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CN-122011018-A - Synthesis method and application of 4- (diacetoxy phosphoryl) -2-methyl-2-ethyl butenoate

CN122011018ACN 122011018 ACN122011018 ACN 122011018ACN-122011018-A

Abstract

The invention discloses a synthesis method and application of 4- (diacetoxy phosphoryl) -2-methyl-2-ethyl butenoate, and relates to the technical field of fine chemical engineering. The synthesis method comprises the following steps of carrying out condensation reaction on halogenated acetaldehyde dimethyl acetal and ethyl propionate to form a first compound, removing methanol from the first compound to form a second compound, and reacting the second compound with triethyl phosphite to obtain the 4- (diacetoxy phosphoryl) -2-methyl-2-ethyl butenoate. The invention provides a novel synthetic route of 4- (diacetoxy phosphoryl) -2-methyl-2-ethyl butenoate, which uses halogenated acetaldehyde dimethyl acetal as an initial raw material, has simple synthetic route, simple and easily obtained raw material, and high yield of the 4- (diacetoxy phosphoryl) -2-methyl-2-ethyl butenoate, and the product yield can reach more than 88 percent.

Inventors

  • WU SHILIN
  • CHEN BING
  • HUANG HAIQING
  • ZHANG GUIDONG
  • DI WEILONG
  • JIANG HUAFENG

Assignees

  • 广州智特奇生物科技股份有限公司

Dates

Publication Date
20260512
Application Date
20251211

Claims (12)

  1. 1. A method for synthesizing 4- (diacetoxy phosphoryl) -2-methyl-2-ethyl butenoate, which is characterized by comprising the following steps: the method comprises the steps of carrying out condensation reaction on halogenated acetaldehyde dimethyl acetal and ethyl propionate to form a first compound, removing methanol from the first compound to form a second compound, and reacting the second compound with triethyl phosphite to obtain the 4- (diacetoxy phosphoryl) -2-methyl-2-ethyl butenoate.
  2. 2. The synthesis method according to claim 1, wherein the mass ratio of the triethyl phosphite to the second compound is (1.1 to 1.8): 1.
  3. 3. The synthesis method according to claim 1 or 2, wherein the reaction temperature of the second compound and triethyl phosphite is 80-150 ℃.
  4. 4. The synthesis method according to claim 1, wherein the molar ratio of the ethyl propionate to the haloacetaldehyde dimethyl acetal is (1-2): 1.
  5. 5. The synthesis method according to claim 1, wherein the temperature of the condensation reaction is 30-100 ℃.
  6. 6. The method according to claim 1 or 5, wherein the condensation reaction is performed in the presence of a basic catalyst comprising at least one of bicyclononenediamine, and triethylenediamine.
  7. 7. The synthesis method according to claim 6, wherein the amount of the basic catalyst is 1 to 50% by mass of the haloacetaldehyde dimethyl acetal.
  8. 8. The method according to claim 1, wherein the condensation reaction is carried out in an organic solvent comprising at least one of methyl t-butyl ether, toluene, chloroform, methylene chloride, n-heptane, cyclohexane, and 1, 4-dioxane.
  9. 9. The synthesis method according to claim 1, wherein the temperature of the methanol removal is 50-100 ℃.
  10. 10. The method according to claim 1 or 9, wherein the methanol removal is performed in the presence of a weak base catalyst, wherein the weak base catalyst comprises at least one of sodium carbonate, sodium bicarbonate, and sodium acetate.
  11. 11. The synthesis method according to claim 10, wherein the amount of the weak base catalyst is 0.5-5% by mass of the haloacetaldehyde dimethyl acetal.
  12. 12. A process for preparing aporate, comprising the synthetic method of any one of claims 1 to 11.

Description

Synthesis method and application of 4- (diacetoxy phosphoryl) -2-methyl-2-ethyl butenoate Technical Field The invention relates to the technical field of fine chemical engineering, in particular to a synthesis method and application of 4- (diacetoxy phosphoryl) -2-methyl-2-ethyl butenoate. Background 4- (Diacetoxyphosphoryl) -2-methyl-2-butenoic acid ethyl ester is used as a key intermediate for synthesizing apo ester, and various synthesis methods exist at present, however, different defects exist in the synthesis methods, and the application effect of the synthesis methods is limited. For example, the ketone with an acetal structure is used as a starting material, and the 4- (diacetoxyphosphoryl) -2-methyl-2-ethyl butenoate is synthesized by four steps of reactions such as Grignard addition, acyl chloride-substitution, oxidation and esterification. The prior art discloses the preparation of alkyl O, O-dialkyl-gamma-phosphate, according to which ethyl 2-methyl-3-butenoate can be used as starting material to prepare ethyl 4- (diacetoxyphosphoryl) -2-methyl-2-butenoate by a multi-step reaction. However, the starting material of the method, namely the 2-methyl-3-ethyl butenoate, is difficult to obtain, and liquid bromine with high toxicity and unpleasant smell is required to be used in the reaction process, so that the method has safety risks, does not meet the environmental protection requirements, and severely restricts the practical application of the route. In addition, there is a process for synthesizing 4- (diacetoxyphosphoryl) -2-methyl-2-butenoic acid ethyl ester by using ethyl pyruvate as a starting material, and a key structure is constructed by reacting with Grignard reagent chlorovinylmagnesium. However, the ethyl pyruvate contains ketone groups and ester groups, and both have strong affinity to Grignard reagent chlorovinylmagnesium, so that the reaction selectivity is poor, byproducts are easy to generate, and the purity and the yield of target products are influenced. Or ethyl propionate, chloroacetaldehyde and triethyl phosphite are used as raw materials, and a one-pot method is tried under the action of an alkaline catalyst and an ammonium salt auxiliary agent to prepare a target product, but the chloroacetaldehyde can not only undergo self condensation and polymerization, but also undergo Wittig-Horner side reaction with the target product under the conditions of alkaline catalysis and high-temperature reaction of the method, so that the purity and the yield of the product are reduced, and the method is not suitable for industrial scale-up production. The prior art also discloses a synthetic route which takes 4-chloro-2-methyl-ethyl butenoate and triethyl phosphite as raw materials, and the raw materials react in a solvent under the action of an Fe-Ni catalyst to generate a target product. However, the preparation method has two technical problems that firstly, the preparation process of the Fe-Ni catalyst is complicated, the production cost and the operation complexity are increased, secondly, the reaction is dependent on a solvent system, and the subsequent solvent recovery process is needed, so that the process cost is increased, and the environment-friendly treatment pressure is possibly brought. Disclosure of Invention The present invention aims to solve at least one of the above technical problems in the prior art. Therefore, one of the purposes of the invention is to provide a synthesis method of 4- (diacetoxy phosphoryl) -2-methyl-2-ethyl butenoate, which has simple synthesis route, easily obtained raw materials and high yield, and is suitable for industrial production. The second purpose of the invention is to provide a preparation process of the aporate. In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: The first aspect of the invention provides a method for synthesizing 4- (diacetoxyphosphoryl) -2-methyl-2-butenoic acid ethyl ester, which comprises the following steps: the method comprises the steps of carrying out condensation reaction on halogenated acetaldehyde dimethyl acetal and ethyl propionate to form a first compound, removing methanol from the first compound to form a second compound, and reacting the second compound with triethyl phosphite to obtain the 4- (diacetoxy phosphoryl) -2-methyl-2-ethyl butenoate. The present invention provides a novel synthetic route for ethyl 4- (diacetoxyphosphoryl) -2-methyl-2-butenoate, which route selects halogenated acetaldehyde dimethyl acetal as a key starting material. The synthesis path is simple and efficient, the operation steps are clear, the raw materials are simple and common, the raw materials are easy to obtain from the market, and the cost is low. Meanwhile, the reaction can be carried out under mild conditions, the side reaction is less, the yield and purity of the final product 4- (diacetoxy phosphoryl) -2-methyl-2-ethyl butenoate are obviously improved, and the method has ex