly dripping 500g of water into the residue under the protection of nitrogen, and controlling the temperature to be not more than 35 ℃ under ice water bath. After the dripping is finished, stirring the mixture for 0.5h in an ice-water bath, extracting the mixture by using ethyl acetate of 500g multiplied by 2, combining organic phases, drying the combined organic phases by anhydrous sodium sulfate, desolventizing the combined organic phases to obtain 147.5g of residues, and carrying out reduced pressure distillation to obtain 136.2g of 2-propyl-4-cyanopiperidine, wherein the purity of the 2-propyl-4-cyanopiperidine is 99.3 percent by HPLC (high performance liquid chromatography), and the yield of the 2-propyl-4-cyanopiperidine is 89.6 percent.
Example 6 Synthesis of 2-propyl-4-cyanopyridine
This example is based on example 5.
Into a 3000ml four-necked reaction flask were charged 120g of 2-propyl-4-cyanopiperidine, 1920g of toluene and Ru/Co 3 O 4 3.6g, start stirring, heat to 100 ℃ and react for 12h (detect raw materials)<0.5%). Cooled to room temperature, filtered, desolventized and concentrated, and the concentrate was distilled under reduced pressure to give 105.6g of 2-propyl-4-cyanopyridine with a purity of 99.5% by HPLC and a yield of 91.7%. The overall yield of the two steps is 82.2%.
In addition to the above embodiments, the present invention may have other embodiments. All technical solutions formed by adopting equivalent substitutions or equivalent transformations fall within the protection scope of the present invention.
Claims (10)
1. A preparation method of 2-propyl-4-cyanopyridine is characterized by comprising the following steps:
dissolving 2-propyl-4-piperidone in a first solvent, adding p-toluenesulfonylmethyl isocyanide, cooling, adding alkali under the protection of inert gas, and heating for reaction; after the reaction is finished, concentrating, adding water, extracting by using an extraction reagent, collecting an organic phase, drying, concentrating, and distilling under reduced pressure to obtain 2-propyl-4-cyanopiperidine; wherein the weight ratio of the first solvent to the 2-propyl-4-piperidone is 5.0-15.0: the equivalent ratio of 1, 2-propyl-4-piperidone to p-toluenesulfonylmethyl isocyanide is 1:1.0-4.0, the equivalent ratio of 2-propyl-4-piperidone to base is 1:2.0-5.0;
secondly, taking 2-propyl-4-cyano piperidine, adding a second solvent and a catalyst, and heating for reaction; after the reaction is finished, cooling, filtering, concentrating the filtrate, and distilling under reduced pressure to obtain 2-propyl-4-cyanopyridine; wherein the second solvent is mixed with 2-propyl-4-cyanogenThe weight ratio of the base piperidine is 10.0-20.0:1, the weight ratio of the catalyst to the 2-propyl-4-cyanopiperidine is 0.01-0.05:1; the catalyst is Ru/Co 3 O 4 、Ru/Al 2 O 3 One or a mixture thereof.
2. The preparation method of 2-propyl-4-cyanopyridine according to claim 1, wherein in the first step, the temperature is reduced to-5 ℃ to 5 ℃ after adding p-toluenesulfonylmethylisocyan; heating reaction, reacting at 30-70 deg.C for 10-24h, and finishing reaction when HPLC detects that 2-propyl-4-piperidone is less than 1.0%; when water is added, the temperature is controlled to be not more than 35 ℃ by using ice water bath.
3. The process for producing 2-propyl-4-cyanopyridine according to claim 2, wherein in the first step, the temperature is raised to 20 ℃ to 30 ℃ before the reaction is carried out at 30 ℃ to 70 ℃.
4. The method for preparing 2-propyl-4-cyanopyridine according to claim 2, wherein in the first step, the first solvent is one of ethylene glycol dimethyl ether, diethylene glycol monomethyl ether, propylene glycol dimethyl ether or any mixture thereof; the alkali is one of potassium tert-butoxide, sodium methoxide and sodium ethoxide or any mixture thereof.
5. The process according to claim 2, wherein the weight ratio of the first solvent to the 2-propyl-4-piperidone in the first step is 10.0 ± 1.0: the equivalent ratio of 1, 2-propyl-4-piperidone to p-toluenesulfonylmethyl isocyanide is 1:1.5-2.5, the equivalent ratio of 2-propyl-4-piperidone to base is 1:3.5-4.5.
6. The process for producing 2-propyl-4-cyanopyridine according to claim 2, wherein the inert gas in the first step is nitrogen; removing the solvent by distillation under normal pressure or reduced pressure during concentration; the extraction reagent is ethyl acetate, and is dried by adopting anhydrous sodium sulfate.
7. The process for preparing 2-propyl-4-cyanopyridine as claimed in claim 1, wherein the reaction is carried out at 60-100 ℃ for 10-20hr and the reaction is completed when the content of 2-propyl-4-cyanopiperidine is less than 0.5% as determined by HPLC; cooling to ambient temperature and filtering.
8. The process according to claim 7, wherein the second solvent is one of toluene, xylene, mesitylene, and benzotrifluoride, or any mixture thereof.
9. The process according to claim 7, wherein the weight ratio of the second solvent to the 2-propyl-4-cyanopiperidine in the second step is 16.0 ± 1.0:1, the weight ratio of the catalyst to the 2-propyl-4-cyanopiperidine is 0.025-0.035:1.
10. the process according to claim 7, wherein the solvent is removed by distillation under normal pressure or reduced pressure during the concentration of the filtrate in the second step.
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| CN113617354A (en) * | 2021-07-08 | 2021-11-09 | 南京红太阳生物化学有限责任公司 | 3-methylpiperidine dehydrogenation catalyst, and preparation method and application thereof |
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