It relates to a method for preparing an L-glufosinate intermediate.
background
[2]
Glufosinate has been widely used as a herbicide having a wide range of permeability, and it is known that the penetrative herbicide properties of glufosinate are effects due to the L-isomer of glufosinate. Accordingly, various methods for preparing the L-isomer of glufosinate have been studied. For example, a method for preparing the L-isomer of glufosinate by selectively separating the L-isomer from a racemic mixture of the D-isomer and the L-isomer was used. In this method, the yield of the L-isomer is reduced to less than half, the unnecessary D-isomer is generated as an excessive by-product, and a resolving agent, a resolving device, etc. are required for separation of the L-isomer. There is a problem that the process is complicated.
[3]
Therefore, there is a need for a method for simply preparing the L-isomer of glufosinate with high optical purity in high yield.
DETAILED DESCRIPTION OF THE INVENTION
technical challenge
[4]
One aspect of the present application is to provide a method for preparing a glufosinate intermediate and L- glufosinate in a simple and high yield for the preparation of L- glufosinate having high optical purity.
means of solving the problem
[5]
According to one aspect, in a method for preparing an intermediate of L-glufosinate from an L-homoserine derivative, L-glufosinate intermediate preparation comprising the step of preparing a compound of Formula 2 from a compound of Formula 1 A method is provided.
[6]

[7]

[8]

[9]

[10]
In the above formulas,
[11]
R 1 is R a -(C=O)-, R a is a substituted or unsubstituted C 1 to C 6 alkyl group, a substituted or unsubstituted C 1 to C 6 alkenyl group, substituted or unsubstituted C 1 to C 1 to an alkynyl group of 6, 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,
[12]
R 2 is a substituted or unsubstituted C 1 to C 6 alkyl group, a substituted or unsubstituted C 1 to C 6 alkenyl group, a substituted or unsubstituted C 1 to C 6 alkynyl group, a substituted or unsubstituted C 3 to C 10 of a cycloalkyl group, 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 each independently a substituted or unsubstituted C 1 to C 6 alkyl group or a substituted or unsubstituted C 6 to C 20 aryl group,
[13]
X is halogen,
[14]
The substituents of the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group and heteroaryl group are each independently halogen, carboxyl group (-COOH), amino group (-NH 2 ), nitro group (-NO 2 ), cyano group ( -CN), at least one selected from 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.
[15]
According to another aspect, in the method for preparing L-glufosinate from an L-homoserine derivative, there is provided a method for preparing L-glufosinate comprising preparing the compound of Formula 2 from the compound of Formula 1 provided
Effects of the Invention
[16]
According to one embodiment, the present invention uses an L-homoserine derivative as a starting material, and by having a synthetic route including a novel intermediate compound, it is possible to simply prepare L-glufosinate having high optical purity.
[17]
In addition, by using the L-homoserine derivative as a starting material, there is no need to introduce a separate protecting group, and the terminal group in the L-homoserine derivative moves to an amine group, so that an intermediate compound containing an amine protecting group can be prepared. No additional compound input is required to introduce a protecting group of Therefore, the process is simple and the generation of by-products can be reduced.
Modes for carrying out the invention
[18]
Hereinafter, the L- glufosinate intermediate or L- glufosinate manufacturing method according to an embodiment will be described in more detail.
[19]
The inventive concept of the present application described below may apply various transformations and may have various embodiments, and specific embodiments will be exemplified and will be described in detail in the detailed description. However, this is not intended to limit the inventive concept of the present application to a specific embodiment, and it should be understood to include all transformations, equivalents or substitutes included in the technical scope of the inventive idea of ​​the present application.
[20]
In this specification, terms such as first, second, third, fourth, etc. may be used to describe various components, but the components should not be limited by these terms. The terms are used only for the purpose of distinguishing one component from another.
[21]
As used herein, the term 'L-glufosinate' refers to the L-isomer of glufosinate. As used herein, the term 'D-glufosinate' is the D-isomer of glufosinate.
[22]
As used herein, the term 'enantiomeric excess (%ee)' refers to the enantiomeric purity of a sample, ie, the percentage of one enantiomer exceeding the other enantiomer in the sample. For example, the enantiomeric excess of L-glufosinate is the percentage of L-glufosinate in glufosinate that exceeds D-glufosinate. For example, the enantiomeric excess of L-glufosinate is expressed by Equation 1 below.
[23]

[24]

[25]
In the method for producing an L-glufosinate intermediate of the present invention, an L-homoserine derivative can be used as a starting material. That is, it may include a step (a step) of preparing a compound of the following formula (2) from the compound of the following formula (1).
[26]

[27]

[28]

[29]

[30]
In the above formulas,
[31]
R 1 is R a -(C=O)-, R a is a substituted or unsubstituted C 1 to C 6 alkyl group, a substituted or unsubstituted C 1 to C 6 alkenyl group, substituted or unsubstituted C 1 to C 1 to an alkynyl group of 6, 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,
[32]
R 2 is a substituted or unsubstituted C 1 to C 6 alkyl group, a substituted or unsubstituted C 1 to C 6 alkenyl group, a substituted or unsubstituted C 1 to C 6 alkynyl group, a substituted or unsubstituted C 3 to C 10 of a cycloalkyl group, 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 each independently a substituted or unsubstituted C 1 to C 6 alkyl group or a substituted or unsubstituted C 6 to C 20 aryl group,
[33]
X is halogen,
[34]
The substituents of the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group and heteroaryl group are each independently halogen, carboxyl group (-COOH), amino group (-NH 2 ), nitro group (-NO 2 ), cyano group ( -CN), at least one selected from 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.
[35]
Preparing the compound of Formula 2 from the compound of Formula 1 (step a) may include the step (step b) of preparing the compound of Formula 3 by reacting the compound of Formula 1 with a first base catalyst can
[36]

[37]

[38]
In Formula 3, R 1 is the same as described above.
[39]
In addition, the step of preparing the compound of Formula 2 from the compound of Formula 1 (step a) is the step of preparing the compound of Formula 4 below by reacting the compound of Formula 3 with a first acid catalyst after step b (c) step) may be included.
[40]

[41]

[42]
In Formula 3, R 1 is the same as described above.
[43]
Subsequently, in the step (a step) of preparing the compound of Formula 2 from the compound of Formula 1, the compound of Formula 2 is reacted with a halogenating agent and at least one R 2 -OH after step c. It may include a step of preparing (step d).
[44]
According to the present invention, an L-homoserine derivative is used as a starting material, and high optical purity is achieved by going through a synthetic route to obtain an intermediate compound containing an amine protecting group, an intermediate compound having a lactone ring, and an intermediate compound that is a halogenated compound. It is possible to prepare L-glufosinate simply in high yield with eggplant.
[45]
More specifically, a first intermediate compound represented by Formula 3 may be prepared by reacting the L-homoserine derivative represented by the following Chemical Formula 1 with a first base catalyst.
[46]
In L- homoserine derivative of the formula 1 R 1 R represented by a (C = O) - functional group is a nitrogen in the first intermediate compound represented by the formula (2) by functional group movement (transfer) reaction in the first base catalyst can be coupled to Therefore, in the first intermediate compound represented by Chemical Formula 2, R 1 may act as a protecting group of the amine, so that an additional compound input for introducing a separate protecting group is not required, so the process is simple and economical. In addition, the generation of by-products can be reduced.
[47]

[48]

[49]

[50]

[51]
In the L-homoserine-based compound represented by Formula 1 and the first intermediate compound represented by Formula 2, for example, R 1 may be acetyl or succinyl. Since the L-homoserine-based compound represented by Formula 1 and the first intermediate compound represented by Formula 3 have such a functional group, L-glufosinate having improved optical purity can be more easily prepared.
[52]
The L-homoserine derivative represented by Formula 1 may be prepared from, for example, a fermentation broth containing the L-homoserine derivative. Accordingly, it is possible to efficiently prepare L-glufosinate by using the L-homoserine derivative represented by Formula 1 generated during the fermentation process.
[53]
As used herein, the term 'fermentation broth containing L-homoserine derivative' may be a fermentation broth containing an L-homoserine derivative generated from a fermentation process. The fermentation broth may be a fermentation broth obtained by culturing microorganisms in a medium containing sugar, or may be a fermentation broth obtained by enzymatic conversion of a fermentation broth obtained by culturing microorganisms. For example, a fermentation broth containing an L-homoserine derivative is a fermentation broth directly producing an L-homoserine derivative by culturing a microorganism in a medium containing sugar, or an amino acid produced by culturing a microorganism in a medium containing sugar. It may be a fermentation broth containing an L-homoserine derivative obtained by enzymatic conversion. The type of microorganism used for the preparation of the fermentation broth containing the L-homoserine derivative is not particularly limited, and any microorganism capable of producing an L-homoserine derivative by direct fermentation or enzymatic conversion in the art is possible.
[54]
The L-homoserine derivative is, for example, O -acetyl-L-homoserine, O -succinyl L-homoserine, but is not limited thereto, but is obtained in a fermentation process and is used in the art at the terminal oxygen of L-homoserine. Any derivative is possible as long as the substituents are linked.
[55]
Fermentation broth containing L- homoserine derivative, for example, disclosed in the second embodiment of the KR 10-2014-0116010 O - succinyl -L- homoserine producing strain CJM-BTJ / pCJ-MetA- CL ( accession No. : KCCM-10872) or O -acetyl-L-homoserine-producing strain CJM-BTJA/pCJ-MetX-CL (Accession No.: KCCM-10873) may be a fermentation broth obtained by fermenting a medium.
[56]
The first base catalyst may be, for example, NH 3 , KOH, NaOH, CaSO 4 , LiOH, NaH, KH, NaOCH 3 , NaOCH 2 CH 3 , NaOC(CH 3 ) 3 , KO C(CH 3 ) 3 , K 2 . CO 3 , Na 2 CO 3 , 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN) , tri(C 1 -C 4 alkyl)amine, pyridine, and at least one selected from n-butyllithium, but the first base catalyst may not necessarily be limited thereto. The first base catalyst may in particular be sodium hydroxide.
[57]
The content of the first base catalyst is, 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 based on 100 parts by weight of the L-homoserine derivative represented by Formula 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. If the content of the first base catalyst is too low, the effect on the reaction rate may be insignificant, and if the content of the first base catalyst is too high, by-products may increase.
[58]
The step of preparing the first intermediate compound may be performed under a solvent. The solvent may be water or an organic solvent. The organic solvent may be, for example, alcohol, toluene, benzene, tetrahydrofuran, chloroform, dichloromethane, acetonitrile and the like. The alcohol may be, for example, but not limited to, methanol, ethanol, propanol, butanol, pentanol, and the like.
[59]
When the first base catalyst 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 . That is, in the step of preparing the first intermediate compound, the reaction solution may be a basic aqueous solution having a pH of 9 to 14. When the reaction solution has a pH in this range, the first intermediate compound can be more easily prepared.
[60]
In the step of preparing the first intermediate compound, the functional group transfer reaction may be performed, for example, at a temperature of 20 to 150 °C, 20 to 100 °C, 20 to 90 °C, 30 to 70 °C, or 40 to 60 °C. have. In the step of preparing the first intermediate compound , the functional group transfer reaction is, for example, 0.1 to 20 hours, 0.1 to 15 hours, 0.5 to 10 hours, 1 to 9 hours, 2 to 8 hours, 3 to 7 hours, or It can be carried out for 4 to 6 hours. The first intermediate compound can be more easily prepared by performing the functional group transfer reaction in this temperature range and time range.
[61]
In the step of preparing the first intermediate compound, the yield of the first intermediate compound is, 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. or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more.
[62]
In the step of preparing the first intermediate compound, the enantiomeric excess of the first intermediate compound is, 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 greater, 98% ee or greater, or 99% ee or greater.
[63]
Next, the second intermediate compound represented by Formula 4 may be prepared by reacting the first intermediate compound represented by Formula 3 with the first acid catalyst. That is, the lactone compound represented by the following Chemical Formula 4 may be obtained by lactonizing the first intermediate compound represented by Chemical Formula 3 using a first acid catalyst. For example, the first intermediate compound represented by Formula 3 may form a lactone ring by the first acid catalyst.
[64]

[65]

[66]

[67]

[68]
In the first intermediate compound represented by Formula 3 and the second intermediate compound represented by Formula 4, for example, R 1 may be acetyl or succinyl. Since the L-homoserine derivative represented by Formula 1 and the first intermediate compound represented by Formula 3 have such functional groups, L-glufosinate having improved optical purity can be more easily prepared.
[69]
The first acid catalyst may be, for example, one or more selected from the group consisting of CH 3 COOH, HCl, H 2 SO 4 , HBr and HI.
[70]
The content of the first acid catalyst may be appropriately selected according to the type of acid used. For example, 0.1 to 100 equivalents of the first acid catalyst may be used with respect to 1 equivalent of the first intermediate compound represented by Formula 2, and specifically, in the case of hydrochloric acid or sulfuric acid, 0.1 to 2 equivalents, 0.3 to 1.8 equivalents, or 0.5 to 1.5 equivalents, in the case of acetic acid, 10 equivalents or more, 20 or more equivalents, 10 to 50 equivalents, or 20 to 40 equivalents. When the content of the first acid catalyst is too low, the effect on the reaction rate is insignificant, and when the content of the first acid catalyst is too large, by-products may increase.
[71]
The step of preparing the second intermediate compound may be performed under a solvent or in a neat condition without a solvent. The solvent may be water or an organic solvent.
[72]
The organic solvent may be, for example, alcohol, toluene, benzene, tetrahydrofuran, acetone, chloroform, dichloromethane, acetonitrile and the like. The alcohol may be, for example, but not limited to, methanol, ethanol, propanol, butanol, pentanol, and the like.
[73]
The step of preparing the second intermediate compound may be performed, for example, at a temperature of 20 to 150 °C, 20 to 100 °C, 30 to 90 °C, 40 to 80 °C, or 50 to 70 °C. The reaction time may in particular be at least 40° C., for example between 40 and 80° C. The step of preparing the second intermediate compound may be performed, for example, for 0.1 to 20 hours, 0.1 to 15 hours, 0.1 to 10 hours, 0.1 to 6 hours, 0.5 to 5 hours, 1 to 4 hours, or 2 to 4 hours. can The second intermediate compound can be more easily prepared by carrying out the lactone-forming reaction in this temperature range and time range.
[74]
In the step of preparing the second intermediate compound, the yield of the second intermediate compound is, 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. or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more.
[75]
In the step of preparing the second intermediate compound, the enantiomeric excess of the second intermediate compound having L-form is, 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 greater, 97% ee or greater, 98% ee or greater, or 99% ee or greater.
[76]
Then, the second intermediate compound represented by Chemical Formula 4 may be reacted with a halogenation agent and at least one R 2 —OH to prepare a third intermediate compound represented by Chemical Formula 2.
[77]
A halogenated compound represented by Formula 2 below by reacting the first intermediate compound represented by Formula 4 with a halogenation agent and at least one R 2 -OH compound with a halogenation/ring-opening reaction this can be obtained. For example, the second intermediate compound is reacted with a halogen to halide is then advanced / R ring-opening reaction of the halogenating agent represented by the formula 4 2 R -OH in the compound 2 - to form a functional group and a substitution reaction proceeds the third intermediate compounds can do.
[78]

[79]

[80]

[81]

[82]
The halogenating agent is, for example, HCl, HBr, HI, phosgene, SOCl 2 , oxalyl chloride, triethylsilane and a combination of palladium chloride and methyl iodide ((C 2 H 5 ) 3 SiH)+PdCl 2 +CH 3 I), POCl 3 , PCl 3 , PCl 5 , PBr 3 , PI 3 , H 2 SO 4 and KBr (H 2 SO 4 +KBr), P and Cl 2 ( P+Cl 2 ), a combination of P and Br 2 (P+Br 2 )), a combination of P and I 2 (P+I 2 ), TiCl 4 , ZnCl 2 , and BBr 3 It may be at least one selected from the group consisting of. The halogenating agent may be, in particular, triethylsilane ((CH 2 CH 3 ) 3 SiH)+palladium chloride (PdCl 2 )+methyl iodide (CH 3 I), SOCl 2 , and the like.
[83]
The content of the halogenating agent is, 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 based on 1 equivalent of the second intermediate compound represented by Formula 4 , 0.1 to 1.3 equivalents, or 1 to 1.1 equivalents.
[84]
One or more R 2 —OH compounds may be used in the reaction to form the third intermediate compound. When a plurality of R 2 -OH compounds are used, each R 2 -OH compound may be the same as or different from each other.
[85]
The R 2 -OH compound may be, for example, at least one selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol, butanol, pentanol, hexanol, benzyl alcohol, phenol and naphthol. By selecting the above-mentioned materials for the R 2 -OH compound, the third intermediate compound may be obtained in a higher yield from the first intermediate compound.
[86]
The content of the R 2 -OH compound may be, for example, 1 to 60 equivalents, 1 to 40 equivalents, 2 to 20 equivalents, or 3 to 10 equivalents based on 1 equivalent of the second intermediate compound.
[87]
In the step of preparing the third intermediate compound from the second intermediate, the halogenation reaction/ring-opening reaction may be performed, for example, at a temperature of 20 to 100°C, 25 to 90°C, or 40 to 80°C.
[88]
In the step of preparing the third intermediate compound, the halogenation reaction/ring-opening reaction is, 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 hours. to 20 hours. By carrying out the halogenation reaction and the substitution reaction in these temperature ranges and time ranges, it is possible to more easily prepare the third intermediate compound, that is, the halogenated compound.
[89]
In the step of preparing the third intermediate compound, the yield of the third intermediate compound is, 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. or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more.
[90]
In the step of preparing the third intermediate compound, the enantiomeric excess of the third intermediate compound having L-form is, 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 greater, 97% ee or greater, 98% ee or greater, or 99% ee or greater.
[91]
According to one embodiment, preparing the compound of Formula 2 from the compound of Formula 1 (step a) may include reacting the compound of Formula 3 with a halogenating agent and at least one R 2 -OH after step b. It may include the step of preparing the compound of Formula 2 (step c-1). That is, the third intermediate compound represented by Formula 2 may be prepared by reacting the first intermediate compound represented by Formula 3 with a halogenation agent and at least one R 2 —OH. For example, the third intermediate compound represented by Formula 2 may be prepared. After the first intermediate represented by 3 is reacted with the halogen of the halogenating agent to undergo a halogenation reaction , a substitution reaction may proceed with one or more R 2 -functional groups of R 2 -OH to form a third intermediate compound.
[92]

[93]

[94]

[95]

[96]
In the first intermediate compound represented by Formula 3 and the third intermediate compound represented by Formula 2, for example, R 1 is R a -(C=O)-, and R a is hydrogen, a substituted or unsubstituted carbon number of 1 to 6 alkyl group, substituted or unsubstituted C 1 to C 6 alkenyl group, substituted or unsubstituted C 1 to C 6 alkynyl group, substituted or unsubstituted C 3 to C 10 cycloalkyl group, substituted or unsubstituted C It may be an aryl group of 6 to 20, or a substituted or unsubstituted heteroaryl group having 2 to 10 carbon atoms. Specifically, R 1 may be acetyl or succinyl.
[97]
In addition, R 2 is a substituted or unsubstituted C 1 to C 6 alkyl group, a substituted or unsubstituted C 1 to C 6 alkenyl group, a substituted or unsubstituted C 1 to C 6 alkynyl group, a substituted or unsubstituted C 3 to 10 cycloalkyl group, or a substituted or unsubstituted C 6 to C 20 aryl group, a substituted or unsubstituted C 2 to C 10 heteroaryl group, or —Si(R b )(R c )(R d ); , R b , R c and R d may each independently represent a substituted or unsubstituted C 1 to C 6 alkyl group or a substituted or unsubstituted C 6 to C 20 aryl group. Specifically, R 2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, benzyl, phenyl, naphthyl, -Si(CH 3 )(tert-butyl) 2 , -Si(C 6 H 5 ) 2 (tert-butyl) ), -Si(iso-propyl) 3 , -Si(C5H 6 )(CH 3 ) 2 , -Si(C 6 H 5 ) 2 (CH 3 ), -Si(C 5 H 6 ) 3 , -Si(CH 3 ) 3 , -Si(CH 2 CH 3 ) 3 , -Si(CH 2 CH 3 ) 2 (CH 3 ), -Si(CH 2 CH 3 )(CH 3 ) 2, or -Si(tert-butyl) 3 . Since the first intermediate compound represented by Formula 3 and the third intermediate compound represented by Formula 2 have such functional groups, L-glufosinate having improved optical purity can be more easily prepared.
[98]
The halogenating agent is, for example, HCl, HBr, HI, phosgene, SOCl 2 , oxalyl chloride, triethylsilane and a combination of palladium chloride and methyl iodide ((C 2 H 5 ) 3 SiH)+PdCl 2 +CH 3 I), POCl 3 , PCl 3 , PCl 5 , PBr 3 , PI 3 , H 2 SO 4 and KBr (H 2 SO 4 +KBr), P and Cl 2 ( P+Cl 2 ), a combination of P and Br 2 (P+Br 2 )), a combination of P and I 2 (P+I 2 ), TiCl 4 , ZnCl 2 , and BBr 3 It may be at least one selected from the group consisting of. The halogenating agent may in particular be HCl, triethylsilane ((CH 2 CH 3 ) 3 SiH)+palladium chloride (PdCl 2 )+methyl iodide (CH 3 I), SOCl 2 and the like.
[99]
The content of the halogenating agent is, 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, based on 1 equivalent of the first intermediate compound represented by Formula 3 , 0.1 to 1.3 equivalents, or 1 to 1.1 equivalents.
[100]
One or more R 2 —OH compounds may be used in the reaction to form the third intermediate compound. When a plurality of R 2 -OH compounds are used, each R 2 -OH compound may be the same as or different from each other.
[101]
The R 2 -OH compound may be, for example, at least one selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol, butanol, pentanol, hexanol, benzyl alcohol, phenol and naphthol. By selecting the above-mentioned materials for the R 2 -OH compound, the third intermediate compound may be obtained in a higher yield from the first intermediate compound. The content of the R 2 -OH compound may be, for example, 1 to 40 equivalents, 2 to 20 equivalents, or 3 to 10 equivalents based on 1 equivalent of the first intermediate compound.
[102]
The step of preparing the third intermediate compound may be performed under a solvent or in a neat condition without a solvent. The solvent may be an organic solvent.
[103]
The organic solvent may be, for example, alcohol, toluene, benzene, tetrahydrofuran, acetone, chloroform, dichloromethane, acetonitrile and the like. Alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, pentanol, and the like.
[104]
In the step of preparing the third intermediate compound, the halogenation reaction may be performed at a temperature of, for example, 20 to 120 °C, 20 to 80 °C, 30 to 70 °C, or 40 to 60 °C. The step of preparing the third intermediate compound may be performed, for example, for 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. can By carrying out the halogenation reaction in this temperature range and time range, it is possible to more easily prepare the third intermediate compound, that is, the halogenated compound.
[105]
In the step of preparing the third intermediate compound, the yield of the third intermediate compound is, 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. or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more.
[106]
In the step of preparing the third intermediate compound, the enantiomeric excess of the third intermediate compound having L-form is, 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 greater, 97% ee or greater, 98% ee or greater, or 99% ee or greater.
[107]
That is, the L-glufosinate intermediate of Formula 2 can be prepared from the compound of Formula 3 by using the compound of Formula 1, which is an L-homoserine derivative, as a starting material, without the preparation step of the compound of Formula 4. Accordingly, it is possible to simplify the manufacturing process of the L- glufosinate intermediate having high optical purity.
[108]
According to another embodiment, the step of preparing the compound of Formula 2 from the compound of Formula 1 (step a) is the step of preparing a compound of Formula 4 below by reacting the compound of Formula 1 with a second acid catalyst ( step b-1) may be included.
[109]
More specifically, the second intermediate compound represented by Formula 4 may be prepared by reacting the L-homoserine derivative represented by Formula 1 with a second acid catalyst. That is, the L-homoserine derivative represented by Formula 1 may be lactonated using a second acid catalyst to obtain a lactone compound represented by Formula 4 below.
[110]

[111]

[112]

[113]

[114]
The second acid catalyst may be, for example, at least one selected from acetic acid , formic acid, butyric acid, pentanoic acid and propionic acid. The second acid catalyst may in particular be acetic acid .
[115]
The content of the second acid catalyst may be 0.1 to 20 equivalents or 0.4 to 19 equivalents based on 1 equivalent of the L-homoserine derivative represented by Formula 1 above.
[116]
In the step of preparing the second intermediate compound, the lactone formation reaction may be performed at a temperature of, for example, 20 to 100°C, 40 to 980°C, 60 to 95°C, or 70 to 90°C. The reaction temperature may in particular be at least 70° C., for example between 70 and 90° C. In the step of preparing the second intermediate compound, the lactone formation reaction may be performed for, for example, 1 to 20 hours, 2 to 18 hours, 4 to 17 hours, or 6 to 16 hours. The second intermediate compound can be more easily prepared by carrying out the lactone-forming reaction in this temperature range and time range.
[117]
Subsequently, a third intermediate compound may be prepared by reacting the prepared second intermediate with a halogenation agent and at least one R 2 —OH. The halogenating agent, R 2 -OH is the same as described above.
[118]
That is, the L-glufosinate intermediate of Formula 2 can be prepared after preparing the compound of Formula 4 without including the step of preparing the compound of Formula 3 by using the compound of Formula 1, which is an L-homoserine derivative, as a starting material. Accordingly, it is possible to simplify the manufacturing process of the L- glufosinate intermediate having high optical purity. In addition, since the terminal group in the L-homoserine derivative moves to an amine group without the need to introduce a separate protecting group, an intermediate compound containing an amine protecting group can be prepared. it may not be
[119]
The method for preparing L-glufosinate of the present invention, in the method for preparing L-glufosinate from an L-homoserine derivative, may include preparing a compound of Formula 2 below from a compound of Formula 1 have.
[120]

[121]

[122]

[123]

[124]
In the step of preparing the compound of Formula 2 from the compound of Formula 1, the above-described method for preparing the L-glufosinate intermediate may be applied as it is.
[125]
If necessary, the method for preparing L-glufosinate may further include the step of preparing L-glufosinate from a third intermediate compound represented by Formula (2). Hereinafter, a method for preparing L-glufosinate from the third intermediate compound of Formula 2 will be described.
[126]
By using the above-mentioned intermediate compound, it is possible to simply prepare L-glufosinate in high yield. To prepare a fourth intermediate compound represented by Formula 6 by reacting the third intermediate compound represented by Formula 2 with the phosphorus compound represented by Formula 5, or reacting the second intermediate compound with the phosphorus compound represented by Formula 5 can
[127]

[128]

[129]

[130]

[131]

[132]

[133]
In the above formula, R 1 is R a -(C=O)-, and R a is hydrogen, a substituted or unsubstituted C 1 to C 6 alkyl group, a substituted or unsubstituted C 1 to C 6 alkenyl group, substituted or unsubstituted A cyclic 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 is,
[134]
R 2 is a substituted or unsubstituted C 1 to C 6 alkyl group, a substituted or unsubstituted C 1 to C 6 alkenyl group, a substituted or unsubstituted C 1 to C 6 alkynyl group, a substituted or unsubstituted C 3 to C 10 of a cycloalkyl group, 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 each independently a substituted or unsubstituted C 1 to C 6 alkyl group or a substituted or unsubstituted C 6 to C 20 aryl group,
[135]
R 3 and R 4 are each independently hydrogen, a substituted or unsubstituted C 1 to C 6 alkyl group, a substituted or unsubstituted C 1 to C 6 alkenyl group, a substituted or unsubstituted C 1 to C 6 alkynyl group,
[136]
R 5 is R 3 or R 4 ,
[137]
X is halogen,
[138]
The substituents of the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, and heteroaryl group are each independently hydrogen, halogen, carboxyl group (-COOH), amino group (-NH 2 ), nitro group (-NO 2 ), at least one selected from 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.
[139]
In the third intermediate compound represented by Formula 2, the phosphorus compound represented by Formula 5, and the fourth intermediate compound represented by Formula 6, for example, R 1 is acetyl or succinyl, R 2 is hydrogen, methyl, Ethyl, propyl, butyl, pentyl, hexyl, benzyl, phenyl, naphthyl, -Si(CH 3 )(tert-butyl) 2 , -Si(C 6 H 5 ) 2 (tert-butyl), -Si(iso- propyl) 3 , -Si(C 5 H 6 )(CH 3 ) 2 , -Si(C 6 H 5 ) 2 (CH 3 ), -Si(C 5 H 6 ) 3 , -Si(CH 3 ) 3 , -Si(CH 2 CH 3 ) 3 , -Si(CH 2 CH 3 ) 2 (CH 3 ), -Si(CH 2 CH 3 )(CH 3 ) 2 , or - Si(tert-butyl) 3 may be R 3 and R 4may be any one selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl. The third intermediate compound represented by Formula 2, the phosphorus compound represented by Formula 5, and the fourth intermediate compound represented by Formula 6 have these functional groups to more easily prepare L-glufosinate having improved optical purity. can The phosphorus-based compound represented by Formula 5 is, in particular, an alkylmethylphosphonite, for example, diethylmethylphosphonite (DMP) or ethylmethylphosphonite (EMP), or butylmethylphosphonite. It may be butylmethylphosphonite (BMP).
[140]
The phosphorus-based compound represented by Formula 5 may 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 based on 1 equivalent of the third intermediate compound represented by Formula 2.
[141]
According to an embodiment, the third acid may be used in the process of preparing the fourth intermediate compound by reacting the third intermediate compound with the phosphorus compound or by reacting the second intermediate compound with the phosphorus compound represented by Formula 5.
[142]
The third acid is, for example, a Lewis acid, and the Lewis acid is, for example, KF+Al 2 O 3 , ZnCl 2 LiBr, ZnBr 2 , BF 3 -Et 2 O(diehtylether), COCl 2 , MgBr 2 , Bu 3 P, Sc(OTf) 3 (OTf=trifluoromethanesulfonate), Sc(NTf 2 ) 3 (Scandium(III) trifluoromethanesulfonimide), TiCl 3 -2AgClO 4 , TiCl 3 (OTf), Sn(OTf) 2 , TMSOTf(TriMethylSilyl trifluoromethanesulfonate) ), La(OTf) 3, Cu(OTf) 2 , and TaCl 5 may be at least one selected from, and in particular, KF+Al 2 O 3 .
[143]
The content of the third acid is, 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 based on 100 parts by weight of the third intermediate compound represented by Formula 2 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. When the content of the tertiary acid is too low, the effect on the reaction rate is insignificant, and when the content of the tertiary acid is too large, by-products may increase. By using the third acid, the fourth intermediate compound can be obtained in a more improved yield.
[144]
According to an embodiment, the third acid may not be added in the above reaction. If the tertiary acid is not added, the reaction time may increase and the reaction temperature may increase. For example, when the third acid is not used, the reaction temperature may be 120 to 180° C. for 1 to 20 hours.
[145]
The reaction temperature may be, 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 ℃, 110 to 140 ℃, 120 to 160 ℃, 120 to 150 ℃, or may be 120 to 140 ℃. Meanwhile, when an acid is added, the reaction temperature may be, for example, 80 to 160° C., and when an acid is not added, the reaction time may increase and the reaction temperature may increase. For example, when no acid is used, the reaction temperature may be 120 to 180°C.
[146]
In the step of preparing the fourth intermediate compound, the reaction is, 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 It can be carried out for 11 to 13 hours.
[147]
The step of preparing the fourth intermediate compound may be performed under a solvent or in a neat condition without a solvent. The solvent may be water or an organic solvent.
[148]
The organic solvent may be, for example, alcohol, toluene, benzene, tetrahydrofuran, acetone, chloroform, dichloromethane, acetonitrile and the like. The alcohol may be, for example, but not limited to, methanol, ethanol, propanol, butanol, pentanol, and the like. When a third acid is used and the solvent is water, the pH of the aqueous solution containing water may be 1 to 3. That is, in the step of preparing the fourth intermediate compound, the reaction solution may be an acidic aqueous solution having a pH of 1 to 3. When the reaction solution has a pH in this range, the fourth intermediate compound can be more easily prepared.
[149]
In the step of preparing the fourth intermediate compound, the reaction is, for example, 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 It may be carried out at a temperature of ℃, 110 to 150 ℃, 110 to 160 ℃, 110 to 140 ℃, 120 to 160 ℃, 120 to 150 ℃, or 120 to 140 ℃. In the step of preparing the fourth intermediate compound, the reaction is, for example, 0.1 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. can be performed. By carrying out the reaction in this temperature range and time range, the fourth intermediate compound can be more easily prepared.
[150]
In the step of preparing the fourth intermediate compound, the yield of the fourth intermediate compound is, 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. or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more.
[151]
In the step of preparing the fourth intermediate compound, the enantiomeric excess of the fourth intermediate compound having L-form is, 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 greater, 97% ee or greater, 98% ee or greater, or 99% ee or greater.
[152]
Finally, L- glufosinate represented by Formula 7 may be prepared by hydrolyzing the fourth intermediate compound under the fourth acid catalyst. That is, L-glufosinate represented by Formula 7 may be obtained by removing terminal functional groups by hydrolysis of the fourth intermediate compound represented by Formula 6 under a fourth acid catalyst.
[153]

[154]

[155]

[156]

[157]
In the fourth intermediate compound represented by Formula 6, for example, R 1 is acetyl or succinyl, and R 2 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, benzyl, phenyl, naphthyl , -Si(CH 3 )(tert-butyl) 2 , -Si(C 6 H 5 ) 2 (tert-butyl), -Si(iso-propyl) 3 , -Si(C 5 H 6 )(CH 3 ) 2 , -Si(C 6 H 5 ) 2 (CH 3 ), -Si(C 5 H 6 ) 3 , -Si(CH 3 ) 3 , -Si(CH 2 CH 3 ) 3 , -Si(CH 2 CH 3 ) 2 (CH 3 ), -Si(CH 2 CH 3 )(CH 3 ) 2 , or -Si(tert-butyl) 3 , R 5 may be R 3 or R 4 . Since the fourth intermediate compound represented by Formula 6 has such a functional group, L-glufosinate having improved optical purity can be more easily prepared.
[158]
The fourth acid is, for example, at least one selected from the group consisting of HCl, H 2 SO 4 , H 2 SO 4 and a combination of KF and Al 2 O 3 (KF+Al 2 O 3 ), but the fourth acid must be It is not limited to, and all are possible as long as it is used as an acid catalyst in the art. The fourth acid may in particular be hydrochloric acid.
[159]
The content of the fourth acid is, 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 based on 100 parts by weight of the fourth intermediate compound represented by Formula 6 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. If the content of the fourth acid is too low, the effect on the reaction rate is insignificant, and if the content of the fourth acid is too high, by-products may increase.
[160]
The step of preparing L-glufosinate may be performed under a solvent or in neat conditions without a solvent.
[161]
When the fourth acid is used and the solvent is water, 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. When the reaction solution has a pH in this range, it is possible to more easily prepare L-glufosinate.
[162]
In the step of preparing L- glufosinate, the hydrolysis reaction may be performed, for example, at a temperature of 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 is, 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. hours, 7 to 9 hours, 10 to 30 hours, 12 to 24 hours, 15 to 20 hours, or 15 to 18 hours. By performing the hydrolysis reaction in this temperature range and time range, it is possible to more easily prepare L-glufosinate.
[163]
In the step of preparing L- glufosinate, the yield of L- glufosinate is, 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.
[164]
The enantiomeric excess of the prepared L-glufosinate is, 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 greater, or 99% ee or greater. By having L-glufosinate such improved optical purity, for example, it can provide a more improved herbicide effect.
[165]
In the present invention, L-glufosinate may include a salt form thereof. Specifically, the salt of L-glufosinate is, for example, hydrochloride of L-glufosinate, sulfate of L-glufosinate, carbonate of L-glufosinate, ammonium salt of L-glufosinate, etc. It is not limited and any salt of L-glufosinate obtained in the above-described method for preparing glufosinate is possible.
[166]
Example 1: Preparation method of L-glufosinate intermediate using O -acetyl-L-homoserine (using lactone intermediate (1))
[167]
(Step 1-1: Preparation of N- acetyl-L-Homoserine)
[168]

[169]
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) was slowly added to prepare a reaction solution of pH 9. Then, 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 reaction solution to neutralize, and concentrated under reduced pressure to prepare a concentrated solution. The prepared concentrate was cooled to 0° C., stirred while adding ethanol, and filtered under reduced pressure to obtain 0.98 g (yield 98%) of N- Acetyl-L-Homoserine (III-1) as a white solid . The structure of N- Acetyl-L-Homoserine (III-1) was confirmed by NMR.
[170]
1 H NMR (400 MHz, DMSO-d6): δ 7.68 (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)
[171]
(Step 1-2: Preparation of N- acetyl-L-Homoserine lactone)
[172]

[173]
To an aqueous solution in which N- Acetyl-L-Homoserine (III-1) (1 g, 6.2 mmol) was dissolved in 30 mL of water, c-HCl (concentrated hydrochloric acid) was slowly added to prepare a reaction solution of pH 2. The prepared reaction solution was stirred at 25° C. for 30 minutes. Then, the reaction solution was heated to 60°C and stirred at 60°C for 3 hours. Then, 1N NaOH (aq) was added to the reaction solution to neutralize, and concentrated under reduced pressure to prepare a concentrated solution. After 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 . The structure of N- acetyl-L-Homoserine lactone was confirmed by NMR.
[174]
1 H NMR (400 MHz, DMSO-d6): δ 3.96 (m, 1H), 3.89 (t, J = 6.8 Hz, 2H), 1.91 (s, 3H), 2.11 (m, 1H), 1.83 (m, 1H)
[175]
(Step 1-3: Preparation of Ethyl-2-(acetamino)-4-chlorobutanoate)
[176]

[177]
To a solution in which 4 g (28 mmol) of N- acetyl-L-Homoserine lactone was dissolved in 60 mL of ethanol, thionyl chloride (6.6 g, 56 mmol) was slowly added at 0° C. to prepare a reaction solution. The prepared reaction solution was stirred at 80° C. for 3 hours. Then, the reaction solution was neutralized by adding 1N NaOH (aq) to the solution, and then concentrated under reduced pressure to prepare a concentrated solution. The prepared concentrate was diluted with ethyl acetate and washed once with brine. The organic layer was dried over anhydrous magnesium sulfate (MgSO 4 ), filtered, and the filtrate was concentrated under reduced pressure to obtain a residue containing Ethyl-2(acetylamino)-4-chlorobutanoate.
[178]
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. The structure of Ethyl-2-(acetylamino)-4-chlorobutanoate was confirmed by NMR.
[179]
1 H NMR (400 MHz, DMSO-d6): δ 4.49 (m, 1H), 4.22 (q, 2H), 3.60 (t, 2H), 2.25 (m, 2H), 1.91 (s, 3H), 1.30 ( t, 3H)
[180]
(Step 1-4: Preparation of Ethyl-2-(acetamino)-4(ethoxymethylphosphinyl)butanoate)
[181]

[182]
Ethyl-2-(acetamino)-4-chlorobutanoate (2.6g, 12.6mmol), and diethyl methylphosphonite (3.4g, 25.2mmol, 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 at 80° C. under reduced pressure of 1 mmHg. The residue was separated by column chromatography (mobile phase, ethyl acetate:isopropanol=4:1 volume ratio) as a colorless oil, Ethyl-2-(acetamino)-4(ethoxymethylphosphinyl)butanoate 2.25 g (yield 64%) was obtained.
[183]
The structure of ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate was confirmed by NMR.
[184]
1 H NMR (400 MHz, CDCl3): δ 4.40 (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 (CDCl 3 , 121.47 MHz) δ 54.28.
[185]
(Steps 1-5: Preparation of L-glufosinate (L-phosphinothricin) hydrochloride)
[186]

[187]
Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate (V) 2g (7.17 mmol) was dissolved in 20mL of 6N HCl, put into a seal 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 1-5 61%). . The structure of L-glufosinate hydrochloride was confirmed by NMR.
[188]
1 H NMR (400 MHz, DO): δ 4.12 (m, 1H), 2.45-1.65 (m, 4H), 1.46 (d, J = 14 Hz, 3H).
[189]
Example 2: Preparation of L-glufosinate using O -succinyl-L-homoserine (using lactone intermediate (2))
[190]
(Step 2-1: Preparation of N- succinyl-L-Homoserine)
[191]

[192]
To an aqueous solution of O- Succinyl-L-Homoserine (II) (1 g, 4.57 mmol) dissolved in 30 mL of water, NaOH (40 wt % aqueous solution) was slowly added to prepare a reaction solution of pH 9.
[193]
Then, 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 reaction solution to neutralize, and concentrated under reduced pressure to prepare a concentrated solution. After the prepared concentrate was cooled 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 . The structure of N -succinyl-L-Homoserine was confirmed by NMR.
[194]
1 H NMR (400 MHz, DMSO-d6): δ 7.68 (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)
[195]
In the following steps 2-2 to 2-5 , white L-Glufosinate hydrochloride salt (L-Glufosinate hydrochloride salt) (2-2) was performed in the same manner as in Example 1, except that N- succinyl-L-Homoserine was used. A total yield of 51%) from steps to steps 2-5 was obtained. The structure of L-glufosinate hydrochloride was confirmed by NMR.
[196]
1 H NMR (400 MHz, DO): δ 4.12 (m, 1H), 2.45-1.65 (m, 4H), 1.46 (d, J = 14 Hz, 3H).
[197]
Example 3: Preparation of L-glufosinate using O -acetyl-L-homoserine (without lactone intermediate (1))
[198]
(Step 3-1: Preparation of N- acetyl-L-Homoserine)
[199]

[200]
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 alkali catalyst was slowly added to prepare a reaction solution of pH 9. Then, 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 reaction solution to neutralize, and concentrated under reduced pressure to prepare a concentrated solution. The prepared concentrate was cooled to 0° C., stirred while adding ethanol, and filtered under reduced pressure to obtain 0.98 g (yield 98%) of N- Acetyl-L-Homoserine (III-1) as a white solid . The structure of N- Acetyl-L-Homoserine was confirmed by NMR.
[201]
(Step 3-2: Preparation of Ethyl-2-(acetamino)-4-chlorobutanoate)
[202]

[203]
To a solution of 3.85 g (24 mmol) of N- acetyl-L-Homoserine in 60 mL of ethanol, thionyl chloride (SOCl 2 ), 6.6 g, 56 mmol) was slowly added at 0° C. to prepare a reaction solution. did The prepared reaction solution was stirred at 80° C. for 3 hours.
[204]
Then, the reaction solution was neutralized by adding 1N NaOH (aq) to the solution, and then concentrated under reduced pressure to prepare a concentrated solution. The prepared concentrate was diluted with ethyl acetate and washed once with brine. The organic layer was dried over anhydrous magnesium sulfate (MgSO 4 ), filtered, and the filtrate was concentrated under reduced pressure to contain ethyl-2-(acetylamino)-4-chloro-butyrate (Ethyl-2-(acetylamino)-4-chlorobutanoate). a residue was obtained.
[205]
The obtained residue was separated by column chromatography (mobile phase, hexane : ethyl acetate = 1:1) and ethyl-2-(acetylamino)-4-chlorobutyrate (Ethyl-2-(acetylamino) as a colorless oil) -4-chlorobutanoate) 5.12 g (yield 88%) was obtained. The structure of ethyl-2-(acetylamino)-4-chlorobutanoate was confirmed by NMR.
[206]
In the following steps 3-3 to 3-4, white L-Glufosinate hydrochloride salt (3-Glufosinate hydrochloride salt) was used in the same manner as in Example 1 using Ethyl-2-(acetamino)-4-chlorobutanoate A total yield of 61%) of steps 3 to 3-4 was obtained. The structure of L-glufosinate hydrochloride was confirmed by NMR.
[207]
Example 4: Preparation of L-glufosinate using O -acetyl-L-homoserine (without lactone intermediate (2))
[208]
(Step 4-1: Preparation of N- acetyl-L-Homoserine)
[209]

[210]
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) was slowly added to prepare a reaction solution of pH 9. Then, 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 reaction solution to neutralize, and concentrated under reduced pressure to prepare a concentrated solution. The prepared concentrate was cooled to 0° C., stirred while adding ethanol, and filtered under reduced pressure to obtain 0.98 g (yield 98%) of N- Acetyl-L-Homoserine (III-1) as a white solid . The structure of N- Acetyl-L-Homoserine (III-1) was confirmed by NMR.
[211]
(Step 4-2: Preparation of Triethylsilyl-2-(acetamino)-4-iodobutanoate)
[212]

[213]
To a solution of 3.85 g (24 mmol) of N- acetyl-L-Homoserine in 10 mL of ethanol, triethylsilane (4.9 mL, 31 mmol) was slowly added at 0°C. Then, at the same temperature, methyl iodide (7.9 g, 56 mmol) and palladium chloride (100 mg, 0.56 mmol) were slowly added to prepare a reaction solution. The prepared reaction solution was stirred at 110° C. for 18 hours. Then, the reaction solution was neutralized by adding 1N NaOH (aq) to the solution, and then concentrated under reduced pressure to prepare a concentrated solution. The prepared concentrate was diluted with ethyl acetate and washed once with brine. The organic layer was dried over anhydrous magnesium sulfate (MgSO 4 ), filtered, and the filtrate was concentrated under reduced pressure to obtain a residue containing triethylsilyl-2-(acetylamino)-4-iodobutanoate.
[214]
The obtained residue was separated by column chromatography (mobile phase, hexane : ethyl acetate = 1:1) to obtain 4.16 g of triethylsilyl-2-(acetylamino) 4-chlorobutanoate (yield 44%) as a colorless oil.
[215]
The structure of triethylsilyl-2-(acetylamino)-4-chlorobutanoate was confirmed by NMR.
[216]
In the following steps 4-3 and 4-4, white L-Glufosinate hydrochloride salt was used in the same manner as in Example 1, except that Triethylsilyl-2-(acetamino)-4-chlorobutanoate was used. (61% of the total yield of steps 4-3 and 4-4) was obtained. The structure of L-glufosinate hydrochloride was confirmed by NMR.
[217]
Example 5: Preparation of L-glufosinate using O -succinyl-L-homoserine (without lactone intermediate (1))
[218]
(Step 5-1: Preparation of N- Succinyl-L-Homoserine)
[219]

[220]
To an aqueous solution of O- Succinyl-L-Homoserine (II) (1 g, 4.57 mmol) dissolved in 30 mL of water, NaOH (40 wt% aqueous solution) was slowly added to prepare a reaction solution of pH 9. Then, 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 reaction solution to neutralize, and concentrated under reduced pressure to prepare a concentrated solution. The prepared concentrate was cooled to 0° C., stirred while adding ethanol, and filtered under reduced pressure to obtain 0.98 g (yield 98%) of N- Succinyl-L-Homoserine (III-1) as a white solid . The structure of N- Succinyl-L-Homoserine was confirmed by NMR.
[221]
Followed in step 5-4 to step 5-2 N Posey Example 3 with L- white glue in the same manner using the -Succinyl-L-Homoserine carbonate hydrochloride (L-Glufosinate hydrochloride salt) (step 5-2 to 5- A total yield of 4 steps (61%) was obtained. The structure of L-glufosinate hydrochloride was confirmed by NMR.
[222]
Example 6: Preparation of L-glufosinate using O- (acetyl)-L-homoserine
[223]
(Step 6-1: Preparation of N- acetyl-L-Homoserine)
[224]

[225]
O-Acetyl-L-Homoserine (II) (1 g, 6.2 mmol) was slowly added to an amount corresponding to 18.2 equivalents of acetic acid (6.77 g, 112.8 mmol) to prepare a reaction solution of pH 1. The prepared reaction solution was stirred at 90° C. for 6 hours. Then, the reaction solution was cooled to 60° C. and stirred for 3 hours. Then, 1N NaOH (aq) was added to the reaction solution to neutralize, and concentrated under reduced pressure to prepare a concentrated solution. After the prepared concentrate was cooled to 0°C, isopropanol was added, stirred, and filtered under reduced pressure to obtain 0.8 g (yield 90%) of N- acetyl-L-Homoserine lactone as a white solid . The structure of N- acetyl-L-Homoserine lactone was confirmed by NMR.
[226]
In the following step 6-2 to step 6-4, N -acetyl-L-Homoserine lactone to the Example 1 in the same manner as white L- glufosinate hydrochloride (L-Glufosinate hydrochloride salt) (step 6-2 to use A total yield of 61%) of steps 6-4 was obtained. The structure of L-glufosinate hydrochloride was confirmed by NMR.
[227]
Comparative Example 1: Preparation of racemic glufosinate
[228]
Glufosinate was prepared according to the method disclosed in Example 1 of USP 6,359,162. The prepared glufosinate was a racemic mixture.
[229]
Comparative Example 2: Comparison with L-glufosinate manufacturing method introducing a protecting group to homoserine lactone
[230]
L- glufosinate was prepared according to Scheme 1 below.
[231]
[Scheme 1]
[232]

[233]
The reaction conditions and reaction results of each reaction step are shown in Table 1 below.
[234]
[Table 1]
[235]
(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)
[236]
As shown in Table 1, when hydrochloric acid is used to prepare the lactone compound from the L-homoserine derivative, the homoserine lactone shown in Scheme 1 is obtained, not the second intermediate compound of Formula 3. After obtaining the homoserine lactone, protecting the amine group in the homoserine lactone with an ethoxycarbonyl group, halogenating it with a halogenating agent, combining with a phosphorus compound and hydrolyzing to prepare L-glufosinate, L-glufosinate It was confirmed that the nate was obtained in a low yield.
[237]
Experimental Example 1: Measurement of enantiomeric excess (% ee)
[238]
The enantiomeric excess of L-glufosinate synthesized in Examples 1 to 6 and Comparative Example 1 was measured using chiral HPLC, and the results are shown in Table 1 below.
[239]
Chiral HPLC analysis was performed by J. Chromatogr . 368, 413 (1986).
[240]
Enantiomeric excess (% ee) was calculated 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. was determined using As the mobile phase, a co-solvent of 0-30% methanol, 0-70% acetonitrile, and 0-70% distilled water or 2 mM aqueous copper sulfate solution was used, and the flow rate was 1.0 mL. /min, the sample injection amount was 10 μL, and the UV detection wavelength was 200 nm to 280 nm.
[241]
[Table 2]
[242]
As shown in Table 2, the enantiomeric excess of L-glufosinate was significantly improved in the glufosinate prepared in Examples 1 to 6 compared to the glufosinate prepared in Comparative Example 1. Therefore, it is possible to simply prepare L-glufosinate in high yield and high purity by the manufacturing method including the intermediate compound of the present invention.
[243]
Experimental Example 2: Review of pH conditions when preparing the first intermediate compound from L-homoserine derivatives
[244]
It was confirmed that the obtained pattern according to the pH of the first intermediate compound represented by the formula (2) from the L-homoserine derivative represented by the formula (1). A first intermediate compound, N-acetyl-L-Homoserine, was obtained in the same manner as in Example 1 (step 1-1) using O-Acetyl-L-homoserine as an L-homoserine derivative as a starting material. , however, the pH during the reaction was changed to 8.2, 9.2, 10.2, 12.7 and 13.4, respectively. The results are shown in Table 3 below.
[245]
[Table 3]
[246]
(OAHS: O-Acetyl-L-Homoserine, NAHS: N-Acetyl-L-Homoserine)
[247]
As shown in Table 3, when the first intermediate compound represented by Formula 2 is prepared from the L-homoserine derivative represented by Formula 1, the yield of N-acetyl-L-Homoserine increases as the pH increases. In particular, when the pH was 9 or higher, N-acetyl-L-Homoserine was obtained in high yield.
[248]
Experimental Example 3: Review of reaction conditions when preparing a second intermediate compound from the first intermediate compound
[249]
The aspect of obtaining according to the reaction conditions of the second intermediate compound represented by Formula 4 from the first intermediate compound represented by Formula 3 was confirmed. Claim 1 as an intermediate compound N , but using -acetyl-L-Homoserine carried out to give the Example 1 (step 1-2) of N-acetyl-L-Homoserine lactone second intermediate compound by the same method as the manufacturing method of, just reaction The equivalent weight of the acid and the reaction temperature were respectively changed as shown in Tables 3 to 5 below, and the results are shown in Tables 4 to 6.
[250]
[Table 4]
[251]
(NAHS: N- Acetyl-L-Homoserine, NAHSL: N- acetyl-L-Homoserine lactone)
[252]
As shown in Table 4, when the second intermediate compound represented by Formula 4 was prepared from the first intermediate compound represented by Formula 3 using acetic acid, N- acetyl-L-Homoserine lactone increased as the acetic acid equivalent increased. was increased, and in particular, when the equivalent of acetic acid was 2.6 or more, N- acetyl-L-Homoserine lactone was obtained in high yield .
[253]
As the reaction temperature increased, the yield of N- acetyl-L-Homoserine lactone increased. In particular, when the reaction temperature was 40°C or higher, N- acetyl-L-Homoserine lactone was obtained with a high yield .
[254]
[Table 5]
[255]
As shown in Table 5 above, when the second intermediate compound represented by Formula 4 was prepared from the first intermediate compound represented by Formula 3 using hydrochloric acid, as the hydrochloric acid equivalent increased to 1.0, N -acetyl-L- The yield of homoserine lactone increased, and when 1.25 equivalents or more of hydrochloric acid was applied, the yield of N- acetyl-L-Homoserine lactone gradually decreased.
[256]
[Table 6]
[257]
As shown in Table 6 above, when the second intermediate compound represented by Formula 4 was prepared from the first intermediate compound represented by Formula 3 using sulfuric acid, as the sulfuric acid equivalent increased to 1.0, N -acetyl-L- The yield of homoserine lactone increased, and when more than 1.5 equivalents of sulfuric acid was applied, the yield of N- acetyl-L-Homoserine lactone gradually decreased.
[258]
Experimental Example 4: Review of reaction conditions when preparing the second intermediate compound from the L-homoserine derivative (not using the first intermediate compound)
[259]
A mode of obtaining the second intermediate compound represented by Formula 4 from the L-homoserine derivative represented by Formula 1 was confirmed according to reaction conditions.
[260]
A reaction solution in which O- Acetyl-L-Homoserine (II) (1g, 6.2 mmol) was dissolved by slowly adding acid without a separate solvent was prepared and stirred for 30 minutes. Then, the reaction solution was heated to the reaction temperature shown in Tables 6 to 10, followed by stirring for the corresponding reaction time. Then, the reaction solution was concentrated under reduced pressure to prepare a concentrate, cooled to 0° C., added isopropanol, stirred, and filtered under reduced pressure to confirm the yield of N- acetyl-L-Homoserine lactone as a white solid . The results according to each reaction condition are shown in Tables 7 to 11 below.
[261]
[Table 7]
[262]
As shown in Table 7, when the second intermediate compound represented by Formula 4 was prepared from the L-homoserine derivative represented by Formula 1 using acetic acid, as the acetic acid equivalent increased, N- acetyl-L-Homoserine lactone was increased, and in particular, when the equivalent of acetic acid was 1.3 or more, N- acetyl-L-Homoserine lactone was obtained in high yield .
[263]
As the reaction temperature increased, the yield of N- acetyl-L-Homoserine lactone increased. In particular, when the reaction temperature was 70° C. or higher, N- acetyl-L-Homoserine lactone was obtained in high yield .
[264]
As the reaction time increased, the yield of N- acetyl-L-Homoserine lactone increased. In particular, when the reaction time was more than 6 hours, N- acetyl-L-Homoserine lactone was obtained with a high yield .
[265]
[Table 8]
[266]
[Table 9]
[267]
As shown in Tables 8 and 9 above, when hydrochloric acid or sulfuric acid is applied as an acid, N- acetyl-L-Homoserine lactone, which is a second intermediate compound, is not obtained, and L-Homoserine lactone (AH) is produced to produce hydrochloric acid or It was confirmed that it was not suitable to use sulfuric acid.
[268]
[Table 10]
[269]
As shown in Table 10, the second intermediate compound represented by Formula 4 can be obtained from the L-homoserine derivative represented by Formula 1 using formic acid, and as the equivalent of formic acid increases, N -acetyl-L- The yield of homoserine lactone was increased.
[270]
[Table 11]
[271]
As shown in Table 11, when propionic acid was used, the second intermediate compound represented by Formula 4 was obtained from the L-homoserine derivative represented by Formula 1 in a yield similar to that of acetic acid. The yield of N- acetyl-L-Homoserine lactone increased as the propionic acid equivalent increased.
[272]
Experimental Example 5: Review of reaction conditions when preparing a third intermediate compound from the second intermediate compound
[273]
The aspect of obtaining according to the reaction conditions of the third intermediate compound represented by Formula 2 from the second intermediate compound represented by Formula 4 was confirmed. Ethyl-2-(acetamino)-4-chlorobutanoate or Methyl as a third intermediate compound in the same manner as in Example 1 (step 1-3) using N- acetyl-L-Homoserine lactone as the second intermediate compound. -2-(acetamino)-4-chlorobutanoate was obtained, except that the equivalent of ethanol or methanol and the reaction temperature during the reaction were changed as shown in Tables 12 and 13 below, respectively, and the results are also shown in Tables 12 and 13 .
[274]
[Table 12]
[275]
(NAHSL: N -acetyl-L-Homoserine lactone, Cl-NAHS-OEt: Ethyl-2-(acetamino)-4-chlorobutanoate)
[276]
As shown in Table 12, when the third intermediate compound represented by Formula 2 was prepared from the second intermediate compound represented by Formula 4 using ethanol, Ethyl-2-(acetamino)- as the ethanol equivalent increased The yield of 4-chlorobutanoate was increased, and in particular, when the equivalent of ethanol was 3 to 10 equivalents, Ethyl-2-(acetamino)-4-chlorobutanoate was obtained in high yield.
[277]
As the reaction temperature increased, the yield of Ethyl-2-(acetamino)-4-chlorobutanoate increased. In particular, when the reaction temperature was 40° C. or higher, Ethyl-2-(acetamino)-4-chlorobutanoate was obtained in high yield.
[278]
[Table 13]
[279]
(NAHSL: N -acetyl-L-Homoserine lactone, Cl-NAHS-OMe: Methyl-2-(acetamino)-4-chlorobutanoate)
[280]
As shown in Table 13 above, when the third intermediate compound represented by Formula 2 was prepared from the second intermediate compound represented by Formula 4 using methanol, as the methanol equivalent increased, Methyl-2-(acetamino)- The yield of 4-chlorobutanoate was increased, and in particular, when the equivalent of methanol was 3 to 10 equivalents, Methyl-2-(acetamino)-4-chlorobutanoate was obtained in high yield.
[281]
As the reaction temperature increased, the yield of Methyl-2-(acetamino)-4-chlorobutanoate increased. In particular, when the reaction temperature was 40° C. or higher, Methyl-2-(acetamino)-4-chlorobutanoate was obtained in high yield.
[282]
Experimental Example 6: Review of reaction conditions when preparing a third intermediate compound from the first intermediate compound
[283]
The obtained aspect according to the reaction conditions from the first intermediate compound represented by Formula 3 to the third intermediate compound represented by Formula 2 was confirmed. Using N- acetyl-L-Homoserine as the first intermediate compound , a third intermediate compound was obtained in the same manner as in Example 3 (step 3-2), except that the alcohol equivalent and reaction temperature during the reaction were Each was changed as shown in Tables 14 to 17 below, and the results are also shown in Tables 14 to 17.
[284]
[Table 14]
[285]
[Table 15]
[286]
[Table 16]
[287]
[Table 17]
[288]
As shown in Tables 14 to 17, it was confirmed that the third intermediate compound represented by Formula 2 could be prepared from the first intermediate compound represented by Formula 2 using methanol, ethanol, isopropanol, and butanol.
Claims
[Claim 1]
In a method for preparing an intermediate of L-glufosinate from an L-homoserine derivative, comprising the step (step a) of preparing a compound of Formula 2 below from a compound of Formula 1, Preparation of an intermediate of L-glufosinate Method: In the above formulas, R 1 is R a -(C=O)-, and R a is a substituted or unsubstituted C 1 to C 6 alkyl group, a substituted or unsubstituted C 1 A to 6 alkenyl group, a substituted or unsubstituted C1 to C6 alkynyl group, a substituted or unsubstituted C3 to C10 cycloalkyl group, a substituted or unsubstituted C6 to C20 aryl group, or a substituted or unsubstituted is a heteroaryl group having 2 to 10 carbon atoms, R 2 is a substituted or unsubstituted C 1 to C 6 alkyl group, a substituted or unsubstituted C 1 to C 6 alkenyl group, or a substituted or unsubstituted C 1 to C 6 alkyl group A nyl group, 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 ), R b , R c and R d are each independently a substituted or unsubstituted C 1 to C 6 alkyl group or a substituted or unsubstituted C 6 to C 20 aryl group, X is halogen, and the alkyl group, alkenyl group, or alkynyl group , The substituents of the cycloalkyl group, the aryl group and the heteroaryl group are each independently halogen, a carboxyl group (-COOH), an amino group (-NH 2 ), a nitro group (-NO 2 ), a cyano group (-CN), and 1 to 6 carbon atoms. at least one selected from an alkyl group, an aryl group having 6 to 10 carbon atoms, and a cycloalkyl group having 3 to 10 carbon atoms.
[Claim 2]
The method of claim 1, wherein step a comprises preparing a compound of Formula 3 below by reacting the compound of Formula 1 with a first base catalyst (step b): < Formula 3> In the above formula, R 1 is R a -(C=O)-, R a is a substituted or unsubstituted C 1 to C 6 alkyl group, a substituted or unsubstituted C 1 to C 6 alkenyl group, substituted or unsubstituted A cyclic 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 am.
[Claim 3]
The L-glufosinate intermediate preparation according to claim 2, wherein step a comprises preparing a compound of Formula 4 below by reacting the compound of Formula 3 with a first acid catalyst after step b (step c) Method: In the above formula, R 1 is R a -(C=O)-, R a is a substituted or unsubstituted C 1 to C 6 alkyl group, a substituted or unsubstituted C 1 to C 6 alkenyl group, A substituted or unsubstituted C1 to C6 alkynyl group, a substituted or unsubstituted C3 to C10 cycloalkyl group, a substituted or unsubstituted C6 to C20 aryl group, or a substituted or unsubstituted C2 to C10 It is a heteroaryl group.
[Claim 4]
According to claim 3, wherein step a comprises the step (step d) of preparing the compound of formula 2 by reacting the compound of formula 4 with a halogenating agent and at least one R 2 -OH after step c - Method for preparing the intermediate glufosinate.
[Claim 5]
The method of claim 2, wherein step a comprises preparing the compound of Formula 2 (step c-1) by reacting the compound of Formula 3 with a halogenating agent and at least one R 2 -OH after step b. which, L- glufosinate intermediate preparation method.
[Claim 6]
The method of claim 1, wherein step a comprises preparing a compound of Formula 4 below by reacting the compound of Formula 1 and a second acid catalyst (step b-1): In the above formula, R 1 is R a -(C=O)-, and R a is a substituted or unsubstituted C 1 to C 6 alkyl group, a substituted or unsubstituted C 1 to C 6 alkenyl group, substituted or An unsubstituted C 1 to C 6 alkynyl group, a substituted or unsubstituted C 3 to C 10 cycloalkyl group, a substituted or unsubstituted C 6 to C 20 aryl group, or a substituted or unsubstituted C 2 to C 10 heteroaryl it's gi
[Claim 7]
The method according to claim 6, wherein step a is a step of preparing a compound represented by Formula 2 by reacting the compound of Formula 4 with a halogenating agent and at least one R 2 -OH after step b-1 (d-1 Step) comprising the L- glufosinate intermediate preparation method.
[Claim 8]
2. The method of claim 1, wherein R 1 is an acetyl, or succinyl, wherein R 2 is any one selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, benzyl, phenyl and naphthyl, L - Method for preparing an intermediate glufosinate.
[Claim 9]
According to claim 1, wherein the compound of Formula 1 is prepared from a fermentation broth containing the compound of Formula 1, L- glufosinate intermediate preparation method.
[Claim 10]
According to claim 2, wherein the first base catalyst is NH 3 , KOH, NaOH, CaSO 4 , LiOH, NaH, KH, NaOCH 3 , NaOCH 2 CH 3 , NaOC(CH 3 ) 3 , KOC(CH 3 ) 3 , K 2 CO 3 , Na 2 CO 3 , 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), 1,5-diazabicyclo[4.3.0]nona-5-ene ( DBN), tri(C 1 -C 4 alkyl) amine, pyridine, and n- butyllithium comprising at least one selected from the group consisting of, L- glufosinate intermediate preparation method.
[Claim 11]
The method according to claim 2, wherein step b is carried out at a pH of 9 to 14, L- glufosinate intermediate preparation method.
[Claim 12]
The method of claim 3, wherein the first acid catalyst comprises at least one selected from the group consisting of CH 3 COOH, HCl, H 2 SO 4 , HBr and HI.
[Claim 13]
12. The method of claim 11, wherein the content of the first acid catalyst is 0.1 to 100 equivalents based on 1 equivalent of the compound of Formula 3, L- glufosinate intermediate preparation method.
[Claim 14]
According to claim 3, wherein step c is carried out for a reaction time of 0.1 to 20 hours at a temperature of 20 to 150 ℃, L- glufosinate intermediate preparation method.
[Claim 15]
The method according to any one of claims 4, 5 and 7, wherein the halogenating agent is HCl, HBr, HI, phosgene, SOCl 2 , oxalyl chloride, 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 , comprising at least one selected from the group consisting of, L- glufosinate intermediate preparation method.
[Claim 16]
8. The method of any one of claims 4, 5 and 7, wherein R 2 -OH is methanol, ethanol, n-propanol, iso-propanol, butanol, pentanol hexanol, benzyl alcohol, phenol and naphthol. L- glufosinate intermediate preparation method comprising at least one selected from the group.
[Claim 17]
The method of claim 5, wherein step c-1 is carried out at a reaction temperature of 20 to 120° C. for a reaction time of 0.1 to 30 hours.
[Claim 18]
The method of claim 4, wherein step d-1 is performed at a reaction temperature of 20 to 100° C. for a reaction time of 0.1 to 30 hours.
[Claim 19]
The method according to any one of claims 4, 5 and 7, wherein the content of the halogenating agent is 1 to 10 equivalents based on 1 equivalent of the compound of Formula 3 or the compound of Formula 4, and the R 2 - OH is 1 to 60 equivalents based on 1 equivalent of the compound of Formula 3 or the compound of Formula 4, L- glufosinate intermediate preparation method.
[Claim 20]
The method of claim 6, wherein the second acid catalyst comprises at least one selected from the group consisting of acetic acid, formic acid, butyric acid, pentanoic acid and propionic acid.
[Claim 21]
The method of claim 6, wherein the content of the second acid catalyst of the second acid catalyst is 0.1 to 20 equivalents based on 1 equivalent of the compound of Formula 1, L- glufosinate intermediate preparation method.
[Claim 22]
The method of claim 6, wherein the preparing of the compound of Formula 4 is performed at a temperature of 20 to 100° C. for a reaction time of 1 to 20 hours.
[Claim 23]
In the method for preparing L-glufosinate from an L-homoserine derivative, the method for preparing L-glufosinate comprising preparing a compound of Formula 2 from the compound of Formula 1 below: 2> In the above formulas, R 1 is R a -(C=O)-, and R a is a substituted or unsubstituted C 1 to C 6 alkyl group, a substituted or unsubstituted C 1 to C 6 alkenyl group, substituted or An unsubstituted C 1 to C 6 alkynyl group, a substituted or unsubstituted C 3 to C 10 cycloalkyl group, a substituted or unsubstituted C 6 to C 20 aryl group, or a substituted or unsubstituted C 2 to C 10 heteroaryl a group, R 2 is a substituted or unsubstituted C 1 to C 6 alkyl group, a substituted or unsubstituted C 1 to C 6 alkenyl group, a substituted or unsubstituted C 1 to C 6 alkynyl group, substituted or unsubstituted C 1 to C 6 A 3 to 10 cycloalkyl group, or a substituted or unsubstituted C 6 to C 20 aryl group, a substituted or unsubstituted C 2 to C 10 heteroaryl group, or —Si(R b )(R c )(R d ) and R b, R c and R d are each independently a substituted or unsubstituted C 1 to C 6 alkyl group or a substituted or unsubstituted C 6 to C 20 aryl group, X is halogen, the alkyl group, alkenyl group, alkynyl group, The substituents of the cycloalkyl group, the aryl group and the heteroaryl group are each independently halogen, a carboxyl group (-COOH), an amino group (-NH 2 ), a nitro group (-NO 2 ), a cyano group (-CN), having 1 to 6 carbon atoms at least one selected from an alkyl group, an aryl group having 6 to 10 carbon atoms, and a cycloalkyl group having 3 to 10 carbon atoms.