CN105026376A - Processes for the preparation of bispyribac sodium and intermediates thereof - Google Patents
Processes for the preparation of bispyribac sodium and intermediates thereof Download PDFInfo
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Abstract
The present disclosure relates to a process for the preparation of Bispyribac-sodium by condensing 2,6-dihydroxy benzoic acid with 2-(alkyl sulfonyl)-4,6-dialkoxy pyrimidine in the presence of at least one base and at least one solvent. The present disclosure also relates to processes for the preparation of 2,6-dihydroxy benzoic acid and 2-(alkyl sulfonyl)-4,6- dialkoxy pyrimidine.
Description
Technical field
The present invention relates to the method for the two careless ether sodium of preparation and intermediate thereof.
Background technology
Two careless ether sodium
IUPAC (IUPAC) names: two (4, the 6-dimethoxypyridin-2-base oxygen base) Sodium Benzoate of 2,6-
Structure:
Chemical formula: C
19h
17n
4naO
8
Molecular weight: 452.4
Physical condition: white powder
Fusing point: 223-224 DEG C
Water-soluble: to be 73.3g/l when 25 DEG C
Binding mode: optionally, systemic action post-emergence herbicide, cauline leaf and root absorption.
Two careless ether sodium is systemic herbicide, penetrates plant tissue and works by disturbing the generation of the required enzyme acetolactate synthase (ALS) of plant-growth.It is for controlling weeds, nutgrass flatsedge and broadleaf weeds, the barnyard grass class particularly in direct seading rice.It is also for suppressing the weed growth under non-agricultural crop situation.
Two careless ether sodium by microbiological deterioration, and has the half life (time spent by active ingredient degradation to half) of 42-115 days.The primary degradation product of two careless ether sodium is 2-(4,6 dimethoxypyridin-2-base) oxygen base-6-(4-hydroxyl-6-Sulfamonomethoxine base-2-base) Sodium Benzoate.Two careless ether sodium is not combined with soil, but the slow permeable soil that appropriateness continues.Experiment shows, the aqueous formulation of two careless ether sodium to fish and invertebrates nontoxic.Two careless ether sodium to birds and Mammals also nontoxic.
In order to synthesize two careless ether sodium, one of intermediate is 4,6-dialkoxy-2-(alkyl sulphonyl) pyrimidine
4,6-dialkoxy-2-(alkyl sulphonyl) pyrimidine
Part prior art document has disclosed the synthetic method of 4,6-dialkoxy-2-(alkyl sulphonyl) pyrimidine.Such as WO2000046212 discloses 4,6-dialkoxy-2-(alkyl sulphonyl) pyrimidine.The method relates to and is mixed in dimethylbenzene, triphenylphosphine oxide and tetrabutylammonium chloride by 2-methylthio group barbituric acid, then heats and passes into phosgene until the reaction of adducts terminates.In follow-up phase, from reactant, remove phosgene, then use water extraction organic phase and react in 50 DEG C with sodium methylate, form 4,6-dimethoxy-2-(alkyl sulphonyl) pyrimidine.Further, add 5mol% sodium wolframate and 5mol% tetrabutylammonium chloride in reaction mixture, mix in 85 DEG C of hydrogen peroxide with 2 molar equivalents.
WO2002008207 discloses for the preparation of 4, 6-dimethoxy-2-(methylsulfonyl)-1, the method of 3-pyrimidine, it passes through 4 in inert organic solvents, the chloro-2-of 6-bis-(methylthio group)-1, 3-pyrimidine and alkali metal methoxide reactant salt, obtain thus 4, 6-dimethoxy-2-(methylthio group)-1, 3-pyrimidine is converted into water-based-acidic medium, be tri-n-octyl methyl ammonium chloride with this compound catalyst of rear oxidation, be wherein purification step after oxidation, in this step, water-based-acidic reaction mixture is adjusted to pH and is 5-8 and stirs under the condition of presence or absence organic solvent by use alkali.
CN 101747283 discloses for the preparation of 4; the method of 6-dimethoxy-2-(methylsulfonyl) pyrimidine; relate to 4; the chlorination of 6-dihydroxyl-2-(methylthio group) pyrimidine; to obtain the chloro-2-of 4,6-bis-(methylthio group) pyrimidine, after its methoxylation, obtain 4; 6-dimethoxy-2-(methylthio group) pyrimidine, is then oxidized.Disclosed in CN 101747283, method have employed trifluoro-methanyl sulfonate, quaternary ammonium salt or organic alkali catalyst especially in methoxylation.Catalyzer is selected from trifluoromethayl sulfonic acid copper, trifluoro-methanyl sulfonate, trifluoromethayl sulfonic acid tin, methyl tricapryl ammonium chloride, tertiary amine muriate and triethylamine.
Another intermediate for the synthesis of two careless ether is resorcylic acid, also referred to as 2,6-DHBA.The synthetic method of 2,6-DHBA is open in various prior art document, such as:
GB 9165481963 discloses the synthesis of 2,6-DHBA, its by 130 DEG C, be RCON (R at chemical formula
1)
2solvent existence under, the anhydrous monopotassium salt of carboxylation resorcin(ol), wherein R is hydrogen or low alkyl group, and R
1for having the low alkyl group of 1 to 4 carbon atom.N, N '-dimethyl methane amide and N, N '-diethylformamide is preferred solvent.By by resorcin(ol) and the reaction of alkali metal hydroxide, carbonate or supercarbonate, form an alkali metal salt of resorcin(ol) in position.The separation of 2,6-DHBA is subject to the impact of hcl acidifying and fractional crystallization subsequently.
US 5304677 discloses the synthesis of 2,6-DHBA, and carbonic acid gas, by being dissolved in by resorcin(ol) in suitable solvent, then under the existence of basic cpd, is blown in solution by it, until carbonic acid gas stops absorbing.Alcohols, alkoxyl group alcohols, dimethyl formamide, water and composition thereof can be used as solvent.Basic cpd can be salt of wormwood, potassium hydroxide or sodium carbonate, and uses with about and the equimolar amount of resorcin(ol).Reaction can be 100 to 200 DEG C in temperature, under normal atmosphere or Carbon dioxide air pressure be 30kg/cm
2under carry out.This patent also discloses the decomposition of 2,4-resorcylic acid, and by having the basic aqueous solution of organic or inorganic acid, it is 5 to 7 that reaction mixture is acidified to pH, and mixture is heated to the boiling temperature of aqueous solution from 90 DEG C.After completing decomposition reaction, add sulfuric acid to mixture and reach 3 to pH, then elimination insoluble substance.Add sulfuric acid further to filtrate, until pH value reaches 1, then in 5 DEG C of filtrations, be finally separated 2,6-DHBA.
But, still there are some defects for the preparation of two careless ether sodium, 4,6-bis-methods replacing-2-alkyl sulfonyl yl pyrimidines and 2,6-DHBA in prior art, such as have that foreign matter content is high, productive rate is low, speed of reaction is slow and cost benefit low etc.Therefore, need simple, economical with the method for the preparation of these compounds that is high yield.
Goal of the invention
Objects more of the present invention are as described below, at least provide an embodiment for realizing these objects:
An object of the present invention is to provide a kind of method for the preparation of two careless ether sodium of simple, high yield.
Another object of the present invention is to provide a kind of time saving method for the preparation of two careless ether sodium.
Another object of the present invention is to provide a kind of method for the preparation of two careless ether sodium, and it adopts weak base to make method economy.
Another object of the present invention is to provide a kind of method for the preparation of two careless ether sodium, and it does not use strong acid.
Another object of the present invention is to provide a kind of method for the preparation of 4,6-dialkoxy-2-(alkyl sulphonyl) pyrimidine.
Another object of the present invention is to provide a kind of method for the preparation of 4,6-dialkoxy-2-(alkyl sulphonyl) pyrimidine of simple, cost-effective.
Another object of the present invention is to provide a kind of method for the preparation of 4,6-dialkoxy-2-(alkyl sulphonyl) pyrimidine of high yield.
Another object of the present invention is for providing a kind of highly purified method for the preparation of 4,6-dialkoxy-2-(alkyl sulphonyl) pyrimidine.
Another object of the present invention is to provide a kind of method for the preparation of 2,6-DHBA.
Another object of the present invention is to provide a kind of method for the preparation of 2,6-DHBA of high yield.
Another object of the present invention is to provide a kind of method for the preparation of 2,6-DHBA of environmental protection.
Another object of the present invention is to provide a kind of method for the preparation of 2,6-DHBA of economy.
When reading following detailed description in detail by reference to the accompanying drawings, other objects of the present invention and advantage will be more obvious, and these accompanying drawings are not intended to limit the scope of the invention.
Summary of the invention
According to a kind of method for the preparation of two careless ether sodium provided by the invention; Described method is included in the temperature of 20 to 80 DEG C, under at least one alkali and at least one solvent exist, 2,6-DHBA and 2-(alkyl sulphonyl)-4,6-dialkoxypyrimidin is carried out condensation.
Usually, described alkali is selected from sodium hydride, potassium cyanide, lithium hydride and hydrolith.
Usually, described solvent is selected from tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, tetramethylene sulfone, monoglyme and diglyme.
Usually, 2-(alkyl sulphonyl)-4,6-dialkoxypyrimidin is 2-(methylsulfonyl)-4,6-dimethoxypyridin.
On the other hand, the invention provides a kind of method for the preparation of 4,6-dialkoxy-2-(alkyl sulphonyl) pyrimidine, said method comprising the steps of:
1) dialkyl malonate and thiocarbamide are reacted under the existence of sodium alkoxide and alcohol, obtain the sodium salt of thiobarbituricacidα-;
2) with the sodium salt alkylation of alkyl chloride by described thiobarbituricacidα-, 2-alkyl sulfenyl-4,6-dihydroxy-pyrimidine is obtained;
3) with phosphoryl chloride (POCl
3) chlorination is carried out to described 2-alkyl sulfenyl-4,6-dihydroxy-pyrimidine, obtain 2-alkyl sulfenyl-4,6-dichloro pyrimidine;
4) with sodium alkoxide, alkoxylate is carried out to described 2-alkyl sulfenyl-4,6-dichloro pyrimidine, obtain 4,6-dialkoxy-2-(alkyl sulfenyl) pyrimidine; With
5) under hydrogen peroxide, acetic acid and catalyzer exist, by described 4,6-dialkoxy-2-(alkyl sulfenyl) pyrimidine oxidation, 4,6-dialkoxy-2-(alkyl sulphonyl) pyrimidine is obtained.
Usually, wherein dialkyl malonate is selected from dimethyl malonate, diethyl malonate, propanedioic acid di-n-propyl ester and propanedioic acid di-n-butyl, and preferably, dialkyl malonate is dimethyl malonate.
Usually, sodium alkoxide is sodium methylate.
Usually, alkyl chloride is methyl chloride.
Usually, 2-alkyl sulfenyl-4,6-dihydroxy-pyrimidine is 2-methylthio group-4,6-dihydroxy-pyrimidine.
Usually, 2-alkyl sulfenyl-4,6-dichloro pyrimidine is 2-methylthio group-4,6-dichloro pyrimidine.
Usually, 4,6-dialkoxy-2-(alkyl sulfenyl) pyrimidine is 4,6-dimethoxy-2-(methylthio group) pyrimidine.
Usually, 4,6-dialkoxy-2-(alkyl sulphonyl) pyrimidine is 4,6-dimethoxy-2-(methylsulfonyl) pyrimidine.
Usually, described alcohol is selected from methyl alcohol, ethanol, n-propyl alcohol and propyl carbinol.
In one embodiment, step (1) comprises dimethyl malonate and thiocarbamide is added to methyl alcohol to obtain material, heat this material to 50 to the temperature of 70 DEG C, the methanol solution of sodium methylate is incorporated to described material to obtain mixture, maintain described mixture in the temperature 1 to 5 hour of 50 to 70 DEG C, remove methyl alcohol to obtain the second material by distillation from described mixture, cool described material to obtain the material cooled, described material is filtered to obtain filter cake; And with filter cake described in methanol wash, then dry, obtain the sodium salt of thiobarbituricacidα-.
In one embodiment, step (2) comprises the sodium salt of thiobarbituricacidα-and sodium hydroxide solution and methanol mixed, obtains material, to be added by methyl chloride in described material and to stir, obtaining 2-methylthio group-4,6-dihydroxy-pyrimidine.
In one embodiment, step (3) comprises 2-methylthio group-4,6-dihydroxy-pyrimidine, POCl
3, at least one aromatic hydrocarbon and the mixing of at least one alkali, obtain mixture, heat described mixture to 40 to the temperature of 90 DEG C, obtain the mixture heated, by POCl
3join in the mixture of described heating with chlorine, then stir in the temperature of 40 to 60 DEG C, obtain 2-methylthio group-4,6-dichloro pyrimidine.
In one embodiment, step (4) comprises and the alcoholic solution of sodium methylate, cuprous chloride and sodium iodide being mixed, obtain mixture, cool described mixture, then at the temperature of 15 to 25 DEG C, add 2-methylthio group-4,6-dichloro pyrimidine to obtain material, at the temperature of 30 to 50 DEG C, heat described material, obtain 4,6-dimethoxy-2-(methylthio group) pyrimidine.
In one embodiment, step (5) comprises and 4,6-dimethoxy-2-(methylthio group) pyrimidine, sodium wolframate and acetic acid being mixed, and obtains mixture, heats described mixture and add hydrogen peroxide (H
2o
2), obtain 4,6-dimethoxy-2-(methylsulfonyl) pyrimidine.
In one embodiment, catalyzer is sodium wolframate.
Usually, aromatic hydrocarbon is selected from mono chloro benzene, orthodichlorobenzene and combination thereof.
Usually, alkali is selected from triethylamine, tripropyl amine, Tributylamine and combination thereof.
On the other hand, the invention provides a kind of method for the preparation of 2,6-DHBA, said method comprising the steps of:
-under the existence of carbonic acid gas and at least one alkali, at least one solvent, at the temperature of 100 to 200 DEG C, by resorcin(ol) carboxylation, obtain the mixture containing 2,6-DHBA, 2,4-resorcylic acids and 4,6-resorcylic acid; And
-use mixture described at least one acid acidifying, obtain the 2,6-DHBA that purity is greater than 95%, wherein acidification step comprises pH≤1 adjusting described mixture.
In one embodiment, 2,6-DHBA is prepared by following steps:
-under the existence of carbonic acid gas and at least one alkali, at least one solvent, at the temperature of 100 to 200 DEG C, by resorcin(ol) carboxylation, obtain the mixture containing 2,6-DHBA, 2,4-resorcylic acids and 4,6-resorcylic acid;
-maintain the temperature 1 to 10 hour that described mixture is in 140 DEG C to 180 DEG C;
-cool this mixture to obtain the mixture cooled;
-with acid, the mixture of described cooling is acidified to pH is 5.5 to 6, then maintain 1 to 20 hour in 90-110 DEG C, obtain the material of acidifying and cool described material;
-with acid, the pH of described material is adjusted to 2 to 3, then by filtering, washing and drying, obtain solid matter and filtrate; And
-add acid to adjust pH to 0.8 to 1 to described filtrate, then stir, cool, filter, wash and drying, obtain the 2,6-DHBA that purity is greater than 95%.
Usually, carbonation step carries out at the temperature of 140 to 180 DEG C.
Usually, described acid is selected from hydrochloric acid, sulfuric acid and acetic acid.
Usually, described alkali is selected from salt of wormwood, potassium hydroxide, sodium carbonate and combination thereof.
Usually, solvent is selected from toluene, DMF, N, N-diethylformamide, ethanol, methyl alcohol, acetone, water and combination thereof.
Usually, carbonation step is 5kg/cm at pressure
2to 45kg/cm
2reactor in carry out.
Usually, drying is carried out at the temperature of 40 to 70 DEG C.
In one embodiment, the purity of 2,6-DHBA is greater than 99%.
In one embodiment, comprise for the preparation of the method for 2,6-DHBA decarboxylation is carried out to obtain resorcin(ol) and to reclaim the step of described resorcin(ol) to 2,4-resorcylic acid and 4,6-resorcylic acid.
Accompanying drawing explanation
Fig. 1 shows the reaction formula according to the two careless ether sodium of preparation of the present invention;
Fig. 2 shows the reaction formula of preparation 2-(alkyl sulphonyl)-4,6-dialkoxypyrimidin.
Embodiment
The invention provides a kind of method for the preparation of two careless ether sodium.The method relates at the temperature of 20 to 80 DEG C, under at least one alkali and at least one solvent exist, 2,6-DHBA and 2-(alkyl sulphonyl)-4,6-dialkoxypyrimidin is carried out condensation.Described alkali is selected from sodium hydride, potassium cyanide, lithium hydride and hydrolith.Described solvent is selected from tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, tetramethylene sulfone, glycol dimethyl ether, monoglyme and diglyme.According to the present invention, 2-(alkyl sulphonyl)-4,6-dialkoxypyrimidin is 2-(methylsulfonyl)-4,6-dimethoxypyridin.
On the other hand, the invention provides a kind of method for the preparation of 4,6-dialkoxy-2-(alkyl sulphonyl) pyrimidine.
The first step, reacts dialkyl malonate and thiocarbamide, obtains the sodium salt of thiobarbituricacidα-under the existence of sodium alkoxide and alcohol.
According to the present invention, dialkyl malonate is selected from dimethyl malonate, diethyl malonate, propanedioic acid di-n-propyl ester and propanedioic acid di-n-butyl.In one embodiment, dialkyl malonate is dimethyl malonate.Alcohol is selected from methyl alcohol, ethanol, n-propyl alcohol and propyl carbinol.
With the salt alkylation of alkyl chloride by obtained thiobarbituricacidα-, obtain 2-alkyl sulfenyl-4,6-dihydroxy-pyrimidine.
In next step, with phosphoryl chloride (POCl
3) chlorination is carried out to 2-alkyl sulfenyl-4,6-dihydroxy-pyrimidine, obtain 2-alkyl sulfenyl-4,6-dichloro pyrimidine, with sodium alkoxide, alkoxylate is carried out to this 2-alkyl sulfenyl-4,6-dichloro pyrimidine, obtain 4,6-dialkoxy-2-(alkyl sulfenyl) pyrimidine.
Finally, under hydrogen peroxide, acetic acid and catalyzer exist, obtained 4,6-dialkoxy-2-(alkyl sulfenyl) pyrimidine is oxidized, obtains 4,6-dialkoxy-2-(alkyl sulphonyl) pyrimidine.
Invention especially provides the method that one prepares 4,6-dimethoxy-2-(methylsulfonyl) pyrimidine.
In a first step, dimethyl malonate and thiocarbamide are reacted under the existence of sodium alkoxide and methyl alcohol, obtains the sodium salt of thiobarbituricacidα-.With the salt alkylation of methyl chloride by obtained thiobarbituricacidα-, obtain 2-methylthio group-4,6-dihydroxy-pyrimidine.
In next step, with phosphoryl chloride (POCl
3) chlorination is carried out to 2-methylthio group-4,6-dihydroxy-pyrimidine, obtain 2-methylthio group-4,6-dichloro pyrimidine, with sodium alkoxide, alkoxylate is carried out to this 2-methylthio group-4,6-dichloro pyrimidine, obtain 4,6-dimethoxy-2-(methylthio group) pyrimidine.
Finally, under hydrogen peroxide, acetic acid and catalyzer exist, by 4,6-obtained dimethoxy-2-(methylthio group) pyrimidine oxidations, obtain 4,6-dimethoxy-2-(methylsulfonyl) pyrimidine.
In one embodiment, the sodium salt preparing thiobarbituricacidα-comprises the following steps:
-dimethyl malonate and thiocarbamide are added to methyl alcohol to obtain material, heat this material to 50 to the temperature of 70 DEG C,
-methanol solution of sodium methylate is incorporated to described material to obtain mixture within the time of 2 hours, maintain described mixture in the temperature 1 to 5 hour of 50 to 70 DEG C,
-remove methyl alcohol to obtain the second material by distillation from described mixture, cool described material to obtain the material cooled, described material is filtered to obtain filter cake;
-with filter cake described in methanol wash, then dry, obtain the sodium salt of thiobarbituricacidα-.
In one embodiment, the preparation of 2-methylthio group-4,6-dihydroxy-pyrimidine comprises the following steps:
-by the sodium salt of thiobarbituricacidα-and sodium hydroxide solution and methanol mixed, obtain material,
-methyl chloride to be added in described material and to stir, obtain 2-methylthio group-4,6-dihydroxy-pyrimidine.
In one embodiment, the preparation of 2-methylthio group-4,6-dichloro pyrimidine comprises the following steps:
-by 2-methylthio group-4,6-dihydroxy-pyrimidine, POCl
3, at least one aromatic hydrocarbon and at least one alkali mixing, obtain mixture,
-heat described mixture to 40 to the temperature of 90 DEG C, obtain the mixture heated,
-by POCl
3join in the mixture of described heating with chlorine, then stir in the temperature of 40 to 60 DEG C, obtain 2-methylthio group-4,6-dichloro pyrimidine.
Aromatic hydrocarbon is selected from mono chloro benzene, orthodichlorobenzene and combination thereof, and alkali is selected from triethylamine, tripropyl amine, Tributylamine and combination thereof.
In one embodiment, prepare 4,6-dimethoxy-2-(methylthio group) pyrimidine to comprise the following steps:
-alcoholic solution of sodium methylate, cuprous chloride and sodium iodide are mixed, obtain mixture,
-cool described mixture, at the temperature of 15 to 25 DEG C, then add 2-methylthio group-4,6-dichloro pyrimidine, obtain material,
-at the temperature of 30 to 50 DEG C, heat described material, obtain 4,6-dimethoxy-2-(methylthio group) pyrimidine.
In one embodiment, the preparation of 4,6-dimethoxy-2-(methylsulfonyl) pyrimidine comprises the following steps:
-4,6-dimethoxy-2-(methylthio group) pyrimidine, sodium wolframate and acetic acid are mixed, obtain mixture,
-heat described mixture and add hydrogen peroxide (H
2o
2), obtain 4,6-dimethoxy-2-(methylsulfonyl) pyrimidine.
On the other hand, the invention provides a kind of method for the preparation of 2,6-DHBA, the method uses resorcin(ol) as parent material.
The method comprises the following steps:
In a first step, under the existence of carbonic acid gas and at least one alkali, at least one solvent, at the temperature of 100 to 200 DEG C, by resorcin(ol) carboxylation, obtain containing 2, the mixture of 6-resorcylic acid, 2,4-resorcylic acids and 4,6-resorcylic acid.With mixture described at least one acid acidifying to obtain 2,6-DHBA.Acidification step comprises pH≤1 adjusting described mixture.The 2,6-DHBA purity that the method obtains is greater than 95%, is preferably greater than 99%.Acid is selected from hydrochloric acid, sulfuric acid and acetic acid, and alkali is selected from salt of wormwood, potassium hydroxide, sodium carbonate and combination thereof, and solvent is selected from toluene, DMF, N, N-diethylformamide, ethanol, methyl alcohol, acetone, water and combination thereof.According to the present invention, carbonation step carries out in the scope of 140 to 180 DEG C.Typically, carbonation step is 5kg/cm at pressure
2to 45kg/cm
2reactor in carry out.
In one embodiment, the method comprises the following steps:
-under the existence of carbonic acid gas and at least one alkali, at least one solvent, at the temperature of 100 to 200 DEG C, by resorcin(ol) carboxylation, obtain the mixture containing 2,6-DHBA, 2,4-resorcylic acids and 4,6-resorcylic acid;
-maintain the temperature 1 to 10 hour that described mixture is in 140 DEG C to 180 DEG C;
-cool this mixture to obtain the mixture cooled;
-with acid, the mixture of described cooling is acidified to pH is 5.5 to 6, then maintain 1 to 20 hour in 90-110 DEG C, obtain the material of acidifying and cool described material;
-with acid, the pH of described material is adjusted to 2 to 3, then by filtering, washing and drying, obtain solid matter and filtrate; And
-add acid to adjust pH to 0.8 to 1 to described filtrate, then stir, cool, filter, wash and drying, obtain the 2,6-DHBA that purity is greater than 95%.
Drying step carries out at the temperature of 40 to 70 DEG C.
In one embodiment, the method comprises and carries out decarboxylation to obtain resorcin(ol) and to reclaim the step of described resorcin(ol) to 2,4-resorcylic acid and 4,6-resorcylic acid.
By non-limiting example below, set forth the present invention further.
The two careless ether sodium (embodiment 1-5) of preparation
Embodiment 1:
154 grams of 2,6-DHBAs settled solution in 500ml dimethyl sulfoxide (DMSO) through 2-3 hour, be added in 30-32 DEG C the mixture purchasing the available 130 grams of sodium hydrides (60% oil based emulsions) be dissolved in 2 liters of dimethyl sulfoxide (DMSO).Material is stirred 2 hours in 30-32 DEG C further, added 480 gram of 4,6-dimethoxy-2-(methylsulfonyl) pyrimidine through 2 hours.Reaction is maintained at 30-32 DEG C until complete, and obtains two careless ether sodium.By high performance liquid chromatography (HPLC) monitoring reaction.Medium, washs by dimethyl sulfoxide (DMSO) (DMSO).Wet solid rejoins 1000ml methyl alcohol pulping, then adds 1000ml 75% methanol aqueous solution pulping.Dry wet solid, obtain 435 grams of two careless ether sodium.This pair of careless ether sodium adds pulping in 1200ml toluene, cooling, filtration drying obtains 385 grams of two careless ether sodium (HPLC purity 98.7%) at reflux temperature again.
Embodiment 2:
154 grams of 2,6-DHBAs settled solution in 500ml dimethyl sulfoxide (DMSO) through 2-3 hour, be added in 30-32 DEG C the mixture purchasing the available 130 grams of sodium hydrides (60% oil based emulsions) be dissolved in 1500ml dimethyl sulfoxide (DMSO).Material is stirred 2 hours in 30-2 DEG C further, added 480 gram of 4,6-dimethoxy-2-(methylsulfonyl) pyrimidine through 2-3 hour.Reaction is maintained at 30-32 DEG C until complete, and obtains two careless ether sodium.By high performance liquid chromatography monitoring reaction.Medium, washs by dimethyl sulfoxide (DMSO).Wet solid rejoins 1000ml methyl alcohol pulping, then adds 1000ml75% methanol aqueous solution pulping.Dry wet solid, obtain 430 grams of two careless ether sodium.This pair of careless ether sodium adds pulping in 1200ml toluene, cooling, filtration drying obtains 380 grams of two careless ether sodium (HPLC purity 98.3%) at reflux temperature again.
Embodiment 3:
The settled solution of 154 grams of 2,6-DHBAs in 500ml dimethyl sulfoxide (DMSO) is added in 30-32 DEG C the mixture purchasing the available 130 grams of sodium hydrides (60% oil based emulsions) be dissolved in 1500ml dimethyl sulfoxide (DMSO).Material is stirred 2 hours in 30 DEG C further, adds the slurry of 480 gram of 4,6-dimethoxy-2-(methylsulfonyl) pyrimidine in 750ml dimethyl sulfoxide (DMSO).Reaction is maintained at 30-32 DEG C until complete, and obtains two careless ether sodium.Medium, washs by dimethyl sulfoxide (DMSO).Wet solid rejoins 1000ml methyl alcohol pulping, then adds 1000ml 75% methanol aqueous solution pulping.Dry wet solid, obtain 440 grams of two careless ether sodium.This pair of careless ether sodium adds pulping in 1200ml toluene, cooling, filtration drying obtains 380 grams of two careless ether sodium (HPLC purity 98.5%) at reflux temperature again.
Embodiment 4:
The settled solution of 154 grams of 2,6-DHBAs in 500ml dimethyl sulfoxide (DMSO) is added in 30-32 DEG C the mixture purchasing the available 130 grams of sodium hydrides (60% oil based emulsions) be dissolved in 2 liters of dimethyl sulfoxide (DMSO).Material is stirred 2 hours in 30 DEG C further, adds the slurry of 480 gram of 4,6-dimethoxy-2-(methylsulfonyl) pyrimidine in 750ml dimethyl sulfoxide (DMSO).Reaction is maintained at 30-32 DEG C until complete, and obtains two careless ether sodium.Medium, washs by dimethyl sulfoxide (DMSO).Wet solid rejoins 1000ml methyl alcohol pulping, then adds 1000ml 75% methanol aqueous solution pulping.Dry wet solid, obtain 435 grams of two careless ether sodium.This pair of careless ether sodium adds pulping in 1200ml toluene, cooling, filtration drying obtains 385 grams of two careless ether sodium (HPLC purity 98.6%) at reflux temperature again.
Embodiment 5:
The settled solution of 154 grams of 2,6-DHBAs in 500ml dimethyl sulfoxide (DMSO) is added in 30-32 DEG C the mixture purchasing the available 130 grams of sodium hydrides (60% oil based emulsions) be dissolved in 1500ml dimethyl sulfoxide (DMSO).Material is stirred 2 hours in 30 DEG C further, adds the settled solution of 480 gram of 4,6-dimethoxy-2-(methylsulfonyl) pyrimidine in 1500ml dimethyl sulfoxide (DMSO).Reaction is maintained at 30-32 DEG C until complete, and obtains two careless ether sodium.Medium, washs by dimethyl sulfoxide (DMSO).Wet solid rejoins 1000ml methyl alcohol pulping, then adds 1000ml 75% methanol aqueous solution pulping.Dry wet solid, obtain 400 grams of two careless ether sodium.This pair of careless ether sodium adds pulping in 1200ml toluene, cooling, filtration drying obtains 350 grams of two careless ether sodium (HPLC purity 98.6%) at reflux temperature again.
Preparation 4,6-dimethoxy-2-(methylsulfonyl) pyrimidine (embodiment 6-10)
Embodiment 6: prepare thiobarbituricacidα-sodium salt
To 1.10m thiocarbamide and 1.0m dimethyl malonate, the solution in 280ml methyl alcohol refluxes, and adds 1.0m sodium methylate be dissolved in solution in 150ml methyl alcohol through 15 to 45 minutes.Material recirculation 4 hours, distillates part methyl alcohol.The material obtained be cooled to lower than 30 DEG C, filter and use methanol wash.The filter cake that drying obtains, obtains thiobarbituricacidα-sodium salt (productive rate 90%).
Filtrate is concentrated into the level of 250-280ml.To this, add 0.1m dimethyl malonate and 0.1m sodium methoxide solution.The reactive material aforesaid method process obtained.The productive rate of thiobarbituricacidα-sodium salt is 2%.
Embodiment 7:
Preparation 2-methylthio group-4,6-dihydroxy-pyrimidine
1.Om thiobarbituricacidα-sodium salt is dissolved in 1.5m 1N aqueous sodium hydroxide solution and 50ml methyl alcohol in stainless steel autoclave, obtains mixture.To this, in 1 to 2 hour, add 0.5m methyl chloride.The reactant obtained is stirred 2 to 6 hours in 25-30 DEG C, in 1 to 2 hour, adds the 0.5m methyl chloride of second batch, stir material 6-8 hour in 25-30 DEG C.To this, add 0.05m methyl chloride, reaction stirred 2-6 hour.After reaction terminates, HPLC indicates 85%2-methylthio group-4,6-dihydroxy-pyrimidine and 5%2-methylthio group-4-methoxyl group-6-hydroxy pyrimidine.
The productive rate of product is 75-80 % by mole.
Embodiment 8:
Preparation 2-methylthio group-4,6-dichloro pyrimidine
1.0m 2-methylthio group-4,6-dihydroxy-pyrimidine is added to 4m mono chloro benzene.To this, in 1 to 2 hour, add 2.2m POCl
3, added 2.2m triethylamine in 40-50 DEG C through 2 to 4 hours.The mixture obtained is heated to 80 DEG C, obtains clear soln, stir 4-8 hour, obtain material.The material obtained is cooled to 60 DEG C.To this, add 2.0m phosphorus trichloride.Then in 6-10 hour, pass into 2.0m chlorine in 60 DEG C, stir 8 to 10 hours in 60 DEG C.Chlorine is passed into, to avoid side-chain chlorination under no light condition.Vacuum distilling POCl
3, add 200ml mono chloro benzene, continue distillation to guarantee to remove POCl completely
3.Reclaim 4.0m to 4.3m POCl
3; Surplus materials 200ml frozen water submergence is also extracted with mono chloro benzene.Add 100ml water to mono chloro benzene layer, and use NaHCO
3neutralization.Be separated each layer, under vacuo concentrated mono chloro benzene layer.The productive rate of product is 85-87%.
Carry out vacuum distilling to product, then carry out crystallization with methyl alcohol, obtain 85mol%, purity is 99%.
Embodiment 9:
Preparation 4,6-dimethoxy-2-(methylthio group) pyrimidine
In the methanol solution of 2.2m 3N sodium methylate, add 2m% cuprous chloride and 2m% sodium iodide, obtain mixture, mixture is cooled to 20 DEG C.1.0m 2-methylthio group-4,6-dichloro pyrimidine is dissolved in 400ml methyl alcohol, it was added in said mixture through 3-6 hour, stir 1 hour in 20 DEG C, obtain reactant.Reactant is warming up to 30 DEG C, is then warming up to 40 DEG C, stirs 6-12 hour, HPLC indicate 95-96%2-methylthio group-4,6-dimethoxypyridin and 0.5%2-methylthio group-4-methoxyl group-6-chloropyrimide in 40 DEG C.Cooling reactant, elimination sodium-chlor.From filtrate, heat up in a steamer methyl alcohol, in remaining material, add water, use methylbenzene extraction.Wash toluene layer with water, then concentrate.The productive rate of product is 90%.
Embodiment 10: preparation 4,6-dimethoxy-2-(methylsulfonyl) pyrimidine
3m% sodium wolframate is added to 200ml acetic acid.To this, add 1.0m 2-methylthio group-4,6-dimethoxypyridin, obtain material (settled solution).Heat this material to 40 DEG C.In the material of heating, 2.1m 30%H is added in 4-8 hour
2o
2, stir 3-5 hour in 40 DEG C.Further, 0.05m 30%H is added
2o
2and be stirred in 40 DEG C and transform completely.React in 40 DEG C.Reaction mixture, filtering solids.Wash the filter cake obtained with acetic acid aqueous solution, then wash with water.Dry cake.Productive rate is 83%.
Filtrate is extracted with Ethylene Dichloride.The concentrated Ethylene Dichloride layer obtained.Weight is 42g, and the productive rate of product is about 1-1.5%.
Prepare 2,6-DHBA (embodiment 11-15)
Embodiment 11: prepare 2,6-DHBA
Stir the mixture of resorcin(ol) (110 grams, 1.0 moles), toluene (250ml) and potassium hydroxide (86%65.1 grams, 1.0 moles) in a kettle., Dean-Stark device is mounted to this reactor, obtains material.By water is removed from the side arm of Dean-Stark device, by the substance dehydrates obtained.Until no longer observe water in the side arm of Dean-Stark device, toluene is distillated completely, add DMF (330ml), obtain solution.
The solution obtained is transferred to dry stainless steel compressive reaction still, with carbon dioxide pressurization, and is heated to 150 DEG C, obtains reaction mixture.Be 9kg/cm at Carbon dioxide air pressure
2condition under, the reaction mixture obtained is maintained 150 DEG C 6 hours.
Mixture is cooled to 50 DEG C, release of carbon dioxide pressure, by Carbon emission to soda-wash tower.Then mixture is transferred to glass reaction still, under 110 DEG C of liquid temperatures and 10mmHg pressure, distillates DMF, obtain reactant.Reactant is cooled to room temperature and is dissolved in water.The HPLC of reactant consists of 56.61%2,6-resorcylic acid, 4.97%2,4-resorcylic acids, 9.32% resorcin(ol), 12.73%4,6-dihydroxyl m-phthalic acids.
With concentrated hydrochloric acid, aqueous substance being acidified to pH value is 5.5 to 6, and maintains 6 hours in 100 DEG C.Reaction process is monitored by HPLC.
Material is cooled to 30 DEG C, being acidified to pH with concentrated hydrochloric acid is 2.85, filters, and washs and be dried in 60 DEG C to obtain 15.35g drying solid (HPLC forms=95.2%4,6-dihydroxyl m-phthalic acid, 2.97%2,6-resorcylic acids).With concentrated hydrochloric acid, the filtrate of 2.85pH being neutralized to pH value is 0.8 to 1, is cooled to 10 DEG C and filters, washing with water.In 60 DEG C of dry wet solids, obtain 53.9 grams of solids containing 96.1%2,6-resorcylic acid by HPLC,
Embodiment-12
The mixture of 220 grams of resorcin(ol)s (2.0 moles), 1300ml 50% (v/v) aqueous ethanolic solution, 276 grams of (2.0 moles) salt of wormwood is added in stainless steel autoclave, with carbonic acid gas mixture be forced into 5kg and be heated to 170 DEG C, mixture is maintained 5 hours in 170 DEG C, and pressure carbon dioxide is 38-39kg/cm
2.
Reaction mixture is cooled to room temperature, release of carbon dioxide, by Carbon emission in soda-wash tower.
Then mixture be transferred to glass reaction still and analyze with HPLC.
HPLC forms: 38.43%-2,6-resorcylic acid, 34.6%-2,4-resorcylic acid, 9.40% resorcin(ol) and 16.42%4,6-dihydroxyl m-phthalic acid.
In 30 DEG C, mixture being neutralized to pH with concentrated hydrochloric acid is 5.5 to 6.Then from mixture, ethanol/water is distillated in 100 DEG C of liquid temperatures.Reaction mixture being maintained backflow 12.5 hours further, by adding the vitriol oil to reaction mixture, making pH value remain on 5.5 to 6 in heat-processed.
After 12.5 hours, temperature maintains 100 DEG C, and the HPLC of reactant consists of 55.25%-2,6-resorcylic acid, 3.6%-2,4-resorcylic acid, 20.35% resorcin(ol) and 19.90%4,6-dihydroxyl m-phthalic acid.
After the decomposition of 2,4-resorcylic acid terminates, add concentrated hydrochloric acid until pH value reaches 2.83 to mixture.By the solid filtering obtained, and the solid pulping in water that will wet further.To this, add concentrated hydrochloric acid until pH reaches 0.90.Filtering solids, washing is also dried to constant weight in 60 DEG C, obtains 11.8 grams of drying solids.(HPLC consists of 93.5%4,6-dihydroxyl m-phthalic acid and 5.84%2,6-resorcylic acid).
Reach 0.9-1.0 by acidification of filtrate to the pH value that pH is 2.83 by concentrated hydrochloric acid and stir 1 hour further.The slurries obtained are cooled to 0 DEG C, stir 1 hour and filter.Further by wet cake again pulping in water, stir 1 hour in 55-60 DEG C, be cooled to 0 DEG C and filter.Wash solid with frozen water, be dried to constant weight in 60 DEG C, obtain 99.2 grams of 2,6-DHBA drying solids (HPLC purity 96.4%).
Embodiment-13
The mixture of 220 grams of resorcin(ol)s (2 moles), 1300ml 50% (v/v) aqueous ethanolic solution, 138 grams of (1.Om) salt of wormwood is added in stainless steel autoclave, with carbonic acid gas mixture be forced into 5kg and be heated to 170 DEG C, mixture is maintained 5 hours in 170 DEG C, and pressure carbon dioxide is 23-25kg/cm
2.
Reaction mixture is cooled to room temperature, release of carbon dioxide, by Carbon emission in soda-wash tower.
In 30 DEG C, mixture being neutralized to pH with the vitriol oil is 5.5 to 6.Then from mixture, ethanol/water is distillated in 98-100 DEG C of liquid temperature.Reaction mixture being maintained backflow 11 hours further, by adding the vitriol oil to reaction mixture, making pH value remain on 5.5 to 6 in heat-processed.
After 11 hours, the HPLC of material consists of 55.72%-2,6-resorcylic acid, 2.81%-2,4-resorcylic acid, 38.14% resorcin(ol) and 2.15%4,6-dihydroxyl m-phthalic acid, in contrast to this, initial value is 52.47%-2,6-resorcylic acid, 20.20%-2,4-resorcylic acid, 24.2% resorcin(ol) and 2.47%4,6-dihydroxyl m-phthalic acid.
Material is cooled to room temperature, in mixture, adds the vitriol oil until pH value arrives 4.Filtering mixt is to remove potassium sulfate.With the vitriol oil, acidification of filtrate is arrived 0.9 to 1.0 to pH value further.Stir material 1 hour.The slurries obtained are cooled to 10 DEG C and stir 1 hour and filter.To be wet solid pulping in water again further, stir 1 hour, be cooled to 25 DEG C and filter in 55-60 DEG C.Wash solid with water, be dried to constant weight in 60 DEG C, obtain 110.4 grams of 2,6-DHBA drying solids (HPLC purity 99.1%).
Aqueous filtrate is mixed, and repeatedly extracts with methyl ethyl ketone.Merge methyl ethyl ketone extract, concentrating under reduced pressure obtains 142 grams of viscous substances, and HPLC consists of 85.7% resorcin(ol), 7.8%2,6-resorcylic acids, 1.6%2,4-resorcylic acids and 2.1%4,6-resorcylic acid.
Distillment after the residue of recovery methyl ethyl ketone, is wherein rich in resorcin(ol).
Embodiment-14
By 142 grams of methyl ethyl ketone enriched material (the 1.107m resorcin(ol)s obtained in embodiment-13; 0.072m 2,6-DHBA) mix with 90.3 grams of new resorcin(ol)s (0.821 mole) (be 2 moles for adjusting the content of resorcin(ol)), 151.8 grams of (1.10m) salt of wormwood and 1300ml 50% (v/v) aqueous ethanolic solution.
With carbonic acid gas mixture be forced into 5kg and be heated to 170 DEG C, mixture is maintained 5 hours in 170 DEG C, and pressure carbon dioxide is 23-25kg/cm
2.
Reaction mixture is cooled to room temperature, release of carbon dioxide, by Carbon emission in soda-wash tower.
In 30 DEG C, mixture being neutralized to pH with the vitriol oil is 5.5 to 6.Then from mixture, ethanol/water is distillated in 98-100 DEG C of liquid temperature.Reaction mixture being maintained backflow 12 hours further, by adding the vitriol oil to reaction mixture, making pH value remain on 5.5 to 6 in heat-processed.
After 12 hours, the HPLC of material consists of 55.48%-2,6-resorcylic acid, 0.1%-2,4-resorcylic acid, 41.04% resorcin(ol) and 0.93%4,6-dihydroxyl m-phthalic acid, in contrast to this, initial value is 35.52%-2,6-resorcylic acid, 30.21%-2,4-resorcylic acid, 26.27% resorcin(ol) and 6.41%4,6-dihydroxyl m-phthalic acid.4,6-dihydroxyl m-phthalic acid shows, and utilizes the complete decarboxylation of the vitriol oil at 100 DEG C.
The vitriol oil is added until pH value arrives 3.96 in mixture.Make slurries balance 1 hour in 30 DEG C, filter to remove potassium sulfate.With the vitriol oil, acidification of filtrate is arrived 0.9 to 1.0 to pH value further, and stir material 1 hour.The slurries obtained are cooled to 10 DEG C and stir 1 hour and filter.
To be wet solid pulping in water again further, stir 1 hour, be cooled to 25 DEG C and filter in 55-60 DEG C.Wash solid with water, be dried to constant weight in 60 DEG C, obtain 76.5 grams of 2,6-DHBA dry cakes (HPLC purity 99.0%).
Embodiment-15
After carrying out embodiment 13 and the main reaction shown in 14 and being separated 2,6-DHBA, reclaim aqueous filtrate.
With salt of wormwood, aqueous filtrate being neutralized to pH is 7, then uses charcoal treatment, elimination charcoal.The content of resorcin(ol) in aqueous filtrate is determined by HPLC, carrys out the shortage amount of polishing 2.0 moles of resorcin(ol)s by adding new resorcin(ol), carries out carboxylation according to method given in embodiment 13 and 14.
The productive rate of 2,6-DHBA is 33% (using new resorcin(ol)), and be 35% after first time recovery aqueous filtrate, second time is 32% after reclaiming aqueous filtrate.
" whenever specifying numerical range, be included in protection scope of the present invention lower than Schwellenwert 10% with higher than the value of maximum 10% respectively.”
Although Special attention will be given to preferred embodiment, will be appreciated that, when not departing from principle of the present invention, also can realize multiple embodiment, and can realize multiple change in a preferred embodiment herein.These changes in a preferred embodiment and other change and other embodiments of the present invention, it seems from content disclosed herein, it will be apparent to those skilled in the art that, thus can be expressly understood, the content of foregoing descriptive is only for explaining the present invention, but not limitation of the present invention.
In this specification, word " comprises ", or its variation is as " comprising " or " containing ", be interpreted as and mean to comprise described key element, integer or step or grouped key elements, integer or step, but do not get rid of any other key element, integer or step or grouped key elements, integer or step.
Express the use of " at least " or " at least one " to represent and use one or more key elements or composition or quantity, this use can realize object or the result of one or more expectation in an embodiment of the present invention.
Only for the invention provides background to the object of any discussion of the file be included in this manual, scheme, material, device, article etc.It should not be regarded as admitting basis that is arbitrary or all these Composition of contents prior aries or common practise in the technical field related to the present invention that is present in before the application's priority date.
The numerical value of various physical parameters, size or the quantity mentioned is just approximate, it is contemplated that higher than/fall within the scope of the present invention, unless the specific descriptions in specification sheets in contrast lower than the value of corresponding parameter, size or quantity numerical value.
Claims (31)
1. the method for the preparation of two careless ether sodium; Under described method is included in the temperature of 20 to 80 DEG C, under at least one alkali and at least one solvent exist, 2,6-DHBA and 2-(alkyl sulphonyl)-4,6-dialkoxypyrimidin are carried out condensation.
2. method according to claim 1, is characterized in that, described alkali is selected from sodium hydride, potassium cyanide, lithium hydride and hydrolith.
3. method according to claim 1, it is characterized in that, described solvent is selected from tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, tetramethylene sulfone, glycol dimethyl ether, monoglyme and diglyme.
4. method according to claim 1, is characterized in that, 2-(alkyl sulphonyl)-4,6-dialkoxypyrimidin is 2-(methylsulfonyl)-4,6-dimethoxypyridin.
5. method according to claim 1, is characterized in that, described 4,6-dialkoxy-2-(alkyl sulphonyl) pyrimidines are prepared by following steps:
1) dialkyl malonate and thiocarbamide are reacted under the existence of sodium alkoxide and alcohol, obtain the sodium salt of thiobarbituricacidα-;
2) with the sodium salt alkylation of alkyl chloride by described thiobarbituricacidα-, 2-alkyl sulfenyl-4,6-dihydroxy-pyrimidine is obtained;
3) with phosphoryl chloride (POCl3), chlorination is carried out to described 2-alkyl sulfenyl-4,6-dihydroxy-pyrimidine, obtain 2-alkyl sulfenyl-4,6-dichloro pyrimidine;
4) with sodium alkoxide, alkoxylate is carried out to described 2-alkyl sulfenyl-4,6-dichloro pyrimidine, obtain 4,6-dialkoxy-2-(alkyl sulfenyl) pyrimidine; With
5) under hydrogen peroxide, acetic acid and catalyzer exist, by described 4,6-dialkoxy-2-(alkyl sulfenyl) pyrimidine oxidation, 4,6-dialkoxy-2-(alkyl sulphonyl) pyrimidine is obtained.
6. method according to claim 5, is characterized in that, wherein dialkyl malonate is selected from dimethyl malonate, diethyl malonate, propanedioic acid di-n-propyl ester and propanedioic acid di-n-butyl, and preferably, dialkyl malonate is dimethyl malonate.
7. method according to claim 5, is characterized in that, sodium alkoxide is sodium methylate.
8. method according to claim 5, is characterized in that, alkyl chloride is methyl chloride.
9. method according to claim 5, is characterized in that, 2-alkyl sulfenyl-4,6-dihydroxy-pyrimidine is 2-methylthio group-4,6-dihydroxy-pyrimidine.
10. method according to claim 5, is characterized in that, 2-alkyl sulfenyl-4,6-dichloro pyrimidine is 2-methylthio group-4,6-dichloro pyrimidine.
11. methods according to claim 5, is characterized in that, 4,6-dialkoxy-2-(alkyl sulfenyl) pyrimidine is 4,6-dimethoxy-2-(methylthio group) pyrimidine.
12. methods according to claim 5, is characterized in that, 4,6-dialkoxy-2-(alkyl sulphonyl) pyrimidine is 4,6-dimethoxy-2-(methylsulfonyl) pyrimidine.
13. methods according to claim 5, is characterized in that, described alcohol is selected from methyl alcohol, ethanol, n-propyl alcohol and propyl carbinol.
14. methods according to claim 5, it is characterized in that, step (1) comprises dimethyl malonate and thiocarbamide is added to methyl alcohol to obtain material, heat this material to 50 to the temperature of 70 DEG C, the methanol solution of sodium methylate is incorporated to described material to obtain mixture, maintain described mixture in the temperature 1 to 5 hour of 50 to 70 DEG C, methyl alcohol is removed to obtain the second material from described mixture by distillation, cool described material to obtain the material cooled, described material is filtered to obtain filter cake; And with filter cake described in methanol wash, then dry, obtain the sodium salt of thiobarbituricacidα-.
15. methods according to claim 5, is characterized in that, step (2) comprises the sodium salt of thiobarbituricacidα-and sodium hydroxide solution and methanol mixed, obtain material, methyl chloride to be added in described material and to stir, obtaining 2-methylthio group-4,6-dihydroxy-pyrimidine.
16. methods according to claim 5, is characterized in that, step (3) comprises 2-methylthio group-4,6-dihydroxy-pyrimidine, POCl
3, at least one aromatic hydrocarbon and the mixing of at least one alkali, obtain mixture, heat described mixture to 40 to the temperature of 90 DEG C, obtain the mixture heated, by POCl
3join in the mixture of described heating with chlorine, then stir in the temperature of 40 to 60 DEG C, obtain 2-methylthio group-4,6-dichloro pyrimidine.
17. methods according to claim 5, it is characterized in that, step (4) comprises and the alcoholic solution of sodium methylate, cuprous chloride and sodium iodide being mixed, obtain mixture, cool described mixture, then at the temperature of 15 to 25 DEG C, add 2-methylthio group-4,6-dichloro pyrimidine is to obtain material, at the temperature of 30 to 50 DEG C, heat described material, obtain 4,6-dimethoxy-2-(methylthio group) pyrimidine.
18. methods according to claim 5, it is characterized in that, step (5) comprises and 4,6-dimethoxy-2-(methylthio group) pyrimidine, sodium wolframate and acetic acid being mixed, obtain mixture, heat described mixture and add hydrogen peroxide (H
2o
2), obtain 4,6-dimethoxy-2-(methylsulfonyl) pyrimidine.
19. methods according to claim 5, is characterized in that, catalyzer is sodium wolframate.
20. methods according to claim 16, is characterized in that, described aromatic hydrocarbon is selected from mono chloro benzene, orthodichlorobenzene and combination thereof.
21. methods according to claim 16, is characterized in that, alkali is selected from triethylamine, tripropyl amine, Tributylamine and combination thereof.
22. methods according to claim 1, is characterized in that, said method comprising the steps of:
1) under the existence of carbonic acid gas and at least one alkali, at least one solvent, at the temperature of 100 to 200 DEG C, by resorcin(ol) carboxylation, the mixture containing 2,6-DHBA, 2,4-resorcylic acids and 4,6-resorcylic acid is obtained; And
2) with mixture described at least one acid acidifying, obtain the 2,6-DHBA that purity is greater than 95%, wherein acidification step comprises pH≤1 adjusting described mixture.
23. methods according to claim 22, is characterized in that, described method comprises:
-under the existence of carbonic acid gas and at least one alkali, at least one solvent, at the temperature of 100 to 200 DEG C, by resorcin(ol) carboxylation, obtain the mixture containing 2,6-DHBA, 2,4-resorcylic acids and 4,6-resorcylic acid;
-maintain the temperature 1 to 10 hour that described mixture is in 140 DEG C to 180 DEG C;
-cool this mixture to obtain the mixture cooled;
-with acid, the mixture of described cooling is acidified to pH is 5.5 to 6, then maintain 1 to 20 hour in 90-110 DEG C, obtain the material of acidifying and cool described material;
-with acid, the pH of described material is adjusted to 2 to 3, then by filtering, washing and drying, obtain solid matter and filtrate; And
-add acid to adjust pH to 0.8 to 1 to described filtrate, then stir, cool, filter, wash and drying, obtain the 2,6-DHBA that purity is greater than 95%.
24. methods according to claim 22 or 23, it is characterized in that, carbonation step carries out at the temperature of 140 to 180 DEG C.
25. methods according to claim 22 or 23, it is characterized in that, described acid is selected from hydrochloric acid, sulfuric acid and acetic acid.
26. methods according to claim 22 or 23, it is characterized in that, described alkali is selected from salt of wormwood, potassium hydroxide, sodium carbonate and combination thereof.
27. methods according to claim 22 or 23, it is characterized in that, solvent is selected from toluene, DMF, N, N-diethylformamide, ethanol, methyl alcohol, acetone, water and combination thereof.
28. methods according to claim 22 or 23, it is characterized in that, carbonation step is 5kg/cm at pressure
2to 45kg/cm
2reactor in carry out.
29. methods according to claim 23, is characterized in that, drying is carried out at the temperature of 40 to 70 DEG C.
30. methods according to claim 22 or 23, it is characterized in that, the purity of 2,6-DHBA is greater than 99%.
31. methods according to claim 22 or 23, is characterized in that, comprise and carry out decarboxylation to obtain resorcin(ol) and to reclaim the step of described resorcin(ol) to 2,4-resorcylic acid and 4,6-resorcylic acid.
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| IN329MU2013 | 2013-02-18 | ||
| IN465MU2013 | 2013-02-18 | ||
| PCT/IN2014/000087 WO2014128719A2 (en) | 2013-02-18 | 2014-02-11 | Processes for the preparation of bispyribac sodium and intermediates thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106083738A (en) * | 2016-07-06 | 2016-11-09 | 淄博新农基农药化工有限公司 | A kind of method utilizing phase transfer catalyst to prepare herbicide bispyribac-sodium |
| CN112552244A (en) * | 2020-12-22 | 2021-03-26 | 内蒙古科硕新材料科技有限公司 | Production process of 4, 6-dimethoxy-2-methylsulfonyl pyrimidine |
| CN112920126A (en) * | 2021-01-13 | 2021-06-08 | 新沂大江化工有限公司 | Preparation method and preparation device of bispyribac-sodium intermediate 2-methylsulfonyl 4, 6-dimethoxypyrimidine |
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| CN112354566B (en) * | 2020-10-30 | 2023-04-21 | 中北大学 | Barbituric acid-polymetallic oxygen cluster hybrid and preparation method thereof |
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| CN106083738A (en) * | 2016-07-06 | 2016-11-09 | 淄博新农基农药化工有限公司 | A kind of method utilizing phase transfer catalyst to prepare herbicide bispyribac-sodium |
| CN112552244A (en) * | 2020-12-22 | 2021-03-26 | 内蒙古科硕新材料科技有限公司 | Production process of 4, 6-dimethoxy-2-methylsulfonyl pyrimidine |
| CN112920126A (en) * | 2021-01-13 | 2021-06-08 | 新沂大江化工有限公司 | Preparation method and preparation device of bispyribac-sodium intermediate 2-methylsulfonyl 4, 6-dimethoxypyrimidine |
Also Published As
| Publication number | Publication date |
|---|---|
| PH12015501798A1 (en) | 2015-11-09 |
| JP6382229B2 (en) | 2018-08-29 |
| PH12015501798B1 (en) | 2015-11-09 |
| BR112015019795A2 (en) | 2017-07-18 |
| KR102075509B1 (en) | 2020-02-10 |
| KR20150121102A (en) | 2015-10-28 |
| BR112015019795B1 (en) | 2020-06-16 |
| WO2014128719A3 (en) | 2014-12-24 |
| MY177976A (en) | 2020-09-28 |
| WO2014128719A2 (en) | 2014-08-28 |
| JP2016509995A (en) | 2016-04-04 |
| CN105026376B (en) | 2018-05-11 |
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