KR102075509B1 - Processes for the preparation of bispyribac sodium and intermediates thereof - Google Patents

Abstract

The present invention condenses 2,6-dihydroxy benzoic acid with 2- (alkyl sulfonyl) -4,6-diakoxy pyrimidine in the presence of at least one base and at least one solvent to prepare bispyribaeksodium. It is about process. The invention also relates to a process for preparing 2,6-dihydroxy benzoic acid and 2- (alkyl sulfonyl) -4,6-diakoxy pyrimidine.

Description

Bispyridosodium and its intermediate product manufacturing process {PROCESSES FOR THE PREPARATION OF BISPYRIBAC SODIUM AND INTERMEDIATES THEREOF}

The present invention relates to a manufacturing process of bispyribac sodium and its intermediate products.

Bispyribac-sodium

IUPAC Name: Sodium 2, 6-bis (4, 6-dimethoxypyrimidin-2-yloxy) benzoate

rescue:

Chemical Formula: C ₁₉ H ₁₇ N ₄ NaO ₈

Molecular Weight: 452.4

Physical state: White powder

Melting Point: 223-224 ℃

Solubility in water: 73.3g / l at 25 ℃

Mode of action: Selective. Systemic action Absorbed by herbicides, leaves and roots after germination.

Bispyribaeksodium works by interfering with the production of acetolactate synthase (ALS), a permeable herbicide that travels throughout plant tissues and is a plant enzyme necessary for growth. It is used to control grass, forage and broadleaf weeds, especially Echinochloa species in straight rice. It is also used to inhibit the growth of weeds in the noncrop state.

Bispyribaeksodium is degraded by bacteria and has a half-life of 42-115 days (the time it takes to decompose half of the active ingredient) The initial decomposition product of bispyribaeksodium is sodium 2- (4,6 dimethoxypyrimidin-2-yl) oxy-6- (4-hydroxy-6-methoxypyrimidin-2-yl) benzoate . Bispyrisodium does not bind to the soil and is reasonably long lasting and travels somewhat well throughout the soil. Testing has shown that the aqueous formulation of bispyribaeksodium is nontoxic to fish and invertebrates. Bispyribaeksodium is also nontoxic to birds and mammals.

One of the intermediates in the synthesis of bispyribaeksodium is 4,6-dialkoxy-2- (alkylsulfonyl) pyrimidine.

4,6-dialkoxy-2- (alkylsulfonyl) pyrimidine

The synthesis of 4,6-dialkoxy-2- (alkylsulfonyl) pyrimidines has been disclosed in the prior art documents. For example, WO2000046212 discloses a process for preparing 4.6-dimethoxy-2- (methylsulfonyl) pyrimidine. This process involves mixing 2-methylthiobarbituric acid with xylene, triphenylphosphine oxide and tetrabutylammonium chloride followed by heating and passing phosgene until the reaction of the adduct is complete. In a later step phosgene is removed from the reaction mass and this organic phase is then extracted with water and reacted with sodium methylate at 50 ° C. to form 4,6-dimethoxy-2-methylthiopyrimidine. In addition, 5 mol% sodium tungstate and 5 mol% tetrabutylammonium chloride are added to this reaction mixture and mixed with 2 molar equivalents of hydrogen peroxide at 85 ° C.

WO2002008207 discloses 4,6-dimethoxy-2- (methylsulfonyl) -1, by reacting 4,6-dichloro-2- (methylthio) -1,3-pyrimidine with alkali metal methoxide in an inert organic solvent. A process for preparing 3-pyrimidine, transferring the resulting 4,6-dimethoxy-2- (methylthio) -1,3-pyrimidine to an aqueous-acid medium and subsequently transferring this compound to tricaprylmethyl chloride A process of oxidizing in the presence of an ammonium catalyst is disclosed, wherein a purification step in which the aqueous-acid reaction mixture is adjusted to a pH in the range of 5-8 using an aqueous base and stirred in the presence or absence of an organic solvent is followed by an oxidation process. Followed by

CN 101747283 discloses a process for the preparation of 4,6-dimethoxy-2- (methanesulfonyl) pyrimidine, which yields 4,6-dimethoxy-2- (methylthio) pyrimidine upon methoxylation. It is accompanied by a chlorination process of 4,6-dihydroxy-2- (methylthio) pyrimidine for obtaining 6-dichloro-2- (methylthio) pyrimidine followed by an oxidation process. This process disclosed in CN 101747283 utilizes trifluoromethane sulfonic acid salts, quaternary ammonium salts or organic base catalysts, especially in methoxylation reactions. The catalyst is selected from the group consisting of copper trifluoromethane sulfonic acid and tin trifluoromethane sulfonic acid, trioctyl methyl chloride ammonium, tertiary ammonium chloride, triethylamine.

Another intermediate for the synthesis of bispyribaeksodium is resoxylic acid, also known as 2,6-dihydroxybenzoic acid. The synthesis of 2, 6-dihydroxybenzoic acid has been described in various prior art documents as follows.

GB 9165481963 discloses a process for the synthesis of 2, 6-dihydroxybenzoic acid by carboxylating the hydrous mono-potassium salt of resorcinol at 130 ° C., in the presence of a solvent having the formula RCON (R ¹ ) ₂ . Where R is hydrogen or a low alkyl group and R ¹ is a low alkyl group having 1-4 carbon atoms. N, N'-dimethylformamide and N, N'-diethylformamide are particularly preferred solvents. Alkali salts of resorcinol can be formed in situ by reacting resorcinol with alkali metal hydroxides or carbonates, hydrogen carbonates. Separation of 2, 6-dihydroxy benzoic acid is carried out by acidification with hydrochloric acid followed by fractional crystallization.

US 5304677 discloses a process for synthesizing 2, 6-dihydroxybenzoic acid by dissolving resorcinol in a suitable solvent and subsequently blowing carbon dioxide into the solution in the presence of a basic compound until the absorption of carbon dioxide is stopped. Alcohols and alkoxy-alcohols, dimethylformamide, water and mixtures thereof can be used as solvents. The basic compound may be potassium carbonate, potassium hydroxide, sodium carbonate, and is used in an approximately molar amount with resorcinol. This reaction can be carried out at temperatures in the range of 100-200 ° C., at atmospheric pressure, or under a carbon dioxide atmosphere of 30 kg / cm ² . The patent also acidifies the base aqueous solution to pH up to 5-7 with organic or inorganic acids and heats the mixture from 90 ° C. to the boiling point of the aqueous solution to decompose 2,4-dihydroxybenzoic acid from the resulting mixture. Initiate the process. After completion of the decomposition reaction, sulfuric acid is added to the mixture to achieve a pH of 3 which is subsequently filtered off. Sulfuric acid is further added to this filtrate until the pH reaches 1, and then 2, 6-dihydroxybenzoic acid is finally separated through filtration at 5 ° C.

However, the prior art methods for the preparation of bispyribacksodium and 4,6-disubstituted 2-alkylsulfonylpyrimidines, 2,6-dihydroxybenzoic acid have high impurity content, low yield, slow reaction rate and It has several shortcomings, such as low cost effectiveness. Thus there is a need for a simple, economical and high yield process for the preparation of these compounds.

Some objects of the invention, in which at least one embodiment is adapted for its provision, are described below.

One object of the present invention is to provide a simple and high yield process for the production of bispyribaeksodium.

Another object of the present invention is to provide a time-saving process for the production of bispyribaeksodium.

It is another object of the present invention to provide a bispyridosodium manufacturing process that makes the process economical with a soft base.

Another object of the present invention is to provide a process for producing bispyribacksodium that eliminates the use of strong acids.

Another object of the present invention is to provide a process for preparing 4,6-dialkoxy 2- (alkylsulfonyl) pyrimidine.

It is another object of the present invention to provide a simple and cost effective process for preparing 4,6-dialkoxy 2- (alkylsulfonyl) pyrimidine.

It is still another object of the present invention to provide a process for producing high yield of 4,6-dialkoxy 2- (alkylsulfonyl) pyrimidine.

It is another object of the present invention to provide a high purity 4,6-dialkoxy 2- (alkylsulfonyl) pyrimidine preparation process.

Another object of the present invention is to provide a 2, 6-dihydroxybenzoic acid production process.

Another object of the present invention is to provide a process for producing 2, 6-dihydroxybenzoic acid having high yield.

Another object of the present invention to provide an environmentally friendly process for producing 2, 6-dihydroxybenzoic acid.

It is yet another object of the present invention to provide an economical process for producing 2, 6-dihydroxybenzoic acid.

Other objects and advantages of the invention will become more apparent from the following description when read in conjunction with the accompanying drawings, which are not intended to limit the scope of the invention.

According to the present invention, a process for the preparation of bispyribaeksodium is provided, wherein the process utilizes 2,6-dihydroxy benzoic acid as 2- (alkyl sulfonyl) -4,6-diakoxy pyrimidine at a temperature of 20-80 ° C. Condensing in the presence of at least one base and at least one solvent.

Typically, this base is selected from the group consisting of sodium hydride, potassium hydroxide, calcium hydroxide and lithium.

Typically, this solvent is selected from the group consisting of tetrahydrofuran and dimethyl sulfoxide, dimethylformamide, dimethyl acetamide, N-methyl pyrrolidone, sulfolane, monoglyme, diglyme. .

Typically, 2- (alkyl sulfonyl) -4,6-dialkoxy pyrimidine is 2- (methyl sulfonyl) -4,6-dimethoxy pyrimidine.

According to another aspect of the present invention, there is provided a process for preparing 4,6-dialkoxy-2- (alkylsulfonyl) pyrimidine, the process comprising the following steps:

i. Reacting the dialkylmalonate and thiourea in the presence of sodium alkoxide and one alcohol to obtain a sodium salt of thiobarbituric acid;

ii. Alkylating the salt of thiobarbituric acid with alkyl chloride to yield 2-alkyl thio-4,6-dihydroxypyrimidine;

iii. Chlorinating the 2-alkylthio-4,6-dihydroxypyrimidine with phosphoryl chloride (POCl ₃ ) to obtain 2-alkylthio-4,6-dichloropyrimidine;

iv. Alkoxylating said 2-alkylthio-4,6-dichloropyrimidine with sodium alkoxide to obtain 4,6-dialkoxy-2- (alkylthio) pyrimidine;

v. Oxidizing the 4,6-dialkoxy-2- (alkylthio) pyrimidine in the presence of hydrogen peroxide and acetic acid, one catalyst to obtain 4,6-dialkoxy-2- (alkylsulfonyl) pyrimidine.

Typically, the dialkylmalonate is selected from the group consisting of dimethylmalonate and diethylmalonate, di-n-propylmalonate, di-n-butylmalonate and preferably the dialkylmalonate is dimethylmalonate to be.

Typically, sodium alkoxide is sodium methoxide.

Typically, alkyl chloride is methyl chloride.

Typically, 2-alkyl thio-4,6-dihydroxypyrimidine is 2-methyl thio-4,6-dihydroxypyrimidine.

Typically, 2-alkyl thio-4,6-dichloropyrimidine is 2-methyl thio-4,6-dichloro pyrimidine.

Typically, 4,6-dialkoxy-2- (alkylthio) pyrimidine is 4,6-dimethoxy-2- (methylthio) pyrimidine.

Typically, 4,6-dialkoxy-2- (alkylsulfonyl) pyrimidine is 4,6-dimethoxy-2- (methylsulfonyl) pyrimidine.

Typically, the alcohol is selected from the group consisting of methanol and ethanol, n-propyl alcohol, n-butyl alcohol.

In one embodiment step (i) comprises adding dimethylmalonate and thiourea to the methanol to obtain a mass, heating the mass to a temperature of 50-70 ° C., treating the methanol solution of sodium methoxide Incorporating into the mass to obtain a mixture, maintaining the mixture at a temperature of 50-70 ° C. for 1-5 hours, removing methanol by distillation from the mixture to obtain a second mass, the mass Quenching to obtain a cooled mass, filtration of the mass to obtain a cake, washing the cake with methanol and subsequent drying to obtain a sodium salt of thiobarbituric acid.

In one embodiment step (ii) is a step of mixing the sodium salt of thiobarbituric acid with sodium hydroxide solution and methanol to obtain a mass, adding methyl chloride to the mass, stirring to 2-methylthio-4, Obtaining 6-dihydroxypyrimidine.

In one embodiment step (iii) comprises mixing 2-methylthio-4,6-dihydroxypyrimidine and POCl ₃ , at least one aromatic hydrocarbon, at least one base to obtain a mixture, the mixture being 40 Heating to a temperature of 90 ° C., adding POCl ₃ and chlorine to the heated mixture and subsequently stirring at a temperature of 40-60 ° C. to obtain 2-methylthio-4,6-dichloropyrimidine do.

In one embodiment step (iv) comprises mixing an alcohol solution of sodium methoxide, cuprous chloride and sodium iodide to obtain a mixture, quenching the mixture and adding 2-methylthio-4,6-dichloropyrimidine. Adding at a temperature of 25 ° C. to obtain a mass, said mass being heated at a temperature of 30-50 ° C. to obtain 4,6-dimethoxy-2- (methylthio) pyrimidine.

In one embodiment step (v) comprises mixing 4,6-dimethoxy-2- (methylthio) pyrimidine and sodium tungstate, acetic acid to obtain a mixture, heating the mixture, hydrogen peroxide (H ₂ O ₂ ) to add 4,6-dimethoxy-2- (methylsulfonyl) pyrimidine.

In one embodiment, the catalyst is sodium tungstate.

Typically, the aromatic hydrocarbon is selected from the group consisting of monochlorobenzene and o-dichlorobenzene, combinations thereof.

Typically, the base is selected from the group consisting of triethylamine and tripropylamine, tributylamine, and combinations thereof.

According to another aspect of the invention there is provided a process for the preparation of 2, 6-dihydroxybenzoic acid, the process comprising the following steps:

-2, 6-dihydroxybenzoic acid and 2, 4-dihydroxy by carboxylating resorcinol at a temperature of 100-200 ° C. in the presence of at least one base dissolved in at least one solvent in the presence of carbon dioxide Obtaining a mixture containing benzoic acid, 4, 6-dihydroxyisophthalic acid;

Acidifying the mixture with at least one acid to obtain 2,6-dihydroxybenzoic acid with a purity> 95%, wherein the acidifying step comprises adjusting the pH of the mixture to ≦ 1.

In one embodiment 2, 6-dihydroxybenzoic acid is prepared according to the following process:

-2, 6-dihydroxybenzoic acid and 2, 4-dihydroxy by carboxylating resorcinol at a temperature of 100-200 ° C. in the presence of at least one base dissolved in at least one solvent in the presence of carbon dioxide Obtaining a mixture containing benzoic acid, 4, 6-dihydroxyisophthalic acid;

Maintaining the mixture at a temperature of 140 ° C.-180 ° C. for 1-10 hours;

Cooling the mixture to obtain a cooled mixture;

Acidifying the cooled mixture to pH 5.5-6 with one acid and then holding at 90-110 ° C. for 1-20 hours to obtain an acidified mass and cooling the mass;

Adjusting the pH of the mass to 2-3 with one acid and then filtration, washing and drying to obtain a solid mass and filtrate;

Adding one acid to the filtrate to adjust the pH to 0.8-1 and then stir, cool, filter, wash and dry to yield 2, 6-dihydroxybenzoic acid with a purity> 95%.

Typically, the carboxylation step is carried out at a temperature of 140-180 ° C.

Typically, the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid.

Typically, the base is selected from the group consisting of potassium carbonate and potassium hydroxide, sodium carbonate, and combinations thereof.

Typically, the solvent is selected from the group consisting of toluene and N, N-dimethylformamide, N, N-diethylformamide, ethanol, methanol, acetone, water, and combinations thereof.

Typically, the carboxylation step is 5 kg / cm ² - is carried out in a reactor having a 45 kg / cm ² pressure.

Typically, the drying step is carried out at a temperature of 40-70 ° C.

In one embodiment, the purity of 2, 6-dihydroxybenzoic acid is> 99%.

In one embodiment, the process for preparing 2,6-dihydroxybenzoic acid comprises the steps of decarboxylating 2,4-dihydroxy benzoic acid and 4,6-dihydroxyisophthalic acid to obtain resorcinol and the rezo Regenerating lecinol.

1 is a schematic of the reaction for the preparation of bispyribaeksodium in accordance with the present invention.
2 is a reaction schematic for the preparation of 2- (alkyl sulfonyl) -4,6-dialkoxy pyrimidine.

According to the present invention a process for the preparation of bispyribagsodium is provided. This process consists of sodium hydride and potassium hydroxide, calcium hydroxide and lithium at a temperature of 20-80 ° C. with 2,6-dihydroxy benzoic acid as 2- (alkyl sulfonyl) -4,6-dialkoxy pyrimidine. In the presence of at least one base selected from at least one selected from the group consisting of tetrahydrofuran and dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methyl pyrrolidone, sulfolane, monoglyme, diglyme In the presence of a solvent, the step of condensation is accompanied by bispyribaeksodium. 2- (alkyl sulfonyl) -4,6-dialkoxy pyrimidine used according to the invention is 2- (methyl sulfonyl) -4,6-dimethoxy pyrimidine.

In another embodiment, a process for preparing 4,6-diakoxy-2- (alkylsulfonyl) pyrimidine is provided.

In the first step, the dialkylmalonate is reacted in the presence of thiourea with sodium alkoxide and one alcohol to obtain the sodium salt of thiobarbituric acid.

According to the invention, the dialkylmalonate is selected from the group consisting of dimethylmalonate and diethylmalonate, di-n-propylmalonate, di-n-butylmalonate. In one embodiment the dialkylmalonate is dimethylmalonate. The alcohol is selected from the group consisting of methanol and ethanol, n-propyl alcohol, n-butyl alcohol.

The salt of thiobarbituric acid obtained above is alkylated with alkyl chloride to give 2-alkyl thio-4,6-dihydroxypyrimidine.

In the next step, 2-alkylthio-4,6-dihydroxypyrimidine is chlorinated with phosphoryl chloride (POCl ₃ ) to give 2-alkylthio-4,6-dichloropyrimidine, which is then sodium alkoxide To alkoxylated to afford 4,6-dialkoxy-2- (alkylthio) pyrimidine.

As a result, the obtained 4,6-dialkoxy-2- (alkylthio) pyrimidine is oxidized in the presence of hydrogen peroxide and acetic acid, catalyst to give 4,6-dialkoxy-2- (alkylsulfonyl) pyrimidine do. The catalyst used in this oxidation step is sodium tungstate.

The present invention particularly provides a process for the preparation of 4,6-dimethoxy-2- (methylsulfonyl) pyrimidine.

In the first step, dimethylmalonate is reacted with thiourea in the presence of sodium methoxide and methanol to obtain the sodium salt of thiobarbituric acid. The salt of thiobarbituric acid obtained is alkylated with methyl chloride to give 2-methyl thio-4,6-dihydroxypyrimidine.

In the next step, 2-methylthio-4,6-dihydroxypyrimidine is chlorinated using phosphoryl chloride (POCl ₃ ) to give 2-methylthio-4,6-dichloropyrimidine, which is then sodium Alkoxylation with methoxide affords 4,6-dimethoxy-2- (methylthio) pyrimidine.

As a result, the obtained 4,6-dimethoxy-2- (methylthio) pyrimidine is oxidized in the presence of hydrogen peroxide and acetic acid, a catalyst to obtain 4,6-dimethoxy-2- (methylsulfonyl) pyrimidine .

In one exemplary embodiment the sodium salt of thiobarbituric acid is accompanied by the following steps:

Adding dimethylmalonate and thiourea to the methanol to obtain one mass and heating the mass to a temperature of 50-70 ° C.,

Incorporating a methanol solution of sodium methoxide in the mass for at least 2 hours and maintaining the mixture at a temperature of 50-70 ° C for 1-5 hours,

Removing methanol by distillation from the mixture to obtain a second mass, cooling the mass to obtain a cooled mass and filtering the mass to obtain a cake,

Washing the cake with methanol and subsequently drying to obtain the sodium salt of thiobarbituric acid.

In one exemplary embodiment the process for preparing 2-methylthio-4,6-dihydroxypyrimidine is accompanied by the following steps:

-Mixing the sodium salt of thiobarbituric acid with sodium hydroxide solution and methanol to obtain a mass,

Adding methyl chloride to the mass and stirring the mass to give 2-methylthio-4,6-dihydroxypyrimidine.

In one exemplary embodiment the process for preparing 2-methylthio-4,6-dichloropyrimidine is accompanied by the following steps:

-Mixing 2-methylthio-4,6-dihydroxypyrimidine and POCl ₃ , at least one aromatic hydrocarbon, at least one base to obtain a mixture,

Heating the mixture to a temperature of 40-90 ° C. to obtain a heated mixture,

POCl ₃ and chlorine are added to this heated mixture and subsequently stirred at a temperature of 40-60 ° C. to give 2-methylthio-4,6-dichloropyrimidine.

The aromatic hydrocarbon is selected from the group consisting of monochlorobenzene and o-dichlorobenzene, combinations thereof and the base is selected from the group consisting of triethylamine and tripropylamine, tributylamine, and combinations thereof.

In one exemplary embodiment the process for preparing 4,6-dimethoxy-2- (methylthio) pyrimidine is accompanied by the following steps:

Stirring an alcohol solution of sodium methoxide and cuprous chloride, sodium iodide to obtain a mixture,

Cooling the mixture and subsequently adding 2-methylthio-4,6-dichloropyrimidine at a temperature of 15-25 ° C. to obtain a mass,

Heating the mass at a temperature of 30-50 ° C. to obtain 4,6-dimethoxy-2- (methylthio) pyrimidine.

In one exemplary embodiment the process for preparing 4,6-dimethoxy-2- (methylsulfonyl) pyrimidine is accompanied by the following steps:

-Mixing 4,6-dimethoxy-2- (methylthio) pyrimidine with sodium tungstate, acetic acid to obtain a mixture,

Hydrogen peroxide (H ₂ O ₂ ) is added to the mixture to give 4,6-dimethoxy-2- (methylsulfonyl) pyrimidine.

In another aspect, a process for preparing 2, 6-dihydroxybenzoic acid using resorcinol as an initiator is provided.

This process is accompanied by the following steps:

In the first step, resorcinol is carboxylated at a temperature of 100-200 ° C. in the presence of carbon dioxide and at least one base dissolved in at least one solvent. The resulting mixture is acidified with at least one acid to give 2, 6-dihydroxybenzoic acid. The acidification step is accompanied by adjusting the pH of the mixture to ≦ 1. The purity of 2, 6-dihydroxybenzoic acid obtained in the process of the present invention is> 95%, preferably at least 99%. The acid is selected from the group consisting of hydrochloric acid and sulfuric acid, acetic acid, while the base is selected from the group consisting of potassium carbonate and potassium hydroxide, sodium carbonate, combinations thereof, and the solvents are toluene and N, N-dimethylformamide, N , N-diethylformamide, ethanol, methanol, acetone, and water. The carboxylation step according to the invention is carried out at a temperature of 140-180 ° C. Typically carboxylation step is 5kg / cm ² - is carried out in a reactor having a pressure of 45 kg / cm ^2.

In one embodiment this process is accompanied by the following steps:

Resorcinol is carboxylated at a temperature of 100-200 ° C. in the presence of carbon dioxide and at least one base dissolved in at least one solvent to give 2, 6-dihydroxybenzoic acid and 2, 4-dihydroxybenzoic acid, Obtaining a mixture containing 4, 6-dihydroxyisophthalic acid;

Maintaining the mixture at a temperature of 140 ° C.-180 ° C. for a period of 1-10 hours;

Cooling the mixture to obtain a cooled mixture;

Acidifying the cooled mixture to pH 5.5-6 with one acid and then holding at 90-110 ° C. for 1-20 hours to obtain an acidified mass and cooling the mass;

Adjusting the pH of the mass to 2-3 and subsequently filtering, washing and drying to obtain a solid mass and filtrate;

Adding one acid to the filtrate to adjust the pH to 0.8-1 followed by stirring, cooling, filtration, washing and drying to obtain 2, 6-dihydroxybenzoic acid with a purity> 95%.

The drying step is carried out at a temperature of 40-70 ° C.

In one embodiment, the process includes decarboxylating 2, 4-dihydroxy benzoic acid and 4, 6-dihydroxyisophthalic acid to obtain resorcinol and regenerating the resorcinol. .

This invention description is also illustrated by the following non-limiting examples.

Preparation of Bispyribaeksodium (Example 1-5)

Example-1

A clear solution of 154 gm of 2,6-dihydroxy benzoic acid dissolved in 500 ml dimethyl sulfoxide was 130 gm dissolved in 2 liters of dimethyl sulfoxide, commercially available (60% oil emulsion) for 2-3 hours or more. To a mixture of sodium hydride was added at 30-32 ° C. The mass was further stirred for 2 hours at 30-32 ° C. and 480 gm of 4,6-dimethoxy-2- (methyl sulfonyl) -pyrimidine was added thereto for at least 2 hours. The reaction was kept at 30-32 ° C. until completion to give bispyribacksodium. The reaction was monitored by HPLC. The mass was filtered and washed with DMSO. The wet solid was resuspended in 1000 ml of methanol and then 1000 ml of 75% aqueous methanol. The wet solid was dried in a furnace to yield 435 gm of bispyribaeksodium. This bispyrisodium sodium was resuspended in reflux at 1200 ml of toluene, cooled, filtered and dried to give 385 gm of bispyrisodium sodium (purity 98.7% HPLC).

Example-2:

A clear solution of 154 gm of 2,6-dihydroxy benzoic acid dissolved in 500 ml dimethylsulfoxide was 130 gm dissolved in 1500 ml of dimethylsulfoxide commercially available (60% oil emulsion) for 2-3 hours or more. To a mixture of sodium hydride was added at 30-32 ° C. Stir the mass further for 2 hours at 30-32 ° C. and add a slurry of 480 gm of 4,6-dimethoxy-2- (methyl sulfonyl) -pyrimidine dissolved in 750 ml of DMSO for 2-3 hours or more. It was. The reaction was kept at 30-32 ° C. until completion to give bispyribacksodium. The reaction was monitored by HPLC. The mass was filtered and washed with DMSO. The wet solid was resuspended in 1000 ml of methanol and then 1000 ml of 75% aqueous methanol. The solid was dried in a furnace to yield 430 gm of bispyribaeksodium. This bispyrisodium sodium was again suspended in 1200 ml of toluene at reflux, cooled, filtered and dried to give 380 gm of bispyrisodium sodium (purity 98.3% HPLC).

Example-3:

A mixture of 130 gm of sodium hydride dissolved in commercially available (60% oil emulsion) 1500 ml of dimethylsulfoxide in a clear solution of 154 gm of 2,6-dihydroxy benzoic acid dissolved in 500 ml dimethylsulfoxide. To 30-32 ° C. The mass was further stirred for 2 hours at 30 ° C. and a slurry of 480 gm of 4,6-dimethoxy-2- (methyl sulfonyl) -pyrimidine dissolved in 750 ml of DMSO was added thereto for 2 hours. The reaction was kept at 30-32 ° C. until completion to give bispyribacksodium. The mass was filtered and washed with DMSO. The wet solid was resuspended in 1000 ml of methanol and then 1000 ml of 75% aqueous methanol. The solid was dried in a furnace to yield 440 gm of bispyribaeksodium. This bispyrisodium powder was resuspended in reflux at 1200 ml of toluene, cooled, filtered and dried to give 380 gm of bispyrisodium sodium (purity 98.5% HPLC).

Example-4:

A mixture of 130 gm of sodium hydride dissolved in commercially available (60% oil emulsion) 1500 ml of dimethylsulfoxide in a clear solution of 154 gm of 2,6-dihydroxy benzoic acid dissolved in 500 ml dimethylsulfoxide. To 30-32 ° C. The mass was further stirred for 2 hours at 30 ° C. and a slurry of 480 gm of 4,6-dimethoxy-2- (methyl sulfonyl) -pyrimidine dissolved in 750 ml of DMSO was added thereto. The reaction was kept at 30-32 ° C. until completion to give bispyribacksodium. The mass was filtered and washed with DMSO. The wet solid was resuspended in 1000 ml of methanol and then 1000 ml of 75% aqueous methanol. The solid was dried in a furnace to yield 435 gm of bispyribaeksodium. This bispyrisodium powder was resuspended in reflux at 1200 ml of toluene, cooled, filtered and dried to give 385 gm of bispyrisodium sodium (purity 98.6% HPLC).

Example-5:

A mixture of 130 gm of sodium hydride dissolved in commercially available (60% oil emulsion) 1500 ml of dimethylsulfoxide in a clear solution of 154 gm of 2,6-dihydroxy benzoic acid dissolved in 500 ml dimethylsulfoxide. To 30-32 ° C. The mass was further stirred for 2 h at 30 ° C. and a clear solution of 480 gm of 4,6-dimethoxy-2- (methyl sulfonyl) -pyrimidine dissolved in 1500 ml of DMSO was added thereto. The reaction was kept at 30-32 ° C. until completion to give bispyribacksodium. The mass was filtered and washed with DMSO. The wet solid was resuspended in 1000 ml of methanol and then 1000 ml of 75% aqueous methanol. The solid was dried in a furnace to yield 440 gm of bispyribaeksodium. This bispyrisodium powder was again suspended in 1200 ml of toluene at reflux, cooled, filtered and dried to obtain 350 gm of bispyrisodium sodium (purity 98.6% HPLC).

Preparation of 4, 6-dimethoxy-2- (methylsulfonyl) pyrimidine [Example 6-10]

Example 6 Preparation of Sodium Thiobarbiturate

A solution of 1.10 m thiourea and 1.0 m dimethylmalonate dissolved in 280 ml methanol was refluxed and a solution of 1.0 m sodium methoxide dissolved in 150 ml methanol was added for 15-45 minutes. The mass was refluxed for 4 hours and a portion of the methanol was distilled off. The resulting mass was cooled below 30 ° C., filtered and washed with methanol. The cake obtained was dried to give sodium thiobarbituric acid sodium salt (yield: 90%).

The filtrate was concentrated to a level of 250-280 ml. To this was added 0.1 m dimethylmalonate and 0.1 m sodium methoxide solution. The obtained reaction mass was mixed as above. The yield of sodium thiobarbiturate salt was 2%.

Example 7:

Preparation of 2-methylthio-4, 6-dihydroxypyrimidine

1.0 m thiobarbituric acid sodium salt was dissolved in an SS autoclave in 1.5 ml IN aqueous sodium hydroxide solution and 50 ml methanol to obtain a mixture. It was fed 0.5 m methyl chloride within 1-2 hours. The resulting reaction mass was stirred for 2-6 hours at 25-30 ° C., a second lot of 0.5m methyl chloride was fed within 1-2 hours and the mass was stirred for 6-8 hours. 0.05 m methyl chloride was fed thereto and the reaction mass was stirred for 2-6 hours. At the end of the reaction HPLC indicated 85% 2-methylthio-4, 6-dihydroxypyrimidine and 5% 2-methylthio-4-methoxy-6-hydroxy pyrimidine. Yield of product was 75-80 mol%.

Example 8:

Preparation of 2-methylthio-4, 6-dichloropyrimidine

To 4 m monochlorobenzene 1.0 m 2-methylthio-4,6-dihydroxypyrimidine was added. To this was added 2.2m POCl ₃ in 1-2 hours and 2.2m triethylamine was added at 40-50 ° C. for 2-4 hours. The resulting mixture was heated to 80 ° C. to give the resultant clear solution and stirred for 4-8 hours to give a mass. This obtained mass was cooled to 60 ° C. To this was added 2.0 m phosphorus trichloride. The next 2.0m chlorine was fed at 60 ° C. for 6-10 hours and stirred at 60 ° C. for 8-10 hours. Cl ₂ feed was run in the absence of light to prevent side chain chlorination. POCl ₃ was vacuum distilled and 200 ml monochloro benzene was added and distillation continued to ensure complete removal of POCl ₃ . 4.0 m-4.3 m POCl ₃ were regenerated and the residual mass was sunk in 200 ml ice water and extracted with monochlorobenzene. 100 ml water was added to this monochlorobenzene layer and neutralized with NaHCO ₃ . These layers were separated and the monochlorobenzene layer was concentrated in vacuo. Yield of product was 85-87%.

The product was vacuum distilled and crystallized with the following methanol to yield 85 mole% with 99% purity.

Example 9:

Preparation of 4, 6-dimethoxy-2- (methylthio) pyrimidine

To a 2.2 m 3 N sodium methoxide solution dissolved in methanolol was added 2 m% cuprous chloride and 2 m% sodium iodide to obtain a mixture which was then cooled to 20 ° C. 2m% cuprous chloride and 2m% sodium iodide were dissolved in 400ml ethanol, added to the mixture for 3-6 hours, and stirred at 20 ° C for 1 hour to obtain a reaction mass. The temperature of the mass was raised to 30 ° C. and then stirred at 40 ° C. for 6-12 hours and HPLC was 95-96% 2-methylthio-4,6-dimethoxypyrimidine and 0.5% 2-methylthio-4- Methoxy-6-chloro pyrimidine is indicated. The mass was cooled and sodium chloride was filtered off. The methanol was distilled from this filtrate and water was added to the residual mass and extracted with toluene. The toluene layer was washed with water and then concentrated. The yield of the product was 90%.

Example 10 Preparation of 4, 6-dimethoxy-2- (methylsulfonyl) pyrimidine

To 200 ml acetic acid was added 3m% sodium tungstate. 1.0 m 2-methylthio-4,6-dimethoxypyrimidine was added thereto to obtain a mass (clear solution). This mass was heated to 40 ° C. 2.1 m 30% H ₂ O ₂ was added to the heated mass for 4-8 hours and stirred at 40 ° C. for 3-5 hours. Also 0.05m 30% H ₂ O ₂ was added and stirred at 40 ° C. until complete transition. The reaction was carried out at 40 ° C. The reaction mixture was cooled and the solid material was filtered off. The cake obtained was washed with aqueous acetic acid and then with water. The cake was then dried. Yield = 83%.

The filtrate was extracted with ethylene dichloride. The obtained ethylene dichloride layer was concentrated. The yield of wt = 42g product is 1-1.5%.

Preparation of 2,6-dihydroxybenzoic acid [Example 11-15]

Example 11: Preparation of 2,6-dihydroxybenzoic acid

A mixture of resorcinol (110 grams, 1.0 mole), toluene (250 ml) and potassium hydroxide (65.1 grams of 86%, 1.0 mole) was stirred in a reactor where a Dean-Stark apparatus was installed to obtain mass. The obtained mass was dehydrated by removing water from the side arm of the Dean-Stark apparatus. If no water was observed in the sidearm of the Dean-Stark apparatus, toluene was distilled off completely and N, N-dimethylformamide (330 ml) was added to give a solution.

The resulting solution was transferred to a dry stainless steel compression reactor, compressed with carbon dioxide gas and heated to 150 ° C. to obtain a reaction mixture. The resulting reaction mixture was placed at 150 ° C. for 6 hours under 9 kg / cm ₂ carbon dioxide pressure.

The mixture was cooled to 50 ° C. and the carbon dioxide pressure was removed and the carbon dioxide was vented in an alkali scrubber. The mixture was then transferred to a glass reactor and N, N-dimethylformamide was distilled at 10 mm Hg pressure at 110 ° C. liquidus temperature to obtain a reaction mass. The resulting mass was cooled to ambient temperature and dissolved in water. The HPLC composition of the reaction mass is 56.61% -2,6-dihydroxybenzoic acid, 4.97% -2,4-dihydroxybenzoic acid, 9.32% resorcinol, 12.73% 4,6-dihydroxyisophthalic acid.

The aqueous mass was acidified to a pH of 5.5-6 with concentrated hydrochloric acid and maintained at 100 ° C. for 6 hours. The progress of the reaction was monitored by HPLC.

The mass was cooled to 30 ° C., acidified to pH 2.85 with concentrated hydrochloric acid, filtered, washed, and dried at 60 ° C. to give 15.35 g of dry solid. (HPLC composition = 95.2% 4,6-dihydroxyisophthalic acid, 2.97% 2,6-dihydroxybenzoic acid). The filtrate at 2.85 pH was neutralized with concentrated hydrochloric acid to a pH value of 0.8-1, cooled to 10 ° C., filtered and washed with water. The wet solid was dried at 60 ° C. to give 53.9 grams of solid with 96.1% 2,6-dihydroxy benzoic acid by HPLC.

Example-12

A mixture of 220 grams resorcinol (2.0 mol), 1300 ml 50% (v / v) aqueous ethanol and 276 grams (2.0 mol) potassium carbonate was added to a dry stainless steel high pressure reactor. The reactor was compressed to 5 kg with carbon dioxide and heated to 170 ° C. The mixture was kept at 170 ° C. for 5 hours while maintaining a carbon dioxide pressure of 38-39 kg / cm ² .

The reaction mixture was cooled to ambient temperature and released carbon dioxide and vented in an alkali scrubber.

The mixture was then transferred to a glass reactor and analyzed by HPLC.

HPLC composition: 38.43% -2,6-dihydroxybenzoic acid, 34.6% -2,4-dihydroxybenzoic acid, 9.40% resorcinol and 16.42% 4,6-dihydroxyisophthalic acid.

The mixture was neutralized with concentrated hydrochloric acid to pH = 5.5-6 at 30 ° C. and distilled from the mixture at 100 ° C. liquid temperature. The reaction mixture was then kept at reflux for 12.5 hours with the addition of concentrated hydrochloric acid and the pH value was maintained at 5.5-6.

The composition of the reaction mass after holding at 12.5 hours at 100 ° C. was 55.25% -2,6-dihydroxybenzoic acid, 3.6% -2,4-dihydroxybenzoic acid, 20.35% resorcinol and 19.90% 4, as determined by HPLC. , 6-dihydroxyisophthalic acid.

After the reduction of 2,4-dihydroxybenzoic acid was completed, concentrated hydrochloric acid was added to the mixture until the pH value reached 2.83. The solid obtained was filtered and the wet solid was again suspended in water. Concentrated hydrochloric acid was added thereto until the pH value reached 0.90. The solid material was filtered, washed and dried at 60 ° C. until yield reached 11.8 grams of dry solid. (HPLC composition was 93.5% 4,6-dihydroxyisophthalic acid and 5.84% 2,6-dihydroxy benzoic acid).

The filtrate, pH 2.83, was acidified with concentrated hydrochloric acid until the pH value was 0.9-1.0 and stirred for 1 hour. The resulting slurry was cooled to 0 ° C, stirred for 1 hour and filtered. The wet cake was resuspended in water and stirred at 55-60 ° C., cooled to 0 ° C. and filtered. The solid was washed with cooling water and dried at 60 ° C. until constant weight yielded 99.2 grams of dry solid 2,6-dihydroxybenzoic acid. (96.4% Purity in HPLC)

Example-13

A mixture of 220 grams resorcinol (2.0 mol), 1300 ml 50% (v / v) aqueous ethanol and 138 grams (2.0 mol) potassium carbonate was added to a stainless steel high pressure reactor. The mixture was compressed to 5 kg with carbon dioxide and heated to 170 ° C. and the mixture was kept at 170 ° C. for 5 hours while maintaining a carbon dioxide pressure of 23-25 kg / cm ² .

The reaction mixture was cooled to ambient temperature and released carbon dioxide and vented in an alkali scrubber.

The mixture was neutralized with concentrated sulfuric acid to pH = 5.5-6 at 30 ° C. Ethanol / water was then distilled from the mixture at 98-100 ° C. liquid temperature. The concentrated sulfuric acid was added to the reaction mixture while maintaining the pH value at 5.5-6 upon heating to maintain the reaction mixture at reflux for 11 hours.

After 11 hours, the HPLC composition of the mass had an initial value of 52.47% -2,6-dihydroxybenzoic acid, 20.20% -2,4-dihydroxybenzoic acid, 24.2% resorcinol and 2.47% 4,6-dihydroxyiso 55.72% -2,6-dihydroxybenzoic acid, 2.81% -2,4-dihydroxybenzoic acid, 38.14% resorcinol, 2.15% 4,6-dihydroxyisophthalic acid as compared to phthalic acid.

The mass was cooled to ambient temperature and concentrated sulfuric acid was added to the mixture until the pH value reached 4. The mixture was filtered to remove potassium sulfate. The filtrate was acidified again with concentrated sulfuric acid until the pH reached 0.9-1.0. The mass was stirred for 1 hour. The resulting slurry was cooled to 10 ° C, stirred for 1 hour and filtered. The wet solid was suspended again with water and stirred for 1 hour at 55-60 ° C., cooled to 25 ° C. and filtered. The solid was washed with water and dried at 60 ° C. until yield reached 110.4 grams of dry solid 2,6-dihydroxybenzoic acid. (HPLC 99.1% Purity)

The aqueous filtrate was mixed and extracted several times with methyl ethyl ketone. The combined methyl ethyl ketone extract was concentrated at low pressure to give an HPLC composition of 85.7% resorcinol, 7.8% -2,6-DHBA, 1.6% 2,4-dihydroxybenzoic acid and 2.1% 4,6-dihydroxy 142 grams of viscous mass of benzoic acid were obtained.

After distillation containing a lot of resorcinol, the residue methyl ethyl ketone was recovered.

Example-14

142 grams of 142 grams of methyl ethyl ketone enriched mass obtained in Example-13 (1.107 m resorcinol; 0.072 m 2,6-DHBA) were prepared with 90.3 grams of resorcinol (2. 0.821 mole) and 151.8 grams (1.10 m) of potassium carbonate and 1300 ml of 50% (v / v) aqueous ethanol.

The mixture was compressed to 5 kg with carbon dioxide and heated to 170 ° C. and the mixture was kept at 170 ° C. for 5 hours while maintaining a carbon dioxide pressure of 23-25 kg / cm ² .

The reaction mixture was cooled to ambient temperature and released carbon dioxide and vented in an alkali scrubber.

The mixture was neutralized with concentrated sulfuric acid to pH = 5.5-6 at 30 ° C. Ethanol / water was then distilled from the mixture at 98-100 ° C. liquid temperature. The reaction mixture was then kept at reflux for 12 days with the addition of concentrated hydrochloric acid to the reaction mixture until the pH value reached 5.5-6.

After holding for 12 hours the HPLC composition had an initial value of 35.52% -2,6-dihydroxybenzoic acid and 30.21% 2,4-dihydroxybenzoic acid, 26.27% resorcinol, 6.41% 4,6-dihydroxyiso 55.48% -2,6-dihydroxybenzoic acid and 0.1% 2,4-dihydroxybenzoic acid, 41.04% resorcinol, 0.93% 4,6-dihydroxyisophthalic acid relative to phthalic acid. 4,6-dihydroisophthalic acid was completely decarboxylated using concentrated sulfuric acid at 100 ° C.

Concentrated sulfuric acid was added to the mixture until the pH was 3.96. The slurry was equilibrated at 30 ° C. for 1 hour and filtered to remove potassium sulfate. The filtrate was again acidified with concentrated sulfuric acid until the pH value was 0.9-1.0 and stirred for 1 hour. The resulting slurry was cooled to 10 ° C, stirred for 1 hour and filtered.

The wet solid was again suspended in water and stirred at 55-60 ° C. for 1 hour, cooled to 25 ° C. and filtered. The solid was washed with water and dried at 60 ° C. until constant, yielding 76.5 grams of 2,6-dihydroxybenzoic acid dry cake. (99.0% purity by HPLC).

Example-15

After basic reaction and separation of 2,6-dihydroxy benzoic acid, the aqueous filtrate was regenerated as given in Examples 13 and 14.

The aqueous filtrate was neutralized to pH 7 with potassium carbonate, treated with charcoal and the charcoal was filtered off. The content of resorcinol in the aqueous filtrate was determined by HPLC and the resorcinol deficiency for the 2.0 molar batch size was compensated by the addition of raw resorcinol and carboxylation was carried out as given in Examples 13 and 14 Was executed.

The yield of 2,6-dihydroxy benzoic acid was 33% (using raw resorcinol), 35% after primary regeneration of the aqueous filtrate, and 32% after secondary regeneration of the aqueous filtrate.

'Whenever a range of values is specified, values up to 10% below the specified range and the lowest and highest numerical values are included in the scope of the invention, respectively.'

Although great emphasis has been placed on preferred embodiments in the present invention, many embodiments can be practiced and many variations can be made on suitable embodiments without departing from the principles of the invention. These and other changes as well as other embodiments of the invention in a suitable embodiment will be apparent to those skilled in the art from the invention. Accordingly, it should be clearly understood that the foregoing descriptions are merely illustrative of the present invention and not of limitation.

Throughout this specification, the variations such as the predicates 'comprise' or 'comprises' or 'comprising' may refer to the element or integer, step, or elements or integers, groups of steps mentioned. It is to be understood that the term includes, but does not exclude any other element or integer, step, or elements or integers, steps.

The use of the expression 'at least' or 'at least one' means the use of one or more elements or components, amounts, which means one or more desirable purposes or consequences. This is because it is used in the embodiments of the present invention to achieve the same.

Any discussion of the documents, acts, materials, devices, products, and the like contained in the present disclosure is solely for the purpose of providing a context for the present invention. It is not admitted that any or all of these were present anywhere prior to the priority date of this application to form part of the prior art or would be of ordinary skill in the relevant art of the present invention.

Various physical parameters, magnitudes or amounts are approximate and fall within the scope of the present invention unless values greater or less than the numerical values assigned to those parameters, magnitudes or amounts are stated to the contrary in the specification. Expected.

Claims (31)

In the process for producing bispyribaeksodium, the process hydrogenates 2,6-dihydroxy benzoic acid as a base in a temperature range of 30-32 ° C. with 2- (methyl sulfonyl) -4,6-dimethoxy pyrimidine. Condensation in the presence of sodium and dimethyl sulfoxide as a solvent.
The method of claim 1,
The 2- (methyl sulfonyl) -4,6-dimethoxy pyrimidine may be prepared by the following steps:
i. Reacting dimethylmalonate with thiourea in the presence of sodium methoxide and methanol to obtain a sodium salt of thiobarbituric acid, wherein the reaction adds dimethylmalonate and thiourea to the methanol to add mass Obtained, and the mass was heated to a temperature range of 50-70 ° C., and the methanol solution of sodium methoxide was incorporated into the mass over a period of 15 minutes to 45 minutes to obtain a mixture, and the mixture was 1-5 hours. Maintained at a temperature in the range of 50-70 ° C. for a period of time, and methanol is removed from the mixture by distillation to obtain a second mass, the second mass is cooled to obtain a cooled mass, and the cooled mass is Filtration to obtain a cake; Washing the cake with methanol and then drying to obtain a sodium salt of thiobarbituric acid;
ii. Alkylating the salt of thiobarbituric acid with methyl chloride to obtain 2-methylthio-4,6-dihydroxypyrimidine, wherein the alkylation is carried out using a sodium salt of thiobarbituric acid with sodium hydroxide solution and Mixing to obtain a mixture, to which the methyl chloride was added to the mixture under stirring to obtain a mass, and then methyl chloride was added to the mass under stirring to obtain 2-methylthio-4,6-dihydroxypyrimidine. What is being done;
iii. Chlorination of the 2-methylthio-4,6-dihydroxypyrimidine with phosphoryl chloride (POCl ₃ ) to obtain 2-methylthio-4,6-dichloropyrimidine, wherein the chlorination is 2-methyl Thio-4,6-dihydroxypyrimidine, POCl ₃ , at least one aromatic hydrocarbon and at least one base to obtain a mixture, which is heated to a temperature range of 40-90 ° C. to heat the heated mixture. Obtaining, and adding POCl ₃ and chlorine to the heated mixture followed by stirring at a temperature of 40-60 ° C. to obtain 2-methylthio-4,6-dichloropyrimidine;
iv. Alkoxylating the 2-methylthio-4,6-dichloropyrimidine with sodium alkoxide to obtain 4,6-dialkoxy-2- (methylthio) pyrimidine, wherein the alkoxylation is sodium methoxide, An alcohol solution of cuprous chloride and sodium iodide was mixed to obtain a mixture, and after cooling the mixture, 2-methylthio-4,6-dichloropyrimidine was added at a temperature range of 15-25 ° C. to obtain a mass. Heating the mass in a temperature range of 30-50 ° C. to obtain 4,6-dimethoxy-2- (methylthio) pyrimidine;
v. Oxidizing the 4,6-dialkoxy-2- (methylthio) pyrimidine in the presence of hydrogen peroxide, acetic acid, and a catalyst to obtain 4,6-dialkoxy-2- (methylsulfonyl) pyrimidine, The oxidation was carried out by mixing 4,6-dimethoxy-2- (methylthio) pyrimidine, sodium tungstate and acetic acid to obtain a mixture, heating the mixture and adding hydrogen peroxide (H ₂ O ₂ ) to 4, Performing by obtaining 6-dimethoxy-2- (methylsulfonyl) pyrimidine;
Process for producing bispyrisodium sodium which is prepared by.
The method of claim 2,
Wherein said aromatic hydrocarbon is selected from the group consisting of monochlorobenzene, o-dichlorobenzene and combinations thereof.
The method of claim 2,
Wherein said base is selected from the group consisting of triethylamine, tripropylamine, tributylamine and combinations thereof. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

Images