KR101038638B1 - Enhanced preparation method of optical R-phenoxypropionic acid-N-methyl-N-2-fluorophenylamide compound - Google Patents

Abstract

The present invention relates to an improved process for the preparation of photoactive (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenylamide compounds, more particularly the compounds of formula (4) in an inert solvent Reacting with to prepare a compound of Formula 3 (Step 1); Preparing a compound of Chemical Formula 6 by chlorination using a chlorination reagent to the compound of Chemical Formula 3 prepared in Step 1 (step 2); And reacting the compound of Formula 6 prepared in Step 2 with the compound of Formula 7 in the presence of an inert solvent and a base to prepare the compound of Formula 1 (Step 3). Photoactive (R) -phenoxypropionic acid- A method for producing an N-methyl-N-2-fluorophenylamide compound. The process for preparing the photoactive (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenylamide compound according to the present invention is easier in chemical synthesis, economical, and complex than the prior art. Hazardous chemical reactions can be excluded, safe, easy to separate and purify, maintain optical activity, high yield and purity of (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenylamide Compounds can be produced.

Photoactive Phenoxypropionic Acid-N-Methyl-N-2-fluorophenylamide, Blood Solvent, Herbicide, Metamifop

Description

Improved preparation method of optical (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenylamide compound (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenylamide compound }

The present invention relates to an improved process for the preparation of photoactive (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenylamide compounds.

Currently, various herbicides have been developed and used, but weed, which is still the most problematic problem in paddy farming, is blood. Therefore, the development of medicines that control blood effectively is the greatest desire for rice farmers. In particular, single herbicides treated after seedling transplanting do not effectively suppress the development of rice blood, and the rice blood is regenerated in the middle of growing rice, causing great damage to rice harvest. When the blood on a profound effect on the yield of rice bar, for example 1 m ² per blood rice yield decreases when the first price occurs is approximately 2%, 1 blood five weeks generation per m ² occurring in paddy rice quantity reduction is It is reported that it is about 10%, about 19% at 10 weeks, and about 35% at 20 weeks.

This phenomenon, despite the fact that a number of paddy herbicides have been known in recent years, the control of the blood of the discussion is still a big problem, and also the decisive factor in reducing the yield of rice, and also in the agricultural economics or pesticide industry The need for herbicides is very large.

The present inventors have studied to develop a herbicide that can effectively control the blood of the present discussion, and as a result, some of the phenoxypropionic acid-N-alkyl-N-2-fluorophenylamide compounds are selected from (R)-or (S). It is confirmed that the stereoisomer is present and that the (R) -stereoisomer has excellent stability to rice and excellent control against ricefield compared to the (S) -stereoisomer or mixture of isomers. Photoactive (R) -2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid-N- (2-fluorophenyl) -N having the herbicidal activity of No. 419853 -Methylamide compounds are disclosed.

Meanwhile, the photoactive (R) -2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid-N- (2-fluorophenyl) -N-methylamide compound is controlled. As the demand for herbicides increased, mass production was required.

Preparation of the Photoactive (R) -2- [4- (6-Chloro-2-benzoxazolyloxy) -phenoxy] propionic acid-N- (2-fluorophenyl) -N-methylamide compound so far known The method is as follows.

In the Republic of Korea Patent No. 314776, dicyclohexylcarbodiimide (DCC) was added to (S) -2-bromopropionic acid and N-methyl-2-fluoroaniline and reacted, as shown in the following scheme. By reaction with hydroquinone to give (R) -N- (2-fluorophenyl) -N-methyl-2- (4-hydroxyphenoxy) propionamide, to which 2,6-dichlorobenzoxazole and base To prepare the final compound (R) -2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid-N- (2-fluorophenyl) -N-methylamide using A method is disclosed.

In addition, Korean Patent No. 419853 discloses 2-fluoroaniline in (R) -2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid, as shown in the following scheme. Triphenylphosphine and triethylamine were added thereto to react with (R) -2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid-N- (2-fluorophenyl) amide After the preparation, the reaction was carried out with methylation using CH ₃ I to give the final compound (R) -2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid-N A method for preparing-(2-fluorophenyl) -N-methylamide is disclosed.

However, DCC or triphenylphosphine used in the reaction generates side reactions such as urea during the reaction, and these are not easy to separate and purify, and thus have a problem of being expensive in the separation and purifying process. In addition, when performing the methylation reaction, an expensive reagent is required, and there is a problem that is harmful to the human body because of the use of strong bases, there is a problem that the optical activity can be changed because the chiral center can be changed during the reaction. Furthermore, when triphenylphosphine is used, there is a problem in that the yield is low and the oily product is generated, making it difficult to sell as a product. Therefore, there is a problem that the method is difficult to use for mass production.

Accordingly, the present inventors believe that photoactive (R) -2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid-N- (2-fluorophenyl) enables economic mass production. While researching to develop a method for preparing -N-methylamide compound, it is easy to chemically synthesize, economical, and complicated and dangerous chemical reactions can be eliminated compared to the prior art, which is safe and Optical activity can be maintained, separation and purification is easy, high yield and high purity photoactivity (R) -2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid-N- It was found how to produce a (2-fluorophenyl) -N-methylamide compound and completed the present invention.

It is an object of the present invention to provide economical mass production of photoactive (R) -2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid-N- (2-fluorophenyl)- An improved method for preparing an N-methylamide compound is provided.

In order to achieve the above object, the present invention

Reacting a compound of formula 4 with a compound of formula 5 in an inert organic solvent to prepare a compound of formula 3 (step 1);

Preparing a compound of formula 6 by chlorination of the compound of formula 3 prepared in step 1 (step 2); And

Photoactive (R) -phenoxypropionic acid-N- comprising the step of preparing the compound of Formula 1 by reacting the compound of Formula 6 prepared in Step 2 with the compound of Formula 7 under an inert organic solvent and a base (Step 3) Provided is a method for preparing a methyl-N-2-fluorophenylamide compound.

The process for preparing the photoactive (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenylamide compound according to the present invention is easier in chemical synthesis, economical, and more complicated than the prior art. Hazardous chemical reactions can be excluded, safe, easy to separate and purify, maintain optical activity, high yield and purity of (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenylamide Compounds can be produced.

The present invention is as shown in Scheme 1,

Reacting a compound of formula 4 with a compound of formula 5 in an inert organic solvent to prepare a compound of formula 3 (step 1);

Preparing a compound of formula 6 by chlorination of the compound of formula 3 prepared in step 1 (step 2); And

Photoactive (R) -phenoxypropionic acid-N- comprising the step of preparing the compound of Formula 1 by reacting the compound of Formula 6 prepared in Step 2 with the compound of Formula 7 under an inert organic solvent and a base (Step 3) Provided is a method for preparing a methyl-N-2-fluorophenylamide compound.

Hereinafter, the present invention will be described in detail step by step.

First, step 1 is carried out by reacting a 2,6-dichlorobenzoxazole compound of formula 4 with (R) -2- (4-hydroxyphenoxy) propionic acid compound of formula 5 in an inert organic solvent to A step of preparing the 2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid compound.

In the preparation method according to the present invention, inert organic solvents to be used include, for example, aliphatic and aromatic hydrocarbons or chlorinated hydrocarbons such as benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane and chlorobenzene; Ethers such as diethyl ether, dibutyl ether, tetrahydrofuran and dioxane; Ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone; And nitriles such as acetonitrile and propionitrile and the like can be used.

In the above reaction, the reaction equivalence ratio of the compound of Formula 4 and the compound of Formula 5 is preferably 1 to 1.5: 1, more preferably 1.05 to 1.1: 1. If the reaction equivalence ratio is less than 1: 1, the compound of Formula 5 remains and there is a problem of yield reduction, and if it exceeds 1.5: 1, there is a problem of removing the excess Formula 4 compound.

At this time, the reaction is preferably made for 20 to 180 ℃, preferably for 5 to 24 hours at 40 ~ 150 ℃. After completion of the reaction, the solvent may be prepared by distilling the solvent under reduced pressure, cooling, and then vacuum filtering and drying the resulting material (FPA).

Next, step 2 is a step of preparing a compound of formula 6 by chlorination of the compound of formula 3 prepared in step 1.

The chlorination reaction is made by reacting a chlorination reagent to the compound represented by Formula 3, wherein the chlorination reagent used may be PCl ₅ , SOCl ₂ , (COCl) ₂ , HCl, POCl ₃ , PCl _3, etc. Preference is given to using (COCl) ₂ or SOCl ₂ .

Of the compound of Formula 3 and chlorinated reagent It is preferable that reaction molar equivalent ratio is 1: 1-5. If the molar equivalent ratio of the compound of Formula 3 to the chlorinated reagent is less than 1: 1, the compound of Formula 3 remains and there is a problem of yield reduction, and if it exceeds 1: 5, there is a problem of removing the excess chlorinated reagent. have.

In addition, the reaction can be used alone chlorinated reagents without using a solvent, when using a solvent, it is preferable to use dichloroethane, toluene, ethyl acetate and the like as a solvent.

Furthermore, the reaction can be carried out using a chlorination reagent under a catalyst. At this time, the catalyst used is preferably dimethylformamide (DMF).

At this time, the reaction is preferably made for 2 to 8 hours at 0 ~ 130 ℃. After completion of the reaction, the compound of formula 6 (FPAC) can be prepared in high yield by distillation under reduced pressure to remove the excess chlorination reagent.

Next, Step 3 is a step of preparing a compound of Formula 1 by reacting the compound of Formula 6 and the compound of Formula 7 prepared in Step 2.

The reaction may be accomplished by reacting the compound of Formula 6 and the compound of Formula 7 prepared in Step 2 in the presence of an inert solvent and a base.

In this case, the base used may be an inorganic base such as potassium hydroxide, lithium hydroxide, sodium hydroxide, sodium hydrogen carbonate, and the like, and in the case of using an organic base such as triethylamine, pyridine or the like Purity is lowered.

As the inert solvent used in the reaction, ethers such as tetrahydrofuran, ethyl acetate, acetonitrile, toluene, xylene, hexane methylene chloride, carbon tetrachloride, dichloroethane and the like can be used.

At this time, the reaction is preferably made for 2 to 4 hours at 0 ~ 60 ℃. After completion of the reaction, water may be added to the organic layer to separate the layers, and the solvent may be evaporated to prepare an optically active compound of Chemical Formula 1.

The present invention also provides a photoactive (R) -phenoxypropionic acid-N-methyl-N- Provided is a method for purifying a 2-fluorophenylamide compound.

The alcohol used may be methanol, ethanol, propyl alcohol, isopropyl alcohol, normal butanol, etc., after crystallization using water and alcohol to add additional water to complete the crystallization, alcohol and normal hexane After crystallization by using the normal hexane can be added to complete the crystallization.

The crystallized reaction solution was cooled to 5 ° C. and filtered and dried to obtain a high purity photoactive (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenylamide compound having a purity of 97% or more and an optical purity of 99% EE. can do.

The photoactive (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenylamide compound obtained above can be confirmed by NMR, mass spectrometry and the like.

The process for preparing the photoactive (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenylamide compound according to the present invention is easier in chemical synthesis, economical, and complex than the prior art. Hazardous chemical reactions can be eliminated, which is safe, maintains optical activity, and can produce high yield and high purity (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenylamide compounds.

Hereinafter, the present invention will be described in detail through examples. However, the following examples are merely to illustrate the present invention and the present invention is not limited by the following examples.

Example 1 Preparation of (R) -2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid-N- (2-fluorophenyl) -N-methylamide compound

Step 1: Preparation of (R) -2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid

Na ₂ CO ₃ (70.2g) was dissolved in water and heated to 40 ° C., and D-HPPA (130 g), acetonitrile (130 g) and DCBO (138 g) of formula 4 were added at 60 ° C. After raising the temperature, Na ₂ CO ₃ (145.8 g) was added and stirred for 2 hours. After the reaction was completed, the solvent was distilled under reduced pressure, crystallized using (solvent), and then filtered and dried to obtain the target compound (219.5 g, yield 97%, purity 98.5%).

NMR (CDCl ₃ ) δ 1.51 (3H, d), 4.87 (1H, m), 6.96 ~ 7.8 (7H, m), 11.00 (1H, 8)

Step 2: Preparation of (R) -2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid chloride

(R) -2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid (219.5 g), dimethylformamide (9.6) prepared in step 1 above in dichloroethane (1317.5 g). g) and oxalyl chloride (91.9 g) were added and stirred at 40 ° C. for 2 hours. Subsequently, dichloroethane was distilled off under reduced pressure to obtain a target compound (231.6 g, yield 100%, purity 98.0%).

NMR (CDCl ₃ ) δ 1.54 (3H, d), 4.73 (1H, m), 6.60 ~ 7.43 (7H, m)

Step 3: Preparation of (R) -2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid-N- (2-fluorophenyl) -N-methylamide

N-methyl-2-fluoroaniline (82.3 g) and sodium hydrogencarbonate (66.3 g) were sequentially added to dichloroethane (878 g), and the reaction mixture was cooled to 5 ° C. Then, (R) -2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid chloride (231.6 g) prepared in step 2 was added dropwise to dichloroethane (329 g). Then, aged for 2 hours.

After the reaction was completed, water was added to the organic layer to separate the layers, and dichloromethane was distilled under reduced pressure. Thereafter, methanol and water were added to crystallize the product, followed by further pouring water to complete crystallization. The crystallized product was cooled to 5 ° C and filtered and dried to obtain the desired compound (278.3 g, yield 96%, purity 97%, optical purity 99% EE).

NMR (CDCl ₃ ) δ 1.42 (3H, t), 3.3 (3H, s), 4.62 (1H, m), 6.8-7.4 (11H, m)

<Example 2>

Step 1

DCBO of formula 4 (22.1 g) was dissolved in acetonitrile (30 g) and then heated to 45 ° C. After the D-HPPA (19.2 g) and 36% -NaOH (24.4g) of the formula 5 was added and stirred for 2 hours at 45 ~ 50 ℃. After the reaction was completed, the solvent was distilled under reduced pressure, crystallized using ethyl acetate, and then filtered and dried to obtain the target compound (31.4 g, yield 94.0%, purity 98.5%).

Step 2 and Step 3

(R) -2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid-N- (2-fluoro in the same manner as in steps 2 and 3 of Example 1; Phenyl) -N-methylamide was obtained.

<Example 3>

Step 1

The target compound was obtained by the same method as the method of Step 1 of Example 2, except that DCBO (22.1 g) of Formula 4 was used for acetone (30 g) (28.4 g, yield 85.0%, purity 92.9%) ).

Step 2 and Step 3

(R) -2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid-N- (2-fluoro in the same manner as in steps 2 and 3 of Example 1; Phenyl) -N-methylamide was obtained.

<Example 4>

Step 1

It was carried out in the same manner as step 1 of Example 1.

Step 2

Ethyl acetate (884.1 g) was used instead of dichloroethane as a solvent, and thionyl chloride (100.7 g) was used instead of oxalyl chloride as a chlorinated reagent. Was obtained (231.6 g, yield 100%, purity 98%).

Step 3

It was carried out in the same manner as step 3 of Example 1.

<Example 5>

Step 1 and Step 2

It was carried out in the same manner as in Step 1 and Step 2 of Example 1.

Step 3

N-methyl-2-fluoroaniline (10.63 g) and sodium hydrogencarbonate (8.57 g) were sequentially added to dichloroethane (113.0 g), and the reaction mixture was cooled to 5 ° C. Thereafter, (R) -2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy] propionic acid chloride (29.9 g) prepared in step 2 was added dropwise to dichloroethane (42.54 g). Then, aged for 2 hours.

After the reaction was completed, water was added to the organic layer to separate the layers, and dichloromethane was distilled under reduced pressure. Thereafter, normal butanol and normal hexane were added to crystallize the product, and then normal hexane was further added to complete crystallization. The crystallized product was cooled to 5 ° C and filtered and dried to obtain the target compound (33.6 g, yield 89.7%, purity 97%, optical purity 99% EE).

<Example 6>

Step 1 and Step 2

It was carried out in the same manner as in Step 1 and Step 2 of Example 1.

Step 3

A target compound was obtained in the same manner as Step 3 of Example 5, except that toluene (113.0 g) was used instead of dichloroethane as a solvent to dissolve N-methyl-2-fluoroaniline (33.6 g, yield 89.7). %, Purity 97%, optical purity 99% EE).

<Example 7>

Step 1 and Step 2

It was carried out in the same manner as in Step 1 and Step 2 of Example 1.

Step 3

Same as Step 3 of Example 5, except that ethyl acetate (113.0 g) was used instead of dichloroethane as a solvent to dissolve N-methyl-2-fluoroaniline and isopropyl alcohol and normal hexane were used as purification solvents. The target compound was obtained by the method (33.6 g, yield 89.7%, purity 96.3%, optical purity 99% EE).

<Example 8>

Step 1 and Step 2

It was carried out in the same manner as in Step 1 and Step 2 of Example 1.

Step 3

Example 7 except that methylene chloride (113.0 g) was used instead of dichloroethane as a solvent to dissolve N-methyl-2-fluoroaniline and triethylamine (12.87 g) was used instead of sodium hydrogen carbonate as the base. The target compound was obtained by the same method as the step 3 (26.2 g, yield 70.0%, purity 75.0%, optical purity 99% EE).

Example 9

Step 1 and Step 2

It was carried out in the same manner as in Step 1 and Step 2 of Example 1.

Step 3

Except for using pyridine (7.73 g) instead of triethylamine as a base in the same manner as in Step 3 of Example 8 to obtain the target compound (31.77 g, yield 84.8%, purity 92.0%, optical purity 99% EE).

Claims (13)

As shown in Scheme 1 below, Reacting a compound of formula 4 with a compound of formula 5 in an inert solvent to prepare a compound of formula 3 (step 1); Preparing a compound of Chemical Formula 6 by chlorination using a chlorination reagent to the compound of Chemical Formula 3 prepared in Step 1 (step 2); And Photoactive (R) -phenoxypropionic acid-N comprising the step of preparing the compound of Formula 1 by reacting the compound of Formula 6 prepared in Step 2 with the compound of Formula 7 in the presence of an inert solvent and a base (Step 3) Process for the preparation of -methyl-N-2-fluorophenylamide compound. Scheme 1

The method of claim 1, wherein the inert solvent of step 1 is benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, acetone, methyl Photoactive (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenylamide selected from the group consisting of ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, acetonitrile and propionitrile Method for preparing the compound. The photoactive (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenyl according to claim 1, wherein the reaction equivalent ratio of the compound of Formula 4 to the compound of Formula 5 is 1 to 1.5: 1. Method for preparing an amide compound. The photoactive (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenylamide compound of claim 1, wherein the reaction of Step 1 is performed at 20 to 180 ° C. for 5 to 24 hours. Manufacturing method. The photoactive (R) -phenoxypropionic acid-according to claim 1, wherein the chlorination reagent of step 2 is selected from the group consisting of PCl ₅ , SOCl ₂ , (COCl) ₂ , HCl, POCl ₃ and PCl ₃ . Method for preparing N-methyl-N-2-fluorophenylamide compound. According to claim 1, wherein the compound of formula 3 and the chlorination reagent A method for producing a photoactive (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenylamide compound, wherein the reaction molar equivalent ratio is 1: 1-5. The photoactive (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenylamide compound of claim 1, wherein the reaction of Step 2 is performed at 0 to 130 ° C. for 2 to 8 hours. Manufacturing method. The photoactive (R) -phenoxypropionic acid-N-methyl-N-2-fluoro according to claim 1, wherein the base used in step 3 is potassium hydroxide, lithium hydroxide, sodium hydroxide or sodium hydrogen carbonate. Process for the preparation of phenylamide compound. The method according to claim 1, wherein the inert solvent used in step 3 is selected from the group consisting of tetrahydrofuran, ethyl acetate, acetonitrile, toluene, xylene, hexane methylene chloride, carbon tetrachloride and dichloroethane. R) -Phenoxypropionic acid-N-methyl-N-2-fluorophenylamide compound. The photoactive (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenylamide compound according to claim 1, wherein the reaction of Step 3 is performed for 2 to 4 hours at 0 to 60 ° C. Manufacturing method. The photoactive (R) -phenoxypropionic acid-N- according to claim 1, further comprising recrystallizing the compound of Formula 1 with at least one solvent selected from the group consisting of water, alcohol and normal hexane. Process for the preparation of a methyl-N-2-fluorophenylamide compound. 12. The method of claim 11, wherein after crystallization using water and alcohol as a recrystallization solvent, additional water is added to complete the crystallization, and after crystallization using alcohol and normal hexane as the recrystallization solvent, an additional normal hexane is added. A method for producing a photoactive (R) -phenoxypropionic acid-N-methyl-N-2-fluorophenylamide compound, characterized by crystallization. 13. The photoactive (R) -phenoxypropionic acid-N-methyl-N according to claim 11 or 12, wherein the alcohol is selected from the group consisting of methanol, ethanol, propyl alcohol, isopropyl alcohol and normal butanol. Method for producing a 2-fluorophenylamide compound.