CN110885311B - 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: firstly, taking an 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 3-aminopyridine, an organic solvent and a chlorinating reagent solution into a primary extraction centrifuge for extraction and centrifugation; the organic and aqueous phases were separated and the organic phase was retained. Secondly, taking an extraction centrifuge as a primary extraction centrifuge; continuously pumping the water phase, hydrochloric acid solution, organic solvent and chloridizing reagent solution separated by the upper extraction centrifuge into the present extraction centrifuge for extraction and centrifugation; the organic phase and the aqueous phase are separated leaving an organic phase. And thirdly, judging whether the next extraction centrifugation is carried out, and if yes, turning to the second step. And fourthly, combining the organic phases reserved by the extraction centrifuges at all levels to obtain a 2-chloro-3-aminopyridine solution. The invention adopts a continuous method to prepare, 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 phthalamide pesticide developed successfully in 2000 by dupont in the united states. The chlorantraniliprole has excellent quick-acting property and lasting effect, has excellent control effect on target pests, is particularly effective in early development stages of the pests, is characterized by unusual larvicide activity and outstanding egg/young co-killing activity, can effectively control a large number of important lepidoptera pests, and can also effectively control other pests such as certain coleoptera, diptera, hemiptera and isoptera pests; and, chlorantraniliprole has very low acute, sub-chronic and chronic toxicity to mammals.
Pirenzepine is a selective anticholinergic agent, is suitable for treating gastric and duodenal ulcers, and can obviously relieve pain of patients and reduce the dosage of antacid.
2-chloro-3-aminopyridine is a key intermediate of chlorantraniliprole and pirenzepine, has wide market development prospect, and the existing literature has made many researches on preparation methods thereof, but has the defects, and the existing preparation methods need to be improved so as to realize larger social and economic benefits.
The preparation method reported in the prior art of 2-chloro-3-aminopyridine mainly comprises the following steps: chinese invention patent grant No. CN101514185B and chinese invention patent grant No. CN103570609B, all of which describe the following processes: nicotinamide is used as a raw material, and 2-chloro-3-aminopyridine is obtained through Huffman degradation and chlorination reaction. The process route can be derived from a process using 3-aminopyridine as a raw material (such as the Chinese patent of patent publication No. CN 102584693B) and a process using 3-cyanopyridine as a raw material. The process is a mature process, but because a large amount of acid is needed in the process, and the amount of hydrochloric acid in the chlorination step is converted into the amount of the hydrogen chloride substance, the amount of the 3-aminopyridine substance is generally about 10 times that of the 3-aminopyridine substance, so that waste acid and waste water are much, and the pollution is serious; and the impurity in the chlorination reaction is larger, so that the yield of the chlorination step is lower, and if a purer product is obtained, a lot of post-treatment is needed to remove the impurity, so that the operation is complicated.
In addition, chinese patent of the issued publication No. CN102153509B, and chinese patent of the issued publication No. CN102532010B, which describe the following processes: the 2-chloro-3-nitropyridine is subjected to chemical reduction or catalytic reduction to obtain the 2-chloro-3-aminopyridine, however, the chemical reduction brings great environmental pollution, and the catalyst also has the principle of higher cost.
Disclosure of Invention
The invention aims at: aiming at the problems in the prior art, a preparation method of 2-chloro-3-aminopyridine is provided, and the method can inhibit the generation of impurities by timely removing products in a reaction system, thereby being beneficial to improving the yield and quality of the products.
The technical scheme for solving the technical problems is as follows:
the preparation method of the 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 and uniformly mixing, and then respectively and simultaneously continuously pumping the hydrochloric acid solution containing 3-aminopyridine, an organic solvent and a chlorinating reagent solution into a primary extraction centrifuge according to a preset unit time volume ratio for extraction centrifugation; thereafter, the organic phase and the aqueous phase are separated and the organic phase is retained; turning to a second step;
taking an extraction centrifuge as a primary extraction centrifuge, and taking the primary extraction centrifuge as a lower extraction centrifuge of an upper extraction centrifuge; respectively and simultaneously continuously pumping the water phase, the hydrochloric acid solution, the organic solvent and the chloridizing reagent solution which are separated by the upper extraction centrifuge into the present extraction centrifuge according to the preset unit time volume ratio for extraction centrifugation; thereafter, the organic phase and the aqueous phase are separated and the organic phase is retained; turning to a third step;
thirdly, judging whether the next extraction centrifugation is carried out, if so, turning to the second step, and if not, turning to the fourth step;
and fourthly, combining the organic phases reserved by the extraction centrifuges at all levels to obtain the 2-chloro-3-aminopyridine solution.
The inventors have conducted intensive and repeated practical studies and found that the chlorination reaction of 3-aminopyridine and the reaction for producing impurities are sequential reactions, and that a large amount of impurities are produced only when the product of the chlorination reaction of 3-aminopyridine reaches a certain concentration. Based on the findings, the inventor obtains the technical proposal through further intensive practical research, the technical proposal adopts a continuous method to prepare, when the system concentration of the product 2-chloro-3-aminopyridine is lower, the 2-chloro-3-aminopyridine can be extracted into an organic phase in time to be reserved, and an aqueous phase is led into a next-stage extraction centrifuge to carry out the next-stage reaction-extraction-centrifugation, thus the generation of impurities can be controlled to the greatest extent, the impurities can not be generated in a large amount, 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 2-chloro-3-aminopyridine, or can be used for subsequent reaction after acid stripping. The continuous reaction of the technical scheme is easy to produce and amplify, the waste water is less, the impurities are less, the yield is high, and the product is easy to treat in the production process.
The further perfected technical scheme of the invention is 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, thereby ensuring the reaction speed under the condition of greatly reducing the acid quantity.
More preferably, in the first step, the amount of the 3-aminopyridine feed material is used as a reference value; the amount of the substance containing the chlorinating agent added into the chlorinating agent solution in the first-stage extraction centrifuge is 0.1 to 0.8 times of the reference value, or the amount of the substance containing the chlorinating agent added into the chlorinating agent solution in 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 containing the chlorinating agent added to the chlorinating agent solution in the present-stage extraction centrifuge is 0.1 to 0.8 times the amount of the substance containing the chlorinating agent added to the chlorinating agent solution in the previous-stage extraction centrifuge, or the amount of the substance containing the chlorinating agent added to the chlorinating agent solution in the present-stage extraction centrifuge is 0.3 to 0.6 times the amount of the substance containing the chlorinating agent added to the chlorinating agent solution in the previous-stage extraction centrifuge.
With this preferred embodiment, the amount of chlorinating agent used can be further optimized.
More preferably, in the first step and the second step, the weight percentage of the chlorinating agent in the chlorinating agent solution 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 feed material is used as a reference value; the amount of the substances of the hydrogen chloride contained in the hydrochloric acid solution which is put into the first-stage extraction centrifugal machine is 0.1-3.0 times of a reference value, or the amount of the substances of the hydrogen chloride contained in the hydrochloric acid solution is 1.1-1.5 times of the reference value;
in the second step, if the upper extraction centrifuge is the first extraction centrifuge, the amount of the substances of hydrogen chloride contained in the hydrochloric acid solution input into the present extraction centrifuge is 0.1-0.5 times of the reference value, or the amount of the substances of hydrogen chloride contained in the hydrochloric acid solution input into the present extraction centrifuge is 0.2-0.3 times of the reference value; if the upper extraction centrifuge is not the first extraction centrifuge, the amount of the substances containing hydrogen chloride in the hydrochloric acid solution in the present extraction centrifuge is 0.1-0.8 times the amount of the substances containing hydrogen chloride in the hydrochloric acid solution in the upper extraction centrifuge, or the amount of the substances containing hydrogen chloride in the hydrochloric acid solution in the present extraction centrifuge is 0.3-0.6 times the amount of the substances containing hydrogen chloride in the hydrochloric acid solution in the upper extraction centrifuge.
With this preferred solution, the amount of hydrochloric acid can be further optimized.
More preferably, in the first step, the weight percentage of hydrochloric acid in the hydrochloric acid solution is 10+/-4%; in the second step, the weight percentage of hydrochloric acid in the hydrochloric acid solution is 31+/-5%.
With this preferred solution, the use concentration of hydrochloric acid can be further optimized.
Preferably, the organic solvent is dichloromethane, chloroform, toluene, xylene, chlorobenzene, or 1, 2-dichloroethane; the organic solvents used in the first and second steps are 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 to 5 times the charged weight of 3-aminopyridine, or the weight of the organic solvent charged in the first-stage extraction centrifuge is 2 to 3 times the charged weight of 3-aminopyridine;
in the second step, the weight of the organic solvent put into the primary extraction centrifuge is 0.1-0.8 times of the weight of the organic solvent put into the upper extraction centrifuge, or the weight of the organic solvent put into the primary extraction centrifuge is 0.3-0.6 times of the weight of the organic solvent put into the upper extraction centrifuge.
With this preferred embodiment, the amount of organic solvent can be further optimized.
Preferably, the number of times of execution of the second step is 1 to 9 times in total, or the number of times of execution of the second step is 3 to 5 times in total.
With the adoption of the preferred scheme, the extraction stage number of the whole process can be further optimized.
Preferably, in the first step, after the dosages of the 3-aminopyridine, the hydrochloric acid solution, the organic solvent and the chloridizing reagent 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 chloridizing reagent solution is taken as the preset volume ratio of unit time;
in the second step, after the dosage of the hydrochloric acid solution, the organic solvent and the chlorinating agent solution is respectively determined, the volume ratio of the water phase, the hydrochloric acid solution, the organic solvent and the chlorinating agent solution separated by the upper extraction centrifuge is taken as the preset volume ratio of unit time;
in the first step and the second step, extraction and centrifugation are respectively carried out at 10-30 ℃; the extraction and centrifugation reaction time is 1-4h respectively.
By adopting the preferred scheme, the process of determining the preset unit time volume ratio 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 carries out chlorination reaction by multistage continuous feeding and discharging 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 can be timely extracted into an organic phase to be reserved, and the water phase is introduced into a next-stage extraction centrifuge to carry out the next-stage reaction-extraction-centrifugation, thereby furthest controlling the generation of impurities, leading the impurities not to be generated in a large amount, and greatly improving the yield and quality of the 2-chloro-3-aminopyridine. Meanwhile, the chlorinating agent (such as sodium hypochlorite) and hydrochloric acid are used for forming the chlorinating agent, so that the higher chlorine concentration can be achieved under the lower acid concentration, and the reaction speed is ensured under the condition of greatly reducing the acid quantity; the invention can overcome the problem of overlarge dichloro impurity in the prior art and improve the purity of the product by strictly controlling the material input proportion in extraction centrifugal reaction at each level. In addition, the preparation method is a continuous reaction, is easy to produce and enlarge, has less waste water, less impurities and high yield and is easy to treat.
Drawings
FIG. 1 is a schematic flow chart of the main body of the method for implementing the invention.
FIG. 2 is a graph showing the results of liquid chromatography test in example 1 of the present invention.
Detailed Description
As shown in FIG. 1, the preparation method of the 2-chloro-3-aminopyridine, which is implemented by the invention, comprises 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 and uniformly mixing, and then respectively and simultaneously continuously pumping the hydrochloric acid solution containing 3-aminopyridine, an organic solvent and a chlorinating reagent solution into a primary extraction centrifuge according to a preset unit time volume ratio for extraction centrifugation; thereafter, the organic phase and the aqueous phase are separated and the organic phase is retained; turning to the second step.
Taking an extraction centrifuge as a primary extraction centrifuge, and taking the primary extraction centrifuge as a lower extraction centrifuge of an upper extraction centrifuge; respectively and simultaneously continuously pumping the water phase, the hydrochloric acid solution, the organic solvent and the chloridizing reagent solution which are separated by the upper extraction centrifuge into the present extraction centrifuge according to the preset unit time volume ratio for extraction centrifugation; thereafter, the organic phase and the aqueous phase are separated and the organic phase is retained; turning to the third step.
And thirdly, judging whether the next extraction centrifugation is carried out, if so, turning to the second step, and if not, turning to the fourth step.
And fourthly, combining the organic phases reserved by the extraction centrifuges at all levels to obtain the 2-chloro-3-aminopyridine solution.
In addition, in the first step and the second step, extraction centrifugation is performed at 10 ℃ to 30 ℃, respectively; the extraction and centrifugation reaction time is 1-4h respectively.
Specifically, (1) regarding hydrochloric acid:
in the first step, taking the amount of 3-aminopyridine material as a reference value; the amount of the hydrogen chloride contained in the hydrochloric acid solution fed into the first-stage extraction centrifuge is 0.1 to 3.0 times the reference value, or the amount of the hydrogen chloride contained in the hydrochloric acid solution is 1.1 to 1.5 times the reference value.
In the second step, if the upper extraction centrifuge is the first extraction centrifuge, the amount of the substances of hydrogen chloride contained in the hydrochloric acid solution input into the present extraction centrifuge is 0.1-0.5 times of the reference value, or the amount of the substances of hydrogen chloride contained in the hydrochloric acid solution input into the present extraction centrifuge is 0.2-0.3 times of the reference value; if the upper extraction centrifuge is not the first extraction centrifuge, the amount of the substances containing hydrogen chloride in the hydrochloric acid solution in the present extraction centrifuge is 0.1-0.8 times the amount of the substances containing hydrogen chloride in the hydrochloric acid solution in the upper extraction centrifuge, or the amount of the substances containing hydrogen chloride in the hydrochloric acid solution in the present extraction centrifuge is 0.3-0.6 times the amount of the substances containing hydrogen chloride in the hydrochloric acid solution in the upper extraction centrifuge.
In addition, in the first step, the weight percentage of hydrochloric acid in the hydrochloric acid solution (i.e., the concentration of the hydrochloric acid solution) is 10+ -4%; in the second step, the weight percentage of hydrochloric acid in the hydrochloric acid solution is 31+/-5 percent.
(2) Regarding the chlorinating reagent solution:
the chloridizing reagent solution is sodium hypochlorite aqueous solution.
In the first step, taking the amount of 3-aminopyridine material as a reference value; the amount of the substance containing the chlorinating agent added to the chlorinating agent solution in the first extraction centrifuge is 0.1 to 0.8 times the reference value, or the amount of the substance containing the chlorinating agent added to the chlorinating agent solution in the first extraction centrifuge is 0.3 to 0.6 times the reference value.
In the second step, the amount of the substance containing the chlorinating agent added to the chlorinating agent solution in the present-stage extraction centrifuge is 0.1 to 0.8 times the amount of the substance containing the chlorinating agent added to the chlorinating agent solution in the previous-stage extraction centrifuge, or the amount of the substance containing the chlorinating agent added to the chlorinating agent solution in the present-stage extraction centrifuge is 0.3 to 0.6 times the amount of the substance containing the chlorinating agent added to the chlorinating agent solution in the previous-stage extraction centrifuge.
In addition, in the first step and the second step, the weight percentage of the chlorinating agent in the chlorinating agent solution was 10.+ -. 4%, respectively.
(3) Regarding the organic solvent:
the organic solvent is dichloromethane, chloroform, toluene, xylene, chlorobenzene, or 1, 2-dichloroethane; the organic solvents used in the first and second steps are the same.
In the first step, the weight of the organic solvent added into the first-stage extraction centrifuge is 0.5-5 times of the weight of the 3-aminopyridine, or the weight of the organic solvent added into the first-stage extraction centrifuge is 2-3 times of the weight of the 3-aminopyridine.
In the second step, the weight of the organic solvent put into the primary extraction centrifuge is 0.1-0.8 times of the weight of the organic solvent put into the upper extraction centrifuge, or the weight of the organic solvent put into the primary extraction centrifuge is 0.3-0.6 times of the weight of the organic solvent put into the upper extraction centrifuge.
(4) Regarding the extraction stage number:
the number of times of execution of the second step is 1 to 9 (i.e., the number of extraction stages is 2 to 10), or the number of times of execution of the second step is 3 to 5 (i.e., the number of extraction stages is 4 to 6).
(5) Regarding a preset unit time volume ratio:
in the first step, after the dosages of the 3-aminopyridine, the hydrochloric acid solution, the organic solvent and the chloridizing reagent 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 chloridizing reagent solution is taken as the preset volume ratio of unit time.
In the second step, after the dosage of the hydrochloric acid solution, the organic solvent and the chlorinating agent solution are respectively determined, the volume ratio of the water phase, the hydrochloric acid solution, the organic solvent and the chlorinating agent solution separated by the upper extraction centrifuge is taken as the preset volume ratio of unit time.
After the preset unit time volume ratio is determined according to the method, each material can be respectively and simultaneously continuously pumped into the extraction centrifuge according to the input speed (such as a plurality of milliliters per minute) which is consistent with the unit time volume ratio.
In the preparation method, the specific reaction route is as follows:
the invention is described in further detail below with reference to the accompanying drawings in combination with embodiments. The invention is not limited to the examples given.
Example 1
3-aminopyridine: 188g (2 mol) of the aqueous solution was dissolved in 10% hydrochloric acid: 900g (content 10%,2.46 mol), after complete dissolution and mixing, the solution was admixed with methylene chloride: 400g, sodium hypochlorite solution: 800g (content 10%,1.07 mol) of the three materials is taken as a preset unit time volume ratio, and then the three materials are respectively and simultaneously and continuously pumped into a first-stage extraction centrifuge for extraction centrifugation at normal temperature (the specific temperature range of the normal temperature is 10-30 ℃); thereafter, the organic and aqueous phases were separated and the organic phase was retained, the aqueous phase, technical hydrochloric acid: 59g (content 31%,0.5 mol), dichloromethane: 200g, and sodium hypochlorite solution: 400g (content 10%,0.54 mol) of the four materials are taken as a preset unit time volume ratio, and then the four materials are respectively and simultaneously continuously pumped into a second-stage extraction centrifuge for extraction centrifugation at normal temperature according to the unit time volume ratio; then separating the organic phase and the aqueous phase, keeping the organic phase, and putting the aqueous phase into a next-stage extraction centrifuge; sequentially reducing the hydrochloric acid amount, the dichloromethane amount and the sodium hypochlorite solution amount used by each extraction centrifuge by half step by step, carrying out five-stage continuous extraction reactions (the extraction and centrifugation reaction time of each stage is 3h respectively), and then merging organic phases to obtain a 2-chloro-3-aminopyridine solution; 962g of solution were obtained. Analyzing by adopting a liquid chromatograph and an external standard method, and calculating the content by the external standard method to obtain the weight of the 2-chloro-3-aminopyridine: 234.5g, molar yield of 2-chloro-3-aminopyridine (calculated as 3-aminopyridine) 91.3% purity 98.4%.
Liquid chromatograph detection wavelength: UV254nm, the spectrum is shown in FIG. 2. 3.2min peak in the graph is taken as raw material 3-aminopyridine, 5.2min peak is taken as 2-chloro-3-aminopyridine, and 7.5min peak is taken as 2, 6-dichloro-3-aminopyridine.
Example 2
3-aminopyridine: 188g (2 mol) of the aqueous solution was dissolved in 10% hydrochloric acid: 900g (content 10%,2.46 mol), after complete dissolution and mixing, the solution was admixed with methylene chloride: 400g, sodium hypochlorite solution: 700g (content 10%,0.94 mol) of the three materials are used as a preset unit time volume ratio, and then the three materials are respectively and simultaneously and continuously pumped 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 were separated and the organic phase was retained, the aqueous phase, technical hydrochloric acid: 59g (content 31%,0.5 mol), dichloromethane: 200g, and sodium hypochlorite solution: the volume ratio of 350g (content 10 percent, 0.47 mol) is taken as a preset unit time volume ratio, and then the four are respectively and simultaneously continuously pumped into a second-stage extraction centrifuge for extraction centrifugation at normal temperature according to the unit time volume ratio; then separating the organic phase and the aqueous phase, keeping the organic phase, and putting the aqueous 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 reduced by half step by step, five stages of continuous extraction reactions (the extraction and centrifugation reaction time of each stage is 3h respectively) are carried out, and then the organic phases are combined to obtain the 2-chloro-3-aminopyridine solution. The molar yield of 2-chloro-3-aminopyridine (calculated as 3-aminopyridine) was 90.1% and the purity was 98.5% by liquid chromatography and external standard method analysis.
Example 3
3-aminopyridine: 188g (2 mol) of the aqueous solution was dissolved in 10% hydrochloric acid: 900g (content 10%,2.46 mol), after complete dissolution and mixing, the solution was admixed with methylene chloride: 400g, sodium hypochlorite solution: 700g (content 10%,0.94 mol) of the three materials are used as a preset unit time volume ratio, and then the three materials are respectively and simultaneously and continuously pumped 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 were separated and the organic phase was retained, the aqueous phase, technical hydrochloric acid: 59g (content 31%,0.5 mol), dichloromethane: 200g, and sodium hypochlorite solution: the volume ratio of 350g (content 10 percent, 0.47 mol) is taken as a preset unit time volume ratio, and then the four are respectively and simultaneously continuously pumped into a second-stage extraction centrifuge for extraction centrifugation at normal temperature according to the unit time volume ratio; then separating the organic phase and the aqueous phase, keeping the organic phase, and putting the aqueous 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 halved step by step, seven stages of continuous extraction reactions (the extraction centrifugal reaction time of each stage is 3h respectively) are carried out, and then the organic phases are combined to obtain the 2-chloro-3-aminopyridine solution. The molar yield of 2-chloro-3-aminopyridine (calculated as 3-aminopyridine) was 90.2% and the purity was 98.6% by liquid chromatography, external standard method analysis.
Example 4
3-aminopyridine: 188g (2 mol) of the aqueous solution was dissolved in 10% hydrochloric acid: 900g (content 10%,2.46 mol), after complete dissolution and mixing, the solution was mixed with chloroform: 400g, sodium hypochlorite solution: 900g (content 10%,1.2 mol) of the three materials are used as a preset unit time volume ratio, and then the three materials are respectively and simultaneously and continuously pumped 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 were separated and the organic phase was retained, the aqueous phase, technical hydrochloric acid: 59g (content 31%,0.5 mol), chloroform: 200g, and sodium hypochlorite solution: 450g (content 10%,0.6 mol) as a preset unit time volume ratio, then respectively and simultaneously continuously pumping the four materials into a second-stage extraction centrifuge for extraction centrifugation at normal temperature according to the unit time volume ratio; then separating the organic phase and the aqueous phase, keeping the organic phase, and putting the aqueous 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 halved step by step, four stages of continuous extraction reactions (the extraction and centrifugation reaction time of each stage is 3h respectively) are carried out, and then the organic phases are combined to obtain the 2-chloro-3-aminopyridine solution. The molar yield of 2-chloro-3-aminopyridine (calculated as 3-aminopyridine) was 93.1% and the purity was 97.8% by analysis using a liquid chromatograph and external standard method.
Example 5
3-aminopyridine: 188g (2 mol) of the aqueous solution was dissolved in 10% hydrochloric acid: 1000g (content 10%,2.74 mol), after complete dissolution and mixing, the solution is reacted with 1, 2-dichloroethane: 400g, sodium hypochlorite solution: 900g (content 10%,1.2 mol) of the three materials are used as a preset unit time volume ratio, and then the three materials are respectively and simultaneously and continuously pumped 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 were separated and the organic phase was retained, the aqueous phase, technical hydrochloric acid: 50g (content 31%,0.42 mol), 1, 2-dichloroethane: 200g, and sodium hypochlorite solution: 450g (content 10%,0.6 mol) as a preset unit time volume ratio, then respectively and simultaneously continuously pumping the four materials into a second-stage extraction centrifuge for extraction centrifugation at normal temperature according to the unit time volume ratio; then separating the organic phase and the aqueous phase, keeping the organic phase, and putting the aqueous 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 halved step by step, four stages of continuous extraction reactions (the extraction and centrifugation reaction time of each stage is 3h respectively) are carried out, and then the organic phases are combined to obtain the 2-chloro-3-aminopyridine solution. The molar yield of 2-chloro-3-aminopyridine (calculated as 3-aminopyridine) was 92.4% and the purity was 98.2% by liquid chromatography, external standard method analysis.
Example 6
3-aminopyridine: 188g (2 mol) of the aqueous solution was dissolved in 10% hydrochloric acid: 900g (content 10%,2.46 mol), after complete dissolution and mixing, the solution was admixed with methylene chloride: 300g, sodium hypochlorite solution: 900g (content 10%,1.2 mol) of the three materials are used as a preset unit time volume ratio, and then the three materials are respectively and simultaneously and continuously pumped 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 were separated and the organic phase was retained, the aqueous phase, technical hydrochloric acid: 59g (content 31%,0.5 mol), dichloromethane: 160g, and sodium hypochlorite solution: 450g (content 10%,0.6 mol) as a preset unit time volume ratio, then respectively and simultaneously continuously pumping the four materials into a second-stage extraction centrifuge for extraction centrifugation at normal temperature according to the unit time volume ratio; then separating the organic phase and the aqueous phase, keeping the organic phase, and putting the aqueous 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 halved step by step, four stages of continuous extraction reactions (the extraction and centrifugation reaction time of each stage is 3h respectively) are carried out, and then the organic phases are combined to obtain the 2-chloro-3-aminopyridine solution. The molar yield of 2-chloro-3-aminopyridine (calculated as 3-aminopyridine) was 92.5% and the purity was 97.2% by liquid chromatography and external standard method analysis.
Example 7
3-aminopyridine: 188g (2 mol) of the aqueous solution was dissolved in 10% hydrochloric acid: 900g (10% content, 2.46 mol) and, after complete dissolution and mixing, the solution was admixed with xylene: 400g, sodium hypochlorite solution: 900g (content 10%,1.2 mol) of the three materials are used as a preset unit time volume ratio, and then the three materials are respectively and simultaneously and continuously pumped 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 were separated and the organic phase was retained, the aqueous phase, technical hydrochloric acid: 59g (content 31%,0.5 mol), xylene: 200g, and sodium hypochlorite solution: 450g (content 10%,0.6 mol) as a preset unit time volume ratio, then respectively and simultaneously continuously pumping the four materials into a second-stage extraction centrifuge for extraction centrifugation at normal temperature according to the unit time volume ratio; then separating the organic phase and the aqueous phase, keeping the organic phase, and putting the aqueous 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 halved step by step, four stages of continuous extraction reactions (the extraction and centrifugation reaction time of each stage is 3h respectively) are carried out, and then the organic phases are combined to obtain the 2-chloro-3-aminopyridine solution. The molar yield of 2-chloro-3-aminopyridine (calculated as 3-aminopyridine) was 91.1% and the purity was 97.4% by liquid chromatography and external standard method analysis.
The invention also includes several other embodiments (numbered examples 1 to 5) with the basic steps being the same as those of embodiment 1, and the specific parameters of each step are shown in the following table
The following examples of the preparation process, which are relatively mature at the present stage, are presented for comparison:
comparative example 1: starting with nicotinamide, the specific routes are described in the literature: CN103570609A
Preparation of 3-aminopyridine: into a 1000 ml four-necked round bottom flask equipped with a stirrer and a thermometer, 150 ml of water was added, 36.6 g (0.3 mol) of nicotinamide was added under stirring, the temperature was lowered to 0℃to 5℃after complete dissolution, 272 g (0.33 mol) of 9.05% sodium hypochlorite solution was then added dropwise during 30 to 60 minutes and within the range of 0℃to 5℃and, after the completion of the addition, the mixture was stirred for 30 minutes.
In another 1000 ml four-neck round bottom flask equipped with a stirrer, a thermometer and a condenser, 240 ml of water is added, the temperature is raised to between 90 and 100 ℃, the above reaction liquid stored at 0 to 5 ℃ is dripped in the temperature range and 30 to 45 minutes, the heat preservation reaction is continued for 2 hours after the dripping is finished, after the reaction is finished, 747 g of the reaction liquid is weighed, the 3-aminopyridine content (liquid chromatograph, external standard method) and the nicotinic acid content (peak area 0.72%) are analyzed, and the molar yield of 3-aminopyridine: 95.2%.
The reaction solution was neutralized to neutrality with 30% aqueous alkali, water was removed by distillation under negative pressure, 300 ml of methylene chloride was used to dissolve 3-aminopyridine at room temperature under stirring, the solution was filtered, the salt was washed with 200 ml of methylene chloride to obtain a methylene chloride solution containing 3-aminopyridine, the methylene chloride solution of 3-aminopyridine was extracted with 360g of industrial hydrochloric acid to obtain a hydrochloric acid solution of 3-aminopyridine, and the molar yield of 3-aminopyridine was 94.1% by analysis with a liquid chromatograph and external standard method.
Preparation of 2-chloro-3-aminopyridine: in a 1000 ml four-neck round bottom flask with a stirring thermometer, adding the 3-aminopyridine solution, dropwise adding 45.4 g (0.36 mol) of 27% hydrogen peroxide at 5-10 ℃ for 1.5-2 hours, keeping the temperature for reaction at 5-10 ℃ for 1 hour, adjusting the reaction temperature to 10-15 ℃ for 1 hour, continuing the reaction for 1 hour, starting sampling analysis, and after the reaction is finished until the peak area of the product is highest and the peak area of impurities is less than or equal to 15%, adding 10 g of sodium bisulphite until the starch potassium iodide test paper does not show blue, and 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: 3-aminopyridine starting materials, specific routes are described in literature: CN103570609A
Into a 1000 ml four-neck round bottom flask with a stirring thermometer, 360g of industrial hydrochloric acid (30.5% in content, 3 mol) and 0.3mol (28.2 g) of 3-aminopyridine are added, stirring is carried out to dissolve, 45.4 g (0.36 mol) of 27% hydrogen peroxide is dropwise added at the temperature of 10-15 ℃ for 1.5-2 hours, the reaction is carried out at the temperature of 10-15 ℃ for 3.5 hours, after the reaction is finished, 10 g of sodium bisulphite is added until the starch potassium iodide test paper does not show blue, and a liquid chromatograph is used for analysis by an external standard method, wherein the molar yield of 2-chloro-3-aminopyridine is 86.5% (calculated by 3-aminopyridine).
As can be seen from the comparison cases, the preparation method of the invention has a remarkable improvement in the molar yield of the 2-chloro-3-aminopyridine. 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 prior preparation process represented by the comparative case.
In addition to the embodiments described above, other embodiments of the invention are possible. All technical schemes formed by equivalent substitution or equivalent transformation fall within the protection scope of the invention.
Claims (8)
1. The preparation method of the 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 and uniformly mixing, and then respectively and simultaneously continuously pumping the hydrochloric acid solution containing 3-aminopyridine, an organic solvent and a chlorinating reagent solution into a primary extraction centrifuge according to a preset unit time volume ratio for extraction centrifugation; thereafter, the organic phase and the aqueous phase are separated and the organic phase is retained; turning to a second step;
taking an extraction centrifuge as a primary extraction centrifuge, and taking the primary extraction centrifuge as a lower extraction centrifuge of an upper extraction centrifuge; respectively and simultaneously continuously pumping the water phase, the hydrochloric acid solution, the organic solvent and the chloridizing reagent solution which are separated by the upper extraction centrifuge into the present extraction centrifuge according to the preset unit time volume ratio for extraction centrifugation; thereafter, the organic phase and the aqueous phase are separated and the organic phase is retained; turning to a third step;
thirdly, judging whether the next extraction centrifugation is carried out, if so, turning to the second step, and if not, turning to the fourth step;
fourth, combining the organic phases reserved by the extraction centrifuges at all levels to obtain a 2-chloro-3-aminopyridine solution;
the chloridizing reagent solution is sodium hypochlorite aqueous solution;
the organic solvent is dichloromethane, chloroform, toluene, xylene, chlorobenzene or 1, 2-dichloroethane; the organic solvents used in the first step and the second step are the same;
in the first step, taking the amount of 3-aminopyridine material as a reference value; the amount of substances of hydrogen chloride contained in the hydrochloric acid solution input into the first-stage extraction centrifuge is 0.1-3.0 times of the reference value;
in the second step, if the upper extraction centrifuge is the first extraction centrifuge, the amount of substances of hydrogen chloride contained in the hydrochloric acid solution input into the first extraction centrifuge is 0.1-0.5 times of the reference value; if the upper extraction centrifuge is not the first extraction centrifuge, the amount of the substances containing hydrogen chloride in the hydrochloric acid solution is 0.1-0.8 times of the amount of the substances containing hydrogen chloride in the hydrochloric acid solution in the upper extraction centrifuge;
in the first step, taking the amount of 3-aminopyridine material as a reference value; the amount of the substances containing the chlorinating agent added into the chlorinating agent solution in the first-stage extraction centrifuge is 0.1-0.8 times of the standard value;
in the second step, the amount of the substances containing the chlorinating agent added into the chlorinating agent solution in the current-stage extraction centrifuge is 0.1-0.8 times of the amount of the substances containing the chlorinating agent added into the chlorinating agent solution in the previous-stage extraction centrifuge;
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 3-aminopyridine;
in the second step, the weight of the organic solvent put into the primary extraction centrifuge is 0.1-0.8 times of the weight of the organic solvent put into the primary extraction centrifuge;
in the first step, after the dosages of the 3-aminopyridine, the hydrochloric acid solution, the organic solvent and the chloridizing reagent 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 chloridizing reagent solution is taken as the preset volume ratio of unit time;
in the second step, after the dosage of the hydrochloric acid solution, the organic solvent and the chlorinating agent solution is respectively determined, the volume ratio of the water phase, the hydrochloric acid solution, the organic solvent and the chlorinating agent solution separated by the upper extraction centrifuge is taken as the preset volume ratio of unit time;
in the first step and the second step, extraction and centrifugation are respectively carried out at 10-30 ℃; the extraction and centrifugation reaction time is 1-4h respectively.
2. The production method according to claim 1, wherein in the first step, the amount of the hydrogen chloride-containing substance contained in the hydrochloric acid solution fed into the first-stage extraction centrifuge is 1.1 to 1.5 times the reference value;
in the second step, if the upper extraction centrifuge is the first extraction centrifuge, the amount of substances of hydrogen chloride contained in the hydrochloric acid solution input into the first extraction centrifuge is 0.2-0.3 times of the reference value; if the upper extraction centrifuge is not the first extraction centrifuge, the amount of the substances containing hydrogen chloride in the hydrochloric acid solution fed into the first extraction centrifuge is 0.3-0.6 times of the amount of the substances containing hydrogen chloride in the hydrochloric acid solution fed into the upper extraction centrifuge.
3. The method according to claim 2, wherein in the first step, the weight percentage of hydrochloric acid in the hydrochloric acid solution is 10±4%; in the second step, the weight percentage of hydrochloric acid in the hydrochloric acid solution is 31+/-5%.
4. The method according to claim 1, wherein in the first step, the amount of the 3-aminopyridine-based material to be charged is used as a reference value; the amount of the substances containing the chlorinating agent added into the chlorinating agent solution in the first-stage extraction centrifuge is 0.3-0.6 times of the standard value;
in the second step, the amount of the substance containing the chlorinating agent added into the chlorinating agent solution in the present-stage extraction centrifuge is 0.3 to 0.6 times the amount of the substance containing the chlorinating agent added into the chlorinating agent solution in the previous-stage extraction centrifuge.
5. The method according to claim 4, wherein the chlorinating agent solutions in the first and second steps have a weight percentage of 10.+ -. 4%, respectively.
6. The method according to claim 1, wherein in the first step, the weight of the organic solvent charged in the first-stage extraction centrifuge is 2 to 3 times the charged weight of 3-aminopyridine;
in the second step, the weight of the organic solvent put into the primary extraction centrifuge is 0.3-0.6 times of the weight of the organic solvent put into the primary extraction centrifuge.
7. The method according to claim 1, wherein the number of times of execution of the second step is 1 to 9.
8. The method according to claim 7, wherein the number of times of execution of the second step is 3 to 5.
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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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| Two-Phase (Bio)Catalytic Reactions in a Table-Top CentrifugalContact Separator;Gerard N. Kraai et al.;《Angew.Chem.》;20080506;第120卷;第3969-3972页 * |
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