CN107304213B - Method and equipment for processing poppy extract - Google Patents
Method and equipment for processing poppy extract Download PDFInfo
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- CN107304213B CN107304213B CN201610243572.1A CN201610243572A CN107304213B CN 107304213 B CN107304213 B CN 107304213B CN 201610243572 A CN201610243572 A CN 201610243572A CN 107304213 B CN107304213 B CN 107304213B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
Abstract
The invention discloses a method for processing poppy extract, which comprises the following steps: a. adding polar solvent into the poppy extract to react to obtain a first treatment solution; b. adding a filter aid into the first treatment solution and filtering to obtain a first extracting solution; c. separating the first extracting solution by a chromatographic column, wherein a filler in the chromatographic column is spherical silica gel bonded with a stationary phase, and a mobile phase is a mixture of alcohol and inorganic acid; d. eluting to obtain alkaloid-containing fraction. Compared with the prior art, the method provided by the invention can separate monomer alkaloids including morphine, codeine, thebaine and the like, and the obtained alkaloid monomer has high purity and high yield.
Description
Technical Field
The present invention relates to a method for separating and purifying monomer medicines of morphine, codeine and thebaine from poppy extract by using industrial preparative chromatography and traditional crystallization method.
Background
Pain is a protective response of the body to noxious stimuli from the environment in and out of the body, with both substantial and potential tissue damage and mental damage. The pain-treating drugs are hundreds of drugs, and the mechanism is different. The search for highly effective, low-toxicity, non-dependency analgesics from natural drugs has been a trend. The active monomer substances contained in the poppy extract are natural alkaloid analgesic drugs which are most widely applied and have the largest market demand in the world at present.
The immature poppy fruit contains a large amount of milky white liquid, and can be dried to form brown or brownish black paste. The poppy extract is a crude alkaloid product obtained by extracting and drying the paste by using an organic solvent such as ethanol, the components of the poppy extract are relatively complex, the known active ingredients have more than 25, the content and the medicinal value of the alkaloid such as morphine, codeine, thebaine and the like are the highest, the poppy extract is industrially extracted and separated in a large quantity, and the poppy extract is prepared into different preparations or synthesized into other medicaments which are widely applied to clinic to treat various symptoms such as pain, cough, diarrhea and the like, and particularly the preparation of morphine and codeine has important medical value.
With the progress of the three-stage pain-relieving guiding principle proposed by the world health organization in China, the management policy of narcotics is continuously adjusted, and the medical consumption of narcotics in China is greatly increased. The isolation of the monomer of an effective alkaloid from an extract of poppy is limited due to the low yield of poppy, high harvesting costs and low availability of poppy plants. Therefore, the conventional method for separating morphine, codeine, thebaine and other alkaloids from the poppy extract has not been able to satisfy the increasing market demand. The novel, efficient and environment-friendly industrial extraction method has good market development and application prospects.
At present, according to the physicochemical properties determined by the specific molecular structure of morphine, the traditional preparation method for separating morphine, codeine and thebaine from poppy extract is prepared by the laggard anion-cation resin adsorption method, please refer to fig. 1, which is the morphine separation method in the prior art. Dissolving poppy extract in water solution with certain pH value to form poppy solution with certain concentration, adsorbing with resin column, washing to eliminate impurity, eluting with solvent to eliminate morphine adsorbed on the resin column, collecting the eluted liquid, decompression concentrating, crystallizing the concentrated liquid, suction filtering to obtain morphine coarse product, and treating the waste water produced in production in waste water pond.
The method uses a traditional resin adsorption method, and because the adsorption selectivity of the resin method is poor, only morphine components with the highest content in poppy extracts can be obtained, other active components with higher medicinal value, such as codeine, thebaine and the like, can not be recovered, the content of obtained morphine crude products is low, generally can only reach about 80 percent, and can not reach medicinal standards, and complex purification treatment is still needed in the later period, so that the yield of the active alkaloids is low. Meanwhile, the resin adsorption has the defects of small adsorption quantity, long adsorption time and the like, so that the method has the disadvantages of long production period, large occupied space of required equipment and high production cost. In addition to the above problems, the resin method generates a large amount of industrial wastewater in the production process, and the wastewater needs to be treated professionally, thereby increasing the production cost virtually and being not suitable for large-scale industrial production.
Disclosure of Invention
The invention aims to provide a method for processing poppy extract, which can separate monomer alkaloids such as morphine, codeine, thebaine and the like from the poppy extract, and the obtained alkaloid monomer has high purity and high yield.
In order to solve the above technical problems, the present invention provides a method for treating poppy extract, comprising:
a. adding polar solvent into the poppy extract to react to obtain a first treatment solution;
b. adding a filter aid into the first treatment solution and filtering to obtain a first extracting solution;
c. separating the first extracting solution by a chromatographic column, wherein a filler in the chromatographic column is spherical silica gel bonded with a stationary phase, and a mobile phase is a mixture of alcohol and inorganic acid;
d. eluting to obtain alkaloid-containing fraction.
Preferably, the filter aid in step b is added in an amount of 5-30% by mass of the poppy extract.
Preferably, the filter aid is diatomaceous earth.
Preferably, the polar solvent is an alcohol-water mixed solution.
Preferably, the step c further comprises a pre-column filtration step before the chromatographic column separation.
Preferably, the stationary phase is C18.
Preferably, the mobile phase is an ethanol-phosphoric acid mixture.
Preferably, the concentration of the ethanol-phosphoric acid mixture is 0.1% -15% ethanol and 0.1% -1% phosphoric acid.
The present invention also provides an apparatus for use in the above method, comprising:
the poppy extract is extracted in a polar solvent, enters the vertical tube array through the bottom end of the tube array, is contacted with a filter aid on the wall of the vertical tube array, then is discharged from the top end of the vertical tube array, is separated through a chromatographic column under the condition that a filler is spherical silica gel of a bonded stationary phase and a mobile phase is an alcohol-inorganic acid mixture, and is eluted to obtain a fraction containing alkaloid. The vertical tube array equipment is shown in figure 3.
Compared with the prior art, the method provided by the invention can separate monomer alkaloids including morphine, codeine, thebaine and the like, and the obtained alkaloid monomer has high purity and high yield. The method introduces the easily-regenerated silica gel separation material and the vertical type tubular filter equipment, realizes the automatic control of separation and purification, reduces the input of production personnel, shortens the batch production period and the regeneration period of the separation material, improves the production efficiency, and reduces the manufacturing cost compared with the traditional production technology.
Drawings
Figure 1 is a process flow diagram of a prior art morphine separation process;
FIG. 2 is a flow chart of the process for preparing the extract of Papaver somniferum L.of the present invention;
FIG. 3 is a drawing of a vertical tube array apparatus
FIG. 4 is a morphia Mass Spectrum (MS)
FIG. 5 is a morphine infrared spectrum (IR)
FIG. 6 is a codeine Mass Spectrum (MS)
FIG. 7 is a codeine infrared spectrum (IR)
FIG. 8 is a thebaine Mass Spectrum (MS)
FIG. 9 is a thebaine infrared spectrum (IR)
Detailed Description
According to the invention, the inventor carries out further research, refines parameters of each step and screens out an optimal scheme, and the specific contents are as follows:
a. adding polar solvent into the poppy extract for extraction, adding filter aid for filtering to obtain extractive solution, wherein the extraction temperature is 0-100 deg.C, the extraction time is 10-100 min, the polar solvent is preferably ethanol/water solvent system, and the mass of the filter aid is 5-30% of the poppy extract.
b. Separating the extractive solution with chromatographic column, filtering with pre-column, and collecting filtrate. When the extract is separated by a chromatographic column, the filler is spherical silica gel bonded with a stationary phase, the fixed item is C18, and the mobile phase is an ethanol-phosphoric acid mixture with gradually increased alcohol concentration. The mobile phase for eluting morphine is a mixture of 0.1-15% ethanol and 0.1-1% phosphoric acid, and morphine fractions are obtained by elution.
When an alcohol-containing solvent is used for crystallization, the morphine fraction is recrystallized by using the alcohol-containing solvent and an ester-containing solvent, preferably a methanol-ethyl acetate solvent.
The molecular structures of various alkaloids in the poppy extract are different, so that the poppy extract has different adsorption capacities on silica gel filler, can be eluted by alcohol-inorganic acid mixtures with different concentrations, has the weakest morphine adsorption capacity, and can be completely eluted by low-concentration alcohol-inorganic acid mixtures. In the prior art, the poppy extract is difficult to separate to obtain high-purity alkaloid, because a plurality of oily impurities exist in the poppy extract, the adsorption force of the impurities is similar to the molecular structure of active alkaloid such as morphine, codeine and the like, the adsorption capability is equivalent, the impurities are eluted together with the active alkaloid in chromatographic separation, and the purity of the obtained fraction is extremely low. In the invention, the filter aid is added before filtration, so that oily impurities in the extraction process of partial poppy shell concentrate can be adsorbed, and the oily impurities are reduced from entering and influencing the next step process. The filter aid is selected from diatomite, perlite, cellulose, asbestos, graphite powder, sawdust, magnesium oxide, gypsum, activated carbon, acid clay and the like. The diatomite has a large specific surface area, can form a filter cake with high porosity while adsorbing impurities, is not easy to block, and can accelerate filtration while adsorbing.
In the invention, the silica gel bonded stationary phase is selected as the filler, because the organic compound is bonded to Si-OH on the surface of the silica gel, a uniform and firm thin layer (or a polymerization layer) can be formed on the surface of the silica gel, gradient elution can be carried out, and the adsorption capacity of a sample is changed by selecting different mobile phase conditions, so that the active alkaloids are eluted one by one. The bonded C8 or C18 is better stationary phase selection, the invention prefers the spherical silica gel with the bonded stationary phase of C18, can form uniform and firm monomolecular thin layer on the surface of the silica gel, can not excessively adsorb a sample to influence the yield, and can achieve better gradient elution effect.
The method has the advantages that the selected process conditions are obtained by gradually amplifying the experimental dosage in the large-scale production process, the method can be easily realized in industrial production, is suitable for large-scale production, has short separation period, can obtain high-purity morphine, codeine, thebaine and other active alkaloid fractions at one time, and can optimize the product properties through simple crystallization of an alcohol-containing solvent. The method can simultaneously separate and obtain a plurality of active alkaloids containing morphine, the purity of the obtained alkaloids containing morphine, codeine and the like is up to more than 98%, and the yield is improved by about five percent compared with the traditional production technology, thereby improving the additional value of alkaloid monomers. The method has the advantages of simple and convenient operation, higher yield and lower cost, and is more suitable for industrial production.
Example 1
Adding polar solvent into the poppy extract for extraction, adding filter aid and filtering to obtain extractive solution; separating the extractive solution with chromatographic column, wherein the filler is bonded stationary phase spherical silica gel, the mobile phase is alcohol-inorganic acid mixture with gradually increased alcohol concentration, and three fractions are obtained by using three mobile phases with different polarities. Concentrating the fractions respectively, crystallizing with alcohol-containing solvent, and vacuum filtering to obtain morphine, codeine and thebaine solid.
Morphine solid: MS (as in fig. 4): m/z 285.13; IR (cm-1) (see FIG. 5): 3347.82, 3208.97, 2938.98, 2823.28, 2395.16, 1814.69, 1652.70, 1633.41, 1604.48, 1473.35, 1446.35, 1369.21, 1307.50, 1247.72, 1197.58, 1118.51, 977.73, 943.02, 802.24, 759.82, 653.75, 522.61.
Codeine solid: MS (as in fig. 6): m/z 299.15; IR (cm-1) (see FIG. 7): 3600.45, 3467.38, 3102.90, 2898.49, 1830.11, 1652.70, 1633.41, 1608.34, 1500.35, 1452.14, 1369.21, 1309.43, 1272.79, 1203.36, 1124.30, 1054.87, 979.66, 790.67, 651.82.
Thebaine solid: MS (as in fig. 8): m/z 311.15; IR (cm-1) (see FIG. 9): 3002.62, 2929.34, 2836.77, 2792.42, 1668.12, 1629.55, 1602.56, 1502.28, 1442.49, 1371.14, 1276.65, 1232.29, 1143.58, 1027.87, 906.38, 867.81, 790.67, 642.18.
Example 2
1. The extraction process steps
Adding 5% ethanol water 15L into 5.0Kg semen Papaveris extract (morphine content is 0.71Kg measured by external standard method), extracting at room temperature for 30min, adding diatomaceous earth 0.5Kg, and stirring for one minute to complete extraction; directly transferring the extract to a filter for filtration after extraction, and collecting the filtrate. The filtrate was concentrated under reduced pressure to about 20L. The resulting concentrate was filtered through a pre-column at a flow rate of 30L/min, and the filtrate was collected. And uniformly recovering the obtained filter cake layer and then incinerating the recovered filter cake layer.
2. Morphine separation process step
(1) Preparation equipment and packing parameters:
preparing a column specification: 300mm 1200mm (about 300mm to 400mm height of the effective packing column)
The type of the filler: 200-mesh 300-mesh spherical silica gel, C18 filler
Filling amount of the filler: 15Kg
Flow rate of mobile phase: 10L/min
(2) Column separation method for morphine
And (3) loading about 30L of the extracting solution into a preparation column, after loading, washing for about 10min by using 10% ethanol and 0.75% phosphoric acid water as mobile phases, respectively collecting fractions once every 1min, wherein the volume of each fraction is about 10L, sequentially marking the obtained fractions as F1-F10, using 30% ethanol and 0.75% phosphoric acid water as mobile phases, continuously washing for 16min, collecting fractions, marking the obtained fractions as F11-F26 according to the method, further washing for 10min by using 50% ethanol and 0.75% phosphoric acid water as mobile phases, collecting fractions, marking the obtained fractions as F27-F36, finally washing the preparation column for about 10min by using 60% ethanol and 0.25% phosphoric acid water as mobile phases, and finishing washing for standby.
(3) Morphine crystallization method
Mixing the above separated fractions F3-F7, adding total amount of 50L, and concentrating under reduced pressure at 30 deg.C to recover ethanol until no ethanol remains in the fractions. The obtained residual liquid is collected and recrystallized by using 25L of methanol and ethyl acetate which are 1: 1, the crystallization liquid is kept still overnight, a large amount of white solid is separated out, the filtration is carried out, a filter cake is collected and dried, and the weight is weighed to obtain approximately 0.69kg of white solid morphine, the purity is 98.87 percent, and the yield is 97.6 percent.
3. Preparation process of codeine
And combining the separated fractions F10-F15, concentrating under reduced pressure at 50 ℃ to obtain yellow oily matter, collecting the obtained residual liquid, adding 60mL of absolute ethyl alcohol, stirring and dissolving at room temperature, slowly dropwise adding acetone into the codeine solution of the ethyl alcohol under stirring until no white solid is separated out, performing suction filtration, and drying to obtain 39.16g of white solid codeine, wherein the purity is 99.03%, and the yield is 82.01%.
4. Process for thebaine isolation
Mixing the separated fractions F18-F23, concentrating under reduced pressure at 50 ℃ until the volume of the solvent is 0.04L, transferring the obtained concentrated solution into a crystallizing tank, taking 3.0L of 5% ethanol and 0.01% -1% phosphoric acid water (3: 2) as recrystallization solvents, stirring at 0 ℃ overnight, separating out a large amount of off-white solids, performing suction filtration, collecting filter cakes, and drying to obtain 16.69g of white solid thebaine with the purity of 98.97% and the yield of 72.98%.
Example 3
1. The extraction process steps
Adding 5% ethanol water 30L into 9.0Kg semen Papaveris extract (morphine content is 1.284Kg measured by external standard method), extracting at room temperature for 20min, adding graphite powder 1.8Kg, stirring for one minute to complete extraction; directly transferring the extract to a filter for filtration after extraction, collecting the filtrate, and concentrating the filtrate under reduced pressure to about 20L. The resulting filtrate was filtered through a pre-column at a flow rate of 20L/min, and the filtrate was collected. And uniformly recovering the obtained filter cake layer and then incinerating the recovered filter cake layer.
2. Morphine separation process step
(1) Preparation equipment and packing parameters:
preparing a column specification: 300mm 1200mm (about 700mm to 800mm height of the effective packing column)
The type of the filler: 200-mesh 300-mesh spherical silica gel, C8 filler
Filling amount of the filler: 30Kg
Flow rate of mobile phase: 10L/min
(2) Column separation method for morphine
And (3) loading about 60L (the combined solution of the primary extraction liquid and the secondary extraction liquid) to the preparation column, after the loading is finished, washing for about 10min by using 1% ethanol and 0.25% phosphoric acid water as mobile phases, respectively collecting fractions once every 1min, wherein the volume of each fraction is about 10L, marking the obtained fractions as F1-F10 in sequence, using 18% ethanol and 0.25% phosphoric acid water as mobile phases, continuing to wash for 16min, collecting the fractions, marking the obtained fractions as F11-F26 according to the method, using 50% ethanol and 0.25% phosphoric acid water as mobile phases, washing for 10min, collecting the fractions, marking the obtained fractions as F27-F36, finally washing the preparation column for about 5min by using 60% ethanol and 0.25% phosphoric acid water as mobile phases, and finishing the washing for standby.
(3) Morphine crystallization method
Mixing the above separated fractions F3-F7, adding total amount of 50L, and concentrating under reduced pressure at 30 deg.C to recover ethanol until no ethanol remains in the fractions. Collecting the obtained residual liquid, recrystallizing with 20L methanol and ethyl acetate at ratio of 1: 1, standing the crystallized liquid overnight, precipitating a large amount of white solid, vacuum filtering, collecting the filter cake, drying, and weighing to obtain 1.26kg of white-like solid morphine with purity of 98.91% and yield of 98.2%.
3. Preparation process of codeine
And combining the separated fractions F10-F15, concentrating under reduced pressure at 50 ℃ to obtain yellow oily matter, collecting the obtained residual liquid, adding 100mL of absolute ethyl alcohol, stirring and dissolving at room temperature, slowly dropwise adding butanone into the codeine solution of the ethyl alcohol under stirring until no white solid is separated out, performing suction filtration, and drying to obtain 71.40g of white solid codeine, wherein the purity is 99.12%, and the yield is 81.89%.
4. Thebaine preparing process
Mixing the separated fractions F18-F23, concentrating under reduced pressure at 50 ℃ until the volume of the solvent is 0.3L, transferring the obtained concentrated solution into a crystallizing tank, taking 4.5L of 5% ethanol and 0.01% -1% phosphoric acid water (3: 2) as recrystallization solvents, stirring at 0 ℃ overnight, separating out a large amount of off-white solids, performing suction filtration, collecting filter cakes, and drying to obtain 30.21g of thebaine as a white solid with the purity of 98.57% and the yield of 72.35%.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and improvements can be made without departing from the principle of the present invention, and these modifications and improvements should also be construed as the protection scope of the present invention.
Claims (5)
1. A method of processing an extract of poppy, comprising:
a. adding polar solvent into the poppy extract to react to obtain a first treatment solution, wherein the polar solvent is ethanol-water mixed solvent;
b. adding a filter aid into the first treatment solution and filtering to obtain a first extracting solution;
c. separating the first extracting solution by using a chromatographic column, wherein a filler in the chromatographic column is spherical silica gel bonded with a stationary phase, and the stationary phase is C18; the mobile phase is ethanol-phosphoric acid mixture with gradually increased alcohol concentration, and the mobile phase for eluting morphine is 0.1% -15% ethanol-0.1% -1% phosphoric acid mixture;
d. eluting to obtain alkaloid-containing fraction.
2. The method of claim 1, wherein the filter aid is added in step b in an amount of 5% to 30% by mass of the poppy extract.
3. The treatment process according to claim 2, characterized in that the filter aid is diatomaceous earth.
4. The process of claim 1, wherein step c further comprises a pre-column filtration step prior to the chromatographic column separation.
5. An apparatus for use in the method of any one of claims 1-4, comprising:
the poppy extract is extracted in a polar solvent, enters the vertical tube array through the bottom end of the tube array, is contacted with a filter aid on the wall of the vertical tube array, then is discharged from the top end of the vertical tube array, is separated through a chromatographic column under the conditions that a filler is spherical silica gel of a bonded stationary phase C18 and a mobile phase is an ethanol-phosphoric acid mixture, and is eluted to obtain a fraction containing alkaloid.
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| CN110615795B (en) * | 2019-09-20 | 2022-04-22 | 甘肃省药物碱厂 | Purification method of crude morphine base product |
| CN110615794B (en) * | 2019-09-20 | 2022-04-19 | 甘肃省药物碱厂 | Method for extracting and separating thebaine from poppy shell |
| CN110698488B (en) * | 2019-09-20 | 2022-05-13 | 甘肃省药物碱厂 | A method for extracting and separating morphine from pericarpium Papaveris |
| CN113105019A (en) * | 2021-04-08 | 2021-07-13 | 广西国睿工程咨询有限公司 | Method for decomposing morphine in pharmaceutical factory waste liquid |
| CN115093424B (en) * | 2022-06-30 | 2023-03-31 | 国药集团工业有限公司 | Industrial CPS extraction process |
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