It relates to a method for preparing L-glufosinate.
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 L- glufosinate having a high optical purity in a simple and high yield.
means of solving the problem
[5]
According to one aspect, there is provided a method for preparing L-glufosinate from an L-lactone derivative compound, the method comprising: preparing a compound of Formula 2 from a compound of Formula 1 below (step a); And it provides a method for preparing L- glufosinate, comprising the step (step b) of preparing L- glufosinate of the following formula (3) from the compound of formula (2).
[6]

[7]

[8]

[9]

[10]

[11]

[12]
In the above formulas, 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 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 is a flag,
[13]
R 2 is 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, 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 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,
[14]
R 5 is hydrogen, 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 alkynyl group,
[15]
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 ), cya at least one selected from the group consisting of a no 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.
Effects of the Invention
[16]
The L- glufosinate manufacturing method according to an embodiment uses a new intermediate compound and has a new synthetic route, so that L- glufosinate having high optical purity can be prepared.
[17]
In addition, L- glufosinate can be prepared in high yield by a simple method.
Modes for carrying out the invention
[18]
Hereinafter, a method for preparing L- glufosinate 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 preparing L-glufosinate according to an embodiment, in the method for preparing L-glufosinate from an L-lactone derivative compound, preparing a compound of Formula 2 below from a compound of Formula 1 (step a) ; and preparing L-glufosinate of Formula 3 from the compound of Formula 2 (step b).
[26]

[27]

[28]

[29]

[30]

[31]

[32]
In the above formulas, 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 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 is a flag,
[33]
R 2 is 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, 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 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,
[34]
R 5 is hydrogen, 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 alkynyl group,
[35]
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 ), cya at least one selected from the group consisting of a no 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.
[36]
More specifically, step a may include preparing a compound of Formula 4 below by reacting the compound of Formula 1 with a halogenation agent and at least one R 2 -OH (step c).
[37]

[38]

[39]
wherein R 1 and R 2 are as defined in claim 1, and X is halogen.
[40]
That is, the first intermediate compound represented by Formula 4 may be prepared by reacting the compound of Formula 1 with a halogenation agent and at least one R 2 -OH. For example, the lactone compound represented by Formula 1 reacts with the halogen of the halogenating agent to undergo a ring opening reaction, followed by a substitution reaction with the R 2 -functional group of one or more R 2 -OH compounds. may proceed to form a second intermediate compound.
[41]

[42]

[43]

[44]

[45]
In the compound of Formula 1 and the first intermediate compound represented by Formula 4, for example, R 1 may be acetyl or succinyl, and R 2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, benzyl, phenyl, naph tyl, -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 can be Since the compound of Formula 1 and the first intermediate compound represented by Formula 4 have such a functional group, L-glufosinate having improved optical purity can be more easily prepared.
[46]
The compound of Formula 1 may be prepared from, for example, a fermentation broth containing a precursor of the compound of Formula 1. Therefore, it is possible to efficiently prepare L-glufosinate by 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 may be, for example, an L-homoserine derivative. The L-homoserine derivative may be, for example, O-acetyl-L-homoserine, which is an O-substituted form of L-homoserine, O-succinyl-L-homoserine, and the like. For example, the compound of Formula 1 may be prepared by isolating an L-homoserine derivative, which is a precursor of the first intermediate compound, from the fermentation broth, and ring-forming from the isolated L-homoserine derivative.
[47]
Furthermore, due to the use of an intermediate compound derived from a derivative of O-substituted L-homoserine, there is no need to use an additional material to introduce a protecting group of an amino group, and all reactions are performed in one reactor. L-glufosinate can be prepared with
[48]
As used herein, the term 'fermentation broth containing the precursor of the compound of Formula 1' may be a fermentation broth containing the precursor of the compound of Formula 1 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, the fermentation broth containing the precursor of the compound of Formula 1 is produced by culturing a microorganism in a medium containing sugar to directly produce the precursor of the compound of Formula 1, or by culturing the microorganism in a medium containing sugar. It may be a fermentation broth containing a precursor of the compound of Formula 1 obtained by enzymatic conversion of one amino acid. The type of microorganism used for the preparation of the fermentation broth containing the precursor of the compound of Formula 1 is not particularly limited, but any microorganism capable of producing an L-homoserine derivative by direct fermentation or enzymatic conversion in the art is possible. The fermentation broth containing the L-homoserine derivative is, for example, 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.
[49]
The halogenating agent is, for example, SOCl 2 , oxalyl chloride (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 3It may include at least one selected from the group consisting of. In particular, the halogenating agent may be triethylsilane ((CH 2 CH 3 ) 3 SiH)+palladium chloride (PdCl 2 )+methyl iodide (CH 3 I) or SOCl 2 .
[50]
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, 0.1 to 1.3 equivalents based on 1 equivalent of the compound of Formula 1 , or 1 to 1.1 equivalents.
[51]
One or more R 2 -OH compounds may be used in the reaction to form the first 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.
[52]
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 first intermediate compound may be obtained in a higher yield from the compound of Formula 1 .
[53]
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 compound of Formula 1. 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 an organic solvent.
[54]
The organic solvent is, for example, alcohol, toluene, benzene, tetrahydrofuran, acetone, chloroform, dichloromethane, acetonitrile, etc., but is not necessarily limited thereto, and any solvent used as a halogenating agent in the art may be used. Alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, pentanol, and the like.
[55]
In the step of preparing the first intermediate compound, the halogenation / ring opening reaction is performed at a temperature of, for example, 20 to 100 °C, 20 to 80 °C, 30 to 70 °C, or 40 to 60 °C. can be In the step of preparing the first intermediate compound, the ring-opening reaction and/or substitution reaction may be performed, for example, in 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. The first intermediate compound can be more easily prepared by performing the halogenation reaction/ring-opening reaction in this temperature range and time range.
[56]
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.
[57]
In the step of preparing the first intermediate compound, the enantiomeric excess of the first 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.
[58]
Subsequently, step a may include reacting the compound of Formula 4 with a compound of Formula 5 after step c to prepare the compound of Formula 2 (step d).
[59]

[60]

[61]
In the above formula, 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, or a substituted or unsubstituted C 1 to C 6 alkynyl group am.
[62]
Next, in the step of preparing the second intermediate compound represented by Formula 2, the first intermediate compound and the first acid are reacted with the phosphorus compound represented by Formula 5, or the first intermediate compound is reacted with Formula 5 without the first acid A second intermediate compound represented by Formula 4 may be prepared by reacting with the phosphorus compound represented by . That is, the second intermediate compound represented by Formula 2 may be obtained by reacting the compound of Formula 4 with a phosphorus compound.
[63]

[64]

[65]

[66]

[67]

[68]

[69]
In the first intermediate compound represented by Formula 4, the phosphorus compound represented by Formula 5, and the second intermediate compound represented by Formula 2, 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 4 may be each independently selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl, and R 5 is R 3 or R 4can be The first intermediate compound represented by Formula 4, the phosphorus compound represented by Formula 5, and the second intermediate compound represented by Formula 2 have such functional groups, thereby making it easier to prepare L-glufosinate having improved optical purity. can
[70]
The phosphorus compound represented by Formula 5 is particularly an alkylmethylphosphonite, for example, diethylmethylphosphonite (DMP) or ethylmethylphosphonite (EMP), or butylmethylphosphonite. (butylmethylphosphonite, BMP).
[71]
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 first intermediate compound represented by Formula 4.
[72]
The first 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 one or more selected from, in particular Al + KF 2 O 3 may be .
[73]
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 100 parts by weight based on 100 parts by weight of the compound of Formula 4 10 parts by weight, 0.1 to 5 parts by weight, or 0.1 to 2 parts by weight. When the content of the first acid is too low, the effect on the reaction rate is insignificant, and when the content of the first acid is too high, by-products may increase.
[74]
By using the first acid, the second intermediate compound can be obtained in a more improved yield. In the step of preparing the second intermediate compound, the reaction is, 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 It may be carried out at a temperature of ℃, 110 to 160 ℃, 110 to 150 ℃, 110 to 160 ℃, 110 to 140 ℃, 120 to 160 ℃, 120 to 150 ℃, or 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. In the step of preparing the second 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. By carrying out the reaction in this temperature range and time range, the second intermediate compound can be more easily prepared.
[75]
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.
[76]
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.
[77]
According to another embodiment, in step a , preparing the compound of Formula 2 by reacting the compound of Formula 1 with a halogenation agent, at least one R 2 -OH, and a compound of Formula 5 below ( step a-1) may be included.
[78]

[79]

[80]
In the above formula, 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, or a substituted or unsubstituted C 1 to C 6 alkynyl group am.
[81]
Specifically, R 1 may be acetyl or succinyl, and R 2 -OH is selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol, butanol, pentanol hexanol, benzyl alcohol, phenol and naphthol. There may be at least one. In addition, R 3 and R 4 may include any one selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl. Since the compound of Formula 1, the phosphorus compound represented by Formula 5, and the second intermediate compound represented by Formula 2 have such functional groups, L-glufosinate having improved optical purity can be more easily prepared.
[82]
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).
[83]
The phosphorus 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 compound of Formula 1.
[84]
The halogenating agent is, for example, HCl, HBr, HI, phosgene, SOCl 2 , oxalyl chloride, triMethylSilyl halide, sodium iodide (NaI), triethylsilane , (CH 2 CH 3 ) 3 SiH) + palladium chloride (PdCl 2 ) + methyl iodide (CH 3 I), POCl 3 , PCl 3 , PCl 5 , PBr 3 , PI 3 , H 2 SO 4 + KBr, P+Cl 2 , P+Br 2 , P+I 2 , TiCl 4 , ZnCl 2And BBr 3 It may include at least one selected from the group consisting of.
[85]
The halogenating agent in the step of preparing the second intermediate compound by reacting the compound of Formula 1 with a halogenating agent, at least one R 2 -OH compound and a phosphorus compound is particularly trimethylsilyl halide, sodium iodide (NaI). ) and so on. 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, based on 1 equivalent of the compound of Formula 1.
[86]
One or more R 2 -OH compounds may be used in the reaction to form the second 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.
[87]
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, a second intermediate compound can be obtained in a higher yield from the compound of Formula 1 .
[88]
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 compound of Formula 1.
[89]
When the second intermediate compound represented by Formula 2 is prepared using the compound of Formula 1, a halogenating agent, and the phosphorus compound of Formula 5, the reaction temperature is 80 to 180° C., 80 to 160° C., 90 to 160° C., 90 to 150°C, 100-160°C, 100-150°C, 100-140°C, 110-160°C, 110-150°C, 110-160°C, 110-140°C, 120-160°C, 120-150°C, or 120 It may be carried out at a temperature of from 140 °C. The reaction time may be specifically carried out for 0.1 to 20 hours.
[90]
Specific reaction conditions may refer to the step of preparing a second intermediate compound represented by Formula 2 from the compound of Formula 1 described above.
[91]
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.
[92]
According to one embodiment, the step of preparing L- glufosinate of Formula 3 below from the compound of Formula 2 (step b) may be performed by hydrolyzing the compound of Formula 2 under an acid catalyst. That is, L-glufosinate represented by Formula 3 may be prepared by reacting the second intermediate compound of Formula 4 with a second acid (acid catalyst) to remove terminal functional groups by hydrolysis.
[93]
The second acid is, for example, at least one selected from the group consisting of HCl, H 2 SO 4 , H 2 SO 4 and KF, and a combination of Al 2 O 3 (KF+Al 2 O 3 ), but the second acid must be It is not limited thereto, and any one used as an acid catalyst in the art is possible. The second acid may in particular be hydrochloric acid.
[94]
The content of the second 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 second 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 second acid is too low, the effect on the reaction rate is insignificant, and when the content of the second acid is too large, by-products may increase.
[95]
When the second 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.
[96]
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.
[97]
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.
[98]
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.
[99]
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.
[100]
According to the present invention, it is possible to simply prepare L- glufosinate having high optical purity in a high yield by going through a synthetic route using the first intermediate compound of Formula 1 .
[101]
Additionally, the compound of Formula 1 is prepared by reacting an L-homoserine derivative represented by Formula 6 with a first base to prepare a third intermediate compound represented by Formula 7, and reacting the third intermediate compound with a third acid can be prepared by That is, preparing a third intermediate compound represented by Formula 7 by reacting an L-homoserine derivative represented by the following Chemical Formula 6 with a first base before step a or step a-1; and reacting a third intermediate compound with a third acid to prepare a compound of Formula 1 may further include.
[102]
More specifically, a third intermediate compound represented by Formula 7 may be prepared by reacting the L-homoserine derivative represented by Formula 6 with a first base. ,
[103]
R in L- homoserine derivative represented by the general formula 6 1 R represented by a - (C = O) - functional group is a nitrogen in the third intermediate compound by a functional group movement (transfer) reaction in the first base represented by the formula (7) can be coupled to For example, in the L-homoserine derivative represented by Formula 6, the functional group represented by R 1 is bonded to nitrogen in the third intermediate compound represented by Formula 7 by a functional group transfer reaction under a first base, and an amine may act as a protecting group of
[104]

[105]

[106]

[107]

[108]
In the above formula,
[109]
R 1 is R e -(C=O)-, and R e 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, the alkyl group; Substituents of an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, and a heteroaryl group are each independently halogen, a carboxyl group (-COOH), an amino group (-NH 2 ), a nitro group (-NO 2 ), a 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.
[110]
In the L-homoserine derivative represented by Formula 6, for example, R 1 may be acetyl or succinyl. Since the L-homoserine derivative represented by Formula 6 has such a functional group, L-glufosinate having improved optical purity can be more easily prepared.
[111]
The L-homoserine derivative represented by Formula 6 may be prepared from, for example, a fermentation broth containing the L-homoserine derivative. Therefore, it is possible to efficiently prepare L-glufosinate by using the L-homoserine derivative represented by Formula 6 generated during the fermentation process.
[112]
As used herein, the term 'fermentation broth containing L-homoserine derivative' may be a fermentation broth containing L-homoserine derivative produced from a fermentation process. Fermentation may be the same as described above.
[113]
The first base can be, for example, 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 , Na2CO 3 , 1,8- diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5- diazabicyclo [4.3.0] nona-5-ene (DBN), tri ( It may be at least one selected from C1-C4alkyl)amine, pyridine, and n-butyllithium.
[114]
The first base may in particular be sodium hydroxide. 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 100 parts by weight of the L-homoserine derivative represented by Formula 6 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 is too low, the effect on the reaction rate may be insignificant, and if the content of the first base is too high, by-products may increase. The step of preparing the third intermediate compound of Formula 7 may be performed under 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. When the reaction solution has a pH in this range, the L-homoserine-based compound can be more easily prepared. In the step of preparing the L-homoserine-based compound, the functional group transfer reaction may be performed, for example, at a temperature of 20 to 150°C. In the step of preparing the L-homoserine-based compound, the functional group transfer reaction may be performed for, for example, 0.1 to 20 hours. The third intermediate compound can be more easily prepared by performing the functional group transfer reaction in this temperature range and time range.
[115]
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.
[116]
In the step of preparing the third intermediate compound, the enantiomeric excess of the third 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.
[117]
Next, the compound of Formula 1 may be prepared by reacting the third intermediate compound represented by Formula 7 under a third acid.
[118]
That is, the lactone compound represented by the following Chemical Formula 1 may be obtained by reacting the third intermediate compound represented by Chemical Formula 7 with a third acid to form lacton. For example, the third intermediate compound represented by Formula 7 may form a lactone ring by a third acid.
[119]

[120]

[121]

[122]

[123]
The third acid may be, for example, at least one selected from the group consisting of acetic acid, HCl, H 2 SO 4 , HBr and HI.
[124]
The content of the third acid may be appropriately selected according to the type of acid used. For example, 0.1 equivalent or more of the third acid may be used with respect to the first intermediate compound represented by Formula 4, 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, it may be 10 equivalents or more, 20 or more equivalents, 10 to 50 equivalents, or 20 to 40 equivalents. 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.
[125]
The step of preparing the compound of Formula 1 may be carried out in a solvent or in a neat condition without a solvent. The solvent may be water or an organic solvent.
[126]
In the step of preparing the compound of Formula 1, the lactone formation reaction may 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 may be performed for, for example, 0.1 to 20 hours. The compound of Formula 1 can be more easily prepared by carrying out the lactone-forming reaction in this temperature range and time range.
[127]
In the step of preparing the compound of Formula 1, the yield of the compound of Formula 1 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.
[128]
In the step of preparing the compound of Formula 1, the enantiomeric excess of the first 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.
[129]
The present application will be described in more detail through the following examples and comparative examples. However, the examples are provided to illustrate the present application, and the scope of the present application is not limited thereto.
[130]
Example 1: Preparation of L-glufosinate using N -acetyl-L-homoserine lactone (using the second intermediate compound (1))
[131]
(Step 1-1: Preparation of Ethyl-2-(acetamino)-4-chlorobutanoate)
[132]

[133]
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.
[134]
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.
[135]
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)
[136]
(Step 1-2: Preparation of Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate)
[137]

[138]
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℃ for 12 hours. did 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.
[139]
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.
[140]
(Step 1-3: Preparation of L-glufosinate (L-phosphinothricin) hydrochloride)
[141]

[142]
Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate 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 1-3 61%). .
[143]
1 H NMR (400 MHz, DO): δ 4.12 (m, 1H), 2.45-1.65 (m, 4H), 1.46 (d, J = 14 Hz, 3H).
[144]
Reference Example 1: Preparation of N-acetyl-L-homoserine lactone
[145]

[146]
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 .
[147]
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)
[148]

[149]
To an aqueous solution in which N- Acetyl-L-Homoserine (1 g, 6.2 mmol) was dissolved in 30 mL of water, c-HCl (concentrated hydrochloric acid) as an 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 .
[150]
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)
[151]
Example 2: Preparation of L-glufosinate using N -succinyl-L-homoserine lactone (using the second intermediate compound (2))
[152]
(Step 2-1: Preparation of Ethyl-2-(succinylamino)-4-chlorobutanoate)
[153]

[154]
Ethyl-2-(succinoamino)-4-chlorobutanoate was prepared in the same manner as in Example 1 using N- succinyl-L-Homoserine lactone.
[155]
Then, white L-Glufosinate hydrochloride salt (L-Glufosinate hydrochloride salt) from Ethyl-2-(succinoamino)-4-chlorobutanoate in the same manner as in Example 1 (4 steps (1-2 steps and 1-3 steps) total Yield 51%) was obtained.
[156]
1 H NMR (400 MHz, DO): δ 4.12 (m, 1H), 2.45-1.65 (m, 4H), 1.46 (d, J = 14 Hz, 3H).
[157]
Reference Example 2: Preparation of N-succinyl-L-homoserine lactone
[158]

[159]
To an aqueous solution of O -Succinyl-L-Homoserine (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.
[160]
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 .
[161]
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)
[162]

[163]
A reaction solution of pH 2 was prepared by slowly adding c-HCl (concentrated hydrochloric acid) as an acid to an aqueous solution in which N- succinyl-L-Homoserine (1 g) was dissolved in 30 mL of water. 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. The prepared concentrate was cooled to 0° C., stirred while adding ethanol, and filtered under reduced pressure to obtain N- succinyl-L-Homoserine lactone as a white solid (yield 98%).
[164]
1 H NMR (400 MHz, DMSO-d6): δ 3.96 (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)
[165]
Example 3: Preparation of L-glufosinate using N -acetyl-L-homoserine lactone (without the use of the second intermediate compound (1))
[166]
(Step 3-1: Preparation of Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate)
[167]

[168]
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 sealed. It was put into a tube (seal tube), and after nitrogen injection, the mixture was stirred at 140°C for 14 hours.
[169]
After the reaction was completed, unreacted diethyl methylphosphonite 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) and Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate as a colorless oil 4.42 g (yield 62.8%) was obtained.
[170]
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). 31 P NMR (CDCl 3 , 121.47 MHz) δ 54.28.
[171]
(Step 3-2: Preparation of L-glufosinate (L-phosphinothricin) hydrochloride)
[172]

[173]
Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate 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 hydrochloride salt, (yield 96%).
[174]
1 H NMR (400 MHz, DO ): δ 4.12 (m, 1H), 2.45-1.65 (m, 4H), 1.46 (d, J = 14 Hz, 3H).
[175]
Example 4: Preparation of L-glufosinate using N -succinyl-L-homoserine lactone (without the use of the second intermediate compound (2))
[176]
(Step 4-1: Preparation of Ethyl-2-(succinylamino)-4-(ethoxyphosphinyl)butanoate)
[177]

[178]
Ethyl-2-(succinylamino)-4-(ethoxyphosphinyl)butanoate was prepared in the same manner as in Example 1 using N- succinyl-L-Homoserine lactone.
[179]
Then, 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%). .
[180]
1 H NMR (400 MHz, DO): δ 4.12 (m, 1H), 2.45-1.65 (m, 4H), 1.46 (d, J = 14 Hz, 3H).
[181]
Comparative Example 1: Preparation of racemic glufosinate
[182]
Glufosinate was prepared according to the method disclosed in Example 1 of USP 6,359,162. The prepared glufosinate was a racemic mixture.
[183]
Comparative Example 2: Comparison with L-glufosinate manufacturing method introducing a protecting group to homoserine lactone
[184]
In order to compare the reaction results with the method for preparing L-glufosinate in which a protecting group is introduced into homoserine lactone, L-glufosinate was prepared according to Scheme 1 below.
[185]
[Scheme 1]
[186]

[187]
The reaction conditions and reaction results of each reaction step are shown in Table 1 below.
[188]
[Table 1]
[189]
(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)
[190]
As shown in Table 1, when hydrochloric acid is used to prepare a lactone compound from an L-homoserine derivative, homoserine lactone shown in Scheme 1 is obtained. 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 produce L-glufosinate, L-glufosinate It was confirmed that the nate was obtained in a low yield.
[191]
Experimental Example 1: Measurement of enantiomeric excess (% ee)
[192]
The enantiomeric 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.
[193]
Chiral HPLC analysis was performed by J. Chromatogr . 368, 413 (1986).
[194]
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.
[195]
[Table 2]
[196]
As shown in Table 2 above, the enantiomeric excess of L-glufosinate was significantly improved in the glufosinate prepared in Examples 1 to 4 compared to the glufosinate prepared in Comparative Example 1. Therefore, it is possible to simply prepare high-purity L-glufosinate by the manufacturing method including the intermediate compound of the present invention.
[197]
Reference Example 1: Review of pH conditions when preparing an L-homoserine-based compound represented by Formula 7 from an L-homoserine derivative
[198]
The aspect of obtaining the L-homoserine-based compound represented by Formula 7 from the L-homoserine derivative represented by Formula 6 according to pH was confirmed. Using O- Acetyl-L-homoserine as an L-homoserine derivative as a starting material, N- acetyl-L-Homoserine, an L- homoserine-based compound, was prepared in the same manner as in Reference Example 1 (step 1-4) . 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.
[199]
[Table 3]
[200]
(OAHS: O-Acetyl-L-Homoserine, NAHS: N-Acetyl-L-Homoserine)
[201]
As shown in Table 3, in the case of preparing the L-homoserine-based compound represented by Formula 7 from the L-homoserine derivative represented by Formula 6, the yield of N- acetyl-L-Homoserine increases as the pH increases. was increased, and in particular, when the pH was 9 or higher, N- acetyl-L-Homoserine was obtained in high yield .
[202]
Reference Example 2: Review of reaction conditions when preparing the first intermediate compound from the L-homoserine-based compound
[203]
The aspect of obtaining the lactone compound represented by Formula 1 from the L-homoserine-based compound represented by Formula 7 was confirmed according to reaction conditions. N- acetyl-L-Homoserine lactone, a compound represented by Formula 1, was obtained in the same manner as in Reference Example 1 (Step 1-5) using N- acetyl-L-Homoserine as an L- homoserine-based compound. However, the acid equivalent and reaction temperature during the reaction were changed as shown in Tables 4 to 6, respectively, and the results are shown in Tables 4 to 6.
[204]
[Table 4]
[205]
(NAHS: N- Acetyl-L-Homoserine, NAHSL: N- acetyl-L-Homoserine lactone)
[206]
As shown in Table 4, when the compound of Formula 1 was prepared from the L-homoserine-based compound represented by Formula 7 using acetic acid, the yield of N- acetyl-L-Homoserine lactone increased as the acetic acid equivalent increased. 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 .
[207]
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 in high yield .
[208]
[Table 5]
[209]
As shown in Table 5, when the compound of Formula 1 was prepared from the L-homoserine-based compound represented by Formula 7 using hydrochloric acid, the yield of N- acetyl-L-Homoserine lactone increased as the sulfuric acid equivalent increased to 1.0. was increased, and the yield of N- acetyl-L-Homoserine lactone gradually decreased when more than 1.5 equivalents of hydrochloric acid was applied .
[210]
[Table 6]
[211]
As shown in Table 6 above, when the compound of Formula 1 was prepared from the L-homoserine-based compound represented by Formula 7 using sulfuric acid, the yield of N- acetyl-L-Homoserine lactone increased as the sulfuric acid equivalent increased to 1.0. was increased, and when more than 1.5 equivalents of sulfuric acid was applied, the yield of N- acetyl-L-Homoserine lactone gradually decreased.
[212]
Experimental Example 2: Review of reaction conditions when preparing the first intermediate compound from the compound of Formula 1
[213]
A mode of obtaining the first intermediate compound represented by Formula 4 from the compound of Formula 1 according to reaction conditions was confirmed. Ethyl-2-(acetamino)-4-chlorobutanoate or Methyl as the first intermediate compound in the same manner as in Example 1 (Step 1-1) using N- acetyl-L-Homoserine lactone as the compound of Formula 1 -2-(acetamino)-4-chlorobutanoate was obtained, except that the equivalent of ethanol or methanol during the reaction and the reaction temperature were changed as shown in Tables 7 and 8, respectively, and the results are also shown in Tables 7 and 8 .
[214]
[Table 7]
[215]
(NAHSL: N -acetyl-L-Homoserine lactone, Cl-NAHS-OEt: Ethyl-2-(acetamino)-4-chlorobutanoate)
[216]
As shown in Table 7, when the first intermediate compound represented by Formula 4 was prepared from the compound of Formula 1 using ethanol, as the ethanol equivalent increased, the yield of Ethyl-2-(acetamino)-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.
[217]
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.
[218]
[Table 8]
[219]
(NAHSL: N -acetyl-L-Homoserine lactone, Cl-NAHS-OMe: Methyl-2-(acetamino)-4-chlorobutanoate)
[220]
As shown in Table 8, when the first intermediate compound represented by Formula 4 was prepared from the compound of Formula 1 using methanol, as the methanol equivalent increased, the yield of Methyl-2-(acetamino)-4-chlorobutanoate was increased, and in particular, when the equivalent of ethanol was 3 to 10 equivalents, Methyl-2-(acetamino)-4-chlorobutanoate was obtained in high yield.
[221]
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.
[222]
Experimental Example 3: Review of reaction conditions when preparing a second intermediate compound from the first intermediate compound
[223]
The obtained aspect according to the reaction conditions from the first intermediate compound represented by Formula 4 to the second intermediate compound represented by Formula 2 was confirmed. A second intermediate compound was obtained in the same manner as in Example 1 (step 1-2) using Ethyl-2-(acetamino)-4-chlorobutanoate as the first intermediate compound, except that The type, equivalent, and reaction temperature were changed as shown in Table 9, respectively, and the results are also shown in Table 9.
[224]
[Table 9]
[225]
(DMP: Diethyl methyl phosphonite, EMP: Ethyl methyl phosphonite, BMP: Butyl methyl phosphonite, P-NAHS-Oet: Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate)
[226]
As shown in Table 9, using an alkyl methyl phosphonite (AMP) such as DMP or EMP or BMP as a phosphorus compound to prepare a second intermediate compound represented by Formula 2 from the first intermediate compound represented by Formula 4 The yield was further increased when 1 equivalent or more of DMP or AMP was used. As the reaction temperature increased, the yield further increased, and in particular, Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate was obtained in a high yield when it was 120° C. or higher.
[227]
Experimental Example 4: Review of reaction conditions when preparing a second intermediate compound from the compound of Formula 1
[228]
The yield pattern according to the reaction conditions from the compound of Formula 1 to the second intermediate compound represented by Formula 2 was confirmed. A second intermediate compound was obtained in the same manner as in Example 2 (step 2-1) using N- acetyl-L-Homoserine lactone as the compound of Formula 1 , except that the type and equivalent of the halogenating agent during the reaction The reaction temperature was changed as shown in Tables 10 to 12, respectively, and the results are also shown in Tables 10 to 12.
[229]
[Table 10]
[230]
[Table 11]
[231]
[Table 12]
[232]
(TMSI: Trimethylsilyl iodide, TMSBr: Trimethylsilyl bromide, TMSCl: Trimethylsilyl chloride, P-NAHS-Oet: Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate)
[233]
As shown in Tables 10 to 12, a second intermediate compound represented by Formula 2 can be prepared from the compound of Formula 1 using trimethylsilyl halide such as TMSI, TMSBr, or TMSCl, or NaI as a halogenating agent, The yield was further increased when 0.5 equivalents or more of trimethylsilyl halide was used. As the reaction temperature increased, the yield further increased, and in particular, Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate was obtained in a high yield when it was 100° C. or higher.
[234]
Of the trimethylsilyl halide, TMSI had the highest reactivity, and the reactivity of TMSBr and TMSCl tended to be somewhat lower in the order, but Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate could be obtained from all of them.
[235]
Experimental Example 5: L- glufosinate reaction conditions in the second intermediate compound
[236]
It was confirmed that the obtained aspect according to the reaction conditions for the second intermediate compound represented by the formula (2). L-glufosinate was obtained in the same manner as in Example 1 (step 1-3) using Ethyl-2-(acetamino)-4-(ethoxymethylphosphinyl)butanoate as the second intermediate compound compound, but used Acid, reaction temperature and reaction time were respectively changed as shown in Table 13 below, and the results are shown in Table 13.
[237]
[Table 13]
[238]
As shown in Table 13, L-glufosinate can be prepared from the second intermediate compound represented by Formula 2 by using 6N hydrochloric acid as an acid at 120° C., and when the reaction time is increased, the yield is showed a further increasing trend. In addition, it was confirmed that when the reaction was carried out for more than 15 hours, the yield increased as the reaction temperature increased.
Claims
[Claim 1]
A method for preparing L-glufosinate from an L-lactone derivative compound, the method comprising: preparing a compound of Formula 2 from a compound of Formula 1 below (step a); And, L- glufosinate manufacturing method comprising the step (b step) for preparing the L- glufosinate of formula (III) from a compound of Formula 2: above formulas In R 1 is R a -(C=O)-, 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 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 group, , R 2 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, substituted or unsubstituted carbon number 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 ), 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, R 5 is 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, the alkyl group, alkenyl group, alkynyl group, cyclo The substituents of the alkyl group, the aryl group and the heteroaryl group are each independently hydrogen, 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 the group consisting of 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 reacting the compound of Formula 1 with a halogenation agent and at least one R 2 -OH to prepare a compound of Formula 4 below (step c), L- glufosinate preparation method: In the above formula, R 1 and R 2 are as defined in claim 1, and X is halogen.
[Claim 3]
According to claim 2, wherein step a comprises the step (step d) of preparing the compound of Formula 2 by reacting the compound of Formula 4 with a compound of Formula 5 after step c), L-glufosinate Preparation method: wherein 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 It is an alkynyl group having 1 to 6 carbon atoms.
[Claim 4]
The method of claim 1, wherein step a is to prepare the compound of Formula 2 by reacting the compound of Formula 1 with a halogenation agent, at least one R 2 -OH, and a compound of Formula 5 below (a) -1 step) comprising, L- glufosinate preparation method: In the above formula, R 3 and R 4 are each independently hydrogen, a substituted or unsubstituted C 1 to C 6 alkyl group, a substituted or unsubstituted an alkenyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted alkynyl group having 1 to 6 carbon atoms.
[Claim 5]
The method of claim 1, wherein R 1 is acetyl, or succinyl.
[Claim 6]
According to claim 1, wherein R 2 Is any one selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, benzyl, phenyl and naphthyl, L- glufosinate preparation method.
[Claim 7]
The method of claim 3 or 4, wherein R 3 and R 4 are each independently selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl.
[Claim 8]
According to claim 1, wherein the compound of Formula 1 is prepared from a fermentation broth containing a precursor of the compound of Formula 1, L- glufosinate production method.
[Claim 9]
According to claim 2 or 4, wherein the halogenating agent HCl, HBr, HI, phosgene (phosgene), SOCl 2 , oxalyl chloride (oxalyl chloride), trimethylsilyl halide (TriMethylSilyl halide), sodium iodide (NaI) ), triethylsilane (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 A method for producing L- glufosinate comprising at least one selected from the group consisting of.
[Claim 10]
5. The method of claim 2 or 4, wherein R 2 -OH is at least one selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol, butanol, pentanol hexanol, benzyl alcohol, phenol and naphthol. Including, L- glufosinate production method.
[Claim 11]
The method of claim 2 or 4, wherein the content of R 2 -OH is 1 to 60 equivalents based on 1 equivalent of the compound of Formula 1, L- glufosinate production method.
[Claim 12]
The method of claim 2 or 4, wherein the amount of the halogenating agent is 0.1 to 10 equivalents based on 1 equivalent of the compound of Formula 1, L- glufosinate production method.
[Claim 13]
The method of claim 2, wherein step c is performed at a temperature of 20 to 100° C. for a reaction time of 0.1 to 30 hours.
[Claim 14]
According to claim 3 or 4, wherein the compound of Formula 5 is diethylmethyl phosphonite (diethylmethylphosphinate, DMP), ethylmethyl phosphonite (ethylmethylphosphinate, EMP) and butyl methyl phosphonite (butylmethylphosphinate, BMP) consisting of At least one selected from the group, L- glufosinate manufacturing method.
[Claim 15]
5. The method of claim 3 or 4, wherein the content of the compound of Formula 5 is 0.5 to 10 equivalents based on 1 equivalent of the compound of Formula 1 or Formula 4, L- glufosinate production method.
[Claim 16]
The method of 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.
[Claim 17]
The method of claim 1, wherein step b is performed by hydrolyzing the compound of Formula 2 under an acid catalyst.
[Claim 18]
The method of claim 17, wherein the acid catalyst comprises at least one selected from the group consisting of acetic acid, HCl, H 2 SO 4 and KF-Al 2 O 3 , L-glufosinate preparation method.
[Claim 19]
According to claim 1, wherein step b is carried out for 0.1 to 30 hours at a temperature of 20 to 150 ℃, L- glufosinate production method.
[Claim 20]
The method according to claim 1, wherein the L-glufosinate is the hydrochloride salt of L-glufosinate, the sulfate salt of L-glufosinate, the carbonate salt of L-glufosinate, the sodium salt of L-glufosinate, and L-glufosinate. A method for producing L-glufosinate, comprising at least one selected from among ammonium salts of nate.