Synthetic method of L-azetidine-2-carboxylic acid

Abstract

The invention belongs to the technical field of compound preparation, and discloses a synthesis method of L-azetidine-2-carboxylic acid. According to the method, halogenated homoserine ester or salt thereof and methionine ester or salt thereof are used as raw materials, and amino protection, ring closing, ester group hydrolysis and deprotection reaction are sequentially performed to obtain a target product. The amino protection reagent is selected from trifluoroacetic anhydride and the like, the additive is halide or halogenated alkyl ester and the like, acid and alkali used in the reaction have specific selection ranges, the material ratio and the reaction time of each step of reaction are correspondingly limited, multi-step one-pot synthesis can be realized, and meanwhile, the amino protection reagent can be recycled. According to the method, a noble metal catalyst is not used, the reaction is completed by adopting a conventional solvent, the process is simple and convenient, reaction conditions are mild, side reactions are few, the total yield can reach 68-74%, an amino protection reagent can be recycled, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of compound preparation technology and relates to a method for synthesizing L-azacyclobutane-2-carboxylic acid. Background Technology

[0002] L-azacyclobutane-2-carboxylic acid is an important four-membered ring compound with high application value, showing promising prospects in agricultural protection, water environment management, and drug synthesis. In agricultural disease control, this compound exhibits excellent control effects against powdery mildew in cucurbits, blocking the disease cycle by directly destroying pathogenic hyphae, inhibiting conidia formation, or causing spore malformation, thus achieving disease control and eradication. In water environment management, it possesses selective algicidal activity, inhibiting cyanobacterial growth at specific concentrations without significantly affecting green algae, making it a potential natural selective algaecide that can effectively control harmful algae in water bodies. Furthermore, this compound can also serve as an important molecular building block, widely used in the synthesis of various drugs, becoming a key intermediate in drug development.

[0003] Given the multiple applications of L-azacyclobutane-2-carboxylic acid, the research and optimization of its synthesis methods have attracted much attention. However, the existing synthetic routes for this compound still have many shortcomings that need to be addressed. Conventional synthetic processes generally suffer from lengthy routes, low reaction yields, high raw material procurement costs, and cumbersome post-processing. Furthermore, some processes require harsh reaction conditions such as low temperatures. These problems directly limit the large-scale industrial preparation of L-azacyclobutane-2-carboxylic acid and make it difficult to achieve widespread practical application in various fields. To improve some of these problems, the applicant proposed an improved synthetic process for L-azacyclobutane-2-carboxylic acid in 2024 and applied for a related invention patent (CN118496138A). Although this scheme can achieve the large-scale synthesis of this compound, the use of expensive reagents and catalysts such as sodium triacetoxyborohydride and palladium on carbon results in high production costs, which still cannot meet the actual needs of low-cost and efficient preparation in industrial production. Summary of the Invention

[0004] The purpose of this invention is to address the numerous shortcomings of existing synthetic processes for L-azacyclobutane-2-carboxylic acid. It addresses the problems of lengthy processes, low reaction yields, high raw material costs, complex post-processing, and reliance on low-temperature reaction conditions in traditional synthetic routes. Furthermore, it resolves the issue of high production costs caused by the use of expensive reagents and precious metal catalysts in the applicant's previous synthetic improvement schemes. This invention provides a simpler, lower-cost synthetic method for L-azacyclobutane-2-carboxylic acid, with milder reaction conditions suitable for industrial production, to meet the practical application needs of this compound in agricultural conservation, water environment management, and pharmaceutical synthesis.

[0005] To achieve the above-mentioned objectives, this invention provides a method for synthesizing L-azacyclobutane-2-carboxylic acid (the core synthetic route is as follows). Figure 1 As shown), the method sequentially prepares compound (II) by amino protection reaction, compound (III) by cyclization reaction, compound (IV) by ester hydrolysis reaction, and L-azacyclobutane-2-carboxylic acid of compound (V) by deprotection reaction;

[0006] 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.

[0007] Furthermore, in the above synthesis method: When preparing compound (II), compound (I) is dissolved in dichloromethane or N,N-dimethylformamide and then reacted with an amino protecting agent and a first base; When preparing compound (III), compound (II) is dissolved in acetonitrile or N,N-dimethylformamide and then reacted with a second base and an additive. When preparing compound (Ⅳ), compound (Ⅲ) is hydrolyzed with a first acid or with a third base and the pH of the reaction system is adjusted to 5-6. When preparing compound (V), compound (IV) is dissolved in methanol and then reacted with the second acid, or dissolved in a methanol-water mixture and then reacted with the fourth base.

[0008] Furthermore, in the above synthesis method, in terms of molar amount: The ratio of compound (I), amino protecting agent, and first base is 1:1.03~1.2:2.0~2.5; The ratio of compound (II), second alkali, and additive is 1:1.1~1.3:0.1~1.1; The ratio of compound (III) to the first acid is 1:0.1~1.5; The ratio of compound (III) to the third base is 1:1.0~3.0; The ratio of compound (Ⅳ) to the second acid is 1:0.5~3.0; The ratio of compound (Ⅳ) to the fourth base is 1:1.0~1.5.

[0009] Furthermore, in the above synthesis method, the first base, the second base, the third base, and the fourth base are each independently at least one of the following: triethylamine, pyridine, sodium phosphate, sodium carbonate, potassium carbonate, potassium phosphate, and sodium hydroxide; The first acid and the second acid are each independently selected from at least one of sulfuric acid, hydrochloric acid, trifluoroacetic acid, trichloroacetic acid, and glacial acetic acid.

[0010] Furthermore, in the above synthetic method, when preparing compound (II), the amino protecting reagent R used in the amino protecting reaction... 1 X is at least one of trifluoroacetic anhydride, trichloroacetyl chloride, dichloroacetyl chloride, and triarylchloromethane.

[0011] Furthermore, in the above synthesis method, when preparing compound (III), the additive used is at least one of the following: sodium iodide, potassium iodide, sodium bromide, potassium bromide, iodomethane, chloromethane, benzyl chloride, benzyl bromide, bromopropylene, chloroacetic acid, ethyl chloroacetate, and ethyl bromoacetate.

[0012] Furthermore, in the above synthesis method: The reaction time for preparing compound (II) is 6-12 h; The reaction time for preparing compound (III) is 5-7 h; The reaction time for preparing compound (Ⅳ) is 0.5–4 h; The reaction time for preparing compound (V) is 2-6 hours. Secondly, the present invention seeks protection for the application of the above-described method for synthesizing L-azacyclobutane-2-carboxylic acid in the preparation of plant disease control agents.

[0013] Furthermore, in the above application, the plant disease control agent is a powdery mildew control agent for cucurbits.

[0014] Thirdly, the present invention seeks protection for the application of the above-described method for synthesizing L-azacyclobutane-2-carboxylic acid in the preparation of harmful algae removers for water environment treatment or molecular building blocks for drug synthesis.

[0015] Compared with the prior art, the technical solution of the present invention has significant beneficial effects: This method eliminates the use of expensive reagents such as precious metal catalysts and sodium triacetoxyborohydride, significantly reducing the raw material and production costs of the synthesis process. At the same time, it avoids the harsh reaction conditions such as low temperature in traditional processes, and the reaction conditions are mild and easy to control.

[0016] This invention systematically optimizes the reagents, solvents, material ratios, and reaction times for each step of the synthesis process, making the entire synthesis process simpler to operate, the post-processing flow more streamlined, and the side reactions fewer. The amino-protecting reagent can also be recycled and reused, further improving the economic efficiency of the process.

[0017] Furthermore, the synthesis method of the present invention can also realize a multi-step one-pot synthesis mode, which effectively shortens the process operation cycle. The overall yield of the entire synthesis route can reach 68-74%, and it can stably realize the large-scale preparation of L-azacyclobutane-2-carboxylic acid, which is fully adapted to the needs of industrial production.

[0018] Through the above-mentioned technical improvements, this invention effectively solves various defects in existing synthesis processes, and the high-purity L-azacyclobutane-2-carboxylic acid obtained can fully meet its application needs in plant disease prevention and control, harmful algae removal, and drug synthesis molecular building blocks, thus promoting the industrial application of this compound in agriculture, environment and medicine. Attached Figure Description

[0019] Figure 1 This is a schematic diagram of the core synthetic route for the target product L-azacyclobutane-2-carboxylic acid, as shown in formula (V) of the invention. It illustrates the overall process route for obtaining the target product L-azacyclobutane-2-carboxylic acid of formula (V) from the starting material of compound (I) through four steps: amino protection, ring closure, ester hydrolysis, and deprotection. Wherein A is the leaving group, R is the substituent, formula (I) is the starting material, formula (II) is the intermediate obtained after the amino protection reaction, formula (III) is the intermediate obtained after the ring closure reaction, formula (IV) is the intermediate obtained after the ester hydrolysis reaction, and formula (V) is the target product L-azacyclobutane-2-carboxylic acid obtained after the deprotection reaction.

[0020] Figure 2 This is a schematic diagram of the synthetic route for the target product L-azacyclobutane-2-carboxylic acid in Example 1, showing the specific reaction route for preparing the target product using chlorohomoserine ethyl ester hydrochloride and trichloroacetyl chloride as starting materials.

[0021] Figure 3The image shows the 1H NMR spectrum of the compound of formula (Ⅱ-1) obtained in Example 1. The horizontal axis fl (ppm) ranges from -1.5 to 10.5, and the compound of formula (Ⅱ-1) is labeled. The values ​​next to the characteristic peaks are intensity-related parameters of the corresponding signal peaks. This spectrum characterizes the resonance features of hydrogen atoms in different chemical environments in the compound of formula (Ⅱ-1).

[0022] Figure 4 The image shows the 1H NMR spectrum of the target product L-azacyclobutane-2-carboxylic acid, as shown in formula (V) obtained in Example 1. The horizontal axis fl (ppm) ranges from 0.0 to 7.0, and the values ​​on the vertical and horizontal axes represent the intensity-related parameters of the signal peaks. This spectrum characterizes the resonance features of hydrogen atoms in different chemical environments within L-azacyclobutane-2-carboxylic acid.

[0023] Figure 5 The image shows the carbon NMR spectrum of the target product L-azacyclobutane-2-carboxylic acid, as shown in formula (V) obtained in Example 1. The horizontal axis fl (ppm) ranges from 0 to 200, and the labeled values ​​represent the specific chemical shifts corresponding to the characteristic carbon signal peaks. This spectrum characterizes the resonance features of carbon atoms in different chemical environments within L-azacyclobutane-2-carboxylic acid.

[0024] Figure 6 This is a schematic diagram of the synthetic route for the target product L-azacyclobutane-2-carboxylic acid in Example 2, showing the specific reaction route for preparing the target product using chlorohomoserine ethyl ester hydrochloride and triphenylchloromethane as starting materials.

[0025] Figure 7 The image shows the 1H NMR spectrum of the compound of formula (Ⅲ-2) obtained in Example 2. The horizontal axis fl (ppm) ranges from -1.5 to 10.5, and the compound of formula (Ⅲ-2) is labeled with its structural formula. Ph is the structural identifier for phenyl. The values ​​next to the characteristic peaks are intensity-related parameters of the corresponding signal peaks. This spectrum characterizes the resonance features of hydrogen atoms in different chemical environments in the compound of formula (Ⅲ-2).

[0026] Figure 8 This is a schematic diagram of the preparation route of the compound shown in formula (Ⅱ-2) in Example 3, showing the preparation of intermediate (Ⅱ-2) using chlorohomoserine ethyl ester hydrochloride and triphenylchloromethane as starting materials.

[0027] Figure 9 This is a schematic diagram of the synthetic route for the target product L-azacyclobutane-2-carboxylic acid in Example 4, showing the specific reaction route for preparing the target product (V) via a deprotection reaction using formula (Ⅳ-2) as an intermediate.

[0028] Figure 10This is a schematic diagram of the synthetic route for the target product L-azacyclobutane-2-carboxylic acid in Example 5, showing the specific reaction route for preparing the target product using chlorohomoserine ethyl ester hydrochloride and triphenylchloromethane as starting materials in a multi-step one-pot method.

[0029] Figure 11 This is a schematic diagram of the synthetic route for the target product L-azacyclobutane-2-carboxylic acid in Example 6, showing the specific reaction route for preparing the target product using methionine ethyl ester hydrochloride and triphenylchloromethane as starting materials. Detailed Implementation

[0030] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0031] Example 1 This embodiment provides a synthetic method for preparing L-azacyclobutane-2-carboxylic acid using chlorohomoserine ethyl ester hydrochloride and trichloroacetyl chloride as starting materials (the synthetic route of L-azacyclobutane-2-carboxylic acid in this embodiment is as follows). Figure 2 (As shown), the specific synthesis steps are as follows: 1. Preparation of compound (Ⅱ-1) 202 g of chlorohomoserine ethyl ester hydrochloride and 222 g of triethylamine were added to a 5 L reaction flask. 2 L of dichloromethane was added and stirred until completely dissolved. 200 g of trichloroacetyl chloride was slowly added dropwise to the solution at room temperature, and the reaction was continued with stirring for 7 h after the addition was complete. After the reaction was complete, the reaction solution was poured into 2 L of water, thoroughly mixed, and then separated. The aqueous layer was discarded, and the resulting organic layer was washed twice with 2 L of water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 295 g of compound (II-1), with a yield of 95%. The 1H NMR spectrum of compound (II-1) is shown below. Figure 3 As shown, Figure 3 The horizontal axis fl (ppm) represents the chemical shift, in parts per million. This 1H NMR spectrum was measured at 400 MHz using deuterated chloroform as the solvent. The 1H NMR data are as follows: 1H NMR(400MHz,Chloroform-d)δ7.43(d,J=7.0Hz,1H),4.68(q,J=6.9,6.2Hz,1H),4.29(q,J=7.2Hz,2H),3 .61(t,J=6.5Hz,2H),2.51(dq,J=12.7,6.3Hz,1H),2.34(dq,J=13.8,6.7Hz,1H),1.33(t,J=7.2Hz,3H).

[0032] 2. Preparation of compound (Ⅲ-1) 295g of the compound of formula (II-1) prepared above and 2L of acetonitrile were added to a 5L reaction flask and stirred at room temperature until completely dissolved. 11g of sodium bromide was added, and the reaction system was heated to 60℃ and maintained at this temperature for 5h. After the reaction was completed, the solvent in the system was removed under reduced pressure. 2L of ethyl acetate was added to the reaction residue, and the resulting organic layer was washed twice with 2L of water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 242g of compound of formula (III-1), with a yield of 93%.

[0033] 3. Preparation of compounds of formula (Ⅳ-1) 242 g of the compound of formula (Ⅲ-1) prepared above and 1 L of methanol were added to a 5 L reaction flask and stirred until completely dissolved. 100 mL of 1 M sulfuric acid aqueous solution was added, and the reaction was carried out at room temperature for 3 h. After the reaction was completed, the solvent in the system was removed under reduced pressure. 1 L of ethyl acetate was added to the reaction residue, and the resulting organic layer was washed twice with 1 L of water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 194 g of compound of formula (Ⅳ-1), with a yield of 89%.

[0034] 4. Preparation of compound L-azacyclobutane-2-carboxylic acid of formula (V) 194g of the compound of formula (Ⅳ-1) prepared above and 1L of methanol were added to a 10L reactor and stirred until completely dissolved. A solution of 135g of Ba(OH)₂ dissolved in 5L of water was then added, and the mixture was reacted at room temperature for 5 hours. After the reaction was complete, dilute sulfuric acid solution was added dropwise to adjust the pH to 5-6. The mixture was then filtered, and the filtrate was extracted once with 5L of dichloromethane. The organic layer was discarded, and the aqueous phase was concentrated under reduced pressure to obtain 68g of compound of formula (Ⅴ) L-azacyclobutane-2-carboxylic acid, with a yield of 86%. The 1H NMR spectrum of compound of formula (Ⅴ) is shown below. Figure 4 As shown, Figure 4 The horizontal axis fl (ppm) represents the chemical shift, in parts per million. This 1H NMR spectrum was tested at a frequency of 400MHz, using heavy water as the solvent. The 1H NMR data are as follows: 1¹H NMR (400MHz, Deuterium Oxide) δ 4.75 (d, J = 7.8 Hz, 1H), 4.05 (p, J = 9.3, 8.9 Hz, 1H), 3.88 (qd, J = 9.6, 5.3 Hz, 1H), 2.73 (dtd, J = 12.4, 9.8, 6.2 Hz, 1H), 2.58–2.39 (m, 1H); ¹H NMR spectrum of compound (V) is as follows: Figure 5 As shown, Figure 5 The horizontal axis fl (ppm) represents the chemical shift, in parts per million. This carbon NMR spectrum was measured at a frequency of 101 MHz, using heavy water as the solvent. The carbon NMR data are as follows: 13 C NMR (101 MHz, Deuterium Oxide) δ 174.11, 58.99, 42.77, 23.36.

[0035] Example 2 This embodiment provides a synthetic process for preparing L-azacyclobutane-2-carboxylic acid from chlorohomoserine ethyl ester hydrochloride and triphenylchloromethane as starting materials (the synthetic route of L-azacyclobutane-2-carboxylic acid in this embodiment is as follows). Figure 6 (As shown), the specific synthesis steps are as follows: 1. Preparation of the compound shown in formula (Ⅱ-2) 202 g of chlorohomoserine ethyl ester hydrochloride, 286 g of triphenylchloromethane, and 344 g of sodium phosphate were added to a 5 L reaction flask. 1 L of N,N-dimethylformamide was added and stirred until completely dissolved. The reaction was carried out at room temperature with continuous stirring for 10 h. After the reaction was complete, the reaction solution was slowly poured into 6 L of water, and a white precipitate formed. The precipitate was filtered, and the filter cake was washed with water and dried to obtain 399 g of the compound shown in formula (Ⅱ-2), with a yield of 98%.

[0036] 2. Preparation of the compound shown in formula (Ⅲ-2) 399g of the compound of formula (II-2) prepared above and 1L of N,N-dimethylformamide were added to a 5L reaction flask. 20g of sodium bromide and 148g of potassium carbonate were added sequentially to the reaction system. After thorough stirring, the reaction system was heated to 100℃ and maintained at this temperature for 6 hours. After the reaction was completed, the system was cooled to room temperature, and then the reaction solution was slowly poured into 6L of water. A yellowish-white precipitate formed in the system. The precipitate was filtered, and the filter cake was washed with water and dried to obtain 333g of the compound of formula (III-2), with a yield of 92%. The proton NMR spectrum of the compound of formula (III-2) is shown below. Figure 7 As shown, the spectrum was tested at a frequency of 400 MHz, the solvent was deuterated chloroform, and its 1H NMR data are as follows: 1H NMR(400MHz,Chloroform-d)δ7.53(d,J=7.8Hz,5H),7.27(t,J=7.7Hz,7H),7.18(t,J=7.3Hz,3H),4.04–3.94(m,1H),3.9 1–3.81(m,1H),3.51(q,J=8.3Hz,2H),2.84–2.75(m,1H),2.35(p,J=8.8Hz,1H),1.59–1.51(m,1H),1.03(t,J=7.1Hz,3H).

[0037] 3. Preparation of the compound shown in formula (Ⅳ-2) 333g of the compound of formula (Ⅲ-2) prepared above and 1L of methanol were added to a 5L reaction flask and stirred until completely dissolved. 0.9L of 1M sodium hydroxide aqueous solution was added and the mixture was reacted at room temperature for 3h. After the reaction was completed, the methanol was removed by vacuum distillation. Then, dilute hydrochloric acid was added to the remaining system to adjust the pH of the reaction solution to 5-6. A large amount of white solid precipitated in the system. The solid was filtered and dried to obtain 284g of the compound of formula (Ⅳ-2), with a yield of 92%.

[0038] 4. Preparation of the target compound L-azacyclobutane-2-carboxylic acid shown in formula (V) 284g of the compound of formula (Ⅳ-2) prepared above and 0.8L of methanol were added to a 5L reaction flask. 35mL of concentrated sulfuric acid was slowly added dropwise to the reaction system, and the reaction was stirred continuously at room temperature for 5h. After the reaction was completed, barium hydroxide aqueous solution was added to the system to adjust the pH value of the system to 5-6. Then, the system was subjected to vacuum distillation to remove methanol. 1L of water was added to the remaining system and the system was filtered. The filtrate was collected and concentrated under vacuum to obtain 74g of the target compound L-azacyclobutane-2-carboxylic acid of formula (Ⅴ), with a yield of 89%.

[0039] Example 3 This embodiment provides a synthetic method for preparing L-azacyclobutane-2-carboxylic acid using chlorohomoserine ethyl ester hydrochloride and triphenylchloromethane as starting materials. First, the compound shown in formula (Ⅱ-2) is prepared. The subsequent operations for synthesizing the target product L-azacyclobutane-2-carboxylic acid of formula (Ⅴ) from the compound shown in formula (Ⅱ-2) are the same as in Example 2.

[0040] Preparation of the compound shown in formula (Ⅱ-2) (the preparation process is as follows) Figure 8As shown): 202g of chlorohomoserine ethyl ester hydrochloride, 286g of triphenylchloromethane, and 242g of triethylamine were added to a 5L reaction flask. 1L of dichloromethane was added and stirred to dissolve the mixture. The reaction was carried out at room temperature for 8 hours. After the reaction was complete, the reaction solution was poured into 1L of water, and the organic phase was collected by separation. The organic phase was extracted twice with 1L of water, dried over anhydrous sodium sulfate, and concentrated to obtain 403g of the compound shown in formula (Ⅱ-2), with a yield of 99%.

[0041] The compound of formula (II-2) obtained above was subjected to a cyclization reaction to prepare the compound of formula (III-2). The proton NMR spectrum of the compound of formula (III-2) is as follows: Figure 7 Its 1H NMR spectrum data is consistent with that of the compound shown in formula (Ⅲ-2) described in Example 2; after obtaining the compound shown in formula (Ⅳ-2) through ester hydrolysis, the target product L-azacyclobutane-2-carboxylic acid shown in formula (Ⅴ) is obtained through deprotection reaction. The 1H NMR spectrum of this target product is as follows: Figure 4 Carbon spectrum is Figure 5 The 1H NMR and 1C NMR data are consistent with the corresponding data of the compound shown in formula (V) in Example 1. The product yield and actual product amount of each reaction step can be obtained by converting the feed ratio in Example 2.

[0042] Example 4 This embodiment provides a synthetic method for preparing L-azacyclobutane-2-carboxylic acid from chlorohomoserine ethyl ester hydrochloride and triphenylchloromethane as starting materials, wherein the compound shown in formula (Ⅳ-2) is prepared according to the complete operation of Example 2; the following are the specific steps for preparing L-azacyclobutane-2-carboxylic acid of formula (Ⅴ) by deprotection reaction from the obtained compound shown in formula (Ⅳ-2) (the preparation process is as follows). Figure 9 (as shown) 103g of the compound shown in formula (Ⅳ-2) and 1L of dichloromethane were added to a 5L reaction flask. Hydrogen chloride gas was continuously bubbled into the reaction solution at 0℃, resulting in a white precipitate. After reacting for 2 hours, 1L of water was added to the reaction solution. After standing and separating the layers, the aqueous phase was collected. The collected aqueous phase was extracted twice with 0.5L of dichloromethane. The dichloromethane phase after extraction contained regenerated triphenylchloromethane, allowing for the recovery and reuse of the amino protecting reagent. The aqueous phase after extraction was concentrated under reduced pressure to obtain 25g of L-azacyclobutane-2-carboxylic acid shown in formula (Ⅴ), with a yield of 83%. The proton NMR spectrum of the precursor intermediate (Ⅲ-2) of the compound shown in formula (Ⅳ-2) is as follows: Figure 7 Its 1H NMR spectrum data is consistent with that of the compound shown in formula (Ⅲ-2) described in Example 2; the 1H NMR spectrum of the target compound shown in formula (Ⅴ) obtained in this example is as follows: Figure 4 Carbon spectrum is Figure 5Its 1H NMR and 1C NMR data are consistent with the corresponding data of the compound shown in formula (V) in Example 1.

[0043] Example 5 This embodiment provides a multi-step one-pot synthesis process for preparing L-azacyclobutane-2-carboxylic acid using chlorohomoserine ethyl ester hydrochloride and triphenylchloromethane as starting materials. The compound shown in formula (Ⅳ-2) is prepared using a multi-step one-pot method. Subsequent operations for synthesizing the target product L-azacyclobutane-2-carboxylic acid (formula (Ⅴ)) from the compound shown in formula (Ⅳ-2) are consistent with those in Example 2 (the preparation process is as follows). Figure 10 (As shown).

[0044] The compound shown in formula (Ⅳ-2) was prepared in a multi-step one-pot reaction: 202 g of chlorohomoserine ethyl ester hydrochloride, 286 g of triphenylchloromethane, and 276 g of potassium carbonate were added to a 5 L reaction flask, along with 1 L of N,N-dimethylformamide. The reaction was carried out at 50 °C for 12 h. After the reaction was complete, no further processing was required. 20 g of sodium bromide and 138 g of potassium carbonate were added directly to the reaction system, and the reaction temperature was increased to 100 °C. After stirring for 6 h, the ring-closing reaction was completed. The system was then cooled to 60 °C, and 1 L of water was added. The reaction was maintained at this temperature for 4 h until the reaction was complete. The pH of the reaction solution was adjusted to 5-6 using dilute hydrochloric acid, and 6 L of water was added to promote the precipitation of product Ⅳ-2. After filtration and drying, 269 g of the compound shown in formula (Ⅳ-2) was obtained. The overall yield of the three-step one-pot reaction was 78%.

[0045] The 1H NMR spectrum of the compound of formula (Ⅲ-2) generated by the ring-closing reaction in this embodiment is as follows: Figure 7 Its 1H NMR spectrum data is consistent with that of the compound of formula (Ⅲ-2) described in Example 2; the 1H NMR spectrum of the target compound of formula (Ⅴ) finally obtained from the compound of formula (Ⅳ-2) prepared above through a deprotection reaction is as follows. Figure 4 Carbon spectrum is Figure 5 The 1H NMR and 1C NMR data are consistent with the corresponding data of the compound shown in formula (V) in Example 1. The product yield and actual product amount of each subsequent reaction step can be obtained by converting the feed ratio in Example 2.

[0046] Example 6 This embodiment provides a synthetic method for preparing L-azacyclobutane-2-carboxylic acid using methionine ethyl ester hydrochloride and triphenylchloromethane as starting materials. First, the compound shown in formula (II-3) and the compound shown in formula (III-2) are prepared sequentially. Subsequent operations for synthesizing the target product L-azacyclobutane-2-carboxylic acid of formula (V) from the compound shown in formula (III-2) are consistent with those in Example 2 (the preparation process is as follows). Figure 11 (As shown).

[0047] 1. Preparation of the compound shown in formula (II-3): 213 g of methionine ethyl ester hydrochloride, 286 g of triphenylchloromethane, and 344 g of sodium phosphate were added to a 5 L reaction flask, and 1 L of N,N-dimethylformamide was added and stirred to dissolve. The mixture was stirred at room temperature for 10 h. After the reaction was completed, the reaction solution was poured into 6 L of water, and a white precipitate formed. After filtration, washing with water, and drying, 406 g of the compound shown in formula (II-3) was obtained, with a yield of 97%.

[0048] 2. Preparation of the compound shown in formula (Ⅲ-2): 406g of the compound shown in formula (Ⅱ-3) and 1L of N,N-dimethylformamide were added to a 5L reaction flask. 178g of ethyl bromoacetate and 148g of potassium carbonate were added sequentially. The reaction system was reacted at 100℃ for 7h. After cooling to room temperature, the reaction solution was poured into 6L of water, resulting in a yellowish-white precipitate. After filtration, washing with water, and drying, 323g of the compound shown in formula (Ⅲ-2) was obtained, with a yield of 90%. The 1H NMR spectrum of the compound shown in formula (Ⅲ-2) obtained in this example is as follows: Figure 7 Its 1H NMR spectrum data is consistent with the 1H NMR spectrum data of the compound shown in formula (Ⅲ-2) described in Example 2.

[0049] The compound of formula (Ⅲ-2) obtained above was subjected to ester hydrolysis to obtain the compound of formula (Ⅳ-2), and then subjected to deprotection reaction to obtain the target compound L-azacyclobutane-2-carboxylic acid of formula (Ⅴ). The operation was carried out in accordance with Example 2. The 1H NMR spectrum of the target compound of formula (Ⅴ) obtained in the end is as follows. Figure 4 Carbon spectrum is Figure 5 The 1H NMR and 1C NMR data are consistent with the corresponding data of the compound shown in formula (V) in Example 1. The product yield and actual product amount of each reaction step can be obtained by converting the feed ratio in Example 2.

[0050] The embodiments described above are only some, not all, of the embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments. All other embodiments obtained by those skilled in the art through related deductions and substitutions based on the inventive concept, without inventive effort, are within the scope of protection of the present invention.

Claims

1. A method for synthesizing L-azacyclobutane-2-carboxylic acid, characterized in that, The method sequentially prepares compound (II) by amino protection reaction, compound (III) by cyclization reaction, compound (IV) by ester hydrolysis reaction, and L-azacyclobutane-2-carboxylic acid of compound (V) by 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. The synthesis method according to claim 1, characterized in that: When preparing compound (II), compound (I) is dissolved in dichloromethane or N,N-dimethylformamide and then reacted with an amino protecting agent and a first base; When preparing compound (III), compound (II) is dissolved in acetonitrile or N,N-dimethylformamide and then reacted with a second base and an additive. When preparing compound (Ⅳ), compound (Ⅲ) is hydrolyzed with a first acid or with a third base and the pH of the reaction system is adjusted to 5-6. When preparing compound (V), compound (IV) is dissolved in methanol and then reacted with the second acid, or dissolved in a methanol-water mixture and then reacted with the fourth base.

3. The synthesis method according to claim 2, characterized in that, In terms of amount of substance: The ratio of compound (I), amino protecting agent, and first base is 1:1.03~1.2:2.0~2.5; The ratio of compound (II), second alkali, and additive is 1:1.1~1.3:0.1~1.1; The ratio of compound (III) to the first acid is 1:0.1~1.5; The ratio of compound (III) to the third base is 1:1.0~3.0; The ratio of compound (Ⅳ) to the second acid is 1:0.5~3.0; The ratio of compound (Ⅳ) to the fourth base is 1:1.0~1.

5.

4. The synthesis method according to claim 3, characterized in that, The first base, the second base, the third base, and the fourth base are each independently selected from at least one of the following: triethylamine, pyridine, sodium phosphate, sodium carbonate, potassium carbonate, potassium phosphate, and sodium hydroxide. The first acid and the second acid are each independently selected from at least one of sulfuric acid, hydrochloric acid, trifluoroacetic acid, trichloroacetic acid, and glacial acetic acid.

5. The synthesis method according to claim 2, characterized in that, When preparing compounds of formula (II), the amino protecting reagent R used in the amino protecting reaction 1 X is at least one of trifluoroacetic anhydride, trichloroacetyl chloride, dichloroacetyl chloride, and triarylchloromethane.

6. The synthesis method according to claim 2, characterized in that, When preparing compound (III), the additive used is at least one of the following: sodium iodide, potassium iodide, sodium bromide, potassium bromide, iodomethane, chloromethane, benzyl chloride, benzyl bromide, bromopropylene, chloroacetic acid, ethyl chloroacetate, and ethyl bromoacetate.

7. The synthesis method according to claim 2, characterized in that: The reaction time for preparing compound (II) is 6-12 h; The reaction time for preparing compound (III) is 5-7 h; The reaction time for preparing compound (Ⅳ) is 0.5–4 h; The reaction time for preparing compound (V) is 2-6 hours.

8. The application of the method for synthesizing L-azacyclobutane-2-carboxylic acid according to claim 1 in the preparation of plant disease control agents.

9. The application according to claim 8, characterized in that, The plant disease control agent is a powdery mildew control agent for cucurbits.

10. The method for synthesizing L-azacyclobutane-2-carboxylic acid according to claim 1 is used in the preparation of harmful algae removal agents for water environment treatment or molecular building blocks for drug synthesis.

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