Synthesis process of L-glufosinate-ammonium intermediate
By using dimethyl sulfoxide and triethylamine as catalysts and auxiliaries, the problems of long reaction time and low raw material utilization in the synthesis process of L-glufosinate were solved, realizing the synthesis of intermediates with high efficiency and low cost, which is suitable for industrial application.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-01-04
- Publication Date
- 2026-04-03
AI Technical Summary
The existing L-glufosinate synthesis process has long reaction time, low raw material utilization rate, many by-products, and high cost, and is not suitable for industrial production.
Dimethyl sulfoxide was used as a catalyst and triethylamine as an auxiliary agent to carry out the Arbuzov reaction under solvent-free conditions. Through the synergistic effect of the catalyst and the auxiliary agent, the reaction rate was improved, the formation of by-products was suppressed, the reaction time was shortened, and the amount of raw materials fed was reduced.
It significantly improves the reaction rate, shortens the reaction cycle, increases the purity of intermediates, and reduces production costs, making it suitable for industrial production and offering high economic and environmental benefits.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pesticide and herbicide technology, and in particular to a synthesis process for an L-glufosinate intermediate. Background Technology
[0002] Glufosinate, a broad-spectrum, highly effective, and environmentally friendly non-selective herbicide, derives its activity primarily from its L-configuration isomer. Compared to commercially available racemic glufosinate, L-glufosinate (refined glufosinate) exhibits higher herbicidal activity. Therefore, developing efficient and economical L-glufosinate production processes is of significant application value. Currently, the main technical routes for the industrial production of L-glufosinate include enzymatic processes and chemical synthesis processes using L-homoserine as a starting material. Among these, the synthetic route using L-homoserine as a precursor has attracted considerable attention due to its cost advantage, thanks to advancements in bio-fermentation technology. However, in actual industrial applications, it still faces challenges such as long reaction times, low raw material utilization rates, and high levels of impurities.
[0003] The key step affecting yield and reaction efficiency in this route is the Arbuzov reaction, which involves the formation of a phosphorus-carbon bond through the reaction of ethyl (2S)-4-chloro-2-ethoxycarbonylaminobutyrate with diethyl methylphosphonite. In existing technologies, this reaction typically requires more than 15 hours at 120-140°C. This excessively long reaction time not only leads to high energy consumption and low equipment utilization, but also causes the main byproduct, ethane chloride, to undergo an Arbuzov reaction with the raw material diethyl methylphosphonite, generating impurities such as ethyl methyl phosphate. The longer the reaction time, the more impurities are produced, and the high boiling point of the byproducts makes subsequent separation difficult, significantly increasing raw material costs and post-processing purification costs.
[0004] To address the aforementioned issues, existing technologies have explored various improvement strategies, but significant shortcomings remain. For instance, some schemes employ excessive amounts (e.g., 3-8 times the normal amount) of diethyl methylphosphonate to increase yield, but this results in high feedstock recovery load, low reaction volume efficiency, and significantly increased production costs and safety risks. To reduce the consumption of diethyl methylphosphonate byproduct chloroethane, another scheme proposes purging with an inert gas during the Arbuzov reaction to promptly remove chloroethane from the system and suppress its side reaction with diethyl methylphosphonate. However, diethyl methylphosphonate is not only highly flammable but also has a very strong, pungent odor; purging entrained diethyl methylphosphonate can lead to environmental pollution and safety accidents. Furthermore, this scheme requires a reaction at 140°C for 20 hours, and experiments revealed that ethyl (2S)-4-chloro-2-ethoxycarbonylamino-butyrate is highly susceptible to degradation at high temperatures, reducing the yield.
[0005] In addition, another approach involves adding solvent to the Arbuzov reaction and refluxing for 36–90 hours to remove chloroethane by utilizing the boiling point difference. While this method can remove some chloroethane and reduce impurity formation to some extent, the introduction of a large amount of solvent not only increases the cost of raw materials and subsequent recovery and treatment but also significantly reduces the effective concentration of the reaction system and the reaction rate, making it unsuitable for large-scale industrial production.
[0006] Therefore, it is of great significance to develop a new process for synthesizing L-glufosinate intermediates that has a short reaction time, high raw material utilization rate, controllable side reactions, and is suitable for industrial production. Summary of the Invention
[0007] To address the problems of long reaction time, low raw material utilization, and high reaction cost in existing processes for synthesizing L-glufosinate intermediates via the Arbuzov reaction, this invention provides a synthesis process for L-glufosinate intermediates. This invention uses dimethyl sulfoxide as a catalyst for the Arbuzov reaction, significantly improving the reaction rate. Simultaneously, triethylamine is added to react with chloroethane, suppressing the formation of the byproduct methyl ethyl phosphate. Furthermore, the reaction process requires no additional reaction solvent, effectively reducing production costs and making it suitable for industrial production applications.
[0008] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows: This invention provides a synthetic process for an L-glufosinate intermediate, wherein the L-glufosinate intermediate is (2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate ethyl ester, comprising the following steps: Under solvent-free conditions, using diethyl methylphosphonite and ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butyrate as raw materials, an Arbuzov reaction is carried out in the presence of a catalyst and triethylamine to obtain an L-glufosinate intermediate; wherein the catalyst includes one or both of dimethyl sulfoxide or N,N-dimethylformamide.
[0009] Specifically, the synthesis process of the L-glufosinate intermediate includes the following steps: Diethyl methylphosphonite, ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butanoate, catalyst and triethylamine were mixed evenly and heated to carry out the Arbuzov reaction. After the reaction was completed, excess diethyl methylphosphonite was removed by distillation to obtain L-glufosinate intermediate.
[0010] Existing traditional methods for synthesizing L-glufosinate intermediate ((2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate ethyl ester) have problems such as low utilization of the raw material diethyl methylphosphonite, long reaction time, high content of by-product ethyl methyl phosphate, and large amount of solvent used.
[0011] Compared with existing technologies, the synthesis process of L-glufosinate intermediate provided by this invention, using dimethyl sulfoxide or N,N-dimethylformamide as catalysts, significantly improves the Arbuzov reaction rate and greatly shortens the reaction cycle. Simultaneously, the addition of triethylamine as an adjuvant serves two purposes: firstly, triethylamine can undergo a nucleophilic substitution reaction with chloroethane to generate tetraethylammonium chloride, promptly consuming chloroethane in the system and inhibiting the formation of impurities such as ethyl methyl phosphate, thus significantly improving the purity of the target intermediate (2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate ethyl ester; secondly, diethyl methylphosphonate does not require a large excess to ensure complete reaction, avoiding the raw material waste and recovery load caused by traditional excessive feeding, significantly improving raw material utilization, reducing production costs, and making it suitable for industrial production. It possesses high economic and environmental benefits and has extremely high application value.
[0012] Furthermore, this invention employs a solvent-free system for the Arbuzov reaction, completely resolving the problems of increased raw material costs, heavy subsequent recovery and treatment burdens, and reduced effective concentration of the reaction system caused by the introduction of large amounts of solvent in existing solvent reflux processes. The solvent-free design not only improves the effective concentration of the reaction system and reactor utilization but also avoids the environmental pollution, safety risks, and recovery costs associated with solvents, making the process more in line with the requirements of high efficiency, low cost, and safety and reliability for large-scale industrial production.
[0013] The synthesis process of L-glufosinate intermediate provided by this invention solves the technical problems of long reaction cycle, low raw material utilization, many impurities, high cost and poor industrial adaptability in existing processes. It realizes the efficient, low-cost and high-quality synthesis of L-glufosinate intermediate, and has significant technical advantages and industrial application value.
[0014] It should be noted that the tetraethylammonium chloride produced by the reaction of triethylamine and chloroethane in this invention does not require additional separation and purification and can be directly used as an adjuvant in the final product L-glufosinate formulation, thus realizing the resource utilization of by-products. This design not only eliminates the impurity separation steps and equipment investment in traditional processes, reducing the emission of waste, but also lowers the procurement cost of adjuvants in formulation production, improving the economic efficiency and environmental friendliness of the process.
[0015] The reaction equation of this invention is as follows:
[0016] Furthermore, the catalyst is dimethyl sulfoxide.
[0017] Dimethyl sulfoxide (DMSO) possesses strong polarity and excellent solvation ability. Adding an appropriate amount of DMSO can effectively catalyze the rapid construction of phosphorus-carbon bonds in the Arbuzov reaction, significantly increasing the reaction rate and shortening the reaction cycle. Furthermore, DMSO is chemically stable and does not undergo side reactions with the raw materials or products under the reaction conditions. Moreover, DMSO is highly compatible with the solvent-free system of this invention, and can exert its catalytic effect without the need to add other solvents, thus avoiding the increased costs, recycling difficulties, and safety risks associated with adding additional organic solvents.
[0018] Furthermore, the molar ratio of diethyl methylphosphonite to ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butyrate is (1.3~2):1.
[0019] More preferably, the molar ratio of diethyl methylphosphonite to ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butyrate is 1.5:1.
[0020] This invention significantly reduces the amount of diethyl methylphosphonate fed into the system through the synergistic effect of the catalyst and triethylamine, thereby significantly reducing the energy consumption and process load of subsequent distillation to remove excess raw materials, and lowering the cost of raw material procurement and recycling.
[0021] Furthermore, the molar ratio of triethylamine to ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butyrate is (0.1~0.6):1.
[0022] More preferably, the molar ratio of triethylamine to ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butyrate is 0.5:1.
[0023] Under this ratio, the amount of triethylamine added can fully react with the chloroethane generated in the reaction system, effectively reducing the content of chloroethane in the system, thereby reducing the consumption of raw material diethyl methylphosphonate by-product chloroethane. At the same time, it can also avoid the impact of excessive triethylamine residue on the quality of L-glufosinate intermediate.
[0024] Furthermore, the molar ratio of the catalyst to ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butyrate is (0.1~0.5):1.
[0025] More preferably, the molar ratio of the catalyst to ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butyrate is 0.2:1.
[0026] Furthermore, the Arbuzov reaction is carried out at a temperature of 110°C to 135°C for a reaction time of 8 to 17 hours.
[0027] More preferably, the Arbuzov reaction is carried out at a temperature of 120°C for a reaction time of 8 to 14 hours.
[0028] Furthermore, the distillation is carried out under reduced pressure, with a pressure of -0.09MPa to -0.097MPa and a temperature of 80℃ to 110℃.
[0029] It should be noted that the Arbuzov reaction described above is carried out under an inert atmosphere. This inert atmosphere can be provided by conventional inert gases in the art, such as nitrogen or argon.
[0030] In summary, this invention provides a synthesis process for L-glufosinate intermediates. This process uses dimethyl sulfoxide or N,N-dimethylformamide as catalysts, significantly improving the reaction rate of the key Arbuzov reaction and thus drastically shortening the reaction cycle. Simultaneously, by introducing triethylamine as an adjuvant, it can undergo nucleophilic substitution with the reaction byproduct chloroethane to generate tetraethylammonium chloride, thereby promptly consuming chloroethane in the system and effectively suppressing the formation of impurities such as methyl ethyl phosphate, significantly improving the purity of the target intermediate. Furthermore, it allows for complete reaction without a large excess of diethyl methylphosphonate, avoiding the waste and recycling burden caused by excessive raw materials in traditional processes. In addition, this invention employs a solvent-free reaction system, completely avoiding the problems of increased raw material costs, difficult recycling, and decreased effective system concentration and reactor utilization caused by adding solvents in existing technologies. In conclusion, the process of this invention has significant advantages in reaction efficiency, product purity, raw material economy, and operational safety, making it highly suitable for large-scale industrial production and possessing extremely high economic, environmental, and promotional application value. Detailed Implementation
[0031] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.
[0032] This invention provides a synthesis process for L-glufosinate intermediates, specifically including the following steps: Diethyl methylphosphonite, ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butanoate, catalyst and triethylamine were mixed evenly and heated to carry out the Arbuzov reaction. After the reaction was completed, excess diethyl methylphosphonite was removed by distillation to obtain L-glufosinate intermediate.
[0033] In some embodiments, the molar ratio of diethyl methylphosphonite to ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butyrate is (1.3~2):1.
[0034] In some embodiments, the molar ratio of triethylamine to ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butyrate is (0.1~0.6):1.
[0035] In some embodiments, the molar ratio of the catalyst to ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butyrate is (0.1~0.5):1.
[0036] In some embodiments, the Arbuzov reaction is carried out at a temperature of 110°C to 135°C for a reaction time of 8 to 17 hours.
[0037] In some embodiments, the distillation is carried out by vacuum distillation, with a pressure of -0.09MPa to -0.097MPa and a temperature of 80℃ to 110℃.
[0038] The core advantage of the L-glufosinate intermediate synthesis process provided by this invention lies in its innovative catalyst and auxiliary design, which systematically solves the key bottlenecks existing in the Arbuzov reaction pathway.
[0039] Specifically, using dimethyl sulfoxide or N,N-dimethylformamide as catalysts significantly improved the reaction rate, greatly shortened the reaction time, and increased equipment utilization. Simultaneously, the innovative introduction of triethylamine as an auxiliary agent effectively captured and converted the byproduct chloroethane into tetraethylammonium chloride, thereby suppressing the formation of key impurities such as ethyl methyl phosphate and improving the purity of the intermediate (2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate. Furthermore, the synergistic effect of the catalyst and triethylamine allowed for the near-stoichiometric feeding of the expensive raw material diethyl methylphosphonate, avoiding the recovery costs and energy losses caused by excessive feeding in traditional processes.
[0040] In addition, the process uses a solvent-free reaction system, which eliminates the separation and purification burden, reduced equipment utilization, and potential environmental and safety risks caused by the introduction of solvents from the source, making the process simpler, more efficient, and greener.
[0041] In summary, this invention achieves synergistic optimization in terms of reaction efficiency, product quality, raw material economy, and process cleanliness, and possesses significant industrial application value and market competitive advantages.
[0042] To better illustrate the present invention, further examples are provided below.
[0043] Unless otherwise specified, the process equipment or apparatus used in the following embodiments are all conventional equipment or apparatus in the art. Unless otherwise specified, the raw materials used in the embodiments of the present invention are all commercially available. Unless otherwise specified, the technical means used in the embodiments of the present invention are all conventional means well known to those skilled in the art.
[0044] Example 1 This embodiment provides a synthesis process for an L-glufosinate intermediate, including the following steps: Under nitrogen protection, 19.46 g (0.087 mol, 1.0 eq) of ethyl (2S)-4-chloro-2-ethoxycarbonylamino-butyrate, 0.88 g (0.0087 mol, 0.1 eq) of triethylamine, 15.47 g (0.114 mol, 1.3 eq) of diethyl methylphosphonite, and 1.36 g (0.0174 mol, 0.2 eq) of dimethyl sulfoxide were added to a 250 mL three-necked flask. After stirring and mixing, the mixture was heated to [temperature missing]. The reaction was carried out at 120℃ for 11 hours. GC analysis showed that (2S)-4-chloro-2-ethoxycarbonylamino-butyrate ethyl ester content was less than 1%, and the impurity methyl ethyl phosphate ethyl ester was generated at 1.67%. 4.53 g of diethyl methylphosphonate was distilled off at -0.093 MPa and 105℃, yielding 23.65 g of (2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate ethyl ester. The product yield was 87.9%, and the product ee value was 96.9% (the raw material ee value was 99.02%). Example 2 Under nitrogen protection, 19.46 g (0.087 mol, 1.0 eq) of ethyl (2S)-4-chloro-2-ethoxycarbonylamino-butyrate, 2.64 g (0.0261 mol, 0.3 eq) of triethylamine, 20.14 g (0.148 mol, 1.7 eq) of diethyl methylphosphonite, and 0.68 g (0.0087 mol, 0.1 eq) of dimethyl sulfoxide were added to a 250 mL three-necked flask. After stirring and mixing, the mixture was heated to 100 °C. The reaction was carried out at 20℃ for 11.7 h. The GC control showed that (2S)-4-chloro-2-ethoxycarbonylamino-butyrate ethyl ester was less than 1%, and the impurity methyl ethyl phosphate ethyl ester was generated at 0.85%. Diethyl methylphosphonate was distilled off at -0.090 MPa and 110℃, yielding 24.52 g of (2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate ethyl ester. The product yield was 91.1%, and the product ee value was 97.5% (the raw material ee value was 99.02%).
[0045] Example 3 Under nitrogen protection, 19.46 g (0.087 mol, 1.0 eq) of ethyl (2S)-4-chloro-2-ethoxycarbonylamino-butyrate, 4.4 g (0.0435 mol, 0.5 eq) of triethylamine, 17.77 g (0.131 mol, 1.5 eq) of diethyl methylphosphonite, and 1.36 g (0.0174 mol, 0.2 eq) of dimethyl sulfoxide were added to a 250 mL three-necked flask. After stirring and mixing, the mixture was heated to 100 °C. The reaction was carried out at 20℃ for 10.9 h. The GC control showed that (2S)-4-chloro-2-ethoxycarbonylamino-butyrate ethyl ester was less than 1%, and the impurity methyl ethyl phosphate ethyl ester was generated at 0.15%. 6.58 g of diethyl methylphosphonite was distilled off at -0.095 MPa and 100℃ to obtain 25.30 g of (2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate ethyl ester. The product yield was 94%, and the product ee value was 98.1% (the raw material ee value was 99.02%).
[0046] Example 4 Under nitrogen protection, 19.46 g (0.087 mol, 1.0 eq) of ethyl (2S)-4-chloro-2-ethoxycarbonylamino-butyrate, 5.28 g (0.0522 mol, 0.6 eq) of triethylamine, 17.77 g (0.131 mol, 1.5 eq) of diethyl methylphosphonite, and 1.36 g (0.0174 mol, 0.2 eq) of dimethyl sulfoxide were added to a 250 mL three-necked flask. After stirring and mixing, the mixture was heated to [temperature missing]. The reaction was carried out at 135℃ for 8.5 h. The GC control showed that (2S)-4-chloro-2-ethoxycarbonylamino-butyrate ethyl ester was less than 1%, and the impurity methyl ethyl phosphate ethyl ester was generated at 0.14%. 6.54 g of diethyl methylphosphonite was distilled off at -0.096 MPa and 90℃ to obtain 25.19 g of (2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate ethyl ester. The product yield was 93.6%, and the product ee value was 97.6% (the raw material ee value was 99.02%).
[0047] Example 5 Under nitrogen protection, 19.46 g (0.087 mol, 1.0 eq) of ethyl (2S)-4-chloro-2-ethoxycarbonylamino-butyrate, 0.88 g (0.0087 mol, 0.1 eq) of triethylamine, 23.69 g (0.175 mol, 2.0 eq) of diethyl methylphosphonite, and 3.40 g (0.0435 mol, 0.5 eq) of dimethyl sulfoxide were added to a 250 mL three-necked flask. After stirring and mixing, the mixture was heated to 11 °C. The reaction was carried out at 0℃ for 14 hours and 55 minutes. The GC control showed that (2S)-4-chloro-2-ethoxycarbonylamino-butyrate ethyl ester was less than 1%, and the impurity methyl ethyl phosphate ethyl ester was generated at 1.57%. 12.76 g of diethyl methylphosphonate was distilled off at -0.092 MPa and 107℃ to obtain 23.68 g of (2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate ethyl ester. The product yield was 88%, and the product ee value was 97.0% (the raw material ee value was 99.02%).
[0048] Example 6 Under nitrogen protection, 19.46 g (0.087 mol, 1.0 eq) of ethyl (2S)-4-chloro-2-ethoxycarbonylamino-butyrate, 0.88 g (0.0087 mol, 0.1 eq) of triethylamine, 17.77 g (0.131 mol, 1.5 eq) of diethyl methylphosphonite, and 1.27 g (0.0174 mol, 0.2 eq) of N,N-dimethylformamide were added to a 250 mL three-necked flask. After stirring and mixing, the mixture was heated to [temperature missing]. The reaction was carried out at 120℃ for 16.5 h. The GC control showed that (2S)-4-chloro-2-ethoxycarbonylamino-butyrate ethyl ester was less than 1%, and the impurity methyl ethyl phosphate ethyl ester was generated at 1.77%. 6.94 g of diethyl methylphosphonite was distilled off at -0.097 MPa and 80℃ to obtain 23.33 g of (2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate ethyl ester. The product yield was 86.7%, and the product ee value was 94.9% (the raw material ee value was 99.02%).
[0049] Comparative Example 1 This comparative example provides a synthetic process for L-glufosinate intermediate, which differs from Example 3 only in that the catalysts dimethyl sulfoxide and triethylamine are not added; otherwise, the process is identical. The specific steps are as follows: Under nitrogen protection, 19.46 g (0.087 mol, 1.0 eq) of ethyl (2S)-4-chloro-2-ethoxycarbonylamino-butyrate and 17.77 g (0.131 mol, 1.5 eq) of diethyl methylphosphonite were added to a 250 mL three-necked flask. After stirring and mixing, the mixture was heated to 120 °C and reacted for 20 h. The GC test showed that ethyl (2S)-4-chloro-2-ethoxycarbonylamino-butyrate was less than 1%, and 35% of the impurity ethyl methyl phosphate was generated. 1.96 g of diethyl methylphosphonite was distilled off at -0.095 MPa and 100 °C to obtain 10.76 g of ethyl (2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate. The product yield was 40%, and the product ee value was 94.0% (the raw material ee value was 99.02%).
[0050] Comparative Example 2 This comparative example provides a synthetic process for an L-glufosinate intermediate, which differs from Example 3 only in that triethylamine is not added; otherwise, the process is identical. The specific steps are as follows: Under nitrogen protection, 19.46 g (0.087 mol, 1.0 eq) of ethyl (2S)-4-chloro-2-ethoxycarbonylamino-butyrate, 17.77 g (0.131 mol, 1.5 eq) of diethyl methylphosphonite, and 1.36 g (0.0174 mol, 0.2 eq) of dimethyl sulfoxide were added to a 250 mL three-necked flask. After stirring and mixing, the mixture was heated to 120 °C and reacted for 11.5 h. The GC control showed that (2S)-4-chloro-2-ethoxycarbonylamino-butyrate ethyl ester was less than 1%, and the impurity methyl ethyl phosphate ethyl ester was generated at 42%. 0.34 g of diethyl methylphosphonite was distilled off at -0.095 MPa and 100 °C to obtain 9.42 g of (2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate ethyl ester. The product yield was 35%, and the product ee value was 94.5% (the raw material ee value was 99.02%).
[0051] Comparative Example 3 This comparative example provides a synthesis process for an L-glufosinate intermediate, which differs from Example 3 only in that the amount of dimethyl sulfoxide is increased. The specific steps are as follows: Under nitrogen protection, 19.46 g (0.087 mol, 1.0 eq) of ethyl (2S)-4-chloro-2-ethoxycarbonylamino-butyrate, 4.4 g (0.0435 mol, 0.5 eq) of triethylamine, 17.77 g (0.131 mol, 1.5 eq) of diethyl methylphosphonite, and 6.80 g (0.0087 mol, 1.0 eq) of dimethyl sulfoxide were added to a 250 mL three-necked flask. After stirring and mixing, the mixture was heated to 12 °C. The reaction was carried out at 0℃ for 19 hours and 55 minutes. The GC control showed that (2S)-4-chloro-2-ethoxycarbonylamino-butyrate ethyl ester was less than 1%, and the impurity methyl ethyl phosphate ethyl ester was generated at 2.02%. 7.53 g of diethyl methylphosphonate was distilled off at -0.095 MPa and 100℃ to obtain 21.80 g of (2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate ethyl ester. The product yield was 81%, and the product ee value was 95.3% (the raw material ee value was 99.02%).
[0052] Comparative Example 4 This comparative example provides a synthesis process for an L-glufosinate intermediate, which differs from Example 3 only in that the catalyst dimethyl sulfoxide is not added. The specific steps are as follows: Under nitrogen protection, 19.46 g (0.087 mol, 1.0 eq) of ethyl (2S)-4-chloro-2-ethoxycarbonylamino-butyrate, 4.4 g (0.0435 mol, 0.5 eq) of triethylamine, and 17.77 g (0.131 mol, 1.5 eq) of diethyl methylphosphonite were added to a 250 mL three-necked flask. After stirring and mixing, the mixture was heated to 120 °C and reacted for 19 h. The reaction was controlled by GC. (2S)-4-chloro-2-ethoxycarbonylamino-butyrate ethyl ester was less than 1%, and methyl ethyl phosphate ethyl ester impurity was generated at 1.71%. 7.04 g of diethyl methylphosphonite was distilled off at -0.095 MPa and 100 °C to obtain 23.14 g of (2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate ethyl ester. The product yield was 86%, and the product ee value was 93.6% (the raw material ee value was 99.02%).
[0053] Comparative Example 5 This comparative example provides a synthesis process for an L-glufosinate intermediate, which differs from Example 3 only in that triethylamine is replaced with pyridine and the catalyst dimethyl sulfoxide is not added. The specific steps are as follows: Under nitrogen protection, 19.46 g (0.087 mol, 1.0 eq) of ethyl (2S)-4-chloro-2-ethoxycarbonylamino-butyrate, 3.44 g (0.0435 mol, 0.5 eq) of pyridine, and 17.77 g (0.131 mol, 1.5 eq) of diethyl methylphosphonite were added to a 250 mL three-necked flask. After stirring and mixing, the mixture was heated to 120 °C and reacted for 17.5 h. GC The yield of (2S)-4-chloro-2-ethoxycarbonylamino-butyrate ethyl ester was less than 1%, and the impurity methyl ethyl phosphate ethyl ester was generated at 37%. 0.74 g of diethyl methylphosphonite was distilled off at -0.095 MPa and 100 °C to obtain 12.11 g of (2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate ethyl ester. The product yield was 45%, and the product ee value was 94.8% (the raw material ee value was 99.02%).
[0054] Comparative Example 6 This comparative example provides a synthetic process for an L-glufosinate intermediate, which specifically includes the following steps: Under nitrogen protection, 19.46 g (0.087 mol, 1.0 eq) of ethyl (2S)-4-chloro-2-ethoxycarbonylamino-butyrate, 17.77 g (0.158 mol, 1.82 eq) of chlorobenzene, and 17.77 g (0.131 mol, 1.5 eq) of diethyl methylphosphonite were added to a 250 mL three-necked flask. After stirring and mixing, the mixture was heated to 120 °C and reacted for 25 h. The reaction was controlled by GC. (2S)-4-chloro-2-ethoxycarbonylamino-butyrate ethyl ester was less than 1%, and methyl ethyl phosphate ethyl ester impurity was generated at 2.5%. 7.91 g of diethyl methylphosphonite was distilled off at -0.095 MPa and 100 °C to obtain 20.58 g of (2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate ethyl ester. The product yield was 76.5%, and the product ee value was 91.8% (the raw material ee value was 99.02%).
[0055] Comparative Example 7 This comparative example provides a synthesis process for L-glufosinate, which differs from Example 3 only in that triethylamine is replaced with trimethylamine. The specific steps include: Under nitrogen protection, 19.46 g (0.087 mol, 1.0 eq) of ethyl (2S)-4-chloro-2-ethoxycarbonylamino-butyrate, 2.55 g (0.0435 mol, 0.5 eq) of trimethylamine, 17.77 g (0.131 mol, 1.5 eq) of diethyl methylphosphonite, and 1.36 g (0.0174 mol, 0.2 eq) of dimethyl sulfoxide were added to a 250 mL three-necked flask. After stirring and mixing, the mixture was heated to a higher temperature. The reaction was carried out at 120℃ for 13.5 h. The GC control showed that (2S)-4-chloro-2-ethoxycarbonylamino-butyrate ethyl ester was less than 1%, and the impurity methyl ethyl phosphate ethyl ester was generated at 15%. 5.56 g of diethyl methylphosphonite was distilled off at -0.095 MPa and 100℃ to obtain 16.95 g of (2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate ethyl ester. The product yield was 63%, and the product ee value was 95.5% (the raw material ee value was 99.02%).
[0056] Comparative Example 8 This comparative example provides a synthesis process for an L-glufosinate intermediate, which differs from Example 3 only in that triethylamine is replaced with tripropylamine. The specific steps are as follows: Under nitrogen protection, 19.46 g (0.087 mol, 1.0 eq) of ethyl (2S)-4-chloro-2-ethoxycarbonylamino-butyrate, 6.25 g (0.0435 mol, 0.5 eq) of tripropylamine, 17.77 g (0.131 mol, 1.5 eq) of diethyl methylphosphonite, and 1.36 g (0.0174 mol, 0.2 eq) of dimethyl sulfoxide were added to a 250 mL three-necked flask. After stirring and mixing, the mixture was heated to a higher temperature. The reaction was carried out at 120℃ for 12 hours. The GC control showed that (2S)-4-chloro-2-ethoxycarbonylamino-butyrate ethyl ester was less than 1%, and the impurity methyl ethyl phosphate ethyl ester was generated at 3.7%. 7.83 g of diethyl methylphosphonite was distilled off at -0.095 MPa and 100℃ to obtain 19.91 g of (2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate ethyl ester. The product yield was 74%, and the product ee value was 96.0% (the raw material ee value was 99.02%).
[0057] Comparative Example 9 This comparative example provides a synthetic process for an L-glufosinate intermediate, the specific steps of which are as follows: Under nitrogen protection, 17.58 g (0.087 mol, 1.0 eq) of (L)-2-amino-4-chloro-butyrate ethyl hydrochloride, 1.61 g (0.0435 mol, 0.1 eq) of triethylamine, 34.23 g (0.304 mol, 3.5 eq) of chlorobenzene, and 17.77 g (0.131 mol, 1.5 eq) of diethyl methylphosphonite were added to a 250 mL three-necked flask. After stirring and mixing, the mixture was heated to a higher temperature. The reaction was carried out at 120℃ for 23 hours. The GC control showed that (L)-2-amino-4-chloro-butyrate ethyl hydrochloride was less than 1%, and the impurity methyl ethyl phosphate ethyl ester was generated at 15%. 2.95 g of diethyl methylphosphonite and 33.95 g of chlorobenzene were distilled off at -0.096 MPa and 105℃ to obtain 4-[ethoxy(methyl)phosphono]-L-homoalanine ethyl hydrochloride. The product yield was 85%, and the product ee value was 25% (the raw material ee value was 99.02%).
[0058] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.
Claims
1. A synthetic process for an L-glufosinate intermediate, wherein the L-glufosinate intermediate is (2S)-2-ethoxycarbonylamino-4-ethoxymethylphosphoryl-butyrate ethyl ester, characterized in that, Under solvent-free conditions, using diethyl methylphosphonite and ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butyrate as raw materials, an Arbuzov reaction is carried out in the presence of a catalyst and triethylamine to obtain L-glufosinate intermediate; wherein the catalyst includes one or both of dimethyl sulfoxide or N,N-dimethylformamide.
2. The synthesis process of the L-glufosinate intermediate as described in claim 1, characterized in that, Specifically, the following steps are included: Diethyl methylphosphonite, ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butanoate, catalyst and triethylamine were mixed evenly and heated to carry out the Arbuzov reaction. After the reaction was completed, excess diethyl methylphosphonite was removed by distillation to obtain L-glufosinate intermediate.
3. The synthesis process of the L-glufosinate intermediate as described in claim 1 or 2, characterized in that, The catalyst is dimethyl sulfoxide.
4. The synthesis process of the L-glufosinate intermediate as described in claim 1 or 2, characterized in that, The molar ratio of diethyl methylphosphonite to ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butyrate is (1.3~2):
1.
5. The synthesis process of the L-glufosinate intermediate as described in claim 1 or 2, characterized in that, The molar ratio of triethylamine to ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butyrate is (0.1~0.6):
1.
6. The synthesis process of the L-glufosinate intermediate as described in claim 4, characterized in that, The molar ratio of triethylamine to ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butyrate is 0.5:
1.
7. The synthesis process of the L-glufosinate intermediate as described in claim 1 or 2, characterized in that, The molar ratio of the catalyst to ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butyrate is (0.1~0.5):
1.
8. The synthesis process of the L-glufosinate intermediate as described in claim 6, characterized in that, The molar ratio of the catalyst to ethyl (2S)-4-chloro-2-ethoxycarbonylamino-4-butyrate is 0.2:
1.
9. The synthesis process of the L-glufosinate intermediate as described in claim 1 or 2, characterized in that, The Arbuzov reaction was carried out at a temperature of 110℃ to 135℃ for a reaction time of 8h to 17h.
10. The synthesis process of the L-glufosinate intermediate as described in claim 9, characterized in that, The Arbuzov reaction was carried out at a temperature of 120°C for 8 to 14 hours.