CN114057631B - Synthetic method of 3-chloro-2-hydrazinopyridine - Google Patents
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- 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
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Abstract
The invention relates to a synthesis method of 3-chloro-2-hydrazinopyridine, which takes 3-chloropyridine as a raw material, firstly carries out sulfonation reaction, and then the obtained intermediate reacts with hydrazine hydrate to obtain the 3-chloro-2-hydrazinopyridine. The method has the advantages of simple route, average product yield not lower than 80 percent and product purity more than 99.50 percent; the reaction condition is mild, the operation is safe and simple, the requirement on equipment is not high, and the method is suitable for industrial production; the raw materials and auxiliary materials are all conventional compounds, the used solvent can be recycled, the catalyst is single, the industrial three wastes are less, and the method is environment-friendly.
Description
Technical Field
The invention relates to a synthetic method of 3-chloro-2-hydrazinopyridine, belonging to the technical field of preparation of medicine and pesticide intermediates.
Background
3-chloro-2-hydrazinopyridine, product CAS:22841-92-5, formula C 5 H 6 ClN 3 It has a molecular weight of 143.57, and is in the form of white or quasi-white crystal insoluble in water. The 3-chloro-2-hydrazinopyridine is an important intermediate for synthesizing novel ryanodine receptor insecticides, namely chlorantraniliprole and cyantraniliprole, and is widely applied to the fields of medicines, pesticides, rubber, dyes and the like. With the wide use of chlorantraniliprole, particularly the rapid development of the pharmaceutical and pesticide industries in China, the demand of 3-chloro-2-hydrazinopyridine is increased remarkably, so that the synthetic process route suitable for industrial production is developed and has great social and economic benefits.
At present, few reports are available on industrial synthesis methods of 3-chloro-2-hydrazinopyridine and derivatives thereof, and only a few researches are carried out on the preparation method of 3-chloro-2-hydrazinopyridine. In the prior literature reports, two main routes are distinguished: one is to take 2,3, 6-trichloropyridine as the starting material, one is to take nicotinamide as the starting material, obtain 3-aminopyridine through Hofmann degradation reaction, then carry out halogenation reaction to obtain an intermediate, and then react with hydrazine hydrate to obtain 3-chloro-2-hydrazinopyridine.
For example, in patent CN106588758A, 2,3,6-trichloropyridine is used as a raw material, and is subjected to hydrogenation reduction to generate 2,3-dichloropyridine, and then the 2,3-dichloropyridine is reacted with hydrazine hydrate to obtain a target product; in patent application CN107778225A, 2,3,6-trichloropyridine is used as raw material to react with hydrazine hydrate, and the obtained product is hydrogenated and reduced to obtain the target product. Both the two synthesis methods require a hydrogenation reaction process, but the use of a catalyst in the hydrogenation reaction and the operation process of the hydrogenation reaction are dangerous, the industrial production has certain dangerousness, the requirement of the hydrogenation reaction on equipment is high, and particularly the requirement of the high-pressure hydrogenation reaction is high.
For another example, in patent application CN103588705A, 2-fluoro-3-chloropyridine and hydrazine hydrate are mixed, and the reaction is performed at normal temperature using ethanol as a solvent, and this method is not suitable for industrial production because the preparation of 2-fluoro-3-chloropyridine as a reaction raw material is difficult.
For another example, in the invention patent application CN111134128A, 2, 3-dichloropyridine is used as a raw material, ethanol is used as a solvent, 80% hydrazine hydrate is added, the mixture is slowly heated to reflux, the reflux reaction is performed for 25 to 30 hours, and the reaction is cooled to room temperature after the reaction is finished, however, when the reaction raw material 2, 3-dichloropyridine is prepared by the prior art, nicotinamide and sodium hypochlorite are generally adopted to obtain 3-aminopyridine through hoffmann degradation reaction, and then the 3-aminopyridine is obtained through chlorination reaction, diazotization and sandmeyer reaction.
Disclosure of Invention
The main purposes of the invention are: the problems in the prior art are overcome, and the synthesis method of the 3-chloro-2-hydrazinopyridine is provided, the raw materials are easy to obtain, the route is simplified, and the product purity and yield are high; the reaction condition is mild, the operation is safe and simple, the requirement on equipment is not high, and the method is suitable for industrial production.
The technical scheme for solving the technical problems of the invention is as follows:
a synthetic method of 3-chloro-2-hydrazinopyridine is characterized by comprising the following steps:
step one, adding 3-chloropyridine, a first solvent and a catalyst into a reactor, uniformly stirring, adding a sulfonation reagent, and heating for reaction; cooling after the reaction is finished, adding a second solvent, continuously cooling, filtering, and carrying out vacuum rectification and purification on a filter cake to obtain 3-chloro-2-pyridinesulfonic acid;
wherein the first solvent is dialkyl sulfate; the second solvent is one of diethyl ether, trichloroethylene and tetrachloropropene or any mixture thereof; the catalyst is heavy metal sulfate; the equivalent ratio of the 3-chloropyridine to the sulfonating reagent to the catalyst is 1: (1.1-5): (0.005-0.2); the weight ratio of the 3-chloropyridine to the first solvent to the second solvent is 1: (2-10): (2-10);
secondly, adding 3-chloro-2-pyridinesulfonic acid, a third solvent, an acid-binding agent and hydrazine hydrate into a reactor, uniformly stirring, and heating for reflux reaction; after the reaction is finished, cooling, filtering, and washing a filter cake to obtain 3-chloro-2-hydrazinopyridine;
wherein the third solvent is one of toluene, xylene, chlorobenzene and n-butanol; the acid-binding agent is organic alkali; the weight ratio of the third solvent to the 3-chloro-2-pyridinesulfonic acid is (2-10): 1; the weight ratio of the 3-chlorine-2-pyridine sulfonic acid to the acid-binding agent is 1: (0.1-0.2); the equivalent ratio of the 3-chloro-2-pyridine sulfonic acid to the hydrazine hydrate is 1 (2.01-10).
The method uses 3-chloropyridine as a raw material, firstly carries out sulfonation reaction, and then the obtained intermediate reacts with hydrazine hydrate to obtain 3-chloro-2-hydrazinopyridine; the average yield is not lower than 80 percent, and the product purity is more than 99.50 percent.
The technical scheme of the invention is further perfected as follows:
preferably, in the first step, the sulfonation reagent is added, then the temperature is raised to 120-220 ℃ for reaction for 6-18 hours, and the reaction is finished when the HPLC detects that the content of 3-chloropyridine is less than 2%; cooling to 20-30 deg.c, adding the second solvent, cooling to 0-5 deg.c, stirring for certain time and filtering.
More preferably, in the first step, adding a sulfonating agent, heating to 140-180 ℃ and reacting for 8-12 hours; the predetermined time is at least 2 hours.
More preferably, in the first step, the sulfonating agent is one of concentrated sulfuric acid, 20% oleum, 65% oleum or any mixture thereof; the equivalent weight of the sulfonating agent is calculated by sulfur trioxide.
More preferably, in the first step, the first solvent is one of dimethyl sulfate, diethyl sulfate or a mixture thereof; the catalyst is HgSO 4 、MnSO 4 、CuSO 4 One or any mixture thereof.
More preferably, in the first step, the temperature is raised to 60 ℃. + -. 5 ℃ first, and then the sulfonation reagent is added dropwise.
After the preferred scheme is adopted, the specific technical details of the first step can be further optimized.
Preferably, in the second step, after being uniformly stirred, the temperature is raised to 110-180 ℃ for reflux and heat preservation reaction for 10-20 hours; when HPLC detects that the content of 3-chloro-2-hydrazinopyridine is more than or equal to 96 percent, the reaction is finished; cooling to 0-10 deg.c, stirring for certain period and filtering; washing the filter cake with a proper amount of clear water; after filtration, the mother liquor is kept stand for layering, the oil phases are combined and the solvent is recovered.
More preferably, after being uniformly stirred, the mixture is heated to 140 to 150 ℃ for reflux heat preservation reaction; the predetermined time is at least 1 hour.
More preferably, the acid-binding agent is one of methanolamine, ethanolamine, N-dimethylformamide, N-dimethylacetamide and triethylamine or any mixture thereof.
More preferably, the hydrazine hydrate adopts 80 percent of hydrazine hydrate by mass.
After the preferred scheme is adopted, the specific technical details of the second step can be further optimized.
Compared with the prior art, the method takes 3-chloropyridine as the starting raw material, the route is simplified, and the product purity and yield are both high; the reaction condition is mild, the operation is safe and simple, the requirement on equipment is not high, and the method is suitable for industrial production; the raw materials and auxiliary materials are all conventional compounds, the used solvent can be recycled, the catalyst is single, the industrial three wastes are less, and the method is environment-friendly.
Drawings
FIG. 1 is a process scheme of the present invention.
FIG. 2 is a schematic representation of the preparation of 3-chloro-2-pyridinesulfonic acid, an intermediate in example 1 of the present invention 1 H NMR chart.
FIG. 3 is a photograph of 3-chloro-2-hydrazinopyridine of example 2 of the present invention 1 H NMR chart.
FIG. 4 is a liquid chromatogram of 3-chloro-2-hydrazinopyridine of example 2 of the present invention.
Detailed Description
In specific implementation, as shown in fig. 1, the method for synthesizing 3-chloro-2-hydrazinopyridine comprises the following steps:
step one, adding 3-chloropyridine, a first solvent and a catalyst into a reactor, uniformly stirring, adding a sulfonation reagent, and heating for reaction; and (3) cooling after the reaction is finished, adding a second solvent, continuously cooling, filtering, and carrying out vacuum rectification and purification on a filter cake to obtain the 3-chloro-2-pyridinesulfonic acid.
Wherein the first solvent is a dialkyl sulfate; the second solvent is one of diethyl ether, trichloroethylene and tetrachloropropene or any mixture thereof; the catalyst is heavy metal sulfate; the equivalent ratio of the 3-chloropyridine to the sulfonating reagent to the catalyst is 1: (1.1-5): (0.005-0.2); the weight ratio of the 3-chloropyridine to the first solvent to the second solvent is 1: (2-10): (2-10).
Specifically, the temperature is raised to 60 +/-5 ℃, and then the sulfonation reagent is dripped. Adding a sulfonation reagent, heating to 120-220 ℃ for reacting for 6-18 hours (preferably heating to 140-180 ℃ for reacting for 8-12 hours), and finishing the reaction when the content of 3-chloropyridine is less than 2% by HPLC (high performance liquid chromatography) detection; cooling to 20-30 deg.c, adding the second solvent, cooling to 0-5 deg.c, stirring for at least 2 hr and filtering.
In addition, the sulfonation reagent is one of concentrated sulfuric acid, 20% oleum and 65% oleum or any mixture thereof; the equivalent weight of the sulfonating agent is calculated by sulfur trioxide. The first solvent is one of dimethyl sulfate and diethyl sulfate or a mixture thereof; the catalyst is HgSO 4 、MnSO 4 、CuSO 4 One or any mixture thereof。
Secondly, adding 3-chloro-2-pyridinesulfonic acid, a third solvent, an acid-binding agent and hydrazine hydrate into a reactor, uniformly stirring, and heating for reflux reaction; and after the reaction is finished, cooling, filtering, and washing a filter cake to obtain the 3-chloro-2-hydrazinopyridine.
Wherein the third solvent is one of toluene, xylene, chlorobenzene and n-butanol; the acid-binding agent is organic alkali; the weight ratio of the third solvent to the 3-chloro-2-pyridinesulfonic acid is (2-10): 1; the weight ratio of the 3-chloro-2-pyridinesulfonic acid to the acid-binding agent is 1: (0.1-0.2); the equivalent ratio of the 3-chloro-2-pyridine sulfonic acid to the hydrazine hydrate is 1 (2.01-10).
Specifically, after being uniformly stirred, the temperature is raised to 110-180 ℃ (preferably 140-150 ℃) for reflux heat preservation reaction for 10-20 hours; when HPLC detects that the content of 3-chloro-2-hydrazinopyridine is more than or equal to 96 percent, the reaction is finished; cooling to 0-10 deg.c, stirring for at least 1 hr and filtering; washing the filter cake with a proper amount of clear water; after filtration, the mother liquor is kept stand for layering, the oil phases are combined and the solvent is recovered. The recovered solvent can be directly applied to the next batch.
In addition, the acid-binding agent is one of methanolamine, ethanolamine, N-dimethylformamide, N-dimethylacetamide and triethylamine or any mixture thereof. The hydrazine hydrate adopts 80 mass percent of hydrazine hydrate.
The present invention will be described in further detail with reference to examples. The invention is not limited to the examples given.
Example 1 Synthesis of intermediate 3-chloro-2-pyridinesulfonic acid
56.5g of 3-chloropyridine, 150g of diethyl sulfate and HgSO were placed in a 1000ml four-necked reaction flask 4 Starting stirring 1.5g, heating to 60 ℃, slowly dropwise adding 100g of 65% fuming sulfuric acid, heating to 140-150 ℃ after dropwise adding, carrying out heat preservation reaction for 12 hours, sampling and detecting, wherein the HPLC (high performance liquid chromatography) of 3-chloropyridine is 1.28%, cooling to 20-25 ℃, adding 200g of diethyl ether, continuously cooling to 0-5 ℃, stirring for 2 hours, filtering, and carrying out high vacuum rectification and purification on a filter cake to obtain 82.5g of an intermediate compound with the yield of 85.67%. Preparation of the intermediate compound 3-chloro-2-pyridinesulfonic acid 1 H NMR 300MHz DMSThe O results are shown in FIG. 2.
Example 2 Synthesis of 3-chloro-2-hydrazinopyridine
Adding 96.7g of intermediate 3-chloro-2-pyridinesulfonic acid, 300g of dimethylbenzene, 10g of ethanolamine and 125g of 80% hydrazine hydrate into a 1000ml four-mouth reaction bottle, starting stirring, heating to 140-150 ℃, preserving heat for 20 hours, performing sampling detection, wherein the HPLC (high performance liquid chromatography) of 3-chloro-2-hydrazinopyridine is 97.30%, then cooling to 0-10 ℃, stirring for 1 hour, starting suction filtration, washing a filter cake with 200g of water, obtaining a wet 3-chloro-2-hydrazinopyridine product, drying by an infrared lamp, weighing and detecting to obtain 68.9g of a finished product, wherein the yield is 96.09%. Preparation of the finished 3-chloro-2-hydrazinopyridine 1 H NMR 300MHz DMSO results are shown in FIG. 3; the purity of HPLC detection is 99.68%, the liquid chromatogram is shown in figure 4 and table 1, and the total yield of the two-step reaction is: 82.32 percent.
TABLE 1
| Peak number | Retention time | Area of | Height | Concentration of |
| 1 | 2.231 | 2015 | 87 | 0.031 |
| 2 | 3.821 | 6405577 | 910727 | 99.681 |
| 3 | 4.687 | 1520 | 260 | 0.024 |
| 4 | 5.233 | 2656 | 251 | 0.041 |
| 5 | 6.998 | 14319 | 1469 | 0.223 |
| Total of | —— | 6426088 | 912794 | —— |
Example 3 Synthesis of intermediate 3-chloro-2-pyridinesulfonic acid
56.5g of 3-chloropyridine, 200g of diethyl sulfate and HgSO are added into a 1000ml four-mouth reaction bottle 4 Starting stirring for 2g, heating to 60 ℃, slowly dropwise adding 200g of 65% fuming sulfuric acid, heating to 155-160 ℃ after dropwise adding, carrying out heat preservation reaction for 10 hours, sampling and detecting, wherein the HPLC content of 3-chloropyridine is 1.31%, cooling to 20-25 ℃, adding 200g of diethyl ether, continuously cooling to 0-5 ℃, stirring for 2 hours, filtering, and carrying out high vacuum rectification and purification on a filter cake to obtain an intermediate82.7g of compound, yield 85.87%.
Example 4 Synthesis of intermediate 3-chloro-2-pyridinesulfonic acid
56.5g of 3-chloropyridine, 200g of dimethyl sulfate and HgSO are added into a 1000ml four-mouth reaction bottle 4 1g、CuSO 4 Starting stirring 0.5g, heating to 60 ℃, slowly dropwise adding 150g of 65% fuming sulfuric acid, heating to 160-170 ℃ after dropwise adding, carrying out heat preservation reaction for 8 hours, sampling and detecting, wherein the HPLC content of the 3-chloropyridine is 1.62%, cooling to 20-25 ℃, adding 200g of diethyl ether, continuously cooling to 0-5 ℃, stirring for 2 hours, filtering, and carrying out high vacuum rectification and purification on a filter cake to obtain 81.3g of an intermediate compound with the yield of 84.42%.
Example 5 Synthesis of intermediate 3-chloro-2-pyridinesulfonic acid
56.5g of 3-chloropyridine, 50g of dimethyl sulfate and 100g of diethyl sulfate were put into a 1000ml four-necked reaction flask 4 0.75g、CuSO 4 0.5g, starting stirring, heating to 60 ℃, slowly dripping 150g of 65% fuming sulfuric acid, heating to 145-150 ℃ after dripping, keeping the temperature for reaction for 10 hours, sampling and detecting, wherein the HPLC (high performance liquid chromatography) of the 3-chloropyridine is 1.79%, cooling to 20-25 ℃, adding 300g of diethyl ether, continuously cooling to 0-5 ℃, stirring for 2 hours, filtering, and carrying out high vacuum rectification and purification on a filter cake to obtain 80.6g of an intermediate compound with the yield of 83.7%.
Example 6 Synthesis of 3-chloro-2-hydrazinopyridine
Adding 96.7g of 3-chloro-2-pyridinesulfonic acid, 300g of dimethylbenzene, 15g of ethanolamine and 190g of 80% hydrazine hydrate into a 1000ml four-mouth reaction bottle, starting stirring, heating to 150 ℃, keeping the temperature for 15 hours, sampling and detecting, wherein the HPLC content of the 3-chloro-2-hydrazinopyridine is 97.74%, then cooling to 0-10 ℃, stirring for 1 hour, starting suction filtration, washing a filter cake with 200g of water, obtaining a wet product of the 3-chloro-2-hydrazinopyridine, drying by an infrared lamp, weighing and detecting, thus obtaining 69.5g of a finished product, the purity of the HPLC detection is 99.58%, and the yield is 96.93%.
Example 7 Synthesis of 3-chloro-2-hydrazinopyridine
Adding 96.7g of 3-chloro-2-pyridinesulfonic acid, 300g of n-butyl alcohol, 10g of N, N-dimethylformamide and 100g of 80% hydrazine hydrate into a 1000ml four-mouth reaction bottle, starting stirring, heating to 145-150 ℃, preserving heat for 20 hours, sampling and detecting, wherein the HPLC (high performance liquid chromatography) content of the 3-chloro-2-hydrazinopyridine is 96.52%, then cooling to 0-10 ℃, stirring for 1 hour, starting suction filtration, washing a filter cake with 400g of water to obtain a wet 3-chloro-2-hydrazinopyridine product, drying by an infrared lamp, weighing and detecting to obtain 68.7g of a finished product, wherein the HPLC detection purity is 99.62%, and the yield is 95.81%.
In addition to the above embodiments, the present invention may have other embodiments. All technical solutions formed by adopting equivalent substitutions or equivalent transformations fall within the protection scope of the present invention.
Claims (10)
1. A synthetic method of 3-chloro-2-hydrazinopyridine is characterized by comprising the following steps:
step one, adding 3-chloropyridine, a first solvent and a catalyst into a reactor, uniformly stirring, adding a sulfonation reagent, and heating for reaction; cooling after the reaction is finished, adding a second solvent, continuously cooling, filtering, and carrying out vacuum rectification and purification on a filter cake to obtain 3-chloro-2-pyridinesulfonic acid;
wherein the first solvent is dialkyl sulfate; the second solvent is one of diethyl ether, trichloroethylene and tetrachloropropene or any mixture thereof; the catalyst is heavy metal sulfate; the equivalent ratio of the 3-chloropyridine to the sulfonating reagent to the catalyst is 1: (1.1-5): (0.005-0.2); the weight ratio of the 3-chloropyridine to the first solvent to the second solvent is 1: (2-10): (2-10);
secondly, adding 3-chloro-2-pyridinesulfonic acid, a third solvent, an acid-binding agent and hydrazine hydrate into a reactor, uniformly stirring, and heating for reflux reaction; cooling after the reaction is finished, filtering, and washing a filter cake to obtain 3-chloro-2-hydrazinopyridine;
wherein the third solvent is one of toluene, xylene, chlorobenzene and n-butanol; the acid-binding agent is organic alkali; the weight ratio of the third solvent to the 3-chloro-2-pyridinesulfonic acid is (2-10): 1; the weight ratio of the 3-chloro-2-pyridinesulfonic acid to the acid-binding agent is 1: (0.1-0.2); the equivalent ratio of the 3-chloro-2-pyridine sulfonic acid to the hydrazine hydrate is 1 (2.01-10).
2. The method for synthesizing 3-chloro-2-hydrazinopyridine according to claim 1, wherein in the first step, a sulfonating reagent is added, then the temperature is raised to 120-220 ℃ for reaction for 6-18 hours, and the reaction is finished when HPLC detects that the content of 3-chloropyridine is less than 2%; cooling to 20-30 ℃, adding the second solvent, continuously cooling to 0-5 ℃, continuously stirring for a preset time, and filtering.
3. The method for synthesizing 3-chloro-2-hydrazinopyridine according to claim 2, wherein in the first step, a sulfonating reagent is added, and then the temperature is raised to 140-180 ℃ for reaction for 8-12 hours; the predetermined time is at least 2 hours.
4. The method for synthesizing 3-chloro-2-hydrazinopyridine according to claim 2, wherein in the first step, the sulfonating agent is one of concentrated sulfuric acid, 20% fuming sulfuric acid, 65% fuming sulfuric acid or any mixture thereof; the equivalent weight of the sulfonating agent is calculated by sulfur trioxide.
5. The method for synthesizing 3-chloro-2-hydrazinopyridine according to claim 2, wherein in the first step, the first solvent is one of dimethyl sulfate, diethyl sulfate or a mixture thereof; the catalyst is HgSO 4 、MnSO 4 、CuSO 4 One or any mixture thereof.
6. The method for synthesizing 3-chloro-2-hydrazinopyridine of claim 2, wherein in the first step, the temperature is raised to 60 ± 5 ℃, and then the sulfonation reagent is added dropwise.
7. The method for synthesizing 3-chloro-2-hydrazinopyridine according to claim 1, wherein in the second step, the temperature is raised to 110 ℃ to 180 ℃ after being uniformly stirred, and the reflux insulation reaction is carried out for 10 to 20 hours; when HPLC detects that the content of 3-chloro-2-hydrazinopyridine is more than or equal to 96 percent, the reaction is finished; cooling to 0-10 deg.c, stirring for certain period and filtering; washing the filter cake with a proper amount of clear water; after filtration, the mother liquor is kept stand for layering, the oil phases are combined and the solvent is recovered.
8. The synthesis method of 3-chloro-2-hydrazinopyridine according to claim 7, wherein the temperature is raised to 140-150 ℃ after the stirring, the reflux and the heat preservation reaction are carried out; the predetermined time is at least 1 hour.
9. The method for synthesizing 3-chloro-2-hydrazinopyridine according to claim 7, wherein the acid-binding agent is one of methanolamine, ethanolamine, N-dimethylformamide, N-dimethylacetamide and triethylamine or any mixture thereof.
10. The method for synthesizing 3-chloro-2-hydrazinopyridine according to claim 7, wherein the hydrazine hydrate is 80% by weight.
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| CN112194618A (en) * | 2020-12-03 | 2021-01-08 | 苏州开元民生科技股份有限公司 | Preparation method of 2, 3-dichloropyridine |
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| JP2003064083A (en) * | 2001-08-23 | 2003-03-05 | Fuji Photo Film Co Ltd | 2,3,3-TRIMETHYL-3H-PYRROLO[2,3-b]PYRIDINE-5-SULFONIC ACID AND DERIVATIVE THEREOF |
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| US6169086B1 (en) * | 1997-01-27 | 2001-01-02 | Daiichi Pharmaceutical Co., Ltd. | Pyrazole derivatives |
| CN107778225A (en) * | 2016-08-26 | 2018-03-09 | 上海雅本化学有限公司 | A kind of preparation method of the chloropyridine of 2 diazanyl 3 |
| CN106588758A (en) * | 2016-11-08 | 2017-04-26 | 江苏富比亚化学品有限公司 | Synthetic process for 2-hydrazinylpyridine derivative |
| CN112194618A (en) * | 2020-12-03 | 2021-01-08 | 苏州开元民生科技股份有限公司 | Preparation method of 2, 3-dichloropyridine |
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