Patent Description:
Glufosinate is an important herbicide. Further information regarding the synthesis of the compound can inter alia be found in <CIT>, <CIT>, "<NPL>); <NPL>); <NPL>; and <NPL>).

Nevertheless, the present invention provides a method for preparing glufosinate of formula (I) or a salt, an enantiomer thereof or a mixture of the enantiomers in all ratios, comprising the following steps:
<CHM>.

The present invention further provides a method for preparing enantiomerically pure glufosinate of formula (I) or a salt thereof,
<CHM>
the method comprises the following steps:.

In certain specific embodiments, one compound of formula (III), e.g., chloro(ethoxy)(methyl)phosphane, is employed.

In certain specific embodiments, a mixture of one compound of formula (IV) and one compound of formula (V) is employed, such as a mixture of dichloro(methyl)phosphane and diethyl methylphosphonite, and the mixture can be further added with a compound of formula (III), e.g., chloro(ethoxy)(methyl)phosphane, in any ratio.

Further, the enantiomeric ratio is (L):(D)-enantiomer or (D):(L)-enantiomer of <NUM>:<NUM> to <NUM>:<NUM>.

Further, the enantiomeric ratio is (L):(D)-enantiomer of <NUM>:<NUM> to <NUM>:<NUM>.

Further, the Hal<NUM> is a chlorine atom.

Further, the R<NUM>, R<NUM>, R<NUM> and R<NUM> are each independently C<NUM>-C<NUM> alkyl, preferably C<NUM>-C<NUM> alkyl.

In certain specific embodiments, the mixture is a mixture of one or more compounds of formula (IV) and one or more compounds of formula (III), and the molar ratio of the compounds of formula (IV) to the compounds of formula (III) is (<NUM>-<NUM>):<NUM> or (<NUM>-<NUM>):<NUM>; or the mixture is a mixture of one or more compounds of formula (V) and one or more compounds of formula (III), and the molar ratio of the compounds of formula (V) to the compounds of formula (III) is (<NUM>-<NUM>):<NUM> or (<NUM>-<NUM>):<NUM>; or the mixture is a mixture comprising one or more compounds of formula (IV) and one or more compounds of formula (V), and the molar ratio of the compounds of formula (IV) to the compounds of formula (V) is (<NUM>-<NUM>):<NUM>.

Further, in aforementioned step a) or a1), the reaction can proceed at room temperature, the reaction temperature can be <NUM>-<NUM>, and preferably <NUM>-<NUM> in consideration of reaction efficiency.

Further, the aforementioned step a) or a1) is carried out in the presence of a base.

Further, the base in aforementioned step a) or a1) is an organic base or ammonia.

Further, in aforementioned step a) or a1), the organic base is selected from the group consisting of an organic amine, pyridine or a pyridine derivative having <NUM>-<NUM> substituents attached to one or more carbon atoms in the heterocycle, piperidine or a piperidine derivative having <NUM>-<NUM> substituents attached to one or more carbon atoms in the heterocycle.

Further, the organic base is selected from the group consisting of triethylamine, piperidine or pyridine.

Further, in aforementioned step a) or a1), the molar ratio of the base to the total amounts of the compound of formula (III) and the compound of formula (V) is (<NUM>-<NUM>):<NUM>.

Further, in aforementioned step a) or a1), the reaction is carried out under a solvent-free condition or in an inert solvent.

Further, in aforementioned step a) or a1), the inert solvent is selected from any one or more of benzene solvents, amide solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, sulfone or sulfoxide solvents, ether solvents or ester solvents; preferably, the inert solvent is selected from any one or more of benzene solvents, amide solvents, halogenated hydrocarbon solvents, ether solvents or ester solvents.

Further, in aforementioned step a) or a1), the inert solvent is selected from any one or more of chlorobenzene, trimethylbenzene, <NUM>,<NUM>-dioxane, <NUM>,<NUM>-dichloroethane, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, petroleum ether, n-heptane, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, ethyl acetate, and butyl acetate.

Further, in aforementioned step a) or a1), the molar ratio of the compound of formula (III) or the mixture to the compound of formula (II) is <NUM>:(<NUM>-<NUM>), preferably <NUM>:(<NUM>-<NUM>); or the molar ratio of the compound of formula (II) to the compound of formula (III) or the mixture is <NUM>:(<NUM>-<NUM>), preferably <NUM>:(<NUM>-<NUM>).

Further, in aforementioned step b) or b1), an inorganic acid or an organic acid is added.

Further, the inorganic acid is hydrochloric acid or sulfuric acid.

Further, in aforementioned step b) or b1), the base is an inorganic base or an organic base.

Further, the base is alkali metal hydroxide, alkali-earth metal hydroxide, alkali metal carbonate, alkali-earth metal carbonate, alkali metal bicarbonate or alkali-earth metal bicarbonate.

Further, the base is NaOH, KOH or Ba(OH)<NUM>.

Further, in aforementioned step b) or b1), the reaction temperature is <NUM>-<NUM>.

As a specific embodiment, the compound of formula (II) is a compound of formula (IIa), and the compound of formula (III) is a compound of formula (IIIa),
<CHM>
and in step b1), an acid (e.g., hydrochloric acid) is then added to obtain L-glufosinate.

A compound of formula (III) can be defined:
<CHM>
wherein Hal<NUM> and R<NUM> are as defined above.

The present invention further provides use of the compound of formula (III), particularly a compound of formula (IIIa), in the preparation of glufosinate or a salt thereof, or L-glufosinate or a salt thereof,
<CHM>.

The present invention further provides a mixture comprising one or more compounds of formula (IV) and one or more compounds of formula (III); or a mixture comprising one or more compounds of formula (V) and one or more compounds of formula (III); or a mixture comprising one or more compounds of formula (III), one or more compounds of formula (IV) and one or more compounds of formula (V);
<CHM>.

The present invention further provides a mixture comprising one or more compounds of formula (IV) and one or more compounds of formula (III), and the molar ratio of the compounds of formula (IV) to the compounds of formula (III) is (<NUM>-<NUM>):<NUM> or (<NUM>-<NUM>):<NUM>; or the mixture is a mixture comprising one or more compounds of formula (V) and one or more compounds of formula (III), and the molar ratio of the compounds of formula (V) to the compounds of formula (III) is (<NUM>-<NUM>):<NUM> or (<NUM>-<NUM>):<NUM>:
<CHM>
wherein Hal<NUM>, R<NUM>, R<NUM> and R<NUM> are as defined herein.

Further, the compound of formula (IV) is diethyl methylphosphonite, and the compound of formula (V) is dichloro(methyl)phosphane.

The present invention further provides use of the aforementioned mixture in the preparation of glufosinate or a salt thereof, or L-glufosinate or a salt thereof.

The method of the present invention is particularly suitable for the preparation of glufosinate, and substantially reduces the steps of the existing preparation processes. In particular, in the preparation of L-glufosinate, the product can effectively maintain the ee value of the raw material. For example, when an enantiomerically pure raw material (e.g., the enantiomeric excess percentage (% ee) is greater than <NUM>%) is employed, the enantiomeric excess percentage (% ee) of the prepared L-glufosinate is greater than e.g., <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>% or <NUM>%.

Unless otherwise specified, the terms used in the specification and claims have the following meanings.

The term "amino protecting group" refers to a group that can be attached to a nitrogen atom in an amino group to protect the amino group from participating the reaction and can be easily removed in the subsequent reactions. Suitable amino protecting groups include, but are not limited to, the following protecting groups:
carbamate group of formula -C(O)O-R, wherein R is methyl, ethyl, tert-butyl, benzyl, phenethyl, CH<NUM>=CH-CH<NUM>-, etc.; amide group of formula -C(O)-R', wherein R' is methyl, ethyl, phenyl, trifluoromethyl, etc.; N-sulfonyl derivative group of formula -SO<NUM>-R", wherein R" is tolyl, phenyl, trifluoromethyl, <NUM>,<NUM>,<NUM>,<NUM>,<NUM>-pentamethylchroman-<NUM>-yl-, <NUM>,<NUM>,<NUM>-trimethyl-<NUM>-methoxybenzene, etc..

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including linear and branched groups having <NUM> to <NUM> carbon atoms. Alkyl having <NUM> to <NUM> carbon atoms, such as methyl, ethyl, propyl, <NUM>-propyl, n-butyl, isobutyl, tert-butyl and pentyl, is preferred. The alkyl can be substituted or unsubstituted, and when substituted, the substituent can be halogen, nitro, sulfonyl, ether oxy, ether thio, ester, thioester or cyano.

The C<NUM>-C<NUM> alkyl is linear or branched, comprising saturated hydrocarbon chain having <NUM> to <NUM> carbon atoms. It can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

The "mixture of the enantiomers in all ratios" as used herein has the same meaning as the "mixture of the enantiomers in any ratio".

<NUM> of L-homoserine lactone hydrochloride (ee value of <NUM>%, <NUM>/mol, <NUM> mol) was weighed into a reaction flask, and <NUM> of ethanol (<NUM>/mol, <NUM> mol, <NUM>/mL) was added (the molar ratio of homoserine lactone hydrochloride to ethanol is <NUM>:<NUM>). The system was cooled to <NUM>, and <NUM> of thionyl chloride (<NUM>/mol, <NUM> mol) was slowly dropwise added (the molar ratio of L-homoserine lactone hydrochloride to thionyl chloride is <NUM>:<NUM>). The system temperature was maintained at <NUM>, and stirred for <NUM> minutes. The reaction was heated to <NUM>, and stirred for <NUM>, during which bubbles were continuously generated. The reaction was monitored by LC-MS. The reaction was stopped, the system was cooled to room temperature, and the remaining thionyl chloride and ethanol were distilled off under reduced pressure. The solid residue was slurried with <NUM> of n-hexane/ethyl acetate mixed solvents (the volume ratio of n-hexane to ethyl acetate is <NUM>:<NUM>), filtered and dried to obtain <NUM> of chloro-homoserine ethyl ester hydrochloride (<NUM>/mol, <NUM> mol), wherein the HPLC purity is <NUM>%, and the yield calculated on the basis of the amount of the reactant L-homoserine lactone hydrochloride is <NUM>%.

The chloro-homoserine ethyl ester hydrochloride solid was reacted with a saturated sodium carbonate solution. The system was adjusted to a pH of <NUM>-<NUM>, and extracted with ethyl acetate for <NUM> times, wherein the amounts of ethyl acetate in the <NUM> extraction processes were <NUM>, <NUM> and <NUM>, respectively. The organic phases were collected, and concentrated to obtain <NUM> of the oily target product, chloro-homoserine ethyl ester (<NUM>/mol, <NUM> mol), wherein the HPLC purity was <NUM>%, the ee value was <NUM>%, and the yield calculated based on the intermediate product chloro-homoserine ethyl ester hydrochloride was <NUM>%.

MS (ESI): m/z [M + H]+ calculated for C6H13ClNO2: <NUM>, found: <NUM>.

<NUM>H NMR (CDCl<NUM>, <NUM>) δ: <NUM> (q, J =<NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J =<NUM>, <NUM>, <NUM>), <NUM> (dddd, J =<NUM>, <NUM>, <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J =<NUM>, <NUM>).

<NUM>C NMR (CDCl<NUM>, <NUM>) δ: <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

Under a nitrogen atmosphere, diethyl methylphosphonite (<NUM>, <NUM> mmol,<NUM> eq) and a solvent <NUM>,<NUM>-dioxane (<NUM>) were added to a round-bottom flask, a <NUM>,<NUM>-dioxane (<NUM>) solution of dichloro(methyl)phosphane (<NUM>, <NUM> mmol, <NUM> eq) were dropwise added through a constant-pressure funnel, and the reaction was stirred at room temperature overnight. <NUM>,<NUM>-dioxane and chloro(ethoxy)(methyl)phosphane (colorless liquid, <NUM>, yield: <NUM>%) were distilled out under reduced pressure.

<NUM>H NMR (D<NUM>O, <NUM>) δ: <NUM> - <NUM> (m, <NUM>), <NUM> (d, J =<NUM>, <NUM>), <NUM> (t, J =<NUM>, <NUM>).

Under a nitrogen atmosphere, compound <NUM> (<NUM>, <NUM> mmol, <NUM> eq), chlorobenzene (<NUM>, <NUM> mmol, <NUM> eq) and triethylamine (<NUM>, <NUM> mmol, <NUM> eq) were respectively added to a three-neck flask, chloro(ethoxy)(methyl)phosphane (<NUM>, <NUM> mmol, <NUM> eq) was dropwise added, and the reaction was stirred at room temperature for <NUM> hours. The reaction was heated to <NUM>, and allowed to proceed for <NUM>. MS detection indicated that the raw material disappeared. The reaction was cooled to room temperature, dropwise added with <NUM>% HCl (<NUM>, <NUM> mmol, <NUM> eq), and heated to reflux until complete reaction of the starting material. The solvent was evaporated, <NUM>% ethanol (<NUM>) and water (<NUM>) were added, and the mixture was heated to reflux until the product was completely dissolved. The mixture was cooled and crystallized, filtered, and dried to obtain L-glufosinate (white crystal, <NUM>, yield: <NUM>%, <NUM>% ee).

MS (ESI): m/z [M + H]+ calculated for C5H13NO4P: <NUM>, found <NUM>.

<NUM>H NMR (D<NUM>O, <NUM>) δ: <NUM> (t, J =<NUM>, <NUM>), <NUM> (dddd, J =<NUM>, <NUM>, <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J =<NUM>, <NUM>).

<NUM>C NMR (D<NUM>O, <NUM>) δ: <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

Under a nitrogen atmosphere, compound <NUM> (<NUM>, <NUM> mmol, <NUM> eq), chlorobenzene (<NUM>, <NUM> mmol, <NUM> eq) and pyridine (<NUM>, <NUM> mmol, <NUM> eq) were respectively added to a three-neck flask, chloro(ethoxy)(methyl)phosphane (<NUM>, <NUM> mmol, <NUM> eq) was dropwise added, and the reaction was stirred at room temperature for <NUM> hours. The reaction was heated to <NUM>, and allowed to proceed for <NUM>. MS detection indicated that the raw material disappeared. The reaction was cooled to room temperature, dropwise added with <NUM>% HCl (<NUM>, <NUM> mmol, <NUM> eq), and heated to reflux until complete reaction of the starting material. The solvent was evaporated, <NUM>% ethanol (<NUM>) and water (<NUM>) were added, and the mixture was heated to reflux until the product was completely dissolved. The mixture was cooled and crystallized, filtered, and dried to obtain L-glufosinate (white crystal, <NUM>, yield: <NUM>%, <NUM>% ee).

Under a nitrogen atmosphere, compound <NUM> (<NUM>, <NUM> mmol, <NUM> eq), chlorobenzene (<NUM>, <NUM> mmol, <NUM> eq) and piperidine (<NUM>, <NUM> mmol, <NUM> eq) were respectively added to a three-neck flask, chloro(ethoxy)(methyl)phosphane (<NUM>, <NUM> mmol, <NUM> eq) was dropwise added, and the reaction was stirred at room temperature for <NUM> hours. The reaction was heated to <NUM>, and allowed to proceed for <NUM>. MS detection indicated that the raw material disappeared. The reaction was cooled to room temperature, dropwise added with <NUM>% HCl (<NUM>, <NUM> mmol, <NUM> eq), and heated to reflux until complete reaction of the starting material. The solvent was evaporated, <NUM>% ethanol (<NUM>) and water (<NUM>) were added, and the mixture was heated to reflux until the product was completely dissolved. The mixture was cooled and crystallized, filtered, and dried to obtain L-glufosinate (white crystal, <NUM>, yield: <NUM>%, <NUM>% ee).

Under a nitrogen atmosphere, compound <NUM> (<NUM>, <NUM> mmol, <NUM> eq) and chlorobenzene (<NUM>, <NUM> mmol, <NUM> eq) were respectively added to a three-neck flask. Chloro(ethoxy)(methyl)phosphane (<NUM>, <NUM> mmol, <NUM> eq) was dropwise added, and ammonia was simultaneously bubbled in until saturation. The reaction was stirred at room temperature for <NUM> hours. The reaction was heated to <NUM>, and allowed to proceed for <NUM>. MS detection indicated that the raw material disappeared. The reaction was cooled to room temperature, dropwise added with <NUM>% HCl (<NUM>, <NUM> mmol, <NUM> eq), and heated to reflux until complete reaction of the starting material. The solvent was evaporated, <NUM>% ethanol (<NUM>) and water (<NUM>) were added, and the mixture was heated to reflux until the product was completely dissolved. The mixture was cooled and crystallized, filtered, and dried to obtain L-glufosinate (white crystal, <NUM>, yield: <NUM>%, <NUM>% ee).

Under a nitrogen atmosphere, compound <NUM> (<NUM>, <NUM> mmol, <NUM> eq), <NUM>,<NUM>-dioxane (<NUM>, <NUM> mmol, <NUM> eq) and triethylamine (<NUM>, <NUM> mmol, <NUM> eq) were respectively added to a three-neck flask, chloro(ethoxy)(methyl)phosphane (<NUM>, <NUM> mmol, <NUM> eq) was dropwise added, and the reaction was stirred at room temperature for <NUM> hours. The reaction was heated to <NUM>, and allowed to proceed for <NUM>. MS detection indicated that the raw material disappeared. The reaction was cooled to room temperature, dropwise added with <NUM>% HCl (<NUM>, <NUM> mmol, <NUM> eq), and heated to reflux until complete reaction of the starting material. The solvent was evaporated, <NUM>% ethanol (<NUM>) and water (<NUM>) were added, and the mixture was heated to reflux until the product was completely dissolved. The mixture was cooled and crystallized, filtered, and dried to obtain L-glufosinate (white crystal, <NUM>, yield: <NUM>%, <NUM>% ee).

Claim 1:
A method for preparing glufosinate of formula (I) or a salt, an enantiomer thereof or a mixture of the enantiomers in all ratios, characterized in that the method comprises the following steps:
<CHM>
a) reacting a compound of formula (II) or a salt, an enantiomer thereof or a mixture of the enantiomers in all ratios,
<CHM>
with one or more compounds of formula (III) or a mixture;
the mixture being a mixture comprising one or more compounds of formula (IV) and one or more compounds of formula (V); or a mixture comprising one or more compounds of formula (IV) and one or more compounds of formula (III); or a mixture comprising one or more compounds of formula (V) and one or more compounds of formula (III); or a mixture comprising one or more compounds of formula (III), one or more compounds of formula (IV) and one or more compounds of formula (V);
<CHM>
b) reacting the intermediate, no matter whether it is isolated or not, in the presence of water and an acid or a base to obtain the glufosinate (I) or a salt, an enantiomer thereof or a mixture of the enantiomers in all ratios;
wherein when PG is an amino protecting group, a step of removing the amino protecting group can be further comprised;
wherein
Hal<NUM> and Hal<NUM> are each independently halogen;
PG is hydrogen or an amino protecting group;
R<NUM>, R<NUM>, R<NUM> and R<NUM> are each independently alkyl, phenyl or substituted phenyl, and when the mixture comprises the mixture of one or more compounds of formula (IV) and one or more compounds of formula (III), or when the mixture comprises the mixture of one or more compounds of formula (III), one or more compounds of formula (IV) and one or more compounds of formula (V), R<NUM> is either R<NUM> or R<NUM>; and
the chiral carbon atom is labeled with *.