L-2-amino-4-halogenated butyric acid derivative-L-tartrate and preparation method thereof

Abstract

The present disclosure describes an L-S2-amino-4-halogenated butyric acid derivative, namely, an L-tartrate salt. The present disclosure also describes a process for the preparation of an L-S-amino-4-halobutyric acid derivative-L-tartrate comprising the steps of: using a mixture of D, L-S2-amino-4-halobutyric acid derivative enantiomers as a raw material, using L-tartrate as a resolving agent, and using an enantiomer mixture of D, L-S2-amino-4-halobutyric acid derivative enantiomers as a resolving agent in the same resolving agent system to resolve the enantiomers of D, L-S2-amino-4-halobutyric acid derivative enantiomers. And carrying out resolution reaction, crystallization and filtration to obtain the L-S2-amino-4-halogenated butyric acid derivative-L-tartrate. Or the enantiomer mixture of the D, L-S2-amino-4-halogenated butyric acid derivative is used as a raw material in the same resolving agent system, L-tartrate is used as a resolving agent, a dynamic resolution reaction is carried out under the catalysis of aromatic aldehyde or the co-catalysis of aromatic aldehyde and organic acid, the method further comprises crystallization and filtration, and the enantiomer mixture of the D, L-S2-amino-4-halogenated butyric acid derivative is obtained. And filtering to obtain the L-S2-amino-4-halogenated butyric acid derivative-L-tartrate.

Description

Technical Field

[0001] The present invention relates to L-2-amino-4-halobutyric acid derivative-L-tartrate and a preparation method thereof. The compound is a chiral intermediate that can be used to produce the herbicide L-phosphinothricin ammonium. Background Art

[0002] In 1987, the German company Hoechst pioneered the development of glufosinate herbicide and successfully commercialized it under the trade name Basta.

[0003] The most commonly used glufosinate is the racemic form of L-glufosinate and D-glufosinate, of which L-glufosinate has a herbicidal effect, while D-glufosinate has almost no activity. Because L-glufosinate has twice the herbicidal activity of ordinary glufosinate, the application amount is only 50% of ordinary glufosinate, and the application cost is basically the same. The research and development and production of L-glufosinate will greatly reduce the amount of glufosinate used, which is very important for improving the cost-effectiveness of products, reducing the amount of pesticides used, and reducing environmental pressure.

[0004] Commercially available glufosinate is mainly D,L-glufosinate, which is mainly produced by the following method.

[0005] Patent US4599207A uses a thermal cracking-ACA method to prepare methyl dichlorophosphine (MDP) through a gas phase reaction of methane and phosphorus trichloride. The most important steps are the preparation of the key block "P" group methyl phosphite monobutyl ester (MPE) and the Michael radical addition of the aminobutyric acid precursor 2-acetoxy-3-butenenitrile (ACA), followed by amination and hydrolysis to obtain glufosinate ammonium.

[0006] Patent CN102276643B uses the Grignard-Strecker method to omit the step of producing MDP. Diethyl methylphosphite as a "P" group block is obtained by a Grignard reagent, and then reacted with acrolein as a precursor of the aminobutyric acid block to obtain aminonitrile by Strecker reaction, which is hydrolyzed to obtain glufosinate.

[0007] Patent application CN106046052A based on previous patents uses an Al-Strecker process. MDP is produced by complexed and uncomplexed phosphorus trichloride, methyl chloride and aluminum chloride, and then diethyl methyl phosphite is synthesized as a "P" group block. The subsequent steps are the same as those in the Grignard-Strecker process, but the advantage is that MDP can be synthesized and can be changed to an ACA process later, making the selection of aminobutyric acid blocks more flexible.

[0008] <pn244392>

[0009] Patent application CN110003269A uses methane and phosphorus trichloride as raw materials for preparing MDP and subsequent "P" group blocks, without using Grignard reagents or aluminum trichloride.

[0010] Generally, the preparation of glufosinate requires two key blocks, namely the "P" block (e.g., monobutyl methyl phosphite, diethyl methyl phosphite, etc.) and the aminobutyric acid block (e.g., ACA, acrolein, etc.). Currently, in the industrialization of the "P" group block, the synthesis of D,L-glufosinate is already very mature.

[0011] At present, the research on the production of L-glufosinate is mainly divided into chemical resolution, asymmetric chiral synthesis, bioenzyme method and chiral source method.

[0012] Chemical splitting mainly targets D,L-phosphinothricin.

[0013] Patent US5767309 discloses a method for splitting D,L-glufosinate, which uses quinine and glufosinate ammonium salt to form a salt, and then uses 3,5-dinitrosalicylic aldehyde in the presence of acetic acid to racemize to obtain L-glufosinate. However, due to the low yield and the high price of quinine, this method has not yet been industrialized.

[0014] Patent application WO2018108797A1 discloses a method for preparing L-glufosinate using ephedrine analogs to induce crystallization. The method allows the conversion of D-glufosinate to L-glufosinate. Ephedrine analogs have a simple structure, but ephedrine belongs to the category of controlled substances, so the method is unlikely to be industrialized.

[0015] Patent application CN112979701A discloses a method for preparing L-phosphinothricin. D, L-phosphinothricin derivatives react with ligands or their hydrochlorides and nickel salts in the presence of a base to obtain a metal complex, which is then hydrolyzed to obtain L-phosphinothricin. The method has a complex route, many steps, low decomposition efficiency, and high ligand cost, so it is not easy to achieve industrialization.

[0016] Asymmetric chiral synthesis starts with the synthesis of achiral phosphine compound precursors, followed by asymmetric synthesis.

[0017] Patent application WO2006104120 discloses a method for asymmetric hydrogenation of dehydrogenated amino acids using a rhodium catalyst and obtaining L-phosphinothricin by hydrolysis conversion. This route uses acrylate as a precursor block of aminobutyric acid, reacts with the "P" group block, then hydrolyzes and aminates it, and then constructs a chiral center by asymmetric hydrogenation with mild reaction conditions and high yield. However, hydrogenation requires chiral phosphorus ligands for rhodium catalyst hydrogenation, which are expensive, difficult to recycle and have high production costs.

[0018] Patent application WO2008035687 discloses the Jacobsen catalyst catalytic synthesis of L-phosphinothricin. The β-phosphinaldehyde obtained by the reaction of the above two blocks is reacted with an aromatic amine to form an imine compound, which is catalyzed by a Jacobsen catalyst, subjected to an asymmetric Strecker reaction with trimethylsilyl cyanide, and converted by hydrolysis to obtain L-phosphinothricin. However, the cost of both the raw materials trimethylsilyl cyanide and the Jacobsen catalyst is high, so it is difficult to achieve industrialization.

[0019] Patent application CN105131032A discloses a method for synthesizing L-phosphinothricin using a chiral quaternary ammonium salt derivative of cinchonidine as a phase transfer catalyst. The patent application uses a benzylidene glycine ester compound as an aminobutyric acid block, and a methyl vinyl phosphonate compound as a "P" block. Under the catalysis of a chiral catalyst, the chiral center of L-phosphinothricin is constructed by asymmetric Michael addition, and L-phosphinothricin is obtained after hydrolysis. However, the catalyst consumption of this route is large and difficult to recover; the ee value and yield are low.

[0020] The bio-enzyme method is mainly divided into bio-enzyme splitting method and transaminase method.

[0021] Patents and patent applications US5618728, US5756800, CN105567780, CN107502647, US9834802B2, CN109384811A all disclose methods for preparing L-glufosinate by using D,L-glufosinate or its derivatives as raw materials through enzyme splitting or conversion, but all have problems such as D-glufosinate not being utilized, complex systems, or difficulty in recovering catalysts.

[0022] JP2589693B2, CN110093327A and CN106916857A all disclose methods for converting a keto group into an amino group to obtain L-phosphinothricin ammonium by transaminase. The patent uses keto acids such as 2-carbonyl-4-(hydroxymethylphosphono)butyric acid as substrates and L-glutamic acid as chiral amino donors, but there is also the problem of product purification difficulties.

[0023] The bioenzymatic production of L-glufosinate does not involve the preparation and reaction related to the above two blocks, but has strict environmental requirements for microorganisms and enzymes. This method produces a large amount of wastewater containing high phosphorus, the cost is difficult to control, the system is complex and the product purification is difficult, so there are few commercial products produced on an industrial scale.

[0024] The chiral source method synthesizes L-phosphinothricin by preparing a chiral aminobutyric acid block and reacting it with a "P" group block.

[0025] Patent US5591861A discloses a method for preparing chiral aminobutyric acid blocks using L-glutamic acid and L-aspartic acid as chiral sources.

[0026]

[0027] The raw material is protected and acylated to obtain a β-haloethyl-L-glycine derivative, which is then reacted with diethyl methylphosphite via the Arbuzov reaction to obtain an L-phosphinothricin derivative, which is further hydrolyzed to obtain L-phosphinothricin hydrochloride. This route has more steps and requires multiple transformations, making it difficult to industrialize.

[0028] CN106083922A discloses a method for preparing chiral aminobutyric acid blocks of 4-halogenated-2-aminobutyrate from L-methionine. L-methionine reacts with α-halogenated carboxylic acid or its derivative under the action of a phase transfer catalyst to obtain L-homoserine lactone hydrogen halide, and then obtains L-phosphinothricin ammonium through subsequent reactions. However, this method has serious sulfur pollution.

[0029]

[0030] Patents and patent applications US5442088, CN111662324A, CN112574119A, CN110845347A, WO2021147894A1, WO2021143713A1 and CN109369432A disclose the preparation of chiral aminobutyric acid block 4-halo-2-aminobutyric acid (ester) by L-homoserine or its lactone hydrochloride. However, the L-homoserine method has problems such as expensive raw materials, serious pollution, harsh ring opening conditions and the need for special reaction equipment, making the method difficult to industrialize.

[0031]

[0032] Patent applications WO2006103696A2 and CN102060721A use tartaric acid to decompose aminobutanamide and aminobutyric acid, respectively. However, aminobutanamide and aminobutyric acid cannot be directly used as intermediates for synthesizing L-phosphinothricin ammonium, and their purpose is not to prepare L-phosphinothricin ammonium.

[0033] As mentioned above, the industrial synthesis of D,L-phosphinothricin by "P" block and aminobutyric acid block is well known. However, the key to preparing L-phosphinothricin is to obtain the chiral intermediate of aminobutyric acid block at low cost. From the current public reports, there is still no route that can prepare chiral aminobutyric acid block in an effective, green and simple way for the synthesis of L-phosphinothricin. In particular, there is no method for obtaining the chiral intermediate of L-phosphinothricin by splitting racemic aminobutyric acid or its derivatives. Therefore, there is an urgent need for a low-cost, simple and industrially feasible chiral aminobutyric acid block synthesis method. Summary of the invention

[0034] One aspect of the present disclosure relates to an L-2-amino-4-halobutyric acid derivative-L-tartrate having a structure of Formula I:

[0035]

[0036] in

[0037] z is the molar ratio of the L-2-amino-4-halobutyric acid derivative to L-tartaric acid, and z is 1 to 2;

[0038] X is Cl or Br; and

[0039] R is OR 1 or NR 2 R 3 , where R 1 is a C1 to C4 aliphatic hydrocarbon, R 2 is H or a C1 to C4 aliphatic hydrocarbon, and R 3 is H or a C1 to C4 aliphatic hydrocarbon.

[0040] Another aspect of the present disclosure is a method for preparing L-2-amino-4-halobutyric acid derivative-L-tartrate, as described in method a) elsewhere in the present disclosure, the method comprising:

[0041] a) mixing a mixture of D,L-2-amino-4-halobutyric acid derivative enantiomers, L-tartaric acid and a solvent to promote a resolution reaction and produce a product comprising L-2-amino-4-halobutyric acid derivative-

[0042] Resolution reaction mixture of L-tartrate;

[0043] b) precipitating the L-2-amino-4-halobutyric acid derivative-L-tartrate; and

[0044] c) isolating the L-2-amino-4-halobutyric acid derivative-L-tartrate from the resolution reaction mixture.

[0045] Yet another aspect of the present disclosure is a method for preparing L-2-amino-4-halobutyric acid derivative-L-tartrate, as described in method b) elsewhere in the present invention, the method comprising:

[0046] <pn244392>

[0047] a) mixing a D-2-amino-4-halobutyric acid derivative or a D,L-2-amino-4-halobutyric acid derivative enantiomer mixture, L-tartaric acid, an aromatic aldehyde or an aromatic aldehyde and an organic acid with a solvent to promote a dynamic resolution reaction and produce a resolution reaction mixture containing an L-2-amino-4-halobutyric acid derivative-L-tartrate;

[0048] b) precipitating the L-2-amino-4-halobutyric acid derivative-L-tartrate; and

[0049] c) isolating the L-2-amino-4-halobutyric acid derivative-L-tartrate from the resolution reaction mixture.

[0050] Other objects and features will be in part apparent and in part pointed out hereinafter. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 The infrared spectrum of ethyl L-2-amino-4-chlorobutyrate-L-tartrate prepared in Example 1 of the present invention is shown.

[0052] Figure 2 The NMR hydrogen spectrum of L-2-amino-4-chlorobutyric acid ethyl ester-L-tartrate prepared in Example 1 of the present invention is shown.

[0053] Figure 3 The NMR carbon spectrum of L-2-amino-4-chlorobutyric acid ethyl ester-L-tartrate prepared in Example 1 of the present invention is shown.

[0054] Figure 4 The infrared spectrum of ethyl L-2-amino-4-bromobutyrate-L-tartrate prepared in Example 6 of the present invention is shown.

[0055] Figure 5 The NMR hydrogen spectrum of L-2-amino-4-bromobutyric acid ethyl ester-L-tartrate prepared in Example 6 of the present invention is shown.

[0056] Figure 6 The NMR carbon spectrum of L-2-amino-4-bromobutyric acid ethyl ester-L-tartrate prepared in Example 6 of the present invention is shown.

[0057] Figure 7 The infrared spectrum of L-2-amino-4-chlorobutyric acid methyl ester-L-tartrate prepared in Example 8 of the present invention is shown.

[0058] Figure 8 The NMR hydrogen spectrum of L-2-amino-4-chlorobutyric acid methyl ester-L-tartrate prepared in Example 8 of the present invention is shown.

[0059] Fig. 9 The NMR carbon spectrum of L-2-amino-4-chlorobutyric acid methyl ester-L-tartrate prepared in Example 8 of the present invention is shown.

[0060] Fig.10 The infrared spectrum of L-2-amino-4-chlorobutyrate isopropyl ester-L-tartrate prepared in Example 10 of the present invention is shown.

[0061] Fig.11 The NMR hydrogen spectrum of L-2-amino-4-chlorobutyrate isopropyl ester-L-tartrate prepared in Example 10 of the present invention is shown.

[0062] Fig.12 The NMR carbon spectrum of L-2-amino-4-chlorobutyrate isopropyl ester-L-tartrate prepared in Example 10 of the present invention is shown.

[0063] Fig.13 The infrared spectrum of L-2-amino-4-chlorobutanamide-L-tartrate prepared in Example 12 of the present invention is shown.

[0064] Fig.14 The NMR hydrogen spectrum of L-2-amino-4-chlorobutanamide-L-tartrate prepared in Example 12 of the present invention is shown.

[0065] Fig.15 The NMR carbon spectrum of L-2-amino-4-chlorobutanamide-L-tartrate prepared in Example 12 of the present invention is shown.

[0066] Corresponding reference characters indicate corresponding parts throughout the several views of the drawings. DETAILED DESCRIPTION

[0067] One aspect of the present disclosure is a L-2-amino-4-halobutyric acid derivative-L-tartrate having the structure of Formula I:

[0068]

[0069] in

[0070] z is the molar ratio of the L-2-amino-4-halobutyric acid derivative to L-tartaric acid, and z is 1 to 2;

[0071] X is Cl or Br; and

[0072] R is OR 1 or NR 2 R 3 , where R 1 is a C1 to C4 aliphatic hydrocarbon, R 2 is H or a C1 to C4 aliphatic hydrocarbon, and R 3 is H or a C1 to C4 aliphatic hydrocarbon.

[0073] Another aspect of the present disclosure is a method for preparing L-2-amino-4-halobutyric acid derivative-L-tartrate, as described in method a) elsewhere in the present disclosure, the method comprising:

[0074] a) mixing a mixture of D,L-2-amino-4-halobutyric acid derivative enantiomers, L-tartaric acid and a solvent to promote a resolution reaction and produce a product comprising L-2-amino-4-halobutyric acid derivative-

[0075] Resolution reaction mixture of L-tartrate;

[0076] b) precipitating the L-2-amino-4-halobutyric acid derivative-L-tartrate; and

[0077] <pn244392>

[0078] c) isolating the L-2-amino-4-halobutyric acid derivative-L-tartrate from the resolution reaction mixture.

[0079] The molar ratio of the L-2-amino-4-halobutyric acid derivative to the D-2-amino-4-halobutyric acid derivative in the enantiomeric mixture of D,L-2-amino-4-halobutyric acid derivatives may be 0.5 to 1.5: 1. The molar ratio of the enantiomeric mixture of D,L-2-amino-4-halobutyric acid derivatives to L-tartaric acid may be 1: 0.2 to 1.5.

[0080] The solvent may be selected from one or more C1 to C4 lower alcohols, or a mixture of one or more C1 to C4 lower alcohols and water; the C1 to C4 lower alcohol is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol; and the mixture of one or more C1 to C4 lower alcohols and water has a volume percentage of 10% to 99.99% of C1 to C4 lower alcohols. The volume of the solvent may be 1 mL / g D, L-2-amino-4-halobutyric acid derivative enantiomer mixture to 30 mL / g D, L-2-amino-4-halobutyric acid derivative enantiomer mixture. The temperature of step a) of the method may be 0°C to the reflux temperature of the system.

[0081] Yet another aspect of the present disclosure is a method for preparing L-2-amino-4-halobutyric acid derivative-L-tartrate, as described in method b) elsewhere in the present invention, the method comprising:

[0082] a) mixing a D-2-amino-4-halobutyric acid derivative or a D,L-2-amino-4-halobutyric acid derivative enantiomer mixture, L-tartaric acid, an aromatic aldehyde or an aromatic aldehyde and an organic acid with a solvent to promote a dynamic resolution reaction and produce a resolution reaction mixture containing an L-2-amino-4-halobutyric acid derivative-L-tartrate;

[0083] b) precipitating the L-2-amino-4-halobutyric acid derivative-L-tartrate; and

[0084] c) isolating the L-2-amino-4-halobutyric acid derivative-L-tartrate from the resolution reaction mixture.

[0085] The molar ratio of the L-2-amino-4-halobutyric acid derivative to the D-2-amino-4-halobutyric acid derivative in the enantiomeric mixture of the D,L-2-amino-4-halobutyric acid derivative may be 0 to 1.5: 1. The molar ratio of the D-2-amino-4-halobutyric acid derivative or the enantiomeric mixture of the D,L-2-amino-4-halobutyric acid derivative to L-tartaric acid may be 1:0.3 to 1.5.

[0086] The aromatic aldehydes may be one or more of benzaldehyde, salicylaldehyde, 5-nitrosalicylicylaldehyde and 3,5-dinitrosalicylicylaldehyde. The molar ratio of the D-2-amino-4-halobutyric acid derivative or the enantiomeric mixture of the D,L-2-amino-4-halobutyric acid derivative to the aromatic aldehyde may be 1:0.01 to 0.5.

[0087] The organic acids may be one or more of formic acid, acetic acid and propionic acid. The molar ratio of the D-2-amino-4-halobutyric acid derivative or the enantiomeric mixture of the D,L-2-amino-4-halobutyric acid derivative to the organic acid may be 1:0.1 to 5.

[0088] The solvent may be selected from one or more C1 to C4 lower alcohols, or a mixture of one or more C1 to C4 lower alcohols and water; the C1 to C4 lower alcohol is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol; and the mixture of one or more C1 to C4 lower alcohols and water has a volume percentage of 80% to 99.99% of C1 to C4 lower alcohols. The volume of the solvent may be 1 mL / g D-2-amino-4-halobutyric acid derivative or D,L-2-amino-4-halobutyric acid derivative enantiomer mixture to 30 mL / g D-2-amino-4-halobutyric acid derivative or D,L-2-amino-4-halobutyric acid derivative enantiomer mixture. The temperature of step a) of the method may be 0°C to the reflux temperature of the system.

[0089] For any of the methods described herein, the L-2-amino-4-halobutyric acid derivative-L-tartrate can be a L-2-amino-4-halobutyric acid derivative-L-tartrate having the structure of Formula I:

[0090]

[0091] in

[0092] z is the molar ratio of the L-2-amino-4-halobutyric acid derivative to L-tartaric acid, and z is 1 to 2;

[0093] X is Cl or Br; and

[0094] R is OR 1 or NR 2 R 3 , where R 1 is a C1 to C4 aliphatic hydrocarbon, R 2 is H or a C1 to C4 aliphatic hydrocarbon, and R 3 is H or a C1 to C4 aliphatic hydrocarbon.

[0095] For any of the methods described herein, the D,L-2-amino-4-halobutyric acid derivative enantiomeric mixture can be a mixture of an L-2-amino-4-halobutyric acid derivative and a D-2-amino-4-halobutyric acid derivative having the structure of Formula II:

[0096]

[0097] <pn244392>

[0098] in

[0099] X is Cl or Br;

[0100] R is OR 1 or NR 2 R 3 , where R 1 is a C1 to C4 aliphatic hydrocarbon, R 2 is H or a C1 to C4 aliphatic hydrocarbon, and R 3 is H or a C1 to C4 aliphatic; and

[0101] w is the molar percentage of the L-2-amino-4-halobutyric acid derivative in the enantiomeric mixture of the D,L-2-amino-4-halobutyric acid derivative.

[0102] In the present disclosure, the inventors found that 4-halo-2-aminobutyric acid and 4-halo-2-aminobutyramide are very unstable, and the existing resolution technology of D,L-aminobutyric acid or D,L-aminobutyramide using L-tartaric acid as directed by patent application WO2006103696A2 and CN102060721A cannot be directly used for the resolution of 4-halo-2-aminobutyric acid and 4-halo-2-aminobutyramide. In their research process, the inventors surprisingly found that 4-halo-2-aminobutyric acid ester and 4-halo-2-aminobutyramide tartrate are structurally stable, and can obtain the tartrate of stable L-2-amino-4-halobutyric acid derivatives after the resolution reaction. L-2-amino-4-halobutyric acid derivatives are important intermediates for preparing L-ammonium glufosinate.

[0103] The present disclosure also provides a simple and feasible method for preparing L-2-amino-4-halobutyric acid derivative-L-tartrate.

[0104] During the study of the resolution of enantiomeric mixtures of D,L-2-amino-4-halobutyric acid derivatives, the present inventors surprisingly found that the resolution can be achieved in one step using the same resolution solvent system according to the method described herein.

[0105] According to method a) described herein, L-2-amino-4-halobutyric acid derivative-L-tartrate can be prepared by a method comprising the following steps: using a mixture of D,L-2-amino-4-halobutyric acid derivative enantiomers as a raw material in the same resolving agent system, using L-tartaric acid as a resolving agent, and performing a resolution reaction, precipitation and filtration to obtain L-2-amino-4-halobutyric acid derivative-L-tartrate.

[0106] According to method b) described herein, L-2-amino-4-halobutyric acid derivative-L-tartrate can be prepared by a method comprising the following steps: in the same resolving agent system, using a mixture of D,L-2-amino-4-halobutyric acid derivative enantiomers as a raw material, using L-tartaric acid as a resolving agent, using aromatic aldehyde or aromatic aldehyde and organic acid as catalyst, performing resolution and racemization simultaneously through a dynamic resolution reaction, and also comprising precipitation and filtration to obtain L-2-amino-4-halobutyric acid derivative-L-tartrate.

[0107] In method a), the main reaction formula for preparing L-2-amino-4-halobutyric acid derivative-L-tartrate is as follows:

[0108]

[0109] The following are preferred technical solutions of method a) of the present disclosure.

[0110] In method a), the molar ratio of L-2-amino-4-halobutyric acid derivatives to D-2-amino-4-halobutyric acid derivatives is 0.5 to 1.5:1. When the content of D-2-amino-4-halobutyric acid derivatives in the raw material is too high, the solid cannot be well precipitated during the splitting process, and the product obtained from the splitting system is still mostly D-configuration, and it takes several recrystallizations to obtain a product rich in L-configuration. Therefore, D, L-2-amino-4-halobutyric acid derivatives rich in D-configuration isomers are not suitable for direct splitting in method a); however, when the L-2-amino-4-halobutyric acid derivatives in the raw material are too high, they can first form salts with L-tartaric acid, and then recrystallize to obtain a product rich in L-configuration. Further preferably, the molar ratio of L-2-amino-4-halobutyric acid derivatives to D-2-amino-4-halobutyric acid derivatives in the raw material is 1 to 1.5:1.

[0111] In method a), the resolving agent used is L-tartaric acid. In a suitable solvent system, the enantiomeric mixture of D,L-2-amino-4-halobutyric acid derivative reacts with L-tartaric acid to form L-2-amino-4-halobutyric acid derivative-L-tartrate (I) and D-2-amino-4-halobutyric acid derivative-L-tartrate, which are enantiomers of each other, and L-2-amino-4-halobutyric acid derivative-L-tartrate (I) can be further separated by utilizing their different solubility in the solvent system.

[0112] In method a), the molar ratio of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivative to L-tartaric acid is 1: 0.2 to 1.5. When the amount of L-tartaric acid is low, the product yield is low; when the amount of L-tartaric acid is large, the splitting effect does not change significantly, and the splitting agent is wasted, which increases the difficulty of post-processing and causes unnecessary pollution. Further preferably, the molar ratio of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivative to L-tartaric acid is 1: 0.2 to 1.

[0113] In method a), the resolution solvent is a mixture of C1 to C4 lower alcohol and water, or C1-C4 lower alcohol; the C1-C4 lower alcohol is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol, more preferably methanol or ethanol. <pn244392>In the mixed solvent, the volume percentage of C1-C4 lower alcohol is 10% to 99.99%. When the volume percentage of C1-C4 lower alcohol is low, the solubility of L-2-amino-4-halobutyric acid derivative-L-tartrate and D-2-amino-4-halobutyric acid derivative-L-tartrate is very large, and their solubility is also different, so the resolution reaction yield is lower. Along with the increase of alcohol volume percentage, the solubility and solubility difference of L-2-amino-4-halobutyric acid derivative-L-tartrate (Formula I structure) and D-2-amino-4-halobutyric acid derivative-L-tartrate all decrease, and product optical purity is poor and productive rate is lower. Further preferably, in the solvent mixture consisting of C1-C4 lower alcohol and water, the volume percentage of C1-C4 lower alcohol is 70% to 95%.

[0114] In method a), the volume of the resolution solvent is 1 mL / g to 30 mL / g of the raw material, that is, 1 g of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives requires 1.5 mL to 30 mL of the resolution solvent. When 1 g of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives uses less than 1.5 mL of the resolution solvent, in addition to most of the L-2-amino-4-halobutyric acid derivative-L-tartrate present in the precipitated solid, there is also a portion of the D-2-amino-4-halobutyric acid derivative-L-tartrate; the resulting product has poor optical purity. When 1 g of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivatives uses more than 30 mL of the resolution solvent, only a small amount of the L-2-amino-4-halobutyric acid derivative-L-tartrate is precipitated, and the product yield is low. More preferably, the volume of the resolution solvent is 3 mL / g to 8 mL / g of the starting material, that is, 1 g of the enantiomeric mixture of D,L-2-amino-4-halobutyric acid derivatives requires 3 mL to 8 mL of the resolution solvent.

[0115] In method a), the temperature of the split reaction is 0 ° C to the reflux temperature of the system. The solubility of L-2-amino-4-halobutyric acid derivative-L-tartrate (I) and D-2-amino-4-halobutyric acid derivative-L-tartrate and their relative solubility differences vary with temperature. At high temperatures, the solubility difference between the two is large, and a product with high optical purity can be obtained, but at high temperature conditions, the solubility of the two is large, so the yield is extremely low. At low temperatures, the solubility difference between the two is small, and the resulting product has poor optical purity. Further preferably, the temperature of the split reaction is 20 ° C to 65 ° C.

[0116] In method b), the main reaction formula for preparing L-2-amino-4-halobutyric acid derivative-L-tartrate is as follows:

[0117]

[0118] The following is a preferred technical solution of method b) of the present disclosure.

[0119] In method b), the molar ratio of L-2-amino-4-halobutyric acid derivative to D-2-amino-4-halobutyric acid derivative is 0 to 1.5: 1. Since the reaction described in b) is a dynamic resolution reaction, when the content of D-2-amino-4-halobutyric acid derivative in the raw material is too high, L-tartaric acid is used as a resolution agent, under the catalysis of aromatic aldehydes or under the co-catalysis of aromatic aldehydes and organic acids, resolution and racemization are carried out simultaneously in the same resolution system. This causes the D-configuration in the reaction system to be converted into the L-configuration and form the corresponding L-2-amino-4-halobutyric acid derivative-L-tartrate, and the solubility difference between the L-configuration tartrate and the D-configuration tartrate in the solvent is used to precipitate a product rich in the L-configuration. When the content of L-2-amino-4-halobutyric acid derivative in the raw material is too high, it can first form a salt with L-tartrate, and then directly purify by recrystallization to obtain L-2-amino-4-halobutyric acid derivative-L-tartrate. Further preferably, the molar ratio of L-2-amino-4-halobutyric acid derivative to D-2-amino-4-halobutyric acid derivative in the raw material is 0 to 1:1.

[0120] In method b), the molar ratio of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivative and L-tartaric acid is 1: 0.3 to 1.5. In the dynamic resolution process, with the continuous carrying out of racemization and resolution reaction, the L-configuration tartrate content in the system is always kept at a lower level. Using the solubility difference of L-configuration tartrate and D-configuration tartrate in the solvent system, the L-configuration tartrate is continuously precipitated, and the tartaric acid dissolved in the consumption system is consumed. When the amount of L-tartaric acid is low, the formation of L-configuration salt will be insufficient and the yield will be too low. When the amount of L-tartaric acid is large, the resolution effect does not change significantly, and the resolution agent is wasted, which increases the difficulty of post-processing and causes unnecessary pollution. Further preferably, the molar ratio of D, L-2-amino-4-halobutyric acid derivative enantiomeric mixture and L-tartaric acid is 1: 0.5 to 1.2.

[0121] <pn244392>

[0122] In method b), the aromatic aldehyde is one or more of benzaldehyde, salicylaldehyde, 5-nitrosalicylicylaldehyde or 3,5-dinitrosalicylicylaldehyde. The use of an aromatic aldehyde having a hydroxyl group at the 2-position of the aldehyde group in dynamic resolution can better catalyze the racemization reaction. Further preferably, the aromatic aldehyde is salicylaldehyde.

[0123] In method b), the molar ratio of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivative to the aromatic aldehyde is 1: 0.01 to 0.5. When the amount of aromatic aldehyde is large, it will not significantly improve the catalytic reaction, waste raw materials, and subsequent treatment is cumbersome. When the amount of aromatic aldehyde is small, it cannot catalyze the reaction well and the product yield is low. Further preferably, the molar ratio of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivative to the aromatic aldehyde is 1: 0.01 to 0.4.

[0124] In method b), in the same resolving agent system, L-tartaric acid is used as a resolving agent, aromatic aldehyde or aromatic aldehyde and organic acid are used for catalysis, and the resolution and racemization are carried out simultaneously through a dynamic resolution reaction. In this case, although the desired effect can be achieved by the aromatic aldehyde catalysis reaction alone, the reaction time is long; when the aromatic aldehyde and organic acid are used for co-catalysis, the reaction time can be significantly shortened and the reaction efficiency can be improved.

[0125] In method b), the organic acid is one or more of formic acid, acetic acid and propionic acid. Further preferred is acetic acid.

[0126] In method b), the molar ratio of the enantiomeric mixture of D,L-2-amino-4-halobutyric acid derivative to the organic acid is 1:0.1 to 5. When the amount of the organic acid is large, it will not significantly improve the catalytic reaction, waste raw materials, and has no practical significance; when the amount of the organic acid is small, it cannot achieve the expected catalytic efficiency. Further preferably, the molar ratio is 1:0.3 to 1.5.

[0127] In method b), the resolution solvent is a mixture of C1 to C4 lower alcohols and water, or C1-C4 lower alcohols; the C1-C4 lower alcohols are one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tert-butanol, and methanol or ethanol is further preferred. In a mixed solvent consisting of C1-C4 lower alcohols and water, the volume percentage of C1-C4 lower alcohols is 80% to 99.99%. When the water content in the resolution solvent is high, the racemization reaction cannot occur well, and the solubility of L-2-amino-4-halobutyric acid derivatives-L-tartrate and D-2-amino-4-halobutyric acid derivatives-L-tartrate is very large, the solubility difference between the two is also very large, and the yield is low. Further preferably, in a solvent mixture consisting of C1-C4 lower alcohols and water, the volume percentage of C1-C4 lower alcohols is 85% to 99.99%.

[0128] In method b), the volume of the resolution solvent is 1 mL / g to 30 mL / g of the raw material, that is, 1 g of the enantiomeric mixture of D,L-2-amino-4-halobutyric acid derivatives requires 1.5 mL to 30 mL of resolution solvent. <pn244392>

[0129] When the agent is used, in addition to most of the L-2-amino-4-halobutyric acid derivative-L-tartrate present in the precipitated solid, there is also a part of the D-2-amino-4-halobutyric acid derivative-L-tartrate; the resulting product has poor optical purity. When 1g of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivative uses more than 30mL of the resolution solvent, only a small amount of L-2-amino-4-halobutyric acid derivative-L-tartrate is precipitated, and the product yield is low. Further preferably, the volume of the resolution solvent is 3mL / g raw material to 8mL / g raw material, that is, 1g of the enantiomeric mixture of D, L-2-amino-4-halobutyric acid derivative requires 3mL to 8mL of resolution solvent.

[0130] In method b), the temperature of the split reaction is 0 ° C to the reflux temperature of the system. The solubility of L-2-amino-4-halobutyric acid derivative-L-tartrate (I) and D-2-amino-4-halobutyric acid derivative-L-tartrate and their relative solubility differences vary with temperature. At high temperatures, the solubility difference between the two is large, and a product with high optical purity can be obtained, but at high temperature conditions, the solubility of the two is large, so the yield is extremely low. At low temperatures, the solubility difference between the two is small, and the resulting product has a poor optical purity. Further preferably, the temperature of the split reaction is 20 ° C to 65 ° C.

[0131] The present invention has the following advantages:

[0132] The L-2-amino-4-halobutyric acid derivative-L-tartrate disclosed in the present invention is a chiral intermediate with stable properties and convenient transportation and storage. It can be converted into an L-2-amino-4-halobutyric acid derivative through simple steps and further used in the synthesis of L-phosphinothricin ammonium.

[0133] The preparation method of L-2-amino-4-halobutyric acid derivative-L-tartrate disclosed in the present invention is applicable to raw materials with various chiral contents.

[0134] The method for preparing L-2-amino-4-halobutyric acid derivative-L-tartrate of the present invention, which is adopted in the same resolution solvent system to complete the resolution reaction, is simple in preparation and operation, and is a low-cost method for preparing the key intermediate of L-phosphinothricin ammonium - chiral aminobutyric acid block.

[0135] Having described the invention in detail, it will be apparent that modifications and variations are possible without departing from the scope of the invention as defined in the appended claims.

[0136] Example

[0137] The following non-limiting examples are provided to further illustrate the invention.

[0138] The present invention is further described below in conjunction with specific embodiments. It should be understood that these embodiments are only intended to illustrate the present invention rather than to limit the scope of the present invention, and that various equivalent modifications made to the present invention by those skilled in the art after reading the present invention all fall within the scope defined by the claims of the present invention.

[0139] Example 1

[0140] In a 250mL three-necked flask, under stirring, 16.56g (0.1mol) of D, L-2-amino-4-chlorobutyric acid ethyl ester enantiomeric mixture (optical purity D:L = 50:50) was added to 100mL ethanol and 20mL water, and then 7.5g (0.05mol) of L-tartaric acid was added. It was stirred at 70°C for 10 minutes until it was dissolved and clarified, slowly cooled to 20°C within 4 hours, and filtered. The filter cake was dried to obtain 9.86g of crude L-2-amino-4-chlorobutyric acid ethyl ester-L-tartrate, with a yield of 40.98% and an optical purity of D:L = 6.4:93.6.

[0141] IR(KBr)ν(cm -1 )3493,3379,2973,1750,1614,1564,1404,1347,1231,1115,1067,1016,915,864,617, such as Figure 1 shown.

[0142] 1 H NMR (500MHz, D2O) δ4.33–4.16(m,J=5.1Hz,4H),3.81–3.53(m,2H),2.48–2.36(m,1H),2.32–2.19(m,1H),1.21(t,J=7.2Hz,3H), such as Figure 2 shown.

[0143] 13 C NMR (126MHz, D2O)δ178.24,169.62,73.68,63.61,50.34,39.90,32.36,13.01, as Figure 3 shown.

[0144] Example 2

[0145] In a 250mL three-necked flask, under stirring, 24.84g (0.15mol) of D, L-2-amino-4-chlorobutyric acid ethyl ester enantiomeric mixture (optical purity D:L = 50:50) was added to 150mL ethanol and 10mL water, and then 6.75g (0.045mol) of L-tartaric acid was added. It was stirred at 60°C for 10 minutes until it was dissolved and clarified, slowly cooled to 20°C within 4 hours, and filtered. The filter cake was dried to obtain 13.12g of crude L-2-amino-4-chlorobutyric acid ethyl ester-L-tartrate, with a yield of 36.35% and an optical purity of D:L = 3.2:96.8.

[0146] Example 3

[0147] In a 250mL three-necked flask, under stirring, 20g (0.12mol) of D, L-2-amino-4-chlorobutyric acid ethyl ester enantiomeric mixture (optical purity D:L=50:50) was added to 100mL ethanol and 4g salicylaldehyde, and then 9.96g (0.066mol) of L-tartaric acid and 10g of acetic acid were added. It was stirred at 60°C for 3 hours, slowly cooled to 20°C within 5 hours, and filtered. The filter cake was dried to obtain 20.39g of crude L-2-amino-4-chlorobutyric acid ethyl ester-L-tartrate, with a yield of 70.17% and an optical purity of D:L=6.2:93.8.

[0148] Example 4

[0149] In a 250 mL three-necked flask, 20 g (0.12 mol) of D,L-2-amino-4-chlorobutyric acid ethyl ester enantiomeric mixture (optical purity D:L = 80:20) was added to 100 mL of ethanol and 4 g of water under stirring. <pn244392>

[0150] Then, 9.96 g (0.066 mol) of L-tartaric acid and 10 g of acetic acid were added to the aldehyde. The mixture was stirred at 60° C. for 3 hours, slowly cooled to 20° C. within 5 hours, and filtered. The filter cake was dried to obtain 18.25 g of crude L-2-amino-4-chlorobutyric acid ethyl ester-L-tartrate, with a yield of 62.8% and an optical purity of D:L=4.8:95.2.

[0151] Example 5

[0152] In a 250mL three-necked flask, under stirring, 20g (0.12mol) of D, L-2-amino-4-chlorobutyric acid ethyl ester enantiomeric mixture (optical purity D:L=50:50) was added to 100mL ethanol and 4g salicylaldehyde, and then 9.96g (0.066mol) of L-tartaric acid and 10g of acetic acid were added. It was stirred at 60°C for 10 hours, slowly cooled to 20°C within 5 hours, and filtered. The filter cake was dried to obtain 14.38g of crude L-2-amino-4-chlorobutyric acid ethyl ester-L-tartrate, with a yield of 49.48% and an optical purity of D:L=5.3:94.7.

[0153] Example 6

[0154] In a 250mL three-necked flask, under stirring, 21g (0.1mol) of D, L-2-amino-4-bromobutyric acid ethyl ester enantiomeric mixture (optical purity D:L = 50:50) was added to 100mL ethanol and 10mL water, and then 7.5g (0.05mol) of L-tartaric acid was added. It was stirred at 60°C for 10 minutes until it was dissolved and clarified, slowly cooled to 20°C within 4 hours, and filtered. The filter cake was dried to obtain 10.55g of crude L-2-amino-4-bromobutyric acid ethyl ester-L-tartrate, with a yield of 37% and an optical purity of D:L = 6.1:93.9.

[0155] IR(KBr)ν(cm -1 )3497,3384,2988,2936,1749,1614,1560,1348,1279,1231,1114,1067,865,694,619,524, such as Figure 4 shown.

[0156] 1 H NMR (500MHz, D2O) δ4.39–4.14(m,4H),3.83–3.39(m,2H),2.61–2.47(m,1H),2.45–2.29(m,1H),1.26(t,J=7.2Hz,3H), such as Figure 5 shown.

[0157] 13 C NMR (126MHz, D2O)δ178.22,169.59,73.76,63.74,51.41,32.69,27.91,13.18, Figure 6 shown.

[0158] Example 7

[0159] In a 250mL three-necked flask, under stirring, 3.15g (0.15mol) of D, L-2-amino-4-bromobutyric acid ethyl ester enantiomeric mixture (optical purity D:L = 50:50) was added to 150mL ethanol and 5g salicylaldehyde, and then 11.25g (0.075mol) of L-tartaric acid and 15g of acetic acid were added. It was stirred at 60°C for 18 hours, slowly cooled to 20°C within 3 hours, and filtered. The filter cake was dried to obtain 27.8g of crude L-2-amino-4-bromobutyric acid ethyl ester-L-tartrate, with a yield of 65% and an optical purity of D:L = 2.7:97.3.

[0160] Example 8

[0161] In a 250mL three-necked flask, under stirring, 15.2g (0.1mol) of D, L-2-amino-4-chlorobutyric acid methyl ester enantiomeric mixture (optical purity D:L = 50:50) was added to 100mL of methanol, and then 7.5g (0.05mol) of L-tartaric acid was added. It was stirred at 60°C for 10 minutes until it was dissolved and clarified, slowly cooled to 20°C within 5 hours, and filtered. The filter cake was dried to obtain 6.93g of crude L-2-amino-4-chlorobutyric acid methyl ester-L-tartrate, with a yield of 30.5% and an optical purity of D:L = 4.3:95.7.

[0162] IR(KBr)ν(cm -1 )3479,3372,3325,2959,2676,1754,1615,1569,1347,1306,1230,1116,1067,806,688,618, such as Figure 7 shown.

[0163] 1 H NMR(500MHz,D2O)δ4.35(t,J=6.6Hz,1H),4.31(s,1H),3.85(s,3H),3.82–3.73(m,2H),2.56–2.45(m,1H),2.42–2.28(m,1H), such as Figure 8 shown.

[0164] 13 C NMR (126MHz, D2O)δ178.32,170.26,73.78,53.69,50.44,40.01,32.48, such as Fig. 9 shown.

[0165] Example 9

[0166] In a 250mL three-necked flask, under stirring, 20g (0.132mol) of D, L-2-amino-4-chlorobutyric acid methyl ester enantiomeric mixture (optical purity D:L = 50:50) was added to 80mL methanol and 4g salicylaldehyde, and then 9.9g (0.066mol) of L-tartaric acid and 10g of acetic acid were added. It was stirred at 50°C for 3 hours, slowly cooled to 20°C within 3 hours, and filtered. The filter cake was dried to obtain 16.3g of crude L-2-amino-4-chlorobutyric acid methyl ester-L-tartrate, with a yield of 54.5% and an optical purity of D:L = 4.8:95.2.

[0167] Example 10

[0168] In a 250mL three-necked flask, under stirring, 17.96g (0.1mol) of D, L-2-amino-4-chlorobutyric acid isopropyl ester enantiomeric mixture (optical purity D:L = 50:50) was added to 80mL of isopropanol and 16g of water, and then 15g (0.1mol) of L-tartaric acid was added. It was stirred at 50°C for 10 minutes until it was dissolved and clarified, slowly cooled to 30°C within 3 hours, and filtered. The filter cake was dried to obtain 12.53g of crude L-2-amino-4-chlorobutyric acid isopropyl ester-L-tartrate, with a yield of 38% and an optical purity of D:L = 1.3:98.7.

[0169] IR(KBr)ν(cm -1 )3321,3277,2982,2869,2592,1871,1736,1577,1503,1411,1305,1263,1215,1103,1067,904,790,680,485, such as Fig.10 shown.

[0170] 1 H NMR(500MHz,D2O)δ5.25–5.02(m,1H),4.52(s,2H),4.31(t,J=6.6Hz,1H),3.97–3.68(m,2H),2.59–2.45(m,1H),2.44–2.27(m,1H),1.31(d,6H), such as Fig.11 Show.

[0171] <pn244392>

[0172] 13 C NMR (126MHz, D2O)δ176.32,169.11,72.80,72.52,50.61,40.06,32.46,20.65, as Fig.12 shown.

[0173] Embodiment 11

[0174] In a 250mL three-necked flask, under stirring, 25.15g (0.14mol) of D, L-2-amino-4-chlorobutyric acid isopropyl ester enantiomeric mixture (optical purity D:L = 50:50) was added to 120mL isopropanol and 5g salicylaldehyde, and then 21g (0.14mol) of L-tartaric acid and 10g of acetic acid were added. It was stirred at 55°C for 3 hours, slowly cooled to 30°C within 3 hours, and filtered. The filter cake was dried to obtain 30.2g of crude L-2-amino-4-chlorobutyric acid isopropyl ester-L-tartrate, with a yield of 65.4% and an optical purity of D:L = 2.9:97.1.

[0175] Example 12

[0176] In a 250 mL three-necked flask, 13.66 g (0.1 mol) of D, L-2-amino-4-chlorobutyramide enantiomeric mixture (optical purity D:L = 50:50), 50 mL of methanol and 10 g of water were mixed in sequence under stirring at 5°C or lower, and then 7.5 g (0.05 mol) of L-tartaric acid was added. After stirring at a temperature below 5°C for 2 hours, the temperature was slowly raised to 60°C and stirred until dissolved and clear, and then slowly cooled to 20°C within 4 hours and filtered. The filter cake was dried to obtain 8.8 g of crude L-2-amino-4-chlorobutyramide-L-tartrate, with a yield of 41.6% and an optical purity of D:L = 5.6:94.4.

[0177] IR(KBr)ν(cm -1 )3459,3414,3376,3221,2975,2699,1678,1562,1403,1286,1215,1128,1086,784,673,575, such as Fig.13 shown.

[0178] 1 H NMR(500MHz,D2O)δ4.51(s,2H),4.23(t,J=6.8Hz,1H),3.74(t,J=6.3Hz,2H),2.45–2.28(m,2H), such as Fig.14 shown.

[0179] 13 C NMR (126MHz, D2O)δ176.36,171.33,72.80,50.88,39.77,33.32, such as Fig.15 shown.

[0180] When introducing elements of the present invention or the preferred embodiments thereof, the articles "a", "an", "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0181] In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

[0182] As various changes could be made in the above products and methods without departing from the scope of the invention, it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.

Claims

1. An L-2-amino-4-halobutyric acid derivative-L-tartrate having a structure of formula I: in z is the molar ratio of the L-2-amino-4-halobutyric acid derivative to L-tartaric acid, and z is 1 to 2; X is Cl or Br; and R is OR 1 or NR 2 R 3 , where R 1 is a C1 to C4 aliphatic hydrocarbon, R 2 is H or a C1 to C4 aliphatic hydrocarbon, and R 3 is H or a C1 to C4 aliphatic hydrocarbon.

2. A method for preparing L-2-amino-4-halobutyric acid derivative-L-tartrate, the method comprising: a) mixing a D,L-2-amino-4-halobutyric acid derivative enantiomer mixture, L-tartaric acid and a solvent to promote a resolution reaction and produce a resolution reaction mixture containing L-2-amino-4-halobutyric acid derivative-L-tartrate; b) precipitating the L-2-amino-4-halobutyric acid derivative-L-tartrate; and c) isolating the L-2-amino-4-halobutyric acid derivative-L-tartrate from the resolution reaction mixture.

3. The method according to claim 2, wherein the molar ratio of the L-2-amino-4-halobutyric acid derivative to the D-2-amino-4-halobutyric acid derivative in the D,L-2-amino-4-halobutyric acid derivative enantiomeric mixture is 0.5 to 1.5:

1.

4. The method according to claim 2 or 3, wherein the molar ratio of the enantiomeric mixture of D,L-2-amino-4-halobutyric acid derivative to L-tartaric acid is 1:0.2 to 1.

5.

5. The method according to any one of claims 2 to 4, wherein the solvent is selected from one or more C1 to C4 lower alcohols, or a mixture of one or more C1 to C4 lower alcohols and water; The C1 to C4 lower alcohol is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol; and The mixture of one or more C1 to C4 lower alcohols and water has a volume percentage of 10% to 99.99% of C1 to C4 lower alcohols.

6. The method according to any one of claims 2 to 5, wherein the volume of the solvent is 1 mL / g D,L-2-amino-4-halobutyric acid derivative enantiomer mixture to 30 mL / g D,L-2-amino-4-halobutyric acid derivative enantiomer mixture.

7. A method for preparing L-2-amino-4-halobutyric acid derivative-L-tartrate, the method comprising: a) mixing a D-2-amino-4-halobutyric acid derivative or a D,L-2-amino-4-halobutyric acid derivative enantiomer mixture, L-tartaric acid, an aromatic aldehyde or an aromatic aldehyde and an organic acid with a solvent to promote a dynamic resolution reaction and produce a resolution reaction mixture containing an L-2-amino-4-halobutyric acid derivative-L-tartrate; b) precipitating the L-2-amino-4-halobutyric acid derivative-L-tartrate; and c) isolating the L-2-amino-4-halobutyric acid derivative-L-tartrate from the resolution reaction mixture.

8. The method according to claim 7, wherein the molar ratio of the L-2-amino-4-halobutyric acid derivative to the D-2-amino-4-halobutyric acid derivative in the D,L-2-amino-4-halobutyric acid derivative enantiomeric mixture is 0 to 1.5:

1.

9. The method according to claim 7 or 8, wherein the molar ratio of the D-2-amino-4-halobutyric acid derivative or the enantiomeric mixture of the D,L-2-amino-4-halobutyric acid derivative to L-tartaric acid is 1:0.3 to 1.

5.

10. The method according to any one of claims 7 to 9, wherein the aromatic aldehyde is one or more of benzaldehyde, salicylaldehyde, 5-nitrosalicylicylaldehyde and 3,5-dinitrosalicylicylaldehyde.

11. The method according to any one of claims 7 to 10, wherein the molar ratio of the D-2-amino-4-halobutyric acid derivative or the enantiomeric mixture of the D,L-2-amino-4-halobutyric acid derivative to the aromatic aldehyde is 1:0.01 to 0.

5.

12. The method according to any one of claims 7 to 11, wherein the organic acid is one or more of formic acid, acetic acid and propionic acid.

13. The method according to any one of claims 7 to 12, wherein the molar ratio of the D-2-amino-4-halobutyric acid derivative or the enantiomeric mixture of the D,L-2-amino-4-halobutyric acid derivative to the organic acid is 1:0.1 to 5.

14. The method according to any one of claims 7 to 13, wherein the solvent is selected from one or more C1 to C4 lower alcohols, or a mixture of one or more C1 to C4 lower alcohols and water; The C1 to C4 lower alcohol is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol; and The mixture of one or more C1 to C4 lower alcohols and water has 80% to 99.99% by volume of the C1 to C4 lower alcohol.

15. The method according to any one of claims 7 to 14, wherein the volume of the solvent is 1 mL / g D-2-amino-4-halobutyric acid derivative or D,L-2-amino-4-halobutyric acid derivative enantiomeric mixture to 30 mL / g D-2-amino-4-halobutyric acid derivative or D,L-2-amino-4-halobutyric acid derivative enantiomeric mixture.

16. The method according to any one of claims 2 to 15, wherein the temperature of step a) is from 0°C to the reflux temperature of the system.

17. The method according to any one of claims 2 to 16, wherein the L-2-amino-4-halobutyric acid derivative-L-tartrate is a L-2-amino-4-halobutyric acid derivative-L-tartrate having the structure of Formula I: in z is the molar ratio of the L-2-amino-4-halobutyric acid derivative to L-tartaric acid, and z is 1 to 2; X is Cl or Br; and R is OR 1 or NR 2 R 3 , where R 1 is a C1 to C4 aliphatic hydrocarbon, R 2 is H or a C1 to C4 aliphatic hydrocarbon, and R 3 is H or a C1 to C4 aliphatic hydrocarbon.

18. The method according to any one of claims 2 to 17, wherein the D,L-2-amino-4-halobutyric acid derivative enantiomeric mixture is a mixture of an L-2-amino-4-halobutyric acid derivative and a D-2-amino-4-halobutyric acid derivative having the structure of Formula II: in X is Cl or Br; R is OR 1 or NR 2 R 3 , where R 1 is a C1 to C4 aliphatic hydrocarbon, R 2 is H or a C1 to C4 aliphatic hydrocarbon, and R 3 is H or C1 to C4 aliphatic; and w is the molar percentage of the L-2-amino-4-halobutyric acid derivative in the enantiomeric mixture of the D,L-2-amino-4-halobutyric acid derivative.

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