A method for preparing ethyl mercaptoacetate

Abstract

This invention belongs to the field of chemical technology, specifically relating to a method for preparing ethyl mercaptoacetate. The method includes the following steps: 4-bromobenzenesulfonic acid acetonitrile and acetonitrile are added dropwise to thioacetic acid and potassium carbonate successively at room temperature. After the reaction is complete, the mixture is purified and concentrated to dryness under reduced pressure to obtain acetyl mercaptoacetate; acetyl mercaptoacetate is added to hydrochloric acid and ethanol, heated to react, and then water and dichloromethane are added. The organic phase is separated, dried, and concentrated to dryness under reduced pressure to obtain ethyl mercaptoacetate. This invention features simple post-processing, is suitable for industrial production, and has a high reaction yield.

Description

Technical Field

[0001] This invention relates to the field of chemical technology, and specifically to a method for preparing ethyl mercaptoside. Background Technology

[0002] The description of the background art in this invention pertains to related technologies and is used merely for illustration and to facilitate understanding of the invention. It should not be construed as the applicant explicitly believing or presuming that the invention was prior art on the filing date of the first application.

[0003] Ethyl mercaptoacetate is an important intermediate for organic compounds and a basic raw material for organic chemicals. It is widely used as a reagent for iron determination, a pharmaceutical intermediate, in the synthesis of cefmetazole, a crosslinking agent and initiator in polymer chemistry, and an intermediate for metal impregnation agents and antioxidants.

[0004] Currently, the conventional synthetic method for ethyl mercaptohydrate mainly involves the esterification of thioglycolic acid and ethanol in the presence of sulfuric acid. The process involves heating thioglycolic acid, ethanol, and sulfuric acid under reflux for 24 hours, followed by fractional distillation at atmospheric pressure, collecting the fraction at 155-158°C to obtain the final product. However, all these methods have certain drawbacks. 1. Seliger, Hartmut; Goertz, Hans-Helmut (Synthetic Communications, 1980, vol. 10, #3, pp. 175-182) reported a method for synthesizing ethyl mercaptohydrate by esterification of thioglycolic acid and ethanol in the presence of sulfuric acid. The process involves heating thioglycolic acid, ethanol, and sulfuric acid under reflux for 24 hours, followed by fractional distillation at atmospheric pressure, collecting the fraction at 155-158°C to obtain the final product. The yield was 70%. The reagents used in this process include thioglycolic acid, which is a hazardous chemical and its source is controlled and difficult to obtain; 2. Kakehi, Akikazu (Bull et al. of the Chemical Society of Japan, 1996, vol. 69, #6, pp. 1769-1776) et al. reported the synthesis of ethyl mercaptoacetate using ethyl 2-thiocyanate and 1-(ethoxycarbonylmethyl)chlorinated pyridine under potassium carbonate conditions, with a reported yield of about 50-60%, but the two raw materials involved require multiple steps to synthesize, resulting in a low overall yield. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing ethyl mercaptoacetate. This invention has simple post-processing, is suitable for industrial production, improves reaction yield, and provides a better method for the synthesis of ethyl mercaptoacetate.

[0006] A method for preparing ethyl mercaptoside, comprising the following steps:

[0007]

[0008] 4-Bromobenzenesulfonic acid acetonitrile and acetonitrile were added dropwise to thioacetic acid and potassium carbonate at room temperature. After the reaction was complete, the mixture was purified and concentrated to dryness under reduced pressure to obtain acetylmercaptoacetonitrile.

[0009] Acetylmercaptoacetonitrile was added to hydrochloric acid and ethanol, heated to react, and then water and dichloromethane were added. The organic phase was separated, dried, and concentrated under reduced pressure to dryness to obtain ethyl mercaptoacetate.

[0010] Further:

[0011]

[0012] 4-Bromobenzenesulfonic acid acetonitrile and acetonitrile were added dropwise under nitrogen protection at room temperature. After 10 minutes, potassium carbonate was slowly added dropwise while stirring at room temperature. The temperature was raised to 30°C and stirred. The reaction was controlled to produce no raw material. The mixture was purified by column chromatography and concentrated to dryness under reduced pressure to obtain acetylmercaptoacetonitrile.

[0013] Acetylmercaptoacetonitrile was added to hydrochloric acid and ethanol, heated to 30°C under nitrogen protection and stirred. Water and dichloromethane were added, and the mixture was stirred and separated to obtain an organic phase. The aqueous phase was extracted again with dichloromethane. The organic phases were combined, dried, and concentrated under reduced pressure to dryness to obtain ethyl mercaptoacetate.

[0014] Further:

[0015]

[0016] 1.338 g of 4.85 mmol of 4-bromobenzenesulfonic acid acetonitrile and 20 ml of acetonitrile were added to the reaction flask under nitrogen protection. 442.5 mg of 5.82 mmol of thioacetic acid was added dropwise at room temperature. After 10 minutes, 735.6 mg of 7.27 mmol of potassium carbonate was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, then heated to 30 °C and stirred for 1 hour. No starting material was found during the reaction. The mixture was purified by column chromatography and concentrated under reduced pressure to dryness to obtain a pale yellow liquid, namely acetylmercaptoacetonitrile.

[0017] 501 mg and 4.36 mmol of acetylmercaptoacetonitrile were added to hydrochloric acid and 5 ml of ethanol, and heated to 30 °C and stirred for 2 h under nitrogen protection. 50 ml of water and 50 ml of dichloromethane were added, and the mixture was stirred and separated to obtain the organic phase. The aqueous phase was extracted again with 40 ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain a colorless liquid, namely ethyl mercaptoacetate.

[0018] Further:

[0019]

[0020] 1 g of 3.61 mmol of 4-bromobenzenesulfonic acid acetonitrile-13C and 18 ml of acetonitrile were added to the reaction flask under nitrogen protection. At room temperature, 329.6 mg of 4.33 mmol of thioacetic acid was added dropwise. After 10 minutes, 548.0 mg of 5.42 mmol of potassium carbonate was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, then heated to 30 °C and stirred for 1 hour. No starting material was found during the reaction. The mixture was purified by column chromatography and concentrated under reduced pressure to dryness to obtain a pale yellow liquid, namely acetylmercaptoacetonitrile-13C.

[0021] 381.5 mg and 3.28 mmol of acetylmercaptoacetonitrile-13C were added to hydrochloric acid and 5 ml of ethanol, and heated to 30 °C and stirred for 2 h under nitrogen protection. 50 ml of water and 50 ml of dichloromethane were added, and the mixture was stirred and separated to obtain the organic phase. The aqueous phase was extracted again with 40 ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain a colorless liquid, namely ethyl mercaptoacetate-1-13C.

[0022] Further:

[0023]

[0024] 1.338 g of 4.85 mmol of 4-bromobenzenesulfonic acid acetonitrile and 20 ml of acetonitrile were added to the reaction flask under nitrogen protection. At room temperature, 442.5 mg of 5.82 mmol of thioacetic acid was added dropwise. After 10 minutes, 735.6 mg of 7.27 mmol of potassium carbonate was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, then heated to 30 °C and stirred for 1 hour. No starting material was found during the reaction. The mixture was purified by column chromatography and concentrated under reduced pressure to dryness to obtain a pale yellow liquid, namely acetylmercaptoacetonitrile.

[0025] 498 mg and 4.32 mmol of acetylmercaptoacetonitrile were added to hydrochloric acid and 5 ml of methanol, and heated to 30 °C and stirred for 2 h under nitrogen protection. 50 ml of water and 50 ml of dichloromethane were added, and the mixture was stirred and separated to obtain the organic phase. The aqueous phase was extracted again with 40 ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a colorless liquid, namely methyl mercaptoacetate.

[0026] The embodiments of the present invention have the following beneficial effects:

[0027] This invention uses 4-bromobenzenesulfonic acid acetonitrile as a raw material to synthesize acetylmercaptoacetonitrile, and then directly obtains ethyl mercaptoacetate by deacetylation and hydrolysis of cyano groups to ester groups in a one-pot process using hydrochloric acid ethanol solution under heating conditions. The post-processing is simple, suitable for industrial production, improves reaction yield, and provides a superior method for the synthesis of ethyl mercaptoacetate.

[0028] This invention avoids the distillation and purification methods used in conventional production processes, making it more user-friendly and applicable for milligram-level feed additions in the laboratory.

[0029] This invention avoids the problems of limited and uncontrollable sources of raw materials, or low overall yield caused by multiple steps of synthesizing raw materials and then synthesizing products. Detailed Implementation

[0030] The present application will be further described below with reference to the embodiments.

[0031] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, in the following description, different "an embodiment" or "an embodiment" do not necessarily refer to the same embodiment. Different embodiments can be substituted or combined, and for those skilled in the art, other implementation methods can be obtained based on these embodiments without creative effort.

[0032] Example 1. Synthesis of ethyl mercaptoside:

[0033]

[0034] 4-Bromobenzenesulfonic acid acetonitrile (1.338 g, 4.85 mmol) and acetonitrile (20 ml) were added to a reaction flask under nitrogen protection. Thioacetic acid (442.5 mg, 5.82 mmol) was added dropwise at room temperature. After 10 minutes, potassium carbonate (735.6 mg, 7.27 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, then heated to 30°C and stirred for 1 hour. No starting material was found during the central reaction. The mixture was purified by column chromatography and concentrated under reduced pressure to dryness, yielding 501 mg (90% yield) of a pale yellow liquid, namely acetylmercaptoacetonitrile.

[0035] The acetylmercaptoacetonitrile (501 mg, 4.36 mmol) obtained above was added to hydrochloric acid and ethanol (5 ml), and heated to 30 °C and stirred for 2 h under nitrogen protection. Water (50 ml) and dichloromethane (50 ml) were added, and the mixture was stirred and separated to obtain the organic phase. The aqueous phase was extracted again with 40 ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain a colorless liquid (482.1 mg) (yield 92%), namely ethyl mercaptoacetate.

[0036] Example 2

[0037] Synthesis of ethyl 2-mercaptoethyl acetate-1-13C

[0038]

[0039] 4-Bromobenzenesulfonic acid acetonitrile-13C (1 g, 3.61 mmol) and acetonitrile (18 ml) were added to a reaction flask under nitrogen protection. Thioacetic acid (329.6 mg, 4.33 mmol) was added dropwise at room temperature. After 10 minutes, potassium carbonate (548.0 mg, 5.42 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, then heated to 30°C and stirred for 1 hour. No starting material was observed during the central reaction. The mixture was purified by column chromatography and concentrated under reduced pressure to dryness to obtain 381.5 mg of a pale yellow liquid (91% yield), namely acetylmercaptoacetonitrile-13C.

[0040] The acetylmercaptoacetonitrile-13C obtained above (381.5 mg, 3.28 mmol) was added to hydrochloric acid and ethanol (5 ml), and heated to 30 °C and stirred for 2 h under nitrogen protection. Water (50 ml) and dichloromethane (50 ml) were added, and the mixture was stirred and separated to obtain the organic phase. The aqueous phase was extracted again with 40 ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain a colorless liquid (357.6 mg) (yield 90%), namely ethyl mercaptoacetate-1-13C.

[0041] Example 3

[0042] Synthesize methyl mercaptoacetate:

[0043]

[0044] 4-Bromobenzenesulfonic acid acetonitrile (1.338 g, 4.85 mmol) and acetonitrile (20 ml) were added to a reaction flask under nitrogen protection. Thioacetic acid (442.5 mg, 5.82 mmol) was added dropwise at room temperature. After 10 minutes, potassium carbonate (735.6 mg, 7.27 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, then heated to 30°C and stirred for 1 hour. No starting material was observed during the central reaction. The mixture was purified by column chromatography and concentrated under reduced pressure to dryness, yielding 498 mg of a pale yellow liquid (89% yield), which is acetylmercaptoacetonitrile.

[0045] The acetylmercaptoacetonitrile (498 mg, 4.32 mmol) obtained above was added to hydrochloric acid and methanol (5 ml), and heated to 30 °C and stirred for 2 h under nitrogen protection. Water (50 ml) and dichloromethane (50 ml) were added, and the mixture was stirred and separated to obtain the organic phase. The aqueous phase was extracted again with 40 ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain a colorless liquid (398.9 mg) (yield 87%), namely methyl mercaptoacetate.

[0046] This invention uses 4-bromobenzenesulfonic acid acetonitrile as a raw material to synthesize acetylmercaptoacetonitrile, and then directly obtains ethyl mercaptoacetate by deacetylation and hydrolysis of cyano groups to ester groups in a one-pot reaction using hydrochloric acid ethanol solution under heating conditions. The post-processing is simple, suitable for industrial production, improves reaction yield, and provides a superior method for the synthesis of ethyl mercaptoacetate.

[0047] This invention avoids the distillation and purification methods used in conventional production processes, making it more user-friendly and applicable for milligram-level feed additions in the laboratory.

[0048] This invention avoids the problems of limited and uncontrollable sources of raw materials, or low overall yield caused by multiple steps of synthesizing raw materials and then synthesizing products.

[0049] It should be noted that, in the synthesis of acetylmercaptoacetonitrile, in addition to using 4-bromobenzenesulfonic acid acetonitrile as a raw material, chloroacetonitrile and bromoacetonitrile, and other haloacetonitrs, can also be used as raw materials. In the final synthesis of mercaptoacetic acid esters, the corresponding mercaptoacetic acid esters (ethyl ester, methyl ester, tert-butyl ester, etc.) can also be obtained using hydrochloric acid solutions of other alcohols (ethanol hydrochloride, methanol hydrochloride, tert-butanol hydrochloride, etc.).

[0050] Furthermore, the present invention is also applicable to the labeled synthesis of isotopes ethyl 2-mercaptoethyl-1-13C and ethyl 2-mercaptoethyl-1-14C.

[0051] It should be noted that the above embodiments can be freely combined as needed. The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention can have various modifications and variations. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A process for the preparation of ethyl mercaptoacetate, characterized in that, Comprising the steps of: 4-bromophenylsulfonic acid acetonitrile and acetonitrile, drop in thioacetic acid and potassium carbonate successively at room temperature, after full reaction, purify, concentrate to dryness under reduced pressure to obtain acetyl mercaptoacetonitrile; Add acetyl mercaptoacetonitrile to hydrochloric acid and ethanol, after heating reaction, add water and dichloromethane, separate the organic phase, dry, concentrate to dryness under reduced pressure to obtain ethyl mercaptoacetate.

2. The method of preparing ethyl mercaptoacetate according to claim 1, characterized in that, Comprising the steps of: 4-bromophenylsulfonic acid acetonitrile and acetonitrile, drop in thioacetic acid under nitrogen protection at room temperature, after 10 minutes, slowly drop in potassium carbonate, stir at room temperature, warm up to 30℃, stir, control the reaction without raw material, purify by column, concentrate to dryness under reduced pressure to obtain acetyl mercaptoacetonitrile; Add acetyl mercaptoacetonitrile to hydrochloric acid and ethanol, heat to 30℃ under nitrogen protection, add water and dichloromethane, after stirring, separate the organic phase, re-extract the aqueous phase with dichloromethane once, combine the organic phase, dry, concentrate to dryness under reduced pressure to obtain ethyl mercaptoacetate.

3. The method for preparing ethyl mercaptoacetate according to claim 2, characterized in that, Comprising the steps of: Add 1.338g, 4.85mmol of 4-bromophenylsulfonic acid acetonitrile and 20ml of acetonitrile in a reaction bottle under nitrogen protection; drop in 442.5mg, 5.82mmol of thioacetic acid at room temperature, after 10 minutes, slowly drop in 735.6mg, 7.27mmol of potassium carbonate, after dropping, stir at room temperature for 10 minutes, warm up to 30℃ and stir for 1h; control the reaction without raw material; purify by column, concentrate to dryness under reduced pressure to obtain acetyl mercaptoacetonitrile as a light yellow liquid; Add 501mg, 4.36mmol of acetyl mercaptoacetonitrile to hydrochloric acid and 5ml of ethanol, heat to 30℃ under nitrogen protection and stir for 2h; add 50ml of water and 50ml of dichloromethane, after stirring, separate the organic phase, re-extract the aqueous phase with 40ml of dichloromethane once, combine the organic phase, dry with anhydrous sodium sulfate, concentrate to dryness under reduced pressure to obtain ethyl mercaptoacetate as a colorless liquid.

4. The method of preparing ethyl mercaptoacetate according to claim 2, characterized by, Comprising the steps of: Add 1g, 3.61mmol of 4-bromophenylsulfonic acid acetonitrile-13C and 18ml of acetonitrile in a reaction bottle under nitrogen protection; drop in 329.6mg, 4.33mmol of thioacetic acid at room temperature, after 10 minutes, slowly drop in 548.0mg, 5.42mmol of potassium carbonate, after dropping, stir at room temperature for 10 minutes, warm up to 30℃ and stir for 1h; control the reaction without raw material; purify by column, concentrate to dryness under reduced pressure to obtain acetyl mercaptoacetonitrile-13C as a light yellow liquid; Add 381.5mg, 3.28mmol of acetyl mercaptoacetonitrile-13C to hydrochloric acid and 5ml of ethanol, heat to 30℃ under nitrogen protection and stir for 2h; add 50ml of water and 50ml of dichloromethane, after stirring, separate the organic phase, re-extract the aqueous phase with 40ml of dichloromethane once, combine the organic phase, dry with anhydrous sodium sulfate, concentrate to dryness under reduced pressure to obtain ethyl mercaptoacetate-1-13C as a colorless liquid.

5. The method for preparing ethyl mercaptoacetate according to claim 2, characterized in that, Comprising the steps of: Into a reaction flask was added 1.338 g, 4.85 mmol of 4-bromobenzenesulfonic acid acetonitrile ester and 20 ml of acetonitrile under nitrogen protection; at room temperature, 442.5 mg, 5.82 mmol of thioacetic acid was added dropwise, after 10 minutes, 735.6 mg, 7.27 mmol of potassium carbonate was added dropwise, and stirred at room temperature for 10 minutes, and then heated to 30°C for 1 hour; the reaction was controlled without raw material; purified by column, concentrated to dryness under reduced pressure to obtain a light yellow liquid; which was acetyl mercaptoacetonitrile; 498 mg, 4.32 mmol of acetyl mercaptoacetonitrile was added to hydrochloric acid and 5 ml of methanol, heated to 30°C under nitrogen protection and stirred for 2 hours; 50 ml of water and 50 ml of dichloromethane were added, stirred and separated to obtain an organic phase, the aqueous phase was extracted with 40 ml of dichloromethane again, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain a colorless liquid, which was mercaptoacetic acid methyl ester.

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