CN108368033A - A kind of new method being used to prepare trifloxystrobin - Google Patents
A kind of new method being used to prepare trifloxystrobin Download PDFInfo
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- CN108368033A CN108368033A CN201680071842.3A CN201680071842A CN108368033A CN 108368033 A CN108368033 A CN 108368033A CN 201680071842 A CN201680071842 A CN 201680071842A CN 108368033 A CN108368033 A CN 108368033A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/12—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reactions not involving the formation of oxyimino groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/08—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reaction of hydroxylamines with carbonyl compounds
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/08—Preparation of carboxylic acid nitriles by addition of hydrogen cyanide or salts thereof to unsaturated compounds
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
- C07C51/29—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with halogen-containing compounds which may be formed in situ
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/18—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group
- C07C67/20—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group from amides or lactams
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/18—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group
- C07C67/22—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group from nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
Abstract
The present invention relates to it is a kind of prepare free form or the acceptable salt form of agrochemicals as pest control agent formula (I) compound (α E) (α (methoxyimino) 2 [[[(E) [1 (3 (trifluoromethyl) phenyl] ethylidene] amino] oxygroup] methyl] methyl phenylacetate (trifloxystrobin) new method.The present invention also relates to a kind of new methods of methyl (2E) [2 (bromomethyl) phenyl] (methoxyimino) acetic acid esters for preparing trifloxystrobin intermediate formula (X).
Description
Technical field
The present invention relates to it is a kind of prepare free form or the acceptable salt form of agrochemicals, it is as pest control agent
Formula (I) (α E)-(α-(methoxyimino) -2 [[[(E)-[and 1- (3- (trifluoromethyl) phenyl] ethylidene] amino] oxygroup] first
Base] methyl phenylacetate (trifloxystrobin) new method.
Background technology
(α E)-(α-(methoxyimino) -2 [[[(E)-[1- (3- (trifluoromethyl) phenyl] ethylidene] amino] oxygroup]
Methyl] methyl phenylacetate belongs to methoxy acrylic bactericide.Trifloxystrobin and preparation method thereof is for the first time in US5238956
It is described.It is most commonly used to banana, cereal, citrus, coffee, corn, cotton, broad bean, grape, hops, nut, ornamental plant
Object, peanut, a kind of fruit, such as apple, pear, etc., potato, rice, fruitlet, soybean, drupe, beet, sunflower, tea, tropical fruit (tree), turf, vegetables and its
His various crops.
CN103787916A teaches the preparation method of trifloxystrobin.The reaction process of synthetic method includes turnout reason
(water diversion treatment).By water process is carried, the water that is formed is effectively prevented from reaction to the shadow of reaction
It rings, to reduce side reaction, and improves product yield and product quality.According to the synthetic method, directly use after the reaction
Reaction liquid solvent is crystallized, and to avoid the change of recrystallisation solvent, and solvent cross infection is avoided, to further increase
Product quality.
WO2013144924 teaches the side of synthesis (2E)-[2- (bromomethyl) phenyl] (methoxyimino) methyl acetate
Method.It is then converted further to (2E)-[2- (bromomethyl) phenyl] (methoxyimino) methyl acetate to substantially pure
Formula (I) compound trifloxystrobin.Prepare the synthetic route of (2E)-[2- (bromomethyl) phenyl] (methoxyimino) methyl acetate such as
Shown in lower：
WO2013144924 also teaches the system of (2E)-[2- (bromomethyl) phenyl] (methoxyimino) methyl acetate
Standby, wherein R is H, is indicated by following route maps.
I=NBS/AIBN or benzoyl peroxide
Ii=NaBrO3/NaHSO3, UV or ordinary ray
Iii=Br/H2O2, UV or ordinary ray
Iv=alkali metal bromides/H2SO4/H2O2, UV or ordinary ray
Rambaud, M. etc., Synthesis, 564 (1988)；With Korean Patent No.88,673 PCT/KR 95/00020)
The method for teaching synthesis (2E)-[2- (bromomethyl) phenyl] (methoxyimino) methyl acetate, as shown in reaction route：
The art methods for being used to prepare (2E)-[2- (bromomethyl) phenyl] (methoxyimino) methyl acetate have one
A or other disadvantages, as low yield, the high circulation time, the formation of by-product and Z and E admixture of isomeric compound formation.This
Outside, the recycling of formula (I) compound is impossible.This leads to the increase of wastewater treatment load, feasibility and high totle drilling cost.
The preparation method of (2E)-disclosed in the prior art [2- (bromomethyl) phenyl] (methoxyimino) methyl acetate
It cannot be to generate E- isomers with high-purity in high yield.In a subsequent step, (2E)-[2- (bromomethyl) phenyl] (first
Oxygroup imino group) methyl acetate is converted into trifloxystrobin.
There are the method for the prior art some can influence the difficulty of integrated artistic cost.Therefore, in WO2013144924
The hydrolysis of method combination acyl cyanide leads to the formation of the 2- methyl benzoic acids formed due to decarboxylic reaction and leads to about 40
To 50% acyl cyanide by-product, the formation of 2- methyl benzoic acids.
According to disadvantages mentioned above, there is exploitation to be used to prepare (2E)-[2- (bromomethyl) phenyl] (methoxy with high-purity in high yield
Base imino group) methyl acetate improved method needs.(2E)-[2- (bromomethyl) phenyl] (methoxyimino) methyl acetate
It is further used for preparing the substantially pure trifloxystrobin of high yield.It needs to develop a kind of viable commercial method, the method tool
There is the ability that product is produced with high yield, high-purity, and also useful with being recycled from the by-product formed in reaction process
Starting material and reagent regulation.
The present invention is directly against disadvantages mentioned above, it is desirable to provide the new method for preparing formula (I) trifloxystrobin is a kind of mild
Reaction condition, shirtsleeve operation, inexpensive effective ways.
Invention content
Goal of the invention
It is an object of the present invention to provide a kind of formulas (I) preparing free form or the acceptable salt form of agrochemicals
(α E)-(α-(methoxyimino) -2 [[[(E)-[and 1- (3- (trifluoromethyl) phenyl] ethylidene] amino] oxygroup] methyl] benzene
The new method of methyl acetate, this method originates in easily acquisition and cheap and easily disposed intermediate, this method can be with simple
Mode and high yield prepare formula (I) trifloxystrobin and are possibly realized.
It is a further object to provide one kind being used to prepare intermediate, formula (X) (2- bromomethyls-phenyl) methoxyl group
The new method of acetimidic acid methyl esters, this method are further used for synthesizing free form or the acceptable salt form of agrochemicals
(α E)-(α-(methoxyimino) -2 [[[(E)-[1- (3- (trifluoromethyl) phenyl] ethylidene] amino] oxygen of final formula (I)
Base] methyl] methyl phenylacetate (trifloxystrobin).
It is also another object of the present invention to provide one kind being used to prepare intermediate, the o- tolylacetic acid of oxygroup-of formula (VI)
New method.
Detailed description of the invention
The present invention provides a kind of (α E)-([[[(E)-[1- (3- (fluoroforms of α-(methoxyimino) -2 preparing formula (I)
Base) phenyl] ethylidene] amino] oxygroup] methyl] methyl phenylacetate (trifloxystrobin) new method.
Therefore, the present invention provides a kind of (α E)-(α-that is simple, economically feasible and being efficiently used to prepare formula (I)
(methoxyimino) -2 [[[(E)-[and 1- (3- (trifluoromethyl) phenyl] ethylidene] amino] oxygroup] methyl] methyl phenylacetate
The method of (trifloxystrobin).
It now will be in conjunction with certain preferred and optional embodiment detailed description present invention, so as to be more fully understood
With understand its various aspects, and be briefly described below.
In an embodiment of the invention, one kind is provided in the presence of acid or sodium pyrosulfite and solvent, is passed through
The 2- tolyl aldehydes of formula (II) are reacted with the cyanidization agent selected from but not limited to Cymag or potassium cyanide, prepare the hydroxyl of formula (III)
The new method of base (2- tolyls)-acetonitrile.
The method that hydroxyl (2- tolyls) acetonitrile of formula (III) is prepared by cyanogenation is the 2- methylbenzenes with formula (II)
The bisulfite adduct of the hydrochloride of formaldehyde or formula (II) 2- tolyl aldehydes with sodium pyrosulfite or with sulfuric acid
The bisulfite adduct of formula (II) 2- tolyl aldehydes carry out.
Solvent appropriate is selected from but not limited to water, alcohols, ketone, dihydric alcohol, trihydroxylic alcohol, esters, amides, ethers, hydrocarbon
Or mixtures thereof class, polar non-solute, polar solvent, chlorinated solvent, nitrile.Polar non-solute such as acetone,
DMF, acetonitrile, DMSO, sulfolane；Alcohols such as methanol, ethyl alcohol, propyl alcohol, butanol；Chlorinated solvent such as dichloromethane, vinyl chloride, chlorine
Imitative, monochloro-benzene；Hydrocarbon solvent such as toluene, dimethylbenzene, heptane, hexamethylene and hexane, more preferable toluene.
In another embodiment of the present invention, it provides a kind of in presence of an acid by hydroxyl (the 2- first of hydrolysis formula (III)
Phenyl) acetonitrile prepares the new method of 2- hydroxyls -2- (2- tolyls) acetamide of formula (IV).In about 50 DEG C~25 DEG C of temperature
Under, aqueous sulfuric acid is added dropwise under stiring to hydrolyze hydroxyl (2- tolyls) acetonitrile of formula (III).The formula (II) of generation
Amide raw product is neutralized by sodium carbonate is added under stiring.
Sodium carbonate is reacted with sulfuric acid in filtrate, to obtain sodium sulphate.
In another embodiment of the present invention, one kind is provided in the presence of acid and solvent, passes through the 2- hydroxyls of formula (IV)
The o- toluene yl acetamides of base -2- react the new method of the o- tolylacetic acid methyl esters of the hydroxyl-to prepare formula (VI) with methanol.
In a further embodiment of the present invention, one kind is provided in the presence of acid and solvent, passes through the hydroxyl of formula (III)
(2- tolyls) acetonitrile reacts the new method of the o- tolylacetic acid methyl esters of the hydroxyl-to prepare formula (VI) with methanol, wherein described
Acid is selected from or mixtures thereof hydrochloric acid and inorganic or organic acid.
Inorganic or organic acid is added into hydrochloric acid solution to generate hydrogen chloride gas.Hydrogen chloride gas is trapped by sulfuric acid
Device enters in cyanalcohol reaction mass.Into the purging for the hydrogen chloride gas for being advanced into reaction mass at about -15 DEG C to 0 DEG C.Chlorination
Hydrogen and methanol continuously purge 2 to 10 hours at -15 to 10 DEG C in reaction mass.
Solvent appropriate is selected from but not limited to water, alcohols, ketone, dihydric alcohol, trihydroxylic alcohol, esters, amides, ethers, hydrocarbon
Or mixtures thereof class, polar non-solute, polar solvent, chlorinated solvent, nitrile.Hydrocarbon solvent such as toluene, dimethylbenzene, heptan
Alkane, hexamethylene and hexane；Polar non-solute such as acetone, DMF, acetonitrile, DMSO, sulfolane；Alcohols such as methanol, second
Alcohol, propyl alcohol, butanol；Chlorinated solvent such as dichloromethane, chloroform, monochloro-benzene and vinyl chloride.
Appropriate inorganic or organic acid is selected from but not limited to.Inorganic acid be minerals acid such as halogen acids (such as hydrobromic acid and
Hydrochloric acid), sulfuric acid, phosphoric acid and nitric acid.Organic acid is aliphatic, alicyclic and aromatic carboxylic acid, dicarboxylic acids, tricarboxylic acids.
The example of these acid is carbonic acid, formic acid, fumaric acid, acetic acid, propionic acid, isopropyl acid, valeric acid, 'alpha '-hydroxy acids (such as glycolic and breast
Acid), monoxone, benzoic acid, methanesulfonic acid and salicylic acid.The example of dicarboxylic acids include oxalic acid, malic acid, succinic acid, tartaric acid and
Maleic acid.The example of tricarboxylic acids is citric acid.
In another embodiment of the present invention, it provides a kind of in the presence of the weak base of oxidant and catalytic amount, passes through formula
(VI) the new side for aoxidizing the o- tolylacetic acid methyl esters of hydroxyl-to prepare formula (VII) of the o- tolylacetic acid methyl esters of oxo-
Method, wherein such as 2,2,6,6- tetramethyl piperidine 1- oxygroups of the weak base, hereinafter referred to as TEMPO.
The o- tolylacetic acid methyl esters of oxo-for the formula (VI) that the above reaction indicates is with oxidant reaction to obtain formula (VII)
The reaction of the o- tolylacetic acid methyl esters of hydroxyl-carries out within the scope of -10 DEG C~10 DEG C, preferably within the scope of -5 DEG C~5 DEG C.'s
Oxidant is used with the amount of 1.0~2.0 molar equivalents ranges of the o- tolylacetic acid methyl esters of oxo-relative to formula (VI).
It is preferable to use halogenated hydrocarbons as solvent, such as dichloromethane, chloroform, carbon tetrachloride and 1,2- dichloroethanes.
Oxidant be selected from sodium hypobromite (NaOBr), potassium hypobromite (KOBr), N- bromo-succinimides, bromine isocyanuric acid,
Peracid, 2KHSO5、KHSO4、K2SO4、H2O2And its mixture.
By anti-in the aqueous solution of the sodium hydroxide or potassium hydroxide of 2 equivalents and the bromine of 1 equivalent within the scope of -5~0 DEG C
It answers, sodium hypobromite and potassium hypobromite [Org.Syn.Coll., 5,8 (1973)] can be easily produced.
After oxidation reaction, unreacted oxidant such as sodium hypobromite can pass through thiosulfate (sodium thiosulfate
100mL water and 124g Na2S2O3·5H2O it) handles and is easily decomposed.If necessary, height can be obtained by conventional method
The required product of purity.
In another embodiment of the present invention, it in the presence of providing a kind of alkali in a solvent, is optionally urged in phase transfer
In the presence of agent, is reacted with methoxamine hydrochloride by the o- tolylacetic acid methyl esters of the oxo-of formula (VII) and prepare formula (VIII)
The new method of the o- tolylacetic acid of methoxyimino-, wherein the phase transfer catalyst such as TBAB, TEBAC, alkali choosing used
From but be not limited to sodium hydroxide, potassium carbonate, sodium carbonate, triethylamine, diethylamine or their mixture.
Solvent appropriate is selected from but not limited to water, alcohols, ketone, dihydric alcohol, trihydroxylic alcohol, esters, amides, ethers, hydrocarbon
Or mixtures thereof class, polar non-solute, polar solvent, chlorinated solvent, nitrile.Polar non-solute such as acetone,
DMF, acetonitrile, DMSO, sulfolane；Alcohols such as methanol, ethyl alcohol, propyl alcohol, butanol；Chlorinated solvent such as dichloromethane, chloroform, a chlorine
Benzene and vinyl chloride；Hydrocarbon solvent such as toluene, dimethylbenzene, heptane, hexamethylene and hexane, more preferable toluene.
In another embodiment of the present invention, one kind is provided in the presence of inorganic or organic acid, passes through the hydroxyl of formula (III)
Base (2- tolyls) acetonitrile is reacted the new method for carrying out the o- tolylacetic acid sodium salt of formula (Va) hydroxyl-.About 25 DEG C-
At a temperature of 50 DEG C, concentrating hydrochloric acid is added dropwise under stiring, is then hydrolyzed in the presence of a base.
Solvent appropriate is selected from but not limited to water and chlorinated solvent such as dichloromethane, dichloroethanes, chloroform, monochloro-benzene, hydrocarbon
Class solvent such as toluene, dimethylbenzene, heptane, hexamethylene and hexane, more preferable toluene.
In another embodiment of the present invention, a kind of metal oxide catalyst and/or weak base in catalytic amount is provided
Deng in the presence of, and in the presence of a phase transfer catalyst, by using sodium hypochlorite or sodium hypobromite oxidation-type (Va)
The o- tolylacetic acid sodium salt of hydroxyl-is come the new method for the o- tolyl-acetic acid of hydroxyl-for preparing formula (V), wherein the metal oxygen
Object catalyst such as platinum, ruthenium, rhodium, molybdenum；Such as 2,2,6,6- tetramethyl piperidine 1- oxygroups of the weak base, hereafter abbreviated with TEMPO
Or derivatives thereof such as 4- acetoxyl groups -2,2,6,6- tetramethyl-piperidyls -1- oxygroups；The phase transfer catalyst was selected from by season
Ammonium cation, quaternary phosphonium salt cation and cyclic polyether such as three decoyl methyl ammoniums, methyltributylammonichloride chloride, methyl three
Butyl ammonium fluoride, tetrabutylammonium bromide, tetrabutyl ammonium fluoride, 4-butyl ammonium hydrogen sulfate, triethyl benzyl ammonia chloride, tetrabutyl bromine
Change the group of phosphine, tetrabutylphosphonium chloride, four octyl bromide phosphines and its mixture composition.
The sodium salt product of obtained oxo-tolyl-acetic acid, then in the presence of solvent, with such as hydrochloric acid or sulfuric acid
Acid processing, to generate the o- tolyl-acetic acid of the oxo-, wherein the solvent such as water and chlorinated solvent such as dichloromethane, two
Chloroethanes, chloroform, monochloro-benzene, hydrocarbon solvent such as toluene, dimethylbenzene, heptane, hexamethylene and hexane, more preferable toluene.
By the reaction of the o- tolylacetic acid of formula (V) oxo-prepared shown in the above-mentioned reaction that is carried out with oxidant -
It is carried out within the scope of 10 DEG C to 50 DEG C, preferably within the scope of -5 DEG C to 5 DEG C.Oxidant is with the o- toluene of hydroxyl-relative to formula (Va)
It is used in the range of 2 moles of % to 10 moles of % of guanidine-acetic acid sodium salt.It is preferable to use halogenated hydrocarbons as solvent, such as dichloromethane
Alkane, chloroform, carbon tetrachloride and 1,2- dichloroethanes, more preferable dichloroethanes.
Oxidant is selected from sodium hypobromite (NaOBr), potassium hypobromite (KOBr), N- bromo-succinimides (NBS), bromine isocyanide
Uric acid, peracid, benzoyl peroxide, radical initiator AIBN, 2KHSO5、KHSO4、K2SO4、H2O2And its mixture.
Within the scope of -5~0 DEG C, reacted in aqueous solution with the bromine of 1 equivalent with the sodium hydroxide of 2 equivalents or potassium hydroxide,
Sodium hypobromite and potassium hypobromite [Org.Syn.Coll., 5,8 (1973)] can be easily produced.
After oxidation reaction, unreacted oxidant such as sodium hypobromite can pass through thiosulfate (sodium thiosulfate 100mL
Water and 124g Na2S2O3·5H2O it) handles and is easily decomposed.If necessary, high-purity can be obtained by conventional method
Required product.
In another embodiment of the present invention, in the presence of a kind of alkali in a solvent is provided, optionally turn in mutually catalysis
It moves in the presence of agent, is reacted with methoxamine hydrochloride by the o- tolyl-acetic acid of oxo-of formula (V), to prepare formula (VIII)
The new method of the o- tolylacetic acid of methoxyimino-, wherein phase catalysis transfer agent was selected from by quaternary ammonium salt cationic, season
Phosphonium salt cation and cyclic polyether such as three decoyl methyl ammoniums, methyltributylammonichloride chloride, methyl tributyl ammonium fluoride, four
Butylammonium bromide, tetrabutyl ammonium fluoride, 4-butyl ammonium hydrogen sulfate, triethyl benzyl ammonia chloride, tetrabutyl phosphonium bromide phosphine, tetrabutyl chlorine
Change the group of phosphine, four octyl bromide phosphines and its mixture composition.The alkali used is selected from but not limited to sodium hydroxide, potassium carbonate, carbonic acid
Or mixtures thereof sodium, triethylamine, diethylamine.
Solvent appropriate is selected from but not limited to water, alcohols, ketone, dihydric alcohol, trihydroxylic alcohol, esters, amides, ethers, hydrocarbon
Or mixtures thereof class, polar non-solute, polar solvent, chlorinated solvent, nitrile.Polar non-solute such as acetone,
DMF, acetonitrile, DMSO, sulfolane；Alcohols such as methanol, ethyl alcohol, propyl alcohol, butanol；Chlorinated solvent is as dichloromethane, chloroform, a chlorine
Benzene and vinyl chloride；Hydrocarbon solvent is as toluene, dimethylbenzene, heptane, hexamethylene and hexane, more preferable toluene.
In another embodiment of the present invention, it provides and a kind of is existed in thionyl chloride or triphosgene using methanol solvate
Under, so that (2E/Z)-(methoxyimino) (2- tolyls) acetic acid of formula (VIII) is carried out methylation reaction to prepare formula (IX)
(2E)-(methoxyimino) (2- tolyls) methyl acetate new method.
The solvent used in demethylation step is chlorinated solvent such as dichloromethane, chloroform, monochloro-benzene and vinyl chloride；Hydro carbons is molten
Agent such as toluene, dimethylbenzene, heptane, hexamethylene and hexane；Polar non-solute such as acetone, DMF, acetonitrile, DMSO, ring fourth
Sulfone；Alcohols such as methanol, ethyl alcohol, propyl alcohol, butanol；Or mixtures thereof.
In another embodiment of the present invention, it provides a kind of in the presence of bromating agent and organic solvent and optional
Ground is in the presence of being mutually catalyzed transfer agent, by (2E)-(methoxyimino) (2- tolyls) methyl acetate for making formula (IX)
Bromination prepares the new method of (2E)-[2- (bromomethyl) phenyl] (methoxyimino) methyl acetate of formula (X).
The solvent used in bromination step is polar non-solute such as acetone, DMF, acetonitrile, DMSO, sulfolane；Alcohol
Class such as methanol, ethyl alcohol, propyl alcohol, butanol；Chlorinated solvent such as dichloromethane, chloroform, monochloro-benzene and ethlyene dichloride；Hydrocarbon solvent is such as
Or mixtures thereof toluene, dimethylbenzene, heptane, hexamethylene and hexane.These solvents are at room temperature liquid and preferably have 35 DEG C
To 130 DEG C of boiling point, more preferably 50 DEG C to 100 DEG C and in particular 75 DEG C to 85 DEG C.
Bromating agent is selected from but not limited to phenyltrimethylammonium bromide；Dibromo dimethyl hydantoin (DBDMH)；Potassium bromide；Bromination
Sodium；Br2；Hydrobromic acid；N- bromophthalimides；N- bromo acetamides, N- bromo-succinimides (NBS) or its mixing
Object.
In the method for the invention, bromating agent is added in the solution of formula (IX) compound in a solvent.In bromination
In the adition process of agent, mixture preferably remains within the temperature range of room temperature to reflux temperature.The addition of bromating agent completes it
Afterwards, reaction mixture preferably stirs additional a few minutes to 5 hours to 50 hours at a temperature of being kept for 20 DEG C to 60 DEG C.In ether
In the presence of or mixtures thereof class organic solvent such as ether, Di Iso Propyl Ether, methyl tertiary butyl ether(MTBE), by recrystallizing purification formula
(X) (2E)-[2- (bromomethyl) phenyl] (methoxyimino) acetic acid adds the crude product of ester.
In one preferred embodiment, the present invention provides a kind of methoxyimino [2- for synthesizing formula (I)
[1- (3- trifluoromethyl-phenyls)-ethyleneimino oxygroup methyl]-phenyl]-methyl acetate new method, the method includes
In the presence of the solvent and optionally in the presence of alkali or phase transfer catalyst, make (2E)-[2- (bromomethyl) benzene of formula (X)
Base] (methoxyimino) acetic acid esters and formula (XI) the reaction of 1- (3- trifluoromethyl-phenyls)-acetophenone oxime.
In a preferred embodiment, alkali be selected from comprising such as alkali or alkaline earth metal hydroxide, alkali or basic carbonate,
In the group of or mixtures thereof alkali or alkali bicarbonate, organo-lithium compound, organo-magnesium compound, organic base etc..Above-mentioned use
Alkali or alkaline earth metal hydroxide, alkali metal or basic carbonate, alkali or alkali bicarbonate be selected from NaOH, KOH, LiOH,
NaHCO3、KHCO3、LiHCO3、Na2CO3、K2CO3、Li2CO3、Mg(OH)2、Ca(OH)2、CaCO3、MgCO3、Ba(OH)2、Be
(OH)2、BaCO3、SrCO3、(CH3)3Or mixtures thereof COK etc..Organo-lithium compound used above is selected from n- BuLi, sec-
BuLi, tert- BuLi, MeLi, PhLi.Organic-magnesium used above is selected from phenyl-magnesium-bromide, ethylmagnesium bromide.It is above used
Organic base be selected from nitrogenous base pyridine, piperidines, dimethyl aminopyridine, picoline, diisopropylethylamine, triethylamine etc.
Or mixtures thereof.
Solvent appropriate is selected from but not limited to water, methyl iso-butyl ketone (MIBK), acetone, DMF, acetonitrile, DMSO, sulfolane；Methanol,
Ethyl alcohol, propyl alcohol, butanol；Dichloromethane, chloroform, monochloro-benzene and ethlyene dichloride；Toluene, dimethylbenzene, heptane, hexamethylene and hexane.
In a preferred embodiment, mutually catalysis transfer agent is selected from by quaternary ammonium cation, quaternary phosphonium salt cationic and ring-type
Polyethers such as three decoyl methyl ammoniums, methyltributylammonichloride chloride, methyl tributyl ammonium fluoride, tetrabutylammonium bromide, four fourths
Base ammonium fluoride, 4-butyl ammonium hydrogen sulfate, triethyl benzyl ammonia chloride, tetrabutyl phosphonium bromide phosphorus, tetrabutyl phosphorus chloride, four octyl brominations
The group of phosphorus and its mixture composition.
Above-mentioned -1 substep of method indicates as follows：
Above-mentioned -2 substep of method indicates as follows：
Specific implementation mode
The method of the present invention is illustrated with reference to following embodiments, it is no intended to be limited the scope of the invention.It is not limiting
In the case of the scope of the invention, any arrangement and modification in this method are all possible
Embodiment 1：The preparation (method A) of the o- methoxyl group-acetonitrile of hydroxyl-
2- tolyl aldehydes (120.15gm 1.0mol) delay at a temperature of 8 DEG C~10 DEG C, under stirring in 0.5 hour
Slowly it is added in the four-neck flask containing water (125mL) and Cymag 49.00gm (1.0mol) solution.The solution is by by cyaniding
Sodium 49.00gm (1mol) is added dropwise in water (125mL) and prepares, and mixture was stirred more than 30 minutes, warm in the process
Degree is maintained at -5 DEG C to 5 DEG C, and temperature is then risen to 8 DEG C~10 DEG C.After addition is completed, reaction mass is stirred 15 minutes,
Then 40% sulfuric acid [83gm sulfuric acid (0.84mol) is in 125ml water] is added in three hours, temperature be maintained at 10 DEG C and
Between 20 DEG C and reaction mixture is stirred 15 minutes.After the reaction was completed, product is extracted with dichloroethanes, uses anhydrous slufuric acid
Sodium is dried.The dichloroethanes layer so obtained be used to react in next step.Containing purity more than 98.5% in dichloroethanes layer, and
Yield is the o- tolyl acetonitrile of 98%~99% hydroxyl-of theoretical amount.
Embodiment 2：The preparation (method B) of the o- methoxyl group-acetonitrile of hydroxyl-
At 0 DEG C, 2- tolyl aldehydes (24.03gm, 0.2mol) are added to the concentrated hydrochloric acid in 200ml three-neck flasks
In the solution of (18ml, 21.6g and 0.2mol) and water (17ml).The mixture of generation is cooled to -5 DEG C to generate hydrochloric acid 2-
Tolyl aldehyde slurries.Sodium cyanide solution (11.00g, 0.22mol) in 40 grams of water is added in reaction mixture, is added dropwise
It is more than 30 minutes to enter and stir mixture, and temperature is maintained at -5 DEG C to -1 DEG C during this period.During the addition process, it is being added about one
A kind of yellow solution is obtained after half cyanide solution, but forms slurries again when addition closes to an end.After addition finishes,
Continue to stir a hour.Add the pH=7 that hydrochloric acid (1ml) makes mixture.After the reaction was completed, ethyl acetate extraction is added
The product taken, and mixture is warming up to 10 DEG C, therefore obtain two hyaline layers.Ethyl acetate layer is removed and is evaporated to obtain
The purity of 28gm is more than 96%, and the o- tolyl acetonitrile of 95% hydroxyl-that yield is theoretical amount.
Embodiment 3：The preparation (method C) of the o- methoxyl group-acetonitrile of hydroxyl-
2- tolyl aldehydes (120.15gm 1.0mol) are added to the water of the sodium hydrogensulfite (105gm 1.0mol) of room temperature
In (475gm) solution, and temperature is maintained at 35 DEG C or less.Cymag (49gm 1.0mol) is added batch-wise into the solution, and
Temperature is maintained between 25 DEG C -35 DEG C.Oil phase is separated as upper layer, and it is detached with lower water layer.Then with two chloroethenes
Alkane aqueous layer extracted, the dichloroethanes extract of generation merge with the oil reservoir detached.Organic layer is dried with anhydrous sodium sulfate, and 40
DEG C heating bath in by vacuum distillation to remove dichloroethanes.Hydroxyl (2- tolyls) acetonitrile that residual obtains is 132 grams.Hydroxyl
The yield of (2- tolyls) acetonitrile is 90%.
Embodiment 4：The preparation (method A) of the o- tolylacetic acid sodium salt of hydroxyl-
The o- tolyl acetonitrile of hydroxyl-(147.17gm 1.0mol) is added, overhead stirrer, thermometer and dropping liquid are housed
In 300ml dichloroethanes in the four-neck flask of funnel, tetrabutylammonium bromide (1.0mol%) is further added.Reaction mass exists
30 DEG C with HCl treatment (125gm, 1.03mol, 30%HCl).Reaction mass is maintained at 30 DEG C 20 to 22 hours.React completion
Afterwards, product detaches in water layer and organic layer.At 30 DEG C, 47% caustic alkali (sodium hydroxide 100gm in 112gm water,
In the presence of 2.5mols), there is the water layer of product further to hydrolyze, and in the presence of 1.0gm tetrabutylammonium bromide, reacts 30
DEG C~40 DEG C at maintain 3~4 hours.After reaction is completed, reaction mass solvent such as toluene, dimethylbenzene, EDC, MDC ETC
Deng washing.The o- tolylacetic acid sodium salt product (182-183gm) of hydroxyl-of acquisition have more than 97% purity and yield be
97 to the 98% of theoretical amount.
Embodiment 5：The preparation (method A) of the o- tolylacetic acid of oxygroup-
(700ml water and the cooling of 96g (2.4mol) sodium hydroxide are anti-for sodium hypobromite (NaOBr) bromine and sodium hydroxide solution
Answer mixture to 5 DEG C) it generates, bromine (62ml 1.2mol) is added in dropping funel, it is molten that sodium hydroxide is slowly dropped in 2 hours
In liquid, keep internal temperature at -5 DEG C to generate sodium hypobromite (NaOBr).
The o- tolylacetic acid sodium salt of hydroxyl-(188.16gm 1mol) in the dichloromethane of 700ml is added to time bromine
Sour sodium (NaOBr) and the solution of 4- acetoxyl group -2,2,6,6- tetramethyl-piperidyl -1- oxygroups (5mol%) and the 1N sulphur of 10ml
In acid, temperature is made to be no more than 0 DEG C.Reaction mixture is stirred 24 hours at room temperature.After reaction is completed, using hydrochloric acid by pH
It is adjusted to 3.0 to 4.0.Organic layer and water layer are detached.Water layer is extracted twice with dichloromethane.It is removed under depressurizing on the rotary evaporator
Solvent is removed to obtain target compound.154.31gm oxos-o- tolylacetic acid, which has, is less than 97% purity and 94% receipts
Rate.
Embodiment 6：The preparation (method B) of the o- tolylacetic acid of oxygroup-
The o- tolylacetic acid sodium salt of oxygroup-(37.63g 200mmol) is dissolved in dichloromethane (100ml) and is added secondary
Sodium chlorate (148.8g 240mmol), and cool down at 5 DEG C.4- acetoxyl groups -2,2,6,6- four is added into reaction mixture
Methyl piperidine base -1- oxygroups (86mg 0.4mmol) and sodium bicarbonate (3.02g 0.18mmol).Reaction mass is maintained at identical
Temperature 24 hours.After disappearance, 5% sodium thiosulfate solutions of 100ml are added and terminate reaction.Organic layer and water layer separation, and
Organic phase is washed with 50 milliliter of 5% sodium thiosulfate solution, is then washed with 100 milliliter of 1% aqueous sodium carbonate.It is rotating
Solvent is removed under evaporator under reduced pressure to obtain the o- tolylacetic acid of oxo-(30.06gm (92% yield).
Embodiment 7：The preparation (method C) of the o- tolylacetic acid of oxygroup-
In 200ml flasks, the o- tolylacetic acid sodium salt of oxygroup-(18.81g 100mmol) is dissolved in dichloromethane
In (50ml) and sodium hypochlorite (72.6g (purity 12.3%, 120mmol)) is added, and in 6 DEG C of coolings.Into reaction mixture
4- acetoxyl groups -2,2 of 43mg (0.2mmol), 6,6- tetramethyl-piperidyl -1- oxygroups are added, and are further added 10ml's
1N hydrochloric acid.Reaction mass is kept for 1 hour.After reaction is completed, 5% sodium thiosulfate solution by the way that 10ml is added stops anti-
It answers, and detaches organic layer and water layer.Organic phase 5% sodium thiosulfate solution of 25ml and 1% sodium carbonate of 50ml are water-soluble
Liquid washs.Decompression is lower on the rotary evaporator removes solvent, obtains compound oxygroup-o- tolylacetic acid.Weight is
16.41gm.Yield is 90%.
Embodiment 8：The preparation (method E) of the o- tolylacetic acid of oxygroup-
According to the same procedure that embodiment 7 describes, the o- tolylacetic acid sodium salt of hydroxyl-(18.81g 100mmol) dissolving
In dichloromethane (50ml), then with 72.6 grams of (purity 12.3%, 120mmol) sodium hypochlorite, 5mol% (2,2,6,6- tetramethyls
Base-piperidin-1-yl) oxygroup (TEMPO), the 1N sulfuric acid jinx processing of 5mol%TBAB and 10ml, to obtain compound oxygroup-
O- tolylacetic acid (15.03g).Yield is 92%.
Embodiment 9：The preparation (method E) of the o- tolylacetic acid of methoxyimino-
In the four-neck flask equipped with blender, thermometer and charging hopper device, the o- tolylacetic acid of oxo-
(164.16gm 1.0mol) is dissolved in 300ml dichloromethane.And in four-neck flask.It is small two at 40 DEG C to 45 DEG C
When interior reaction mass in be slowly added to tetrabutylammonium bromide (2.0gm) and sodium hydroxide solution.The addition of sodium hydroxide solution
After completion, reaction mass is maintained at 45 DEG C 2 to 3 hours.After 0.5 hour sedimentation time, organic layer and water layer are detached.
In water layer, 300ml dichloromethane and 30% methoxamine hydrochloride solution (125gm, 1.5mol) are added at 30 DEG C to 40 DEG C.Instead
Material is answered to be maintained at 45 DEG C 1 hour.By layer separation after 0.5 hour sedimentation time, organic layer and water layer are detached, by reactant
Matter detaches.Organic layer contains the o- tolylacetic acid of methoxyimino-(197gm), and such product carries out azeotropic water removing.
Obtained final product is the o- tolylacetic acid of methoxyimino-(181.60gm).% yield=94%；% purity=
97% (E＆Z isomers).
Embodiment 10：The preparation (method A) of (2E)-(methoxyimino) (2- tolyls) methyl acetate
N,N-dimethylformamide (5gm) and 380ml EDC are added to equipped with overhead stirrer, thermometer and dropping funel
Four-neck flask in.The o- tolylacetic acid of methoxyimino-in EDC and thionyl chloride (178.5gm 1.50mol)
(193.20gm 1.0mol) is added in 2 to 3 hours, at 40 DEG C to 45 DEG C in reaction mass.Reaction is maintained at 60 DEG C
10 to 12 hours, until the transformation of z- isomers is less than 1%.After reaction is completed, being purged by nitrogen makes reaction mass de- for 1 hour
Gas, to remove HCl and SO2Gas.Solvent is by air-distillation and finally recycles under reduced pressure.Then it is added in reaction mass
200ml methanol, and flow back 2 hours until obtaining clear solution.Then reaction mass is gradually cooling to 10 DEG C, filters reactant
Expect and obtains filter cake with refrigerated methanol carrying out washing treatment.The weight of (2E)-(methoxyimino) (2- tolyls) methyl acetate=
186.50gm.% yield=90%；% purity>97%
Embodiment 11：The preparation method B of (2E)-(methoxyimino) (2- tolyls) methyl acetate
N,N-dimethylformamide (5gm) in 300ml EDC is added to equipped with thermometer, blender and charging hopper
In the four-neck flask of device.At 40 DEG C to 45 DEG C, the methoxyimino-in EDC and triphosgene (119gm 0.40mol)
O- tolylacetic acid (193.20gm 1.0mol) is added in 2 to 3 hours in reaction mass, and further reaction is protected
It holds at 60 DEG C 10 to 12 hours, until the conversion of z- isomers is less than 1%.Three are added again if z- isomers is more than 1%
Phosgene is kept for additional two hours.Being purged 1 hour by nitrogen makes reaction mass deaerate, to remove HCl and SO2Gas.Solvent
It finally recycles by air-distillation and under reduced pressure.Then in reaction mass be added 190ml methanol, and flow back 2 hours until
Obtain clear solution.Then reaction mass is gradually cooling to 10 DEG C.Filtering reaction mass is simultaneously obtained with refrigerated methanol carrying out washing treatment
To filter cake.Weight=195gm to the 196gm of (2E)-(methoxyimino) (2- tolyls) methyl acetate.% is arrived yield=94
95%；% purity>97%
Embodiment 12：The preparation of (2E)-[2- (bromomethyl) phenyl] (methoxyimino) methyl acetate
(2E)-(methoxyimino) (2- tolyls) methyl acetate (207.23gm, 1.0mol) and N- bromo succinyl
Amine (232gm 1.30mol) is added in 1000ml acetonitriles.Reaction mixture is maintained at 58 DEG C to 62 DEG C 2 to 4 hours.Reaction
Recycle acetonitrile under reduced pressure after the completion.Reaction mixture color becomes micro- red, and this reaction process is monitored by TLC.Reaction
Recycle acetonitrile under reduced pressure after the completion.100ml water and 300ml diisopropyl ethers are added in reaction mixture.10% sulphur of the solution
2 × 300ml the washings of sour hydrogen sodium solution.Finally washed with 2 × 300ml of water.Organic layer is dried with sodium sulphate, is cooled to -5 DEG C and mistake
Filter.The diisopropyl ether of solid cooling is to obtain (2E)-[2- (bromomethyl) phenyl] (methoxyimino) methyl acetate.
Weight=241gm of product, % purity=98% of product；% yield=84%.
The preparation of 13 trifloxystrobin of embodiment
(2- bromomethyls-phenyl) methoxyimino methyl acetate (315gm, 1.10mol) is dissolved in 1500ml methyl
In isobutyl ketone.At room temperature, intermediate-II (203.16gm 1.0mol) is added into the solution and is subsequently added into potassium carbonate
(145gm 1.05mol).Reaction mixture is heated to 115 DEG C and is kept for 12 hours.After reaction is completed, mixture is cooled to
Room temperature simultaneously filters removal potassium bromide by-product and excessive potassium carbonate.The solid obtained after filtering washed with methyl iso-butyl ketone (MIBK) and
Prepared by next batch recycles in trifloxystrobin.Filtrate water washs, and is dried with anhydrous sodium sulfate, and is concentrated in vacuo and is slightly produced
Object.Crude product is recrystallized in methyl alcohol to obtain trifloxystrobin product=348gm of white.% yield=85%；% purity>
98%.
Claims (according to the 19th article of modification of treaty)
1. a kind of new method preparing trifloxystrobin, the described method comprises the following steps：
A) in the presence of thionyl chloride or triphosgene and solvent, make compound (2E/Z)-(the methoxyl group Asia of formula (VIII)
Amino) (2- tolyls) methyl, to obtain compound (2E)-(methoxyimino) (2- tolyls) second of formula (IX)
Sour methyl esters；
B) in the presence of bromating agent and organic solvent, and optionally in the presence of a phase transfer catalyst, make the chemical combination of formula (IX)
Object (2E)-(methoxyimino) (2- tolyls) methyl acetate bromination, to obtain (2E)-[2- (bromomethyl) benzene of formula (X)
Base] (methoxyimino) methyl acetate,
C) in the presence of the solvent, and optionally in the presence of alkali or phase transfer catalyst, make the compound and formula of formula (X)
(XI) compound reaction, wherein the solvent is selected from toluene, dimethylbenzene, methyl iso-butyl ketone (MIBK), acetonitrile, N, N- dimethyl formyls
Amine,
2. new method as described in claim 1, wherein solvent appropriate is selected from by dichloromethane, chloroform, monochloro-benzene, chloroethene
Alkene, toluene, dimethylbenzene, heptane, hexamethylene, hexane, acetone, DMF, acetonitrile, DMSO, sulfolane, methanol, ethyl alcohol, propyl alcohol, butanol
Or mixtures thereof composition group.
3. new method as described in claim 1, wherein bromating agent is selected from by phenyltrimethylammonium bromide；Dibromo dimethyl sea
Because of (DBDMH)；Potassium bromide；Sodium bromide；Br2；Hydrobromic acid；N- bromophthalimides；N- bromo acetamides, N- bromo fourths
Imidodicarbonic diamide (NBS) or mixtures thereof is combined the group of composition with AIBN or benzoyl peroxide.
4. new method as described in claim 1, wherein phase transfer catalyst is selected from by tetrabutylammonium bromide, tetrabutyl chlorination
Ammonium, quaternary ammonium cation, quaternary phosphonium salt cation and cyclic polyether such as three decoyl methyl ammoniums, methyltributylammonichloride chloride,
Methyl tributyl ammonium fluoride, tetrabutylammonium bromide, tetrabutyl ammonium fluoride, 4-butyl ammonium hydrogen sulfate, triethyl benzyl ammonia chloride, four
The group of butyl bromide phosphine, tetrabutylphosphonium chloride, four octyl bromide phosphines and its mixture composition.
5. new method as described in claim 1, wherein the method are used to prepare formula (VIII) compound, including following step
Suddenly：
A) in the presence of acid and water, the compound of formula (II) is made to be reacted with metal cyanides to obtain the compound of formula (III)；
B) in the presence of the solvent, the compound hydrolysis of formula (III) is made to obtain formula (Va) by using acid and sodium hydroxide
Compound；
C) using the compound oxidation of oxidant formula (Va) to obtain the compound of formula (V)；
D) in the presence of alkali and chlorinated solvent, the compound of formula (V) is made to be reacted with methoxamine hydrochloride to obtain formula (VIII)
Compound, wherein the chlorinated solvent is selected from the group being made of dichloroethanes, dichloromethane, toluene, dimethylbenzene, monochloro-benzene,
6. new method as described in claim 1, wherein the method are used to prepare formula (VIII) compound, including following step
Suddenly：
A) in the presence of acid and water, the compound of formula (II) is made to be reacted with metal cyanides to obtain the compound of formula (III)
B) in the presence of acid, hydroxyl (2- tolyls) acetonitrile of formula (III) is made to hydrolyze to obtain the change of the compound of formula (IV)
Close object；
C) in the presence of acid, the o- toluene yl acetamides of compound 2- hydroxyls -2- and methanol for making formula (IV) are reacted to obtain formula
(VI) compound of compound,
Or
In the presence of acid, hydroxyl (2- tolyls) acetonitrile and methanol for making formula (III) are reacted to obtain the compound of formula (VI)
Compound；
D) in the presence of 2,2,6, the 6- tetramethyl piperidine 1- oxygroups (TEMPO) of weak base of oxidant and catalytic amount, make formula (VI)
The o- tolylacetic acid methyl esters of oxo-aoxidize to obtain the compound of formula (VII)；
E) in the presence of base, and optionally in the presence of a phase transfer catalyst, make the o- tolyl second of the oxo-of formula (VII)
Sour methyl esters is reacted with methoxamine hydrochloride to obtain the compound of formula (VIII),
7. the new method as described in claim 6 and 7, wherein the metal cyanides is Cymag, potassium cyanide, cuprous cyanide.
8. the new method as described in claim 6 and 7, wherein the acid is concentrated hydrochloric acid or hydrogen chloride gas.
9. the new method as described in claim 6 and 7, wherein oxidant is sodium hypochlorite (NaOCl), sodium hypobromite
(NaOBr)。
10. the new method as described in claim 6 and 7, wherein oxidation catalyst be selected from by ruthenic oxide, Tempo (2,2,6,
6- tetramethyls-piperidin-1-yl) oxygroup, 4- acetoxyl group -2,2,6,6- tetramethyl-piperidyl -1- oxygroups, tetrabutylammonium bromide or
The group of its mixture composition.
11. the new method as described in claim 6 and 7, wherein carry out methoxyl group imido grpup, the alkali in the presence of base
Selected from the group being made of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
12. a kind of new method preparing formula (I) compound, the method by the presence of the solvent, and optionally in alkali or
In the presence of phase transfer catalyst, the compound of the compound and formula (XI) that make formula (X) is reacted to prepare the compound of formula (I),
The solvent is selected from toluene, dimethylbenzene, methyl iso-butyl ketone (MIBK), acetonitrile, n,N-Dimethylformamide,
13. new method as claimed in claim 12, wherein alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, three
Ethamine.
14. new method as claimed in claim 12, wherein phase transfer catalyst be selected from by quaternary ammonium cation, quaternary phosphonium salt sun from
Son and cyclic polyether such as three decoyl methyl ammoniums, methyltributylammonichloride chloride, methyl tributyl ammonium fluoride, tetrabutyl bromine
Change ammonium, tetrabutyl ammonium fluoride, 4-butyl ammonium hydrogen sulfate, triethyl benzyl ammonia chloride, tetrabutyl phosphonium bromide phosphine, tetrabutylphosphonium chloride,
The group of four octyl bromide phosphines and its mixture composition.
15. new method as claimed in claim 12, wherein the compound of the formula (I) of the acquisition has pure more than 97%
Degree.
Claims (15)
1. a kind of new method preparing formula (X) compound, the described method comprises the following steps：
A) in the presence of thionyl chloride or triphosgene and solvent, make compound (2E/Z)-(the methoxyl group Asia of formula (VIII)
Amino) (2- tolyls) methyl, to obtain compound (2E)-(methoxyimino) (2- tolyls) second of formula (IX)
Sour methyl esters；
B) in the presence of bromating agent and organic solvent, and optionally in the presence of a phase transfer catalyst, make the chemical combination of formula (IX)
Object (2E)-(methoxyimino) (2- tolyls) methyl acetate bromination, to obtain (2E)-[2- (bromomethyl) benzene of formula (X)
Base] (methoxyimino) methyl acetate,
2. new method as described in claim 1, wherein solvent appropriate is selected from by dichloromethane, chloroform, monochloro-benzene, chloroethene
Alkene, toluene, dimethylbenzene, heptane, hexamethylene, hexane, acetone, DMF, acetonitrile, DMSO, sulfolane, methanol, ethyl alcohol, propyl alcohol, butanol
Or mixtures thereof composition group.
3. new method as described in claim 1, wherein bromating agent is selected from by phenyltrimethylammonium bromide；Dibromo dimethyl sea
Because of (DBDMH)；Potassium bromide；Sodium bromide；Br2；Hydrobromic acid；N- bromophthalimides；N- bromo acetamides, N- bromo fourths
Imidodicarbonic diamide (NBS) or mixtures thereof is combined the group of composition with AIBN or benzoyl peroxide.
4. new method as described in claim 1, wherein phase transfer catalyst is selected from by tetrabutylammonium bromide, tetrabutyl chlorination
Ammonium, quaternary ammonium cation, quaternary phosphonium salt cation and cyclic polyether such as three decoyl methyl ammoniums, methyltributylammonichloride chloride,
Methyl tributyl ammonium fluoride, tetrabutylammonium bromide, tetrabutyl ammonium fluoride, 4-butyl ammonium hydrogen sulfate, triethyl benzyl ammonia chloride, four
The group of butyl bromide phosphine, tetrabutylphosphonium chloride, four octyl bromide phosphines and its mixture composition.
5. a kind of new method preparing formula (VIII) compound, the described method comprises the following steps：
A) in the presence of acid and water, the compound of formula (II) is made to be reacted with metal cyanides to obtain the compound of formula (III)；
B) in the presence of the solvent, the compound hydrolysis of formula (III) is made to obtain formula (Va) by using acid and sodium hydroxide
Compound；
C) using the compound oxidation of oxidant formula (Va) to obtain the compound of formula (V)；
D) in the presence of alkali and chlorinated solvent, the compound of formula (V) is made to be reacted with methoxamine hydrochloride to obtain formula (VIII)
Compound, wherein the chlorinated solvent is selected from the group being made of dichloroethanes, dichloromethane, toluene, dimethylbenzene, monochloro-benzene,
6. a kind of new method preparing formula (VIII) compound, the described method comprises the following steps：
A) in the presence of acid and water, the compound of formula (II) is made to be reacted with metal cyanides to obtain the compound of formula (III)；
B) in the presence of acid, hydroxyl (2- tolyls) acetonitrile of formula (III) is made to hydrolyze to obtain the change of the compound of formula (IV)
Close object；
C) in the presence of acid, the o- toluene yl acetamides of compound 2- hydroxyls -2- and methanol for making formula (IV) are reacted to obtain formula
(VI) compound of compound,
Or
In the presence of acid, hydroxyl (2- tolyls) acetonitrile and methanol for making formula (III) are reacted to obtain the compound of formula (VI)
Compound；
D) in the presence of 2,2,6, the 6- tetramethyl piperidine 1- oxygroups (TEMPO) of weak base of oxidant and catalytic amount, make formula (VI)
The o- tolylacetic acid methyl esters of oxo-aoxidize to obtain the compound of formula (VII)；
E) in the presence of base, and optionally in the presence of a phase transfer catalyst, make the o- tolyl second of the oxo-of formula (VII)
Sour methyl esters is reacted with methoxamine hydrochloride to obtain the compound of formula (VIII),
7. the new method as described in claim 6 and 7, wherein the metal cyanides is Cymag, potassium cyanide, cuprous cyanide.
8. the new method as described in claim 6 and 7, wherein the acid is concentrated hydrochloric acid or hydrogen chloride gas.
9. the new method as described in claim 6 and 7, wherein oxidant is sodium hypochlorite (NaOCl), sodium hypobromite
(NaOBr)。
10. the new method as described in claim 6 and 7, wherein oxidation catalyst be selected from by ruthenic oxide, Tempo (2,2,6,
6- tetramethyls-piperidin-1-yl) oxygroup, 4- acetoxyl group -2,2,6,6- tetramethyl-piperidyl -1- oxygroups, tetrabutylammonium bromide or
The group of its mixture composition.
11. the new method as described in claim 6 and 7, wherein carry out methoxyl group imido grpup, the alkali in the presence of base
Selected from the group being made of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
12. a kind of improved method preparing formula (I) compound, the method is by the presence of the solvent, and optionally in alkali
Or in the presence of phase transfer catalyst, the compound of the compound and formula (XI) that make formula (X) is reacted to prepare the chemical combination of formula (I)
Object, the solvent are selected from toluene, dimethylbenzene, methyl iso-butyl ketone (MIBK), acetonitrile, n,N-Dimethylformamide,
13. new method as claimed in claim 12, wherein alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, three
Ethamine.
14. new method as claimed in claim 12, wherein phase transfer catalyst be selected from by quaternary ammonium cation, quaternary phosphonium salt sun from
Son and cyclic polyether such as three decoyl methyl ammoniums, methyltributylammonichloride chloride, methyl tributyl ammonium fluoride, tetrabutyl bromine
Change ammonium, tetrabutyl ammonium fluoride, 4-butyl ammonium hydrogen sulfate, triethyl benzyl ammonia chloride, tetrabutyl phosphonium bromide phosphine, tetrabutylphosphonium chloride,
The group of four octyl bromide phosphines and its mixture composition.
15. new method as claimed in claim 12, wherein the compound of the formula (I) of the acquisition has pure more than 97%
Degree.
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| PCT/IN2016/050411 WO2017085747A2 (en) | 2015-11-19 | 2016-11-18 | A novel process for the preparation of trifloxystrobin |
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| WO2023004964A1 (en) * | 2021-07-30 | 2023-02-02 | 海南海神同洲制药有限公司 | Method for synthesizing 3-bromomethyl-7-chlorobenzo[b]thiophene |
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2016
- 2016-11-18 CN CN201680071842.3A patent/CN108368033B/en active Active
- 2016-11-18 WO PCT/IN2016/050411 patent/WO2017085747A2/en active Application Filing
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023004964A1 (en) * | 2021-07-30 | 2023-02-02 | 海南海神同洲制药有限公司 | Method for synthesizing 3-bromomethyl-7-chlorobenzo[b]thiophene |
| CN114436833A (en) * | 2021-12-27 | 2022-05-06 | 南京红太阳医药研究院有限公司 | Preparation method of telmisartan key intermediate 4' -methylbiphenyl-2-carboxylic ester |
Also Published As
| Publication number | Publication date |
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| WO2017085747A4 (en) | 2017-10-26 |
| WO2017085747A2 (en) | 2017-05-26 |
| WO2017085747A3 (en) | 2017-08-03 |
| CN108368033B (en) | 2021-05-04 |
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