KR20150121102A - Processes for the preparation of bispyribac sodium and intermediates thereof - Google Patents

Abstract

The present invention relates to a process for the preparation of bispyridine sodium by condensing 2,6-dihydroxybenzoic acid with 2- (alkylsulfonyl) -4,6-dialkoxypyrimidine in the presence of at least one base and at least one solvent ≪ / RTI > The present invention also relates to a process for preparing 2,6-dihydroxybenzoic acid and 2- (alkylsulfonyl) -4,6-dialkoxypyrimidines.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for preparing bispyridyl sodium and an intermediate product thereof,

The present invention relates to a process for the preparation of Bispyribac sodium and its intermediates.

Bispyribac-sodium < RTI ID = 0.0 >

IUPAC name: sodium 2,6-bis (4,6-dimethoxypyrimidin-2-yloxy) benzoate

rescue:

C ₁₉ H ₁₇ N ₄ NaO ₈

Molecular weight: 452.4

Physical state: white powder

Melting point: 223-224 DEG C

Solubility in water: 73.3 g / l at 25 ° C

Mode of action: Absorbed by herbicides, leaves and roots after selective, systemic germination.

Bisphosphate sodium is a penetrating herbicide that migrates throughout plant tissues and interferes with the production of acetolactate synthase (ALS), a plant enzyme required for growth. It is used to control grass, shoot and light weeds, especially Echinochloa species in direct rice. It is also used to inhibit the growth of weeds in non-crop conditions.

Bispivalite sodium is degraded by bacteria and has a half-life of 42-115 days (half of the active ingredient is decomposed). The initial degradation product of bispyridyl sodium is sodium 2- (4,6-dimethoxypyrimidin-2-yl) oxy-6- (4-hydroxy-6-methoxypyrimidin-2- yl) benzoate . Bisphyllite sodium is not associated with the soil, is adequately effective, and moves somewhat well throughout the soil. Tests show that the aqueous formulations of bispivalite sodium are non-toxic to fish and invertebrates. Bispyridyl sodium is also non-toxic to birds and mammals.

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

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

Synthesis of 4,6-dialkoxy-2- (alkylsulfonyl) pyrimidines is disclosed in the prior art documents. For example, WO2000046212 discloses a process for the preparation of 4.6-dimethoxy-2- (methylsulfonyl) pyrimidine. This process involves the step of mixing 2-methylthiobarbituric acid with xylene, triphenylphosphine phosphate and tetrabutylammonium chloride followed by heating and passing the phosgene until the reaction of the adduct is complete. In a later step, the phosgene is removed from the reaction mass, which is then extracted with water and reacted with sodium methylate at 50 ° C to form 4,6-dimethoxy-2-methylthiopyrimidine. Further, 5 mol% of sodium tungstate and 5 mol% of tetrabutylammonium chloride are added to the reaction mixture and mixed with hydrogen peroxide at 85 DEG C in an amount of 2 mol or so.

WO2002008207 discloses that 4,6-dichloro-2- (methylthio) -1,3-pyrimidine is reacted with an alkali metal methoxide in an inert organic solvent to give 4,6-dimethoxy-2- (methylsulfonyl) 3-pyrimidine, the step of transferring the resultant 4,6-dimethoxy-2- (methylthio) -1,3-pyrimidine to an aqueous-acidic medium and subsequently this compound is reacted with tricaprylmethyl chloride Wherein the aqueous-acidic reaction mixture is adjusted to a pH in the range of 5-8 using an aqueous base and the purge step stirring under conditions where an organic solvent is present or absent is carried out in an oxidation step .

CN 101747283 discloses a process for the preparation of 4,6-dimethoxy-2- (methanesulfonyl) pyrimidine, which comprises 4, 6-dimethoxy-2- (methylthio) pyrimidine, Followed by a chlorination process of 4,6-dihydroxy-2- (methylthio) pyrimidine to give 6-dichloro-2- (methylthio) pyrimidine followed by an oxidation process. The process disclosed in CN 101747283 uses a trifluoromethane sulfonic acid salt, a quaternary ammonium salt or an organic base catalyst, especially in the methoxylation reaction. The catalyst is selected from the group consisting of copper trifluoromethanesulfonate and tin trifluoromethanesulfonate, trioctylmethylammonium chloride, tertiary ammonium chloride, and triethylamine.

Another intermediate product for the synthesis of bispyridyl sodium is resorcinol, also known as 2,6-dihydroxybenzoic acid. Synthesis of 2,6-dihydroxybenzoic acid has been disclosed as follows in various prior art documents.

GB 9165481963 discloses a process for synthesizing 2, 6-dihydroxybenzoic acid by carboxylating a mono-potassium salt of resorcinol at 130 ° C in the presence of a solvent having the formula RCON (R ¹ ) ₂ Wherein R is a hydrogen or lower alkyl group and R < ¹ > is a lower alkyl group having 1-4 carbon atoms. N, N'-dimethylformamide and N, N'-diethylformamide are particularly preferred solvents. The alkali salt of resorcinol can be formed in situ by reacting resorcinol with an alkali metal hydroxide or carbonate or hydrogen carbonate. The separation of 2, 6-dihydroxybenzoic acid is carried out by acidification with hydrochloric acid followed by fractional crystallization.

US 5304677 discloses a process for preparing 2,6-dihydroxybenzoic acid by dissolving resorcinol in a suitable solvent and then bubbling carbon dioxide into this solution in the presence of a basic compound until absorption of the 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 or sodium carbonate and is used in an approximate equimolar amount to resorcinol. The reaction can be carried out at a temperature in the range of 100-200 ° C, at atmospheric pressure, or under a carbon dioxide pressure of 30 kg / cm ² . This patent also discloses that acidic aqueous base solution is acidified to a pH of from 5 to 7 using organic or inorganic acids and the mixture is heated from 90 DEG C to the boiling point of the aqueous solution to decompose the 2,4-dihydroxybenzoic acid from the resulting mixture And starts the process. After completion of the decomposition reaction, sulfuric acid is added to the mixture to achieve a pH of 3, and the insoluble material is subsequently filtered off. Sulfuric acid is further added to the filtrate until the pH reaches 1, and then the 2,6-dihydroxybenzoic acid is finally separated by filtration at 5 占 폚.

However, the prior art methods for the preparation of bispyridyl sodium and 4,6-disubstituted 2-alkylsulfonylpyrimidine, 2,6-dihydroxybenzoic acid have high impurity content, low yield, slow reaction rate , And low cost effectiveness. There is therefore a need for a simple, economical and high yield process for the preparation of these compounds.

Some of the objects of the present invention in which at least one embodiment is adapted for providing are described below.

It is an object of the present invention to provide a simple and high yield process for the preparation of bispyrite sodium.

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

Another object of the present invention is to provide a bispivalite sodium manufacturing process which makes the process economical using a soft base.

Another object of the present invention is to provide a bispivalite sodium production process which eliminates the use of strong acid.

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

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

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

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

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

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

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

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

Other objects and advantages of the present invention will become more apparent from the following description when taken 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 bispyridine sodium is provided and the process comprises reacting 2,6-dihydroxybenzoic acid with 2- (alkylsulfonyl) -4,6-dialkoxypyrimidine at a temperature of 20-80 < In the presence of at least one base and at least one solvent.

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

Typically, the solvent is selected from the group consisting of tetrahydrofuran and dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, sulfolane, monoglyme, diglyme .

Typically, the 2- (alkylsulfonyl) -4,6-dialkoxypyrimidine is 2- (methylsulfonyl) -4,6-dimethoxypyrimidine.

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

i. Reacting dialkyl malonate and thiourea in the presence of sodium alkoxide and one alcohol to obtain a sodium salt of thiovarbitalic acid;

ii. Alkylating the salt of thiobarbituric acid with alkyl chloride to obtain 2-alkylthio-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 the 2-alkylthio-4,6-dichloropyrimidine with sodium alkoxylate 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 dialkyl malonate is selected from the group consisting of dimethyl malonate and diethyl malonate, di-n-propyl malonate, di-n-butyl malonate and preferably the dialkyl malonate is dimethyl malonate to be.

Typically, the alkoxylated sodium is sodium methoxide.

Typically, the alkyl chloride is methyl chloride.

Typically, the 2-alkylthio-4,6-dihydroxypyrimidine is 2-methylthio-4,6-dihydroxypyrimidine.

Typically, 2-alkylthio-4,6-dichloropyrimidine is 2-methylthio-4,6-dichloropyrimidine.

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

Typically, the 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 the steps of adding dimethyl malonate and thiourea to the methanol to obtain a mass, heating the mass to a temperature of from 50 to 70 占 폚, adding a methanol solution of sodium methoxide Adding the mass to the mixture to obtain a mixture, maintaining the mixture at a temperature of 50 to 70 DEG C for 1-5 hours, distilling the methanol in the mixture by distillation to obtain a second mass, Filtering 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) comprises mixing the sodium salt of thiobarbituric acid with a solution of sodium hydroxide and methanol to obtain a mass, adding methyl chloride to the mass, stirring to yield 2-methylthio-4, Dihydroxypyrimidine. ≪ / RTI >

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, - adding to the step of heating to a temperature of 90 ℃, the heating of the POCl ₃ and chlorine mixture and subsequent 40-stirred at a temperature of 60 ℃ comprising the steps of obtaining a 2-methylthio-4,6-dichloropyrimidine do.

In one embodiment, step (iv) comprises admixing an alcoholic solution of sodium methoxide, cuprous chloride and sodium iodide to obtain a mixture, the mixture is allowed to stand, and 2-methylthio-4,6-dichloropyrimidine Adding at a temperature of 25 DEG C to obtain a mass, heating the mass at a temperature of 30 to 50 DEG C to obtain 4,6-dimethoxy-2- (methylthio) pyrimidine.

Step in one example (v) is a step of heating the 4,6-dimethoxy-2 (methylthio) pyrimidine and sodium tungstate, further, the mixture to give a mixture a mixture of acetic acid, hydrogen peroxide (H ₂ O ₂ ) is added to obtain 4,6-dimethoxy-2- (methylsulfonyl) pyrimidine.

In one embodiment, the catalyst is sodium tungstate.

Typically, aromatic hydrocarbons are 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 present invention there is provided a process for the preparation of 2,6-dihydroxybenzoic acid comprising the steps of:

- carboxylation of resorcinol at temperatures of from 100 to 200 DEG C in the presence of at least one base dissolved in at least one solvent in the presence of carbon dioxide to give 2,6-dihydroxybenzoic acid and 2,4-dihydroxy Benzoic acid, 4, 6-dihydroxyisophthalic acid;

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

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

- carboxylation of resorcinol at temperatures of from 100 to 200 DEG C in the presence of at least one base dissolved in at least one solvent in the presence of carbon dioxide to give 2,6-dihydroxybenzoic acid and 2,4-dihydroxy Benzoic acid, 4, 6-dihydroxyisophthalic acid;

Maintaining said mixture at a temperature between 140 DEG C and 180 DEG C for 1-10 hours;

≪ RTI ID = 0.0 > - < / RTI >

Acidifying said ascended mixture to pH 5.5-6 with one acid and then keeping it at 90-110 < 0 > C for 1-20 hours to obtain an acidified mass and descending said mass;

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

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

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

Typically, the acid is selected from the group consisting of hydrochloric acid and 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 carried out in a reactor having a pressure of 5 kg / cm ² to 45 kg / cm ² .

Typically, the drying step is carried out at a temperature of 40-70 < 0 > 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 decarboxylating 2,4-dihydroxybenzoic acid and 4, 6-dihydroxyisophthalic acid to obtain resorcinol, And regenerating the ricinol.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a reaction schematic diagram for the preparation of bispyridine sodium according to the present invention.
Figure 2 is a reaction schematic diagram for the preparation of 2- (alkylsulfonyl) -4,6-dialkoxypyrimidines.

A process for the preparation of bispyridyl sodium is provided in accordance with the present invention. The process comprises reacting 2,6-dihydroxybenzoic acid with 2- (alkylsulfonyl) -4,6-dialkoxypyrimidine at a temperature of 20-80 < 0 > C in the presence of a base such as sodium hydroxide and a group of potassium hydroxide, calcium hydroxide and lithium At least one selected from the group consisting of tetrahydrofuran and dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, sulfolane, monoglyme and diglyme in the presence of at least one base selected from Followed by condensation in the presence of a solvent to yield bispyridine sodium. The 2- (alkylsulfonyl) -4,6-dialkoxypyrimidine used in accordance with the present invention is 2- (methylsulfonyl) -4,6-dimethoxypyrimidine.

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

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

According to the present invention, the dialkyl malonate is selected from the group consisting of dimethyl malonate and diethyl malonate, di-n-propyl malonate, di-n-butyl malonate. In one embodiment, the dialkyl malonate is dimethyl malonate. The alcohol is selected from the group consisting of methanol and ethanol, n-propyl alcohol, n-butyl alcohol.

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

In the next step, the 2-alkylthio-4,6-dihydroxypyrimidine is chlorinated with phosphoryl chloride (POCl ₃ ) to give 2-alkylthio-4,6-dichloropyrimidine which is converted to the sodium alkoxide To give 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, a catalyst to obtain 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 preparing 4,6-dimethoxy-2- (methylsulfonyl) pyrimidine.

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

In the next step, 2-methylthio-4,6-dihydroxypyrimidine is chlorinated with chlorophosphoryl chloride (POCl ₃ ) to give 2-methylthio-4,6-dichloropyrimidine, Alkoxylated with methoxide to give 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, catalyst to give 4,6-dimethoxy-2- (methylsulfonyl) pyrimidine .

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

Adding dimethyl malonate and thiourea to the methanol to obtain one mass and heating the mass to a temperature of from 50 to 70 DEG 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 DEG C for 1-5 hours,

Removing the methanol in the mixture by distillation to obtain a second mass and subjecting the mass to quenching to obtain a quenched mass and filtering the mass to obtain a cake,

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

The process for preparing 2-methylthio-4,6-dihydroxypyrimidine in one exemplary embodiment involves the following steps:

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

-Methyl chloride is added to the mass and the mass is stirred to obtain 2-methylthio-4,6-dihydroxypyrimidine.

The process for preparing 2-methylthio-4,6-dichloropyrimidine in one exemplary embodiment involves the following steps:

- 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 from 40 to 90 DEG C to obtain a heated mixture,

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

The aromatic hydrocarbons are 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.

The process for preparing 4,6-dimethoxy-2- (methylthio) pyrimidines in one exemplary embodiment involves the following steps:

Stirring an alcoholic 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 DEG C to obtain a mass,

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

The process for preparing 4,6-dimethoxy-2- (methylsulfonyl) pyrimidine in one exemplary embodiment involves the following steps:

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

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

In another embodiment, a process for preparing 2,6-dihydroxybenzoic acid using resorcinol as the starting material is provided.

This process involves 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 a step of adjusting the pH of the mixture to < = 1. The purity of the 2,6-dihydroxybenzoic acid obtained in the process of the present invention is > 95%, preferably 99% or more. 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, and combinations thereof, and the solvent is selected from the group consisting of toluene and N, N-dimethylformamide, N , N-diethylformamide, ethanol, methanol, acetone, water. According to the invention, the carboxylation step is carried out at a temperature of 140-180 < 0 > C. Typically, the carboxylation step is carried out in a reactor having a pressure of 5 kg / cm ² to 45 kg / cm ² .

In one embodiment, the process involves the following steps:

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

Maintaining said mixture at a temperature of from 140 DEG C to 180 DEG C for a period of from 1 to 10 hours;

Cooling the mixture to obtain a cooled mixture;

Acidifying the cooled mixture to pH 5.5-6 with one acid and then maintaining it 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 subsequent filtration, washing and drying to obtain a solid mass and a filtrate;

- one acid is added to the filtrate to adjust the pH to 0.8-1 and subsequent 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 캜.

In one embodiment, the process includes decarboxylating 2,4-dihydroxybenzoic 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 Bispyridyl Sodium (Examples 1-5)

Example-1:

A clear solution of 154 gm of 2,6-dihydroxybenzoic acid dissolved in 500 ml dimethylsulfoxide was added to a commercially available (60% oil emulsion) solution containing 2 l of dimethylsulfoxide, Of sodium hydride at 30-32 < 0 > C. At 30-32 [deg.] C, the mass was further stirred for 2 hours and 480 gm of 4,6-dimethoxy-2- (methylsulfonyl) -pyrimidine was added thereto over 2 hours. The reaction was maintained at 30-32 < 0 > C until complete, resulting in bispivalite sodium. 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 in 1000 ml of 75% aqueous methanol. The wet solid was dried in the oven to give 435 gm of bispyrite sodium. The bispyridyl sodium was suspended again in 1200 ml of toluene at reflux temperature, cooled, filtered and dried to obtain 385 g of bispyridyl sodium (purity 98.7% HPLC).

Example-2:

A clear solution of 154 gm 2,6-dihydroxybenzoic acid dissolved in 500 ml dimethylsulfoxide was added to a commercially available (60% oil emulsion) solution containing 1500 gm Of sodium hydride at 30-32 < 0 > C. The mass was further stirred for 2 hours at 30-32 ° C and a slurry of 480 gm of 4,6-dimethoxy-2- (methylsulfonyl) -pyrimidine dissolved in 750 ml of DMSO was added thereto over a period of 2-3 hours Respectively. The reaction was maintained at 30-32 < 0 > C until complete, resulting in bispivalite sodium. 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 in 1000 ml of 75% aqueous methanol. The solid was dried in the oven to give 430 gm of bispyrite sodium. The bispyridyl sodium was suspended again in 1200 ml of toluene at reflux temperature, cooled, filtered and dried to obtain 380 gm of bispyridyl sodium (purity 98.3% HPLC).

Example-3:

A clear solution of 154 gm 2,6-dihydroxybenzoic acid dissolved in 500 ml dimethylsulfoxide was added to a commercially available (60% oil emulsion) mixture of 130 gm sodium hydride in 1500 ml dimethylsulfoxide At 30-32 < 0 > C. The mass was further stirred at 30 ° C for 2 hours and a slurry of 480 gm of 4,6-dimethoxy-2- (methylsulfonyl) -pyrimidine dissolved in 750 ml of DMSO was added thereto for 2 hours. The reaction was maintained at 30-32 < 0 > C until complete, resulting in bispivalite sodium. The mass was filtered and washed with DMSO. The wet solid was resuspended in 1000 ml of methanol and then in 1000 ml of 75% aqueous methanol. The solid was dried in the oven to give 440 gm of bispyrite sodium. The bispyrite sodium powder was suspended again in 1200 ml of toluene at reflux temperature, cooled, filtered and dried to obtain 380 gm of bispyridyl sodium (purity 98.5% HPLC).

Example-4:

A clear solution of 154 gm 2,6-dihydroxybenzoic acid dissolved in 500 ml dimethylsulfoxide was added to a commercially available (60% oil emulsion) mixture of 130 gm sodium hydride in 1500 ml dimethylsulfoxide At 30-32 < 0 > C. The mass was further stirred at 30 DEG C for 2 hours and a slurry of 480 gm of 4,6-dimethoxy-2- (methylsulfonyl) -pyrimidine dissolved in 750 ml of DMSO was added thereto. The reaction was maintained at 30-32 < 0 > C until complete, resulting in bispivalite sodium. The mass was filtered and washed with DMSO. The wet solid was resuspended in 1000 ml of methanol and then in 1000 ml of 75% aqueous methanol. The solid was dried in the oven to give 435 gm of bispyrite sodium. The bispyrite sodium powder was suspended again in 1200 ml of toluene at reflux temperature, cooled, filtered and dried to obtain 385 g of bispyridyl sodium (purity 98.6% HPLC).

Example-5:

A clear solution of 154 gm 2,6-dihydroxybenzoic acid dissolved in 500 ml dimethylsulfoxide was added to a commercially available (60% oil emulsion) mixture of 130 gm sodium hydride in 1500 ml dimethylsulfoxide At 30-32 < 0 > C. The mass was further stirred at 30 DEG C for 2 hours and a clear solution of 480 gm of 4,6-dimethoxy-2- (methylsulfonyl) -pyrimidine dissolved in 1500 ml of DMSO was added thereto. The reaction was maintained at 30-32 < 0 > C until complete, resulting in bispivalite sodium. The mass was filtered and washed with DMSO. The wet solid was resuspended in 1000 ml of methanol and then in 1000 ml of 75% aqueous methanol. The solid was dried in the oven to give 440 gm of bispyridyl sodium. The bispyrite sodium powder was suspended again in 1200 ml of toluene at reflux temperature, cooled, filtered and dried to obtain 350 gm of bispyridyl sodium (purity 98.6% HPLC).

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

Example 6: Preparation of sodium salt of thiobarbituric acid

A solution of 1.10 m thiourea dissolved in 280 ml methanol and 1.0 m dimethyl malonate 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. The resulting mass was cooled to below 30 < 0 > C, filtered and washed with methanol. The resulting cake was dried to obtain a thiobarbital sodium salt (yield: 90%).

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

Practical Example 7:

Preparation of 2-methylthio-4,6-dihydroxypyrimidine

1.0 m thiovarbitalic acid sodium salt was dissolved in 1.5 ml of 1 N aqueous sodium hydroxide solution and 50 ml of methanol in a SS autoclave to give a mixture. 0.5 m of methyl chloride was supplied thereto within 1-2 hours. The resulting reaction mass was stirred for 2-6 hours at 25-30 ° C, and the second lot of 0.5m methyl chloride was fed within 1-2 hours and the mass was stirred for 6-8 hours. To this was added 0.05m methyl chloride 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-hydroxypyrimidine. The yield of the product was 75-80 mol%.

Practical Example 8:

Preparation of 2-methylthio-4,6-dichloropyrimidine

To 4 m monochlorobenzene was added 1.0 m 2-methylthio-4,6-dihydroxypyrimidine. 2.2m POCl ₃ was added thereto within 1-2 hours and 2.2m triethylamine was added at 40-50 ° C for 2-4 hours. The resulting mixture was heated to 80 < 0 > C to give a clear solution which was stirred for 4-8 hours to afford mass. The resultant mass was cooled to 60 占 폚. To this was added 2.0m phosphorus trichloride. The next 2.0 m chlorine was fed at 60 ° C for 6-10 hours and stirred at 60 ° C for 8-10 hours. The Cl ₂ feed was carried out in the absence of light to prevent side chain chlorination. POCl ₃ was vacuum distilled, 200 ml monochlorobenzene was added and distillation was continued to ensure complete removal of POCl ₃ . 4.0 m - 4.3 m POCl ₃ was regenerated and the residual mass was submerged in 200 ml ice water and extracted with monochlorobenzene. To this monochlorobenzene layer was added 100 ml of water and neutralized with NaHCO ₃ . These layers were separated and the monochlorobenzene layer was concentrated in vacuo. The yield of the product was 85-87%.

The product was vacuum distilled and crystallized using the following methanol to give 85 mole% having 99% purity.

Practical Example 9:

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

To a 2.2 m 3 N sodium methoxide solution dissolved in methanol was added 2 m% cuprous chloride and 2m% sodium iodide to give a mixture which was then cooled to 20 ° C. 2m% cuprous chloride and 2m% sodium iodide were dissolved in 400ml methanol and added to the mixture for 3-6 hours and stirred for 1 hour at 20 ° C to obtain a reaction mass. The temperature of the mass was raised to 30 ° C and the mixture was stirred at 40 ° C for 6-12 hours. HPLC was performed using 95-96% 2-methylthio-4,6-dimethoxypyrimidine and 0.5% Methoxy-6-chloropyrimidine. The mass was cooled and the sodium chloride was filtered off. The methanol was distilled from the filtrate, water was added to the remaining 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

3m% sodium tungstate was added to 200ml acetic acid. 1.0 m 2-methylthio-4,6-dimethoxypyrimidine was added thereto to obtain a mass (clear solution). This mass was heated to 40 占 폚. To the heated mass was added 2.1m 30% H ₂ O ₂ for 4-8 hours and stirred at 40 ° C for 3-5 hours. 0.05m 30% H ₂ O ₂ was added and stirred at 40 ° C until complete transition. The reaction was carried out at 40 < 0 > C. The reaction mixture was cooled and the solid material was filtered. The resulting cake 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. wt = 42 g The yield of the 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 the reactor and a Dean-Stark apparatus was installed to obtain mass. The resulting mass was dehydrated by removing water from the side arm of the Dean-Stark apparatus. If no more water was observed in the sidearm of the Dean-Stark apparatus, the toluene was completely distilled and a solution was obtained by adding N, N-dimethylformamide (330 ml).

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

The mixture was allowed to warm to 50 < 0 > C, the carbon dioxide pressure was removed and the carbon dioxide was vented in an alkali scrubber. The mixture was transferred to the next glass reactor and N, N-dimethylformamide was distilled at a liquid temperature of 110 ° C and 10 mm Hg pressure 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 with concentrated hydrochloric acid to a pH of 5.5-6 and maintained at 100 < 0 > 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 a dry solid. (HPLC composition = 95.2% 4,6-dihydroxyisophthalic acid, 2.97% 2,6-dihydroxybenzoic acid). The filtrate at pH 2.85 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 < 0 > C to yield 53.9 grams of solid with 96.1% 2,6-dihydroxybenzoic acid by HPLC.

Example-12

A mixture of 220 gram resorcinol (2.0 mole), 1300 ml 50% (v / v) aqueous ethanol and 276 grams (2.0 mole) 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 < 0 > C. The mixture was held at 170 캜 for 5 hours while maintaining a carbon dioxide pressure of 38-39 kg / cm ² .

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

The mixture was transferred to the next 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 < 0 > C and distilled from the mixture at a liquidus temperature of 100 < 0 > C. The following reaction mixture was kept at reflux for 12.5 hours while adding concentrated hydrochloric acid and the pH value was maintained at 5.5-6.

After 12.5 hours at 100 캜, the composition of the reaction mass was 55.25% -2,6-dihydroxybenzoic acid, 3.6% -2,4-dihydroxybenzoic acid, 20.35% resorcinol and 19.90% 4 , 6-dihydroxyisophthalic acid.

After the reduction of 2,4-dihydroxybenzoic acid was complete, concentrated hydrochloric acid was added to the mixture until a pH value of 2.83 was reached. The resulting solid was filtered and the wet solid was suspended again in water. To this was added concentrated hydrochloric acid until a pH value of 0.90 was reached. The solid material was filtered, washed and dried at 60 < 0 > C until a constant weight was reached, yielding 11.8 grams of a dry solid. (HPLC composition was 93.5% 4,6-dihydroxyisophthalic acid and 5.84% 2,6-dihydroxybenzoic acid).

The filtrate at pH 2.83 was acidified with concentrated hydrochloric acid to a pH value of 0.9-1.0 and stirred for 1 hour. The resulting slurry was cooled to 0 C and stirred for 1 hour and filtered. The wet cake was suspended again in water, stirred at 55-60 [deg.] C, cooled to 0 [deg.] C and filtered. The solid was washed with cooling water and dried at 60 < 0 > C until constant weight yielded 99.2 grams of dry solid 2,6-dihydroxybenzoic acid. (96.4% purity on HPLC)

Example-13

A mixture of 220 grams resorcinol (2.0 mole), 1300 ml 50% (v / v) aqueous ethanol and 138 grams (2.0 mole) 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 DEG C and the mixture was maintained at 170 DEG 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 the carbon dioxide was vented and vented in an alkali scrubber.

The mixture was neutralized to pH = 5.5-6 at 30 < 0 > C using concentrated sulfuric acid. The ethanol / water was then distilled from the mixture at a liquid temperature of 98-100 ° C. The concentrated sulfuric acid was added to the reaction mixture while maintaining the pH value at 5.5-6 when heated, and the reaction mixture was maintained at reflux for 11 hours.

After 11 hours, the HPLC composition of the mass was 52.47% -2,6-dihydroxybenzoic acid, 20.20% -2,4-dihydroxybenzoic acid, 24.2% resorcinol and 2.47% 4,6-dihydroxyiso Dihydroxybenzoic acid, 2.81% -2,4-dihydroxybenzoic acid, 38.14% resorcinol, and 2.15% 4,6-dihydroxyisophthalic acid in comparison with phthalic acid.

The mass was cooled to ambient temperature and concentrated sulfuric acid was added to the mixture until a pH value of 4 was reached. 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 < 0 > C, stirred for 1 hour and filtered. The wet solid was suspended again in water, stirred at 55-60 < 0 > C for 1 hour, cooled to 25 [deg.] C and filtered. The solid was washed with water and dried at 60 < 0 > C until constant weight yielded 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 extracts were concentrated under reduced pressure to give a mixture of 85.7% resorcinol, 7.8% -2,6-DHBA, 1.6% 2,4-dihydroxybenzoic acid and 2.1% 4,6-dihydroxy Benzoic acid as a viscous mass.

The residue methyl ethyl ketone was regenerated after distillation containing a lot of resorcinol.

Example-14

142 grams of 142 grams of methyl ethyl ketone concentrated mass obtained from Example-13 (1.107 m Resorcinol; 0.072 m 2,6-DHBA) was mixed with 90.3 grams of Sure Resorcinol 0.821 moles) 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 DEG C and the mixture was maintained at 170 DEG 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 the carbon dioxide was vented and vented in an alkali scrubber.

The mixture was neutralized to pH = 5.5-6 at 30 < 0 > C using concentrated sulfuric acid. The ethanol / water was then distilled from the mixture at 98-100 < 0 > C liquid temperature. The following reaction mixture was kept at reflux for 12 h while adding concentrated hydrochloric acid to the reaction mixture until the pH value reached 5.5-6.

After 12 hours of holding, the HPLC composition contained 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 Dihydroxybenzoic acid and 0.1% 2,4-dihydroxybenzoic acid, 41.04% resorcinol, and 0.93% 4,6-dihydroxyisophthalic acid in comparison with phthalic acid. The 4,6-dihydroisophthalic acid was completely decarboxylated using concentrated sulfuric acid at 100 < 0 > C.

The concentrated sulfuric acid was added to the mixture until the pH reached 3.96. The slurry was equilibrated at 30 < 0 > C for 1 hour and filtered to remove potassium sulfate. The filtrate was acidified to pH 0.9-1.0 with concentrated sulfuric acid and stirred for 1 hour. The resulting slurry was cooled to 10 < 0 > C and stirred for 1 hour and filtered.

The wet solid was suspended in water again, stirred at 55-60 < 0 > C for 1 hour, cooled to 25 [deg.] C and filtered. The solids were washed with water and dried to constant weight at 60 ° C to yield 76.5 grams of 2,6-dihydroxybenzoic acid dry cake. (99.0% pure by HPLC).

Example-15

After the basic reaction was carried out and the 2,6-dihydroxybenzoic acid was isolated, 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 filtered of charcoal. The resorcinol content in the aqueous filtrate was determined by HPLC, and the lack of resorcinol for the 2.0 molar batch size was compensated by the addition of raw resorcinol and the carboxylation was carried out according to the procedure given in Examples 13 and 14 Respectively.

The yield of 2,6-dihydroxybenzoic acid was 33% (using raw resorcinol), 35% after first regeneration of the aqueous filtrate, and 32% after second regeneration of the aqueous filtrate.

'Each time a range of values is specified, values up to 10% below the specified range and the minimum and maximum values are included in the scope of the invention, respectively.

While the present invention has been particularly shown and described with reference to preferred embodiments thereof, many embodiments may be practiced without departing from the principles of the invention, and many changes may be made in the preferred embodiment. These and other variations of the invention as well as other embodiments of the invention in a suitable embodiment will be apparent to those skilled in the art from the present invention. It is therefore to be expressly understood that the foregoing description is only intended to illustrate the present invention and not to limit it.

Throughout this document, the terms " comprises, " or variations such as " comprises, " or " comprising ", include the referenced elements or integers, steps, or elements or integers, But does not exclude any other element or integer, step, or element or integer, step.

The use of the phrases " at least " or " at least one " means the use of one or more elements or components, In the embodiments of the present invention.

Any theory of the literature, acts, materials, devices, products, etc. included in the present description is only intended to provide the context of the present invention. It is not admitted that any or all of these are present anywhere prior to the date of priority of this application to form part of the prior art or become a conventional knowledge of the relevant field of the present invention.

It is to be understood that the various physical parameters, sizes or amounts are only approximations and that values greater than or less than the numbers assigned to these parameters, sizes or quantities are within the scope of the present invention unless otherwise stated in the description .

Claims (31)

In the process for the preparation of bispyridyl sodium, the process comprises reacting 2,6-dihydroxybenzoic acid with 2- (alkylsulfonyl) -4,6-dialkoxypyrimidine at 20-80 ° C with at least one base and at least And condensing in the presence of one solvent.
The process according to claim 1, wherein the base is selected from the group consisting of sodium hydroxide and potassium hydroxide, calcium hydroxide and lithium.
The method according to claim 1, wherein the solvent is selected from the group consisting of tetrahydrofuran and dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, sulfolane, monoglyme, diglyme Process.
The process according to claim 1, wherein the 2- (alkylsulfonyl) -4,6-dialkoxypyrimidine is 2- (methylsulfonyl) -4,6-dimethoxypyrimidine.
The method of claim 1, wherein the 4,6-dialkoxy-2- (alkylsulfonyl) pyrimidines are prepared by the steps of:
i. Reacting a dialkyl malonate and a thiourea in the presence of sodium alkoxide and one alcohol to obtain a sodium salt of thiovarbitalic acid;
ii. Alkylating the salt of thiobarbituric acid with alkyl chloride to obtain 2-alkylthio-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 the 2-alkylthio-4,6-dichloropyrimidine with sodium alkoxylate 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)
≪ / RTI >
6. The composition of claim 5 wherein the dialkyl malonate is selected from the group consisting of dimethyl malonate and diethyl malonate, di-n-propyl malonate, di-n-butyl malonate, Lt; RTI ID = 0.0 > dimethylmalonate. ≪ / RTI >
6. The process of claim 5, wherein the sodium alkoxide is sodium methoxide.
6. The process according to claim 5, wherein the alkyl chloride is methyl chloride.
6. The process according to claim 5, wherein the 2-alkylthio-4,6-dihydroxypyrimidine is 2-methylthio-4,6-dihydroxypyrimidine.
6. The process according to claim 5, wherein the 2-alkylthio-4,6-dichloropyrimidine is 2-methylthio-4,6-dichloropyrimidine.
6. The process of claim 5, wherein the 4,6-dialkoxy-2- (alkylthio) pyrimidine is 4,6-dimethoxy-2- (methylthio) pyrimidine.
6. The process according to claim 5, wherein the 4,6-dialkoxy-2- (alkylsulfonyl) pyrimidine is 4,6-dimethoxy-2- (methylsulfonyl) pyrimidine.
6. The process according to claim 5, wherein the alcohol is selected from the group consisting of methanol and ethanol, n-propyl alcohol, n-butyl alcohol.
6. The method of claim 5, wherein step (i) comprises: adding dimethyl malonate and a thiourea to the methanol to obtain a mass, heating the mass to a temperature of 50 to 70 DEG C, adding a methanol solution of sodium methoxide To obtain a mixture, maintaining the mixture at a temperature of 50 to 70 DEG C for 1 to 5 hours, distilling the methanol in the mixture by distillation to obtain a second mass, cooling the mass To obtain a cooled mass; filtering the mass to obtain a cake; washing the cake with methanol and subsequent drying to obtain a sodium salt of thiobarbituric acid.
6. The method of claim 5, wherein step (ii) comprises: mixing the sodium salt of thiobarbituric acid with a sodium hydroxide solution and methanol to obtain a mass, adding methyl chloride to the mass, 4,6-dihydroxypyrimidine. ≪ / RTI >
The method of claim 5, wherein step (iii) to obtain a 2-methylthio-4,6-dihydroxy-pyrimidine and the POCl _3, at least one aromatic hydrocarbon mixture by mixing at least one base, and the mixture Heating the mixture to a temperature of 40 to 90 ° C., adding POCl ₃ and chlorine to the heated mixture, and stirring the mixture at a temperature of 40 to 60 ° C. to obtain 2-methylthio-4,6-dichloropyrimidine ≪ / RTI >
6. The method of claim 5, wherein step (iv) comprises: mixing an alcoholic solution of sodium methoxide, cuprous chloride and sodium iodide to obtain a mixture, cooling the mixture and 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 ≪ / RTI >
6. The method of claim 5, wherein step (v) comprises the steps of mixing 4,6-dimethoxy-2- (methylthio) pyrimidine and sodium tungstate, acetic acid to obtain a mixture, heating the mixture, H ₂ O ₂ ) is added to obtain 4,6-dimethoxy-2- (methylsulfonyl) pyrimidine.
6. The process of claim 5, wherein the catalyst is sodium tungstate.
17. The process of claim 16, wherein the aromatic hydrocarbon is selected from the group consisting of monochlorobenzene and o-dichlorobenzene, and combinations thereof.
17. The process of claim 16, wherein the base is selected from the group consisting of triethylamine and tripropylamine, tributylamine, and combinations thereof.
The method of claim 1, wherein the 2, 6-dihydroxybenzoic acid is selected from the group consisting of:
i. In the presence of carbon dioxide, resorcinol is carboxylated at a temperature of from 100 to 200 DEG C in the presence of at least one base dissolved in at least one solvent to give 2,6-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid And 4, 6-dihydroxyisophthalic acid;
ii. Acidifying the mixture with at least one acid comprising adjusting the pH of the mixture to < RTI ID = 0.0 > 1, < / RTI > to obtain 2,6-dihydroxybenzoic acid with a purity of >
≪ / RTI >
23. The method of claim 22,
- carboxylation of resorcinol at temperatures of from 100 to 200 DEG C in the presence of at least one base dissolved in at least one solvent in the presence of carbon dioxide to give 2,6-dihydroxybenzoic acid and 2,4-dihydroxy Benzoic acid, 4, 6-dihydroxyisophthalic acid;
Maintaining said mixture at a temperature between 140 DEG C and 180 DEG 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 keeping it at 90-110 < 0 > 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 filtering, washing and drying to obtain a solid mass and a filtrate;
Adding one acid to the filtrate to adjust the pH to 0.8-1 and subsequent stirring, cooling, filtering, washing and drying to give 2,6-dihydroxybenzoic acid in a purity of>95%;≪ / RTI >
24. Process according to claim 22 or 23, characterized in that the carboxylation step is carried out at a temperature of 140-180 < 0 > C.
24. The process according to claim 22 or 23, wherein the acid is selected from the group consisting of hydrochloric acid, sulfuric acid and acetic acid.
24. The process according to claim 22 or 23, wherein the base is selected from the group consisting of potassium carbonate and potassium hydroxide, sodium carbonate, and combinations thereof.
24. The method of claim 22 or 23, wherein the solvent is selected from the group consisting of toluene and N, N-dimethylformamide, N, N-diethylformamide, ethanol, methanol, acetone, water, ≪ / RTI >
Claim 22 according to any one of claims 23, wherein the carboxylation step is 5 kg / cm ² - a step of being run in a reactor having a pressure of 45 kg / cm ^2.
24. The process according to claim 23, wherein the drying step is carried out at a temperature of 40-70 < 0 > C.
24. Process according to claim 22 or 23, characterized in that the purity of 2,6-dihydroxybenzoic acid is > 99%.
24. The method of claim 22 or 23, comprising decarboxylating 2,4-dihydroxybenzoic acid and 4, 6-dihydroxyisophthalic acid to obtain resorcinol and regenerating the resorcinol ≪ / RTI >

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