阅读说明：本技术 一种（4-异丙氧基-2-甲基）苯基异丙基酮的制备方法 (Preparation method of (4-isopropoxy-2-methyl) phenyl isopropyl ketone ) 是由 刘伟 吴少祥 高瑞 王瑞 王文军 于 2020-05-28 设计创作，主要内容包括：本发明涉及一种(4-异丙氧基-2-甲基)苯基异丙基酮的制备方法,所述制备方法具体包括：将间甲酚与硫氰酸盐在催化剂作用下反应,得到产物A；将所述产物A和卤代异丙烷在碱、催化剂作用下反应,得到产物B；将所述产物B与异丙基卤化镁反应,经处理后得到所述(4-异丙氧基-2-甲基)苯基异丙基酮。经过以上步骤制备得到的(4-异丙氧基-2-甲基)苯基异丙基酮纯度为99％以上,总收率为79％以上。本发明所述方法避免了有毒试剂的使用以及大量酸性废水的产生,降低了反应温度,提高了反应收率,工艺路线简单高效且降低成本,所得产品纯度高,大幅度提升生产安全性,易于工业化推广。(The invention relates to a preparation method of (4-isopropoxy-2-methyl) phenyl isopropyl ketone, which specifically comprises the following steps: m-cresol and thiocyanate react under the action of a catalyst to obtain a product A; reacting the product A with halogenated isopropane under the action of alkali and a catalyst to obtain a product B; and reacting the product B with isopropyl magnesium halide, and treating to obtain the (4-isopropoxy-2-methyl) phenyl isopropyl ketone. The purity of the (4-isopropoxy-2-methyl) phenyl isopropyl ketone prepared by the steps is more than 99%, and the total yield is more than 79%. The method avoids the use of toxic reagents and the generation of a large amount of acidic wastewater, reduces the reaction temperature, improves the reaction yield, has simple and efficient process route and reduces the cost, and the obtained product has high purity, greatly improves the production safety and is easy for industrialized popularization.)

1. A preparation method of (4-isopropoxy-2-methyl) phenyl isopropyl ketone is characterized by comprising the following steps:

(1) reacting m-cresol and thiocyanate under the action of a catalyst, filtering to obtain filtrate, recovering the catalyst, and concentrating and crystallizing the filtrate to obtain a product A;

(2) reacting the product A with halogenated isopropane under the action of alkali and a catalyst, filtering to obtain filtrate, and concentrating the filtrate to obtain a product B;

(3) reacting the product B with isopropyl magnesium halide to obtain a reaction mixture; acidifying the reaction mixture, standing and layering to obtain an organic phase; and (4-isopropoxy-2-methyl) phenyl isopropyl ketone is obtained by heating and reduced pressure distillation of the organic phase in sequence.

2. The method for preparing (4-isopropoxy-2-methyl) phenylisopropyl ketone according to claim 1, wherein in step (1), the catalyst is one or more of fuming sulfuric acid, methanesulfonyl chloride, chlorosulfonic acid, or sulfuryl chloride.

3. The process for preparing (4-isopropoxy-2-methyl) phenylisopropyl ketone according to claim 2, wherein the catalyst is attached to a silica or alumina support to form a solid catalyst that can be recycled.

4. The process for preparing (4-isopropoxy-2-methyl) phenylisopropyl ketone according to claim 1, wherein in step (1), the thiocyanate is KSCN, NaSCN, NH₄One or more of SCN; the reaction temperature is 50-120 ℃, and the reaction time is 8-16 h.

5. The process for preparing (4-isopropoxy-2-methyl) phenylisopropyl ketone according to claim 1, wherein in step (2), the base is one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, or sodium hydroxide.

6. The process for producing (4-isopropoxy-2-methyl) phenylisopropyl ketone according to claim 1, wherein in step (2), the catalyst is one or more selected from pyridine, 4-dimethylaminopyridine, DABCO, Me-DABCO and tetramethylammonium hydroxide.

7. The process for producing (4-isopropoxy-2-methyl) phenylisopropyl ketone according to claim 1, wherein in step (2), the halogenated isopropyl propane is one or more of chloroisopropyl, bromoisopropyl or iodoisopropyl; the reaction temperature is 25-80 ℃, and the reaction time is 1-10 hours.

8. The process for producing (4-isopropoxy-2-methyl) phenylisopropyl ketone according to claim 1, wherein in step (3), the isopropyl magnesium halide is one or more of isopropyl magnesium chloride, isopropyl magnesium bromide, or isopropyl magnesium iodide; the reaction temperature of the product B and isopropyl magnesium halide is 45-70 ℃, and the reaction time is 1-5 hours.

9. The process for producing (4-isopropoxy-2-methyl) phenylisopropyl ketone according to claim 1, wherein in step (3), the acidification is carried out by: dripping the reaction mixture at 15-40 deg.C into 5-36% hydrochloric acid, and stirring for 30-90 min.

10. The process for producing (4-isopropoxy-2-methyl) phenylisopropyl ketone according to claim 1, wherein in step (3), the heating temperature is 80 to 150 ℃; the temperature of the reduced pressure distillation is 134 ℃ and 138 ℃, and the pressure is 1-5 Torr.

Technical Field

The invention belongs to the field of organic chemistry, and particularly relates to a preparation method of (4-isopropoxy-2-methyl) phenyl isopropyl ketone.

Background

The target compound (4-isopropoxy-2-methyl) phenyl isopropyl ketone (formula IV) is an intermediate of the bactericide isofamid. Isofenamid is the latest succinate dehydrogenase inhibitor (SDHI) broad-spectrum bactericide developed from stone sources, has the functions of protection, systemic absorption and treatment, can generate adverse effects on plant and fungal respiration, is used for preventing and treating leaf surface and soil-borne diseases, and is used for preventing and treating various diseases caused by botrytis and sclerotinia on crops such as grapes, lettuce, rape, dwarf berries, turf and the like.

WO2006016708 discloses a chemical synthesis method of (4-hydroxy-2-methyl) phenylisopropyl ketone of intermediate formula (v), the reaction process is as follows:

the method takes m-cresol and isobutyryl chloride shown in formula (I) as raw materials, aluminum trichloride as a catalyst and carbon disulfide as a solvent, and the intermediate shown in formula (V) is obtained through mixing reaction and post-treatment. The intermediate formula (V) can react with halogenated isopropane to obtain a product formula (IV). In the process of synthesizing the intermediate formula (V), the selectivity of the reaction is poor, the yield is low, a large amount of acidic wastewater can be generated in the reaction, the environment is not friendly, and the pure product of the formula (V) is obtained through column chromatography, so that the industrial production is not facilitated.

In view of the prior art, the synthesis of formula (V) by Friedel-crafts acylation reaction and the synthesis of formula (IV) by etherification has the problems of low yield, large amount of three wastes and high cost, and the development of a novel synthesis method which is suitable for industrial application, simple, low in cost, high in yield and environment-friendly, thereby overcoming the defects of the prior art.

Disclosure of Invention

In order to solve the problems in the prior art, the invention provides a simple, effective, easy-to-operate and environment-friendly preparation method of (4-isopropoxy-2-methyl) phenyl isopropyl ketone. The purity of (4-isopropoxy-2-methyl) phenyl isopropyl ketone prepared by the method is more than 99%, and the yield is more than 79% based on m-cresol.

The technical scheme adopted by the invention is as follows:

a preparation method of (4-isopropoxy-2-methyl) phenyl isopropyl ketone comprises the following steps:

(1) reacting m-cresol and thiocyanate under the action of a catalyst, filtering to obtain filtrate, recovering the catalyst, and concentrating and crystallizing the filtrate to obtain a product A;

(2) reacting the product A with halogenated isopropane under the action of alkali and a catalyst, filtering to obtain filtrate, and concentrating the filtrate to obtain a product B;

(3) reacting the product B with isopropyl magnesium halide to obtain a reaction mixture; acidifying the reaction mixture, standing and layering to obtain an organic phase; and (4-isopropoxy-2-methyl) phenyl isopropyl ketone is obtained by heating and reduced pressure distillation of the organic phase in sequence.

Further, in the step (1), the catalyst is one or more of fuming sulfuric acid, methanesulfonyl chloride, chlorosulfonic acid or sulfuryl chloride.

Further, the catalyst is attached to a silica or aluminum trioxide carrier to form a solid catalyst which can be recycled.

Further, the catalyst is silica-supported chlorosulfonic acid or silica-supported sulfonyl chloride.

Further, in the step (1), the sulfurCyanate is KSCN, NaSCN, NH₄One or more of SCN.

Further, the thiocyanate is KSCN.

Further, in the step (1), the reaction temperature is 50-120 ℃, and the reaction time is 8-16 h.

Further, in the step (2), the alkali is one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide or sodium hydroxide.

Further, the base is potassium carbonate.

Further, in the step (2), the catalyst is one or more of pyridine, 4-dimethylaminopyridine, DABCO (chemical name: 1,4-Diazabicyclo [2.2.2] octane; alias: triethylene diamine, English name: 1,4-Diazabicyclo [2.2.2] octane; triethylene diamine), Me-DABCO (chemical name: 2-methyl-1, 4-Diazabicyclo [2.2.2] octane) or tetramethylammonium hydroxide.

Further, the catalyst is tetramethylammonium hydroxide.

Further, in the step (2), the halogenated isopropane is one or more of chlorinated isopropane, brominated isopropane or iodoisopropane.

Further, the halogenated isopropane is chlorinated isopropane.

Further, in the step (2), the reaction temperature is 25-80 ℃, and the reaction time is 1-10 hours.

Further, in the step (3), the isopropyl magnesium halide is one or more of isopropyl magnesium chloride, isopropyl magnesium bromide or isopropyl magnesium iodide.

Further, isopropyl magnesium halide is isopropyl magnesium chloride.

Further, the reaction temperature of the product B and isopropyl magnesium halide is 45-70 ℃, and the reaction time is 1-5 hours.

Further, in the step (3), the specific operation of acidification is as follows: dripping the reaction mixture at 15-40 deg.C into 5-36% hydrochloric acid, and stirring for 30-90 min.

Further, in the step (3), the heating temperature is 80-150 ℃; the temperature of the reduced pressure distillation is 134 ℃ and 138 ℃, and the pressure is 1-5 Torr.

The following are the structures of the compounds involved in the preparation process of the present invention:

the invention has the beneficial effects that:

the preparation method of (4-isopropoxy-2-methyl) phenyl isopropyl ketone specifically comprises the following steps: reacting m-cresol and thiocyanate under the action of a catalyst, filtering to obtain filtrate, recovering the catalyst, and concentrating and crystallizing the filtrate to obtain a product A; reacting the product A with halogenated isopropane under the action of alkali and a catalyst, filtering to obtain filtrate, and concentrating the filtrate to obtain a product B; reacting the product B with isopropyl magnesium halide to obtain a reaction mixture; acidifying the reaction mixture, standing and layering to obtain an organic phase; and (3) desolventizing the organic phase to obtain a concentrate, and distilling the concentrate under reduced pressure to obtain the (4-isopropoxy-2-methyl) phenyl isopropyl ketone. The purity of (4-isopropoxy-2-methyl) phenyl isopropyl ketone prepared by the method is more than 99%, and the yield is more than 79% based on m-cresol.

The method introduces the cyano group of the product A by using m-cresol and thiocyanate under the action of the catalyst, avoids the use of toxic reagents such as CuCN, KCN or NaCN, reduces the reaction temperature, is simple to operate, can recycle the catalyst after being washed by the solvent, and reduces the cost; the product B is reacted with isopropyl magnesium halide, namely isopropionyl is introduced through the reaction of Grignard reagent and cyano, the conventional Friedel-crafts acylation reaction method is replaced, a large amount of acidic wastewater is effectively avoided in the whole reaction process, the reaction yield is improved, and a series of influences on the environment caused by post-treatment are reduced; compared with the existing Friedel-crafts acylation route, the method has the advantages of simple operation, high yield, less waste water generation and suitability for industrial production.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.

FIG. 1 shows the preparation of (4-isopropoxy-2-methyl) phenylisopropyl ketone obtained in example 1¹H-NMR spectrum.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the examples given herein without any inventive step, are within the scope of the present invention.