CN111072533A - Preparation method of 2-mercaptoisobutyric acid - Google Patents
Preparation method of 2-mercaptoisobutyric acid Download PDFInfo
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- CN111072533A CN111072533A CN202010100654.7A CN202010100654A CN111072533A CN 111072533 A CN111072533 A CN 111072533A CN 202010100654 A CN202010100654 A CN 202010100654A CN 111072533 A CN111072533 A CN 111072533A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/36—Nitrogen atoms
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Abstract
The invention relates to a preparation method of 2-mercapto isobutyric acid, in particular to a method for preparing isothiourea salt by reacting methyl (ethyl) 2-bromoisobutyrate with thiourea, and then obtaining 2-mercapto isobutyric acid by alkaline hydrolysis and acidification. The method has the advantages of low cost, mild reaction conditions and high yield, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 2-mercaptoisobutyric acid.
Background
2-mercapto isobutyric acid is an important intermediate for synthesizing biological medicines and materials. In terms of biomedical synthesis, a drug for buclizine, prevention or treatment of non-alcoholic steatohepatitis, an anti-leukemia active drug, a potassium channel opener vasodilator, a thiol-based angiotensin converting enzyme inhibitor, a CGRP receptor antagonist that can relieve headache, an orexin receptor antagonist, an opener of KATP channel, an HDAC inhibitor of a mercaptoacetamide-based ligand, etc.; for the synthesis of 2-thiazolethio (alk) one derivatives, novel cyclic disulfides and episulfide derivatives; and also for the synthesis of nematicides and fungicides. In the aspect of material synthesis, the method is used for synthesizing a concrete high molecular compound and low-epoxy mercapto carboxylic acid polyol ester. 2-mercapto-isobutyric acid and downstream products thereof have strong market demands, and the development of the research on the industrial scale production process of 2-mercapto-isobutyric acid is particularly important.
According to the reports of domestic and foreign documents, the synthetic route of 2-mercaptoisobutyric acid mainly comprises the following steps.
1. 2-ethylxanthate isobutyric acid is obtained by reacting 2-bromoisobutyric acid with potassium ethylxanthate, and 2-mercaptoisobutyric acid is obtained by hydrolyzing (Nuclear Medicine and Biology, 33(3),381-390; 2006). However, potassium ethylxanthate is expensive, and the use of aqueous ammonia as a hydrolysis liquid requires high storage and use, so that this method is limited in practical production.
2. Methyl 2-chloroisobutyrate is reacted with a methanolic solution of sodium methyl mercaptide in a saturated hydrogen sulfide environment to give methyl 2-mercaptoisobutyrate, which is hydrolyzed to give 2-mercaptoisobutyric acid (Jpn. Kokai Tokkyo Koho, 63010755, 18Jan 1988). Wherein, the hydrogen sulfide has bad smell and high toxicity, the source of the raw material 2-chloro methyl isobutyrate is less, and the industrial production process is difficult to develop.
3. Isothiouronium salt is formed by reacting 2-bromoisobutyric acid with thiourea and is hydrolyzed to give 2-mercaptoisobutyric acid (Journal of the American Chemical Society, 139(51), 18476-18479; 2017) according to the following reaction equation. The temperature required by the reflux reaction of the process is very high, the control is not easy, the thiourea is easy to decompose at high temperature, the utilization rate is low, and the process is not beneficial to the industrial production process.
Disclosure of Invention
The invention aims to provide a novel method for preparing 2-mercaptoisobutyric acid, which has the advantages of mild reaction conditions, low cost and high yield and is more suitable for the requirement of industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme.
A preparation method of 2-mercaptoisobutyric acid is characterized in that ethanol and thiourea are added into an ① reaction kettle, methyl (ethyl) 2-bromoisobutyrate is added after heating and dissolving, reflux reaction is carried out for 3-10 h, ethanol solvent is evaporated at normal pressure after reflux is finished, recycling is carried out, ② alkali liquor is added into the reaction kettle, reflux reaction is carried out for 3-8 h, cooling is carried out, hydrochloric acid is dropwise added for acidification, ③ chloroform is added into the acidified kettle, the mixture is stirred fully and then stands for layering, a lower organic phase is collected, chloroform is recovered through normal pressure distillation, and liquid in the kettle is cooled, crystallized and dried in vacuum to obtain the 2-mercaptoisobutyric acid.
Wherein the molar ratio of the methyl (ethyl) 2-bromoisobutyrate to the thiourea in the step ① is 1: 1-1.5.
Wherein the mass of the ethanol in the step ① is 3-6 times of that of the thiourea.
Wherein the heating and dissolving temperature in the step ① is 40-60 ℃, and the reflux reaction temperature is 70-90 ℃.
Wherein the alkali liquor in the step ② is an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like, preferably an aqueous solution of sodium hydroxide, the mass fraction of which is 20-32%, and the molar weight of which is 3-5 times that of thiourea.
Wherein the reflux reaction temperature in the step ② is 90-110 ℃.
Wherein, in the step ②, the acidifying agent can be at least one of aqueous solutions of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like, preferably a hydrochloric acid solution, the mass fraction is 20% -35%, and the molar weight is 1-1.4 times of that of sodium hydroxide.
Wherein the mass of the extracting agent chloroform in the step ③ is 2-5 times of that of methyl (ethyl) 2-bromoisobutyrate.
The reaction equation for the process of the present invention is shown below.
Compared with the prior art, the method has the advantages that: 2-bromoisobutyrate is used as a raw material, the price is low, the reaction condition is mild, and the yield can reach more than 95 percent; the organic solvent can be recycled in the reaction, and the pollution is small.
Detailed Description
The technical solution of the present invention is further described in detail with reference to the following examples, but the scope of the present invention is not limited thereto.
Example 1
① adding ethanol 370g and thiourea 62.5g into a reaction kettle, heating to 50 ℃ to dissolve, adding methyl 2-bromoisobutyrate 148.4g, heating to 75 ℃ to carry out reflux reaction for 5h, distilling under normal pressure to recover ethanol after the reaction is finished, adding ② g of sodium hydroxide aqueous solution with the mass fraction of 32% into the reaction kettle, keeping the reflux for 5h at 110 ℃, cooling to room temperature after the reflux is finished, dropwise adding hydrochloric acid with the mass fraction of 30%, ③ adding chloroform 350g into the acidified kettle, fully stirring, extracting, standing, layering, collecting a lower organic phase, distilling under normal pressure to recover chloroform, cooling, crystallizing and drying under vacuum to obtain 94.4g of 2-mercaptoisobutyric acid with the yield of 95.8%.
Example 2
① of reaction kettle is added with 425g of ethanol and 85g of thiourea, the mixture is heated to 55 ℃ to be dissolved, 160g of ethyl 2-bromoisobutyrate is added, the temperature is raised to 83 ℃ for reflux reaction for 4 hours, ethanol is recovered by atmospheric distillation after the reaction is finished, ② of reaction kettle is added with 440g of sodium hydroxide aqueous solution with the mass fraction of 32%, the reflux is maintained at 110 ℃ for 4 hours, 430g of hydrochloric acid with the mass fraction of 30% is added after the reflux is finished and cooled, ③ of reaction kettle is added with 480g of chloroform, the mixture is fully stirred, extracted, kept stand and layered, a lower organic phase is collected, chloroform is recovered by atmospheric distillation, 94.8g of 2-mercaptoisobutyric acid is obtained after the liquid in the kettle is cooled, crystallized and dried in vacuum, and the yield is 96.2%.
Example 3
① adding 400g of ethanol and 82g of thiourea into a reaction kettle, heating to 55 ℃ to dissolve, adding 160g of ethyl 2-bromoisobutyrate, heating to 83 ℃ to perform reflux reaction for 6 hours, distilling at normal pressure to recover ethanol after the reaction is finished, adding ② g of 25 mass percent sodium hydroxide aqueous solution into the reaction kettle, maintaining the reflux for 4 hours at 110 ℃, dropwise adding 420g of 35 mass percent hydrochloric acid after the reflux is finished and cooling, ③ adding 450g of chloroform into the acidified kettle, fully stirring and extracting, standing for layering, collecting a lower organic phase, distilling at normal pressure to recover chloroform, cooling and crystallizing the liquid in the kettle, and drying in vacuum to obtain 94.1g of 2-mercaptoisobutyric acid with the yield of 95.5%.
Claims (8)
1. A preparation method of 2-mercaptoisobutyric acid is characterized by comprising the steps of adding ethanol and thiourea into an ① reaction kettle, heating to dissolve, adding methyl (ethyl) 2-bromoisobutyrate, carrying out reflux reaction for 3-10 hours, carrying out reflux, distilling off ethanol solvent at normal pressure after the reflux is finished, recycling, adding ② alkali liquor into the reaction kettle, carrying out reflux reaction for 3-8 hours, cooling, dropwise adding hydrochloric acid for acidification, adding ③ chloroform into the acidified kettle, fully stirring, standing for layering, collecting a lower organic phase, carrying out normal-pressure distillation to recover chloroform, cooling, crystallizing and carrying out vacuum drying on liquid in the kettle to obtain the 2-mercaptoisobutyric acid.
2. The method of claim 1, wherein the molar ratio of methyl (ethyl) 2-bromoisobutyrate to thiourea in step ① is 1: 1 to 1.5.
3. The method of claim 1, wherein the amount of ethanol used in step ① is 3 to 6 times the amount of thiourea.
4. The method of claim 1, wherein the heating temperature in step ① is 40 to 60 ℃ and the reflux reaction temperature is 70 to 90 ℃.
5. The method for preparing 2-mercaptoisobutyric acid according to claim 1, wherein the alkali solution in step ② is an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., preferably an aqueous solution of sodium hydroxide, with a mass fraction of 20% to 32%, and a molar amount of 3 to 5 times that of thiourea.
6. The method of claim 1, wherein the reflux reaction temperature in step ② is 90 to 110 ℃.
7. The method of claim 1, wherein the acidifying agent in step ② is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, etc., preferably hydrochloric acid solution, in an aqueous solution, with a mass fraction of 20% to 35%, and a molar amount of 1 to 1.4 times that of sodium hydroxide.
8. The method of claim 1, wherein the mass of the extraction agent chloroform in step ③ is 2 to 5 times that of methyl (ethyl) 2-bromoisobutyrate.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010100654.7A CN111072533A (en) | 2020-02-19 | 2020-02-19 | Preparation method of 2-mercaptoisobutyric acid |
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| CN202010100654.7A CN111072533A (en) | 2020-02-19 | 2020-02-19 | Preparation method of 2-mercaptoisobutyric acid |
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2020
- 2020-02-19 CN CN202010100654.7A patent/CN111072533A/en not_active Withdrawn
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