CN110885311A - Preparation method of 2-chloro-3-aminopyridine - Google Patents
Preparation method of 2-chloro-3-aminopyridine Download PDFInfo
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
Abstract
The invention relates to a preparation method of 2-chloro-3-aminopyridine, which comprises the following steps: step one, taking an extraction centrifuge as a current-stage extraction centrifuge; dissolving 3-aminopyridine in a hydrochloric acid solution, uniformly mixing, and continuously pumping the hydrochloric acid solution containing the 3-aminopyridine, an organic solvent and a chlorinated reagent solution into a primary extraction centrifuge for extraction centrifugation; the organic and aqueous phases were separated and the organic phase was retained. Secondly, taking an extraction centrifuge as the extraction centrifuge of the current stage; continuously pumping the water phase, the hydrochloric acid solution, the organic solvent and the chlorinated reagent solution separated by the previous stage of extraction centrifuge into the current stage of extraction centrifuge for extraction centrifugation; the organic phase and the aqueous phase were separated leaving the organic phase. And thirdly, judging whether the next-stage extraction centrifugation is performed or not, and if so, turning to the second step. And step four, combining the organic phases reserved by the extraction centrifuges at all stages to obtain the 2-chloro-3-aminopyridine solution. The invention adopts a continuous method for preparation, and can improve the yield and quality of the product.
Description
Technical Field
The invention relates to a preparation method of 2-chloro-3-aminopyridine, belonging to the technical field of compound synthesis.
Background
Chlorantraniliprole is a phthalic diamide insecticide successfully developed by DuPont in 2000. Chlorantraniliprole has excellent quick action and persistence, has excellent control effect on target pests, is particularly effective in the early development stage of the pests, shows extraordinary larvicidal activity and outstanding egg/young co-killing activity, can efficiently control a large number of important lepidoptera pests, and can also effectively control other pests, such as certain coleoptera, diptera, hemiptera and isoptera pests; also, chlorantraniliprole has very low acute, sub-chronic and chronic toxicity to mammals.
Pirenzepine is a selective anticholinergic drug, is suitable for treating gastric and duodenal ulcers, can significantly relieve pain of patients, and reduces the dosage of antacids.
The 2-chloro-3-aminopyridine is a key intermediate of two compounds of chlorantraniliprole and pirenzepine, has wide market development prospect, has many researches on preparation methods thereof in the prior literature, but has defects, and needs to improve the prior preparation methods to realize greater social and economic benefits.
The preparation method of 2-chloro-3-aminopyridine reported in the prior art mainly comprises the following steps: the Chinese patent with the grant publication number CN101514185B and the Chinese patent with the grant publication number CN103570609B both describe the following processes: nicotinamide is used as a raw material, and 2-chloro-3-aminopyridine is obtained through Hofmann degradation and chlorination reaction. The process route can derive the process taking 3-aminopyridine as the raw material (such as the Chinese patent with the publication number of CN 102584693B) and the process taking 3-cyanopyridine as the raw material. The process is a mature process, but a large amount of acid is needed in the process, and the amount of hydrochloric acid in the chlorination step is about 10 times of the amount of 3-aminopyridine substances in general compared with the amount of hydrogen chloride substances, so that a lot of waste acid and waste water are generated, and the pollution is serious; and the chlorination reaction has larger impurities, so that the yield of the chlorination step is lower, and if purer products are obtained, a plurality of post-treatments are needed to remove the impurities, so that the operation is complicated.
In addition, the Chinese patent with the publication number CN102153509B and the Chinese patent with the publication number CN102532010B describe the following processes: 2-chloro-3-nitropyridine is subjected to chemical reduction or catalyst reduction to obtain 2-chloro-3-aminopyridine, however, the chemical reduction causes great environmental pollution, and the catalyst reduction causes high cost.
Disclosure of Invention
The invention aims to: aiming at the problems in the prior art, the preparation method of the 2-chloro-3-aminopyridine is provided, and the method can inhibit the generation of impurities by removing the product in the reaction system in time, thereby being beneficial to improving the yield and quality of the product.
The technical scheme for solving the technical problems of the invention is as follows:
a preparation method of 2-chloro-3-aminopyridine is characterized by comprising the following steps:
taking an extraction centrifuge as a primary extraction centrifuge, and taking the primary extraction centrifuge as a primary extraction centrifuge; dissolving 3-aminopyridine in a hydrochloric acid solution, uniformly mixing, and continuously pumping the hydrochloric acid solution containing the 3-aminopyridine, an organic solvent and a chlorinated reagent solution into a primary extraction centrifuge for extraction centrifugation according to a preset unit time volume ratio; thereafter, the organic and aqueous phases are separated and the organic phase is retained; turning to a second step;
taking an extraction centrifuge as a current-stage extraction centrifuge, and taking the current-stage extraction centrifuge as a lower-stage extraction centrifuge of a previous-stage extraction centrifuge; respectively and simultaneously and continuously pumping the water phase, the hydrochloric acid solution, the organic solvent and the chlorinated reagent solution separated by the previous stage of extraction centrifuge into the current stage of extraction centrifuge according to a preset unit time volume ratio for extraction centrifugation; thereafter, the organic and aqueous phases are separated and the organic phase is retained; turning to the third step;
thirdly, judging whether next-stage extraction centrifugation is carried out or not, if so, turning to the second step, and otherwise, turning to the fourth step;
and step four, combining the organic phases reserved by the extraction centrifuges at all stages to obtain the 2-chloro-3-aminopyridine solution.
The inventor of the present invention has extensively repeated practical studies to find that the chlorination reaction of 3-aminopyridine and the reaction for generating impurities are consecutive reactions, and a large amount of impurities are generated only when the product of the chlorination reaction of 3-aminopyridine reaches a certain concentration. On the basis of the discovery, the inventor further obtains the technical scheme through intensive practical research, the technical scheme adopts a continuous method to prepare the product, when the system concentration of the product 2-chloro-3-aminopyridine is lower, the 2-chloro-3-aminopyridine is extracted into an organic phase in time to be reserved, and a water phase is led into a next-stage extraction centrifuge to be subjected to next-stage reaction-extraction-centrifugation, so that the generation of impurities can be controlled to the maximum extent, the impurities cannot be generated in large quantity, and the yield and the quality of the 2-chloro-3-aminopyridine are greatly improved. The 2-chloro-3-aminopyridine solution finally obtained by the technical scheme can be simply distilled to obtain the 2-chloro-3-aminopyridine, and can also be used for the reaction of the subsequent step after being added with acid for back extraction. The continuous reaction of the technical scheme is easy to produce and amplify, the production process has less wastewater, less impurities, high yield and easy product treatment.
The technical scheme of the invention is further perfected as follows:
preferably, the chlorinating reagent solution is an aqueous sodium hypochlorite solution.
By adopting the preferred scheme, the chlorinating agent consists of hydrochloric acid and sodium hypochlorite, so that the whole system can reach higher chlorine concentration under lower acid concentration, and the reaction speed is ensured under the condition of greatly reducing the acid amount.
More preferably, in the first step, the amount of the fed material of the 3-aminopyridine is taken as a reference value; the amount of the substance of the chlorination reagent contained in the chlorination reagent solution fed into the first-stage extraction centrifuge is 0.1-0.8 times of the reference value, or the amount of the substance of the chlorination reagent contained in the chlorination reagent solution fed into the first-stage extraction centrifuge is 0.3-0.6 times of the reference value;
in the second step, the amount of the substance of the chlorination reagent contained in the chlorination reagent solution fed into the current-stage extraction centrifuge is 0.1 to 0.8 times of the amount of the substance of the chlorination reagent contained in the chlorination reagent solution fed into the previous-stage extraction centrifuge, or the amount of the substance of the chlorination reagent contained in the chlorination reagent solution fed into the current-stage extraction centrifuge is 0.3 to 0.6 times of the amount of the substance of the chlorination reagent contained in the chlorination reagent solution fed into the previous-stage extraction centrifuge.
With this preferred embodiment, the amount of chlorinating agent can be further optimized.
More preferably, the weight percentage of the chlorinating agent in the chlorinating agent solution in the first step and the second step is 10 ± 4%, respectively.
With this preferred embodiment, the concentration of the chlorinating agent used can be further optimized.
Preferably, in the first step, the amount of the 3-aminopyridine fed material is taken as a reference value; the amount of the substance of the hydrogen chloride contained in the hydrochloric acid solution fed into the first-stage extraction centrifuge is 0.1 to 3.0 times of the reference value, or the amount of the substance of the hydrogen chloride contained in the hydrochloric acid solution is 1.1 to 1.5 times of the reference value;
in the second step, if the previous stage of extraction centrifuge is the first stage of extraction centrifuge, the amount of the substance of hydrogen chloride contained in the hydrochloric acid solution fed into the current stage of extraction centrifuge is 0.1 to 0.5 times of the reference value, or the amount of the substance of hydrogen chloride contained in the hydrochloric acid solution fed into the current stage of extraction centrifuge is 0.2 to 0.3 times of the reference value; if the previous stage of extraction centrifuge is not the first stage of extraction centrifuge, the amount of the substance of hydrogen chloride contained in the hydrochloric acid solution fed into the current stage of extraction centrifuge is 0.1-0.8 times of the amount of the substance of hydrogen chloride contained in the hydrochloric acid solution fed into the previous stage of extraction centrifuge, or the amount of the substance of hydrogen chloride contained in the hydrochloric acid solution fed into the current stage of extraction centrifuge is 0.3-0.6 times of the amount of the substance of hydrogen chloride contained in the hydrochloric acid solution fed into the previous stage of extraction centrifuge.
By adopting the preferred scheme, the dosage of the hydrochloric acid can be further optimized.
More preferably, in the first step, the weight percentage of the hydrochloric acid in the hydrochloric acid solution is 10 +/-4%; in the second step, the weight percentage of the hydrochloric acid in the hydrochloric acid solution is 31 +/-5%.
By adopting the preferable scheme, the use concentration of the hydrochloric acid can be further optimized.
Preferably, the organic solvent is dichloromethane, trichloromethane, toluene, xylene, chlorobenzene, or 1, 2-dichloroethane; the organic solvent used in the first and second steps is the same.
With this preferred embodiment, the specific selection range of the organic solvent can be further optimized.
More preferably, in the first step, the weight of the organic solvent charged in the first stage extraction centrifuge is 0.5-5 times of the weight of the 3-aminopyridine charge, or the weight of the organic solvent charged in the first stage extraction centrifuge is 2-3 times of the weight of the 3-aminopyridine charge;
in the second step, the weight of the organic solvent put into the extraction centrifuge of the stage is 0.1-0.8 times of the weight of the organic solvent put into the extraction centrifuge of the previous stage, or the weight of the organic solvent put into the extraction centrifuge of the stage is 0.3-0.6 times of the weight of the organic solvent put into the extraction centrifuge of the previous stage.
With this preferred embodiment, the amount of organic solvent used can be further optimized.
Preferably, the number of execution times of the second step is 1 to 9 times in total, or the number of execution times of the second step is 3 to 5 times in total.
By adopting the preferred scheme, the extraction stage number of the whole process can be further optimized.
Preferably, in the first step, after the usage amounts of the 3-aminopyridine, the hydrochloric acid solution, the organic solvent and the chlorinating agent solution are respectively determined, the 3-aminopyridine is dissolved in the hydrochloric acid solution and uniformly mixed to obtain a hydrochloric acid solution containing the 3-aminopyridine, and then the volume ratio of the hydrochloric acid solution containing the 3-aminopyridine, the organic solvent and the chlorinating agent solution is used as a preset unit time volume ratio;
in the second step, after the dosages of the hydrochloric acid solution, the organic solvent and the chlorination reagent solution are respectively determined, the volume ratio of the water phase, the hydrochloric acid solution, the organic solvent and the chlorination reagent solution separated by the previous-stage extraction centrifuge is used as a preset unit time volume ratio;
in the first step and the second step, the extraction centrifugation is respectively carried out at 10-30 ℃; the extraction centrifugation reaction time is 1-4h respectively.
By adopting the preferable scheme, the process of determining the preset volume ratio per unit time can be further optimized, and the reaction temperature and the reaction time are optimized.
Compared with the prior art, the preparation method adopts a continuous method to prepare the 2-chloro-3-aminopyridine, and the multistage continuous feeding and discharging are carried out for chlorination under the condition of extraction centrifugation, so that when the system concentration of the product 2-chloro-3-aminopyridine is lower, the 2-chloro-3-aminopyridine is extracted into an organic phase in time to be reserved, and a water phase is led into a next-stage extraction centrifuge for next-stage reaction-extraction-centrifugation, so that the generation of impurities can be controlled to the maximum extent, the impurities cannot be generated in large quantity, and the yield and the quality of the 2-chloro-3-aminopyridine are greatly improved. Meanwhile, the chlorination agent is composed of a chlorination reagent (such as sodium hypochlorite) and hydrochloric acid, and can reach higher chlorine concentration under lower acid concentration, so that the reaction speed is ensured under the condition of greatly reducing the acid amount; the invention also can overcome the problem of overlarge double-chloro impurities in the prior art by strictly controlling the material input proportion in each level of extraction centrifugal reaction, and improve the product purity. In addition, the preparation method is a continuous reaction, is easy to produce and amplify, and has the advantages of less wastewater, less impurities, high yield and easy product treatment in the production process.
Drawings
FIG. 1 is a schematic block diagram of the present invention.
FIG. 2 is a liquid chromatography result chart of example 1 of the present invention.
Detailed Description
As shown in FIG. 1, the preparation method of 2-chloro-3-aminopyridine according to the embodiment of the present invention comprises:
taking an extraction centrifuge as a primary extraction centrifuge, and taking the primary extraction centrifuge as a primary extraction centrifuge; dissolving 3-aminopyridine in a hydrochloric acid solution, uniformly mixing, and continuously pumping the hydrochloric acid solution containing the 3-aminopyridine, an organic solvent and a chlorinated reagent solution into a primary extraction centrifuge for extraction centrifugation according to a preset unit time volume ratio; thereafter, the organic and aqueous phases are separated and the organic phase is retained; and turning to the second step.
Taking an extraction centrifuge as a current-stage extraction centrifuge, and taking the current-stage extraction centrifuge as a lower-stage extraction centrifuge of a previous-stage extraction centrifuge; respectively and simultaneously and continuously pumping the water phase, the hydrochloric acid solution, the organic solvent and the chlorinated reagent solution separated by the previous stage of extraction centrifuge into the current stage of extraction centrifuge according to a preset unit time volume ratio for extraction centrifugation; thereafter, the organic and aqueous phases are separated and the organic phase is retained; and turning to the third step.
And thirdly, judging whether the next-stage extraction centrifugation is carried out or not, if so, turning to the second step, and otherwise, turning to the fourth step.
And step four, combining the organic phases reserved by the extraction centrifuges at all stages to obtain the 2-chloro-3-aminopyridine solution.
In addition, in the first step and the second step, the extraction centrifugation is respectively carried out at 10-30 ℃; the extraction centrifugation reaction time is 1-4h respectively.
Specifically, (1) with respect to hydrochloric acid:
in the first step, the amount of a feeding substance of 3-aminopyridine is taken as a reference value; the amount of the substance of the hydrogen chloride contained in the hydrochloric acid solution fed into the first-stage extraction centrifuge is 0.1 to 3.0 times of the reference value, or the amount of the substance of the hydrogen chloride contained in the hydrochloric acid solution is 1.1 to 1.5 times of the reference value.
In the second step, if the previous stage of extraction centrifuge is the first stage of extraction centrifuge, the amount of the substance of hydrogen chloride contained in the hydrochloric acid solution fed into the current stage of extraction centrifuge is 0.1 to 0.5 times of the reference value, or the amount of the substance of hydrogen chloride contained in the hydrochloric acid solution fed into the current stage of extraction centrifuge is 0.2 to 0.3 times of the reference value; if the previous stage of extraction centrifuge is not the first stage of extraction centrifuge, the amount of the substance of hydrogen chloride contained in the hydrochloric acid solution fed into the current stage of extraction centrifuge is 0.1-0.8 times of the amount of the substance of hydrogen chloride contained in the hydrochloric acid solution fed into the previous stage of extraction centrifuge, or the amount of the substance of hydrogen chloride contained in the hydrochloric acid solution fed into the current stage of extraction centrifuge is 0.3-0.6 times of the amount of the substance of hydrogen chloride contained in the hydrochloric acid solution fed into the previous stage of extraction centrifuge.
In addition, in the first step, the weight percentage of the hydrochloric acid in the hydrochloric acid solution (namely the concentration of the hydrochloric acid solution) is 10 +/-4%; in the second step, the weight percentage of the hydrochloric acid in the hydrochloric acid solution is 31 +/-5%.
(2) With respect to the chlorinating reagent solution:
the chlorinating agent solution is an aqueous sodium hypochlorite solution.
In the first step, the amount of a feeding substance of 3-aminopyridine is taken as a reference value; the amount of the substance of the chlorinating agent contained in the chlorinating agent solution fed into the first-stage extraction centrifuge is 0.1 to 0.8 times of the reference value, or the amount of the substance of the chlorinating agent contained in the chlorinating agent solution fed into the first-stage extraction centrifuge is 0.3 to 0.6 times of the reference value.
In the second step, the amount of the substance of the chlorination reagent contained in the chlorination reagent solution fed into the extraction centrifuge of the current stage is 0.1 to 0.8 times of the amount of the substance of the chlorination reagent contained in the chlorination reagent solution fed into the extraction centrifuge of the previous stage, or the amount of the substance of the chlorination reagent contained in the chlorination reagent solution fed into the extraction centrifuge of the current stage is 0.3 to 0.6 times of the amount of the substance of the chlorination reagent contained in the chlorination reagent solution fed into the extraction centrifuge of the previous stage.
In addition, in the first step and the second step, the weight percentage of the chlorinating agent in the chlorinating agent solution is 10 +/-4 percent respectively.
(3) With respect to the organic solvent:
the organic solvent is dichloromethane, trichloromethane, toluene, xylene, chlorobenzene or 1, 2-dichloroethane; the organic solvent used in the first and second steps is the same.
In the first step, the weight of the organic solvent put into the first-stage extraction centrifuge is 0.5-5 times of the weight of the 3-aminopyridine fed material, or the weight of the organic solvent put into the first-stage extraction centrifuge is 2-3 times of the weight of the 3-aminopyridine fed material.
In the second step, the weight of the organic solvent put into the extraction centrifuge of the stage is 0.1 to 0.8 times of the weight of the organic solvent put into the extraction centrifuge of the previous stage, or the weight of the organic solvent put into the extraction centrifuge of the stage is 0.3 to 0.6 times of the weight of the organic solvent put into the extraction centrifuge of the previous stage.
(4) Regarding the number of extraction stages:
the number of execution times of the second step is 1-9 times (i.e., the number of extraction stages is 2-10 stages), or the number of execution times of the second step is 3-5 times (i.e., the number of extraction stages is 4-6 stages).
(5) With respect to the preset volume ratio per unit time:
in the first step, after the dosages of 3-aminopyridine, hydrochloric acid solution, organic solvent and chlorination reagent solution are respectively determined, 3-aminopyridine is dissolved in the hydrochloric acid solution and uniformly mixed to obtain hydrochloric acid solution containing 3-aminopyridine, and then the volume ratio of the hydrochloric acid solution containing 3-aminopyridine, the organic solvent and the chlorination reagent solution is used as a preset unit time volume ratio.
In the second step, after the dosages of the hydrochloric acid solution, the organic solvent and the chlorination reagent solution are respectively determined, the volume ratio of the water phase, the hydrochloric acid solution, the organic solvent and the chlorination reagent solution separated by the previous-stage extraction centrifuge is used as the preset volume ratio per unit time.
After the predetermined volume per unit time ratio is determined in the above manner, the respective materials may be continuously pumped into the extraction centrifuge at a separate and simultaneous input rate (e.g., several milliliters per minute) consistent with the volume per unit time ratio.
In the preparation method, the specific reaction route is as follows:
the invention is described in further detail below with reference to embodiments and with reference to the drawings. The invention is not limited to the examples given.
Example 1
Mixing 3-aminopyridine: 188g (2mol) in 10% hydrochloric acid: 900g (content 10%, 2.46mol), after complete dissolution and mixing, the solution is mixed with dichloromethane: 400g, sodium hypochlorite solution: the volume ratio of 800g (content 10%, 1.07mol) of the three is taken as the preset volume ratio per unit time, and then the three are respectively and simultaneously continuously pumped into a first-stage extraction centrifuge for extraction centrifugation at normal temperature (the specific temperature range of the normal temperature is the same at 10 ℃ -30 ℃) according to the volume ratio per unit time; thereafter, the organic and aqueous phases are separated and the organic phase is retained, the aqueous phase, industrial hydrochloric acid: 59g (content 31%, 0.5mol), dichloromethane: 200g, and sodium hypochlorite solution: taking the volume ratio of 400g (content: 10%, 0.54mol) of the four as a preset unit time volume ratio, and then respectively and simultaneously continuously pumping the four into a second-stage extraction centrifuge for extraction centrifugation at normal temperature according to the unit time volume ratio; then, separating an organic phase and a water phase, reserving the organic phase, and putting the water phase into a next-stage extraction centrifuge; the hydrochloric acid amount, the dichloromethane amount and the sodium hypochlorite solution amount used by each subsequent extraction centrifuge are gradually reduced by half, five-stage continuous extraction reaction is carried out (the extraction centrifugation reaction time of each stage is 3 hours respectively), and then the organic phases are combined to obtain the 2-chloro-3-aminopyridine solution; in total 962g of solution were obtained. Adopting a liquid chromatograph, analyzing by an external standard method, calculating the content by the external standard method to be 24.4 percent, and converting the weight of the 2-chloro-3-aminopyridine into the following weight percent: 234.5g, 2-chloro-3-aminopyridine molar yield 91.3% (based on 3-aminopyridine), purity 98.4%.
Detecting wavelength by a liquid chromatograph: UV254nm with a spectrum as shown in FIG. 2. The peak in the atlas is 3-aminopyridine at 3.2min, 2-chloro-3-aminopyridine at 5.2min, and 2, 6-dichloro-3-aminopyridine at 7.5 min.
Example 2
Mixing 3-aminopyridine: 188g (2mol) in 10% hydrochloric acid: 900g (content 10%, 2.46mol), after complete dissolution and mixing, the solution is mixed with dichloromethane: 400g, sodium hypochlorite solution: taking the volume ratio of 700g (content: 10%, 0.94mol) of the three as a preset unit time volume ratio, and then respectively and simultaneously continuously pumping the three into a first-stage extraction centrifuge for extraction centrifugation at normal temperature according to the unit time volume ratio; thereafter, the organic and aqueous phases are separated and the organic phase is retained, the aqueous phase, industrial hydrochloric acid: 59g (content 31%, 0.5mol), dichloromethane: 200g, and sodium hypochlorite solution: taking the volume ratio of 350g (content: 10%, 0.47mol) of the four as a preset unit time volume ratio, and then respectively and simultaneously continuously pumping the four into a second-stage extraction centrifuge for extraction centrifugation at normal temperature according to the unit time volume ratio; then, separating an organic phase and a water phase, reserving the organic phase, and putting the water phase into a next-stage extraction centrifuge; the hydrochloric acid amount, the dichloromethane amount and the sodium hypochlorite solution amount used by each subsequent extraction centrifuge are gradually reduced by half, five-stage continuous extraction reaction is carried out (the extraction centrifugation reaction time of each stage is respectively 3h), and then the organic phase is combined to obtain the 2-chloro-3-aminopyridine solution. The molar yield of the 2-chloro-3-aminopyridine is 90.1 percent (calculated by 3-aminopyridine) and the purity is 98.5 percent by adopting a liquid chromatograph and an external standard method for analysis.
Example 3
Mixing 3-aminopyridine: 188g (2mol) in 10% hydrochloric acid: 900g (content 10%, 2.46mol), after complete dissolution and mixing, the solution is mixed with dichloromethane: 400g, sodium hypochlorite solution: taking the volume ratio of 700g (content: 10%, 0.94mol) of the three as a preset unit time volume ratio, and then respectively and simultaneously continuously pumping the three into a first-stage extraction centrifuge for extraction centrifugation at normal temperature according to the unit time volume ratio; thereafter, the organic and aqueous phases are separated and the organic phase is retained, the aqueous phase, industrial hydrochloric acid: 59g (content 31%, 0.5mol), dichloromethane: 200g, and sodium hypochlorite solution: taking the volume ratio of 350g (content: 10%, 0.47mol) of the four as a preset unit time volume ratio, and then respectively and simultaneously continuously pumping the four into a second-stage extraction centrifuge for extraction centrifugation at normal temperature according to the unit time volume ratio; then, separating an organic phase and a water phase, reserving the organic phase, and putting the water phase into a next-stage extraction centrifuge; the hydrochloric acid amount, the dichloromethane amount and the sodium hypochlorite solution amount used by each subsequent extraction centrifuge are gradually reduced by half, seven stages of continuous extraction reaction (the extraction centrifugation reaction time of each stage is respectively 3h), and then the organic phase is combined to obtain the 2-chloro-3-aminopyridine solution. The molar yield of the 2-chloro-3-aminopyridine is 90.2 percent (calculated by 3-aminopyridine) and the purity is 98.6 percent by adopting a liquid chromatograph and an external standard method for analysis.
Example 4
Mixing 3-aminopyridine: 188g (2mol) in 10% hydrochloric acid: 900g (content 10%, 2.46mol), after complete dissolution and mixing, the solution is mixed with chloroform: 400g, sodium hypochlorite solution: the volume ratio of 900g (content: 10%, 1.2mol) of the three is taken as the preset volume ratio per unit time, and then the three are respectively and simultaneously continuously pumped into a first-stage extraction centrifuge for extraction centrifugation at normal temperature according to the volume ratio per unit time; thereafter, the organic and aqueous phases are separated and the organic phase is retained, the aqueous phase, industrial hydrochloric acid: 59g (content: 31%, 0.5mol), chloroform: 200g, and sodium hypochlorite solution: taking the volume ratio of 450g (content: 10%, 0.6mol) of the four as a preset unit time volume ratio, and then respectively and simultaneously continuously pumping the four into a second-stage extraction centrifuge for extraction centrifugation at normal temperature according to the unit time volume ratio; then, separating an organic phase and a water phase, reserving the organic phase, and putting the water phase into a next-stage extraction centrifuge; the hydrochloric acid amount, the chloroform amount and the sodium hypochlorite solution amount used by each subsequent extraction centrifuge are gradually reduced by half, four-stage continuous extraction reaction is carried out (the extraction centrifugation reaction time of each stage is respectively 3 hours), and then the organic phase is combined to obtain the 2-chloro-3-aminopyridine solution. The molar yield of the 2-chloro-3-aminopyridine is 93.1 percent (calculated by 3-aminopyridine) and the purity is 97.8 percent by adopting a liquid chromatograph and an external standard method for analysis.
Example 5
Mixing 3-aminopyridine: 188g (2mol) in 10% hydrochloric acid: 1000g (10% content, 2.74mol), after complete dissolution and mixing, the solution is mixed with 1, 2-dichloroethane: 400g, sodium hypochlorite solution: the volume ratio of 900g (content: 10%, 1.2mol) of the three is taken as the preset volume ratio per unit time, and then the three are respectively and simultaneously continuously pumped into a first-stage extraction centrifuge for extraction centrifugation at normal temperature according to the volume ratio per unit time; thereafter, the organic and aqueous phases are separated and the organic phase is retained, the aqueous phase, industrial hydrochloric acid: 50g (content: 31%, 0.42mol), 1, 2-dichloroethane: 200g, and sodium hypochlorite solution: taking the volume ratio of 450g (content: 10%, 0.6mol) of the four as a preset unit time volume ratio, and then respectively and simultaneously continuously pumping the four into a second-stage extraction centrifuge for extraction centrifugation at normal temperature according to the unit time volume ratio; then, separating an organic phase and a water phase, reserving the organic phase, and putting the water phase into a next-stage extraction centrifuge; the hydrochloric acid amount, the 1, 2-dichloroethane amount and the sodium hypochlorite solution amount used by each subsequent extraction centrifuge are gradually reduced by half, four-stage continuous extraction reaction is carried out (the extraction centrifugation reaction time of each stage is respectively 3 hours), and then the combined organic phase is the 2-chloro-3-aminopyridine solution. The molar yield of the 2-chloro-3-aminopyridine is 92.4 percent (calculated by 3-aminopyridine) and the purity is 98.2 percent by adopting a liquid chromatograph and an external standard method for analysis.
Example 6
Mixing 3-aminopyridine: 188g (2mol) in 10% hydrochloric acid: 900g (content 10%, 2.46mol), after complete dissolution and mixing, the solution is mixed with dichloromethane: 300g, sodium hypochlorite solution: the volume ratio of 900g (content: 10%, 1.2mol) of the three is taken as the preset volume ratio per unit time, and then the three are respectively and simultaneously continuously pumped into a first-stage extraction centrifuge for extraction centrifugation at normal temperature according to the volume ratio per unit time; thereafter, the organic and aqueous phases are separated and the organic phase is retained, the aqueous phase, industrial hydrochloric acid: 59g (content 31%, 0.5mol), dichloromethane: 160g, and sodium hypochlorite solution: taking the volume ratio of 450g (content: 10%, 0.6mol) of the four as a preset unit time volume ratio, and then respectively and simultaneously continuously pumping the four into a second-stage extraction centrifuge for extraction centrifugation at normal temperature according to the unit time volume ratio; then, separating an organic phase and a water phase, reserving the organic phase, and putting the water phase into a next-stage extraction centrifuge; the hydrochloric acid amount, the dichloromethane amount and the sodium hypochlorite solution amount used by each subsequent extraction centrifuge are gradually reduced by half, four-stage continuous extraction reaction is carried out (the extraction centrifugation reaction time of each stage is respectively 3 hours), and then the organic phase is combined to obtain the 2-chloro-3-aminopyridine solution. The molar yield of the 2-chloro-3-aminopyridine is 92.5 percent (calculated by 3-aminopyridine) and the purity is 97.2 percent by adopting a liquid chromatograph and an external standard method for analysis.
Example 7
Mixing 3-aminopyridine: 188g (2mol) in 10% hydrochloric acid: 900g (content 10%, 2.46mol), after complete dissolution and mixing, the solution is mixed with xylene: 400g, sodium hypochlorite solution: the volume ratio of 900g (content: 10%, 1.2mol) of the three is taken as the preset volume ratio per unit time, and then the three are respectively and simultaneously continuously pumped into a first-stage extraction centrifuge for extraction centrifugation at normal temperature according to the volume ratio per unit time; thereafter, the organic and aqueous phases are separated and the organic phase is retained, the aqueous phase, industrial hydrochloric acid: 59g (content 31%, 0.5mol), xylene: 200g, and sodium hypochlorite solution: taking the volume ratio of 450g (content: 10%, 0.6mol) of the four as a preset unit time volume ratio, and then respectively and simultaneously continuously pumping the four into a second-stage extraction centrifuge for extraction centrifugation at normal temperature according to the unit time volume ratio; then, separating an organic phase and a water phase, reserving the organic phase, and putting the water phase into a next-stage extraction centrifuge; the hydrochloric acid amount, the dimethylbenzene amount and the sodium hypochlorite solution amount used by each subsequent extraction centrifuge are gradually reduced by half, four-stage continuous extraction reaction is carried out (the extraction centrifugation reaction time of each stage is respectively 3 hours), and then the organic phase is combined to obtain the 2-chloro-3-aminopyridine solution. The molar yield of the 2-chloro-3-aminopyridine is 91.1 percent (calculated by 3-aminopyridine) and the purity is 97.4 percent by adopting a liquid chromatograph and an external standard method for analysis.
The invention also includes several other examples (numbered as examples 1 to 5) whose basic steps are the same as example 1, and the specific parameters of each step are shown in the following table
The following examples of relatively mature preparation methods are listed for comparison:
comparative example 1: the specific route is shown in the literature: CN103570609A
Preparation of 3-aminopyridine: adding 150 ml of water into a 1000 ml four-neck round-bottom flask with a stirring thermometer, adding 36.6 g (0.3mol) of nicotinamide while stirring, cooling to 0-5 ℃ after complete dissolution, then adding 272 g (0.33mol) of 9.05% sodium hypochlorite solution dropwise during 30-60 minutes and within the range of 0-5 ℃, and stirring for 30min after the dropwise addition is finished.
Adding 240 ml of water into another 1000 ml four-neck round-bottom flask with a stirrer, a thermometer and a condenser, heating to 90-100 ℃, dropwise adding the reaction solution stored at 0-5 ℃ in the temperature range and during 30-45 minutes, continuing the heat preservation reaction for 2 hours after the dropwise adding is finished, and after the reaction is finished, weighing 747 g of the reaction solution, analyzing the content of 3-aminopyridine (liquid chromatograph, external standard method), the content of nicotinic acid (peak area is 0.72 percent), the molar yield of 3-aminopyridine: 95.2 percent.
Neutralizing the reaction liquid to be neutral by using 30% liquid alkali, distilling under negative pressure to remove water, dissolving 3-aminopyridine by using 300 ml of dichloromethane at room temperature under stirring, filtering, washing salt by using 200 ml of dichloromethane to obtain dichloromethane solution containing 3-aminopyridine, extracting the dichloromethane solution of the 3-aminopyridine by using 360g of industrial hydrochloric acid to obtain hydrochloric acid solution of the 3-aminopyridine, and analyzing by using a liquid chromatograph and an external standard method to obtain the 3-aminopyridine with the molar yield of 94.1%.
Preparation of 2-chloro-3-aminopyridine: adding the 3-aminopyridine solution into a 1000 ml four-neck round-bottom flask with a stirring thermometer, dropwise adding 45.4 g (0.36mol) of 27% hydrogen peroxide at 5-10 ℃, keeping the dropwise adding time for 1.5-2 hours, carrying out heat preservation reaction at 5-10 ℃, after 1 hour of reaction, adjusting the reaction temperature to 10-15 ℃, continuing the reaction for 1 hour, starting sampling and analyzing, when the reaction is finished until the peak area of the product is the highest and the peak area of impurities is less than or equal to 15%, adding 10 g of sodium bisulfite until the potassium iodide starch test paper does not show blue, analyzing by a liquid chromatograph and an external standard method, wherein the molar yield of 2-chloro-3-aminopyridine is 85.2% (calculated by 3-aminopyridine).
Comparative example 2: the specific route of the 3-aminopyridine starting material is shown in the literature: CN103570609A
The above 360g industrial hydrochloric acid (content: 30.5%, 3mol) and 0.3mol (28.2g) 3-aminopyridine are added into a 1000 ml four-neck round-bottom flask with a stirring thermometer, stirred and dissolved, 45.4 g (0.36mol) of 27% hydrogen peroxide is added dropwise at 10-15 ℃ for 1.5-2 hours, the mixture is kept at 10-15 ℃ for reaction, after 3.5 hours of reaction, 10 g sodium bisulfite is added until potassium iodide starch test paper does not show blue color, and the molar yield of 2-chloro-3-aminopyridine (calculated by 3-aminopyridine) is 86.5% by a liquid chromatograph and an external standard method.
As can be seen from the comparison examples, the preparation method provided by the invention has the advantage that the molar yield of the 2-chloro-3-aminopyridine is remarkably improved. In addition, after the 2-chloro-3-aminopyridine solution is prepared by the preparation method, a special impurity removing procedure is not needed, so that the preparation method is obviously superior to the comparative case and the existing preparation process represented by the comparative case.
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 claims of the present invention.
Claims (10)
1. A preparation method of 2-chloro-3-aminopyridine is characterized by comprising the following steps:
taking an extraction centrifuge as a primary extraction centrifuge, and taking the primary extraction centrifuge as a primary extraction centrifuge; dissolving 3-aminopyridine in a hydrochloric acid solution, uniformly mixing, and continuously pumping the hydrochloric acid solution containing the 3-aminopyridine, an organic solvent and a chlorinated reagent solution into a primary extraction centrifuge for extraction centrifugation according to a preset unit time volume ratio; thereafter, the organic and aqueous phases are separated and the organic phase is retained; turning to a second step;
taking an extraction centrifuge as a current-stage extraction centrifuge, and taking the current-stage extraction centrifuge as a lower-stage extraction centrifuge of a previous-stage extraction centrifuge; respectively and simultaneously and continuously pumping the water phase, the hydrochloric acid solution, the organic solvent and the chlorinated reagent solution separated by the previous stage of extraction centrifuge into the current stage of extraction centrifuge according to a preset unit time volume ratio for extraction centrifugation; thereafter, the organic and aqueous phases are separated and the organic phase is retained; turning to the third step;
thirdly, judging whether next-stage extraction centrifugation is carried out or not, if so, turning to the second step, and otherwise, turning to the fourth step;
and step four, combining the organic phases reserved by the extraction centrifuges at all stages to obtain the 2-chloro-3-aminopyridine solution.
2. The method according to claim 1, wherein the chlorinating reagent solution is an aqueous sodium hypochlorite solution.
3. The process according to claim 1, wherein the amount of the feed material of 3-aminopyridine is used as a reference value in the first step; the amount of the substance of the hydrogen chloride contained in the hydrochloric acid solution fed into the first-stage extraction centrifuge is 0.1 to 3.0 times of the reference value, or the amount of the substance of the hydrogen chloride contained in the hydrochloric acid solution is 1.1 to 1.5 times of the reference value;
in the second step, if the previous stage of extraction centrifuge is the first stage of extraction centrifuge, the amount of the substance of hydrogen chloride contained in the hydrochloric acid solution fed into the current stage of extraction centrifuge is 0.1 to 0.5 times of the reference value, or the amount of the substance of hydrogen chloride contained in the hydrochloric acid solution fed into the current stage of extraction centrifuge is 0.2 to 0.3 times of the reference value; if the previous stage of extraction centrifuge is not the first stage of extraction centrifuge, the amount of the substance of hydrogen chloride contained in the hydrochloric acid solution fed into the current stage of extraction centrifuge is 0.1-0.8 times of the amount of the substance of hydrogen chloride contained in the hydrochloric acid solution fed into the previous stage of extraction centrifuge, or the amount of the substance of hydrogen chloride contained in the hydrochloric acid solution fed into the current stage of extraction centrifuge is 0.3-0.6 times of the amount of the substance of hydrogen chloride contained in the hydrochloric acid solution fed into the previous stage of extraction centrifuge.
4. The method according to claim 3, wherein in the first step, the hydrochloric acid solution contains 10 ± 4% by weight of hydrochloric acid; in the second step, the weight percentage of the hydrochloric acid in the hydrochloric acid solution is 31 +/-5%.
5. The process according to claim 2, wherein the amount of the feed material of 3-aminopyridine is used as a reference value in the first step; the amount of the substance of the chlorination reagent contained in the chlorination reagent solution fed into the first-stage extraction centrifuge is 0.1-0.8 times of the reference value, or the amount of the substance of the chlorination reagent contained in the chlorination reagent solution fed into the first-stage extraction centrifuge is 0.3-0.6 times of the reference value;
in the second step, the amount of the substance of the chlorination reagent contained in the chlorination reagent solution fed into the current-stage extraction centrifuge is 0.1 to 0.8 times of the amount of the substance of the chlorination reagent contained in the chlorination reagent solution fed into the previous-stage extraction centrifuge, or the amount of the substance of the chlorination reagent contained in the chlorination reagent solution fed into the current-stage extraction centrifuge is 0.3 to 0.6 times of the amount of the substance of the chlorination reagent contained in the chlorination reagent solution fed into the previous-stage extraction centrifuge.
6. The method according to claim 5, wherein the chlorinating agent is contained in the chlorinating agent solution in an amount of 10. + -. 4% by weight in each of the first and second steps.
7. The production method according to claim 1, wherein the organic solvent is dichloromethane, chloroform, toluene, xylene, chlorobenzene, or 1, 2-dichloroethane; the organic solvent used in the first and second steps is the same.
8. The process according to claim 7, wherein in the first step, the weight of the organic solvent fed into the first-stage extraction centrifuge is 0.5 to 5 times the weight of the feed of 3-aminopyridine, or the weight of the organic solvent fed into the first-stage extraction centrifuge is 2 to 3 times the weight of the feed of 3-aminopyridine;
in the second step, the weight of the organic solvent put into the extraction centrifuge of the stage is 0.1-0.8 times of the weight of the organic solvent put into the extraction centrifuge of the previous stage, or the weight of the organic solvent put into the extraction centrifuge of the stage is 0.3-0.6 times of the weight of the organic solvent put into the extraction centrifuge of the previous stage.
9. The method according to claim 1, wherein the number of execution of the second step is 1 to 9 in total, or the number of execution of the second step is 3 to 5 in total.
10. The preparation method according to claim 1, wherein in the first step, after the amounts of the 3-aminopyridine, the hydrochloric acid solution, the organic solvent and the chlorinating agent solution are respectively determined, the 3-aminopyridine is dissolved in the hydrochloric acid solution and uniformly mixed to obtain the hydrochloric acid solution containing the 3-aminopyridine, and then the volume ratio of the hydrochloric acid solution containing the 3-aminopyridine, the organic solvent and the chlorinating agent solution is used as a preset volume ratio per unit time;
in the second step, after the dosages of the hydrochloric acid solution, the organic solvent and the chlorination reagent solution are respectively determined, the volume ratio of the water phase, the hydrochloric acid solution, the organic solvent and the chlorination reagent solution separated by the previous-stage extraction centrifuge is used as a preset unit time volume ratio;
in the first step and the second step, the extraction centrifugation is respectively carried out at 10-30 ℃; the extraction centrifugation reaction time is 1-4h respectively.
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| CN103570609A (en) * | 2013-10-28 | 2014-02-12 | 南通天泽化工有限公司 | Preparation method for 2,3-dichloropyridine |
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| CN102584693A (en) * | 2012-02-09 | 2012-07-18 | 苏州雅本化学股份有限公司 | Preparation method for high purity 2-chlorine-3-aminopyridine hydrochloride |
| CN103570609A (en) * | 2013-10-28 | 2014-02-12 | 南通天泽化工有限公司 | Preparation method for 2,3-dichloropyridine |
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