KR102033852B1 - Method for manufacturing Etofenprox intermediate - Google Patents

Abstract

The present invention is a method for efficiently preparing the 2- (4-Ethoxyphenyl) -2-methylpropan-1-ol, which is an Etofenprox intermediate, can easily increase the yield than the conventional process, and can be used in the development of Etofenprox. It is about a method.

Description

Method for manufacturing Etofenprox intermediate

The present invention is a method for efficiently preparing the 2- (4-Ethoxyphenyl) -2-methylpropan-1-ol, which is an Etofenprox intermediate, can easily increase the yield than the conventional process, and can be used in the development of Etofenprox. It is about a method.

Etofenprox is a pyrethroid insecticide developed by Mitsui, Japan, and its IUPAC name is 2- (4-ethoxyphenyl) -2-methylpropyl 3-phenoxybenzyl. It is a pesticide with a mechanism that destroys the insect nervous system after direct contact or ingestion. The main crops used are rice, vegetables, corn, fruit crops and soybeans, and are mainly used in North America, Europe, Asia, especially the United States, Germany, Japan and China.

Etofenprox structural formula

2- (4-Ethoxyphenyl) -2-methylpropan-1-ol is a key intermediate used in the manufacture of Etofenprox, which uses a compound that is difficult and expensive to manufacture. Although mentioned in many patented technologies, they are difficult to apply to mass production.

[Existing Manufacturing Process]

Etofenprox is a compound with a functional group at the para position. However, in the ethoxybenzene, the Fridelcraft reaction produces ethoxybenzene derivatives substituted at the o- and p-positions, and the compounds substituted at the o-positions are also difficult to separate and thus cannot be easily synthesized.

[Fridelcraft Reaction]

In order to overcome this problem, a process that can be produced without a Fridelcraft reaction has emerged, and the alcohol compound, which is a key intermediate, is prepared through several steps using a compound having a functional group at a para position as a starting material as follows. However, the manufacturing process 1 below has a problem that the cost of alcohol compounds is high because there are many processes.

[Manufacturing Process 1]

In addition, the manufacturing process 2 is a Grignard reaction, and the reaction conditions are difficult and the yield is low. Therefore, the continuous supply cannot be assured, causing problems in the long term.

[Manufacturing Process 2]

Republic of Korea Patent Registration 10-0923835 Republic of Korea Patent Publication 10-2017-0101275 Republic of Korea Patent Publication 10-2016-0113719

Accordingly, the present invention has been made to solve the above problems, the first of the core technology of the patent obtains a dichloro compound substituted with chloro in the ortho and para position, the second is a dichloro compound unpurified acetate And the process of dechlorination at the same time as hydrolysis to obtain the desired 2- (4-Ethoxyphenyl) -2-methylpropan-1-ol (at least 98% purity) as crystals, simplifying the process and It is possible to reduce the cost and to obtain a low cost Etofenprox intermediate to provide a method for producing an Etofenprox intermediate that can compete with existing processes.

The problem to be solved of the present invention is not limited to those mentioned above, other problems not mentioned will be clearly understood by those skilled in the art from the following description.

To this end, the method for preparing an Etofenprox intermediate according to the present invention comprises the step S1 of preparing a dichloro compound by reacting chloroethoxybenzene with sulfuric acid and chloroalkene; A step S2 of reacting the dichloro compound with a metal acetate salt, a base, a solvent, and a reaction catalyst to produce a chloroacetate compound; And a step S3 of preparing an alcoholic compound by reacting the chloroacetate compound with a base, a solvent, and a reaction catalyst. The metal acetate salt of step S2 is characterized by consisting of acetate salts of alkali metals and alkaline earth metals.

In addition, in the method for producing an Etofenprox intermediate according to the present invention, the base is selected from the group consisting of alkali metal carbonate, alkali metal hydroxide, ammonia water and trialkylamine.

In addition, in the method for producing an Etofenprox intermediate according to the present invention, the alkali metal carbonate is sodium carbonate or potassium carbonate, the alkyl hydroxide metal is sodium bicarbonate, sodium oxide or potassium hydroxide, and the trialkylamine is trimethylamine. It is done.

In addition, in the method for producing an Etofenprox intermediate according to the present invention, the solvent is characterized in that it is selected from the group consisting of water, N-methyl pyrrolidine, N, N-dimethylimidazolidinone.

Accordingly, the present invention has been made to solve the above problems, the method for preparing an Etofenprox intermediate according to the present invention by efficiently preparing the 2- (4-Ethoxyphenyl) -2-methyl propan-1-ol which is an Etofenprox intermediate The process is simpler than the process, and the yield is increased, which is useful for developing low-cost Etofenprox.

The effects of the present invention are not limited to those mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

1 shows the 1H-NMR spectrum of 2-chloro-4- (1-chloro-2-methylpropan-2-yl) -1-ethoxybenzene of Example 1,
2 shows the 1H-NMR spectrum of 2- (3-chloro-4-ethoxyphenyl) -2-methylpropyl acetate of Example 2,
3 shows the 13C-NMR spectrum of 2- (3-chloro-4-ethoxyphenyl) -2-methylpropyl acetate of Example 2,
Figure 4 shows the 1H-NMR spectrum of 2- (4-ethoxyphenyl) -2-methylpropan-1-ol of Example 3.

Hereinafter, an embodiment of the present invention will be described in detail.

In describing the present invention, if it is determined that the detailed description of the related known function or configuration may unnecessarily obscure the subject matter of the present invention, the detailed description thereof will be omitted. In addition, terms to be described below are terms defined in consideration of functions in the present invention, which may vary according to intention or precedent of a user or an operator. Therefore, the definition should be made based on the contents throughout the specification.

 The present invention provides 2- (4-Ethoxyphenyl) -2-methyl propan-1-ol (I), which is an Etofenprox intermediate represented by the following formula (4).

[Formula 4]

The preparation process of the Etofenprox intermediate represented by Formula 4 is shown in Scheme 1 below.

Scheme 1

The first step, the Fridelcraft reaction, established the conditions for maximizing the yield of dichloro compound (2) as a target compound and generating less side reactions, as shown in Scheme 1-1 below.

Scheme 1-1 Fridelcraft reaction

Preferably, 0.5 equivalent to 2.0 equivalents of sulfuric acid and 1 to 3 equivalents of chloroethoxybenzene (1) are used in 1 equivalent of chloroalkenes, and more preferably 0.7-1 equivalents of sulfuric acid and chloroethoxybenzene (1) are used in 1 equivalent of chloroalkenes. ) 1.5 to 2 equivalents. Here, reaction temperature becomes like this. Preferably it is -10-10 degreeC, More preferably, it can illustrate that it is -5-0 degreeC.

As a second step, the acetate reaction was established to maximize the yield of the target compound acetate compound (3) and to produce less side reactions, as shown in Scheme 1-2 below.

Reaction Scheme 1-2

Here, the proportion of potassium acetate is preferably 1.0 to 5.0 equivalents, more preferably 2.0 to 4.0 equivalents, for 1.0 equivalent of dichloro compound (2). Reaction temperature becomes like this. Preferably it is 80-200 degreeC, More preferably, it is 110-130 degreeC.

The reaction solvent is DMSO, DMF, NMP, DMI useful for high temperature reaction, and preferably NMP, DMI solvent is used. Tetrabutylammonium bromide (TBAB) is used as a reaction catalyst for easier acetate formation, and the ratio is preferably 0.5 to 2.0 equivalents, more preferably 0.7 to 1.0 equivalents, for 1.0 equivalent of dichloro compound (2). It is equivalent to using. In the production method according to the present invention, the base used may be an alkali metal carbonate such as sodium carbonate or potassium carbonate; Alkali metal hydroxides such as sodium bicarbonate, sodium oxide and potassium hydroxide; ammonia; Trialkylamines, such as trimethylamine, etc. are mentioned.

The third step, hydrolysis and dechlorination reaction, established the conditions for maximizing the yield of alcohol compound (I) as a target compound and generating less side reactions, as shown in Schemes 1-3 below.

Scheme 1-3 Hydrolysis and Dechlorination

Here, examples of the base used may include potassium hydroxide and sodium hydroxide, but are not limited thereto, and alkali metal carbonates such as sodium carbonate and potassium carbonate and trialkylamines such as sodium bicarbonate, ammonia water and trimethylamine may be used. .

The base is preferably 10.0 to 3.0 equivalents, more preferably 4.0 to 7.0 equivalents, in 1.0 equivalent of chloroacetate compound (3). The metal used in the dechlorination reaction may generally use Pd / C, PdCl ₂ , PtO ₂ , and the like, and preferably 5% Pd / C.

As the reaction solvent, DMSO, DMF, Dioxane, methanol, and ethanol, which are polar solvents capable of dissolving inorganic bases, may be used. Preferably, methanol, ethanol solvents are used.

Reaction temperature becomes like this. Preferably it is 20-100 degreeC, More preferably, it is 50-70 degreeC.

Finally, the fourth recrystallization step is a step of recrystallization using the alcohol compound (I) obtained in Scheme 1-3 as a nonpolar solvent.

In this case, non-polar solvents such as hexane, heptane, toluene, and xylene were used. In this case, preferably 1.0 to 10.0 volumes of crude alcohol (I) is used, and more preferably 3.0 to 5.0 volumes. Is to use.

Hereinafter, the present invention will be described in more detail with reference to Examples.

2- Chloro -4- (1- Chloro -2- Methylpropane -2-yl) -1- Ethoxybenzene  Synthesis of (2)

10 ml of heptane is added to a three neck flask, and 10 g of 1-chloro-2-ethoxybenzene is added and stirred. 4 g of concentrated sulfuric acid is added dropwise for about 1 hour in the range of -5 to 0 ° C. After completion of the concentrated dropwise addition of 5 g of 3-chloro-2-methylpropene was added dropwise to the reaction solution for about 1 hour. After completion of the dropping, remove the ice bath outside the flask and naturally warm the reactor to room temperature and stir for an additional 2 hours (but do not exceed 20 ° C).

After confirming the completion of reaction by HPLC, 100 ml of heptane and 100 ml of water were added sequentially, and the reaction solution was allowed to stand. Then, the heptane layer was separated from the reaction mixture, and the water in heptane was dehydrated using 3 g of sodium sulfate and distilled under reduced pressure. 2-chloro-4- (1-chloro-2-methyl-propan-2-yl) -1-ethoxy-benzene (2) was obtained 12g (yield 76%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40 (d, J = 2.3 Hz, 1H), 7.21 (dd, J = 8.7, 2.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.13 (q, 2H), 3.63 (s, 2H), 1.49 (t, J = 6.8 Hz, 3H), 1.41 (s, 6H)

2- (3- Chloro -4- Ethoxyphenyl )-2- Methylpropyl  Synthesis of Acetate (3)

In a prepared three-necked flask, 5 ml of N-methyl-2-pyrrolidinone, 10 g of 2-chloro-4- (1-chloro-2-methylpropan-2-yl) -1-ethoxybenzene, 12 g of potassium acetate, and potassium carbonate Add 1 g in sequence. Then, add 3 g of tetrabutylammonium bromide as a reaction catalyst and stir at 180 ° C. for 18-20 hours.

After completion of the reaction, the temperature of the reaction solution was slowly cooled to room temperature, and 100 ml of ethyl acetate was added to the reaction solution, and the ethyl acetate layer was washed with 100 ml of water. 8.8 g of ethyl acetate layer (5) of 2- (3 -chloro- 4 -ethoxyphenyl ) -2-methylpropyl acetate , a chloroacetate compound, was removed by distillation under reduced pressure using 5 g of anhydrous sodium sulfate to remove moisture in the ethyl acetate layer. Yield 80%).

¹ HNMR (400 MHz, CDCl ₃ ) δ7.38 (d, J = 2.4 Hz, 1H), 7.20 (dd, J = 8.6, 2.4 Hz, 1H), 6.89 (d, J = 8.6 Hz, 1H), 4.12 ( dd, J = 15.1, 8.1 Hz, 4H), 2.04 (s, 3H), 1.48 (t, J = 7.0 Hz, 3H), 1.35 (s, 6H). ¹³ CNMR (101 MHz, CDCl 3) δ 171.02,152.73,139.38,128.11,125.11,122.45,113.04,72.82,64.71,37.62,25.81,20.87,14.75.

2- (4- Ethoxyphenyl )-2- Methylpropane Synthesis of -1-ol (I)

Dissolve 3 g of 2- (3-chloro-4-ethoxyphenyl) -2-methylpropyl acetate in 15 ml of methanol. Dissolve 3.7 g of Potassium Hydroxide in 5 ml of water and add to the stomach solution. 0.1 g of 5% palladium is added to the reaction solution, and the reaction is carried out at 70 ° C. for 18 hours while maintaining a hydrogen pressure of about 5 atmospheres.

After completion of the reaction, the mixture was filtered under reduced pressure, 80 ml of ethyl acetate was added to the filtrate, and the organic layer was washed three times with 80 ml of water. The ethyl acetate layer was dehydrated with 5 g of anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain 1.72 g (yield 80%) of the final target compound.

¹ HNMR (400 MHz, DMSO) δ 7.27 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8, Hz, 2H), 3.98 (q, 2H), 3.38 (s, 2H), 1.32 ( t, J = 9.8 Hz, 3H), 1.20 (s, 6H).

On the other hand, in the detailed description of the present invention has been described with respect to specific embodiments, the present invention is not limited to the disclosed embodiments, but a range that does not depart from the spirit of the present invention for those skilled in the art to which the present invention pertains. Various substitutions, modifications and variations are possible within the scope of the invention. Therefore, the scope of the present invention should not be limited to the described embodiments, but should be construed as including not only the claims below but also equivalents thereof.

Claims (5)

Step S1 of preparing a dichloro compound represented by the following Chemical Formula 2 by reacting chloroethoxybenzene represented by the following Chemical Formula 1 with sulfuric acid and 3-chloro-2-methylpropene;
S2 step of preparing a chloroacetate compound represented by the following formula 3 by reacting the dichloro compound with potassium potassium, potassium potassium carbonate, N-methyl-2-pyrrolidinone, and tetra butyl ammonium bromide;
S3 step of preparing an alcohol compound represented by the following Chemical Formula 4 by reacting the chloroacetate compound with potassium potassium, methanol, and palladium;
Etofenprox intermediate production method comprising a.
[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

delete delete delete 2- (3-Chloro-4-ethoxyphenyl) -2-methylpropyl acetate represented by Chemical Formula 3 of claim 1.

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