Process for the preparation of (s)-2-amino-4-chlorobutyric acid alkyl esters and salts thereof

Abstract

This invention provides a method for preparing (S)-2-amino-4-chlorobutyric acid alkyl ester and its salt, comprising the following steps: (1) reacting a compound of formula I with a base to generate a compound of formula II; (2) reacting a compound of formula II with a chlorinating agent to generate a dichloride; and (3) reacting the dichloride with an alcohol to generate a compound of formula III. The preparation method of this invention improves the physicochemical properties of the reaction by constructing a dimer intermediate from the intramolecular bifunctional group of the compound of formula I, then achieving hydroxyl chlorination with a chlorinating agent, and finally, under the action of an alcohol, achieving the one-pot preparation of (S)-2-amino-4-chlorobutyric acid alkyl ester hydrochloride. This method effectively reduces the amount of chlorinating agent and alcohol used, significantly improves the atom economy and effective conversion rate of the reaction, has mild reaction conditions, produces products without significant racemization, has controllable impurities, and simplifies post-processing and purification. The by-product waste salt can be recycled, making it suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical process synthesis technology, specifically relating to a method for preparing (S)-2-amino-4-chlorobutyric acid alkyl ester and its salt. Background Technology

[0002] Glufosinate, chemically known as 2-amino-4-[hydroxy(methyl)phosphono]butyrate ammonium, is a highly effective, low-toxicity, broad-spectrum, non-selective contact organophosphorus herbicide with broad market prospects. It was first synthesized and developed by Hoechst (Bayer) in Germany in the 1980s and launched on the market in 1986.

[0003] L-Glufosinate was originally isolated from microorganisms as a monoisomer of an L-type amino acid. This amino acid is a glutamine inhibitor, with twice the herbicidal activity of racemic glufosinate, and is also known as refined glufosinate. Because its molecular structure is very similar to glutamic acid, it can reversibly bind to the active site of glutamine synthase, effectively inhibiting L-glutamine synthesis in plants. This leads to nitrogen metabolism disorders, excessive ammonia accumulation, chloroplast disintegration, and ultimately, photosynthesis inhibition, resulting in plant death. The use of L-glufosinate can reduce the amount of glufosinate used per unit area by more than 50%, showing significant effectiveness in reducing application costs and alleviating environmental pressure.

[0004] Currently, the methods for preparing L-glufosinate mainly fall into two categories: chemical methods and biological methods. Among them, chemical synthesis methods have seen rapid development in recent years. The main chemical synthesis methods for L-glufosinate include chiral auxiliary agent induction, chiral source introduction, and asymmetric catalytic synthesis. The chiral source introduction method has attracted widespread attention due to its advantages such as low raw material cost and promising industrial application prospects. Alkyl (S)-2-amino-4-chlorobutyrate is a key intermediate in the synthesis of L-glufosinate; therefore, it is particularly important to find a method for preparing (S)-2-amino-4-chlorobutyrate with high conversion rate, simple operation, and convenient post-processing.

[0005] Chinese patents CN 110845347 B and CN 117486742 A report that (S)-2-amino-4-chlorobutyric acid alkyl esters can be obtained by using (S)-3-aminodihydro-2(3H)-furanone hydrochloride or L-homoserine as raw materials, alcohol as reaction reagent and solvent, and ring-opening via thionyl chloride chlorination, as shown in the following equation:

[0006]

[0007] This method can synthesize (S)-2-amino-4-chlorobutyric acid alkyl esters in one step. However, due to the poor solubility of the raw materials in alcohols, the mass and heat transfer effects during chlorination and esterification are not good, resulting in a low conversion rate. It is necessary to increase the reaction temperature and the amount of thionyl chloride, a chlorinating agent, to promote the conversion of the raw materials. Even so, it is difficult to control the generation of ether and ester impurities, making separation and purification difficult and product quality difficult to control.

[0008] Chinese patents CN 115093339 A and CN 117776945 A report the following method for obtaining (S)-2-amino-4-chlorobutyric acid alkyl esters by chlorination with high-concentration HCl followed by protonic acid-catalyzed esterification using L-homoserine or (S)-3-aminodihydro-2(3H)-furanone hydrochloride as raw materials: The reaction equation is as follows:

[0009]

[0010] This method requires a large amount and concentration of acid for the chlorination reaction. The strong acid system makes the product chiral racemization and waste treatment difficult. At the same time, it places higher demands on the corrosion resistance of the reaction and post-treatment equipment, which is not conducive to large-scale production.

[0011] In summary, there is an urgent need for a method to prepare (S)-2-amino-4-chlorobutyric acid alkyl esters with high conversion rate, high atom economy, chirality retention, and suitability for industrial production, in order to accelerate the industrialization of low-cost L-glufosinate. Summary of the Invention

[0012] The purpose of this invention is to provide a method for preparing (S)-2-amino-4-chlorobutyric acid alkyl esters and their salts that has high conversion rate, good atom economy and is suitable for industrial production.

[0013] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0014] This invention provides a method for preparing (S)-2-amino-4-chlorobutyric acid alkyl ester hydrochloride, comprising the following steps:

[0015] (1) When compound I is reacted with a base, compound II is produced. The reaction equation is as follows:

[0016]

[0017] (2) The compound of formula II is reacted with a chlorinating reagent to generate a dichloride;

[0018] (3) The dichloride is reacted with an alcohol to produce a compound of formula III. The reaction equation is as follows:

[0019]

[0020] The alcohol has the structural formula ROH, and the R in Formula III is the same as the R in the structural formula of the alcohol and is selected from alkyl groups having 1 to 4 carbon atoms. The compound of Formula III is (S)-2-amino-4-chlorobutyrate alkyl ester hydrochloride.

[0021] This invention utilizes the bifunctional groups within the compound of formula I to generate compound II through dimerization and cyclization under alkaline conditions. This improves the lipophilicity of the reaction substrate, facilitating mass and heat transfer in the subsequent one-pot chlorination and esterification reactions, increasing the effective conversion rate, and significantly reducing the amount of highly corrosive thionyl chloride required. The chlorination reaction can be completed with a thionyl chloride dosage close to the stoichiometric ratio. Furthermore, the addition of the aforementioned alkaline material avoids the overflow of excess byproduct HCl, reducing equipment corrosion and the need for waste treatment. Through the addition of alcohol and the catalysis of residual HCl in the chlorination reaction, the chloride of compound II achieves one-step ring-opening esterification without the generation of impurities such as ethers, esters, or haloalkanes, significantly reducing the amount of alcohol used. It eliminates the need for recycling and has extremely high atom economy, few side reactions, and is environmentally friendly. The chiral groups in the substrate are fully preserved, the post-processing purification operation is simple, and the product quality is high.

[0022] Preferably, the reaction temperature in step (1) is controlled to be -10℃ to 20℃.

[0023] More preferably, the reaction temperature in step (1) is controlled to be -5℃ to 5℃.

[0024] In some embodiments, the reaction time of step (1) is controlled to be 1.5h to 4h, and more preferably 2h to 3h.

[0025] Preferably, the alkali in step (1) is selected from one or more of triethylamine, diethylamine, sodium hydroxide, sodium carbonate, sodium bicarbonate, and ammonia.

[0026] Preferably, the molar ratio of the compound of formula I to the alkali in step (1) is 1:(0.5-2.0), more preferably 1:(0.9-1.5), and even more preferably 1:(0.95-1.1).

[0027] Preferably, the reaction in step (1) is carried out in the presence of a solvent selected from one or more of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, butyl acetate, ethyl acetate, 1,4-dioxane, dichloromethane, and dichloroethane.

[0028] More preferably, the mass ratio of the compound of formula I to the solvent is 1:(2-7), even more preferably 1:(2.5-4), and even more preferably 1:(2.9-3.5).

[0029] Preferably, the chlorinating agent is thionyl chloride.

[0030] Preferably, the molar ratio of the compound of formula II to the chlorinating agent is 1:(0.5-2.0), more preferably 1:(0.8-1.2), and even more preferably 1:(0.9-1.1).

[0031] Preferably, step (2) specifically includes: after the reaction in step (1) is completed, the chlorination reagent is added to it, and the temperature is controlled at -10℃ to 20℃ during the process. After the chlorination reagent is added, the system is heated to 40℃ to 120℃ for reaction.

[0032] More preferably, step (2) specifically includes: after the reaction in step (1) is completed, the chlorination reagent is added to it, and the temperature is controlled at 0℃~10℃ during the process. After the chlorination reagent is added, the system is heated to 40℃~60℃ for reaction.

[0033] Preferably, the reaction time of step (2) is controlled to be 6h to 12h, and more preferably 6h to 8h.

[0034] Preferably, the alcohol is selected from one or more of methanol, ethanol, isopropanol, n-propanol, and n-butanol.

[0035] Preferably, the molar ratio of the compound of formula I to the alcohol is 1:(1-2), more preferably 1:(1-1.5), and even more preferably 1:(1-1.2).

[0036] Preferably, the reaction temperature in step (3) is 10℃~80℃, and more preferably 20℃~40℃.

[0037] Preferably, the preparation method further includes removing part of the solvent from the reaction system of step (3), and then obtaining the compound of formula III by filtration, rinsing and drying.

[0038] More preferably, the desolventizing temperature is controlled to be no higher than 80°C, and even more preferably 40°C to 80°C.

[0039] In some embodiments, petroleum ether is used for the rinsing.

[0040] This invention also provides a method for preparing (S)-2-amino-4-chlorobutyrate alkyl ester, comprising steps (1), (2), and (3) as described above, and further comprising step (4), wherein step (4) includes: reacting a compound of formula III with a base to generate a compound of formula IV, wherein the compound of formula IV is (S)-2-amino-4-chlorobutyrate alkyl ester, and its structural formula is [insert structural formula here]. The bases in steps (1) and (4) may be the same or different, and the R in formula IV is the same as the R in formula III.

[0041] This invention innovatively develops a one-pot process route for preparing (S)-2-amino-4-chlorobutyric acid alkyl esters and their salts from compounds of Formula I via dimerization, chlorination, and esterification through the regulation of alkali, chlorination reagents, and alcohols. Compared with existing processes, this route significantly reduces the amount of highly corrosive reagents and alcohol reagents, resulting in high effective conversion rates, fewer side reactions, environmental friendliness, full preservation of the chiral groups in the substrate, simple post-processing purification, high product quality, no excessive waste gas or waste liquid generation, and by-product waste salts that meet the conditions for external sale after crystallization. The reaction solvent achieves closed-loop utilization, reducing the cost of waste treatment and engineering investment.

[0042] Preferably, the alkali in step (4) is selected from one or more of triethylamine, sodium hydroxide, potassium hydroxide, and ammonia.

[0043] Preferably, the molar ratio of the compound of formula I to the alkali in step (4) is 1:(1.0 to 1.5), and more preferably 1:(1.0 to 1.2).

[0044] Preferably, the reaction in step (4) is carried out in the presence of a protective solvent selected from one or more of methyl tert-butyl ether, toluene, chlorobenzene, dichloroethane, and dichloromethane.

[0045] More preferably, the mass ratio of the compound of formula I to the protective solvent is 1:(3-8), and more preferably 1:(3-4).

[0046] Preferably, the reaction temperature in step (4) is 0 to 20°C.

[0047] Preferably, after the reaction in step (4) is completed, the reaction system is extracted to obtain the (S)-2-amino-4-chlorobutyric acid alkyl ester.

[0048] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0049] The preparation method of this invention utilizes the intramolecular bifunctional group of the compound of formula I to construct a dimer intermediate, thereby improving the physicochemical properties of the reaction substrate. Then, hydroxyl chlorination is achieved by a chlorinating reagent, and finally, (S)-2-amino-4-chlorobutyric acid alkyl ester hydrochloride is prepared in a one-pot process under the action of an alcohol. This method effectively reduces the amount of chlorinating reagent and alcohol used, significantly improves the atom economy and effective conversion rate of the reaction, has mild reaction conditions, no obvious racemization of the product, controllable impurities, simple post-processing and purification, and the by-product waste salt can be recycled, making it suitable for large-scale industrial production. Attached Figure Description

[0050] Figure 1 The LC spectrum of compound (II) from Example 1 is shown.

[0051] Figure 2 MS (ESI, [M+H) of the reaction product (S)-2-amino-4-chlorobutyrate ethyl hydrochloride from Example 1. + ) Spectrum;

[0052] Figure 3 MS (ESI, [M+H)) of the reaction product (S)-2-amino-4-chlorobutyrate butyl hydrochloride from Example 5. + ) Spectrum. Detailed Implementation

[0053] The present invention will be further described below with reference to embodiments. However, the present invention is not limited to the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to different requirements of specific applications, and the implementation conditions not specified are conventional conditions in the industry. The technical features involved in the various embodiments of the present invention can be combined with each other as long as they do not conflict with each other.

[0054] To determine the optical purity of the product obtained during the preparation process, a catalytic ion-pairing method was used, and high-performance liquid chromatography (HPLC) was employed to detect its optical purity. The specific test conditions were as follows: Agilent ZORBAX SAX 4.6×250mm×5μm; mobile phase: (0.05mol / L diammonium hydrogen phosphate, 2.75mL / L tetrabutylammonium hydroxide, water (pH=3.6)): acetonitrile = 92:8; flow rate: 1.0mL / min; column temperature: 35℃; detection wavelength: 195nm; injection volume: 5μL; retention time: (R)-3-aminodihydro-2(3H)-furanone hydrochloride: 3.0min, (S)-2-amino-4-chlorobutyrate alkyl ester: 3.4min.

[0055] The analytical conditions for the ee value of ethyl (S)-2-amino-4-chlorobutyrate (the ee values ​​of butyl (S)-2-amino-4-chlorobutyrate and isopropyl (S)-2-amino-4-chlorobutyrate can be obtained by transesterification) are as follows: Sumika Chemical Analysis Service OA-5000L 4.6×150mm×5μm; mobile phase: 1mM CuSO4, 0.3% acetonitrile aqueous solution; flow rate: 0.4mL / min; column temperature: 30℃; detection wavelength: 254nm; injection volume: 5μL; retention time: L-body 17.0min, D-body 12.5min.

[0056] Unless otherwise specified, the following examples use (S)-3-aminodihydro-2(3H)-furanone hydrochloride (compound of formula I) which was prepared in-house, as detailed below:

[0057] 119 g of L-homoserine (1 mol) and 119 g of water were weighed and added to a reaction flask. 203 g of concentrated hydrochloric acid (36% by mass, 2 mol) was added, and the mixture was reacted at 25 °C for 3 h. After the reaction was complete, the reaction system was concentrated and crystallized from ethanol to obtain (S)-3-aminodihydro-2(3H)-furanone hydrochloride, a white solid, with a molar yield of 95.2% and an HPLC purity of 99.0%.

[0058] Example 1

[0059]

[0060] 27.51 g of (S)-3-aminodihydro-2(3H)-furanone hydrochloride (0.2 mol) and 85 g of N-methylpyrrolidone were added to a four-necked flask. The temperature was lowered to 0 °C, and 3.57 g of NH3 (0.21 mol) was bubbled into the system. The mixture was kept at this temperature for 2 h to obtain compound (II). The reaction solution was filtered to remove the byproduct ammonium chloride. The temperature of the filtrate was controlled at 0 °C to 5 °C throughout the process. Subsequently, at this temperature, 24.98 g of... SOCl2 (0.21 mol) was added dropwise to the reaction system at a uniform rate, and the reaction temperature was controlled to be below 5°C during the addition. After the addition was complete, the system was heated to 50°C and reacted for 6 hours. After the complete conversion of compound (II) was monitored by LC (liquid chromatography), the reaction temperature was controlled at 20°C, and 9.67 g of anhydrous ethanol (0.21 mol) was slowly added to the system. The mixture was kept at this temperature for 2 hours, during which solids were continuously precipitated. When the content of the chlorinated intermediate was less than 1% by LC, about 50 g of solvent was removed under negative pressure and at a temperature not exceeding 80°C. After cooling to room temperature, the mixture was filtered, washed with petroleum ether, and dried to obtain 39.61 g of (S)-2-amino-4-chlorobutyrate ethyl hydrochloride as a white solid. The molar yield of the product was 96.24%, the purity was 98.20%, and the ee value was 99.0%.

[0061] The HPLC control spectrum of compound II (CAS No.: 50975-79-6) generated by the ammonia reaction of (S)-3-aminodihydro-2(3H)-furanone hydrochloride is shown below. Figure 1 The LC-MS spectrum of the reaction product (S)-2-amino-4-chlorobutyrate ethyl hydrochloride is shown in [reference needed]. Figure 2 .

[0062] Example 2

[0063] 27.51 g of (S)-3-aminodihydro-2(3H)-furanone hydrochloride (0.2 mol) and 85 g of N-methylpyrrolidone were added to a four-necked flask. The temperature was lowered to 0 °C, and 20.24 g of triethylamine (0.2 mol) was added to the system. The mixture was kept at this temperature for 2 h to obtain compound (II). The reaction solution was filtered to remove the byproduct triethylamine hydrochloride. The temperature of the filtrate was controlled between 0 °C and 5 °C throughout the process. Subsequently, at this temperature, 24.98 g of... SOCl2 (0.21 mol) was added dropwise to the reaction system at a uniform rate, and the reaction temperature was controlled to be below 5°C during the addition. After the addition was complete, the system was heated to 50°C and reacted for 6 hours. After the complete conversion of compound (II) was monitored by LC, the reaction temperature was controlled at 20°C, and 9.67 g of anhydrous ethanol (0.21 mol) was slowly added to the system. The temperature was maintained for 2 hours, during which solids were continuously precipitated. When the content of the chlorinated intermediate was less than 1% by LC, about 50 g of solvent was removed under negative pressure and at a temperature not exceeding 80°C. After cooling to room temperature, the solution was filtered, washed with petroleum ether, and dried to obtain 39.73 g of grayish-white solid (S)-2-amino-4-chlorobutyrate ethyl hydrochloride. The molar yield of the product was 95.85%, the purity was 97.50%, and the ee value was 98.7%.

[0064] Example 3

[0065] 27.51 g of (S)-3-aminodihydro-2(3H)-furanone hydrochloride (0.2 mol) and 85 g of N-methylpyrrolidone were added to a four-necked flask. The temperature was lowered to 0 °C, and 8.0 g of sodium hydroxide (0.2 mol) was added to the system. The mixture was kept at this temperature for 2 h to obtain compound (II). The reaction solution was filtered to remove the byproduct triethylamine hydrochloride. The temperature of the filtrate was controlled at 0 °C to 5 °C throughout the process. Subsequently, at this temperature, 24.98 g of... SOCl2 (0.21 mol) was added dropwise to the reaction system at a uniform rate, and the reaction temperature was controlled to be below 5°C during the addition. After the addition was complete, the system was heated to 50°C and reacted for 6 hours. After the complete conversion of compound (II) was monitored by LC, the reaction temperature was controlled at 20°C, and 9.67 g of anhydrous ethanol (0.21 mol) was slowly added to the system. The temperature was maintained for 2 hours, during which solids were continuously precipitated. When the content of the chlorinated intermediate was less than 1% by LC, about 50 g of solvent was removed under negative pressure and at a temperature not exceeding 80°C. After cooling to room temperature, the solution was filtered, washed with petroleum ether, and dried to obtain 39.58 g of brown solid (S)-2-amino-4-chlorobutyrate ethyl hydrochloride. The molar yield of the product was 94.22%, the purity was 96.20%, and the ee value was 98.1%.

[0066] Comparative Example 1

[0067] The specific steps of Comparative Example 1 are basically the same as those of Example 1, except that the ammonia inlet temperature and reaction temperature are different during the formation of compound (II), as detailed below:

[0068] 27.51 g of (S)-3-aminodihydro-2(3H)-furanone hydrochloride (0.2 mol) and 85 g of N-methylpyrrolidone were added to a four-necked flask. The system temperature was maintained at 20 °C, and 3.57 g of NH3 (0.21 mol) was bubbled into the system. The mixture was kept at this temperature for 2 h to obtain compound (II). The reaction solution was filtered to remove the byproduct ammonium chloride. Subsequently, 24.98 g of... SOCl2 (0.21 mol) was added dropwise to the reaction system at a uniform rate, and the reaction temperature was controlled to be below 5°C during the addition. After the addition was complete, the system was heated to 50°C and reacted for 6 hours. After the complete conversion of compound (II) was monitored by LC, the reaction temperature was controlled at 20°C, and 9.67 g of anhydrous ethanol (0.21 mol) was slowly added to the system. The temperature was maintained for 2 hours, and solids were continuously precipitated during this period. When the content of the chlorinated intermediate was less than 1% by LC, about 50 g of solvent was removed under negative pressure and at a temperature not exceeding 50°C. After cooling to room temperature, the product was filtered, washed with petroleum ether, and dried to obtain 39.62 g of brown solid (S)-2-amino-4-chlorobutyrate ethyl hydrochloride. The molar yield of the product was 96.11%, the purity was 98.05%, and the ee value was 90.2%.

[0069] By comparing Example 1 and Comparative Example 1, it was found that in the process of generating compound (II) by ammonia through (S)-3-aminodihydro-2(3H)-furanone hydrochloride, excessively high ammonia temperature and reaction temperature will affect the ee value of the product. Therefore, as a preferred method, the reaction temperature and alkali addition temperature for generating compound (II) by (S)-3-aminodihydro-2(3H)-furanone hydrochloride should be below 20°C, preferably -10°C to 15°C.

[0070] Example 4

[0071] 27.51 g of (S)-3-aminodihydro-2(3H)-furanone hydrochloride (0.2 mol) and 85 g of dichloroethane were added to a four-necked flask. The temperature was lowered to 0 °C, and 3.57 g of NH3 (0.21 mol) was bubbled into the system. The mixture was kept at this temperature for 2 h to obtain compound (II). The reaction solution was filtered to remove the byproduct ammonium chloride. The temperature of the filtrate was controlled between 0 °C and 5 °C throughout the process. Then, at this temperature, 24.98 g of SOCl2 (0.21 mol) was added dropwise to the reaction system at a uniform rate. During the addition, the temperature rise was controlled to be below 5 °C. After the addition was completed, the system was heated to 50 °C and reacted for 6 h. After the conversion of compound (II) was complete, the reaction temperature was controlled at 20 °C, and the mixture was slowly bubbled into the system. 7.69 g of anhydrous methanol (0.24 mol) was added to the solution, and the mixture was kept at this temperature for 2 h. During this time, solids continuously precipitated out. When the content of the chlorinated intermediate was less than 1% by LC monitoring, about 50 g of solvent was removed from the reaction solution under negative pressure and at a temperature not exceeding 40 °C. After cooling to room temperature, the solution was filtered, washed with petroleum ether, and dried to obtain 36.58 g of grayish-white solid (S)-2-amino-4-chlorobutyrate methyl hydrochloride. The molar yield of the product was 95.12%, the purity was 97.8%, and the ee value was 98.6%.

[0072] Example 5

[0073] 27.51 g of (S)-3-aminodihydro-2(3H)-furanone hydrochloride (0.2 mol) and 85 g of dichloroethane were added to a four-necked flask. The temperature was lowered to 0 °C, and 3.57 g of NH3 (0.21 mol) was bubbled into the system. The mixture was kept at this temperature for 2 h to obtain compound (II). The reaction solution was filtered to remove the byproduct ammonium chloride. The temperature of the filtrate was controlled between 0 °C and 5 °C throughout the process. Then, at this temperature, 24.98 g of SOCl2 (0.21 mol) was added dropwise to the reaction system at a uniform rate. During the addition, the temperature rise was controlled to be below 5 °C. After the addition was completed, the system was heated to 50 °C and reacted for 6 h. After the conversion of compound (II) was complete, the reaction temperature was controlled at 20 °C, and the mixture was slowly bubbled into the system. 17.79 g of n-butanol (0.24 mol) was added to the solution and kept at this temperature for 2 h. During this time, solids continuously precipitated out. When the content of the chlorinated intermediate was less than 1% by LC monitoring, about 50 g of solvent was removed from the reaction solution under negative pressure and at a temperature not exceeding 40 °C. After cooling to room temperature, the solution was filtered, washed with petroleum ether, and dried to obtain 44.87 g of (S)-2-amino-4-chlorobutyrate butyl hydrochloride, a grayish-white solid. The product molar yield was 94.76%, the purity was 97.2%, and the ee value was 98.4%.

[0074] The LC-MS spectrum of the reaction product ((S)-2-amino-4-chlorobutyrate butyl hydrochloride) is shown in [reference needed]. Figure 3 .

[0075] Example 6

[0076] Based on Example 1, the esterification reaction solution was concentrated, then protected with an organic solvent, washed with alkaline water, and extracted to obtain (S)-2-amino-4-chlorobutyrate ethyl ester product, as detailed below:

[0077] The esterification reaction solution (i.e., the reaction solution after the addition of anhydrous ethanol and the completion of the reaction) was concentrated at 40℃, dried, and then 100g of methyl tert-butyl ether was added as a protective solvent for neutralization. The temperature was lowered to 5-10℃, and under the condition that the system was uniformly dispersed, 33.74g of dilute ammonia aqueous solution (0.22mol) was slowly added dropwise. The temperature was controlled at 5-10℃ throughout the dropwise addition process. After extraction twice with methyl tert-butyl ether, 32.22g of (S)-2-amino-4-chlorobutyrate ethyl ester product was obtained. The molar yield of the product was 95.8%, the purity was 98.4%, and the ee value was 99.0%.

[0078] The present invention has been described in detail above, with the aim of enabling those skilled in the art to understand and implement the invention. However, this description should not be construed as limiting the scope of protection of the invention. All equivalent changes or modifications made in accordance with the spirit and essence of the invention should be included within the scope of protection of the invention.

Claims

1. A method for preparing (S)-2-amino-4-chlorobutyric acid alkyl ester hydrochloride, characterized in that, Includes the following steps: (1) When compound I is reacted with a base, compound II is produced. The reaction equation is as follows: (2) The compound of formula II is reacted with a chlorinating reagent to generate a dichloride; (3) The dichloride is reacted with an alcohol to produce a compound of formula III. The reaction equation is as follows: The alcohol has the structural formula ROH, and the R in Formula III is the same as the R in the structural formula of the alcohol and is selected from alkyl groups having 1 to 4 carbon atoms. The compound of Formula III is (S)-2-amino-4-chlorobutyrate alkyl ester hydrochloride.

2. The preparation method according to claim 1, characterized in that, The reaction temperature in step (1) is controlled to be -10℃ to 20℃.

3. The preparation method according to claim 2, characterized in that, The reaction temperature in step (1) is controlled to be -5℃ to 5℃.

4. The preparation method according to claim 1, characterized in that, The alkali used in step (1) is selected from one or more of triethylamine, diethylamine, sodium hydroxide, sodium carbonate, sodium bicarbonate, and ammonia; and / or, The molar ratio of compound I to alkali in step (1) is 1:(0.5-2.0).

5. The preparation method according to claim 1, characterized in that, The reaction in step (1) is carried out in the presence of a solvent selected from one or more of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, butyl acetate, ethyl acetate, 1,4-dioxane, dichloromethane, and dichloroethane.

6. The preparation method according to claim 1, characterized in that, The chlorinating agent is thionyl chloride; and / or, The molar ratio of the compound of formula II to the chlorinating agent is 1:(0.5–2.0); and / or, The specific steps (2) include: after the reaction in step (1) is completed, the chlorination reagent is added to it, and the temperature is controlled at -10℃ to 20℃ during the process. After the chlorination reagent is added, the system is heated to 40℃ to 120℃ for reaction.

7. The preparation method according to claim 1, characterized in that, The alcohol is selected from one or more of methanol, ethanol, isopropanol, n-propanol, and n-butanol; and / or, The molar ratio of the compound of formula I to the alcohol is 1:(1-2); and / or, The reaction temperature in step (3) is 10℃~80℃.

8. A method for preparing an alkyl (S)-2-amino-4-chlorobutyrate, characterized in that, Including steps (1), (2), and (3) as described in any one of claims 1 to 7, the preparation method further includes step (4), which comprises: reacting the compound of formula III with a base to generate the compound of formula IV, wherein the compound of formula IV is an alkyl (S)-2-amino-4-chlorobutyrate ester with the following structural formula: The bases in steps (1) and (4) may be the same or different, and the R in formula IV is the same as the R in formula III.

9. The method for preparing (S)-2-amino-4-chlorobutyric acid alkyl ester according to claim 8, characterized in that, The alkali used in step (4) is selected from one or more of triethylamine, sodium hydroxide, potassium hydroxide, and ammonia water; and / or, The molar ratio of the compound of formula I to the alkali in step (4) is 1:(1.0 to 1.5).

10. The method for preparing (S)-2-amino-4-chlorobutyric acid alkyl ester according to claim 8, characterized in that, The reaction in step (4) is carried out in the presence of a protective solvent selected from one or more of methyl tert-butyl ether, toluene, chlorobenzene, dichloroethane, and dichloromethane; and / or, The reaction temperature in step (4) is 0 to 20°C.

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