Preparation method of ethyl thioglycolate

Abstract

The invention belongs to the technical field of chemistry, and particularly relates to a preparation method of ethyl thioglycolate. Comprising the following steps: successively dropwise adding thioacetic acid and potassium carbonate into # imgabs0 # 4-bromobenzenesulfonic acid acetonitrile and acetonitrile at room temperature, fully reacting, purifying, and concentrating under reduced pressure until the mixture is dry to obtain acetyl mercaptoacetonitrile; hydrochloric acid and ethanol are added into acetyl mercaptoacetonitrile, water and dichloromethane are added after heating reaction, an organic phase is obtained through phase splitting, and the organic phase is dried and concentrated under reduced pressure to be dry to obtain ethyl mercaptoacetate. The method is simple in post-treatment, suitable for industrial production and high in reaction yield.

Description

Technical Field

[0001] The invention relates to the technical field of chemistry, and in particular to a method for preparing ethyl thioglycolate. Background Art

[0002] The description of the background technology in the present invention belongs to the related technology related to the present invention, which is only used to illustrate and facilitate the understanding of the invention content of the present invention, and should not be understood as the applicant explicitly believes or inferred that the applicant believes that it is the prior art of the present invention on the filing date of the first application.

[0003] Ethyl mercaptoacetate is an important organic compound intermediate and basic organic chemical raw material. It is widely used as a reagent for the determination of iron, a pharmaceutical intermediate, the synthesis of cefmetazole, a cross-linking agent and initiator in polymer chemistry, and an intermediate for metal impregnants and antioxidants.

[0004] At present, the conventional process synthesis method of ethyl thioglycolate is mainly to obtain it by esterification of thioglycolic acid and ethanol in the presence of sulfuric acid. Thioglycolic acid, ethanol and sulfuric acid are heated to reflux for 24 hours, fractionated at normal pressure, and the 155-158°C fraction is collected to obtain the finished product, but there are certain disadvantages. 1. Seliger, Hartmut; Goertz, Hans-He lmut (Synthetic Communications, 1980, vol. 10, #3, p. 175-182) reported that thioglycolic acid and ethanol are esterified in the presence of sulfuric acid. Thioglycolic acid, ethanol and sulfuric acid are heated to reflux for 24 hours, fractionated at normal pressure, and the 155-158°C fraction is collected to obtain the finished product. The yield is 70%. The reagents used in this process include thioglycolic acid, which is a hazardous chemical and the source of the raw materials is controlled and difficult to obtain; 2. Kakehi, Akikazu (Bull et al. of the Chemistry Society of Japan, 1996, vol. 69, #6, p. 1769-1776) et al. reported the synthesis of ethyl thioglycolate using 2-ethyl thiocyanate and 1-(ethoxycarbonylmethyl)pyridinium chloride under potassium carbonate conditions, with a reported yield of about 50-60%, but the two raw materials involved had to be synthesized in multiple steps, and the overall yield was not high. Summary of the invention

[0005] The purpose of the embodiment of the present invention is to provide a method for preparing ethyl thioglycolate. The method is simple in post-processing, suitable for industrial production, improves the reaction yield, and provides a better method for synthesizing ethyl thioglycolate.

[0006] A method for preparing ethyl thioglycolate comprises the following steps:

[0007]

[0008] 4-bromobenzenesulfonic acid acetonitrile and acetonitrile are added dropwise at room temperature in succession to thioacetic acid and potassium carbonate, and after sufficient reaction, the mixture is purified and concentrated to dryness under reduced pressure to obtain acetylmercaptoacetonitrile;

[0009] Add hydrochloric acid and ethanol to acetylmercaptoacetonitrile, heat for reaction, add water and dichloromethane, separate the phases to obtain an organic phase, dry it, and concentrate it to dryness under reduced pressure to obtain ethyl mercaptoacetate.

[0010] Further:

[0011]

[0012] 4-bromobenzenesulfonic acid acetonitrile and acetonitrile, under nitrogen protection, add thioacetic acid dropwise at room temperature, 10 minutes later, slowly add potassium carbonate dropwise, stir at room temperature, heat to 30°C and stir, there is no raw material in the middle control reaction, column purification, and reduced pressure concentration to dryness to obtain acetyl mercaptoacetonitrile;

[0013] Add hydrochloric acid and ethanol to acetylmercaptoacetonitrile, heat to 30°C and stir under nitrogen protection, add water and dichloromethane, stir and separate the phases to obtain an organic phase, extract the aqueous phase again with dichloromethane, combine the organic phases, dry, and concentrate to dryness under reduced pressure to obtain ethyl mercaptoacetate.

[0014] Further:

[0015]

[0016] Add 1.338g, 4.85mmol of 4-bromobenzenesulfonic acid acetonitrile and 20ml of acetonitrile to the reaction flask under nitrogen protection; add 442.5mg, 5.82mmol of thioacetic acid dropwise at room temperature, and after 10 minutes, slowly add 735.6mg, 7.27mmol of potassium carbonate dropwise, stir at room temperature for 10 minutes, heat to 30°C and stir for 1h; no raw material is left in the intermediate control reaction; purify by column, and concentrate under reduced pressure to dryness to obtain a light yellow liquid, namely acetylmercaptoacetonitrile;

[0017] Add hydrochloric acid and 5 ml of ethanol to 501 mg and 4.36 mmol of acetylmercaptoacetonitrile, heat to 30 °C and stir for 2 h under nitrogen protection; add 50 ml of water and 50 ml of dichloromethane, stir and separate the phases to obtain an organic phase, extract the aqueous phase again with 40 ml of dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to dryness under reduced pressure to obtain a colorless liquid, i.e., ethyl mercaptoacetate.

[0018] Further:

[0019]

[0020] Add 1g, 3.61mmol of 4-bromobenzenesulfonic acid acetonitrile-13C and 18ml of acetonitrile to the reaction flask under nitrogen protection; at room temperature, drop 329.6mg, 4.33mmol of thioacetic acid, 10 minutes later, slowly drop 548.0mg, 5.42mmol of potassium carbonate, stir at room temperature for 10 minutes, heat to 30℃ and stir for 1h; no raw material in the middle control reaction; purify by column, concentrate under reduced pressure to dryness to obtain a light yellow liquid, namely acetylmercaptoacetonitrile-13C;

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

[0022] Further:

[0023]

[0024] Add 1.338g, 4.85mmol of 4-bromobenzenesulfonic acid acetonitrile and 20ml of acetonitrile to the reaction flask under nitrogen protection; at room temperature, drop 442.5mg, 5.82mmol of thioacetic acid, 10 minutes later, slowly drop 735.6mg, 7.27mmol of potassium carbonate, stir at room temperature for 10 minutes, heat to 30℃ and stir for 1h; no raw material in the middle control reaction; Column purification, concentrated under reduced pressure to dryness to obtain a light yellow liquid; namely acetylmercaptoacetonitrile;

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

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

[0027] The invention adopts 4-bromobenzenesulfonic acid acetonitrile as a raw material to synthesize acetyl mercaptoacetonitrile, and then uses hydrochloric acid ethanol solution to deacetylate and hydrolyze cyano group to ester group under heating condition to directly obtain ethyl mercaptoacetate in one pot. The post-treatment is simple, suitable for industrial production, and the reaction yield is improved, thereby providing a better method for synthesizing ethyl mercaptoacetate.

[0028] The invention avoids using a distillation purification method of a conventional production process, and is more friendly to milligram-level feeding in a laboratory and has stronger applicability.

[0029] The present invention avoids the problem that the source of the raw materials used is less controlled and difficult to obtain, or the raw materials are synthesized in multiple steps and then the products are synthesized, resulting in a low total yield. DETAILED DESCRIPTION

[0030] The present application is further described below in conjunction with embodiments.

[0031] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, in the following description, different "one embodiment" or "embodiment" does not necessarily refer to the same embodiment. Different embodiments can be replaced or combined, and for ordinary technicians in this field, other implementation methods can be obtained based on these embodiments without creative work.

[0032] Example 1. Synthesis of ethyl mercaptoacetate:

[0033]

[0034] Add 4-bromobenzenesulfonic acid acetonitrile (1.338g, 4.85mmol) and acetonitrile (20ml) to the reaction flask under nitrogen protection. Add thioacetic acid (442.5mg, 5.82mmol) dropwise at room temperature. After 10 minutes, slowly add potassium carbonate (735.6mg, 7.27mmol) dropwise. Stir at room temperature for 10 minutes, warm to 30℃ and stir for 1h. There is no raw material in the intermediate control reaction. Purify by column and concentrate under reduced pressure to dryness to obtain 501mg (yield 90%) of light yellow liquid, namely acetylmercaptoacetonitrile.

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

[0036] Example 2

[0037] Synthesis of ethyl 2-mercaptoacetate-1-13C

[0038]

[0039] 4-Bromobenzenesulfonic acid acetonitrile-13C (1g, 3.61mmol) and acetonitrile (18ml) were added to the reaction flask under nitrogen protection. Thioacetic acid (329.6mg, 4.33mmol) was added dropwise at room temperature. After 10 minutes, potassium carbonate (548.0mg, 5.42mmol) was slowly added dropwise. After the addition was completed, the mixture was stirred at room temperature for 10 minutes, and the mixture was heated to 30°C and stirred for 1h. There was no raw material in the intermediate control reaction. The mixture was purified by column and concentrated to dryness under reduced pressure to obtain 381.5mg (yield 91%) of a light yellow liquid, namely acetylmercaptoacetonitrile-13C.

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

[0041] Example 3

[0042] Synthesis of methyl thioglycolate:

[0043]

[0044] Add 4-bromobenzenesulfonic acid acetonitrile (1.338g, 4.85mmol) and acetonitrile (20ml) to the reaction flask under nitrogen protection. At room temperature, add thioacetic acid (442.5mg, 5.82mmol) dropwise. After 10 minutes, slowly add potassium carbonate (735.6mg, 7.27mmol) dropwise. Stir at room temperature for 10 minutes, warm to 30℃ and stir for 1h. There is no raw material in the intermediate control reaction. Purify by column, concentrate under reduced pressure to dryness to obtain 498mg (yield 89%) of light yellow liquid, namely acetylmercaptoacetonitrile.

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

[0046] The invention uses 4-bromobenzenesulfonic acid acetonitrile as a raw material to synthesize acetyl mercaptoacetonitrile, and then uses hydrochloric acid ethanol solution to deacetylate and hydrolyze cyano groups to ester groups under heating conditions to directly obtain ethyl mercaptoacetate. The post-treatment is simple, suitable for industrial production, and the reaction yield is improved, thereby providing a better method for synthesizing ethyl mercaptoacetate.

[0047] The invention avoids using a distillation purification method of a conventional production process, and is more friendly to milligram-level feeding in a laboratory and has stronger applicability.

[0048] The present invention avoids the problem that the source of the raw materials used is less controlled and difficult to obtain, or the raw materials are synthesized in multiple steps and then the products are synthesized, resulting in a low total yield.

[0049] It should be noted that in the synthesis of acetylmercaptoacetonitrile, in addition to using 4-bromobenzenesulfonic acid acetonitrile of the present invention as a raw material, halogenated acetonitrile such as chloroacetonitrile and bromoacetonitrile can also be used as a raw material. In the final synthesis of thioglycolate, hydrochloric acid solutions of other alcohols (ethanol hydrochloride, methanol hydrochloride, tert-butyl alcohol hydrochloride, etc.) can also be used to obtain corresponding thioglycolates (ethyl ester, methyl ester, tert-butyl ester, etc.).

[0050] In addition, the present invention is also applicable to the labeling synthesis of isotope 2-mercaptoethyl acetate-1-13C and 2-mercaptoethyl acetate-1-14C.

[0051] It should be noted that the above embodiments can be freely combined as needed. The above description is only the 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 changes and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing ethyl thioglycolate, characterized in that: The steps include: 4-bromobenzenesulfonic acid acetonitrile and acetonitrile are added dropwise at room temperature in succession to thioacetic acid and potassium carbonate, and after sufficient reaction, the mixture is purified and concentrated to dryness under reduced pressure to obtain acetylmercaptoacetonitrile; Add hydrochloric acid and ethanol to acetylmercaptoacetonitrile, heat for reaction, add water and dichloromethane, separate the phases to obtain an organic phase, dry it, and concentrate it to dryness under reduced pressure to obtain ethyl mercaptoacetate.

2. The method for preparing ethyl thioglycolate according to claim 1, wherein The steps include: 4-bromobenzenesulfonic acid acetonitrile and acetonitrile, under nitrogen protection, add thioacetic acid dropwise at room temperature, 10 minutes later, slowly add potassium carbonate dropwise, stir at room temperature, heat to 30°C and stir, there is no raw material in the middle control reaction, column purification, and reduced pressure concentration to dryness to obtain acetyl mercaptoacetonitrile; Add hydrochloric acid and ethanol to acetylmercaptoacetonitrile, heat to 30°C and stir under nitrogen protection, add water and dichloromethane, stir and separate the phases to obtain an organic phase, extract the aqueous phase again with dichloromethane, combine the organic phases, dry, and concentrate to dryness under reduced pressure to obtain ethyl mercaptoacetate.

3. The method for preparing ethyl thioglycolate according to claim 2, wherein The steps include: Add 1.338g, 4.85mmol of 4-bromobenzenesulfonic acid acetonitrile and 20ml of acetonitrile to the reaction flask under nitrogen protection; add 442.5mg, 5.82mmol of thioacetic acid dropwise at room temperature, and after 10 minutes, slowly add 735.6mg, 7.27mmol of potassium carbonate dropwise, stir at room temperature for 10 minutes, heat to 30°C and stir for 1h; no raw material is left in the intermediate control reaction; purify by column, and concentrate under reduced pressure to dryness to obtain a light yellow liquid, namely acetylmercaptoacetonitrile; Add hydrochloric acid and 5 ml of ethanol to 501 mg and 4.36 mmol of acetylmercaptoacetonitrile, heat to 30 °C and stir for 2 h under nitrogen protection; add 50 ml of water and 50 ml of dichloromethane, stir and separate the phases to obtain an organic phase, extract the aqueous phase again with 40 ml of dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to dryness under reduced pressure to obtain a colorless liquid, i.e., ethyl mercaptoacetate.

4. The method for preparing ethyl thioglycolate according to claim 2, wherein The steps include: Add 1g, 3.61mmol of 4-bromobenzenesulfonic acid acetonitrile-13C and 18ml of acetonitrile to the reaction flask under nitrogen protection; at room temperature, drop 329.6mg, 4.33mmol of thioacetic acid, 10 minutes later, slowly drop 548.0mg, 5.42mmol of potassium carbonate, stir at room temperature for 10 minutes, heat to 30℃ and stir for 1h; no raw material in the middle control reaction; purify by column, concentrate under reduced pressure to dryness to obtain a light yellow liquid, namely acetylmercaptoacetonitrile-13C; 381.5 mg, 3.28 mmol of acetylmercaptoacetonitrile-13C was added with hydrochloric acid and 5 ml of ethanol, heated to 30°C and stirred for 2 h under nitrogen protection; 50 ml of water and 50 ml of dichloromethane were added, the mixture was stirred and separated to obtain an organic phase, the aqueous phase was extracted once more with 40 ml of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain a colorless liquid, namely, ethyl mercaptoacetate-1-13C.

5. The method for preparing ethyl thioglycolate according to claim 2, wherein The steps include: Add 1.338g, 4.85mmol of 4-bromobenzenesulfonic acid acetonitrile and 20ml of acetonitrile to the reaction flask under nitrogen protection; at room temperature, drop 442.5mg, 5.82mmol of thioacetic acid, 10 minutes later, slowly drop 735.6mg, 7.27mmol of potassium carbonate, stir at room temperature for 10 minutes, heat to 30℃ and stir for 1h; no raw material in the middle control reaction; Column purification, concentrated under reduced pressure to dryness to obtain a light yellow liquid; namely acetylmercaptoacetonitrile; 498 mg, 4.32 mmol of acetylmercaptoacetonitrile was added with hydrochloric acid and 5 ml of methanol, heated to 30°C and stirred for 2 h under nitrogen protection; 50 ml of water and 50 ml of dichloromethane were added, the mixture was stirred and separated to obtain an organic phase, the aqueous phase was extracted once more with 40 ml of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain a colorless liquid, namely, methyl thioglycolate.

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