CN113430546B - Preparation method of homocysteine thiolactone hydrochloride - Google Patents
Preparation method of homocysteine thiolactone hydrochloride Download PDFInfo
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- CN113430546B CN113430546B CN202110640974.6A CN202110640974A CN113430546B CN 113430546 B CN113430546 B CN 113430546B CN 202110640974 A CN202110640974 A CN 202110640974A CN 113430546 B CN113430546 B CN 113430546B
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Abstract
The invention discloses a preparation method of homocysteine thiolactone hydrochloride, which is characterized in that homocysteine thiolactone hydrochloride is obtained by electrolytic reduction of homocysteine; wherein, the electrolytic reduction is carried out in an ion diaphragm electrolyzer; the catholyte is hydrochloric acid solution of homocysteine, and the anolyte is dilute sulfuric acid solution; the cathode adopts titanium wires, and a carbon felt net is fixed at the bottom of the titanium wires; the anode adopts lead wires; the metal ion content in the product is low; in the synthesis process, the operation is safe, no waste water or waste gas is generated, and the method is environment-friendly. In addition, the method has high product yield.
Description
Technical Field
The invention relates to a preparation method of homocysteine thiolactone hydrochloride.
Background
The homocysteine thiolactone hydrochloride is an important biochemical reagent and a drug intermediate, and can be used for preparing medicines such as cetirisone, erdosteine and the like. Cetirizine is mainly used for acute craniocerebral trauma and conscious disturbance after brain operation; erdosteine is used for respiratory tract obstruction caused by viscous sputum of acute and chronic bronchitis.
At present, homocysteine thiolactone hydrochloride is synthesized by reducing homocysteine by using zinc or tin and hydrochloric acid.
However, the homocysteine thiolactone hydrochloride synthesized by the method has high metal ion content in the homocysteine thiolactone hydrochloride product; secondly, the method needs to use a large amount of zinc or tin and hydrochloric acid to generate a large amount of hydrogen, has high operation risk, and also generates a large amount of zinc salt or tin salt wastewater, thus polluting the environment very much; thirdly, the method has low yield, and the calculated yield is about 50-60% when the homocysteine is used as a raw material.
Disclosure of Invention
In view of the above-mentioned shortcomings, it is necessary to provide a novel process for preparing homocysteine thiolactone hydrochloride.
A method for preparing homocysteine thiolactone hydrochloride comprises the steps of carrying out electrolytic reduction on homocysteine to obtain homocysteine thiolactone hydrochloride;
wherein, the electrolytic reduction is carried out in an ion diaphragm electrolyzer; the catholyte is hydrochloric acid solution of homocysteine, and the anolyte is dilute sulfuric acid solution; the cathode adopts titanium wires, and a carbon felt net is fixed at the bottom of the titanium wires; the anode adopts lead wires.
The preparation method has low metal ion content in the product; in the synthesis process, the operation is safe, no waste water or waste gas is generated, and the method is environment-friendly. In addition, the method has high product yield.
Preferably, the electrolytic reduction adopts a constant current power supply, and the electrolytic time is 8 h-10 hours.
Preferably, the current of the constant current power supply is 3A.
Preferably, the ion membrane in the ion membrane electrolyzer is a cation membrane.
Preferably, before the electrolytic reduction, inert gas is introduced into the cathode chamber for 3-5 min.
Preferably, after the electrolytic reduction, the method further comprises the steps of:
concentrating the catholyte, filtering, washing the filtered product with absolute ethyl alcohol, vacuum drying, and collecting the first product; vacuum concentrating the absolute ethanol washing liquid, vacuum drying the concentrate, and collecting a second product; the first product and the second product are collected in combination.
Preferably, the temperature of electrolytic reduction is 30-70 ℃.
Preferably, the concentration of the dilute sulfuric acid solution is 1-3 mol/L; the Gao Guang amino acid hydrochloric acid solution is formed by dissolving homocysteine crystals in 1-3 mol/L hydrochloric acid.
Preferably, the homocysteine in the catholyte is obtained by:
methionine and concentrated sulfuric acid are mixed according to the mole ratio of 1: 2-5 feeding, reacting at 70-110 ℃, adjusting the pH to 5-6 after the reaction is completed, and filtering out solid to obtain homocysteine.
Preferably, the homocysteine in the catholyte is obtained by:
methionine reacts with 10% -60% hydrobromic acid and concentrated sulfuric acid, the reaction is carried out under the heating of inert atmosphere, the pH value is regulated to 5-6 after the reaction is finished, and the separated solid is filtered to obtain homocysteine.
Drawings
FIG. 1 is a nuclear magnetic resonance image of the product of example 2.
Detailed Description
The present invention will be described in further detail with reference to the following embodiments in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the detailed description is presented by way of example only and is not intended to limit the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
A method for preparing homocysteine thiolactone hydrochloride comprises the steps of carrying out electrolytic reduction on homocysteine to obtain homocysteine thiolactone hydrochloride;
wherein, the electrolytic reduction is carried out in an ion diaphragm electrolyzer; the catholyte is hydrochloric acid solution of homocysteine, and the anolyte is dilute sulfuric acid solution; the cathode adopts titanium wires, and a carbon felt net is fixed at the bottom of the titanium wires; the anode adopts lead wires.
Because the cathode adopts titanium wires, and a carbon felt net is fixed at the bottom of the titanium wires; thus, the overpotential of the cathode can be effectively reduced, and the area of the cathode is increased, so that more hydrogen is generated by electrolysis in unit time, and the electrolytic reduction reaction is facilitated. The anode and the cathode are made of different materials, and the anode is made of lead wires; is beneficial to reducing the resistance of the whole electrolysis. If the same material as the cathode is used as the anode, the anolyte is dilute sulfuric acid solution, so that the whole electrolytic resistance is extremely large, and the current is almost zero.
The whole electrolytic electrode is simple and durable, has high mechanical strength and is suitable for mass production.
Wherein, the homocysteine of the invention can be D-homocysteine, L-homocysteine or DL-homocysteine; the corresponding homocysteine is D-homocysteine, L-homocysteine or DL-homocysteine.
Preferably, the electrolytic reduction adopts a constant current power supply, and the electrolytic time is 8 h-10 hours. The power supply device for electrolytic reduction is constant-current and constant-voltage power supply device, can control constant current or constant voltage and provides direct current.
Preferably, the current of the constant current power supply is 3A.
Preferably, the ion diaphragm in the ion diaphragm electrolyzer is a cation diaphragm, so that H can be led to + Ion passage, increase H in catholyte + Concentration of ions. When the cationic diaphragm is selected, the cationic diaphragm is preferably certain in acid resistance and high temperature resistance.
Preferably, before the electrolytic reduction, inert gas is introduced into the cathode chamber for 3-5 min. And inert gas is introduced for 3-5 min, so that air is discharged, and interference is avoided.
Preferably, after the electrolytic reduction, the method further comprises the steps of:
concentrating the catholyte, filtering, washing the filtered product with absolute ethyl alcohol, vacuum drying, and collecting the first product; vacuum concentrating the absolute ethanol washing liquid, vacuum drying the concentrate, and collecting a second product; the first product and the second product are collected in combination.
Preferably, the temperature of electrolytic reduction is 30-70 ℃.
Preferably, the concentration of the dilute sulfuric acid solution is 1-3 mol/L; the Gao Guang amino acid hydrochloric acid solution is formed by dissolving homocysteine crystals in 1-3 mol/L hydrochloric acid.
Preferably, the homocysteine in the catholyte is obtained by:
methionine and concentrated sulfuric acid are mixed according to the mole ratio of 1: 2-5 feeding, reacting at 70-110 ℃, adjusting the pH to 5-6 after the reaction is completed, and filtering out solid to obtain homocysteine.
Preferably, the homocysteine in the catholyte is obtained by:
methionine reacts with 10% -60% hydrobromic acid and concentrated sulfuric acid, the reaction is carried out under the heating of inert atmosphere, the pH value is regulated to 5-6 after the reaction is finished, and the separated solid is filtered to obtain homocysteine.
The corresponding methionine is D-methionine, L-methionine, DL-methionine according to DL-properties of the final product.
The invention is further illustrated below with reference to specific examples.
Example 1
Adding 1kg of homocysteine into 8L of hydrochloric acid solution with the concentration of 2mol/L, and uniformly mixing to form a solution serving as a catholyte; a sulfuric acid solution of 1mol/L was used as the anolyte.
The cathode adopts titanium wires, a carbon felt net with proper size is fixed at the bottom of the titanium wires, and the anode adopts lead wires. The cathode and anode chambers of the electrolytic cell are separated by a cation membrane.
The electrolysis condition is kept at constant current of 3.0A, the electrolysis temperature is 45 ℃, and the electrolysis is carried out for 8 hours; the detection cathode was free of DL-homocysteine. Then concentrating the crystalline catholyte, filtering, washing with absolute ethyl alcohol, vacuum drying, vacuum concentrating the absolute ethyl alcohol filtrate again, vacuum drying the concentrate, mixing to obtain 1.01kg of solid, the yield is 95% (calculated by taking homocysteine as a base number), and the purity is 99.03%.
Example 2
2kg of methionine and 4kg of concentrated sulfuric acid (the mass fraction is 98%) are sequentially added into a reaction kettle, and the internal temperature is kept at 100 ℃ for reaction for 8 hours to obtain hydrolysate. The hydrolysis liquid is neutralized to pH 5-6 by sodium hydroxide alkali liquor, solid is separated out, and after cooling, suction filtration and water washing are carried out, thus obtaining 1.084kg of homocysteine with the yield of 54.2% (calculated by taking methionine as the base number).
1.084kg of homocysteine was dissolved in 2mol/L of 8.7L hydrochloric acid solution as catholyte and 1mol/L sulfuric acid solution as anolyte. The cathode of the electrolytic tank adopts titanium wires, a carbon felt net with proper size is fixed at the bottom of the electrolytic tank, and the anode adopts lead wires. The cathode and anode chambers of the electrolytic cell are separated by a cationic diaphragm, and the cathode and anode are applied to the cationic diaphragm electrolytic cell. And (3) under the electrolysis condition, maintaining constant current at 3.0A, and electrolyzing for 9 hours at the electrolysis temperature of 45 ℃ to detect that the cathode has no homocysteine. Then concentrating the crystal cathode liquid, filtering, washing with absolute ethyl alcohol, vacuum drying, vacuum concentrating the absolute ethyl alcohol filtrate, vacuum drying the concentrate, and mixing to obtain 1.187kg of solid.
The product was analyzed by high performance liquid chromatography in a yield of 95.5% (calculated on the basis of homocysteine) and 53.9% (calculated on the basis of methionine) and had a purity of 99.4%.
Nuclear magnetic resonance was performed on the product, and the result was shown in fig. 1.
Example 3
2kg of methionine and 6.94kg of 40% hydrobromic acid are sequentially added into a reaction kettle, 2.68kg of concentrated sulfuric acid (the mass fraction is 98%) is added dropwise at low temperature, after the dropwise addition is finished, the system is heated, and the internal temperature is kept at 120 ℃ for reaction for 6 hours, so that hydrolysate is obtained. Neutralizing the hydrolysis solution with sodium hydroxide alkali liquor to pH of about 5-6, precipitating solid, cooling, suction filtering, and washing with water to obtain homocysteine 1.69kg with 94% (calculated by taking methionine as base number).
1.69kg of homocysteine was dissolved in 2mol/L of 13.5L of hydrochloric acid solution as catholyte and 1mol/L of sulfuric acid solution as anolyte. The cathode of the electrolytic tank adopts titanium wires, a carbon felt net with proper size is fixed at the bottom of the electrolytic tank, and the anode adopts lead wires. The cathode and anode chambers of the electrolytic cell are separated by a cationic diaphragm, and the cathode and anode are applied to the cationic diaphragm electrolytic cell. And (3) under the electrolysis condition, maintaining constant current at 3.0A, and electrolyzing for 10 hours at the electrolysis temperature of 45 ℃ to detect that the cathode has no homocysteine. Then concentrating the crystalline catholyte, filtering, washing with absolute ethyl alcohol, vacuum drying, vacuum concentrating the absolute ethyl alcohol filtrate again, vacuum drying the concentrate, mixing to obtain 1.86kg of solid, 96.1% of yield (calculated by taking homocysteine as a base number), 90.3% of yield (calculated by taking methionine as a base number) and 99.6% of purity.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (9)
1. A preparation method of homocysteine thiolactone hydrochloride is characterized in that homocysteine thiolactone hydrochloride is obtained by electrolytic reduction of homocysteine;
wherein, the electrolytic reduction is carried out in an ion diaphragm electrolyzer; the catholyte is hydrochloric acid solution of homocysteine, and the anolyte is dilute sulfuric acid solution; the cathode adopts titanium wires, and a carbon felt net is fixed at the bottom of the titanium wires; the anode adopts lead wires;
the homocysteine in the catholyte is obtained by:
methionine reacts with 10% -60% hydrobromic acid and concentrated sulfuric acid, the reaction is carried out under the heating of inert atmosphere, the pH value is regulated to 5-6 after the reaction is finished, and the separated solid is filtered to obtain homocysteine.
2. The method for preparing homocysteine thiolactone hydrochloride according to claim 1, wherein the electrolytic reduction adopts a constant current power supply, and the electrolytic time is 8 h-10 h.
3. The method for preparing homocysteine thiolactone hydrochloride according to claim 2 wherein the current of the constant current power source is 3A.
4. The method for preparing homocysteine thiolactone hydrochloride according to claim 1 wherein the ion membrane in the ion membrane electrolyzer is a cation membrane.
5. The method for preparing homocysteine thiolactone hydrochloride according to claim 1, wherein inert gas is introduced into the cathode chamber for 3 min-5 min before the electrolytic reduction.
6. The method for preparing homocysteine thiolactone hydrochloride according to claim 1 further comprising the steps of, after electrolytic reduction:
concentrating the catholyte, filtering, washing the filtered product with absolute ethyl alcohol, vacuum drying, and collecting the first product; vacuum concentrating the absolute ethanol washing liquid, vacuum drying the concentrate, and collecting a second product; the first product and the second product are collected in combination.
7. The method for preparing homocysteine thiolactone hydrochloride according to claim 1 wherein the temperature of the electrolytic reduction is 30-70 ℃.
8. The method for preparing homocysteine thiolactone hydrochloride according to claim 1, wherein the concentration of the dilute sulfuric acid solution is 1-3 mol/L; the Gao Guang amino acid hydrochloric acid solution is formed by dissolving homocysteine crystals in 1-3 mol/L hydrochloric acid.
9. The method for preparing homocysteine thiolactone hydrochloride according to claim 1 wherein the homocysteine in the catholyte is obtained by:
methionine and concentrated sulfuric acid are mixed according to the mole ratio of 1: 2-5 feeding, reacting at 70-110 ℃, adjusting the pH to 5-6 after the reaction is completed, and filtering out solid to obtain homocysteine.
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| CN1036408C (en) * | 1992-12-31 | 1997-11-12 | 福建师范大学 | Special electrode for preparing L-semicystine by electrolytic reduction |
| CN1232091A (en) * | 1998-04-13 | 1999-10-20 | 华中师范大学 | Electrolytic bath for pollution-free electrolytic synthesis of L-cysteine hydrochloride and glyoxalic acid |
| CN101144169A (en) * | 2007-08-24 | 2008-03-19 | 湖北新生源生物工程股份有限公司 | Method for producing DL-homocysteine lactone hydrochlorate |
| CN206298653U (en) * | 2016-12-21 | 2017-07-04 | 罗江晨明生物制品有限公司 | A kind of electrolysis unit for preparing cysteine |
| CN109943860B (en) * | 2019-04-26 | 2019-12-31 | 武汉本杰明医药股份有限公司 | Synthesis method of DL-homocysteine thiolactone hydrochloride |
| CN111004209A (en) * | 2019-12-24 | 2020-04-14 | 浙江工业大学 | Continuous production method of DL-homocysteine thiolactone hydrochloride |
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| 电化学方法合成DL-高半胱氨酸硫内酯盐酸盐;何文秀等;《广东化工》;第57卷(第414期);83-84 * |
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