阅读说明：本技术 一种酶法合成噁唑酰草胺的方法 (Method for synthesizing metamifop by enzyme method ) 是由 田轮 王宇 周灿亮 胡志彬 刘林波 陈三龙 杨紫冬 许树涛 于 2019-12-19 设计创作，主要内容包括：本发明公开了一种酶法合成噁唑酰草胺的方法。该方法是以(R)-2-[4-(6-氯-2-苯并噁唑氧基)苯氧基]丙酸衍生物与N-甲基-2-氟苯胺为原料,在溶剂中经生物酶催化反应,反应结束后与酶分离,除去溶剂后经纯化可得噁唑酰草胺。该方法反应条件温和、副产物少、操作简单、环境友好、生产成本低,具有较好的工业利用价值。(The invention discloses a method for synthesizing metamifop by an enzyme method. The method takes (R) -2- [4- (6-chloro-2-benzoxazolyl-oxy) phenoxy ] propionic acid derivatives and N-methyl-2-fluoroaniline as raw materials, the raw materials are subjected to biological enzyme catalytic reaction in a solvent, the raw materials are separated from the enzyme after the reaction is finished, and the metamifop can be obtained after the solvent is removed and the purification is carried out. The method has the advantages of mild reaction conditions, few byproducts, simple operation, environmental friendliness, low production cost and good industrial utilization value.)

1. A method for synthesizing metamifop by an enzyme method is characterized in that: taking (R) -2- [4- (6-chloro-2-benzoxazolyl) phenoxy ] propionic acid derivatives and N-methyl-2-fluoroaniline as raw materials, carrying out biological enzyme catalytic reaction in a solvent for a certain time under a certain condition, separating the enzyme after the reaction is finished, removing the solvent, and purifying to obtain the metamifop.

2. The method for synthesizing metamifop by the enzyme method according to claim 1, characterized in that: the structural formula of the (R) -2- [4- (6-chloro-2-benzoxazolyl-oxy) phenoxy ] propionic acid derivative is as follows:

wherein R is-CH₃or-CH₂CH₃。

3. The method for synthesizing metamifop by the enzyme method according to claim 1, characterized in that: the biological enzyme is Novozym 435.

4. The method for synthesizing metamifop by the enzyme method according to claim 1, characterized in that: the reaction solvent is one of methanol, ethanol, n-hexane, tert-butanol or methyl isobutyl ketone, and the total dosage of the reaction solvent is 1.33L per mole of the (R) -2- [4- (6-chloro-2-benzoxazolyl-oxy) phenoxy ] propionic acid derivative.

5. The method for synthesizing metamifop by the enzyme method according to claim 1, characterized in that: the molar ratio of the (R) -2- [4- (6-chloro-2-benzoxazolyl) phenoxy ] propionic acid derivative to the N-methyl-2-fluoroaniline is 1: 1-1: 1.3.

6. The method for synthesizing metamifop by the enzyme method according to claim 1, characterized in that: the dosage of the enzyme is 6000-10000U added to each mole of (R) -2- [4- (6-chloro-2-benzoxazolyl) phenoxy ] propionic acid derivative.

7. The method for synthesizing metamifop by the enzyme method according to claim 1, characterized in that: the reaction temperature is 30-70 ℃.

8. The method for synthesizing metamifop by the enzyme method according to claim 1, characterized in that: the (R) -2- [4- (6-chloro-2-benzoxazolyl) phenoxy ] propionic acid derivative is slowly dropped into a reaction system, the dropping time is 2 hours, and the reaction time is 4-5 hours.

9. The method for synthesizing metamifop by the enzyme method according to claim 1, characterized in that: the purification method comprises the steps of dissolving the crude product by using ethanol, cooling, adding water, dissolving out crystals, filtering and drying to obtain the metamifop.

10. The purification process according to claim 9, characterized in that: the volume of the ethanol is 1.67L per mole of the (R) -2- [4- (6-chloro-2-benzoxazolyl-oxy) phenoxy ] propionic acid derivative, the volume ratio of the ethanol to the water is 1: 1-1: 4, and the crystallization temperature is 0-10 ℃.

Technical Field

The invention relates to a method for synthesizing metamifop by an enzyme method, belonging to the technical field of biochemical engineering.

Background

Metamifop (Metamifop) is a novel aryloxy phenoxy propionate herbicide developed by Korean chemical technology research institute, can well prevent and kill most annual gramineous weeds, is different from most herbicides, is safe to rice, can effectively prevent and kill main weeds in paddy fields, such as barnyard grass, moleplant seed, large crabgrass and goosegrass, and is mainly used for weeding in transplanted and direct-seeded paddy fields. The metamifop has low toxicity, is environment-friendly, has wide miscibility, is expected to be used for weeding other crops and lawns, and is a herbicide with great development prospect. The structural formula is as follows:

at present, the synthesis of metamifop is a chemical synthesis method, and the following methods are mainly adopted:

(1) in patent CN01823753.3, (R) -2- [4- (6-chloro-2-benzoxazolyloxy) phenoxy ] propionic acid and N-methyl-2-fluoroaniline are used as raw materials, triethylamine is used as a catalyst, triphenylphosphine is used as a linker, refluxing is performed in tetrahydrofuran for 12h, and after acidification, extraction and column chromatography, the metamifop is obtained, and the total yield reported in literature is 23%. The method has low yield of target products, is difficult to carry out post-treatment, generates a large amount of phosphorus-containing waste brine, and is not suitable for industrial production.

(2) KR100314776B1 patent uses N- (2-fluorophenyl) -N-methyl-2-bromopropanamide and hydroquinone as raw materials, and K is₂CO₃In the presence of_NThe nucleophilic substitution of 2 generates N- (2-fluorophenyl) -N-methyl-2- (4-hydroxyphenoxy) propionamide, and then the N- (2-fluorophenyl) -N-methyl-2- (4-hydroxyphenoxy) propionamide reacts with 2, 6-dichlorobenzoxazole to generate metamifop, and the total yield is reported to be 68 percent in literature. In the method, N- (2-fluorophenyl) -N-methyl-2-bromopropionamide is prepared from optically active 2-bromopropionic acid and N-methyl-2-fluoroaniline, and the first step S is_NThe nucleophilic substitution has inversion of configuration, and more byproducts are generated, so that the cost is high, and the method is not suitable for industrial production.

(3) Patent KR100419853B1 takes 2- [4- (6-chloro-2-benzoxazolyloxy) -phenoxy ] propionic acid-N- (2-fluorophenyl) amide and methyl iodide as raw materials, anhydrous tetrahydrofuran as a solvent, and the metamifop is synthesized under the action of sodium hydride, and the total yield is reported to be 70.8 percent in literature. The method has the advantages of difficult raw material source, lower economy of iodomethane atoms, complex post-treatment and more three wastes, and is not suitable for industrial production.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention provides the method for synthesizing the metamifop by the enzyme method, and the method has the advantages of mild reaction conditions, less side reactions, simple post-treatment operation, short reaction time, environmental friendliness, low production cost and better industrial utilization value.

In order to realize the technical purpose, the invention provides a method for synthesizing metamifop by an enzyme method, which takes (R) -2- [4- (6-chloro-2-benzoxazolyl-oxy) phenoxy ] propionic acid derivatives and N-methyl-2-fluoroaniline as raw materials, carries out enzyme catalytic reaction in a solvent for a certain time under certain conditions, separates the raw materials from enzyme after the reaction is finished, and purifies the raw materials after the solvent is removed to obtain the metamifop. The reaction is as follows:

the method for synthesizing metamifop by the enzyme method is characterized by comprising the following steps: the structural formula of the (R) -2- [4- (6-chloro-2-benzoxazolyl-oxy) phenoxy ] propionic acid derivative is as follows:

wherein R is-CH₃or-CH₂CH₃；

The method for synthesizing metamifop by the enzyme method is characterized by comprising the following steps: the biological enzyme is Novozym 435;

the method for synthesizing metamifop by the enzyme method is characterized by comprising the following steps: the reaction solvent is one of methanol, ethanol, n-hexane, tert-butanol or methyl isobutyl ketone, and the total dosage of the reaction solvent is 1.33L per mole of (R) -2- [4- (6-chloro-2-benzoxazolyl-oxy) phenoxy ] propionic acid derivative;

the method for synthesizing metamifop by the enzyme method is characterized by comprising the following steps: the molar ratio of the (R) -2- [4- (6-chloro-2-benzoxazolyl) phenoxy ] propionic acid derivative to the N-methyl-2-fluoroaniline is 1: 1-1: 1.3;

the method for synthesizing metamifop by the enzyme method is characterized by comprising the following steps: the enzyme dosage is 6000-10000U added into each mole of (R) -2- [4- (6-chloro-2-benzoxazolyl-oxy) phenoxy ] propionic acid derivative;

the method for synthesizing metamifop by the enzyme method is characterized by comprising the following steps: the reaction temperature is 30-70 ℃;

the method for synthesizing metamifop by the enzyme method is characterized by comprising the following steps: the (R) -2- [4- (6-chloro-2-benzoxazolyl) phenoxy ] propionic acid derivative is slowly dropped into a reaction system, the dropping time is 2 hours, and the reaction time is 4-5 hours;

the method for synthesizing metamifop by the enzyme method is characterized by comprising the following steps: dissolving the crude product with ethanol, cooling, adding water, dissolving out crystals, filtering, and drying to obtain metamifop;

the purification method is characterized in that: the volume of the ethanol is 1.67L per mole of the (R) -2- [4- (6-chloro-2-benzoxazolyl-oxy) phenoxy ] propionic acid derivative, the volume ratio of the ethanol to the water is 1: 1-1: 4, and the crystallization temperature is 0-10 ℃.

Compared with the prior art, the invention has the following advantages:

the biological enzyme catalyst is adopted to catalyze the (R) -2- [4- (6-chloro-2-benzoxazolyl-oxy) phenoxy ] propionic acid derivative and the N-methyl-2-fluoroaniline to synthesize the metamifop, the catalysis efficiency is high, and the reaction time is short; the enzyme catalysis reaction is specific, the yield of the target product is high, and the side reaction is less; the reaction process is simple to operate, reaction impurities are simple and easy to purify, and the product purity is high; the biological enzyme can be used repeatedly, and the production cost is low; mild reaction condition, less three wastes and environment-friendly property.

Detailed Description

The invention is further described below with reference to specific preferred embodiments, without thereby limiting the scope of protection of the invention.