A method for synthesizing benzfuracarb

Abstract

The application relates to the technical field of organic synthesis, and discloses a synthesis method of benzthiazuron, which comprises the following steps: step 1, addition reaction of alpha-methyl styrene and hydrogen chloride gas, and degassing to obtain a first reaction liquid; step 2, substitution reaction of the first reaction liquid and cyanate in the presence of a zinc chloride catalyst, and filtration to obtain a second reaction liquid containing isocyanate; and step 3, construction of an inorganic salt aqueous solution system with a density of 1.05-1.10 g / ml and a pH of 9-10, dropwise addition of the second reaction liquid into the system for condensation reaction with o-chlorobenzylamine, and post-treatment and refinement to obtain a target product. The non-phosgene route of chloro-isocyanate substitution is adopted, and the use of the toxic phosgene is completely avoided; the salting-out effect and interface control generated by the specific high-density salt solution effectively inhibit the isocyanate hydrolysis side reaction, and the reaction yield and product purity are obviously improved.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for synthesizing benzalkonium chloride. Background Technology

[0002] Urea compounds are a very important type of organic chemical, widely found in various natural products and synthetic chemicals, such as pesticides, herbicides, and drug molecules.

[0003] The following are some of the currently reported methods for synthesizing urea:

[0004] (1) The target product is obtained by reacting amines with phosgene. However, phosgene is a highly toxic chemical, and the byproduct HCl can also cause serious equipment corrosion and environmental problems.

[0005] (2) The reaction of amines with triphosgene (see Chinese patent document, publication number: CN104725280A). However, phosgene is used in the synthesis of triphosgene, and triphosgene itself will slowly decompose to generate phosgene and diphosgene. At the same time, the reaction will also produce HCl byproducts.

[0006] (3) The reaction of amines with chloroformates (see Chinese patent document, publication number: CN104513180A) has poor atom economy and produces alcohols and HCl as byproducts.

[0007] (4) The amine reacts with the isocyanate (see Chinese patent document, publication number: CN113444024A). The synthesis of isocyanate requires the use of phosgene, and isocyanate itself is also toxic.

[0008] (5) The reaction of amines with carbonates (see Chinese patent document, publication number: CN105439908A) also has the problem of atom utilization, and carbonates need to be pre-synthesized.

[0009] (6) Use amines to react with azides and carbon monoxide. Azides are hazardous chemicals, but their synthesis is difficult.

[0010] (7) The reaction of amines with haloalkanes under light (see Chinese Patent Document, Publication No.: CN112920089A) produces toxic halogens. Therefore, there is still a need to develop an environmentally friendly method with high atom utilization that can synthesize urea at room temperature and pressure. Summary of the Invention

[0011] To address the shortcomings of existing technologies, this invention provides a method for synthesizing benzalkonium chloride, solving the problems of high production costs and significant pollution associated with existing synthesis technologies.

[0012] The first aspect of this invention provides a method for synthesizing benzalkonium chloride, the method comprising the following steps:

[0013] Step 1: α-Methylstyrene is subjected to an addition reaction with hydrogen chloride gas. After removing the residual gas, the first reaction solution is obtained.

[0014] Step 2: In the presence of a catalyst, the first reaction solution obtained in Step 1 is reacted with cyanate in a first solvent to undergo a substitution reaction. After the reaction is completed, the mixture is filtered to obtain a second reaction solution.

[0015] Step 3: The second reaction solution is added to a second solvent containing o-chlorobenzylamine to carry out a condensation reaction, and benzalkonium chloride is obtained after post-treatment;

[0016] The second solvent is an aqueous solution of an inorganic salt.

[0017] In one embodiment of the present invention, the addition reaction in step 1 is an electrophilic addition reaction of the double bond of α-methylstyrene under the action of hydrogen chloride, generating an intermediate mainly composed of 2-chloro-2-phenylpropane. To suppress polymerization side reactions and ensure conversion rate, the reaction temperature is controlled at 5℃ to 25℃; the molar ratio of α-methylstyrene to hydrogen chloride gas is controlled at 1:1.2 to 1.5.

[0018] In one embodiment of the present invention, the substitution reaction in step 2 is a nucleophilic substitution process catalyzed by a Lewis acid. The catalyst is zinc chloride, which utilizes its empty orbitals to coordinate with the chlorine atom of the chloroalkane intermediate, activating the C-Cl bond and promoting the substitution of the cyanate ion to generate α,α-dimethylbenzyl isocyanate in situ. The cyanate is selected from sodium cyanate or potassium cyanate; the first solvent is selected from tetrahydrofuran, acetonitrile, dichloromethane, or dichloroethane.

[0019] In one embodiment of the present invention, to ensure the completeness of the substitution reaction and inhibit the high-temperature polymerization of isocyanate, the molar ratio of cyanate to α-methylstyrene in step 2 is controlled to be 1.3:1 to 1.5:1; the temperature of the substitution reaction is controlled to be 15°C to 30°C. Specifically, a dropwise addition mode is adopted, that is, the first solvent, cyanate, and catalyst are pre-added to the reaction vessel, and the first reaction solution is added dropwise under temperature control.

[0020] In one embodiment of the invention, step 3 constructs a specific liquid-liquid heterogeneous reaction system. The second solvent is configured as an aqueous solution of an inorganic salt with a density in the range of 1.05 g / ml to 1.1 g / ml. This density range is not arbitrarily chosen, but rather designed to create a specific ionic strength and phase density difference in the aqueous phase. The high-density salt environment produces a salting-out effect, reducing the solubility of the organic isocyanate in the aqueous phase while increasing the density gradient between the two phases. This facilitates the rapid condensation reaction of isocyanate with o-chlorobenzylamine dissolved in the system at the interface or within the oil phase droplets, while simultaneously inhibiting the contact and hydrolysis reaction between isocyanate and water molecules, thereby reducing the formation of the byproduct disubstituted urea.

[0021] In one embodiment of the present invention, the inorganic salt aqueous solution is prepared from water and an inorganic salt, wherein the inorganic salt is selected from one or more of sodium chloride, potassium chloride, potassium sulfate, or sodium sulfate. Furthermore, the pH value of the inorganic salt aqueous solution is adjusted to 9-10. This weakly alkaline environment helps maintain the free state of o-chlorobenzylamine, enhances its nucleophilic attack ability, and promotes the forward condensation reaction.

[0022] In one embodiment of the present invention, the molar ratio of o-chlorobenzylamine to α-methylstyrene in step 3 is controlled to be 1.15:1 to 1.2:1; the temperature of the condensation reaction is controlled to be 20°C to 30°C.

[0023] In one embodiment of the present invention, the method further includes a step 4 of purifying the crude product. The post-treatment in step 3 includes filtration and washing to obtain crude benzalkonium chloride. The crude product is then added to a third solvent, heated to 50°C–70°C, and stirred to dissolve or disperse it. Afterwards, it is cooled to crystallize, filtered, washed, and dried. The third solvent is selected from toluene, dichloroethane, or tetrahydrofuran. This purification process utilizes the difference in solubility of the product at different temperatures to effectively remove trace amounts of inorganic salts and organic impurities that may remain during the reaction.

[0024] This invention provides a method for synthesizing bensulfuron-methyl. It has the following beneficial effects:

[0025] 1. This invention uses α-methylstyrene, hydrogen chloride, and cyanate as raw materials to synthesize benzalkonium chloride via a chloro-isocyanate substitution route, completely avoiding the use of highly toxic chemicals such as phosgene or triphosgene in existing technologies. This route uses solid cyanate as the carbonyl source, and the byproducts generated during the reaction are mainly chemically stable inorganic salts, effectively reducing the toxicity risk during production and lessening the corrosion of equipment and the burden on subsequent waste treatment.

[0026] 2. This invention introduces zinc chloride as a catalyst in the substitution reaction step, utilizing its Lewis acid properties to activate the C-Cl bond of the intermediate, enabling the nucleophilic substitution reaction of cyanate ions to proceed efficiently at room temperature. This catalytic system achieves in-situ generation and direct conversion of unstable isocyanate intermediates, eliminating the need for intermediate separation and purification, simplifying the process, avoiding decomposition losses of intermediates during separation, and improving the overall reaction yield.

[0027] 3. In the condensation step, this invention uses an inorganic salt aqueous solution with a density of 1.05 g / ml to 1.1 g / ml and a pH of 9 to 10 as the reaction medium. This salt solution system with a specific density utilizes the salting-out effect to reduce the solubility of the organic phase in water, and combined with pH control, effectively suppresses the hydrolysis side reaction of the isocyanate intermediate. This interfacial reaction control method significantly improves the selectivity of the condensation reaction, resulting in a substantial increase in the purity of the crude product, thereby obtaining a high-quality bensulfuron product. Attached Figure Description

[0028] Figure 1 This is a flowchart of the steps of the present invention;

[0029] Figure 2 The chemical reaction equation of this invention is as follows;

[0030] Figure 3 The HPLC chromatogram of the present invention Figure 1 ;

[0031] Figure 4 The HPLC chromatogram of the present invention Figure 2 . Detailed Implementation

[0032] The technical solution of the present invention will now be clearly and completely described with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0033] In the following embodiments of the present invention, unless otherwise specified, all raw materials are commercially available industrial grade or analytical grade products.

[0034] For the synthesis method of this benzalkonium chloride, please refer to the appendix. Figures 1-2 Its general synthesis process is as follows:

[0035] Step 1: Add α-methylstyrene to the reactor, start stirring, lower the temperature to the set point, and introduce hydrogen chloride gas into the reactor. After introducing the specified weight, take a sample for testing until the reaction is complete, and then degas for later use. The reaction temperature is 5–25°C, preferably 10–20°C; the molar ratio of α-methylstyrene to hydrogen chloride gas is 1:1.2–1.5, preferably 1:1.2.

[0036] Step 2: Add solvent, sodium cyanate, and zinc chloride to another reactor. Add the organic phase obtained in Step 1 dropwise to the reactor. After the addition is complete, continue the reaction at the set temperature for a set time. Take a sample for testing until the reaction is complete, filter, and obtain the organic phase. The solvent is one of dichloromethane, dichloroethane, or tetrahydrofuran, and the molar ratio of sodium cyanate to α-methylstyrene is 1.3~1.5:1, preferably 1.4:1.

[0037] Step 3: Add solvent and o-chlorobenzylamine to another reactor, and add the organic phase from Step 2 dropwise under rapid stirring. Keep warm for 1 hour, filter, and wash to obtain the target product. The solvent is a salt solution of sodium chloride, potassium chloride, potassium sulfate, or sodium sulfate with a density of 1.05~1.1 g / ml and a pH of 8~9, preferably a sodium chloride solution.

[0038] Step 4: Add solvent to another reactor, add the crude product, heat to 50-70℃, stir for 2 hours, cool, filter, wash, and dry to obtain a qualified product. The solvent is one of dichloromethane, dichloroethane, tetrahydrofuran, and toluene, preferably toluene.

[0039] The following are specific embodiments; please refer to the appendix. Figures 3-4 :

[0040] Example 1: Step 1: Add 500g of α-methylstyrene to a 1L reactor, start stirring, cool to below 10°C, and introduce hydrogen chloride gas into the reactor. When the tail gas absorbs a large amount of gas and produces bubbles, the reaction ends. Remove the dissolved HCl gas under negative pressure to obtain approximately 650g of product.

[0041] Step 2: Add 400g of tetrahydrofuran, 390g of sodium cyanate, and 28g of zinc chloride to another 1L reactor. Add the liquid from Step 1 dropwise while stirring, keeping the temperature at around 20℃. After the addition is complete, keep the temperature for 2 hours, filter, and obtain about 1000g of mother liquor.

[0042] Step 3: Add 4000g of 10% sodium chloride solution (the density of this solution was measured to be approximately 1.07g / ml) to a 5L reactor, adjust the pH to approximately 9, add 585g of o-chlorobenzylamine, control the temperature at 20~30℃, stir rapidly, add the solution from step 2 dropwise, stir for 1 hour after completion, filter, and obtain approximately 1300g of wet product. HPLC analysis showed a content of 87.9%.

[0043] Step 4: Add 4000g of toluene and the crude product from Step 3 to a 5L reactor, heat to 60-70℃, keep warm for 2 hours, filter, and dry to obtain 1100g of bensulfuron product with a yield of 87.8% and a content of 99.7% as determined by HPLC.

[0044] Example 2: Step 1: Add 500g of α-methylstyrene to a 1L reactor, start stirring, cool to below 10°C, and introduce hydrogen chloride gas into the reactor. When the tail gas absorbs a large amount of gas and produces bubbles, the reaction ends. Remove the dissolved HCl gas under negative pressure to obtain approximately 652g of product.

[0045] Step 2: Add 600g of dichloroethane, 390g of sodium cyanate, and 28g of zinc chloride to another 1L reactor. Add the liquid from Step 1 dropwise while stirring, keeping the temperature at around 20℃. After the addition is complete, keep the temperature for 2 hours, filter, and obtain approximately 1200g of mother liquor.

[0046] Step 3: Add 4000g of 10% potassium chloride solution (the density of this solution was measured to be approximately 1.06g / ml) to a 5L reactor, adjust the pH to approximately 9, add 585g of o-chlorobenzylamine, control the temperature at 20~30℃, stir rapidly, add the solution from step 2 dropwise, stir for 1 hour after completion, filter, and obtain approximately 1310g of wet product.

[0047] Step 4: Add 4500g of dichloroethane to a 5L reactor, add the crude product from Step 3, heat to 60~70℃, keep warm for 2h, filter, dry, and obtain 1095g of bensulfuron product with a content of 99.4% and a yield of 87.7%.

[0048] Example 3: Step 1: Add 500g of α-methylstyrene to a 1L reactor, start stirring, cool to below 10°C, and introduce hydrogen chloride gas into the reactor. When the tail gas absorbs a large amount of gas and produces bubbles, the reaction ends. Remove the dissolved HCl gas under negative pressure to obtain approximately 648g of product.

[0049] Step 2: Add 600g of dichloromethane, 390g of sodium cyanate, and 28g of zinc chloride to another 1L reactor. Add the liquid from Step 1 dropwise while stirring, keeping the temperature at around 20℃. After the addition is complete, keep the temperature for 2 hours, filter, and obtain approximately 1200g of mother liquor.

[0050] Step 3: Add 4000g of 10% sodium sulfate solution (the density of this solution was measured to be approximately 1.09g / ml) to a 5L reactor, adjust the pH to approximately 9, add 585g of o-chlorobenzylamine, control the temperature at 20~30℃, stir rapidly, add the solution from step 2 dropwise, stir for 1 hour after completion, filter, and obtain approximately 1320g of wet product.

[0051] Step 4: Add 4000g of tetrahydrofuran to a 5L reactor, add the crude product from step 3, heat to 50~60℃, keep warm for 2h, filter, dry, and obtain 1120g of bensulfuron product with a content of 99.2% and a yield of 89.4%.

[0052] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing bensulfuron-methyl, characterized in that, Includes the following steps: Step 1: α-Methylstyrene is subjected to an addition reaction with hydrogen chloride gas. After removing the residual gas, the first reaction solution is obtained. Step 2: In the presence of a catalyst, the first reaction solution obtained in Step 1 is reacted with cyanate in a first solvent to undergo a substitution reaction. After the reaction is completed, the mixture is filtered to obtain a second reaction solution. Step 3: Add the second reaction solution to a second solvent containing o-chlorobenzylamine to carry out a condensation reaction, and then perform post-treatment to obtain benzalkonium chloride; wherein, the second solvent is an aqueous solution of an inorganic salt. In step 3, the second solvent is an aqueous solution of an inorganic salt with a density in the range of 1.05 g / ml to 1.1 g / ml; The inorganic salt aqueous solution is prepared from water and inorganic salt, wherein the inorganic salt is selected from sodium chloride, potassium chloride, potassium sulfate or sodium sulfate; the pH value of the inorganic salt aqueous solution is 9 to 10.

2. The method for synthesizing bensulfuron-methyl according to claim 1, characterized in that: In step 1, the reaction temperature is controlled between 5°C and 25°C; the molar ratio of α-methylstyrene to hydrogen chloride gas is 1:1.2 to 1.

5.

3. The method for synthesizing bensulfuron-methyl according to claim 1, characterized in that: In step 2, the cyanate is selected from sodium cyanate or potassium cyanate; the catalyst is selected from zinc chloride; and the first solvent is selected from tetrahydrofuran, acetonitrile, dichloromethane, or dichloroethane.

4. The method for synthesizing bensulfuron-methyl according to claim 1, characterized in that: In step 2, the molar ratio of the cyanate to α-methylstyrene is 1.3 to 1.5:1; The temperature of the substitution reaction is controlled between 15°C and 30°C.

5. The method for synthesizing bensulfuron-methyl according to claim 1, characterized in that: Step 2 specifically involves adding the first solvent, cyanate, and catalyst to the reaction vessel, controlling the temperature, and then adding the first reaction solution dropwise to initiate the reaction.

6. The method for synthesizing bensulfuron-methyl according to claim 1, characterized in that: In step 3, the molar ratio of o-chlorobenzylamine to α-methylstyrene is 1.15 to 1.2:1; the temperature of the condensation reaction is controlled at 20°C to 30°C.

7. The method for synthesizing bensulfuron-methyl according to claim 1, characterized in that: The post-processing described in step 3 includes filtration and washing; It also includes step 4, refining the bensulfuron obtained in step 3; The refining process involves adding crude bensulfuron-methyl to a third solvent, heating it to 50°C–70°C and stirring to dissolve or disperse it, then cooling it to crystallize, filtering, washing, and drying.

8. The method for synthesizing bensulfuron-methyl according to claim 7, characterized in that: The third solvent is selected from toluene, dichloroethane, or tetrahydrofuran.

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