KR101067418B1 - One-pot process for producing o-sulfobenzimide - Google Patents

Abstract

The present invention is a method for producing o-chlorobenzimide of the following structural formula,

(1) reacting o-chlorobenzoic acid with a sulfonating agent in the presence of a copper catalyst to convert a chlorine atom of o-chlorobenzoic acid into a sulfonate to convert to a sulfonic acid group, (2) o-sulfobenzoic acid obtained in the first step Reacting with alcohol in the presence of an acid catalyst to alkylester the carboxyl group of o-sulfobenzoic acid, and (3) the o-sulfobenzoic acid alkylester obtained in the second step is reacted with a chlorinating agent in an inert organic solvent. replacing the hydroxyl group contained in the sulfone group of the o-sulfobenzoic acid alkyl ester with a chlorine atom, and (4) the o-sulfochloride benzoic acid alkyl ester obtained in the third step is reacted with ammonia to be contained in the sulfochloride group of the reactant. Substituting a chlorine atom with an amino group and simultaneously cyclizing to prepare o-sulfobenzimid, wherein all of steps (1) to (4) are intermediate Without separating a solid form a single reactor (one-port), to a method that will be carried out at. This will enable mass production of high purity and high yield of o-sulfobenzimid, which is still useful as a pesticide intermediate.

o-chlorobenzimid, o-chlorobenzoic acid, o-sulfobenzoic acid alkyl ester, o-sulfochloride benzoic acid alkyl ester, single reactor, one-port reactor, pesticide intermediate

Description

One-pot process for producing o-sulfobenzimide}

Although the present invention has been rapidly used in soft drinks after being approved in the United States as artificial sweeteners or food additives since 1957, the FDA restricts the use of artificial sweeteners in 1977 as the results of animal experiments revealed that excessive intake causes bladder cancer. It relates to a one-pot manufacturing method of o-sulfobenzimide (1.2-benzoisothiazol-3-one-1.1-dioxide; also known as saccharin) that has been announced.

In more detail, a four-step process using o-chlorobenzoic acid as a raw material is performed without filtering, drying and separating and purifying intermediates in one reactor, without generating toluene sulfonamide compounds suspected of harmful substances. It is related with the one-pot manufacturing method of o-sulfobenzimide of purity.

Although such o-sulfobenzimide is limited to being used as a substitute sugar for diabetics in the medical field or as a sugar substitute sweetener in the field of food additives, it is still used as an agrochemical intermediate and thus has a high purity and high yield. There is a need for a new one-port method for the synthesis of new continuous reactions.

As a method for preparing o-sulfobenzimide represented by the following chemical formula (1)

(1) firstly, a first step of chlorosulfonating toluene,

(2) a second step of separating and purifying o-toluene sulfochloride and p-toluene sulfochloride produced in the first step,

(3) a third step of reacting the o-toluene sulfochloride separated in the second step with ammonia,

(4) A method consisting of a fourth step of oxidizing o-toluene sulfonimide produced in the third step in the presence of concentrated sulfuric acid and dichromate was known for a long time (see J. Am. Chem. Soc., 1, page 426, 1879; British Patent No. 174,913 and British Patent No. 682,800.

(Scheme 1)

The biggest drawback in this conventional method is that neither o-toluene sulfonimide and by-product p-toluene sulfonimide produced in the third step are suspected as carcinogenic substances. Therefore, as long as this conventional method is used, separate purification operations must be performed to directly deal with these substances suspected of being hazardous substances, and their compounds are incorporated into o-sulfobenzimid in the final product and adversely affect the human body. There is a concern that such a conventional method was not a hygienic safe manufacturing method.

In addition, an o-sulfobenzimid ammonium salt was prepared by reacting the o-sulfochloride benzoic acid methyl ester produced through the first step of reacting phthalic anhydride with ammonia and further 6 steps to ammonia, followed by acid treatment. Also known is a method for preparing o-sulfobenzimide consisting of an eighth step (Chemical Engineering, Vol. 61, No. 7, page 128, 1954).

Since the conventional method using phthalic anhydride as a raw material has to go through a considerable complicated step of eight steps, the operation is extremely complicated, and the desired o-sulfobenzimide cannot be produced in high yield, which is the largest in terms of economic efficiency. Had a flaw.

In consideration of these problems, Korean Patent Publication No. 79-00766 (published date: June 30, 1979) uses o-chlorobenzoic acid as a raw material as follows.

(1) the first step of replacing the chlorine atom of o-chlorobenzoic acid with sulfonic acid,

(2) a second step of alkylating the carboxyl group of o-sulfobenzoic acid produced in the first step,

(3) a third step of replacing the hydroxyl group contained in the sulfone group of the o-sulfobenzoic acid alkyl ester produced in the second step with a chlorine atom,

(4) preparing o-sulfobenzimide comprising the fourth step of cyclizing the chlorine atom contained in the sulfochloride group of the o-sulfochloride benzoic acid alkyl ester produced in the third step and cyclizing the amino group It is proposed how to.

However, the Korean Patent Publication discloses that the reaction process is short in four steps, and can be easily operated without separating and purifying the intermediate. However, in the detailed description or the examples, the one-port method is not mentioned at all. Not.

In more detail, in the prior art, the first step of the reaction is to terminate the reaction in an autoclave (reactor 1), which is an internal pressure vessel, and then cooled to filter the reaction solution, and the filtrate is transferred to another vessel (reactor 2) for acid treatment. The reaction mixture was extracted with ether in a separating rod and separated into layers to transfer the reactor (reactor 3), and distilled under reduced pressure to remove water to obtain a solid.

In the second step, the solid obtained above was added to methanol in a four-necked flask (reactor 4), followed by esterification, and excess methanol was distilled and concentrated under reduced pressure to obtain a white solid. In another reactor (reactor 5), an organic solvent such as dichlorobenzene, which is heavier than water, is mixed with the solid obtained above, chlorinated with thionyl chloride, the excess chlorinating agent is removed, and the reaction is washed four times with water. It is said.

In the final fourth step, the chlorinated reaction product obtained in step 3 is placed in another reactor (reactor 7), and the reaction is terminated by adding ammonia water, followed by layer separation to obtain an aqueous layer, and acid treatment by adding hydrochloric acid to the aqueous solution obtained. It is described that the precipitated product is filtered, washed with water and then dried to obtain the final product.

As described in the prior art, when washing with water in the third step, the organic solvent is heavy, the specific gravity of the water layer becomes the upper layer has a problem to move the reactor (reactor 6) several times in the fourth wash, and also As a result of obtaining a product through a complicated process using two reactors, it is quite troublesome in terms of economic and industrial aspects, and has various problems in that the price competitiveness of the product is low.

Furthermore, this patent publication only mentions that 'phosgene' can be used as the chlorinating agent, and the examples are also used as specific chlorinating agents limited to thionyl chloride (SOCl 2) and phosphorus pentachloride (PCl 5). However, the phosphorus contaminants used in this conventional process are expensive, and the product obtained in this step is dark in color, must remove by-products, and the process is complicated, resulting in a significant drop in yield.

The method of using phosphorus pentachloride or a mixture of phosphorus pentachloride and phosphorus oxychloride as the chlorinating agent of the conventional method is not only expensive, but also phosphorus oxychloride or methane phosphorus (by Due to the aging process, it is impossible to purify the chloro sulfonyl benzoyl chloride obtained by distillation. Furthermore, by-product phosphorus oxychloride or metain is a major problem for pollution prevention.

Therefore, there is a lot of problems in the one-pot process for producing high purity and high yield of o-sulfobenzimide from methylbenzoate-o-sulfonate by this conventional method.

On the other hand, U.S. Patent No. 4,076,721 (published on Feb. 28, 1978) proposes the following method using phosgene in place of an expensive phosphorus chlorinating agent, phosphorus oxychloride.

(1) the following methylbenzoate-o-sulfonate is reacted with phosgene in the presence of dimethylformamide (DMF),

(2) The reaction product obtained above is reacted with ammonia to prepare o-sulfobenzimide.

In addition, the intermediate methylbenzoate-o-sulfonate is prepared by the following procedure,

(3) reacting o-chlorobenzene with sodium sulfite under a catalyst of copper sulfate,

(4) after adjusting the obtained reaction mixture to pH 2-4 with concentrated hydrochloric acid,

(5) It is mentioned that it can be prepared separately by precipitating a metal salt of o-sulfobenzoic acid by adding calcium chloride or the like to the obtained acidic solution.

However, even in this US patent publication, it can be operated simply, but it is described and there is no mention of the one-port method. In particular, in this conventional method, the intermediate, methylbenzoate-o-sulfonate, is first prepared and purified, and then reacted with phosgene to obtain o- in high yield without complex separation or purification of methyl-o-chlorosulfonylbenzoate. It only mentions that sulfobenzimides can be prepared.

In other words, there is no mention of a method for producing high yield and high purity o-sulfobenzimide in a one-port manner using o-chlorobenzoic acid as a starting material.

The present invention uses thionyl chloride (phosphene, phosphorus pentachloride can also be used) as a chlorinating agent, but can be carried out in one-pot mode or in a continuous reaction mode in a single reaction solvent, so that even after obtaining the reaction intermediates In order to obtain the form, it is intended to provide a new synthesis method without the complicated process of filtration, dry separation and purification.

This new synthesis method

(1) reacting o-chlorobenzoic acid with a sulfonating agent in the presence of a copper catalyst to replace the chlorine atom of o-chlorobenzoic acid with a sulfonate and converting to a sulfonic acid group,

(2) reacting the o-sulfobenzoic acid obtained in the first step with an alcohol in the presence of an acid catalyst to alkylesterize the carboxyl group of o-sulfobenzoic acid,

(3) reacting the o-sulfobenzoic acid alkyl ester obtained in the second step with a chlorinating agent (thionyl chloride) in an inert organic solvent to replace the hydroxyl group contained in the sulfone group of the o-sulfobenzoic acid alkyl ester with a chlorine atom,

(5) The o-sulfochloride benzoic acid alkyl ester obtained in the third step is reacted with ammonia to replace the chlorine atom in the sulfochloride group of the reactant with an amino group and to cyclize the same to prepare o-sulfobenzimide. It can be achieved by a one-pot synthesis method of o-sulfobenzimide comprising the step of.

(Scheme 2)

In this formula,

M is hydrogen, sodium, or potassium,

R is methanol, ethanol or an alkyl group.

Thus, when the o-sulfobenzimide is manufactured by the one-pot method of the present invention, the active ingredient is prevented from being partially converted and can be produced at a high yield by preventing the extraction from the purification process, thereby enabling mass production through cost reduction. will be.

The present inventors have conducted various studies on the synthesis method of o-sulfobenzimide, and as a result, a continuous reaction process using o-chlorobenzoic acid as a raw material to safely and efficiently produce the desired o-sulfobenzimide with high purity After finding out how to complete the present invention.

Specific one-pot synthesis method of the present invention is composed of four steps by the reaction scheme (2), wherein all of the steps (1) to (4) are carried out in a single reactor without separating the intermediate into a solid form It is characterized by. First, specific reactants used in the present invention are shown in the following Reaction Scheme 3, and the present invention will be described in detail with reference to the following.

(Scheme 3)

In the first step of the present invention, under the catalyst of copper, benzoic acid and sulfite or hydrogen sulfite are reacted in an aqueous solution of metal hydroxide, followed by acidification by adding an inorganic acid to the reaction solution.

As the copper catalyst used at this time, metal copper such as powdered copper, copper sulfate, copper acetate, copper hydroxide, preferably copper sulfate and copper acetate are suitable.

As the sulfite used as the sulfonating agent in the present invention, calcium sulfite, sodium sulfite, calcium sulfite and the like are suitable, and as hydrogen sulfite, calcium hydrogen sulfite, sodium hydrogen sulfite, calcium hydrogen sulfite and the like are suitable. The amount of these sulfonating agents is from 1.0 to 1.1 molar equivalents (based on o-chlorobenzoic acid).

The reaction of the first step of the present invention is carried out at a temperature range of 140 to 190 ° C, preferably 150 to 175 ° C, and the reaction is carried out in a total pressure vessel. Here, hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, etc. are preferable as the inorganic acid used for pH adjustment of the reaction solution. pH adjustment is carried out at a temperature range of 20 to 30 ℃, preferably 25 ℃, usually acid treatment in the same reaction vessel, the water in the reactor is distilled off under reduced pressure or atmospheric pressure, toluene, monochlorobenzene, dichlorobenzene, An inert organic solvent such as xylene is added to distill off the remaining water as much as possible, and it is preferable that o-sulfobenzoic acid, an inorganic substance and an organic solvent are contained in the same reactor.

The reaction in the second step of the present invention, in the presence of an acid catalyst, is heated to reflux by adding alcohols to the reaction product produced in the first step. The acid catalysts used at this time are inorganic acids such as hydrogen chloride, sulfuric acid, acetic acid and phosphoric acid, and organic technical acids such as paratoluenesulfonic acid. The amount of the acid catalyst used is 0.01 to 0.15 molar equivalents (based on sulfonates of o-chlorobenzoic acid).

As alcohols, primary alcohols such as methyl alcohol, n-propyl alcohol, n-butyl alcohol, n-alcohol and secondary alcohols such as isopropyl alcohol, 2-butyl alcohol and cyclohexyl alcohol are suitable. Although these alcohols are required by theoretical amount with respect to benzoic acid, it is normally used in excess, and it is common to collect and use excess alcohol.

The reaction of the second step is carried out by heating and stirring under normal pressure or under pressure, and the reaction temperature is preferably performed at the reflux temperature of the alcohol used. By this reaction, the carboxyl group of o-sulfobenzoic acid produced in the second step is esterified to become o-sulfobenzoic acid alkyl ester. After completion of the reaction, excess alcohol and a small amount of byproduct water are removed under reduced pressure to proceed to the next reaction in the same reactor.

The reaction in the third step of the present invention is to react the concentrate obtained by removing the excess alcohol under reduced pressure in the second step with thionyl chloride or phosgene as a chlorinating agent in an inert organic solvent.

As the inert organic solvent used at this time, halogen-substituted aliphatic hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane and dichloropropane and aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and dichlorobenzene are suitable.

In the third step of the present invention, it is carried out in the presence of a catalyst of dimethylformamide (DMF), dimethylformamide used in the present invention, 0.01 to 0.3 moles, preferably 1 mole of the o-sulfobenzoic acid alkyl ester It is enough to use 0.03-0.1 mol below. Even if excessive use of dimethylformamide in this process does not interfere with the reaction, but it is not economically desirable. Thionyl chloride or phosgene is used in a theoretical amount, preferably 5 to 20% excess of the theoretical amount.

At this time, the chlorinating agent may be introduced directly into the reaction system, or may be used after being dissolved in an inert solvent such as carbon tetrachloride or toluene. Inert organic solvents used in the reaction include aliphatic hydrocarbons such as cyclohexane and n-hexane, halogenated hydrocarbons such as chloroform, carbon tetrachloride, trichloroethylene and tetrachloroethylene, benzene, toluene, xylene, chlorobenzene and the like. Aromatic hydrocarbons, ethers such as diethyl ether, dibutyl ether, dioxane, ketones such as acetone, methyl ethyl ketone, and methyl isoprophyl ketone, nitriles such as acetonitrile and propionitrile, ethyl acetate, Ester of butyl acetate is mentioned.

The reaction temperature and reaction time are not constant due to the introduction rate of the chlorinating agent, etc., but the reaction temperature is selected in the range of 20 ° C to 150 ° C, and usually in the range of 40 ° C to 100 ° C. After the chlorination reaction is completed, the excess chlorination agent is removed by the nitrogen stream or by distillation and the next reaction proceeds in the same reactor.

In the reaction of the fourth step of the present invention, ammonia water is added to the reaction solution obtained in the third step, stirred and sufficiently reacted, and then the stirring is stopped to separate the layers and the organic solvent and the aqueous layer are separated. The same inorganic acid as in the first step was added to the obtained aqueous layer to adjust the pH to 1.0 to 1.5 to acidify.

At this time, it is preferable to use 5 to 30% aqueous ammonia solution including 3.5 molar equivalents of ammonia with respect to 1 mole of o-chlorobenzoic acid used. The reaction temperature is in the range of 5 to 25 ° C, preferably 20 ° C. If necessary, the reaction is preferably performed while cooling.

Here, after the reaction with ammonia, the o-sulfochloride benzoic acid alkyl ester produced in the fourth step becomes a sulfobenzimid ammonium salt and is separated into an aqueous solution, and the aqueous solution is adjusted to pH = 1.0 to 1.5 with a predetermined inorganic acid. The desired o-sulfobenzimide is precipitated into crystals.

(Example 1)

 (1) 45 g (0.287 mol) o-chlorobenzoic acid, 11.45 g (0.287 mol) NaOH, 0.15 g (0.001 mol) CuSO4, 39.3 g (0.312 mol) Na2SO3 and 150 ml H2O sequentially After the injection, check whether the pressure vessel is sealed and then react for 24 hours at a temperature of 175 ° C. and a pressure of 6-7 kg / cm 3.

After completion of the reaction, 40.3 g (0.387 mol) of 35% concentrated HCl was added to the reaction and allowed to stand for 1 hour adjusted to pH = 1.2. The reaction mixture is distilled at atmospheric pressure or reduced pressure to remove H 2 O. As H2O is distilled off, solids are generated in the reactor, so that stirring is not easy. At the time point of removing about 100 ml of H2O, 200 ml of MCB (monochlorobenzene) is added to completely remove the remaining amount of H2O.

(2) Thereafter, the MCB removed with H2O at azeotropic phase was separated and re-injected into the reactor, followed by the addition of 2.84 g (0.029 mol) of H2SO4 and 85 ml (3.36 mol) of MeOH, and the mixture was refluxed at about 67 ° C. React for 18 hours. After completion of the reaction, the mixture was cooled to room temperature, and stirred for 0.5 hour by adding 3 g (0.029 mol) of Na 2 CO 3, and then excess MeOH and a small amount of H 2 O were distilled off.

(3) After that, 1 g (0.017 mol) of DMF (dimethylformamide) was added, 42.8 g (0.36 mol) of SOCl 2 was slowly added thereto, and the mixture was heated and stirred at 78 ° C. for 15 hours. After the reaction is completed, excess SOCl 2 and by-product gas are distilled off and depressurized. The reactor is cooled and a mixed solution of 68 g of 25% NH 4 OH and 100 g of H 2 O is slowly added to the reactor. After the addition was completed, the reaction was terminated after stirring for 6 hours at room temperature.

(4) After completion of the reaction, the MCB layer and the H2O layer were separated by layers to remove the MCB layer. Then, 100 ml of MCB was added thereto, followed by layer separation to remove the organic layer. After cooling, 44.8 g (0.43 mol) of 35% HCl was added to the H 2 O layer to adjust pH = 1.5, followed by stirring at 5 ° C. for 1 hour. After stirring, the resulting solid is filtered to give a white solid (o-sulfobenzimide; saccharin). The filtered solid was dried to give 49.0 g of o-sulfobenzimide (yield 93% based on starting material o-chlorobenzoic acid; purity 99.6 area% by HPLC).

(Example 2)

(1) 23 g (0.147 mol) o-chlorobenzoic acid, 5.8 g (0.147 mol) NaOH, 0.08 g (0.0005 mol) CuSO4, 20.4 g (0.162 mol) Na2SO3 and 100 ml H2O After the addition, check whether the pressure vessel is sealed and then react for 24 hours at a temperature of 175 ° C. and a pressure of 6-7 kg / cm 3.

After completion of the reaction, 40.3 g (0.387 mol) of 35% concentrated HCl was added to the reaction and left to stand for 1 hour at which pH = 1.5 was adjusted. The reaction mixture is distilled at atmospheric pressure or reduced pressure to remove H 2 O. As H 2 O is distilled off, solids are generated in the reactor, so that stirring is not easy. At the time point of removing about 100 ml of H 2 O, 100 ml of toluene is added to completely remove the remaining amount of H 2 O.

 (2) Then, the toluene removed with H2O at azeotropic phase was separated and re-injected into the reactor, and then 1.47 g (0.015 mol) of H2SO4 and 35 ml (0.863 mol) of MeOH were added, followed by reflux (about 67 ° C). The reaction is carried out under conditions for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and stirred for 0.5 hour by adding 1.59 g (0.015 mol) of Na 2 CO 3, and then excess MeOH and a small amount of H 2 O were distilled off.

(3) After that, 0.5 g (0.0068 mol) of DMF was added, and 22.7 g (0.19 mol) of SOCl 2 was slowly added thereto, followed by heating at 78 ° C. for 20 hours. After the reaction is completed, excess SOCl 2 and by-product gas are distilled off and depressurized. Cool the reactor and slowly add 34.7 g (0.51 mol) of 25% NH4OH and 70 g of H2O to the reactor. After the addition was completed, the reaction was terminated after stirring at room temperature for 15 hours.

(4) After the completion, the toluene layer and the H 2 O layer were separated by layers to remove the toluene layer, and 100 ml of toluene was added again, followed by re-separation to remove the organic layer. Thereafter, while cooling, 21.9 g (0.21 mol) of 35% HCl was added to the H 2 O layer to adjust pH = 1.5, followed by stirring at 5˜10 ° C. for 1 hour. After stirring, it was filtered and washed with water to obtain a white solid (saccharin). The filtered solid was dried to give 24.7 g of o-sulfobenzimide (yield 91.8%; purity 99.5 area% by HPLC).

(Example 3)

(1) In a 1 L pressure reactor, 38.7 g (0.247 mol) o-chlorobenzoic acid, 9.90 g (0.247 mol) NaOH, 0.15 g (0.001 mol) CuSO4, 34.2 g (0.272 mol) Na2SO3 and 150 ml H2O sequentially After the addition, the reaction was carried out at a temperature of 175 ° C. at a pressure of 6-7 kg / cm 3 for 24 hours.

After completion of the reaction, 35.9 g (0.345 mol) of 35% concentrated HCl was added to the reaction, and the mixture was left to stand for 1 hour adjusted to pH = 1.3. The reaction mixture is distilled at atmospheric pressure or reduced pressure to remove H 2 O. As H2O is distilled off, solids are generated in the reactor, so that stirring is not easy. At the time point of removing about 100 ml of H2O, 200 ml of ODCB (ortho-dichlorobenzene) is added to completely remove the remaining amount of H2O.

(2) Later, the ODCB removed together with H2O at azeotropic phase was re-inserted into the reactor, followed by the addition of 2.45 g (0.025 mol) of H2SO4 and 85 ml (3.36 mol) of MeOH, followed by reflux (about 67 ° C). React for 25 hours. After completion of the reaction, the mixture was cooled to room temperature, and stirred for 0.5 hour by adding 2.65 g (0.025 mol) of Na 2 CO 3, and then excess MeOH and a small amount of H 2 O were distilled off.

(3) After that, 1 g (0.017 mol) of DMF was added, and 38.2 g (0.32 mol) of SOCl 2 was slowly added thereto, followed by heating at 78 ° C. for 17 hours. After the reaction is completed, excess SOCl 2 and by-product gas are distilled off and depressurized. Cool down the reactor and add 58.8 g of 25% NH 4 OH and 100 g of H 2 O to the reactor slowly. After the addition was completed, the reaction was terminated after stirring at room temperature for 15 hours.

(4) After completion of the reaction, the ODCB layer and the H2O layer were separated by layers to remove the ODCB layer, and 100 ml of ODCB was added thereto, followed by re-layer separation to remove the organic layer. After cooling, 38.5 g (0.37 mol) of 35% HCl was added to the H 2 O layer to adjust pH = 1.5, followed by stirring at 5 ° C. for 1 hour. The solid produced after stirring was filtered to give a white solid (o-sulfobenzimide; saccharin). The filtered solid was dried to give 40.8 g (yield 90.2%; purity 99.4 area% by HPLC) of o-sulfobenzimide.

Comparative Example (In accordance with Example 1 of Korean Patent Publication No. 79-00766)

(1) 20 g (0.128 mol) of o-chlorobenzoic acid, 5.3 g (0.128 mol) of NaOH, 0.06 g (0.00038 mol) of CuSO 4, 17.6 g (0.140 mol) of Na 2 SO 3 and 150 ml of H 2 O were sequentially added to a 300 ml capacity autoclave reactor. After the addition, check whether the pressure vessel is sealed, and then react for 8 hours at a temperature of 160-170 ° C. and a pressure of 10 kg / cm 3.

After the reaction was completed, the reaction mixture was cooled, the reaction solution in the oatclave was filtered, the filtrate was transferred to a 300 ml vessel, and 35% concentrated sulfuric acid was added thereto to adjust the pH to 2, followed by stirring for 1 hour. This was transferred to a separator and washed once with 150 ml of ether, and then the water was distilled off under reduced pressure to give a white concentrate.

(2) The total amount of the concentrate obtained in (1) was added to a 250 ml four-necked flask, and then 150 g (4.7 mol) of methanol and 1.3 g (0.013 mol) of 98% sulfuric acid were added thereto, followed by heating to 65 DEG C while stirring. It is refluxed and reacted for 10 hours. After completion of the reaction, excess methanol is distilled off under reduced pressure to obtain a white concentrate.

(3) The total amount of the concentrate obtained in (2) was added to a 200 ml four-necked flask, and then 100 ml of dichlorobenzene was added, followed by gradually heating and stirring the mixture at 17.9 g (0.15 mol) of SOCl2 and heating it to 78 ° C. And reacted for 10 hours. After the reaction, excess SOCl 2 is distilled off and poured into cold water, and then the reaction solution is washed four times with 100 ml of water.

(4) The reaction solution obtained in (3) was transferred to a 300 ml flask, and then 90 g of a 10% aqueous ammonia solution was added thereto, and the mixture was stirred at 20 ° C. for 4 hours. After completion of the reaction, the reaction solution was corrected with a separator, and concentrated HCl was added to the aqueous solution obtained by layer separation of the H 2 O layer to form a pH of 1, and the precipitated crystals were separated by filtration and washed twice with 20 ml of cold water. Drying then yields 19.9 g (yield 85.0%; 99.8 area% by HPLC) of crystals of the desired white o-sulfobenzimide.

(Comparison of test results according to the present invention and the prior art)

Comparison of the prior art in which o-sulfobenzimid was prepared in a separate reactor by purifying the intermediate by separating the yields of Examples 1 to 3 and three stages by the one-pot method of the present invention. In order to compare the yield of the examples, a comparison table of test results is shown below.

Example menstruum Saccharin Production yield(%) water(%) One MCB 49.0 g 93.0 99.6 2 toluene 24.7 g 91.8 99.5 3 ODCB 40.8 g 90.2 99.4 Comparative Example ether 19.9 g 85.0 99.8

Examples 1 to 3 of the present invention, the yield is slightly different depending on the solvent used, the best case of MCB (monochlorobenzene), this difference may be the experimental error range, usually 90.2 ~ 93.0% range While very high, the yield of the comparative example by the conventional method was relatively low as 85.0%.

In particular, in the case of the other embodiments 3 to 9 of the prior art Korean Patent Publication No. 79-00766, depending on the catalyst, sulfite or hydride used in the first step, depending on the acid catalyst, alcohol or the like used in the second step, Although slightly different depending on the reaction solvent or chlorinating agent used in the third process, the yield by the conventional method was relatively low in the range of 81 to 84.0%.

As described above, the yield in the method of preparing the o-sulfobenzimid in a separate reactor by purifying the intermediate by separating it by three stages is lower than the yield by the one-pot method of the present invention. It is considered that the loss of the active material from the starting material is due to. Therefore, the method for producing o-sulfobenzimide by the one-pot method of the present invention can be produced in high yield by participating in the next step of the reaction without any loss of the active ingredient by separation and purification, and the intermediate step for each reaction step. The product can be manufactured in a single reactor without separation, filtration and drying, thereby enabling mass production through cost reduction.

On the other hand, Examples 1 to 3 of the present invention, depending on the reaction solvent used, there is a difference in purity, but also in this case may be within the experimental error range, slightly different from the purity of the comparative example by the conventional method, Since the case may also be within the experimental error range, this difference is not considered to be significant.

Although the use of sugar substitutes in the field of food additives is limited by the one-pot method of preparing o-sulfobenzimid, the o-sulfobenzimide, which is still usefully used as a pesticide intermediate, has high purity and high yield. Mass production will be possible.

Persons skilled in the art may make various changes and / or modifications to the spirit and embodiment of the present invention, but it should be appreciated that such modifications and / or modifications may be made without departing from the spirit of the present invention. . Accordingly, the appended claims are intended to cover all such equivalent methods that fall within the spirit and scope of the invention.

Claims (11)

As a method for producing o-chlorobenzimide of the following structural formula, (1) reacting o-chlorobenzoic acid with a sulfonating agent in the presence of a copper catalyst to convert the chlorine atom of o-chlorobenzoic acid into a sulfonate to convert it to a sulfonic acid group, (2) reacting o-sulfobenzoic acid obtained in the first step with an alcohol in the presence of an acid catalyst to distill off excess alcohol and water while alkylesterizing the carboxyl group of o-sulfobenzoic acid, (3) The o-sulfobenzoic acid alkyl ester obtained in the second step is reacted with a chlorinating agent in a inert organic solvent under a catalyst of dimethylformamide to replace the hydroxyl group contained in the sulfone group of the o-sulfobenzoic acid alkyl ester with a chlorine atom. step, (4) The o-sulfochloride benzoic acid alkyl ester obtained in the third step is reacted with ammonia to replace the chlorine atom in the sulfochloride group of the reactant with an amino group and to cyclize the same to prepare o-sulfobenzimid. Including the steps of: Wherein all of steps (1) to (4) are carried out in a single reactor (one-port) without separating intermediates in solid form.

In this formula, M is hydrogen, sodium, or potassium, R is methanol, ethanol or an alkyl group. The method of claim 1, wherein the sulfonating agent is potassium sulfite (K2SO3), sodium sulfite (Na2SO3), calcium sulfite (CaSO3), potassium hydrogen sulfite (KSO3H), sodium hydrogen sulfite (NaSO3H), and calcium hydrogen sulfite (Ca (SO3H) ) 2). The method of claim 1, wherein the copper catalyst is selected from metal copper powder, copper sulfate, copper acetate, copper hydroxide, copper oxide, copper iodide, and copper chloride. The process of claim 1 wherein said acid catalyst is selected from hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid as inorganic acid, and paratoluenesulfonic acid, trifluoromethanesulfonic acid as eutectic acid. The process according to claim 1, wherein the inert organic solvent is selected from chloroform, carbon tetrachloride, dichloroethane, dichloropropane as the halogen-substituted aliphatic hydrocarbon, and benzene, toluene, xylene, chlorobenzene, dichlorobenzene as the aromatic hydrocarbon. The method according to any one of claims 1 to 5, further comprising distilling off water using an organic solvent in the first step. delete The method according to any one of claims 1 to 5, wherein the chlorinating agent of the third step is selected from thionyl chloride, phosgene. The method of claim 6, wherein the organic solvent in the first step is toluene. The method of claim 9, wherein the amount of the dimethylformamide is used in the range of 0.03 to 0.1 mole per mole of the o-sulfobenzoic acid alkyl ester. The method according to any one of claims 1 to 5, wherein, after the ammonia reaction step of the fourth step, the aqueous phase of the reaction product is separated from the organic phase, and then the pH of the aqueous phase is adjusted to 1 to 2 to obtain the o-. Process for preparing sulfobenzimide.