A process for the preparation of L-chlorohomoserine ethyl (methyl) ester or a salt thereof

Abstract

The application belongs to the technical field of pesticide synthesis method, and relates to a preparation method of L-chlorohomoserine ethyl (methyl) ester or a salt thereof. Specifically, the application discloses a preparation method of a compound of formula I or a salt thereof, which takes a compound of formula A or a salt thereof as raw material, and reacts with a compound of formula B in an organic solvent in the presence of a solid acid catalyst to obtain L-chlorohomoserine ethyl (methyl) ester or a salt thereof. The method is simple in process, simple in post-treatment and purification process, the catalyst can be recycled by filtration, the reaction solvent containing no water can be directly recycled and reused, the product is high in purity and yield, the method is environment-friendly, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the technical field of pesticide synthesis methods, and relates to a method for synthesizing an L-glufosinate intermediate, particularly a method for preparing L-chlorohomoserine ethyl (methyl) ester or its salt. Background Technology

[0002] Glufosinate ammonium is a broad-spectrum organophosphorus contact herbicide developed by Hearst Corporation in the 1980s. With the widespread use of glyphosate, weeds have gradually developed resistance to it. As a new generation of non-selective herbicides, glufosinate ammonium is gaining increasing market favor, leading to more and more related synthesis and research.

[0003] Glufosinate includes L-glufosinate and racemic DL-glufosinate, with L-glufosinate exhibiting twice the herbicidal activity of racemic DL-glufosinate. Currently, commercially available glufosinate formulations are generally racemic DL-glufosinate. If glufosinate products could be used in the pure optical isomer of the L-configuration, the amount of glufosinate used could be reduced by approximately 50%. This would be of great significance for improving atom economy, reducing usage costs, and alleviating environmental pressure.

[0004] There are two main methods for preparing L-glufosinate: the first is to first synthesize racemic glufosinate, and then synthesize L-glufosinate through chemical resolution or biocatalysis; the second is to directly prepare L-glufosinate from chiral starting materials. The second method uses L-chlorohomoserine hydrochloride as the starting material, and through L-chlorohomoserine ethyl (methyl) ester hydrochloride as the intermediate, finally prepares L-glufosinate as the target product.

[0005] When preparing L-chlorohomoserine ethyl (methyl) ester hydrochloride from L-chlorohomoserine hydrochloride, esterification is usually employed. Concentrated sulfuric acid or p-toluenesulfonic acid is typically used as a catalyst, and the esterification reaction is carried out in excess ethanol (2-10 times) at elevated temperature. However, this method has drawbacks such as difficulty in recovering the acidic catalyst and difficulty in removing the water generated during the reaction.

[0006] After optimization, a strong acidic cation exchange resin is used instead of traditional liquid acids (concentrated sulfuric acid, p-toluenesulfonic acid, etc.) for esterification reaction. After the reaction is complete, the solid resin can be recovered by filtration, which can effectively solve the problem of difficult recovery of acidic catalysts. However, the water generated in the reaction is still difficult to remove.

[0007] Furthermore, using L-chlorohomoserine hydrochloride as raw material and a strongly acidic cation exchange resin as a catalyst, esterification is completed in ethanol (methanol) (2-10 times the concentration). After filtering the resin, the filtrate needs to be distilled under reduced pressure to recover the solvent. However, the solvent used in the esterification reaction is anhydrous ethanol (methanol), while the solvent recovered after the reaction is ethanol (methanol) with a water content of 2%-5%. It needs to be dehydrated before further use, resulting in numerous post-processing steps and high costs for industrial production. Summary of the Invention

[0008] The problem the invention aims to solve

[0009] To address the existing problems, this disclosure aims to provide a method for preparing L-chlorohomoserine ethyl (methyl) ester or its salts. This method is simple in process, with straightforward post-processing and purification. The catalyst can be recovered by filtration, the reaction solvent is anhydrous and can be directly recycled, and the product has high purity and yield. It is environmentally friendly and suitable for industrial production.

[0010] Solution for solving the problem

[0011] [1] A method for preparing a compound of formula I or a salt thereof, comprising:

[0012] Using compound A or its salt as a raw material, in the presence of a solid acid catalyst, it reacts with compound B in an organic solvent to obtain compound I or its salt.

[0013]

[0014] in,

[0015] R is a C1-C4 alkyl group.

[0016] [2] The preparation method according to [1] is characterized in that,

[0017] The salt is a hydrochloride or a sulfate, preferably a hydrochloride.

[0018] [3] The preparation method according to [1] or [2] is characterized in that,

[0019] R is methyl or ethyl.

[0020] [4] The preparation method according to any one of [1] to [3] is characterized in that,

[0021] The molar ratio of the compound of formula A or its salt to the compound of formula B is 1:1 to 1:5, preferably 1:1 to 1:3, and more preferably 1:2.

[0022] [5] The preparation method according to any one of [1] to [4] is characterized in that,

[0023] The solid acid catalyst is an acidic ion exchange resin, HND260 solid acid, or HND580 solid acid, preferably a strong acidic ion exchange resin, HND260 solid acid, or HND580 solid acid, and more preferably a 732 type strong acidic ion exchange resin, a T-62MP type solid acid catalyst resin, an amberlyst15 type ion exchange resin, HND260 solid acid, or HND580 solid acid.

[0024] [6] The preparation method according to any one of [1] to [5] is characterized in that,

[0025] The weight ratio of the compound of formula A or its salt to the solid acid catalyst is 1:0.05 to 1:0.5, preferably 1:0.1 to 1:0.3, and more preferably 1:0.2.

[0026] [7] The preparation method according to any one of [1] to [6] is characterized in that,

[0027] The organic solvent is a straight-chain or branched C1-C4 alcohol;

[0028] Preferably, the organic solvent is methanol or ethanol;

[0029] More preferably, when R is methyl, the organic solvent is methanol; when R is ethyl, the organic solvent is ethanol.

[0030] [8] The preparation method according to any one of [1] to [7] is characterized in that,

[0031] The weight ratio of the compound of formula A or its salt to the organic solvent is 1:2 to 1:10, preferably 1:3 to 1:6, and more preferably 1:5.

[0032] [9] The preparation method according to any one of [1] to [8] is characterized in that,

[0033] The reaction temperature is controlled between 40°C and 80°C, preferably between 50°C and 80°C, and more preferably between 60°C and 80°C.

[0034]

[10] The preparation method according to any one of [1] to [9] is characterized in that,

[0035] The reaction is carried out under negative pressure conditions; preferably, the negative pressure conditions are controlled between 0 kPa and -50 kPa, more preferably between 0 kPa and -20 kPa, and even more preferably between -10 kPa and -20 kPa.

[0036] The effects of the invention

[0037] This invention uses L-chlorohomoserine hydrochloride as a raw material and performs transesterification with carbonate under the catalysis of solid acid, which can obtain the target product with relatively ideal yield and purity.

[0038] The preparation method of the present invention avoids the generation of water in conventional esterification reactions and the subsequent solvent dehydration step in the workshop, significantly reducing workshop operation steps and making it more conducive to industrial production.

[0039] The byproduct anhydrous ethanol can be recovered and sold after the invention, and the byproduct carbon dioxide gas can also be sold after further treatment and purification, resulting in high atom utilization. Detailed Implementation

[0040] Example 1

[0041] 17.4 g (0.1 mol) of chlorohomoserine hydrochloride was weighed into a reactor, and 87 g of methanol, 9.0 g (0.1 mol) of dimethyl carbonate, and 3.5 g of 732 type strong acid ion exchange resin were added. The mixture was stirred and heated to 60-65 °C, and kept at a gentle boil for 6 h. After cooling to 20-30 °C, the mixture was filtered. The filtrate was distilled under reduced pressure at -0.90 kPa at 20-30 °C to remove about 80% of the solvent. The reaction solution became viscous. 52.4 g of isohexane was added at 20-30 °C, and the mixture was stirred and slurried at 20-30 °C for 0.5 h. After filtration and drying, 13.7 g of grayish-white solid was obtained, with an HPLC absolute content of 96% and an absolute yield of 70%.

[0042] Example 2

[0043] 17.4 g (0.1 mol) of chlorohomoserine hydrochloride was weighed into a reactor, and 87 g of methanol, 18.0 g (0.2 mol) of dimethyl carbonate, and 3.5 g of 732 type strong acid ion exchange resin were added. The mixture was stirred and heated to 60-65 °C, and kept at a gentle boil for 6 h. After cooling to 20-30 °C, the mixture was filtered. The filtrate was distilled under reduced pressure at -0.90 kPa at 20-30 °C to remove about 80% of the solvent. The reaction solution became viscous. 52.4 g of isohexane was added at 20-30 °C, and the mixture was stirred and slurried at 20-30 °C for 0.5 h. After filtration and drying, 16.5 g of grayish-white solid was obtained, with an HPLC absolute purity of 97% and an absolute yield of 85%.

[0044] Example 3

[0045] Weigh 17.4 g (0.1 mol) of chlorohomoserine hydrochloride into a reactor, add 87 g of methanol, 18.0 g (0.2 mol) of dimethyl carbonate, and 3.5 g of type 732 strong acid ion exchange resin. Stir and heat to 55-60℃, controlling the vacuum degree to -10 to -20 kPa. Maintain the temperature under slight boiling (lower vacuum degree lowers the boiling point of methanol; slight boiling is to prevent excessive boiling and solvent loss; the system uses slight negative pressure to prevent the reaction from producing...). (To remove carbon dioxide, promote the forward reaction, and increase the reaction yield) Stir the reaction for 6 hours, cool to 20-30℃, and filter. After removing about 80% of the solvent by vacuum distillation at -0.90 kPa at 20-30℃, the reaction solution becomes viscous. Add 52.4 g of isohexane at 20-30℃, stir and slurry at 20-30℃ for 0.5 hours, filter, and dry to obtain 17.4 g of grayish-white solid with an HPLC absolute purity of 97% and an absolute yield of 90%.

[0046] Example 4

[0047] 17.4 g (0.1 mol) of chlorohomoserine hydrochloride was weighed into a reactor, and 87 g of ethanol, 23.6 g (0.2 mol) of diethyl carbonate, and 3.5 g of 732 type strong acid ion exchange resin were added. The mixture was stirred and heated to 75-80 °C, and kept at a gentle boil for 6 h. After cooling to 20-30 °C, the mixture was filtered. The filtrate was distilled under reduced pressure at -0.90 kPa at 20-30 °C to remove about 80% of the solvent. The reaction solution became viscous. 52.4 g of isohexane was added at 20-30 °C, and the mixture was stirred and slurried at 20-30 °C for 0.5 h. After filtration and drying, 16.1 g of grayish-white solid was obtained, with an HPLC absolute purity of 97% and an absolute yield of 77%.

[0048] Example 5

[0049] 17.4 g (0.1 mol) of chlorohomoserine hydrochloride was weighed into a reactor, and 87 g of ethanol, 35.4 g (0.3 mol) of diethyl carbonate, and 3.5 g of 732 type strong acid ion exchange resin were added. The mixture was stirred and heated to 75-80 °C, and kept at a gentle boil for 6 h. After cooling to 20-30 °C, the mixture was filtered. The filtrate was distilled under reduced pressure at -0.90 kPa at 20-30 °C to remove about 80% of the solvent. The reaction solution became viscous. 52.4 g of isohexane was added at 20-30 °C, and the mixture was stirred and slurried at 20-30 °C for 0.5 h. After filtration and drying, 15.4 g of grayish-white solid was obtained, with an HPLC absolute purity of 96% and an absolute yield of 73%.

[0050] Example 6

[0051] 17.4 g (0.1 mol) of chlorohomoserine hydrochloride was weighed into a reactor, and 87 g of ethanol, 23.6 g (0.2 mol) of diethyl carbonate, and 3.5 g of 732 type strong acid ion exchange resin were added. The mixture was stirred and heated to 70-75 °C, and the reaction vacuum was controlled at -10 to -20 kPa. The mixture was stirred and kept at a gentle boil for 6 h. After cooling to 20-30 °C, the mixture was filtered. The filtrate was distilled under reduced pressure at -0.90 kPa at 20-30 °C to remove about 80% of the solvent. The reaction solution became viscous. 52.4 g of isohexane was added at 20-30 °C, and the mixture was stirred and slurried at 20-30 °C for 0.5 h. After filtration and drying, 19.0 g of grayish-white solid was obtained. The absolute purity of the solid was 98% and the absolute yield was 88%.

[0052] Example 7

[0053] 17.4 g (0.1 mol) of chlorohomoserine hydrochloride was weighed into a reactor, and 87 g of ethanol, 23.6 g (0.2 mol) of diethyl carbonate, and 3.5 g of T-62MP solid acid catalyst were added. The mixture was stirred and heated to 70-75 °C, and the reaction vacuum was controlled at -10 to -20 kPa. The mixture was stirred and kept at a gentle boil for 6 h. After cooling to 20-30 °C, the mixture was filtered. The filtrate was distilled under reduced pressure at -0.90 kPa at 20-30 °C to remove about 80% of the solvent. The reaction solution became viscous. 52.4 g of isohexane was added at 20-30 °C, and the mixture was stirred and slurried at 20-30 °C for 0.5 h. After filtration and drying, 18.7 g of grayish-white solid was obtained. The absolute purity of the solid was 97% and the absolute yield was 90%.

[0054] Example 8

[0055] 17.4 g (0.1 mol) of chlorohomoserine hydrochloride was weighed into a reactor, and 87 g of ethanol, 23.6 g (0.2 mol) of diethyl carbonate, and 3.5 g of Amberlyst 15 ion exchange resin were added. The mixture was stirred and heated to 70-75 °C, and the reaction vacuum was controlled at -10 to -20 kPa. The mixture was stirred and kept at a gentle boil for 6 h. After cooling to 20-30 °C, the mixture was filtered. The filtrate was distilled under reduced pressure at -0.90 kPa at 20-30 °C to remove about 80% of the solvent. The reaction solution became viscous. 52.4 g of isohexane was added at 20-30 °C, and the mixture was stirred and slurried at 20-30 °C for 0.5 h. After filtration and drying, 18.3 g of grayish-white solid was obtained. The absolute purity of the solid was 97% and the absolute yield was 88%.

[0056] The reactants, reaction conditions, contents, and yields in the above examples are summarized and listed in the table below:

[0057]

[0058]

[0059] This invention uses L-chlorohomoserine hydrochloride as a raw material and carries out a transesterification reaction with carbonate in a suitable alcohol solvent under solid acid catalysis. By adjusting the reaction temperature and vacuum, suitable reaction conditions were discovered for the preparation of L-chlorohomoserine methyl (ethyl) ester hydrochloride. This method achieves high yield, produces the corresponding methyl (ethyl) alcohol as a byproduct, does not generate water, and allows for solvent recovery and reuse, making it suitable for industrial production.

Claims

1. A method for preparing a compound of formula I or a salt thereof, comprising: Using compound A or its salt as a raw material, in the presence of a solid acid catalyst, it reacts with compound B in an organic solvent to obtain compound I or its salt. ； in, R is a C1-C4 alkyl group; The solid acid catalyst is a strong acid ion exchange resin, HND260 solid acid, or HND580 solid acid. The reaction is carried out under negative pressure conditions; the negative pressure conditions are controlled between -10 kPa and -20 kPa.

2. The preparation method according to claim 1, characterized in that, The salt is a hydrochloride or a sulfate.

3. The preparation method according to claim 1 or 2, characterized in that, The salt is a hydrochloride salt.

4. The preparation method according to claim 1 or 2, characterized in that, R is methyl or ethyl.

5. The preparation method according to claim 1 or 2, characterized in that, The molar ratio of compound A or its salt to compound B is 1:1 to 1:

5.

6. The preparation method according to claim 1 or 2, characterized in that, The molar ratio of compound A or its salt to compound B is 1:1 to 1:

3.

7. The preparation method according to claim 1 or 2, characterized in that, The molar ratio of compound A or its salt to compound B is 1:

2.

8. The preparation method according to claim 1 or 2, characterized in that, The solid acid catalyst is a 732 type strong acid ion exchange resin, a T-62MP type solid acid catalyst resin, an amberlyst15 type ion exchange resin, an HND260 solid acid, or an HND580 solid acid.

9. The preparation method according to claim 1 or 2, characterized in that, The weight ratio of the compound of formula A or its salt to the solid acid catalyst is 1: 0.05 to 1:0.

5.

10. The preparation method according to claim 1 or 2, characterized in that, The weight ratio of the compound of formula A or its salt to the solid acid catalyst is from 1:0.1 to 1:0.

3.

11. The preparation method according to claim 1 or 2, characterized in that, The weight ratio of the compound of formula A or its salt to the solid acid catalyst is 1:0.

2.

12. The preparation method according to claim 1 or 2, characterized in that, The organic solvent is a straight-chain or branched C1-C4 alcohol.

13. The preparation method according to claim 1 or 2, characterized in that, The organic solvent is methanol or ethanol.

14. The preparation method according to claim 1 or 2, characterized in that, When R is methyl, the organic solvent is methanol; when R is ethyl, the organic solvent is ethanol.

15. The preparation method according to claim 1 or 2, characterized in that, The weight ratio of the compound of formula A or its salt to the organic solvent is 1:2 to 1:

10.

16. The preparation method according to claim 1 or 2, characterized in that, The weight ratio of the compound of formula A or its salt to the organic solvent is 1:3 to 1:

6.

17. The preparation method according to claim 1 or 2, characterized in that, The weight ratio of the compound of formula A or its salt to the organic solvent is 1:

5.

18. The preparation method according to claim 1 or 2, characterized in that, The reaction temperature is controlled between 40°C and 80°C.

19. The preparation method according to claim 1 or 2, characterized in that, The reaction temperature is controlled between 50°C and 80°C.

20. The preparation method according to claim 1 or 2, characterized in that, The reaction temperature is controlled between 60°C and 80°C.

Images