Preparation method of L-phosphinothricin ammonium intermediate

Abstract

The invention discloses a preparation method of a key intermediate of L-glufosinate-ammonium, wherein (3S, 6S)-3,6-bis(2-substituted ethyl)-2,5-diketopiperazine is reacted with metal reagents such as zinc and palladium or a lithium chloride auxiliary agent is added to prepare a Turbo reagent reaction, and then reacted with methyl (alkoxy) phosphonyl chloride or dimethoxyphosphonium chloride to obtain an intermediate (3S, 6S)-3,6-bis(2-methyl (alkoxy) phosphonoethyl)-2,5-diketopiperazine (I) or (3S, 6S)-3,6-bis(2-methyl (methoxy) phosphonoethyl)-2,5-diketopiperazine (II), and then L-glufosinate-ammonium is obtained by acidolysis and ammoniation in an acidic medium. The method has many advantages such as a simple process route, superior synthesis cost, safe and reliable operation, and environmental protection, and the chemical yield reaches 82%, and the optical purity is more than 98%ee, which is a feasible preparation method for L-glufosinate-ammonium.

Description

Technical Field

[0001] The invention relates to a preparation method of an L-glufosinate intermediate, namely a preparation method of key L-glufosinate intermediates (3S, 6S)-3,6-bis(2-methyl(alkoxy)phosphonoethyl)-2,5-diketopiperazine and (3S, 6S)-3,6-bis(2-methyl(methoxy)phosphonoethyl)-2,5-diketopiperazine, and preparation of L-glufosinate by using the two intermediates, and belongs to the fields of organic synthetic chemistry and pesticide chemistry. Background Art

[0002] L-glufosinate-ammonium (Butanoic acid, 2-amino-4-(hydroxymethyl phosphinyl)-, ammonium salt (1:1), (2S)-), also known as refined glufosinate-ammonium, refined glufosinate-ammonium salt, L-phosphinothricin, chemical name is (S)-4-(hydroxy(methyl)phosphinoyl)-L-homoalanine monoammonium salt, CAS: 73777-50-1, molecular formula: C5H 12 NO4P . H3N, melting point: 209-210℃, specific rotation: [α] D 25 = +13.4 (c = 1 in water), acidity coefficient: pKa = 2.22 ± 0.10 (Predicted). L-Glufosinate is a highly effective, broad-spectrum, low-toxic non-selective herbicide developed by Hoechst (now Bayer) in Germany. It is a glutamine synthesis inhibitor. Studies have shown that its herbicidal activity is limited to the L-isomer. Although the popular product on the market is the DL-mixture, the D-isomer does not have biological herbicidal activity, so the biological activity of L-Glufosinate is twice that of the DL-racemic isomer at the same concentration.

[0003] With the ban and restriction of paraquat around the world and the emergence of a large number of glyphosate-resistant weeds, the market demand for L-glufosinate will continue to grow. Glufosinate has become one of the world's largest tonnage herbicides and the second largest GM crop tolerant herbicide after glyphosate. With the spread of glyphosate-resistant weeds, the market demand for glufosinate is even more obvious. On the other hand, glufosinate is the only approved GM rice tolerant herbicide. Once glufosinate-resistant GM crops are widely planted and used around the world, glufosinate will have a broader market.

[0004] The amino acid part of L-phosphinothricin is L-amino acid or S-amino acid. The synthesis methods reported so far mainly include bioenzyme method and stereochemical synthesis method. For example:

[0005] 1. Preparation of L-phosphinothricin by enzymatic hydrolysis

[0006] L-phosphinothricin is a new herbicide discovered on the basis of bisalaphos. Bisalaphos is a natural tripeptide compound that can be hydrolyzed by protease to obtain L-phosphinothricin and L-alanine, which exerts a herbicidal effect.

[0007]

[0008] Natchev et al. (Bulletin of the Chemical Society of Japan, 1988, 61: 3699-3704) reported that L-3-acetylamino-2-pyrrolidone was used as a raw material, and L-3-acetylamino-4-(hydroxymethylphosphonyl)butyramide was obtained by Michaelis Becker reaction, and the acetate group was removed by hydrolysis. After the action of phosphodiesterase I, acylase I, and glutaminase, L-phosphinothricin was obtained with a yield of 75.7%.

[0009]

[0010] 2. Preparation of L-phosphinothricin by transaminase method

[0011] Transaminase is a type of enzyme that catalyzes the conversion of amino groups from amino acids to keto acids. The transaminase method mostly uses 2-carbonyl-4-(hydroxymethylphosphonyl)butyric acid as a substrate, and different optically active amino acids or inorganic ammonium salts as amino donors to achieve the preparation of L-phosphinothricin. Fang JM (Journal of the Chemical Society, Perkin Transactions I, 1995: 967-978) et al. reported that glutamate dehydrogenase was used to prepare L-phosphinothricin in ammonium phosphate buffer using 2-carbonyl-4-(hydroxymethylphosphonyl)butyric acid as a substrate, with a yield of 25% and an ee% value of 89.2%. Schulz (Applied and Environmental Microbiology, 1990, 56: 1-6) et al. isolated transaminase from E. coli K-12, used 2-carbonyl-4-(hydroxymethylphosphonyl)butyric acid as a substrate, and L-glutamic acid as an amino acid donor to prepare L-phosphinothricin, with an ee% value of more than 99.9%. Yang Lirong (CN 106916857A), Hu Lei (CN 107630052A) and others prepared L-glufosinate using other enzymes in a similar manner.

[0012]

[0013] 3. Preparation of L-phosphinothricin by Enzymatic Resolution

[0014] The enzymatic splitting principle uses DL-phosphinothricin derivatives as substrates and utilizes enzymes such as α-trypsin, deacetylase, and amidase to selectively hydrolyze a single configuration to achieve the splitting of glufosinate.

[0015] Natchev et al. (Journal of the Chemical Society, Perkin Transactions I. 1989, 1: 125-131) used α-trypsin to split bialaphos diethyl ester to prepare L-glufosinate. First, racemic glufosinate was derived into bialaphos diethyl ester, then the carbon terminal ester was hydrolyzed by mesinterico peptidase, and the peptide bond of L-bialaphos ethyl ester was selectively hydrolyzed by α-chymotrypsin to obtain L-glufosinate ethyl ester. Finally, phosphodiesterase I was used to hydrolyze the phosphine terminal ester to obtain L-glufosinate.

[0016]

[0017] CN104558033A discloses that DL-phosphinothricin-N-carboxylic anhydride is stereoselectively hydrolyzed with ester hydrolase of Arthrobacter nicotinicum WYG001 (CCTCC NO: M2014054) to obtain L-phosphinothricin-N-anhydride, which is then hydrolyzed with dilute hydrochloric acid to obtain L-phosphinothricin.

[0018]

[0019] 4. Preparation of L-phosphinothricin by chiral auxiliary method

[0020] The chiral auxiliary group method is to utilize the chiral group to combine with the achiral raw material and use its own steric hindrance to complete the construction of the chiral intermediate in the next reaction.

[0021] Zeiss (Tetrahedron Letters, 1987, 28 (12): 1255-1258) used D-valine methyl ester and glycine to form a bis-lactam imine ether, which was dehydrogenated with n-butyl lithium and then alkylated with β-chloroethyl methyl phosphinate to construct a chiral center, which was further hydrolyzed to obtain L-phosphinothricin with a yield of 51% and an ee value of 79%, as shown in reaction formula (1). Minowa (BullChem Sol Jpn, 1987, 60 (5): 1761-1766) used (S)-2-hydroxy-3-pinene to form a Schiff base with glycine, and then reacted with methyl vinyl phosphine methyl ester to complete the construction of the chiral center, as shown in reaction formula (2).

[0022]

[0023] 5. Preparation of L-phosphinothricin by chiral source method

[0024] The chiral source method for preparing glufosinate is to use natural L-amino acids as raw materials and prepare L-glufosinate through phosphination. Zeiss (Pesticide Science, 1994, 41 (3): 269-277; Tetrahedron, 1992, 48 (38): 8263-8270) used L-glutamic acid partially protected by amino acids as raw materials, prepared L-vinylglycine derivatives through thermal elimination, and then reacted with monobutyl methylphosphite to undergo free radical addition reaction, and hydrolyzed to obtain L-glufosinate with an optical purity of 99.4% ee.

[0025]

[0026] Xue Song XU (Chinese Chemical Letters, 2006, 17(2): 177-179) reported that L-homoserine was first prepared using L-methionine as a chiral source. After ring closure and ring opening, L-homoserine obtained (S)-2-methoxycarbonylamino-4-chlorobutyric acid methyl ester, which underwent Arbuzov reaction with diethyl methylphosphite and was hydrolyzed to obtain L-phosphinothricin ammonium with a total yield of 42.3% and an ee value of 93.5%.

[0027]

[0028] In addition, CN 108516991 also discloses that diethyl methylphosphite and (3S,6S)-3,6-bis(2-haloethyl)-2,5-diketopiperazine undergo high temperature Arbuzov rearrangement to obtain an important intermediate, which is then hydrolyzed to obtain L-phosphinothricin with a yield of 75-93%. The %ee value is not reported.

[0029]

[0030] 6. Preparation of L-phosphinothricin by asymmetric synthesis

[0031] The asymmetric synthesis of L-phosphinothricin ammonium mainly includes asymmetric catalytic hydrogenation, asymmetric Strecker reaction, and asymmetric Michael addition. Zeiss (J Org Chem, 1991, 56: 1783-1788) et al. used 2-carbonyl-4-(hydroxymethylphosphonyl)butyric acid to react with acetamide to prepare (Z)-2-acetylamino-4-(hydroxymethylphosphonyl)but-2-enoic acid, and then asymmetric catalytic hydrogenation reaction was carried out on a chiral phosphorus ligand rhodium catalyst to hydrolyze L-phosphinothricin ammonium. The ee value is above 90%.

[0032]

[0033] WO2008035687A1 derives the aldehyde group of methyl methyl propionaldehyde phosphonate to obtain aromatic imine compounds, uses Jacobsen catalyst to catalyze the asymmetric Strecker reaction of the imine with trimethylsilyl cyanide, and then hydrolyzes it to obtain L-phosphinothionimmonium, with an ee value of up to 94%.

[0034]

[0035] CN201510450698 discloses the use of cinchonidine quaternary ammonium salt derivatives to catalyze the preparation of glufosinate. Glycine methyl ester reacts with benzophenone to generate a Schiff base, which then undergoes an asymmetric Michael addition with vinylphosphine and is hydrolyzed to obtain L-glufosinate, with an ee value of up to 81%.

[0036]

[0037] 7. Preparation of L-phosphinothricin by racemic separation method

[0038] US5767309 disclosed in 1998 that quinine and glufosinate ammonium were used to form salts and then crystallized to obtain high-purity L-glufosinate ammonium quinine salt, and then liberated with alkali to obtain L-glufosinate ammonium, with an ee value of up to 99%.

[0039]

[0040] In summary, the racemic resolution method prepares L-phosphinothricin ammonium, and both the bioenzymatic method and the chemical resolution can obtain L-phosphinothricin ammonium with high optical purity, but the D-type phosphorothicin ammonium cannot be well utilized and causes waste. Both the aminotransferase method and the asymmetric hydrogenation method require 2-carbonyl-4-(hydroxymethylphosphonyl)butyric acid as a raw material, but the preparation steps are cumbersome and the yield is low. The chiral auxiliary group induction method and the chiral catalyst catalysis method are based on the suspension phosphorothicin ammonium synthesis route, and the chiral center is constructed using its intermediates. In addition to the expensive chiral catalyst and the racemization of the chiral auxiliary group, the preparation of the key intermediates methyl propionaldehyde phosphonic acid methyl ester and vinyl phosphine is also a difficult problem for industrial production.

[0041] The chiral source stereochemical synthesis of L-phosphinothricin ammonium is the most promising method. However, the synthesis is relatively cumbersome and costly, especially the need for flammable and explosive raw materials such as diethyl methylphosphite. In particular, the Arbuzov rearrangement reaction requires high-temperature heating above 160°C, which poses a great safety hazard, high energy consumption, and stringent equipment requirements, making it even more difficult to achieve industrial production.

[0042] The above shortcomings and problems restrict the development of L-glufosinate preparation industry. Therefore, it is urgent to seek a rational industrial approach with easy raw materials, simple synthesis, reasonable price, simple conditions, high safety factor and less waste. Summary of the invention

[0043] Objective of the invention: The first objective of the present invention is to provide a simple and easy method for preparing a key intermediate (I) or intermediate (II) of L-glufosinate ammonium. The second objective of the present invention is to provide a feasible method for preparing L-glufosinate ammonium using the intermediate.

[0044] Technical solution: The method for preparing the L-glufosinate-ammonium intermediate of the present invention comprises the following steps:

[0045] (1) (3S,6S)-3,6-bis(2-substituted ethyl)-2,5-diketopiperazine reacts with a metal reagent M to generate a zinc reagent or a palladium reagent of (3S,6S)-3,6-bis(2-metal-substituted ethyl)-2,5-diketopiperazine, or the generated zinc reagent is combined with lithium chloride to form a Turbo Grignard reagent;

[0046] (2) The intermediate (I) is obtained by reacting with the zinc reagent, palladium reagent or Turbo Grignard reagent generated in step (1). The reaction equation is shown in (1):

[0047]

[0048] Among them, R1 is a C1-C5 straight chain or branched alkyl, phenyl, benzyl, X is a halogen element chlorine, bromine or iodine, or a methanesulfonyloxy group (MsO-), a benzenesulfonyloxy group (PhSO3-), or a p-toluenesulfonyloxy group (TsO-); M is metal zinc or palladium chloride, tetrakistriphenylphosphine palladium or dichlorobistriphenylphosphine palladium, or a combination of zinc and palladium chloride, tetrakistriphenylphosphine palladium or dichlorobistriphenylphosphine palladium.

[0049] Furthermore, the By replacing with dimethoxyphosphorus chloride, the intermediate (II) is obtained, and the reaction equation is shown in formula (2):

[0050]

[0051] Furthermore, dimethoxyphosphonium chloride is reacted with a zinc reagent or a palladium reagent of (3S,6S)-3,6-bis(2-metal-substituted ethyl)-2,5-diketopiperazine, and then undergoes an Arbuzov rearrangement reaction to obtain an intermediate (3S,6S)-3,6-bis(2-methyl(methoxy)phosphonoethyl)-2,5-diketopiperazine (II), wherein the temperature of the Arbuzov rearrangement reaction is 25°C to 220°C, and the time of the Arbuzov rearrangement reaction is 0.5 to 36 hours.

[0052] Furthermore, in the reaction equation (1) or (2), the reaction temperature for preparing the intermediate (I) or the intermediate (II) is -78°C to 220°C, and the reaction time is 0.5 to 72 hours.

[0053] Furthermore, the palladium reagent is a compound obtained by reacting (3S,6S)-3,6-bis(2-substituted ethyl)-2,5-diketopiperazine with palladium chloride, tetrakistriphenylphosphine palladium or dichlorobistriphenylphosphine palladium.

[0054] Furthermore, in the reaction equation, (3S,6S)-3,6-bis(2-metal-substituted ethyl)-2,5-diketopiperazine and Or the molar ratio of dimethoxyphosphorus chloride is 1:1-6.

[0055] Furthermore, the zinc reagent of (3S,6S)-3,6-bis(2-metal substituted ethyl)-2,5-diketopiperazine is complexed with lithium chloride to form a Turbo Grignard reagent, and the molar ratio of the zinc reagent of (3S,6S)-3,6-bis(2-metal substituted ethyl)-2,5-diketopiperazine to anhydrous lithium chloride is 1:0.01-10.

[0056] Furthermore, in the formula (1) or (2), the reaction solvent is one or more combinations of dialkyl ethers, cycloalkyl ethers, glycol diethers, alkanes, aromatic hydrocarbons, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, hexamethylphosphoric triamide, acetone, petroleum ether, silicone ether, and gasoline solvents.

[0057] Furthermore, the dialkane ether is ethyl ether, diisopropyl ether, di-n-butyl ether, methyl ethyl ether or methyl isopropyl ether, the cycloalkane ether is tetrahydrofuran, 2-methyltetrahydrofuran or dioxane, the ethylene glycol diether is ethylene glycol dimethyl ether or ethylene glycol diethyl ether, the alkanes are n-pentane, n-hexane, cyclopentane, cyclohexane or decahydronaphthalene, and the aromatic hydrocarbons are benzene, toluene, xylene, trimethylbenzene, ethylbenzene or diethylbenzene.

[0058] The intermediates (I) and (II) obtained by the preparation method of the present invention are used in the preparation of the herbicide L-phosphinothricin ammonium.

[0059] Furthermore, L-glufosinate ammonium is obtained by cleavage and amination of the L-glufosinate ammonium intermediate described in the present invention.

[0060] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0061] (1) The present invention provides a simple and easy method for preparing a key intermediate (I) or intermediate (II) of L-phosphinothricin.

[0062] (2) The intermediate (I) or the intermediate (II) is subjected to cracking and ammoniation in an acidic medium to obtain L-phosphinothricin. The preparation method has many advantages such as a simple process route, superior synthesis cost, safe and reliable operation, and obvious environmental advantages. The reaction chemical yield of the preparation method reaches more than 82%, and the optical purity can reach more than 98% ee. After amplification verification, it is a simple, safe and feasible method for preparing L-phosphinothricin. DETAILED DESCRIPTION

[0063] The present invention is further described in detail below through specific implementation examples.

[0064] Example 1

[0065] (1) Preparation of (3S,6S)-3,6-bis(2-chlorozincethyl)-2,5-diketopiperazine tetrahydrofuran solution

[0066] Under nitrogen protection, add 525.6g of active zinc powder and 280mL of tetrahydrofuran to a 2L four-necked bottle. Under nitrogen protection, heat to 65°C, add 2mL of dibromoethane to initiate, and then add 1200mL of tetrahydrofuran solution containing 826g of (3S, 6S)-3,6-bis(2-chloroethyl)-2,5-diketopiperazine under reflux, keep at 65°C and continue to react for 12h to obtain (3S, 6S)-3,6-bis(2-chlorozincethyl)-2,5-diketopiperazine tetrahydrofuran solution.

[0067] (2) Preparation of (3S,6S)-3,6-bis(2-methyl(methoxy)phosphonoethyl)-2,5-diketopiperazine

[0068] Under nitrogen protection, 410 g of methyl (methoxy)phosphonyl chloride and 420 mL of tetrahydrofuran were added to a 3 L four-necked flask, and the temperature was lowered to -25 °C. The tetrahydrofuran solution of (3S, 6S)-3,6-bis(2-(chlorozincethyl)-2,5-diketopiperazine) obtained in the above experiment (1) was added dropwise. After the addition was completed, the temperature was slowly raised to 25 °C and the reaction was kept warm for 10 h. First, the tetrahydrofuran was recovered by vacuum distillation, and then 50 mL of ethyl acetate was added for slurrying. A saturated ammonium chloride solution (33 g / 100 mL) was added dropwise to quench the reaction. The crude solid was filtered and recrystallized to obtain 1028.6 g of (3S, 6S)-3,6-bis(2-methyl (methoxy)phosphonylethyl)-2,5-diketopiperazine. The purity of the crude solid was 96% by HPLC analysis, and the reaction yield was 91%.

[0069] Example 2

[0070] (1) Preparation of (3S,6S)-3,6-bis(2-chlorozincethyl)-2,5-diketopiperazine tetrahydrofuran solution

[0071] The experimental process is the same as step (1) in Example 1.

[0072] (2) Preparation of (3S,6S)-3,6-bis(2-methyl(methoxy)phosphonoethyl)-2,5-diketopiperazine

[0073] Under nitrogen protection, add the tetrahydrofuran solution of (3S,6S)-3,6-bis(2-chlorozincethyl)-2,5-diketopiperazine obtained in the above experiment (1), 119g tetratriphenylphosphine palladium, 45g potassium iodide, 63.7g tetrabutylammonium iodide, and 300mL tetrahydrofuran to a 3L four-necked bottle. Add 408g methyl(methoxy)phosphonyl chloride and 380mL tetrahydrofuran under stirring, slowly heat to 60°C, and keep warm for 8h. First, vacuum distill tetrahydrofuran to recover, then add 50mL dichloroethane to slurry, drop 100mL of dilute hydrochloric acid solution (3mol / L) to quench the reaction, filter, and recrystallize from isopropanol to obtain 1005.8g (3S,6S)-3,6-bis(2-methyl(methoxy)phosphonylethyl)-2,5-diketopiperazine, with a HPLC analysis purity of 95% and a reaction yield of 89%.

[0074] Example 3

[0075] (1) Preparation of Metal Reagent Toluene Solution of (3S,6S)-3,6-Bis(2-chlorozincethyl)-2,5-diketopiperazine

[0076] Under nitrogen protection, add 525.6g of active zinc powder, 15g of potassium iodide, 330g of lithium chloride and 220mL of toluene to a 2L four-necked bottle. Under nitrogen protection, heat to 145°C and dehydrate azeotropically for 2h. Cool to 55°C, add 2mL of dibromoethane and 0.2mL of trimethylsilyl chloride to initiate, add 826g of (3S, 6S)-3,6-bis(2-chloroethyl)-2,5-diketopiperazine after initiation, add 1200mL of toluene, keep at 100°C and continue to react for 8h to obtain a metal reagent toluene solution of (3S, 6S)-3,6-bis(2-chlorozincethyl)-2,5-diketopiperazine.

[0077] (2) Preparation of (3S,6S)-3,6-bis(2-methyl(methoxy)phosphonoethyl)-2,5-diketopiperazine

[0078] Under nitrogen protection, add 410g of methyl (methoxy)phosphonyl chloride and 400mL of toluene to a 3L four-necked flask, cool to -10°C, and drop the metal reagent toluene solution of (3S, 6S)-3,6-bis(2-chlorozincethyl)-2,5-diketopiperazine obtained in the above experiment (1). After the dropwise addition, slowly raise the temperature to 25°C and keep the temperature for 8h. First, vacuum distill the toluene to recover it, pass the measured amount of hydrogen chloride, filter, and recrystallize to obtain 971.5g of (3S, 6S)-3,6-bis(2-methyl (methoxy)phosphonylethyl)-2,5-diketopiperazine solid, with a purity of 96% according to HPLC analysis and a reaction yield of 86%.

[0079] Example 4

[0080] (1) Preparation of (3S,6S)-3,6-bis(2-metallated ethyl)-2,5-diketopiperazine DMF solution

[0081] Under nitrogen protection, add 525.6g of active zinc powder, 340g of anhydrous lithium chloride, 110g of tetrakistriphenylphosphine palladium, 42.3g of potassium iodide and 220mL of N,N-dimethylformamide (DMF) to a 2L four-necked bottle. Under nitrogen protection, heat to 65°C, add 2mL of dibromoethane and 0.2mL of trimethylsilyl chloride to initiate, cool after initiation, add 1625.6g of (3S, 6S)-3,6-bis(2-toluenesulfonyloxyethyl)-2,5-diketopiperazine and 1600mL of N,N-dimethylformamide, keep at 120°C and continue to react for 8h to obtain (3S, 6S)-3,6-bis(2-metal substituted ethyl)-2,5-diketopiperazine DMF solution.

[0082] (2) Preparation of (3S,6S)-3,6-bis(2-methyl(ethoxy)phosphonoethyl)-2,5-diketopiperazine

[0083] Under nitrogen protection, add 440g of methyl (ethoxy) phosphonyl chloride and 380mL of DMF to a 3L four-necked flask, cool to -15°C, and drop the (3S, 6S)-3,6-bis (2-metal substituted ethyl) -2,5-diketopiperazine DMF solution obtained in the above experiment (1). After the dropwise addition, slowly raise the temperature to 25°C and keep the temperature for 8h. First, vacuum distill the DMF to recover it, drop 100mL of 3mol / L dilute hydrochloric acid solution to quench the reaction, filter, and recrystallize to obtain 982.6Kg of (3S, 6S) -3,6-bis (2-methyl (ethoxy) phosphonylethyl) -2,5-diketopiperazine solid, the HPLC analysis purity is 95%, and the reaction yield is 88%.

[0084] Example 5

[0085] (1) Preparation of (3S,6S)-3,6-bis(2-metallated ethyl)-2,5-diketopiperazine DMF solution

[0086] Under nitrogen protection, add 525.6g of active zinc powder, 110g of tetrakistriphenylphosphine palladium, 42.3g of potassium iodide, and 260mL of N,N-dimethylformamide (DMF) to a 2L four-necked bottle. Under nitrogen protection, heat to 65°C, add a small amount of 0.8g of iodine and 2mL of dibromoethane to initiate, cool slightly after initiation, drop 1600mL of DMF solution containing 1625.6g of (3S,6S)-3,6-bis(2-toluenesulfonyloxyethyl)-2,5-diketopiperazine, keep at 120°C and continue to react for 8h to obtain (3S,6S)-3,6-bis(2-chlorozincethyl)-2,5-diketopiperazine DMF solution.

[0087] (2) Preparation of (3S,6S)-3,6-bis(2-methyl(methoxy)phosphonoethyl)-2,5-diketopiperazine

[0088] Under nitrogen protection, add 410g of dimethoxyphosphoryl chloride and 400mL of N,N-dimethylformamide (DMF) to a 3L four-necked flask, cool to -35°C, and drop the (3S,6S)-3,6-bis(2-metal substituted ethyl)-2,5-diketopiperazine DMF solution obtained in the above experiment (1). After the dropwise addition is completed, slowly heat to 25°C and keep warm for 8h. Cool to -10°C, pass 10.9g of hydrogen chloride to quench the reaction, filter to remove salt, heat the mother liquor to 160°C, and react for 4h. Cool to obtain 982.6g of (3S,6S)-3,6-bis(2-methyl(methoxy)phosphonylethyl)-2,5-diketopiperazine solid, with a HPLC analysis purity of 95% and a reaction yield of 86%.

[0089] Example 6L- Preparation of Glufosinate

[0090] Under nitrogen protection, add 986g (3S, 6S) -3,6-bis (2-methyl (methoxy) phosphonoethyl) -2,5-diketopiperazine solid and 1280mL 30% hydrochloric acid to a 2L four-necked bottle, heat to 100 ° C, and keep warm for 8 hours. First, vacuum distill to remove the dilute hydrochloric acid for recovery, add 1600mL methanol, pass ammonia to alkalinity, heat and extract the solid three times with triple methanol while hot, combine and add activated carbon to reflux for decolorization, vacuum remove part of the methanol, add 18mL water, stand for crystallization, centrifuge and dry to obtain 982.6g L-phosphinothion white solid, HPLC analysis purity 96%, reaction chemical yield 88%, optical purity 98% ee.

Claims

1. A method for preparing an L-phosphinothricin intermediate, characterized in that: The steps include: (1) (3S,6S)-3,6-bis(2-substituted ethyl)-2,5-diketopiperazine reacts with a metal reagent M to generate a zinc reagent or a palladium reagent of (3S,6S)-3,6-bis(2-metal-substituted ethyl)-2,5-diketopiperazine, or the generated zinc reagent is combined with lithium chloride to form a Turbo Grignard reagent; (2) The intermediate (I) is obtained by reacting with the zinc reagent, palladium reagent or Turbo Grignard reagent generated in step (1). The reaction equation is shown in (1): Wherein R1 is a C1-C5 straight or branched alkyl, phenyl or benzyl group; X is a halogen element such as chlorine, bromine or iodine, or a methanesulfonyloxy group, a benzenesulfonyloxy group or a p-toluenesulfonyloxy group; and M is metal zinc or palladium chloride, tetrakistriphenylphosphine palladium or dichlorobistriphenylphosphine palladium, or a combination of zinc and palladium chloride, tetrakistriphenylphosphine palladium or dichlorobistriphenylphosphine palladium.

2. The method for preparing the L-phosphinothricin-ammonium intermediate according to claim 1, characterized in that: Said By replacing with dimethoxyphosphorus chloride, the intermediate (II) is obtained, and the reaction equation is shown in formula (2):

3. The method for preparing the L-phosphinothricin-ammonium intermediate according to claim 2, characterized in that: Dimethoxyphosphonium chloride reacts with zinc reagent or palladium reagent of (3S,6S)-3,6-bis(2-metal substituted ethyl)-2,5-diketopiperazine, and then undergoes Arbuzov rearrangement reaction to obtain intermediate (3S,6S)-3,6-bis(2-methyl(methoxy)phosphonoethyl)-2,5-diketopiperazine (II), wherein the temperature of the Arbuzov rearrangement reaction is 25°C to 220°C, and the time of the Arbuzov rearrangement reaction is 0.5 to 36 hours.

4. The method for preparing the L-phosphinothricin-ammonium intermediate according to claim 1 or 2, characterized in that: In the reaction equation (1) or (2), the reaction temperature for preparing the intermediate (I) or the intermediate (II) is -78°C to 220°C, and the reaction time is 0.5 to 72 hours.

5. The method for preparing the L-phosphinothricin-ammonium intermediate according to claim 1 or 2, characterized in that: In the reaction equation, the zinc reagent or palladium reagent or Turbo Grignard reagent of (3S,6S)-3,6-bis(2-metal substituted ethyl)-2,5-diketopiperazine and Or the molar ratio of dimethoxyphosphorus chloride is 1:1-6.

6. The method for preparing the L-phosphinothricin-ammonium intermediate according to claim 1 or 2, characterized in that: The zinc reagent of (3S,6S)-3,6-bis(2-metal substituted ethyl)-2,5-diketopiperazine is combined with lithium chloride to form a Turbo Grignard reagent, and the molar ratio of the zinc reagent of (3S,6S)-3,6-bis(2-metal substituted ethyl)-2,5-diketopiperazine to lithium chloride is 1:0.01-10.

7. The method for preparing the L-phosphinothricin-ammonium intermediate according to claim 1 or 2, characterized in that: In the formula (1) or (2), the reaction solvent is one or more combinations of dialkyl ethers, cycloalkyl ethers, glycol diethers, alkanes, aromatic hydrocarbons, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, hexamethylphosphoric triamide, acetone, petroleum ether, silicone ether, and gasoline solvents.

8. The method for preparing the L-phosphinothricin-ammonium intermediate according to claim 7, characterized in that: The dialkane ether is ethyl ether, diisopropyl ether, di-n-butyl ether, methyl ethyl ether or methyl isopropyl ether, the cycloalkane ether is tetrahydrofuran, 2-methyltetrahydrofuran or dioxane, the ethylene glycol diether is ethylene glycol dimethyl ether or ethylene glycol diethyl ether, the alkanes are n-pentane, n-hexane, cyclopentane, cyclohexane or decahydronaphthalene, and the aromatic hydrocarbons are benzene, toluene, xylene, trimethylbenzene, ethylbenzene or diethylbenzene.

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