CN106117072B - A kind of levodopa crystalline powder and its manufacture method - Google Patents
A kind of levodopa crystalline powder and its manufacture method Download PDFInfo
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Abstract
The invention discloses a kind of levodopa crystalline powder and its manufacture method, this method obtains the mixed solution containing levodopa by tyrosine phenol lyase bioconversion, mixed solution pH is adjusted to slant acidity with acid solution, centrifuge or be collected by filtration coarse crystal, acid adjustment is then proceeded to redissolve, add heating stirring decolouring after activated carbon, crossing cleaner liquid, alkali tune is crystallized, dried after filtering again, obtains levodopa crystalline powder.The method of the present invention has effectively filtered out remaining substrate, albumen and pigment in conversion process on the basis of industrialized production is realized；Using vacuum microwave drying technology, reduce the effect of the external force such as the drum hot blast by traditional drying, stirring and caused by product be lost, avoid levodopa caused product appearance brown stain after high-temperature oxydation destroys or decomposes, improve the moisture homogeneity after product drying；The crystalline powder quality that this method obtains is high, and total impurities is not more than 0.05% by HPLC appearances area percentage, and the crystallinity of crystalline powder is more than 90%.
Description
Technical field
The present invention relates to biochemical industry and isolate and purify field, relate in particular to a kind of levodopa crystalline powder and its
Manufacture method.
Background technology
Levodopa (3,4-dihydroxylphenylalanine, Levodopa), also known as L-3,4 dihydroxyphenylalanine, chemical name are
3,4- Dihydroxyphenylalanines, CAS：59-92-7；White crystalline powder, odorless, tasteless；It is a kind of important in organism
Bioactive substance, it is the important intermediate during TYR to catechol or the biochemical metabolism approach of melanin.Its
Structural formula is as follows：
Levodopa and Benserazide (such as Madopar) treatment common geriatric disease Parkinson's disease oneself have more than 40 years
History, it is still to treat the maximally effective medicine of Parkinson's, and better tolerance so far, can not only improves bradykinesia, alleviate main
Symptom, and the life-span of Parkinsonian can be extended.Levodopa ranking 100,2009 in world's best-selling drugs in 2007
Realize that global yield reaches 250 tons, consumption sum in 2010 oneself more than 1,500,000,000 dollars.Global yield in 2015 close to 1000 tons,
Sales volume hundred million U.S. dollar more than 30.
Domestic and international scientist is continually striving to improve the production yields of levodopa.It is reported that the production of levodopa
Method has extracted form natural plant method, chemical synthesis and microbial enzyme conversion method.
Traditional preparation method is to be extracted from plant cat beans through science, and Chinese patent CN 103641730A are disclosed
A kind of preparation method of levodopa, cat beans are flattened by machinery, with acetic acid flooding, leaching liquor removes egg with trichloroacetic acid
In vain, cream is condensed into, is dissolved with water, regulation pH to isoelectric point separates out coarse crystallization, is dissolved with hot acid water, activated carbon decolorizing, room temperature weight
Crystallization.Chinese patent CN 103664669A disclose a kind of process for preparing high-purity levodopa, using cat beans as original
Material, is extracted, extract solution is enriched with and separated to levodopa by electrodialysis with sour water.Plant extraction method is due to by original
Expect the limitation in source, yield is small, far from meeting current market demand.
The chemical synthesis of levodopa is more.At present, the chemical method of industrialized production levodopa bulk drug comes from
1987, vanillin (vanillic aldehyde) and hydantoin (hydantoins) were, it is necessary to which the reaction by 8 steps is made.But run into one
Individual main difficulty is the mixture that the product being synthesized is D- types and L-type, and the two separated process control difficulties are big,
The problems such as production cost is high, environmental pollution is serious simultaneously be present.
Using micro-organisms levodopa, some enzymes in metabolic pathway are exactly make use of, such as tyrosinase, tyrosine
Different substrates is transformed into levodopa by phenols cracking enzyme, transferase, can obtain substantial amounts of levodopa, many countries give birth to it
Production has carried out substantial amounts of research, takes many different synthetic methods.The end of the sixties in last century, some external scholars start to cause
Power is in the research of microbial enzyme method synthesis levodopa.The beginning of the seventies, Japanese scholars Yamada etc. synthesizes left to microbial enzyme method
Rotation DOPA is conducted in-depth research, and work was put into aginomoto company in 1993 by the optimization of strain improvement and fermentation condition
Industry metaplasia is produced.Chinese patent CN 103122361A are disclosed by building recombinant strain, there is provided it is a kind of using TYR as
The method that substrate synthesizes levodopa.Chinese patent CN 104726513A disclose a kind of method that enzyme process prepares levodopa,
Tyrosinase is produced with Pseudomonas Maltophilia (Pseudomonas maltophilia), is converted and made as raw material using TYR
Standby levodopa.However, preparing levodopa currently with bioanalysis realizes that industrialized report is actually rare.Existing biology
Method prepares levodopa and reaction time length be present, and accessory substance is more, and conversion ratio is low, and substrate residual concentration is high, and finished product color and luster is poor,
A series of problems, such as crystallinity is relatively low, and impurity content is high.
The content of the invention
Goal of the invention：It is an object of the invention to provide one kind in high yield, crystallized suitable for the levodopa of industrialized production
The manufacture method of powder, the high-purity obtained it is a still further object of the present invention to provide preceding method production, high-crystallinity, high printing opacity
The levodopa crystalline powder of rate.
Technical scheme：In order to realize foregoing invention purpose, a kind of manufacture method of levodopa crystalline powder of the invention,
By tyrosine phenol lyase bioconversion obtain containing levodopa, tyrosine phenol lyase, remaining substrate, albumen, pigment,
The alkaline mixed solution of salt, mixed solution pH is adjusted to slant acidity with acid solution, centrifuges or is collected by filtration coarse crystal, then proceed to
Acid adjustment is redissolved, heating stirring is decolourized after addition activated carbon, and crossing cleaner liquid, alkali tune is crystallized, dried after filtering again, obtains levodopa
Crystalline powder.
The present invention is point that the mixed solution obtained based on the reaction of tyrosine phenols cracking method carries out levodopa crystalline powder
From and purifying.The tyrosine phenol lyase enzyme process is existing in coenzyme (PLP) using tyrosine phenol lyase
Under the conditions of, it is stirred with basic substrate, reaction produces levodopa.Basic substrate is catechol/pyruvic acid ammonium or adjacent benzene
Diphenol/pyruvic acid/concentrated ammonia liquor.
As shown in formula (I), tyrosine phenol lyase is in NH4 +, can be by the catechol of a molecule under conditions of being present in excess
Pyruvic acid with a molecule is through single step reaction biosynthesis levodopa.The residue of the reaction includes：Unnecessary pyruvic acid, neighbour
The impurity such as benzenediol, ammonium salt, zymoprotein, and the pigment such as catechol oxide, residual enzyme protein solution.
Mixed solution first time acid adjustment pH is adjusted to 5~5.5, close to the isoelectric point of levodopa, advantageously reduces left-handed more
Bar solubility, complement filter can effectively remove the impurity such as substantial amounts of water-solubility protein, pigment, remaining substrate and salt.Filtering
Method include but is not limited to centrifugal filtration or plate compression, collect and obtain higher degree, hypopigmented coarse crystal；Second
Acid adjustment pH is adjusted to 0.95~1.05 and is used to be completely dissolved levodopa coarse crystal, and accelerates beneficial to by a small amount of zymoprotein in coarse crystal
Denaturation and flocculation, binding activity charcoal adsorb the purpose for reaching separation；When alkali tune crystallization pH is adjusted to 3.0~5.5, levodopa starts
Crystallize, it is preferable that when pH is controlled 3.9~4.3, and control crystallization temperature early stage to be slowly stirred between 30~40 DEG C,
The levodopa of generation is fine granularity crystal, and crystallinity reaches more than 90%.
Further, feed temperature is down to 5~10 DEG C during first time acid adjustment, centrifugal rejection filter or plate compression after standing, and
Uniformly eluted with a small amount of water, throw aside clear liquid after centrifuging and collect crystal.
Second of acid adjustment is the 0.3~2.0%, preferably 0.5% of cumulative volume by quality percent by volume addition activated carbon,
50~55 DEG C are warming up to after addition activated carbon to be slowly stirred 0.8~2 hour, and activated carbon is filtered out with plate-frame filtering or press filtration cylinder press filtration
The albumen floccule being denatured on a small quantity.
Alkali tune crystallization by quality percent by volume add 25~30% alkali lye, the alkali lye include sodium hydroxide solution,
The combination of any one or more in potassium hydroxide solution, ammonia spirit.
When alkali tune crystallizes, the crystallization temperature of material is controlled between 30~40 DEG C, when alkali tune is to desired pH, is slowly stirred
After 1~2 hour, when feed temperature is down into 5~10 DEG C, centrifugal rejection filter after standing, crystal is collected after being eluted with pure water.
In order to mitigate degree of oxidation of the levodopa in processing procedure, improve the finished product color and luster of levodopa, alkali tune knot
The antioxidant added before brilliant concentration in total feed liquid is 0.3~0.7g/L, and the antioxidant includes NaHSO3、Na2SO3、
Na2S2O5Or the combination of any one or more in its sylvite, vitamin C or its sodium salt or sylvite.
The acid solution that the first time acid adjustment and second of acid adjustment add includes hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid
In the combination of any one or more.
Explanation is needed exist for, tyrosine phenol lyase Biocatalysis method of the present invention is known technology, used
Tyrosine phenol lyase can directly buy acquisition, can also be used containing tyrosine phenol lyase oneself know restructuring E.coli fermentation tables
Up to obtaining the thalline zymotic fluid containing enzyme, then concentrate through film, mechanical breaking-wall method, bactofugation slag obtain concentration enzyme liquid.
The levodopa crystalline powder yield that the method for the invention obtains is not less than 85%.
A kind of levodopa crystalline powder, is obtained, total impurities goes out peak area by HPLC by method as claimed in claim 1
Percentages are not more than 0.05%, and the crystallinity of anhydrous crystal is 90%, and crystalline flour end grain diameter size is 120 μm~250 μm.
Beneficial effect：The method of the present invention improves levodopa crystalline powder on the basis of industrialized production is realized
Yield, accurate control reaction acid-base property and temperature have effectively filtered out remaining substrate, albumen and the pigment in conversion process；Adopt
With vacuum microwave drying technology, reduce the effect of the external force such as the drum hot blast by traditional drying, stirring and caused by product be lost, avoid
Levodopa caused product appearance brown stain after high-temperature oxydation destroys or decomposes, improves the moisture homogeneity after product drying；
The crystalline powder quality that this method obtains is substantially better than EP and USP requirements, and total impurities is little by HPLC appearance area percentages
In 0.05% (EP 1.0%, USP 1.1%) of gross weight, single impurity is by HPLC appearances area percentage no more than gross weight
0.05% (EP and USP highests are 0.5%), the crystallinity of crystalline powder is more than 90%.
Brief description of the drawings
Fig. 1 is the efficient liquid phase chromatographic analysis result of the embodiment of the present invention 2；
Fig. 2 is the efficient liquid phase chromatographic analysis result of the embodiment of the present invention 3；
Fig. 3 is levodopa and the (conversion of the HPLC collection of illustrative plates of catechol situation of change in the conversion process of the embodiment of the present invention 1
Carry out to 40 minutes 1 hour)；
Fig. 4 is levodopa and the (conversion of the HPLC collection of illustrative plates of catechol situation of change in the conversion process of the embodiment of the present invention 1
Carry out to 3 hours)；
Fig. 5 is levodopa and the (conversion of the HPLC collection of illustrative plates of catechol situation of change in the conversion process of the embodiment of the present invention 1
Carry out to 4.5 hours).
Embodiment
The present invention is further described with reference to embodiment.
The tyrosine phenol lyase living things catalysis technique of embodiment 1
Xiang Shuizhong launches initial acetone acid, and pH is controlled 7.0~9.0 with concentrated ammonia liquor；Add antioxidant, chelating successively again
Agent, ammonium salt, PLP, pH is controlled 7.0~9.0 with concentrated ammonia liquor again, add the weight that concentration is 80~200g/L
The enzyme liquid of group tyrosine phenol lyase, nitrogen is passed through, adjustment temperature to reaction temperature, ammoniacal liquor regulation pH to 7.0~9.0, is added
Catechol starts to react；It is 1: 1~1.5 that initial basis substrate catechol launches mol ratio with pyruvic acid and its sodium salt.It
Afterwards, substrate catechol and pyruvic acid (or pyruvic acid ammonium, hereafter unless otherwise indicated an equal pyruvic acid) are added respectively per 10min
For 2g/L, catechol it is final add concentration be 50~70g/L (being calculated using initial volume), pyruvic acid finally add concentration as
50~70g/L (is calculated) with initial volume, as substrate catechol residual >=5g/L, stops feeding intake, continue stir 0.5h~
Reaction terminates after 1h, obtains levodopa conversion fluid.Reaction conversion ratio >=95%, levodopa content is up to 100 in conversion fluid
~120g/L.
In step of converting, it is also necessary to add 0.2mol/L~0.3mol/L ammonium salt, including but not limited to ammonium formate, acetic acid
Any one or more combination in ammonium, ammonium chloride, ammonium sulfate.
After putting into pyruvic acid or its ammonium salt, also put into the antioxidant of substrate quality 1%~5%, antioxidant include but
It is not limited to NaHSO3、Na2SO3、Na2S2O5, vitamin C and its sodium salt the combination of any one or more.
After putting into pyruvic acid and antioxidant, 0.5g/L~1.5g/L chelating agent is also put into, chelating agent includes but unlimited
In any one of tartaric acid and its k-na salt, ethylenediamine tetra-acetic acid (EDTA) and its disodium salt.
As shown in Figures 3 to 5, catalytic reaction has been carried out 4.5 hours, and levodopa content gradually increases in system, adjacent benzene
Diphenol concentration all the time≤5g/L；At the end of reaction, the remaining content of catechol only has 0.71g/L.
The 650L transformation systems of embodiment 2
The levodopa conversion fluid that Example 1 obtains, add concentrated hydrochloric acid and adjust pH to 5.1, it is 650L to obtain cumulative volume, dense
Spend the levodopa mixed liquor for 110g/L, temperature is down to 6 DEG C, after standing 4 hours, with centrifuge rejection filter, and with drinking on a small quantity
Water wash, centrifuge material outlet have no that obvious liquid outflow can collect levodopa crude product.The levodopa crude product of collection
Gross weight is 97.5kg, and it is 67.5kg to calculate levodopa content by dry product, and the levodopa yield that crude product centrifuges to obtain is
94.4%.
In the 97.5kg levodopas crude product input enamel reaction still that centrifugation is obtained, 570L drinking water, control temperature are added
30~35 DEG C of degree.Stirring is opened, adds concentrated hydrochloric acid, adjusts pH to 0.97, concentrated hydrochloric acid dosage is 48kg, and now cumulative volume is about
650L.The activated carbon of cumulative volume 0.5%, about 3.25kg are added by quality percent by volume into reactor.Start to warm up to 50
DEG C, and keeping temperature 1 hour.
After insulation terminates, this material removes activated carbon through press filtration cylinder, and clear liquid enters essence after accurate filter and dries bag
In enamel reaction still in workshop.Stirring is opened, the sodium sulfite solution 2.2L that concentration is 150g/L is added into reactor, this
When reactor in the concentration of sodium sulfite be 0.5g/L.
30 DEG C or so of control material temperature, stirring is opened, 25% NaOH solution is slowly added to by quality percent by volume,
PH is adjusted to 4.0, after being slowly stirred 1~2 hour, when feed temperature is down into 8 DEG C, stops stirring, stands still for crystals 5 hours.
Crystal is collected by centrifugation with basket centrifuge.During centrifugation, with Water spray is purified 2 times, each dosage is 6L water, is finally used
Bubble is washed once, and dosage is 10L water.It is 75kg that Total crystal weight is collected after drying, loads layer of polyethylene bag, to be dried.
To after centrifugation crystal material carry out vacuum microwave drying, dried material 5 ± 0.5cm of thickness, 45 DEG C of drying temperature,
Microwave power control is in 7 native 0.5kW, vacuum -0.099~-0.092Mpa, 20~30min of dry duration.
Gross weight is 62kg after drying, therefore it is 91.8% to recrystallize yield, total recovery 86.7%.After testing, dry
To product meet EP and USP requirement：Total impurities is not more than 0.05% by HPLC appearances area percentage, crystalline powder
For crystallinity more than 90%, grain diameter is 120 μm~250 μm.
By EP requirements, each index is respectively：Outward appearance is white crystalline powder, differentiates that IR is consistent with reference substance IR collection of illustrative plates,
Sample size measure main peak retention time is consistent with reference substance peak retention time, and it is molten that solution colour is not deeper than BY6 standard colorimetrics
Liquid, loss on drying 0.22%, pH 5.8, residue≤0.1%, heavy metal≤10mg/kg, relevant material is qualified, optical purity
For 99.8%, content is detected as 99.6% with titration.
By USP requirements, indices are respectively：Outward appearance is white crystalline powder, differentiates IR and reference substance IR collection of illustrative plates one
Cause, sample size measure main peak retention time it is consistent with reference substance peak retention time, loss on drying 0.22%, optical activity be-
163 °, residue≤0.1%, heavy metal≤10mg/kg, content is detected as 99.3% with high performance liquid chromatography, defects inspecting symbol
Close and require.
The 6500L transformation systems of embodiment 3
The levodopa conversion fluid that Example 1 obtains, add the concentrated sulfuric acid that mass volume ratio is 50% and adjust pH to 5.4,
It is 6500L to obtain cumulative volume, and concentration is 104g/L levodopa mixed liquor, and temperature is down to 9 DEG C, and after standing 4 hours, use is board-like
Filter press filtration, and washed with a small amount of purified water top, purified liquor outlet has no that obvious liquid outflow can collect levodopa crude product.Receive
The levodopa crude product gross weight integrated is 858kg, and it is 643.6kg to calculate levodopa content by dry product, and plate filter obtains
Levodopa yield be 95.2%.
In the 858kg levodopas crude product input enamel reaction still that plate filter is obtained, 5700L drinking water is added,
Control 30~35 DEG C of temperature.Stirring is opened, adds concentrated hydrochloric acid, adjusts pH to 1.03, concentrated hydrochloric acid dosage is 465kg, now cumulative volume
About 6500L.The activated carbon of cumulative volume 0.5%, about 32.5kg are added by quality percent by volume into reactor.Start to warm up
To 55 DEG C, and keeping temperature 1.5 hours.
After insulation terminates, this material removes activated carbon through press filtration cylinder, and clear liquid enters essence after accurate filter and dries bag
In enamel reaction still in workshop.Stirring is opened, the solution of sodium bisulfite 24L that concentration is 150g/L is pressed into reactor,
Now the concentration of the sodium hydrogensulfite in reactor is about 0.5g/L.
40 DEG C or so of control material temperature, stirring is opened, 30% KOH solution is slowly added to by quality percent by volume,
PH is adjusted to 4.2, after being slowly stirred 1~2 hour, when feed temperature is down into 8 DEG C, stops stirring, stands still for crystals 5 hours.
Crystal is collected by centrifugation with basket centrifuge.During centrifugation, with Water spray is purified 2 times, each dosage is 6L water, is finally used
Bubble is washed once, and dosage is 10L water.It is 689kg that Total crystal weight is collected after drying, loads layer of polyethylene bag, to be dried.
To after centrifugation crystal material carry out vacuum microwave drying, dried material 5 ± 0.5cm of thickness, 45 DEG C of drying temperature,
Microwave power control is in 7 ± 0.5kW, vacuum -0.099~-0.092Mpa, 20~30min of dry duration.
Gross weight is 590kg after drying, therefore it is 91.7% to recrystallize yield, total recovery 87.3%.After testing, dry
To product meet EP and USP requirement：Total impurities is not more than 0.05% by HPLC appearances area percentage, crystalline powder
For crystallinity more than 90%, grain diameter is 120 μm~250 μm.
By EP requirements, each index is respectively：Outward appearance is white crystalline powder, differentiates that IR is consistent with reference substance IR collection of illustrative plates,
Sample size measure main peak retention time is consistent with reference substance peak retention time, and it is molten that solution colour is not deeper than BY6 standard colorimetrics
Liquid, loss on drying 0.16%, pH 5.3, residue≤0.1%, heavy metal≤10mg/kg, relevant material is qualified, optical purity
For 99.7%, content is detected as 99.5% with titration.
By USP requirements, indices are respectively：Outward appearance is white crystalline powder, differentiates IR and reference substance IR collection of illustrative plates one
Cause, sample size measure main peak retention time it is consistent with reference substance peak retention time, loss on drying 0.16%, optical activity be-
164 °, residue≤0.1%, heavy metal≤10mg/kg, content is detected as 99.2% with high performance liquid chromatography, defects inspecting symbol
Close and require.
Test example
HPLC analyzes the impurity of above-described embodiment 2 and the product of embodiment 3, and its result is as shown in Figure 1 and Figure 2.
The levodopa anhydrous crystal powder HPLC analysis results of 1 embodiment of table 2
| Retention time | Area | % areas | Highly | Integral type | |
| 1 | 4.467 | 4885 | 0.02 | 727 | BV |
| 2 | 6.154 | 31024963 | 99.97 | 2655425 | BB |
| 3 | 25.237 | 2758 | 0.01 | 412 | BB |
The levodopa anhydrous crystal powder HPLC analysis results of 2 embodiment of table 3
| Retention time | Area | % areas | Highly | Integral type | |
| 1 | 5.158 | 316515629 | 99.98 | 2658925 | BV |
| 2 | 22.694 | 7575 | 0.02 | 808 | BB |
Table 1, table 2 correspond to Figure of description Fig. 1, Fig. 2 HPLC collection of illustrative plates respectively.The present invention prepares work according to existing production
Skill, used raw material is soluble in water, therefore organic solvent need not be used in production process.Impurity content is remote in obtained product
The product obtained far below other technique productions, purity are above 99.95%.
Described above is only the preferred embodiment of the present invention, it should be pointed out 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.
Claims (11)
1. a kind of manufacture method of levodopa crystalline powder, obtained by tyrosine phenol lyase bioconversion containing left-handed more
Bar, the alkaline mixed solution of tyrosine phenol lyase, remaining substrate, albumen, pigment, salt, it is characterised in that：Is carried out first
Acid adjustment, feed temperature is down to 5 ~ 10 DEG C, mixed solution pH is adjusted to 5 ~ 5.5 with acid solution, centrifuges or be collected by filtration coarse-grain
Body, heating stirring decolouring after second of acid adjustment redissolution, addition activated carbon is then carried out, crossing cleaner liquid, alkali tune crystallizes, after filtering again
Dry, obtain levodopa crystalline powder.
A kind of 2. manufacture method of levodopa crystalline powder according to claim 1, it is characterised in that：Second of acid adjustment
PH is adjusted to 0.95 ~ 1.05, and alkali tune crystallization pH is adjusted to 3.9 ~ 4.3.
A kind of 3. manufacture method of levodopa crystalline powder according to claim 2, it is characterised in that：This method obtains
Levodopa crystalline powder yield be not less than 85%.
A kind of 4. manufacture method of levodopa crystalline powder according to claim 1, it is characterised in that：First time acid adjustment
Centrifugal rejection filter or plate compression after standing, and uniformly eluted with a small amount of water, throw aside clear liquid after centrifuging and collect crystal.
A kind of 5. manufacture method of levodopa crystalline powder according to claim 1, it is characterised in that：Second of acid adjustment
Activated carbon 0.5% is added by quality percent by volume, being warming up to 50 ~ 55 DEG C after addition activated carbon is slowly stirred 0.8 ~ 2 hour, uses
Plate-frame filtering or press filtration cylinder press filtration filter out activated carbon and albuminate floccule.
A kind of 6. manufacture method of levodopa crystalline powder according to claim 1, it is characterised in that：Alkali tune crystallization is pressed
Quality percent by volume adds 25 ~ 30% alkali lye, and the alkali lye includes sodium hydroxide solution, potassium hydroxide solution, ammonia spirit
In the combination of any one or more.
A kind of 7. manufacture method of levodopa crystalline powder according to claim 6, it is characterised in that：Alkali tune crystallizes
When, the crystallization temperature of material is controlled between 30 ~ 40 DEG C, when alkali tune is to desired pH, after being slowly stirred 1 ~ 2 hour, by feed liquid
When temperature is down to 5 ~ 10 DEG C, centrifugal rejection filter after standing, crystal is collected after being eluted with pure water.
A kind of 8. manufacture method of levodopa crystalline powder according to claim 7, it is characterised in that：Before alkali tune crystallization
The antioxidant of addition concentration in total feed liquid is 0.3 ~ 0.7g/L, and the antioxidant includes NaHSO3、Na2SO3、Na2S2O5
Or the combination of any one or more in its sylvite, vitamin C or its sodium salt or sylvite.
A kind of 9. manufacture method of levodopa crystalline powder according to claim 4 or 5, it is characterised in that：Described
The acid solution that acid adjustment and second of acid adjustment add include in hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid any one or
A variety of combinations.
A kind of 10. manufacture method of levodopa crystalline powder according to claim 1, it is characterised in that：Alkali tune crystallizes
Drying steps afterwards, it is that 5 ± 0.5cm of solid accumulation is thick, under temperature 45 C, microwave power is controlled in 7 ± 0.5 kW, vacuum
- 0.099 ~ -0.092 Mpa, dry 20 ~ 30min.
11. the levodopa crystalline powder that method manufacture as claimed in claim 1 obtains, it is characterised in that：Total impurities presses HPLC
Appearance area percentage is not more than 0.05%, and for the crystallinity of crystalline powder more than 90%, grain diameter is 120 μm ~ 250 μm.
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| CN106318989A (en) * | 2016-11-17 | 2017-01-11 | 山东鲁抗医药股份有限公司 | Fermentation method for preparing levodopa |
| 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 |
| CN107382760B (en) * | 2017-08-18 | 2020-04-24 | 山东鲁抗医药股份有限公司 | Separation and purification method of levodopa |
| 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 |
| CN109161568A (en) * | 2018-08-10 | 2019-01-08 | 浙江工业大学 | A method of improving levodopa product quality and yield |
| CN109485581B (en) * | 2018-11-19 | 2021-07-09 | 广西壮族自治区中医药研究院 | Method for refining levodopa |
| CN110331153B (en) * | 2019-06-24 | 2021-04-30 | 浙江工业大学 | Kluyveromyces tyrosol lyase mutant and application thereof |
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| US20050277174A1 (en) * | 2004-03-29 | 2005-12-15 | Hidehiko Kumagai | Mutant tyrosine repressor, a gene encoding the same, and a method for producing L-DOPA |
| CN104402748A (en) * | 2014-12-05 | 2015-03-11 | 南宁知本康业生物技术有限公司 | Microwave-assisted method for extracting levodopa from cat beans |
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