Method of producing l-glufosinate

Abstract

Provided is a method for preparing L-glufosinate from an L-homoserine derivative compound, the method including a step (step a) of preparing a compound of Chemical Formula 2 from a compound of Chemical Formula 1, and a step (step b) of preparing a compound of Chemical Formula 3 from the compound of Chemical Formula 2.

Description

Method for manufacturing L-glufosinate

[0001] It relates to a method for manufacturing L-glufosinate.

[0002] Glufosinate has been widely used as a herbicide with a wide range of penetration properties, and it is known that the systemic herbicidal properties of glufosinate are due to the effect of the L-isomer of glufosinate. Accordingly, various methods for producing the L-isomer of glufosinate have been studied. For example, a method for producing the L-isomer of glufosinate by selectively separating the L-isomer from a racemic mixture of the D-isomer and the L-isomer has been used. However, this method has the problem that the yield of the L-isomer is reduced by more than half, an excessive amount of unnecessary D-isomer is generated as a byproduct, and the process is complicated because a resolving agent and a resolving device are required to separate the L-isomer.

[0003] Therefore, a method for simply producing the L-isomer of glufosinate with high optical purity in high yield is required.

[0004] One aspect of the present application is to provide a simple and high yield method for preparing L-glufosinate having high optical purity.

[0005] According to one aspect, a method for producing L-glufosinate from an L-lactone derivative compound is provided, comprising the steps of: (a) preparing a compound of the following formula 2 from a compound of the following formula 1; and (b) preparing L-glufosinate of the following formula 3 from the compound of the following formula 2.

[0006] <Chemical Formula 1>

[0007]

[0008] <Chemical Formula 2>

[0009]

[0010] <Chemical Formula 3>

[0011]

[0012] In the above equations, R1 is R a -(C=O)- and R a is hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, or a substituted or unsubstituted heteroaryl group having 2 to 10 carbon atoms,

[0013] R2 is hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, a substituted or unsubstituted heteroaryl group having 2 to 10 carbon atoms, or -Si(R b )(R c )(R d ) and R b , R c and R d are independently a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms,

[0014] R5 is hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted alkynyl group having 1 to 6 carbon atoms,

[0015] The substituents of the above alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group and heteroaryl group are independently at least one selected from the group consisting of hydrogen, halogen, carboxyl group (-COOH), amino group (-NH2), nitro group (-NO2), cyano group (-CN), alkyl group having 1 to 6 carbon atoms, aryl group having 6 to 10 carbon atoms and cycloalkyl group having 3 to 10 carbon atoms.

[0016] The method for producing L-glufosinate according to the present invention enables the production of L-glufosinate with high optical purity by using a new intermediate compound and having a new synthetic route.

[0017] In addition, L-glufosinate can be produced in high yield by a simple method.

[0018] Hereinafter, a method for manufacturing L-glufosinate according to an embodiment will be described in more detail.

[0019] The inventive concept of the present application described below is capable of various modifications and embodiments. Specific embodiments are exemplified and described in detail in the detailed description. However, this is not intended to limit the inventive concept of the present application to specific embodiments, and it should be understood that all modifications, equivalents, or alternatives falling within the technical scope of the inventive concept of the present application are included.

[0020] Although terms such as first, second, third, and fourth may be used in this specification to describe various components, the components should not be limited by these terms. The terms are used solely to distinguish one component from another.

[0021] As used herein, the term 'L-glufosinate' is the L-isomer of glufosinate. As used herein, the term 'D-glufosinate' is the D-isomer of glufosinate.

[0022] As used herein, the term 'enantiomeric excess (%ee)' refers to the enantiomeric purity of a sample, i.e., the percentage of one enantiomeric enantiomeric enantiomer in excess of the other enantiomeric enantiomer in the sample. For example, the enantiomeric excess of L-glufosinate is the percentage of L-glufosinate in excess of D-glufosinate in the glufosinate. For example, the enantiomeric excess of L-glufosinate is expressed by the following mathematical formula (1).

[0023] <Mathematical Formula 1>

[0024]

[0025] A method for producing L-glufosinate according to one embodiment may include a step (a) of preparing a compound of the following formula 2 from a compound of the following formula 1 in a method for producing L-glufosinate from an L-lactone derivative compound; and a step (b) of preparing L-glufosinate of the following formula 3 from the compound of the following formula 2.

[0026] <Chemical Formula 1>

[0027]

[0028] <Chemical Formula 2>

[0029]

[0030] <Chemical Formula 3>

[0031]

[0032] In the above equations, R1 is R a -(C=O)- and R ais hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, or a substituted or unsubstituted heteroaryl group having 2 to 10 carbon atoms,

[0033] R2 is hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, a substituted or unsubstituted heteroaryl group having 2 to 10 carbon atoms, or -Si(R b )(R c )(R d ) and R b , R c and R d are independently a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms,

[0034] R5 is hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted alkynyl group having 1 to 6 carbon atoms,

[0035] The substituents of the above alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group and heteroaryl group are independently at least one selected from the group consisting of hydrogen, halogen, carboxyl group (-COOH), amino group (-NH2), nitro group (-NO2), cyano group (-CN), alkyl group having 1 to 6 carbon atoms, aryl group having 6 to 10 carbon atoms and cycloalkyl group having 3 to 10 carbon atoms.

[0036] More specifically, the step a may include a step (step c) of preparing a compound of the following chemical formula 4 by reacting the compound of the above chemical formula 1 with a halogenation agent and one or more R2-OH.

[0037] <Chemical Formula 4>

[0038]

[0039] In the above formula, R1 and R2 are as defined in the first term, and X is halogen.

[0040] That is, a first intermediate compound represented by Chemical Formula 4 can be prepared by reacting a compound of Chemical Formula 1 with a halogenating agent and one or more R2-OH groups. For example, a lactone compound represented by Chemical Formula 1 can react with a halogen of a halogenating agent to undergo a ring opening reaction, and then undergo a substitution reaction with an R2- functional group of one or more R2-OH compounds to form a second intermediate compound.

[0041] <Chemical Formula 1>

[0042]

[0043] <Chemical Formula 4>

[0044]

[0045] In the compound of formula 1 and the first intermediate compound represented by formula 4, for example, R1 may be acetyl or succinyl, and R2 may be methyl, ethyl, propyl, butyl, pentyl, hexyl, benzyl, phenyl, naphthyl, -Si(CH3)(tert-butyl)2, -Si(C6H5)2(tert-butyl), -Si(iso-propyl)3, -Si(C5H6)(CH3)2, -Si(C6H5)2(CH3), -Si(C5H6)3, -Si(CH3)3, -Si(CH2CH3)3, -Si(CH2CH3)2(CH3), -Si(CH2CH3)(CH3)2, or -Si(tert-butyl)3. L-glufosinate having improved optical purity can be more easily produced by the compound of chemical formula 1 and the first intermediate compound represented by chemical formula 4 having such a functional group.

[0046] The compound of formula 1 can be prepared, for example, from a fermentation broth containing a precursor of the compound of formula 1. Therefore, efficient production of L-glufosinate is possible using the compound of formula 1 derived from the precursor of the compound of formula 1 produced during the fermentation process. The precursor of the compound of formula 1 can be, for example, an L-homoserine derivative. The L-homoserine derivative can be, for example, an O-substituted form of L-homoserine, such as O-acetyl-L-homoserine or O-succinyl-L-homoserine. For example, an L-homoserine derivative, which is a precursor of a first intermediate compound, can be separated from the fermentation broth, and a compound of formula 1 can be prepared by a ring formation reaction from the separated L-homoserine derivative.

[0047] Furthermore, since an intermediate compound derived from a derivative of O-substituted L-homoserine is used, there is no need to use an additional substance to introduce a protecting group for the amino group, and L-glufosinate can be produced in a one-pot process in which all reactions are performed in one reactor, which is efficient.

[0048] In the present application, the term 'fermentation broth containing a precursor of a compound of chemical formula 1' may be a fermentation broth containing a precursor of a compound of chemical formula 1 produced from a fermentation process. The fermentation broth may be a fermentation broth obtained by culturing a microorganism in a medium containing sugar, or may be a fermentation broth obtained by enzymatically converting a fermentation broth obtained by culturing a microorganism. For example, the fermentation broth containing a precursor of a compound of chemical formula 1 may be a fermentation broth obtained by directly producing a precursor of a compound of chemical formula 1 by culturing a microorganism in a medium containing sugar, or a fermentation broth containing a precursor of a compound of chemical formula 1 obtained by enzymatically converting an amino acid produced by culturing a microorganism in a medium containing sugar. The type of microorganism used in the production of the fermentation broth containing a precursor of a compound of chemical formula 1 is not particularly limited, but any microorganism capable of producing an L-homoserine derivative directly through fermentation or through enzymatic conversion in the art may be used. The fermentation broth containing an L-homoserine derivative may be, for example, a fermentation broth obtained by fermenting a medium containing CJM-BTJ / pCJ-MetA-CL (Accession No.: KCCM-10872), an O-succinyl-L-homoserine producing strain disclosed in Example 2 of KR 10-2014-0116010, or CJM-BTJA / pCJ-MetX-CL (Accession No.: KCCM-10873), an O-acetyl-L-homoserine producing strain.

[0049] The halogenating agent may include at least one selected from the group consisting of, for example, SOCl2, oxalyl chloride, Triethylsilane ((CH2CH3)3SiH)+palladium chloride (PdCl2)+methyl iodide (CH3I), POCl3, PCl3, PCl5, PBr3, PI3, H2SO4+KBr, P+Cl2, P+Br2, P+I2, TiCl4, ZnCl2, and BBr3. In particular, the halogenating agent may be Triethylsilane ((CH2CH3)3SiH)+palladium chloride (PdCl2)+methyl iodide (CH3I), or SOCl2.

[0050] The content of the halogenating agent may be, for example, 1 to 10 equivalents, 1 to 5 equivalents, 1 to 4 equivalents, 1 to 3 equivalents, 1 to 2 equivalents, 1 to 1.5 equivalents, 0.1 to 1.3 equivalents, or 1 to 1.1 equivalents relative to 1 equivalent of the compound of formula 1.

[0051] More than one R2-OH compound may be used in the reaction to form the first intermediate compound. When multiple R2-OH compounds are used, each R2-OH compound may be the same or different.

[0052] The R2-OH compound may be at least one selected from the group consisting of, for example, methanol, ethanol, n-propanol, iso-propanol, butanol, pentanol, hexanol, benzyl alcohol, phenol, and naphthol. By selecting the above-mentioned materials as the R2-OH compound, the first intermediate compound can be obtained from the compound of formula 1 in a higher yield.

[0053] The content of the R2-OH compound may be, for example, 1 to 60 equivalents, 1 to 40 equivalents, 2 to 20 equivalents, or 3 to 10 equivalents relative to 1 equivalent of the compound of formula 1. The step of preparing the second intermediate compound may be performed under a solvent or under neat conditions without a solvent. The solvent may be an organic solvent.

[0054] Organic solvents include, but are not limited to, alcohol, toluene, benzene, tetrahydrofuran, acetone, chloroform, dichloromethane, acetonitrile, and the like, and any solvent used with a halogenating agent in the relevant technical field may be used. Alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, pentanol, and the like.

[0055] In the step of preparing the first intermediate compound, the halogenation / ring opening reaction can be performed at a temperature of, for example, 20 to 100°C, 20 to 80°C, 30 to 70°C, or 40 to 60°C. In the step of preparing the first intermediate compound, the ring opening reaction and / or substitution reaction can be performed for, for example, 0.1 to 30 hours, 1 to 30 hours, 5 to 30 hours, 10 to 30 hours, 15 to 25 hours, 17 to 23 hours, or 18 to 20 hours. By performing the halogenation / ring opening reaction within these temperature and time ranges, the first intermediate compound can be prepared more easily.

[0056] In the step of preparing the first intermediate compound, the yield of the first intermediate compound may be, for example, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more.

[0057] In the step of preparing the first intermediate compound, the enantiomeric excess of the first intermediate compound having the L-form may be, for example, 10% ee or more, 20% ee or more, 30% ee or more, 40% ee or more, 50% ee or more, 60% ee or more, 70% ee or more, 80% ee or more, 90% ee or more, 91% ee or more, 92% ee or more, 93% ee or more, 94% ee or more, 95% ee or more, 96% ee or more, 97% ee or more, 98% ee or more, or 99% ee or more.

[0058] Next, the step a may include a step (step d) of preparing a compound of the chemical formula 2 by reacting the compound of the chemical formula 4 with a compound of the chemical formula 5 after the step c.

[0059] <Chemical Formula 5>

[0060]

[0061] In the above formula, R3 and R4 are independently hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted alkynyl group having 1 to 6 carbon atoms.

[0062] Next, in the step of preparing a second intermediate compound represented by Chemical Formula 2, the second intermediate compound represented by Chemical Formula 4 can be prepared by reacting the first intermediate compound with a first acid and a phosphorus compound represented by Chemical Formula 5, or by reacting the first intermediate compound with a phosphorus compound represented by Chemical Formula 5 without the first acid. That is, the second intermediate compound represented by Chemical Formula 2 can be obtained by reacting the compound of Chemical Formula 4 with a phosphorus compound.

[0063] <Chemical Formula 4>

[0064]

[0065] <Chemical Formula 5>

[0066]

[0067] <Chemical Formula 2>

[0068]

[0069] In the first intermediate compound represented by chemical formula 4, the phosphorus compound represented by chemical formula 5, and the second intermediate compound represented by chemical formula 2, for example, R1 may be acetyl or succinyl, R2 may be hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, benzyl, phenyl, naphthyl, -Si(CH3)(tert-butyl)2, -Si(C6H5)2(tert-butyl), -Si(iso-propyl)3, -Si(C5H6)(CH3)2, -Si(C6H5)2(CH3), -Si(C5H6)3, -Si(CH3)3, -Si(CH2CH3)3, -Si(CH2CH3)2(CH3), -Si(CH2CH3)(CH3)2, or -Si(tert-butyl)3, and R3 and R4 may be independently methyl, ethyl, propyl, butyl, pentyl, and Any one selected from the group consisting of hexyl may be selected, and R5 may be R3 or R4. By having such functional groups in the first intermediate compound represented by chemical formula 4, the phosphorus compound represented by chemical formula 5, and the second intermediate compound represented by chemical formula 2, L-glufosinate having improved optical purity can be more easily produced.

[0070] The phosphorus compound represented by chemical formula 5 may be, in particular, an alkylmethylphosphonite, for example, diethylmethylphosphonite (DMP), ethylmethylphosphonite (EMP), or butylmethylphosphonite (BMP).

[0071] The phosphorus compound represented by chemical formula 5 can be used in an amount of 0.5 to 10 equivalents, 0.7 to 8 equivalents, 0.9 to 7 equivalents, or 1 to 6 equivalents relative to 1 equivalent of the first intermediate compound represented by chemical formula 4.

[0072] The first acid is, for example, a Lewis acid, and the Lewis acid may be at least one selected from among KF+Al2O3, ZnCl2LiBr, ZnBr2, BF3-Et2O(diehtylether), COCl2, MgBr2, Bu3P, Sc(OTf)3(OTf=trifluoromethanesulfonate), Sc(NTf2)3(Scandium(III) trifluoromethanesulfonimide), TiCl3-2AgClO4, TiCl3(OTf), Sn(OTf)2, TMSOTf(TriMethylSilyl trifluoromethanesulfonate), La(OTf)3, Cu(OTf)2, and TaCl5, and in particular, may be KF+Al2O3.

[0073] The content of the first acid may be, for example, 0.1 to 100 parts by weight, 0.1 to 50 parts by weight, 0.1 to 40 parts by weight, 0.1 to 30 parts by weight, 0.1 to 20 parts by weight, 0.1 to 10 parts by weight, 0.1 to 5 parts by weight, or 0.1 to 2 parts by weight, based on 100 parts by weight of the compound of Chemical Formula 4. If the content of the first acid is too low, the effect on the reaction rate is minimal, and if the content of the first acid is too high, byproducts may increase.

[0074] By using the first acid, the second intermediate compound can be obtained with a further improved yield. In the step of preparing the second intermediate compound, the reaction can be performed at a temperature of, for example, 80 to 180°C, 80 to 160°C, 90 to 160°C, 90 to 150°C, 100 to 160°C, 100 to 150°C, 100 to 140°C, 110 to 160°C, 110 to 150°C, 110 to 160°C, 110 to 140°C, 120 to 160°C, 120 to 150°C, or 120 to 140°C. Meanwhile, when the acid is added, the reaction temperature can be, for example, 80 to 160°C, and when the acid is not added, the reaction time and the reaction temperature can increase. For example, when no acid is used, the reaction temperature may be 120 to 180°C. In the step of preparing the second intermediate compound, the reaction may be performed for, for example, 0.1 to 20 hours, 1 to 20 hours, 1 to 18 hours, 5 to 15 hours, 6 to 14 hours, 8 to 14 hours, 10 to 14 hours, or 11 to 13 hours. By performing the reaction within these temperature and time ranges, the second intermediate compound can be prepared more easily.

[0075] In the step of preparing the second intermediate compound, the yield of the second intermediate compound may be, for example, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more.

[0076] In the step of preparing the second intermediate compound, the enantiomeric excess of the second intermediate compound having the L-form may be, for example, 10% ee or more, 20% ee or more, 30% ee or more, 40% ee or more, 50% ee or more, 60% ee or more, 70% ee or more, 80% ee or more, 90% ee or more, 91% ee or more, 92% ee or more, 93% ee or more, 94% ee or more, 95% ee or more, 96% ee or more, 97% ee or more, 98% ee or more, or 99% ee or more.

[0077] According to another embodiment, the step a may include a step (step a-1) of preparing a compound of the formula 2 by reacting the compound of the formula 1 with a halogenation agent, one or more R2-OH, and a compound of the formula 5 below.

[0078] <Chemical Formula 5>

[0079]

[0080] In the above formula, R3 and R4 are independently hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted alkynyl group having 1 to 6 carbon atoms.

[0081] Specifically, R1 may be acetyl or succinyl, and R2-OH may be at least one selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol, butanol, pentanol hexanol, benzyl alcohol, phenol, and naphthol. In addition, R3 and R4 may include any one selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl. L-glufosinate having improved optical purity can be more easily prepared by having the compound of formula 1, the phosphorus compound represented by formula 5, and the second intermediate compound represented by formula 2 having such functional groups.

[0082] The phosphorus compound represented by chemical formula 5 may be, in particular, an alkylmethylphosphonite, for example, diethylmethylphosphonite (DMP), ethylmethylphosphonite (EMP), or butylmethylphosphonite (BMP).

[0083] The phosphorus compound represented by chemical formula 5 can be used in an amount of 0.5 to 10 equivalents, 0.7 to 8 equivalents, 0.9 to 7 equivalents, or 1 to 6 equivalents relative to 1 equivalent of the compound of chemical formula 1.

[0084] The halogenating agent may include at least one selected from the group consisting of, for example, HCl, HBr, HI, phosgene, SOCl2, oxalyl chloride, TriMethylSilyl halide, sodium iodide (NaI), triethylsilane ((CH2CH3)3SiH)+palladium chloride (PdCl2)+methyl iodide (CH3I), POCl3, PCl3, PCl5, PBr3, PI3, H2SO4+KBr, P+Cl2, P+Br2, P+I2, TiCl4, ZnCl2, and BBr3.

[0085] In the step of preparing a second intermediate compound by reacting the compound of formula 1 with a halogenating agent, one or more R2-OH compounds, and a phosphorus compound, the halogenating agent may be, in particular, trimethylsilyl halide, sodium iodide (NaI), etc. The content of the halogenating agent may be, for example, 0.1 to 10 equivalents, 0.2 to 8 equivalents, 0.3 to 6 equivalents, or 0.5 to 5 equivalents relative to 1 equivalent of the compound of formula 1.

[0086] More than one R2-OH compound may be used in the reaction to form the second intermediate compound. When multiple R2-OH compounds are used, each R2-OH compound may be the same or different.

[0087] The R2-OH compound may be at least one selected from the group consisting of, for example, methanol, ethanol, n-propanol, iso-propanol, butanol, pentanol, hexanol, benzyl alcohol, phenol, and naphthol. By selecting the above-mentioned materials as the R2-OH compound, the second intermediate compound can be obtained from the compound of formula 1 in a higher yield.

[0088] The content of the R2-OH compound may be, for example, 1 to 60 equivalents, 1 to 40 equivalents, 2 to 20 equivalents, or 3 to 10 equivalents relative to 1 equivalent of the compound of formula 1.

[0089] When preparing a second intermediate compound represented by Chemical Formula 2 using a compound of Chemical Formula 1, a halogenating agent, and a phosphorus compound of Chemical Formula 5, the reaction temperature may be 80 to 180°C, 80 to 160°C, 90 to 160°C, 90 to 150°C, 100 to 160°C, 100 to 150°C, 100 to 140°C, 110 to 160°C, 110 to 150°C, 110 to 160°C, 110 to 140°C, 120 to 160°C, 120 to 150°C, or 120 to 140°C. The reaction time may be specifically performed for 0.1 to 20 hours.

[0090] Specific reaction conditions may refer to the step of preparing a second intermediate compound represented by Chemical Formula 2 from the compound of Chemical Formula 1 described above.

[0091] In addition, in the step of preparing the second intermediate compound, the yield of the second intermediate compound and the enantiomeric excess of the second intermediate compound having the L-form are the same as described above.

[0092] According to one embodiment, the step (step b) of preparing L-glufosinate of the following chemical formula 3 from the compound of the chemical formula 2 may be performed by hydrolyzing the compound of the above chemical formula 2 in the presence of an acid catalyst. That is, L-glufosinate represented by the chemical formula 3 may be prepared by reacting the second intermediate compound of the chemical formula 4 with a second acid (acid catalyst) to remove terminal functional groups through hydrolysis.

[0093] The second acid is, for example, at least one selected from the group consisting of HCl, H2SO4, a combination of H2SO4 and KF, and Al2O3 (KF+Al2O3), but the second acid is not necessarily limited to these and any acid used as an acid catalyst in the art may be used. The second acid may be hydrochloric acid in particular.

[0094] The content of the second acid may be, for example, 0.1 to 100 parts by weight, 0.1 to 50 parts by weight, 0.1 to 40 parts by weight, 0.1 to 30 parts by weight, 0.1 to 20 parts by weight, 0.1 to 10 parts by weight, 0.1 to 5 parts by weight, or 0.1 to 2 parts by weight, based on 100 parts by weight of the second intermediate compound represented by Chemical Formula 2. If the content of the second acid is too low, the effect on the reaction rate is minimal, and if the content of the second acid is too high, byproducts may increase.

[0095] When the solvent is water when using the second acid, the pH of the aqueous solution containing water may be 1 to 3. That is, in the step of preparing L-glufosinate, the reaction solution may be an acidic aqueous solution having a pH of 1 to 3. By having the reaction solution have a pH within this range, L-glufosinate can be prepared more easily.

[0096] In the step of preparing L-glufosinate, the hydrolysis reaction can be carried out at a temperature of, for example, 20 to 150°C, 40 to 140°C, 60 to 130°C, 80 to 120°C, or 90 to 110°C. In the step of preparing L-glufosinate, the hydrolysis reaction can be carried out for, for example, 0.1 to 30 hours, 1 to 20 hours, 1 to 15 hours, 3 to 13 hours, 4 to 12 hours, 5 to 11 hours, 6 to 10 hours, 7 to 9 hours, 10 to 30 hours, 12 to 24 hours, 15 to 20 hours, or 15 to 18 hours. L-glufosinate can be prepared more easily by carrying out the hydrolysis reaction in such a temperature range and time range.

[0097] In the step of preparing L-glufosinate, the yield of L-glufosinate can be, for example, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more.

[0098] The enantiomeric excess of the manufactured L-glufosinate can be, for example, 10% ee or more, 20% ee or more, 30% ee or more, 40% ee or more, 50% ee or more, 60% ee or more, 70% ee or more, 80% ee or more, 90% ee or more, 91% ee or more, 92% ee or more, 93% ee or more, 94% ee or more, 95% ee or more, 96% ee or more, 97% ee or more, 98% ee or more, or 99% ee or more. L-glufosinate having such improved optical purity can provide, for example, a more improved herbicidal effect.

[0099] In the present invention, L-glufosinate may include its salt form. Specifically, the salt of L-glufosinate is, for example, L-glufosinate hydrochloride, L-glufosinate sulfate, L-glufosinate carbonate, L-glufosinate ammonium salt, etc., but is not necessarily limited thereto, and any salt of L-glufosinate obtained by the above-described glufosinate production method may be used.

[0100] According to the present invention, it is possible to simply produce L-glufosinate having high optical purity in a high yield by following a synthetic route using the first intermediate compound of chemical formula 1.

[0101] Additionally, the compound of formula 1 can be prepared by a step of reacting an L-homoserine derivative represented by formula 6 below with a first base to prepare a third intermediate compound represented by formula 7, and a step of reacting the third intermediate compound with a third acid. That is, before step a or step a-1, the process may further include a step of reacting an L-homoserine derivative represented by formula 6 below with a first base to prepare a third intermediate compound represented by formula 7; and a step of reacting the third intermediate compound with a third acid to prepare a compound of formula 1.

[0102] More specifically, a third intermediate compound represented by chemical formula 7 can be prepared by reacting an L-homoserine derivative represented by chemical formula 6 below with a first base.

[0103] R represented by R1 in the L-homoserine derivative represented by chemical formula 6 a The -(C=O)- functional group can be bonded to nitrogen in the third intermediate compound represented by chemical formula 7 through a functional group transfer reaction in the presence of a first base. For example, the functional group represented by R1 in the L-homoserine derivative represented by chemical formula 6 can be bonded to nitrogen in the third intermediate compound represented by chemical formula 7 through a functional group transfer reaction in the presence of a first base, thereby acting as a protecting group of the amine.

[0104] <Chemical Formula 6>

[0105]

[0106] <Chemical Formula 7>

[0107]

[0108] In the above formula,

[0109] R1 is R e -(C=O)- and R eis a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, or a substituted or unsubstituted heteroaryl group having 2 to 10 carbon atoms, and the substituents of the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the aryl group, and the heteroaryl group are each independently at least one selected from a halogen, a carboxyl group (-COOH), an amino group (-NH2), a nitro group (-NO2), a cyano group (-CN), an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, and a cycloalkyl group having 3 to 10 carbon atoms.

[0110] In the L-homoserine derivative represented by chemical formula 6, for example, R1 may be acetyl or succinyl. By having such a functional group in the L-homoserine derivative represented by chemical formula 6, L-glufosinate having improved optical purity can be more easily produced.

[0111] The L-homoserine derivative represented by chemical formula 6 can be prepared, for example, from a fermentation solution containing the L-homoserine derivative. Therefore, efficient production of L-glufosinate is possible using the L-homoserine derivative represented by chemical formula 6 produced during the fermentation process.

[0112] In this application, the term 'fermentation solution containing an L-homoserine derivative' may refer to a fermentation solution containing an L-homoserine derivative produced from a fermentation process. The fermentation may be the same as described above.

[0113] The first base may be, for example, one or more selected from NH3, KOH, NaOH, CaSO4, LiOH, NaH, KH, NaOCH3, NaOCH2CH3, NaOC(CH3)3, KOC(CH3)3, K2CO3, Na2CO3, 1,8-diazabicyclo[5.4.0]undeca-7-ene(DBU), 1,5-diazabicyclo[4.3.0]nona-5-ene(DBN), tri(C1-C4alkyl)amine, pyridine and n-butyllithium.

[0114] The first base may be sodium hydroxide in particular. The content of the first base may be, for example, 0.1 to 100 parts by weight, 0.1 to 50 parts by weight, 0.1 to 40 parts by weight, 0.1 to 30 parts by weight, 0.1 to 20 parts by weight, 0.1 to 10 parts by weight, 0.1 to 5 parts by weight, or 0.1 to 2 parts by weight, based on 100 parts by weight of the L-homoserine derivative represented by the chemical formula 6. If the content of the first base is too low, the effect on the reaction rate may be minimal, and if the content of the first base is too high, by-products may increase. The step of preparing the third intermediate compound of the chemical formula 7 may be performed in a solvent. The solvent may be water or an organic solvent. When the first base is used and the solvent is water, the pH of the aqueous solution containing water may be 9 to 14, 10 to 14, or 12 to 14. Since the reaction solution has a pH within this range, the L-homoserine compound can be prepared more easily. In the step of preparing the L-homoserine compound, the functional group transfer reaction can be performed at a temperature of, for example, 20 to 150°C. In the step of preparing the L-homoserine compound, the functional group transfer reaction can be performed for, for example, 0.1 to 20 hours. By performing the functional group transfer reaction within this temperature and time range, the third intermediate compound can be prepared more easily.

[0115] In the step of preparing the third intermediate compound, the yield of the third intermediate compound may be, for example, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more.

[0116] In the step of preparing the third intermediate compound, the enantiomeric excess of the third intermediate compound may be, for example, 10% ee or more, 20% ee or more, 30% ee or more, 40% ee or more, 50% ee or more, 60% ee or more, 70% ee or more, 80% ee or more, 90% ee or more, 91% ee or more, 92% ee or more, 93% ee or more, 94% ee or more, 95% ee or more, 96% ee or more, 97% ee or more, 98% ee or more, or 99% ee or more.

[0117] Next, the third intermediate compound represented by chemical formula 7 can be reacted in the presence of a third acid to prepare a compound of chemical formula 1.

[0118] That is, the third intermediate compound represented by chemical formula 7 can be lactonized by reacting it with a third acid to obtain a lactone compound represented by chemical formula 1 below. For example, the third intermediate compound represented by chemical formula 7 can form a lactone ring by the third acid.

[0119] <Chemical Formula 7>

[0120]

[0121] <Chemical Formula 1>

[0122]

[0123] The third acid may be, for example, one or more selected from the group consisting of acetic acid, HCl, H2SO4, HBr and HI.

[0124] The content of the third acid can be appropriately selected depending on the type of acid used. For example, for the first intermediate compound represented by Chemical Formula 4, 0.1 equivalent or more of the third acid can be used, and specifically, in the case of hydrochloric acid or sulfuric acid, it can be 0.1 to 2 equivalents, 0.3 to 1.8 equivalents, or 0.5 to 1.5 equivalents, and in the case of acetic acid, it can be 10 equivalents or more, 20 equivalents or more, 10 to 50 equivalents, or 20 to 40 equivalents. If the content of the third acid is too low, the effect on the reaction rate is minimal, and if the content of the third acid is too high, by-products may increase.

[0125] The step of preparing the compound of formula 1 may be performed in the presence of a solvent or under neat conditions without a solvent. The solvent may be water or an organic solvent.

[0126] In the step of preparing the compound of chemical formula 1, the lactone formation reaction can be performed at a temperature of, for example, 20 to 150°C. In the step of preparing the first intermediate compound, the lactone formation reaction can be performed for, for example, 0.1 to 20 hours. By performing the lactone formation reaction within these temperature and time ranges, the compound of chemical formula 1 can be prepared more easily.

[0127] In the step of preparing the compound of formula 1, the yield of the compound of formula 1 may be, for example, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more.

[0128] In the step of preparing the compound of formula 1, the enantiomeric excess of the first intermediate compound having the L-form may be, for example, 10% ee or more, 20% ee or more, 30% ee or more, 40% ee or more, 50% ee or more, 60% ee or more, 70% ee or more, 80% ee or more, 90% ee or more, 91% ee or more, 92% ee or more, 93% ee or more, 94% ee or more, 95% ee or more, 96% ee or more, 97% ee or more, 98% ee or more, or 99% ee or more.

[0129] The present application is described in more detail through the following examples and comparative examples. However, the examples are intended to illustrate the present application and are not intended to limit the scope of the present application.

[0130] Example 1: Preparation of L-glufosinate using N-acetyl-L-homoserine lactone (using the second intermediate compound (1))

[0131] (Step 1-1: Preparation of Ethyl-2-(acetamino)-4-chlorobutanoate)

[0132]

[0133] A reaction solution was prepared by slowly adding thionyl chloride (6.6 g, 56 mmol) to a solution of 4 g (28 mmol) of N-acetyl-L-homoserine lactone in 60 mL of ethanol at 0°C. The prepared reaction solution was stirred at 80°C for 3 hours. Then, 1 N NaOH (aq) was added to the completed reaction solution to neutralize it, and the resulting concentrate was concentrated under reduced pressure to prepare a concentrate. The concentrate was diluted with ethyl acetate and washed once with brine. The organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered, and the filtrate was concentrated under reduced pressure to obtain a residue containing ethyl-2(acetylamino)-4-chlorobutanoate.

[0134] The obtained residue was separated by column chromatography (mobile phase, hexane:ethyl acetate = 1:1) to obtain 5.12 g (yield 88%) of Ethyl-2-(acetylamino)-4 chlorobutanoate as a colorless oil.

[0135] 1 H NMR (400 MHz, DMSO-d6): δ4.49 (m, 1H), 4.22 (q, 2H), 3.60 (t, 2H), 2.25 (m, 2H), 1.91 (s, 3H), 1.30 (t, 3H)

[0136] (Step 1-2: Preparation of Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate)

[0137]

[0138] Ethyl-2-(acetamino)-4-chlorobutanoate (2.6 g, 12.6 mmol) and diethyl methylphosphonite (3.4 g, 25.2 mmol, 2 equiv.) were dissolved, nitrogen was injected, and the mixture was stirred at 120°C for 12 hours. After the reaction was completed, unreacted diethylmethylphosphonite was removed under reduced pressure of 1 mmHg at 80°C. The residue was separated by column chromatography (mobile phase, ethyl acetate: isopropanol = 4:1 by volume) to obtain 2.25 g (yield 64%) of ethyl-2-(acetamino)-4(ethoxymethylphosphinyl)butanoate as a colorless oil.

[0139] 1 H NMR (400 MHz, CDCl3): δ4.40 (m, 1H), 4.20 (q, 2H), 3.99 (q, 2H), 2.01 (m, 4H), 1.91 (s, 3H), 1.45 (d, J= 14 Hz, 3H), 1.30 (t, 3H), 1.26 (t, 3H). 31P NMR (CDCl3, 121.47 MHz) δ 54.28.

[0140] (Step 1-3: Preparation of L-glufosinate (L-phosphinothricin) hydrochloride)

[0141]

[0142] 2 g (7.17 mmol) of ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate was dissolved in 20 mL of 6N HCl, placed in a sealed tube, and stirred at 120°C for 15 hours. After the hydrolysis reaction was completed, the solvent was removed under reduced pressure to obtain 1.49 g of white L-glufosinate hydrochloridesalt (yield 96%; total yield of steps 1-1 to 1-3 61%).

[0143] 1 H NMR (400 MHz, DO): δ 4.12 (m, 1H), 2.45-1.65 (m, 4H), 1.46 (d,J=14 Hz, 3H).

[0144] Reference Example 1: Preparation of N-acetyl-L-homoserine lactone

[0145]

[0146] To an aqueous solution of O-Acetyl-L-Homoserine (II) (1 g, 6.2 mmol) dissolved in 30 mL of water, NaOH (40 wt% aqueous solution) as an alkaline catalyst was slowly added to prepare a reaction solution having a pH of 9. The prepared reaction solution was then stirred at 25°C for 30 minutes. Subsequently, the reaction solution was heated to 50°C and stirred at 50°C for 5 hours. Subsequently, 1 N HCl (aq) was added to the solution after the reaction was completed to neutralize it, and the concentrate was prepared by concentrating under reduced pressure. The prepared concentrate was cooled to 0°C, stirred with the addition of ethanol, and filtered under reduced pressure to obtain 0.98 g (yield 98%) of N-Acetyl-L-Homoserine (III-1) as a white solid.

[0147] 1H NMR (400 MHz, DMSO-d6): δ7.68 (d, J= 8 Hz, 1H), 3.96 (m, 1H), 3.40 (t, J= 6.8 Hz, 2H), 1.83 (s, 3H), 1.81 (m, 1H), 1.61 (m, 1H)

[0148]

[0149] To a solution of N-Acetyl-L-Homoserine (1 g, 6.2 mmol) dissolved in 30 mL of water, c-HCl (concentrated hydrochloric acid) was slowly added as an acid to prepare a reaction solution of pH 2. The prepared reaction solution was stirred at 25°C for 30 minutes. Subsequently, the reaction solution was heated to 60°C and stirred at 60°C for 3 hours. Subsequently, 1N NaOH (aq) was added to the solution after the reaction was completed to neutralize it, and the concentrate was prepared by concentrating under reduced pressure. The prepared concentrate was cooled to 0°C, isopropanol was added, stirred, and filtered under reduced pressure to obtain 0.87 g (yield 98%) of N-acetyl-L-Homoserine lactone as a white solid.

[0150] 1 H NMR (400 MHz, DMSO-d6): δ3.96 (m, 1H), 3.89 (t, J= 6.8 Hz, 2H), 1.91 (s, 3H), 2.11 (m, 1H), 1.83 (m, 1H)

[0151] Example 2: Preparation of L-glufosinate using N-succinyl-L-homoserine lactone (using the second intermediate compound (2))

[0152] (Step 2-1: Preparation of Ethyl-2-(succinylamino)-4-chlorobutanoate)

[0153]

[0154] Ethyl-2-(succinoamino)-4-chlorobutanoate was prepared using N-succinyl-L-Homoserine lactone in the same manner as in Example 1.

[0155] Afterwards, white L-glufosinate hydrochloride salt (4 steps (steps 1-2 and 1-3) total yield 51%) was obtained from Ethyl-2-(succinoamino)-4-chlorobutanoate using the same method as in Example 1.

[0156] 1 H NMR (400 MHz, DO): δ 4.12 (m, 1H), 2.45-1.65 (m, 4H), 1.46(d,J=14 Hz,3H).

[0157] Reference Example 2: Preparation of N-succinyl-L-homoserine lactone

[0158]

[0159] A reaction solution of pH 9 was prepared by slowly adding NaOH (40 wt% aqueous solution) to an aqueous solution of O-Succinyl-L-Homoserine (1 g, 4.57 mmol) dissolved in 30 mL of water.

[0160] Next, the prepared reaction solution was stirred at 25°C for 30 minutes. Then, the reaction solution was heated to 50°C and stirred at 50°C for 5 hours. Then, 1N HCl(aq) was added to the solution in which the reaction was completed to neutralize it, and then concentrated under reduced pressure to prepare a concentrate. After cooling the prepared concentrate to 0°C, ethanol was added, stirred, and filtered under reduced pressure to obtain 0.98 g (yield 98%) of N-succinyl-L-Homoserine as a white solid.

[0161] 1H NMR (400 MHz, DMSO-d6): δ7.68 (d,J= 8 Hz, 1H), 3.96 (m, 1H), 3.40 (t,J= 6.8 Hz, 2H), 2.55 (t,J= 13 Hz, H), 2.31 (t,J= 13 Hz, 2H), 1.83 (s, 3H), 1.81 (m, 1H), 1.61 (m, 1H)

[0162]

[0163] N-succinyl-L-Homoserine (1 g) was dissolved in 30 mL of water, and c-HCl (concentrated hydrochloric acid) was slowly added as an acid to prepare a reaction solution of pH 2. The prepared reaction solution was stirred at 25°C for 30 minutes. Subsequently, the reaction solution was heated to 60°C and stirred at 60°C for 3 hours. Subsequently, 1N NaOH (aq) was added to the solution in which the reaction was completed to neutralize it, and the concentrate was prepared by concentrating under reduced pressure. The prepared concentrate was cooled to 0°C, stirred with the addition of ethanol, and filtered under reduced pressure to obtain N-succinyl-L-Homoserine lactone as a white solid (yield 98%).

[0164] 1 H NMR (400 MHz, DMSO-d6): δ3.96 (m, 1H), 3.89 (t,J= 6.8 Hz, 2H), 2.45 (t,J= 13 Hz, 2H), 2.31 (t,J= 13 Hz, 2H), 1.81 (m, 1H), 1.61 (m, 1H)

[0165] Example 3: Preparation of L-glufosinate using N-acetyl-L-homoserine lactone (without using the second intermediate compound (1))

[0166] (Step 3-1: Preparation of Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate)

[0167]

[0168] After dissolving 1.8 g (12.6 mmol) of N-acetyl-L-Homoserine lactone in 20 ml of ethanol, diethyl methylphosphonite (3.4 g, 25.2 mmol, 2 equiv.) and Trimethylsilyl iodide (5.0 g, 25.2 mmol, 2 equiv.) were added to a sealed tube, and after nitrogen injection, the mixture was stirred at 140°C for 14 hours.

[0169] After the reaction was completed, unreacted diethyl methylphosphonite was removed under reduced pressure of 1 mmHg at 80°C. The residue was separated by column chromatography (mobile phase, ethyl acetate:isopropanol = 4:1 by volume) to obtain 4.42 g (yield 62.8%) of Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate as a colorless oil.

[0170] 1 H NMR (400 MHz, CDCl3): δ4.40 (m, 1H), 4.20 (q, 2H), 3.99 (q, 2H), 2.01 (m, 4H), 1.91 (s, 3H), 1.45 (d, J= 14 Hz, 3H), 1.30 (t, 3H), 1.26(t, 3H). 31 P NMR (CDCl3, 121.47 MHz) δ54.28.

[0171] (Step 3-2: Preparation of L-glufosinate (L-phosphinothricin) hydrochloride)

[0172]

[0173] 2 g (7.17 mmol) of ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate was dissolved in 20 mL of 6N HCl, placed in a sealed tube, and stirred at 120°C for 15 hours. After the hydrolysis reaction was completed, the solvent was removed under reduced pressure to obtain 1.49 g (yield 96%) of white L-glufosinate hydrochloride salt.

[0174] 1 H NMR (400 MHz, DO): δ4.12 (m, 1H), 2.45-1.65 (m, 4H), 1.46(d, J= 14 Hz, 3H).

[0175] Example 4: Preparation of L-glufosinate using N-succinyl-L-homoserine lactone (without using the second intermediate compound (2))

[0176] (Step 4-1: Preparation of Ethyl-2-(succinylamino)-4-(ethoxyphosphinyl)butanoate)

[0177]

[0178] Ethyl-2-(succinylamino)-4-(ethoxyphosphinyl)butanoate was prepared using N-succinyl-L-Homoserine lactone in the same manner as in Example 1.

[0179] Afterwards, Ethyl-2-(succinylamino)-4-(ethoxyphosphinyl)butanoate was hydrolyzed in the same manner as in Example 1 to obtain white L-glufosinate hydrochloride salt (yield 96%).

[0180] 1H NMR (400 MHz, DO): δ 4.12 (m, 1H), 2.45-1.65 (m, 4H), 1.46(d,J=14 Hz,3H).

[0181] Comparative Example 1: Preparation of racemic glufosinate

[0182] Glufosinate was prepared according to the method disclosed in Example 1 of USP 6,359,162. The prepared glufosinate was a racemic mixture.

[0183] Comparative Example 2: Comparison with the L-glufosinate manufacturing method that introduces a protecting group into homoserine lactone.

[0184] The following content compares the L-glufosinate manufacturing method and reaction results of introducing a protecting group to homoserine lactone, and L-glufosinate was manufactured according to the following reaction scheme 1.

[0185] [Reaction Formula 1]

[0186]

[0187] The reaction conditions and reaction results of each reaction step are shown in Table 1 below.

[0188]

[0189] (OAHS: O-Acetylhomoserine, HSL: Homoserine lactone, NecHSL: N-ethoxycarbonylhomoserine lactone, Cl-NecHSL-OEt: Ethyl-2-(ethoxycarbonylamino)-4-chlorobutanoate, P-NecHSL-OEt: Ethyl-2-(ethoxycarbonylamino)-4-(ethoxymethylphosphinyl)butanoate)

[0190] As shown in Table 1, when hydrochloric acid is used in preparing a lactone compound from an L-homoserine derivative, homoserine lactone as shown in the above reaction scheme 1 is obtained. When the homoserine lactone is obtained, the amine group in the homoserine lactone is protected with an ethoxycarbonyl group, and then halogenated with a halogenating agent, combined with a phosphorus compound, and then hydrolyzed to prepare L-glufosinate, it was confirmed that L-glufosinate was obtained in a low yield.

[0191] Experimental Example 1: Measurement of enantiomeric excess (% ee)

[0192] The mirror image excess of L-glufosinate synthesized in Examples 1 to 4 and Comparative Example 1 was measured using chiral HPLC, and the results are shown in Table 2 below.

[0193] Chiral HPLC analysis was performed with reference to the method disclosed in J. Chromatogr. 368, 413 (1986).

[0194] The mirror image excess (% ee) was determined using Sumichiral OA6100 (4.6 X 150 mm), Chiracel® OD-H (4.6 X 250 mm), Sumichiral OA5000 (4.6 X 150 mm), or Chiralpak zwix (4.0 X 150 mm) chiral columns. The mobile phase consisted of a co-solvent of 0–30% methanol, 0–70% acetonitrile, and 0–70% distilled water, or a 2 mM copper sulfate aqueous solution. The flow rate was 1.0 mL / min, the sample injection volume was 10 μL, and the UV detection wavelength was 200–280 nm.

[0195]

[0196] As shown in Table 2 above, the glufosinate produced in Examples 1 to 4 had a significantly improved mirror image excess of L-glufosinate compared to the glufosinate produced in Comparative Example 1. Therefore, it is possible to simply produce high-purity L-glufosinate by a production method including the intermediate compound of the present invention.

[0197] Reference Example 1: Examination of pH conditions when preparing an L-homoserine compound represented by chemical formula 7 from an L-homoserine derivative.

[0198] The yield pattern of the L-homoserine compound represented by the chemical formula 7 from the L-homoserine derivative represented by the chemical formula 6 was confirmed according to the pH. Using O-Acetyl-L-homoserine as the starting material as the L-homoserine derivative, N-acetyl-L-Homoserine as the L-homoserine compound was obtained in the same manner as the preparation method of Reference Example 1 (Step 1-4), except that the pH during the reaction was different to 8.2, 9.2, 10.2, 12.7, and 13.4, respectively. The results are shown in Table 3 below.

[0199]

[0200] (OAHS: O-Acetyl-L-Homoserine, NAHS: N-Acetyl-L-Homoserine)

[0201] As shown in Table 3 above, when producing an L-homoserine compound represented by chemical formula 7 from an L-homoserine derivative represented by chemical formula 6, the yield of N-acetyl-L-Homoserine increased as the pH increased, and in particular, when the pH was 9 or higher, N-acetyl-L-Homoserine was obtained in a high yield.

[0202] Reference Example 2: Review of reaction conditions for preparing the first intermediate compound from an L-homoserine compound.

[0203] The yield pattern of the lactone compound represented by chemical formula 1 according to the reaction conditions was confirmed from the L-homoserine compound represented by chemical formula 7. Using N-acetyl-L-Homoserine as the L-homoserine compound, N-acetyl-L-Homoserine lactone, a compound represented by chemical formula 1, was obtained in the same manner as the preparation method of Reference Example 1 (Step 1-5), except that the equivalent amount of acid and the reaction temperature during the reaction were changed as shown in Tables 4 to 6 below, respectively, and the results are shown in Tables 4 to 6.

[0204]

[0205] (NAHS:N-Acetyl-L-Homoserine, NAHSL:N-acetyl-L-Homoserine lactone)

[0206] As shown in Table 4 above, when the compound of formula 1 was prepared from the L-homoserine compound represented by formula 7 using acetic acid, the yield of N-acetyl-L-Homoserine lactone increased as the equivalent of acetic acid increased, and in particular, when the equivalent of acetic acid was 2.6 or more, N-acetyl-L-Homoserine lactone was obtained in a high yield.

[0207] As the reaction temperature increased, the yield of N-acetyl-L-Homoserine lactone increased, and in particular, when the reaction temperature was 40°C or higher, N-acetyl-L-Homoserine lactone was obtained in high yield.

[0208]

[0209] As shown in Table 5 above, when the compound of formula 1 was prepared from the L-homoserine compound represented by formula 7 using hydrochloric acid, the yield of N-acetyl-L-Homoserine lactone increased as the sulfuric acid equivalent increased up to 1.0, and when 1.5 equivalents or more of hydrochloric acid were applied, the yield of N-acetyl-L-Homoserine lactone gradually decreased.

[0210]

[0211] As shown in Table 6 above, when the compound of formula 1 was prepared from the L-homoserine compound represented by formula 7 using sulfuric acid, the yield of N-acetyl-L-Homoserine lactone increased as the sulfuric acid equivalent increased up to 1.0, and when 1.5 equivalents or more of sulfuric acid were applied, the yield of N-acetyl-L-Homoserine lactone gradually decreased.

[0212] Experimental Example 2: Examination of reaction conditions for preparing the first intermediate compound from the compound of chemical formula 1.

[0213] The yield pattern of the first intermediate compound represented by Chemical Formula 4 according to the reaction conditions from the compound of Chemical Formula 1 was confirmed. Using N-acetyl-L-Homoserine lactone as the compound of Chemical Formula 1, the first intermediate compound, Ethyl-2-(acetamino)-4-chlorobutanoate or Methyl-2-(acetamino)-4-chlorobutanoate, was obtained in the same manner as the preparation method of Example 1 (Step 1-1), except that the equivalent amount of ethanol or methanol and the reaction temperature during the reaction were changed as shown in Tables 7 and 8 below, respectively, and the results are also shown in Tables 7 and 8.

[0214]

[0215] (NAHSL:N-acetyl-L-Homoserine lactone, Cl-NAHS-OEt: Ethyl-2-(acetamino)-4-chlorobutanoate)

[0216] As shown in Table 7 above, when the first intermediate compound represented by Chemical Formula 4 was prepared from the compound represented by Chemical Formula 1 using ethanol, the yield of Ethyl-2-(acetamino)-4-chlorobutanoate increased as the ethanol equivalent increased, and in particular, when the ethanol equivalent was 3 to 10 equivalents, Ethyl-2-(acetamino)-4-chlorobutanoate was obtained in a high yield.

[0217] As the reaction temperature increased, the yield of Ethyl-2-(acetamino)-4-chlorobutanoate increased, and in particular, when the reaction temperature was 40°C or higher, Ethyl-2-(acetamino)-4-chlorobutanoate was obtained in a high yield.

[0218]

[0219] (NAHSL:N-acetyl-L-Homoserine lactone, Cl-NAHS-OMe: Methyl-2-(acetamino)-4-chlorobutanoate)

[0220] As shown in Table 8 above, when the first intermediate compound represented by Chemical Formula 4 was prepared from the compound represented by Chemical Formula 1 using methanol, the yield of Methyl-2-(acetamino)-4-chlorobutanoate increased as the methanol equivalent increased, and in particular, when the equivalent of ethanol was 3 to 10 equivalents, Methyl-2-(acetamino)-4-chlorobutanoate was obtained in a high yield.

[0221] As the reaction temperature increased, the yield of Methyl-2-(acetamino)-4-chlorobutanoate increased, and in particular, when the reaction temperature was 40°C or higher, Methyl-2-(acetamino)-4-chlorobutanoate was obtained in a high yield.

[0222] Experimental Example 3: Examination of reaction conditions for preparing a second intermediate compound from a first intermediate compound.

[0223] The yield pattern according to the reaction conditions for the second intermediate compound represented by the chemical formula 2 from the first intermediate compound represented by the chemical formula 4 was confirmed. The second intermediate compound was obtained in the same manner as the manufacturing method of Example 1 (Step 1-2) using Ethyl-2-(acetamino)-4-chlorobutanoate as the first intermediate compound, but the type and equivalent of the phosphorus compound and the reaction temperature during the reaction were changed as shown in Table 9 below, and the results are also shown in Table 9.

[0224]

[0225] (DMP: Diethyl methyl phosphonite, EMP: Ethyl methyl phosphonite, BMP: Butyl methyl phosphonite, P-NAHS-Oet: Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate)

[0226] As shown in Table 9 above, the second intermediate compound represented by Chemical Formula 2 can be prepared from the first intermediate compound represented by Chemical Formula 4 using DMP or an AMP (alkyl methyl phosphonite) such as EMP or BMP as a phosphorus compound, and the yield further increased when 1 equivalent or more of DMP or AMP was used. The yield further increased as the reaction temperature increased, and in particular, when the reaction temperature was 120°C or higher, Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate was obtained in a high yield.

[0227] Experimental Example 4: Examination of reaction conditions for preparing a second intermediate compound from the compound of chemical formula 1.

[0228] The yield pattern according to the reaction conditions for the second intermediate compound represented by Chemical Formula 2 from the compound of Chemical Formula 1 was confirmed. The second intermediate compound was obtained in the same manner as the production method of Example 2 (Step 2-1) using N-acetyl-L-Homoserine lactone as the compound of Chemical Formula 1, but the type and equivalent of the halogenating agent and the reaction temperature during the reaction were changed as shown in Tables 10 to 12, respectively, and the results are also shown in Tables 10 to 12.

[0229]

[0230]

[0231]

[0232] (TMSI: Trimethylsilyl iodide, TMSBr: Trimethylsilyl bromide, TMSCl: Trimethylsilyl chloride, P-NAHS-Oet: Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate)

[0233] As shown in Tables 10 to 12 above, a second intermediate compound represented by Chemical Formula 2 can be prepared from a compound represented by Chemical Formula 1 using a trimethylsilyl halide such as TMSI, TMSBr, TMSCl, or NaI as a halogenating agent, and the yield further increased when 0.5 equivalents or more of trimethylsilyl halide was used. The yield further increased as the reaction temperature increased, and in particular, when the reaction temperature was 100°C or higher, Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate was obtained in a high yield.

[0234] Among the trimethylsilyl halides, TMSI was the most reactive, and the reactivity tended to decrease slightly in the order of TMSBr and TMSCl, but Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate could be obtained from all of them.

[0235] Experimental Example 5: Reaction conditions for L-glufosinate in the second intermediate compound

[0236] The yield pattern according to the reaction conditions for the second intermediate compound represented by Chemical Formula 2 was confirmed. L-glufosinate was obtained in the same manner as the manufacturing method of Example 1 (Step 1-3) using Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate as the second intermediate compound, but the acid used, reaction temperature, and reaction time were changed as shown in Table 13 below, and the results are shown in Table 13.

[0237]

[0238] As shown in Table 13 above, L-glufosinate can be produced from the second intermediate compound represented by Chemical Formula 2 using 6N hydrochloric acid as an acid at 120°C, and the yield tended to increase further as the reaction time increased. In addition, it was confirmed that the yield increased further as the reaction temperature increased when the reaction was performed for 15 hours or longer.

Claims

1. A method for producing L-glufosinate from an L-lactone derivative compound, comprising the steps of: preparing a compound of the following chemical formula 2 from a compound of the following chemical formula 1 (step a); and preparing L-glufosinate of the following chemical formula 3 from the compound of the following chemical formula 2 (step b): <Chemical Formula 1> <Chemical Formula 2> <Chemical Formula 3> In the above equations, R1 is R a -(C=O)- and R a is hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, or a substituted or unsubstituted heteroaryl group having 2 to 10 carbon atoms, R2 is hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, a substituted or unsubstituted heteroaryl group having 2 to 10 carbon atoms, or -Si(R b )(R c )(R d ) and R b , R c and R d are independently a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, R5 is hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted alkynyl group having 1 to 6 carbon atoms, The substituents of the above alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group and heteroaryl group are independently at least one selected from the group consisting of hydrogen, halogen, carboxyl group (-COOH), amino group (-NH2), nitro group (-NO2), cyano group (-CN), alkyl group having 1 to 6 carbon atoms, aryl group having 6 to 10 carbon atoms and cycloalkyl group having 3 to 10 carbon atoms.

2. In the first paragraph, the step a comprises a step (step c) of preparing a compound of the following chemical formula 4 by reacting the compound of the chemical formula 1 with a halogenation agent and at least one R2-OH, wherein the method for producing L-glufosinate: <Chemical Formula 4> In the above formula, R1 and R2 are as defined in the first term, and X is halogen.

3. In the second paragraph, the step a comprises a step (step d) of preparing a compound of the chemical formula 2 by reacting the compound of the chemical formula 4 with a compound of the chemical formula 5 after the step c: L-glufosinate manufacturing method: <Chemical Formula 5> In the above formula, R3 and R4 are independently hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted alkynyl group having 1 to 6 carbon atoms.

4. In the first paragraph, the step a comprises a step (step a-1) of preparing a compound of the chemical formula 2 by reacting the compound of the chemical formula 1 with a halogenation agent, one or more R2-OH, and a compound of the chemical formula 5 below: L-glufosinate production method: <Chemical Formula 5> In the above formula, R3 and R4 are independently hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted alkynyl group having 1 to 6 carbon atoms.

5. A method for producing L-glufosinate, wherein in the first paragraph, R1 is acetyl or succinyl.

6. A method for producing L-glufosinate, wherein in the first paragraph, R2 is any one selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, benzyl, phenyl, and naphthyl.

7. A method for producing L-glufosinate, wherein in the third or fourth paragraph, R3 and R4 are independently any one selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl.

8. A method for producing L-glufosinate, wherein the compound of formula 1 is prepared from a fermentation solution containing a precursor of the compound of formula 1.

9. A method for producing L-glufosinate according to claim 2 or 4, wherein the halogenating agent comprises at least one selected from the group consisting of HCl, HBr, HI, phosgene, SOCl2, oxalyl chloride, trimethylsilyl halide, sodium iodide (NaI), triethylsilane ((CH2CH3)3SiH) + palladium chloride (PdCl2) + methyl iodide (CH3I), POCl3, PCl3, PCl5, PBr3, PI3, H2SO4 + KBr, P+Cl2, P+Br2, P+I2, TiCl4, ZnCl2, and BBr3.

10. A method for producing L-glufosinate, wherein in the second or fourth paragraph, R2-OH comprises at least one selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol, butanol, pentanol hexanol, benzyl alcohol, phenol, and naphthol.

11. A method for producing L-glufosinate, wherein in the second or fourth paragraph, the content of R2-OH is 1 to 60 equivalents relative to 1 equivalent of the compound of chemical formula 1.

12. A method for producing L-glufosinate, wherein the content of the halogenating agent in the second or fourth paragraph is 0.1 to 10 equivalents relative to 1 equivalent of the compound of the chemical formula 1.

13. A method for producing L-glufosinate in the second paragraph, wherein step c is performed at a temperature of 20 to 100°C for a reaction time of 0.1 to 30 hours.

14. A method for producing L-glufosinate in claim 3 or 4, wherein the compound of formula 5 comprises at least one selected from the group consisting of diethylmethylphosphinate (DMP), ethylmethylphosphinate (EMP), and butylmethylphosphinate (BMP).

15. A method for producing L-glufosinate, wherein the content of the compound of formula 5 in the third or fourth paragraph is 0.5 to 10 equivalents relative to 1 equivalent of the compound of formula 1 or the compound of formula 4.

16. A method for producing L-glufosinate according to claim 3 or 4, wherein step a-1 or step d is performed at a temperature of 80 to 180°C for 0.1 to 20 hours.

17. A method for producing L-glufosinate, wherein step b is performed by hydrolyzing the compound of the chemical formula 2 in the presence of an acid catalyst.

18. A method for producing L-glufosinate in claim 17, wherein the acid catalyst comprises at least one selected from the group consisting of acetic acid, HCl, H2SO4, and KF-Al2O3.

19. A method for producing L-glufosinate, wherein step b is performed at a temperature of 20 to 150°C for 0.1 to 30 hours in the first paragraph.

20. A method for producing L-glufosinate, wherein in the first paragraph, the L-glufosinate comprises at least one selected from the group consisting of a hydrochloride salt of L-glufosinate, a sulfate salt of L-glufosinate, a carbonate salt of L-glufosinate, a sodium salt of L-glufosinate, and an ammonium salt of L-glufosinate.