CN100384840C - 2-pyrimidine oxy-benzoic acid [2-(pyrimidine amino methyl)]benester compound, its preparation and use thereof - Google Patents
2-pyrimidine oxy-benzoic acid [2-(pyrimidine amino methyl)]benester compound, its preparation and use thereof Download PDFInfo
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Abstract
The present invention relates to a 2-pyrimidine oxy-benzoic acid [2-(pyrimidine amino methyl)]benester compound, a preparation method and an application as an agricultural chemical herbicide. A structural formula is shown in the specification, wherein D1, D2, E1 and E2 equal to halogen, C1 to C4 alkyl group and C1 to C4 alkoxyl group; X equals to hydrogen, halogen, nitro group, cyano group and C1 to C8 alkoxyl group; Y equals to hydrogen, halogen and C1 to C8 alkyl group; A equals to O or S.
Description
Technical field
The present invention relates to the new 2-pyrimidine oxy-benzoic acid of a class [2-(pyrimidine amino methyl)] benester compound, preparation method and as the purposes of agrochemicals weedicide.
Background technology
The present invention relates to the new 2-pyrimidine oxy-benzoic acid of a class [2-(pyrimidine amino methyl)] benester compound, preparation method and as the purposes of agrochemicals weedicide.
Agricultural chemicals is the human grain that obtains, and guarantees agriculture stable yields, the indispensable production means of getting bumper crops, and in the last hundred years, agricultural chemicals such as sterilant, sterilant, weedicide etc. have been made huge contribution for human.In recent years, continuous growth along with world population, human needs to grain are also in continuous increase, but the speed of the growth of ploughing does not catch up with population growth's speed far away, solve this global problem, must rely on the grain yield that improves unit surface and improve crop quality 1 that this just must adopt various means, as breeding, cultivation, fertilising etc., and the application of agricultural chemicals also is one of requisite means wherein.But what should see is, agricultural chemicals is when making huge contribution for human civilization, because the limitation of understanding aspect, the agricultural chemicals of high poison, high residue has also brought negative impact to the environment that the mankind depend on for existence.Along with the raising of the progress of society and civilization, exploitation is efficient, low toxicity, easily degraded, security and the good environment friendly agricultural of Environmental compatibility, has become the direction of current novel pesticide initiative to replace those poor efficiencys, high poison, high residue and the high traditional agricultural chemicals of resistance.
2-pyrimidinyl oxy benzene analog derivative can be used as chemical herbicide early has bibliographical information, as Agr.Biol.Chem., and Vol.30, P896 (1966); Japanese Patent 79-55729; United States Patent (USP) 4,248,619 and 4,427,437., recently, on the basis of 2-pyrimidinyl oxy benzene analog derivative, a class has the compound of excellent weeding activity--and pyrimidine salicylic acid derivative is found, as European patent 223,406,249,708,287,072,287,079,315,889,321,846,330,990,335,409,346,789,363,040,402,751,435,170,435,186,457,505,459,243,468,690,658,549 and 768034; Japanese Patent 04368361; English Patent 2,237,570; German Patent 3,942,476 etc.Wherein representative example has: pyrithiobacsodium (Pyrithiobac-sodium, KIH-2031, European patent 315889), two careless ether (Bispyribac-sodium, KIH-2023, European patent 321846), KIH 6127 (Pyriminobac-methyl, KIH-6127, Japanese Patent 04368361), pyribenzoxim (Pyribenzoxim, European patent 658549) and ring grease grass ether (Pyriftalid, European patent 768034), their mechanism of action is identical with sulfonylurea herbicide, is the inhibitor of acetolactate synthestase (ALS), destroys plant vivo acid such as Xie Ansuan, synthesizing of leucine and Isoleucine.Though the pyrimidine salicylic acid compounds has very high weeding activity, be only applicable to the weeding of cotton field and rice terrace at present.
People such as Lv Long have reported the new 2-pyrimidinyl oxy-benzyl substituted aryl amino derivative of a class, preparation method and as agrochemicals herbicide applications (ZL00130735.5, ZL01112689.2, ZL01113199.3, CN1513321A and CN 1488626A), they have very high weeding activity, and still different with above-mentioned pyrimidine salicylic acid weedicide is that the weedicide of therefrom developing has good security to rape.Obviously, continually develop new agricultural chemicals initiative kind and be still our research topic.
Summary of the invention
The problem to be solved in the present invention provides a kind of new compound, i.e. 2-pyrimidine oxy-benzoic acid [2-(pyrimidine amino methyl)] benester compound.
The problem that the present invention also will solve provides the preparation method of above-claimed cpd.
Another problem that the present invention will solve provides a kind of purposes of above-claimed cpd.
The structural formula that the invention provides a kind of 2-pyrimidine oxy-benzoic acid [2-(pyrimidine amino methyl)] benester compound is shown in (I):
Wherein:
D
1, D
2, E
1, E
2=halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group; X=hydrogen, halogen, nitro, cyano group, C
1-C
8Alkoxyl group; Y=hydrogen, halogen, C
1-C
8Alkyl; A=O or S.
Below, we list in table one with typical compound involved in the present invention.
Table one
Compound 2-pyrimidine oxy-benzoic acid involved in the present invention [2-(pyrimidine amino methyl)] benester compound can be synthetic with following reactions steps:
D in the above-mentioned reaction formula
1, D
2, E
1, E
2, X, Y, A representative substituting group as previously mentioned.
Synthetic 2-halo-4-D, the 6-E-substituted pyrimidines or the 2-methylsulfonyl-4-D of passing through of intermediate (II)
1, 6-E
1-substituted pyrimidines and Whitfield's ointment be prepared in reaction under alkaline condition, and mol ratio is 1: 1 to 2: 1.Solvent can be varsols such as benzene, toluene or dimethylbenzene; Halogenated hydrocarbon solvents such as methylene dichloride, ethylene dichloride or chloroform; Ether solvent such as tetrahydrofuran (THF) or dioxane; Ketones solvent such as acetone or methyl iso-butyl ketone (MIBK); Alcoholic solvents such as methyl alcohol, ethanol or Virahol; Also can use the mixture of dimethyl formamide, methyl-sulphoxide, acetonitrile and above-mentioned solvent, the optimum solvent of this reaction is a dimethyl formamide.Temperature of reaction be room temperature to solvent boiling point, the reaction times is 0.5 to 24 hour.In this step reaction, used alkali can be hydride, alcoxyl metallic compound or its carbonate of monovalence or divalent metal, as sodium hydride, potassium hydride KH, hydrolith; Sodium methylate or sodium ethylate, potassium methylate or potassium ethylate; Yellow soda ash, salt of wormwood or lime carbonate etc. also can be organic basess such as triethylamine, pyridine.
Key intermediate in the reaction (III) is by following prepared in reaction:
The synthetic 2-halo-4-D that passes through of intermediate (IV)
2, 6-E
2-substituted pyrimidines or 2-methylsulfonyl-4-D
2, 6-E
2-substituted pyrimidines and salicylic aldehyde be prepared in reaction under alkaline condition, and in organic solvent, 2-halo-4-D2,6-E2-substituted pyrimidines or 2-methylsulfonyl-4-D2,6-E2-substituted pyrimidines and salicylic aldehyde react under alkaline condition and made intermediate (IV) in 0.5-24 hour; 2-halo-4-D2,6-E2-substituted pyrimidines or 2-methylsulfonyl-4-D2, the 6-E2-substituted pyrimidines, the mol ratio of salicylic aldehyde and alkali is 1: 1.0-2.0: 1.0-5.0.In this step reaction, used alkali can be hydride, alcoxyl metallic compound or its carbonate of monovalence or divalent metal, as sodium hydride, potassium hydride KH, hydrolith; Sodium methylate or sodium ethylate, potassium methylate or potassium ethylate; Yellow soda ash, salt of wormwood or lime carbonate etc. also can be organic basess such as triethylamine, pyridine.Organic solvent can be varsols such as benzene, toluene or dimethylbenzene; Halogenated hydrocarbon solvents such as methylene dichloride, ethylene dichloride or chloroform; Ether solvent such as tetrahydrofuran (THF) or dioxane; Ketones solvent such as acetone or methyl iso-butyl ketone (MIBK); Alcoholic solvents such as methyl alcohol, ethanol or Virahol; Also can use the mixture of dimethyl formamide, methyl-sulphoxide, acetonitrile and above-mentioned solvent.Temperature of reaction be room temperature to solvent boiling point, the reaction times is 0.5 to 24 hour.
In organic solvent, the synthetic of intermediate (III) can make by (IV) ammonification hydrogenation.This intermediate (III) can make with hydrogen reducing after with the ammonia ammonification under the effect of catalyzer with compound (IV), catalyzer can be Lay Buddhist nun nickel (Raney Ni), palladium carbon or platinum black etc., the mol ratio of reactant (IV), ammonia, hydrogen and catalyzer is 1: 1-1000: 1-1000: 0.01-0.5, use more ammonia, hydrogen to not influence of reaction, pressure 1-100 normal atmosphere.Temperature of reaction be room temperature to 100, the reaction times is 0.5 to 24 hour, solvent can be varsols such as benzene, toluene or dimethylbenzene; Ether solvent such as tetrahydrofuran (THF) or dioxane; Methyl alcohol, alcoholic solvents such as ethanol or Virahol; Also can use the mixture of dimethyl formamide, methyl-sulphoxide, acetonitrile and above-mentioned solvent, the optimum solvent of this reaction is an alcohols.
In addition, the synthetic of intermediate (III) can also make after reduction by generating compound (V) after compound (IV) and the oxammonium hydrochloride condensation.Compound (IV) can be hydride, alcoxyl metallic compound or its carbonate of monovalence or divalent metal with the used alkali of oxammonium hydrochloride condensation reaction, as sodium hydride, potassium hydride KH, hydrolith; Sodium methylate or sodium ethylate, potassium methylate or potassium ethylate; Yellow soda ash, salt of wormwood or lime carbonate etc. also can be organic basess such as triethylamine, pyridine.Solvent can be varsols such as benzene, toluene or dimethylbenzene; Halogenated hydrocarbon solvents such as methylene dichloride, ethylene dichloride or chloroform; Ether solvent such as tetrahydrofuran (THF) or dioxane; Ketones solvent such as acetone or methyl iso-butyl ketone (MIBK); Alcoholic solvents such as methyl alcohol, ethanol or Virahol; Also can use dimethyl formamide, methyl-sulphoxide, acetonitrile, the mixture of water and above-mentioned solvent.Temperature of reaction be room temperature to solvent boiling point, the reaction times is 0.5 to 24 hour.Compound (V) reduction generates (III) reaction can be with the chemical reagent reduction as iron powder/hydrochloric acid, zinc powder/ammonium chloride, sulfide, sodium borohydride, the reduction such as (ammonium formiates) of palladium carbon/formic acid, and described compound (V) is 1 with the chemical reagent mol ratio: 1-10; Also can under the effect of catalyzer, make with hydrogen reducing, catalyzer can be Lay Buddhist nun nickel (Raney Ni), palladium carbon or platinum black etc., the mol ratio of reactant (V), hydrogen and catalyzer is 1: 1-1000: 0.01-0.5, use more hydrogen to not influence of reaction.Temperature of reaction be room temperature to 100, the reaction times is 0.5 to 24 hour, solvent can be varsols such as benzene, toluene or dimethylbenzene; Ether solvent such as tetrahydrofuran (THF) or dioxane; Methyl alcohol, alcoholic solvents such as ethanol or Virahol; Also can use the mixture of dimethyl formamide, methyl-sulphoxide, acetonitrile and above-mentioned solvent, the optimum solvent of this reaction is an alcohols.
At last, in organic solvent, intermediate (II) and intermediate (III) are made target product (I) after condensation.In this step reaction, used condensing agent can be DCC, DIC, CDI; In this step reaction, used alkali can be hydride, alcoxyl metallic compound or its carbonate of monovalence or divalent metal, as sodium hydride, potassium hydride KH, hydrolith; Sodium methylate or sodium ethylate, potassium methylate or potassium ethylate; Yellow soda ash, salt of wormwood or lime carbonate etc. also can be triethylamine, pyridine, N, N-dimethyl aminopyridine (DMAP), organic basess such as diisopropyl ethyl amine.Reaction solvent can be varsols such as benzene, toluene or dimethylbenzene; Halogenated hydrocarbon solvents such as methylene dichloride, ethylene dichloride or chloroform; Ether solvent such as tetrahydrofuran (THF) or dioxane; Ketones solvent such as acetone or methyl iso-butyl ketone (MIBK); Methyl alcohol, alcoholic solvents such as ethanol or Virahol; Also can use the mixture of dimethyl formamide, methyl-sulphoxide, acetonitrile and above-mentioned solvent, the optimum solvent of this reaction is an ethers.Temperature of reaction be room temperature to solvent boiling point, the reaction times is 0.5 to 24 hour.Intermediate (IV), 2-halo-4-D
2, 6-E
2-substituted pyrimidines or 2-methylsulfonyl-4-D
2, 6-E
2The mol ratio of-substituted pyrimidines and alkali is 1: 1.0-1.2: 1-5.Final product can be further purified through silica gel column chromatography or recrystallization.
The invention provides the purposes of above-mentioned 2-pyrimidine oxy-benzoic acid [2-(pyrimidine amino methyl)] benester compound, promptly can be used for weedicide.
With the active constituent of compound of the present invention as the chemistry of pesticide weedicide, be mixed with various liquors, missible oil, suspension agent, aqueous suspension, microemulsion, (water) emulsion, pulvis, wettable powder, soluble powder, (water dispersible) granule or capsule etc., can be used for the control of weeds of farm crop such as paddy rice, soybean, wheat, cotton, corn and rape.
The weight percentage of active constituent is recommended as 5～90% in the preparation, and all the other are carrier, and carrier comprises two kinds at least, and wherein at least a is tensio-active agent.Carrier can be solid or liquid.Suitable solid carrier comprises natural or synthetic clay and silicate, for example natural silica and diatomite; Magnesium Silicate q-agent is talcum for example; Magnesium aluminum silicate is kaolinite, kaolin, polynite and mica for example; White carbon black, lime carbonate, light calcium carbonate; Calcium sulfate; Wingdale; Sodium sulfate; Amine salt such as ammonium sulfate, hexamethylene diamine.Liquid vehicle comprises water and organic solvent, and when water was cooked solvent or thinner, organic solvent also can be used as auxiliary or antifreeze additive.Appropriate organic solvent comprises aromatic hydrocarbons for example benzene, dimethylbenzene, toluene etc.; Hydrochloric ether, for example chlorinated benzene, vinylchlorid, trichloromethane, methylene dichloride etc.; Aliphatic hydrocarbon, for example petroleum fractions, hexanaphthene, light mineral oil; Alcohols, for example Virahol, butanols, ethylene glycol, glycerol and hexalin etc.; And their ether and ester; Also have ketone, for example acetone, pimelinketone and dimethyl formamide and N-methyl-pyrrolidone.
Tensio-active agent can be emulsifying agent, dispersion agent or wetting agent; Can be ionic or non-ionic type.Nonionic emulsifier is polyoxyethylene fatty acid fat, polyoxyethylene aliphatic alcohol ether, polyoxyethylene fatty amine for example, and commercially available emulsifying agent: agricultural newborn 2201B, agricultural newborn 0203B, farming breast 100
#, farming breast 500
#, farming breast 600
#, agricultural newborn 600-2
#, farming breast 1601, farming breast 2201, agricultural newborn NP-10, agricultural newborn NP-15, farming breast 507
#, agricultural newborn OX-635, agricultural newborn OX-622, agricultural newborn OX-653, agricultural newborn OX-667, peaceful breast 36
#Dispersion agent comprises sodium lignosulfonate, draws back powder, calcium lignin sulphonate, condensation compound of methyl naphthalene sulfonic acid and formaldehyde etc.Wetting agent is: sodium laurylsulfate, Sodium dodecylbenzene sulfonate, sodium alkyl naphthalene sulfonate etc.
These preparations can be prepared by method in common.For example, active substance is mixed with liquid solvent and/or solid carrier, add tensio-active agent such as emulsifying agent, dispersion agent, stablizer, wetting agent simultaneously, can also add other auxiliary agent as tackiness agent, defoamer, oxygenant etc.
Weeding active compound of the present invention can with sterilant, sterilant, nematocides, plant-growth regulator, fertilizer, and other weedicide or other agrochemicals use that is mixed.
Compound of the present invention and preparation thereof have following characteristics and advantage:
1, have weeding activity efficiently, herbicidal effect after not only showing preferably bud under 75～150gai/ha low dosage, and show preferably herbicidal effect before the bud.
2, the grass spectrum is wider extremely, can not only effectively prevent and kill off gramineous weeds in the farmland, and can prevent and kill off broadleaf weeds and nutgrass flatsedge.
3, have selectivity preferably, to some crop safety, as: wheat, corn, paddy rice etc.
4, above the average age for marriage susceptible weeds also had highly effective weeding activity.
5, residual period, is short in soil, and the succession crop growth is had no adverse effects.
6, have rational toxicity, eco-toxicity and Environmental compatibility, belong to the environmentally friendly agricultural chemicals of low toxicity.
Structural formula provided by the present invention is the compound of (I), simple synthetic method not only, and have weeding activity and crop-selective, can be used for weedicide.Its preparation can be prevented and treated most of farmland weeds effectively, effectively prevent and treat responsive Gramineae down than low dosage, broadleaf weeds and nutgrass flatsedge, concrete controlling object comprises barnyard grass grass (Echinochloa crusgalli), lady's-grass (Digitaria sanguinalis), Herba Eleusines Indicae (Eleusine indica), Herba Setariae Viridis (Setaria viridis), annual bluegrass (Poa annua), wild avena sativa (Avena fatua), amur foxtail (Alopecurus aequalis), Japan amur foxtail (Alopecurus japonicus), Amaranthus retroflexus (Amaranthus retroflexus), thorn amaranth (Amaranthus spinosus), lamb's-quarters (Chenopodium album), leaf mustard (Brassica juncea), purslane (Portulaca oleracea), Herba Acalyphae (Acalypha australis), Herba Cyperi Difformis (Cyperus difformis), Semen Euphorbiae (Leptochloa chinensis), Rhizoma Cyperi (Cyperus rotundus), grass (Fimbristylis miliacea) floats sunshine, chickweed (Stallaria media), Stellaria alsine Grim. (Stellaria alsine), Herba Erigerontis Annui (Erigeron annuus), short arrowhead (Sagittaria sagittifolia), Herba seu Flos Convolvuli arvensis (Convolvulus arvensis) etc.
Embodiment
Following example helps to understand the present invention, but the present invention not merely is confined in the scope of following example.Wherein with compound of the present invention as the active substance component, in the example of processing preparation several herbicides formulation, all " % " all refer to weight percent, " g ai/ha " all refers to every gram actives/hectare.
Example
Example 1
Intermediate (IV-1) is synthetic
D
2＝OMe，E
2＝OMe
With salicylic aldehyde 415g (3.398mol), 4,6-dimethoxy-2-methylsulfonyl pyrimidine 740g (3.398mol), salt of wormwood 938g (6.796mol) placed the 3500mlDMF stirring at room 2 days, TLC tracks to fully, then with reaction product under mechanical stirring, pour into slowly in the 15L water, stir 2h, there are a large amount of solids to separate out, leave standstill 1h, filter, air-dry, weigh IV-1 800g.
Example 2
Intermediate (IV-1) is synthetic
D
2＝OMe，E
2＝OMe
With 13.4g (0.11mol) salicylic aldehyde and 21.8g (0.1mol) 4,6-dimethoxy-2-methylsulfonyl pyrimidine, 20.7g (0.15mol) salt of wormwood refluxed 4.5 hours in the 4-dioxane 1, cooling back suction filtration, 1,4-dioxane drip washing filter cake, the pressure reducing and steaming solvent gets yellow solid, ethyl acetate: sherwood oil=1: 10 recrystallization gets the white crystal IV-1 of pyrimidine salicylic aldehyde, 18.4 grams.
Example 3
Intermediate (IV-11) is synthetic
D
2＝OMe，E
2＝OMe
With 17.1g (0.11mol) 6-chloro-salicylic aldehyde and 21.8g (0.1mol) 4,6-dimethoxy-2-methylsulfonyl pyrimidine, 20.7g (0.15mol) salt of wormwood refluxed 14 hours in the 4-dioxane 1, cooling back suction filtration, 1,4-dioxane drip washing filter cake, the pressure reducing and steaming solvent gets yellow solid, ethyl acetate: sherwood oil=1: 10 recrystallization gets the white crystal IV-11 of pyrimidine salicylic aldehyde, 15.8 grams.
Example 4
Intermediate (IV-12) is synthetic
D
2＝OMe，E
2＝OMe
With 15.4g (0.11mol) 6-fluorine salicylic aldehyde and 21.8g (0.1mol) 4,6-dimethoxy-2-methylsulfonyl pyrimidine, 20.7g (0.15mol) salt of wormwood refluxed 14 hours in the 4-dioxane 1, cooling back suction filtration, 1,4-dioxane drip washing filter cake, the pressure reducing and steaming solvent gets yellow solid, ethyl acetate: sherwood oil=1: 10 recrystallization gets the white crystal IV-12 of pyrimidine salicylic aldehyde, 12.8 grams.
Example 5
Intermediate (IV-13) is synthetic
D
2＝OMe，E
2＝OMe
With 14.9g (0.11mol) 4-Methyl Salicylaldehyde and 21.8g (0.1mol) 4,6-dimethoxy-2-methylsulfonyl pyrimidine, 20.7g (0.15mol) salt of wormwood refluxed 14 hours in the 4-dioxane 1, cooling back suction filtration, 1,4-dioxane drip washing filter cake, the pressure reducing and steaming solvent gets yellow solid, ethyl acetate: sherwood oil=1: 10 recrystallization gets the white crystal IV-13 of pyrimidine salicylic aldehyde, 10.2 grams.
Example 6
Intermediate (IV-17) is synthetic
D
2＝Me，E
2＝OMe
With 13.4g (0.11mol) salicylic aldehyde and 15.8g (0.1mol) 4-methoxyl group-6-methyl-2-chloropyrimide, 20.7g (0.15mol) salt of wormwood is 1, refluxed 4.5 hours in the 4-dioxane, cooling back suction filtration, 1,4-dioxane drip washing filter cake, the pressure reducing and steaming solvent, get yellow solid, ethyl acetate: sherwood oil=1: 10 recrystallization gets the white crystal IV-17 of pyrimidine salicylic aldehyde, 15.8 grams.
Example 7
Synthesizing of intermediate (V-1)
D
1＝OMe，E
1＝OMe
With pyrimidine salicylic aldehyde IV-1 208.2g, oxammonium hydrochloride 55.6g drops in the mixing solutions of ethanol 3200ml and water 1600ml, gradation adds sodium bicarbonate 67.2g under the stirring at room, and TLC tracks to and reacts completely, and adds entry 1600ml again, continue to stir 1h, leave standstill 30min, filter, air-dry, be weighed as 198g, productive rate is 90%.
Example 8
Synthesizing of intermediate (V-11)
D
1＝OMe，E
1＝OMe
With 6-chloropyrimide salicylic aldehyde IV-11 174g, oxammonium hydrochloride 55.6g drops in the mixing solutions of ethanol 3200ml and water 1600ml, gradation adds sodium bicarbonate 67.2g under the stirring at room, TLC tracks to and reacts completely, and adds entry 1600ml again, continues to stir 1h, leave standstill 30min, filter, air-dry, the intermediate of weighing (V-11) 140g.
Example 9
Synthesizing of intermediate (V-12)
D
1＝OMe，E
1＝OMe
With 6-fluorine pyrimidine salicylic aldehyde IV-12 128g, oxammonium hydrochloride 55.6g drops in the mixing solutions of ethanol 3200ml and water 1600ml, gradation adds sodium bicarbonate 67.2g under the stirring at room, TLC tracks to and reacts completely, and adds entry 1600ml again, continues to stir 1h, leave standstill 30min, filter, air-dry, the intermediate of weighing (V-12) 130g.
Example 10
Synthesizing of intermediate (V-13)
D
1＝OMe，E
1＝OMe
With 6-chloropyrimide salicylic aldehyde IV-11 189g, oxammonium hydrochloride 55.6g drops in the mixing solutions of ethanol 3200ml and water 1600ml, gradation adds sodium bicarbonate 67.2g under the stirring at room, TLC tracks to and reacts completely, and adds entry 1600ml again, continues to stir 1h, leave standstill 30min, filter, air-dry, the intermediate of weighing (V-13) 190g.
Example 11
Synthesizing of intermediate (V-17)
D
2＝Me，E
2＝OMe
With pyrimidine salicylic aldehyde IV-17 180g, oxammonium hydrochloride 55.6g drops in the mixing solutions of ethanol 3200ml and water 1600ml, gradation adds sodium bicarbonate 67.2g under the stirring at room, and TLC tracks to and reacts completely, and adds entry 1600ml again, continue to stir 1h, leave standstill 30min, filter, air-dry, be weighed as 174g, productive rate is 91%.
Example 12
Synthesizing of intermediate (III-1)
D
1＝OMe，E
1＝OMe
80g is dissolved in earlier in the ethanol with pyrimidine salicylaldoxime (V), under the magnetic agitation, adds 10gPd-C, adds ammonium formate more in batches, and TLC follows the tracks of to put and reacts completely, and filters, and filtrate revolves 2/3, and the solid filtering with separating out is product.Gained filter cake THF thermosol for the first time, filtered while hot, filtrate is spin-dried for, and is product, does recrystallization with ethyl acetate/petroleum ether, must 45g intermediate (III).Productive rate is 56.25%.
Example 13
Intermediate (III-1) is synthetic
D
1＝OMe，E
1＝OMe
2.6g (0.01mol) the pyrimidine salicylic aldehyde joins in the saturated ammonia ethanolic soln of 20ml, the thunder formula nickel (Raney Ni) of adding 10%, pressurized with hydrogen is to 60atm, 80 ℃ were reacted 8 hours, filtered while hot is fallen thunder formula nickel (Raney Ni), and the ethanol drip washing filter cake of heat boils off about 1/2 ethanol, leaving standstill crystallization. ethyl alcohol recrystallization gets white crystal (yield is 60%).Nuclear-magnetism (
1HNMR) (CDCl
3) (ppm): 7.27 (1H, d, J=7.2Hz), 7.10 (1H, m), 6.86 (1H, d, J=8.1Hz), 6.80 (1H, t, J=7.2Hz), 5.39 (1H, s), 4.54 (2H, s), 3.83 (6H, s)
Mass spectrum (MS) (m/e, %): 261 (M
+, 100), 244 (M
+-NH
3, 7.88)
Infrared (IR) (max/cm
-1): 3241,3155 (N-H), 3074 (Ph-H), 2951 (C-H), 1621 (Ph-H), 1220,1155 (O-)
Ultimate analysis (Elemental Analysis)
Calcd：C59.77；H5.75；N 16.09
Found：C59.93；H5.98；N16.22
Example 14
Synthesizing of intermediate (III-11)
D
1＝OMe，E
1＝OMe
90g is dissolved in earlier in the ethanol with 6-chloropyrimide salicylaldoxime (V-11), under the magnetic agitation, adds 10gPd-C, adds ammonium formate more in batches, and TLC follows the tracks of to put and reacts completely, and filters, and filtrate revolves 2/3, and the solid filtering with separating out is product.Gained filter cake THF thermosol for the first time, filtered while hot, filtrate is spin-dried for, and is product, does recrystallization with ethyl acetate/petroleum ether, must 55g intermediate (III-11).
Example 15
Synthesizing of intermediate (III-12)
D
1＝OMe，E
1＝OMe
60g is dissolved in earlier in the ethanol with 6-fluorine pyrimidine salicylaldoxime (V-12), under the magnetic agitation, adds 10gPd-C, adds ammonium formate more in batches, and TLC follows the tracks of to put and reacts completely, and filters, and filtrate revolves 2/3, and the solid filtering with separating out is product.Gained filter cake THF thermosol for the first time, filtered while hot, filtrate is spin-dried for, and is product, does recrystallization with ethyl acetate/petroleum ether, must 55g intermediate (III-12).
Example 16
Synthesizing of intermediate (III-13)
D
1＝OMe，E
1＝OMe
54g is dissolved in earlier in the ethanol with 4-methylpyrimidine salicylaldoxime (V-13), under the magnetic agitation, adds 10gPd-C, adds ammonium formate more in batches, and TLC follows the tracks of to put and reacts completely, and filters, and filtrate revolves 2/3, and the solid filtering with separating out is product.Gained filter cake THF thermosol for the first time, filtered while hot, filtrate is spin-dried for, and is product, does recrystallization with ethyl acetate/petroleum ether, must 23g intermediate (III-13).
Example 17
Synthesizing of intermediate (III-17)
D
2＝Me，E
2＝OMe
80g is dissolved in earlier in the ethanol with pyrimidine salicylaldoxime (V-17), under the magnetic agitation, adds 10gPd-C, adds ammonium formate more in batches, and TLC follows the tracks of to put and reacts completely, and filters, and filtrate revolves 2/3, and the solid filtering with separating out is product.Gained filter cake THF thermosol for the first time, filtered while hot, filtrate is spin-dried for, and is product, does recrystallization with ethyl acetate/petroleum ether, must 35g intermediate (III-17).Productive rate is 43.6%.
Example 18
Synthesizing of intermediate (II-1)
With Whitfield's ointment 100g (724mmol), 4,6-dimethoxy-2-methylsulfonyl pyrimidine 158g (724mmol), salt of wormwood 350g (2172mmol) places 600mlDMF 40-50 ℃ of following mechanical stirring 2 days, filters, and filter cake is washed 1-2 time with ethyl acetate, then filter cake is poured in the water, the elimination insolubles, filtrate transfers PH to 4-5 with hydrochloric acid, has a large amount of white solids to separate out, standing over night, filter, drying gets 80g intermediate (II-1) (yield 40%).
Example 19
Synthesizing of intermediate (II-1)
In the 500ml round-bottomed bottle, add 13.7g (0.1mol) Whitfield's ointment, 21.8g (0.1mol) and 41.4g (0.3mol) salt of wormwood, in 250mlDMF, be heated to 65 ℃, after 6 hours in the impouring 1000ml water, concentrated hydrochloric acid is regulated pH value between the 4-5, leave standstill crystallization, get faint yellow solid intermediate (II-1) (yield 85%).
Example 20
Synthesizing of intermediate (II-2)
In the 500ml round-bottomed bottle, add 15.6g (0.1mol) 5-fluorosalicylic acid, 21.8g (0.1mol) 4,6-dimethoxy-2-methylsulfonyl pyrimidine and 41.4g (0.3mol) salt of wormwood, in 250mlDMF, be heated to 65 ℃, after 6 hours in the impouring 1000ml water, concentrated hydrochloric acid is regulated pH value between the 4-5, leaves standstill crystallization, gets faint yellow solid intermediate (II-2) (yield 75%).
Example 21
Synthesizing of intermediate (II-3)
In the 500ml round-bottomed bottle, add 16.8g (0.1mol) 4-methoxyl group Whitfield's ointment, 21.8g (0.1mol) 4,6-dimethoxy-2-methylsulfonyl pyrimidine and 41.4g (0.3mol) salt of wormwood, in 250mlDMF, be heated to 65 ℃, after 6 hours in the impouring 1000ml water, concentrated hydrochloric acid is regulated pH value between the 4-5, leaves standstill crystallization, gets faint yellow solid intermediate (II-3) (yield 82.8%).
Example 22
Synthesizing of intermediate (II-4)
In the 500ml round-bottomed bottle, add 17.2g (0.1mol) 3-chloro-salicylic acid, 21.8g (0.1mol) 4,6-dimethoxy-2-methylsulfonyl pyrimidine and 41.4g (0.3mol) salt of wormwood, in 250mlDMF, be heated to 65 ℃, after 8 hours in the impouring 1000ml water, concentrated hydrochloric acid is regulated pH value between the 4-5, leaves standstill crystallization, gets yellow solid intermediate (II-4) (yield 87%).
Example 23
Synthesizing of intermediate (II-5)
In the 500ml round-bottomed bottle, add 21.7g (0.1mol) 5-bromo Whitfield's ointment, 21.8g (0.1mol) 4,6-dimethoxy-2-methylsulfonyl pyrimidine and 41.4g (0.3mol) salt of wormwood, in 250mlDMF, be heated to 65 ℃, after 6 hours in the impouring 1000ml water, concentrated hydrochloric acid is regulated pH value between the 4-5, leaves standstill crystallization, gets white look solid intermediate (II-5) (yield 79%).
Example 24
Synthesizing of intermediate (II-6)
In the 500ml round-bottomed bottle, add 16.3g (0.1mol) 3-methoxyl group Whitfield's ointment, 21.8g (0.1mol) 4,6-dimethoxy-2-methylsulfonyl pyrimidine and 41.4g (0.3mol) salt of wormwood, in 250mlDMF, be heated to 65 ℃, after 6 hours in the impouring 1000ml water, concentrated hydrochloric acid is regulated pH value between the 4-5, leaves standstill crystallization, gets faint yellow solid intermediate (II-6) (yield 94%).
Example 25
Synthesizing of intermediate (II-7)
In the 500ml round-bottomed bottle, add 15.4g (0.1mol) 2-Thiosalicylic acid, 21.8g (0.1mol) 4,6-dimethoxy-2-methylsulfonyl pyrimidine and 41.4g (0.3mol) salt of wormwood, in 250mlDMF, be heated to 65 ℃, after 6 hours in the impouring 1000ml water, concentrated hydrochloric acid is regulated pH value between the 4-5, leaves standstill crystallization, gets faint yellow solid intermediate (II-7) (yield 74%).
Example 26
Synthesizing of intermediate (II-8)
In the 500ml round-bottomed bottle, add 17.2g (0.1mol) 5-chloro-salicylic acid, 21.8g (0.1mol) 4,6-dimethoxy-2-methylsulfonyl pyrimidine and 41.4g (0.3mol) salt of wormwood, in 250mlDMF, be heated to 65 ℃, after 6 hours in the impouring 1000ml water, concentrated hydrochloric acid is regulated pH value between the 4-5, leaves standstill crystallization, gets faint yellow solid intermediate (II-8) (yield 69%).
Example 27
Synthesizing of intermediate (II-9)
In the 500ml round-bottomed bottle, add 18.5g (0.1mol) 5-nitrosalicylic acid, 21.8g (0.1mol) 4,6-dimethoxy-2-methylsulfonyl pyrimidine and 41.4g (0.3mol) salt of wormwood, reflux in 250mlDMF, after 6 hours in the impouring 1000ml water, concentrated hydrochloric acid is regulated pH value between the 4-5, leaves standstill crystallization, gets faint yellow solid intermediate (II-8) (yield 71%).
Example 28
Synthesizing of intermediate (II-10)
In the 500ml round-bottomed bottle, add 16.3g (0.1mol) 5-cyano group Whitfield's ointment, 21.8g (0.1mol) 4,6-dimethoxy-2-methylsulfonyl pyrimidine and 41.4g (0.3mol) salt of wormwood, reflux in 250mlDMF, after 6 hours in the impouring 1000ml water, concentrated hydrochloric acid is regulated pH value between the 4-5, leaves standstill crystallization, gets faint yellow solid intermediate (II-8) (yield 85%).
Example 29
Synthesizing of intermediate (II-14)
In the 500ml round-bottomed bottle, add 13.7g (0.1mo1) Whitfield's ointment, 22.2g 4-chloro-6-methoxyl group-2-methylsulfonyl pyrimidine (0.1mo1) and 41.4g (0.3mo1) salt of wormwood, in 250mlDMF, be heated to 65 ℃, after 6 hours in the impouring 1000m1 water, concentrated hydrochloric acid is regulated pH value between the 4-5, leave standstill crystallization, get faint yellow solid intermediate (II-1) (yield 70%).
Example 30
Synthesizing of intermediate (II-15)
In the 500ml round-bottomed bottle, add 13.7g (0.1mol) Whitfield's ointment, 20.2g 4-methoxyl group-6-methyl-2-methylsulfonyl pyrimidine (0.1mol) and 41.4g (0.3mol) salt of wormwood, in 250mlDMF, be heated to 65 ℃, after 6 hours in the impouring 1000ml water, concentrated hydrochloric acid is regulated pH value between the 4-5, leave standstill crystallization, get faint yellow solid intermediate (II-1) (yield 60%).
Example 31
Synthesizing of intermediate (II-16)
In the 500ml round-bottomed bottle, add 15.2g (0.1mol) 5-cresotinic acid, 21.8g (0.1mol) 4,6-dimethoxy-2-methylsulfonyl pyrimidine and 41.4g (0.3mol) salt of wormwood, room temperature reaction in 250mlDMF, after 48 hours in the impouring 1000ml water, concentrated hydrochloric acid is regulated pH value between the 4-5, leaves standstill crystallization, gets faint yellow solid intermediate (II-8) (yield 75%).
Example 32
Synthesizing of compound (I-1)
In the exsiccant reaction tubes with 261mg (1mmol) intermediate (III-1), 278mg (1mmol) pyrimidine Whitfield's ointment, and 10mgDMAP is suspended in the 2ml tetrahydrofuran (THF), maintain the temperature at below 0 ℃, the dichloromethane solution that slowly adds 226mg (1.1mmol) DCC, add half an hour, keeping temperature to rise to room temperature reaction after 1 hour spends the night. place more than 4 hours for-20 ℃ in the refrigerator, the elimination insoluble solids, ethyl acetate behind the mother liquor evaporate to dryness: sherwood oil=1: 4 column chromatography, the white solid (yield 74%) of compound (I-1).
1HNMR(CDCl
3)(ppm)：8.17(1H，d，J＝5.7)，7.66(1H，m)，7.36(5H，m)，6.90(1H，m)，5.72(1H，s)，5.37(1H，s)，5.25(1H，br)，4.51(2H，d，J＝6)，3.90(6H，s)，3.78(6H，s)
MS(m/e，％)：519(M
+，7.71)，259(100)
IR(max/cm
-1)：3251(N-H)，3012(Ph-H)，1737(CO-N)，1247，1160(-O-)
Elemental Analysis：Calcd：C60.12；H4.81；N13.48
Found：C60.44；H5.20；N13.37
Example 33
Synthesizing of compound (I-2)
In the exsiccant reaction tubes with 261mg (1mmol) intermediate (III-1), 294mg (1mmol) 5-fluorine pyrimidine Whitfield's ointment, and 10mgDMAP is suspended in the 2ml tetrahydrofuran (THF), maintain the temperature at below 0 ℃, the dichloromethane solution that slowly adds 226mg (1.1mmol) DCC, add half an hour, keeping temperature to rise to room temperature reaction after 1 hour spends the night. place more than 4 hours for-20 ℃ in the refrigerator, the elimination insoluble solids, ethyl acetate behind the mother liquor evaporate to dryness: sherwood oil=1: 4 column chromatography, the white solid (yield 80%) of compound (I-2).
MS(m/e，％)：537(M
+，10.23)，260(63.11)，277(100)
High performance liquid chromatography (HPLC): 89.86%
Example 34
Synthesizing of compound (I-3)
In the exsiccant reaction tubes with 261mg (1mmol) intermediate (III-1), 306mg (1mmol) 4-methoxy pyrimidine Whitfield's ointment, and 10mgDMAP is suspended in the 2ml tetrahydrofuran (THF), maintain the temperature at below 0 ℃, the dichloromethane solution that slowly adds 226mg (1.1mmol) DCC, add half an hour, keeping temperature to rise to room temperature reaction after 1 hour spends the night. place more than 4 hours for-20 ℃ in the refrigerator, the elimination insoluble solids, ethyl acetate behind the mother liquor evaporate to dryness: sherwood oil=1: 4 column chromatography, the white solid (yield 88%) of compound (I-3).
1HNMR(CDCl
3)(ppm)：8.11(1H，s，J＝7.5)，7.83(1H，d，J＝8.1)，7.60(1H，m)，7.55(1H，m)，7.44(1H，m)，7.23(2H，m)，6.95(1H，m)，5.69(1H，s)，5.37(1H，s)，5.27(1H，br)，4.55(2H，br)，3.87(3H，s)，3.79(6H，s)，3.72(6H，s)，
MS(m/e，％)：549(M
+，5.75)，550(M
++1，7.18)，261(45.88)，289(100)
IR(max/cm
-1)：3243(N-H)，3074(Ph-H)，2973(C-H)，1673(CO-N)
Elemental Analysis：Calcd：C59.01；H4.92；N12.75
Found：C59.37；H5.18；N12.47
HPLC：97％
Example 35
Synthesizing of compound (I-4)
In the exsiccant reaction tubes with 261mg (1mmol) intermediate (III-1), 310mg (1mmol) 3-chloropyrimide Whitfield's ointment, and 10mgDMAP is suspended in the 2ml tetrahydrofuran (THF), maintain the temperature at below 0 ℃, the dichloromethane solution that slowly adds 226mg (1.1mmol) DCC, add half an hour, keeping temperature to rise to room temperature reaction after 1 hour spends the night. place more than 4 hours for-20 ℃ in the refrigerator, the elimination insoluble solids, ethyl acetate behind the mother liquor evaporate to dryness: sherwood oil=1: 4 column chromatography, the white solid (yield 72%) of compound (I-4).
1HNMR(CDCl
3)(ppm)：8.10(1H，m)，7.62(1H，m)，7.44(1H，m)，7.27(3H，m)，6.86(1H，d，J＝7.8)，5.74(1H，m)，5.57(1H，br)，4.52(2H，m)，3.85(6H，s)3.78(6H，s)
MS(m/e，％)：553(M
+，7.98)，293(100)，260(68.51)
IR(max/cm
-1)：3419(N-H)，2949(C-H)，1750(CO-N)
Example 36
Synthesizing of compound (I-5)
In the exsiccant reaction tubes with 261mg (1mmol) intermediate (III-1), 355mg (1mmol) 5-bromo pyrimi piperidine Whitfield's ointment, and 10mgDMAP is suspended in the 2ml tetrahydrofuran (THF), maintain the temperature at below 0 ℃, the dichloromethane solution that slowly adds 226mg (1.1mmol) DCC, add half an hour, keeping temperature to rise to room temperature reaction after 1 hour spends the night. place more than 4 hours for-20 ℃ in the refrigerator, the elimination insoluble solids, ethyl acetate behind the mother liquor evaporate to dryness: sherwood oil=1: 4 column chromatography, the white solid (yield 87%) of compound (I-5).
1HNMR(CDCl
3)(ppm)：8.23(1H，d)，7.75(1H，m)，7.44(1H，m)，7.23(3H，m)，6.85(1H，d)，5.74(1H，m)，5.38(1H，s)，4.49(2H，d)，3.79(6H，s)3.77(6H，s)
ESI：598,600
HPLC：96.8％
Example 37
Synthesizing of compound (I-6)
In the exsiccant reaction tubes with 261mg (1mmol) intermediate (III-1), 355mg (1mmol) 3-methoxy pyrimidine Whitfield's ointment, and 10mgDMAP is suspended in the 2ml tetrahydrofuran (THF), maintain the temperature at below 0 ℃, the dichloromethane solution that slowly adds 226mg (1.1mmol) DCC, add half an hour, keeping temperature to rise to room temperature reaction after 1 hour spends the night. place more than 4 hours for-20 ℃ in the refrigerator, the elimination insoluble solids, ethyl acetate behind the mother liquor evaporate to dryness: sherwood oil=1: 4 column chromatography, the white solid (yield 84%) of compound (I-6).
1HNMR(CDCl
3)(ppm)：7.63(1h，M)，7.43(1h，d，J＝7.5)，7.22(5H，m)，6.87(1H，d，J＝7.8)，5.71(1H，s)，5.50(1H，br)，5.37(1H，s)，4.50(2H，d，J＝5.7)3.89(3H，s)，3.79(6H，s)，3.76(6H，s)
MS(m/e，％)：549(M
+，9.22)，289(100)，260(28.59)
IR(max/cm
-1)：3418，3254(N-H)，2949(C-H)，1747(CO-N)，1590(Ph-H)，1163(-O-)
Elemental Analysis：Calcd：C59.01；H4.92；N12.75
Found：C59.2 1；H5.38；N12.25
HPLC：98.85％
Example 38
Synthesizing of compound (I-7)
In the exsiccant reaction tubes with 261mg (1mmol) intermediate (III-1), 292mg (1mmol) 2-pyrimidine Thiosalicylic acid, and 10mgDMAP is suspended in the 2ml tetrahydrofuran (THF), maintain the temperature at below 0 ℃, the dichloromethane solution that slowly adds 226mg (1.1mmol) DCC, add half an hour, keeping temperature to rise to room temperature reaction after 1 hour spends the night. place more than 4 hours for-20 ℃ in the refrigerator, the elimination insoluble solids, ethyl acetate behind the mother liquor evaporate to dryness: sherwood oil=1: 4 column chromatography, the white solid (yield 67%) of compound (I-7).
1HNMR(CDCl
3)(ppm)：8.15(1H，m)，7.63(1H，m)，7.56(1H，m)，7.27(4H，m)，6.88(1H，d，J＝6.6)，5.76(1H，m)，5.58(1H，br)，5.38(1H，m)，4.53(2H，m)，3.81(12H，m)
MS(m/e，％)：535(M
+，4.81)，537(M
++2，2.51)，275(100)，261(21.46)
IR(max/cm
-1)：3419，3253(N-H)，3074(Ph-H)，2950(C-H)，1751(CO＝N)，1591(Ph-H)1215，1164(-O-)
Elemental Analysis：Calcd：C58.31；H4.67；N13.08
Found：C58.54；H4.69；N13.29
Example 39
Synthesizing of compound (I-8)
In the exsiccant reaction tubes with 261mg (1mmol) intermediate (III-1), 310mg (1mmol) 5-chloropyrimide Whitfield's ointment (II-8), and 10mgDMAP is suspended in the 2ml tetrahydrofuran (THF), maintain the temperature at below 0 ℃, the dichloromethane solution that slowly adds 226mg (1.1mmol) DCC, add half an hour, keeping temperature to rise to room temperature reaction after 1 hour spends the night. place more than 4 hours for-20 ℃ in the refrigerator, the elimination insoluble solids, ethyl acetate behind the mother liquor evaporate to dryness: sherwood oil=1: 4 column chromatography, the white solid (yield 80%) of compound (I-7).
1HNMR(CDCl
3)(ppm)：8.07(1H，d)，7.60(1H，m)，7.43(1H，m)，7.25(3H，m)，6.87(1H，d)，5.73(1H，m)，5.37(1H，s)，4.49(2H，d)，3.79(6H，s)3.77(6H，s)
Electrospray ionization mass spectrum (ESI): 554,556
HPLC：99.6％
Example 40
Synthesizing of compound (I-9)
In the exsiccant reaction tubes with 261mg (1mmol) intermediate (III-1), 320mg (1mmol) 5-nitro-pyrimidine Whitfield's ointment (II-9), and 10mgDMAP is suspended in the 2ml tetrahydrofuran (THF), maintain the temperature at below 0 ℃, the dichloromethane solution that slowly adds 226mg (1.1mmol) DCC, add half an hour, keeping temperature to rise to room temperature reaction after 1 hour spends the night. place more than 4 hours for-20 ℃ in the refrigerator, the elimination insoluble solids, ethyl acetate behind the mother liquor evaporate to dryness: sherwood oil=1: 4 column chromatography, the white solid (yield 90%) of compound (I-9).
Elemental Analysis：Calcd：C55.32；H4.29；N14.89
Found：C55.29；H4.31；N114.87
ESI：564.53
Example 41
Synthesizing of compound (I-10)
In the exsiccant reaction tubes with 261mg (1mmol) intermediate (III-1), 300mg (1mmol) 5-cyanopyrimidine Whitfield's ointment (II-10), and 10mgDMAP is suspended in the 2ml tetrahydrofuran (THF), maintain the temperature at below 0 ℃, the dichloromethane solution that slowly adds 226mg (1.1mmol) DCC, add half an hour, keeping temperature to rise to room temperature reaction after 1 hour spends the night. place more than 4 hours for-20 ℃ in the refrigerator, the elimination insoluble solids, ethyl acetate behind the mother liquor evaporate to dryness: sherwood oil=1: 4 column chromatography, the white solid (yield 92%) of compound (I-10).
Elemental Analysis：Calcd：C59.56；H4.44；N15.43
Found：C59.55；H4.45；N15.43
ESI：544.53
Example 42
Synthesizing of compound (I-11)
In the exsiccant reaction tubes with 295mg (1mmol) intermediate (III-11), 278mg (1mmol) pyrimidine Whitfield's ointment (II-1), and 10mgDMAP is suspended in the 2ml tetrahydrofuran (THF), maintain the temperature at below 0 ℃, the dichloromethane solution that slowly adds 226mg (1.1mmol) DCC, add half an hour, keeping temperature to rise to room temperature reaction after 1 hour spends the night. place more than 4 hours for-20 ℃ in the refrigerator, the elimination insoluble solids, ethyl acetate behind the mother liquor evaporate to dryness: sherwood oil=1: 4 column chromatography, the white solid (yield 93%) of compound (I-11).
Elemental Analysis：Calcd：C56.37；H4.34；N2.64
Found：C56.37；H4.36；N2.62
ESI：553.96
Example 43
Synthesizing of compound (I-12)
In the exsiccant reaction tubes with 279mg (1mmol) intermediate (III-12), 278mg (1mmol) pyrimidine Whitfield's ointment (II-1), and 10mgDMAP is suspended in the 2ml tetrahydrofuran (THF), maintain the temperature at below 0 ℃, the dichloromethane solution that slowly adds 226mg (1.1mmol) DCC, add half an hour, keeping temperature to rise to room temperature reaction after 1 hour spends the night. place more than 4 hours for-20 ℃ in the refrigerator, the elimination insoluble solids, ethyl acetate behind the mother liquor evaporate to dryness: sherwood oil=1: 4 column chromatography, the white solid (yield 93%) of compound (I-12).
Elemental Analysis：Calcd：C58.10；H4.50；N13.03
Found：C58.15；H4.51；N13.05
ESI：537.54
Example 44
Synthesizing of compound (I-13)
In the exsiccant reaction tubes with 275mg (1mmol) intermediate (III-12), 278mg (1mmol) pyrimidine Whitfield's ointment (II-1), and 10mgDMAP is suspended in the 2ml tetrahydrofuran (THF), maintain the temperature at below 0 ℃, the dichloromethane solution that slowly adds 226mg (1.1mmol) DCC, add half an hour, keeping temperature to rise to room temperature reaction after 1 hour spends the night. place more than 4 hours for-20 ℃ in the refrigerator, the elimination insoluble solids, ethyl acetate behind the mother liquor evaporate to dryness: sherwood oil=1: 4 column chromatography, the white solid (yield 63%) of compound (I-13).
Elemental Analysis：Calcd：C60.78；H5.10；N13.13
Found：C60.80；H5.10；N13.15
ESI：533.55
Example 45
Synthesizing of compound (I-14)
In the exsiccant reaction tubes with 261mg (1mmol) intermediate (III-1), 310mg (1mmol) (II-14), and 10mgDMAP is suspended in the 2ml tetrahydrofuran (THF), maintain the temperature at below 0 ℃, the dichloromethane solution that slowly adds 226mg (1.1mmol) DCC, add half an hour, keeping temperature to rise to room temperature reaction after 1 hour spends the night. place more than 4 hours for-20 ℃ in the refrigerator, the elimination insoluble solids, ethyl acetate behind the mother liquor evaporate to dryness: sherwood oil=1: 4 column chromatography, the white solid (yield 73%) of compound (I-14).
Elemental Analysis：Calcd：C57.31；H4.23；N13.37
Found：C57.34；H4.21；N13.38
ESI：523.94
Example 46
Synthesizing of compound (I-15)
In the exsiccant reaction tubes with 261mg (1mmol) intermediate (III-1), 290mg (1mmol) (II-15), and 10mgDMAP is suspended in the 2ml tetrahydrofuran (THF), maintain the temperature at below 0 ℃, the dichloromethane solution that slowly adds 226mg (1.1mmol) DCC, add half an hour, keeping temperature to rise to room temperature reaction after 1 hour spends the night. place more than 4 hours for-20 ℃ in the refrigerator, the elimination insoluble solids, ethyl acetate behind the mother liquor evaporate to dryness: sherwood oil=1: 4 column chromatography, the white solid (yield 83%) of compound (I-14).
Elemental Analysis：Calcd：C62.02；H5.00；N13.91
Found：C62.00；H5.01；N13.92
ESI：503.50
Example 47
Synthesizing of compound (I-16)
In the exsiccant reaction tubes with 279mg (1mmol) intermediate (III-16), 278mg (1mmol) (II-1), and 10mgDMAP is suspended in the 2ml tetrahydrofuran (THF), maintain the temperature at below 0 ℃, the dichloromethane solution that slowly adds 226mg (1.1mmol) DCC, add half an hour, keeping temperature to rise to room temperature reaction after 1 hour spends the night. place more than 4 hours for-20 ℃ in the refrigerator, the elimination insoluble solids, ethyl acetate behind the mother liquor evaporate to dryness: sherwood oil=1: 4 column chromatography, the white solid (yield 64%) of compound (I-14).
Elemental Analysis：Calcd：C60.78；H5.10N13.13
Found：C60.808；H5.11N13.11
ESI：533.55
Example 48
Synthesizing of compound (I-17)
In the exsiccant reaction tubes with 279mg (1mmol) intermediate (III-1), 245mg (1mmol) (II-17), and 10mgDMAP is suspended in the 2ml tetrahydrofuran (THF), maintain the temperature at below 0 ℃, the dichloromethane solution that slowly adds 226mg (1.1mmol) DCC, add half an hour, keeping temperature to rise to room temperature reaction after 1 hour spends the night. place more than 4 hours for-20 ℃ in the refrigerator, the elimination insoluble solids, ethyl acetate behind the mother liquor evaporate to dryness: sherwood oil=1: 4 column chromatography, the white solid (yield 84%) of compound (I-17).
Elemental Analysis：Calcd：C62.02；H5.00N13.91
Found：C62.0；H5.01N13.94
ESI：503.52
Following example 23 to example 27 provides with compound of the present invention as the active substance component, and the concrete instance of processing preparation several herbicides formulation it is to be noted that the present invention not merely is confined in the scope of following example.
Example 49
Wettable powder (WP) prescription: the compound with 15% (I-1) (table one), 5% sulfonated lignin (M
q), 1% ethoxylated dodecyl alcohol (JFC), 40% diatomite and 44% light calcium carbonate mix equably, pulverizes, and promptly gets wettable powder.
Example 50
Missible oil (EC) prescription: No. 602, the compound with 10% (I-1) (table one), 5% farming breast No. 500 (calcium salts), 5% farming breast, 5% N-N-methyl-2-2-pyrrolidone N-and 75% dimethylbenzene heated and stirred are even, promptly get 10% missible oil.
Example 51
Granule (GR) prescription: the compound with 5% (I-1) (table one), 1% polyvinyl alcohol (PVA), 4% naphthalenesulfonic acid-formaldehyde condensate (NMO) and 90% clay mix equably; pulverize; add 20 parts of water to these 100 parts of mixtures then; mediate; with the extruding granulator; make 14-32 purpose particle, drying promptly gets 5% granule.
Example 52
Aqueous emulsion (EW) prescription: the compound with 15% (I-1) (table one), 8% alkylaryl formaldehyde resin Soxylat A 25-7,10% calcium dodecylbenzene sulphonate, 3% tetradecanol, 10% dimethyl formamide, 5% propylene glycol, surplus is a water, according to each constitutive property, make oil phase and water respectively, then under high-speed stirring, the two is mixed, form 15% aqueous emulsion of favorable dispersity.
Example 53
Water suspending agent (SC) prescription: the compound with 15% (I-1) (table one), 5% calcium lignin sulphonate, 0.5% white carbon black, 4% ethylene glycol, 1% defoamer, surplus are water, in the adding sand milling still, are ground to certain fineness, make 15% suspension agent.
Example 54
Biological activity determination:
Below implement to provide and use compound of the present invention to carry out the example of biological activity determination, it is to be noted that the present invention not merely is confined in the scope of following example.
The weeding activity evaluation test is carried out according to following method:
Test is the sandy loam of preparation with soil, and the weeding activity test is 9.5cm with basin alms bowl diameter, and safety testing is 12.0cm with basin alms bowl diameter.
The basin alms bowl of testing processing before the bud carries out the soil surface spraying one day after in sowing to be handled, and the soup of processing is organic solvent dissolutions such as compound acetone, DMF, and adds the laboratory preparation of 0.5% tween-80, and thin up is needs dosage again.
The basin alms bowl that test is handled behind the bud was after planting put into hot-house culture after 7～9 days, carrying out foliar spray handles, the soup of handling is organic solvent dissolutions such as compound acetone, DMF, and adds the laboratory preparation of 0.5% tween-80, and thin up is needs dosage again.
For the first time the compound treatment concentration of active determination test is 300 g ai/ha or 150g ai/ha, and the compound treatment concentration of active determination test is 75,150 and 300g ai/ha or 37.5,75 and 150g ai/ha for the second time.After the basin alms bowl of handling leaves standstill 1 day, put into the greenhouse, regularly water the weeding activity of appearance method observed and recorded compound after 14～21 days.
With the weeding activity of hazard of plant symptom (inhibition, deformity, yellow, albefaction) performance degree range estimation compound, 0 expression does not have herbicidal effect or to crop safety, weeds or crop are killed in 100% expression fully.
Weeding activity and crop safety appearance method judgement criteria are as follows:
| Phytotoxicity (%) | Weeding activity comment (inhibition, deformity, albefaction etc.) | Crop safety comment (inhibition, deformity, albefaction etc.) |
| 0 | With contrast, anti-, eliminate | With contrast, anti-, normal |
| 10-20 | Gently, influential slightly, eliminate | Gently, influential slightly, can consider |
| 30-40 | Gently, influential, eliminate | Sensitivity, influential, eliminate |
| 50-60 | Sensitivity, influential, can consider further transformation | Responsive, poisoning is heavy, eliminates |
| 70-80 | Responsive, can consider | Extremely responsive, poisoning is heavy, eliminates |
| 90-100 | Extremely responsive, good | Extremely responsive, poisoning is heavy, eliminates |
For the first time the weeding activity test-results handled of high dosage sees Table 1 and table 2; The weeding activity test-results that reduces for the second time dosage sees Table 3 and table 4; The crop safety test-results sees Table 5
Giving birth to test tests the result and show: The compounds of this invention has good weeding activity, and has the wider grass spectrum of killing, and the gramineous weeds and the broadleaved herb in farmland all had the good control effect.
The weeds and the crop species of the biological activity determination test usefulness of selecting are as follows:
| Chinese name | English name | The science title | Abbreviation |
| The barnyard grass grass | barnyardgrass | Echinochloa crusgalli | ECHCG |
| Lady's-grass | Crabgrass | Digitaria sanguinalis | DIGSA |
| Herba Eleusines Indicae | Bullgrass | Eleusine indica | ELEIN |
| Herba Setariae Viridis | Giant foxtail | Setaria faberii | SETEFA |
| Leaf mustard | Leaf mustard | Brassica juncea | BRAJU |
| Amaranthus retroflexus | Amaranth pigweed | Amaranthus retroflexus | AMARE |
| Purslane | Common purslane | Portulaca oleracea | POROL |
| Little lamb's-quarters | Lambsquarters | Chenopodium album | CHEAL |
| Corn | Corn | Zea mays | ZEAMX |
| Soybean | Soybean | Glycine max | GLXMA |
| Cotton | Cotton | Gossypium hispitum | GOSHI |
| Wheat | Wheat | Triticum aestivum | TRZAW |
| Paddy rice | Rice | Oryza sativa | ORYSD |
| Rape | Rape | Brassica napus | BRSNW |
The weeding activity test-results first time that cauline leaf is handled behind table 1 bud
| Compound number | Dosage (g ai/ha) | The barnyard grass grass | Lady's-grass | Herba Eleusines Indicae | Leaf mustard | Amaranthus retroflexus | Purslane |
| I-1 | 300 | 85 | 70 | 80 | 70 | 100 | 0 |
| I-2 | 300 | 90 | 70 | 100 | 100 | 100 | 95 |
| I-5 | 75 | 0 | 65 | 70 | 40 | 0 | 60 |
| I-6 | 150 | 0 | 0 | 0 | 30 | 40 | 0 |
| I-8 | 75 | 60 | 70 | 75 | 40 | 80 | 80 |
| I-9 | 75 | 60 | 75 | 40 | 60 | 70 | 60 |
| I-11 | 300 | 80 | 80 | 70 | 40 | 40 | 60 |
| I-12 | 300 | 40 | 40 | 30 | 70 | 50 | 0 |
| I-13 | 300 | 80 | 60 | 70 | 80 | 60 | 40 |
| I-14 | 300 | 85 | 60 | 90 | 40 | 100 | 20 |
| I-15 | 300 | 80 | 80 | 60 | 70 | 80 | 10 |
| I-16 | 300 | 50 | 40 | 40 | 50 | 60 | 40 |
| I-17 | 300 | 70 | 70 | 70 | 50 | 30 | 20 |
Table 2: the weeding activity test-results first time of soil treatment before the bud
| Compound number | Dosage (g ai/ha) | The barnyard grass grass | Lady's-grass | Herba Eleusines Indicae | Leaf mustard | Amaranthus retroflexus | Purslane |
| I-1 | 300 | 40 | 0 | 50 | 0 | 0 | 0 |
| I-2 | 300 | 60 | 40 | 80 | 90 | 90 | 90 |
| I-5 | 75 | 20 | 0 | 20 | 70 | 20 | 20 |
| I-6 | 150 | 30 | 30 | 0 | 20 | 30 | 0 |
| I-8 | 75 | 20 | 0 | 0 | 0 | 20 | 0 |
The weeding activity size evaluation result second time that cauline leaf is handled behind table 3 bud
Table 4: the weeding activity size evaluation result second time of soil treatment before the bud
Table 5: the crop safety test-results of foliar treatment behind the seedling
Claims (8)
1. a 2-pyrimidine oxy-benzoic acid [2-(pyrimidine amino methyl)] benester compound, its structural formula is as follows:
Wherein:
D
1, D
2, E
1Or E
2=halogen, C
1-C
4Alkyl or C
1-C
4Alkoxyl group; X=hydrogen, halogen, nitro, cyano group or C
1-C
8Alkoxyl group; Y=hydrogen, halogen or C
1-C
8Alkyl; A=O or S.
2. a kind of 2-pyrimidine oxy-benzoic acid as claimed in claim 1 [2-(pyrimidine amino methyl)] benester compound is characterized in that in the described structural formula D
1, D
2, E
1And E
2Be methoxyl group.
3. the preparation method of an a kind of 2-pyrimidine oxy-benzoic acid as claimed in claim 1 [2-(pyrimidine amino methyl)] benester compound is characterized in that making by following method:
(1) in organic solvent, temperature of reaction be room temperature to solvent boiling point, 2-halo-4-D
2, 6-E
2-substituted pyrimidines or 2-methylsulfonyl-4-D
2, 6-E
2-substituted pyrimidines and salicylic aldehyde react under alkaline condition and made intermediate (IV) in 0.5-24 hour; 2-halo-4-D
2, 6-E
2-substituted pyrimidines or 2-methylsulfonyl-4-D
2, 6-E
2-substituted pyrimidines, the mol ratio of salicylic aldehyde and alkali are 1: 1.0-2.0: 1.0-5.0;
(2) in organic solvent and room temperature to solvent boiling point, compound (IV) is making intermediate (III) with hydrogen reducing 0.5-24 hour after with the ammonia ammonification under the effect of catalyzer, and the mol ratio of described compound (IV), ammonia, hydrogen and catalyzer is 1: 1-1000: 1-1000: 0.01-0.5;
Or in organic solvent and room temperature to solvent boiling point, compound (IV) and oxammonium hydrochloride generate compound (V) after the condensation under alkaline condition, through hydro-reduction, or make intermediate (III) after chemical reagent reduces in the presence of catalyzer; The mol ratio of described compound (IV) and oxammonium hydrochloride is 1: 1-2; Described alkali is hydride, alcoxyl metallic compound or its carbonate, triethylamine or the pyridine of monovalence or divalent metal; Reaction times is 0.5-24 hour; Reduction is iron powder/hydrochloric acid, zinc powder/ammonium chloride, sulfide, sodium borohydride, palladium carbon/formic acid or ammonium formiate with chemical reagent; The mol ratio of reactant (V), hydrogen and catalyzer is 1: 1-1000: 0.01-0.5; Described compound (V) is 1 with the chemical reagent mol ratio: 1-10;
Described hydrogenation catalyst is Lay Buddhist nun nickel, palladium carbon or platinum black;
(3) the organic solvent neutral temperature be room temperature to solvent boiling point, intermediate (II) and intermediate (III) reacted under the condensing agent effect 0.5 to 24 hour, made target product shown in claim 1 formula (I); The mol ratio of described intermediate (II), intermediate (III) and condensing agent is 1: 1.0-1.2: 1-5; Condensing agent is N, N '-dicyclohexyl carbodiimide, N, N '-di-isopropyl carbodiimide or carbonyl dimidazoles;
Above-mentioned intermediate (II), intermediate (III), intermediate (IV), intermediate (V) structural formula are distinguished as follows:
Wherein, D
1, D
2, E
1, E
2, X, Y, A be shown in claim 1.
4. the preparation method of a kind of 2-pyrimidine oxy-benzoic acid as claimed in claim 3 [2-(pyrimidine amino methyl)] benester compound, it is characterized in that in the described reaction (1) that described alkali is hydride, alcoxyl metallic compound or its carbonate or the organic bases of monovalence or divalent metal.
5. the preparation method of a kind of 2-pyrimidine oxy-benzoic acid as claimed in claim 3 [2-(pyrimidine amino methyl)] benester compound is characterized in that described solvent is a dimethyl formamide in the described reaction (1); In the described reaction (2), described solvent is an alcoholic solvent; In the described reaction (3), described solvent is methylene dichloride and ether solvent.
6. the preparation method of a kind of 2-pyrimidine oxy-benzoic acid as claimed in claim 3 [2-(pyrimidine amino methyl)] benester compound is characterized in that target product is through silica gel column chromatography or recrystallization purifying.
7. the purposes of an a kind of 2-pyrimidine oxy-benzoic acid as claimed in claim 1 [2-(pyrimidine amino methyl)] benester compound is characterized in that being used for the agrochemicals weedicide.
8. the purposes of a 2-pyrimidine oxy-benzoic acid as claimed in claim 1 [2-(pyrimidine amino methyl)] benester compound, it is characterized in that the pesticide composition as the agrochemicals weedicide, wherein contain acceptable carrier in claim 1 compound of herbicidally effective amount and the weeding.
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