A process for the preparation of (s)-(2-oxotetrahydrofuran-3-yl)-carbamic acid esters

Abstract

The application discloses a preparation method of (S)-(2-oxotetrahydrofuran-3-yl)-carbamate, characterized in that the method comprises the following steps: S1: taking L-homoserine and dimethyl carbonate as reaction raw materials, and performing reaction in a methanol solvent under the action of a synergistic catalytic system composed of sodium ethoxide and zinc acetate to obtain compound (1); and S2: performing a cyclization reaction on the compound (1) under an acid condition to obtain (S)-(2-oxotetrahydrofuran-3-yl)-carbamate. The preparation method does not use a large amount of an acid-binding agent, uses a catalyst with high efficiency and low dosage, selects an amino protecting agent with low price, reduces costs and three wastes, and is beneficial to scale-up production.

Description

Technical Field

[0001] This invention belongs to the technical field of pesticide intermediate synthesis, specifically relating to a method for preparing the chemical intermediate (S)-(2-oxotetrahydrofuran-3-yl)-carbamate. Background Technology

[0002] The information disclosed in this background section is intended only to enhance some understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that the information constitutes prior art known to those skilled in the art.

[0003] L-glufosinate, also known as glufosinate-ammonium, is a monoisomer of L-amino acid isolated from microbial strains in the 1970s. Like glufosinate, it is a glutamine inhibitor, acting as a contact herbicide with partial systemic activity by inhibiting glutamine synthesis in the plant. It exhibits higher herbicidal activity than glufosinate-ammonium, requires a lower dosage, and causes less environmental pollution. Shortly after application, it disrupts ammonium metabolism in the plant, leading to a rapid accumulation of ammonium ions that inhibit photosynthesis and ultimately kill weeds.

[0004] (S)-(2-oxotetrahydrofuran-3-yl)-carbamate is an important intermediate in the synthesis of L-glufosinate, and its synthesis has been reported.

[0005] CN110204517A reports a method for synthesizing (S)-(2-oxotetrahydrofuran-3-yl)-carbamate, which uses L-homoserine and ethyl chloroformate as raw materials, performs an amino protection reaction, and then performs a cyclization reaction under hydrochloric acid conditions to prepare L-homoserine protected lactone.

[0006] CN117603166A reports a method for synthesizing (S)-(2-oxotetrahydrofuran-3-yl)-carbamate, which involves alkalizing L-homoserine lactone hydrochloride with an inorganic base to obtain L-homoserine lactone, and then adding an amino protecting agent under acid-binding conditions to carry out a protective reaction to obtain L-homoserine protected lactone.

[0007] Option 1 uses a large amount of acid-binding agent and ethyl chloroformate as an amino-protecting agent, which is expensive; Option 2 uses L-homoserine lactone hydrochloride as raw material, which is not easy to obtain and uses ethyl chloroformate as an amino-protecting agent, which is costly and not conducive to scale-up production. Summary of the Invention

[0008] To address the shortcomings of existing technologies, the purpose of this invention is to find a catalyst with high efficiency and low dosage, select an inexpensive amino protectant, reduce costs and waste, and facilitate large-scale production.

[0009] The technical solution adopted in this invention is as follows:

[0010] This invention provides a method for preparing (S)-(2-oxotetrahydrofuran-3-yl)-carbamate, the method comprising the following steps:

[0011] S1: Using L-homoserine and dimethyl carbonate as reactants, the reaction was carried out in methanol solvent under the synergistic catalytic system of sodium ethoxide and zinc acetate to obtain compound (1).

[0012] S2: Compound (1) under concentrated hydrochloric acid acid conditions undergoes a cyclization reaction to give (S)-(2-oxotetrahydrofuran-3-yl)-carbamate;

[0013] Between steps S1 and S2, there is also a step of recovering methanol solvent: adding concentrated hydrochloric acid dropwise until the reaction solution is weakly acidic, and then recovering methanol solvent.

[0014] In one or more embodiments of the present invention, in step S1, the molar ratio of L-homoserine, dimethyl carbonate and sodium ethoxide is (2~4):(2~5):1.

[0015] In one or more embodiments of the present invention, in step S1, the molar ratio of sodium ethoxide to zinc acetate is (800~1500):1.

[0016] Step S1 employs a synergistic catalytic system consisting of sodium ethoxide and a small amount of zinc acetate. Sodium ethoxide, as a strong base, is responsible for activating the reactants and promoting the reaction; while the zinc ions (Zn) in zinc acetate... 2+ It can chelate with the amino and hydroxyl groups in L-homoserine, pre-organizing the conformation of the reactants, which not only improves the reactivity and selectivity but may also inhibit side reactions. Experiments have verified that the synergistic effect of the two significantly accelerates the reaction rate and improves the conversion rate of raw materials and the yield of products.

[0017] In one or more embodiments of the present invention, the reaction temperature in step S1 is 0°C. Experiments have verified that a low-temperature reaction at 0°C can effectively suppress side reactions, control the reaction rate, and optimize catalyst efficiency and stability.

[0018] In one or more embodiments of the present invention, in step S2, the acidic conditions are provided by concentrated hydrochloric acid, the mass concentration of which is 36-38%, and the mass ratio of concentrated hydrochloric acid to L-homoserine is (1-2):(1-2).

[0019] In one or more embodiments of the present invention, in step S2, the cyclization reaction temperature is 100~120°C. The reaction ends when the theoretical water output no longer increases.

[0020] Compared with the related technologies known to the inventors, one of the technical solutions of the present invention has the following beneficial effects:

[0021] The preparation method of this invention does not use a large amount of acid-binding agent, uses a catalyst with high efficiency and low dosage, selects an inexpensive amino-protecting agent, reduces costs and waste, and is conducive to scale-up production. Attached Figure Description

[0022] The accompanying drawings, which form part of this specification, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0023] Figure 1 Flowchart of the preparation process of (S)-(2-oxotetrahydrofuran-3-yl)-carbamate.

[0024] Figure 2 HPLC chromatogram of (S)-(2-oxotetrahydrofuran-3-yl)-carbamate standard (Example 1).

[0025] Figure 3 HPLC chromatogram of (S)-(2-oxotetrahydrofuran-3-yl)-carbamate solution (Example 1).

[0026] Figure 4 : (S)-(2-oxotetrahydrofuran-3-yl)-carbamate 1H NMR spectrum. Detailed Implementation

[0027] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0028] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the exemplary embodiments of the present invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, and / or combinations thereof.

[0029] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0030] Example 1: The preparation process flow chart is as follows Figure 1 The preparation method of (S)-(2-oxotetrahydrofuran-3-yl)-carbamate includes the following steps:

[0031] S1: Add 50g L-homoserine (0.41mol) and 200g methanol to a 500ml reaction flask, add 68.05g 20% ​​sodium ethoxide solution (0.2mol), 0.05g zinc acetate as catalyst, and then add 44.28g dimethyl carbonate (0.49mol). Cool to 0℃ and stir the reaction. Monitor the liquid phase until the reaction is complete.

[0032] S2: Add 21.3g of 37wt% concentrated hydrochloric acid dropwise until the reaction solution is weakly acidic, then recover the methanol solvent by vacuum distillation. The resulting concentration The condensate can be used directly in the S3 cyclization reaction. ;

[0033] S3: Add 50g of 37wt% concentrated hydrochloric acid, heat to 110℃ and reflux to separate water. After the water separation reaction is complete, cool to room temperature, add 100g of water and 200g of 1,2-dichloroethane for extraction to obtain (S)-(2-oxotetrahydrofuran-3-yl)-carbamate solution. The content was quantified as 21.38% using HPLC external standard method. Figure 2 and Figure 3 Based on a solution mass of 293.35 g, the absolute yield of (S)-(2-oxotetrahydrofuran-3-yl)-carbamate was calculated to be 96.22%. The 1H NMR spectrum is shown below. Figure 4 .

[0034] The specific reaction mechanism in this embodiment is as follows: S1: Carbamate reaction mechanism

[0035] In methanol solvent at 0℃:

[0036] Sodium ethoxide extracts the amino proton (-NH3) from L-homoserine. + →-NH2), activates amino groups; Zn in zinc acetate 2+ The amino and hydroxyl groups are chelated to fix the reactive groups in a favorable conformation; the activated amino group attacks the carbonyl carbon of dimethyl carbonate, and after addition, methanol is removed to generate N-methoxycarbonyl-L-homoserine (compound 1); sodium ethoxide provides an alkaline environment, and zinc acetate improves selectivity through chelation. The two work together to achieve a conversion rate of over 96%.

[0037] S2: Solvent recovery: Add concentrated hydrochloric acid dropwise until weakly acidic to neutralize excess sodium ethoxide and terminate the S1 reaction; then recover methanol by vacuum distillation. The cyclization reaction does not occur at this temperature.

[0038] S3: Cyclization reaction: Concentrated hydrochloric acid was added, and the mixture was heated to 110°C and refluxed to separate water. Under strong acid and high temperature conditions, the carboxyl group of compound 1 was protonated and dehydrated to form an acyl cation intermediate, which was then attacked by the intramolecular hydroxyl oxygen atom, resulting in intramolecular esterification and the formation of a five-membered lactone ring, yielding the target product.

[0039] The key role of temperature: The cyclization reaction requires a high temperature of 100~120℃ to drive it. The reaction does not occur during low-temperature neutralization and solvent recovery, thus ensuring the controllability of the reaction.

[0040] Example 2: S1: 100g L-homoserine (0.82mol) and 400g methanol were added to a 1000ml reaction flask, along with 136.1g of 20w / w% sodium ethoxide solution (0.4mol), 0.1g of zinc acetate as a catalyst, and then 88.56g of dimethyl carbonate (0.98mol). The mixture was cooled to 0℃ and stirred to ensure complete reaction under liquid-phase monitoring.

[0041] S2: Add 42.6g of 37wt% concentrated hydrochloric acid dropwise until the reaction solution becomes weakly acidic, then recover the methanol solvent by vacuum distillation. The resulting residue The product is directly used in the S3 cyclization reaction. ;

[0042] S3: Add 100g of 37wt% concentrated hydrochloric acid, heat to 110℃ and reflux to separate water. After the water separation reaction is completed, cool to room temperature, add 200g of water and 400g of 1,2-dichloroethane to extract and obtain (S)-(2-oxotetrahydrofuran-3-yl)-carbamate solution. The content was quantified as 21.57% by HPLC external standard method. Based on the solution mass of 584.55g, the absolute yield of (S)-(2-oxotetrahydrofuran-3-yl)-carbamate was calculated to be 96.71%.

[0043] Comparative Example 1: S1 cooled to 5℃

[0044] S1: Add 50g L-homoserine (0.41mol) and 200g methanol to a 500ml reaction flask, add 68.05g 20% ​​sodium ethoxide (0.2mol) and 0.05g zinc acetate as catalysts, then add 44.28g dimethyl carbonate (0.49mol), cool to 5℃ and stir to react. Monitor the reaction in the liquid phase until it is complete.

[0045] S2: Add 21.3g of 37wt% concentrated hydrochloric acid dropwise until the reaction solution becomes weakly acidic, then recover the methanol solvent by vacuum distillation. The resulting residue The product is directly used in the S3 cyclization reaction. ;

[0046] S3: Add 50g of 37wt% concentrated hydrochloric acid, heat to 110℃ and reflux to separate water. After the water separation reaction is completed, cool to room temperature, add 100g of water and 200g of 1,2-dichloroethane to extract and obtain (S)-(2-oxotetrahydrofuran-3-yl)-carbamate solution. The content was quantified as 18.85% by HPLC external standard method. Based on the solution mass of 294.12g, the absolute yield of (S)-(2-oxotetrahydrofuran-3-yl)-carbamate was calculated to be 85.05%.

[0047] Comparative Example 2: The catalysts were sodium carbonate and zinc acetate.

[0048] S1: Add 50g L-homoserine (0.41mol) and 200g methanol to a 500ml reaction flask, add 21.2g sodium carbonate (0.2mol) and 0.05g zinc acetate as catalysts, then add 44.28g dimethyl carbonate (0.49mol), cool to 0℃ and stir to react. The reaction is carried out by liquid phase monitoring.

[0049] S2: Add 21.3g of 37wt% concentrated hydrochloric acid dropwise until the reaction solution becomes weakly acidic, then recover the methanol solvent by vacuum distillation. The resulting residue The product is directly used in the S3 cyclization reaction. ;

[0050] S3: Add 50g of 37wt% concentrated hydrochloric acid, heat to 110℃ and reflux to separate water. After the water separation reaction is completed, cool to room temperature, add 100g of water and 200g of 1,2-dichloroethane to extract and obtain (S)-(2-oxotetrahydrofuran-3-yl)-carbamate solution. The content was quantified by HPLC external standard method as 17.84%. Based on the solution mass of 293.56g, the absolute yield of (S)-(2-oxotetrahydrofuran-3-yl)-carbamate was calculated to be 80.33%.

[0051] Comparative Example 3: The catalyst was sodium carbonate.

[0052] S1: Add 50g L-homoserine (0.41mol) and 200g methanol to a 500ml reaction flask, add 21.2g sodium carbonate (0.2mol) as a catalyst, and then add 44.28g dimethyl carbonate (0.49mol). Cool to 0℃ and stir to react. Monitor the reaction in the liquid phase until it is complete.

[0053] S2: Add 21.3g of 37wt% concentrated hydrochloric acid dropwise until the reaction solution becomes weakly acidic, then recover the methanol solvent by vacuum distillation. The resulting residue The product is directly used in the S3 cyclization reaction. ;

[0054] S3: Add 50g of 37wt% concentrated hydrochloric acid, heat to 110℃ and reflux to separate water. After the water separation reaction is completed, cool to room temperature, add 100g of water and 200g of 1,2-dichloroethane to extract and obtain (S)-(2-oxotetrahydrofuran-3-yl)-carbamate solution. The content was quantified as 12.50% by HPLC external standard method. Based on the solution mass of 393.02g, the absolute yield of (S)-(2-oxotetrahydrofuran-3-yl)-carbamate was calculated to be 75.34%.

[0055] Comparative Example 4: The raw material was diethyl carbonate.

[0056] S1: Add 50g L-homoserine (0.41mol) and 200g methanol to a 500ml reaction flask, add 68.05g 20w / w% sodium ethoxide solution (0.2mol), 0.05g zinc acetate as catalyst, and then add 57.88g diethyl carbonate (0.49mol). Cool to 0℃ and stir the reaction. Monitor the liquid phase until the reaction is complete.

[0057] S2: Add 21.3g of 37wt% concentrated hydrochloric acid dropwise until the reaction solution becomes weakly acidic, then recover the methanol solvent by vacuum distillation. The resulting residue The product is directly used in the S3 cyclization reaction. ;

[0058] S3: Add 50g of 37wt% concentrated hydrochloric acid, heat to 110℃ and reflux to separate water. After the water separation reaction is complete, cool to room temperature, add 100g of water and 200g of 1,2-dichloroethane to extract and obtain (S)-(2-oxotetrahydrofuran-3-yl)-aminoacetic acid ester solution. The product content was quantified as 18.55% by HPLC external standard method. Based on the solution mass of 287.73g, the absolute yield of (S)-(2-oxotetrahydrofuran-3-yl)-aminoacetic acid ester was calculated to be 75.25%.

[0059] Comparative Example 5: Low dosage of sodium ethoxide

[0060] S1: Add 50g L-homoserine (0.41mol) to a 500ml reaction flask, add 51.04g 20w / w% sodium ethoxide solution (0.15mol), 0.05g zinc acetate as catalyst, and then add 44.28g dimethyl carbonate (0.49mol). Cool to 0℃ and stir the reaction. Monitor the liquid phase until the reaction is complete.

[0061] S2: Add 21.3g of concentrated hydrochloric acid dropwise until the reaction solution becomes weakly acidic, then recover the methanol solvent by vacuum distillation. The obtained residue Used for S3 cyclization reaction ;

[0062] S3: Add 50g of 37wt% concentrated hydrochloric acid, heat to 110℃ and reflux to separate water. After the water separation reaction is completed, cool to room temperature, add 100g of water and 200g of 1,2-dichloroethane to extract and obtain (S)-(2-oxotetrahydrofuran-3-yl)-carbamate solution. The content was quantified by HPLC external standard method as 20.49%. Based on the solution mass of 273.45g, the absolute yield of (S)-(2-oxotetrahydrofuran-3-yl)-carbamate was calculated to be 85.93%.

[0063] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A method for preparing (S)-(2-oxotetrahydrofuran-3-yl)-carbamate, characterized in that, The method includes the following steps: S1: Using L-homoserine and dimethyl carbonate as reactants, the reaction was carried out in methanol solvent under the action of a synergistic catalytic system composed of sodium ethoxide and zinc acetate to obtain compound (1). ; The molar ratio of L-homoserine, dimethyl carbonate, and sodium ethoxide is (2~4):(2~5):1; The molar ratio of sodium ethoxide to zinc acetate is (800~1500):1; The reaction temperature is 0°C; S2: Compound (1) under acidic conditions of concentrated hydrochloric acid undergoes a cyclization reaction to yield (S)-(2-oxotetrahydrofuran-3-yl)-carbamate; Between steps S1 and S2, there is also a step of recovering methanol solvent: adding concentrated hydrochloric acid dropwise until the reaction solution is weakly acidic, and then recovering methanol solvent.

2. The method for preparing (S)-(2-oxotetrahydrofuran-3-yl)-carbamate as described in claim 1, characterized in that, In step S2, the mass concentration of the concentrated hydrochloric acid is 36-38%.

3. The method for preparing (S)-(2-oxotetrahydrofuran-3-yl)-carbamate as described in claim 1, characterized in that, In step S2, the cyclization reaction temperature is 100~120℃.

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