CN118084697A - Preparation method of (S) -chlorohomoserine alkyl ester - Google Patents

Abstract

The invention discloses a preparation method of (S) -chloro-homoserine alkyl ester, which takes L-homoserine as a substrate and prepares the (S) -chloro-homoserine alkyl ester by reaction in a chloro reagent, a catalyst and an organic solvent. Compared with the traditional preparation of the compounds, the preparation method has the advantages of high yield, simple operation, economical steps, industrialized production and the like by optimizing the reaction conditions.

Description

Preparation method of (S) -chlorohomoserine alkyl ester

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of (S) -chlorohomoserine alkyl ester.

Background

Glufosinate is a high-efficiency low-toxicity biocidal herbicide, is easy to degrade and belongs to a biological friendly phosphorus-containing herbicide. The glufosinate has long lasting period and broad weed killing spectrum, does not damage the root system of crops in the process, has good safety and quick acting property, and has better preventing and killing effect on some resistant weeds. Glufosinate is a chiral compound with two optical isomers, L-glufosinate and D-glufosinate. L-glufosinate is an effective body which truly exerts herbicidal activity, and D-glufosinate is an ineffective body. L-glufosinate, also known as smart glufosinate, is more rapid, thorough and safer than ordinary glufosinate. Compared with chemical synthesis herbicides such as glyphosate, diquat and the like, the smart glufosinate is more environment-friendly, safer to use and has activity which is 2 times that of common glufosinate and 4 times that of glyphosate. The glufosinate-ammonium has the advantages that the dosage is only 1/2 of that of the traditional glufosinate-ammonium, the environmental pollution is small, and the application cost is low.

The current method for producing the glufosinate-ammonium mainly depends on a biological method, but is limited in that the mass production cannot be realized, and the market demand cannot be met. The chemical synthesis method is an efficient production method, can stabilize the industrialization of bulk chemicals and provides good supply requirements. Currently, there are reports on chemical synthesis methods of an important intermediate (S) -chlorohomoserine ethyl ester of glufosinate and salts thereof.

In 2021, published patent CN109369432B of Yongnong bioscience Co., ltd reports that (S) -2-aminobutyric acid is subjected to ring opening alcoholysis under the catalysis of organic or inorganic sulfonic acid to obtain corresponding S-homoserine ester, and then the corresponding S-homoserine ester is subjected to chlorination to obtain a target product.

In the same year, published patent CN110845347B and WO2021098712A1 of Lier chemical Co., ltd report that chlorohomoserine alkyl ester is obtained by chlorine ring opening of thionyl chloride by taking alcohol as a reaction reagent and a solvent and taking homoserine lactone as a starting material.

In 2022, published patent CN115093339A of Yongnong bioscience Co., ltd reports that the synthesized (S) -chlorohomoserine hydrochloride is catalyzed and esterified by taking protonic acid as a catalyst after the L-homoserine lactone hydrochloride is subjected to ring-opening chlorination by hydrochloric acid, and the (S) -chlorohomoserine lactone product is obtained after post-treatment.

The starting material of the chemical synthesis method is L-homoserine lactone and hydrochloride thereof, and the cost of the starting material is high. Or L-methionine is used as an initial raw material for preparation, which relates to an expensive phase transfer catalyst, and byproducts contain sulfur elements, so that the cost is high and the environmental protection and economy are poor. The (S) -chlorohomoserine alkyl ester is synthesized by taking L-homoserine as a raw material, an intermediate L-homoserine lactone and hydrochloride thereof need to be separated and purified, and the step economy is poor. Therefore, development of a synthetic method which is simple in operation, lower in cost, lower in environmental protection pressure, higher in yield and capable of being industrialized is needed.

Disclosure of Invention

In view of the shortcomings of the prior art, the invention provides a preparation method of (S) -chlorohomoserine alkyl ester, which aims at improving the condition parameters (reaction starting materials, catalysts, reaction material proportions, temperature and time) and operation steps in the reaction steps through the whole flow of a synthetic route. Compared with the reported method for synthesizing the chlorohomoserine alkyl ester, the method has the advantages of high yield, simple operation, economical steps, industrialized production and the like.

In order to achieve the above object, according to one aspect of the present invention, there is provided a process for preparing (S) -chlorohomoserine alkyl esters, comprising the steps of:

L-homoserine, a chloro reagent and a catalyst are stirred in an organic solvent at a certain temperature for reaction for 1-10 hours, and the (S) -chloro homoserine alkyl ester is obtained by separation.

Preferably, the chlorinating agent in the step is one or more of thionyl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, chlorine gas, trichloroisocyanuric acid, N-chlorosuccinimide, methylsulfonyl chloride, or p-toluenesulfonyl chloride.

Preferably, the catalyst is one or more of iodine simple substance, sodium iodide, potassium bromide, zinc chloride, triethylamine, sodium ethoxide and sodium methoxide.

Preferably, the organic solvent is one or more of toluene, ethanol, methanol, chlorobenzene, acetone, dichloromethane and acetonitrile.

Preferably, the certain temperature is 25-100 ℃, and the reaction time is 1-10 hours.

Preferably, the molar ratio of L-homoserine to chloro reagent is 1:1-1:5.

Preferably, the molar ratio of L-homoserine to catalyst is 1:0.01-1:0.5.

In general, compared with the prior art, the technical scheme of the invention has the following advantages:

Compared with the existing route for synthesizing the intermediate (S) -halogenated homoserine alkyl ester of the spermicofos, the invention provides a novel method for preparing the important intermediate (S) -halogenated homoserine alkyl ester of the spermicofos. The conventional preparation of (S) -halogenated homoserine alkyl esters employs a two-step process, in which homoserine is condensed to homoserine lactone hydrochloride in the first step and ring-opened chloroesterified in the second step. The invention adopts a one-step method to directly synthesize the (S) -halogenated homoserine alkyl ester from the L-homoserine, has simple operation and proper temperature, and has good economy of reaction steps. Compared with the traditional starting material of homoserine lactone (and salts thereof), the novel method has higher economic value because the starting material of the reaction is L-homoserine. The reaction in the alcohol system is not only a reactant, but also a reaction solvent, and has the characteristic of green. The organic chlorinated reagent has high yield, and part of byproducts of the organic chlorinated reagent can be recycled through chlorination, so that the raw materials are saved, the byproducts are reduced, the safety and the no peculiar smell are realized, and the three-waste treatment capacity is reduced. The yield can be up to 60% or more, more preferably up to 70% or more, still more preferably up to 80% or more, still more preferably up to 90% or more, still more preferably up to 93% or more, by optimizing the conditions (catalyst, reaction mass ratio, temperature and time), and the reaction has good selectivity. The main reactions involved are as follows:

Wherein in the step (1), the structural formula 1a represents L-homoserine, and the structural formula 2a represents (S) -chlorohomoserine alkyl ester.

In conclusion, the invention synthesizes and prepares the important intermediate (S) -halogenated homoserine alkyl ester of the glufosinate-ammonium by taking L-homoserine as a starting material, and compared with the prior art, the invention has the characteristics of economical reaction steps, mild conditions, simple operation and low raw material cost. The preparation method of the invention takes (S) -halogenated homoserine alkyl ester as raw material, and prepares the (S) -halogenated homoserine alkyl ester after the chlorination esterification of chloridizing reagent, alcohol and Lewis acid catalyst.

Detailed Description

The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention. In addition, the technical features of the embodiments of the present invention described below may be combined with each other as long as they do not collide with each other.

The preparation method of the (S) -chlorohomoserine alkyl ester is mainly realized by the following steps:

L-homoserine, a catalyst and an organic solvent were added to a reaction flask equipped with a magneton, and a chloro reagent was added at a certain temperature and stirred for several hours. After completion, thin layer chromatography or high performance liquid chromatography detects that the reaction raw materials are consumed, and the reaction reaches the end point. The solvent was distilled off under reduced pressure to give a white solid. After the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, an organic solvent was added to extract the fractions. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a pale yellow oil.

The above scheme will be described in detail below with different reaction conditions.

The following are examples:

example 1

L-homoserine (10.00 g,83.95 mmol), sodium iodide (0.63 g,4.20 mmol) and ethanol (50 mL) were successively added to a three-necked flask equipped with a magnetic stirrer, heated to 80℃and thionyl chloride (19.98 g,167.90mmol,12.18 mL) was added thereto with maintaining the temperature followed by reflux reaction for 8 hours. After the consumption of the reaction raw materials for high performance liquid phase detection, the reaction liquid is cooled to room temperature, and the solvent ethanol is removed by reduced pressure distillation to obtain white solid. After the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, methylene chloride (50 mL) was added to extract the fractions 3 times. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a pale yellow oil (9.59 g) in 69% yield. Thin layer chromatography Rf value 0.4 (petroleum ether: ethyl acetate=1:1, ninhydrin developer color); the high resolution mass spectrum was detected as HRMS (positive):m/z=166.0627 [ M+1] ⁺.

Example 2

L-homoserine (10.00 g,83.95 mmol), zinc chloride (0.57 g,4.20 mmol), ethanol (10 mL) and toluene (40 mL) were successively added to a three-necked flask equipped with a magnetic stirrer, heated to 100℃and thionyl chloride (19.98 g,167.90mmol,12.18 mL) was added at this temperature, followed by reaction for 10 hours. After the consumption of the reaction raw materials for high performance liquid phase detection, the reaction liquid is cooled to room temperature, and the solvent ethanol and toluene are removed by reduced pressure distillation to obtain white solid. After the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, methylene chloride (50 mL) was added to extract the fractions 3 times. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a pale yellow oil (10.15 g) in 73% yield. Thin layer chromatography Rf value 0.4 (petroleum ether: ethyl acetate=1:1, ninhydrin developer color); the high resolution mass spectrum was detected as HRMS (positive):m/z=166.0627 [ M+1] ⁺.

Example 3

L-homoserine (10.00 g,83.95 mmol), elemental iodine (0.53 g,2.10 mmol), sodium ethoxide (0.14 g,2.10 mmol) and methylene chloride (50 mL) were successively added to a three-necked flask equipped with a magnetic stirrer, heated to 50℃and phosphorus oxychloride (25.74 g,167.90mmol,15.65 mL) was added at this temperature, followed by reflux reaction for 5 hours. After the high performance liquid detection reaction raw materials are consumed, the reaction liquid is cooled to room temperature. After the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, methylene chloride (50 mL) was added to extract the fractions 3 times. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a pale yellow oil (10.41 g) in 75% yield. Thin layer chromatography Rf value 0.4 (petroleum ether: ethyl acetate=1:1, ninhydrin developer color); the high resolution mass spectrum was detected as HRMS (positive):m/z=166.0627 [ M+1] ⁺.

Example 4

L-homoserine (10.00 g,83.95 mmol), potassium bromide (0.50 g,4.20 mmol), ethanol (10 mL) and acetone (40 mL) were successively added to a three-necked flask equipped with a magnetic stirrer, the temperature was raised to 60℃and phosphorus oxychloride (25.74 g,167.90mmol,15.65 mL) was added at this temperature, followed by reflux reaction for 8 hours. After the consumption of the reaction raw materials for high performance liquid phase detection, the reaction liquid is cooled to room temperature, and the solvent is removed by reduced pressure distillation to obtain white solid. After the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, acetone (50 mL) was added to extract the fractions 3 times. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a pale yellow oil (10.56 g) in 76% yield. Thin layer chromatography Rf value 0.4 (petroleum ether: ethyl acetate=1:1, ninhydrin developer color); the high resolution mass spectrum was detected as HRMS (positive):m/z=166.0627 [ M+1] ⁺.

Example 5

L-homoserine (10.00 g,83.95 mmol), zinc chloride (0.57 g,4.20 mmol) and methanol (50 mL) were successively added to a three-necked flask equipped with a magnetic stirrer, heated to 70℃and phosphorus trichloride (11.53 g,83.95mmol,7.31 mL) and oxalyl chloride (10.66 g,83.95mmol,7.10 mL) were added thereto while maintaining the temperature, followed by reflux reaction for 9 hours. After the consumption of the reaction raw materials for high performance liquid phase detection, the reaction liquid is cooled to room temperature, and the solvent is removed by reduced pressure distillation to obtain white solid. After the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, ethyl acetate (50 mL) was added to extract the separated liquid 3 times. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a pale yellow oil (9.82 g) in 77% yield. Thin layer chromatography Rf value 0.4 (petroleum ether: ethyl acetate=1:1, ninhydrin developer color); high resolution mass spectrometry detection was HRMS (positive):m/z=152.0471 [ m+1] ⁺.

Example 6

L-homoserine (10.00 g,83.95 mmol), zinc chloride (0.29 g,2.10 mmol), sodium methoxide (0.57 g,2.10 mmol) and chlorobenzene (50 mL) were successively added to a three-necked flask equipped with a magnetic stirrer, heated to 100℃and N-chlorosuccinimide (22.42 g,167.90 mmol) was added while maintaining the temperature, followed by reaction for 3 hours. After the high performance liquid detection reaction raw materials are consumed, the reaction liquid is cooled to room temperature. Filtering, and performing chlorination on the solid by sodium hypochlorite to generate N-chlorosuccinimide; the solvent was distilled off from the filtrate under reduced pressure to give a white solid. After the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, methylene chloride (50 mL) was added to extract the fractions 3 times. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a colorless oil (11.21 g) in 88% yield. Thin layer chromatography Rf value 0.4 (petroleum ether: ethyl acetate=1:1, ninhydrin developer color); high resolution mass spectrometry detection was HRMS (positive):m/z=152.0471 [ m+1] ⁺.

Example 7

L-homoserine (10.00 g,83.95 mmol), sodium iodide (0.63 g,4.20 mmol) and ethanol (50 mL) were successively added to a three-necked flask equipped with a magnetic stirrer, the temperature was raised to 80℃and trichloroisocyanuric acid (19.51 g,83.95 mmol) was added thereto while maintaining the temperature, followed by reflux reaction for 8 hours. After the high performance liquid detection reaction raw materials are consumed, the reaction liquid is cooled to room temperature. Filtering, and treating the solid with sodium hydroxide and chlorine to regenerate trichloroisocyanuric acid; the solvent was distilled off from the filtrate under reduced pressure to give a white solid. After the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, methylene chloride (50 mL) was added to extract the fractions 3 times. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a colorless oil (12.65 g) in 91% yield. Thin layer chromatography Rf value 0.4 (petroleum ether: ethyl acetate=1:1, ninhydrin developer color); the high resolution mass spectrum was detected as HRMS (positive):m/z=166.0627 [ M+1] ⁺.

Example 8

L-homoserine (10.00 g,83.95 mmol), triethylamine (0.25 g,2.5 mmol), potassium bromide (0.30 g,2.5 mmol), ethanol (10 mL) and acetonitrile (40 mL) were successively added to a three-necked flask equipped with a magnetic stirrer, heated to 90℃and p-toluenesulfonyl chloride (32.01 g,167.90 mmol) was added at this temperature, followed by reflux reaction for 8 hours. After the consumption of the reaction raw materials for high performance liquid phase detection, the reaction liquid is cooled to room temperature, and the solvent is removed by reduced pressure distillation to obtain white solid. After the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, acetone (50 mL) was added to extract the fractions 3 times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatographed to give a colorless oil (12.53 g) in 90% yield. Thin layer chromatography Rf value 0.4 (petroleum ether: ethyl acetate=1:1, ninhydrin developer color); the high resolution mass spectrum was detected as HRMS (positive):m/z=166.0627 [ M+1] ⁺.

Example 9

L-homoserine (10.00 g,83.95 mmol), zinc chloride (0.55 g,4.00 mmol), elemental iodine (0.25 g,1.00 mmol) and methanol (50 mL) were successively added to a three-necked flask equipped with a magnetic stirrer, heated to 70℃and then reacted under reflux while maintaining the temperature at which methanesulfonyl chloride (19.23 g,167.90mmol,13.00 mL) was added. After the consumption of the reaction raw materials for high performance liquid phase detection, the reaction liquid is cooled to room temperature, and the solvent is removed by reduced pressure distillation to obtain white solid. After the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, methyl tert-butyl ether (50 mL) was added to extract the fractions 3 times. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a pale yellow oil (11.84 g) in 93% yield. Thin layer chromatography Rf value 0.4 (petroleum ether: ethyl acetate=1:1, ninhydrin developer color); high resolution mass spectrometry detection was HRMS (positive):m/z=152.0471 [ m+1] ⁺.

In addition to the specific types of chlorinating agents, catalysts, and organic solvent materials employed in the above examples, other chlorinating agents, catalysts, and organic solvents may be employed.

Unless otherwise specified, the various reaction starting materials (e.g., L-homoserine) in the present invention are commercially available, and the purity is preferably of analytical grade.

It will be readily appreciated by those skilled in the art that the foregoing description is merely a preferred embodiment of the invention and is not intended to limit the invention, but any modifications, equivalents, improvements or alternatives falling within the spirit and principles of the invention are intended to be included within the scope of the invention.

Claims (8)

1. A preparation method of (S) -chlorohomoserine alkyl ester is characterized by comprising the following specific steps: l-homoserine, a chloro reagent and a catalyst are stirred in an organic solvent at a certain temperature for reaction for 1-10 hours, and the (S) -chloro homoserine alkyl ester is obtained by separation.

2. The method of claim 1, wherein the chlorinating agent is one or more of thionyl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, chlorine gas, trichloroisocyanuric acid, N-chlorosuccinimide, methylsulfonyl chloride, or p-toluenesulfonyl chloride.

3. The preparation method of claim 1, wherein the catalyst is one or more of elemental iodine, sodium iodide, potassium bromide, zinc chloride, triethylamine, sodium ethoxide and sodium methoxide.

4. The preparation method according to claim 1, wherein the molar ratio of homoserine, chloro reagent and catalyst is 1:1-5:0.01-0.5.

5. The method of claim 1, wherein the organic solvent is one or more of toluene, ethanol, methanol, chlorobenzene, acetone, dichloromethane, acetonitrile.

6. The method according to claim 1, wherein the certain temperature is 25 to 100 ℃ and the reaction time is 1 to 10 hours.

7. The process according to claim 1, wherein the obtained product is cooled to room temperature, distilled under reduced pressure, and the concentrate is subjected to pH adjustment to neutrality, and the separated liquid is extracted with an organic solvent; the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (S) -chlorohomoserine alkyl ester.

8. The method of claim 7, wherein the organic solvent is one of dichloromethane, ethyl acetate, methyl t-butyl ether and acetone.