CN114478222A - Method for preparing curcumin compound monomer crystal and application thereof - Google Patents
Method for preparing curcumin compound monomer crystal and application thereof Download PDFInfo
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- CN114478222A CN114478222A CN202210237146.2A CN202210237146A CN114478222A CN 114478222 A CN114478222 A CN 114478222A CN 202210237146 A CN202210237146 A CN 202210237146A CN 114478222 A CN114478222 A CN 114478222A
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- bisdemethoxycurcumin
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- VFLDPWHFBUODDF-FCXRPNKRSA-N Curcumin Natural products C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 title claims abstract description 84
- 239000013078 crystal Substances 0.000 title claims abstract description 77
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- 239000004148 curcumin Substances 0.000 title claims abstract description 46
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 title claims abstract description 43
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- JYTVKRNTTALBBZ-UHFFFAOYSA-N bis demethoxycurcumin Natural products C1=CC(O)=CC=C1C=CC(=O)CC(=O)C=CC1=CC=CC(O)=C1 JYTVKRNTTALBBZ-UHFFFAOYSA-N 0.000 claims abstract description 75
- PREBVFJICNPEKM-YDWXAUTNSA-N bisdemethoxycurcumin Chemical compound C1=CC(O)=CC=C1\C=C\C(=O)CC(=O)\C=C\C1=CC=C(O)C=C1 PREBVFJICNPEKM-YDWXAUTNSA-N 0.000 claims abstract description 75
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- 239000002994 raw material Substances 0.000 claims abstract description 18
- UEPVWRDHSPMIAZ-UHFFFAOYSA-N p-hydroxycinnamoyl feruloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(O)=CC(=O)C=CC=2C=CC(O)=CC=2)=C1 UEPVWRDHSPMIAZ-UHFFFAOYSA-N 0.000 claims abstract description 16
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- UEPVWRDHSPMIAZ-IZTHOABVSA-N (1e,4z,6e)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)hepta-1,4,6-trien-3-one Chemical compound C1=C(O)C(OC)=CC(\C=C\C(\O)=C\C(=O)\C=C\C=2C=CC(O)=CC=2)=C1 UEPVWRDHSPMIAZ-IZTHOABVSA-N 0.000 claims abstract description 12
- NMRUIRRIQNAQEB-UHFFFAOYSA-N demethoxycurcumin Natural products OC(=CC(C=CC1=CC(=C(C=C1)O)OC)=O)C=CC1=CC=C(C=C1)O NMRUIRRIQNAQEB-UHFFFAOYSA-N 0.000 claims abstract description 12
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 10
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- NCDMQHRPDYHDKA-UHFFFAOYSA-N 1-phenylpent-1-enylbenzene Chemical class C=1C=CC=CC=1C(=CCCC)C1=CC=CC=C1 NCDMQHRPDYHDKA-UHFFFAOYSA-N 0.000 description 1
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- C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
- C07C49/24—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups
- C07C49/245—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing hydroxy groups containing six-membered aromatic rings
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Abstract
The invention relates to the technical field of substance separation and purification, and particularly discloses a method for preparing curcumin compound monomer crystals and application thereof. In the method for preparing the curcumin compound monomer crystal, the curcumin compound monomer crystal is a bisdemethoxycurcumin crystal, and the method comprises the steps of extracting raw materials, evaporating and crystallizing, and cooling and crystallizing; the raw material is a mixture of curcumin monomer, demethoxycurcumin and bisdemethoxycurcumin, and the extraction does not adopt a chromatography process. The content of bisdemethoxycurcumin in the bisdemethoxycurcumin crystal obtained by the method is not less than 90%, the product is orange red in appearance, the crystal is spherical or quasi-spherical, and the granularity is uniform; and the process is simple, the operation is convenient, the method is suitable for industrial production, and the product yield can reach more than 60%.
Description
Technical Field
The invention relates to the technical field of substance separation and purification, in particular to a method for preparing curcumin compound monomer crystals and application thereof.
Background
Turmeric (Curcuma longa L.) is a dried rhizome of Curcuma longa L, a plant of Curcuma longa of the family zingiberaceae, commonly used as a flavor and dye, grown in north to north of east asia to south thunberg, from india to australia, and in asia for up to thousand years. The turmeric can extract effective components of curcumin (3.5-5%) and curcuma oil (about 5%), and the curcumin has various biological activities such as antitumor activity, antiviral activity, Alzheimer's disease inhibition activity, arthritis resistance activity and the like through more than 30 years of research.
The curcumin compound is the most important component in the turmeric, is a general name of diphenyl heptene substances contained in the turmeric, and also refers to diphenyl pentene compounds with similar structures. The curcumin monomer, demethoxycurcumin and bisdemethoxycurcumin are three compounds with the highest content in the compounds. The structure is shown in figure 1, and the compounds are very rare diketone substances in nature, two benzene rings are positioned at two ends of a molecule, chain beta-diketone is clamped between the two benzene rings, and a conjugated system is formed by the two benzene rings and the beta-diketone, so that a special dumbbell is formed.
Due to the difference of the structures of the three monomers, the pharmacological activities of the three monomers are different, and in some researches, aiming at a specific action target point for inhibiting or killing tumor cells, the bisdemethoxycurcumin is superior to other two monomers in partial neuroprotection action mechanism and certain bacteriostasis action mechanism. According to the structural analysis of the three monomers, after the two methoxyl groups of the bisdemethoxycurcumin are removed, the bisdemethoxycurcumin is superior to the curcumin monomer and the demethoxycurcumin in the aspects of stability and biological utilization rate, and has good application prospect.
With the research on different pharmacological activities of curcumin, demethoxycurcumin and bisdemethoxycurcumin monomer compounds, the separation of the monomer compounds has very important significance. However, since the three monomers have very similar structures and properties, it is difficult to separate the three monomers by conventional methods such as resin or solvent crystallization.
In the prior art, a chromatography process is mainly adopted for separating three monomers, for example, CN201310531494.1 adopts polyamide resin as a chromatography filler and chloroform-methanol-glacial acetic acid as an eluent, and three monomer compounds are obtained by respectively collecting eluents, concentrating and recrystallizing; CN201010103117.4 describes separating and purifying with macroporous resin, eluting with acetone-2% glacial acetic acid (50: 50), and collecting curcumin, demethoxycurcumin and dimethoxycurcumin fractions respectively; CN200910074614.3 placing the oleoresin on chromatographic separation medium for gradient elution, collecting eluate, and concentrating to obtain curcumin, demethoxycurcumin and bisdemethoxycurcumin crystals; the separation of monomeric compounds by chromatographic separation is a conventional method, but the method has the disadvantages of small treatment capacity, large solvent consumption and high consumption, and can only be applied to laboratories at present. CN201711352560.3 discloses bisdemethoxycurcumin obtained by multiple crystallization from turmeric raw material, but the method has more steps, poor stability and low product yield.
In view of the above, further research on the separation method of curcumin monomeric compounds is still needed.
Disclosure of Invention
In view of the problems of the prior art, it is an object of the present invention to provide a method for efficiently producing bisdemethoxycurcumin crystals with high purity.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for preparing curcumin compound monomer crystals, which are bisdemethoxycurcumin crystals, comprises the steps of raw material extraction, evaporation crystallization and cooling crystallization; the raw material is a mixture of curcumin monomer, demethoxycurcumin and bisdemethoxycurcumin, and the extraction does not adopt a chromatography process.
The invention successfully prepares the bisdemethoxycurcumin crystal with high purity and high yield by directly and simply extracting the mixture of the curcumin monomer, the demethoxycurcumin and the bisdemethoxycurcumin and combining the two-stage crystallization process, abandons the use of the traditional chromatography process and improves the industrial production efficiency of the crystal preparation.
The above-mentioned conventional chromatographic process in the present invention refers to a technique established by utilizing the difference in physicochemical properties of different substances. It consists of two phases: one is a stationary phase and the other is a mobile phase. When the mixture to be separated passes through the stationary phase with the mobile phase, the distribution (content ratio) in the two phases is different due to the difference in the physicochemical properties of the components, the ability to interact (adsorb, dissolve, bind, etc.) with the two phases, and the components are constantly redistributed in the two phases as the mobile phase moves forward. The effluent liquid is collected in a fractional way, so that each single component contained in the sample can be obtained, and the aim of separating each component is fulfilled.
As a specific embodiment, the preparation method of the present invention comprises the steps of:
step 1: extraction: the method comprises the following steps of (1) adding a certain proportion of an extracting agent into bisdemethoxycurcumin as a raw material, and extracting the curcumin to obtain an extract;
step 2: and (3) crystallization: and (3) evaporating and crystallizing the extract obtained in the step (1) under a certain condition, then cooling and crystallizing, then carrying out solid-liquid separation to obtain a bisdemethoxycurcumin crude product, and further drying to obtain the bisdemethoxycurcumin.
In the extraction step of the method, the used extracting agent is an alcohol solvent containing more than 1 hydroxyl and 2-4C; preferably ethanol, isopropanol or n-butanol.
More preferably, the extractant used is ethanol.
In the method, the weight volume ratio of the raw material to the extracting agent is 1 (5-30) g/mL; preferably 1 (5-10) g/mL.
Or preferably, the weight-volume ratio of the raw material to the extracting agent is 1 (8-12) g/mL, so that the solvent consumption can be saved, and an ideal non-target object removing effect can be realized.
According to the invention, the extraction agent and the dosage thereof are researched, and in a preferred scheme, the extraction agent can be better matched with a subsequent two-stage crystallization link to obtain better purity and yield.
In the method, the mass percentage of the bisdemethoxycurcumin in the raw material is not less than 30%, preferably more than 35%, and more preferably more than 40%. Efficient extraction can be further ensured.
In the method, during evaporation and crystallization, evaporation is carried out at the speed of 50-200 ml/h, so that the total solid content of the solution obtained after the evaporation and crystallization is finished is 10-30%; the temperature of the evaporative crystallization is 60-80 ℃, the pressure is-0.03 to-0.06 MPa, and the stirring speed is 10-60 r/min;
and/or during cooling crystallization, the cooling rate is 2-10 ℃/h until the end temperature is 25-35 ℃.
Preferably, during the evaporation crystallization, evaporation is carried out at a rate of 50 ml/h-100 ml/h, so that the total solid content of the solution obtained after the evaporation crystallization is finished is 15% -20%; and during cooling crystallization, the temperature is reduced at a rate of 4-7 ℃/h until the end temperature is 25-30 ℃.
According to the invention, a great deal of research is carried out on the control of the crystallization process, and finally, the bisdemethoxycurcumin product with high purity and high yield is obtained by matching with the selection of the extracting agent and the two-stage crystallization condition, so that the whole process is simple and is suitable for industrial production.
The invention also provides a bisdemethoxycurcumin crystal which is prepared by the method; preferably, the content of the bisdemethoxycurcumin in the bisdemethoxycurcumin crystals is not less than 90%, the crystals are orange red in appearance, the crystal habit is spherical or quasi-spherical, the particle size is uniform, and the crystallinity is good.
The invention also provides the method or the application of the bisdemethoxycurcumin crystal in preparing health-care products or medicines.
The invention has the beneficial effects that:
the method can obtain the bisdemethoxycurcumin crystal with an orange crystal habit of spherical crystal or spheroidal crystal, and the product has good granularity and high crystallinity, and the content of the bisdemethoxycurcumin is not less than 90 percent. The preparation method is simple and convenient, is suitable for industrial production, and has the product yield of over 60 percent.
Drawings
Fig. 1 is a structural diagram of curcumin monomer, demethoxycurcumin and bisdemethoxycurcumin.
Fig. 2 is a crystal habit photograph of the bisdemethoxycurcumin crystal obtained in example 1 of the present invention observed under a polarization microscope.
Fig. 3 is an XRD pattern of the bisdemethoxycurcumin crystals obtained in example 1 of the present invention.
Fig. 4 is an SEM image of bisdemethoxycurcumin crystals obtained in example 1 of the present invention.
Fig. 5 is a liquid phase detection spectrum of curcumin standard.
Fig. 6 is a liquid phase detection spectrum of the bisdemethoxycurcumin crystal product prepared in example 1 of the present invention.
Detailed Description
Preferred embodiments of the present invention will be described in detail with reference to the following examples. It is to be understood that the following examples are given for illustrative purposes only and are not intended to limit the scope of the present invention. Various modifications and alterations of this invention will become apparent to those skilled in the art without departing from the spirit and scope of this invention.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. Materials, reagents and the like used in the following examples are commercially available or can be prepared by a method conventional in the art unless otherwise specified.
In the invention, the curcumin raw material (mixture containing curcumin monomer, demethoxycurcumin and bisdemethoxycurcumin) and the content of the curcumin monomer, the demethoxycurcumin and the bisdemethoxycurcumin are measured according to a detection method of T/CCCHIPIE 1.48-2019 plant extract curcumin.
The crystal habit and particle size of the crystals were observed and measured by a microscope.
The total solid content calculation formula is as follows: total solids content is the weight of non-volatile material in the solution/total solution weight.
Curcumin materials used in the following examples are commercially available from Chenguang Biotechnology group, Inc.
Example 1
The embodiment provides a preparation method of bisdemethoxycurcumin crystals, which specifically comprises the following steps:
and (3) extraction: curcumin with curcumin monomer content of 29.2%, mono-demethoxycurcumin content of 17.3% and bisdemethoxycurcumin content of 50% is used as raw material, 10 times of ethanol (mL) is added based on curcumin weight (g) is added to extract curcumin, and ethanol extract is obtained by filtering;
evaporation and crystallization: evaporating the obtained ethanol extract at the conditions of 65 ℃, pressure of-0.04 MPa and stirring speed of 40r/min at an evaporation rate of 100ml/h to obtain a concentrated solution with the total solid content of 20%;
cooling and crystallizing: cooling the concentrated solution to 25 deg.C at 65 deg.C at a cooling rate of 5 deg.C/h, maintaining for 5h for crystal growth, performing solid-liquid separation to obtain bisdemethoxycurcumin crystal crude product, and oven drying at 105 deg.C for 2h to obtain bisdemethoxycurcumin crystal.
Through the preparation method of the bisdemethoxycurcumin crystal, the obtained bisdemethoxycurcumin crystal is orange, the crystal habit is spherical crystal or spheroidal, the content of the bisdemethoxycurcumin is 95.8 percent, and the yield of the bisdemethoxycurcumin is 73.6 percent.
The crystal habit photograph observed under a polarization microscope is shown in fig. 2, the XRD spectrum of the bisdemethoxycurcumin crystal obtained in this example is shown in fig. 3, the SEM spectrum is shown in fig. 4, the liquid phase detection spectrum of the curcumin standard product in the bisdemethoxycurcumin content test is shown in fig. 5, and the liquid phase detection spectrum of the bisdemethoxycurcumin crystal product prepared in this example is shown in fig. 6.
Example 2
The embodiment provides a preparation method of bisdemethoxycurcumin crystals, which specifically comprises the following steps:
and (3) extraction: curcumin with curcumin monomer content of 47.2%, mono-demethoxycurcumin content of 19.5% and di-demethoxycurcumin content of 30% is used as raw material, 30 times of isopropanol (based on curcumin weight (g), 30 times of volume (mL) of isopropanol) is added to extract curcumin, and isopropanol extract is obtained by filtration;
evaporation and crystallization: evaporating the obtained isopropanol extract at the temperature of 70 ℃, the pressure of-0.06 MPa and the stirring speed of 60r/min at the evaporation rate of 200ml/h until a concentrated solution with the total solid content of 10 percent is obtained;
cooling and crystallizing: cooling the concentrated solution to 35 deg.C at 80 deg.C at a cooling rate of 2 deg.C/h, maintaining for 8h for crystal growth, performing solid-liquid separation on the obtained crystals to obtain bisdemethoxycurcumin crystal crude product, and oven drying at 105 deg.C for 2h to obtain bisdemethoxycurcumin crystal.
By the preparation method of the bisdemethoxycurcumin crystal, the obtained bisdemethoxycurcumin crystal is orange, the crystal habit is spherulite or spheroidal, the content of the bisdemethoxycurcumin is 92.5%, and the yield of the bisdemethoxycurcumin is 61.3%.
Example 3
The embodiment provides a preparation method of bisdemethoxycurcumin crystals, which specifically comprises the following steps:
and (3) extraction: taking curcumin with curcumin monomer content of 36.4%, mono-demethoxycurcumin content of 21.6% and di-demethoxycurcumin content of 40% as raw material, adding 20 times of n-butanol (based on curcumin weight (g), adding 20 times of n-butanol volume (mL)) as solvent to extract curcumin, and filtering to obtain n-butanol extract;
and (3) evaporation and crystallization: evaporating the n-butanol extractive solution at 80 deg.C under-0.06 MPa and stirring speed of 10r/min at an evaporation rate of 50ml/h to obtain concentrated solution with total solid content of 15%;
cooling and crystallizing: cooling the concentrated solution to 30 ℃ at the temperature of 80 ℃ according to the cooling rate of 10 ℃/h, preserving the temperature for 10h to grow crystals, performing solid-liquid separation on the obtained crystals to obtain a bisdemethoxycurcumin crystal crude product, and drying at 105 ℃ for 2h to obtain bisdemethoxycurcumin crystals.
Through the preparation method of the bisdemethoxycurcumin crystal, the obtained bisdemethoxycurcumin crystal is orange red, the crystal habit is spherical crystal or spheroidal, the content of the bisdemethoxycurcumin is 90.5%, and the yield of the bisdemethoxycurcumin is 64.7%.
Example 4
The embodiment provides a preparation method of bisdemethoxycurcumin crystals, which specifically comprises the following steps:
and (3) extraction: curcumin with curcumin monomer content of 46.1%, mono-demethoxycurcumin content of 15.2% and di-demethoxycurcumin content of 35% as raw material is added with 5 times of ethanol (based on curcumin weight (g), 5 times of ethanol (mL)) as solvent to extract curcumin, and filtered to obtain ethanol extract;
evaporation and crystallization: evaporating the obtained ethanol extract at the temperature of 60 ℃, the pressure of-0.06 MPa and the stirring speed of 40r/min at the evaporation rate of 100ml/h until a concentrated solution with the total solid content of 30 percent is obtained;
cooling and crystallizing: cooling the concentrated solution to 25 deg.C at 60 deg.C at a cooling rate of 2 deg.C/h, maintaining for 15h for crystal growth, performing solid-liquid separation on the obtained crystals to obtain bisdemethoxycurcumin crystal crude product, and oven drying at 105 deg.C for 2h to obtain bisdemethoxycurcumin crystal.
By the preparation method of the bisdemethoxycurcumin crystal, the obtained bisdemethoxycurcumin crystal is orange, the crystal habit is spherulite or spheroidal, the content of the bisdemethoxycurcumin is 93.6%, and the yield of the bisdemethoxycurcumin is 69.3%.
Comparative experiment 1
This comparative experiment compares the effects of the preparation of example 1 with comparative examples 1 to 6.
The experimental parameters of comparative examples 1-6 were the same as the conditional parameters of example 1, except for the values of the experimental condition parameters explicitly listed in table 1. In addition, table 1 also shows the preparation performance index of the bisdemethoxycurcumin obtained under different experimental conditions.
TABLE 1
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. A method for preparing curcumin compound monomer crystals, which are bisdemethoxycurcumin crystals, is characterized by comprising the steps of extracting raw materials, evaporating and crystallizing and cooling and crystallizing; the raw material is a mixture of curcumin monomer, demethoxycurcumin and bisdemethoxycurcumin, and the extraction does not adopt a chromatography process.
2. The method of claim 1, wherein in the extraction step, the extractant used is an alcohol solvent containing more than 1 hydroxyl group and 2-4C; preferably ethanol, isopropanol or n-butanol.
3. The method of claim 2, wherein the extractant used in the extraction step is ethanol.
4. The method according to claim 2 or 3, wherein the weight-to-volume ratio of the raw material to the extracting agent is 1 (5-30) g/mL; preferably 1 (5-10) g/mL.
5. The method according to claim 3, wherein the weight-to-volume ratio of the raw material to the extracting agent is 1 (8-12) g/mL.
6. The process according to any one of claims 1 to 5, wherein the mass percentage of bisdemethoxycurcumin in the starting material is not less than 30%, preferably 35% or more, more preferably 40% or more.
7. The method according to any one of claims 1 to 6, wherein in the evaporation crystallization, evaporation is carried out at a rate of 50ml/h to 200ml/h, so that the total solid content of the solution obtained after the evaporation crystallization is finished is 10% to 30%; the temperature of the evaporative crystallization is 60-80 ℃, the pressure is-0.03 to-0.06 MPa, and the stirring speed is 10-60 r/min;
and/or during cooling crystallization, the cooling rate is 2-10 ℃/h until the end temperature is 25-35 ℃.
8. The method according to claim 7, characterized in that during the evaporation crystallization, evaporation is carried out at a rate of 50ml/h to 100ml/h, so that the total solid content of the solution obtained after the evaporation crystallization is finished is 15% to 20%; and during cooling crystallization, the temperature is reduced at a rate of 4-7 ℃/h until the end temperature is 25-30 ℃.
9. A bisdemethoxycurcumin crystal produced by the method of any one of claims 1 to 8;
the bisdemethoxycurcumin crystal has 2 θ peaks in an X-ray powder diffraction pattern at least at about 12.8 °, 13.4 °, 18.6 °, 19.3 °, 20.1 °, 21.3 °, 21.9 °, 24.0 °, 24.4 °, 25.3 °, 26.0 °, 29.1 °, and 30.3 °;
preferably, the content of the bisdemethoxycurcumin in the bisdemethoxycurcumin crystals is not less than 90%, the appearance of the crystals is orange red, and the crystal habit is spherical crystal or spheroidal crystal.
10. Use of the method of any one of claims 1 to 8, or the bisdemethoxycurcumin crystal of claim 9 for the preparation of a health product or a pharmaceutical product.
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