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CN-121974948-A - Synthesis method of (Z) -type conjugated enol phosphate

CN121974948ACN 121974948 ACN121974948 ACN 121974948ACN-121974948-A

Abstract

The invention discloses a synthesis method of (Z) conjugated enol phosphate, which comprises the following steps of (1) synthesizing 4-chloroacetoacetate and phosphite ester, wherein LC-MS detection is finished, products are separated and purified to obtain the enol phosphate, (2) synthesizing (Z) conjugated enol phosphate, mixing the enol phosphate, triethylamine and acetonitrile, stirring and reacting at room temperature, LC-MS detection is finished, and products are separated and purified to obtain the (Z) conjugated enol phosphate. The method has the advantages of milder reaction conditions, higher efficiency, higher yield and better selectivity.

Inventors

  • ZHANG YULONG
  • WANG MAO
  • CHEN YUNFEI
  • SUN XING

Assignees

  • 杭州福斯特药业有限公司

Dates

Publication Date
20260505
Application Date
20251219

Claims (6)

  1. 1. The synthesis method of the (Z) -type conjugated enol phosphate is characterized by comprising the following steps of: (1) Synthesizing enol phosphate, namely reacting 4-chloroacetoacetate with phosphite ester, ending LC-MS detection, and separating and purifying the product to obtain the enol phosphate; (2) And (3) synthesizing the (Z) conjugated enol phosphate, namely mixing the enol phosphate, triethylamine and acetonitrile, stirring at room temperature for reaction, and separating and purifying a product to obtain the (Z) conjugated enol phosphate after LC-MS detection is finished.
  2. 2. The synthetic method according to claim 1, wherein the 4-chloroacetoacetate is methyl 4-chloroacetoacetate, ethyl 4-chloroacetoacetate, benzyl 4-chloroacetoacetate or isopropyl 4-chloroacetoacetate.
  3. 3. The synthesis method according to claim 1, wherein, the phosphite is trimethoxy phosphite, triethoxy phosphite, phenyl dimethoxy phosphonite or methoxy diphenyl phosphonite.
  4. 4. The synthesis method according to claim 1, wherein in the step (1), the molar ratio of 4-chloroacetoacetate to phosphite is 1:1.2-2.
  5. 5. The synthetic method of claim 1 wherein in step (1) the reaction temperature is 25-40 ℃.
  6. 6. The synthesis method according to claim 1, wherein in the step (2), the ratio of the enol phosphate to the triethylamine to the acetonitrile is 1mmol, and the ratio is 0.1-0.2mmol, and the ratio is 15-20 mL.

Description

Synthesis method of (Z) -type conjugated enol phosphate Technical Field The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing (Z) -type conjugated enol phosphate. Background The conjugated enol phosphate compound has wide bioactivity, is a core skeleton of a series of important pesticides, such as dichlorvos, monocrotophos, phosphamide and the like, and is a pesticide with wide application. From the inverse synthetic analysis, the key of the synthesis of (Z) -conjugated enol phosphate is how to construct stereospecific enol double bonds which are connected with phosphate and conjugated with carbonyl. 2 synthetic routes reported in the literature respectively adopt 2-chloroacetoacetic acid ethyl ester and acetoacetic acid ethyl ester as reactants to construct phosphoric acid ester containing conjugated olefin, and the 2 synthetic routes have advantages and disadvantages, but the obtained conjugated enol phosphoric acid ester is not a product with a single configuration, particularly the content of a high-activity isomer Z configuration is not high enough, and the yield is only moderate. Prior art Synthesis route one Adding trimethyl phosphite into ethyl 2-chloroacetoacetate serving as a raw material, and reacting for 24 hours at 80 ℃ to obtain a compound A and a compound B (compound A: B=1:2.6) with two configurations; 。 Synthesis route two of the prior art Starting from ethyl acetoacetate, reacting with dimethyl phosphate, providing alkaline conditions by using potassium tert-butoxide, taking carbon tetrachloride as a polyhalogenation reagent and acetonitrile as a solvent, and reacting at room temperature for 30 minutes to obtain a compound A and a compound B (compound A: compound B=3:7) with two configurations; 。 In the process of repeating the methods reported in the prior art, we find that the construction of conjugated enol phosphate in both methods results in a mixture of conjugated enol phosphate in two Z/E configurations, while the high-activity configuration of the conjugated enol phosphate pesticide is Z configuration. The currently used method can not prepare a single high-activity configuration by taking 2-chloro acetoacetic acid ethyl ester or acetoacetic acid ethyl ester as a raw material, and the yield of the product is only moderate. These shortcomings have prompted those skilled in the art to find a process route that is milder, more efficient, more productive, and more selective. Disclosure of Invention The invention aims to provide a synthesis method of (Z) -type conjugated enol phosphate, which has the advantages of milder reaction conditions, higher efficiency, higher yield and better selectivity. The technical scheme adopted for solving the technical problems is as follows: a method for synthesizing (Z) -type conjugated enol phosphate comprises the following steps: (1) Synthesizing enol phosphate, namely reacting 4-chloroacetoacetate with phosphite ester, ending LC-MS detection, and separating and purifying the product to obtain the enol phosphate; (2) And (3) synthesizing the (Z) conjugated enol phosphate, namely mixing the enol phosphate, triethylamine and acetonitrile, stirring at room temperature for reaction, and separating and purifying a product to obtain the (Z) conjugated enol phosphate after LC-MS detection is finished. The reaction route of the invention is as follows: R is ethoxy, methoxy, benzyloxy or isopropoxy, R 1 is methoxy, ethoxy or phenyl, and R 2 is methoxy, ethoxy or phenyl. Preferably, the 4-chloroacetoacetate is methyl 4-chloroacetoacetate, ethyl 4-chloroacetoacetate, benzyl 4-chloroacetoacetate or isopropyl 4-chloroacetoacetate. Preferably, the phosphite is trimethoxyphosphite, triethoxyphosphite, phenyldimethoxy phosphonite or methoxy diphenyl phosphonite. Preferably, in the step (1), the molar ratio of the 4-chloroacetoacetate to the phosphite is 1:1.2-2. Preferably, in step (1), the reaction temperature is 25-40 ℃. Preferably, in the step (2), the ratio of the enol phosphate to the triethylamine to the acetonitrile is 1mmol, and the ratio is 0.1-0.2mmol and 15-20 mL. The beneficial effects of the invention are as follows: (1) The synthesis method takes 4-chloroacetoacetate as an initial raw material, and obtains the target conjugated enol phosphate through Perkow reaction and 1, 3-hydrogen migration reaction in 2 steps, has stereospecificity, and can realize the synthesis of the high-activity single Z-configuration conjugated enol phosphate; (2) The raw materials used in the reaction route are 4-chloroacetoacetate, phosphite ester and triethylamine, which are common chemicals with low price and easy availability in the market; (3) The reaction route has mild reaction condition, simple purification method and high yield of the target product (the second step is more than 92%). Detailed Description The technical scheme of the invention is further specifically described by the following specific examples.