CN107382760A - A kind of isolation and purification method of levodopa - Google Patents
A kind of isolation and purification method of levodopa Download PDFInfo
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- CN107382760A CN107382760A CN201710711008.2A CN201710711008A CN107382760A CN 107382760 A CN107382760 A CN 107382760A CN 201710711008 A CN201710711008 A CN 201710711008A CN 107382760 A CN107382760 A CN 107382760A
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- levodopa
- mixed solution
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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
- C07C227/44—Stabilisation; Use of additives
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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
Abstract
The invention provides a kind of isolation and purification method of levodopa, in the presence of ascorbic acid antioxidant, first adjusts solution to alkalescence, levodopa is dissolved, solution is then adjusted to acidity, separates out levodopa crystallization.The present invention uses antioxidant of the ascorbic acid as course of reaction, avoids levodopa from being oxidized during isolating and purifying, so as to improve the yield of levodopa；The present invention is not only avoided acidity too strong, is influenceed the levodopa precipitation speed of growth, realize the control to the levodopa precipitation speed of growth, improve the amount of precipitation of levodopa precipitation using acetic acid precipitation levodopa；Also it is avoided that and introduces the acidic materials with oxidisability, the possibility being oxidized during levodopa isolates and purifies is reduced, so as to improve the yield of levodopa.The result of embodiment shows that for the product yield of method provided by the present invention up to 88%~91%, purity meets CP/USP/EP requirements more than 99.8%.
Description
Technical field
The present invention relates to medicinal chemistry art, specifically, is related to a kind of isolation and purification method of levodopa.
Background technology
Levodopa also known as 3,4-dihydroxyphenyl-L-alanine, it is a kind of important bioactive substance.Levodopa is god
Precursor through neurotransmitter dopamine, it can reach central nervous system by blood-brain barrier into Brain circlulation, taken off at nervous centralis
In the presence of carboxylic acid, dopamine is converted into, so that DOPAMINE CONTENT IN RABBIT increase in brain tissue, so as to treat Parkinson disease.Remove
Outside this, levodopa also has the function that to treat amblyopia and heart failure, although being had after much time using
Side effect, but went in more than 40 years, still occur at present without more preferable alternative medicine.
According to statistics, the global marketing total value of levodopa in 2015 has reached 3.3 hundred million dollars, the ranking in world's best-selling drugs
97th, its total output has reached more than 2000 tons, it is contemplated that following 5-10 global marketings total value is expected to reach 1,000,000,000 dollars.It is existing
Have in technology, levodopa extracting mode typically by conversion fluid carry out two-step crystallization, or to conversion fluid carry out film mistake
Filter, adds dissolving with hydrochloric acid, is then crystallized to obtain.But the levodopa product yield that above two method obtains is relatively low.
The content of the invention
In view of this, it is left-handed more to improve it is an object of the invention to provide a kind of isolation and purification method of levodopa
Bar yield.
The invention provides a kind of isolation and purification method of levodopa, comprise the following steps：
1) material liquid containing levodopa is mixed with ascorbic acid, obtains the first mixed solution；
2) pH value for the first mixed solution that the step 1) obtains is adjusted to alkalescence, obtains alkaline mixed solution；
3) alkaline mixed solution obtained to the step 2) carries out separation of solid and liquid, obtains supernatant；
4) supernatant that the step 3) obtains is mixed with ascorbic acid, obtains the second mixed solution；
5) pH value for the second mixed solution that the step 4) obtains is adjusted using acetic acid to 3~5, separates out levodopa.
Preferably, the concentration of levodopa is not less than 30g/L in the step 1) material liquid.
Preferably, the concentration of ascorbic acid and the mixed solution of step 4) second in the mixed solution of step 1) first
The concentration of middle ascorbic acid independently is 0.5~2g/L.
Preferably, the pH value of step 2) the neutral and alkali mixed solution is 10~13.
Preferably, the regulation of pH value includes the first acid regulation successively in the step 5) and the second acidity is adjusted；
Described first acid regulation includes：The pH for the second mixed solution that the step 4) obtains is adjusted using the first acetic acid
It is worth to 6~7；
Described second acid regulation includes：Using the pH of the mixed solution after the described first acid regulation of the second acetic acid regulation
It is worth to 3~5.
Preferably, also include after pH value regulation in the step 5)：The obtained acidic mixed solution that adjusts is carried out
Crystallization treatment.
Preferably, the temperature of the crystallization treatment is 2~7 DEG C.
Preferably, the time of the crystallization treatment is 2~3 hours.
Preferably, also include before the supernatant that step 3) obtains being mixed with ascorbic acid：Using activated carbon on described
Clear liquid carries out decolorization.
Preferably, after levodopa separates out in the step 5), separation of solid and liquid is carried out to the feed liquid that precipitation obtains, obtained
Solid matter is levodopa.
It is first in the presence of ascorbic acid antioxidant the invention provides a kind of isolation and purification method of levodopa
Solution is adjusted to alkalescence, levodopa is dissolved, solution is then adjusted to acidity, separates out levodopa crystallization.The present invention makes
By the use of ascorbic acid as the antioxidant of course of reaction, levodopa is avoided to be oxidized during isolating and purifying, so as to improve
The yield of levodopa；The mixed solution of levodopa and ascorbic acid is adjusted to alkalescence again, can be farthest by a left side
DOPA dissolving is revolved, so as to improve the yield of levodopa.The present invention not only avoids acidity using acetic acid precipitation levodopa
It is too strong, the levodopa precipitation speed of growth is influenceed, so as to realize the control to the levodopa precipitation speed of growth, is improved left-handed more
Bar precipitation amount of precipitation；Also it is avoided that and introduces the acidic materials with oxidisability, reduces during levodopa isolates and purifies
Oxidized possibility, so as to also further increasing the yield of levodopa.The result of embodiment shows that the present invention is carried
For the product yield of supplier's method up to 88%~91%, purity meets CP/USP/EP requirements more than 99.8%.
Brief description of the drawings
Fig. 1 is isolation and purification method flow chart provided by the invention.
Embodiment
The invention provides a kind of isolation and purification method of levodopa, comprise the following steps：
1) material liquid containing levodopa is mixed with ascorbic acid, obtains the first mixed solution；
2) pH value for the first mixed solution that the step 1) obtains is adjusted to alkalescence, obtains alkaline mixed solution；
3) alkaline mixed solution obtained to the step 2) carries out separation of solid and liquid, obtains supernatant；
4) supernatant that the step 3) obtains is mixed with ascorbic acid, obtains the second mixed solution；
5) pH value for the second mixed solution that the step 4) obtains is adjusted using acetic acid to 3~5, separates out levodopa.
The levodopa has stereochemical structure shown in Formulas I：
The present invention mixes the material liquid containing levodopa with ascorbic acid, obtains the first mixed solution.
In the present invention, the concentration of levodopa is not less than 30g/L in the material liquid containing levodopa, further
Preferably 30~200g/L.The present invention does not have particular/special requirement to the source of the material liquid containing levodopa, using ability
The levodopa material liquid for separating-purifying known to field technique personnel.In an embodiment of the present invention, it is described to contain
The material liquid for having levodopa is specially the conversion fluid for carrying out living things catalysis acquisition to substrate using tyrosine phenol lyase；It is described
Substrate includes catechol, pyruvic acid and ammonia.The present invention is not special to the living things catalysis mode of the tyrosine phenol lyase
It is required that using well-known to those skilled in the art.
In the present invention, the tyrosine phenol lyase carries out living things catalysis to substrate and preferably includes following steps：
(1) substrate solution is provided, according to mass parts meter, the substrate solution includes 8~12 parts of catechol, 10~14
Part Sodium Pyruvate, 40~50 parts of ammonium acetate, 1~3 part of sodium sulfite, 0.5~2 part of ethylenediamine tetra-acetic acid, 0.05~
0.2 part of phosphopyridoxal pyridoxal phosphate and 700~800 parts of water；
(2) pH value of the substrate solution is adjusted to 8.15~8.2 using ammoniacal liquor, obtains alkaline substrate solution；
(3) alkaline substrate solution progress biocatalytic reaction is obtained to described using tyrosine phenol lyase solution, obtained
Material liquid containing levodopa.
In the present invention, the substrate solution is preferably by by catechol, Sodium Pyruvate, ammonium acetate, sodium sulfite, second
Ethylenediamine tetraacetic acid (EDTA) and phosphopyridoxal pyridoxal phosphate are mixed to get in water；The temperature of the mixing is preferably 20~22 DEG C.
In the present invention, the volume of the tyrosine phenol lyase solution and the mass ratio of catechol be preferably 95~
105mL:8~12g；The mass concentration of the tyrosine phenol lyase solution is 5%~10%.In the present invention, the biology
Catalytic reaction is preferably carried out in a nitrogen atmosphere；The temperature of the biocatalytic reaction is preferably 15~18 DEG C；The biology is urged
Change reaction preferably to carry out under agitation, the speed of the stirring is preferably 200~230rpm.
The present invention does not have particular/special requirement to the time of the biocatalytic reaction, not regenerate levodopa in mixed liquor
It is defined.
The present invention preferably determines whether also have levodopa to generate in mixed liquor by detection substrate residual quantity.Specifically
The residual quantity of catechol and Sodium Pyruvate is measured by sampling in ground, the present invention per hour, when catechol and Sodium Pyruvate remain
When amount no longer reduces, illustrate not regenerate levodopa in mixed liquor.
Present invention preferably employs the method for HPLC detections to detect catechol and Sodium Pyruvate content.
The residual quantity of catechol and Sodium Pyruvate is measured by sampling in the present invention per hour, when catechol concentration is less than 5
During~7g/L, catechol is added, the concentration of catechol is maintained 5~7g/L；When Sodium Pyruvate concentration less than 7~
During 9g/L, Sodium Pyruvate is added, Sodium Pyruvate concentration is maintained 7~9g/L.Ensure substrate in tyrosine phenols cracking with this
Under enzyme effect, levodopa is sufficiently converted into.
After completing the biocatalytic reaction, mixed liquor and sulfuric acid that the present invention preferably obtains the biocatalytic reaction
Solution mixes, and obtains the material liquid containing levodopa.The mass concentration of the sulfuric acid solution is preferably 50%~55%, described
The volume of sulfuric acid solution and the mass ratio of catechol in the substrate solution are preferably 20~30mL:8~12g.
In the present invention, the material liquid containing levodopa can also originate from levodopa concentration 30g/L with
On other solution.
The present invention does not have particular/special requirement to the hybrid mode of the material liquid containing levodopa and ascorbic acid, uses
Solution hybrid mode well-known to those skilled in the art.
In the present invention, the concentration of ascorbic acid is preferably 0.5~2g/L in first mixed solution, further preferably
For 1~1.5g/L.
After obtaining first mixed solution, the present invention adjusts the pH value of first mixed solution to alkalescence, obtains alkali
Property mixed solution.The regulation of pH value is carried out to first mixed solution present invention preferably employs highly basic；The highly basic is preferably
Sodium hydroxide and/or potassium hydroxide.In the present invention, the highly basic is molten to the described first mixing preferably in the form of strong base solution
The pH value of liquid is adjusted；Quality-volumetric concentration of the strong base solution is preferably 300~500g/L.
In the present invention, the strong base solution is preferably added in first mixed solution by the regulation of the pH value；
The addition speed of the strong base solution is preferably：20~40mL/min.
The present invention does not have particular/special requirement to the usage amount of the highly basic, can realize the pH value to first mixed solution
Regulation, obtains alkaline mixed solution and is defined.In the present invention, the pH value of the alkaline mixed solution is preferably 10~13, enters one
Step is preferably 11~12.The present invention pH value of first mixed solution is adjusted to target zone, can farthest by
Levodopa dissolves, so as to improve the yield of levodopa.
In the present invention, the regulation of the pH value is preferably carried out under agitation；The speed of the stirring is preferably 300
~500rpm.
After obtaining alkaline mixed solution, the present invention carries out separation of solid and liquid to the alkaline mixed solution, obtains supernatant.
In the present invention, the separation of solid and liquid is preferably to centrifuge；The temperature of the centrifugation is preferably 0~8 DEG C, further preferably
For 3~5 DEG C；The rotating speed of the centrifugation is preferably 3000~5000rpm, more preferably 3500~4500rpm；It is described
The time of centrifugation is preferably 10~60min, more preferably 20~50min.
After obtaining supernatant, the present invention mixes the supernatant with ascorbic acid, obtains the second mixed solution.
In the present invention, the concentration of ascorbic acid is preferably 0.5~2g/L in second mixed solution.
The hybrid mode of the supernatant and ascorbic acid is not particularly limited the present invention, can realize the supernatant
With being sufficiently mixed for ascorbic acid.
In the present invention, preferably also include before supernatant and the ascorbic acid mixing：Using activated carbon to the supernatant
Liquid carries out decolorization.In the present invention, the decolorization is preferably and mixes the supernatant with activated carbon, is decolourized
Processing.In the present invention, the quality of the activated carbon and the volume ratio of supernatant are preferably 0.02~0.04g：1L.In the present invention
In, the mixing is preferably carried out under agitation；The speed of the stirring is preferably 100~200rpm, more preferably
150~180rpm.The present invention carries out decolorization in the mixed process of the supernatant and activated carbon and realizes activated carbon to upper
The absorption of color in clear liquid.In the present invention, the temperature of the decolorization is preferably 30~50 DEG C, more preferably 35~
45℃；The time of the decolorization is preferably 2~3 hours.
After the decolorization, the present invention is preferred to remove activated carbon.The embodiment that the present invention removes to activated carbon
There is no particular/special requirement, using the removing method of solid in solution well-known to those skilled in the art.The present invention preferably adopts
Activated carbon is removed with the mode for centrifuging or filtering.
After obtaining the second mixed solution, the pH value that the present invention adjusts second mixed solution using acetic acid is analysed to 3~5
Go out levodopa.The present invention realizes that levodopa separates out from solution during the pH value is adjusted to 3~5.The present invention
There is no particular/special requirement to the usage amount of the acetic acid, so that the regulation of the pH value to second mixed solution can be realized.
In the present invention, the acetic acid adds preferably in the form of acetum, and the mass concentration of the acetic acid is preferably：90%~
99%.The present invention does not have particular/special requirement to the source of the acetic acid, using acetic acid well-known to those skilled in the art.
In the present invention, the regulation of the pH value is preferably carried out under agitation；The speed of the stirring is preferably 100
~200rpm, more preferably 150~180rpm.
In the present invention, the acetic acid is preferably added in the second mixed solution by the regulation of the pH value, the acetic acid
The speed of addition is preferably：15-20mL/min.Acetic acid is added in the second mixed solution by the present invention, without using second
Mixed solution is added to the hybrid mode in acetic acid, is advantageous to levodopa and as often as possible crystallizes, so as to be advantageous to improve product
Yield.
In the present invention, the first acid regulation is preferably included using vinegar acid for adjusting pH value successively and the second acidity is adjusted；Institute
Stating the first acid regulation further preferably includes：The pH value of second mixed solution is adjusted to 6~7 using the first acetic acid；Institute
The second acid regulation is stated to preferably include：Using the pH value of the mixed solution after the described first acid regulation of the second acetic acid regulation to 3
~5.
In the present invention, the described first acid regulation and the second acid regulation are independently preferably carried out under agitation；
The stir speed (S.S.) of described first acid regulation and the stir speed (S.S.) of the second acid regulation are preferably independently 100~200rpm, are entered
One step is preferably 120~180rpm；The mixing time of described first acid regulation and the mixing time of the second acid regulation are independent
Ground is preferably 1~2.5 hour, more preferably 1.5~2 hours.
In the present invention, first acetic acid and the second acetic acid independently add preferably in the form of acetum；It is described
The mass concentration of first acetum and the second acetum is preferably independently：90%-99%.
The present invention is adjusted the pH value of second mixed solution to after 6~7 using the first acetic acid, then using the second acetic acid
Continue to adjust pH value to 3~5 substep pH value regulative mode, both enough made dissolved state beneficial to the growing the grain of levodopa, and can
Levodopa sufficiently separate out crystallization, and then improve the yield of levodopa.
After the regulation for completing the acetic acid pH value, it is molten that the present invention preferably also includes the mixing after being adjusted to the acetic acid pH value
The crystallization treatment of liquid.In the present invention, the temperature of the crystallization treatment is preferably 2~7 DEG C, more preferably 3~5 DEG C；Institute
The time for stating crystallization treatment is preferably 2~3 hours.In the present invention, the crystallization treatment is preferably：The mixed solution is existed
Stood under crystallization temperature.The present invention can promote levodopa in solution fully to analyse the crystallization treatment of the mixed solution
Go out, further improve the yield of levodopa.The present invention only need to carry out One-step crystallization, you can obtain purity and yield is higher
Levodopa, crystallized compared to two steps, whole extraction process simple possible, product loss is less.
After the levodopa separates out, the feed liquid that preferred pair of the present invention separates out to obtain carries out separation of solid and liquid, obtained solid
Material is levodopa.The present invention does not have particular/special requirement to the method for separation of solid and liquid, and use is well-known to those skilled in the art
Solid-liquid separating method.Present invention preferably employs the method for centrifuging or being separated by filtration to collect solid levorotatory DOPA.
After the separation of solid and liquid, the solid obtained described in preferred pair of the present invention is washed and dried successively.In the present invention
In, the detergent is preferably ethanol and/or acetone.In the present invention, the drying is preferably to be dried in vacuo, and the vacuum is done
Dry vacuum is preferably -0.07~-0.1Mpa.In the present invention, the time of the drying is preferably 25~35min；It is described
Dry temperature is preferably 40~50 DEG C.
Described above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should
It is considered as protection scope of the present invention.
A kind of isolation and purification method of levodopa provided by the invention is described in detail with reference to embodiment,
But they can not be interpreted as limiting the scope of the present invention.
Embodiment 1
The preparation of material liquid containing levodopa：
Substrate solution is configured first：By catechol 10g, Sodium Pyruvate 12g, ammonium acetate 45g, sodium sulfite 2g, second two
Amine tetraacethyl 1g, phosphopyridoxal pyridoxal phosphate 0.1g mix with 720mL pure water, are heated to 20 DEG C, dissolve while stirring.
Ammoniacal liquor is added into above-mentioned substrate solution, regulation pH value is settled to 900ml, it is dense to add commercially available quality to 8.15
The tyrosine phenol lyase crude enzyme liquid 100mL for 5% is spent, then reaction vessel is sealed, is filled with nitrogen, at 15 DEG C, 200rpm
Biocatalytic reaction is carried out under shaking table or stirring condition.
In addition to 0min, the residual quantity of catechol and Sodium Pyruvate is all measured by sampling per hour, when catechol and acetone
When sour sodium content is relatively low, appropriate catechol and Sodium Pyruvate are added so that the concentration of catechol is in 6g/L, pyruvic acid
Na concn is in 8g/L.
When levodopa content is not further added by, 50% sulfuric acid 25ml is added, obtains the material liquid containing levodopa.
Take the material liquid 500L containing levodopa, the concentration of levodopa is 60g/L in material liquid.To the material liquid
Separating-purifying comprises the following steps：
1) 500g ascorbic acid is added in material liquid, is stirred, fully dissolving；
2) in material liquid under 400rpm rotating speed rapid mixing conditions, to be slowly added to quality-volumetric concentration as 400g/L
Sodium hydroxide solution, regulation solution ph to 12, obtain alkaline mixed solution；The addition speed of the sodium hydroxide is：
30mL/min；
3) alkaline mixed solution obtained to step 2) is at 4 DEG C, rotating speed carried out under the conditions of being 4000rpm low-temperature and high-speed from
The heart, centrifugation time 20min, supernatant is collected, altogether 500L；
4) 15kg powdered activated carbons are added in the supernatant obtained to step 3), 40 DEG C are warming up to, under 150rpm rotating speeds
Stirring 2 hours；
5) filter and remove activated carbon, collect supernatant；
6) 500g ascorbic acid, fully dissolving are added in the supernatant obtained to step 5), obtains the second mixed solution；
7) be added dropwise acetum under conditions of the stirring of the second mixed solution, the rotating speed of stirring is 150rpm, stirring when
Between be 1 hour, regulation solution ph is to 7.0；
The rate of addition of the acetum is：20mL/min.
8) continue under agitation, the pH value obtained to step 7) is that acetum is added dropwise in 7.0 solution, described to stir
The rotating speed mixed is 150rpm, and the time of stirring is 1 hour, regulation solution ph to 4.0；
The rate of addition of the acetum is：15mL/min.
9) the acidic mixed solution that the pH value and then by step 8) obtained is 4.0 stands 2 hours at 4 DEG C；Filtered
Obtain crystal；
10) 20~30min of crystal is washed successively with 300L ethanol and 300L acetone respectively；
11) dry 30min under vacuum to the crystal after washing, drying temperature is 45 DEG C, vacuum for-
0.07Mpa, finally give levodopa dry powder 26.5Kg, yield 88.3%.
The product obtained to embodiment 1 carries out quality testing, under indices are as shown in table 1：
The performance test results for the levodopa that the embodiment 1 of table 1 is prepared
| Levodopa purity | 99.8% |
| Specific rotation | -165° |
| Absorption coefficient | 141 |
| Clarity | Clear, colorless |
| Chloride | 0.01% |
| Loss on drying | 0.4% |
| Ignition residue | 0.06% |
| Heavy metal | 8ppm |
From the data of table 1, levodopa isolation and purification method product yield provided by the invention and purity are higher.
Embodiment 2
Substrate solution is prepared according to the methods described of embodiment 1, is catalyzed to obtain levodopa content through tyrosine phenol lyase
For 70g/L material liquid.The material liquid 500L that levodopa content is 70g/L is taken, the separating-purifying of the material liquid is included such as
Lower step：
1) 500g ascorbic acid is added in material liquid, is stirred, fully dissolving；
2) in material liquid under 300rpm rotating speed rapid mixing conditions, to be slowly added to quality-volumetric concentration as 350g/L
Potassium hydroxide solution, regulation solution ph to 12.5, obtain alkaline mixed solution；The addition speed of the potassium hydroxide is：
20mL/min；
3) alkaline mixed solution obtained to step 2) is at 5 DEG C, rotating speed carried out under the conditions of being 4500rpm low-temperature and high-speed from
The heart, centrifugation time 30min, supernatant is collected, altogether 500L；
4) 20kg powdered activated carbons are added in the supernatant obtained to step 3), 40 DEG C are warming up to, under 200rpm rotating speeds
Stirring 3 hours；
5) filter and remove activated carbon, collect supernatant；
6) 500g ascorbic acid, fully dissolving are added in the supernatant obtained to step 5), obtains the second mixed solution；
7) be added dropwise acetum under conditions of the stirring of the second mixed solution, the rotating speed of stirring is 200rpm, stirring when
Between be 1.5 hours, regulation solution ph is to 6.5；
The rate of addition of the acetum is：20mL/min；
8) continue under agitation, the pH value obtained to step 7) is that acetum is added dropwise in 6.5 solution, described to stir
The rotating speed mixed is 200rpm, and the time of stirring is 1.5 hours, regulation solution ph to 3.5；
The rate of addition of the acetum is：15mL/min；
9) the acidic mixed solution that the pH value and then by step 8) obtained is 3.5 stands 3 hours at 5 DEG C；Filtered
Obtain crystal；
10) crystal 30min is washed successively with 350L ethanol and 350L acetone respectively；
11) dry 30min under vacuum to the crystal after washing, drying temperature is 50 DEG C, vacuum for-
0.1Mpa, finally give levodopa dry powder 31.2Kg, yield 89.1%.
The product obtained to embodiment 2 carries out quality testing, under indices are as shown in table 2：
The performance test results for the levodopa that the embodiment 2 of table 2 is prepared
| Levodopa purity | 100% |
| Specific rotation | -162° |
| Absorption coefficient | 143 |
| Clarity | Clear, colorless |
| Chloride | 0.02% |
| Loss on drying | 0.3% |
| Ignition residue | 0.04% |
| Heavy metal | 7ppm |
From the data of table 2, levodopa isolation and purification method product yield provided by the invention and purity are higher.
Embodiment 3
Take the material liquid 500L containing levodopa, the concentration of levodopa is 50g/L in material liquid.To the material liquid
Separating-purifying comprises the following steps：
3) 500g ascorbic acid is added in material liquid, is stirred, fully dissolving；
4) in material liquid under 400rpm rotating speed rapid mixing conditions, to be slowly added to quality-volumetric concentration as 380g/L
Sodium hydroxide solution, regulation solution ph to 13, obtain alkaline mixed solution；The addition speed of the sodium hydroxide is：
25mL/min；
3) alkaline mixed solution obtained to step 2) is at 4 DEG C, rotating speed carried out under the conditions of being 4000rpm low-temperature and high-speed from
The heart, centrifugation time 20min, supernatant is collected, altogether 500L；
4) 15kg powdered activated carbons are added in the supernatant obtained to step 3), 40 DEG C are warming up to, under 150rpm rotating speeds
Stirring 2.5 hours；
5) filter and remove activated carbon, collect supernatant；
6) 500g ascorbic acid, fully dissolving are added in the supernatant obtained to step 5), obtains the second mixed solution；
7) be added dropwise acetum under conditions of the stirring of the second mixed solution, the rotating speed of stirring is 150rpm, stirring when
Between be 1 hour, regulation solution ph is to 6.0；
The rate of addition of the acetum is：18mL/min；
8) continue under agitation, the pH value obtained to step 7) is that acetum is added dropwise in 6.0 solution, described to stir
The rotating speed mixed is 150rpm, and the time of stirring is 1 hour, regulation solution ph to 3.8；
The rate of addition of the acetum is：16mL/min；
9) the acidic mixed solution that the pH value and then by step 8) obtained is 4.0 stands 2 hours at 4 DEG C；Filtered
Obtain crystal；
10) 20~30min of crystal is washed successively with 300L ethanol and 300L acetone respectively；
11) dry 30min under vacuum to the crystal after washing, drying temperature is 45 DEG C, vacuum for-
0.07Mpa, finally give levodopa dry powder 22.7Kg, yield 90.8%.
The product obtained to embodiment 3 carries out quality testing, under indices are as shown in table 3：
The performance test results for the levodopa that the embodiment 3 of table 3 is prepared
From the data of table 3, levodopa isolation and purification method product yield provided by the invention and purity are higher.
From the result of above example, the levodopa isolation and purification method that the application provides is relatively simple, only needs
One-step crystallization is the purifies and separates that levodopa can be achieved, and levodopa isolation and purification method product yield and purity compared with
It is high.
Claims (10)
1. a kind of isolation and purification method of levodopa, comprises the following steps：
1) material liquid containing levodopa is mixed with ascorbic acid, obtains the first mixed solution；
2) pH value for the first mixed solution that the step 1) obtains is adjusted to alkalescence, obtains alkaline mixed solution；
3) alkaline mixed solution obtained to the step 2) carries out separation of solid and liquid, obtains supernatant；
4) supernatant that the step 3) obtains is mixed with ascorbic acid, obtains the second mixed solution；
5) pH value for the second mixed solution that the step 4) obtains is adjusted using acetic acid to 3~5, separates out levodopa.
2. isolation and purification method according to claim 1, it is characterised in that the concentration of levodopa is not in the material liquid
Less than 30g/L.
3. isolation and purification method according to claim 1, it is characterised in that the first mixed solution of step 1) moderate resistance is bad
The concentration of hematic acid and the concentration of ascorbic acid in the mixed solution of step 4) second independently are 0.5~2g/L.
4. isolation and purification method according to claim 1, it is characterised in that the pH of step 2) the neutral and alkali mixed solution
It is worth for 10~13.
5. isolation and purification method according to claim 1, it is characterised in that the regulation of pH value is wrapped successively in the step 5)
Include the first acid regulation and the second acid regulation；
Described first acid regulation includes：Using the first acetic acid adjust the pH value of the second mixed solution that the step 4) obtains to
6~7；
Described second acid regulation includes：Using the mixed solution after the described first acid regulation of the second acetic acid regulation pH value to
3~5.
6. isolation and purification method according to claim 1 or 5, it is characterised in that in the step 5) after pH value regulation also
Including：Crystallization treatment is carried out to the obtained acidic mixed solution that adjusts.
7. isolation and purification method according to claim 6, it is characterised in that the temperature of the crystallization treatment is 2~7 DEG C.
8. isolation and purification method according to claim 7, it is characterised in that the time of the crystallization treatment is 2~3 small
When.
9. isolation and purification method according to claim 1, it is characterised in that the supernatant and Vitamin C for obtaining step 3)
Also include before acid mixing：Decolorization is carried out to the supernatant using activated carbon.
10. isolation and purification method according to claim 1, it is characterised in that after levodopa separates out in the step 5),
Separation of solid and liquid is carried out to the feed liquid that precipitation obtains, obtained solid matter is levodopa.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111362821A (en) * | 2020-03-31 | 2020-07-03 | 广西中医药大学 | Environment-friendly and efficient levodopa production method |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664669A (en) * | 2012-09-05 | 2014-03-26 | 李叶华 | Process method for preparing high-purity levodopa |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664669A (en) * | 2012-09-05 | 2014-03-26 | 李叶华 | Process method for preparing high-purity levodopa |
| 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 |
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| 巫世红等: "左旋多巴的强降解实验研究", 《中国药业》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111362821A (en) * | 2020-03-31 | 2020-07-03 | 广西中医药大学 | Environment-friendly and efficient levodopa production method |
| CN111362821B (en) * | 2020-03-31 | 2022-09-23 | 广西中医药大学 | Environment-friendly and efficient levodopa production method |
| 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 |
| 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 |
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