CN1303061C - Liquid phase synthesis process of oxime strain ester by poly-ethandiol - Google Patents

Abstract

The present invention discloses a liquid phase synthesis process of trifloxystrobin by polyethyleneglycol, wherein (a) by means of hydroxyl on polyethyleneglycol to make a condensation reaction with 2-methylacetophenone acid, the 2-methylacetophenone acid is loaded onto the polyethyleneglycol to obtain 2-(2'-methylphenyl)-2-polyglycol carboxy acetate; (b) the 2-(2'-methylphenyl)-2-polyglycol carboxy acetate obtained in step (a) reacts with a methoxyamine hydrochloride to obtain 2-(2'-methylphenyl)-2-polyglycol carboxy acetate-O-methyl ketone oxime; (c) the compound obtained in step (b) is bromized to obtain 2-(2'-bromomethylphenyl)-2-polyglycol carboxy acetate-O-methyl ketone oxime; (d) under an alkaline condition, the compound obtained in step (c) is condensed together with meta-trifluoromethyl acetophenone oxime to obtain 2-[1'-{[(3'-trifluoromethylphenyl)-ethyl-imine]O}-O-tolyl]-2-polyglycol carboxy acetate-O-methyl ketone oxime; (e) the ester exchange reaction of the compound obtained in step (d) and methanol is carried out to obtain trifloxystrobin. On the basis of not changing the property of the trifloxystrobin as a product, the present invention simplifies the steps of separation and purification in a reaction process and reduces costs.

Description

Method for Synthesizing Trifloxystrobin in Polyethylene Glycol Liquid Phase

technical field

The present invention relates to a kind of preparation method of organic compound pesticide, relate in particular to a kind of liquid phase synthesis trifloxystrobin ((E,E)-2-[1'-(3'-trifluoromethylbenzene) with polyethylene glycol loading base)-ethyl-imine-oxygen-tolyl]-2-methyl oxoacetate-O-ketone oxime) synthetic method.

Background technique

Trifloxystrobin broad-spectrum fungicides are a new class of fluorine-containing fungicides successfully developed from natural products Strobilurins as fungicide lead compounds. Its characteristics are: high efficiency, broad spectrum, protection, treatment, eradication, penetration, systemic activity, resistance to rain erosion, and long-lasting effect. It is effective for strains resistant to 1,4-demethylase inhibitors, benzamides, dicarboxamides and benzimidazoles, and has no cross-resistance with existing fungicides. It has good activity against almost all fungal diseases (Ascomycetes, Basidiomycetes, Oomycetes and Deuteromycetes) such as powdery mildew, rust, blight, net spot, downy mildew, rice blast, etc. . In addition to having special effects on powdery mildew and leaf spot, it has good activity on rust, downy mildew, blight and apple black blight. It is safe for crops, and it is safe for the environment because it can be rapidly degraded in soil and water.

Liquid-phase synthesis on polyethylene glycol has been widely used in the synthesis of polypeptide nucleotides and oligosaccharides and small molecule combinatorial libraries, but has not been used in the synthesis of trifloxystrobin.

Contents of the invention

The object of the present invention is to provide a method for synthesizing trifloxystrobin in liquid phase supported by polyethylene glycol.

The present invention is achieved through the following technical solutions:

1. 2-(2'-methylphenyl)-2-oxoacetic acid polyethylene glycol ester

The hydroxyl group on polyethylene glycol is condensed with o-methylacetophenone acid to obtain polyethylene glycol 2-(2'-methylphenyl)-2-oxoacetic acid. The reaction medium of this synthesis is methanol, dichloro Methane, chloroform, acetonitrile or N, N-dimethylformamide, the temperature is 0-40 ° C, the preferred temperature is 20 ° C, the condensing agent is DCC (dicyclohexylcarbodiimide), HOBt (1- hydroxybenzotriazole) or by reacting the acid with an acid chloride followed by condensation with polyethylene glycol.

2. Synthesis of 2-(2'-methylphenyl)-2-polyethylene glycol oxoacetate-O-methyl ketone oxime

2-(2'-methylphenyl)-2-oxoacetic acid polyethylene glycol reacts with methoxylamine hydrochloride under alkaline conditions. The reaction medium used in this synthesis is methanol, dichloromethane, tris Chloromethane, acetonitrile or N,N-dimethylformamide, the basic reagents are triethylamine, pyridine, sodium hydroxide, potassium hydroxide, etc., the temperature is 10-80°C, the preferred temperature is 60°C, and the pH value is 8-13, with a preferred pH of 10.

3. Synthesis of 2-(2'-bromomethylphenyl)-2-polyethylene glycol oxoacetate-O-methyl ketone oxime

2-(2'-methylphenyl)-2-oxoacetic acid polyethylene glycol ester-O-methyl ketoxime is brominated to obtain 2-(2'-bromomethylphenyl)-2-oxoacetic acid polyoxyethylene Ethylene glycol ester-O-methyl ketone oxime, the reaction medium used in this synthesis is methanol, dichloromethane, chloroform, acetonitrile or N,N-dimethylformamide, bromination reagent is bromine, NBS(N -bromosuccinimide), the reaction temperature is 10-70°C, preferably 50°C.

4. 2-[1'-{[(3'-trifluoromethylphenyl)-ethyl-imine]oxy}-O-tolyl]-2-oxoacetic acid polyethylene glycol ester-O-form Synthesis of Ketoxime

2-(2'-bromomethylphenyl)-2-oxoacetic acid polyethylene glycol ester-O-methyl ketone oxime is condensed with m-trifluoromethyl acetophenone oxime under alkaline conditions to obtain 2-[ 1'-{[(3'-Trifluoromethylphenyl)-ethyl-imine]oxy}-O-tolyl]-2-oxoacetic acid polyethylene glycol ester-O-methylketoxime. The base used for the reaction is sodium hydride, calcium hydride, sodium hydroxide, potassium hydroxide, sodium amide, etc. The reaction temperature is 20-70°C, preferably 60°C. The reaction medium is methanol, dichloromethane, chloroform, acetonitrile or N,N-dimethylformamide. The molar ratio of base to trifluoromethylacetophenone oxime is 0.8-2.5:1, preferably 1.2:1.

5. Synthesis of trifloxystrobin

2-[1'-{[(3'-Trifluoromethylphenyl)-ethyl-imine]oxy}-O-tolyl]-2-oxoacetic acid polyethylene glycol ester-O-methyl ketone Under the catalysis of strong acid resin and concentrated sulfuric acid, oxime is transesterified with methanol to obtain trifloxystrobin, the amount of catalyst is 0.1-1%, methanol and 2-[1'-{[(3'-trifluoromethylphenyl )-Ethyl-imine] oxygen}-O-tolyl]-2-oxoacetic acid polyethylene glycol ester-O-methyl ketoxime molar ratio is 1-20:1, and the reaction temperature is 20-65°C .

The present invention uses polyethylene glycol to support liquid phase synthesis of trifloxystrobin, on the basis of not changing the properties of the product, simplifies the steps of separation and purification in the reaction process, and provides a broader idea for the use of polyethylene glycol in organic synthesis.

Detailed ways

1. Polyethylene glycol 2-(2'-methylphenyl)-2-oxoacetic acid

Add 2g (0.01mol) 2-(2'-methylphenyl)-2-oxoacetic acid and 5ml thionyl chloride to a 100ml round-bottomed flask equipped with a stirring and reflux condenser, stir at room temperature for 5 hours, and rotovap To remove excess thionyl chloride, add a small amount of dry n-heptane, rotate to evaporate n-heptane, add 20ml of dichloromethane and 10g of polyethylene glycol in the flask, react at room temperature for 8 hours, distill off the dichloromethane, add Diethyl ether, 2-(2'-methylphenyl)-2-carbonyl acetate polyethylene glycol was precipitated, dissolved in dichloromethane, evaporated dichloromethane, added diethyl ether to obtain 9.8g of relatively pure 2-( 2'-Methylphenyl)-2-oxoacetic acid polyethylene glycol ester.

2. Synthesis of 2-(2'-methylphenyl)-2-polyethylene glycol oxoacetate-O-methyl ketone oxime

Add 9.8g 2-(2'-methylphenyl)-2-oxopolyethylene glycol acetate, 0.8g (0.01mol) methoxyamine hydrochloride and 20ml95% ethanol in a 100ml three-necked flask, add Adjust the pH to 10 with 1ml of triethylamine and the temperature to 60°C. After stirring and refluxing for 10 hours, the solvent was evaporated, ether was added, and 2-(2'-methylphenyl)-2-oxoacetic acid polyethylene glycol was precipitated. -O-Methyl ketone oxime, add dichloromethane to dissolve the precipitate, add ether, precipitate out, and get 9.5g of 2-(2'-methylphenyl)-2-oxoacetic acid polyethylene glycol ester-O-methyl Ketoxime.

3. Synthesis of 2-(2'-bromomethylphenyl)-2-polyethylene glycol oxoacetate-O-methyl ketone oxime

9.5g 2-(2'-methylphenyl)-2-oxoacetic acid polyethylene glycol ester-O-methyl ketoxime was dissolved in 20ml carbon tetrachloride and placed in a 100ml three-necked bottle, and 1.5g (0.012 mol) NBS (N-bromosuccinimide) and 0.2g BPO (benzoyl peroxide), irradiated with a 250W mercury lamp. The reaction temperature is 50°C, react for 8 hours, distill off the solvent, add diethyl ether, precipitate out, dissolve the precipitate in dichloromethane, add diethyl ether to obtain 9.3g of 2-(2'-bromomethylphenyl)-2-oxoacetic acid Polyethylene glycol ester-O-methylketoxime.

4. 2-[1'-{[(3'-trifluoromethylphenyl)-ethyl-imine]oxy}-O-tolyl]-2-oxoacetic acid polyethylene glycol ester-O-form Synthesis of Ketoxime

Add 1g (0.04mol) NaH to 50ml tetrahydrofuran, add 2g (0.01mol) m-trifluoromethylacetophenone oxime at room temperature, heat and stir for 1 hour, then add 9g 2-(2'-bromomethyl Phenyl)-2-oxoacetic acid polyethylene glycol ester-O-methyl ketone oxime and 20ml tetrahydrofuran, continue to heat and stir for 5 hours, the reaction temperature is controlled at about 60°C, distill off the solvent, add ether, precipitate, precipitate Dissolve in dichloromethane and add ether to give 8.9g 2-[1'-{[(3'-trifluoromethylphenyl)-ethyl-imine]oxy}-O-tolyl]-2-carbonyl Polyethylene glycol acetate-O-methylketoxime solid.

5. Synthesis of trifloxystrobin

9g 2-[1'-{[(3'-trifluoromethylphenyl)-ethyl-imine]oxy}-O-tolyl]-2-oxoacetic acid polyethylene glycol ester-O-methanol Ketoxime and 20ml methanol were placed in a three-necked flask, heated to reflux for 8 hours, the solvent was evaporated, the product was dissolved with ethyl acetate, the solvent was evaporated, and recrystallized with petroleum ether to obtain 0.6g trifloxystrobin, melting point: 70°C

¹ H NMR (CDCl ₃ ): δ=2.21(s, 3H), 3.82(s, 3H), 3.93(s, 3H), 5.13(s, 2H), 7.1-7.8(m, 7H).

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the scope of the present invention. All equivalent changes and modifications made according to the present invention are covered by the patent scope of the present invention.

Claims (6)

1, a kind of polyoxyethylene glycol liquid phase synthesis type (I) oxime bacterium ester ((E, E)-2-[1 '-(3 '-trifluoromethyl)-ethyl-imines-oxygen-tolyl]-2-carbonylic acetic acid methyl esters-O-ketoxime) method, this method comprises the steps:

Oxime bacterium ester (I)

(a) 2-(2 '-aminomethyl phenyl)-2-carbonylic acetic acid macrogol ester

By hydroxyl on the polyoxyethylene glycol and the condensation reaction of o-methyl-benzene acetonic acid, the o-methyl-benzene acetonic acid is loaded on the polyoxyethylene glycol, get 2-(2 '-aminomethyl phenyl)-2-carbonylic acetic acid macrogol ester;

(b) 2-(2 '-aminomethyl phenyl)-2-carbonylic acetic acid macrogol ester-O-methyl ketoxime is synthetic

2-(2 '-aminomethyl phenyl)-2-carbonylic acetic acid macrogol ester reacts with methoxy amine hydrochlorate under alkaline condition, gets the synthetic of 2-(2 '-aminomethyl phenyl)-2-carbonylic acetic acid macrogol ester-O-methyl ketoxime;

(c) 2-(2 '-2-bromomethylphenyl)-2-carbonylic acetic acid macrogol ester-O-methyl ketoxime is synthetic

2-(2 '-aminomethyl phenyl)-2-carbonylic acetic acid macrogol ester-O-methyl ketoxime obtains 2-(2 '-2-bromomethylphenyl)-2-carbonylic acetic acid macrogol ester-O-methyl ketoxime through bromination;

(d) 2-[1 '-{ [(3 '-trifluoromethyl)-ethyl-imines] oxygen }-O-tolyl]-2-carbonylic acetic acid macrogol ester-O-methyl ketoxime synthetic

2-(2 '-2-bromomethylphenyl)-2-carbonylic acetic acid macrogol ester-O-methyl ketoxime under alkaline condition with the condensation of m-trifluoromethyl acetophenone oxime, 2-[1 '-{ [(3 '-trifluoromethyl)-ethyl-imines] oxygen }-O-tolyl]-2-carbonylic acetic acid macrogol ester-O-methyl ketoxime;

(e) oxime bacterium ester is synthetic

2-[1 '-{ [(3 '-trifluoromethyl)-ethyl-imines] oxygen }-O-tolyl]-2-carbonylic acetic acid macrogol ester-O-methyl ketoxime and methyl alcohol carries out transesterify and gets oxime bacterium ester.

The method of 2, synthesizing oxime bacterium ester according to the described polyoxyethylene glycol liquid phase of claim 1, it is characterized in that: the reaction medium in described (a) and (b), (c) step is organic solvent methyl alcohol, methylene dichloride, trichloromethane, acetonitrile or N, a kind of in the dinethylformamide.

3, according to the method for the synthetic oxime bacterium ester of the described polyoxyethylene glycol liquid phase of claim 1, it is characterized in that:

Used condensing agent is dicyclohexylcarbodiimide or 1-hydroxy benzo triazole or with acid and acyl chloride reaction, again with the polyoxyethylene glycol condensation in described (a) step.

4. according to the method for the synthetic oxime bacterium ester of the described polyoxyethylene glycol liquid phase of claim 1, it is characterized in that: the alkali of reaction (b) usefulness is a kind of in triethylamine, pyridine, sodium hydroxide or the potassium hydroxide.

5. according to the method for the synthetic oxime bacterium ester of the described polyoxyethylene glycol liquid phase of claim 1, it is characterized in that: used bromide reagent is a kind of in bromine or the N-bromo-succinimide in the described step (c).

6. according to the method for the synthetic oxime bacterium ester of the described polyoxyethylene glycol liquid phase of claim 1, it is characterized in that:

Reaction (d) used alkali is a kind of in sodium hydride, hydrolith, sodium amide, sodium hydroxide or the potassium hydroxide.