Optically active tryptophan derivative glufosinate salts and preparation method

Abstract

The present disclosure is generally directed to an optically active glufosinate-tryptophan derivative salt with a specific structure. The present invention also discloses a method for preparing the optically active glufosinate-tryptophan derivative salt, which includes mixing D,L-glufosinate or its salt as the raw material, and D-tryptophan derivative or L-tryptophan derivative as the resolution agent in a suitable resolution solvent to facilitate a resolution reaction that produces a resolution reaction mixture comprising an optically active glufosinate-tryptophan derivative salt, crystallizing the glufosinate-tryptophan derivative salt, and separating the glufosinate-tryptophan derivative salt from the resolution reaction mixture. The L-glufosinate-D-tryptophan derivative salt or D-glufosinate-L-tryptophan derivative salt obtained have the structure of Formula (I) or Formula (II), respectively.

Description

OPTICALLY ACTIVE TRYPTOPHAN DERIVATIVE GLUFOSINATE SALTS AND PREPARATION METHODFIELD OF THE INVENTION

[0001] This disclosure involves optically active glufosinate salts, in particular, L-glufosinate-D-tryptophan derivative salts and D-glufosinate-L-tryptophan derivative salts. This disclosure also involves methods of preparing these salts from D,L- glufosinate or salt thereof and optically active tryptophan derivatives and use of these salts in agriculture to control unwanted plants, including in the propagation of transgenic crop plants.BACKGROUND OF INVENTION

[0002] Glufosinate-ammonium, also known as 2-Amino-4- (hydroxymethylphosphinyl)butyric acid ammonium salt, was first developed by Hoechst in 1987 and successfully commercialized under the trade name BASTA.

[0003] Glufosinate-ammonium belongs to the group of organophosphorus herbicides, which is one of the three major non-selective herbicides in the world. At present, the expanding global ban on paraquat, the continuing problem of glyphosate resistance, and the promotion of genetically modified technology are effectively driving the rapid increase of glufosinate demand. In recent years, glufosinate-resistant transgenic crops have been promoted and planted in select countries in Asia and Europe and in Australia, and the glufosinate resistant genes have been introduced into more than 20 crops including rice, wheat, com, sugar beet, tobacco, soybean, cotton, potato, tomato, rapeseed, and sugarcane. Glufosinate-ammonium has become the second largest transgenic crop herbicide in the w orld.

[0004] There are two optical isomers of glufosinate, L- and D-glufosinate. but only the L-configuration has a substantial herbicidal effect. The D-configuration has almost no herbicidal activity. L-glufosinate, also known as glufosinate-P, has twice the herbicidal activity7of common, racemic glufosinate. Thus, the application dosage is only 50% of glufosinate per acre for L-glufosinate compared to D, L-glufosinate, andthe application cost is basically the same for both. Since glufosinate in the market is generally the racemate of L- and D- glufosinate, the development and production of pure optical isomers of L-glufosinate will greatly reduce the required amount of the herbicidal active ingredient, which is very important to improve the product economics, reduce the amount of herbicide use, and reduce environmental pressure.

[0005] At present, the preparation methods of L-glufosinate can be divided into synthetic methods and resolution methods from the perspective of raw materials. From the perspective of preparation means, the synthetic and resolution methods can be further divided into biological methods and chemical methods respectively.

[0006] The biological synthesis method is mainly based on the ketoacid method, in which 2-oxo-4-(hydroxymethylphosphinyl)butyric acid (PPO) is used as the substrate to synthesize L-glufosinate by the amination reaction of transaminase or amino acid dehydrogenase. However, there are problems such as expensive raw materials, low conversion rate, complex system, and difficult separation process, which make the method difficult to industrialize.

[0007] The chemical synthesis method includes chiral auxiliary method, asymmetric catalytic method, and chiral source method. The auxiliary method uses expensive chiral auxiliaries, with demanding reaction conditions. The asymmetric catalytic method uses expensive catalysts, which are difficult to recover and recycle. Therefore, the method is difficult to industrialize because of uncontrollable costs. The chiral source method uses expensive raw materials, has complex reaction steps, requires demanding reaction conditions and equipment requirements, produces many byproducts, and causes serious pollution. In short, chemical synthesis methods all face challenges in industrialization.

[0008] The biological resolution method involves ketoacid and acylation methods, both featuring the involvement of biological enzymes, such as US9834802 and CN108690854. But the biological resolution method involves a few biological enzymes and amine donor, leading to complicated reaction systems, challenges in product purification, challenges in recycling the catalysts, production of high phosphorus content wastewater, among other problems. Due to challenges in overallindustrialization cost it is rare to see commercialized and industrialized products in large quantities on the market.

[0009] The chemical resolution method mainly involves the resolution of the enantiomeric isomers of D,L-glufosinate or salts thereof with different chemical resolution agents such as EP0499376A1 , DE4407197A, EP16204249A, EP16204245A. and CN112979701A, which respectively disclose the use of bromocamphorsulfonic acid, quinine, cinchonine, ephedrine, and ligands to resolve the enantiomeric isomers of D,L-glufosinate. However, bromocamphorsulfonic acid, quinine, and cinchonine are expensive, ephedrine is a controlled substance, and the ligands are costly with complicated reactions and heavy metal wastewater streams. For those reasons, the above chemical resolution patents have not been successfully industrialized.

[0010] It can be seen that there is still no efficient, green, and simple resolution process that can use D,L-glufosinate or salts thereof as raw material. In particular, there is no such industrial method to obtain L-glufosinate by chemical resolution. Thus, there is an urgent need for a low-cost, simple, and industrially feasible chemical resolution process of L-glufosinate.SUMMARY OF INVENTION

[0011] The present disclosure provides a method for producing an optically active glufosinate-tryptophan derivative salt, the method comprising:

[0012] a) mixing an enantiomeric mixture of D.L-glufosinate or salt thereof, a resolution agent comprising an optically active tryptophan derivative, and a solvent to facilitate a resolution reaction that produces a resolution reaction mixture comprising an optically active glufosinate-tryptophan derivative salt;

[0013] b) crystallizing the glufosinate-tryptophan derivative salt; and

[0014] c) separating the glufosinate-tryptophan derivative salt from the resolution reaction mixture;

[0015] wherein the optically active tryptophan derivative is a compound with the structure of Formula III:(Formula III); or the structure of Formula IV:(Formula IV);

[0019] wherein R is alkoxy, amino, or alkylamino.

[0020] The present disclosure is further directed to an optically active glufosinate-tryptophan derivative salt selected from the group consisting of a compound with the structure of Formula I:

[0021] (Formula I); and

[0022] a compound with the structure of Formula II:

[0024] wherein R is alkoxy, amino, or alkylamino.

[0025] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 shows the13C NMR spectrum of L-tryptophan methyl ester prepared in Example 1.

[0027] Figure 2 shows the ’H NMR spectrum of L-tryptophan methyl ester prepared in Example 1.

[0028] Figure 3 shows the13C NMR spectrum of D-glufosinate-L-tryptophan methyl ester prepared in Example 1.

[0029] Figure 4 shows the 'H NMR spectrum of D-glufosinate-L-tryptophan methyl ester prepared in Example 1.

[0030] Figure 5 shows the13C NMR spectrum of L-glufosinate-D-tryptophan methyl ester prepared in Example 2.

[0031] Figure 6 shows the 'H NMR spectrum of L-glufosinate-D-tryptophan methyl ester prepared in Example 2.

[0032] Figure 7 shows the13C NMR spectrum of D-tryptophan ethyl ester prepared in Example 3.

[0033] Figure 8 shows the3H NMR spectrum of D-tryptophan ethyl ester prepared in Example 3.

[0034] Figure 9 shows the13C NMR spectrum of L-glufosinate-D-tryptophan ethyl ester prepared in Example 3.

[0035] Figure 10 shows theNMR spectrum of L-glufosinate-D-tryptophan ethyl ester prepared in Example 3.

[0036] Figure 11 shows the13C NMR spectrum of L-tryptophan propyl ester prepared in Example 4.

[0037] Figure 12 shows the 'H NMR spectrum of L-tryptophan propyl ester prepared in Example 4.

[0038] Figure 13 shows the13C NMR spectrum of D-glufosinate-L-tryptophan propyl ester prepared in Example 4.

[0039] Figure 14 shows theNMR spectrum of D-glufosinate-L-tryptophan propyl ester prepared in Example 4.

[0040] Figure 15 shows the13C NMR spectrum of D-tryptophan butyl ester prepared in Example 5.

[0041] Figure 16 shows the 'H NMR spectrum of D-tryptophan butyl ester prepared in Example 5.

[0042] Figure 17 shows the13C NMR spectrum of L-glufosinate-D-tryptophan butyl ester prepared in Example 5.

[0043] Figure 18 shows the 'H NMR spectrum of L-glufosinate-D-tryptophan buty l ester prepared in Example 5.

[0044] Figure 19 shows the13C NMR spectrum of L-tryptophan amide prepared in Example 6.

[0045] Figure 20 shows the1H NMR spectrum of L-tryptophan amide prepared in Example 6.

[0046] Figure 21 shows the13C NMR spectrum of D-glufosinate-L-tryptophan amide prepared in Example 6.

[0047] Figure 22 shows the1H NMR spectrum of D-glufosinate-L-tryptophan amide prepared in Example 6.

[0048] Figure 23 shows the13C NMR spectrum of (R)-2-amino-3-(lH-indol-3- yl)-N-methylpropanamide prepared in Example 7.

[0049] Figure 24 shows theNMR spectrum of (R)-2-amino-3-(lH-indol-3- yl)-N-methylpropanamide prepared in Example 7.

[0050] Figure 25 shows the13C NMR spectrum of L-glufosinate-(R)-2-amino- 3-(lH-indol-3-yl)-N-methylpropanamide prepared in Example 7.

[0051] Figure 26 shows theNMR spectrum of L-glufosinate-(R)-2-amino- 3-(lH-indol-3-yl)-N-methylpropanamide prepared in Example 7.

[0052] Figure 27 shows the13C NMR spectrum of (S)-2-amino-3-(lH-indol-3- yl)-N-ethylpropanamide prepared in Example 8.

[0053] Figure 28 shows theNMR spectrum of (S)-2-amino-3-(lH-indol-3- yl)-N-ethylpropanamide prepared in Example 8.

[0054] Figure 29 shows the13C NMR spectrum of D-glufosinate-(S)-2-amino- 3-(lH-indol-3-yl)-N-ethylpropanamide prepared in Example 8.

[0055] Figure 30 shows theNMR spectrum of D-glufosinate-(S)-2-amino- 3-(lH-indol-3-yl)-N-ethylpropanamide prepared in Example 8.

[0056] Figure 31 shows the13C NMR spectrum of (R)-2-amino-3-(lH-indol-3- yl)-N-propylpropanamide prepared in Example 9.

[0057] Figure 32 shows theXH NMR spectrum of (R)-2-amino-3-(lH-indol-3- yl)-N-propylpropanamide prepared in Example 9.

[0058] Figure 33 shows the13C NMR spectrum of L-glufosinate-(R)-2-amino- 3-(lH-indol-3-yl)-N-propylpropanamide prepared in Example 9.

[0059] Figure 34 shows theNMR spectrum of L-glufosinate-(R)-2-amino- 3-(lH-indol-3-yl)-N-propylpropanamide prepared in Example 9.

[0060] Figure 35 shows the13C NMR spectrum of (S)-2-amino-3-(lH-indol-3- yl)-N-butylpropanamide prepared in Example 10.

[0061] Figure 36 shows theNMR spectrum of (S)-2-amino-3-(lH-indol-3- yl)-N-butylpropanamide prepared in Example 10.

[0062] Figure 37 shows the13C NMR spectrum of D-glufosinate-(S)-2-amino- 3-( 1 H-indol-3-yl)-N-butylpropanamide prepared in Example 10.

[0063] Figure 38 shows theNMR spectrum of D-glufosinate-(S)-2-amino- 3-( 1 H-indol-3-yl)-N-bulylpropanamide prepared in Example 10.DETAILED DESCRIPTION OF INVENTION

[0064] The present disclosure provides optically active glufosinate-tryptophan derivative salts, such as L-glufosinate-D-tryptophan derivative salts and D-glufosinate- L-tryptophan derivative salts, and methods for their preparation.

[0065] The L-glufosinate-D-tryptophan derivative salt is a compound with the structure of Formula I:(Formula I);

[0067] wherein R is alkoxy, amino, or alkylamino.

[0068] The D-glufosinate-L-tryptophan derivative salt is a compound with the structure of Formula II :

[0069] (Formula II);

[0070] wherein R is alkoxy, amino, or alkydamino.

[0071] In certain embodiments, R is C1-C4 alkoxy. In other embodiments, R is C1-C4 alkylamino. In certain embodiments, R is OCH3, OCH2CH3, O(CH2)2CH3,O(CH2)3CH?, NH2, NHCH3, NHCH2CH3, NH(CH2)2CH3, or NH(CH2)3CH3.

[0072] In specific embodiments, the optically active glufosinate-tryptophan derivative salt can be selected from the group consisting of D-glufosinate-L-tryptophan methyl ester salt, L-glufosinate-D-tryptophan methyl ester salt, D-glufosinate-L- tryptophan ethyl ester salt, L-glufosinate-D-tryptophan ethyl ester salt, D-glufosinate-L-tryptophan propyl ester salt, L-glufosinate-D-tryptophan propyl ester salt, D- glufosinate-L-tryptophan butyl ester salt, L-glufosinate-D-tryptophan butyl ester salt, D-glufosinate-L-tryptophanamide salt, L-glufosinate-D-tryptophanamide salt, D- glufosinate-(S)-2-amino-3-(lH-indol-3-yl)-N-methylpropanamide salt, L-glufosinate-(R)-2-amino-3-(lH-indol-3-yl)-N-methylpropanamide salt, D-glufosinate-(S)-2- amino-3-(lH-indol-3-yl)-N-ethylpropanamide salt, L-glufosinate-(R)-2-amino-3-(lH- indol-3-yl)-N-ethylpropanamide salt, D-glufosinate-(S)-2-amino-3-(lH-indol-3-yl)-N- propylpropanamide salt, L-glufosinate-(R)-2-amino-3-(lH-indol-3-yl)-N- propylpropanamide salt, D-glufosinate-(S)-2-amino-3-(lH-indol-3-yl)-N- butylpropanamide salt, and L-glufosinate-(R)-2-amino-3-(lH-indol-3-yl)-N- butylpropanamide salt.

[0073] The present disclosure also provides a simple and highly operable method for preparing optically active glufosinate-tryptophan derivative salts. In one embodiment, the method for producing an optically active glufosinate-tryptophan derivative salt comprises:

[0074] a) mixing an enantiomeric mixture of D,L-glufosinate or salt thereof, a resolution agent comprising an optically active tryptophan derivative, and a solventto facilitate a resolution reaction that produces a resolution reaction mixture comprising an optically active glufosinate-tryptophan derivative salt;

[0075] b) crystallizing the glufosinate-tryptophan derivative salt; and

[0076] c) separating the glufosinate-tryptophan derivative salt from the resolution reaction mixture;

[0077] wherein the optically active tryptophan derivative is a compound with the structure of Formula IH: (Formula III); or the structure of Formula IV:(Formula IV);

[0081] wherein R is alkoxy, amino, or alkylamino.

[0082] In certain embodiments, R is C1-C4 alkoxy. In other embodiments, R is C1-C4 alkylamino.

[0083] The preparation method can comprise using D,L-glufosinate or a salt thereof as the raw material, a D-tryptophan derivative or a L-tryptophan derivative as the resolution agent, and conducting a resolution reaction, crystallization, and filtration to obtain a L-glufosinate-D-tryptophan derivative salt or a D-glufosinate-L- tryptophan derivative salt. The main reaction equations are as follows:so ven Raw Material D-Tryptophaa derivatives fso venRaw Material L-Tryptophan derivatives II wherein R is alkoxy, amino, or alkylamino.

[0084] In certain embodiments, R is C1-C4 alkoxy. In other embodiments, R is C1-C4 alkylamino.

[0085] In accordance with the present invention, it has been discovered that glufosinate can form stable salt compounds with optically active tryptophan derivatives in suitable solvents and precipitate in solid form, obtaining optically active tryptophan derivative salts.

[0086] Specifically, it has been found:

[0087] 1) Using D,L-glufosinate or a salt thereof as raw materials and D- tryptophan derivative as a resolution agent in a suitable resolution system, it is easier to precipitate L-glufosinate-D-tryptophan derivative salt of Formula (I) due to its lower solubility. Therefore, the separation results in a high optical purity L-glufosinate-D- tr ptophan derivative salt of Formula (I); and

[0088] 2) Using L-tryptophan derivative as a resolution agent, the solubility of D-glufosinate-L-tryptophan derivative salt of Formula (H) is lower, making it easier to precipitate. Therefore, the separation results in a high optical purity D-glufosinate-L- tryptophan derivative salt of Formula (II).

[0089] The following is a description of various aspects of the preparation method of the invention.

[0090] In the preparation method, the resolution agent can be an optically active tryptophan derivative. In a suitable solvent system, D,L-glufosinate reacts with the corresponding optically active tryptophan derivative to form an optically active tryptophan derivative salt. Based on the difference in solubility in the resolution system, the corresponding optically active tryptophan derivative salt is further separated.

[0091] The molar ratio of L-configuration to D-configuration in the enantiomeric D,L-glufosinate or salt thereof used as the raw material is typically fromabout 0.25: 1 to about 4:1. When preparing the L-glufosinate-D-tryptophan derivative salt of Formula (I), if the content of D-glufosinate or salt thereof in the raw material is too high, the L-glufosinate-tryptophan derivative salt cannot be well precipitated in the separation process. In the obtained product, the D-glufosinate-tryptophan derivative salt is still the majority, and it needs to undergo multiple recrystallizations to obtain a product rich in the Formula (I) structure, which is cumbersome to operate and has low yield. Therefore, raw materials rich in D-configuration are less suitable for preparing the L-glufosinate-tryptophan derivative salt of Formula (I). Similarly, raw materials rich in L-configuration are less suitable for preparing D-glufosinate-tryptophan derivative salt of Formula (II). Moreover, when the content of a certain single configuration of glufosinate in the raw material is too high, it can be obtained by simple recrystallization, and there is no need for separation. In one embodiment, the molar ratio of L-configuration to D-configuration in the enantiomeric raw material D,L- glufosinate or salt thereof is from about 0.3: 1 to about 3: 1. In another embodiment, the enantiomeric raw material D,L-glufosinate or salt thereof is a racemic mixture of the L- and D-configurations.

[0092] The D,L-glufosinate salt can be D,L-glufosinate ammonium salt.

[0093] In the preparation method, the molar ratio of D.L-glufosinate or salt thereof to the optically active tryptophan derivative resolution agent is typically from about 1:0.2 to about 1:2. When the amount of optically active tryptophan derivative used for separation is low, the product yield is low. When the amount of optically active tryptophan derivative is large, there is no significant change in the resolution effect, and it wastes the resolution agent, increases the difficulty of post-processing, and causes unnecessary pollution. In accordance with one embodiment, the molar ratio of D,L- glufosinate or salt thereof to the optically active tryptophan derivative resolution agent is from about 1:0.4 to about 1: 1.5.

[0094] In the preparation method, the resolution solvent comprises a C1-C4 lower alcohol and water. The C1-C4 lower alcohol can be selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tertbutanol, and combinations thereof. In some embodiments, the C1-C4 lower alcohol isselected from the group consisting of methanol, ethanol, isopropanol, tert-butanol and combinations thereof.

[0095] In the preparation method, the volume ratio of water in the resolution solvent is 1% to about 70%. When the proportion of water in the resolution solvent is high, the solubility of the two salts formed by the enantiomers of D,L-glufosinate and the optically active tryptophan derivative in the resolution solvent is relatively high and the solubility difference is small, resulting in less effective resolution effect and low resolution yield, which is less desirable for the resolution reaction. When the proportion of water in the resolution solvent is low, or even if the amount of water in the resolution solvent is extremely low, there is still a good resolution effect so long as the composition of the resolution solvent including the C1-C4 lower alcohol or combination thereof is property selected. In one embodiment, the volume ratio of water in the resolution solvent is 1% to about 50%.

[0096] In the preparation method, the volume of the solvent can be 1 mL to 30 mL per gram of the D,L-glufosinate or salt thereof. When the amount of solvent used is less than 1 mL / gram of D,L-glufosinate or salt thereof, the solubility of the salts formed by the corresponding enantiomer and optically active tryptophan derivative is relatively small, resulting in low optical purity of the precipitated solid. When the amount of solvent used exceeds 30 mL / gram of D,L-glufosinate, the optical purity of the precipitated product is good, but the yield is extremely low. In one embodiment, the volume of the resolution solvent is from about 3 mL to 18 mL / gram of D,L-glufosinate raw material or salt thereof.

[0097] In the preparation method, the resolution reaction can be conducted at a temperature of from about 0 to about 90°C. At high temperatures, there is a large difference in solubility between the salts formed by the enantiomers and the optically active tryptophan derivatives, which can result in a higher optical purity product. However, at high temperatures, the solubility of both salts is high, resulting in lower yield. At low temperatures, the solubility difference between the two salts is small, resulting in poor optical purity of the product. In accordance with one embodiment, the resolution reaction is conducted at a temperature of from about 15 to about 65 °C. Inaccordance with another embodiment, the resolution reaction is conducted at a temperature of from about 40 to about 60°C.

[0098] In the preparation method, the glufosinate-tryptophan derivative salt can be crystallized by lowering the temperature of the resolution reaction mixture. This can comprise lowering the temperature of the resolution reaction mixture to room temperature, typically to a temperature of from about 20°C to about 25°C.

[0099] In the preparation method, the glufosinate-tryptophan derivative salt can be separated from the resolution reaction mixture by any suitable means including filtration or centrifugation.

[0100] The present invention has the following advantages:

[0101] The L-glufosinate-D-tryptophan derivative salts and D-glufosinate-L- tryptophan derivative salts are optically active salts with stable properties. The two salts can be separated through a simple method to obtain optically active glufosinate (D- or L-configuration). For example, the salt of the glufosinate-tryptophan derivative can be dissolved in water, then the resulting solution is adjusted to a proper pH (for example, from about 8 to about 9) with ammonia. The tryptophan derivatives can then be extracted using organic solvents (e.g. dichloromethane, etc.). Layered at rest, the aqueous solution is optically active glufosinate ammonium salt solution. Alternatively, glufosinate ammonium can be isolated by column separation.

[0102] The optically active tryptophan derivatives mentioned above can be further used as resolution agents and efficiently reused through simple extraction and separation.

[0103] The optically active tryptophan derivatives are prepared using tryptophan as the raw material, which is widely available and inexpensive.

[0104] The method for preparing optically active try ptophan derivative salts is completed in the same solvent, with simple operation and low cost for preparing L- glufosinate.

[0105] As used in this application, including the appended claims, the singular forms "a," "an," and "the" include plural references unless the content clearlydictates otherwise, and are used interchangeably with "at least one" and "one or more."

[0106] The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.EXAMPLES

[0107] The following specific examples are provided to further illustrate the present invention. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the scope of the present invention. After reading the present invention, those skilled in the art will be able to make various modifications to the present invention within the scope defined by the claims of the present invention.EXAMPLE 1 : PREPARATION OF D-GLUFOSINATE-L-TRYPTOPHAN METHYL ESTER SALT

[0108] Preparation of L-tryptophan Methyl Ester

[0109] Under stirring, 100 g (0.49 mol) of L-tryptophan and 600 mL of methanol were added to a 1000 mL reaction flask. The mixture was stirred thoroughly and cooled to 0°C, and the reaction temperature was maintained at 0-5°C. Then, 65 g (0.54 mol) of thionyl chloride was added dropwise over a period of about 2 hours. The temperature was slowly raised to room temperature, and the reaction was allowed to proceed for 1 hour. Then, the temperature w as raised to reflux and maintained for 4-6 hours. During reflux, the reaction was monitored by HPLC until the starting material was completely reacted. The reaction was then terminated. Under reduced pressure, the solvent was concentrated and removed to obtain the solid product, L-tryptophan methyl ester hydrochloride. The obtained solid L-tryptophan methyl ester hydrochloride was dissolved in 200 mL of w ater and cooled to 5-10°C, and the pH was adjusted to around 9 with ammonia w ater. Then, 300 mL of dichloromethane was added for extraction twice. After combining the organic layers, the mixture was dried with anhydrous magnesium sulfate. After removing the solvent, solid L-tryptophan methyl ester wasobtained with a yield of 100.2 g (93.8% yield) and a purity of 100% as analyzed by HPLC.

[0110] NMR of L-Tryptophan Methyl Ester:

[0111] 13C NMR (126 MHz, Chloroform-d) 5 175.88, 136.42, 127.46, 123.34, 122.00, 119.39, 118.67, 1 11 .47, 1 10.54, 54.99, 52.16, 30.88.

[0112] 'H NMR (500 MHz, Chloroform-d) 5 8.92 (s, 1H), 7.57 (dd, J = 7.9, 1.1 Hz, 1H), 7.23 (dt, J = 8.2, 1.0 Hz, 1H), 7.14 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.08 (ddd, J = 8.0, 7.0, 1. 1 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 3.82 (dd, J = 7.8. 4.7 Hz, 1H), 3.67 (s, 3H), 3.25 (ddd, J = 14.4, 4.7, 0.9 Hz, 1H), 3.01 (dd, J = 14.4, 7.8 Hz, 1H), 1.57 (s, 2H).

[0113] Preparation of D-Glufosinate-L-Tryptophan Methyl Ester Salt

[0114] Under nitrogen atmosphere. 35 g of water, 20 g of L-tryptophan methyl ester, and 17 g of D,L-glufosinate were added to a 250 mL three-necked flask. The mixture was stirred thoroughly and heated to 50°C until completely dissolved. The temperature was maintained at 45-50°C, and then 140 g of isopropanol was slowly added. As isopropanol was added, solid precipitated in the system. After maintaining the temperature at 40°C for 2 hours for crystallization, the mixture was cooled to room temperature, filtered, and dried to obtain D-glufosinate-L-tryptophan methyl ester salt with a yield of 16.5 g (44.6% yield) and an optical purity of 97.0% as analyzed by HPLC.

[0115] NMR of D-Glufosinate-L-Tryptophan Methyl Ester Salt:

[0116] 13C NMR (126 MHz, Deuterium Oxide) 5 174.08. 170.43, 136.25,126.36, 125.35, 122.20, 119.56, 118.01, 112.04, 105.97, 55.21, 55.09, 53.53, 53.26,27.36, 26.63. 25.65, 24.16. 24.14, 15.27. 14.53.

[0117] iH NMR (500 MHz, Deuterium Oxide) 5 7.49 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H). 7.22 - 7.14 (m, 2H). 7.09 (td. J = 7.4. 6.9, 1.0 Hz, 1H), 4.33 (dd, J = 6.7, 5.7 Hz, 1H), 3.72 - 3.64 (m, 4H), 3.42 - 3.29 (m, 2H), 2.07 - 1.90 (m, 2H), 1.52 (dtdd, J = 37.3, 14.5, 10.6, 6.0 Hz, 2H), 1.16 (d, J = 13.4 Hz, 3H).EXAMPLE 2: PREPARATION OF L-GLUFOSINATE-D-TRYPTOPHAN METHYLESTER SALT

[0118] Using the preparation method of Example 1, D-tryptophan was used as the starting material to prepare D-tryptophan methyl ester.

[0119] Furthermore, using D-tryptophan methyl ester as a resolution agent, 30 g of water, 15 g of D-tryptophan methyl ester, and 12.5 g of D,L-glufosinate were added to a 250 mL three-necked flask. The mixture was heated to 40°C and stirred until fully dissolved. Then, 165 g of ethanol was added to the reaction system, and the temperature was slowly lowered to room temperature for 4-6 hours to allow crystallization. The solid was filtered, and the filter cake was washed with 95% ethanol and dried to obtain L-glufosinate-D-tryptophan methyl ester salt with a yield of 12.65 g (46% yield) and an optical purity of 95.6% as analyzed by HPLC.

[0120] NMR of L-Glufosinate-D-Tryptophan Methyl Ester Salt:

[0121] 13C NMR (126 MHz, Deuterium Oxide) 5 174.06. 170.40, 136.20, 126.30, 125.32, 122.17, 119.53, 117.97, 112.00, 105.91, 55.15, 55.03, 53.49, 53.22, 27.29, 26.56. 25.61, 24.11. 24.10, 15.21, 14.47.

[0122] 'H NMR (500 MHz, Deuterium Oxide) 5 7.47 (dd, J = 7.9, 1.1 Hz, 1H), 7.43 - 7.36 (m, 1H), 7.21 - 7.11 (m, 2H), 7.06 (ddd, J = 8. 1, 7.0, 1.1 Hz, 1H), 4.31 (dd, J = 6.9, 5.6 Hz, 1H), 3.72 - 3.61 (m, 4H), 3.39 - 3.27 (m, 2H), 2.03 - 1.85 (m, 2H), 1.58 - 1.37 (m. 2H), 1.12 (d. J = 13.5 Hz, 3H).EXAMPLE 3: PREPARATION OF L-GLUFOSINATE-D-TRYPTOPHAN ETHYL ESTER SALT

[0123] Preparation of D-Tryptophan Ethyl Ester

[0124] Under stirring, 100 g (0.49 mol) of D-tryptophan and 500 mL of ethanol were added to a 1000 mL reaction flask. The mixture was stirred thoroughly and cooled to 0°C. The reaction temperature was maintained at 0-5°C. Then, 70 g (0.59 mol) of thionyl chloride was added dropwise over approximately 2 hours. The temperature was slowly raised to room temperature, and the reaction was allowed to proceed for 1 hour. The temperature was then raised to reflux, and the reaction wasrefluxed for 6-8 hours. During reflux, the reaction was monitored by HPLC until the starting material was completely consumed. The reaction was then terminated. Under reduced pressure, the solvent was concentrated and removed to obtain the solid product, D-tryptophan ethyl ester hydrochloride. The obtained solid was dissolved in 300 mL of water and cooled to 5-10°C, and the pH was adjusted to around 9 with ammonia water. 300 mL of dichloromethane was added to the mixture twice for extraction. After combining the organic layers, the solution was dried with anhydrous magnesium sulfate. After removing the solvent, the solid D-tryptophan ethyl ester was obtained with a yield of 105 g. corresponding to 92. 1%. The purity was determined to be 100% by HPLC.

[0125] D-Tryptophan Ethyl Ester NMR:

[0126] 13C NMR (126 MHz, Chloroform-d) 5 175.34, 136.28, 127.43, 123.08, 121.96, 119.32, 118.66, 111.27, 110.82, 60.97, 54.98, 30.79, 14.16.

[0127] 'H NMR (500 MHz. Chloroform-d) 5 8.66 (s, 1H), 7.64 - 7.58 (m, 1H), 7.32 - 7.26 (m, 1H), 7.16 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.10 (ddd, J = 8.1, 7.1, 1.1 Hz. 1H), 6.95 (d. J = 2.3 Hz. 1H), 4.16 (qd, J = 7.2, 2.3 Hz. 2H), 3.81 (dd, J = 7.9, 4.8 Hz, 1H), 3.27 (ddd, J = 14.5, 4.8, 0.9 Hz, 1H), 3.03 (ddd, J = 14.3, 7.9, 0.7 Hz, 1H), 1.60 (s. 2H), 1.23 (t, J = 7.2 Hz, 3H).

[0128] Preparation of L-Glufosinate-D-Tryptophan Ethyl Ester Salt

[0129] Using D-tryptophan ethyl ester as a resolution agent, water (40 g). D- tryptophan ethyl ester (15 g), and D,L-glufosinate ammonium salt (12.1 g) were added to a 250 mL three-neck flask. The mixture was heated to 55°C and thoroughly dissolved. Under reduced pressure, ammonia water (12 g) was removed. Isopropanol (90 g) was added to the system while still hot, and the temperature was slowly lowered to room temperature for 1-2 hours to allow crystallization. The solid was precipitated, filtered, and dried to obtain L-glufosinate-D-tryptophan ethyl ester salt with a yield of 10.7 g, corresponding to 41%. The optical purity of L-glufosinate was determined to be99.6% by HPLC.

[0130] L-glufosinate-D-Tiyptophan Ethyl Ester Salt NMR:

[0131] 13C NMR (126 MHz, Deuterium Oxide) 5 174.09, 170.00, 136.24, 126.41, 125.30, 122.18, 119.51, 118.04, 112.01, 106.06, 63.55, 55.21, 55.09, 53.34, 27.36, 26.64, 25.73, 24.16, 24.14, 15.28, 14.54, 12.99.

[0132] 'H NMR (500 MHz. Deuterium Oxide) 5 7.50 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.24 - 7. 14 (m, 2H), 7.09 (t, J = 7.5 Hz, 1H), 4.29 (t, J = 6.4 Hz, 1H), 4.16 - 4.06 (m, 2H), 3.67 (dd, J = 6.5, 5.1 Hz, 1H), 3.41 - 3.28 (m, 2H), 2.05 - 1.90 (m, 2H), 1.62 - 1.41 (m, 2H), 1.21 - 1.04 (m, 6H).EXAMPLE 4: D-GLUFOSINATE-L-TRYPTOPHAN PROPYL ESTER SALT

[0133] Preparation of L-Try ptophan Isopropyl Ester

[0134] Under stirring, 40 g (0.196 mol) of L-tryptophan and 300 mL of isopropanol were added to a 500 mL reaction flask. The mixture was stirred thoroughly and cooled to 0°C. The reaction temperature was maintained at 0-5°C. Then, 35 g (0.294 mol) of thionyl chloride was added dropwise over approximately 1 hour. The temperature was slowly raised to room temperature, and the reaction was allowed to proceed for 30 minutes. The temperature was then raised for refluxed reaction. During reflux, the reaction was monitored by HPLC until the starting material was completely consumed. The reaction was then terminated. Under reduced pressure, the solvent was concentrated and removed to obtain the solid product, L-tryptophan isopropyl ester hydrochloride. The obtained solid L-tryptophan isopropyl ester was dissolved in 100 mL of water and cooled to 5-10°C, and the pH was adjusted to around 9 with ammonia water. The mixture was extracted twice with 100 mL of di chloromethane. After combining the organic layers, the solution was dried with anhydrous magnesium sulfate. After removing the solvent, the solid L-tryptophan isopropyl ester was obtained with a yield of 42.4 g, corresponding to 88%. The purity7was determined to be 100% by HPLC.

[0135] L-Tryptophan Isopropyl Ester NMR:

[0136] 13C NMR (126 MHz, Chloroform-d) 5 175.45, 136.28, 127.44, 123.01, 122.00, 119.36, 118.68, 111.25, 110.93, 66.57, 55.02, 30.87, 21.90, 10.34.

[0137] ’H NMR (500 MHz, Chloroform-d) 5 8.57 (s, 1H), 7.64 - 7.58 (m, 1H), 7.30 (dt, J = 8.2, 0.9 Hz, 1H), 7.17 (ddd, J = 8.2. 7.0, 1.2 Hz, 1H), 7.11 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 6.97 (d, J = 2.3 Hz, 1H), 4.06 (td, J = 6.7, 1.8 Hz, 2H), 3.83 (dd, J = 7.9, 4.9 Hz. 1H), 3.28 (ddd, J = 14.3, 4.8, 0.9 Hz, 1H), 3.03 (ddd, J = 14.4, 7.8, 0.6 Hz, 1H), 1.69 - 1.57 (m, 4H), 0.90 (t, J = 7.5 Hz, 3H).

[0138] Preparation of D-glufosinate-L -Try ptophan Propyl Ester Salt

[0139] 40 g of water, 24.6 g of L-tryptophan propyl ester, and 20 g of D,L- glufosinate were added to a 250 mL three-necked reaction flask. The mixture was stirred well and heated to 60°C until completely dissolved. The temperature of the system was maintained at 45-50°C. 185 g of tert-butanol was slowly added, and the mixture was slowly cooled to room temperature for crystallization. The mixture was filtered and dried to obtain 16.3 g of D-glufosinate-L-tryptophan propyl ester salt, with a yield of 38.1%. HPLC analysis showed an optical purity7of 96.0% for D-glufosinate.

[0140] NMR of D-glufosinate-L-Tryptophan Propyl Ester Salt:

[0141] 13C NMR (126 MHz, Deuterium Oxide) 5 174.06, 170.11, 136.24,126.36. 125.21, 122.14, 119.47. 117.99, 111.99, 105.99. 68.88, 55.16, 55.05. 53.32,27.31, 26.58, 25.79, 24.12, 24.11, 21.01, 15.23, 14.49, 9.33.

[0142] 'H NMR (500 MHz. Deuterium Oxide) 5 7.44 (dt. J = 7.9, 1.0 Hz, 1H), 7.37 (dt, J = 8.3, 0.9 Hz, 1H), 7.15 - 7.08 (m, 2H), 7.02 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 4.25 (t, J = 6.4 Hz, 1H), 4.01 - 3.89 (m, 2H), 3.61 (dd, J = 6.5, 5.2 Hz, 1H), 3.34 - 3.25 (m, 2H), 1.99 - 1.84 (m, 2H), 1.57 - 1.34 (m, 4H), 1.10 (d, J = 13.4 Hz, 3H), 0.65 (t. J = 7.5 Hz. 3H).EXAMPLE 5: PREPARATION OF L-GLUFOSINATE-D-TRYPTOPHAN BUTYL ESTER SALT

[0143] Preparation of D-Try ptophan Butyl Ester

[0144] 100 g (0.49 mol) of D-tryptophan and 500 g of n-butanol were added to a 1 L reaction flask. The mixture was stirred and cooled to 0°C, and then 65 g (0.54 mol) of thionyl chloride was slowly added. After 1 hour of dropwise addition, the reaction proceeded at room temperature for 30 minutes. The mixture was then slowlyheated to 80°C, and the reaction continued for 8-10 hours. Once the reaction was complete, the solvent was removed under pressure to obtain a solid. 200 g of water and 300 g of dichloromethane was added to the solid, and the mixture was stirred to dissolve. The mixture was cooled to 5°C, adjusted pH to 9 with ammonia water, and extracted twice. The organic layers were combined, and magnesium sulfate was added for drying for 2 hours. The mixture was filtered, and the filtrate was evaporated under reduced pressure to obtain 106 g of D-tryptophan butyl ester with a yield of 82%. The liquid phase analysis showed a purity of 100%.

[0145] NMR of D-Try ptophan Butyl Ester:

[0146] 13C NMR (126 MHz, Chloroform-d) 5 175.51, 136.36, 127.50, 123.10, 122.05, 119.41, 118.73, 111.32, 110.95, 64.94, 55.08, 30.93, 30.63, 19.13, 13.77.

[0147] 'H NMR (500 MHz, Chloroform-d) 5 8.61 (s, 1H), 7.60 (dt, J = 7.9, 0.9 Hz. 1H), 7.29 (dt, J = 8.1, 1.0 Hz. 1H), 7.17 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H). 7.10 (ddd, J = 7.9, 7.0, 1.1 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 4.10 (td, J = 6.7, 1.7 Hz, 2H),3.82 (dd, J = 7.8, 4.9 Hz, 1H), 3.28 (ddd. J = 14.3, 4.9, 0.9 Hz. 1H), 3.03 (ddd. J = 14.4, 7.8, 0.7 Hz, 1H), 1.62 - 1.53 (m, 4H), 1.32 (dq, J = 14.7, 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz. 3H).

[0148] Preparation of L-glufosinate-D-Tryptophan Butyl Ester Salt

[0149] 50 g of water, 26 g of D-tryptophan butyl ester, and 20 g of D,L- glufosinate ammonium salt were added to a 500 mL three-necked reaction flask. The mixture was stirred well and heated to 60°C until completely dissolved. Under reduced pressure, 15 g of ammonia water was removed. The temperature of the system was maintained at 45-50°C. 330 g of methanol was slowly added, and the mixture was slowly cooled to room temperature for crystallization. The mixture was filtered and dried to obtain 18.5 g of L-glufosinate-D-tryptophan butyl ester salt, with a yield of 42%. HPLC analysis showed an optical purity of 98.5% for L-glufosinate.

[0150] NMR of L-glufosinate-D-Tryptophan Butyl Ester Salt:

[0151] 13C NMR (126 MHz, Deuterium Oxide) 5 174.09, 170.18, 136.28,126.40, 125.19, 122.17, 119.50, 118.00, 112.02, 106.05, 67.17, 55.21, 55.09, 53.36,29.50, 27.35, 26.63, 25.87, 24.15, 24.14, 18.25, 15.26, 14.52, 12.80.

[0152] 'H NMR (500 MHz. Deuterium Oxide) 5 7.44 (dd, J = 7.9, 1.0 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.15 - 7.08 (m, 2H), 7.03 (ddd, J = 8.0, 6.9, 1.0 Hz, 1H), 4.25 (t, J = 6.4 Hz, 1H). 3.98 (td, J = 6.6. 2.1 Hz, 2H), 3.62 (dd, J = 6.5, 5.2 Hz, 1H), 3.30 (d, J = 6.4 Hz, 2H), 1.92 (dddd, J = 12.3, 10.7, 9.0, 5.8 Hz, 2H), 1.56 - 1.37 (m, 2H), 1.37 - 1.29 (m. 2H), 1.10 (d. J = 13.4 Hz, 3H), 1.03 (dl. J = 15.0, 7.5 Hz. 2H), 0.67 (t, J = 7.4 Hz, 3H).EXAMPLE 6: PREPARATION OF D-GLUFOSINATE-L-TRYPTOPHANAMIDE SALT

[0153] Preparation of L-Tryptophanamide

[0154] 50 g (0.23 mol) of L-tryptophan methyl ester (prepared according to Example 1) and 200 g of a 20% methanol solution of ammonia were added to a 500 mL reaction flask. The mixture was stirred at room temperature for 40 hours until the reaction was complete based on HPLC monitoring. The solvent was removed under reduced pressure to obtain 48.5 g of L-tryptophanamide with a liquid phase purity of 97.5%.

[0155] NMR of L-Tryptophanamide:

[0156] 1?C NMR (126 MHz, Methanol-d4) 5 178.88, 136.77, 127.47, 123.49, 121.25. 118.61, 118.21, 11 1.10, 109.96, 55.16, 31.01.

[0157] iH NMR (500 MHz, Methanol-d4) 5 7.64 (dt, J = 7.9, 1.0 Hz, 1H), 7.35 (dd, J = 8.2. 1.0 Hz. 1H), 7. 14 - 6.96 (m. 3H), 3.62 (dd, J = 7.7, 5.5 Hz, 1H), 3.35 (s, 1H), 3.25 - 3.16 (m, 1H), 2.94 (dd, J = 14.3, 7.7 Hz, 1H).

[0158] Preparation of D-Glufosinate-L-Tryptophanamide Salt

[0159] 80 g of water, 40.6 g of L-tryptophanamide, and 40 g of D,L- glufosinate ammonium salt were added to a 500 mL three-necked reaction flask. The mixture was stirred thoroughly and heated to 60°C until complete dissolution. 13.5 g of ammonia water was removed under reduced pressure. The system was maintained at45-50°C, and 320 g of tert-butanol was slowly added. The mixture was slowly cooled to room temperature for crystallization, filtered, and dried to obtain 29.5 g of D- glufosinate-L-tryptophanamide salt with a yield of 38.4%. HPLC analysis showed an optical purity of 87. 1% for D-glufosinate.

[0160] NMR of D-Glufosinate-L-Tryptophanamide Salt:

[0161] 13C NMR (126 MHz, Deuterium Oxide) 5 174.06. 173.00, 136.11, 126.51, 125.14, 122.02, 119.37, 118.19, 111.88, 106.66, 55.13, 55.02, 53.33, 27.29, 27.24, 26.56, 24.11, 24.09. 15.21, 14.47.

[0162] 'HNMR (500 MHz, Deuterium Oxide) S 7.51 (t, J = 6.2 Hz, 1H), 7.34 (dq, J = 11.0. 7.0, 5.0 Hz, 1H), 7.18 - 6.97 (m, 3H), 4.00 (s, 1H), 3.59 (tt, J = 6.9, 4.0 Hz, 1H), 3.37 - 2.87 (m, 3H), 2.01 - 1.83 (m, 2H), 1.55 - 1.34 (m, 2H), 1.09 (dd, J = 13.4, 2.7 Hz, 3H).EXAMPLE 7: PREPARATION OF L-GLUFOSINATE-(R)-2-AMINO-3-(lH- INDOL-3-YL)-N-METHYLPROPANAMIDE SALT

[0163] Preparation of (R)-2-amino-3-(lH-indol-3-yl)-N-methylpropanamide

[0164] 50 g (0.23 mol) of D-tryptophan methyl ester and 200 g of a 23% methanol solution of methylamine were added to a 500 mL reaction flask. The mixture was stirred at room temperature for 20 hours until the reaction is complete based on HPLC monitoring. The solvent was removed under reduced pressure to obtain 49.5 g of (R)-2-amino-3-(lH-indol-3-yl)-N-methylpropanamide with a liquid phase purity of 98.7%.

[0165] NMR of (R)-2-amino-3-(lH-indol-3-yl)-N-methylpropanamide:

[0166] 13C NMR (126 MHz. Methanol-d4) 6 176.51, 136.76, 127.42, 123.25. 121.07, 118.38, 118.07, 110.90, 109.87, 55.58, 30.94, 24.84.

[0167] 'H NMR (500 MHz. Methanol-d4) 5 7.57 (dt, J = 7.8. 1.0 Hz. 1H). 7.33 (dt, J = 8.2, 1.0 Hz, 1H), 7.12 - 7.04 (m, 2H), 7.00 (ddd, J = 7.9, 6.9, 1.0 Hz, 1H), 3.55 (dd, J = 7.0, 6. 1 Hz, 1H), 3. 14 (ddd, J = 14. 1, 6. 1, 0.7 Hz, 1H), 2.97 (dd, J = 14.2, 7.0 Hz, 1H), 2.63 (s, 3H).

[0168] Preparation of L-Glufosinate-(R)-2-amino-3-(lH-indol-3-yl)-N- methylpropanamide Salt

[0169] 40 g of water, 20.3 g of (R)-2-amino-3-(lH-indol-3-yl)-N- methylpropanamide, and 18.1 g of D,L-glufosinate were added to a 250 mL three-neck reaction flask. The mixture was stirred thoroughly and heated to 40°C until completely dissolved. The temperature of the system was maintained at 45-50°C, and 135 g of butanol was slowly added. The mixture was slowly cooled to room temperature to allow crystallization. The mixture was fdtered and dried to obtain 16.9 g of L-glufosinate- (R)-2-amino-3-(lH-indol-3-yl)-N-methylpropanamide salt with a yield of 44%. HPLC analysis showed an optical purity of 83.8% for L-glufosinate.

[0170] NMR of L-Glufosinate-(R)-2-amino-3-(lH-indol-3-yl)-N- methylpropanamide Salt:

[0171] 13C NMR (126 MHz, Deuterium Oxide) 5 174.09, 169.74, 136.15, 126.50. 125.14, 122.08, 119.48. 118.07, 111.94, 106.43. 55.20, 55.08, 53.71. 27.35, 26.85, 26.62, 25.76, 24.15, 24.13, 15.26, 14.52.

[0172] 'H NMR (500 MHz. Deuterium Oxide) 5 7.49 (d, J = 8.0 Hz. 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.21 - 7.13 (m, 2H), 7.09 (t, J = 7.5 Hz, 1H), 4.08 (t, J = 6.9 Hz. 1H), 3.66 (t, J = 5.8 Hz, 1H), 3.30 - 3.18 (m, 2H), 2.51 (s, 3H). 1.97 (dtt. J = 15.6, 9.7, 5.7 Hz, 2H), 1.61 - 1.44 (m, 2H), 1.15 (d, J = 13.4 Hz, 3H).EXAMPLE 8: PREPARATION OF D-GLUFOSINATE-(S)-2-AMINO-3-(lH- INDOL-3-YL)-N-ETHYLPROP AN AMIDE SALT

[0173] Preparation of (S)-2-amino-3-(lH-indol-3-yl)-N-ethylpropanamide

[0174] 50 g (0.23 mol) of L-tryptophan methyl ester and 200 g of 70% aqueous ethylamine solution were added to a 500 mL reaction flask and stirred. The reaction was allowed to proceed at room temperature for 20 hours until the reaction was complete based on HPLC monitoring. The reaction solution was extracted with DCM, and the solvent was removed under reduced pressure to obtain 43.9 g of (S)-2-amino- 3-(lH-indol-3-yl)-N-ethylpropanamide with a purity of 94.7% according to liquid phase analysis.

[0175] NMR of (S)-2-amino-3-(lH-indol-3-yl)-N-ethylpropanamide:

[0176] 13C NMR (126 MHz, Chloroform-d) 5 175.36, 136.77, 127.55, 123.72, 121.91, 119.23, 118.78, 111.69, 110.97, 55.64, 34.12, 31.09, 14.83.

[0177] 'H NMR (500 MHz, Chloroform-d) 5 9.67 (d, J = 2.5 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.38 - 7.28 (m, 2H), 7.11 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.01 (ddd, J = 7.9, 7.0, 1.0 Hz, 1H). 6.93 (d, J = 2.4 Hz, 1H), 3.61 (dd, J = 8.9, 4.3 Hz, 1H), 3.31 (dd, J = 14.5, 4.3 Hz, 1H), 3.26 - 3.18 (m, 2H), 2.87 (dd, J = 14.4, 8.8 Hz, 1H), 1.38 (s, 2H), 1.02 (1, J = 7.3 Hz, 3H).

[0178] Preparation of D-Glufosinate-(S)-2-amino-3-(lH-indol-3-yl)-N- ethylpropanamide Salt

[0179] 80 g of water, 47 g of (S)-2-amino-3-(lH-indol-3-yl)-N- ethylpropanamide, and 40 g of D.L-glufosinate ammonium salt were added to a 500 mL three-neck reaction flask. The mixture was stirred thoroughly and heated to 60°C until completely dissolved. Ammonia was removed under reduced pressure, maintaining the temperature of the system at 45-50°C. 335 g of isopropanol was slowly added, and the mixture was slowly cooled to room temperature to allow crystallization. The mixture was filtered and dried to obtain 36.5 g of D-glufosinate-(S)-2-amino-3- (lH-indol-3-yl)-N-ethylpropanamide salt with a yield of 44.3%. HPLC analysis showed an optical purity of 90. 1% for D-glufosinate.

[0180] NMR of D-Glufosinate-(S)-2-amino-3-(lH-indol-3-yl)-N- ethylpropanamide Salt:

[0181] 13C NMR (126 MHz, Deuterium Oxide) 5 174.06. 168.80, 136.11, 126.53, 125.09, 122.01, 119.39, 118.09, 111.89, 106.48, 55.17, 55.05, 53.74, 34.51, 27.33, 26.83. 26.60, 24.14. 24.12, 15.26. 14.52, 12.90.

[0182] iH NMR (500 MHz, Deuterium Oxide) 5 7.51 (dd, J = 8.1, 1.1 Hz, 1H), 7.43 (d. J = 8.1 Hz. 1H), 7.22 - 7.14 (m. 2H). 7.09 (td, J = 7.5. 7.1. 1.0 Hz. 1H). 4.04 (dd, J = 8.2, 6.2 Hz, 1H), 3.68 (ddd, J = 7.0, 5.2, 1.9 Hz, 1H), 3.23 (qd, J = 14.6, 7.2 Hz, 2H), 3.04 - 2.88 (m, 2H), 2.08 - 1.90 (m, 2H), 1.53 (dtdd, J = 37.7, 14.5, 10.6, 6.1 Hz, 2H), 1.18 (d, J = 13.4 Hz, 3H). 0.75 (t. J = 7.3 Hz, 3H).EXAMPLE 9: PREPARATION OF L-GLUFOSINATE-(R)-2-AMINO-3-(lH-INDOL-3-YL)-N-PROPYLPROP AN AMIDE SALT

[0183] Preparation of (R)-2-amino-3-(lH-indol-3-yl)-N-propylpropanamide

[0184] 50 g (0.23 mol) of D-tryptophan methyl ester and 100 g of n- propylamine were added to a 250 mL reaction flask and stirred. The reaction was allowed to proceed at room temperature for 20 hours until the reaction was complete based on HPLC monitoring. The solvent was removed under reduced pressure to obtain55.6 g of (R)-2-amino-3-(lH-indol-3-yl)-N-propylpropanamide with a purity of 96.7% according to HPLC analysis.

[0185] NMR of (R)-2-amino-3-(lH-indol-3-yl)-N-propylpropanamide:

[0186] 13C NMR (126 MHz, Chloroform-d) 5 174.87, 136.46, 127.45, 123.20. 122.07, 119.41, 118.86, 111.55, 111.33. 55.64, 40.76. 30.88, 22.78, 11.37.

[0187] 'H NMR (500 MHz, Chloroform-d) 5 8.73 (s, 1H), 7.64 (dd, J = 7.9, 1.0 Hz. 1H), 7.40 - 7.30 (m. 2H), 7.18 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H). 7.09 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H), 7.04 (d, J = 2.3 Hz, 1H), 3.70 (dd, J = 9.1, 4.1 Hz, 1H), 3.39 (ddd, J = 14.5, 4. 1, 0.9 Hz, 1H), 3.21 (dt. J = 7.8. 6.5 Hz. 2H), 2.90 (dd, J = 14.5, 9.0 Hz, 1H), 1.52 - 1.43 (m, 4H), 0.88 (t, J = 7.4 Hz, 3H).

[0188] Preparation of L-Glufosinate-(R)-2-amino-3-(lH-indol-3-yl)-N- propylpropanamide Salt

[0189] 100 g of water, 49 g of (R)-2-amino-3-(lH-indol-3-yl)-N- propylpropanamide, and 40 g of D,L-glufosinate were added to a 1000 mL three-necked flask. The mixture was stirred thoroughly and heated to 60°C until completely dissolved. The temperature of the system was maintained at 45-50°C. 110 g of tertbutanol and 460 g of isopropanol were slowly added. The mixture was slowly cooled to room temperature for cry stallization. The mixture was filtered and dried to obtain36.6 g of L-glufosinate-(R)-2-amino-3-(lH-indol-3-yl)-N-propylpropanamide salt with a yield of 43%. HPLC analysis showed an optical purity of 97.5% for L-glufosinate.

[0190] NMR of L-Glufosinate-(R)-2-amino-3-(lH-indol-3-yl)-N- propylpropanamide Salt:

[0191] 13C NMR (126 MHz, Deuterium Oxide) 5 174.04, 169.00, 136.17, 126.48, 125.02, 122.02, 119.38, 118.07, 111.92, 106.49, 55.14, 55.03, 53.80, 41.26, 27.30, 26.90, 26.58, 24.12, 21.31, 21.29, 15.24, 14.50, 10.30.

[0192] TlNMR ^OO MHz, Deuterium Oxide) 5 7.48 (p, J = 8.0, 7.3 Hz, 1H), 7.38 (p, J = 7.9, 7.2 Hz, 1H), 7.24 - 6.99 (m, 3H), 4.03 (q, J = 10.3, 7.2 Hz, 1H), 3.65 (dq, J = 12.7. 6.4, 5.7 Hz, 1H), 3.21 (th, J = 14.6, 7.6 Hz, 2H), 2.92 (dp, J = 13.6, 8.1, 6.9 Hz, 1H), 2.79 (dp, J = 13.7, 7.1, 6.6 Hz, 1H), 2.04 - 1.95 (m, 1H), 1.93 (t, J = 8.0 Hz, 1H), 1.49 (dddd, J = 29.8, 16.8, 12.0, 6.3 Hz, 2H), 1. 12 (dpt, J = 21.5, 14.1, 6.3 Hz, 5H), 0.49 (dt, J = 14.4, 6.9 Hz, 3H).EXAMPLE 10: PREPARATION OF D-GLUFOSINATE-(S)-2-AMINO-3-(lH- INDOL-3 -YL)-N-BUTYLPROP ANAMIDE SALT

[0193] Preparation of (S)-2-amino-3-(lH-indol-3-yl)-N-butylpropanamide

[0194] 50 g (0.23 mol) of L-tryptophan methyl ester and 80 g of n-butylamine were added to a 250 mb reaction flask and stirred. The reaction was carried out at 35°C for 24 hours. After the completion of the reaction based on HPLC monitoring, the excess n-butylamine was removed under reduced pressure to obtain 50.5 g of (S)-2- amino-3-(lH-indol-3-yl)-N-butylpropanamide. The HPLC analysis analysis showed a purity of 99.2%.

[0195] NMR of (S)-2-amino-3-(lH-indol-3-yl)-N-butylpropanamide:

[0196] 1?C NMR (126 MHz, Chloroform-d) 5 174.97, 136.56, 127.50, 123.31. 122.07, 119.41. 118.88, 111.51, 111.42. 55.69, 38.87, 31.64, 30.97. 20.10, 13.81.

[0197] 'H NMR (500 MHz. Chloroform-d) 5 8.89 (s. 1H), 7.62 (dd, J = 7.9. 1.0 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.30 (t, J = 5.9 Hz, 1H), 7.17 (ddd, J = 8.2, 7.0, 1.2 Hz. 1H), 7.08 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H). 7.02 (d, J = 2.3 Hz, 1H). 3.69 (dd. J = 9.0.4.2 Hz, 1H), 3.38 (ddd, J = 14.4, 4.2, 0.9 Hz, 1H), 3.24 (tdd, J = 7.3, 5.9, 1.8 Hz, 2H), 2.89 (dd, J = 14.5, 9.1 Hz, 1H), 1.48 - 1.35 (m, 4H), 1.34 - 1.23 (m, 2H), 0.89 (t, J =7.3 Hz, 3H).

[0198] Preparation of D-Glufosinate-(S)-2-amino-3-(lH-indol-3-yl)-N- butylpropanamide Salt

[0199] 100 g of water, 52 g of (S)-2-amino-3-(lH-indol-3-yl)-N- butylpropanamide, and 47 g of D,L-glufosinate were added to a 1000 mL three-necked flask. The mixture was stirred thoroughly and heated to 60°C until completely dissolved. The temperature of the system was maintained at 45-50°C. 350 g of isopropanol and 80 g of tert-butanol were slowly added. The mixture was slowly cooled to room temperature for crystallization. The mixture was fdtered and dried to obtain 40.6 g of D-glufosinate-(S)-2-amino-3-(lH-indol-3-yl)-N-butylpropanamide salt with a yield of 46%. HPLC analysis showed an optical purity of 92.5% for D-glufosinate.

[0200] NMR of D-Glufosinate-(S)-2-amino-3-(lH-indol-3-yl)-N- butylpropanamide Salt:

[0201] 13C NMR (126 MHz, Deuterium Oxide) 5 173.91, 168.88, 136.18, 126.49. 124.96, 122.02, 119.38. 118.08, 111.94, 106.53. 55.06, 54.94, 53.81. 39.17, 29.88, 27.25, 26.91, 26.52, 24.07, 24.05, 19.03, 15.21, 14.47, 12.83.

[0202] 'H NMR (500 MHz. Deuterium Oxide) 5 7.44 (dd, J = 8.0, 1.1 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.15 - 6.97 (m, 3H), 3.98 (dd, J = 9.0, 6.0 Hz, 1H), 3.63 (dd, J = 6.5, 5.2 Hz, 1H). 3.24 - 3.08 (m, 2H). 2.93 (dt, J = 13.6, 6.8 Hz, 1H). 2.73 (dt, J = 13.6, 6.9 Hz, 1H), 1.93 (dddd, J = 14.9, 10.6, 8.4, 5.9 Hz, 2H), 1.58 - 1.37 (m, 2H), 1.11 (d. J = 13.5 Hz, 3H), 0.93 (p, J = 7.2 Hz, 2H), 0.75 (tp, J = 14.0, 7.3 Hz, 2H), 0.57 (t, J = 7.3 Hz, 3H).EXAMPLE 11 : RECOVERY OF L-TRYPTOPHAN METHYL ESTER

[0203] Under stirring. 60 g of L-tryptophan methyl ester hydrochloride was dissolved in 200 mL of water in a 500 mL three-neck flask. The reaction temperature was maintained below 25°C. Ammonia gas was introduced into the reaction mixture to adjust the pH to 8-9, or ammonia water was used to adjust the pH to 8-9. The reaction was terminated. Dichloromethane (100 mL) was added for extraction twice, and the organic layers were combined. Anhydrous magnesium sulfate (10 g) was added, and the mixture was dried for two hours. After removing the solvent, L-tryptophan methylester solid (32.3 g) was obtained with a recover}' rate of 99% and a chiral purity of 100% as analyzed by HPLC.

[0204] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0205] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the preceding description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method for producing an optically active glufosinate-tryptophan derivative salt, the method comprising: a) mixing an enantiomeric mixture of D,L-glufosinate or salt thereof, a resolution agent comprising an optically active tryptophan derivative, and a solvent to facilitate a resolution reaction that produces a resolution reaction mixture comprising an optically active glufosinate-tryptophan derivative salt; b) crystallizing the glufosinate-tryptophan derivative salt; and c) separating the glufosinate-tryptophan derivative salt from the resolution reaction mixture; wherein the optically active tryptophan derivative is a compound with the structure of Formula III:H e.NH2 / "RO (Formula III); or a compound with the structure of Formula IV:HC oNH2 / ~~RO (Formula IV); wherein R is alkoxy, amino, or alkylamino.

2. The method of claim 1, wherein the enantiomeric mixture of D,L-glufosinate or salt thereof comprises D.L-glufosinate ammonium salt.

3. The method of claim 1, wherein the molar ratio of L-configuration to D- configuration in the enatiomeric mixture of D.L-glufosinate or salt thereof is 0.25 : 1 to 4:1.

4. The method of claim 1, wherein the molar ratio of L-configuration to D- configuration in the enantiomeric mixture of D,L-glufosinate or salt thereof is 0.3: 1 to5. The method of claim 1, wherein the enantiomeric mixture of D,L-glufosinate or salt thereof is racemic.

6. The method of claim 1, wherein the molar ratio of D,L-glufosinate or salt thereof to the optically active tryptophan derivative is 1 :0.2 to 1:2.

7. The method of claim 1 , wherein the molar ratio of D,L-glufosinate or salt thereof to the optically active tryptophan derivative is 1 :0.4 to 1: 1.5.

8. The method of any one of claims 1 to 7, wherein the solvent comprises a C1-C4 lower alcohol and water.

9. The method of claim 8, wherein the C1-C4 lower alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, and combinations thereof.

10. The method of claim 8, wherein the C1-C4 lower alcohol is selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, and combinations thereof.

11. The method of any one of claims 1 to 7, wherein the volume ratio of water in the solvent is 1 to 70%.

12. The method of any one of claims 1 to 7, wherein the volume ratio of water in the resolution solvent is 1 to 50%.

13. The method of any one of claims 1 to 7, wherein the volume of the solvent is1 mL to 30 mL per gram of the D,L-glufosinate or salt thereof.

14. The method of any one of claims 1 to 7, wherein the volume of the solvent is3 mL to 18 mL per gram of the D,L-glufosinate or salt thereof.

15. The method of any one of claims 1 to 7, wherein the resolution reaction is conducted at a temperature of from about 0 to about 90°C.

16. The method of any one of claims 1 to 7, wherein the resolution reaction is conducted at a temperature of from about 15 to about 65°C.

17. The method of any one of claims 1 to 7, wherein the resolution reaction is conducted at a temperature of from about 40 to about 60°C.

18. The method of any one of claims 1 to 7, wherein crystallizing the glufosinate- tryptophan derivative salt comprises lowering the temperature of the resolutionreaction mixture.

19. The method of claim 18. wherein the temperature is lowered to from about 20°C to about 25 °C.

20. The method of any one of claims 1 to 7, wherein separating the glufosinate- tryptophan derivative salt from the resolution reaction mixture comprises filtration or centrifugation.

21. The method of any one of claims 1 to 7, wherein the glufosinate-tryptophan derivative salt is a L-glufosinate-D-tryptophan derivative salt or a D-glufosinate-L- tiyptophan derivative salt.

22. The method of any one of claims 1 to 7. wherein the glufosinate-tr ptophan derivative salt is a compound with the structure of Formula I:(Formula I) ; or a compound with the structure of Formula II:(Formula II) ; wherein R is alkoxy, amino, or alkylamino.

23. The method of any one of claims 1 to 7, wherein R is C1-C4 alkoxy.

24. The method of any one of claims 1 to 7, wherein R is C1-C4 alkylamino.

25. The method of any one of claims 1 to 7, wherein R is amino.

26. The method of any one of claims 1 to 7, wherein the optically active glufosinate- tryptophan derivative salt is selected from the group consisting of D-glufosinate-L- tryptophan methyl ester salt, L-glufosinate-D-tryptophan methyl ester salt, D- glufosinate-L-tryptophan ethyl ester salt, L-glufosinate-D-tryptophan ethyl ester salt, D-glufosinate-L-tryptophan propyl ester salt, L-glufosinate-D-tryptophan propyl ester salt, D-glufosinate-L-tryptophan butyl ester salt. L-glufosinate-D-tryptophan butyl ester salt, D-glufosinate-L-tryptophanamide salt, L-glufosinate-D-tryptophanamidesalt D-glufosinate-(S)-2-amino-3-(lH-indol-3-yl)-N-methylpropanamide salt L- glufosinate-(R)-2-amino-3-(lH-indol-3-yl)-N-methylpropanamide salt, D-glufosinate- (S)-2-amino-3-(lH-indol-3-yl)-N-ethylpropanamide salt, L-glufosinate-(R)-2-amino- 3-(lH-indol-3-yl)-N-ethylpropanamide salt, D-glufosinate-(S)-2-amino-3-(lH-indol- 3-yl)-N-propylpropanamide salt, L-glufosinate-(R)-2-amino-3-(lH-indol-3-yl)-N- propylpropanamide salt, D-glufosinate-(S)-2-amino-3-(lH-indol-3-yl)-N- butylpropanamide salt, and L-glufosinate-(R)-2-amino-3-(lH-indol-3-yl)-N- butylpropanamide salt.

27. An optically active glufosinate-tryptophan derivative salt selected from the group consisting of a compound with the structure of Formula I:(Formula I) ; and a compound with the structure of Formula II:(Formula II) ; wherein R is alkoxy, amino, or alkylamino.

28. The optically active glufosinate-tryptophan derivative salt of claim 27, wherein R is C1-C4 alkoxy.

29. The optically active glufosinate-tryptophan derivative salt of claim 27, wherein R is C1-C4 alkylamino.

30. The optically active glufosinate-tryptophan derivative salt of claim 27, wherein R is amino.

31. The optically active glufosinate-tryptophan derivative salt of claim 27, wherein the optically active glufosinate-tryptophan derivative salt is selected from the group consisting of D-glufosinate-L-tryptophan methyl ester salt, L-glufosinate-D- tryptophan methyl ester salt, D-glufosinate-L-tryptophan ethyl ester salt, L- glufosinate-D-tryptophan ethyl ester salt, D-glufosinate-L-tryptophan propyl estersalt, L-glufosinate-D-tryptophan propyl ester salt, D-glufosinate-L-tryptophan butyl ester salt, L-glufosinate-D-tryptophan butyl ester salt, D-glufosinate-L- tryptophanamide salt, L-glufosinate-D-tryptophanamide salt, D-glufosinate-(S)-2- amino-3-(lH-indol-3-yl)-N-methylpropanamide salt, L-glufosinate-(R)-2-amino-3- (lH-indol-3-yl)-N-methylpropanamide salt, D-glufosinate-(S)-2-amino-3-(lH-indol- 3-yl)-N-ethylpropanamide salt, L-glufosinate-(R)-2-amino-3-(lH-indol-3-yl)-N- ethylpropanamide salt, D-glufosinate-(S)-2-amino-3-(lH-indol-3-yl)-N- propylpropanamide salt, L-glufosinate-(R)-2-amino-3-(lH-indol-3-yl)-N- propylpropanamide salt, D-glufosinate-(S)-2-amino-3-(lH-indol-3-yl)-N- butylpropanamide salt, and L-glufosinate-(R)-2-amino-3-(lH-indol-3-yl)-N- butylpropanamide salt.

Images