CN108383813B - Penicic acid crystal form I and preparation method and application thereof - Google Patents
Penicic acid crystal form I and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a penicillic acid crystal form I and a preparation method and application thereof. The invention provides a penicillic acid crystal form I, which has characteristic peaks at 13.8 +/-0.2, 14.6 +/-0.2, 15.2 +/-0.2, 16.8 +/-0.2, 20.8 +/-0.2, 22.6 +/-0.2, 24.1 +/-0.2, 27.8 +/-0.2 and 29.0 +/-0.2 in an X-ray powder diffraction pattern expressed by a 2 theta diffraction angle by using Cu/Kalpha radiation. Compared with penicillic acid solid in the prior art, the stability and MRSA (methicillin-resistant staphylococcus aureus) resisting activity of the penicillic acid crystal form I are obviously enhanced.
Description
Technical Field
The invention belongs to the field of crystal forms, and particularly relates to a penicillic acid crystal form I and a preparation method and application thereof.
Background
Penicic acid is a mycotoxin, has two alternative forms of linear substituted keto acid and lactone, has a molecular weight of 170.16, and is easily soluble in hot water, ethanol, diethyl ether and chloroform.
The pharmacological activity and toxicity of penicillic acid are reported to be more, and the penicillic acid has pharmacological activities such as antibacterial activity, antifungal activity, antiviral activity, antitumor activity, acetylcholinesterase inhibition, NF-kB activation inhibition and the like, and has toxicity to human and animals, mainly causes damage to organs such as heart, liver, kidney and the like, and has potential carcinogenicity.
No report about penicillic acid crystal forms is found in the prior art, and the development of one penicillic acid crystal form is very important for deeply researching the pharmacological and toxicological effects of the penicillic acid crystal form.
Disclosure of Invention
Aiming at the defects of the prior art, the penicillic acid is prepared in a large scale by using marine fungus Penicillium sp.HK1-6, and the penicillic acid crystal form I with good stability and excellent antibacterial activity and the preparation method thereof are provided.
The invention provides a penicillic acid crystal form I, which is characterized in that: an X-ray powder diffraction pattern expressed by a 2 theta diffraction angle using Cu/K alpha radiation has characteristic peaks at 13.8 +/-0.2, 14.6 +/-0.2, 15.2 +/-0.2, 16.8 +/-0.2, 20.8 +/-0.2, 22.6 +/-0.2, 24.1 +/-0.2, 27.8 +/-0.2 and 29.0 +/-0.2.
Another embodiment of the present invention provides a crystalline form I of penicillic acid characterized by: an X-ray powder diffraction pattern expressed by a 2 theta diffraction angle using Cu/K alpha radiation has characteristic peaks at 13.8 +/-0.2, 14.6 +/-0.2, 14.8 +/-0.2, 15.2 +/-0.2, 16.8 +/-0.2, 17.7 +/-0.2, 20.8 +/-0.2, 22.6 +/-0.2, 24.1 +/-0.2, 27.8 +/-0.2 and 29.0 +/-0.2. Penicilic acid form I may also have characteristics substantially as represented by the X-ray powder diffraction pattern shown in FIG. 1.
Another embodiment of the present invention provides a crystalline form I of penicillic acid characterized by: the X-ray powder diffraction pattern of the crystal form is basically as shown in figure 1 by using Cu/Kalpha radiation.
The X-ray powder diffraction data for form I in figure 1 are summarized below:
it will be appreciated by those skilled in the art that the relative intensities of the 2 θ characteristic peaks in the XRPD pattern may vary for various reasons when measured in respect of substantially the same crystal form.
The infrared spectrum of the penicillic acid crystal form I is about 3471, 3114, 1715 and 1636cm-1Has a characteristic absorption peak at the position of (2). Penicillic acid form I may also have characteristics represented by an infrared spectrum substantially as shown in figure 2.
According to the inventionThe X-ray powder diffraction analysis of the penicillic acid crystal form I is carried out by a Cu/K alpha source of a D8 advanced polycrystalline X-ray diffractometer of Bruker-AXS company in Germany under the conditions of ambient temperature and ambient humidity
The assay was complete. The infrared spectroscopic analysis of the present invention was carried out by KBr pellet method measurement using a 670-IR +610-IR type microscopic infrared spectrometer from Varian corporation, USA, at ambient temperature and humidity. "ambient temperature" is generally 0-40 ℃; "ambient humidity" is typically 30% to 80% relative humidity.
The X-ray powder diffraction spectrum and the infrared spectrum of the penicillic acid crystal form I are listed in the attached drawing of the specification. The 'representative X-ray powder diffraction pattern or infrared pattern' means that the X-ray powder diffraction characteristics or infrared characteristics of the crystal form basically accord with the overall appearance displayed by the pattern, and it can be understood that in the test process, the peak-appearing positions or peak intensities of the X-ray powder diffraction pattern or infrared pattern measured by the same crystal form have certain differences due to the influence of various factors (such as the granularity of a test sample, the processing method of the test sample, an instrument, test parameters, test operation and the like). The experimental error of the diffraction peak 2 theta value in the X-ray powder diffraction spectrum is generally +/-0.2 degrees; the experimental error of the absorption peak in the infrared spectrum is generally +/-2 to +/-4 cm-1。
The invention provides a preparation method of the penicillic acid crystal form I, which comprises the steps of crystallizing a crude penicillic acid product from a proper solvent, separating and drying; wherein the mass content of penicillic acid in the crude penicillic acid product is more than 80%, the crystallization temperature is below 40 ℃, preferably 0-30 ℃, and the penicillic acid can be static or stirred during crystallization; separating comprises filtering or centrifuging to collect the precipitated solid; the drying temperature is 20-50 deg.C, and can be normal pressure drying or reduced pressure drying; suitable solvents are selected from one or more of dichloromethane, chloroform, carbon tetrachloride, THF, dioxane, ethyl acetate, methyl acetate, methanol, ethanol, isopropanol, benzene, toluene, acetic acid, formic acid, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, diethyl ether, isopropyl ether, acetonitrile, water, petroleum ether, N-hexane, N-pentane and acetone, wherein one or more of dichloromethane, ethyl acetate, petroleum ether, N-hexane, N-pentane, diethyl ether, ethanol, methanol, water and acetone is preferably selected.
The method specifically comprises the following steps:
(1) dissolving the penicillic acid crude product in a suitable solvent, wherein the suitable solvent is selected from one or a mixture of more of dichloromethane, chloroform, carbon tetrachloride, THF, dioxane, ethyl acetate, methyl acetate, methanol, ethanol, isopropanol, benzene, toluene, acetic acid, formic acid, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, diethyl ether, isopropyl ether, acetonitrile, water, petroleum ether, N-hexane, N-pentane and acetone, and preferably one or a mixture of more of dichloromethane, ethyl acetate, petroleum ether, N-hexane, N-pentane, diethyl ether, ethanol, methanol, water and acetone.
(2) Controlling the crystallization at a temperature below 40 deg.C, preferably 0-30 deg.C, by dissolving penicillic acid in a relatively large amount of solvent to obtain solution, and allowing crystallization to start at a temperature below 40 deg.C; or dissolving penicillic acid with small amount of solvent with good solubility (such as one or more of ethyl acetate, ethanol, diethyl ether, hot water, chloroform, methanol, dichloromethane, and acetone), controlling temperature below 40 deg.C, and adding another solvent with poor solubility (such as one or more of petroleum ether, n-hexane, and n-pentane) for crystallization. The crystallization may be carried out either statically or with stirring.
(3) And separating, including filtering or centrifuging to collect the precipitated solid.
(4) Drying the solid obtained by the separation in the step (3), wherein the drying temperature is selected from 20-50 ℃, and the drying can be carried out under normal pressure or reduced pressure.
In another embodiment of the present invention, there is provided a pharmaceutical composition characterized by comprising the penicillic acid crystalline form I of the present invention as an active ingredient. The pharmaceutical composition is used for preventing and/or treating diseases caused by methicillin-resistant staphylococcus aureus.
In another embodiment of the invention, there is provided the use of crystalline penicillic acid form I according to the invention for the preparation of a medicament for the prevention and/or treatment of a disease caused by methicillin-resistant staphylococcus aureus; and the use thereof for the preparation of a candidate medicament for the prevention and/or treatment of a disease caused by methicillin-resistant Staphylococcus aureus; and the application in the preparation of the medicine lead compound for preventing and/or treating diseases caused by methicillin-resistant staphylococcus aureus.
Compared with the existing commercially available penicillic acid or penicillic acid obtained in Chinese patent 201610831163.3, the penicillic acid crystal form I has better chemical and physical stability and lower hygroscopicity, is suitable for long-term storage, and has enhanced antibacterial activity.
The melting point of form I of the present invention is 92-93 c, about 10 c higher than that of penicillic acid of the prior art, and it will be understood by those skilled in the art that factors such as purity and presence of solvents may affect the melting point.
The crystalline form of the crystals is related to the kinetics and equilibrium conditions of the individual crystal modifications under specific conditions. Thus, the skilled person will appreciate that the resulting crystal modification is dependent on the kinetics and thermodynamics of the crystallization process. Under some thermodynamic conditions (solvent system, temperature, pressure, and concentration of the compound of the invention), one crystal modification may be more stable than another (or indeed any other). However, crystal modifications with relatively low thermodynamic stability may be kinetically favored. Thus, in addition to the above conditions, kinetic factors such as time, impurity distribution, agitation, presence or absence of seeds, etc., also affect the crystalline modification of the crystals.
It is to be understood that within the scope of the present invention, the above-described technical features of the present invention and the technical features specifically described below (e.g., examples) may be combined with each other to constitute a new or preferred technical solution. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of crystalline penicillic acid form I of the present invention;
FIG. 2 is an infrared spectrum of crystalline penicillic acid form I of the present invention;
FIG. 3 shows the results of bacteriostatic experiments on the penicillic acid crystalline form I of the invention at concentrations of 10. mu.g/mL and 25. mu.g/mL against S.aureus ATCC 43300;
FIG. 4 shows the results of bacteriostatic experiments on S.aureus ATCC43300 with penicillic acid A at concentrations of 10. mu.g/mL and 25. mu.g/mL;
FIG. 5 results of bacteriostatic experiments on S.aureus ATCC43300 with penicillic acid B at concentrations of 10. mu.g/mL and 25. mu.g/mL.
Detailed Description
In order to facilitate a further understanding of the invention, the following examples are provided to illustrate it in more detail. However, these examples are only for better understanding of the present invention and are not intended to limit the scope or the principle of the present invention, and the embodiments of the present invention are not limited to the following.
Example 1
(1) Culture of marine fungus Penicillium sp.HK1-6 strain
Culture medium for the cultivation of a strain of the fungus Penicillium sp (HK1-6) the following were added per 1000mL of water: boiling 200g of potatoes to obtain juice, 20g of glucose, 30g of crude sea salt and 15g of agar; when in use, the mixture is poured into a glass culture dish to prepare a culture medium plate. The fungal strains were inoculated into medium plates and shake-cultured at 20 ℃ for 3 days.
(2) Fermentation of marine fungus Penicillium sp.HK1-6
The fermentation medium used for the fermentation culture of the fungus Penicillium sp.HK1-6 was, per 1000mL of water: boiling 200g of potatoes to obtain juice, 20g of glucose and 30g of crude sea salt; when in use, the mixture is packed in a conical flask. The fungus strain is inoculated in a culture medium of a conical flask and is subjected to static culture at 15-20 ℃ for 28 days.
(3) Isolation and extraction of penicillic acid
Taking 30L of the fermentation product obtained in the step (2), separating the fermentation liquor from the thalli, extracting the fermentation liquor for 3-5 times by using ethyl acetate, and concentrating the extract under reduced pressure to obtain a fermentation liquor extract; leaching the thalli with methanol for 3-5 times, and concentrating under reduced pressure to obtain thalli extract; mixing the fermentation liquid extract and the thallus extract, and firstly carrying out normal phase silica gel column chromatographic separation, wherein the fixed phase is as follows: 200-300 mesh silica gel, mobile phase: 10-60% (volume percentage, same below) of ethyl acetate-petroleum ether mixed solvent, and separating to obtain crude penicillic acid (18g, HPLC showed 85.3% of penicillic acid content).
(4) Preparation of penicillic acid crystal form I
Dissolving the penicillic acid crude product (1.0g) obtained in the step (3) in 25mL of ethanol at 40 ℃, dropwise adding a proper amount of n-hexane, naturally cooling to room temperature, standing overnight for crystallization, filtering, and drying to obtain a white solid (0.72g), namely a penicillic acid crystal form I;1H NMR(CDCl3，600MHz)δ：5.47(1H，s，H-2)，5.19(1H，brs，H-6a)，5.12(1H，brs，H-6b)，3.92(3H，s，H-8)，1.77(3H，s，H-7)；ESIMS m/z 171[M+H]+the X-ray powder diffraction spectrum is shown in figure 1, and the infrared spectrum is shown in figure 2.
Example 2
Taking a commercially available penicillic acid crude product (10mg) with the purity of 90 percent, dissolving the penicillic acid crude product in 1mL ethyl acetate at room temperature, standing and crystallizing at the temperature of 15-25 ℃ for 48 hours, filtering, and drying a filter cake at the temperature of 40-50 ℃ to obtain a white solid (8.1mg), namely penicillic acid crystal form I, wherein the X-ray powder diffraction spectrum of the penicillic acid crystal form I is shown in figure 1, and the infrared spectrum of the penicillic acid crystal form I is shown in figure 2.
Example 3
Dissolving crude penicillic acid (10g) in 120mL of hot water, controlling the temperature at 5-15 ℃, standing for crystallization for 24 hours, centrifugally collecting precipitated solid, and drying at 30-40 ℃ to obtain a penicillic acid crystal form I, wherein an X-ray powder diffraction spectrum is shown in figure 1, and an infrared spectrum is shown in figure 2.
Example 4
Dissolving the crude penicillic acid (10g) in 100mL of mixed solution of ethyl acetate and petroleum ether (volume ratio is 1: 1), controlling the temperature at 10-15 ℃, standing for crystallization for 36 hours, filtering and collecting solids, placing the solids in a vacuum drying oven at room temperature for drying for 12 hours to obtain a penicillic acid crystal form I, wherein the X-ray powder diffraction spectrum of the penicillic acid crystal form I is shown in figure 1, and the infrared spectrum of the penicillic acid crystal form I is shown in figure 2.
Example 5
Dissolving the crude penicillic acid (10g) in 110mL of acetone, controlling the temperature at 0-5 ℃, standing for crystallization for 72 hours, filtering and collecting solids, placing the solids at room temperature in a vacuum drying oven for drying for 12 hours to obtain a penicillic acid crystal form I, wherein the X-ray powder diffraction spectrum of the penicillic acid crystal form I is shown in figure 1, and the infrared spectrum of the penicillic acid crystal form I is shown in figure 2.
Example 6
Dissolving the crude penicillic acid (5g) in 60mL of dichloromethane, controlling the temperature at 5-10 ℃, dropwise adding a proper amount of n-pentane, stirring for crystallization for 12 hours, filtering and collecting solids, and drying at 30-40 ℃ to obtain a penicillic acid crystal form I, wherein the X-ray powder diffraction spectrum of the penicillic acid crystal form I is shown in figure 1, and the infrared spectrum of the penicillic acid crystal form I is shown in figure 2.
Example 7
Dissolving the crude penicillic acid (5g) in 50mL of diethyl ether, controlling the temperature at 0-5 ℃, standing for crystallization for 72 hours, filtering and collecting solids, placing the solids at room temperature in a vacuum drying oven for drying for 12 hours to obtain a penicillic acid crystal form I, wherein the X-ray powder diffraction spectrum of the penicillic acid crystal form I is shown in figure 1, and the infrared spectrum of the penicillic acid crystal form I is shown in figure 2.
Example 8 storage stability test
The penicillic acid crystal form I of the present invention, a prior art penicillic acid (commercially available, hereinafter abbreviated as penicillic acid a), and a penicillic acid obtained in chinese patent 201610831163.3 (hereinafter abbreviated as penicillic acid B) were stored in open containers at 40 ℃, 75% relative humidity (results are shown in table 1) and 50 ℃, respectively, and the storage stability after 2 months was examined. With respect to storage stability, the purity of each test compound was measured initially and after 2 months of storage by HPLC and the results were compared (see methods described in WO2009128421a1 for specific methods).
TABLE 1 storage stability test at 40 ℃ and 75% relative humidity
As can be seen from the test results in table 1, the penicillic acid crystal form I of the present invention has extremely excellent storage stability, and in addition, the test in an open container at 50 ℃ also shows that the purity of penicillic acid crystal form I is almost unchanged (less than 0.2%) after two months, while the purity of penicillic acid a and penicillic acid B is reduced by more than 2.5%, so that the penicillic acid crystal form I of the present invention also has the advantage of ultra-high stability, which is convenient for long-term storage.
Example 9 antimicrobial Activity test
The inhibition zones of the penicillic acid crystal form I, the penicillic acid A and the penicillic acid B to methicillin-resistant staphylococcus aureus S.aureus ATCC43300 when the concentrations are 10 mu g/mL and 25 mu g/mL are tested by a filter paper method.
The results show that the diameter of the inhibition zone of the penicillic acid crystal form I is almost 2 times of the diameter of the inhibition zone of penicillic acid A and penicillic acid B (see the figures 3-5). In FIGS. 3 to 5, the upper and lower groups on the left side are parallel experimental groups each having a concentration of 10. mu.g/mL, and the upper and lower groups on the right side are parallel experimental groups each having a concentration of 25. mu.g/mL. Therefore, the penicillic acid crystal form I has good stability, and the MRSA activity is well enhanced.
All documents mentioned in this application are incorporated by reference into this application as if each were individually incorporated by reference. The Chinese and English acronyms, code numbers and the like used in the invention can be found in reference documents or technical manuals, textbooks and tool books in the prior art. Furthermore, it should be understood that various changes and modifications can be made by those skilled in the art after reading the above disclosure, and equivalents also fall within the scope of the invention as defined by the appended claims.
Claims (10)
1. A crystalline form I of penicillic acid characterized by: an X-ray powder diffraction pattern expressed by a 2 theta diffraction angle using Cu/K alpha radiation has characteristic peaks at 13.8 +/-0.2, 14.6 +/-0.2, 15.2 +/-0.2, 16.8 +/-0.2, 20.8 +/-0.2, 22.6 +/-0.2, 24.1 +/-0.2, 27.8 +/-0.2 and 29.0 +/-0.2.
2. A crystalline form I of penicillic acid characterized by: an X-ray powder diffraction pattern expressed by a 2 theta diffraction angle using Cu/K alpha radiation has characteristic peaks at 13.8 +/-0.2, 14.6 +/-0.2, 14.8 +/-0.2, 15.2 +/-0.2, 16.8 +/-0.2, 17.7 +/-0.2, 20.8 +/-0.2, 22.6 +/-0.2, 24.1 +/-0.2, 27.8 +/-0.2 and 29.0 +/-0.2.
3. Crystalline penicillic acid form I according to any one of claims 1-2, wherein the crystalline penicillic acid form I has an IR spectrum at about 3471 cm-1Has a characteristic absorption peak at the position of (2).
4. Crystalline penicillic acid form I according to any one of claims 1-2, wherein said crystalline penicillic acid form I has an IR spectrum at about 3114 cm-1Has a characteristic absorption peak at the position of (2).
5. Crystalline penicillic acid form I according to any one of claims 1-2, wherein the crystalline penicillic acid form I has an IR spectrum at about 1715 cm-1Has a characteristic absorption peak at the position of (2).
6. Crystalline penicillic acid form I according to any one of claims 1-2, wherein said crystalline penicillic acid form I has an IR spectrum of about 1636cm-1Has a characteristic absorption peak at the position of (2).
7. Process for the preparation of the crystalline penicillic acid form I according to any one of claims 1 to 6, characterized in that it comprises the steps of crystallization from a suitable solvent, separation and drying of the crude penicillic acid product having a penicillic acid content higher than 80% by mass and a crystallization temperature of 40oBelow C, the suitable solvent is one or more selected from dichloromethane, ethyl acetate, ethanol, diethyl ether, water, petroleum ether, n-hexane and acetone.
8. Pharmaceutical composition characterized by comprising crystalline penicillic acid form I according to any one of claims 1 to 6 as active principle.
9. Pharmaceutical composition according to claim 8, characterized in that it is used for the prevention and/or treatment of diseases caused by methicillin-resistant Staphylococcus aureus.
10. Use of crystalline penicillic acid form I according to any one of claims 1 to 6 for the preparation of a medicament for the prevention and/or treatment of a disease caused by methicillin-resistant Staphylococcus aureus.
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| Tautomerism of penicillic acid;Munday, C. W.;《Nature》;19491231;第163卷;第443页右栏 * |
| Two New Compounds Isolated from A Seaweed-associated Fungus, Aspergillus sp. AF044;DONG Zhuo et al.;《 Chinese Journal of Natural Medicines》;20100930;第8卷(第5期);第370页右栏2.3 萃取和分离，第371页左栏第1段和右栏第3段，第372页左栏第1段 * |
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