阅读说明：本技术 一种制备氯氟醚菌唑中间体的方法 (Method for preparing chlorofluoromethrizole intermediate ) 是由 谭徐林 李生学 王志会 焦体 李星强 于 2020-05-21 设计创作，主要内容包括：本发明涉及杀菌剂氯氟醚菌唑的制备技术,公开了一种制备式(I)所示的化合物的方法,该方法包括：在极性非质子溶剂和碱性物质存在下,将式(II)所示的化合物与对氯苯酚进行接触反应。本发明制备式(I)所示的化合物的工艺中避免使用格氏试剂和重金属催化剂,有效降低原材料的成本,减少工艺过程中产生的三废,同时产物收率高。(The invention relates to a preparation technology of a bactericide of chlorofluoroether ipconazole, and discloses a method for preparing a compound shown as a formula (I), which comprises the following steps: the compound shown in the formula (II) and parachlorophenol are subjected to contact reaction in the presence of a polar aprotic solvent and a basic substance. The process for preparing the compound shown in the formula (I) avoids using a Grignard reagent and a heavy metal catalyst, effectively reduces the cost of raw materials, reduces three wastes generated in the process, and has high product yield.)

1. A process for preparing a compound of formula (I), comprising:

in the presence of polar aprotic solvent and alkaline substance, the compound shown in the formula (II) and parachlorophenol are subjected to contact reaction,

2. the process according to claim 1, wherein, in the contact reaction, the compound represented by the formula (II) is used in a molar ratio of the basic substance to the p-chlorophenol of 1: 0.8-2: 0.8-2.

3. The process according to claim 1, wherein, in the contact reaction, the compound represented by the formula (II) is used in a molar ratio of the basic substance to the p-chlorophenol of 1: 0.9-1.2: 0.9-1.2.

4. The method according to any one of claims 1 to 3, wherein the basic substance is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

5. The process according to any one of claims 1 to 4, wherein the polar aprotic solvent is selected from at least one of acetonitrile, dioxane, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide and N-methylpyrrolidone.

6. The method of any one of claims 1-5, wherein the conditions of the contact reaction comprise: the temperature is 80-210 ℃ and the time is 3-20 h.

7. The method of claim 6, wherein the conditions of the contact reaction comprise: the temperature is 100-160 ℃, and the time is 5-13 h.

8. The method of any one of claims 1-7, wherein the contacting comprises:

(a) mixing and heating the polar aprotic solvent, the alkaline substance, and the p-chlorophenol to obtain a mixed material I with a temperature of 80 ℃ or higher;

(b) mixing the mixed material I and the compound shown in the formula (II) and heating to be more than 100 ℃.

9. The method of any one of claims 1-8, wherein the method further comprises: and (3) carrying out solvent removal treatment on the material obtained after the contact reaction to obtain a mixed material II, and carrying out purification treatment on the mixed material II to obtain the refined compound shown in the formula (I).

10. The method of claim 9, wherein the purifying process comprises: extracting, washing and separating the mixed material II in sequence;

preferably, the extractant in the extraction process is an ether solvent, and preferably, the ether solvent is methyl tert-butyl ether;

preferably, the detergent in the washing process is water or an alkaline aqueous solution.

Technical Field

The invention relates to a preparation technology of a bactericide of chlorofluoromethane, in particular to a method for preparing a chlorofluoromethane intermediate.

Background

Chlorofloxacin (common name: Mefentrifluconazole) is a newly developed triazole fungicide with epoch-making significance by Pasteur, and is officially marketed in 2019, and the market in the future is expected to exceed $ 10 million per year. The cloroxen difenoconazole has the functions of broad spectrum, high efficiency, systemic absorption, eradication, protection and the like, particularly has excellent biological activity on various fungal diseases which are difficult to control, can obviously enhance the control of more than 60 crop diseases, such as field crops of corn, grain, soybean and the like, economic crops of green pepper, grape and the like, and can also be used for treating lawns, seeds and the like. It has high bioactivity, good environmental properties, low toxicity to mammals and bees, and high safety.

The 4- (4-chlorophenoxy) -2-trifluoromethyl acetophenone is a key intermediate for synthesizing the chlorofluoromethrin, and the chlorofluoromethrin is prepared through epoxidation and ring-opening substitution reaction, and has simple process and high yield. The prior art for producing 4- (4-chlorophenoxy) -2-trifluoromethylacetophenone is mostly referred to the technology disclosed in the prior art CN 103649057A. Preparing a Grignard reagent in a tetrahydrofuran solution by taking 2-bromo-4-fluoro-benzotrifluoride as a raw material, dropwise adding acetyl chloride, preparing 4-fluoro-2-trifluoromethylacetophenone by processes of extraction, washing and the like after the reaction is finished, and then reacting with parachlorophenol to synthesize the 4- (4-chlorophenoxy) -2-trifluoromethylacetophenone.

In the preparation process of the 4-fluoro-2-trifluoromethyl acetophenone, a Grignard reaction is needed, the conditions are harsh, and a large amount of magnesium-containing wastewater is generated after the reaction and is difficult to treat.

In addition, WO2019/016115a1 discloses that when 4- (4-chlorophenoxy) -2-trifluoromethyl acetophenone is synthesized by etherification reaction, the catalyst is not only required to be applied to palladium noble metal catalysts, and has large waste acid amount, high industrial cost and low product yield.

Therefore, the existing method has the defects of large amount of three wastes, bad production environment, high cost and the like when preparing the 4-p-chlorophenoxy acetophenone compounds.

Disclosure of Invention

The invention aims to solve the problems of large amount of three wastes, high cost and the like in the preparation of 4- (4-chlorophenoxy) -2-trifluoromethyl acetophenone in the prior art.

In order to achieve the above object, the present invention provides a method for preparing a compound represented by formula (I), which comprises: in the presence of polar aprotic solvent and alkaline substance, the compound shown in the formula (II) and parachlorophenol are subjected to contact reaction,

in the present invention, the compound represented by the formula (II) can be synthesized by a method known in the art, or can be commercially available.

In the present invention, in the contact reaction, the compound represented by the formula (II) and the basic substance and the p-chlorophenol are used in a molar ratio of 1: 0.8-2: 0.8-2. Preferably, in the contact reaction, the molar ratio of the compound represented by the formula (II) to the basic substance and the p-chlorophenol is 1: 0.9-1.2: 0.9-1.2.

Preferably, the basic substance is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. More preferably, the alkaline substance is sodium hydroxide, potassium hydroxide or potassium carbonate. The inventors have found that in this preferred embodiment, the scheme of the present invention has the advantage of further increasing the yield of the compound of formula (I).

In the present invention, the polar aprotic solvent is at least one selected from the group consisting of acetonitrile, dioxane, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, and N-methylpyrrolidone. Preferably, the polar aprotic solvent is N, N-dimethylformamide. The inventors have found that in this preferred embodiment, the solution of the invention has the advantage of further increasing the reaction rate of the contact reaction.

In the present invention, preferably, the conditions of the contact reaction include: the temperature is from 80 ℃ to 210 ℃, and may be, for example, any value in the range of 80 ℃, 100 ℃, 120 ℃, 140 ℃, 160 ℃, 180 ℃, 200 ℃, 210 ℃ and any two of these values, preferably 100 ℃ to 160 ℃; the time is 3 to 20 hours, and may be, for example, 3 hours, 5 hours, 7 hours, 9 hours, 11 hours, 13 hours, 15 hours, 17 hours, 20 hours, or any value in the range of any two of these points, and preferably 5 to 13 hours. The inventors have found that, in this preferred embodiment, the contact reaction of the compound represented by the formula (II) with p-chlorophenol proceeds more easily.

In the present invention, the contact reaction may be a reaction in which the polar aprotic solvent, the basic substance, the compound represented by formula (II), and the p-chlorophenol are mixed so that the compound represented by formula (II) and the p-chlorophenol can contact each other.

Preferably, the process of the contact reaction comprises: (a) mixing and heating the polar aprotic solvent, the alkaline substance, and the p-chlorophenol to obtain a mixed material I with a temperature of 80 ℃ or higher; (b) mixing the mixed material I and the compound shown in the formula (II) and heating to be more than 100 ℃. The inventors found that, in the preferred embodiment, there are advantages in further increasing the reaction rate of the contact reaction and increasing the conversion rate and yield of the contact reaction.

In the present invention, the process for preparing the compound represented by the formula (I) further comprises: and (3) carrying out solvent removal treatment on the material obtained after the contact reaction to obtain a mixed material II, and carrying out purification treatment on the mixed material II to obtain the refined compound shown in the formula (I). Illustratively, the solvent removal treatment removes the polar aprotic solvent from the material obtained after the contact reaction by distillation to obtain the mixed material II.

Preferably, the purification treatment comprises: extracting, washing and separating the mixed material II in sequence; the extractant in the extraction process is preferably an ether solvent, the ether solvent can be isopropyl ether, methyl tert-butyl ether or n-butyl ether, and the ether solvent is preferably methyl tert-butyl ether; the detergent in the washing process is preferably water or an aqueous alkaline solution.

Illustratively, the purification treatment process comprises the steps of mixing the mixed material II with an extracting agent and a washing agent, layering to obtain an organic layer containing the compound shown in the formula (I), and removing the extracting agent from the organic layer to obtain the refined compound shown in the formula (I). The inventors have found that in this preferred embodiment, the scheme of the invention has the advantage of further improving the purity of the compound of formula (I).

Through the technical scheme, the process for preparing the compound shown in the formula (I) avoids using a Grignard reagent and a heavy metal catalyst, effectively reduces the cost of raw materials, reduces three wastes generated in the process, and has high product yield.

Detailed Description

The following describes in detail specific embodiments of the present invention. It should be understood that the description herein of specific embodiments is only for purposes of illustration and understanding and is not intended to limit the invention.

The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.

The present invention will be described in detail below by way of examples. In the following examples:

the amounts of reactants and products were determined by liquid chromatography (Agilent HPLC 1260).

The conversion and selectivity of the reaction are calculated by the following formulas:

conversion rate (molar amount of raw material charged-molar amount of raw material remaining in the product)/molar amount of raw material charged × 100%.

Selectivity ═ actual molar amount of target product/theoretical molar amount of target product × 100%

In the case where no particular mention is made, the starting materials used are commercially available products, and the content of the compound represented by the formula (I) means the mass percentage of the compound represented by the formula (I) in the final product.

Example 1

(1) Adding 0.11mol of 98 wt% of p-chlorophenol and 150mL of N, N-dimethylformamide into a four-mouth bottle provided with a mechanical stirrer, a thermometer and a condenser, adding 0.12mol of 99 wt% of solid sodium hydroxide, heating to 120 ℃, stirring and reacting for 3 hours, and continuously evaporating water generated by the reaction to obtain a mixed material I;

(2) slightly cooling the mixed material I obtained in the step (1), adding 0.1mol of 98 wt% of a compound shown as a formula (II), heating to 115 ℃, continuing to react for 5 hours, and monitoring the completion of the reaction by using HPLC to obtain a reaction material;

(3) distilling off N, N-dimethylformamide from the reaction material obtained in the step (2), adding methyl tert-butyl ether, washing with water, layering to obtain an organic layer containing the compound shown in the formula (I), and removing the methyl tert-butyl ether from the organic layer to obtain the refined compound shown in the formula (I) (namely 4- (4-chlorophenoxy) -2-trifluoromethylacetophenone), wherein the content of the refined compound is 98 percent, and the yield is 96 percent (calculated by taking the compound shown in the formula (II) as a reference).

Example 2

(1) Adding 0.12mol of 98 wt% of p-chlorophenol and 150mL of N, N-dimethylformamide into a four-mouth bottle provided with a mechanical stirrer, a thermometer and a condenser, adding 0.11mol of 99 wt% of solid sodium hydroxide, heating to 110 ℃, stirring and reacting for 4 hours, and continuously evaporating water generated by the reaction to obtain a mixed material I;

(2) slightly cooling the mixed material I obtained in the step (1), adding 0.1mol of 98 wt% of a compound shown as a formula (II), heating to 105 ℃, continuing to react for 7 hours, and monitoring the completion of the reaction by using HPLC to obtain a reaction material;

(3) distilling off N, N-dimethylformamide from the reaction material obtained in the step (2), adding methyl tert-butyl ether, washing with water for layering to obtain an organic layer containing the compound shown in the formula (I), and removing the methyl tert-butyl ether from the organic layer to obtain the refined compound shown in the formula (I) (namely 4- (4-chlorophenoxy) -2-trifluoromethylacetophenone), wherein the content of the compound is 97.8 percent, and the yield is 95.6 percent (calculated by taking the compound shown in the formula (II) as a reference).

Example 3

(1) Adding 0.11mol of 98 wt% of p-chlorophenol and 150mL of N, N-dimethylformamide into a four-mouth bottle provided with a mechanical stirrer, a thermometer and a condenser, adding 0.09mol of 99 wt% of solid sodium hydroxide, heating to 155 ℃, stirring for reaction for 2 hours, and continuously evaporating water generated by the reaction to obtain a mixed material I;

(2) slightly cooling the mixed material I obtained in the step (1), adding 0.1mol of 98 wt% of a compound shown as a formula (II), heating to 140 ℃, continuing to react for 6 hours, and monitoring the completion of the reaction by using HPLC to obtain a reaction material;

(3) distilling off N, N-dimethylformamide from the reaction material obtained in the step (2), adding methyl tert-butyl ether, washing with water, layering to obtain an organic layer containing the compound shown in the formula (I), and removing the methyl tert-butyl ether from the organic layer to obtain the refined compound shown in the formula (I) (namely 4- (4-chlorophenoxy) -2-trifluoromethylacetophenone), wherein the content of the compound is 97.2 percent, and the yield is 95 percent (calculated by taking the compound shown in the formula (II) as a reference).

Example 4

(1) Adding 0.11mol of 98 wt% of p-chlorophenol and 150mL of N, N-dimethylformamide into a four-mouth bottle provided with a mechanical stirrer, a thermometer and a condenser, adding 0.12mol of 99 wt% of solid sodium hydroxide, heating to 90 ℃, stirring and reacting for 6 hours, and continuously evaporating water generated by the reaction to obtain a mixed material I;

(2) slightly cooling the mixed material I obtained in the step (1), adding 0.1mol of 98 wt% of a compound shown as a formula (II), heating to 100 ℃, continuing to react for 12 hours, and monitoring the completion of the reaction by using HPLC to obtain a reaction material;

(3) distilling off N, N-dimethylformamide from the reaction material obtained in the step (2), adding methyl tert-butyl ether, washing with water, layering to obtain an organic layer containing the compound shown in the formula (I), and removing the methyl tert-butyl ether from the organic layer to obtain the refined compound shown in the formula (I) (namely 4- (4-chlorophenoxy) -2-trifluoromethylacetophenone), wherein the content of the compound is 97 percent, and the yield is 94.7 percent (calculated by taking the compound shown in the formula (II) as a reference).

Example 5

(1) Adding 0.11mol of 98 wt% of p-chlorophenol and 150mL of N, N-dimethylformamide into a four-mouth bottle provided with a mechanical stirrer, a thermometer and a condenser, adding 0.12mol of 99 wt% of solid sodium hydroxide, heating to 200 ℃, stirring for reacting for 2 hours, and continuously evaporating water generated by the reaction to obtain a mixed material I;

(2) slightly cooling the mixed material I obtained in the step (1), adding 0.1mol of 98 wt% of a compound shown as a formula (II), heating to 190 ℃, continuing to react for 2 hours, and monitoring the completion of the reaction by using HPLC to obtain a reaction material;

(3) distilling off N, N-dimethylformamide from the reaction material obtained in the step (2), adding isopropyl ether, washing with water for layering to obtain an organic layer containing the compound shown in the formula (I), and removing the isopropyl ether from the organic layer to obtain the purified compound shown in the formula (I) (namely 4- (4-chlorophenoxy) -2-trifluoromethylacetophenone), wherein the content of the compound is 96.8 percent, and the yield is 94.4 percent (calculated by taking the compound shown in the formula (II) as a reference).

The results of the above examples show that the process for preparing 4- (4-chlorophenoxy) -2-trifluoromethylacetophenone (i.e., the compound shown in formula (I)) of the present invention can achieve the advantage of high product yield without using grignard reagents and heavy metal catalysts, and at the same time, can effectively reduce the cost of raw materials and reduce three wastes generated during the process.

The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.