A process for the preparation of 2-methyl-4-chloro-2-butenoic acid ethyl ester

Abstract

The application discloses a preparation method of 2-methyl-4-chloro-2-butenoic acid ethyl ester, which comprises the following steps: taking an ethoxycarbonyl ethyl triphenyl phosphonium salt aqueous solution and a monochloroacetaldehyde aqueous solution as raw materials, and performing a Wittig reaction under the action of an alkali to obtain 2-methyl-4-chloro-2-butenoic acid ethyl ester, wherein the content of alkali metal ions in the 2-methyl-4-chloro-2-butenoic acid ethyl ester is 1-3 ppm. The method has the advantages of high reaction yield, simple and mild process conditions, moderate residual amount of metal ions in the product, good storage stability of the product and the like.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing ethyl 2-methyl-4-chloro-2-butenoate. Background Technology

[0002] β-Apo-8'-carotene ethyl ester, also known as apoester, is a type of carotenoid compound widely used in food and feed coloring and is a highly efficient carotenoid additive. 2-Methyl-4-chloro-2-butenoate ethyl ester is the main raw material for the synthesis of apoester, specifically the key intermediate 4-(diethoxyphosphoryl)-2-methyl-2-butenoate ethyl ester, and plays a crucial role in the synthesis of apoester.

[0003] Currently, some studies have been conducted on the synthesis of ethyl 2-methyl-4-chloro-2-butenoate.

[0004] The reporting route for patent US4937308 is as follows:

[0005]

[0006] This route requires the use of chlorine halogenation, which is highly dangerous and can corrode equipment. Furthermore, the post-processing is complex and the reaction yield is low.

[0007] Patent CN115304482A discloses a coupling reaction method for preparing ethyl 2-methyl-4-chloro-2-butenoate using C3 phosphine chloride and chloroacetaldehyde as raw materials, a solid base as the catalyst, and a copper salt as an additive. This method boasts high yields and avoids the use of highly hazardous halogens; however, metal ions from the catalyst and additives can remain in the product, resulting in poor storage stability. Furthermore, the catalyst is highly sensitive to the raw materials, therefore only pure C3 phosphine salts can be used. Summary of the Invention

[0008] In view of the above-mentioned problems in the prior art, the present invention provides a method for preparing ethyl 2-methyl-4-chloro-2-butenoate, which has high process safety and good product storage stability.

[0009] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0010] A method for preparing ethyl 2-methyl-4-chloro-2-butenoate includes the following steps: using an aqueous solution of ethoxyformyl ethyl triphenylphosphine salt (C3 phosphine salt) and an aqueous solution of monochloroacetaldehyde as raw materials, a Wittig reaction is carried out under the action of an alkali to obtain ethyl 2-methyl-4-chloro-2-butenoate, wherein the content of metal ions in the ethyl 2-methyl-4-chloro-2-butenoate is 1-3 ppm.

[0011] The structural formula of the ethoxyformylethyltriphenylphosphine salt (C3 phosphine salt) of this invention is as follows:

[0012]

[0013] X is selected from Cl and Br, with Br being preferred;

[0014] The structural formula of monochloroacetaldehyde is:

[0015] ;

[0016] The structural formula of ethyl 2-methyl-4-chloro-2-butenoate is:

[0017] .

[0018] The alkali metal ions include one or more of lithium ions, sodium ions, potassium ions, rubidium ions, and cesium ions.

[0019] The alkali described in this invention is one or more of lithium carbonate, sodium carbonate, and potassium carbonate, with potassium carbonate being preferred;

[0020] The C3 phosphine salt aqueous solution of the present invention has a mass fraction of 2-5%, preferably 3-4%; the monochloroacetaldehyde aqueous solution has a mass fraction of 20-45%, preferably 30-40%.

[0021] In the preparation method described in this invention, an aqueous solution of C3 phosphine salt and an aqueous solution of monochloroacetaldehyde are used as a base. At the reaction temperature, an aqueous solution of alkali is added dropwise, and the reaction is continued at the temperature after the addition is completed.

[0022] The aqueous solution of the alkali described in this invention has a mass fraction of 5-30%, preferably 10-20%.

[0023] The molar ratio of C3 phosphine salt to monochloroacetaldehyde in this invention is 1:1.1-2, preferably 1:1.3-1.5; the molar ratio of C3 phosphine salt to alkali is 1:1.3-2, preferably 1:1.5-1.8.

[0024] The reaction temperature of the present invention is -5 to 10°C, preferably 0 to 5°C; the dropping time is 0.5 to 2 hours, preferably 1 to 1.5 hours; and the reaction time after the dropping is completed is 5 to 20 hours, preferably 7 to 10 hours.

[0025] The product separation process after the reaction of this invention is as follows: the reaction solution is restored to room temperature, and an organic solvent is added dropwise under stirring; the solution is filtered, the filtrate is separated, and the resulting organic phase is concentrated to obtain the product.

[0026] The organic solvent used in this invention is a C4-C8 hydrocarbon, preferably n-hexane, n-heptane, or cyclohexane; the amount of organic solvent used is 8-20 times the mass of the C3 phosphine salt (based on pure product), preferably 10-15 times; the dropping time is 0.25h-1h, preferably 0.5-1h; and the stirring speed is 200-500rpm, preferably 300-400rpm.

[0027] The preparation method described in this invention has a conversion rate greater than 99.5% and a yield greater than 97%.

[0028] The separation method described in this invention yields a solid with a purity greater than 98% triphenylphosphine oxide after filtration, which can be washed and dried and is recyclable.

[0029] The method described in this invention has the following advantages compared with the prior art:

[0030] 1. The process route is simple, avoiding the use of highly hazardous halogen elements and catalysts / auxiliaries containing heavy metals, resulting in high process safety and facilitating industrial scale-up. Furthermore, the residual alkali metal ions in the product are moderate, within the range of 1-3 ppm, and it contains no heavy metal ions. Studies have shown that within this range, the residual alkali metal ions contribute to the product's high storage stability; the content shows no significant change after 12 months of storage under nitrogen conditions.

[0031] Based on experimental analysis, it is speculated that if the residual amount of alkali metal ions exceeds the specified range, it will catalyze the hydrolysis of ester bonds in the product, resulting in a decrease in product content. However, alkali metal ions have a certain protective effect on double bonds, and if the amount is below the specified value, the double bonds in the product are easily oxidized, resulting in a decrease in content.

[0032] 2. In the preferred embodiment, carbonates are used as the base in the reaction, which makes it less likely for alkali metals to remain. The content of alkali metal ions in the product is easy to control, and the product will not undergo side reactions such as hydrolysis. Therefore, the reaction yield is high, the product purity is high, the process yield is not less than 97.5%, and the product purity is not less than 97%.

[0033] 3. The process is highly adaptable to raw materials, and can be used not only for pure C3 phosphine salts, but also directly for the aqueous reaction solution obtained during the preparation of C3 phosphine salts.

[0034] 4. The entire reaction process uses water as a solvent, making it green, environmentally friendly, and with strong process safety.

[0035] 5. The TPPO byproduct obtained during the separation process has a high purity of not less than 98%, which makes it easy to sell as a byproduct in the industrial process and reduce the cost of the process route. Detailed Implementation

[0036] The technical solution of the present invention will be further described below, but it is not limited thereto. Any modifications or equivalent substitutions to the technical solution of the present invention that do not depart from the scope of the technical solution of the present invention should be covered within the protection scope of the present invention.

[0037] C3 phosphine salt and chloroacetaldehyde aqueous solution: both purchased from Aladdin Reagent Website.

[0038] C3 phosphine salt reaction solution: prepared according to Example 1 of patent CN103910759B.

[0039] Unless otherwise specified, all other ingredients are ordinary commercially available ingredients.

[0040] Gas chromatography analysis method: Online determination was performed using an Agilent HP-5 polysiloxane column with a two-stage temperature program: initial temperature 50℃, held for 1 minute, then increased to 80℃ at a rate of 5℃ / min; then increased to 250℃ at a rate of 10℃ / min. High-purity N2 was used as the carrier gas with a split ratio of 100:1. The injection temperature was 250℃, and the detector was an FID detector at 250℃. The injection volume was 0.2 μL.

[0041] Ion content was tested using ICP, instrument model: Agilent 5800ICP-OES

[0042] Example 1

[0043] Dissolve 44.32 g of ethoxyformylethyltriphenylphosphine bromide in water to obtain a 4.1% aqueous solution, and mix it with 25.51 g of a 40 wt% aqueous solution of monochloroacetaldehyde. Stir and cool to 0°C. Add 207.32 g of a 10 wt% aqueous solution of potassium carbonate dropwise over 1 hour. After the addition is complete, continue the reaction at this temperature for 7 hours.

[0044] After the reaction was complete, the temperature was restored to 25°C, and 443.32 g of n-hexane was added within 0.5 h. The mixture was filtered, and the filtrate was separated. The organic phase was collected and concentrated until no fraction was distilled off. The conversion rate was 99.8%, the yield was 98.0%, and the product purity was 97.8%. The metal ion content in the product was 2 ppm K. + .

[0045] The solid was filtered, washed, and dried, and the content of triphenylphosphine oxide was found to be 98.5%.

[0046] The product's storage stability is as follows:

[0047] Storage time / month content / % 0 97.8 1 97.8 3 97.8 5 97.8 8 97.7 12 97.6

[0048] Example 2

[0049] Prepare a 4.8% aqueous solution by dissolving 44.3g of ethoxyformylethyltriphenylphosphine bromide in water. Mix this solution with 43.18g of a 20% aqueous solution of chloroacetaldehyde and stir while cooling to -5°C. Add 105.99g of a 20% aqueous solution of sodium carbonate dropwise over 2 hours. After the addition is complete, continue the reaction at this temperature for another 5 hours.

[0050] After the reaction was complete, the temperature was restored to 25°C, and 354.66 g of cyclohexane was added over 0.25 h. The mixture was filtered, and the filtrate was separated. The organic phase was collected and concentrated until no fraction was distilled off. The conversion rate was 99.6%, and the yield was 97.7%. The product purity was 97.5%. The metal ion content in the product was 3 ppm Na. + .

[0051] The solid was filtered, washed, and dried, and the content of triphenylphosphine oxide was found to be 98.2%.

[0052]

[0053]

[0054] Example 3

[0055] Take 1734.22g of 2.3% ethoxyformylethyltriphenylphosphine chloride aqueous solution and mix it with 52.33g of 30% chloroacetaldehyde aqueous solution. Stir and cool down to 10℃. Add 192.11g of 5% lithium carbonate aqueous solution dropwise over 0.5h. After the addition is complete, continue the reaction at the temperature for 20h.

[0056] After the reaction was complete, the temperature was restored to 25°C, and 797.74 g of n-heptane was added within 1 hour. The mixture was filtered, and the filtrate was separated. The organic phase was collected and concentrated until no fraction was distilled off. The conversion rate was 99.7%, and the yield was 97.5%. The product purity was 97.3%. The metal ion content in the product was 1 ppm Li. + .

[0057] The solid was filtered, washed, and dried, and the content of triphenylphosphine oxide was found to be 98.4%.

[0058] Storage time / month content / % 0 97.3 1 97.3 3 97.3 5 97.3 8 97.2 12 97.1

[0059] Example 4

[0060] Dissolve 44.32 g of ethoxyformylethyltriphenylphosphine bromide in water to obtain a 3.5% aqueous solution, and mix it with 31.4 g of a 30 wt% aqueous solution of monochloroacetaldehyde. Stir and cool to 3°C. Add 231 g of an 18 wt% aqueous solution of rubidium carbonate dropwise over 1 hour. After the addition is complete, continue the reaction at this temperature for 11 hours.

[0061] After the reaction was complete, the temperature was restored to 25°C, and 443.2 g of cyclopentane was added within 1 hour. The mixture was filtered, and the filtrate was separated. The organic phase was collected and concentrated until no fraction was distilled off. The conversion rate was 99.7%, the yield was 97.4%, and the product purity was 97.3%. The metal ion content in the product was 3 ppm Cs. + .

[0062] The solid was filtered, washed, and dried, and the content of triphenylphosphine oxide was found to be 98.3%.

[0063] The product's storage stability is as follows:

[0064] Storage time / month content / % 0 97.3 1 97.3 3 97.3 5 97.3 8 97.2 12 97.1

[0065] Example 5

[0066] Dissolve 44.32 g of ethoxyformylethyltriphenylphosphine bromide in water to obtain a 3.8% aqueous solution, and mix it with 36.63 g of a 30 wt% aqueous solution of monochloroacetaldehyde. Stir and cool to 5°C. Add 391.2 g of a 15 wt% aqueous solution of cesium carbonate dropwise over 1.5 h. After the addition is complete, continue the reaction at this temperature for 15 h.

[0067] After the reaction was complete, the temperature was restored to 25°C, and 886.4 g of n-pentane was added over 0.75 h. The mixture was filtered, and the filtrate was separated. The organic phase was collected and concentrated until no fraction was distilled off. The conversion rate was 99.6%, the yield was 97.3%, and the product purity was 97.2%. The metal ion content in the product was 2 ppm Cs. + .

[0068] The solid was filtered, washed, and dried, and the content of triphenylphosphine oxide was found to be 98.5%.

[0069] The product's storage stability is as follows:

[0070] Storage time / month content / % 0 97.2 1 97.2 3 97.2 5 97.2 8 97.1 12 97.0

[0071] Example 6

[0072] Following the method described in Example 1, trace amounts of AlCl3, MgCl2, and CuCl2 were added to the obtained product until the ion content reached K. + 2ppm, Al 3+ 2ppm, Mg 2+ 2ppm, Cu 2+ 10ppm.

[0073] The product's storage stability is as follows:

[0074] Storage time / month content / % 0 97.8 1 97.8 3 97.8 5 97.8 8 97.7 12 97.6

[0075] Comparative Example 1

[0076] Following the method described in Example 2 of patent CN115304482A, the product yield was 95.7%, and the product purity was 96.4%. The metal ion content was K. + 5ppm, Al 3+ 2ppm, Mg 2+ 2ppm, Cu 2+ 10ppm.

[0077] The product's storage stability is as follows:

[0078] Storage time / month content / % 0 96.4 1 96.4 3 96.3 5 96.1 8 95.8 12 95.4

[0079] Comparative Example 2

[0080] Following the method described in Example 1, the alkali was replaced with a 0.5 mol 10% potassium carbonate aqueous solution. The conversion rate was tested to be 99.7%, and the yield was 97.4%. The product purity was 97.4%. The metal ion content in the product was 5 ppm Na. + The product's storage stability is as follows:

[0081] Storage time / month content / % 0 97.4 1 97.4 3 97.3 5 97.3 8 97.0 12 96.7

[0082] Comparative Example 3

[0083] Following the method described in Example 1, the prepared product was dissolved in 100g of dichloromethane, washed three times with 100g of water each time, and the organic phase solvent was concentrated to obtain the treated product with a purity of 97.9%. The metal ion content in the product was 0.7ppm K. + .

[0084] The product's storage stability is as follows:

[0085] Storage time / month content / % 0 97.9 1 97.9 3 97.8 5 97.8 8 97.6 12 97.3

Claims

1. A method for preparing ethyl 2-methyl-4-chloro-2-butenoate, characterized in that the step... include: Using an aqueous solution of ethoxyformyl ethyl triphenylphosphine salt and an aqueous solution of monochloroacetaldehyde as raw materials, a Wittig reaction is carried out under the action of an alkali to obtain ethyl 2-methyl-4-chloro-2-butenoate, wherein the content of alkali metal ions in the ethyl 2-methyl-4-chloro-2-butenoate is 1-3 ppm. The alkali is one or more of lithium carbonate, sodium carbonate, and potassium carbonate; The alkali metal ions include lithium ions, sodium ions, and potassium ions.

2. The preparation method according to claim 1, characterized in that, The structural formula of the ethoxyformylethyltriphenylphosphine salt is: X is selected from Cl and Br.

3. The preparation method according to claim 2, characterized in that, X is selected from Br.

4. The preparation method according to claim 1, characterized in that, The structural formula of monochloroacetaldehyde is: 。 5. The preparation method according to claim 1, characterized in that, The structural formula of ethyl 2-methyl-4-chloro-2-butenoate is: 。 6. The preparation method according to claim 1, characterized in that, The alkali is potassium carbonate.

7. The preparation method according to claim 1, characterized in that, The reaction process involves spreading an aqueous solution of ethoxyformylethyltriphenylphosphine salt and an aqueous solution of chloroacetaldehyde at the bottom, lowering the temperature to the reaction temperature, adding an aqueous solution of alkali dropwise, and continuing the reaction at the temperature after the addition is complete.

8. The preparation method according to claim 7, characterized in that, The aqueous solution of the alkali has a mass fraction of 5-30%.

9. The preparation method according to claim 8, characterized in that, The aqueous solution of the alkali has a mass fraction of 10-20%.

10. The preparation method according to claim 1, characterized in that, The molar ratio of the ethoxyformylethyltriphenylphosphine salt to monochloroacetaldehyde is 1:1.1-2; and / or, the molar ratio of the ethoxyformylethyltriphenylphosphine salt to the base is 1:1.3-2.

11. The preparation method according to claim 10, characterized in that, The molar ratio of the ethoxyformylethyltriphenylphosphine salt to monochloroacetaldehyde is 1:1.3-1.5; and / or, the molar ratio of the ethoxyformylethyltriphenylphosphine salt to the base is 1:1.5-1.

8.

12. The preparation method according to claim 1, characterized in that, The reaction temperature is -5 to 10℃; the dropping time is 0.5 to 2 hours; and the reaction continues for 5 to 20 hours after the dropping is completed.

13. The preparation method according to claim 12, characterized in that, The reaction temperature is 0-5℃; the dropping time is 1-1.5h; and the reaction continues for 7-10h after the dropping is completed.

14. The preparation method according to claim 1, characterized in that, The product separation process after the reaction is completed is as follows: the reaction solution is restored to room temperature, and an organic solvent is added dropwise with stirring; the solution is filtered, the filtrate is separated, and the resulting organic phase is concentrated to obtain the product.

15. The preparation method according to claim 14, characterized in that, The organic solvent is a C4-C8 hydrocarbon; the amount of the organic solvent used is 8-20 times the mass of ethoxyformylethyltriphenylphosphine salt; And / or, the dripping time is 0.25h-1h; And / or, the stirring rate is 200-500 rpm.

16. The preparation method according to claim 15, characterized in that, The organic solvent is n-hexane, n-heptane, or cyclohexane; The amount of organic solvent used is 10-15 times the mass of ethoxyformylethyltriphenylphosphine salt; And / or, the dripping time is 0.5-1 hour; And / or, the stirring rate is 300-400 rpm.

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