阅读说明：本技术 一种氯舒隆的合成方法 (Synthesis method of clorsulon ) 是由 闫玉 张葵 于 2021-08-20 设计创作，主要内容包括：本发明提供一种氯舒隆的合成方法,所述方法以间硝基苯甲醛和三氯甲烷为初始原料,依次经缩合反应、氯代反应、消去反应、还原反应、氯磺化反应、胺化反应制得氯舒隆；其中,所述还原反应在含有盐酸、铁粉和硅藻土的体系中进行。本发明方法所获得的产品质量稳定,收率高,并且工艺相对简单,可操作性强,安全系数高,具备良好的工业化前景。(The invention provides a synthesis method of clorsulon, which takes m-nitrobenzaldehyde and trichloromethane as initial raw materials and prepares the clorsulon by condensation reaction, chlorination reaction, elimination reaction, reduction reaction, chlorosulfonation reaction and amination reaction in sequence; wherein the reduction reaction is carried out in a system containing hydrochloric acid, iron powder and diatomaceous earth. The product obtained by the method has stable quality, high yield, relatively simple process, strong operability, high safety factor and good industrialization prospect.)

1. A method for synthesizing chlorsulfuron is characterized in that m-nitrobenzaldehyde and trichloromethane are used as initial raw materials, and chlorsulfuron is prepared by condensation reaction, chlorination reaction, elimination reaction, reduction reaction, chlorosulfonation reaction and amination reaction in sequence; wherein the reduction reaction is carried out in a system containing hydrochloric acid, iron powder and diatomaceous earth.

2. The method for synthesizing clorsulon according to claim 1, wherein the weight ratio of the iron powder to the diatomite is 1: (1.0-1.2);

or the particle size of the iron powder is 200-300 meshes;

or, the concentration of the hydrochloric acid is 4-8mol/L, and the molar volume ratio of the iron powder to the hydrochloric acid is 1 mol: (0.8-0.9) L.

3. A synthesis method of clorsulon according to claim 1 or 2, characterized in that the reduction reaction is carried out in the presence of methanol or ethanol;

or, the temperature of the reduction reaction is 20-25 ℃;

or the mass ratio of the iron powder to the product 3-trichloroethylnitrobenzene obtained by the elimination reaction is (0.8-0.85): 1.

4. a synthesis method of clorsulon according to any of claims 1-3, wherein the condensation reaction is carried out in the presence of a first catalyst and a first solvent, and the molar ratio of m-nitrobenzaldehyde, chloroform and the first catalyst is 1 (1.5-1.6): (1-1.12);

or, the first catalyst is selected from any one of piperidine, pyrrolidine;

or, the first solvent is selected from any one of dichloromethane, N-dimethylformamide, dimethyl sulfoxide, dichloroethane and trichloromethane;

or the temperature of the condensation reaction is-5-0 ℃.

5. The synthesis method of clorsulon according to claim 1 or 4, wherein the chlorination reaction is carried out in the presence of a chlorination reagent and an acid-binding agent, and the molar ratio of the chlorination reagent, the acid-binding agent and the product trichloromethyl-3-nitrobenzyl alcohol obtained by the condensation reaction is (0.5-0.6): (1.1-1.2): 1;

or, the chlorinating agent is selected from any one of thionyl chloride, phosphorus oxychloride and phosphorus pentachloride;

or the acid-binding agent is pyridine or triethylamine;

or, the temperature of the chlorination reaction is below 30 ℃.

6. The synthesis method of clorsulon according to claim 1 or 5, wherein the elimination reaction is performed in the presence of a second catalyst and a second solvent, and the molar ratio of the second catalyst to the product of the chlorination reaction, namely 3-tetrachloroethylnitrobenzene, is (1.05-1.1): 1;

or, the second catalyst is selected from any one of sodium hydroxide, potassium hydroxide and sodium ethoxide;

or, the second solvent is methanol or ethanol;

or, the temperature of the elimination reaction is 25-40 ℃.

7. The synthesis method of clorsulon according to claim 1 or 6, wherein the sulfonation reagent used in the chlorosulfonation reaction is chlorosulfonic acid or concentrated sulfuric acid; the chlorination reagent used is thionyl chloride;

or, the temperature of the chlorosulfonation reaction is 100-130 ℃.

8. The synthesis method of clorsulon according to claim 1 or 7, wherein the amination reagent used in the amination reaction is ammonia gas or ammonia water;

or, the temperature of the amination reaction is 20-25 ℃.

9. The method for synthesizing clorsulone according to any one of claims 1-8, wherein the method further comprises purifying the product of amination reaction, wherein the purification comprises temperature-reduction crystallization and recrystallization.

10. The method for synthesizing clorsulon according to claim 9, wherein the solvent adopted for cooling crystallization is one or more of ethyl acetate, dichloromethane, n-heptane and n-hexane; the solvent adopted by recrystallization is one or more of methanol, ethanol and water.

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a synthesis method of clorsulon.

Background

Clorsulon is named as clorsolon and clorsolon, and the molecular formula is as follows: c₈H₈Cl₃N₃O₄S₂Is a benzene sulfonamide compound, is an anti-blood worm medicine and is used for treating blood worm diseases.

The chemical structural formula of the clorsulon is as follows:

CN104557623A discloses a preparation method of 4-amino-6- (trichloroethylene) -1, 3-benzenedisulfonamide, wherein an iridium complex catalyst is adopted in the reduction reaction, and is expensive, which is not beneficial to industrial production.

CN104230767A discloses a preparation method of clorsulon, wherein hydrazine hydrate is adopted in the reduction reaction, ferric trichloride is taken as a catalyst, and activated carbon is taken as a catalyst carrier. The reaction speed is slow, the catalytic reduction effect is not ideal, the suction filtration speed is slow in the post-treatment process, and the generated carbon sludge can only be treated as hazardous waste, so that the method is not beneficial to industrial production.

The invention is especially provided in view of various defects of the existing preparation method of the clorsulon.

Disclosure of Invention

The invention aims to provide a synthesis method of clorsulon.

Specifically, the invention provides the following technical scheme:

a method for synthesizing clorsulon uses m-nitrobenzaldehyde and trichloromethane as initial raw materials, and prepares the clorsulon through condensation reaction, chlorination reaction, elimination reaction, reduction reaction, chlorosulfonation reaction and amination reaction in sequence; wherein the reduction reaction is carried out in a system containing hydrochloric acid, iron powder and diatomaceous earth.

The invention carries out a great deal of research on the synthesis method of the clorsulon, particularly on the reduction reaction, and finds that the diatomite is added into the reduction system of the iron powder/hydrochloric acid, so that the yield is ensured, the reduction rate of the 3-trichloroethylnitrobenzene is accelerated, the reaction time is shortened, the hydrogen of the reaction by-product is slowly released, the reaction safety is improved, the post-treatment process is simplified, and the method is suitable for industrial production.

The synthetic route is as follows:

in a preferred embodiment of the present invention, the weight ratio of the iron powder to the diatomaceous earth is 1: (1.0-1.2).

Further, the particle size of the iron powder is 200-300 meshes.

Further, the concentration of the hydrochloric acid is 4-8mol/L, the molar volume ratio of the iron powder to the hydrochloric acid is 1 mol: (0.8-0.9) L.

In a preferred embodiment of the present invention, the reduction reaction is carried out in the presence of methanol or ethanol.

Further, the temperature of the reduction reaction is 20-25 ℃.

Further, the mass ratio of the iron powder to the product 3-trichloroethylnitrobenzene obtained by the elimination reaction is (0.8-0.85): 1.

in a preferred embodiment of the invention, the condensation reaction is carried out in the presence of a first catalyst and a first solvent, and the molar ratio of m-nitrobenzaldehyde, chloroform and the first catalyst is 1 (1.5-1.6): (1-1.12).

Further, the first catalyst is selected from any one of piperidine, pyrrolidine.

Further, the first solvent is selected from any one of dichloromethane, N-dimethylformamide, dimethyl sulfoxide and dichloroethane.

Further, the temperature of the condensation reaction is-5-0 ℃.

In a preferred embodiment of the invention, the chlorination reaction is carried out in the presence of a chlorination reagent and an acid-binding agent, wherein the molar ratio of the chlorination reagent, the acid-binding agent and the product trichloromethyl-3-nitrobenzyl alcohol obtained by the condensation reaction is (0.5-0.6): (1.1-1.2): 1.

further, the chlorinating agent is selected from any one of thionyl chloride, phosphorus oxychloride and phosphorus pentachloride.

Further, the acid-binding agent is pyridine or triethylamine.

Further, the temperature of the chlorination reaction is 30 ℃ or lower.

In a preferred embodiment of the present invention, the elimination reaction is carried out in the presence of a second catalyst and a second solvent, and the molar ratio of the second catalyst to the product 3-tetrachloroethylnitrobenzene obtained by the chlorination reaction is (1.05-1.1): 1.

further, the second catalyst is selected from any one of sodium hydroxide, potassium hydroxide and sodium ethoxide.

Further, the second solvent is methanol or ethanol.

Further, the temperature of the elimination reaction is 25 to 40 ℃.

In a preferred embodiment of the present invention, the sulfonation reagent used in the chlorosulfonation reaction is chlorosulfonic acid or concentrated sulfuric acid; the chlorinating agent used is thionyl chloride.

Further, the temperature of the chlorosulfonation reaction is 100-130 ℃.

In a preferred embodiment of the present invention, the amination reagent used in the amination reaction is ammonia gas or aqueous ammonia.

Further, the temperature of the amination reaction is 20-25 ℃.

In a preferred embodiment of the present invention, the process further comprises purifying the product of the amination reaction, said purifying comprising temperature-reduced crystallization and recrystallization.

Further, the solvent adopted by the cooling crystallization is one or more of ethyl acetate, dichloromethane, n-heptane and n-hexane; the solvent adopted by recrystallization is one or more of methanol, ethanol and water.

The invention has the beneficial effects that:

the product obtained by the method has stable quality, high yield, relatively simple process, strong operability, high safety factor and good industrialization prospect.

Detailed Description

The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.

The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products available from regular distributors, not indicated by the manufacturer.

Example 1

The embodiment provides a synthesis method of clorsulon, which comprises the following steps:

(1) condensation reaction

1. Preparing a round-bottom glass flask, adding 30 g of p-nitrobenzaldehyde into the flask, measuring 45 ml of trichloromethane and 120 ml of DMF, adding magnetons, stirring and dissolving, starting an ice maker to set the temperature to be-5 ℃, and cooling the mixed system to be-5-0 ℃ for later use.

2. 15 ml of piperidine is measured and put into a beaker, 30 ml of methanol is added and evenly mixed, and then the mixture is transferred into a dropping funnel for standby.

3. Slowly dropwise adding the methanol solution of the piperidine obtained in 1.2 into the mixed system obtained in 1.1 under stirring, keeping the low temperature (-5 ℃) for more than 30min after the dropwise adding is finished, adding a certain amount of dilute hydrochloric acid under stirring for neutralization reaction, adding 150 ml of toluene under the condition that the pH value is monitored to be close to neutrality, continuously stirring for two hours, taking out the flask, heating to 25 ℃, and collecting a toluene layer (upper layer) by using a separating funnel. The organic phase was washed twice with water to remove methanol and salts and DMF residues.

4. Adding 20 g of activated carbon into the organic phase obtained in the step 1.3, heating to 40 ℃, stirring for more than 30min, and carrying out suction filtration. The organic phase was washed once with 5% sodium carbonate and once with purified water.

5. Concentrating the organic phase under reduced pressure to dryness, adding 30 ml of n-hexane, cooling to-2 ℃ after dissolving and cleaning, carrying out suction filtration to obtain crystals, washing the n-hexane, and drying to obtain trichloromethyl-3-nitrobenzyl alcohol, wherein the yield is 91.5%, and the HPLC (high performance liquid chromatography) is 98.9%.

(2) Chlorination reaction

1. In a 1000 ml three-neck flask, a thermometer is arranged and mechanical stirring is carried out, a separating funnel is added into the other neck, 30 g of phosphorus pentachloride and 90 ml of dichloromethane are added into the flask, and the mixture is dissolved under stirring and can be completely dissolved by heating if the mixture is not completely dissolved. And (5) standby.

2. 30 g of trichloromethane-3-nitrobenzyl alcohol is dissolved in 90 ml of dichloromethane, and the solution is completely dissolved under heating and transferred into a dropping funnel for standby.

3. Slowly dripping the solution obtained in the step 2.2 into a three-necked bottle of the step 2.1 for about 1 hour, controlling the temperature of a reaction system to be below 30 ℃ after finishing dripping, stirring for more than 3 hours, judging the completeness of the reaction by TLC, and confirming that the reaction is finished after the reaction origin disappears.

4. And adding small ice slag after the reaction is finished to terminate the reaction, stirring vigorously, stopping adding the ice slag after no hydrogen chloride gas is discharged, and continuing stirring for 1 hour. Standing, layering and collecting an organic phase, adding one half volume of dichloromethane into the water phase, extracting again, standing, layering and collecting the organic phase, and combining the two organic phases. Washing with saturated saline solution, then with purified water, then with sodium hydroxide solution (saturated), neutralizing residual hydrogen chloride in organic phase, and finally washing with purified water until pH value is near neutral. And combining organic phases, washing with water, concentrating under reduced pressure until the organic phases are dried to be golden yellow oily liquid, cooling to be colorless crystal sugar, and packaging the crystal. Drying for later use to obtain the 3-tetrachloro ethyl nitrobenzene, the yield is 98.1 percent, and the HPLC is 99.2 percent.

(3) Elimination reaction

1. 30 g of sodium hydroxide is dissolved in 100 ml of methanol at normal temperature, and the solution is led into a 1000 ml three-neck bottle after being dissolved, and mechanical stirring and a thermometer are added for standby.

2. 30 g of 3-tetrachloroethyl nitrobenzene is dissolved in 150 ml of methanol, the solution is led into a dropping funnel after being dissolved, the dropping speed is controlled to be slowly dropped, and the dropping is finished within 1 hour.

3. The temperature of the system can be slowly increased in the reaction process, the treatment can be omitted, and white solid is separated out in the reaction process. And (5) after the dropwise addition, continuously stirring for about 2 hours, adding concentrated hydrochloric acid to neutralize sodium hydroxide, and obtaining the product with the pH close to neutral. Filtering, washing and drying to obtain the product trichlorovinylnitrobenzene with the yield of 89.2 percent and the HPLC of 97.2 percent.

(4) Reduction reaction

1. 30 g of trichloroethylnitrobenzene, 27 g of reduced iron powder and 30 g of diatomaceous earth were placed in a round-bottomed flask, 150 ml (m/v) of 50% ethanol aqueous solution (v/v) of trichloroethylnitrobenzene was added, and the temperature was raised to about 50 ℃ with mechanical stirring.

2. 40 ml of 4M hydrochloric acid was added to the dropping funnel, and 40 ml of 50% aqueous ethanol was added dropwise with stirring.

3. After the dropwise addition, the temperature is raised to 95-100 ℃, reflux is carried out for 1.5-2 hours, the mixture is filtered under reduced pressure while the mixture is hot, the solid is washed with 50% ethanol water solution for three times, and the filtrate is collected. To increase the yield, the filter cake can be washed once with hot ethanol, all ethanol solutions combined and neutralized with saturated sodium carbonate solution to neutral pH.

4. The aqueous ethanol solution was extracted with 0.5BV of dichloromethane, the dichloromethane solution was washed three times with saturated brine and then dried over anhydrous sodium sulfate to give the product 3-trichlorovinylaniline, yield 89.5%, HPLC 93.5%, as a reaction intermediate for future use.

(5) Chlorosulfonation reaction

1. 130 ml of chlorosulfonic acid is dripped into the dehydrated dichloromethane solution of the 3-trichloro-vinylaniline, the temperature is controlled within 10 ℃, and the dripping time is 5 min.

2. After the dropwise addition, generation of colloidal viscous substances can be observed, the temperature is raised to 130 ℃ under stirring, and the reaction system is black caramel after stirring for two hours.

3. After TLC tracking the original point of 3-trichloro-vinyl aniline disappeared, 70 ml of thionyl chloride was added dropwise, and after the addition, the mixture was heated to reflux for 2 hours. A large amount of bubbles are generated in the reaction process.

4. And (3) precipitating a product after cooling, adding an ice solution of dichloromethane into the reaction system, performing suction filtration under stirring to obtain a solid, washing with water, and drying to obtain the 4-amino-6-trichloroethylene-1, 3-benzenedisulfonyl chloride, wherein the yield is 75.6%, and the HPLC (high performance liquid chromatography) is 91.5%.

(6) Amination reaction

1. Dissolving 30 g of 4-amino-6-trichloroethylene-1, 3-benzene disulfonyl chloride in 60 ml of dichloromethane, adding 240 ml of ammonia water under stirring, continuously stirring for more than 12 hours,

2. adjusting the pH value to about 10, precipitating a large amount of product, performing suction filtration to obtain a solid product, and performing coarse drying.

3. Dissolving the crude product with ethyl acetate, adding purified water with three times volume, stirring, collecting organic phase, extracting water phase with a certain amount of ethyl acetate, mixing organic phases, washing ethyl acetate phase with 10% saline, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to dryness.

4. Adding normal hexane for hot melting, forming the product into slurry, adding ethyl acetate and normal hexane at a ratio of 20:7 for ice bath for 2 hours, and performing suction filtration to obtain the product. Drying gave a white solid.

5. Recrystallizing with methanol and water, and vacuum drying at 60-80 deg.C to obtain final product with total yield of 54.2% and HPLC of 99.8%.

Example 2

This example provides a method for synthesizing clorsulon, which differs from example 1 only in that in the condensation reaction: a15 ml piperidine beaker is measured, 30 ml ethanol is added and mixed evenly, and then the mixture is transferred into a dropping funnel for standby. The yield of the product trichloromethyl-3-nitrobenzyl alcohol obtained by the condensation reaction is 90.1 percent, and the HPLC is 98.4 percent.

Comparative example 1

This comparative example provides a method of synthesizing clorsulon, which is different from example 1 only in the reduction reaction. The comparative example did not have diatomaceous earth added. The yield of the product 3-trichloro-vinyl aniline obtained by the reduction reaction is 81.5 percent, and the HPLC is 91.2 percent.

Comparative example 2

This comparative example provides a method of synthesizing clorsulon, which is different from example 1 only in the reduction reaction. This comparative example replaces the diatomaceous earth with an equal amount of activated carbon. In the hot reduced pressure filtration step, filtration was found to be difficult and the filtration rate was found to be slow. The yield of the product 3-trichloro-vinyl aniline obtained by the reduction reaction is 82.7 percent, and the HPLC (high performance liquid chromatography) is 91.5 percent. The yield and purity of the activated carbon replacing diatomite are lower than those of diatomite, and the product is subjected to dead adsorption by the activated carbon in preliminary analysis, so that the yield is low.

Comparative example 3

This comparative example provides a method of synthesizing clorsulon, which is different from example 1 only in the reduction reaction. The amount of diatomaceous earth added in this comparative example was 15 grams. The yield of the product 3-trichloro-vinyl aniline obtained by the reduction reaction is 83.9 percent, and the HPLC (high performance liquid chromatography) is 91.9 percent.

Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.