CN108863845A - A kind of preparation method of trifloxystrobin and its intermediate - Google Patents

Abstract

The present invention relates to a kind of preparation method of trifloxystrobin; The preparation reaction of trifloxystrobin is as follows: R is selected from: C ₂ ~ C ₅ straight chain alkyl or C ₃ ~ C ₅ branched chain alkyl; in the bromination reaction, the bromination agent is selected from NBS or 1,3-dibromo-5,5-dimethyl seawater because.

Description

A kind of preparation method of trifloxystrobin and its intermediate

technical field

The invention relates to a preparation method of a compound, in particular to a preparation method of trifloxystrobin and its intermediate 2-methyl-α-methoxyiminophenylacetamide.

Background technique

Trifloxystrobin (Trifloxystrbin, trade name Flint) chemical name: (2Z)-2-methoxyimino-2-[2-[[1-[3-(trifluoromethyl)phenyl]ethyleneamino ]oxymethyl]phenyl]methyl acetate:

Trifloxystrobin is a highly efficient, safe and environmentally friendly methoxyacrylate fungicide. As a new type of mitochondrial respiration inhibitor, it has the characteristics of high efficiency, broad spectrum, low toxicity, environmental friendliness and unique mechanism of action. , has become a hotspot in fungicide research. It is mainly used for stem and leaf treatment. It has special effects on powdery mildew and leaf spot, and has good activity on rust, downy mildew, blight and apple scab.

Chinese patent [CN 1049426C,2000] uses methyl o-bromomethylphenylacetate as the starting material, first reacts with benzyl hydroxyamine acid for etherification, and then reacts with methanol under acidic conditions to obtain methyl o-methoxyaminophenylacetic acid , and then carry out oximation reaction with m-trifluoromethyl acetophenone, and obtain trifloxystrobin through oximation of tert-butyl nitrite and methylation of dimethyl sulfate, with a total yield of 40.5%:

This route has five steps altogether, and reaction step is comparatively reasonable, but used the more expensive methyl o-bromomethyl phenylacetate in the reaction.

The world patent [WO 9520569,1995] has studied trifloxystrobin, first carried out etherification reaction with o-bromomethylphenylboronic acid and m-trifluoromethyl acetophenone oxime, and then reacted with 2-chloro The condensation reaction of methyl 2-methoxyiminoacetate produces trifloxystrobin:

The synthesis route is relatively short, but the raw material o-bromomethylbenzeneboronic acid is expensive; the yield is low due to the harsh synthesis conditions of methyl 2-chloro-2-methoxyiminoacetate and the existence of isomerization.

U.S. Patent [US 5194662,1993] takes methyl o-toluene acetate as the initial raw material, obtains methyl o-bromomethyl phenylacetate after bromination reaction, then condenses with m-trifluoromethyl acetophenone oxime, and then Oxidation and oximation reactions give trifloxystrobin:

The third step oxidation reaction of this route is more difficult.

Ni Yuebiao et al [CN 101941921,2011] and Jiang Wentao et al [Organic Chemistry, 2014, 34 (4), 774-782] take toluene or substituted toluene as raw materials, under the catalysis of anhydrous aluminum trichloride, and oxalyl chloride monomethyl The ester undergoes Friedel-Crafts acylation reaction, then oximation and chlorination, and finally condenses with m-trifluoromethyl acetophenone oxime to obtain trifloxystrobin with a total yield of 50.2%:

Friedel-Crafts acylation reaction in this route, selectivity is lower, causes yield lower; Monomethyl oxalyl chloride price is higher.

[Journal of Central China Normal University, 2005, 39(1), 54-56] used o-bromotoluene as raw material, and obtained o-methylbenzene by coupling reaction with monomethyl oxalyl chloride under the action of organic copper lithium reagent Methyl formylformate, then oximated with methoxamine hydrochloride to obtain the intermediate oxime ester, and then brominated and oximated to obtain trifloxystrobin, with a total yield of 25%:

The coupling reaction in the first step of this route is complicated, the conditions are harsh, and there are many by-products, and the process requires relatively high equipment.

Chinese patent [CN 1560027,2005; CN 1793115,2006]] uses o-methyl acetophenone as raw material, oxidizes with potassium permanganate under weakly alkaline conditions, then undergoes esterification, oximation, bromination, and finally Then condense with m-trifluoromethyl acetophenone oxime to obtain trifloxystrobin with a total yield of 39%:

Chen Wei et al [Chemical Research, 2014, 25 (1), 16-19] used o-methylphenylacetic acid as a raw material, first oxidized by potassium permanganate under alkaline conditions, and then esterified, oximated and brominated Reaction, finally generate trifloxystrobin through condensation reaction, total yield 17%:

In the method of potassium permanganate oxidation, it is difficult to control the reaction process by using potassium permanganate as an oxidizing agent, and the methyl group may also be oxidized.

World Patent [WO 2013144924, US 5221762,1993], Chen Can et al. [Fine Chemical Intermediates, 2004,34(5), 25-26] and Luo Zheng et al. -21] using o-toluic acid as raw material, reflux with thionyl chloride to obtain o-toluoyl chloride; the intermediate obtained through cyanation, esterification, oximation and bromination is then combined with m-trifluoroform Trifloxystrobin was obtained by etherification of acetophenone oxime with a total yield of 16.2%:

The raw materials of this route are cheap and easy to operate, but the second step reaction uses highly toxic sodium cyanide.

[Pesticides, 2011, 50 (3), 187-191] and Chinese patent [CN 101139308, 2008] use o-hydroxymethylbenzoic acid lactone as a raw material to generate o-chloromethylbenzoyl chloride through ring opening, and then Using sodium cyanide as the cyanide source, the reaction produces o-chloromethylbenzoyl nitrile, and finally the intermediate obtained through esterification and oximation is etherified with m-trifluoromethyl acetophenone oxime to obtain trifloxystrobin. Rate 22%:

This route uses phthalide ring-opening to generate acid chloride and chloromethyl, and the reaction conditions of each step are relatively mild; but the second step reaction uses highly toxic sodium cyanide.

Chinese patent [CN 103524378,2015] uses o-methylphenylacetic acid as raw material to synthesize trifloxystrobin through ring formation, oxidation, hydrolysis, oximation, chlorination and etherification, with a yield of 50.6%:

The raw materials of this route are cheap and easy to obtain, and the yield is high. But the oxidation process uses the expensive oxidant CAT9901.

Chinese patent [CN 105294490,2016] and world patent [WO 2010089267] use o-hydroxymethyl phenylacetic acid lactone method as raw material, and get trifloxystrobin through 4-step reaction, with a total yield of 25%:

The price of the raw material o-hydroxymethylphenylacetic acid lactone of this route is relatively high, and the first step oximation reaction requires anhydrous and oxygen-free operation.

Chai Bing et al. [Pesticides, 2013,52(4), 258-259] and Li Yan et al. [Organic Chemistry, 2006,26(1), 110-115] used o-methylaniline as raw material, after diazotization reaction, Methylation reaction, bromination reaction, and finally etherification with m-trifluoromethyl acetophenone oxime to obtain trifloxystrobin with a total yield of 31%:

The diazotization reaction conditions taken by this route are more demanding and have more by-products.

Li Renhong [Master's Thesis of Hebei University of Science and Technology, 2015] synthesized trifloxystrobin by oxilation, methylation, hydrolysis, hydrolysis, bromination and etherification with o-methylphenylacetonitrile as raw material, with a yield of 30.8%:

The raw materials of this route are cheap and easy to obtain, and the reaction conditions are relatively mild. However, concentrated sulfuric acid is used in the esterification process, which is highly corrosive to equipment.

Zhu Xiaomeng [Shandong Normal University master thesis, 2013] using o-methylbenzyl chloride as the starting material, obtained the key intermediate 2-bromomethyl of trifloxystrobin through cyanation, oximation, methylation, esterification and bromination Base-α-methoxyiminophenylacetic acid methyl ester, yield 41.6%.

The conditions of this route are relatively mild, but highly toxic sodium cyanide is used.

U.S. Patent [US 5145980,1992] uses o-methylbenzaldehyde as raw material, reacts with methoxylamine hydrochloride after cyanation and oxidation, and then obtains 2-bromomethyl-α-methoxymethoxylate through bromination Methyl aminophenylacetate, total yield 16%:

This route is long, and total yield is very low, and the first step reaction has used the big potassium cyanide of toxicity.

Wei Xinghui et al[Zhejiang Chemical Industry, 2013,44(2),7-9] synthesized 2-bromomethyl-α-methoxy from o-methylphenylacetic acid through esterification, oximation, methylation and bromination Methyl iminophenylacetate, total yield 32%:

The reaction condition of this route is relatively mild, and it is a better method for preparing 2-bromomethyl-α-methoxyiminophenylacetic acid methyl ester.

Chinese patent [CN 101711232,2010] uses o-chlorobenzyl chloride as a raw material, protects methylene with morpholine, and then undergoes four steps of Grignard reaction, esterification, and oximation to obtain 2-chloromethyl-α-methoxyimino Methyl phenylacetate, total yield 22%:

The second step of the route is difficult to control, and the yield is 30.3%.

The world patent [WO 9714688,1997] uses o-methyl phenylacetonitrile as a raw material and reacts in 5 steps to obtain 2-chloromethyl-α-methoxyiminophenylacetic acid methyl ester with a total yield of 23%:

The third step reaction of this route requires anhydrous and oxygen-free operation.

U.S. Patent [US 5756811,1998] uses N,N-dimethylbenzylamine and dimethyl oxalate as raw materials to obtain the intermediate 2-chloromethyl-α-methoxyimino of trifloxystrobin through 3-step reaction Methyl phenylacetate, total yield 55%:

The route is relatively simple and the yield is high, but the first step requires the use of n-butyllithium, and the reaction conditions are harsh.

In summary, the existing technology for preparing trifloxystrobin has disadvantages such as difficult and expensive source of raw materials, long synthetic route, harsh reaction conditions, difficult process control, high requirements for production equipment, high pressure on safety and environmental protection, and low yield.

Contents of the invention

The object of the present invention is to provide the preparation method of 2-methyl-α-methoxyiminophenylacetamide shown in chemical structural formula I; It is characterized in that its preparation reaction is as follows:

R is selected from: C ₂ -C ₅ straight chain alkyl or C ₃ -C ₅ branched chain alkyl.

The object of the present invention is to provide the preparation method of 2-methyl-alpha-methoxyiminophenylacetamide: it is characterized in that its preparation operation process is as follows:

12mmol sodium hydroxide and 10mL methanol were stirred and dissolved at 40°C, 5mmol o-tolueneacetonitrile was added, 7.5mmol tert-butyl nitrite was added, the temperature was raised to 60°C, and the reaction was carried out for 1h. After post-treatment, 2-methyl-α-hydroxyiminophenylacetonitrile was obtained with a yield of 100%.

4mmol 2-methyl-α-hydroxyiminophenylacetonitrile, 15mL acetonitrile and 8mmol KOH or NaOH, stirred at 35-40°C for 0.5h, cooled, and slowly added dropwise 4.8mmol dimethyl sulfate at a temperature lower than 10°C , Stirring at 35°C for 3h, after post-treatment, 0.626g of light yellow oily liquid was obtained, yield 90%.

In 5mmol 2-methyl-α-methoxyiminophenylacetonitrile and 5mL ethanol, add 5mmol 20% potassium hydroxide solution, react at 60°C for 3h, and obtain 0.900g single-configuration (E)- 2-Methyl-α-methoxyiminophenylacetamide, the yield is 92.5%, and the melting point is 123-125°C.

The object of the present invention also provides a method for preparing trifloxystrobin through 2-methyl-α-methoxyiminophenylacetamide shown in chemical structural formula I; it is characterized in that its preparation reaction is as follows:

R is selected from: C ₂ ～C ₅ straight chain alkyl or C ₃ ～C ₅ branched chain alkyl; in the bromination reaction, the bromination agent is NBS or 1,3-dibromo-5,5-dimethylseawater because.

Compared with the prior art, the present invention has the following advantages: mild reaction conditions, cheap and easy-to-obtain raw materials, simple post-treatment and high total yield (43.5%). The present invention is the first to prepare trifloxystrobin through the key intermediate of 2-methyl-α-methoxyiminophenylacetamide.

Detailed ways

The following examples are intended to illustrate the present invention without further limiting the invention.

Example 1

Preparation of 2-methyl-α-hydroxyiminophenylacetonitrile

0.480g (12mmol) of sodium hydroxide and 10mL of methanol were stirred and dissolved at 40°C, 0.655g (5mmol) of o-tolueneacetonitrile was added, 0.773g (7.5mmol) of tert-butyl nitrite was added, the temperature was raised to 60°C, and monitored by TLC. Reaction 1h. Recover methanol by precipitation under reduced pressure, add 20 mL of water, adjust the pH to neutral with hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, recover ethyl acetate by precipitation, the yield is 100%, and use it directly in the next step. (E)-2-Methyl-α-hydroxyiminophenylacetonitrile: ¹ H NMR (400MHz, CDCl ₃ ) δ: 13.78 (s, 1H, OH), 7.53～7.32 (m, 4H, C ₆ H ₄ ), 2.44 (s, 3H, CH ₃ ). (Z)-2-methyl-α-hydroxyiminophenylacetonitrile: ¹ H NMR (400MHz, CDCl ₃ ) δ: 13.78 (s, 1H, OH), 7.46-7.33 (m, 4H, C ₆ H ₄ ), 2.25 (s, 3H, CH ₃ ).

Example 2

Preparation of 2-methyl-α-methoxyiminophenylacetonitrile

0.640g (4mmol) 2-methyl-α-hydroxyiminophenylacetonitrile, 15mL acetonitrile, 0.448g (8mmol) powdered KOH, stirred at 35-40°C for 0.5h, cooled, and slowly dropped at a temperature lower than 10°C Add 0.605g (4.8mmol) of dimethyl sulfate, stir at 35°C for 3h, and monitor by TLC. Stand still, filter with suction, and recover acetonitrile by rotary evaporation. The residue was dissolved in ethyl acetate, neutralized with dilute hydrochloric acid, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, precipitated, and separated by column chromatography (PE:EA=8:1) to obtain 0.626g of 2-methyl-α- Methoxyiminophenylacetonitrile, the yield is 90%. (E)-2-Methyl-α-methoxyiminophenylacetonitrile: ¹ H NMR (400MHz, CDCl ₃ ) δ: 7.56～7.25 (m, 4H, C ₆ H ₄ ), 4.20(s, 3H, NOCH ₃ ), 2.51(s, 3H, CH ₃ ); (Z)-2-methyl-α-methoxyiminophenylacetonitrile: ¹ HNMR (400MHz, CDCl ₃ ) δ: 7.38～7.25(m, 4H , C ₆ H ₄ ), 4.06 (s, 3H, NOCH ₃ ), 2.31 (s, 3H, CH ₃ ).

Example 3

Preparation of 2-methyl-α-methoxyiminophenylacetamide

0.870g (5mmol) 2-methyl-α-methoxyiminophenylacetonitrile and 5mL ethanol, add 1.400g (5mmol) 20% potassium hydroxide or NaOH solution, react at 60°C for 3h, monitor by TLC. The solvent was recovered by rotary evaporation, and the residue was poured into 20 mL of ice water. The solid precipitated, filtered with suction, and washed with water. The filter cake was dried, and the filtrate was extracted with ethyl acetate, dried with anhydrous sodium sulfate, precipitated, and dried to obtain 0.900g of 2-methyl-α-methoxyiminophenylacetamide with a yield of 92.5% and a melting point of 123～ 125°C. ¹ H NMR (400MHz, DMSO-d ₆ ) δ: 7.97(s, 1H, NH ₂ ), 7.73(s, 1H, NH ₂ ), 7.40～7.22(m, 4H, C ₆ H ₄ ), 3.89(s , 3H, NOCH ₃ ), 2.42 (s, 3H, CH ₃ ).

Example 4

Preparation of 2-methyl-α-methoxyiminophenylacetic acid methyl ester

0.960g (5mmol) of 2-methyl-α-methoxyiminophenylacetamide and methanol, hydrogen chloride gas was passed through, stirred at 60°C for 12h, monitored by TLC, desolvated under reduced pressure, added 20mL of water, washed with ethyl acetate Extraction, washing with saturated sodium bicarbonate, washing with water, drying over anhydrous sodium sulfate, precipitation under reduced pressure, and drying to obtain 2-methyl-α-methoxyiminophenylacetic acid methyl ester with a yield of 90.5% and a melting point of 69-71°C . ¹ H NMR (400MHz, DMSO-d ₆ ) δ: 7.34～7.09 (m, 4H, C ₆ H ₄ ), 3.94 (s, 3H, NOCH ₃ ), 3.76 (s, 3H, OCH ₃ ), 2.09 (s , 3H, CH ₃ ).

Example 5

Preparation of (E)-2-bromomethyl-α-methoxyiminophenylacetic acid methyl ester

0.414g (2.00mmol) (E)-2-methyl-α-methoxyimino-phenylacetic acid methyl ester, 5mL dichloroethane, 0.300g (1.05mmol) 1,3-dibromo-5,5- Dimethylhydantoin (dibromohydantoin for short), 0.100g (0.61mmol) AIBN, reacted at 82°C for 5.0h, monitored by TLC, and precipitated. Add 5 mL of water, extract with ethyl acetate, wash with sodium hydroxide solution, dry over anhydrous sodium sulfate, remove the solvent, and separate by column chromatography (PE:EA=20:1) to obtain (E)-2-bromomethyl-α - Methoxyiminophenylacetic acid methyl ester 0.472g, yield 82.5%. ¹ H NMR (400MHz, CDCl ₃ ) δ: 7.52-7.35, 7.17-7.12 (m, 4H, C ₆ H ₄ ), 4.34 (s, 2H, CH ₂ ), 4.07 (s, 3H, NOCH ₃ ), 3.88 (s, 3H, _OCH3 ).

Example 6

Preparation of m-trifluoromethylacetophenone oxime

1.000g (5.0mmol) m-trifluoromethylacetophenone, 0.5g (7.0mmol) hydroxylamine hydrochloride, 10mL ethanol, add 0.350g (8.8mmol) sodium hydroxide to adjust pH to 8.0, reflux for 1.0h, pour into ice water , adjusted the pH to 2.0 with hydrochloric acid, a large amount of white solid was precipitated, filtered by suction, washed with water and dried to obtain 0.965 g of white solid m-trifluoromethylacetophenone oxime with a yield of 95.5%. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.92-7.48 (m, 4H, C ₆ H ₄ ), 2.32 (s, 3H, CH ₃ ).

Example 7

Preparation of Trifloxystrobin

0.25g (1.22mmol) m-trifluoromethylacetophenone, 4mL DMF, 0.133g (2.46mmol) sodium methoxide, stirred at room temperature for 15min, cooled to 5°C, added 0.422g (1.47mmol) (E)-2-bromomethyl Methyl-α-methoxyiminophenylacetic acid methyl ester, reacted at room temperature for 5h, poured into ice water, extracted with ethyl acetate, washed with dilute hydrochloric acid, washed with water, separated by column chromatography (PE:EA=20:1) to obtain 0.375g oxime Strostrobin, yield 70%. ¹ H NMR (400MHz, CDCl ₃ ) δ: 7.90～7.15 (m, 8H, 2×C ₆ H ₄ ), 5.15 (s, 2H, CH ₂ ), 4.03 (s, 3H, NOCH ₃ ), 3.82 (s , 3H, OCH ₃ ), 2.22 (s, 3H, CH ₃ ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ: 163.34, 153.66, 149.58, 137.23, 135.99, 129.84, 129.42, 129.28, 128.83, 128.80, 128.56 , 127.79, 125.65, 125.61, 122.91, 122.87, 74.94, 63.81, 52.90, 12.54.

Claims (2)

1. a preparation method of 2-methyl-alpha-methoxyiminophenylacetamide shown in chemical structural formula I; It is characterized in that its preparation reaction is as follows: Wherein, R is selected from: C ₂ -C ₅ straight-chain alkyl or C ₃ -C ₅ branched-chain alkyl; The preparation operation process of 2-methyl-alpha-methoxyiminophenylacetamide is as follows: 12mmol sodium hydroxide and 10mL methanol were stirred and dissolved at 40°C, and 5mmol o-tolueneacetonitrile and 7.5mmol tert-butyl nitrite were reacted at 60°C for 1 hour; after post-treatment, 2-methyl-α-hydroxyiminophenylacetonitrile was obtained , the yield is 100%; 4mmol 2-methyl-α-hydroxyiminophenylacetonitrile, 15mL acetonitrile and 8mmol KOH, stirred at 35-40°C for 0.5h, cooled to below 10°C, added dropwise 4.8mmol dimethyl sulfate, at 35°C After stirring for 3 hours, 0.626 g of 2-methyl-α-methoxyiminophenylacetonitrile was obtained after post-processing, with a yield of 90%; In 5mmol 2-methyl-α-methoxyiminophenylacetonitrile and 5mL ethanol, add 5mmol 20% potassium hydroxide solution, react at 60°C for 3h, and obtain 0.900g single-configuration (E)- 2-Methyl-α-methoxyiminophenylacetamide, the yield is 92.5%, and the melting point is 123-125°C. 2. A preparation method of trifloxystrobin; It is characterized in that its preparation reaction is as follows: Among them, R is selected from: C ₂ ~ C ₅ straight chain alkyl or C ₃ ~ C ₅ branched chain alkyl; in the bromination reaction, the bromination agent is NBS or 1,3-dibromo-5,5-dimethyl Gene Hein.