Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
  • A01P13/00—Herbicides; Algicides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
  • C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
  • A01N57/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds
  • A01N57/20—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds containing acyclic or cycloaliphatic radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• This disclosure involves optically active glufosinate salts including L- glufosinate-D-lysine salt, D-glufosinate-D-lysine salt, L-glufosinate-L-lysine salt, and D- glufosinate-L-lysine salt.
• This disclosure also involves methods of preparing these salts from D,L-glufosinate and optically active lysine and use of these salts in agriculture to control unwanted plants, including in the propagation of transgenic crop plants.
• 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.
• Glufosinate-ammonium belongs to the group of organophosphorus herbicides, which is one of the three major non-selective herbicides in the world.
• organophosphorus herbicides which is one of the three major non-selective herbicides in the world.
• 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.
• 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 world.
• L-glufosinate There are two optical isomers of glufosinate, L- and D-glufosinate, but only L-configuration has an herbicidal effect. D-configuration has almost no herbicidal activity. L-glufosinate, also known as glufosinate-P, has twice the herbicidal activity of common, racemic glufosinate. Thus, the application dosage is only 50% of glufosinate per acre for L-glufosinate compared to D, L-glufosinate, and the application cost is basically the same for both.
• 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.
• 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.
• the biological synthesis method is mainly based on the keto acid 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.
• PPO 2-oxo-4-(hydroxymethylphosphinyl)butyric acid
• 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.
• the biological resolution method involves ketoacid and acylation methods, both featuring the involvement of biological enzymes, such as US9834802 and CN108690854.
• 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 overall industrialization cost, it is rare to see commercialized and industrialized products in large quantities on the market.
• the chemical resolution method mainly involves the resolution of the enantiomeric isomers of D, L-glufosinate or its salts with different chemical resolution agents such as EP0499376A1, DE4407197A, EP16204249A, EP16204245A, and CN112979701 A, which respectively disclose the use of bromocamphorsulfonic acid, quinine, cinchonine, ephedrine, and ligands to resolve the enantiomeric isomers of D,L- glufosinate.
• different chemical resolution agents such as EP0499376A1, DE4407197A, EP16204249A, EP16204245A, and CN112979701 A, which respectively disclose the use of bromocamphorsulfonic acid, quinine, cinchonine, ephedrine, and ligands to resolve the enantiomeric isomers of D,L- glufosinate.
• 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.
• the present disclosure provides optically active, glufosinate-lysine salts and methods for their preparation.
• the optically active, glufosinate-lysine salts include L-glufosinate-D-lysine salt, D-glufosinate-D-lysine salt, L-glufosinate-L-lysine salt, and D-glufosinate-L-lysine salt.
• the disclosure is directed to a method of producing an optically active glufosinate-lysine salt.
• the method comprises a) mixing an enantiomeric mixture of D,L- glufosinate or its salt, a resolution agent comprising optically active lysine, and a solvent to facilitate a resolution reaction that produces a resolution reaction mixture comprising the optically active glufosinate-lysine salt; b) crystallizing the glufosinate-lysine salt; and c) separating the glufosinate-lysine salt from the resolution reaction mixture.
• the optically active glufosinate-lysine salt is selected from the group consisting of L-glufosinate-D-lysine salt, D-glufosinate-D-lysine salt, L-glufosinate-L- lysine salt, and D-glufosinate-L-lysine salt.
• the resolution solvent for the preparation of D-glufosinate-D-lysine salt or L-glufosinate-L-lysine salt is an anhydrous system.
• the resolution solvent for the preparation of L-glufosinate-D-lysine salt or D-glufosinate-L-lysine salt is an aqueous system.
• L-glufosinate-D-lysine salt is a compound of the structure of formula
• D-glufosinate-D-lysine salt is a compound of the structure of formula I
• L-glufosinate-L-lysine salt is a compound of the structure of formula I
• D-glufosinate-L-lysine salt is a compound of the structure of formula
• Figure 1 depicts NMR 13 C of D-glufosinate-L-lysine salt (IV) prepared in Example 1.
• Figure 2 depicts NMR 'H of D-glufosinate-L-lysine salt (IV) prepared in Example 1.
• Figure 3 depicts NMR 13 C of L-glufosinate-D-lysine salt (I) prepared in Example 3;
• Figure 4 depicts NMR 'H of L-glufosinate-D-lysine salt (I) prepared in Example 3.
• Figure 5 depicts NMR 13 C of L-glufosinate-L-lysine salt (III) prepared in Example 4.
• Figure 6 depicts NMR 'H of L-glufosinate-L-lysine salt (III) prepared in Example 4.
• Figure 7 depicts NMR 13 C of D-glufosinate-D-lysine salt (II) prepared in Example 5.
• Figure 8 depicts NMR 'H of D-glufosinate-D-lysine salt (II) prepared in Example 5.
• Corresponding reference characters indicate corresponding parts throughout the drawings.
• optically active amino acid salts include L- glufosinate-D-lysine salt, D-glufosinate-D-lysine salt, L-glufosinate-L-lysine salt, and D- glufosinate-L-lysine salt.
• L-glufosinate-D-lysine salt described is a compound of the structure of formula (I).
• D-glufosinate-L-lysine salt described is a compound of the structure
• the present invention also provides a simple and workable method for the preparation of optically active amino acid salts.
• the preparation method comprises: using D,L-glufosinate or its salt as raw material, using D-lysine or L-lysine as the resolution agent, and obtaining L-glufosinate-D-lysine salt, D-glufosinate-D-lysine salt,
• Glufosinate and lysine can form stable salt compounds in suitable solvents and crystallize as solids to obtain optically active glufosinate-lysine salts.
• L-glufosinate-L-lysine salt (III) when L-lysine is used as the resolution agent, L-glufosinate-L-lysine salt (III) has lower solubility and can be crystallized more easily, so the resolution obtained is L-glufosinate-L-lysine salt (III).
• D-lysine when D-lysine is used as the resolution agent, D-glufosinate-D-lysine salt (II) has lower solubility and can be crystallized more easily, so the resolution obtained is D- glufosinate-D-lysine salt (II).
• D-glufosinate-L-lysine salt (IV) has lower solubility and crystallize more easily, so the resolution results in D-glufosinate-L-lysine salt (IV).
• L-glufosinate-D-lysine salt (I) has lower solubility and crystallize more easily, so the resolution results in L-glufosinate-D-lysine salt (I).
• optically active glufosinate can be obtained from the resolution product or resolution mother liquor obtained by the present invention by methods well known to those skilled in the art. These methods can include filtration and centrifugation.
• D001 macro-reticular type ion exchange resin to separate L-glufosinate-D-lysine salt.
• the resin can be put in the chromatography column, and 5% ammonia solution can be used to substitute the positive ions in the resin with ammonium ions.
• a water solution of a suitable amount of L-glufosinate-D-lysine can be prepared, and the ammonium ion loaded resin can be used for column chromatography. It can then be washed with pure water to obtain high-purity L- glufosinate-ammonium water solution, and then L-glufosinate-ammonium can be obtained through crystallization.
• D-lysine obtained After washing with pure water, 5% ammonia solution can be used to wash out the absorbed D-lysine in the resin to obtain a D-lysine water solution, and D-lysine can be obtained after crystallization. D-lysine obtained this way can be used in the resolution reaction disclosed in this patent. Lysine obtained through column chromatography does not change its optical activity and has a high rate of recovery.
• the molar ratio of the L-configuration to the D-configuration in the enantiomeric mixture of the raw material D,L-glufosinate or its salt can be from 0.25: 1 to 4: 1.
• L-glufosinate lysine amino acid salts (I and III) are prepared and the content of D-glufosinate or D-glufosinate salt in the raw material is too high, the resolution process cannot crystallize the salt of L-glufosinate well.
• the products obtained by resolution are still mostly D-glufosinate amino acid salts (II and IV), which need to be recrystallized several times to obtain the products rich in I and III structures. In addition, the operation is time consuming, and the yield is very low.
• D-configuration- rich raw materials are less suitable for the preparation of L-glufosinate lysine salts (I and III).
• L-configuration-rich raw materials are also less suitable for the preparation of D-glufosinate lysine salts (II and IV).
• the product of glufosinate rich in the single configuiration can be obtained by simple recrystallization without the need of resolution reaction.
• the molar ratio of the L-configuration to the D- configuration in the raw material D,L-glufosinate or its salt is further preferred to be 0.3: 1 to 3:l.
• the resolution agent is optically active lysine
• D,L-glufosinate reacts with the corresponding optically active lysine to form optically active glufosinate-lysine salts, which are further separated according to their differences in solubility in the resolution system to obtain the corresponding optically active glufosinate-lysine salts.
• the molar ratio of the D,L-glufosinate or its salt to the resolution agent lysine can be from 1 :0.2 to 1 :2.
• the amount of optically active lysine used for resolution is low, the product yield is low.
• the amount of optically active lysine is large, it does not significantly change the resolution result and wastes the resolution agent, increases the difficulty of post-treatment, and causes unnecessary pollution. Therefore, the molar ratio of D,L-glufosinate or its salt to the resolution agent lysine is further preferred to be 1 :0.4 to 1 : 1.5.
• the resolution solvent can be a mixture of two or more solvents selected from the group consisting of Ci to C4 mono- or polyols, dimethylformamide, acetone, acetonitrile, methyl ethylene glycol, and water.
• the Ci to C4 mono- or polyols can be one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, propylene glycol, butylene glycol, or glycerol.
• the volume of water in the resolution solvent can be from 0 to 70%.
• the Ci to C4 mono-alcohol or polyol is one or more of methanol, ethanol, isopropanol, ethylene glycol, or propylene glycol.
• the resolution solvent can be an anhydrous system, preferably comprising one or more of ethanol, isopropanol, methyl ethylene glycol, acetonitrile, and dimethylformamide, and with propylene glycol or glycerol.
• the resolution solvent can be an aqueous system, preferably comprising one or more of methanol, ethanol, isopropanol, tert-butanol, methyl ethylene glycol, and acetone with water.
• the volume of water in the resolution solvent can be from 0 to 70%.
• the percentage of water is 0%.
• the solubility of both salts formed by D,L-glufosinate enantiomeric isomers and optically active lysine during the resolution process is relatively large in the resolution solvent, and the difference in solubility is small.
• the resolution effect is poor, and the resolution yield is extremely low, which is less suitable for the resolution reaction.
• the volume of water in the resolution solvent is further preferred to be 0-50%.
• the volume of the resolution solvent can be lmL-20mL/g of raw material, i.e. 1g of D,L-glufosinate or its salt requires lmL-20mL of resolution solvent.
• the used resolution solvent is lower than ImL/g of raw material, the solubility of the salt formed by the corresponding isomer of the raw material and the chiral amino acid is relatively low, and the optical purity of the product in the crystallized solid is low.
• the solvent volume is higher than 20 mL/g of raw material, the optical purity of the crystallized product is better, but the yield is extremely low.
• the volume of the resolution solvent is further preferred to be 3mL-18mL/g of raw material.
• the temperature of the resolution reaction can be 0-90°C.
• the difference in solubility of the salt formed by the enantiomeric isomer and the chiral amino acid is large, and a product with high optical purity can be obtained.
• the solubility of both is high under high temperature conditions, but the yield is extremely low; at low temperature, the difference in solubility of both is small, and the product obtained has poor optical purity.
• the resolution temperature of the resolution method is further preferred to be 15-65°C.
• the addition of the target product’s crystal seed can speed up the crystallization process; the product crystal can also be obtained without the addition of the corresponding crystal seed but with much longer crystallization time.
• the present invention has the following advantages.
• the L-glufosinate-D-lysine salt, D-glufosinate-D-lysine salt, L- glufosinate-L-lysine salt and D-glufosinate-L-lysine salt in the present invention are optically active amino acid salts with stable properties, which can be separated from the two amino acids by a simple method to obtain a single optically pure glufosinate (D- configuration or L-configuration) or to prepare glufosinate of different chiral purity as needed.
• the resolution agent used in the present invention is optically active lysine, and the raw material is widely available and inexpensive.
• the method of the present disclosure for preparing optically active amino acid salts using the resolution done in the same resolution solvent system, is simple to prepare and highly operative, and can prepare L-glufosinate at low cost.
• L-glufosinate-D-lysine salt (I) crystal After stirring, 0.1 g of L-glufosinate-D-lysine salt (I) crystal were added, and the mixture was slowly cooled down to room temperature for crystallization while stirring. After 15h crystallization, the crystallized mixture was filtered at room temperature, and the filtered solids were dried to obtain L-glufosinate-D- lysine salt 16.2g with a yield of 33% and HPLC analysis L-glufosinate optical purity of 94.2%.
• L-glufosinate-D-lysine salt (I) crystal After stirring, 0.1 g of L-glufosinate-D-lysine salt (I) crystal were added, and the mixture was slowly cooled down to room temperature for crystallization while stirring. After 15h crystallization, the crystallized mixture was filtered at room temperature, and the filtered solids were dried to obtain L-glufosinate-D- lysine salt 16.2g with

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