阅读说明：本技术 一种啶酰菌胺中间体2-(4’-氯苯基)苯胺的合成方法 (Synthetic method of boscalid intermediate 2- (4' -chlorphenyl) aniline ) 是由 王世银 雷进海 谭永清 黄卫荣 彭军 陈锐东 覃建海 于 2020-06-08 设计创作，主要内容包括：本发明公开了一种啶酰菌胺中间体2-(4’-氯苯基)苯胺的合成方法,属于农药中间体合成的技术领域。本发明以9-芴酮为起始原料,经过开环、氯化、酰氯化、氨化以及霍夫曼降解反应制得2-(4’-氯苯基)苯胺,该制备方法避免了昂贵金属催化剂的使用,起始原料廉价易得,具有反应操作简单和收率高的特点,在工业生产上具有较高的价值。(The invention discloses a method for synthesizing boscalid intermediate 2- (4' -chlorphenyl) aniline, belonging to the technical field of pesticide intermediate synthesis. The preparation method of the 2- (4' -chlorphenyl) aniline, which takes the 9-fluorenone as a starting material and carries out ring opening, chlorination, acyl chlorination, ammoniation and Hofmann degradation reaction, avoids the use of expensive metal catalysts, has the characteristics of cheap and easily obtained starting materials, simple reaction operation and high yield, and has higher value in industrial production.)

1. A synthetic method of a boscalid intermediate, which is characterized in that the boscalid intermediate is 2- (4' -chlorophenyl) aniline, and comprises the following steps: in a solvent, 2- (4 '-chlorphenyl) benzamide undergoes Hofmann degradation reaction in the presence of alkali and hypohalite to obtain 2- (4' -chlorphenyl) aniline.

2. The synthesis method according to claim 1, wherein in the Hofmann degradation reaction, the molar ratio of the 2- (4 '-chlorophenyl) benzamide to the base to the hypohalite is 2- (4' -chlorophenyl) benzamide: alkali: hypohalite ═ 1: 2-10: 2.5 to 10.

3. The synthesis method according to claim 1, wherein in the Hofmann degradation reaction, the hypohalite is at least one of hypobromite and hypochlorite, the base is an inorganic base, and the solvent is at least one of water, methanol, ethanol, n-butanol, tetrahydrofuran, dioxane, DMF and acetonitrile.

4. The method of synthesis according to any one of claims 1 to 3, characterized in that the method of synthesis of 2- (4' -chlorophenyl) benzamide comprises the following steps: carrying out acyl chlorination on 2- (4 '-chlorphenyl) benzoic acid in a solvent in the presence of an acyl chlorination reagent to obtain a reaction solution after the reaction is finished, and adding the reaction solution into an ammoniation reagent to carry out ammoniation reaction to obtain the 2- (4' -chlorphenyl) benzamide.

5. The synthesis method according to claim 4, wherein in the acyl chlorination reaction, the molar ratio of the 2- (4 '-chlorophenyl) benzoic acid to the acyl chlorination reagent is 2- (4' -chlorophenyl) benzoic acid: acyl chloride reagent ═ 1: 1-2; in the ammoniation reaction, the molar ratio of the 2- (4 '-chlorphenyl) benzoic acid to the ammoniation reagent is 2- (4' -chlorphenyl) benzoic acid: ammoniation reagent 1: 4-15.

6. The synthesis method according to claim 4, wherein in the acyl chlorination reaction, the solvent is at least one of toluene, tetrahydrofuran, dichloromethane and dichloroethane, and the acyl chlorination reagent is thionyl chloride; in the ammoniation reaction, an ammoniation reagent is ammonia water.

7. The method of synthesizing according to claim 4, wherein said method of synthesizing 2- (4' -chlorophenyl) benzoic acid comprises the steps of: in a solvent, 2-phenylbenzoic acid is subjected to chlorination reaction in the presence of a chlorination reagent to obtain the 2- (4' -chlorphenyl) benzoic acid.

8. The synthesis method according to claim 7, wherein in the chlorination reaction, the solvent is at least one of dichloroethane, tetrahydrofuran, 1, 4-dioxane and acetonitrile, the chlorinating reagent is at least one of sulfuryl chloride, chlorine and N-chlorosuccinimide, and the reaction temperature is-10 ℃ to 80 ℃.

9. The method of synthesizing as claimed in claim 7, wherein the method of synthesizing 2-phenylbenzoic acid comprises the steps of: in a solvent, carrying out a ring-opening reaction on 9-fluorenone in the presence of alkali, adding water after the reaction is finished to obtain a water phase, and acidifying the water phase by adopting acid to separate out a solid to obtain the 2-phenylbenzoic acid.

10. The synthesis method according to claim 9, wherein in the ring-opening reaction, the solvent is at least one of toluene, xylene, diphenyl ether, dimethyl sulfoxide, tetrahydrofuran and dichloromethane, the base is at least one of sodium hydroxide, potassium hydroxide, barium hydroxide, potassium tert-butoxide and sodium tert-butoxide, and the molar ratio of 9-fluorenone to base is 9-fluorenone: base 1: 3-20 ℃ and the reaction temperature is 25-150 ℃.

Technical Field

The invention belongs to the technical field of pesticide intermediate synthesis, and particularly relates to a synthetic method of boscalid intermediate 2- (4' -chlorphenyl) aniline.

Background

2- (4' -chlorophenyl) aniline is an important intermediate for the manufacture of boscalid. Boscalid is a novel systemic fungicide of nicotinamide developed by basf company in germany, is a succinate coenzyme Q reductase inhibitor in mitochondrial respiratory chain, is mainly used for preventing and treating powdery mildew, gray mold, sclerotinia, brown rot, root rot and other diseases, and can be used for preventing and treating diseases related to crops such as rape, grapes, fruit trees, tomatoes, vegetables, field crops and the like. The bactericide has a special action mechanism, has no cross resistance with other medicines, is safe to crops, cannot damage ecology, is an important novel bactericide, and has great market potential. The countries where boscalid was first registered worldwide in 2004 are uk, germany and switzerland.

The method for synthesizing boscalid intermediate 2- (4' -chlorophenyl) aniline is reported as follows: taking p-chlorobenzene boric acid and o-chloronitrobenzene as raw materials, and performing Suzuki reaction in a solution of N, N-dimethylacetamide and water by taking palladium-carbon as a catalyst and potassium carbonate as a cocatalyst to obtain 2- (4' -chlorphenyl) nitrobenzene; and then, reducing in an ethanol solution by taking zinc powder or iron powder as a reducing agent under reflux to obtain the key intermediate 2- (4' -chlorphenyl) aniline of the novel bactericide boscalid. It has also been reported that p-chloroaniline or aniline is used as a raw material, the p-chloroaniline is reacted with aniline in the presence of water and hydrochloric acid under the action of sodium nitrite to form a diazonium salt, and then the p-chloroaniline is reacted with aniline in the presence of water, tetrahydrofuran, DMF or a mixed solvent thereof as a solvent under an alkaline condition to produce a Gonberg-Bakmann reaction.

Therefore, there is a need to research a process for synthesizing 2- (4' -chlorophenyl) aniline, which has the advantages of simple process, low cost, cleanness and environmental protection.

Disclosure of Invention

In order to solve the defects and shortcomings in the prior art, the invention aims to provide a synthetic method of boscalid intermediate 2- (4' -chlorophenyl) aniline.

The invention provides a method for synthesizing boscalid intermediate 2- (4' -chlorphenyl) aniline, which comprises the following steps: in a solvent, 2- (4 '-chlorphenyl) benzamide undergoes Hofmann degradation reaction in the presence of alkali and hypohalite to obtain 2- (4' -chlorphenyl) aniline.

The synthesis method can obtain the target product 2- (4 '-chlorphenyl) aniline through one-step reaction without using expensive catalysts, has simple process, and has high yield of the 2- (4' -chlorphenyl) aniline, which is more than 80%.

Preferably, in the hofmann degradation reaction, the molar ratio of the 2- (4 '-chlorophenyl) benzamide to the base to the hypohalite is 2- (4' -chlorophenyl) benzamide: alkali: hypohalite ═ 1: 2-10: 2.5 to 10.

The amount of the solvent used in the hofmann degradation reaction can be adjusted according to actual needs, and the ratio of the 2- (4 '-chlorophenyl) benzamide to the solvent is preferably 2- (4' -chlorophenyl) benzamide: solvent 1 mol: 2000 and 4000 mL.

Preferably, the Hofmann degradation reaction is performed for 0.3 to 1 hour at 0 to 5 ℃ and then for 2 to 6 hours at 45 to 55 ℃, under the specific conditions, the yield of the 2- (4' -chlorophenyl) aniline is higher.

Preferably, in the hofmann degradation reaction, the hypohalite is at least one of hypobromite and hypochlorite. Wherein, the hypobromite is preferably at least one of sodium hypobromite and potassium hypobromite, and the hypochlorite is preferably at least one of sodium hypochlorite and potassium hypochlorite.

Preferably, in the hofmann degradation reaction, the base is an inorganic base. Wherein the inorganic base can be sodium hydroxide, potassium hydroxide, etc., and any combination thereof.

Preferably, in the hofmann degradation reaction, the solvent is at least one of water, methanol, ethanol, n-butanol, tetrahydrofuran, dioxane, DMF and acetonitrile.

Preferably, the hypohalite is a hypohalite solution, and the hypohalite solution is added dropwise to the 2- (4' -chlorophenyl) benzamide.

Preferably, the hypohalite solution is added dropwise at a temperature of 0 ℃ or lower.

After the hofmann degradation reaction is finished, for example, the hofmann degradation reaction can be quenched with saturated salt solution, and then the target product is extracted by using an organic solvent, and if the solvent used in the reaction is an organic reagent, the solvent can be partially or completely removed before the extraction. Among them, saturated salt solutions include saturated sodium sulfite solutions, saturated potassium sulfite solutions, and the like; examples of the organic solvent used for the extraction include toluene. The mass purity of the 2- (4' -chlorophenyl) aniline thus purified was 97% or more, and the yield was 80% or more.

Preferably, the synthesis method of the 2- (4' -chlorphenyl) benzamide comprises the following steps: carrying out acyl chlorination on 2- (4 '-chlorphenyl) benzoic acid in a solvent in the presence of an acyl chlorination reagent to obtain a reaction solution after the reaction is finished, and adding the reaction solution into an ammoniation reagent to carry out ammoniation reaction to obtain the 2- (4' -chlorphenyl) benzamide. The method for synthesizing the 2- (4 '-chlorphenyl) benzamide has simple process, does not need a catalyst, and has high yield of the obtained 2- (4' -chlorphenyl) benzamide, which is more than 85 percent.

Preferably, in the acyl chlorination reaction, the molar ratio of the 2- (4 '-chlorophenyl) benzoic acid to the acyl chlorinating reagent is 2- (4' -chlorophenyl) benzoic acid: acyl chloride reagent ═ 1: 1-2; in the ammonification reaction, the molar ratio of the 2- (4 '-chlorophenyl) benzoic acid to the ammonification reagent is 2- (4' -chlorophenyl) benzoic acid: ammoniation reagent 1: 4-15.

More preferably, in the acyl chlorination reaction, the molar ratio of the 2- (4 '-chlorophenyl) benzoic acid to the acyl chlorinating reagent is 2- (4' -chlorophenyl) benzoic acid: acyl chloride reagent ═ 1: 1.05 to 1.2; in the ammonification reaction, the molar ratio of the 2- (4 '-chlorophenyl) benzoic acid to the ammonification reagent is 2- (4' -chlorophenyl) benzoic acid: ammoniation reagent 1: 5 to 8.

Preferably, in the acyl chlorination reaction, the ratio of the 2- (4 '-chlorophenyl) benzoic acid to the solvent is 2- (4' -chlorophenyl) benzoic acid: solvent 1 mol: 900-1100 mL.

Preferably, in the acyl chlorination reaction, the solvent is at least one of toluene, tetrahydrofuran, dichloromethane and dichloroethane.

Preferably, in the above-mentioned acid chlorination reaction, the acid chlorination reagent is thionyl chloride.

Preferably, the acyl chloride reagent is added dropwise to the 2- (4' -chlorophenyl) benzoic acid.

Preferably, the above-described acid chlorination reaction is carried out at room temperature. The above-described acid chlorination reaction can be carried out at room temperature, e.g., 25 ℃, without heating or cooling.

Preferably, the time of the acyl chlorination reaction is 3-5 h.

Preferably, in the amination reaction, the amination reagent is ammonia water. When the ammoniation reagent is ammonia water, the mass concentration of the ammonia in the ammonia water is preferably 10-30%.

Preferably, the amination is carried out at a temperature of 20 ℃ or less.

Preferably, the time of the amination reaction is 1.5 to 3 hours.

Preferably, the reaction solution obtained by the acyl chlorination reaction is added dropwise to the ammoniating reagent.

Preferably, the reaction solution obtained by the acylation reaction is added dropwise to the ammoniating reagent at a temperature of 0 ℃ or lower.

Preferably, the synthesis method of the 2- (4' -chlorphenyl) benzoic acid comprises the following steps: in a solvent, 2-phenylbenzoic acid is subjected to chlorination reaction in the presence of a chlorination reagent to obtain the 2- (4' -chlorphenyl) benzoic acid. The synthesis method of the 2- (4 '-chlorphenyl) benzoic acid does not need to use a catalyst, is simple, and has high yield of the obtained 2- (4' -chlorphenyl) benzoic acid, which is more than 95%.

Preferably, in the chlorination reaction, the molar ratio of the 2-phenylbenzoic acid to the chlorinating reagent is 2-phenylbenzoic acid: the chlorinating reagent is 1: 10-20.

Preferably, in the chlorination reaction, the ratio of the 2-phenylbenzoic acid to the solvent is 2-phenylbenzoic acid: solvent 1 mol: 900-.

Preferably, in the chlorination reaction, the solvent used is at least one of dichloroethane, tetrahydrofuran, 1, 4-dioxane, and acetonitrile.

Preferably, in the chlorination reaction, the chlorinating reagent is at least one of sulfuryl chloride, chlorine and N-chlorosuccinimide,

preferably, the temperature of the chlorination reaction is-10 ℃ to 80 ℃.

Preferably, the time of the chlorination reaction is 3-6 h.

Preferably, the chlorinating agent is added dropwise to the 2-phenylbenzoic acid.

Preferably, the synthesis method of the 2-phenylbenzoic acid comprises the following steps: in a solvent, carrying out a ring-opening reaction on 9-fluorenone in the presence of alkali, adding water after the reaction is finished to obtain a water phase, and acidifying the water phase by adopting acid to separate out a solid to obtain the 2-phenylbenzoic acid. The method for synthesizing the 2-phenylbenzoic acid does not need a catalyst, and the yield of the 2-phenylbenzoic acid is high and is over 95 percent.

Preferably, in the ring-opening reaction, the molar ratio of 9-fluorenone to base is 9-fluorenone: base 1: 3 to 20.

Preferably, in the ring-opening reaction, the ratio of 9-fluorenone to solvent is 9-fluorenone: solvent 1 mol: 3000 and 4000 mL.

Preferably, in the ring-opening reaction, the solvent used is at least one of toluene, xylene, diphenyl ether, dimethyl sulfoxide, tetrahydrofuran and dichloromethane.

Preferably, the base used in the ring-opening reaction is at least one of sodium hydroxide, potassium hydroxide, barium hydroxide, potassium tert-butoxide, and sodium tert-butoxide.

Preferably, the ring-opening reaction is carried out at a temperature of 25 ℃ to 150 ℃.

Preferably, the ring-opening reaction is carried out for 1 to 12 hours.

Compared with the prior art, the invention has the following advantages: the synthetic method of boscalid intermediate 2- (4' -chlorphenyl) aniline does not need to use an expensive metal catalyst, is simple to operate, clean in process and high in yield, can also use cheap and easily-obtained 9-fluorenone as a starting material, is low in cost, and has high industrial production value.

Detailed Description

The invention is further illustrated by the following examples in order to better illustrate the objects, aspects and advantages of the invention. It is apparent that the following examples are only a part of the embodiments of the present invention, and not all of them. It should be understood that the embodiments of the present invention are only for illustrating the technical effects of the present invention, and are not intended to limit the scope of the present invention.