阅读说明：本技术 一种精异丙甲草胺的制备方法 (Preparation method of s-metolachlor ) 是由 李舸 刘婷 李海林 苏宏文 张建现 彭自祥 张明明 于 2019-11-11 设计创作，主要内容包括：本发明提供了一种精异丙甲草胺的制备方法,所述方法包括以下步骤：甲醇与(R)-环氧丙烷反应得到(R)-1-甲氧基-2-丙醇,使其与磺酰氯化合物反应得到式I所示化合物,式I所示化合物与2-甲基-6-乙基苯胺反应得到S-(-)-N-(R-甲基-2’-羟乙基)-2-甲基-6-乙基苯胺,再使其与氯乙酰氯发生反应,得到(S)-异丙甲草胺。本方法合成路线短,反应步骤少,避免使用昂贵的手性不对称氢化催化剂和高压、氢化的危险生产工序,简单实用,生产收率高,具有良好的工业化前景。(The invention provides a preparation method of s-metolachlor, which comprises the following steps: reacting methanol with (R) -epoxypropane to obtain (R) -1-methoxyl-2-propanol, reacting the (R) -1-methoxyl-2-propanol with sulfonyl chloride to obtain a compound shown in a formula I, reacting the compound shown in the formula I with 2-methyl-6-ethyl aniline to obtain S- (-) -N- (R-methyl-2 '-hydroxyethyl) -2-methyl-6-ethyl aniline, and reacting the S- (-) -N- (R-methyl-2' -hydroxyethyl) -2-methyl-6-ethyl aniline with chloroacetyl chloride to obtain (S) -metolachlor. The method has the advantages of short synthetic route, few reaction steps, avoidance of expensive chiral asymmetric hydrogenation catalysts and dangerous production procedures of high pressure and hydrogenation, simplicity, practicality, high production yield and good industrial prospect.)

1. A preparation method of s-metolachlor is characterized by comprising the following steps:

(1) the reaction of methanol with (R) -propylene oxide gives (R) -1-methoxy-2-propanol of the following formula:

(2) (R) -1-methoxy-2-propanol and sulfonyl chloride compound obtained in step (1)Reacting to generate a compound shown in a formula I, wherein the reaction formula is as follows:

(3) and (3) reacting the compound shown in the formula I obtained in the step (2) with 2-methyl-6-ethylaniline to obtain S- (-) -N- (R-methyl-2' -hydroxyethyl) -2-methyl-6-ethylaniline, wherein the reaction formula is as follows:

(4) reacting the S- (-) -N- (R-methyl-2' -hydroxyethyl) -2-methyl-6-ethyl aniline obtained in the step (3) with chloroacetyl chloride to obtain (S) -metolachlor, wherein the reaction formula is as follows:

wherein R is₁Is C1-C5 alkyl or substituted or unsubstituted phenyl.

2. The process according to claim 1, wherein the molar ratio of methanol to (R) -propylene oxide in step (1) is 1.0:1.0 to 10.0:1.0, preferably 3.0:1.0 to 5.0: 1.0.

3. The production method according to claim 1 or 2, wherein the reaction of step (1) is carried out in the presence of a basic substance; the alkaline substance is preferably one or the combination of at least two of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, cesium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide or magnesium tert-butoxide;

preferably, the amount of the basic substance is 1 to 8% by mass of the (R) -propylene oxide.

4. The method of any one of claims 1 to 3, wherein the temperature of the reaction of step (1) is 20 ℃ to 100 ℃, preferably 60 ℃ to 80 ℃;

preferably, the reaction time in step (1) is 5 to 20 hours, preferably 8 to 15 hours.

5. The production method according to any one of claims 1 to 4, wherein the sulfonyl chloride compound of step (2)

preferably, the (R) -1-methoxy-2-propanol of the step (2) is further mixed with a sulfonyl chloride compoundIn a molar ratio of 1:0.8 to 1:3.0, preferably 1:1 to 1: 1.2.

6. The production method according to any one of claims 1 to 5, wherein the reaction of step (2) is carried out in the presence of a basic substance, preferably triethylamine;

preferably, the molar ratio of the basic substance to (R) -1-methoxy-2-propanol is 1.0:1.0-1.5: 1.0;

preferably, the solvent for the reaction in step (2) is any one or a combination of at least two of dichloromethane, toluene, ethyl acetate or DMF;

preferably, the temperature of the reaction in the step (2) is-10 ℃ to 40 ℃;

preferably, the reaction time in step (2) is 3 to 10 hours.

7. The process according to any one of claims 1 to 6, wherein the molar ratio of the compound of formula I to 2-methyl-6-ethylaniline in step (3) is from 0.8:1.0 to 3.0:1.0, preferably from 1.0:1.0 to 1.5: 1.0.

8. The production method according to any one of claims 1 to 7, characterized in that the reaction of step (3) is carried out in the presence of a basic substance, preferably one or a combination of at least two of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, cesium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, or magnesium tert-butoxide;

preferably, the solvent for the reaction in step (3) is any one or a combination of at least two of dichloromethane, dichloroethane, toluene, ethyl acetate or DMF;

preferably, the temperature of the reaction of step (3) is from 30 ℃ to 100 ℃, preferably from 50 ℃ to 80 ℃;

preferably, the reaction time in step (3) is 6 to 12 hours.

9. The process according to any one of claims 1 to 8, wherein the molar ratio of S- (-) -N- (R-methyl-2' -hydroxyethyl) -2-methyl-6-ethylaniline to chloroacetyl chloride in step (4) is from 0.8:1.0 to 1.2: 1.0;

preferably, the temperature of the reaction in the step (4) is-5 ℃ to 50 ℃, preferably 0 ℃ to 15 ℃;

preferably, the reaction time of step (4) is 8 to 20 hours, preferably 10 to 15 hours;

preferably, the solvent for the reaction of step (4) is any one or a combination of at least two of dichloromethane, toluene or DMF.

10. The production method according to any one of claims 1 to 9, comprising the steps of:

(1) reacting methanol and (R) -propylene oxide at a molar ratio of 1.0:1.0-10.0:1.0 at 20-100 ℃ for 5-20 hours in the presence of an alkaline substance to obtain (R) -1-methoxy-2-propanol;

(2) (R) -1-methoxy-2-propanol and sulfonyl chloride compound obtained in step (1)

(3) reacting the compound shown in the formula I obtained in the step (2) with 2-methyl-6-ethylaniline according to a molar ratio of 0.8:1.0-3.0:1.0 in the presence of a basic substance at 30-100 ℃ for 6-12 hours to obtain S- (-) -N- (R-methyl-2' -hydroxyethyl) -2-methyl-6-ethylaniline;

(4) reacting the S- (-) -N- (R-methyl-2' -hydroxyethyl) -2-methyl-6-ethyl aniline obtained in the step (3) with chloroacetyl chloride for 8-20 hours at the temperature of-5-50 ℃ in a molar ratio of 0.8:1.0-1.2:1.0 to obtain (S) -metolachlor;

wherein R is₁Is C1-C5 alkyl or substituted or unsubstituted phenyl.

Technical Field

The invention belongs to the technical field of herbicide synthesis, and relates to a preparation method of s-metolachlor.

Background

Metolachlor is a chloroacetamide type efficient herbicide developed and popularized by Ciba-Jiaji company, the present Zhangda company. It is a systemic herbicide with high efficiency, low toxicity and high selectivity. The product has excellent performance and excellent drug effect, and one reason is because of the chiral structure of the product and the super-efficient activity of the chiral structure isomer. Due to the great difficulty of chiral synthesis of this product, the major market and production supply of this product has long been occupied exclusively by the first right. In order to enter and share the production and supply markets of the product, the synthesis process route of the herbicide becomes a research hotspot of domestic enterprises and research institutions.

At present, the following synthesis methods are mainly used for synthesizing the metolachlor: resolution method, method using optical rotation reagent and directional synthesis method.

The method comprises the following steps: the resolution method comprises the following synthetic route:

the resolution principle is that N- (2-methyl-6-ethyl phenyl) alanine ester is subjected to chemical or enzymatic kinetic resolution, and then subjected to reduction, acylation, methylation and the like to obtain S-metolachlor. From an atomic economic point of view, the process first synthesizes the racemate metolachlor and then discards at least half of the R-isomer content by resolution. Therefore, the cost of raw materials and the preparation process of the product is high, and the economical efficiency is poor.

The second method comprises the following steps: the synthesis method of the chiral raw material comprises the following synthetic route:

the chiral raw material synthesis method specifically comprises the steps of using D-methyl lactate or D-ethyl lactate as a raw material, firstly reacting with p-toluenesulfonyl chloride to generate R-2-p-toluenesulfonyloxy propionate, then reacting with 2-methyl-6-ethylaniline to obtain S- (-) -N- (2-methyl-6-ethylphenyl) alanine ester, then reacting with reducing agent sodium borohydride to obtain S- ⑴ -N- (R-methyl-2' -hydroxyethyl) -2-methyl-6-ethylaniline, further acylating with chloroacetyl chloride, and finally methylating to obtain (S) -metolachlor.

The third method comprises the following steps: the asymmetric hydrogenation synthesis method of imine comprises the following synthetic route:

the method is a current research and adopts a plurality of synthesis routes, mainly uses 2, 6-methyl ethyl aniline and methoxy acetone as raw materials, carries out asymmetric hydrogenation under the action of a chiral catalyst after imine synthesis, and obtains the refined metolachlor through acylation reaction.

Therefore, it is desired in the art to develop a simple and inexpensive method for producing s-metolachlor in high overall yield.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide the preparation method of the s-metolachlor, which has the advantages of short synthetic route, simple operation, high overall yield and low cost and is suitable for industrial production.

In order to achieve the purpose, the invention adopts the following technical scheme:

the invention provides a preparation method of s-metolachlor, which comprises the following steps:

(1) the reaction of methanol with (R) -propylene oxide gives (R) -1-methoxy-2-propanol of the following formula:

(2) (R) -1-methoxy-2-propanol and sulfonyl chloride compound obtained in step (1)

Reacting to generate a compound shown in a formula I, wherein the reaction formula is as follows:

(3) and (3) reacting the compound shown in the formula I obtained in the step (2) with 2-methyl-6-ethylaniline to obtain S- (-) -N- (R-methyl-2' -hydroxyethyl) -2-methyl-6-ethylaniline, wherein the reaction formula is as follows:

(4) reacting the S- (-) -N- (R-methyl-2' -hydroxyethyl) -2-methyl-6-ethyl aniline obtained in the step (3) with chloroacetyl chloride to obtain (S) -metolachlor, wherein the reaction formula is as follows:

wherein R is₁Is C1-C5 alkyl or substituted or unsubstituted phenyl.

The preparation method of the invention uses cheap and easily obtained (R) -propylene oxide as chiral starting raw material, obtains the product through the simple four-step reaction, has short synthetic route, less process side reaction, high synthetic yield, good product quality, convenient purification, avoids using expensive chiral asymmetric hydrogenation catalyst, has easily obtained raw material and low price, and is suitable for industrialized batch production.

Preferably, the molar ratio of methanol to (R) -propylene oxide in step (1) is 1.0:1.0-10.0:1.0, such as 1.0:1.0, 1.5:1.0, 2.0:1.0, 2.5:1.0, 3.0:1.0, 3.5:1.0, 3.8:1.0, 4.0:1.0, 4.5:1.0, 5.0:1.0, 5.5:1.0, 6.0:1.0, 6.5:1.0, 7.0:1.0, 7.5:1.0, 8.0:1.0, 8.5:1.0, 9.0:1.0, 10.0:1.0, etc., preferably 3.0:1.0-5.0: 1.0.

Methanol serves as both a reactant and a solvent for the reaction in step (1).

Preferably, the reaction of step (1) is carried out in the presence of a basic substance; the alkaline substance is preferably one or a combination of at least two of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, cesium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide or magnesium tert-butoxide.

Preferably, the basic substance is used in an amount of 1 to 8% by mass, for example 1%, 1.3%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5% or 8% by mass, of the (R) -propylene oxide.

Preferably, the temperature of the reaction of step (1) is 20 ℃ to 100 ℃, such as 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃ or 100 ℃, preferably 60 ℃ to 70 ℃.

Preferably, the reaction time in step (1) is 5 to 20 hours, such as 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 14 hours, 15 hours, 17 hours, 19 hours, 20 hours, etc., preferably 8 to 15 hours.

In the present invention, the sulfonyl chloride compound of step (2)

In R₁Is C1-C5 alkyl (C1, C2, C3, C4 or C5 alkyl) or substituted or unsubstituted phenyl.

Preferably, the sulfonyl chloride compound of step (2)

In, R₁Is methyl, p-methylphenyl, m-nitrophenyl or p-nitrophenyl. Namely, the corresponding sulfonyl chloride compound is methanesulfonyl chloride, p-toluenesulfonyl chloride, m-nitrobenzenesulfonyl chloride or p-nitrobenzenesulfonyl chloride.

Preferably, the (R) -1-methoxy-2-propanol of the step (2) is further mixed with a sulfonyl chloride compound

In a molar ratio of 1:0.8 to 1:3.0, such as 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.5, 1:1.8, 1:2, 1:2.2, 1:2.5, 1:2.8 or 1:3, preferably 1:1 to 1: 1.2.

The reaction of step (2) is carried out in the presence of a basic substance, preferably triethylamine.

Preferably, the molar ratio of the basic substance to (R) -1-methoxy-2-propanol is 1.0:1.0-1.5:1.0, such as 1.0:1.0, 1.05:1.0, 1.1:1.0, 1.15:1.0, 1.2:1.0, 1.25:1.0, 1.3:1.0, 1.35:1.0, 1.4:1.0, 1.45:1.0 or 1.5: 1.0.

Preferably, the solvent for the reaction of step (2) is any one or a combination of at least two of dichloromethane, toluene, ethyl acetate or DMF.

Preferably, the temperature of the reaction in step (2) is-10 ℃ to 40 ℃, such as-10 ℃, -8 ℃, -5 ℃, -3 ℃, 0 ℃, 2 ℃, 5 ℃, 8 ℃, 10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃ or 40 ℃.

Preferably, the reaction time in step (2) is 3 to 10 hours, such as 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours or 10 hours.

Preferably, the molar ratio of the compound of formula I to 2-methyl-6-ethylaniline in step (3) is 0.8:1.0-3.0:1.0, such as 0.8:1.0, 0.9:1.0, 1.0:1.0, 1.2:1.0, 1.5:1.0, 1.8:1.0, 2.0:1.0, 2.2:1.0, 2.5:1.0, 2.8:1.0 or 3.0:1.0, preferably 1.0:1.0-1.5: 1.0.

Preferably, the reaction of step (3) is carried out in the presence of a basic substance, preferably one or a combination of at least two of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, cesium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, or magnesium tert-butoxide.

Preferably, the solvent for the reaction in step (3) is any one or a combination of at least two of dichloromethane, dichloroethane, toluene, ethyl acetate or DMF.

Preferably, the temperature of the reaction in step (3) is 30-100 ℃, such as 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 95 ℃ or 100 ℃, preferably 50-80 ℃.

Preferably, the reaction time in step (3) is 10-20 hours, such as 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours or 20 hours.

Preferably, the molar ratio of S- (-) -N- (R-methyl-2' -hydroxyethyl) -2-methyl-6-ethylaniline to chloroacetyl chloride in step (4) is 0.8:1.0 to 1.2:1.0, such as 0.8:1.0, 0.85:1.0, 0.9:1.0, 0.95:1.0, 1.0:1.0, 1.1:1.0 or 1.2:1.0, etc.

Preferably, the reaction in step (4) is carried out at a temperature of-5 ℃ to 50 ℃, e.g., -5 ℃, 0 ℃, 5 ℃, 10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃ or 50 ℃, etc., preferably 0 to 15 ℃.

Preferably, the reaction time in step (4) is 8 to 20 hours, such as 8 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours or 20 hours, preferably 10 to 15 hours.

Preferably, the solvent for the reaction of step (4) is any one or a combination of at least two of dichloromethane, toluene or DMF.

As a preferred technical scheme of the invention, the preparation method of the metolachlor concretely comprises the following steps:

(1) reacting methanol and (R) -propylene oxide at a molar ratio of 1.0:1.0-10.0:1.0 at 20-100 ℃ for 5-20 hours in the presence of an alkaline substance to obtain (R) -1-methoxy-2-propanol;

(2) (R) -1-methoxy-2-propanol and sulfonyl chloride compound obtained in step (1)

Reacting for 5-20 hours at the temperature of minus 10-40 ℃ in a molar ratio of 1:0.8-1:3.0 to generate a compound shown in a formula I;

(3) reacting the compound shown in the formula I obtained in the step (2) with 2-methyl-6-ethylaniline according to a molar ratio of 0.8:1.0-3.0:1.0 in the presence of a basic substance at 30-100 ℃ for 6-12 hours to obtain S- (-) -N- (R-methyl-2' -hydroxyethyl) -2-methyl-6-ethylaniline;

(4) reacting the S- (-) -N- (R-methyl-2' -hydroxyethyl) -2-methyl-6-ethyl aniline obtained in the step (3) with chloroacetyl chloride for 8-20 hours at the temperature of-5-50 ℃ in a molar ratio of 0.8:1.0-1.2:1.0 to obtain (S) -metolachlor;

wherein R is₁Is C1-C5 alkyl or substituted or unsubstituted phenyl.

Compared with the prior art, the invention has the following beneficial effects:

the preparation method has the advantages of short synthetic route, less process side reaction, high synthetic yield, good product quality, convenient purification, mild reaction conditions and high reaction safety, avoids the defects of high reaction risk and high environmental protection pressure in some methods in the prior art, can avoid using expensive chiral asymmetric hydrogenation catalysts, has easily available raw materials and low price, and is suitable for industrial batch production.

Detailed Description

The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.