WO2024198078A1

WO2024198078A1 - Amino acid derivative, preparation method therefor, and method for synthesizing l-glufosinate ammonium using amino acid derivative as intermediate

Info

Publication number: WO2024198078A1
Application number: PCT/CN2023/097690
Authority: WO
Inventors: 史鲁秋; 李平; 张莎莎; 李华山
Original assignee: 南京华狮新材料有限公司; 南京盛德生物科技研究院有限公司
Priority date: 2023-03-28
Filing date: 2023-06-01
Publication date: 2024-10-03
Also published as: CN118724833A

Abstract

Disclosed are an amino acid derivative, a preparation method therefor, and a method for synthesizing L-glufosinate ammonium using the amino acid derivative as an intermediate. The derivative is obtained from L-homoserine by means of a conventional chemical reaction. The method for preparing glufosinate ammonium, particularly L-glufosinate ammonium, using the derivative comprises the following steps: conducting a condensation reaction on the amino acid derivative (compound (I)) and methyl phosphite in a proper solvent to obtain compound (II), and further hydrolyzing and salifying the compound II to obtain the glufosinate ammonium. The preparation method of the present invention features a high reaction speed and a high raw material conversion rate, the obtained product has a high optical rotation purity, and the raw materials used are cheap and readily available, such that the preparation method is very suitable for scale production.

Description

Amino acid derivative and preparation method thereof and method for synthesizing L-phosphinothricin as an intermediate

Technical Field

The invention belongs to the technical field of synthesis of organic matter and its intermediates, and specifically relates to an amino acid derivative and a preparation method thereof, and a method for synthesizing L-glufosinate as a chiral intermediate.

Background Art

Glufosinate ammonium (phosphinothricin) is a broad-spectrum contact herbicide developed by the former German company AIGFO (later owned by Bayer) in the 1980s.

Glufosinate contains a chiral center and has two optical isomers, L and D, but only L-glufosinate has herbicidal activity. Currently, the glufosinate herbicides on the market are mainly racemic products with a D:L=1:1 ratio. If the glufosinate product only contains the L-configuration optical isomer, the theoretical amount of glufosinate used per acre can be reduced by 50%, which is of great significance for reducing the cost of using pesticides and alleviating environmental pressure. L-glufosinate has therefore become one of the important development trends of the glufosinate industry.

At present, the synthesis methods of glufosinate ammonium at home and abroad can be summarized into two types: one is biological fermentation method, and the other is chemical synthesis method. At present, its manufacturing adopts chemical synthesis method, and biological fermentation method is still a long way from industrial production.

Chinese patent CN106083922 and Chinese Chemical Letters Vol.17, No.2, pp177-179, 2006 use natural amino acid L-methionine as the starting material, synthesize γ-butyrolactone hydrochloride through methylation, hydrolysis, cyclization and other steps, and then obtain L-phosphinothricin ammonium through protection, ring opening, absolv, hydrolysis and other reactions. However, the starting material L-methionine is relatively expensive, the reaction steps are relatively long, and there are many three wastes in the process. The cost of this route is extremely high and it is difficult to achieve industrialization.

In the article "Research Progress of Chemical Synthesis of Glufosinate-ammonium", several methods for preparing glufosinate-ammonium by chemical method are reviewed, namely chiral auxiliary reagent method, natural amino acid chiral source method and asymmetric catalysis method. These methods have obvious disadvantages. The chiral auxiliary reagent method and asymmetric catalysis method require expensive catalysts, which undoubtedly increases the cost. In particular, the metal catalysts used in the asymmetric catalysis method have certain environmental hazards, which increases the pressure on environmental protection. Most of the routes used in the natural amino acid chiral source method are long or have low yields, and the process is cumbersome.

Chinese patent CN113316580 uses halogenated butyrate or butyrolactone to react with diethyl methylphosphite, but the reaction yield is between 60-65%, which is still relatively low for industrial production and still needs further improvement.

Chinese patent CN202011270812 provides a high-efficiency, high-yield, and low-cost production process for L-homoserine, making it possible to synthesize L-glufosinate from the chiral raw material L-homoserine.

In order to overcome the shortcomings of the above-mentioned L-phosphinothricin synthesis technology, the present invention provides a new method for synthesizing L-phosphinothricin from L-homoserine. The synthesis method has a short route, high yield, high optical purity and low cost.

Summary of the invention

The object of the present invention is to provide an L-homoserine derivative (Compound I) and a method for preparing L-glufosinate-ammonium with high optical purity in a simple and high yield.

The purpose of the present invention and the solution to the technical problem are achieved by adopting the following technical solutions.

One aspect of the present invention provides a compound I, which is a homoserine derivative, and its chemical structure is as follows:

wherein _R1 is hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms, or phenyl, p-tolyl, or p-nitrophenyl;

_R2 is hydrogen, substituted or unsubstituted alkyl having 1 to 6 carbon atoms, substituted or unsubstituted alkenyl having 1 to 6 carbon atoms, substituted or unsubstituted alkynyl having 1 to 6 carbon atoms, substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, or substituted or unsubstituted aryl having 6 to 20 carbon atoms, substituted or unsubstituted heteroaryl having 2 to 10 carbon atoms;

The substituents of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl groups are independently selected from at least one group consisting of hydrogen, halogen, carboxyl, amino, nitro, cyano, alkyl groups having 1 to 6 carbon atoms, aryl groups having 6 to 10 carbon atoms and cycloalkyl groups having 3 to 10 carbon atoms.

Another aspect of the present invention also provides a method for preparing compound I, which comprises the following steps: dissolving 4-(2-hydroxyethyl)-5-oxooxazolidine-3-carboxylate in a suitable solvent, adding sulfonyl chloride dropwise under the catalysis of a base, and then washing with alkali, washing with water, drying, and concentrating to obtain compound I; the solvent comprises dichloromethane, chloroform, DMF, DMSO, ethyl acetate, toluene, xylene, cyclohexane, acetonitrile, ethanol, isopropanol, and methanol.

Another aspect of the present invention also provides a method for preparing L-glufosinate ammonium, which is prepared using the above-mentioned compound I or the compound I obtained according to the above-mentioned preparation method as a raw material, and the preparation method comprises the following steps:

S1: Compound I and compound II are subjected to condensation reaction in a certain ratio in a suitable solvent to obtain compound III, the chemical reaction formula of which is:

S2: The compound III obtained above is subjected to hydrolysis in the presence of an acid to deprotect the group to obtain L-phosphinothricin ammonium, and the chemical reaction formula is:

Furthermore, the compound II in step S1 is methylphosphite, and its structural formula is as follows:

Among them, _R3 is methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl.

Further, the compound II is any one selected from the group consisting of diethyl methylphosphite, ethyl methylphosphite and butyl methylphosphite.

Furthermore, in step S1, the amount ratio of compound I to compound II is 1:1-100.

Furthermore, in step S1, the solvent is added in a mass ratio of 0.1-100:1 to compound I, preferably, the mass ratio is 5-10:1.

Furthermore, the solvent in step S1 is at least one selected from the group consisting of ethyl formate, ethyl acetate, methanol, ethanol, isopropanol, benzene, toluene, chlorobenzene, dichlorobenzene, nitrobenzene, dichloroethane, chloroform, DMSO, DMF, HMPA, and compound II.

Furthermore, the condensation reaction conditions in step S1 are: temperature 20-200° C., preferably 80-150° C., most preferably 90-110° C.; time 1-24 h, preferably 3-12 h, most preferably 6-8 h.

Furthermore, the acid in step S2 is at least one selected from the group consisting of acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, phosphoric acid, hydrofluoric acid, hydrobromic acid and hydroiodic acid.

Furthermore, the hydrolysis conditions in step S2 are: temperature 60-180° C., time 0.5-24 h.

Furthermore, the L-glufosinate is selected from at least one of the hydrochloride of L-glufosinate, the sulfate of L-glufosinate, the carbonate of L-glufosinate, the sodium salt of L-glufosinate and the ammonium salt of L-glufosinate.

The expected effects and advantages of the invention are as follows:

1) The method for preparing L-glufosinate-ammonium of the present invention can simply produce L-glufosinate-ammonium with high optical purity by using a new intermediate compound I and having a new synthetic route.

2) The present invention uses homoserine as a starting material, activates the γ-hydroxyl group, and then condenses it with phosphite to introduce a phosphite group, and finally undergoes acid hydrolysis, neutralization, etc. to obtain the target end product.

3) The present invention has high reaction activity between the active intermediate and the phosphite, fast raw material conversion speed and high conversion rate, and the amount of phosphite used is much lower than that of the existing process, so the production cost is much lower than that of the existing technology.

4) The raw materials used in the preparation method of the present invention are cheap and easily available, which can effectively reduce the cost.

5) In the preparation method of the present invention, most of the solvent is water or the substrate itself, which has good social benefits in terms of energy saving and environmental protection.

6) The preparation method of the present invention has a wide range of applications, and similar compounds can be synthesized using this method, which has great industrial and commercial value.

The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and implement it according to the contents of the specification, the preferred embodiments of the present invention are described in detail as follows.

DETAILED DESCRIPTION

In order to make the technical means, creative features, objectives and effects of the present invention easy to understand, the technical solutions in the embodiments of the present invention will be clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

Example 1 Preparation of L-phosphinothricin

The preparation method of L-phosphinothion in this embodiment is as follows:

1) 5.0 g of methyl 4-(2-methylsulfonyloxyethyl)-5-oxooxazolidine-3-carboxylate and 50 ml of diethyl methyl phosphite were added to the reaction flask in sequence, and nitrogen was introduced into the system twice while maintaining the nitrogen atmosphere. The temperature was raised to 90° C. and the reaction was carried out for 6 h. The reaction was completed after TLC detection. The mixture was concentrated to dryness and separated by column chromatography to obtain a light yellow oil with a yield of 90.7%.

2) 4.5 g of the above oil and 45 ml of 6 mol/L hydrochloric acid were added to the reaction flask in sequence, and then heated to 120°C for reflux reaction for 8 h. After the reaction was completed, the mixture was concentrated to dryness by vacuum distillation, ethanol was added, and the solid was precipitated by stirring, filtered and dried. The yield was 91.2% and the ee% value was 98.9%.

The obtained L-glufosinate was subjected to nuclear magnetic resonance analysis, and its nuclear magnetic data (HNMR, D2O, 500MHz) were obtained: δppm3.70～3.75(1H, t, CH), 2.00～2.05(2H, m, CH2), 1.50～1.60(2H, m, CH2), 1.14～1.21(3H, d, CH3).

Example 2 Preparation of L-phosphinothricin

The preparation method of L-phosphinothion in this embodiment is as follows:

1) 5.0 g of tert-butyl 4-(2-methylsulfonyloxyethyl)-5-oxoxazolidine-3-carboxylate, 20 ml of diethyl methylphosphite, and 100 ml of toluene were added to the reaction flask in sequence. Under nitrogen protection, the temperature was raised to 90° C. for 6 h. The reaction was completed by TLC detection. The mixture was concentrated to dryness and separated by column chromatography to obtain a light yellow oil with a yield of 98.7%. The reaction formula of the process is:

2) 4.5 g of the above oil and 45 ml of 6 mol/L hydrochloric acid were added to the reaction flask in sequence, and then heated to 120°C for reflux reaction for 8 h. After the reaction was completed, the mixture was concentrated to dryness by vacuum distillation, ethanol was added, and the solid was precipitated by stirring, filtered and dried. The yield was 92.8% and the ee% value was 98.3%.

Example 3 Preparation of L-phosphinothricin

The preparation method of L-phosphinothion in this embodiment is as follows:

1) 5.0 g of tert-butyl 4-(2-p-nitrobenzenesulfonyloxyethyl)-5-oxoxazolidine-3-carboxylate, 30 ml of diethyl methylphosphite, and 150 ml of chlorobenzene were added to the reaction flask in sequence. Under nitrogen protection, the temperature was raised to 90° C. for 6 h. The reaction was completed after TLC detection. The mixture was concentrated to dryness and separated by column chromatography to obtain a light yellow oil with a yield of 98.7%. The reaction formula of the process is:

2) Add 4.5 g of the above oil and 45 ml of 6 mol/L hydrochloric acid to the reaction flask at once, and then heat to The reaction was continued for 8 hours. After the reaction was completed, the mixture was concentrated to dryness by distillation under reduced pressure. Ethanol was added and stirred to precipitate solids, which were filtered and dried. The yield was 97.0% and the ee% value was 98.9%.

Example 4 Preparation of L-phosphinothricin

The preparation method of L-phosphinothion in this embodiment is as follows:

1) 5.0 g of ethyl 4-(2-methylsulfonyloxyethyl)-5-oxooxazolidine-3-carboxylate and 50 ml of diethyl methylphosphite were added to the reaction flask in sequence. Under nitrogen protection, the temperature was raised to 90° C. for reaction for 6 h. The reaction was completed after TLC detection. The mixture was concentrated to dryness and separated by column chromatography to obtain a light yellow oil with a yield of 93.7%.

2) 4.5 g of the above oil and 45 ml of 6 mol/L hydrochloric acid were added to the reaction flask in sequence, and then heated to 120°C for reflux reaction for 8 h. After the reaction was completed, the mixture was concentrated to dryness by vacuum distillation, ethanol was added, and the solid was precipitated by stirring, filtered and dried. The yield was 89.9% and the ee% value was 99.5%.

The above is only a preferred embodiment of the present invention, and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment, it is not used to limit the present invention. Any technician familiar with the profession can make some changes or modifications to equivalent embodiments of equivalent changes using the methods and technical contents disclosed above without departing from the scope of the technical solution of the present invention. However, all contents that do not depart from the technical solution of the present invention are based on this invention. Any simple modification, equivalent changes and modifications made to the above embodiments by the technical essence of the invention still fall within the scope of the technical solution of the present invention.

Claims

Compound I, characterized in that the compound I is a homoserine derivative, and its chemical structure formula is as follows:

wherein R1 is hydrogen, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms, or phenyl, p-tolyl, or p-nitrophenyl;

R2 is hydrogen, substituted or unsubstituted alkyl having 1 to 6 carbon atoms, substituted or unsubstituted alkenyl having 1 to 6 carbon atoms, substituted or unsubstituted alkynyl having 1 to 6 carbon atoms, substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, or substituted or unsubstituted aryl having 6 to 20 carbon atoms, substituted or unsubstituted heteroaryl having 2 to 10 carbon atoms;

The substituents of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl groups are independently selected from at least one group consisting of hydrogen, halogen, carboxyl, amino, nitro, cyano, alkyl groups having 1 to 6 carbon atoms, aryl groups having 6 to 10 carbon atoms and cycloalkyl groups having 3 to 10 carbon atoms.
The method for preparing compound I according to claim 1, characterized in that the method comprises the following steps: dissolving 4-(2-hydroxyethyl)-5-oxooxazolidine-3-carboxylate in a suitable solvent, adding sulfonyl chloride dropwise under the catalysis of a base, and then washing with alkali, washing with water, drying, and concentrating to obtain compound I; the solvent includes dichloromethane, chloroform, DMF, DMSO, ethyl acetate, toluene, xylene, cyclohexane, acetonitrile, ethanol, isopropanol, and methanol.
A method for preparing L-glufosinate ammonium, characterized in that the compound I according to claim 1 or the compound I obtained by the preparation method according to claim 2 is used as a raw material for preparation, and the preparation method comprises the following steps:

S1: Compound I and compound II are subjected to condensation reaction in a certain ratio in a suitable solvent to obtain compound III, the chemical reaction formula of which is:

S2: The compound III obtained above is subjected to hydrolysis in the presence of an acid to deprotect the group to obtain L-phosphinothricin ammonium, and the chemical reaction formula is:
The method for preparing L-glufosinate according to claim 3, characterized in that the compound II in step S1 is methylphosphite, and its structural formula is as follows:

Among them, R3 is methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl.
The method for preparing L-glufosinate according to claim 3, characterized in that the amount ratio of compound I and compound II in step S1 is 1:1-100.
The method for preparing L-glufosinate according to claim 3, characterized in that the solvent in step S1 is added in a mass ratio of 0.1-100:1 to compound I, preferably, the mass ratio is 5-10:1.
The method for preparing L-glufosinate according to claim 3, characterized in that the solvent in step S1 is selected from at least one of the group consisting of ethyl formate, ethyl acetate, methanol, ethanol, isopropanol, benzene, toluene, chlorobenzene, dichlorobenzene, nitrobenzene, dichloroethane, chloroform, DMSO, DMF, HMPA, and compound II.
The method for preparing L-glufosinate according to claim 3, characterized in that the condensation reaction conditions in step S1 are: temperature 20-200° C., preferably 80-150° C., most preferably 90-110° C.; time 1-24 h, preferably 3-12 h, most preferably 6-8 h.
The method for preparing L-glufosinate according to claim 3, characterized in that the acid in step S2 is selected from at least one of the group consisting of acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, phosphoric acid, hydrofluoric acid, hydrobromic acid and hydroiodic acid.
The method for preparing L-glufosinate according to claim 3, characterized in that the hydrolysis conditions in step S2 are: temperature 60-180° C., time 0.5-24 h.