CN1279028C - Preparing method for technical grade and drug grade of phenylsulfonyl carbamide herbicide - Google Patents
Preparing method for technical grade and drug grade of phenylsulfonyl carbamide herbicide Download PDFInfo
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- CN1279028C CN1279028C CN 02139566 CN02139566A CN1279028C CN 1279028 C CN1279028 C CN 1279028C CN 02139566 CN02139566 CN 02139566 CN 02139566 A CN02139566 A CN 02139566A CN 1279028 C CN1279028 C CN 1279028C
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Abstract
The present invention relates to a preparation method of an original drug of phenylsulfonyl carbamide herbicide and a preparation thereof, which is characterized in that the original drug of phenylsulfonyl carbamide herbicide is prepared from triphosgene and saccharine as raw materials. The preparation technology for preparing the original drug of phenylsulfonyl carbamide herbicide from the triphosgene and the saccharine has the following steps that (1) saccharine with safe use and convenience and triphosgene react under the action of an initiator, and then, react with 2-amidogen (or 2-substituent ammonia)-4, 6 di-substituted-pyrimidine or s-triazine derivatives to prepare an N-substituted saccharine derivative, namely an <1> intermediate; phenylsulfonyl carbamide sodium salt, namely an <2> intermediate, is prepared from the <1> intermediate and sodium alcoholate by nucleophilic substitution reaction; (3) the original drug of phenylsulfonyl carbamide is prepared from the <2> intermediate by dilute acid neutralization to the pH to be from 2 to 5. The preparation method of the original drug of phenylsulfonyl carbamide herbicide and the preparation thereof has the advantages of good safety performance of production, low production cost and product quality improvement.
Description
Affiliated technical field: the preparation method who the invention relates to former medicine of benzene sulfonyl carbamide weedicide and preparation thereof.
Background technology: the former drug compound of benzene sulfonyl carbamide weedicide has following general structure:
In the formula, R
1=CH
3, C
2H
5R
2=H, CH
3Z=CH, N;
X＝CH
3，OCH
3，OC
2H
5，OCHF
2，CL；
Y＝CH
3，OCH
3，NHCH
3，OCHF
2
They are the important members in the sulfonylurea herbicide family, and the commercialization of a plurality of kinds is arranged, as metsulfuronmethyl (metsulfuron-methyl) sulfometuron-methyl (sulfometuron-methyl) etc.
The known synthetic method of benzene sulfonyl carbamide compound of general formula I mainly contains following three kinds:
1, phosgenation (isocyanic ester method):
Promptly set out by adjacent alkoxyl formyl benzene sulfonyl chloride, elder generation and ammonia react change sulphonamide into; with phosgene reaction, make the isocyanic ester intermediate then, last and 2-amino (or 2-substituted-amino)-4; 6 disubstituted pyrimidines or pyrrolotriazine derivatives reaction make the former medicine of benzene sulfonyl urea.The main reference document has: US.Patent 4,305, and 884 (1981); 4,721,520 (1988); 5,153,324 (1992) etc.
This method adopts the phosgene of severe toxicity to prepare the isocyanic ester intermediate, and is very strict to equipment requirements, and device for recovering tail gas is arranged.Carelessness is arranged slightly, just may cause serious security incident.Also need special phosgene generating unit.The isocyanic ester intermediate need separate under comparatively high temps and condition of high vacuum degree.
2, cyanate method:
Promptly by neighbour-alkoxyl formyl benzene sulfonyl chloride, cyanate and 2-amino (or 2-substituted-amino)-4,6-disubstituted pyrimidines or pyrrolotriazine derivatives reflux in acetonitrile, can make the former medicine of benzene sulfonyl urea.The main reference document has US.Patent 4,546, and 179 (1985).
Though this method technological process is simple, the poor heat stability of the adjacent alkoxyl formyl benzene sulfonyl chloride of one of starting raw material, very easily hydrolysis in the air, thereby can only organize production in lower season at temperature.And the yield of benzene sulfonyl urea is very big to the dependency of this raw materials quality, and the yield of benzene sulfonyl urea is fluctuateed between 20-70%.
3, carbamate method:
Promptly by N-[(2-alkoxyl formyl phenyl) alkylsulfonyl] Urethylane and 2-amino (or 2-substituted-amino)-4,6-disubstituted pyrimidines or pyrrolotriazine derivatives condensation can make the former medicine of benzene sulfonyl urea.The main reference document has US, Patent 4,518,776 (1985). and " colleges and universities' chemical engineering journal " 1999, (5), 459-465.
The main drawback of this method is that the preparation technology of intermediate carbamate is comparatively complicated:
In preparation process, need to use two kinds of organic solvents, acetone and alcohol all need reclaim also and could reuse behind the drying and dehydrating, have a large amount of waste water to produce simultaneously, could discharge after needing to handle.The reaction that intermediate could drop into next step after then needing thoroughly to dry.
The benzene sulfonyl urea is changed into their alkali metal salts or ammonium salt, make aqueous suspension then, soluble powder or granule, be to use formulation easily, in the document all with the former medicine of benzene sulfonyl urea at water or organic solvent, as chloroform, with alkali metal hydroxide or alkaline carbonate or phosphate reaction, change it into soluble salt in the methylene dichloride.The main reference document has EP.124, and 295 (1984); 304,282 (1989).These methods require to use the former medicine of high-purity benzene sulfonylurea, and react in organic solvent, just can make high-load solid dosage.These must increase the complicacy and the production cost of technology.
Summary of the invention: the objective of the invention is main drawback for the whole bag of tricks that overcomes above-mentioned former medicine of preparation benzene sulfonyl urea and high-content soluble solid medicament form, the preparation method of former medicine of a kind of benzene sulfonyl carbamide weedicide and preparation thereof is provided, its production safety performance is good, production cost is low, has improved quality product.
Technical scheme of the present invention is: design the preparation method of the former medicine of a kind of benzene sulfonyl carbamide weedicide, it is characterized in that: it adopts solid phosgene is the former medicine of weedicide that feedstock production has following general structure:
In the formula, R
1=CH
3, C
2H
5R
2=H, CH
3Z=CH, N;
X＝CH
3，OCH
3，OC
2H
5，OCHF
2，CL；
Y＝CH
3，OCH
3，NHCH
3，OCHF
2
The preparation method of the former medicine of described benzene sulfonyl carbamide weedicide, it adopts solid phosgene and the benzsulfamide with following general structure to react in the presence of initiator:
Add 2-amino (or 2-substituted-amino)-4,6 disubstituted pyrimidines or S-pyrrolotriazine derivatives then and continue reaction, generate the former medicine of benzene sulfonyl carbamide weedicide.
The preparation method of the former medicine of described benzene sulfonyl carbamide weedicide, it adopts solid phosgene and asccharin is the former medicine of feedstock production benzene sulfonyl carbamide weedicide.
The preparation method of the former medicine of described benzene sulfonyl carbamide weedicide, its employing solid phosgene and asccharin are that the step of preparation process of the former medicine of feedstock production benzene sulfonyl carbamide weedicide is as follows:
(1) by safe in utilization, asccharin and solid phosgene react under the initiator effect easily, then with 2-amino (or 2-substituted-amino)-4,6-disubstituted pyrimidines or the reaction of S-pyrrolotriazine derivatives generate the Saccharine derivatives that N-replaces, promptly 1
#Intermediate;
(2) 1
#Intermediate and sodium alkoxide generation nucleophilic substitution reaction generate benzene sulfonyl urea sodium salt, and promptly 2
#Intermediate;
(3) 2
#Intermediate is neutralized to PH2-5 with diluted acid, promptly generates the former medicine of benzene sulfonyl urea.
The preparation method of the former medicine of described benzene sulfonyl carbamide weedicide adopts 1
#Intermediate and 2
#Intermediate does not separate out, and whole technological process is all operated in a reactor successively, and promptly " one kettle way synthesis technique " operated, thereby operating process is greatly simplified.
The preparation method of the former medicine of described benzene sulfonyl carbamide weedicide, initiator is an organic bases, comprises N, dinethylformamide (DMF), triethylamine, pyridine, 1,4-diazabicyclo [2,2,2] octane (DABCO) and 1,8-diazabicyclo [5,4,0]+-carbene-7 (DBU) tertiary amine-type organic bases, also can be K
2CO
3, CaCO
3, mineral alkali; The organic solvent that is adopted when asccharin and solid phosgene reaction comprises toluene, dimethylbenzene, dichlorobenzene, methylene dichloride, ethylene dichloride, acetone, tetrahydrofuran (THF).
The preparation method of the former medicine of described benzene sulfonyl carbamide weedicide, the method of its synthetic benzene sulfonyl urea sodium salt is: by asccharin, solid phosgene (three surpalites) and 2-amino (or substituted-amino)-4, the reaction of the dibasic pyrimidine of 6-or S-pyrrolotriazine derivatives, preparation N-replaces Saccharine derivatives, and promptly 1
#Intermediate;
(1) 1
#Intermediate and sodium alkoxide reaction can make benzene sulfonyl urea sodium salt.This technological process can adopt " one kettle way synthesis technique " promptly 1
#Intermediate does not separate out, and whole technological operation all can be carried out in a reactor successively.
The preparation method of described benzene sulfonyl urea sodium salt, the method for preparing benzene sulfonyl urea aqueous suspension is:
With benzene sulfonyl urea sodium salt reaction mixture, evaporate most of alcohol after, in residue, add dispersion agent, thickening material, stablizer, anti-hard caking agent and suitable quantity of water, just make benzene sulfonyl carbamide weedicide aqueous suspension after wet grinding, wherein the content of effective ingredient is between 10-30%.
The preparation method of described benzene sulfonyl urea sodium salt, the method for preparing benzene sulfonyl urea soluble powder is: with benzene sulfonyl urea sodium salt reaction mixture, evaporate most of alcohol after, separate after filtration, drying operation makes benzene sulfonyl urea sodium salt, with itself and dispersion agent, thickening material, anti-drift agent, synergistic agent, after filler mixes and grinds, sieves, just make benzene sulfonyl carbamide weedicide soluble powder, wherein effective component content is between 10-80%.
The described method for preparing benzene sulfonyl urea soluble powder, its prescription is: it comprises benzene sulfonyl urea sodium salt (2
#Intermediate) 10%-80% (wt); Sodium lignosulfonate 1%-3%; Xanthan gum (XG) 0.1%-0.5%; Sodium sulfate anhydrous.min(99) 60%-6.0%.
Characteristics of the present invention are: because the preparation method of former medicine of a kind of benzene sulfonyl carbamide weedicide and preparation thereof is provided, and as shown below:
R in the formula
1, R
2, Z, X, the group of Y representative or atom described as defined above.Solid phosgene, have another name called three surpalites (triphosgene) chemical name and be two-(trichloromethyl) carbonic ether (bis-(trichloromethyl) carbonate), the synthetic just as far back as 1880, but up to 1987 just by Eckert and Forster (Eckert, H.; Forster, B.Angew.chem.Int, Ed.Engl.1987,26 (9), 894) at first propose to be used for organic synthesis as the phosgene surrogate.Because it is at room temperature stable, under 206 ℃ of boiling points, also have only slight decomposition, thereby in transportation, store and the use aspect all than phosgene safety many, so after 1987, in organic synthesis, obtained gradually to be extensive use of, but do not seen that reported in literature is used for the synthetic of benzene sulfonyl urea.
Use this safe, asccharin and solid phosgene easily, under action of evocating, in organic solvent, react, add 2-amino (or 2-substituted-amino)-4 then, 6-disubstituted pyrimidines or pyrrolotriazine derivatives carry out next step reaction, then can make N-[[(4,6-disubstituted pyrimidines or triazine-2-yl) alkylamino] carbonyl] asccharin, be called for short 1
#Intermediate:
1
#Intermediate then reacts with sodium alkoxide, just can change 2 into
#Intermediate, this is the sodium salt of benzene sulfonyl urea.Just can be directly used in the preparation of high-load soluble solids preparation by it, both simple, convenient again.
2
#Intermediate is neutralized to PH2-5 with diluted acid, just changes the former medicine of benzene sulfonyl urea into.The former medicine that we adopt this method to make, purity can reach 97-99%, and yield can reach (in asccharin) more than 90%
To react employed initiator be organic bases for phosgene and asccharin to make solid phosgene dissociate, as N, and N dimethyl formamide (DMF), triethylamine, pyridine, 1,4-diazabicyclo-[2,2,2] octane tertiary amine-type organic basess such as (DABCO) also can be K
2CO
3, CaCO
3Mineral alkali.
Spendable organic solvent has toluene, dimethylbenzene, dichlorobenzene, methylene dichloride, acetone etc. when asccharin and solid phosgene reaction.Temperature of reaction can be from room temperature to solvent reflux temperature.
From the reaction of asccharin and solid phosgene, a step acid neutralization to the last generates the whole technological processs till the former medicine of benzene sulfonyl urea, can proceed step by step, promptly separate making 1 earlier
#Intermediate, and then carry out next step reaction, make and isolate 2
#Intermediate, and then carry out sour neutralization reaction, make the former medicine of benzene sulfonyl urea.
Whole technological process also can be carried out successively continuously, and promptly the intermediate of each step generation needn't be separated, and proceeds next step reaction in same reactor, until making the former medicine of the finished product benzene sulfonyl urea.This promptly so-called " one kettle way synthesis technique ".
Solid phosgene also can be earlier and neighbour-alkoxyl formyl benzsulfamide reaction, and then with 2-amino (or 2-substituted-amino)-4,6-disubstituted pyrimidines or pyrrolotriazine derivatives reaction make the former medicine of benzene sulfonyl urea equally:
The present invention will be further described below in conjunction with embodiment.
Example 1, N-[[(4,6-dimethyl pyrimidine-2-yl) amino] carbonyl] asccharin (1
#Synthesizing intermediate).
At the bottom of being equipped with the four-hole garden of mechanical stirring, thermometer, reflux exchanger and feed hopper, 250ml adds 9.3 gram (0.05mol) 99% saccharin insoluble in the flask, 50ml dimethylbenzene and 0.25 gram DMF, stir down mixture is warming up to backflow, then under this temperature by feed hopper to wherein adding the solution that 6 gram (0.02mol) 98% solid phosgenes and 100ml dimethylbenzene are formed, dropwised in more than 3 hour, continue reaction 2 hours then, boil off dimethylbenzene under the decompression.Residue is chilled to room temperature, adds the 50ml ethylene dichloride, stir and make material dissolution, drip in room temperature with under stirring by 6.15 gram 2-amino-4, the mixture that 6-dimethyl pyrimidine and 100ml ethylene dichloride are formed then.Add in about two hours, continue reaction 3 hours then.Filter, with a small amount of ethylene dichloride drip washing filter cake, 70 ℃ of oven dry down get the 16g topic and claim compound, white solid, mp.186-190 ℃, yield 96.4%.
Example 2. sulfometuron-methyl sodium salts (2
#Synthesizing intermediate)
Mechanical stirring is being housed, at the bottom of three mouthfuls of gardens of thermometer and reflux exchanger in the flask, add successively under room temperature that 16 gram examples 1 make 1
#Intermediate, 100ml anhydrous methanol and 13ml25% methanol solution of sodium methylate are heated to backflow then, and stirring and refluxing 5 hours, boil off most of methyl alcohol, residue is chilled to room temperature, filters small amount of methanol drip washing, 70 ℃ of oven dry down get 17.8 gram sulfometuron-methyl sodium salts, and mp.169-172 ℃, yield 95.7%.
Synthesizing of example 3 sulfometuron-methyls
The sulfometuron-methyl sodium salt that example 2 is made (promptly 2
#Intermediate) 17.8 grams are dissolved in the 170ml water, remove by filter insoluble impurity, and filtrate is neutralized to PH5 with dilute acetic acid, separates out white precipitate, leave standstill 2 hours after, filter, wash twice, 90 ℃ of oven dry down, 16.5 restrain white solids, mp.198-200 ℃, through IR,
1H-NMR analyzes, and is in full accord with the collection of illustrative plates of sulfometuron-methyl standard specimen.In asccharin, the yield of sulfometuron-methyl is 90.7%, and the HPLC method is measured and shown that the purity of sample is 98.7%.
Example 4 one kettle ways synthesize sulfometuron-methyl
At 1 liter mechanical stirring is housed, add 37 gram (0.2mol) 99% saccharin insoluble in the four-hole boiling flask of thermometer, reflux exchanger and feed hopper, 200ml dimethylbenzene and 1 gram DMF, be warming up to backflow under stirring, then under this temperature to the solution that wherein slowly adds 24.5 gram (0.08mol) 98% solid phosgenes and 300ml dimethylbenzene compositions, added in about 3 hours, continued back flow reaction then 2 hours.Boil off dimethylbenzene under the decompression, residue is chilled to room temperature, adds the 200ml ethylene dichloride, stirs to make the residue dissolving, drips by the 2-amino-4.6-dimethyl pyrimidine of 25.4 gram (0.2mol) 97% and the solution that the 400ml ethylene dichloride is formed down in 20-25 ℃ then.Add a half, it is muddy that system becomes, and the adularescent solid generates.Add in about 2 hours, continued stirring reaction 3 hours.Boil off ethylene dichloride under the decompression, residue is chilled to room temperature, add 400ml anhydrous methanol and 65ml25% methanol solution of sodium methylate. be heated to backflow under stirring, and kept 5 hours, boil off most of methyl alcohol, residue 700ml water dissolution removes by filter insoluble impurity, filtrate is returned in the round-bottomed flask, be neutralized to PH5 with dilute acetic acid and separate out white precipitate, left standstill 2 hours, filter, washing, 90 ℃ of oven dry down get mp.196-200 ℃ of 67.0 gram sulfometuron-methyl, in asccharin, it is 98.4% that yield 92.0%, HPLC are measured its purity; IR (KBr) cm
-1: 1732,1701,1605,1556 (literature value: 1750,1700,1600,1550cm
-1);
1H-NMR(DMSO-d6)，ppm：2，4(s，6H)；3.8(s，3H)；7.0(s，1H)；7.7-8.3(m，4H)；10.4-10.6(d，1H)。
Embodiment 5:70% sulfometuron-methyl soluble powder
The sulfometuron-methyl sodium salt that example 2 makes, sulfometuron-methyl content are 93-94%, are mixed with proper assistant and solid packing by it, pulverize, and sieve, and can make the high-content soluble powder, and the prescription of one 70% sulfometuron-methyl soluble powder is composed as follows:
Sulfometuron-methyl sodium salt (2# intermediate, sulfometuron-methyl content 93.0%) 75.3%
Sodium lignosulfonate 2.0%
Beta-naphthalenesulfonic-acid formaldehyde condensation compound 2.0%
XG 0.5％
Sodium sulfate anhydrous.min(99) 20.2%
Add up to 100.0%
After five kinds of components were mixed in proportion, after pulverizing 100 mesh sieves, packing promptly got 70% sulfometuron-methyl soluble powder.
Embodiment 6: generally the consisting of of sulfometuron-methyl soluble solids preparation:
Sulfometuron-methyl sodium salt (2# intermediate) 1.00-80%
Tensio-active agent 1.00-5% such as dispersion agent
0.50-3% such as the anti-drift agent of thickening material
Filler 95.00-10%
Claims (6)
1, the preparation method of the former medicine of a kind of benzene sulfonyl carbamide weedicide, wherein shown in the following general formula of the structure of the former medicine of benzene sulfonyl carbamide weedicide:
In the formula, R
1=CH
3, C
2H
5R
2=H, CH
3Z=CH, N;
X＝CH
3，OCH
3，OC
2H
5，OCHF
2，Cl；
Y＝CH
3，OCH
3，NHCH
3，OCHF
2；
This method comprises:
(1) reacted under the initiator effect by asccharin and solid phosgene, replace or unsubstituted amino-4 with 2-then, 6-disubstituted pyrimidines or the reaction of S-pyrrolotriazine derivatives generate N-and replace Saccharine derivatives, and promptly 1
#Intermediate;
(2) 1
#Intermediate and sodium alkoxide generation nucleophilic substitution reaction generate benzene sulfonyl urea sodium salt, and promptly 2
#Intermediate;
(3) 2
#It is 2-5 that intermediate is neutralized to the pH value with acid, promptly generates the former medicine of benzene sulfonyl urea.
2, the preparation method of the former medicine of the described benzene sulfonyl carbamide weedicide of claim 1 can proceed step by step, and promptly earlier by asccharin, solid phosgene and 2-(replacements) amino-4,6-disubstituted pyrimidines or S-pyrrolotriazine derivatives three react, and make 1
#Intermediate; With 1
#Intermediate is separated and is dried, and with the sodium alkoxide reaction, makes 2 then
#Intermediate; With 2
#Intermediate is separated and is dried, and again with the diluted acid effect, generates the former medicine of benzene sulfonyl urea.
3, the preparation method of the former medicine of the described benzene sulfonyl carbamide weedicide of claim 1 can adopt " one kettle way synthesis technique ", promptly in same reactor, synthesizes 1 successively
#Intermediate, 2
#The reaction of intermediate and the former medicine of benzene sulphur ester urea.
4, the preparation method of the former medicine of the described benzene sulfonyl carbamide weedicide of claim 1, initiator wherein can be N, dinethylformamide, triethylamine, pyridine, 1,4-diazabicyclo [2,2,2] octane or 1,8-diazabicyclo [5,4,0]+one carbene-7 tertiary amine-type organic bases also can be mineral alkalis such as salt of wormwood or lime carbonate; Synthetic 1
#The organic solvent that is adopted during intermediate comprises toluene, methylene dichloride, ethylene dichloride, acetone or tetrahydrofuran (THF) etc.
5,, adopt " one kettle way synthesis technique " to synthesize 2 according to the method for claim 3
#Behind the intermediate, steaming desolventizes, and adds dispersion agent, thickening material, stablizer, anti-hard caking agent and suitable quantity of water then in residue, can make benzene sulfonyl carbamide weedicide aqueous suspension, and wherein the amount of effective constituent is between 10-30%.
6,, adopt " one kettle way synthesis technique " to synthesize 2 according to the method for claim 3
#Behind the intermediate, steaming desolventizes, and filters and tells 2
#Intermediate, oven dry makes benzene sulfonyl urea sodium salt, can further make benzene sulfonyl carbamide weedicide soluble powder by it, and wherein active constituent content is between 10-80%.
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