WO2024067610A1 - 利用膦试剂制备l-草铵膦的方法 - Google Patents

利用膦试剂制备l-草铵膦的方法 Download PDF

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WO2024067610A1
WO2024067610A1 PCT/CN2023/121636 CN2023121636W WO2024067610A1 WO 2024067610 A1 WO2024067610 A1 WO 2024067610A1 CN 2023121636 W CN2023121636 W CN 2023121636W WO 2024067610 A1 WO2024067610 A1 WO 2024067610A1
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reaction
glufosinate
reagent
group
methyl
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French (fr)
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邱贵森
陆成樑
王宏磊
文泽星
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摩珈(上海)生物科技有限公司
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • 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)]
    • 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)]
    • C07F9/32—Esters thereof
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales

Definitions

  • the present application relates to a method for preparing L-glufosinate-ammonium using a phosphine reagent (e.g., a phosphate reagent). More specifically, the present application relates to a method for preparing L-glufosinate-ammonium using a cyclic lactone as a raw material and a substituted phosphate as a phosphine reagent, through addition, rearrangement ring-opening reaction, and subsequent post-treatment, and no leaving group reagent is used in the method.
  • a phosphine reagent e.g., a phosphate reagent
  • Glufosinate also known as glufosinate, has a chemical name of 2-amino-4-[hydroxy(methyl)phosphonyl]butyrate ammonium, and is a highly efficient, broad-spectrum, low-toxic non-selective herbicide developed by Hoechst, Germany.
  • glufosinates are racemic, but in fact only L-glufosinate has herbicidal activity. Therefore, the development of a more optimized L-glufosinate production process is of great significance for improving atom economy, reducing costs, and alleviating environmental pressure.
  • US Patent No. 5767309A reports a method that uses quinine and glufosinate to form salts and then crystallizes, and then uses 3,5-dinitrosalicylic aldehyde to racemize under acetic acid conditions to finally obtain L-glufosinate with a yield of 86% and an ee value of 99%.
  • This method can achieve the conversion from D-glufosinate to L-glufosinate, but the yield is low, and the raw materials quinine and 3,5-dinitrosalicylic aldehyde are relatively expensive, and the recovery rate has a greater impact on the cost.
  • Patent WO2006104120A1 reports the preparation of L-phosphinothricin ammonium by asymmetric catalytic hydrogenation. Specifically, after the reaction of phosphorous acid monoester with ethyl acrylate, it is subjected to Claisen condensation reaction with diethyl oxalate. The product is eliminated by heat to obtain a keto acid intermediate, which is then reacted with acetamide to prepare the substrate enamine of the asymmetric hydrogenation reaction. The asymmetric hydrogenation reaction is catalyzed by a chiral phosphorus ligand rhodium catalyst, and refined glufosinate is obtained by hydrolysis conversion, with the highest ee value of 95.6%.
  • This route constructs a chiral center by asymmetric hydrogenation, and the reaction conditions are It is mild and has a high yield, but requires a chiral phosphorus ligand rhodium catalyst, which is difficult to hydrogenate and has a high production cost.
  • Chinese patent CN107502647B introduces a one-pot method using two enzymes to achieve the conversion from DL-phosphinothricin to L-phosphinothricin, in which D-phosphinothricin is oxidized by D-amino acid oxidase and then reduced to DL-phosphinothricin under the action of reductase and NADPH, while L-phosphinothricin is not oxidized by D-amino acid oxidase.
  • the yield of L-phosphinothricin in this method is 95% and the ee value is 98.8%.
  • the coenzyme NADPH is expensive, requires an additional regeneration system, the regeneration rate needs to be verified, the enzyme system and the coenzyme system are relatively complex, and the difficulty of purifying L-phosphinothricin is relatively large.
  • Patent CN113316580A discloses a method for preparing L-phosphinothricin ammonium, which mainly utilizes the reaction between an L-lactone derivative and a phosphine reagent, wherein the yield of the product L-phosphinothricin ammonium is 81.4%, and a leaving reagent such as trimethylsilyl iodide is used during the reaction, resulting in high costs.
  • the present invention aims to overcome the above-mentioned technical challenges encountered in the field of L-glufosinate synthesis, and hopes to provide a method for preparing L-glufosinate with high atom economy, environmental friendliness and low cost.
  • the present application provides a method for preparing L-phosphinothricin from a cyclic lactone, the method comprising:
  • step (2) adding a phosphine reagent and an alkali reagent to a mixed solution of the cyclic lactone and an organic solvent obtained in step (1), so that the cyclic lactone and the phosphine reagent react in the presence of the alkali reagent to obtain an L-phosphinothricin ammonium precursor compound;
  • a prerequisite is that no leaving group reagent is used in the method.
  • the cyclic lactone in step (1) is dihydrofuran-2,3-dione.
  • the dihydrofuran-2,3-dione is prepared by the following method:
  • the elimination reaction conditions in step (b) above include using 98% concentrated sulfuric acid.
  • the cyclic lactone in step (1) is L-aminovalerolactone.
  • the L-aminovalerolactone is prepared by the following method:
  • the method for preparing L-aminovalerolactone further comprises:
  • the elimination reaction conditions in step (ii) include using a 49% sulfuric acid solution.
  • the amino protecting group is selected from the group consisting of tert-butyloxycarbonyl (Boc), p-toluenesulfonyl (Ts), methanesulfonyl (Ms), methyl (CH 3 ), benzoyl (Bz) and benzyl (Bn).
  • the amino protecting group is selected from the group consisting of p-toluenesulfonyl, methanesulfonyl, benzoyl and benzyl.
  • the amino protecting group is selected from the group consisting of p-toluenesulfonyl, methanesulfonyl and benzyl.
  • the amino protecting group is selected from the group consisting of p-toluenesulfonyl and methanesulfonyl. In some embodiments, the amino protecting group is p-toluenesulfonyl.
  • the organic solvent in step (1) is selected from the group consisting of C 1-6 alkanols, tetrahydrofuran, toluene, dimethylformamide and C 1-6 chloroalkanes. In some embodiments, the organic solvent in step (1) is selected from the group consisting of methanol, ethanol, n-propanol, n-butanol, toluene, dichloromethane, chloroform, carbon tetrachloride, dimethylformamide and tetrahydrofuran. In some embodiments, the organic solvent in step (1) is selected from the group consisting of n-propanol, n-butanol and toluene. In some embodiments, the organic solvent in step (1) is selected from the group consisting of n-butanol and toluene. In some embodiments, the organic solvent in step (1) is n-butanol.
  • the phosphine reagent described in step (2) is selected from the group consisting of methyl phosphonic acid alkyl esters or salts thereof, methyl phosphonic acid substituted phenyl esters or salts thereof, methyl dialkyl phosphites and methyl disubstituted phenyl phosphites. In some embodiments, the phosphine reagent described in step (2) is selected from the group consisting of methyl phosphonic acid alkyl esters or metal phosphonic acid salts thereof, methyl phosphonic acid substituted phenyl esters or metal phosphonic acid salts thereof, methyl dialkyl phosphites and methyl disubstituted phenyl phosphites.
  • the phosphine reagent described in step (2) is selected from the group consisting of methyl phosphite, methyl phosphite ethyl ester, methyl isopropyl phosphite, methyl n-butyl phosphite, methyl phosphite phenyl ester, methyl benzyl phosphite, methyl chlorophenyl phosphite, methyl dimethyl phosphite, methyl diethyl phosphite and methyl diphenyl phosphite.
  • the phosphine reagent described in step (2) is selected from the group consisting of methyl benzyl phosphite, methyl n-butyl phosphite, methyl isopropyl phosphite, methyl phosphite ethyl ester, methyl phosphite, methyl phenyl phosphite and methyl dimethyl phosphite.
  • the phosphine reagent described in step (2) is selected from the group consisting of ethyl methyl phosphite, methyl methyl phosphite, phenyl methyl phosphite and dimethyl methyl phosphite.
  • the phosphine reagent described in step (2) is selected from the group consisting of methyl methyl phosphite and dimethyl methyl phosphite. In some embodiments, the phosphine reagent described in step (2) is dimethyl methyl phosphite.
  • the alkaline reagent described in step (2) is selected from the group consisting of alkali metal carbonates, alkali metal hydroxides, C 1-6 sodium alcoholates, organic lithium compounds, and alkali metal hydrides. In some embodiments, the alkaline reagent described in step (2) is selected from the group consisting of sodium methoxide, sodium ethoxide, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium diisopropylamide, n-butyl lithium, lithium aluminum hydride, and sodium hydride.
  • the alkaline reagent described in step (2) is selected from the group consisting of lithium aluminum hydride, sodium hydride, n-butyl lithium, lithium diisopropylamide, sodium methoxide, and sodium ethoxide. In some embodiments, the alkaline reagent described in step (2) is selected from the group consisting of n-butyl lithium, sodium methoxide, and sodium ethoxide. In some embodiments, the alkaline reagent described in step (2) is sodium methoxide.
  • the step (2) comprises a two-step reaction.
  • the step (2) comprises a carbonyl addition reaction and a ring-opening reaction.
  • the step (2) comprises a carbonyl addition reaction and a heating rearrangement ring-opening reaction.
  • the reaction temperature of the first reaction in step (2) is controlled at 0-45°C, and the reaction temperature of the second reaction is controlled at 90-120°C.
  • step (2) is performed in the presence of a catalyst.
  • the catalyst is a solid acid catalyst.
  • the solid acid catalyst is SO 4 2- /ZrO 2 -SnO 2 -Nd 2 O 3 .
  • the catalyst is added after the first reaction and before the second reaction in step (2).
  • the reaction time of the first reaction in step (2) is controlled to be 20-40 minutes, and the reaction time of the second reaction is controlled to be 4-6 hours.
  • the temperature is programmed to be raised to the temperature required for the second reaction within 0.5-1.5 hours.
  • the temperature is lowered to 0-20°C.
  • the pH value is adjusted to below 7 after the second reaction in step (2) is completed. In some embodiments, the pH value is adjusted to 4-5 after the second reaction in step (2) is completed. In some embodiments, the pH value of the reaction solution is adjusted to 6-8 before adding the catalyst.
  • the method for preparing L-glufosinate from cyclic lactones of the present invention does not use a leaving group reagent, and the leaving group reagent is a halogenating agent. In some embodiments, the method for preparing L-glufosinate from cyclic lactones of the present invention does not use a leaving group reagent, and the leaving group reagent is selected from the group consisting of HCl, HBr, HI, phosgene, SOCl 2 , oxalyl chloride, trimethylsilyl halide, sodium iodide (NaI), triethylsilane+palladium chloride+methyl iodide, POCl 3 , PCl 3 , PCl 5 , PBr 3 , PI 3 , H 2 SO 4 +KBr, P+Cl 2 , P+Br 2 , P+I 2 , TiCl 4 , ZnCl 2 , BBr 3
  • the step (2) further comprises an amino conversion reaction.
  • the amino conversion reaction comprises reacting a transaminase with an amino donor.
  • the amino donor is selected from the group consisting of alanine, ⁇ -methylbenzylamine, glutamic acid, phenylalanine, glycine, 3-aminobutyric acid, isopropylamine, 2-aminobutane, ⁇ -aminobutyric acid, ethylenediamine, propylenediamine, butylenediamine, pentamethylenediamine, hexamethylenediamine, and any salt thereof.
  • the amino donor is alanine.
  • the amino donor is L-alanine.
  • the transaminase is selected from the following group: Escherichia coli ⁇ -aminase (Genbank Accession No. NP_417544.5), Bacillus lividans ⁇ -aminase (Genbank Accession No. AAQ59697.1), Pseudomonas aeruginosa ⁇ -aminase (Genbank Accession No. AAG08191.1), Pseudomonas syringae ⁇ -aminase (Genbank Accession No. AAY39893.1), Rhodobacter sphaeroides ⁇ -aminase (Genbank Accession No. ABA81135.1), and Vibrio fluvialis ⁇ -aminase (Genbank Accession No. AEA39183.1).
  • the step (3) comprises subjecting the L-phosphinothricin precursor compound to a hydrolysis reaction under alkaline conditions.
  • the pH of the reaction solution is adjusted to a range of 5-6 at -10 to 10° C.
  • the pH value is adjusted by dripping an acidic solution (e.g., hydrochloric acid).
  • the L-glufosinate comprises an L-glufosinate salt.
  • the L-glufosinate salt is selected from the group consisting of L-glufosinate hydrochloride, L-glufosinate sulfate, L-glufosinate carbonate, L-glufosinate ammonium salt, L-glufosinate sodium salt, and L-glufosinate potassium salt.
  • the L-glufosinate salt is an L-glufosinate ammonium salt.
  • Headings and other identifiers such as (1), (2), (a), (b), (i), (ii), etc., are provided only to facilitate reading of the specification and claims.
  • the use of headings or other identifiers in the specification or claims does not necessarily require that the steps or elements be performed in alphabetical or numerical order or in the order in which they are presented.
  • the term "about” is used to indicate that a value includes the standard deviation of the error of the device or method used to determine the value. Generally, the term “about” is intended to indicate a possible variation of up to 10%. Thus, variations within the range of 1% to 10% (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% and values between any two of the above) of a value are included in the term “about”. Unless otherwise indicated, the term “about” used before a range also applies to both endpoints of the range.
  • C ij indicates a range of carbon number, wherein i and j are integers, and the range of carbon number includes the endpoints (i.e., i and j) and each integer point therebetween, and wherein j is greater than i.
  • C 1-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, and six carbon atoms.
  • alkyl refers to a saturated straight or branched hydrocarbon group.
  • Cij alkyl refers to an alkyl group having i to j carbon atoms.
  • examples of " C1-6 alkyl” include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, and isopentyl.
  • the compounds of the present application may include asymmetric centers and may therefore exist in various stereoisomeric forms.
  • enantiomers Therefore, the compounds of the present invention and compositions thereof may be in the form of individual enantiomers, or may be in the form of mixtures of stereoisomers.
  • the compounds of the present application are enantiomerically pure compounds.
  • optical pure means that the compound includes a significantly greater proportion of one enantiomer.
  • the compound includes at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound includes at least about 95%, 98%, or 99% by weight of the preferred enantiomer.
  • L- or "D-” refers to the L-isomer or D-isomer of a compound having an asymmetric center.
  • L-phosphinothricin is the L-isomer of glufosinate
  • D-phosphinothricin is the D-isomer of glufosinate.
  • % enantiomeric excess refers to the enantiomeric purity of a sample, i.e., the percentage of one enantiomer in excess of the other enantiomer in the sample.
  • the enantiomeric excess of L-glufosinate is the percentage of L-glufosinate in excess of D-glufosinate in glufosinate.
  • the enantiomeric excess of L-glufosinate is represented by the following equation 1:
  • the % enantiomeric excess can be characterized by conventional techniques in the art (such as chiral high performance liquid chromatography (chiral-HPLC)), and the measurement error is affected by the sensitivity and accuracy of the selected detector.
  • chiral-HPLC chiral high performance liquid chromatography
  • common detectors such as ultraviolet absorption detector (UV), fluorescence detector (FLD), parallax refractive index detector (RID) or diode array detector (DAD)
  • UV ultraviolet absorption detector
  • FLD fluorescence detector
  • RID parallax refractive index detector
  • DAD diode array detector
  • phosphinothricin ammonium refers to 2-amino-4-[hydroxy(methyl)phosphonyl]butyric acid or 2-amino-4-[hydroxy(methyl)phosphonyl]butyric acid and any salt, solvate, hydrate, stereoisomer, derivative, etc. thereof.
  • 2-amino-4-[hydroxy(methyl)phosphonyl]butyric acid is referred to as phosphinothricin.
  • Acid salts are also referred to as "phosphinothricin salts”.
  • hydrochloride of 2-amino-4-[hydroxy(methyl)phosphonyl]butyric acid is referred to as "phosphinothricin hydrochloride”
  • phosphinothricin sulfate 2-amino-4-[hydroxy(methyl)phosphonyl]butyric acid
  • the glufosinate of the present invention includes any form of salt of glufosinate, for example, hydrochloride, sulfate, carbonate, ammonium salt, sodium salt, potassium salt, etc. of glufosinate.
  • L-glufosinate of the present invention comprises L-glufosinate salt.
  • the L-glufosinate salt is selected from the group consisting of L-glufosinate hydrochloride, L-glufosinate sulfate, L-glufosinate carbonate, L-glufosinate ammonium salt, L-glufosinate sodium salt and L-glufosinate potassium salt.
  • the L-glufosinate salt is L-glufosinate ammonium salt.
  • the present application provides a method for preparing L-phosphinothricin from a cyclic lactone, the method comprising:
  • step (2) adding a phosphine reagent and an alkali reagent to a mixed solution of the cyclic lactone and an organic solvent obtained in step (1), so that the cyclic lactone and the phosphine reagent react in the presence of the alkali reagent to obtain an L-phosphinothricin ammonium precursor compound;
  • a prerequisite is that no leaving group reagent is used in the method.
  • step (1) describes in detail step (1), step (2) and step (3) of the method for preparing L-glufosinate ammonium described in the present application.
  • step (1) comprises mixing the cyclic lactone with an organic solvent.
  • cyclic lactone refers to a cyclic organic compound containing at least one (e.g., 1, 2, 3, 4, 5 or more) ester group (-COO-), and at least one ester group Located on the ring.
  • the cyclic structure of the cyclic lactone may contain one carbonyl group (-CO-) or multiple (for example, 2, 3, 4, 5 or more) carbonyl groups.
  • the cyclic lactone described in step (1) is selected from: cyclic lactones containing chiral amino groups and cyclic lactones not containing chiral amino groups.
  • the cyclic lactone described in step (1) is selected from: dihydrofuran-2,3-dione and L-aminovalerolactone. In another specific embodiment, the cyclic lactone described in step (1) is dihydrofuran-2,3-dione. In a specific embodiment, the cyclic lactone described in step (1) is L-aminovalerolactone.
  • the cyclic lactone in step (1) is dihydrofuran-2,3-dione and has the following chemical formula: (Also referred to as "Compound B" in this application).
  • the dihydrofuran-2,3-dione is prepared by the following method:
  • the elimination reaction conditions in step (b) include the use of sulfuric acid (e.g., concentrated sulfuric acid), e.g., 98% concentrated sulfuric acid.
  • sulfuric acid e.g., concentrated sulfuric acid
  • the ratio of 2-oxo-4-hydroxybutyrate sodium to concentrated sulfuric acid as needed. In some embodiments, based on 1 equivalent of 2-oxo-4-hydroxybutyrate sodium, the amount of concentrated sulfuric acid is 0.1 to 10 equivalents.
  • the amount of concentrated sulfuric acid is 0.1 equivalent, 0.2 equivalent, 0.3 equivalent, 0.4 equivalent, 0.5 equivalent, 0.6 equivalent, 0.7 equivalent, 0.8 equivalent, 0.9 equivalent, 1 equivalent, 2 equivalents, 3 equivalents, 4 equivalents, 5 equivalents, 6 equivalents, 7 equivalents, 8 equivalents, 9 equivalents or 10 equivalents, including any value or range between any values.
  • the yield of dihydrofuran-2,3-dione prepared from sodium 2-oxo-4-hydroxybutyrate is at least 10%. In some embodiments, the yield of dihydrofuran-2,3-dione prepared from sodium 2-oxo-4-hydroxybutyrate is at least 10%.
  • the yield of 2,3-diketone is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.
  • the cyclic lactone in step (1) is L-aminovalerolactone and has the following chemical formula: (also referred to as "Compound D" in this application), wherein R 1 is hydrogen or a protecting group for an amino group.
  • the protecting group for the amino group may be a common protecting group that can be understood by a person skilled in the art, such as: alkyl (including arylalkyl), alkoxycarbonyl, sulfonyl or acyl.
  • the protecting group for the amino group is selected from the group consisting of: tert-butyloxycarbonyl (Boc), p-toluenesulfonyl (Ts), methanesulfonyl (Ms), C 1-6 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl), benzoyl (Bz) and benzyl (Bn).
  • the protecting group for the amino group is selected from the group consisting of: Ts, Ms, Bz and Bn.
  • the protecting group for the amino group is selected from the group consisting of: Ts, Ms and Bn.
  • the protecting group for the amino group is selected from the group consisting of: Ts and Ms. In some embodiments, the protecting group for the amino group is Ts.
  • R 1 is hydrogen
  • Compound D is also referred to as “Compound DH”
  • Compound D is also referred to as “Compound D-Ts”.
  • the L-aminovalerolactone is prepared by the method described below:
  • homoserine salt e.g., homoserine sodium salt
  • a homoserine salt eg, homoserine sodium salt
  • the elimination reaction conditions in step (ii) include the use of sulfuric acid. In some embodiments, the elimination reaction conditions in step (ii) include the use of 49% sulfuric acid solution.
  • a person skilled in the art can adjust the ratio of homoserine salt (e.g., homoserine sodium salt) to sulfuric acid as needed. In some embodiments, based on 1 equivalent of homoserine sodium salt, the amount of sulfuric acid is 0.1 to 10 equivalents.
  • the amount of sulfuric acid is 0.1 equivalent, 0.2 equivalents, 0.3 equivalents, 0.4 equivalents, 0.5 equivalents, 0.6 equivalents, 0.7 equivalents, 0.8 equivalents, 0.9 equivalents, 1 equivalent, 2 equivalents, 3 equivalents, 4 equivalents, 5 equivalents, 6 equivalents, 7 equivalents, 8 equivalents, 9 equivalents or 10 equivalents, including any value or range between any values.
  • the yield of L-aminovalerolactone prepared by homoserine salt is at least 10%. In some embodiments, the yield of L-aminovalerolactone prepared by homoserine salt is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.
  • step (1) when the cyclic lactone is L-aminovalerolactone, in step (1), after L-aminovalerolactone is mixed with an organic solvent, the amino group on L-aminovalerolactone is not protected, in other words, R 1 is hydrogen (H). In some embodiments, in step (1), after L-aminovalerolactone is mixed with an organic solvent, the amino group on L-aminovalerolactone is protected.
  • the amino protecting group may be selected from the group consisting of tert-butyloxycarbonyl (Boc), p-toluenesulfonyl (Ts), methanesulfonyl (Ms), C 1-6 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl), benzoyl (Bz) and benzyl (Bn).
  • the amino protecting group is selected from the group consisting of Ts, Ms, Bz and Bn. More preferably, the amino protecting group is selected from the group consisting of Ts, Ms and Bn. Even more preferably, the amino protecting group is selected from the group consisting of Ts and Ms. Even more preferably, the amino protecting group is Ts.
  • organic solvent used in this application refers to a common organic solvent that can be understood by those skilled in the art.
  • exemplary organic solvents include, but are not limited to: C 1-6 alkanols, tetrahydrofuran (THF), toluene, dimethylformamide (DMF), C 1-6 chloroalkanes.
  • the organic solvent is selected from the group consisting of methanol, ethanol, n-propanol, n-butanol, toluene, methylene chloride, chloroform, carbon tetrachloride, DMF, and THF.
  • the organic solvent is selected from the group consisting of n-propanol, n-butanol, and toluene. In some embodiments, the organic solvent is selected from the group consisting of n-butanol and toluene. Even more preferably, in some embodiments, the organic solvent is n-butanol.
  • the organic solvent in step (1) is selected from the group consisting of C 1-6 alkanol, tetrahydrofuran (THF), toluene, dimethylformamide (DMF) and C 1-6 chloroalkane.
  • the organic solvent described in step (1) is selected from the group consisting of methanol, ethanol, n-propanol, n-butanol, toluene, dichloromethane, chloroform, carbon tetrachloride, DMF and THF.
  • the organic solvent described in step (1) is selected from the group consisting of n-propanol, n-butanol and toluene. More preferably, the organic solvent described in step (1) is selected from the group consisting of n-butanol and toluene. Even more preferably, the organic solvent described in step (1) is n-butanol.
  • the amount of the organic solvent is 0.1 to 10 parts by weight. In other embodiments, based on 1 part by weight of the cyclic lactone, the amount of the organic solvent is 0.1 part by weight, 0.2 part by weight, 0.3 part by weight, 0.4 part by weight, 0.5 part by weight, 0.6 part by weight, 0.7 part by weight, 0.8 part by weight, 0.9 part by weight, 1 part by weight, 2 parts by weight, 3 parts by weight, 4 parts by weight, 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight or 10 parts by weight, including any value therebetween or the range between any values.
  • step (2) comprises: adding a phosphine reagent and an alkali reagent to a mixed solution of the cyclic lactone and an organic solvent obtained in step (1), allowing the cyclic lactone and the phosphine reagent to react in the presence of the alkali reagent to obtain an L-glufosinate precursor compound.
  • phosphine reagent refers to any reagent that can react with a cyclic lactone to produce a
  • the phosphorus element in the phosphine reagent is pentavalent phosphorus.
  • the phosphorus element in the phosphine reagent is trivalent phosphorus.
  • the phosphine reagent may include the formula
  • the phosphorus compound or its phosphine salt (for example, metal phosphine salt) represented by is wherein Ra and Rb are each independently selected from an alkyl group (such as methyl, ethyl, propyl, butyl) or an optionally substituted phenyl group (such as phenyl, tolyl, chlorophenyl).
  • the phosphine reagent is selected from the group consisting of methyl phosphonic acid alkyl esters or salts thereof, methyl phosphonic acid Acid-substituted phenyl esters or salts thereof, dialkyl methyl phosphites and disubstituted phenyl methyl phosphites.
  • the phosphine reagent is selected from the group consisting of alkyl methyl phosphites or metal phosphine salts thereof, substituted phenyl methyl phosphites or metal phosphine salts thereof, dialkyl methyl phosphites or disubstituted phenyl methyl phosphites.
  • the phosphine reagent is selected from the group consisting of methyl phosphite, ethyl methyl phosphite, isopropyl methyl phosphite, n-butyl methyl phosphite, phenyl methyl phosphite, benzyl methyl phosphite, chlorophenyl methyl phosphite, dimethyl methyl phosphite, diethyl methyl phosphite and diphenyl methyl phosphite.
  • the phosphine reagent is selected from the group consisting of benzyl methyl phosphite, n-butyl methyl phosphite, isopropyl methyl phosphite, ethyl methyl phosphite, methyl phosphite, phenyl methyl phosphite and dimethyl methyl phosphite.
  • the phosphine reagent is selected from the group consisting of ethyl methyl phosphite, methyl phosphite, phenyl methyl phosphite or dimethyl methyl phosphite.
  • the phosphine reagent is selected from the group consisting of methyl phosphite and dimethyl methyl phosphite. In some embodiments, the phosphine reagent is dimethyl methyl phosphite.
  • the amount of the phosphine reagent is 0.1 to 10 equivalents. In some embodiments, based on 1 equivalent of the cyclic lactone, the amount of the phosphine reagent is 0.1 equivalents, 0.2 equivalents, 0.3 equivalents, 0.4 equivalents, 0.5 equivalents, 0.6 equivalents, 0.7 equivalents, 0.8 equivalents, 0.9 equivalents, 1 equivalent, 1.1 equivalents, 1.2 equivalents, 1.3 equivalents, 1.4 equivalents, 1.5 equivalents, 1.6 equivalents, 1.7 equivalents, 1.8 equivalents, 1.9 equivalents, 2 equivalents, 3 equivalents, 4 equivalents, 5 equivalents, 6 equivalents, 7 equivalents, 8 equivalents, 9 equivalents or 10 equivalents, including any value or range between any values.
  • alkaline reagent used in this application refers to a Bronsted Alkaline reagents including alkali and Lewis base.
  • exemplary bases include, but are not limited to, alkali metal carbonates, alkali metal hydroxides, C 1-6 sodium alcoholates, organic lithium compounds, and alkali metal hydrides.
  • the alkaline reagent is selected from the group consisting of sodium methoxide, sodium ethoxide, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium diisopropylamide (LDA), n-butyl lithium, lithium aluminum hydride, and sodium hydride.
  • LDA lithium diisopropylamide
  • the alkaline reagent is selected from the group consisting of lithium aluminum hydride, sodium hydride, n-butyl lithium, LDA, sodium methoxide, and sodium ethoxide. In some embodiments, the alkaline reagent is selected from the group consisting of n-butyl lithium, sodium methoxide, and sodium ethoxide. In some embodiments, the alkaline reagent is Sodium methoxide.
  • the amount of the base reagent is 0.1 to 10 equivalents. In some embodiments, based on 1 equivalent of the cyclic lactone, the amount of the base reagent is 0.1 equivalent, 0.2 equivalent, 0.3 equivalent, 0.4 equivalent, 0.5 equivalent, 0.6 equivalent, 0.7 equivalent, 0.8 equivalent, 0.9 equivalent, 1 equivalent, 1.1 equivalent, 1.2 equivalent, 1.3 equivalent, 1.4 equivalent, 1.5 equivalent, 1.6 equivalent, 1.7 equivalent, 1.8 equivalent, 1.9 equivalent, 2 equivalents, 3 equivalents, 4 equivalents, 5 equivalents, 6 equivalents, 7 equivalents, 8 equivalents, 9 equivalents or 10 equivalents, including any value or range between any values.
  • L-phosphinothricin precursor compound refers to a compound that can generate L-phosphinothricin after one or more steps of reaction.
  • the L-phosphinothricin precursor compound has the following chemical formula (also referred to as "Compound F" in this application): Wherein R 1 is hydrogen or a protecting group of an amino group, and R 2 is hydrogen or any other substituent (e.g., an alkyl group) or a protecting group.
  • the L-phosphinothricin precursor compound can be a 2-amino 4-[alkoxy(methyl)phosphono]-L-butyric acid with protected or unprotected amino groups.
  • the L-phosphinothricin precursor compound When R 1 is hydrogen, the L-phosphinothricin precursor compound is also referred to as “compound FH” in this application; when R 1 is Ts, the L-phosphinothricin precursor compound is also referred to as “compound F-Ts" in this application.
  • step (2) includes a two-step reaction, i.e., a carbonyl addition reaction and a heating rearrangement ring-opening reaction.
  • a carbonyl addition reaction i.e., a carbonyl addition reaction and a heating rearrangement ring-opening reaction.
  • the first reaction the cyclic lactone and the phosphine reagent undergo a carbonyl addition reaction in the presence of an alkaline reagent to form an intermediate.
  • the intermediate undergoes a heating rearrangement ring-opening under heating conditions to obtain an L-phosphine ammonium precursor compound.
  • the cyclic lactone and dimethyl methylphosphite undergo a carbonyl addition reaction in the presence of a base to form an intermediate, and then the intermediate undergoes a heating rearrangement ring-opening reaction to form a chain butyric acid product.
  • the carbonyl addition reaction and the heating rearrangement ring-opening reaction are shown in Scheme 1 below.
  • the reaction temperature in the first reaction of step (2), is controlled at 0-45°C. In some embodiments, the reaction temperature is 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C or 45°C, including any value or range between any values therein. It should be understood that the temperature described in this application is characterized and controlled by methods common in the art (such as alcohol or electronic thermometers). The reaction temperature is affected by factors such as temperature control medium, reactor capacity and material. Generally, the measurement error of the reaction temperature is about ⁇ 5°C.
  • the reaction time is controlled to be 20-40 minutes. In some embodiments, the reaction time is 20 minutes, 25 minutes, 30 minutes, 35 minutes or 40 minutes, including any value or range between any values.
  • step (2) is performed in the presence of a catalyst.
  • the catalyst is a solid acid catalyst. The inventors of the present invention unexpectedly found that adding a solid acid catalyst in step (2) can avoid the use of a leaving group reagent.
  • leaving group refers to an atom or atom group that breaks away from a substrate molecule with at least one pair of electrons in a substitution reaction between a substrate (e.g., a cyclic lactone in the present application) and a nucleophile (e.g., a phosphine reagent in the present application).
  • a substrate e.g., a cyclic lactone in the present application
  • a nucleophile e.g., a phosphine reagent in the present application
  • Exemplary leaving groups include, but are not limited to, halogens (e.g., chlorine (Cl), bromine (Br), iodine (I)), hydroxyl (or its protonated form), sulfonyloxy (e.g., p-toluenesulfonyloxy (TsO), methanesulfonyloxy (MsO), trifluoromethanesulfonyloxy (TfO), or its protonated form), carboxylate (e.g., acetoxy (AcO), benzoyloxy (BzO), or its protonated form) and carbonate (e.g., tert-butyloxycarbonyloxy (BocO), or its protonated form).
  • halogens e.g., chlorine (Cl), bromine (Br), iodine (I)
  • hydroxyl or its protonated form
  • sulfonyloxy e.g.,
  • leaving group reagent refers to a reagent that introduces a leaving group into a substrate during the reaction between a substrate (e.g., a cyclic lactone in the present application) and a nucleophilic reagent (e.g., a phosphine reagent in the present application). Reagent.
  • a substrate e.g., a cyclic lactone in the present application
  • a nucleophilic reagent e.g., a phosphine reagent in the present application.
  • the method for preparing L-phosphinothricin from cyclic lactones of the present invention does not use a leaving group reagent, and the leaving group reagent includes a halogenating agent.
  • Exemplary leaving group reagents include, but are not limited to: HCl, HBr, HI, phosgene, SOCl 2 , oxalyl chloride, trimethylsilyl halide, sodium iodide (NaI), triethylsilane ((CH 2 CH 3 ) 3 SiH) + palladium chloride (PdCl 2 ) + methyl iodide (CH 3 I), POCl 3 , PCl 3 , PCl 5 , PBr 3 , PI 3 , H 2 SO 4 +KBr, P+Cl 2 , P+Br 2 , P+I 2 , TiCl 4 , ZnCl 2 and BBr 3 .
  • the method for preparing L-phosphinothricin from cyclic lactones of the present invention does not use a leaving group reagent, and the leaving group reagent is trimethyl iodosilane.
  • the method for preparing L-glufosinate from cyclic lactone provided by the present invention does not use a leaving group reagent.
  • the present invention first discovered that adding a solid acid catalyst in step (2) of the method of the present invention can avoid the use of a leaving group reagent, in particular, there is no need to use a leaving group reagent such as trimethyl iodosilane, which is expensive.
  • compound D and a phosphine reagent are directly catalyzed by a solid acid catalyst to generate an L-glufosinate precursor compound (i.e., compound F), which reduces the reaction steps, saves costs, and improves the final yield of the target product L-glufosinate.
  • the solid acid catalyst is SO 4 2- /ZrO 2 -SnO 2 -Nd 2 O 3 .
  • the solid acid catalyst used in the present invention is commercially available, or can be prepared by methods known in the art (e.g., Li Shumin et al., "Preparation of Rare Earth Solid Superacid SO 4 2- /ZrO 2 -SnO 2 -Nd 2 O 3 and Catalytic Synthesis of Pinyl Acetate", Applied Chemistry, Vol. 26, No. 5, May 2009), such as impregnating an oxide mixture containing a rare earth oxide (e.g., Nd 2 O 3 ) in sulfuric acid, followed by calcination.
  • the solid acid catalyst SO 4 2- /ZrO 2 -SnO 2 -Nd 2 O 3 is prepared by the method described in Example V of the present application.
  • step (2) when an achiral compound is used as a starting material, the target product L-phosphinothricin ammonium can also be obtained in fewer steps, and the yield is significantly improved compared to the prior art method.
  • step (2) when the cyclic lactone used in step (1) is a cyclic lactone that does not contain a chiral amino group, step (2) also includes an amino conversion reaction.
  • the amino conversion reaction includes reacting a transaminase with an amino donor.
  • amino donor refers to a compound that can provide an amino group.
  • the amino donor is selected from the group consisting of alanine, ⁇ -methylbenzylamine, glutamic acid, phenylalanine, glycine, 3-aminobutyric acid, isopropylamine, 2-aminobutane, ⁇ -aminobutyric acid, ethylenediamine, propylenediamine, butylenediamine, pentanediamine, hexamethylenediamine, and salts of any one of them.
  • the amino donor is alanine.
  • the amino donor is L-alanine.
  • the amino conversion reaction introduces a chiral amino group.
  • the amino conversion reaction introduces an L-amino group.
  • the amino group in the amino donor can be transferred to the keto group of the amino acceptor (e.g., the cyclic lactone in the present invention) using methods known in the art.
  • a transaminase can catalyze the transfer of an amino group, a pair of electrons and a proton from an amino donor to the carbonyl group of the cyclic lactone, thereby producing a compound with a chiral amine.
  • a variety of transaminases are known in the prior art.
  • Escherichia coli ⁇ -transaminase (Genbank accession number NP_417544.5), Bacillus violaceus ⁇ -transaminase (Genbank accession number AAQ59697.1), Pseudomonas aeruginosa ⁇ -transaminase (Genbank accession number AAG08191.1), Pseudomonas syringae ⁇ -transaminase (Genbank accession number AAY39893.1), Rhodobacter sphericalus ⁇ -transaminase (Genbank accession number ABA81135.1), Vibrio fluvii ⁇ -transaminase (Genbank accession number AEA39183.1).
  • the conversion rate of the transamination reaction is at least 10%. In some embodiments, the conversion rate of the transamination reaction is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 98%.
  • the solid acid catalyst is added after the first reaction in step (2) and before the second reaction.
  • the pH value of the reaction solution is adjusted to 6-8 (e.g., 6, 6.5, 7, 7.5, 8 or any value between any two of the above values) before the solid acid catalyst is added.
  • the pH value of the reaction solution is adjusted to 7 before the solid acid catalyst is added.
  • the amount of the solid acid catalyst is 0.01 to 1 part by weight based on 100 parts by weight of the cyclic lactone. In some embodiments, the amount of the solid acid catalyst is 0.01 parts by weight, 0.02 parts by weight, 0.03 parts by weight, 0.04 parts by weight, 0.05 parts by weight, 0.06 parts by weight, 0.07 parts by weight, 0.08 parts by weight, 0.09 parts by weight, 0.10 parts by weight, 0.11 parts by weight, 0.12 parts by weight, 0.13 parts by weight, 0.14 parts by weight, 0.15 parts by weight, 0.16 parts by weight, 0.17 parts by weight, 0.18 parts by weight, 0.19 parts by weight, 0.20 parts by weight, 0.21 parts by weight, 0.22 parts by weight, 0.23 parts by weight, 0.24 parts by weight, 0.25 parts by weight, 0.26 parts by weight, 0.27 parts by weight, 0.28 parts by weight, 0.29 parts by weight, 0.30 parts by weight, 0.31 parts by weight, 0.32 parts by weight, 0.33 parts by weight, 0.34 parts by weight, 0.35 parts
  • the reaction temperature is controlled at 90-120° C.
  • the reaction temperature is 90° C., 95° C., 100° C., 105° C., 110° C., 111° C., 112° C., 113° C., 114° C., 115° C., 116° C., 117° C., 118° C., 119° C., or 120° C., including any value or range between any values therein.
  • the temperature is programmed to the temperature required for the second reaction within 0.5-1.5 hours. Not limited by any theory, but it is believed that programmed temperature increase is conducive to the reaction.
  • the heating time is 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 1.1 hours, 1.2 hours, 1.3 hours, 1.4 hours or 1.5 hours.
  • the reaction time is controlled to be 4-6 hours. In some embodiments, the reaction time is 4 hours, 4.5 hours, 4.6 hours, 4.7 hours, 4.8 hours, 4.9 hours, 5 hours, 5.1 hours, 5.2 hours, 5.3 hours, 5.4 hours, 5.5 hours or 6 hours, including any value or range between any values.
  • the temperature is lowered to 0-20° C. after the second reaction of step (2) is completed. In some embodiments, the temperature is lowered to no higher than 20° C., no higher than 15° C., no higher than 10° C., no higher than 5° C., or no higher than 0° C., including any value or range between any values, after the second reaction of step (2) is completed.
  • the pH value is adjusted to 7. In some embodiments, the pH value is adjusted to below 7, below 6.5, below 6, below 5.5, below 5, below 4.5, below 4, below 3.5, or below 3 at the end of the second reaction in step (2). In some embodiments, the pH value is adjusted to between 7-6.5, 6.5-6, 6-5.5, 5.5-5, 5-4.5, 4.5-4, 4-3.5, or 3.5-3 at the end of the second reaction in step (2).
  • the yield of the L-phosphinothricin ammonium precursor compound prepared in step (2) is at least 10%. In some embodiments, the yield of the L-phosphinothricin ammonium precursor compound prepared in step (2) is at least 10% at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.
  • step (3) comprises: treating the L-glufosinate precursor compound by chemical or biological methods to obtain the product L-glufosinate.
  • the step (3) includes subjecting the L-phosphinothionyl ammonium precursor compound to a hydrolysis reaction under alkaline conditions.
  • the pH of the reaction solution is adjusted under a condition not higher than 10°C.
  • the pH of the reaction solution is adjusted under a condition of -10 to 10°C.
  • the pH of the reaction solution is adjusted under a condition not higher than 10°C, not higher than 9°C, not higher than 8°C, not higher than 7°C, not higher than 6°C, not higher than 5°C, not higher than 4°C, not higher than 3°C, not higher than 2°C, not higher than 1°C, not higher than 0°C, not higher than -1°C, not higher than -2°C, not higher than -3°C, not higher than -4°C, not higher than -5°C, not higher than -6°C, not higher than -7°C, not higher than -8°C, not higher than -9°C, or not higher than -10°C.
  • the pH of the reaction solution is adjusted to within the range of 1 to 7. In some embodiments, after the hydrolysis reaction in step (3) is completed, the pH of the reaction solution is adjusted to within the range of 1 to 7, within the range of 1 to 6, within the range of 2 to 6, within the range of 3 to 6, within the range of 4 to 6, or within the range of 5 to 6.
  • the pH value is adjusted by adding an acidic solution.
  • the pH value is adjusted by dropping an inorganic acid or organic acid solution.
  • the pH value is adjusted by dropping sulfuric acid, sulfurous acid, hydrochloric acid, hydrobromic acid, phosphoric acid, phosphorous acid, hypophosphorous acid, metaphosphoric acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid or formic acid solution.
  • the pH value is adjusted by dropping a hydrochloric acid solution.
  • the pH is adjusted by adding about 0.1N, about 0.2N, about 0.3N, about 0.4N, about 0.5N, about 0.6N, about 0.7N, about 0.8N, about 0.9N, about 1N, about 1.1N, about 1.2N, about 1.3N, about 1.4N, about 1.5N, about 1.6N, about 1.7N, about 1.8N, about 1.9N, about 2N, about 3N, about 4N, about 5N, about 6N, about 7N, about 8N, about 9N, about 10N, about 11N or about 12N hydrochloric acid solution.
  • the pH is adjusted by adding about 1N hydrochloric acid solution.
  • the yield of L-glufosinate in step (3) is at least 10%. In some embodiments, the yield of L-glufosinate in step (3) is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.
  • the ee value of L-glufosinate prepared in step (3) is at least 80%. In some embodiments, the ee value of L-glufosinate prepared in step (3) is at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8% or at least 99.9%.
  • the prior art has disclosed a method for preparing L-phosphinothricin by reacting L-aminovalerolactone with a phosphine reagent, but a leaving group reagent is required during the process of the method.
  • the synthetic route of the method disclosed in the prior art is shown in Scheme II below.
  • G is a leaving group
  • Ra varies depending on the reaction conditions and reagents.
  • Ra can be hydrogen, alkyl (for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.), aryl (for example, benzyl, phenyl, naphthyl, etc.), -Si( CH3 )(tert-butyl) 2 , -Si(phenyl) 2 (tert-butyl), -Si(isopropyl) 3 , -Si(phenyl)( CH3 ) 2 , -Si(phenyl) 2 ( CH3 ), -Si(phenyl) 3 , -Si ( CH3 ) 3 , -Si( CH2CH3 ) 3 , -Si(CH2CH3) 2 ( CH3 ), -Si ( CH2CH3 )( CH3 ) 2 , or
  • homoserine sodium salt (compound C, sodium L-2-amino-4-hydroxybutyrate) is cyclized to form L-aminovalerolactone (compound D), trimethylsilyl iodide or other leaving group reagents are added to obtain compound H, which is then reacted with a phosphine reagent to obtain an L-phosphinothricin precursor compound (i.e., compound F), which is then deprotected and alkalized or otherwise treated to obtain the target product L-phosphinothricin. Since this prior art method uses leaving group reagents such as trimethylsilyl iodide, the cost is relatively high, and the final yield of the target product L-phosphinothricin is still to be improved.
  • the present invention can use non-chiral cyclic lactone as a starting material to prepare L-phosphinothricin.
  • the synthesis route of the present invention is shown in the following scheme III.
  • sodium 2-oxo-4-hydroxybutyrate forms dihydrofuran-2,3-dione (compound B) through elimination reaction in the presence of concentrated sulfuric acid, and the compound B is the non-chiral starting material used in the present invention.
  • Compound B can directly undergo carbonyl addition reaction with a phosphine reagent to generate a carbonyl carboxylic acid compound E.
  • Compound E can easily undergo amino conversion reaction under the action of transaminase, and a chiral amino group is introduced through the chiral reactant L-alanine to obtain an optically pure precursor compound of glufosinate (compound F).
  • the precursor compound F can obtain the target product L-glufosinate by a simple chemical or biological method.
  • the present invention also found that when a chiral compound is used as a starting material (e.g., compound C used in the above prior art, sodium L-2-amino-4-hydroxybutyrate), the target compound L-phosphinothricin ammonium can be prepared without using a relatively expensive leaving group reagent. As shown in the following Scheme IV.
  • a chiral compound e.g., compound C used in the above prior art, sodium L-2-amino-4-hydroxybutyrate
  • R1 is a protecting group of amino group.
  • homoserine sodium salt (compound C, sodium L-2-amino-4-hydroxybutyrate) is firstly cyclized to form L-aminovalerolactone (compound D).
  • Compound D is then directly reacted with a phosphine reagent under the catalytic action of a solid acid catalyst (e.g., SO 4 2- /ZrO 2 -SnO 2 -Nd 2 O 3 ) to obtain compound F, which is then deprotected and alkalized or otherwise treated to obtain the target product, L-phosphinothricin ammonium.
  • a solid acid catalyst e.g., SO 4 2- /ZrO 2 -SnO 2 -Nd 2 O 3
  • the following scheme V shows a comparison between the synthetic route of the present invention when using a non-chiral cyclic lactone or a chiral cyclic lactone as a starting material and the synthetic route of the prior art. It can be seen that when a non-chiral cyclic lactone is used as a starting material ("method 1 of the present invention"), starting from the initial differently substituted hydroxybutyric acid until the final target product L-phosphinothricin ammonium is obtained, the total number of steps used in the route of the present invention and the prior art route is the same, both comprising 4 steps.
  • the difference between the two is that the cyclic lactone of the prior art method must be treated with a leaving group reagent before reacting with the phosphine reagent, while the cyclic lactone of the method of the present invention can directly react with the phosphine reagent, but its product needs to undergo an additional amino conversion reaction to obtain the L-phosphinothricin ammonium precursor compound (compound F), so the total number of steps of the two is the same.
  • the leaving group reagent treatment step involved in the prior art method requires the use of expensive leaving group reagents such as trimethyl iodosilane.
  • the amino conversion step involved in the method of the present invention only requires the use of cheap reagents such as L-alanine and transaminase, and the reaction conditions are mild and easy to implement.
  • the method of the present invention does not introduce chiral compounds until the precursor formation step, so the early reaction will inevitably not involve the processing process of chiral separation. It can be seen that in this method of the present invention, the starting material does not need to contain chiral amino groups, nor does it need to carry out high-cost processing steps, such as chiral separation processing, on the reactants before the critical reaction with the phosphine reagent.
  • the present invention uses the same chiral cyclic lactone (L-aminovalerolactone, compound D) as the starting material as the prior art ("method 2 of the present invention")
  • the synthetic route of the present invention only requires 3 steps to obtain the final target product L-glufosinate-ammonium
  • the synthetic route of the prior art requires 4 steps to obtain the final target product L-glufosinate-ammonium. Therefore, the method of the present invention eliminates the use of a more expensive leaving group reagent and related steps, reduces costs, and achieves the advantage of obtaining the product with fewer steps.
  • the present invention provides the following embodiments.
  • Embodiment 1 A method for preparing L-phosphinothricin from a cyclic lactone, the method comprising:
  • step (2) adding a phosphine reagent and an alkali reagent to a mixed solution of the cyclic lactone and an organic solvent obtained in step (1), so that the cyclic lactone and the phosphine reagent react in the presence of the alkali reagent to obtain an L-phosphinothricin ammonium precursor compound;
  • a prerequisite is that no leaving group reagent is used in the method.
  • Embodiment 2 The method according to embodiment 1, wherein the ring in step (1)
  • the ester is dihydrofuran-2,3-dione.
  • Embodiment 3 The method according to embodiment 2, wherein the dihydrofuran-2,3-dione is prepared by the method described below:
  • Embodiment 4 The method according to embodiment 3, wherein the elimination reaction conditions in step (b) include using 98% concentrated sulfuric acid.
  • Embodiment 5 The method according to embodiment 1, wherein the cyclic lactone in step (1) is L-aminovalerolactone.
  • Embodiment 6 The method according to embodiment 5, wherein the L-aminovalerolactone is prepared by the method described below:
  • Embodiment 7 The method according to embodiment 6, wherein the method does not include protecting the amino group on L-aminovalerolactone.
  • Embodiment 8 The method according to embodiment 6, further comprising:
  • Embodiment 9 The method according to any one of embodiments 6 to 8, wherein the elimination reaction conditions in step (ii) include using a 49% sulfuric acid solution.
  • Embodiment 10 The method according to embodiment 8, wherein the protecting group of the amino group is selected from the group consisting of tert-butyloxycarbonyl, p-toluenesulfonyl, methylsulfonyl, methyl, benzoyl and benzyl.
  • Embodiment 11 The method according to embodiment 8, wherein the protecting group of the amino group is selected from the group consisting of p-toluenesulfonyl, methanesulfonyl, benzoyl and benzyl.
  • Embodiment 12 The method according to embodiment 8, wherein the protecting group of the amino group is selected from the group consisting of p-toluenesulfonyl, methanesulfonyl and benzyl.
  • Embodiment 13 The method according to embodiment 8, wherein the protecting group of the amino group is selected from the group consisting of p-toluenesulfonyl and methanesulfonyl.
  • Embodiment 14 The method according to embodiment 8, wherein the protecting group of the amino group is p-toluenesulfonyl.
  • Embodiment 15 The method according to any of the preceding embodiments, wherein the organic solvent in step (1) is selected from the group consisting of C 1-6 alkanols, tetrahydrofuran, toluene, dimethylformamide , and C 1-6 chloroalkanes.
  • Embodiment 16 A method according to any one of the preceding embodiments, wherein the organic solvent described in step (1) is selected from the group consisting of methanol, ethanol, n-propanol, n-butanol, toluene, dichloromethane, chloroform, carbon tetrachloride, dimethylformamide and tetrahydrofuran.
  • the organic solvent described in step (1) is selected from the group consisting of methanol, ethanol, n-propanol, n-butanol, toluene, dichloromethane, chloroform, carbon tetrachloride, dimethylformamide and tetrahydrofuran.
  • Embodiment 17 The method according to any one of the preceding embodiments, wherein the organic solvent in step (1) is selected from the group consisting of n-propanol, n-butanol and toluene.
  • Embodiment 18 The method according to any one of the preceding embodiments, wherein the organic solvent in step (1) is selected from the group consisting of n-butanol and toluene.
  • Embodiment 19 The method according to any one of the preceding embodiments, wherein the organic solvent in step (1) is n-butanol.
  • Embodiment 20 A method according to any one of the preceding embodiments, wherein the phosphine reagent in step (2) is selected from the group consisting of alkyl methyl phosphates or salts thereof, substituted phenyl methyl phosphates or salts thereof, dialkyl methyl phosphites, and disubstituted phenyl methyl phosphites.
  • Embodiment 21 The method according to any one of the preceding embodiments, wherein in step (2)
  • the phosphine reagent is selected from the group consisting of methyl phosphite, ethyl phosphite, isopropyl phosphite, n-butyl phosphite, phenyl phosphite, benzyl phosphite, chlorophenyl phosphite, dimethyl phosphite, diethyl phosphite and diphenyl phosphite.
  • Embodiment 22 A method according to any one of the preceding embodiments, wherein the phosphine reagent described in step (2) is selected from the group consisting of methyl benzyl phosphite, methyl n-butyl phosphite, methyl isopropyl phosphite, methyl ethyl phosphite, methyl methyl phosphite, methyl phenyl phosphite and methyl dimethyl phosphite.
  • the phosphine reagent described in step (2) is selected from the group consisting of methyl benzyl phosphite, methyl n-butyl phosphite, methyl isopropyl phosphite, methyl ethyl phosphite, methyl methyl phosphite, methyl phenyl phosphite and methyl dimethyl phosphite.
  • Embodiment 23 A method according to any one of the preceding embodiments, wherein the phosphine reagent in step (2) is selected from the group consisting of ethyl methylphosphite, methyl methylphosphite, phenyl methylphosphite and dimethyl methylphosphite.
  • Embodiment 24 The method according to any one of the preceding embodiments, wherein the phosphine reagent in step (2) is selected from the group consisting of methyl phosphite and dimethyl phosphite.
  • Embodiment 25 A method according to any one of the preceding embodiments, wherein the phosphine reagent in step (2) is dimethyl methylphosphite.
  • Embodiment 26 A method according to any one of the preceding embodiments, wherein the alkaline reagent in step (2) is selected from the group consisting of alkali metal carbonates, alkali metal hydroxides, sodium C 1-6 alkoxides, organic lithium compounds, and alkali metal hydrides.
  • Embodiment 27 A method according to any one of the preceding embodiments, wherein the alkaline reagent described in step (2) is selected from the following group: sodium methoxide, sodium ethoxide, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium diisopropylamide, n-butyl lithium, lithium aluminum hydride and sodium hydride.
  • the alkaline reagent described in step (2) is selected from the following group: sodium methoxide, sodium ethoxide, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium diisopropylamide, n-butyl lithium, lithium aluminum hydride and sodium hydride.
  • Embodiment 28 A method according to any one of the preceding embodiments, wherein the alkaline reagent described in step (2) is selected from the group consisting of lithium aluminum hydride, sodium hydride, n-butyl lithium, lithium diisopropylamide, sodium methoxide, and sodium ethoxide.
  • Embodiment 29 The method according to any one of the preceding embodiments, wherein the alkaline reagent in step (2) is selected from the group consisting of n-butyl lithium, sodium methoxide and sodium ethoxide.
  • Embodiment 30 The method according to any one of the preceding embodiments, wherein the alkaline reagent in step (2) is sodium methoxide.
  • Embodiment 31 A method according to any one of the preceding embodiments, wherein step (2) comprises a two-step reaction.
  • Embodiment 32 The method according to embodiment 31, wherein the reaction temperature of the first reaction in step (2) is controlled at 0-45°C, and the reaction temperature of the second reaction is controlled at 90-120°C.
  • Embodiment 33 The method according to any of the preceding embodiments, wherein step (2) is performed in the presence of a catalyst.
  • Embodiment 34 The method of embodiment 33, wherein the catalyst is a solid acid catalyst.
  • Embodiment 35 The method of embodiment 34, wherein the solid acid catalyst is SO 4 2 ⁇ /ZrO 2 —SnO 2 —Nd 2 O 3 .
  • Embodiment 36 The method according to any one of embodiments 33-35, wherein the catalyst is added after the first reaction and before the second reaction in step (2).
  • Embodiment 37 The method according to any one of embodiments 32-36, wherein the reaction time of the first reaction in step (2) is controlled to be 20-40 minutes, and the reaction time of the second reaction is controlled to be 4-6 hours.
  • Embodiment 38 A method according to any one of embodiments 32-37, wherein after the first reaction in step (2) is completed, the temperature is programmed to rise to the temperature required for the second reaction within 0.5-1.5 hours.
  • Embodiment 39 The method according to any one of embodiments 32-38, wherein the temperature is lowered to 0-20°C after the second reaction in step (2) is completed.
  • Embodiment 40 The method according to any one of embodiments 32-39, wherein the pH value is adjusted to below 7 after the second reaction in step (2) is completed.
  • Embodiment 41 The method according to embodiment 40, wherein the pH value is adjusted to 4-5 after the second reaction in step (2) is completed.
  • Embodiment 42 A method according to any one of embodiments 33-41, wherein the pH value of the reaction solution is adjusted to 6-8 before adding the catalyst.
  • Embodiment 43 A method according to any one of the preceding embodiments, wherein the leaving group reagent is a halogenating agent.
  • Embodiment 44 The method according to embodiment 43, wherein the leaving group reagent is selected from the group consisting of HCl, HBr, HI, phosgene, SOCl2 , oxalyl chloride, trimethylsilyl halide, sodium iodide (NaI), triethylsilane+palladium chloride+methyl iodide, POCl3 , PCl3 , PCl5 , PBr3 , PI3 , H2SO4 +KBr, P+ Cl2 , P + Br2 , P+ I2 , TiCl4 , ZnCl2 , BBr3 , and any combination thereof.
  • the leaving group reagent is selected from the group consisting of HCl, HBr, HI, phosgene, SOCl2 , oxalyl chloride, trimethylsilyl halide, sodium iodide (NaI), triethylsi
  • Embodiment 45 The method of embodiment 44, wherein the leaving group reagent is iodotrimethylsilane.
  • Embodiment 46 A method according to any one of embodiments 2 to 4, wherein step (2) also includes an amino conversion reaction.
  • Embodiment 47 A method according to embodiment 46, wherein the amino conversion reaction comprises reacting a transaminase with an amino donor.
  • Embodiment 48 A method according to embodiment 47, wherein the amino donor is selected from the following group: alanine, ⁇ -methylbenzylamine, glutamic acid, phenylalanine, glycine, 3-aminobutyric acid, isopropylamine, 2-aminobutane, ⁇ -aminobutyric acid, ethylenediamine, propylenediamine, butylenediamine, pentanediamine, hexamethylenediamine and any salt thereof.
  • the amino donor is selected from the following group: alanine, ⁇ -methylbenzylamine, glutamic acid, phenylalanine, glycine, 3-aminobutyric acid, isopropylamine, 2-aminobutane, ⁇ -aminobutyric acid, ethylenediamine, propylenediamine, butylenediamine, pentanediamine, hexamethylenediamine and any salt thereof.
  • Embodiment 49 A method according to embodiment 48, wherein the amino donor is alanine.
  • Embodiment 50 The method according to embodiment 49, wherein the amino donor is L-alanine.
  • Embodiment 51 A method according to any one of the preceding embodiments, wherein step (3) comprises subjecting the L-phosphinothricin precursor compound to a hydrolysis reaction under alkaline conditions.
  • Embodiment 52 A method according to embodiment 51, wherein after the hydrolysis reaction in step (3) is completed, the pH of the reaction solution is adjusted to a range of 5-6 at -10 to 10°C.
  • Embodiment 53 The method according to embodiment 52, wherein the pH value is adjusted by dropwise addition of an acidic solution (e.g., hydrochloric acid).
  • an acidic solution e.g., hydrochloric acid
  • Embodiment 54 The method of any one of the preceding embodiments, wherein the L-glufosinate comprises an L-glufosinate salt.
  • Embodiment 55 A method according to embodiment 54, wherein the L-glufosinate salt is selected from the group consisting of L-glufosinate hydrochloride, L-glufosinate sulfate, L-glufosinate carbonate, L-glufosinate ammonium salt, L-glufosinate sodium salt and L-glufosinate potassium salt.
  • the L-glufosinate salt is selected from the group consisting of L-glufosinate hydrochloride, L-glufosinate sulfate, L-glufosinate carbonate, L-glufosinate ammonium salt, L-glufosinate sodium salt and L-glufosinate potassium salt.
  • Embodiment 56 The method of embodiment 55, wherein the L-glufosinate salt is L-glufosinate ammonium salt.
  • Agilent 1260 high performance liquid chromatograph with diode array detector and autosampler; Agilent chromatography workstation; Milli-Qreference ultrapure water preparation system: stainless steel chromatographic column: 150 mm ⁇ 4.6 mm, filled with SUMICHIRAL OA-5000L (5 ⁇ m) filler.
  • a SUMICHIRAL OA-5000 chiral column was used as the chromatographic column, and a mixture of 0.5 g copper sulfate, 3 mL acetonitrile and water to make up to 1000 mL was used as the mobile phase, with a flow rate of 0.5 mL/min.
  • This example specifically includes the synthesis of two differently substituted cyclic lactones, namely, dihydrofuran-2,3-dione or L-aminovalerolactone.
  • This example prepares L-glufosinate from a non-chiral cyclic lactone (dihydrofuran-2,3-dione), which includes three synthetic steps in total.
  • Pure dihydrofuran-2,3-dione (100 g, 1 mol, compound B) was mixed with 100 ml of n-butanol as an organic solvent.
  • the mother liquor was then added with 0.2 g of SO 4 2- /ZrO 2 -SnO 2 -Nd 2 O 3 as a catalyst. After the addition was completed, a temperature program was started. The reaction solution was heated to 118°C over 1 hour, maintained at 118°C and reacted for 5 hours, and then cooled to 10°C. The pH value was adjusted to 4-5 with 1N hydrochloric acid, and then the solvent was removed. 100 ml of water was added, and then ethyl acetate (100 ml ⁇ 2) was added to extract the reaction system, and the organic phase was separated. Removal of solvent gave crude compound E, which was used in the next step without further purification.
  • Table 1 lists the results of the yield and ee value of the final product L-phosphine ammonium obtained by using different organic solvents while fixing the base reagent and the phosphine reagent in Example II-1 of the present invention (synthesis of compound E from compound B).
  • Table 2 lists the results of the yield and ee value of the final product L-phosphine ammonium obtained by using different alkali reagents while fixing the organic solvent and the phosphine reagent in Example II-1 of the present invention (synthesis of compound E from compound B).
  • the alkaline reagents n-butyl lithium, sodium methoxide, and sodium ethoxide all showed acceptable results, including higher yields and higher ee values.
  • sodium methoxide showed the best results, with a yield of 96.2% and an ee value of 99.6% for L-phosphinothion.
  • Table 3 lists the results of the yield and ee value of the final product L-phosphine ammonium obtained by using different phosphine reagents while keeping the organic solvent and the alkaline reagent fixed in Example II-1 of the present invention (synthesis of compound E from compound B).
  • the phosphine reagents ethyl methyl phosphite, methyl phosphite, phenyl methyl phosphite, and dimethyl methyl phosphite all showed acceptable results, including higher yields and higher ee values.
  • dimethyl methyl phosphite showed the best results, with a L-phosphine yield of 96.2% and an ee value of 99.6%.
  • L-phosphinothricin is prepared from a chiral cyclic lactone (L-aminovalerolactone).
  • L-aminovalerolactone (101 g, 1 mol, compound D-H) was mixed with 200 ml of dichloromethane and cooled to 0°C. To the mixture was slowly added p-toluenesulfonyl chloride (190 g, 1 mol) as a protecting group reagent. After the addition was complete, the temperature of the reaction mixture was returned to room temperature and stirred at this temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was crude p-toluenesulfonyl (Ts) protected L-aminovalerolactone (compound D-Ts), which was used in the next step without further purification.
  • Ts p-toluenesulfonyl
  • Table 5 lists the results of the yield and ee value of the final product L-phosphinothion in Example III-1 of the present invention (synthesis of Compound F from Compound D) when using or not using a catalyst while keeping all other conditions fixed.
  • Example III-1 200 ml of sodium hydroxide aqueous solution was added to the compound F-H obtained in Example III-1, and the mixture was heated to 60°C and reacted at this temperature for 3 hours. The progress of the reaction was monitored by liquid chromatography. When the starting material content was observed to be ⁇ 0.1%, the hydrolysis reaction was completed.
  • Comparative Example IV corresponds to the prior art method for preparing L-glufosinate described above, which includes the following three steps in total.
  • the mixture was stirred at 60° C. for 3 hours to obtain a methanol solution of compound H-Ts-I.
  • Methanol was removed by distillation under reduced pressure to obtain a crude compound H-Ts-I.
  • the crude compound H-Ts-I obtained in comparative example IV-1 is dissolved in 200 ml of n-butanol.
  • Sodium methoxide (64.8 g, 1.2 mol) as an alkaline reagent and dimethyl methyl phosphite (108 g, 1 mol) as a phosphine reagent are added thereto.
  • the mixture is reacted at 120°C for 6 hours.
  • the system is cooled to 10°C.
  • the pH value is adjusted to 4-5 with 1N hydrochloric acid, and the solvent is removed.
  • 100 ml of water is added, followed by ethyl acetate (100 ml ⁇ 2) to extract the reaction system, and the organic phase is separated. After removing the solvent, the crude compound F-Ts is obtained.
  • the method of the present invention has the advantages of short steps, high yield and high purity, cheap and easy to obtain raw materials, mild reaction conditions and easy to achieve, etc.

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Abstract

本申请提供了一种L-草铵膦的制备方法，该方法主要包括以下步骤：以取代磷酸酯类膦试剂与环内酯进行加成、重排开环反应，随后经后处理得到L-草铵膦。在本申请中，利用取代磷酸酯类化合物与环内酯化合物反应的方法来制备L-草铵膦，并且在所述方法中不使用离去基试剂。该方法具有步骤短、收率高、由于原料为手性化合物而使部分路线无需拆分等优点。

Description

利用膦试剂制备L-草铵膦的方法 技术领域
本申请涉及一种利用膦试剂(例如，磷酸酯类试剂)制备L-草铵膦的方法。更具体地，本申请涉及以环内酯为原料、以取代磷酸酯为膦试剂，经过加成、重排开环反应、以及随后的后处理制备L-草铵膦的方法，并且在所述方法中不使用离去基试剂。
背景技术
草铵膦，又名草丁膦，化学名称为2-氨基-4-[羟基(甲基)膦酰基]丁酸铵，是德国赫斯特(Hoechst)公司开发的高效、广谱、低毒的非选择性除草剂。目前市售草铵膦多为外消旋体，但是实际上只有L-草铵膦具有除草活性。因此，开发更为优化的L-草铵膦生产工艺对于提高原子经济性、降低成本、减轻环境压力等方面均具有非常重要的意义。
美国专利US5767309A报道了一种方法，其利用奎宁与草铵膦成盐后结晶，再利用3,5-二硝基水杨醛在乙酸条件下消旋，最终得到L-草铵膦，获得收率86％，ee值99％。该方法能够实现从D-草铵膦到L-草铵膦的转化，但收率偏低，且原料奎宁和3,5-二硝基水杨醛价格较高，回收率对成本影响较大。
专利WO2006104120A1报道以不对称催化加氢法制备L-草铵膦。具体地，亚磷酸单酯与丙烯酸乙酯反应后，与草酸二乙酯进行克莱森缩合反应，产物经热消除后得到酮酸中间体，再与乙酰胺反应制备不对称氢化反应的底物烯胺。以手性磷配体铑催化剂催化不对称氢化反应，经水解转化得到精草铵膦，ee值最高为95.6％。该路线以不对称氢化法构建手性中心，反应条件 温和，收率高，但需要手性磷配体铑催化剂加氢回收困难，生产成本高。
中国专利CN107502647B介绍了采用两种酶的一锅法实现从DL-草铵膦到L-草铵膦的转化，其中D-草铵膦被D-氨基酸氧化酶氧化，再在还原酶和NADPH的作用下被还原成DL-草氨膦，而L-草铵膦则不被D-氨基酸氧化酶氧化。该方法的L-草铵膦收率为95％，ee值为98.8％。但是辅酶NADPH价格较贵，需要额外的再生系统，再生率需要验证，酶的体系及辅酶体系比较复杂，L-草铵膦提纯的难度较大。
专利CN113316580A公开了一种L-草铵膦的制备方法，其主要利用了L-内酯衍生物和膦试剂之间的反应，其中产物L-草铵膦收率为81.4％，并且反应过程中会使用三甲基碘硅烷等离去试剂，成本较高。
因此，本发明想要克服L-草铵膦合成领域所遇到的上述技术挑战，期望提供一种原子经济性高、环境友好、成本较低的制备L-草铵膦的方法。
发明内容
本申请提供了由环内酯制备L-草铵膦的方法，所述方法包括：
(1)将环内酯与有机溶剂混合；
(2)向步骤(1)得到的环内酯与有机溶剂的混合溶液中加入膦试剂和碱试剂，使环内酯与膦试剂在碱试剂的存在下进行反应，得到L-草铵膦前体化合物；
(3)通过化学或生物方法处理L-草铵膦前体化合物，得到产物L-草铵膦；
前提条件是在所述方法中不使用离去基试剂。
在一些实施方式中，上述步骤(1)中所述的环内酯为二氢呋喃-2,3-二酮。在一些实施方式中，通过如下所述的方法制备所述二氢呋喃-2,3-二酮：
(a)提供2-氧代-4-羟基丁酸钠；
(b)在消去反应条件下，使2-氧代-4-羟基丁酸钠进行消去反应，得到二 氢呋喃-2,3-二酮。
在一些实施方式中，上述步骤(b)中的消去反应条件包括使用98％浓硫酸。
在一些实施方式中，所述步骤(1)中所述的环内酯为L-氨基戊内酯。在一些实施方式中，通过如下所述的方法制备所述L-氨基戊内酯：
(i)提供高丝氨酸盐；
(ii)在消去反应条件下，使高丝氨酸盐进行消去反应，得到L-氨基戊内酯；
在一些实施方式中，所述制备L-氨基戊内酯的方法还包括：
(iii)对L-氨基戊内酯上的氨基进行保护。
在一些实施方式中，所述步骤(ii)中的消去反应条件包括使用49％硫酸溶液。
在一些实施方式中，所述氨基的保护基团选自下组：叔丁氧羰基(Boc)、对甲苯磺酰基(Ts)、甲磺酰基(Ms)、甲基(CH3)、苯甲酰基(Bz)和苄基(Bn)。在一些实施方式中，所述氨基的保护基团选自下组：对甲苯磺酰基、甲磺酰基、苯甲酰基和苄基。在一些实施方式中，所述氨基的保护基团选自下组：对甲苯磺酰基、甲磺酰基和苄基。在一些实施方式中，所述氨基的保护基团选自下组：对甲苯磺酰基和甲磺酰基。在一些实施方式中，所述氨基的保护基团为对甲苯磺酰基。
在一些实施方式中，所述步骤(1)中所述的有机溶剂选自下组：C1-6烷醇、四氢呋喃、甲苯、二甲基甲酰胺和C1-6氯代烷烃。在一些实施方式中，所述步骤(1)中所述的有机溶剂选自下组：甲醇、乙醇、正丙醇、正丁醇、甲苯、二氯甲烷、氯仿、四氯化碳、二甲基甲酰胺和四氢呋喃。在一些实施方式中，所述步骤(1)中所述的有机溶剂选自下组：正丙醇、正丁醇和甲苯。在一些实 施方式中，所述步骤(1)中所述的有机溶剂选自下组：正丁醇和甲苯。在一些实施方式中，所述步骤(1)中所述的有机溶剂为正丁醇。
在一些实施方式中，所述步骤(2)中所述的膦试剂选自下组：甲基磷酸烷基酯或其盐、甲基磷酸取代苯酯或其盐、甲基亚磷酸二烷基酯和甲基亚磷酸二取代苯酯。在一些实施方式中，所述步骤(2)中所述的膦试剂选自下组：甲基磷酸烷基酯或其金属膦盐、甲基磷酸取代苯酯或其金属膦盐、甲基亚磷酸二烷基酯和甲基亚磷酸二取代苯酯。在一些实施方式中，所述步骤(2)中所述的膦试剂选自下组：甲基次磷酸甲酯、甲基次磷酸乙酯、甲基次磷酸异丙酯、甲基次磷酸正丁酯、甲基次磷酸苯酯、甲基次磷酸苯甲酯、甲基次磷酸氯苯酯、甲基亚磷酸二甲酯、甲基亚磷酸二乙酯和甲基亚磷酸二苯酯。在一些实施方式中，所述步骤(2)中所述的膦试剂选自下组：甲基次磷酸苯甲酯、甲基次磷酸正丁酯、甲基次磷酸异丙酯、甲基次磷酸乙酯、甲基次磷酸甲酯、甲基次磷酸苯酯和甲基亚磷酸二甲酯。在一些实施方式中，所述步骤(2)中所述的膦试剂选自下组：甲基次磷酸乙酯、甲基次磷酸甲酯、甲基次磷酸苯酯和甲基亚磷酸二甲酯。在一些实施方式中，所述步骤(2)中所述的膦试剂选自下组：甲基次磷酸甲酯和甲基亚磷酸二甲酯。在一些实施方式中，所述步骤(2)中所述的膦试剂为甲基亚磷酸二甲酯。
在一些实施方式中，所述步骤(2)中所述的碱试剂选自下组：碱金属碳酸盐、碱金属氢氧化物、C1-6醇钠、有机锂化合物和碱金属氢化物。在一些实施方式中，所述步骤(2)中所述的碱试剂选自下组：甲醇钠、乙醇钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、二异丙基氨基锂、正丁基锂、氢化铝锂和氢化钠。在一些实施方式中，所述步骤(2)中所述的碱试剂选自下组：氢化铝锂、氢化钠、正丁基锂、二异丙基氨基锂、甲醇钠和乙醇钠。在一些实施方式中，所述步骤(2)中所述的碱试剂选自下组：正丁基锂、甲醇钠和乙醇钠。在一些实施方式中，所述步骤(2)中所述的碱试剂为甲醇钠。
在一些实施方式中，所述步骤(2)包括两步反应。在一些实施方式中，所 述步骤(2)包括羰基加成反应和开环反应。在一些实施方式中，所述步骤(2)包括羰基加成反应和加热重排开环反应。
在一些实施方式中，所述步骤(2)中的第一个反应的反应温度控制在0-45℃，第二个反应的反应温度控制在90-120℃。
在一些实施方式中，所述步骤(2)在催化剂的存在下进行。在一些实施方式中，所述催化剂为固体酸催化剂。在一些实施方式中，所述固体酸催化剂为SO4 2-/ZrO2-SnO2-Nd2O3。在一些实施方式中，在所述步骤(2)中的所述第一个反应之后、所述第二个反应之前加入所述催化剂。
在一些实施方式中，在所述步骤(2)中的所述第一个反应的反应时间控制在20-40分钟，所述第二个反应的反应时间控制在4-6小时。在一些实施方式中，在所述步骤(2)中的所述第一个反应结束之后，在0.5-1.5小时内程序升温至所述第二个反应所需的温度。在一些实施方式中，在所述步骤(2)中的所述第二个反应结束之后降温至0-20℃。
在一些实施方式中，在所述步骤(2)中的所述第二个反应结束之后将pH值调节至7以下。在一些实施方式中，在所述步骤(2)中的所述第二个反应结束之后将pH值调节至4-5。在一些实施方式中，在加入所述催化剂之前调整反应液的pH值至6-8。
在一些实施方式中，本发明所述的由环内酯制备L-草铵膦的方法中不使用离去基试剂，所述离去基试剂是卤化剂。在一些实施方式中，本发明所述的由环内酯制备L-草铵膦的方法中不使用离去基试剂，所述离去基试剂选自下组：HCl、HBr、HI、碳酰氯、SOCl2、草酰氯、三甲基硅卤化物、碘化钠(NaI)、三乙基硅烷+氯化钯+甲基碘、POCl3、PCl3、PCl5、PBr3、PI3、H2SO4+KBr、P+Cl2、P+Br2、P+I2、TiCl4、ZnCl2、BBr3及其任何组合。在一些实施方式中，本发明所述的由环内酯制备L-草铵膦的方法中不使用离去基试剂，所述离去基试剂为三甲基碘硅烷。
在一些实施方式中，所述步骤(2)还包括氨基转换反应。在一些实施方式中，所述氨基转换反应包括将转氨酶与氨基供体进行反应。在一些实施方式中，所述氨基供体选自下组：丙氨酸、α-甲基苄基胺、谷氨酸、苯丙氨酸、甘氨酸、3-氨基丁酸、异丙胺、2-氨基丁烷、γ-氨基丁酸、乙二胺、丙二胺、丁二胺、戊二胺、己二胺和其中任何一种的盐。在一些实施方式中，所述氨基供体为丙氨酸。在一些实施方式中，所述氨基供体为L-丙氨酸。
在一些实施方式中，所述转氨酶选自下组：大肠杆菌ω-转氨酶(Genbank登录号NP_417544.5)、青紫色杆菌ω-转氨酶(Genbank登录号AAQ59697.1)、铜绿假单胞菌ω-转氨酶(Genbank登录号AAG08191.1)、丁香假单胞菌ω-转氨酶(Genbank登录号AAY39893.1)、球形红杆菌ω-转氨酶(Genbank登录号ABA81135.1)、河流弧菌ω-转氨酶(Genbank登录号AEA39183.1)。
在一些实施方式中，所述步骤(3)包括使所述L-草铵膦前体化合物在碱性条件下进行水解反应。在一些实施方式中，步骤(3)中的所述水解反应完成之后，在-10至10℃条件下将反应溶液的pH调节至5-6的范围内。在一些实施方式中，其中通过滴加酸性溶液(例如，盐酸)调节所述pH值。
在一些实施方式中，所述L-草铵膦包含L-草铵膦盐。在一些实施方式中，所述L-草铵膦盐选自下组：L-草铵膦盐酸盐、L-草铵膦硫酸盐、L-草铵膦碳酸盐、L-草铵膦铵盐、L-草铵膦钠盐和L-草铵膦钾盐。在一些实施方式中，所述L-草铵膦盐为L-草铵膦铵盐。
具体实施方式
在下文中，将更详细地描述L-草铵膦的制备方法。
以下描述的本申请的发明构思可以以各种形式进行修改并且可以具有各种实施方式，因此将详细说明和描述具体实施方式。然而，所述实施方式并非旨在限制本申请的发明构思，而应当理解的是，本发明包括属于本申请的发明构思的技术范围的所有修改方案、等同方案和替换方案。
标题和其它标识符，例如(1)、(2)、(a)、(b)、(i)、(ii)等，仅为了便于阅读说明书和权利要求书而给出。在说明书或权利要求书中使用标题或其它标识符时不是必须要求步骤或要素以字母或数字顺序或它们被呈现的顺序执行。
当在权利要求书和/或说明书中与术语“包括”、“包含”、“含有”等结合使用时，使用的词语“一”或“一个”可表示“一种”，但也可以与“一种或多种”、“至少一种”和“一种或多于一种”的含义一致。
定义
术语“约”用于表示数值包括使用的装置或方法的误差的标准偏差以便确定该数值。通常，术语“约”意在表示至多10％的可能的变化。因此，某数值的1％～10％(例如，1％、2％、3％、4％、5％、6％、7％、8％、9％、10％以及上述任何两个数值之间的数值)范围内的变化包括在术语“约”中。除非另有说明，否则在某范围前使用的术语“约”也适用于该范围的两个端点。
本申请使用的术语“包含”(和任何形式的包含)、“具有”(和任何形式的具有)、“包括”(和任何形式的包括)或“含有”(和任何形式的含有)是包容性或开放式的，且不排除另外的未记载的要素、工艺或方法步骤。
如本文中所使用，术语“Ci-j”指示碳原子数的范围，其中i和j为整数，并且碳原子数的范围包括端点(即i和j)和介于其间的每个整数点，并且其中j大于i。举例来说，C1-6指示一至六个碳原子的范围，包括一个碳原子、两个碳原子、三个碳原子、四个碳原子、五个碳原子和六个碳原子。
不论作为另一术语的一部分还是独立地使用，如本文中所使用，术语“烷基”是指饱和直链或分支链烃基。术语“Ci-j烷基”是指具有i至j个碳原子的烷基。例如，“C1-6烷基”的实例包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、新戊基和异戊基。
本申请的化合物可包括不对称中心，并且因此可以各种立体异构形式存 在，例如对映异构体。因此，本发明化合物和其组合物可呈个别对映异构体，或可呈立体异构体的混合物形式。在某些实施方式中，本申请的化合物是对映纯化合物。
当特定对映异构体为优选的时，在一些实施方式中其可提供为基本上不含相对对映异构体，并且还可称作“光学纯”。如本文中所使用，“光学纯”意指化合物包括显著较大比例的一种对映异构体。在某些实施方式中，化合物包括至少约90重量％的优选对映异构体。在其它实施方式中，化合物包括至少约95重量％、98重量％或99重量％的优选对映异构体。
如本文所用，术语“L-”或“D-”是指具有不对称中心的化合物的L-异构体或D-异构体。例如，术语“L‐草铵膦”是草铵膦的L‐异构体，术语“D‐草铵膦”是草铵膦的D‐异构体。
术语“％对映体过量”、“％ee”或“ee值”是指样品的对映体纯度，即样品中一种对映体的超出另一种对映体的百分比。例如，L‐草铵膦的对映体过量是草铵膦中L‐草铵膦的超出D‐草铵膦的百分比。例如，L‐草铵膦的对映体过量由以下等式1表示：
应理解，％对映体过量可以通过本领域常规技术手段(如手性高效液相色谱(chiral-HPLC))表征，其测量误差受所选用的检测器的灵敏度和精确度的影响。使用常用检测器如紫外吸收检测器(UV)、荧光检测器(FLD)、视差折光检测器(RID)或二极管阵列检测器(DAD)时，％对映体过量的误差通常为约±5％。
本文所使用的术语“草铵膦”指的是2-氨基-4-[羟基(甲基)膦酰基]丁酸铵或者2-氨基-4-[羟基(甲基)膦酰基]丁酸及其任何形式的盐、溶剂化物、水合物、立体异构体、衍生物等。在本申请中，2-氨基-4-[羟基(甲基)膦酰基]丁 酸的盐也称为“草铵膦盐”。例如，2-氨基-4-[羟基(甲基)膦酰基]丁酸的盐酸盐称为“草铵膦盐酸盐”，2-氨基-4-[羟基(甲基)膦酰基]丁酸的硫酸盐称为“草铵膦硫酸盐”。
在一些实施方式中，本发明所述的草铵膦包括草铵膦的任何形式的盐，例如，草铵膦的盐酸盐、硫酸盐、碳酸盐、铵盐、钠盐、钾盐等。在一些实施方式中，本发明所述的L-草铵膦包含L-草铵膦盐。在一些实施方式中，所述L-草铵膦盐选自下组：L-草铵膦盐酸盐、L-草铵膦硫酸盐、L-草铵膦碳酸盐、L-草铵膦铵盐、L-草铵膦钠盐和L-草铵膦钾盐。在一些实施方式中，所述L-草铵膦盐为L-草铵膦铵盐。
制备方法
本申请提供了一种由环内酯制备L-草铵膦的方法，所述方法包括：
(1)将环内酯与有机溶剂混合；
(2)向步骤(1)得到的环内酯与有机溶剂的混合溶液中加入膦试剂和碱试剂，使环内酯与膦试剂在碱试剂的存在下进行反应，得到L-草铵膦前体化合物；
(3)通过化学或生物方法处理L-草铵膦前体化合物，得到产物L-草铵膦；
前提条件是在所述方法中不使用离去基试剂。
以下分别详细描述本申请所述的L-草铵膦的制备方法的步骤(1)、步骤(2)和步骤(3)。
步骤(1)
在本申请的由环内酯制备L-草铵膦的方法中，步骤(1)包括将环内酯与有机溶剂混合。
本申请中的术语“环内酯”指的是含有至少一个(例如，1个、2个、3个、4个、5个或更多个)酯基(-COO-)的环状有机物，并且至少一个酯基 位于环上。环内酯的环状结构上可以含有一个羰基(-CO-)，也可以含有多个(例如，2个、3个、4个、5个或更多个)羰基。在某些实施方式中，在本发明所述由环内酯制备L-草铵膦的方法中，步骤(1)中所述的环内酯选自：含有手性氨基的环内酯、不含手性氨基的环内酯。在某些实施方式中，步骤(1)中所述的环内酯选自：二氢呋喃-2,3-二酮、L-氨基戊内酯。在另一种具体的实施方式中，步骤(1)中所述的环内酯为二氢呋喃-2,3-二酮。在一种具体的实施方式中，步骤(1)中所述的环内酯为L-氨基戊内酯。
在一些实施方式中，步骤(1)中所述的环内酯为二氢呋喃-2,3-二酮，并且具有如下化学式：(在本申请中也称为“化合物B”)。在某些实施方式中，通过如下所述的方法制备所述二氢呋喃-2,3-二酮：
(a)提供2-氧代-4-羟基丁酸钠；
(b)在消去反应条件下，使2-氧代-4-羟基丁酸钠进行消去反应，得到二氢呋喃-2,3-二酮。
本领域技术人员可以使用本领域已知的方法调整步骤(b)的消去反应条件。在一些实施方式中，步骤(b)中的消去反应条件包括使用硫酸(例如，浓硫酸)，例如，98％浓硫酸。本领域技术人员可以根据需要调整2-氧代-4-羟基丁酸钠与浓硫酸的配比。在一些实施方式中，基于1当量的2-氧代-4-羟基丁酸钠，浓硫酸的量是0.1至10当量。在一些实施方式中，基于1当量的2-氧代-4-羟基丁酸钠，浓硫酸的量是0.1当量、0.2当量、0.3当量、0.4当量、0.5当量、0.6当量、0.7当量、0.8当量、0.9当量、1当量、2当量、3当量、4当量、5当量、6当量、7当量、8当量、9当量或10当量，包括其间任何值或任意值之间的范围。
在一些实施方式中，由2-氧代-4-羟基丁酸钠制备二氢呋喃-2,3-二酮的收率为至少10％。在一些实施方式中，由2-氧代-4-羟基丁酸钠制备二氢呋喃- 2,3-二酮的收率为至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％、至少95％、至少96％、至少97％、至少98％或至少99％。
在一些实施方式中，步骤(1)中所述的环内酯为L-氨基戊内酯，并且具有如下化学式：(在本申请中也称为“化合物D”)，其中R1为氢或者氨基的保护基。所述氨基的保护基可以是本领域技术人员能理解的常见的保护基，如：烷基(包括芳基烷基)、烷氧羰基、磺酰基或酰基。具体地，在一些实施方式中，氨基的保护基团选自下组：叔丁氧羰基(Boc)、对甲苯磺酰基(Ts)、甲磺酰基(Ms)、C1-6烷基(例如，甲基、乙基、丙基、丁基、戊基、己基)、苯甲酰基(Bz)和苄基(Bn)。在一些实施方式中，氨基的保护基团选自下组：Ts、Ms、Bz和Bn。在一些实施方式中，氨基的保护基团选自下组：Ts、Ms和Bn。在一些实施方式中，氨基的保护基团选自下组：Ts和Ms。在一些实施方式中，氨基的保护基团为Ts。当R1为氢时，化合物D也称为“化合物D-H”；当R1为Ts时，化合物D也称为“化合物D-Ts”。
在一些实施方式中，通过如下所述的方法制备所述L-氨基戊内酯：
(i)提供高丝氨酸盐(例如，高丝氨酸钠盐)；
(ii)在消去反应条件下，使高丝氨酸盐(例如，高丝氨酸钠盐)进行消去反应，得到L-氨基戊内酯。
本领域技术人员可以使用本领域已知的方法调整步骤(ii)的消去反应条件。在一些实施方式中，步骤(ii)中的消去反应条件包括使用硫酸。在一些实施方式中，所述步骤(ii)中的消去反应条件包括使用49％硫酸溶液。本领域技术人员可以根据需要调整高丝氨酸盐(例如，高丝氨酸钠盐)与硫酸的配比。在一些实施方式中，基于1当量的高丝氨酸钠盐，硫酸的量是0.1至10当量。在一些实施方式中，基于1当量的高丝氨酸钠盐，硫酸的量是0.1当量、 0.2当量、0.3当量、0.4当量、0.5当量、0.6当量、0.7当量、0.8当量、0.9当量、1当量、2当量、3当量、4当量、5当量、6当量、7当量、8当量、9当量或10当量，包括其间任何值或任意值之间的范围。
在一些实施方式中，由高丝氨酸盐制备L-氨基戊内酯的收率为至少10％。在一些实施方式中，由高丝氨酸盐制备L-氨基戊内酯的收率为至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％、至少95％、至少96％、至少97％、至少98％或至少99％。
在一些实施方式中，当环内酯为L-氨基戊内酯时，在步骤(1)中，将L-氨基戊内酯与有机溶剂混合之后，不对L-氨基戊内酯上的氨基进行保护，换言之，R1为氢(H)。在一些实施方式中，在步骤(1)中，将L-氨基戊内酯与有机溶剂混合之后，对L-氨基戊内酯上的氨基进行保护。在一些实施方式中，氨基的保护基团可以选自下组：叔丁氧羰基(Boc)、对甲苯磺酰基(Ts)、甲磺酰基(Ms)、C1-6烷基(例如，甲基、乙基、丙基、丁基、戊基、己基)、苯甲酰基(Bz)和苄基(Bn)。优选地，氨基的保护基团选自下组：Ts、Ms、Bz和Bn。更优选地，氨基的保护基团选自下组：Ts、Ms和Bn。再更优选地，氨基的保护基团选自下组：Ts和Ms。再更优选地，氨基的保护基团为Ts。
本申请所使用的术语“有机溶剂”是指本领域技术人员所能理解的常见有机溶剂。示例性的有机溶剂包括但不限于：C1-6烷醇、四氢呋喃(THF)、甲苯、二甲基甲酰胺(DMF)、C1-6氯代烷烃。具体地，在一些实施方式中，有机溶剂选自下组：甲醇、乙醇、正丙醇、正丁醇、甲苯、二氯甲烷、氯仿、四氯化碳、DMF和THF。在一些实施方式中，有机溶剂选自下组：正丙醇、正丁醇和甲苯。在一些实施方式中，有机溶剂选自下组：正丁醇和甲苯。再更优选地，在一些实施方式中，有机溶剂为正丁醇。
在一些实施方式中，例如当环内酯为二氢呋喃-2,3-二酮时，步骤(1)中所述的有机溶剂选自下组：C1-6烷醇、四氢呋喃(THF)、甲苯、二甲基甲酰胺 (DMF)和C1-6氯代烷烃。具体地，步骤(1)中所述的有机溶剂选自下组：甲醇、乙醇、正丙醇、正丁醇、甲苯、二氯甲烷、氯仿、四氯化碳、DMF和THF。优选地，步骤(1)中所述的有机溶剂选自下组：正丙醇、正丁醇和甲苯。更优选地，步骤(1)中所述的有机溶剂选自下组：正丁醇和甲苯。再更优选地，步骤(1)中所述的有机溶剂为正丁醇。
在一些实施方式中，基于1重量份的环内酯，有机溶剂的量是0.1至10重量份。在另一些实施方式中，基于1重量份的环内酯，有机溶剂的量是0.1重量份、0.2重量份、0.3重量份、0.4重量份、0.5重量份、0.6重量份、0.7重量份、0.8重量份、0.9重量份、1重量份、2重量份、3重量份、4重量份、5重量份、6重量份、7重量份、8重量份、9重量份或10重量份，包括其间任何值或任意值之间的范围。
步骤(2)
在本申请的由环内酯制备L-草铵膦的方法中，步骤(2)包括：向步骤(1)得到的环内酯与有机溶剂的混合溶液中加入膦试剂和碱试剂，使环内酯与膦试剂在碱试剂的存在下进行反应，得到L-草铵膦前体化合物。
本申请所使用的术语“膦试剂”指的是任何可以与环内酯进行反应，并产生带有基团的反应产物的磷系化合物，其中R2为氢(H)或任何其他取代基或保护基。在一些实施方式中，膦试剂中的磷元素为五价磷。在一些实施方式中，膦试剂中的磷元素为三价磷。例如，膦试剂可以是包括化学式所表示的磷系化合物或其膦盐(例如，金属膦盐)，其中Ra和Rb各自独立地选自烷基(如：甲基、乙基、丙基、丁基)或任选地取代的苯基(如：苯基、甲苯基、氯苯基)。
在一些实施方式中，膦试剂选自下组：甲基磷酸烷基酯或其盐、甲基磷 酸取代苯酯或其盐、甲基亚磷酸二烷基酯和甲基亚磷酸二取代苯酯。在一些实施方式中，膦试剂选自下组：甲基磷酸烷基酯或其金属膦盐、甲基磷酸取代苯酯或其金属膦盐、甲基亚磷酸二烷基酯或甲基亚磷酸二取代苯酯。具体地，在一些实施方式中，膦试剂选自下组：甲基次磷酸甲酯、甲基次磷酸乙酯、甲基次磷酸异丙酯、甲基次磷酸正丁酯、甲基次磷酸苯酯、甲基次磷酸苯甲酯、甲基次磷酸氯苯酯、甲基亚磷酸二甲酯、甲基亚磷酸二乙酯和甲基亚磷酸二苯酯。在一些实施方式中，膦试剂选自下组：甲基次磷酸苯甲酯、甲基次磷酸正丁酯、甲基次磷酸异丙酯、甲基次磷酸乙酯、甲基次磷酸甲酯、甲基次磷酸苯酯和甲基亚磷酸二甲酯。在一些实施方式中，膦试剂选自：甲基次磷酸乙酯、甲基次磷酸甲酯、甲基次磷酸苯酯或甲基亚磷酸二甲酯。在一些实施方式中，膦试剂选自下组：甲基次磷酸甲酯和甲基亚磷酸二甲酯。在一些实施方式中，膦试剂为甲基亚磷酸二甲酯。
在一些实施方式中，基于1当量的环内酯，膦试剂的量是0.1至10当量。在一些实施方式中，基于1当量的环内酯，膦试剂的量是0.1当量、0.2当量、0.3当量、0.4当量、0.5当量、0.6当量、0.7当量、0.8当量、0.9当量、1当量、1.1当量、1.2当量、1.3当量、1.4当量、1.5当量、1.6当量、1.7当量、1.8当量、1.9当量、2当量、3当量、4当量、5当量、6当量、7当量、8当量、9当量或10当量，包括其间任何值或任意值之间的范围。
本申请所使用的术语“碱试剂”是指本领域技术人员所能理解的包括布朗斯特碱和路易斯(Lewis)碱在内的具有碱性的试剂。示例性的碱包括但不限于：碱金属碳酸盐、碱金属氢氧化物、C1-6醇钠、有机锂化合物和碱金属氢化物。具体地，在一些实施方式中，碱试剂选自下组：甲醇钠、乙醇钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、二异丙基氨基锂(LDA)、正丁基锂、氢化铝锂和氢化钠。在一些实施方式中，碱试剂选自下组：氢化铝锂、氢化钠、正丁基锂、LDA、甲醇钠和乙醇钠。在一些实施方式中，碱试剂选自下组：正丁基锂、甲醇钠和乙醇钠。在一些实施方式中，碱试剂为 甲醇钠。
在一些实施方式中，基于1当量的环内酯，碱试剂的量是0.1至10当量。在一些实施方式中，基于1当量的环内酯，碱试剂的量是0.1当量、0.2当量、0.3当量、0.4当量、0.5当量、0.6当量、0.7当量、0.8当量、0.9当量、1当量、1.1当量、1.2当量、1.3当量、1.4当量、1.5当量、1.6当量、1.7当量、1.8当量、1.9当量、2当量、3当量、4当量、5当量、6当量、7当量、8当量、9当量或10当量，包括其间任何值或任意值之间的范围。
本文所使用的术语“L-草铵膦前体化合物”是指经过一步或者多步反应之后可以生成L-草铵膦的化合物。在某些实施方式中，L-草铵膦前体化合物具有如下化学式(在本申请中也称为“化合物F”)：其中R1为氢或者氨基的保护基，R2为氢或任何其他取代基(例如，烷基)或保护基。例如，L-草铵膦前体化合物可以是氨基被保护的或未被保护的2-胺基4-[烷氧基(甲基)膦酰基]-L-丁酸。当R1为氢时，L-草铵膦前体化合物在本申请中也称为“化合物F-H”；当R1为Ts时，L-草铵膦前体化合物在本申请中也称为“化合物F-Ts”。
在某些实施方式中，步骤(2)包括两步反应，即，羰基加成反应和加热重排开环反应。在第一个反应中，环内酯与膦试剂在碱试剂的存在下进行羰基加成反应，形成中间体。在第二个反应中，中间体在加热条件下经历加热重排开环，得到L-草铵膦前体化合物。以甲基亚磷酸二甲酯为具体的膦试剂为例，环内酯与甲基亚磷酸二甲酯在碱的存在下经历羰基加成反应形成中间体，然后该中间体经加热重排开环反应形成链状丁酸产物。羰基加成反应和加热重排开环反应如以下方案I所示。
方案I
在一些实施方式中，在步骤(2)的第一个反应中，反应温度控制在0-45℃。在一些实施方式中，反应温度为0℃、5℃、10℃、15℃、20℃、25℃、30℃、35℃、40℃或45℃，包括其间任何值或任意值之间的范围。应理解，本申请所述的温度由本领域常见的方式(如酒精或电子温度计)表征和控制。反应温度受到控温介质、反应器容量和材质等因素影响。一般地，反应温度的测量误差为约±5℃。
在一些实施方式中，在步骤(2)的第一个反应中，反应时间控制在20-40分钟。在一些实施方式中，反应时间为20分钟、25分钟、30分钟、35分钟或40分钟，包括其间任何值或任意值之间的范围。
在一些实施方式中，所述步骤(2)在催化剂的存在下进行。在一些实施方式中，所述催化剂为固体酸催化剂。本发明的发明人意想不到地发现，在步骤(2)中加入固体酸催化剂可以避免使用离去基试剂。
本申请所使用的术语“离去基”是指在底物(例如，本申请中的环内酯)与亲核试剂(例如，本申请中的膦试剂)发生的取代反应中，从底物分子中带着至少一对电子断裂出去的原子或原子团。示例性的离去基包括但不限于：卤素(如：氯(Cl)、溴(Br)、碘(I))、羟基(或其质子化形式)、磺酰氧基(如：对甲苯磺酰氧基(TsO)、甲磺酰氧基(MsO)、三氟甲磺酰氧基(TfO)，或其质子化形式)、羧酸酯基(如：乙酰氧基(AcO)、苯甲酰氧基(BzO)，或其质子化形式)和碳酸脂基(如叔丁氧羰氧基(BocO)，或其质子化形式)。
本申请所使用的术语“离去基试剂”是指在底物(例如，本申请中的环内酯)与亲核试剂(例如，本申请中的膦试剂)反应中向底物中引入离去基 的试剂。在一些实施方式中，本发明所述的由环内酯制备L-草铵膦的方法中不使用离去基试剂，所述离去基试剂包括卤化剂。示例性的离去基试剂包括但不限于：HCl、HBr、HI、碳酰氯、SOCl2、草酰氯、三甲基硅卤化物、碘化钠(NaI)、三乙基硅烷((CH2CH3)3SiH)+氯化钯(PdCl2)+甲基碘(CH3I)、POCl3、PCl3、PCl5、PBr3、PI3、H2SO4+KBr、P+Cl2、P+Br2、P+I2、TiCl4、ZnCl2和BBr3。在一些实施方式中，本发明所述的由环内酯制备L-草铵膦的方法中不使用离去基试剂，所述离去基试剂是三甲基碘硅烷。
在某些实施方式中，本发明提供的由环内酯制备L-草铵膦的方法中(例如，在步骤(2)中)不使用离去基试剂。本发明首次发现，在本发明所述方法的步骤(2)中加入固体酸催化剂可以避免使用离去基试剂，特别是无需使用高成本的三甲基碘硅烷等离去基试剂。例如，在本发明中，化合物D与膦试剂经固体酸催化剂的催化直接生成L-草铵膦前体化合物(即，化合物F)，减少了反应步骤，节省了成本，并且提高了目标产物L-草铵膦的最终收率。在一些实施方式中，所述固体酸催化剂为SO4 2-/ZrO2-SnO2-Nd2O3。本发明中使用的固体酸催化剂是可商购的，或者是可以通过本领域已知的方法(例如，李淑敏等，“稀土固体超强酸SO4 2-/ZrO2-SnO2-Nd2O3的制备及催化合成乙酸松油酯”，应用化学，第26卷第5期，2009年5月)制备，例如在硫酸中浸渍含有稀土氧化物(例如，Nd2O3)的氧化物混合物，随后焙烧。在某些实施方式中，通过本申请实施例V所述的方法制备固体酸催化剂SO4 2-/ZrO2-SnO2-Nd2O3。
在本发明中，当采用非手性化合物作为起始原料时，也可以在较少的步骤中得到目标产物L-草铵膦，而且收率比现有技术方法显著提高。在一些实施方式中，例如当步骤(1)中使用的环内酯是不含手性氨基的环内酯时，步骤(2)还包括氨基转换反应。在一些实施方式中，所述氨基转换反应包括将转氨酶与氨基供体进行反应。
本文中的术语“氨基供体”指的是能够提供氨基的化合物。在一些实施 方式中，所述氨基供体选自下组：丙氨酸、α-甲基苄基胺、谷氨酸、苯丙氨酸、甘氨酸、3-氨基丁酸、异丙胺、2-氨基丁烷、γ-氨基丁酸、乙二胺、丙二胺、丁二胺、戊二胺、己二胺和其中任何一种的盐。在一些实施方式中，所述氨基供体为丙氨酸。在一些实施方式中，所述氨基供体为L-丙氨酸。在一些实施方式中，氨基转换反应引入的是手性氨基。在一些实施方式中，氨基转换反应引入的是L-氨基。
可以使用本领域中已知的方法将氨基供体中的氨基转移至氨基受体(例如，本发明中的环内酯)的酮基团。例如，转氨酶可以催化氨基基团、一对电子和质子从氨基供体转移至环内酯的羰基基团，从而产生带有手性胺的化合物。现有技术中已知多种转氨酶。例如，大肠杆菌ω-转氨酶(Genbank登录号NP_417544.5)、青紫色杆菌ω-转氨酶(Genbank登录号AAQ59697.1)、铜绿假单胞菌ω-转氨酶(Genbank登录号AAG08191.1)、丁香假单胞菌ω-转氨酶(Genbank登录号AAY39893.1)、球形红杆菌ω-转氨酶(Genbank登录号ABA81135.1)、河流弧菌ω-转氨酶(Genbank登录号AEA39183.1)。
在一些实施方式中，氨基转换反应的转化率为至少10％。在一些实施方式中，氨基转换反应的转化率为至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％、至少95％或至少98％。
在一些实施方式中，在步骤(2)中的所述第一个反应之后、所述第二个反应之前加入所述固体酸催化剂。在一些实施方式中，在加入所述固体酸催化剂之前调整反应液的pH值至6-8(例如，6、6.5、7、7.5、8或上述任何两个数值之间的任何值)。在一些实施方式中，在加入所述固体酸催化剂之前调整反应液的pH值至7。
在一些实施方式中，基于100重量份的环内酯，固体酸催化剂的量是0.01至1重量份。在一些实施方式中，基于100重量份的环内酯，固体酸催化剂的量是0.01重量份、0.02重量份、0.03重量份、0.04重量份、0.05重量份、 0.06重量份、0.07重量份、0.08重量份、0.09重量份、0.1重量份、0.11重量份、0.12重量份、0.13重量份、0.14重量份、0.15重量份、0.16重量份、0.17重量份、0.18重量份、0.19重量份、0.2重量份、0.21重量份、0.22重量份、0.23重量份、0.24重量份、0.25重量份、0.26重量份、0.27重量份、0.28重量份、0.29重量份、0.3重量份、0.4重量份、0.5重量份、0.6重量份、0.7重量份、0.8重量份、0.9重量份或1重量份，包括其间任何值或任意值之间的范围。
在一些实施方式中，在步骤(2)的第二个反应中，反应温度控制在90-120℃。在一些实施方式中，反应温度为90℃、95℃、100℃、105℃、110℃、111℃、112℃、113℃、114℃、115℃、116℃、117℃、118℃、119℃、或120℃，包括其间任何值或任意值之间的范围。
在一些实施方式中，在步骤(2)中的所述第一个反应结束之后，在0.5-1.5小时内程序升温至所述第二个反应所需的温度。不受任何理论的限制，但是认为程序升温有利于反应的进行。在一些实施方式中，升温时间为0.5小时、0.6小时、0.7小时、0.8小时、0.9小时、1小时、1.1小时、1.2小时、1.3小时、1.4小时或1.5小时。
在一些实施方式中，在步骤(2)的第二个反应中，反应时间控制在4-6小时。在一些实施方式中，反应时间为4小时、4.5小时、4.6小时、4.7小时、4.8小时、4.9小时、5小时、5.1小时、5.2小时、5.3小时、5.4小时、5.5小时或6小时，包括其间任何值或任意值之间的范围。
在一些实施方式中，在步骤(2)的第二个反应结束之后降温至0-20℃。在一些实施方式中，在步骤(2)的第二个反应结束之后降温至不高于20℃、不高于15℃、不高于10℃、不高于5℃或不高于0℃，包括其间任何值或任意值之间的范围。
在一些实施方式中，在步骤(2)的第二个反应结束之后将pH值调节至7 以下。在一些实施方式中，在步骤(2)的第二个反应结束之将pH值调节至7以下、6.5以下、6以下、5.5以下、5以下、4.5以下、4以下、3.5以下或3以下。在一些实施方式中，在步骤(2)的第二个反应结束之将pH值调节至7-6.5、6.5-6、6-5.5、5.5-5、5-4.5、4.5-4、4-3.5或3.5-3之间。
在一些实施方式中，步骤(2)制备L-草铵膦前体化合物的收率为至少10％。在一些实施方式中，步骤(2)制备L-草铵膦前体化合物的收率为至少10％至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％、至少95％、至少96％、至少97％、至少98％或至少99％。
步骤(3)
在本申请的由环内酯制备L-草铵膦的方法中，步骤(3)包括：通过化学或生物方法处理L-草铵膦前体化合物，得到产物L-草铵膦。
在一些实施方式中，所述步骤(3)包括使所述L-草铵膦前体化合物在碱性条件下进行水解反应。在一些实施方式中，所述步骤(3)中的所述水解反应完成之后，在不高于10℃的条件下调节反应溶液的pH。在一些实施方式中，所述步骤(3)中的所述水解反应完成之后，在-10至10℃的条件下调节反应溶液的pH。在一些实施方式中，所述步骤(3)中的所述水解反应完成之后，在不高于10℃、不高于9℃、不高于8℃、不高于7℃、不高于6℃、不高于5℃、不高于4℃、不高于3℃、不高于2℃、不高于1℃、不高于0℃、不高于-1℃、不高于-2℃、不高于-3℃、不高于-4℃、不高于-5℃、不高于-6℃、不高于-7℃、不高于-8℃、不高于-9℃、或不高于-10℃的条件下调节反应溶液的pH。在一些实施方式中，所述步骤(3)中的所述水解反应完成之后，将反应溶液的pH调节至1-7的范围内。在一些实施方式中，所述步骤(3)中的所述水解反应完成之后，将反应溶液的pH调节至1-7的范围内、1-6的范围内、2-6的范围内、3-6的范围内、4-6的范围内或5-6的范围内。
在一些实施方式中，通过滴加酸性溶液调节所述pH值。在一些实施方 式中，通过滴加无机酸或有机酸溶液调节所述pH值。在一些实施方式中，通过滴加硫酸、亚硫酸、盐酸、氢溴酸、磷酸、亚磷酸、次磷酸、偏磷酸、对甲苯磺酸、乙酸、三氟乙酸或甲酸溶液调节所述pH值。在一些实施方式中，通过滴加盐酸溶液调节所述pH值。在一些实施方式中，通过滴加约0.1N、约0.2N、约0.3N、约0.4N、约0.5N、约0.6N、约0.7N、约0.8N、约0.9N、约1N、约1.1N、约1.2N、约1.3N、约1.4N、约1.5N、约1.6N、约1.7N、约1.8N、约1.9N、约2N、约3N、约4N、约5N、约6N、约7N、约8N、约9N、约10N、约11N或约12N盐酸溶液调节所述pH值。在一些实施方式中，通过滴加约1N盐酸溶液调节所述pH值。
在一些实施方式中，步骤(3)制备L-草铵膦的收率为至少10％。在一些实施方式中，步骤(3)制备L-草铵膦的收率为至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％、至少95％、至少96％、至少97％、至少98％或至少99％。
在一些实施方式中，步骤(3)制备得到的L-草铵膦的ee值为至少80％。在一些实施方式中，步骤(3)制备L-草铵膦的ee值为至少80％、至少90％、至少95％、至少96％、至少97％、至少98％、至少99％、至少99.1％、至少99.2％、至少99.3％、至少99.4％、至少99.5％、至少99.6％、至少99.7％、至少99.8％或至少99.9％。
示例方法
在本发明产生之前，现有技术已经公开了一种利用L-氨基戊内酯和膦试剂之间的反应来制备L-草铵膦的方法，但是该方法过程中需要使用离去基试剂。现有技术中公开的方法的合成路线如下方案II所示。
方案II
其中，G为离去基，Ra根据反应条件和试剂的不同而不同，例如，Ra可以是氢、烷基(例如，甲基、乙基、丙基、丁基、戊基、己基等)、芳基(例如，苄基、苯基、萘基等)、-Si(CH3)(叔丁基)2、-Si(苯基)2(叔丁基)、-Si(异丙基)3、-Si(苯基)(CH3)2、-Si(苯基)2(CH3)、-Si(苯基)3、-Si(CH3)3、-Si(CH2CH3)3、-Si(CH2CH3)2(CH3)、-Si(CH2CH3)(CH3)2或-Si(叔丁基)3。
具体地，高丝氨酸钠盐(化合物C，L-2-氨基-4-羟基丁酸钠)成环形成L-氨基戊内酯(化合物D)，加入三甲基碘硅烷或其它离去基试剂，得到化合物H，该化合物H再与膦试剂反应得到L-草铵膦前体化合物(即，化合物F)，再经过脱保护及碱化或其它处理，得到目标产物L-草铵膦。由于该现有技术方法会用到例如三甲基碘硅烷等离去基试剂，成本较高，而且目标产物L-草铵膦的最终收率还有待提高的空间。
本发明可以使用非手性环内酯作为起始原料来制备L-草铵膦。在一些实施方式中，本发明的合成路线如以下方案III所示。
方案III
具体地，2-氧代-4-羟基丁酸钠(化合物A)在浓硫酸存在下经由消去反应成环形成二氢呋喃-2,3-二酮(化合物B)，该化合物B即为本发明使用的非手性起始原料。化合物B可以直接与膦试剂进行羰基加成反应生成羰基羧酸化合物E。化合物E在转氨酶的作用下可容易进行氨基转换反应，通过手性反应物L-丙氨酸引入手性氨基基团，得到光学纯的草铵膦的前体化合物(化合物F)。前体化合物F经过简单的化学或生物方法即可得到目标产物L-草铵膦。
而且，本发明还发现，当使用具有手性的化合物作为起始原料(如，上述现有技术中使用的化合物C，L-2-氨基-4-羟基丁酸钠)时，也可以在不使用较为昂贵的离去基试剂的情况下制备得到目标化合物L-草铵膦。如以下方案IV所示。
方案IV
其中，R1是氨基的保护基。
具体地，同上述现有技术方法，首先使高丝氨酸钠盐(化合物C，L-2-氨基-4-羟基丁酸钠)成环形成L-氨基戊内酯(化合物D)。然后直接使化合物D与膦试剂在固体酸催化剂(例如，SO4 2-/ZrO2-SnO2-Nd2O3)的催化作用下进行反应，得到化合物F，再经过脱保护及碱化或其它处理，得到目标产物L-草铵膦。
以下方案V中显示了对本发明使用非手性环内酯或手性环内酯为起始原料时的合成路线和现有技术合成路线的比较。可以看出，当采用非手性环内酯为起始原料时(“本发明方法1”)，从最初的不同取代的羟基丁酸起始直至得到最终的目标产物L-草铵膦，本发明路线和现有技术路线所用的总步骤数目相同，都是包含4个步骤。两者的不同在于，现有技术方法的环内酯在与膦试剂反应之前必须经过离去基试剂的处理，而本发明方法的环内酯可以直接与膦试剂反应，但是其产物需多经历一步氨基转换反应才能得到L-草铵膦前体化合物(化合物F)，因此两者总步骤数目相同。现有技术方法的涉及的离去基试剂处理步骤需要用到价格昂贵的三甲基碘硅烷等离去基试剂。相 比之下，本发明方法所涉及的氨基转换步骤仅需要用到L-丙氨酸和转氨酶等价格低廉的试剂，并且反应条件温和易于实现。而且，本发明方法直到前体形成步骤中才引入手性化合物，因此前期的反应中必然不会涉及到手性拆分的处理过程。由此可见，在本发明的该种方法中，起始原料无需含有手性氨基，也不需要在进行关键性的与膦试剂之间的反应之前，对反应物进行需要高成本处理步骤，例如手性拆分处理。本发明方法的所有步骤只需要相对廉价易得的试剂，反应条件温和易实现，而且所需步骤数目合理。另外，本发明方法的最后一步由前体化合物合成目标产物L-草铵膦的收率相比于现有技术方法显著提高。
另外，当本发明使用与现有技术相同的手性环内酯(L-氨基戊内酯，化合物D)为起始原料时(“本发明方法2”)，通过比较本发明的合成路线与现有技术合成路线的可以看出，本发明的该方法仅需3个步骤即可获得最终的目标产物L-草铵膦，而现有技术合成路线需4个步骤才能获得最终的目标产物L-草铵膦。因此，本发明所述的方法消除了对使用较昂贵离去基试剂的使用以及相关的步骤，降低了成本，并且实现了以较少步骤获得产物的优势。
方案V
本发明提供了如下实施方式。
实施方式1.一种由环内酯制备L-草铵膦的方法，所述方法包括：
(1)将环内酯与有机溶剂混合；
(2)向步骤(1)得到的环内酯与有机溶剂的混合溶液中加入膦试剂和碱试剂，使环内酯与膦试剂在碱试剂的存在下进行反应，得到L-草铵膦前体化合物；
(3)通过化学或生物方法处理L-草铵膦前体化合物，得到产物L-草铵膦；
前提条件是在所述方法中不使用离去基试剂。
实施方式2.根据实施方式1所述的方法，其中步骤(1)中所述的环内 酯为二氢呋喃-2,3-二酮。
实施方式3.根据实施方式2所述的方法，其中通过如下所述的方法制备所述二氢呋喃-2,3-二酮：
(a)提供2-氧代-4-羟基丁酸钠；
(b)在消去反应条件下，使2-氧代-4-羟基丁酸钠进行消去反应，得到二氢呋喃-2,3-二酮。
实施方式4.根据实施方式3所述的方法，其中步骤(b)中的消去反应条件包括使用98％浓硫酸。
实施方式5.根据实施方式1所述的方法，其中步骤(1)中所述的环内酯为L-氨基戊内酯。
实施方式6.根据实施方式5所述的方法，其中通过如下所述方法制备所述L-氨基戊内酯：
(i)提供高丝氨酸盐；
(ii)在消去反应条件下，使高丝氨酸盐进行消去反应，得到L-氨基戊内酯。
实施方式7.根据实施方式6所述的方法，其中不包括对L-氨基戊内酯上的氨基进行保护。
实施方式8.根据实施方式6所述的方法，其中还包括：
(iii)对L-氨基戊内酯上的氨基进行保护。
实施方式9.根据实施方式6至8中任一项所述的方法，其中步骤(ii)中的消去反应条件包括使用49％硫酸溶液。
实施方式10.根据实施方式8所述的方法，其中氨基的保护基团选自下组：叔丁氧羰基、对甲苯磺酰基、甲磺酰基、甲基、苯甲酰基和苄基。
实施方式11.根据实施方式8所述的方法，其中氨基的保护基团选自下组：对甲苯磺酰基、甲磺酰基、苯甲酰基和苄基。
实施方式12.根据实施方式8所述的方法，其中氨基的保护基团选自下组：对甲苯磺酰基、甲磺酰基和苄基。
实施方式13.根据实施方式8所述的方法，其中氨基的保护基团选自下组：对甲苯磺酰基和甲磺酰基。
实施方式14.根据实施方式8所述的方法，其中氨基的保护基团为对甲苯磺酰基。
实施方式15.根据前述实施方式中任一项所述的方法，其中步骤(1)中所述的有机溶剂选自下组：C1-6烷醇、四氢呋喃、甲苯、二甲基甲酰胺和C1- 6氯代烷烃。
实施方式16.根据前述实施方式中任一项所述的方法，其中步骤(1)中所述的有机溶剂选自下组：甲醇、乙醇、正丙醇、正丁醇、甲苯、二氯甲烷、氯仿、四氯化碳、二甲基甲酰胺和四氢呋喃。
实施方式17.根据前述实施方式中任一项所述的方法，其中步骤(1)中所述的有机溶剂选自下组：正丙醇、正丁醇和甲苯。
实施方式18.根据前述实施方式中任一项所述的方法，其中步骤(1)中所述的有机溶剂选自下组：正丁醇和甲苯。
实施方式19.根据前述实施方式中任一项所述的方法，其中步骤(1)中所述的有机溶剂为正丁醇。
实施方式20.根据前述实施方式中任一项所述的方法，其中步骤(2)中所述的膦试剂选自下组：甲基磷酸烷基酯或其盐、甲基磷酸取代苯酯或其盐、甲基亚磷酸二烷基酯和甲基亚磷酸二取代苯酯。
实施方式21.根据前述实施方式中任一项所述的方法，其中步骤(2)中 所述的膦试剂选自下组：甲基次磷酸甲酯、甲基次磷酸乙酯、甲基次磷酸异丙酯、甲基次磷酸正丁酯、甲基次磷酸苯酯、甲基次磷酸苯甲酯、甲基次磷酸氯苯酯、甲基亚磷酸二甲酯、甲基亚磷酸二乙酯和甲基亚磷酸二苯酯。
实施方式22.根据前述实施方式中任一项所述的方法，其中步骤(2)中所述的膦试剂选自下组：甲基次磷酸苯甲酯、甲基次磷酸正丁酯、甲基次磷酸异丙酯、甲基次磷酸乙酯、甲基次磷酸甲酯、甲基次磷酸苯酯和甲基亚磷酸二甲酯。
实施方式23.根据前述实施方式中任一项所述的方法，其中步骤(2)中所述的膦试剂选自下组：甲基次磷酸乙酯、甲基次磷酸甲酯、甲基次磷酸苯酯和甲基亚磷酸二甲酯。
实施方式24.根据前述实施方式中任一项所述的方法，其中步骤(2)中所述的膦试剂选自下组：甲基次磷酸甲酯和甲基亚磷酸二甲酯。
实施方式25.根据前述实施方式中任一项所述的方法，其中步骤(2)中所述的膦试剂为甲基亚磷酸二甲酯。
实施方式26.根据前述实施方式中任一项所述的方法，其中步骤(2)中所述的碱试剂选自下组：碱金属碳酸盐、碱金属氢氧化物、C1-6醇钠、有机锂化合物和碱金属氢化物。
实施方式27.根据前述实施方式中任一项所述的方法，其中步骤(2)中所述的碱试剂选自下组：甲醇钠、乙醇钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、二异丙基氨基锂、正丁基锂、氢化铝锂和氢化钠。
实施方式28.根据前述实施方式中任一项所述的方法，其中步骤(2)中所述的碱试剂选自下组：氢化铝锂、氢化钠、正丁基锂、二异丙基氨基锂、甲醇钠和乙醇钠。
实施方式29.根据前述实施方式中任一项所述的方法，其中步骤(2)中所述的碱试剂选自下组：正丁基锂、甲醇钠和乙醇钠。
实施方式30.根据前述实施方式中任一项所述的方法，其中步骤(2)中所述的碱试剂为甲醇钠。
实施方式31.根据前述实施方式中任一项所述的方法，其中步骤(2)包括两步反应。
实施方式32.根据实施方式31所述的方法，其中步骤(2)中的第一个反应的反应温度控制在0-45℃，第二个反应的反应温度控制在90-120℃。
实施方式33.根据前述实施方式中任一项所述的方法，其中步骤(2)在催化剂的存在下进行。
实施方式34.根据实施方式33所述的方法，其中所述催化剂为固体酸催化剂。
实施方式35.根据实施方式34所述的方法，其中所述固体酸催化剂为SO4 2-/ZrO2-SnO2-Nd2O3。
实施方式36.根据实施方式33-35中任一项所述的方法，其中在步骤(2)中的所述第一个反应之后、所述第二个反应之前加入所述催化剂。
实施方式37.根据实施方式32-36中任一项所述的方法，其中步骤(2)中的所述第一个反应的反应时间控制在20-40分钟，所述第二个反应的反应时间控制在4-6小时。
实施方式38.根据实施方式32-37中任一项所述的方法，其中步骤(2)中的所述第一个反应结束之后，在0.5-1.5小时内程序升温至所述第二个反应所需的温度。
实施方式39.根据实施方式32-38中任一项所述的方法，其中在步骤(2)中的所述第二个反应结束之后降温至0-20℃。
实施方式40.根据实施方式32-39中任一项所述的方法，其中在步骤(2)中的所述第二个反应结束之后将pH值调节至7以下。
实施方式41.根据实施方式40所述的方法，其中在步骤(2)中的所述第二个反应结束之后将pH值调节至4-5。
实施方式42.根据实施方式33-41中任一项所述的方法，其中在加入所述催化剂之前调整反应液的pH值至6-8。
实施方式43.根据前述实施方式中任一项所述的方法，其中所述离去基试剂是卤化剂。
实施方式44.根据实施方式43所述的方法，其中所述离去基试剂选自下组：HCl、HBr、HI、碳酰氯、SOCl2、草酰氯、三甲基硅卤化物、碘化钠(NaI)、三乙基硅烷+氯化钯+甲基碘、POCl3、PCl3、PCl5、PBr3、PI3、H2SO4+KBr、P+Cl2、P+Br2、P+I2、TiCl4、ZnCl2、BBr3及其任何组合。
实施方式45.根据实施方式44所述的方法，其中所述离去基试剂为三甲基碘硅烷。
实施方式46.根据实施方式2至4中任一项所述的方法，其中步骤(2)还包括氨基转换反应。
实施方式47.根据实施方式46所述的方法，其中所述氨基转换反应包括将转氨酶与氨基供体进行反应。
实施方式48.根据实施方式47所述的方法，其中所述氨基供体选自下组：丙氨酸、α-甲基苄基胺、谷氨酸、苯丙氨酸、甘氨酸、3-氨基丁酸、异丙胺、2-氨基丁烷、γ-氨基丁酸、乙二胺、丙二胺、丁二胺、戊二胺、己二胺和其中任何一种的盐。
实施方式49.根据实施方式48所述的方法，其中所述氨基供体为丙氨酸。
实施方式50.根据实施方式49所述的方法，其中所述氨基供体为L-丙氨酸。
实施方式51.根据前述实施方式中任一项所述的方法，其中步骤(3)包括使所述L-草铵膦前体化合物在碱性条件下进行水解反应。
实施方式52.根据实施方式51所述的方法，其中步骤(3)中的所述水解反应完成之后，在-10至10℃条件下将反应溶液的pH调节至5-6的范围内。
实施方式53.根据实施方式52所述的方法，其中通过滴加酸性溶液(例如，盐酸)调节所述pH值。
实施方式54.根据前述实施方式中任一项所述的方法，其中所述L-草铵膦包含L-草铵膦盐。
实施方式55.根据实施方式54所述的方法，其中所述L-草铵膦盐选自下组：L-草铵膦盐酸盐、L-草铵膦硫酸盐、L-草铵膦碳酸盐、L-草铵膦铵盐、L-草铵膦钠盐和L-草铵膦钾盐。
实施方式56.根据实施方式55所述的方法，其中所述L-草铵膦盐为L-草铵膦铵盐。
实施例
以下结合实施例和对比例对本申请作更详细的说明。但是，这些实施例仅用于说明目的，本申请的范围并不限于此。以下实施例和对比例中所使用的试剂，除非特别注明，均是商购的，且未经进一步处理直接使用。
以下表格总结了本文所涉及的化合物编号和化合物结构，其在本文范围内任意地可相互替代地使用。

主要表征方法
高效液相色谱(HPLC)
使用Agilent 1260高效液相色谱仪，具二极管阵列检测器和自动进样器；Agilent色谱工作站；Milli—Qreference超纯水制备系统：不锈钢色谱柱：150mm×4.6mm，内装SUMICHIRAL OA—5000L(5μm)填充物。
核磁共振谱(NMR)
使用Bruker 400HMz核磁共振波谱仪。
手性液相色谱(Chiral-HPLC)
以SUMICHIRAL OA-5000手性柱为色谱柱，以0.5g硫酸铜、3mL乙腈用水定容至1000mL的混合液作流动相，流速为0.5mL/min。
实施例I：环内酯的合成
本实施例具体地包括两种不同取代的环内酯的合成，即，二氢呋喃-2,3-二酮或L-氨基戊内酯。
实施例I-1二氢呋喃-2,3-二酮(化合物B)的合成
将2-氧代4-羟基-丁酸钠盐(140g，1mol，化合物A)溶于120g水中。然后于25℃向溶液中缓慢滴加98％浓硫酸(60g，0.6mol)。滴加完毕后，将反应混合物升温至50℃并在该温度反应3小时。通过液相色谱监测反应进程。当观察到原料含量<0.1％时，表明反应完全。
加入乙酸乙酯(150ml×2)对反应体系进行萃取，分液取有机相，然后脱除溶剂。将残余物放置于精馏塔进行精制，收集得到主馏分(20mmHg、140℃)，其为97.5g无色液体，即为二氢呋喃-2,3-二酮。收率97.5％，纯度99.9％。
实施例I-2 L-氨基戊内酯(化合物D-H)的合成
于50℃向高丝氨酸钠盐(141g，1mol，化合物C)中加入49％硫酸溶液 (120g，0.6mol)。加入完成后，将混合物在50℃搅拌1小时，然后升温至70℃并搅拌1小时。通过液相色谱监测反应进程。当反应完全时，将反应混合物用乙酸乙酯萃取，分液取有机相。脱除有机溶剂后得到粗制L-氨基戊内酯。收率97.7％，纯度94.8％。
实施例II：由非手性环内酯(二氢呋喃-2,3-二酮)制备L-草铵膦
本实施例由非手性环内酯(二氢呋喃-2,3-二酮)制备L-草铵膦，其总共包括3个合成步骤。
实施例II-1 由化合物B合成化合物E
将纯二氢呋喃-2,3-二酮(100g，1mol，化合物B)与100ml作为有机溶剂的正丁醇混合。于25℃向其中加入作为膦试剂的甲基亚磷酸二甲酯(108g，1mol)、作为碱试剂的甲醇钠(64.8g，1.2mol)、50ml正丁醇的混合溶液，加完，将反应液在该温度搅拌30分钟，通入1mol氯化氢气体中和，过滤，母液随后加入0.2g作为催化剂的SO4 2-/ZrO2-SnO2-Nd2O3，加完，开始程序升温，历时1小时使反应液升温至118℃，保持在118℃并反应5小时，然后降温至10℃。用1N盐酸将pH值调节至4-5，然后脱除溶剂。加入100ml水，随后加入乙酸乙酯(100ml×2)对反应体系进行萃取，分液取有机相。脱除溶剂后得到粗制化合物E，其无需进一步纯化即可用于下一步骤中。
对于采用其它膦试剂、有机溶剂、以及碱试剂的平行实验，其方法步骤除了所选的一种因素之外其它方面均与以上过程完全相同。
以下表1列出了在本发明的实施例II-1(由化合物B合成化合物E)中，当固定碱试剂和膦试剂的情况下使用不同有机溶剂，所得到的最终产物L-草铵膦的收率和ee值的结果。
表1：溶剂对最终结果的影响
从表1中的数据可以看出，溶剂正丙醇、正丁醇和甲苯均显示出可接受的结果，包括较高的收率和较高的ee值。在所有的溶剂之中，正丁醇显示出了最好的结果，其得到的L-草铵膦收率为96.2％，ee值为99.6％。
以下表2列出了在本发明的实施例II-1(由化合物B合成化合物E)中，当固定有机溶剂和膦试剂的情况下使用不同碱试剂，所得到的最终产物L-草铵膦的收率和ee值的结果。
表2：碱试剂对最终结果的影响

从表2中的数据可以看出，碱试剂正丁基锂、甲醇钠、乙醇钠均显示出可接受的结果，包括较高的收率和较高的ee值。在所有的碱试剂之中，甲醇钠显示出了最好的结果，其得到的L-草铵膦收率为96.2％，ee值为99.6％。
以下表3中列出了在本发明的实施例II-1(由化合物B合成化合物E)中，当固定有机溶剂和碱试剂的情况下使用不同膦试剂，所得到的最终产物L-草铵膦的收率和ee值的结果。
表3：膦试剂对最终结果的影响

从表3中的数据可以看出，膦试剂甲基次磷酸乙酯、甲基次磷酸甲酯、甲基次磷酸苯酯、甲基亚磷酸二甲酯均显示出可接受的结果，包括较高的收率和较高的ee值。在所有的膦试剂之中，甲基亚磷酸二甲酯显示出了最好的结果，其得到的L-草铵膦收率为96.2％，ee值为99.6％。
实施例II-2 由化合物E合成化合物F-H
向以上实施例II-1中所获得的粗制化合物E中加入200ml磷酸盐酸缓冲溶液、表达ω-转氨酶(来源于Escherichia coli str.K-12 substr.MG1655的Genbank登录号为NP_417544.5)的大肠杆菌全细胞(10g)、磷酸吡哆醛(1g)、L-丙氨酸(100g)。将该混合物在pH值7-10、温度30-60℃条件下保持8小时，在该期间发生转化反应。反应结束后，产物经过简单纯化后即可得到浅色液体，即化合物F-H的水溶液，转化率为98.8％。
实施例II-3 由化合物F-H合成L-草铵膦
向化合物F-H中加入200ml氢氧化钠水溶液，将其升温至60℃并在该 温度反应3小时。通过液相色谱监测反应进程。当观察到原料含量<0.1％时，表明水解反应完成。
然后于0℃向上述反应液中缓慢滴加1N盐酸，直到将pH值调节至5-6。调节完成之后，将体系搅拌30分钟。当体系的pH值稳定之后，加入25％氨水(1.2eq)，将混合物搅拌1小时，之后减压脱水。向体系中加入150ml甲醇进行重结晶，得到192.5g白色固体，即L-草铵膦。收率为95.6％，ee值为99.6％。
1HNMR：400MHz，D2Oδ：3.94(s,1H),2.10(d,2H),1.85-1.46(m,2H),1.34(d,3H)。
实施例III：由手性环内酯(L-氨基戊内酯)制备L-草铵膦
本实施例由手性环内酯(L-氨基戊内酯)制备L-草铵膦。
实施例III-1 由化合物D合成化合物F
将L-氨基戊内酯(101g，1mol，化合物D-H)与200ml二氯甲烷混合，并将其降温至0℃。向混合物中缓慢滴加作为保护基试剂的对甲苯磺酰氯(190g，1mol)。加入完毕之后，将反应混合物的温度恢复到室温，并在该温度搅拌1小时。减压脱除溶剂，残余物即为粗制的对甲苯磺酰基(Ts)保护的L-氨基戊内酯(化合物D-Ts)，其无需进一步纯化即可用于下一步骤中。
将粗制的Ts保护的L-氨基戊内酯(190.5g，1mol，化合物D-Ts)与200ml作为有机溶剂的正丁醇混合。于25℃向其中加入作为膦试剂的甲基亚磷酸二甲酯(108g，1mol)、作为碱试剂的甲醇钠(64.8g，1.2mol)、50ml正丁醇的混合溶液，加完，将反应液在该温度搅拌30分钟，通入1mol氯化氢气体中和，过滤，母液加入0.4g作为催化剂的SO4 2-/ZrO2-SnO2-Nd2O3，加完，1小时使 反应液升温至118℃，保持在118℃并反应5小时，然后降温至10℃。用1N盐酸将pH值调节至4-5，然后脱除溶剂。加入100ml水，随后加入乙酸乙酯(100ml×2)对反应体系进行萃取，分液取有机相。脱除溶剂后得到粗制的化合物F-Ts，其无需进一步纯化即可用于下一步骤中。
向粗制的化合物F-Ts中加入150ml氨水甲醇溶液，回流7小时。通过液相色谱监测显示保护基团Ts的脱保护反应完成。
对于采用其它保护基团的平行实验，其方法步骤除了用不同的保护试剂之外其它方面均与以上过程完全相同。
以下表4中列出了在本发明的实施例III-1(由化合物D合成化合物F)中，当固定所有其它条件的情况下使用不同保护基团，所得到的最终产物L-草铵膦的收率和ee值的结果。
表4：氨基的保护基团对最终结果的影响
从表4中的数据可以看出，当反应物化合物D上的氨基由Ts、Ms这些保护基团保护或者不含有任何保护基团时，最终产物L-草铵膦均可显示出可接受的结果，包括较高的收率和较高的ee值。在所有的氨基保护基团之中， 保护基团Ts显示出了最好的结果，其得到的L-草铵膦收率为97.2％，ee值为99.9％。
以下表5中列出了在本发明的实施例III-1(由化合物D合成化合物F)中，当固定所有其它条件的情况下使用或不使用催化剂，所得到的最终产物L-草铵膦的收率和ee值的结果。
表5：催化剂对最终结果的影响
实施例III-2 由化合物F-H合成L-草铵膦
向实施例III-1中获得的化合物F-H中加入200ml氢氧化钠水溶液，将其升温至60℃并在该温度反应3小时。通过液相色谱监测反应进程。当观察到原料含量<0.1％时，表明水解反应完成。
然后于0℃向上述反应液中缓慢滴加1N盐酸，直到将pH值调节至5-6。调节完成之后，将体系搅拌30分钟。当体系的pH值稳定之后，加入25％氨水(1.2eq)，将混合物搅拌1小时，之后减压脱水。向体系中加入150ml甲醇进行重结晶，得到192.5g白色固体，即L-草铵膦。收率97.2％，ee值99.9％。
1HNMR：400MHz，D2Oδ：3.94(s,1H),2.10(d,2H),1.85-1.46(m,2H), 1.34(d,3H)。
对比实施例IV：使用离去基试剂制备L-草铵膦
对比实施例IV对应于上文所述的制备L-草铵膦的现有技术方法，其总共包括以下三个步骤。
对比实施例IV-1 由化合物D-Ts合成化合物H-Ts-I
将对甲苯磺酰基(Ts)保护的L-氨基戊内酯(190.5g，1mol，化合物D-Ts)溶于200ml甲醇中，向其中加入作为离去基试剂的三甲基碘硅烷(200g，1mol，)，其中离去基团G为I。将混合物在60℃搅拌3小时，得化合物H-Ts-I的甲醇溶液。减压蒸馏除去甲醇，得到粗制化合物H-Ts-I。
对比实施例IV-2 由化合物H-Ts合成化合物F-Ts
将对比实施例IV-1中所得到的粗制化合物H-Ts-I溶于200ml正丁醇中。向其中加入作为碱试剂的甲醇钠(64.8g，1.2mol)和作为膦试剂的甲基亚磷酸二甲酯(108g，1mol)。加入完毕后，将混合物在120℃反应6小时。反应结束后，将体系降温至10℃。然后用1N盐酸将pH值调节至4-5，脱除溶剂。加入100ml水，随后加入乙酸乙酯(100ml×2)对反应体系进行萃取，分液取有机相。脱除溶剂后得到粗制化合物F-Ts。
对比实施例IV-3 由化合物F-Ts合成L-草铵膦
与上述本发明实施例III-1和III-2采用的过程相同。在对比实施例IV-3中，L-草铵膦收率为81.4％，ee值为99.8％。
比较上述实施例II、实施例III，相比于制备L-草铵膦的现有技术方法，本发明的方法具有步骤短、收率高且纯度高、原料廉价易得、反应条件温和易于实现等优点。
实施例V：催化剂的合成
称取3.55g Zr(SO4)2·4H2O配成质量分数为10％的水溶液(27.6ml水)，用体积分数为25％的氨水沉淀至pH值为8-9，根据锆(Zr)、锡(Sn)原子比为1：7，称取相应质量的SnCl4·5H2O(约24.75g)，配合质量分数为5％的水溶液(359ml水)，用氨水沉淀至pH值约为6，将上述两种分别置于70℃水浴中陈化1小时，然后混合，按照稀土氧化物占总体氧化物质量分数4％，称取0.505g的细粉状Nd2O3，加入到混合沉淀中，大力搅拌使混合均匀，再陈化5小时，抽滤，洗涤至中性，120℃干燥12h，研磨并过0.125mm筛孔，粉体在1.5mol/L的硫酸中浸渍1小时(按每克粉体15ml浸渍液的比例)，抽滤，干燥，600℃焙烧3小时，得固体催化剂SO4 2-/ZrO2-SnO2-Nd2O3。

Claims (29)

  1. 一种由环内酯制备L-草铵膦的方法，所述方法包括：
    (1)将环内酯与有机溶剂混合；
    (2)向步骤(1)得到的环内酯与有机溶剂的混合溶液中加入膦试剂和碱试剂，使环内酯与膦试剂在碱试剂的存在下进行反应，得到L-草铵膦前体化合物；
    (3)通过化学或生物方法处理L-草铵膦前体化合物，得到产物L-草铵膦；
    前提条件是在所述方法中不使用离去基试剂。
  2. 根据权利要求1所述的方法，其中步骤(1)中所述的环内酯为二氢呋喃-2,3-二酮或L-氨基戊内酯。
  3. 根据前述权利要求中任一项所述的方法，其中步骤(1)中所述的有机溶剂选自下组：甲醇、乙醇、正丙醇、正丁醇、甲苯、二氯甲烷、氯仿、四氯化碳、二甲基甲酰胺和四氢呋喃。
  4. 根据前述权利要求中任一项所述的方法，其中步骤(2)中所述的膦试剂选自下组：甲基磷酸烷基酯或其盐、甲基磷酸取代苯酯或其盐、甲基亚磷酸二烷基酯和甲基亚磷酸二取代苯酯。
  5. 根据前述权利要求中任一项所述的方法，其中步骤(2)中所述的膦试剂选自下组：甲基次磷酸甲酯、甲基次磷酸乙酯、甲基次磷酸异丙酯、甲基次磷酸正丁酯、甲基次磷酸苯酯、甲基次磷酸苯甲酯、甲基次磷酸氯苯酯、甲基亚磷酸二甲酯、甲基亚磷酸二乙酯和甲基亚磷酸二苯酯。
  6. 根据前述权利要求中任一项所述的方法，其中步骤(2)中所述的碱试剂选自下组：碱金属碳酸盐、碱金属氢氧化物、C1-6醇钠、有机锂化合物和碱金属氢化物。
  7. 根据前述权利要求中任一项所述的方法，其中步骤(2)中所述的碱 试剂选自下组：甲醇钠、乙醇钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、二异丙基氨基锂、正丁基锂、氢化铝锂和氢化钠。
  8. 根据前述权利要求中任一项所述的方法，其中步骤(2)包括两步反应。
  9. 根据权利要求8所述的方法，其中步骤(2)中的第一个反应的反应温度控制在0-45℃，第二个反应的反应温度控制在90-120℃。
  10. 根据前述权利要求中任一项所述的方法，其中步骤(2)在催化剂的存在下进行。
  11. 根据权利要求10所述的方法，其中所述催化剂为固体酸催化剂。
  12. 根据权利要求11所述的方法，其中所述固体酸催化剂为SO4 2-/ZrO2-SnO2-Nd2O3。
  13. 根据权利要求10-12中任一项所述的方法，其中在步骤(2)中的所述第一个反应之后、所述第二个反应之前加入所述催化剂。
  14. 根据权利要求9-13中任一项所述的方法，其中步骤(2)中的所述第一个反应的反应时间控制在20-40分钟，所述第二个反应的反应时间控制在4-6小时。
  15. 根据权利要求9-14中任一项所述的方法，其中步骤(2)中的所述第一个反应结束之后，在0.5-1.5小时内程序升温至所述第二个反应所需的温度。
  16. 根据权利要求9-15中任一项所述的方法，其中在步骤(2)中的所述第二个反应结束之后降温至0-20℃。
  17. 根据权利要求9-16中任一项所述的方法，其中在步骤(2)中的所述第二个反应结束之后将pH值调节至7以下。
  18. 根据权利要求17所述的方法，其中在步骤(2)中的所述第二个反应 结束之后将pH值调节至4-5。
  19. 根据权利要求10-18中任一项所述的方法，其中在加入所述催化剂之前调整反应液的pH值至6-8。
  20. 根据前述权利要求中任一项所述的方法，其中所述离去基试剂是卤化剂。
  21. 根据权利要求20所述的方法，其中所述离去基试剂选自下组：HCl、HBr、HI、碳酰氯、SOCl2、草酰氯、三甲基硅卤化物、碘化钠(NaI)、三乙基硅烷+氯化钯+甲基碘、POCl3、PCl3、PCl5、PBr3、PI3、H2SO4+KBr、P+Cl2、P+Br2、P+I2、TiCl4、ZnCl2、BBr3及其任何组合。
  22. 根据权利要求21所述的方法，其中所述离去基试剂为三甲基碘硅烷。
  23. 根据权利要求2所述的方法，其中步骤(2)还包括氨基转换反应。
  24. 根据权利要求23所述的方法，其中所述氨基转换反应包括将转氨酶与氨基供体进行反应。
  25. 根据权利要求24所述的方法，其中所述氨基供体选自下组：丙氨酸、α-甲基苄基胺、谷氨酸、苯丙氨酸、甘氨酸、3-氨基丁酸、异丙胺、2-氨基丁烷、γ-氨基丁酸、乙二胺、丙二胺、丁二胺、戊二胺、己二胺和其中任何一种的盐。
  26. 根据前述权利要求中任一项所述的方法，其中步骤(3)包括使所述L-草铵膦前体化合物在碱性条件下进行水解反应。
  27. 根据权利要求26所述的方法，其中步骤(3)中的所述水解反应完成之后，在-10至10℃条件下将反应溶液的pH调节至5-6的范围内。
  28. 根据前述权利要求中任一项所述的方法，其中所述L-草铵膦包含L-草铵膦盐。
  29. 根据权利要求28所述的方法，其中所述L-草铵膦盐选自下组：L-草铵膦盐酸盐、L-草铵膦硫酸盐、L-草铵膦碳酸盐、L-草铵膦铵盐、L-草铵膦钠盐和L-草铵膦钾盐。
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