Preparation method of refined glufosinate-ammonium

Abstract

The invention provides a preparation method of refined glufosinate-ammonium, which comprises the following steps: a) converting a compound as shown in a formula II or a salt thereof and a protective reagent into a compound as shown in a formula III in a first organic solvent; in the formula, R1 is alkyl with 1 to 12 carbon atoms; and b) converting the compound as shown in the formula III and methyl phosphite into a compound as shown in a formula IV in a second organic solvent through an Abrchiff reaction, and then converting into a compound as shown in a formula I or a salt thereof through hydrolysis to obtain refined glufosinate-ammonium. Compared with the prior art, the preparation method provided by the invention has the advantages that specific raw materials are selected to be matched with specific process step conditions and parameters, overall better interaction is realized, glufosinate-ammonium containing enantiomers in all proportions is successfully prepared, sulfur-containing raw materials and reagents do not need to be used, the three wastes are few, the operation is simple, and the potential industrialization value is realized.

Description

Technical Field

[0001] The invention relates to the technical field of fine chemical industry, and more specifically to a method for preparing refined glufosinate ammonium. Background Art

[0002] Glufosinate ammonium, also known as L-type glufosinate ammonium, is a broad-spectrum, contact-type, and lethal herbicide. As an L-type amino acid isolated from the fermentation broth of biological bacteria by Bayer AG of Germany and Meiji Confectionery Co., Ltd. of Japan in the 1970s, it can bind to the active site of glutamine synthetase (GS), inhibit glutamine synthesis, lead to excessive accumulation of ammonia in plants, nitrogen metabolism disorders, disintegration of chloroplasts, thereby inhibiting photosynthesis and ultimately leading to plant death. Compared with glufosinate ammonium, L-glufosinate has the advantages of higher herbicidal activity, less dosage, and more environmental friendliness.

[0003] In 2016, patent CN106083922A disclosed a method of synthesizing L-homoserine lactone hydrogen halide using L-methionine and α-halogenated carboxylic acid as reaction raw materials, promoting the reaction through a quaternary ammonium salt phase transfer catalyst, protecting the amino group, and then using dihalogenated sulfoxides, triphosgene (BTC) and other halogenating agents for ring opening halogenation, and then reacting with methylphosphite diester under the action of a catalyst through an Abuzov reaction, hydrolyzing under acidic conditions to obtain refined glufosinate ammonium, with a total yield of 69.2%. The starting raw material of this method is the sulfur-containing compound L-methionine, and there are many sulfur-containing wastes during the synthesis process, and the amino group needs to be protected, which increases the synthesis cost.

[0004] The synthetic route is as follows:

[0005]

[0006] In 2021, patent WO2021143712 disclosed a method using L-homoserine lactone hydrochloride as the starting material, chlorinating with thionyl chloride, neutralizing with an inorganic base, purifying and separating to obtain chlorohomoserine ethyl ester, and then reacting with diethyl methylphosphonate through the Abzov reaction, and hydrolyzing under acidic conditions to obtain refined glufosinate ammonium, with a total yield of 48.6%. This method theoretically requires 2 equivalents of thionyl chloride, and produces sulfur-containing waste gas, hydrogen chloride and waste salt in the process, which is not friendly to the environment.

[0007] The synthetic route is as follows:

[0008]

[0009] In summary, how to solve the problems of complex operation, three wastes treatment, low yield, etc. in the synthesis process of refined glufosinate ammonium is of great significance for the clean production of refined glufosinate ammonium and the improvement of the process level. Summary of the invention

[0010] In view of this, the object of the present invention is to provide a method for preparing refined glufosinate ammonium, which can solve a series of problems in the prior art such as long reaction steps, low yield, and more three wastes.

[0011] The present invention provides a method for preparing refined glufosinate-ammonium, comprising the following steps:

[0012] a) converting the compound represented by formula II or its salt with a protecting agent in a first organic solvent into the compound represented by formula III;

[0013]

[0014] Among them, R 1 C1~C 12 alkyl;

[0015] b) converting the compound represented by formula III and methylphosphite into the compound represented by formula IV by Abzov reaction in a second organic solvent, and then converting it into the compound represented by formula I or its salt by hydrolysis to obtain refined glufosinate;

[0016]

[0017] Preferably, the R 1 It is methyl, ethyl, propyl, isopropyl, n-butyl, pentyl or octyl.

[0018] Preferably, in step a), the first organic solvent is selected from one or more of toluene, tetrahydrofuran, dichloromethane, 1,4-ethylene oxide, 1,2-dichloroethane, methyl tert-butyl ether and ethyl acetate.

[0019] Preferably, the protective agent in step a) is phosgene, diphosgene, triphosgene or methyl chloroformate;

[0020] The molar ratio of the protective agent to the compound represented by formula II or its salt is (0.3-3):1.

[0021] Preferably, the temperature of the conversion in step a) is 20° C. to 120° C., and the time is 1 h to 8 h.

[0022] Preferably, in step b), the second organic solvent is selected from chlorobenzene, toluene, xylene, mesitylene, ethanol, methanol or no solvent.

[0023] Preferably, the temperature of the Abuzov reaction in step b) is 50° C. to 150° C., and the time is 2 h to 10 h.

[0024] Preferably, the hydrolysis process in step b) is carried out under acidic conditions; the acidic conditions are provided by hydrochloric acid; the concentration of the hydrochloric acid is 5% to 37%.

[0025] Preferably, the hydrolysis temperature in step b) is 25°C to 110°C.

[0026] Preferably, after the hydrolysis in step b), the process further comprises:

[0027] Recrystallization; the crystallization solvent of the recrystallization is methanol, ethanol or acetonitrile.

[0028] The present invention provides a method for preparing refined glufosinate ammonium, comprising the following steps: a) converting a compound represented by formula II or a salt thereof with a protective agent in a first organic solvent to a compound represented by formula III; wherein R 1 C1~C 12 alkyl; b) converting the compound represented by formula III and methylphosphite into the compound represented by formula IV in a second organic solvent through the Abzov reaction, and then converting it into the compound represented by formula I or its salt through hydrolysis to obtain refined glufosinate. Compared with the prior art, the preparation method provided by the present invention selects specific raw materials and matches specific process step conditions and parameters to achieve overall good interaction, successfully prepares glufosinate including all proportions of enantiomers, does not need to use sulfur-containing raw materials and reagents, has less three wastes, is simple to operate, and has potential industrial value. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The refined glufosinate ammonium obtained in Example 3 of the present invention 1 HNMR data;

[0030] Figure 2 HPLC data of refined glufosinate-ammonium obtained in Example 3 of the present invention;

[0031] Figure 3 HPLC data of refined glufosinate-ammonium obtained in Example 4 of the present invention;

[0032] Figure 4 HPLC data of refined glufosinate-ammonium obtained in Example 7 of the present invention;

[0033] Figure 5 HPLC data of refined glufosinate-ammonium obtained in Example 8 of the present invention;

[0034] Figure 6 HPLC data of refined glufosinate-ammonium obtained in Example 10 of the present invention;

[0035] Figure 7 HPLC data of refined glufosinate-ammonium obtained in Example 11 of the present invention;

[0036] Figure 8 , Fig. 9 LC-MS data of raw material II in Example 1 of the present invention;

[0037] Fig.10 , Fig.11 LC-MS data of compound III obtained in Example 1 of the present invention. DETAILED DESCRIPTION

[0038] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0039] The present invention provides a method for preparing refined glufosinate-ammonium, comprising the following steps:

[0040] a) converting the compound represented by formula II or its salt with a protecting agent in a first organic solvent into the compound represented by formula III;

[0041]

[0042] Among them, R 1 C1~C 12 alkyl;

[0043] b) converting the compound represented by formula III and methylphosphite into the compound represented by formula IV by Abzov reaction in a second organic solvent, and then converting it into the compound represented by formula I or its salt by hydrolysis to obtain refined glufosinate;

[0044]

[0045] The present invention provides a method for chemically synthesizing refined glufosinate ammonium, which uses fermentation or chemical synthesis of o-alkanoyl-L-homoserine or its enantiomers or a mixture of enantiomers in all proportions as a starting material, and prepares L-glufosinate acid or D-glufosinate ammonium or a mixture of enantiomers in all proportions through simple protection, abzov, and hydrolysis reactions. It is a completely new synthesis route, and the overall technical route is as follows:

[0046]

[0047] The present invention first converts the compound represented by formula II or its salt into the amino and carboxylic acid protected compound represented by formula III by reacting the compound represented by formula II with a protecting agent in a first organic solvent.

[0048] In the present invention, R 1 C1~C 12 The alkyl group is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, a pentyl group or an octyl group. In a preferred embodiment of the present invention, o-alkanoyl-L-homoserine is used as a raw material.

[0049] In the present invention, the first organic solvent is preferably selected from one or more of toluene, tetrahydrofuran, dichloromethane, 1,4-ethylene oxide, 1,2-dichloroethane, methyl tert-butyl ether, and ethyl acetate, and more preferably tetrahydrofuran and / or toluene. The present invention has no particular limitation on the source of the first organic solvent, and commercially available products known to those skilled in the art can be used.

[0050] In the present invention, the protective agent is preferably phosgene, diphosgene, triphosgene or methyl chloroformate, more preferably triphosgene or methyl chloroformate. The present invention has no special restrictions on the source of the protective agent, and commercially available products well known to those skilled in the art can be used. In a preferred embodiment of the present invention, the triphosgene and diphosgene can be depolymerized without adding substances, and one or more of N,N-dimethylformamide, triethylamine, and pyridine can also be selected.

[0051] In the present invention, the molar ratio of the protecting agent to the compound represented by formula II or its salt is preferably (0.3-3):1, more preferably (0.35-1.5):1.

[0052] In the present invention, the conversion temperature is preferably 20°C to 120°C, more preferably 30°C to 60°C, and even more preferably 50°C to 55°C; the conversion time is preferably 1h to 8h, and more preferably 3h to 6h.

[0053] After obtaining the compound shown in formula III, the present invention converts the compound shown in formula III and methyl phosphite into a compound shown in formula IV in a second organic solvent through an Abzov reaction, wherein the alkyl ester is a characteristic by-product of this type of reaction; regardless of whether the intermediate compound shown in formula IV is separated or not, it is then hydrolyzed and converted into a compound shown in formula I or a salt thereof to obtain refined glufosinate.

[0054] In the present invention, the second organic solvent is preferably selected from chlorobenzene, toluene, xylene, mesitylene, ethanol, methanol or no solvent, more preferably chlorobenzene, toluene or xylene. The present invention has no particular limitation on the source of the second organic solvent, and commercially available products known to those skilled in the art can be used.

[0055] In the present invention, the Abzov reaction can be carried out under Lewis acid catalysis or without catalysis, the temperature is preferably 50°C to 150°C, more preferably 120°C to 150°C, the time is preferably 2h to 10h, more preferably 4h to 8h.

[0056] In the present invention, the hydrolysis process is preferably carried out under acidic conditions; the acidic conditions are preferably provided by hydrochloric acid; the concentration of the hydrochloric acid is preferably 5% to 37%, more preferably 10% to 30%. The present invention has no special restrictions on the source of the hydrochloric acid, and commercially available products known to those skilled in the art can be used.

[0057] In the present invention, the hydrolysis temperature is preferably 25°C to 110°C.

[0058] In the present invention, after the hydrolysis, preferably further comprising:

[0059] Recrystallization: the crystallization solvent of the recrystallization is preferably methanol, ethanol or acetonitrile, more preferably methanol or ethanol. The present invention has no special restrictions on the source of the crystallization solvent, and commercially available products known to those skilled in the art can be used.

[0060] The preparation method provided by the present invention selects specific raw materials and matches specific process step conditions and parameters to achieve overall good interaction: O-alkanoyl-L-homoserine or its enantiomers or a mixture of enantiomers in all proportions is used as a starting raw material, and glufosinate ammonium including enantiomers in all proportions is prepared through a three-step reaction, without the need to use sulfur-containing raw materials and reagents, with less three wastes, simple operation, and potential industrial value; the beneficial effects include: (1) the Abzov reaction produces alkyl esters as a by-product, which can significantly reduce the unit consumption of methylphosphite compared to traditional chloroalkane by-products, and reduce the formation of by-products; (2) the entire process route has a high yield, is simple to operate, has less three wastes, and is green and environmentally friendly.

[0061] The present invention provides a method for preparing refined glufosinate ammonium, comprising the following steps: a) converting a compound represented by formula II or a salt thereof with a protective agent in a first organic solvent to a compound represented by formula III; wherein R 1 C1~C 12 alkyl; b) converting the compound represented by formula III and methylphosphite into the compound represented by formula IV in a second organic solvent through the Abzov reaction, and then converting it into the compound represented by formula I or its salt through hydrolysis to obtain refined glufosinate. Compared with the prior art, the preparation method provided by the present invention selects specific raw materials and matches specific process step conditions and parameters to achieve overall good interaction, successfully prepares glufosinate including all proportions of enantiomers, does not need to use sulfur-containing raw materials and reagents, has less three wastes, is simple to operate, and has potential industrial value.

[0062] In order to further illustrate the present invention, the following examples are provided for detailed description. The raw materials used in the following examples of the present invention are all commercially available products.

[0063] Example 1

[0064] Synthesis of compound III:

[0065]

[0066] To a 1000mL four-necked reaction bottle, 50g of 98% o-acetyl-L-homoserine (0.30mol) and 200mL of tetrahydrofuran were added, 297.7g of 20% triphosgene toluene solution (0.20mol) was prepared and slowly added, the temperature was raised to 50°C and the reaction was carried out for 3 hours. The reaction was detected by LC-MS. After the reaction was completed, ammonia water was added to quench the reaction, and the solvent was evaporated under reduced pressure to obtain a white crude product. The crude product was recrystallized, filtered, and dried to obtain 54.1g of a white solid with a purity of 98% and a yield of 93.2%.

[0067] Example 2

[0068] To a 1000mL four-necked reaction flask, add 50g of 98% o-acetyl-L-homoserine (0.30mol) and 150g of water, stir at room temperature, slowly add 32.2g of sodium carbonate, keep warm for 30 minutes, add 38.1g of 98% methyl chloroformate (0.40mol) dropwise, control the temperature below 30°C during the process, and keep warm for 6 hours after the addition is completed. After the reaction was completed, ether was added for extraction (100 mL * 3). The pH of the aqueous phase was adjusted to 1-2 with 3N hydrochloric acid. The mixture was dried at 60 ° C. The remaining material was extracted with hot ethyl acetate (100 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain a light yellow oil. Ethyl acetate was added to crystallize to obtain a white solid. 500g of 1,2-dichloroethane was added to the white solid to dissolve it, and 50.1g of 98% trichlorophosphine was slowly added dropwise. The temperature was raised to reflux for reaction for 24 hours. LC-MS detected that the reaction was completed, and 48.1g of light yellow oil was obtained by reduced pressure rotary evaporation with a purity of 78% and a yield of 65.9%.

[0069]

[0070] Example 3

[0071] Synthesis of compound IV:

[0072] Under a nitrogen atmosphere, 47.2 g of 98% diethyl methylphosphite (1.2 equivalents), 54.1 g of compound III (Example 1) and 127.5 g of chlorobenzene (4.0 equivalents) were added to a 500 mL four-necked flask, stirred and mixed evenly, and the temperature was raised to 140 ° C for 6 hours. The reaction was detected by LC-MS. After the reaction was completed, the solvent and excess diethyl methylphosphite were removed by reduced pressure evaporation to obtain an oily crude compound IV.

[0073]

[0074] The crude compound IV (Compound IV is calculated at a yield of 100%) is added to a 500mL four-necked reaction bottle, 276mL of a 30% aqueous hydrochloric acid solution is added, the temperature is raised to reflux for hydrolysis, and the reaction is detected by LC-MS. After the reaction is completed, the acid water is removed by rotary evaporation under reduced pressure to obtain a white solid, the pH is adjusted to 3-4, and 45.1g of L-glufosinate ammonium is obtained by recrystallization, with a purity of 96.1%, D:L=2:98, and the total yield of separation is 78.7% calculated based on o-acetyl-L-homoserine. Ammonia is further passed or KOH and NaOH are added to obtain glufosinate ammonium salt and other glufosinate ammonium salts.

[0075]

[0076] Embodiments 4 to 12

[0077] The following table lists the key parameters of different embodiments and comparative examples with reference to Example 3, wherein the raw material o-alkanoyl-L-homoserine represents the preparation of the corresponding compound III and diethyl methylphosphite with o-alkanoyl-L-homoserine through Abzov reaction, hydrolysis, neutralization and purification to obtain the separation yield, and the reaction process is controlled by LC-MS.

[0078] Table 1

[0079]

[0080]

[0081] a In the Abuzov reaction, 0.1 equivalent of zinc chloride catalyst is added, the reaction temperature is 140°C, and the reaction time is 3 hours.

[0082] Characterization map see Figures 1 to 11 .

[0083] The above description of the disclosed embodiments enables those skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for preparing refined glufosinate-ammonium, comprising the following steps: a) converting the compound represented by formula II or its salt with a protecting agent in a first organic solvent into the compound represented by formula III; Among them, R 1 C1~C 12 alkyl; b) converting the compound represented by formula III and methylphosphite into the compound represented by formula IV by Abzov reaction in a second organic solvent, and then converting it into the compound represented by formula I or its salt by hydrolysis to obtain refined glufosinate; 2. The preparation method according to claim 1, characterized in that: The R 1 It is methyl, ethyl, propyl, isopropyl, n-butyl, pentyl or octyl.

3. The preparation method according to claim 1, characterized in that: In step a), the first organic solvent is selected from one or more of toluene, tetrahydrofuran, dichloromethane, 1,4-ethylene oxide, 1,2-dichloroethane, methyl tert-butyl ether and ethyl acetate.

4. The preparation method according to claim 1, characterized in that: The protective agent in step a) is phosgene, diphosgene, triphosgene or methyl chloroformate; The molar ratio of the protective agent to the compound represented by formula II or its salt is (0.3-3):

1.

5. The preparation method according to claim 1, characterized in that: The temperature of the conversion in step a) is 20° C. to 120° C., and the time is 1 h to 8 h.

6. The preparation method according to claim 1, characterized in that: In step b), the second organic solvent is selected from chlorobenzene, toluene, xylene, mesitylene, ethanol, methanol or no solvent.

7. The preparation method according to claim 1, characterized in that: The temperature of the Abuzov reaction in step b) is 50° C. to 150° C., and the time is 2 h to 10 h.

8. The preparation method according to claim 1, characterized in that: The hydrolysis process in step b) is carried out under acidic conditions; the acidic conditions are provided by hydrochloric acid; the concentration of the hydrochloric acid is 5% to 37%.

9. The preparation method according to claim 1, characterized in that: The hydrolysis temperature in step b) is 25°C to 110°C.

10. The preparation method according to claim 1, characterized in that: After the hydrolysis in step b), the method further comprises: Recrystallization; the crystallization solvent of the recrystallization is methanol, ethanol or acetonitrile.

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