The preparation method of sulfonylurea herbicide foramsulfuron intermediateTechnical field
The present invention relates to the production technical field of agricultural sulfonylurea herbicide, more particularly, to a kind of sulfonylurea herbicideThe preparation method of foramsulfuron intermediate.
Background technology
Formamido group Sulfometuron Methyl is the inhibitor of branched-amino acid enzyme, and safener isoxadifen can reduce formyl ammoniaConduction in Semen Maydiss for the base Sulfometuron Methyl, strengthens its selectivity to Semen Maydiss. and this product is systemic herbicide, is mainly used in Semen MaydissField, is used for preventing and kill off 1 year or perennial grassy weed and broad leaved weed after Semen Maydiss sprout；Simultaneously formamido group is phoneticSulphur is grand to can be additionally used in lawn, and its structural formula is as follows:
.
Formamido group Sulfometuron Methyl, is found in nineteen ninety-five by Ai Gefu company, now by Bayer Cropscience Co., Ltd's exploitation, Long ShaCompany produces, and Tao benefit agriculture also assisted in the market development of this product later.Formamido group Sulfometuron Methyl listed in calendar year 2001,The sales volume all achieving 1.05 hundred million dollars in 2005 and 2007,2,003 2007 years, its sales growth rate was 52.2%, and this 4Compound annual growth rate between year is 11.07%；The sales volume of formamido group Sulfometuron Methyl in 2008 is 1.15 hundred million dollars, increases by a year-on-year basis9.52%；2010, the sales volume of this product increased 9.09%；2011, its sales volume was 1.30 hundred million dollars, increases on year-on-year basis again8.33%, account for the 5.50% of sulfonylurea herbicide 23.74 hundred million dollar amount of sales, in such herbicide, rank the 7th.
The method preparing formamido group Sulfometuron Methyl at present on the market is varied, wherein by middleware n, n- dimethyl-2- (n- (n- (4,6- dimethoxypyridin -2- base)-amino carbonyl)-amino-sulfonyl) -4- nitrobenzamide prepares formylThe method of amino Sulfometuron Methyl, is most convenient and efficient production method on the market, the structure of this intermediate is as follows:
(i).
At present, the preparation (i) for intermediate on the market, the synthetic method of domestic and foreign literature report is as follows；
1) method disclosed in patent wo97/16419, us6500952 adopts 5- nitro -2- dimethylamino carbonyl benzsulfamide and 4,6- dimethoxy -2-((phenyloxycarbonyl) amino) pyrimidine is condensed to yield:
The method will use somewhat expensive acid binding agent dbu, and product impurity content is high, and purity is poor, general content 90% about,And dissolubility poor it is difficult to isolate and purify.
2) method disclosed in wo95/29899, ep-a-757679 adopt 5- nitro -2- dimethylamino carbonyl benzsulfamide and4,6- dimethoxy -2- pyrimidine isocyanates are condensed to yield:
This method 4, the preparation of 6- dimethoxy -2- pyrimidine isocyanates is difficult, and the three wastes are more, and the product purity after condensation is difficult to carryHigh.
3) method disclosed in patent wo00/0522, de19540701 adopts n, the chloro- 4- nitre of n- dimethyl -2- aminosulfonylYl-benzamide first become isocyanates or become Carbimide. quaternary ammonium salt, then with 4,6- dimethoxy -2- pyrimidinamine (or its slaine)Condensation reaction prepare compound i；
Isocyanates prepare cyanate adopt, and generally require and just can carry out in the presence of a phase transfer catalyst, reaction difficulty,Three-waste pollution is larger；, with greater need for tert-butylamine catalysis, three-waste pollution is also very big for the preparation of isocyanates sulphonyl quaternary ammonium salt, and product needsPurified with silicagel column.
4) method disclosed in patent wo2001042226 adopts 5- nitro -2- dimethylamino carbonyl benzsulfamide and acetic acid secondEster is original, in the presence of Fu's acid agent triethylamine, sulfonylisocyanates is obtained through solid light, then passes through and 4,6- dimethoxyBase -2- pyrimidinamine condensation reaction prepare compound i；
Above-mentioned preparation method, method 1) by-product phenol, serious environment pollution；Method 2) reaction yield is low, and by-product is difficult in a large numberUsing environmental contaminants；Method 3) to be typically due to condensation reaction yield low, leads to product needed recrystallization or column chromatography for separation；Method 4) used by Fu's acid agent triethylamine environmental pollution serious, solid photolysis generation poisonous gass, and prepare a large amount of nothing of product by-productMachine salt.And yield low (58%).The defect that these preparation methods (i) exist is unfavorable for industrialized production.
Content of the invention
For in above-mentioned prior art synthesis foramsulfuron intermediate exist yield low, be not easily purified, cost of materialHeight, intermediate needs purification it is impossible to the technical problem such as large-scale production, present invention aim at providing the sulphonyl after a kind of improvementThe preparation method of carbamide herbicides foramsulfuron intermediate.
In order to achieve the above object, the technical solution used in the present invention is as follows: a kind of sulfonylurea herbicide Methanamide sulphurThe preparation method of grand intermediate is it is characterised in that described preparation method includes following operating procedure:
1) with 5- nitro -2- dimethylamino carbonyl benzsulfamide v and haloformate iii as raw material, containing acid binding agent potassium carbonateAprotic polar solvent in react, adjust ph to 2～3, decompression and solvent recovery, filtering drying, obtain compound ii,
.
2) the compound ii that need not purify that step 1) is obtained directly with 4,6- dimethoxy -2- pyrimidinamine iv in inertiaCarry out condensation reaction, freezing and filtering in solvent, obtain intermediate n, n- dimethyl -2- (n- (n- (4,6- dimethoxypyridin -2-Base)-amino carbonyl)-amino-sulfonyl) -4- nitrobenzamide i,
；
In haloformate iii of the present invention, x is cl or br, and r is the alkane of c1～c4.
Haloformate of the present invention is in ethyl chloroformate, methylchloroformate, bromine methyl formate or bromine Ethyl formateOne kind；Using bromine methyl formate or ethyl ester, reaction raw materials are relatively costly；During using propyl chloroformate. or butyl ester, also can increaseConsumption of raw materials, cost improves, and due to temperature raising during dealcoholization, energy consumption also can increase；Given this preferred methylchloroformateOr ethyl chloroformate.
Aprotic polar solvent of the present invention is dimethyl sulfoxide, n, one of n- dimethylformamide, acetone；AdoptWith dimethyl sulfoxide or n, during the reaction of the high boiling solvent such as n- dimethylformamide, difficult solvent recovery, precipitation temperature improves, and leads toImpurity in products increases, then from economical, facilitate production operation from the aspect of, preferably acetone.
Atent solvent of the present invention is aromatic hydrocarbons or saturated alkyl varsol；Atent solvent of the present invention isIn normal hexane, normal heptane, petroleum ether, hexamethylene, hexahydrotoluene, toluene, dimethylbenzene, trimethylbenzene, chlorobenzene or dichloro-benzenes oneKind；When saturated alkane normal hexane, normal heptane equal solvent dealcoholization, reaction is slow, and the response time is longer, and production economy is relativelyDifference；Trimethylbenzene, chlorobenzene or dichloro-benzenes etc. also can be used for this reaction, reclaim difficulty because price is slightly expensive, boiling point is high, lead to produce intoThis increase；It is preferably toluene or dimethylbenzene.
In step 1) of the present invention, 5- nitro -2- dimethylamino carbonyl benzsulfamide v and haloformate iii is carried outThe mol ratio of reaction is 1:1～2.5, and reaction temperature is -5～60 DEG C；Chloro-formate iii stable under alkaline conditions is slightly worse, usesAmount is not enough, cannot make reaction completely at all, lead to starting material left, purifying products are difficult, also due to stability is poor, easily decomposes,Determine reaction temperature unsuitable too high, compare through conditional filtering and optimize, wherein 5- nitro -2- dimethylamino carbonyl benzsulfamide vPreferred mol ratio is 1:2.0 with haloformate iii, and preferred reaction temperature is 0～25 DEG C.
Step 2 of the present invention) in the mol ratio reacted of compound ii and 4,6- dimethoxy -2- pyrimidinamine ivFor 1:1～2.0, reaction temperature is 60～150 DEG C；Compound ii and 4,6- dimethoxy -2- pyrimidinamine iv condensation reaction dealcoholysis,Compound ii poor solubility in a solvent, preferably, therefore, iv can use 4,6- dimethoxy -2- pyrimidinamine iv dissolubilityAmount, makes raw material ii try one's best and reacts completely, ii is remaining, and purifying products are difficult, but iv is excessive nor too many, otherwise, cost increasesCause to waste, equally too many iv is not easy to purification and removes；In order that reaction is completely, reaction temperature should not too low it is necessary to be higher thanThe boiling point that reaction generates alcohol and reaction dissolvent mixed solvent just can make dealcoholization completely, wherein compound ii and 4,6- dimethoxyThe preferred mol ratio of base -2- pyrimidinamine iv is 1:1.0～1.1, and preferred reaction temperature is 80～120 DEG C.
Compound i obtained by the production method of the present invention, is put in the solvent of anhydrous formic acid, in pd/c catalysisHydrogenate in the presence of agent, Catalyzed by Sodium Molybdate agent, reduce, formylated, a step obtains final product high purity product foramsulfuron.
It is an advantage of the current invention that: the invention provides a kind of efficient intermediate n, n- dimethyl -2- (n- (n- (4,6-Dimethoxypyridin -2- base)-amino carbonyl)-amino-sulfonyl) and -4- nitrobenzamide i preparation method, be existing preparation5- nitro -2- dimethylamino carbonyl benzsulfamide v and haloformate iii is reacted life by the important improvement of the synthetic method of i firstBecome compound ii, compound ii not to purify and obtain high yield and height with the synthesis of 4,6- dimethoxy -2- pyrimidinamine iv condensation reactionThe compound i of content, the compound i being obtained using the method due to content height can directly in formic acid solution catalytic hydrogenation enterRow reduction, formylation reaction obtain herbicide foramsulfuron.
The method of the present invention overcome original prepare that in foramsulfuron method, reaction efficiency is low, need highly basic to be condensed, differentCyanic acid esterification is difficult, and in the foramsulfuron product obtaining, by-products content is high, and the shortcomings of product is not easily purified, the method isA kind of method of the production foramsulfuron intermediate being worthy to be popularized.
The compound ii that the inventive method obtains and 2- amino-4,6-dimethoxy pyrimidine iv condensation reaction, response speedHurry up, moderate temperature, selectivity high, almost no coupling product generates, easy and simple to handle；Esterification can be carried out under compared with temperate condition,By-product is little, and reaction waste amount is also little, and generating inorganic salt can be reclaimed with by-product, solvent recoverable.
Cost of material of the present invention is relatively low, and operation is easy, and pollution is little, esterification, condensation reaction yield up to more than 92%；It is subsequently used for the reduction of finished product preparation, formylated two step yield is also up to more than 90%, is that foramsulfuron provides one kind veryEffectively intermediate preparation method, is especially suitable for industrialized production.
Specific embodiment
With reference to specific embodiment, the present invention is described in further detail.
Embodiment 1:n, the preparation (ii) of n- dimethyl -2- sulfonylcarbamic acid methyl ester -4- nitrobenzamide:
In 2000ml four-hole bottle, add 5- nitro -2- dimethylamino carbonyl benzsulfamide 300g, acetone 1000g, potassium carbonate400g, opens stirring, and frozen water is cooled to 5 DEG C, starts the solution that Deca methylchloroformate 208g is dissolved in acetone 200g, drips and finishes, opensBegin to be incubated 5-10 DEG C and react substantially to disappear to raw material, react about 12h；Reaction finishes, and add water 1360g, stirring, 20 DEG C of temperature control withUnder, the hydrochloric acid of Deca 30% adjusts ph to 2-3, is incubated 30 minutes, starts recovered under reduced pressure acetone to dry to the greatest extent.Filter, filter cake washing twoSecondary, each 300g, dry faint yellow or yellow powdery solid, weight: 349g, yield: 95.8%, content: 99.2%.
N, n- dimethyl -2- (n- (n- (4,6- dimethoxypyridin -2- base)-amino carbonyl)-amino-sulfonyl) -4- nitreYl-benzamide preparation (i):
In the 5000ml four-hole bottle that device has reflux condensing tube, add n, n- dimethyl -2- sulfonylcarbamic acid methyl ester -4-Nitrobenzamide (ii) 331.3g, 2- amino-4,6-dimethoxy pyrimidine 155.2g, toluene 2000g, open stirring；And byGradually it is warming up to backflow and separates the methanol that reaction generates simultaneously, stirring reaction (ii) disappears substantially to raw material, has a large amount of white solidsSeparate out, reaction takes around 8-10 hour；Reaction finishes, and is cooled to room temperature, and is incubated the 10-15 DEG C of abundant crystallize of cooling, filters,Drain, a small amount of washing, 50 DEG C of solid dries to obtain white powdery solids, weight: 447.3g, yield: 98.4%, content: 98.5%.
1hnmr (400mhz, dmso) δ: 2.764 (s, 3h ,=n-ch3), 2.944 (s, 3h ,=n-ch3),
3.931(s,6h,=o-ch3),6.012(s,1h,=c-h),7.796-7.817(d,1h,=ph-h),8.586-8.607(d,1h,=ph-h),8.795-8.801(d,1h,=ph-h),10.750(s,1h,co-nh),12.826(s,1h,so2-nh).
Embodiment 2:n, the preparation (ii) of n- dimethyl -2- sulfonylcarbamic acid ethyl ester -4- nitrobenzamide:
In 2000ml four-hole bottle, add 5- nitro -2- dimethylamino carbonyl benzsulfamide 300g, acetone 1000g, potassium carbonate400g, opens stirring, and frozen water is cooled to 5 DEG C, starts the solution that Deca ethyl chloroformate 238.8g is dissolved in acetone 200g, drips and finishes,Start to be incubated 5-10 DEG C and react substantially to disappear to raw material, react about 12h；Reaction finishes, and add water 1360g, stirring, 20 DEG C of temperature controlHereinafter, the hydrochloric acid of Deca 30% adjusts ph to 2～3, is incubated 30 minutes, starts (- 0.06 mpa -0.07mpa) recovery acetone that reduces pressureTo dry to the greatest extent.Filter, filter cake is washed twice, each 300g dries to obtain light brown yellow or yellow powdery solid, weight: 361.6g,Yield: 95.2%, content: 99.1%.
N, n- dimethyl -2- (n- (n- (4,6- dimethoxypyridin -2- base)-amino carbonyl)-amino-sulfonyl) -4- nitreYl-benzamide preparation (i):
In the 5000ml four-hole bottle that device has reflux condensing tube, add n, n- dimethyl -2- sulfonylcarbamic acid ethyl ester -4-Nitrobenzamide (ii) 345.3g, 2- amino-4,6-dimethoxy pyrimidine 155.2g, toluene 2000g, open stirring；And byGradually it is warming up to backflow, meanwhile, separate the methanol that reaction generates, stirring reaction disappears substantially to starting compound ii, has white in a large numberColor solid separates out, and reaction takes around 8-10 hour；Reaction finishes, and is cooled to room temperature, and is incubated the 10-15 DEG C of abundant crystallize of cooling,Filter, drain, a small amount of washing, 50 DEG C of solid dries to obtain white powdery solids, weight: 442.6g, yield: 97.4%, hplc containAmount: 98.3 %
Embodiment 3: foramsulfuron preparation；
In the logical hydrogen mouth of equipment, the stainless steel autoclave of the 5l of cooling circulating water, pressure gauge and electric heater unit, add noWater beetle acid 1250g, compound (i) 400g, stirring adds 10% palladium carbon 25g to be suspended in the suspension in 375g anhydrous formic acid, molybdic acidSodium dihydrate 2.5g, then with 125g anhydrous formic acid flushing pipe, close kettle；It is passed through hydrogen to intrinsic pressure 10-15kgf/cm2, and controlWarm 20-30 DEG C of stirring reaction, period will be added hydrogen and no longer decline to pressure.Hplc monitoring raw material (i) disappears or content substantiallyLess than 0.5%；Reaction finishes, reactant liquor sucking filtration, and filtering residue is washed 2 times with formic acid, each 100ml.Solid palladium carbon recovery；
Filtrate is put 2l and is dried in four-hole bottle, and recovered under reduced pressure formic acid is to dry to the greatest extent, a large amount of solids precipitations；Stirring instills methanol 600g, soonSpeed stirring 30 minutes, slowly cools to 0-5 DEG C of crystallize 1h, filters, drains, solid is dug with water and is washed till neutrality, then with methanol100g rinses, 50 DEG C of normal pressures dry off-white color to white powdery solids, weight: 362.5g, content: greater than 95%；Yield:91.02%.
1hnmr(400mhz,dmso)δ:2.741(s,3h,=n-ch3),2.886(s,3h,=n-ch3),
3.935(s,6h,=o-ch3),5.996(s,1h,=c-h),7.402-7.423(d,1h,=ph-h),7.993-8.014(d,1h,=ph-h),8.360-8.377(d,1h,=ph-h),10.620(s,1h,so2-nh),10.726(s,1h,co-nh),12.477(s,1h,o=c-h).
Embodiment 4: in the case that other reaction conditions are constant, the condition in the production method of the present invention is contrastedTest, the result obtaining is as shown in the table:
As seen from the above table: select haloformate in technical scheme as the primary raw material producing, when adopting chloro-carbonic acidThe purity of the compound ii obtaining during pentyl ester declines, and setting-up point need to greatly improve, and leads to product i needs through entering oneThe separation of step and purification, complex operation, production cost greatly improves, and is unfavorable for large-scale commercial production, and yield also drops significantlyLow；Simultaneously the mol ratio of compound reaction also contributes to the yield of final products, when the mol ratio of reactant changesWhen, the yield of intermediate product and final products and purity all can glide, and be unfavorable for the production of product.
When being produced using chloracetate, because meeting produces other side reactions, it is adopted the method for the present invention give birth toIt is impossible to obtain purpose product of the present invention during product.
Embodiment 5: in the case that other reaction conditions are constant, the condition in the production method of the present invention is contrastedTest, the result obtaining is as shown in the table:
As seen from the above table: when in the production process of the present invention, when in the production process of the present invention, ph changes, step 2) inThere is certain decline, the h in reactant liquor in the yield of the compound i producing+Concentration determine the yield of subsequent product, excessivelyOr very few h+All the yield of product compound i can be made a difference.
Using different solvents also can produce certain impact, the production of different solvents to the yield of compound i and iiCost and aftertreatment technology are different, using acetone and toluene as two-step reaction solvent, not only convenient post-treatment, Er QieshengProduce cost and compare relatively low, the product yield that obtains is compared with degree higher.
It should be noted that above-mentioned is only presently preferred embodiments of the present invention, not it is used for limiting the protection model of the present inventionEnclose, the combination in any made on the basis of above-described embodiment or equivalents belong to protection scope of the present invention.