WO2024198077A1 - Amino acid derivative and preparation method therefor, and method for using amino acid derivative as intermediate to synthesize l-glufosinate-ammonium - Google Patents

Abstract

Disclosed in the present invention are an amino acid derivative and a preparation method therefor, and a method for using the amino acid derivative as an intermediate to synthesize L-glufosinate-ammonium. The derivative is obtained from L-homoserine by means of a conventional chemical reaction. The method for preparing glufosinate ammonium, particularly preparing L-glufosinate-ammonium by using the derivative comprises the following steps: an amino acid derivative (compound (I)) and methyl phosphite undergo a condensation reaction in a proper solvent to obtain a compound (II), and the compound (II) then undergoes hydrolysis and salification to obtain glufosinate ammonium. The preparation method disclosed by the present invention has a high reaction speed and a high raw material conversion rate, the obtained product has high optical purity, the used raw materials are cheap and easy to obtain, and the method is suitable for large-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 in particular, 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 Refined 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, 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, substituted or unsubstituted aryl having 6 to 20 carbon atoms, or substituted or unsubstituted heteroaryl having 2 to 10 carbon atoms;

_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;

_R3 is hydrogen, substituted or unsubstituted alkyl having 1 to 6 carbon atoms, substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, or phenyl, p-tolyl, or p-nitrophenyl;

X is a methylene group, a methine group, or a heteroatom such as O or NH;

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 N-acyl homoserine ester in a suitable solvent, adding sulfonyl chloride dropwise for esterification under the catalysis of a base, then performing alkali washing, water washing, drying steps, and concentrating to obtain compound I; the solvent comprises dichloromethane, dichloroethane, chloroform, ethyl acetate, DMF, and DMSO; the base comprises sodium carbonate, ammonium bicarbonate, sodium bicarbonate, potassium carbonate, triethylamine, and pyridine; and the sulfonyl chloride comprises methanesulfonyl chloride, p-toluenesulfonyl chloride, and p-nitrobenzenesulfonyl chloride.

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 Compound III, its chemical reaction formula 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, _R4 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 N-acetyl-O-methylsulfonyl-L-homoserine ethyl ester

The preparation method of N-acetyl-O-methylsulfonyl-L-homoserine ethyl ester in this embodiment is as follows:

To a dry 100mL three-necked reaction flask, add 6.0g of N-acetyl-L-homoserine ethyl ester, 100mL of dichloromethane, 3.5g of triethylamine, and 0.2g of DMAP in sequence, stir to dissolve, cool to 0-5°C in an ice-salt bath, add dropwise a solution of 4.0g of methanesulfonyl chloride and 40mL of dichloromethane, and complete the addition in about 3 hours. Naturally warm to room temperature, stir the reaction overnight, and TLC detection shows that the raw material has reacted completely. Cool to 0-5°C, add dropwise 30mL of purified water, separate the liquids, wash the lower organic phase with 30mL of 5% sodium bicarbonate aqueous solution and 30mL of deionized water in sequence, add sodium sulfate to dry, and concentrate to obtain a white solid with a yield of 98.2%. Mass spectrum: m+1=268.08.

Example 2 Preparation of L-phosphinothricin

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

1) 5.0 g of N-acetyl-O-methylsulfonyl-L-homoserine ethyl ester and 50 ml of diethyl methyl phosphite obtained in Example 1 were added to the reaction flask in sequence, and nitrogen was introduced 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) Add 4.5g of the above oil and 45ml of 6mol/L hydrochloric acid to the reaction bottle at one time, then heat to 120℃ and reflux for 8h. After the reaction is completed, distill and concentrate to dryness under reduced pressure, add ethanol, stir to precipitate solid, filter and dry, the yield is 93.3%; ee% value is 99.0%. The obtained L-phosphinothricin was subjected to nuclear magnetic resonance analysis, and its nuclear magnetic data (HNMR, D2O, 500MHz) were obtained: δppm 3.70～3.74 (1H, t, CH), 2.01～2.05 (2H, m, CH2), 1.50～1.60 (2H, m, CH2), 1.15～1.20 (3H, d, CH3).

Example 3 Preparation of N-acetyl-O-methylsulfonyl-L-homoserine methyl ester

The preparation method of N-acetyl-O-methylsulfonyl-L-homoserine methyl ester in this embodiment is as follows:

To a dry 100mL three-necked reaction flask, add 6.0g of N-acetyl-L-homoserine methyl ester, 100mL of dichloromethane, 3.5g of triethylamine, and 0.2g of DMAP in sequence, stir to dissolve, cool to 0-5°C in an ice-salt bath, add dropwise a solution of 4.0g of methanesulfonyl chloride and 40mL of dichloromethane, and complete the addition in about 3 hours. Naturally warm to room temperature, stir the reaction overnight, and TLC detects that the raw material has reacted completely. Cool to 0-5°C, add dropwise 30mL of purified water, separate the liquids, wash the lower organic phase with 5% sodium bicarbonate aqueous solution and deionized water in sequence, dry with sodium sulfate, and concentrate to obtain a white solid with a yield of 99.2%. Mass spectrum: m+1=254.08.

Example 4 Preparation of L-phosphinothricin

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

1) 5.0 g of N-acetyl-O-methylsulfonyl-L-homoserine methyl ester and 50 ml of diethyl methyl phosphite obtained in Example 3 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 94.7%.

2) 4.5 g of the above oil and 45 ml of 5 mol/L hydrochloric acid were added to the reaction flask in sequence, and then heated to 125°C for reflux reaction for 9 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 79.3% and the ee% value was 98.5%.

Example 5 Preparation of N-acetyl-O-methylsulfonyl-L-homoserine propyl ester

The preparation method of N-acetyl-O-methylsulfonyl-L-homoserine propyl ester in this embodiment is as follows:

To a dry 100mL three-necked reaction flask, add 6.0g of N-acetyl-L-homoserine propyl ester, 100mL of dichloromethane, 3.5g of triethylamine, and 0.2g of DMAP in sequence, stir to dissolve, cool to 0-5°C in an ice-salt bath, add dropwise a solution of 4.0g of methanesulfonyl chloride and 40mL of dichloromethane, and complete the addition in about 3 hours. Naturally warm to room temperature, stir the reaction overnight, and TLC detects that the raw material has reacted completely. Cool to 0-5°C, add dropwise 30mL of purified water, separate the liquids, wash the lower organic phase with 5% aqueous sodium bicarbonate solution and deionized water in sequence, dry with sodium sulfate, and concentrate to obtain a white solid with a yield of 95.9%. Mass spectrum: m+1=282.1.

Example 6 Preparation of L-phosphinothricin

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

1) Add N-acetyl-O-methylsulfonyl-L-homoserine obtained in Example 5 into the reaction flask in sequence. Ester 5.0g, methyl phosphite diethyl ester 50ml, nitrogen was introduced into the system for replacement twice and the nitrogen atmosphere was maintained, the temperature was raised to 90℃ for reaction for 6h, 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 91.3%.

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 128°C for reflux reaction for 7 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 76.1% and the ee% value was 94.3%.

Example 7 Preparation of N-ethoxycarbonyl-O-methylsulfonyl-L-homoserine ethyl ester

The preparation method of N-ethoxyformyl-O-methylsulfonyl-L-homoserine ethyl ester in this embodiment is as follows:

Into a dry 100mL three-necked reaction flask, 6.0g of N-ethoxycarbonyl-L-homoserine ethyl ester, 100mL of dichloromethane, 3.5g of triethylamine, and 0.2g of DMAP were added in sequence, and stirred to dissolve. The mixture was cooled to 0-5°C in an ice-salt bath, and a solution of 4.0g of methanesulfonyl chloride and 40mL of dichloromethane was added dropwise. The mixture was allowed to drip after about 3 hours, and the mixture was naturally warmed to room temperature. The reaction was stirred overnight. TLC detected that the raw material had reacted completely. The mixture was cooled to 0-5°C, and 30mL of purified water was added dropwise. The mixture was separated, and the lower organic phase was washed with 5% aqueous sodium bicarbonate solution and deionized water in sequence, dried with sodium sulfate, and concentrated to obtain a white solid with a yield of 92.1%. Mass spectrum: m+1=298.09.

Example 8 Preparation of L-phosphinothricin

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

1) 5.0 g of N-ethoxycarbonyl-O-methylsulfonyl-L-homoserine ethyl ester obtained in Example 7 and 50 ml of diethyl methyl phosphite were added to the reaction flask in sequence, and the atmosphere was replaced with nitrogen 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 98.7%.

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 85.3% and the ee% value was 99.2%.

Example 9 Preparation of N-methoxyformyl-O-methylsulfonyl-L-homoserine ethyl ester

The preparation method of N-methoxyformyl-O-methylsulfonyl-L-homoserine ethyl ester in this embodiment is as follows:

To a dry 100 mL three-necked reaction bottle, add 6.0 g of N-methoxyformyl-L-homoserine ethyl ester, 100 mL of dichloromethane, and 4.5 g of 2,6-lutidine in sequence, stir to dissolve, cool to 0-5 ° C in an ice-salt bath, and drop 4.0 g of methanesulfonyl chloride. The mixture was added with 40 mL of dichloromethane and the temperature was naturally raised to room temperature. The reaction was stirred overnight. TLC detected that the reaction of the raw materials was complete. The mixture was cooled to 0-5°C and 30 mL of purified water was added dropwise. The lower organic phase was washed with 5% aqueous sodium bicarbonate solution and deionized water in turn, dried with sodium sulfate, and concentrated to obtain a white solid. The yield was 96.2%. Mass spectrum: m+1=284.08.

Example 10 Preparation of L-phosphinothricin

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

1) To the reaction flask, 5.0 g of N-methoxyformyl-O-methylsulfonyl-L-homoserine ethyl ester and 50 ml of diethyl methyl phosphite obtained in Example 9 were added 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 99.1%.

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 88.2% and the ee% value was 97.4%.

Example 11 Preparation of N-propoxycarbonyl-O-methylsulfonyl-L-homoserine ethyl ester

The preparation method of N-propoxycarbonyl-O-methylsulfonyl-L-homoserine ethyl ester in this Example 11 is as follows:

Into a dry 100mL three-necked reaction flask, 6.0g of N-propoxycarbonyl-L-homoserine ethyl ester, 100mL of dichloromethane, 3.5g of triethylamine, and 0.2g of DMAP were added in sequence, and stirred to dissolve. The mixture was cooled to 0-5°C in an ice-salt bath, and a solution of 4.0g of methanesulfonyl chloride and 40mL of dichloromethane was added dropwise. The mixture was allowed to drip after about 3 hours, and the mixture was naturally warmed to room temperature. The reaction was stirred overnight. TLC detected that the raw material had reacted completely. The mixture was cooled to 0-5°C, and 30mL of purified water was added dropwise. The mixture was separated, and the lower organic phase was washed with 5% aqueous sodium bicarbonate solution and deionized water in sequence, dried with sodium sulfate, and concentrated to obtain a white solid with a yield of 93.2%. Mass spectrum: m+1=312.11.

Example 12 Preparation of L-phosphinothricin

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

1) Add 5.0 g of N-propoxycarbonyl-O-methylsulfonyl-L-homoserine ethyl ester and 50 ml of diethyl methylphosphite obtained in Example 11 to the reaction flask in sequence, introduce nitrogen into the system twice while maintaining the nitrogen atmosphere, and heat the mixture to 40 °C. The mixture was heated to 90°C and reacted for 6 hours. The reaction was completed when detected by TLC. The mixture was concentrated to dryness and separated by column chromatography to obtain a light yellow oil with a yield of 93.7%.

To the reaction bottle, add 4.5 g of the above oil and 45 ml of 6 mol/L hydrochloric acid at one time, then heat to 120°C and reflux for 8 h. After the reaction is completed, distill and concentrate to dryness under reduced pressure, add ethanol, stir to precipitate solid, filter and dry. The yield is 86.3% and the ee% value is 98.6%.

Example 13 Preparation of Compound N-ethoxycarbonyl-O-toluenesulfonyl-L-homoserine ethyl ester

The preparation method of N-ethoxyformyl-O-toluenesulfonyl-L-homoserine ethyl ester in this embodiment is as follows:

To a dry 100mL three-necked reaction flask, add 6.0g of N-ethoxycarbonyl-L-homoserine ethyl ester, 100mL of dichloromethane, 3.5g of triethylamine, and 0.2g of DMAP in sequence, stir to dissolve, cool to 0-5°C in an ice-salt bath, add dropwise a solution of 7.0g of p-toluenesulfonyl chloride and 40mL of dichloromethane, and complete the addition in about 3 hours. Naturally warm to room temperature, stir the reaction overnight, and TLC detection shows that the raw material has reacted completely. Cool to 0-5°C, add dropwise 30mL of purified water, separate the liquids, wash the lower organic phase with 5% sodium bicarbonate aqueous solution and deionized water in sequence, dry with sodium sulfate, and concentrate to obtain a white solid with a yield of 91.7%. Mass spectrum: m+1=374.12.

Example 14 Preparation of L-phosphinothricin

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

1) To the reaction flask, 5.0 g of N-ethoxycarbonyl-O-toluenesulfonyl-L-homoserine ethyl ester and 50 ml of diethyl methyl phosphite obtained in Example 13 were added 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 9 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 89.6%.

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 65.9% and the ee% value was 96.4%.

Example 15 Preparation of N-ethoxycarbonyl-O-p-nitrobenzenesulfonyl-L-homoserine ethyl ester

The preparation method of N-ethoxyformyl-O-p-nitrobenzenesulfonyl-L-homoserine ethyl ester in this embodiment is as follows:

To a dry 100 mL three-necked reaction flask, 6.0 g of N-ethoxycarbonyl-L-homoserine ethyl ester, 2-chloro- 100 mL of methane, 3.5 g of triethylamine, and 0.2 g of DMAP were stirred to dissolve, cooled to 0-5°C in an ice-salt bath, and a solution of 12.0 g of p-nitrobenzenesulfonyl chloride and 40 mL of dichloromethane was added dropwise. The mixture was added after about 3 hours of dropping. The mixture was naturally warmed to room temperature and stirred overnight. The reaction of the raw materials was complete by TLC detection. The mixture was cooled to 0-5°C, and 30 mL of purified water was added dropwise. The mixture was separated, and the lower organic phase was washed with 5% aqueous sodium bicarbonate solution and deionized water in turn, dried with sodium sulfate, and concentrated to obtain a white solid with a yield of 92.7%. Mass spectrum: m+1=405.09.

Example 16 Preparation of L-phosphinothricin

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

1) To the reaction flask, 5.0 g of N-ethoxycarbonyl-O-nitrobenzenesulfonyl-L-homoserine ethyl ester and 50 ml of diethyl methyl phosphite obtained in Example 15 were added 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 10 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 90.8%.

Add 4.5 g of the above oil and 45 ml of 6 mol/L hydrochloric acid into the reaction bottle at one time, then heat to 119°C and reflux for 8 h. After the reaction is completed, distill and concentrate to dryness under reduced pressure, add ethanol, stir to precipitate solid, filter and dry. The yield is 86.7% and the ee% value is 98.6%.

Example 17 Preparation of N-tert-butyloxycarbonyl-O-methylsulfonyl-L-homoserine ethyl ester

The preparation method of N-tert-butyloxycarbonyl-O-methylsulfonyl-L-homoserine ethyl ester in this embodiment is as follows:

Into a dry 100mL three-necked reaction flask, 6.0g of N-tert-butyloxycarbonyl-L-homoserine ethyl ester, 100mL of dichloromethane, 3.5g of triethylamine, and 0.2g of DMAP were added in sequence, and stirred to dissolve. The mixture was cooled to 0-5°C in an ice-salt bath, and a solution of 4.0g of methanesulfonyl chloride and 40mL of dichloromethane was added dropwise. The mixture was allowed to drip after about 3 hours. The mixture was naturally warmed to room temperature and stirred overnight. The reaction was completed by TLC detection. The mixture was cooled to 0-5°C, and 30mL of purified water was added dropwise. The mixture was separated and the lower organic phase was washed with 30mL of 5% sodium bicarbonate aqueous solution and 30mL of deionized water in sequence. Sodium sulfate was added for drying and the mixture was concentrated to obtain a white solid with a yield of 93.7%. Mass spectrum: m+1=326.12.

Example 18 Preparation of L-phosphinothricin

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

1) Add N-tert-butyloxycarbonyl-O-methylsulfonyl-L-hydroxysuccinyl obtained in Example 17 into the reaction flask in sequence. 5.0 g of amino acid ethyl ester and 50 ml of diethyl methyl phosphite were added, and nitrogen was introduced into the system for replacement twice while maintaining the nitrogen atmosphere. The temperature was raised to 90°C and the reaction was carried out for 6 hours. 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 93.6%.

2) 4.5 g of the above oil and 45 ml of a 2 mol/L hydrochloric acid solution in dioxane were added to the reaction flask in sequence, and then heated under reflux for 3 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 90.2% and the ee% value was 98.5%.

Example 19 Preparation of N-benzyloxycarbonyl-O-methylsulfonyl-L-homoserine methyl ester

The preparation method of N-benzyloxycarbonyl-O-methylsulfonyl-L-homoserine methyl ester in this embodiment is as follows:

Into a dry 100mL three-necked reaction flask, 6.0g of N-benzyloxycarbonyl-L-homoserine methyl ester, 100mL of dichloromethane, 3.5g of triethylamine, and 0.2g of DMAP were added in sequence, and stirred to dissolve. The mixture was cooled to 0-5°C in an ice-salt bath, and a solution of 4.0g of methanesulfonyl chloride and 40mL of dichloromethane was added dropwise. The mixture was added after about 3 hours of dripping, and the mixture was naturally warmed to room temperature. The reaction was stirred overnight. TLC detected that the raw material had reacted completely. The mixture was cooled to 0-5°C, and 30mL of purified water was added dropwise. The mixture was separated, and the lower organic phase was washed with 5% aqueous sodium bicarbonate solution and deionized water in sequence, dried with sodium sulfate, and concentrated to obtain a white solid with a yield of 97.7%. Mass spectrum: m+1=360.11.

Example 20 Preparation of L-phosphinothricin

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

1) To the reaction flask, 5.0 g of N-benzyloxycarbonyl-O-methylsulfonyl-L-homoserine methyl ester obtained in Example 19 and 50 ml of diethyl methyl phosphite were added in sequence. 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 91.5%.

2) Add 4.5 g of the above oil, 25 mL of acetic acid and 30 mL of 33% hydrobromic acid to the reaction flask in sequence, and then react at room temperature for 3 h, raise the temperature to 60 ° C and continue to react for 1 h. The reaction is completed after monitoring by TLC, and the mixture is concentrated to dryness by vacuum distillation. 95% ethanol is added, and the solid is precipitated by stirring, filtered and dried. The yield is 90.3%; the ee% value is 99.2%.

The above description 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 intended to limit the present invention. Any person skilled in the art will be able to understand the present invention. Personnel, without departing from the scope of the technical solution of the present invention, can use the above-disclosed methods and technical contents to make slight changes or modifications to equivalent embodiments of equivalent changes. However, any simple modifications, equivalent changes and modifications made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention are still within the scope of the technical solution of the present invention.

Claims (10)

Compound I, characterized in that the compound I is a homoserine derivative, and its chemical structure formula is as follows:
wherein _R1 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, substituted or unsubstituted aryl having 6 to 20 carbon atoms, or substituted or unsubstituted heteroaryl having 2 to 10 carbon atoms; _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; _R3 is hydrogen, substituted or unsubstituted alkyl having 1 to 6 carbon atoms, substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, or phenyl, p-tolyl, or p-nitrophenyl; X is a methylene group, a methine group, or a heteroatom such as O or NH; 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 N-acyl homoserine ester in a suitable solvent, adding sulfonyl chloride dropwise for esterification under the catalysis of a base, and then performing alkali washing, water washing, and drying steps, and concentrating to obtain compound I; the solvent includes dichloromethane, dichloroethane, chloroform, ethyl acetate, DMF, and DMSO, the base includes sodium carbonate, ammonium bicarbonate, sodium bicarbonate, potassium carbonate, triethylamine, and pyridine, and the sulfonyl chloride includes methanesulfonyl chloride, p-toluenesulfonyl chloride, and p-nitrobenzenesulfonyl chloride. 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, _R4 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.