Search

CN-121990961-A - Synthesis method of L-azetidine-2-carboxylic acid

CN121990961ACN 121990961 ACN121990961 ACN 121990961ACN-121990961-A

Abstract

The invention belongs to the technical field of compound preparation, and discloses a synthesis method of L-azetidine-2-carboxylic acid. The method takes halogenated homoserine ester or salt thereof and methionine ester or salt thereof as raw materials, and obtains a target product through amino protection, ring closure, ester group hydrolysis and deprotection reaction in sequence, wherein an amino protection reagent adopts trifluoroacetic anhydride and other types, an additive is halide or halogenated alkyl ester and the like, the acid and alkali used in the reaction have specific selection ranges, the material proportion and the reaction time of each reaction are correspondingly limited, the multi-step one-pot synthesis can be realized, and the amino protection reagent can be recovered. The method does not use noble metal catalyst, adopts conventional solvent to complete reaction, has simple and convenient process, mild reaction condition and less side reaction, has the total yield of 68-74 percent, can recover amino protecting reagent, and is suitable for industrial production.

Inventors

  • ZHANG JIWEN
  • QIAN HAO
  • WU WENJUN

Assignees

  • 西北农林科技大学

Dates

Publication Date
20260508
Application Date
20260213

Claims (10)

  1. 1. A synthesis method of L-azetidine-2-carboxylic acid is characterized in that the method sequentially comprises the steps of preparing a compound of a formula (II), preparing a compound of a formula (III) through an amino protection reaction, preparing a compound of a formula (IV) through an ester hydrolysis reaction, and preparing L-azetidine-2-carboxylic acid of a formula (V) through a deprotection reaction; The synthetic route of the method is as follows: ; wherein A is a leaving group selected from Cl, br or methylthio; R is methyl or ethyl.
  2. 2. The synthesis method according to claim 1, wherein: When the compound of the formula (II) is prepared, the compound of the formula (I) is dissolved in dichloromethane or N, N-dimethylformamide and then mixed with an amino protecting reagent and a first base for reaction; In the preparation of the compound of formula (III), the compound of formula (II) is dissolved in acetonitrile or N, N-dimethylformamide and then mixed with a second base and an additive for reaction; When the compound shown in the formula (IV) is prepared, the compound shown in the formula (III) is hydrolyzed with first acid or is hydrolyzed with third alkaline hydrolysis, and the pH value of the reaction system is adjusted to 5-6; In the preparation of the compound of formula (V), the compound of formula (IV) is dissolved in methanol and then reacted with a second acid, or dissolved in a methanol-water mixture and then reacted with a fourth base.
  3. 3. The synthesis method according to claim 2, wherein the amount of the substance is: The ratio of the compound of the formula (I) to the amino protecting reagent to the first alkali is 1:1.03-1.2:2.0-2.5; The proportion of the compound of the formula (II), the second base and the additive is 1:1.1-1.3:0.1-1.1; the ratio of the compound of the formula (III) to the first acid is 1:0.1-1.5; the ratio of the compound of the formula (III) to the third alkali is 1:1.0-3.0; the ratio of the compound of the formula (IV) to the second acid is 1:0.5-3.0; the ratio of the compound of the formula (IV) to the fourth base is 1:1.0-1.5.
  4. 4. The synthesis method according to claim 3, wherein the first base, the second base, the third base and the fourth base are at least one of triethylamine, pyridine, sodium phosphate, sodium carbonate, potassium phosphate and sodium hydroxide; the first acid and the second acid are at least one of sulfuric acid, hydrochloric acid, trifluoroacetic acid, trichloroacetic acid and glacial acetic acid respectively and independently.
  5. 5. The synthesis method according to claim 2, wherein the amino protecting reagent R 1 X used in the amino protecting reaction in the preparation of the compound of formula (II) is at least one of trifluoroacetic anhydride, trichloroacetyl chloride, dichloroacetyl chloride and triarylchloromethane.
  6. 6. The method according to claim 2, wherein the additive used in the preparation of the compound of formula (III) is at least one of sodium iodide, potassium iodide, sodium bromide, potassium bromide, methyl iodide, methyl chloride, benzyl bromide, bromopropene, chloroacetic acid, ethyl chloroacetate, and ethyl bromoacetate.
  7. 7. The synthesis method according to claim 2, characterized in that: the reaction time for preparing the compound of the formula (II) is 6-12 hours; The reaction time for preparing the compound of the formula (III) is 5-7 hours; the reaction time for preparing the compound of the formula (IV) is 0.5-4 h; the reaction time for preparing the compound of formula (V) is 2-6 hours.
  8. 8. Use of the synthesis method of L-azetidine-2-carboxylic acid according to claim 1 for the preparation of a plant disease control agent.
  9. 9. The use according to claim 8, wherein the plant disease control agent is a powdery mildew control agent for melons.
  10. 10. The use of the synthesis method of L-azetidine-2-carboxylic acid according to claim 1 for the preparation of harmful algae remover for water environmental treatment or molecular building blocks for drug synthesis.

Description

Synthesis method of L-azetidine-2-carboxylic acid Technical Field The invention belongs to the technical field of compound preparation, and relates to a synthesis method of L-azetidine-2-carboxylic acid. Background The L-azetidine-2-carboxylic acid is an important four-membered ring compound, has extremely high application value, and has good application prospect in the fields of agricultural protection, water environment treatment and drug synthesis. In the aspect of agricultural disease control, the compound has excellent control effect on powdery mildew of melons, can block disease circulation in a mode of directly destroying pathogenic hyphae, inhibiting conidium formation or leading to spore deformity, realizes disease control and eradication, has selective algae inhibition activity, can inhibit blue algae growth at a specific concentration and has no obvious influence on green algae, is a potential natural selective algicide, can effectively control harmful algae in water, can be used as an important molecular building block, and is widely applied to the synthesis process of various medicines, thus becoming a key intermediate in the field of medicine research and development. In view of the multiple application value of the L-azetidine-2-carboxylic acid, the research and optimization of the synthesis method are focused, but the synthesis route of the compound in the prior art still has a plurality of defects to be solved, the conventional synthesis process generally has the problems of long process route, low reaction yield, higher raw material purchase cost, complex post-treatment operation and the like, and part of the process also needs to rely on harsh reaction conditions such as low temperature and the like, so that the problem directly limits the large-scale industrial preparation of the L-azetidine-2-carboxylic acid, and the problem is difficult to realize wide practical landing in various application fields. In order to solve the above problems, the applicant has proposed an improvement scheme of the synthesis process of L-azetidine-2-carboxylic acid in 2024 and filed a related patent of invention (CN 118496138 a), which can realize the large-scale synthesis of the compound, but the use of sodium triacetoxyborohydride, palladium-carbon catalyst and other expensive reagents and catalysts results in high production cost in the synthesis process, and the practical requirements of low cost and high efficiency in industrial production cannot be met. Disclosure of Invention The invention aims to solve a plurality of defects of the L-azetidine-2-carboxylic acid synthesis process in the prior art, solves the problems of long process, low reaction yield, high raw material cost, complex post-treatment operation and low-temperature reaction condition dependence of part of the process in the traditional synthesis route, and solves the problem of high production cost caused by the use of expensive reagents and noble metal catalysts in the synthesis improvement scheme proposed by the applicant. In order to achieve the above object, the present invention provides a method for synthesizing L-azetidine-2-carboxylic acid (the core synthesis route is shown in fig. 1), wherein the method comprises the steps of preparing a compound of formula (II) through an amino protection reaction, preparing a compound of formula (III) through a ring closure reaction, preparing a compound of formula (IV) through an ester hydrolysis reaction, and preparing L-azetidine-2-carboxylic acid of formula (V) through a deprotection reaction; The synthetic route of the method is as follows: ; wherein A is a leaving group selected from Cl, br or methylthio; R is methyl or ethyl. Further, in the above synthesis method: When the compound of the formula (II) is prepared, the compound of the formula (I) is dissolved in dichloromethane or N, N-dimethylformamide and then mixed with an amino protecting reagent and a first base for reaction; In the preparation of the compound of formula (III), the compound of formula (II) is dissolved in acetonitrile or N, N-dimethylformamide and then mixed with a second base and an additive for reaction; When the compound shown in the formula (IV) is prepared, the compound shown in the formula (III) is hydrolyzed with first acid or is hydrolyzed with third alkaline hydrolysis, and the pH value of the reaction system is adjusted to 5-6; In the preparation of the compound of formula (V), the compound of formula (IV) is dissolved in methanol and then reacted with a second acid, or dissolved in a methanol-water mixture and then reacted with a fourth base. Further, in the above synthetic method, the amount of the substance is as follows: The ratio of the compound of the formula (I) to the amino protecting reagent to the first alkali is 1:1.03-1.2:2.0-2.5; The proportion of the compound of the formula (II), the second base and the additive is 1:1.1-1.3:0.1-1.1; the ratio of the compound of the formula (III) to the firs