CN109485581B - Method for refining levodopa - Google Patents
Method for refining levodopa Download PDFInfo
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- CN109485581B CN109485581B CN201811372460.1A CN201811372460A CN109485581B CN 109485581 B CN109485581 B CN 109485581B CN 201811372460 A CN201811372460 A CN 201811372460A CN 109485581 B CN109485581 B CN 109485581B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
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Abstract
The invention discloses a method for refining levodopa, which comprises the following steps: (1) preparing a leaching solution, (2) dissolving, (3) removing impurities, (4) removing phenol, and (5) recrystallizing to obtain refined levodopa. The leaching liquor used by the invention can fully dissolve the levodopa and impurities thereof, most of the impurities can be removed by separating out the levodopa after crystallization, the quality of the finished levodopa is ensured, and meanwhile, a good environment is provided for removing tyrosine in the subsequent steps, so that the tyrosine is removed more thoroughly. The purity of the refined levodopa prepared by the invention is more than or equal to 99 percent, and the tyrosine content in the product is less than or equal to 0.1 percent according to the detection of the method of United states pharmacopoeia UPS38 edition.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a method for refining levodopa.
Background
Levodopa (3, 4-dihydrophenyl alanine, L-Dopa) belongs to phenylalanine compounds, is the most common and effective medicament for treating essential paralysis agitans and non-drug-induced paralysis agitans syndrome (Parkinson disease) at present, and is one of the main effective active ingredients of velvet bean and velvet bean. White or off-white crystalline powder, chemical name: 3-hydroxy-L-tyrosine, molecular formula: c9H11NO4Molecular weight: 197.19, english name: levodopa, CAS accession number: 59-92-7, EINECS No: 200-445-2. Levodopa is an amphoteric amino acid, has an isoelectric point of 3.5, is readily soluble in dilute acid, is slightly soluble in aqueous solutions with a pH of greater than 3.5, and is insoluble in ethanol, diethyl ether and chloroform. Levodopa is one of the effective drugs for treating paralysis agitans at present, is one of precursors for synthesizing norepinephrine, dopamine and the like in vivo, and belongs to catecholamine. Levodopa can enter the brain through the blood brain barrier and is converted into dopamine through the decarboxylation of polymaleate decarboxylase to play a role.
At present, the preparation method of levodopa mainly comprises chemical synthesis, extraction from natural plants, biological enzyme catalysis and microbial fermentation. The production mainly comprises a hydroalcoholic method, an acid-water method, a solvent extraction method, an isoelectric precipitation method, an acid-water-resin method and the like. However, the purity of the produced levodopa often cannot meet the standards of exported America or European Union, and tyrosine and specific medicines such as levodopa and antidepressant drugs have interactive influence. According to the detection standard of Chinese pharmacopoeia, the tyrosine content in levodopa is required to be lower than 0.5%; according to the detection standard of the United states pharmacopoeia, the tyrosine content is required to be lower than 0.1 percent. The tyrosine content in the levodopa is the main reason for the insufficient purity of the levodopa. Therefore, the research on the method for refining the levodopa to reduce the tyrosine content of the levodopa has important significance.
Disclosure of Invention
Aiming at the defects, the invention provides a method for refining levodopa, aiming at reducing the content of tyrosine in the levodopa, the leaching liquor used by the invention can fully dissolve the levodopa and impurities thereof, the levodopa separated out after crystallization can remove most of the impurities, the quality of the finished levodopa is ensured, and meanwhile, a good environment is provided for removing tyrosine in the subsequent steps, so that the tyrosine is removed more thoroughly. The purity of the refined levodopa prepared by the invention is more than or equal to 99 percent, and the tyrosine content in the product is less than or equal to 0.1 percent according to the detection of the method of United states pharmacopoeia UPS38 edition.
The invention is realized by the following technical scheme:
a method of refining levodopa comprising the steps of:
(1) preparing a leaching solution: mixing phenol and water according to a weight ratio of 1: 3-5, and heating to 65-70 ℃ to mix and dissolve the phenol and the water to obtain a leaching solution;
(2) dissolving: taking a levodopa crude product, adding leaching liquor which is 3-5 times of the levodopa crude product in weight, dissolving the levodopa crude product to saturation at 65-70 ℃, standing for 40-60 min to fully dissolve the levodopa crude product, and then filtering at 65-70 ℃; the levodopa crude product is extracted from plant croton or other plants containing levodopa;
(3) removing impurities: cooling the filtrate to precipitate levodopa and phenol, and filtering to obtain precipitate;
(4) removing phenol: adding absolute ethanol with the weight 5-10 times of that of the precipitate obtained in the step (3), dissolving phenol, removing to obtain a solid levodopa, and repeating the operation for 1-2 times;
(5) and (3) recrystallization: and (3) adding hydrochloric acid which is 5-8 times of the weight of the solid levodopa into the solid levodopa, adjusting the pH value to 1.0-1.5, heating to boil, adding the solid levodopa into the mixture to dissolve the solid levodopa to a saturated state, cooling to crystallize and separate the levodopa out, collecting the separated crystal, and drying to obtain the fine levodopa.
The mass fraction of the hydrochloric acid is 0.05-0.2 mol/L.
Generally, levodopa immediately denatures after the pH of the solution is greater than 6.5, which causes the solution to immediately turn black. The applicant of the invention finds out through countless tests that the phenol-water system is slightly acidic, can well protect the invariance of the levodopa and can well dissolve the levodopa, which is a place different from the traditional process that the crude product is directly hot-dissolved by a strong acid solution and then is cold-precipitated. The method provided by the invention can be used for dissolving the crude levodopa product at 65-70 ℃, has high solubility and strong selectivity on levodopa, has relatively low solubility on tyrosine, can remove most impurities after levodopa is crystallized and precipitated, ensures the quality of finished levodopa, and provides a good environment for tyrosine removal in subsequent steps, so that tyrosine is removed more thoroughly. In addition, in the recrystallization step, the pH value is adjusted to be 1.0-1.5, and the solid levodopa is dissolved to be in a saturated state at 50-60 ℃, so that the levodopa precipitated under the condition of the invention cannot be oxidized, and the refined levodopa obtained by crystallization has high purity and high quality.
Levodopa is an amphoteric amino acid, has an isoelectric point of 3.5, is readily soluble in acids, and is sparingly soluble in aqueous solutions having a pH of > 3.5. Levodopa is one of the effective drugs for treating paralysis agitans at present, is one of precursors for synthesizing norepinephrine, dopamine and the like in vivo, and belongs to catecholamine. Levodopa is an intermediate product of the formation of catecholamines from tyrosine, i.e., a precursor of dopamine. About 95% of the L-dopa absorbed into the blood is decarboxylated by dopa decarboxylase in peripheral tissues to form catecholamine, which is not easy to pass through the blood brain barrier and causes many adverse reactions. Only 1% of L-dopa enters the brain circulation and reaches the central nervous system, where it is converted into catecholamine for therapeutic effect. The structural formula is as follows:
the chemical name of tyrosine (tyrosine; Tyr) is 2-amino-3-p-hydroxyphenylpropionic acid, which is also called Chinese: (S) -2-amino-3-p-hydroxy, (2S,3R) -2-amino-3-p-hydroxyphenylpropionic acid, L- β -p-hydroxyphenyl- β -alanine, L- β -p-hydroxyphenyl- α -aminopropionic acid, english name: tyrosine. The molecular formula is as follows: c9H11NO3Molecular weight: 181.18900. it is an aromatic polar alpha-amino acid containing phenolic hydroxyl group, and is white crystalline powder, and is crystallized from water into needle or sheet. The relative density is 1.456(20 ℃), and the isoelectric point is 5.66; melting point: levorotatory isomer decomposes at 290-295 ℃ (slow heating), decomposes at 314-318 ℃ (fast heating), decomposes at 290-295 ℃ (slow heating) and decomposes at 340 ℃ (fast heating). Soluble in water, ethanol, acids and bases, insoluble in diethyl ether.
Phenol (Phenol) with the molecular formula C6H5OH, melting point of 43 ℃, is colorless acicular crystal with special smell, is slightly soluble in water at normal temperature, is easily soluble in organic solvent, and can be dissolved in ethanol, ether, chloroform and glycerol; when the temperature is higher than 65 ℃, the water-soluble polymer can be mutually dissolved with water in any proportion. Phenol belongs to phenolic substances, has weak acidity, has pH of 5-6 when dissolved in water, and can be dissolved stably under the weak acidity condition without blackening to influence quality.
The lower the tyrosine content in the levodopa, the better the treatment effect for the levodopa entering through the blood brain barrier, and the tyrosine can influence the drug effect of the levodopa. According to the detection standard of Chinese pharmacopoeia, the tyrosine content in levodopa is required to be lower than 0.5%; according to the detection standard of the United states pharmacopoeia, the tyrosine content is required to be lower than 0.1 percent. According to the process of the invention, tyrosine contents of less than 0.1% can be achieved by strict control, and the standards for export to the United states (according to the United states pharmacopoeia UPS 38).
The invention has the beneficial effects that:
1. the method for refining the levodopa greatly reduces the content of tyrosine, improves the purity of the levodopa, ensures that the purity of the prepared levodopa is more than or equal to 99 percent, and has the tyrosine content of less than or equal to 0.1 percent according to the detection of the method of United states pharmacopoeia UPS38 edition, compared with the levodopa produced according to the common process, the tyrosine content is reduced by 2-5 times, thereby meeting the requirement of the United states FDA on the tyrosine content of the levodopa.
2. The method for refining the levodopa has the advantages of simple process, high yield of finished products and low equipment requirement, and can be used for industrial production. The method does not need resin to absorb tyrosine for purification, can greatly reduce the manpower and material resources consumed for sewage treatment, reduces the production cost, and improves the quality of fine levodopa.
3. According to the method for refining the levodopa, the used leaching liquor is formed by mixing phenol and water according to the weight ratio of 1: 3-5, the levodopa and a small amount of impurities are fully dissolved by adopting a similar compatibility principle, a levodopa crude product is dissolved at 65-70 ℃, the solubility to the levodopa is the largest, the selectivity is strong, the solubility to the tyrosine is relatively small, most impurities can be removed after the levodopa is crystallized and precipitated, the quality of the finished levodopa is guaranteed, meanwhile, a good environment is provided for removing the tyrosine in the subsequent steps, and the tyrosine is removed more thoroughly.
4. In the recrystallization step, the pH value is adjusted to be 1.0-1.5, the solid levodopa is dissolved at 50-60 ℃ to be in a saturated state, the levodopa precipitated under the condition cannot be oxidized, and the refined levodopa obtained by crystallization has high purity and high quality.
Detailed Description
In order to make the technical solutions and advantages of the present invention clearer, the following describes the technical solutions of the present invention clearly and completely in combination with the embodiments of the present invention.
Example 1
A method for refining levodopa comprises the following steps:
(1) preparing a leaching solution: mixing phenol and water according to the weight ratio of 1:3, and heating to 70 ℃ to mix and dissolve the phenol and the water to obtain a leaching solution;
(2) dissolving: taking a levodopa crude product, adding leaching liquor with the weight 3 times of that of the levodopa crude product, dissolving to saturation at 70 ℃, standing for 40min, and then filtering at 65 ℃;
(3) removing impurities: cooling the filtrate to precipitate levodopa and phenol, and filtering to obtain precipitate;
(4) removing phenol: adding absolute ethanol with the weight 5 times of that of the precipitate obtained in the step (3), dissolving phenol, and removing to obtain a solid levodopa;
(5) and (3) recrystallization: adding hydrochloric acid with the mass fraction of 0.05 mol/L, the weight of which is 8 times that of the solid levodopa, adjusting the pH value to 1.5, heating to boil, adding the solid levodopa to dissolve to a saturated state, cooling to crystallize and separate the levodopa, collecting separated crystals, and drying to obtain the refined levodopa.
Example 2
A method for refining levodopa comprises the following steps:
(1) preparing a leaching solution: mixing phenol and water according to the weight ratio of 1:4, and heating to 68 ℃ to mix and dissolve the phenol and the water to obtain a leaching solution;
(2) dissolving: taking a levodopa crude product, adding leaching liquor with the weight 5 times of the levodopa crude product, dissolving to saturation at 68 ℃, standing for 50min, and then filtering at 68 ℃;
(3) removing impurities: cooling the filtrate to precipitate levodopa and phenol, and filtering to obtain precipitate;
(4) removing phenol: adding absolute ethanol with the weight 7 times that of the precipitate obtained in the step (3), dissolving phenol, removing to obtain solid levodopa, and repeating the operation again;
(5) and (3) recrystallization: adding hydrochloric acid with the mass fraction of 0.1 mol/L, which is 6 times of the weight of the solid levodopa, into the solid levodopa, adjusting the pH to 1.2, heating to boil, adding the solid levodopa to dissolve to a saturated state, cooling to crystallize and separate the levodopa, collecting the separated crystals, and drying to obtain the refined levodopa.
Example 3
A method for refining levodopa comprises the following steps:
(1) preparing a leaching solution: mixing phenol and water according to the weight ratio of 1: 5, and heating to 65 ℃ to mix and dissolve the phenol and the water to obtain a leaching solution;
(2) dissolving: taking a levodopa crude product, adding a leaching liquor with the weight 4 times that of the levodopa crude product, dissolving to saturation at 65 ℃, standing for 60min, and then filtering at 70 ℃;
(3) removing impurities: cooling the filtrate to precipitate levodopa and phenol, and filtering to obtain precipitate;
(4) removing phenol: adding absolute ethanol with the weight 8 times of that of the precipitate obtained in the step (3), dissolving phenol, removing to obtain solid levodopa, and repeating the operation for 2 times;
(5) and (3) recrystallization: adding hydrochloric acid with the mass fraction of 0.12 mol/L, which is 6 times of the weight of the solid levodopa, into the solid levodopa, adjusting the pH to 1.0, heating to boil, adding the solid levodopa to dissolve to a saturated state, cooling to crystallize and separate the levodopa, collecting the separated crystals, and drying to obtain the refined levodopa.
Example 4
A method for refining levodopa comprises the following steps:
(1) preparing a leaching solution: mixing phenol and water according to the weight ratio of 1:3, and heating to 68 ℃ to mix and dissolve the phenol and the water to obtain a leaching solution;
(2) dissolving: taking a levodopa crude product, adding leaching liquor with the weight 5 times of the levodopa crude product, dissolving to saturation at 68 ℃, standing for 60min, and then filtering at 68 ℃;
(3) removing impurities: cooling the filtrate to precipitate levodopa and phenol, and filtering to obtain precipitate;
(4) removing phenol: adding 10 times of anhydrous ethanol into the precipitate obtained in the step (3), dissolving phenol, removing to obtain solid levodopa, and repeating the operation;
(5) and (3) recrystallization: adding hydrochloric acid with the mass fraction of 0.2 mol/L, the weight of which is 8 times that of the solid levodopa, adjusting the pH value to 1.0, heating to 55 ℃, adding the solid levodopa to dissolve to a saturated state, cooling to crystallize and separate the levodopa, collecting the separated crystals, and drying to obtain the refined levodopa.
The fine levodopa prepared in the embodiment of the invention can meet the standard requirements by detection according to a method of United states pharmacopoeia UPS38 edition, and the detection result is as follows:
Claims (2)
1. a method for refining levodopa, characterized in that: the method comprises the following steps:
(1) preparing a leaching solution: mixing phenol and water according to a weight ratio of 1: 3-5, and heating to 65-70 ℃ to mix and dissolve the phenol and the water to obtain a leaching solution;
(2) dissolving: taking a levodopa crude product, adding leaching liquor which is 3-5 times of the levodopa crude product in weight, dissolving the levodopa crude product to saturation at 65-70 ℃, standing for 40-60 min, and then filtering at 65-70 ℃;
(3) removing impurities: cooling the filtrate to precipitate levodopa and phenol, and filtering to obtain precipitate;
(4) removing phenol: adding absolute ethanol with the weight 5-10 times of that of the precipitate obtained in the step (3), dissolving phenol, removing to obtain a solid levodopa, and repeating the operation for 1-2 times;
(5) and (3) recrystallization: and (3) adding hydrochloric acid which is 5-8 times of the weight of the solid levodopa into the solid levodopa, adjusting the pH value to 1.0-1.5, heating to boil, adding the solid levodopa into the mixture to dissolve the solid levodopa to a saturated state, cooling to crystallize and separate the levodopa out, collecting the separated crystal, and drying to obtain the fine levodopa.
2. The method of refining levodopa according to claim 1, wherein: the mass fraction of the hydrochloric acid is 0.05-0.2 mol/L.
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| CN111116393A (en) * | 2020-01-03 | 2020-05-08 | 海山都(上海)生物技术有限公司 | Method for removing overproof tyrosine in levodopa by resin method |
| CN113788763B (en) * | 2021-10-26 | 2023-08-15 | 四川大学 | Method for synthesizing levodopa based on bionic hydroxylation system |
| CN117142973B (en) * | 2023-11-01 | 2024-01-09 | 欧尚元智能装备有限公司 | Levodopa and separation and purification method thereof |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102267919A (en) * | 2011-05-31 | 2011-12-07 | 南宁市一锋生物科技有限公司 | Preparation method of L-dopa from Mucuna pruriens |
| US20120077994A1 (en) * | 2009-06-09 | 2012-03-29 | Sartorius Stedim Biotech Gmbh | Method of obtaining secondary plant constituents |
| CN106117072A (en) * | 2016-07-08 | 2016-11-16 | 长兴制药股份有限公司 | A kind of levodopa crystalline powder and manufacture method thereof |
| CN106565425A (en) * | 2016-11-09 | 2017-04-19 | 浙江华海药业股份有限公司 | Method for recycling catechol and levodopa from levodopa mother liquor |
| CN106946721A (en) * | 2017-03-30 | 2017-07-14 | 湖南华诚生物资源股份有限公司 | A kind of method for extracting high-purity tyrosine and levodopa in the beans from cat simultaneously |
| CN107141229A (en) * | 2017-06-30 | 2017-09-08 | 山东鲁抗医药股份有限公司 | A kind of method that levodopa is extracted from conversion fluid |
| CN108484425A (en) * | 2018-05-29 | 2018-09-04 | 上海华堇生物技术有限责任公司 | A kind of polishing purification method of natural levodopa |
| CN108546237A (en) * | 2018-06-15 | 2018-09-18 | 那坡康正天然植物提取有限责任公司 | A method of extracting levodopa by raw material of cat beans |
-
2018
- 2018-11-19 CN CN201811372460.1A patent/CN109485581B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120077994A1 (en) * | 2009-06-09 | 2012-03-29 | Sartorius Stedim Biotech Gmbh | Method of obtaining secondary plant constituents |
| CN102267919A (en) * | 2011-05-31 | 2011-12-07 | 南宁市一锋生物科技有限公司 | Preparation method of L-dopa from Mucuna pruriens |
| CN106117072A (en) * | 2016-07-08 | 2016-11-16 | 长兴制药股份有限公司 | A kind of levodopa crystalline powder and manufacture method thereof |
| CN106565425A (en) * | 2016-11-09 | 2017-04-19 | 浙江华海药业股份有限公司 | Method for recycling catechol and levodopa from levodopa mother liquor |
| CN106946721A (en) * | 2017-03-30 | 2017-07-14 | 湖南华诚生物资源股份有限公司 | A kind of method for extracting high-purity tyrosine and levodopa in the beans from cat simultaneously |
| CN107141229A (en) * | 2017-06-30 | 2017-09-08 | 山东鲁抗医药股份有限公司 | A kind of method that levodopa is extracted from conversion fluid |
| CN108484425A (en) * | 2018-05-29 | 2018-09-04 | 上海华堇生物技术有限责任公司 | A kind of polishing purification method of natural levodopa |
| CN108546237A (en) * | 2018-06-15 | 2018-09-18 | 那坡康正天然植物提取有限责任公司 | A method of extracting levodopa by raw material of cat beans |
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Application publication date: 20190319 Assignee: Guangxi Houde Pharmaceutical Co.,Ltd. Assignor: GUANGXI INSTITUTE OF CHINESE MEDICINE & PHARMACEUTICAL SCIENCE Contract record no.: X2022450000405 Denomination of invention: A method for refining levodopa Granted publication date: 20210709 License type: Common License Record date: 20221227 |