CN109485581A - A method of purification levodopa - Google Patents
A method of purification levodopa Download PDFInfo
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- CN109485581A CN109485581A CN201811372460.1A CN201811372460A CN109485581A CN 109485581 A CN109485581 A CN 109485581A CN 201811372460 A CN201811372460 A CN 201811372460A CN 109485581 A CN109485581 A CN 109485581A
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- levodopa
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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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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of methods for refining levodopa, comprising the following steps: (1) prepares leaching liquor, (2) dissolution, (3) removal of impurities, (4) remove phenol, and (5) recrystallization obtains fine work levodopa.The leaching liquor that the present invention uses can sufficiently dissolve levodopa and its impurity, levodopa is precipitated after crystallization can remove most of impurity, it ensure that the quality of finished product levodopa, while providing good environment to remove tyrosine in subsequent step, tyrosine is made to remove more thorough.Fine work levodopa purity >=99% prepared by the present invention is detected, tyrosine content≤0.1% in product by UPS38 editions methods of United States Pharmacopeia.
Description
Technical field
The present invention relates to pharmaceutical technology field, especially a kind of method for refining levodopa.
Background technique
Levodopa (3,4-Dihydrox ylphenylalanine, L-Dopa) belongs to phenylalanine class compound, is
Treatment primary parkinsonism and non-medicine originality paralysis agitans syndrome (Parkinson's disease) are the most commonly used, effective at present
Drug, it is one of the main effective active composition of cat beans, multitude's beans.White or off-white color crystalline powder, chemical name: 3-
Hydroxyl-l-tyrosine, molecular formula: C9H11NO4, molecular weight: 197.19, English name: Levodopa, CAS accession number: 59-
92-7, No. EINECS: 200-445-2.Levodopa is amphoteric amino acids, and isoelectric point 3.5 is soluble in diluted acid, is slightly soluble in pH
The aqueous solution of > 3.5 does not dissolve in ethyl alcohol, ether and chloroform.Levodopa is one of the active drug of current treatment shaking plasy,
For one of the precursor for synthesizing norepinephrine, dopamine etc. in vivo, belong to catecholamine.Levodopa can by blood-brain barrier into
Enter in brain, be converted to dopamine through Thomas's decarboxylase decarboxylation and play a role.
The preparation method of levodopa mainly has chemical synthesis, extracts in natural plants, biological enzyme and micro- life at present
Object fermentation.Its production mainly has water alcohol method, Acid-water method, solvent extraction method, isoelectric point precipitation and sour water-resin method etc..But
The standard of the outlet U.S. or European Union, tyrosine and levodopa and anti-suppression is often not achieved in its purity of the levodopa produced
The certain drugs such as strongly fragrant medicine can generate reciprocal effect.By the examination criteria of Chinese Pharmacopoeia, it is desirable that tyrosine content is low in levodopa
In 0.5%；And press the examination criteria of United States Pharmacopeia, it is desirable that tyrosine content is lower than 0.1%.The content of tyrosine in levodopa,
It is the main reason for causing levodopa purity inadequate.Therefore, the method that research purification levodopa reduces its tyrosine content
Have great importance.
Summary of the invention
In view of the above deficiencies, the present invention provides a kind of methods for refining levodopa, it is therefore an objective to reduce in levodopa
The content of tyrosine, the leaching liquor that the present invention uses can sufficiently dissolve levodopa and its impurity, levodopa are precipitated after crystallization
Most of impurity can be removed, ensure that the quality of finished product levodopa, while providing well to remove tyrosine in subsequent step
Environment, so that tyrosine is removed more thorough.Fine work levodopa purity >=99% prepared by the present invention, by United States Pharmacopeia UPS38
Version method detects, tyrosine content≤0.1% in product.
The invention is realized by the following technical scheme:
A method of purification levodopa, comprising the following steps:
(1) it prepares leaching liquor: taking phenol and water, mixed according to weight ratio 1:3~5, being heated to 65~70 DEG C keeps its miscible, obtains
Leaching liquor；
(2) it dissolves: taking levodopa crude product, the leaching liquor of 3~5 times of its weight is added, be dissolved under the conditions of 65~70 DEG C full
With, stand 40~60min, dissolve it sufficiently, then filtered under the conditions of 65~70 DEG C；The levodopa crude product be from
Plant crotons or other plant extracts containing levodopa；
(3) it cleans: taking filtrate cooling, levodopa and phenol is precipitated, consider taking precipitate；
(4) it removes phenol: taking step (3) resulting sediment, the dehydrated alcohol of 5~10 times of its weight is added, removed after dissolving phenol
It goes, obtains levodopa solid content, repeat this operation 1~2 time；
(5) it recrystallizes: taking levodopa solid content, the hydrochloric acid of 5~8 times of its weight is added, adjust pH 1.0~1.5, be heated to boiling
It rises, levodopa solid content is added and is dissolved to saturation state, letting cool is precipitated levodopa crystallization, and the crystal for collecting precipitation is dry
It is dry to get fine work levodopa.
The mass fraction of the hydrochloric acid is 0.05~0.2 mol/L.
Under normal circumstances, after solution ph is greater than 6.5, levodopa can be denaturalized immediately, make the blackening immediately of its solution.This
Patent application people has found that phenol-aqueous systems are in subacidity by countless tests, can protect levodopa invariance well, and
And levodopa can be dissolved well, this is also the place that the present invention is different from traditional handicraft, and traditional handicraft directly will
Crude product carries out thermosol with strong acid solution, then cold analysis.The present invention dissolves levodopa crude product under the conditions of 65~70 DEG C, to left-handed
DOPA solubility is big, and selectivity is strong, relatively small to junket Ammonia solubility, and crystallization can remove most of impurity after levodopa is precipitated,
It ensure that the quality of finished product levodopa, while providing good environment to remove tyrosine in subsequent step, remove tyrosine
Except it is more thorough.In addition, adjusting pH 1.0~1.5 in re-crystallization step of the present invention, dissolving levodopa under the conditions of 50~60 DEG C
Solid content is to saturation state, and oxidative phenomena will not occur for the levodopa being precipitated under the conditions of the present invention, and what is crystallized is left-handed
DOPA fine work purity is high, quality are high.
Levodopa is amphoteric amino acids, and isoelectric point 3.5 is soluble in acid, is slightly soluble in the aqueous solution of pH > 3.5.It is left-handed
DOPA is one of the active drug of current treatment shaking plasy, for synthesis norepinephrine, dopamine etc. in vivo precursor it
One, belong to catecholamine.Levodopa is the intermediate product that catecholamine is formed by tyrosine, i.e. the precursor of dopamine.It is absorbed
Enter the L-3,4 dihydroxyphenylalanine about 95% of blood by DOP Adecarboxylase decarboxylation in peripheral organization, forms catecholamine, not easily pass through blood-brain barrier, instead
And cause many adverse reactions.Only 1% L-3,4 dihydroxyphenylalanine enters Brain circlulation, and reaches central nervous system, is changed into catecholamine hair
Wave therapeutic effect.Its structural formula is as follows:
Tyrosine (tyrosine；Tyr chemical name) is 2- amino -3- p-hydroxyphenyl propionic acid, Chinese nickname: (S) -2- ammonia
Base -3- is to hydroxyl, (2S, 3R) -2- amino -3- p-hydroxyphenyl propionic acid, L- β-p-hydroxyphenyl-Beta-alanine, L- β-p-hydroxyphenyl-α -
Alanine, English name: tyrosine.Molecular formula: C9H11NO3, molecular weight: 181.18900.It is that one kind contains phenolic hydroxyl group
Aromatic series polarity a-amino acid, be white crystalline powder, from water crystallization be needle-shaped or plates.Relative density 1.456
(20 DEG C), isoelectric point 5.66；Fusing point: decomposing (slow heating) at 290~295 DEG C of levo form, decomposes at 314~318 DEG C (quick
Heating), (slow heating) is decomposed at 290~295 DEG C of raceme, and 340 DEG C of whens decompose and (quickly heat).Be dissolved in water, ethyl alcohol, acid and
Alkali does not dissolve in ether.
Phenol (Phenol), molecular formula C6H5OH, 43 DEG C of fusing point, be a kind of colourless acicular crystal with special odor,
It is slightly soluble in water under room temperature, is soluble in organic solvent, is miscible in ethyl alcohol, ether, chloroform, glycerol；It, can be with when temperature is higher than 65 DEG C
Water is dissolved each other with arbitrary proportion.Phenol belongs to phenolic substances, there is faintly acid, and pH is 5~6 when being dissolved in water, and levodopa is in this weak acid
Property under the conditions of steady dissolution, will not blackening influence quality.
Tyrosine content is lower in levodopa, for levodopa enter through blood-brain barrier into therapeutic effect get over
Good, tyrosine will affect the drug action of levodopa.By the examination criteria of Chinese Pharmacopoeia, it is desirable that tyrosine contains in levodopa
Amount is lower than 0.5%；And press the examination criteria of United States Pharmacopeia, it is desirable that tyrosine content is lower than 0.1%.According to side of the present invention
Method can reach tyrosine content lower than 0.1% by strict control, can reach the standard in the outlet U.S. (by United States Pharmacopeia UPS38
Version).
Beneficial effects of the present invention:
1, the method for present invention purification levodopa, greatly reduces the content of tyrosine, improves the purity of levodopa, is made
Levodopa purity >=99%, by United States Pharmacopeia UPS38 editions methods detection, tyrosine content≤0.1% in product, compared to according to
The levodopa of common process production, tyrosine content reduce 2~5 times, reach U.S. FDA for tyrosine in levodopa
The requirement of content.
2, the method for present invention purification levodopa, simple process, product yield is high, and equipment requirement is low, can carry out industry
Metaplasia produces.The present invention can greatly reduce the manpower and material resources that processing sewage needs to expend without the purification of Resin Absorbent tyrosine,
Production cost is reduced, and improves the quality of fine work levodopa.
3, the method for present invention purification levodopa, the leaching liquor used are that phenol and water are mixed according to weight ratio 1:3~5
It closes, so that it is sufficiently dissolved levodopa and its a small amount of impurity using the principle of similar compatibility, dissolved under the conditions of 65~70 DEG C left
DOPA crude product is revolved, maximum to levodopa solubility, selectivity is strong, and relatively small to junket Ammonia solubility, levodopa is precipitated in crystallization
After can remove most of impurity, ensure that the quality of finished product levodopa, at the same for removed in subsequent step tyrosine provide it is good
Good environment, makes tyrosine remove more thorough.
4, in re-crystallization step of the present invention, pH 1.0~1.5 is adjusted, levodopa solid content is dissolved under the conditions of 50~60 DEG C
To saturation state, oxidative phenomena will not occur for the levodopa being precipitated with this condition, and the levodopa fine work crystallized is pure
Degree is high, and quality is high.
Specific embodiment
In order to keep technical solution of the present invention and advantage clearer, below with reference to the embodiment of the present invention, to the present invention
Technical solution be clearly and completely described.
Embodiment 1
A method of purification levodopa, step are as follows:
(1) it prepares leaching liquor: taking phenol and water, mixed according to weight ratio 1:3, being heated to 70 DEG C keeps its miscible, obtains leaching liquor；
(2) it dissolves: taking levodopa crude product, the leaching liquor of 3 times of its weight is added, saturation is dissolved under the conditions of 70 DEG C, stand
Then 40min is filtered under the conditions of 65 DEG C；
(3) it cleans: taking filtrate cooling, levodopa and phenol is precipitated, consider taking precipitate；
(4) it removes phenol: taking step (3) resulting sediment, the dehydrated alcohol of 5 times of its weight is added, remove, obtain after dissolving phenol
To levodopa solid content；
(5) it recrystallizes: taking levodopa solid content, the mass fraction that 8 times of its weight is added is the hydrochloric acid of 0.05 mol/L, adjusts pH
1.5, it is heated to boiling, levodopa solid content is added and is dissolved to saturation state, letting cool is precipitated levodopa crystallization, collects analysis
Crystal out is dry to get fine work levodopa.
Embodiment 2
A method of purification levodopa, step are as follows:
(1) it prepares leaching liquor: taking phenol and water, mixed according to weight ratio 1:4, being heated to 68 DEG C keeps its miscible, obtains leaching liquor；
(2) it dissolves: taking levodopa crude product, the leaching liquor of 5 times of its weight is added, saturation is dissolved under the conditions of 68 DEG C, stand
Then 50min is filtered under the conditions of 68 DEG C；
(3) it cleans: taking filtrate cooling, levodopa and phenol is precipitated, consider taking precipitate；
(4) it removes phenol: taking step (3) resulting sediment, the dehydrated alcohol of 7 times of its weight is added, remove, obtain after dissolving phenol
To levodopa solid content, this operation is repeated again；
(5) it recrystallizes: taking levodopa solid content, the mass fraction that 6 times of its weight is added is the hydrochloric acid of 0.1 mol/L, adjusts pH
1.2, it is heated to boiling, levodopa solid content is added and is dissolved to saturation state, letting cool is precipitated levodopa crystallization, collects analysis
Crystal out is dry to get fine work levodopa.
Embodiment 3
A method of purification levodopa, step are as follows:
(1) it prepares leaching liquor: taking phenol and water, mixed according to weight ratio 1:5, being heated to 65 DEG C keeps its miscible, is extracted
Liquid；
(2) it dissolves: taking levodopa crude product, the leaching liquor of 4 times of its weight is added, saturation is dissolved under the conditions of 65 DEG C, stand
Then 60min is filtered under the conditions of 70 DEG C；
(3) it cleans: taking filtrate cooling, levodopa and phenol is precipitated, consider taking precipitate；
(4) it removes phenol: taking step (3) resulting sediment, the dehydrated alcohol of 8 times of its weight is added, remove, obtain after dissolving phenol
To levodopa solid content, this operation 2 times is repeated；
(5) it recrystallizes: taking levodopa solid content, the mass fraction that 6 times of its weight is added is the hydrochloric acid of 0.12 mol/L, adjusts pH
1.0, it is heated to boiling, levodopa solid content is added and is dissolved to saturation state, letting cool is precipitated levodopa crystallization, collects analysis
Crystal out is dry to get fine work levodopa.
Embodiment 4
A method of purification levodopa, step are as follows:
(1) it prepares leaching liquor: taking phenol and water, mixed according to weight ratio 1:3, being heated to 68 DEG C keeps its miscible, obtains leaching liquor；
(2) it dissolves: taking levodopa crude product, the leaching liquor of 5 times of its weight is added, saturation is dissolved under the conditions of 68 DEG C, stand
Then 60min is filtered under the conditions of 68 DEG C；
(3) it cleans: taking filtrate cooling, levodopa and phenol is precipitated, consider taking precipitate；
(4) it removes phenol: taking step (3) resulting sediment, the dehydrated alcohol of 10 times of its weight is added, removed after dissolving phenol,
Levodopa solid content is obtained, repeats this operation again；
(5) it recrystallizes: taking levodopa solid content, the mass fraction that 8 times of its weight is added is the hydrochloric acid of 0.2 mol/L, adjusts pH
1.0,55 DEG C are heated to, levodopa solid content is added and is dissolved to saturation state, letting cool is precipitated levodopa crystallization, collects analysis
Crystal out is dry to get fine work levodopa.
The fine work levodopa being prepared in the embodiment of the present invention, it is reachable by UPS38 editions method detections of United States Pharmacopeia
To standard requirements, testing result is as follows:
| Purity (%) | Tyrosine content (%) | |
| Embodiment 1 | 99.35% | 0.07% |
| Embodiment 2 | 99.20% | 0.06% |
| Embodiment 3 | 99.42% | 0.06% |
| Embodiment 4 | 99.38% | 0.05 |
Claims (2)
1. a kind of method for refining levodopa, it is characterised in that: the following steps are included:
(1) it prepares leaching liquor: taking phenol and water, mixed according to weight ratio 1:3~5, being heated to 65~70 DEG C keeps its miscible, obtains
Leaching liquor；
(2) it dissolves: taking levodopa crude product, the leaching liquor of 3~5 times of its weight is added, be dissolved under the conditions of 65~70 DEG C full
With, stand 40~60min, then filtered under the conditions of 65~70 DEG C；
(3) it cleans: taking filtrate cooling, levodopa and phenol is precipitated, consider taking precipitate；
(4) it removes phenol: taking step (3) resulting sediment, the dehydrated alcohol of 5~10 times of its weight is added, removed after dissolving phenol
It goes, obtains levodopa solid content, repeat this operation 1~2 time；
(5) it recrystallizes: taking levodopa solid content, the hydrochloric acid of 5~8 times of its weight is added, adjust pH 1.0~1.5, be heated to boiling
It rises, levodopa solid content is added and is dissolved to saturation state, letting cool is precipitated levodopa crystallization, and the crystal for collecting precipitation is dry
It is dry to get fine work levodopa.
2. refining the method for levodopa according to claim 1, it is characterised in that: the mass fraction of the hydrochloric acid is
0.05~0.2 mol/L.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN113788763A (en) * | 2021-10-26 | 2021-12-14 | 四川大学 | Method for synthesizing levodopa and derivatives thereof based on bionic hydroxylation system |
| CN117142973A (en) * | 2023-11-01 | 2023-12-01 | 欧尚元智能装备有限公司 | Levodopa and separation and purification method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| CN113788763A (en) * | 2021-10-26 | 2021-12-14 | 四川大学 | Method for synthesizing levodopa and derivatives thereof based on bionic hydroxylation system |
| CN113788763B (en) * | 2021-10-26 | 2023-08-15 | 四川大学 | Method for synthesizing levodopa based on bionic hydroxylation system |
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| CN109485581B (en) | 2021-07-09 |
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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 |
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