CN113149947B - Michellac dimethylamine lactone-p-hydroxybenzoate as well as preparation method and application thereof - Google Patents
Michellac dimethylamine lactone-p-hydroxybenzoate as well as preparation method and application thereof Download PDFInfo
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- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 title claims abstract description 146
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
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Abstract
The invention provides michelia dimpled lactone-p-hydroxybenzoate as well as a preparation method and application thereof, wherein the molecular formula of the michelia dimpled lactone-p-hydroxybenzoate is C 31 H 39 NO 9 (ii) a The crystallography characteristics of the michelia lactone-P-hydroxybenzoate salt of dimethylamine comprise that the space group is P2 1 2 1 2 1 Cell parameter of
α =90 °, β =90 °, γ =90 °, cell volume of
The michelia lactone-p-hydroxybenzoate prepared by the method has good hygroscopicity and physical and chemical stability, and has good drug development prospect; the preparation method has the advantages of simple operation, mild condition, good repeatability, environmental protection, low toxicity and safety.
Description
Technical Field
The invention belongs to the technical field of medical crystallization, and particularly relates to michelia lactone-p-hydroxybenzoate dimethylamine, and a preparation method and application thereof.
Background
The michelia lactone of dimethylamine belongs to sesquiterpene lactone compounds, and the molecular formula is C 17 H 27 NO 3 Is white powdery solid, has poor water solubility, can be degraded after being placed for a long time, and is stable in physical and chemical propertiesThe properties are poor.
WO2015006893A1 discloses the application of sesquiterpene lactone compounds including dimethylamine michelia lactone and derivatives thereof in treating rheumatoid arthritis and cancers, and provides a method for preparing dimethylamine michelia lactone hydrochloride and fumarate by using a dichloromethane solvent. The dichloromethane belongs to two types of organic solvents, has certain toxicity and carcinogenicity, has extremely low boiling point, has anesthetic property of steam, causes acute poisoning due to large-scale inhalation, has the problems of headache, vomit, impaired hematopoietic function and the like, and brings certain potential safety hazard for industrial mass production.
CN104876899A indicates that dimethylamine michelia lactone hydrochloride has serious moisture absorption and can be seriously degraded under high temperature and high humidity conditions, and although the moisture absorption performance of the dimethylamine michelia lactone fumarate is slightly improved compared with the dimethylamine michelia lactone hydrochloride, the problem of poor stability of the product is still not solved.
CN103724307B, CN111303097A, CN111303100A, CN111303098A and CN111303099A, etc. successively disclose 6 different crystal forms of dimethylamine michelia lactone fumarate and a preparation method thereof. Different crystal forms of the same drug have significant differences in solubility, melting point, dissolution behavior, fluidity, bioavailability and the like, thereby affecting the stability, bioavailability and curative effect of the drug.
The crystal form has important influence on the properties and use of the pharmaceutical product, and a stable preparation process with high reproducibility is required to ensure the effective crystal form of the product. Due to the existence of the polycrystalline type, the quality stability of the michelia lactone fumarate is difficult to control in production, and experimental researches find that different crystal forms of the michelia lactone fumarate are mutually converted under the conditions of a certain solvent, temperature, humidity and the like.
The currently disclosed michelia lactone hydrochloride and michelia lactone fumarate do not have obvious advantages in the aspects of hygroscopicity, physical and chemical stability, controllability of product quality and the like, and the properties are crucial to the research and development and scale-up production of medicaments.
Therefore, it is necessary to develop a new salt form of michelia lactone dimethylamide which is excellent in safety, stability, post-processing properties and hygroscopicity.
Disclosure of Invention
The invention provides michelia lactone-p-hydroxybenzoate dimethylamine and a preparation method and application thereof, aiming at solving the technical problems of high hygroscopicity, poor stability, easy mutual transformation of crystal forms, complex preparation process, strong toxicity of used solvents, poor controllability of process and product quality and the like in the existing michelia lactone salt type dimethylamine and the preparation method thereof. The michelia lactone-p-hydroxybenzoate of dimethylamine provided by the invention has the advantages of low hygroscopicity, high physical and chemical stability, safe preparation process, low toxicity of used solvent, small dosage, good repeatability, strong operability and mild conditions, and is beneficial to industrial production and subsequent drug development.
One purpose of the invention is to provide michelia lactone-p-hydroxybenzoate dimethylamine, and the molecular formula of the michelia lactone-p-hydroxybenzoate dimethylamine is C 31 H 39 NO 9 。
The michelia lactone-P-hydroxybenzoate of dimethylamine is characterized in that the space group is P2 1 2 1 2 1 Cell parameter of
α =90 °, β =90 °, γ =90 °, unit cell volume of
See figure 1.
In the invention, in the X-ray powder diffraction spectrum of the michelia lactone-p-hydroxybenzoate, characteristic peaks exist at 2 theta diffraction angles of 5.5 +/-0.2 degrees, 7.3 +/-0.2 degrees, 9.5 +/-0.2 degrees, 10.7 +/-0.2 degrees, 12.4 +/-0.2 degrees, 13.2 +/-0.2 degrees, 13.9 +/-0.2 degrees, 14.9 +/-0.2 degrees, 16.9 +/-0.2 degrees, 17.2 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.5 +/-0.2 degrees, 20.0 +/-0.2 degrees, 20.5 +/-0.2 degrees, 21.5 +/-0.2 degrees, 22.0 +/-0.2 degrees, 22.8 +/-0.2 degrees, 24.2 +/-0.2 degrees, 25.7 +/-0.2 degrees, 27.3 +/-0.2 degrees and 29.3 +/-0.2 degrees.
In the invention, the differential scanning calorimetry DSC analysis chart of the dimethylamine michelia lactone-p-hydroxybenzoate type has a characteristic melting peak at 145 +/-2 ℃.
The water content of the michelia lactone-p-hydroxybenzoate sample provided by the invention is only 0.55 +/-0.02% when the environmental temperature is 25 ℃ and the relative humidity reaches 95%. In an accelerated stability experiment in which the temperature is controlled to be 40 ℃ and the humidity is 75% for 12 weeks, the melting point of the michelia lactone-p-hydroxybenzoate dimethylamine sample provided by the invention is not obviously changed compared with that of an initial sample, and the weight loss before decomposition is less than 0.1%, which shows that the michelia lactone-p-hydroxybenzoate dimethylamine sample provided by the invention has higher stability and lower hygroscopicity. In a buffer solution simulating the pH =6.8 of human intestinal fluid, the michelia lactone-p-hydroxybenzoate dimethylamine sample provided by the invention has no crystal form transformation and no degradation in the suspension experiment process for 5 h.
The invention also aims to provide a preparation method of michelia lactone-p-hydroxybenzoate, which comprises the following steps:
(1) Reacting michelia lactone dimethylamine with p-hydroxybenzoic acid to obtain a michelia lactone-p-hydroxybenzoate crude product;
(2) And (2) cooling and crystallizing the crude product of the michelia lactone-p-hydroxybenzoate obtained in the step (1) to obtain the michelia lactone-p-hydroxybenzoate.
Compared with other preparation processes, the cooling crystallization preparation method of the michelia lactone-p-hydroxybenzoate of dimethylamine provided by the invention has the advantages of simple operation, mild conditions, easy preparation, good repeatability, green, environment-friendly, low-toxicity and safety, and is suitable for large-scale production, and the selected solvents are three solvents. The product purity can reach more than 99 percent, the product yield is more than 90 percent, the product is blocky and crystal-like, has good fluidity and is beneficial to filtration and drying.
In the present invention, the molar ratio of the michelia lactone and p-hydroxybenzoic acid in step (1) is 1 (2.0-2.5), such as 1:2, 1.
In the present invention, the reaction temperature is 40-60 deg.C, such as 40 deg.C, 42 deg.C, 45 deg.C, 47 deg.C, 50 deg.C, 52 deg.C, 55 deg.C, 57 deg.C, 60 deg.C, etc., and the reaction time is 10-30min, such as 10min, 12min, 15min, 18min, 20min, 22min, 25min, 28min, 30min, etc.
In the present invention, the reaction in step (1) is carried out in an organic solvent.
In the present invention, the organic solvent includes any one of alcohols, ketones, nitriles, or esters, or a combination of at least two thereof.
In the present invention, the organic solvent includes any one of methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, acetonitrile, methyl acetate or isopropyl acetate or a combination of at least two thereof.
In the present invention, the amount of michelia lactone dimethylamine to be added is 20 to 100mg, for example, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, etc., and the amount of the organic solvent to be added is 1mL.
In the invention, the cooling rate of the cooling crystallization in the step (2) is 2-5 ℃/h, such as 2 ℃/h, 3 ℃/h, 4 ℃/h, 5 ℃/h and the like.
In the present invention, the temperature of the cooling crystallization in the step (2) is-10 to 15 ℃, for example, -10 ℃, -8 ℃, -5 ℃, -3 ℃, 0 ℃,2 ℃,5 ℃, 7 ℃, 10 ℃, 12 ℃, 15 ℃ and the like.
In the invention, the step (2) further comprises the steps of sequentially carrying out solid-liquid separation, washing and drying on the mixture obtained by cooling and crystallizing.
In the present invention, the solid-liquid separation method is filtration.
In the present invention, the drying is carried out at 25 to 40 ℃ (e.g., 25 ℃, 28 ℃, 30 ℃, 32 ℃, 35 ℃, 38 ℃, 40 ℃, etc.) for 1 to 3 hours (e.g., 1 hour, 1.2 hours, 1.5 hours, 1.8 hours, 2 hours, 2.2 hours, 2.5 hours, 2.8 hours, 3 hours, etc.) under normal pressure.
As a preferred technical scheme of the invention, the preparation method comprises the following steps:
(1) Putting michelia lactone dimethylamine and p-hydroxybenzoic acid with the molar ratio of 1 (2.0-2.5) into an organic solvent to react for 10-30min at 40-60 ℃ to obtain a crude michelia lactone dimethylamine-p-hydroxybenzoate, wherein the organic solvent comprises any one or the combination of at least two of alcohols, ketones, nitriles or esters;
(2) And (2) cooling the crude product of the michelia lactone-p-hydroxybenzoate obtained in the step (1) to-10-15 ℃ at a cooling rate of 2-5 ℃/h for cooling crystallization, and then sequentially filtering, cleaning and drying at 25-40 ℃ for 1-3h under normal pressure to obtain the michelia lactone-p-hydroxybenzoate.
The invention also aims to provide the application of the michelia lactone p-hydroxybenzoate as one of the aims in an anti-rheumatic drug or an anti-cancer drug.
Compared with the prior art, the invention has the following beneficial effects:
the michelia lactone-p-hydroxybenzoate provided by the invention has lower hygroscopicity and higher physical and chemical stability, and is easy to store and transport; the preparation method of the michelia lactone-p-hydroxybenzoate of dimethylamine is simple, the raw materials are easy to obtain, the price is low, the safety and the low toxicity are realized, and the industrial large-scale production and application are convenient; the michelia lactone-p-hydroxybenzoate salt of dimethylamine provides a new choice for the preparation of medicaments, has important significance for the development of medicaments, and is better used for clinical treatment.
Drawings
FIG. 1 is a crystal structure diagram of michelia lactone-p-hydroxybenzoate salt of dimethylamine prepared in example 1.
FIG. 2X-ray diffraction Pattern (PXRD) of michelia lactone-p-hydroxybenzoate salt of dimethylamine prepared in example 1.
FIG. 3 Differential Scanning Calorimetry (DSC) of michelia lactone-p-hydroxybenzoate salt of dimethylamine prepared in example 1.
FIG. 4 is a graph showing the dynamic water absorption of michelia lactone-p-hydroxybenzoate salt of dimethylamine prepared in example 1.
Figure 5 is a drawing of the dynamic water uptake of michelia lactone fumarate.
FIG. 6 is an X-ray diffraction pattern of michelia lactone-p-hydroxybenzoate salt dimethylamine prepared in example 1, after dynamic moisture adsorption.
FIG. 7 is an X-ray diffraction diagram of michelia lactone fumarate before and after dynamic moisture adsorption.
Fig. 8 is a graph comparing the stability tests of michelia lactone-p-hydroxybenzoate prepared in example 1, wherein PXRD patterns of 0 day, 1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks are sequentially performed from bottom to top.
Fig. 9 is a comparison of PXRD patterns of dimethylamine michelia lactone-p-hydroxybenzoate, dimethylamine michelia lactone fumarate and dimethylamine michelia lactone prepared in example 1 suspended in a phosphate buffer solution with PH =6.8 for 5h, wherein the PXRD patterns are PXRD pattern of dimethylamine michelia lactone-p-hydroxybenzoate before suspension, PXRD pattern of dimethylamine michelia lactone-p-hydroxybenzoate after suspension, PXRD pattern of dimethylamine michelia lactone fumarate before suspension, PXRD pattern of dimethylamine michelia lactone before suspension and PXRD pattern of dimethylamine michelia lactone after suspension in sequence from bottom to top.
Detailed Description
The foregoing and other aspects of the present invention will be apparent from, and elucidated with reference to, the embodiments described hereinafter, without being construed as limited by the scope of the subject matter of the invention set forth in the claims. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
It is noted that in X-ray powder diffraction spectroscopy, the diffraction pattern obtained from a crystalline compound tends to be characteristic for a particular crystalline form, where the relative intensities of characteristic peaks may vary due to the dominant orientation effect resulting from differences in crystallization conditions, particle size, and other measurement conditions. Thus, the relative intensities of the diffraction peaks are not characteristic of the crystal form in question. When judging whether the crystal form is the same as the known crystal form, the relative positions of the peaks are more important to be noticed rather than the relative intensities. Furthermore, for any given crystallization, the position of the peaks may deviate somewhat due to equipment and operating conditions, and characteristic peaks within the error range may be considered to be the same characteristic peak, as is also well known in the crystallography art. For example, the position of the peak may shift due to a change in temperature when analyzing the sample, sample movement, calibration of the instrument, or the like, and the measurement error of the 2 θ value is sometimes about ± 0.2 °. Therefore, this error should be taken into account when determining each crystal structure. For the same crystal form of the same compound, the peak positions of PXRD spectrums have similarity on the whole, and the relative intensity error is likely to be larger.
(1) PXRD test instrument: x-ray powder diffractometer
The instrument model is as follows: rigaku D/max-2500, japan;
the test method comprises the following steps: cu-Kalpha radiation of copper target
The voltage is 40kV, the current is 100mA, the test angle is 2-40 degrees, the step length is 8 degrees/min, the exposure time is 0.2s, the test temperature is room temperature (25 ℃), the width of the light tube slit is 1mm, and the width of the detector slit is 2.7mm.
(2) DSC instrument: differential calorimetric scanner
The instrument model is as follows: mettler-Tollido Corp Mettler Toledo DSC1/500;
the test method comprises the following steps: the sample amount is 5-10mg, the heating rate is 10 ℃/min, and the flow rate of protective gas nitrogen is 50mL/min.
(3) SCXRD test instrument: single crystal X-ray diffractometer
The instrument model is as follows: rigaku Saturn model 70 single crystal diffractometer in Japan;
the test method comprises the following steps: CCD Detector (graphite monochromator), molybdenum target Mo-Ka ray
The temperature 113K was collected.
(4) DVS dynamic water adsorption instrument: dynamic steam adsorption instrument
The instrument model is as follows: VTI-SA + type dynamic moisture adsorption apparatus (TA instruments, USA);
the test method comprises the following steps: the sample amount is 5-20mg, the temperature is constant at 25 ℃, and the relative humidity is from 1-95%.
Example 1
1.5g of dimethylamine michelia lactone solid, 1.414g of p-hydroxybenzoic acid solid and 75mL of isopropyl acetate are added into a reaction bottle, heated to 60 ℃, and stirred for 30min to ensure that the raw materials fully react. Cooling to 0 deg.C at a rate of 5 deg.C/h, filtering the obtained product, and drying at 40 deg.C under normal pressure for 3h to obtain minoxidil-p-hydroxybenzoate.
FIG. 1 shows the crystallographic characteristics of the product prepared in example 1, as can be seen from FIG. 1: space group is P2 1 2 1 2 1 Cell parameter of
α =90 °, β =90 °, γ =90 °, cell volume of
FIG. 2 is a powder X-ray diffraction pattern of the product prepared in example 1, and it can be seen from FIG. 2 that characteristic peaks are shown at 5.5 °, 7.3 °, 9.5 °, 10.7 °, 12.4 °, 13.2 °, 13.9 °, 14.9 °, 16.9 °, 17.2 °, 18.8 °, 19.5 °, 20.0 °, 20.5 °, 21.5 °, 22.0 °, 22.8 °, 24.2 °, 25.7 °, 27.3 °, and 29.3 ° with a diffraction angle 2 θ.
FIG. 3 is a DSC of the product prepared in example 1, and it can be seen from FIG. 3 that the product has a characteristic melting peak at 145 ℃.
The following performance tests were carried out on the product obtained in example 1:
(1) And (3) conventional performance test:
the purity (HPLC) of the product obtained in example 1 was 99.2%, the yield of the product was 95%, and the crystal habit (scanning electron microscope) of the product was bulk crystal habit.
(2) Moisture wicking test:
test objects: the product obtained in example 1 and dimethylamine michelia lactone fumarate (CN 111303097 a);
testing an instrument: VTI-SA + Type dynamic moisture adsorbers (TA instruments, usa);
the test method comprises the following steps: placing a 5mg sample in a moisture adsorption instrument, keeping the temperature constant at 25 ℃, keeping the relative humidity from 1-95%, and observing the change of the water content of the sample;
and (3) testing results: the product prepared in example 1 had a water content varying from only 0.01% to 0.55% (see fig. 4), whereas the dimethylamine sphaelactone fumarate (CN 111303097 a) had a water content varying from 0.01% to 4.3% (see fig. 5), as indicated by the comparison: the product obtained in example 1 has a low hygroscopicity.
(3) And (3) stability testing:
and (3) stability testing:
test object(s): the product obtained in example 1 after the end of the hygroscopicity test and dimethylamine michelia lactone fumarate (CN 111303097 a);
testing an instrument: an X-ray diffractometer;
and (3) testing results: after the water adsorption experiment is finished, the X-ray powder diffraction pattern of the sample does not have a new diffraction peak (see fig. 6) compared with that of fig. 1, which indicates that the sample does not have crystal form transformation before and after the dynamic water adsorption experiment, and indicates that the michelia lactone-p-hydroxybenzoate salt is good in stability.
After the water adsorption experiment is finished, new characteristic peaks (shown in figure 7) appear at 7.8 degrees, 10.5 degrees, 11.1 degrees and 12.6 degrees in the michelia dimpled lactone fumarate (CN 111303097A), and the X-ray powder diffraction pattern of a sample is obviously changed.
In conclusion, the dimethylamine michelia lactone-p-hydroxybenzoate prepared in the embodiment 1 can well overcome the defects of high hygroscopicity and poor stability of dimethylamine michelia lactone fumarate, and the quality controllability and the safety of the medicament are improved.
And (5) testing the stability:
test objects: the product obtained in example 1;
the test method comprises the following steps: uniformly spreading the michelia lactone-p-hydroxybenzoate dimethylamine sample in an open culture dish, wherein the thickness of the sample is less than 5mm, sealing the sample in a dryer, placing the sample for 12 weeks, controlling the temperature at 40 ℃ and the humidity at 75%, then respectively carrying out PXRD, TGA and DSC detection on the samples placed for 1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks, and comparing the detection result with the detection result on the day 0;
and (3) testing results: PXRD spectrum is shown in figure 8, TGA and DSC detailed data are shown in table 1;
TABLE 1
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| Weight loss (%) TGA before decomposition | 0.05 | 0.05 | 0.08 | 0.07 | 0.08 | 0.09 |
| T onset (℃)DSC | 144.75 | 144.68 | 144.53 | 144.87 | 145.02 | 144.65 |
As can be seen from fig. 8 and table 1: PXRD spectrum, weight loss amount of TGA and melting point on DSC of the michelia dimpled lactone-p-hydroxybenzoate sample are not obviously changed, and therefore the michelia dimpled lactone-p-hydroxybenzoate sample is proved to have no crystal form transformation and good stability.
And (3) testing the stability:
test objects: the product prepared in example 1, a sample of michelia dimethylamine fumarate (CN 111303097 a), a sample of michelia dimethylamine (CN 102234259B);
the test method comprises the following steps: adding the three samples into 3 penicillin bottles containing 15mL of phosphate buffer solution (PH = 6.8), placing the penicillin bottles on a constant-temperature heating stirrer at 37 ℃, performing a suspension experiment at a stirring speed of 300r/min, centrifuging and filtering the suspension after 5 hours, drying the suspension at room temperature for 3 hours to obtain corresponding solid samples, and then performing PXRD characterization on 3 groups of solid samples;
and (3) testing results: the specific comparison map of PXRD is shown in fig. 9, and it can be seen from fig. 9 that: only the solid sample of the michelia lactone-p-hydroxybenzoate of the invention has no obvious change, but the PXRD patterns of the solid samples corresponding to the michelia lactone and the michelia lactone fumarate have obvious new diffraction peaks, which shows that a new phase is generated, and proves that the michelia lactone-p-hydroxybenzoate of the invention solves the problems of poor stability and easy degradation of the michelia lactone of the dimethylamine, and overcomes the obstacle that the product quality is difficult to control because the michelia lactone fumarate of the dimethylamine is easy to generate crystal form conversion.
Example 2
3g of solid michelia lactone dimethylamine, 3.111g of solid p-hydroxybenzoic acid and 30mL of methanol are added into a reaction bottle, heated to 55 ℃, and stirred for 10min to ensure that the raw materials are fully reacted. Cooling to-10 deg.C at a rate of 2 deg.C/h, filtering the obtained product, and drying at 30 deg.C under normal pressure for 2h to obtain minoxidil-p-hydroxybenzoate.
The product obtained in example 2 was subjected to the crystallographic test, the test results being the same as in example 1.
The product obtained in example 2 was subjected to PXRD test, which revealed that: the diffraction angle 2 theta indicates that the diffraction grating has characteristic peaks at 5.6 degrees, 7.5 degrees, 9.7 degrees, 10.8 degrees, 12.5 degrees, 13.4 degrees, 13.8 degrees, 14.9 degrees, 16.8 degrees, 17.2 degrees, 18.8 degrees, 19.6 degrees, 20.1 degrees, 20.6 degrees, 21.7 degrees, 22.2 degrees, 22.9 degrees, 24.4 degrees, 25.9 degrees, 27.5 degrees and 29.4 degrees.
The DSC test of example 2 revealed that: the product has an endothermic peak at 145.2 ℃.
The following performance tests were carried out by using the same method as in example 1 for the product obtained in example 2:
(1) And (3) conventional performance test:
the purity of the product obtained in example 2 was 99.2%, the yield of the product was 93%, and the crystal habit of the product was bulk.
(2) Moisture wicking test:
the water content of the product prepared in example 2 varied from only 0.01% to 0.56%, whereas the water content of minocycline fumarate (CN 111303097 a) varied from 0.01% to 4.7%, as indicated by the comparison: the product obtained in example 2 has a low hygroscopicity.
(3) And (3) stability testing:
and (3) stability test I:
after the water adsorption experiment is finished, the X-ray powder diffraction pattern of the sample does not have a new diffraction peak compared with that in fig. 1, which indicates that the sample does not have crystal form transformation before and after the dynamic water adsorption experiment, and shows that the dimethylamine michelia lactone-p-hydroxybenzoate disclosed by the invention has good stability.
After the water adsorption experiment is finished, new characteristic peaks appear at 7.7 degrees, 10.4 degrees, 11.0 degrees and 12.5 degrees in the michelia dimpled lactone fumarate (CN 111303097A), and the X-ray powder diffraction pattern of a sample is obviously changed.
In conclusion, the michelia lactone-p-hydroxybenzoate prepared in the embodiment 2 can well overcome the defects of high hygroscopicity and poor stability of the michelia lactone fumarate, and the controllability and the safety of the quality of the medicine are improved.
And (5) testing the stability:
the PXRD pattern, the weight loss of TGA and the melting point on DSC of the michelia lactone-p-hydroxybenzoate sample prepared in example 2 do not change significantly, which proves that the michelia lactone-p-hydroxybenzoate does not undergo crystal transformation and has good stability.
And (3) testing the stability:
the solid sample of the michelia figo lactone-p-hydroxybenzoate prepared in the embodiment 2 has no obvious change, but the PXRD patterns of the solid samples corresponding to the michelia figo lactone (CN 102234259B) and the michelia figo lactone fumarate (CN 111303097 a) have obvious new diffraction peaks, which indicates that a new phase is generated, and the difficulties of poor stability and easy degradation of the michelia figo lactone are proved to be solved by the michelia figo lactone-p-hydroxybenzoate, and the obstacle that the product quality is difficult to control due to the fact that the michelia figo lactone fumarate is easy to generate crystal transformation is overcome.
Example 3
6g of michelia lactone dimethylamine solid, 7.065g of p-hydroxybenzoic acid solid and 120mL of acetone are added into a reaction bottle, heated to 45 ℃, and stirred for 20min to ensure that the raw materials are fully reacted. Cooling to 15 deg.C at a rate of 3 deg.C/h, filtering the obtained product, and drying at 25 deg.C under normal pressure for 3h to obtain minoxidil-p-hydroxybenzoate.
The product obtained in example 3 was subjected to the crystallographic test, the test results being the same as in example 1.
The product obtained in example 3 was subjected to PXRD test, which revealed that: the diffraction angle 2 theta indicates that the diffraction grating has characteristic peaks at 5.3 degrees, 7.1 degrees, 9.3 degrees, 10.5 degrees, 12.2 degrees, 13.0 degrees, 13.7 degrees, 14.7 degrees, 16.8 degrees, 17.1 degrees, 18.6 degrees, 19.3 degrees, 20.1 degrees, 20.3 degrees, 21.3 degrees, 21.9 degrees, 22.6 degrees, 24.0 degrees, 25.5 degrees, 27.1 degrees and 29.1 degrees.
The DSC test of example 3 revealed that: the product has an endothermic peak at 145.5 ℃.
The following performance tests were carried out by using the same method as in example 1 for the product obtained in example 3:
(1) And (3) conventional performance test:
the purity of the product obtained in example 3 was 99.2%, the yield of the product was 90.5%, and the crystal habit of the product was bulk.
(2) Moisture wicking test:
the water content of the product prepared in example 3 varied from only 0.01% to 0.54%, whereas the water content of minocycline fumarate (CN 111303097 a) varied from 0.01% to 4.9%, as indicated by the comparison: the product obtained in example 3 has a low hygroscopicity.
(3) And (3) testing the stability:
and (3) stability test I:
after the water adsorption experiment is finished, the X-ray powder diffraction pattern of the sample does not have a new diffraction peak compared with that in fig. 1, which indicates that the sample does not have crystal form transformation before and after the dynamic water adsorption experiment, and shows that the dimethylamine michelia lactone-p-hydroxybenzoate disclosed by the invention has good stability.
After the water adsorption experiment is finished, new characteristic peaks appear at 7.9 degrees, 10.5 degrees, 11.2 degrees and 12.6 degrees in dimethylamine michelia lactone fumarate (CN 111303097A), and an X-ray powder diffraction pattern of a sample is obviously changed.
In conclusion, the michelia lactone-p-hydroxybenzoate prepared in the embodiment 3 can well overcome the defects of high hygroscopicity and poor stability of the michelia lactone fumarate, and the controllability and the safety of the quality of the medicine are improved.
And (5) testing the stability:
the PXRD pattern, the weight loss of TGA and the melting point on DSC of the michelia lactone-p-hydroxybenzoate sample prepared in example 3 do not change significantly, which proves that the michelia lactone-p-hydroxybenzoate does not undergo crystal transformation and has good stability.
And (5) testing the stability:
the solid sample of the michelia figo lactone-p-hydroxybenzoate prepared in the embodiment 3 has no obvious change, but the PXRD patterns of the solid samples corresponding to the michelia figo lactone (CN 102234259B) and the michelia figo lactone fumarate (CN 111303097 a) have obvious new diffraction peaks, which indicates that a new phase is generated, and the difficulties of poor stability and easy degradation of the michelia figo lactone are proved to be solved by the michelia figo lactone-p-hydroxybenzoate, and the obstacle that the product quality is difficult to control due to the fact that the michelia figo lactone fumarate is easy to generate crystal transformation is overcome.
Example 4
Adding 1.5g of michelia lactone dimethylamine solid, 1.414g of p-hydroxybenzoic acid solid and 30mL of ethanol into a reaction bottle, heating to 40 ℃, and stirring for 10min to ensure that the raw materials fully react. Cooling to 5 ℃ at the speed of 5 ℃/h, filtering the obtained product, and then drying for 1h at the temperature of 25 ℃ under normal pressure to obtain the dimethylamine michelia lactone-p-hydroxybenzoate.
The product obtained in example 4 was subjected to the crystallographic test, the test results being the same as in example 1.
The product obtained in example 4 was subjected to PXRD test, which revealed that: the diffraction angle 2 theta indicates that the diffraction grating has characteristic peaks at 5.7 degrees, 7.5 degrees, 9.7 degrees, 10.9 degrees, 12.6 degrees, 13.4 degrees, 13.7 degrees, 14.8 degrees, 16.8 degrees, 17.4 degrees, 18.6 degrees, 19.7 degrees, 20.2 degrees, 20.7 degrees, 21.7 degrees, 22.2 degrees, 23.0 degrees, 24.4 degrees, 25.9 degrees, 27.5 degrees and 29.5 degrees.
The DSC test of example 4 revealed that: the product has an endothermic peak at 144.8 ℃.
The following performance tests were carried out by using the same method as in example 1 for the product obtained in example 4:
(1) And (3) conventional performance test:
the purity of the product obtained in example 4 was 99.2%, the yield of the product was 90.2%, and the crystal habit of the product was bulk.
(2) Moisture wicking test:
the product prepared in example 4 had a water content varying from only 0.01% to 0.55%, whereas the dimethylamine smilactone fumarate (CN 111303097 a) had a water content varying from 0.01% to 4.4%, as indicated by the comparison: the product obtained in example 4 has a low hygroscopicity.
(3) And (3) stability testing:
and (3) stability test I:
after the water adsorption experiment is finished, the X-ray powder diffraction pattern of the sample does not have a new diffraction peak compared with that in fig. 1, which indicates that the sample does not have crystal form transformation before and after the dynamic water adsorption experiment, and shows that the michelia lactone-p-hydroxybenzoate dimethylamine prepared in the embodiment of the invention has good stability.
After the water adsorption experiment is finished, new characteristic peaks appear at 7.7 degrees, 10.6 degrees, 11.2 degrees and 12.5 degrees in the michelia dimpled lactone fumarate (CN 111303097A), and the X-ray powder diffraction pattern of a sample is obviously changed.
In conclusion, the dimethylamine michelia lactone-p-hydroxybenzoate prepared in the embodiment 4 can well overcome the defects of high hygroscopicity and poor stability of the dimethylamine michelia lactone fumarate, and the quality controllability and the safety of the medicament are improved.
And (5) testing the stability:
the PXRD pattern, the weight loss of TGA and the melting point on DSC of the michelia lactone-p-hydroxybenzoate sample prepared in example 4 do not change significantly, which proves that the michelia lactone-p-hydroxybenzoate does not undergo crystal transformation and has good stability.
And (3) testing the stability:
the solid sample of the michelia figo lactone-p-hydroxybenzoate prepared in the embodiment 4 has no obvious change, but the PXRD patterns of the solid samples corresponding to the michelia figo lactone (CN 102234259B) and the michelia figo lactone fumarate (CN 111303097 a) have obvious new diffraction peaks, which indicates that a new phase is generated, and the difficulties of poor stability and easy degradation of the michelia figo lactone are proved to be solved by the michelia figo lactone-p-hydroxybenzoate, and the obstacle that the product quality is difficult to control due to the fact that the michelia figo lactone fumarate is easy to generate crystal transformation is overcome.
Example 5
Adding 0.5g of michelia lactone dimethylamine solid, 0.542g of p-hydroxybenzoic acid solid and 10mL of acetonitrile into a penicillin bottle, heating to 50 ℃, and stirring for 15min to ensure that the raw materials fully react. Cooling to 10 deg.C at a rate of 2 deg.C/h, filtering the obtained product, and drying at 30 deg.C under normal pressure for 2h to obtain minoxidil-p-hydroxybenzoate.
The product obtained in example 5 was subjected to the crystallographic test, the test results being the same as in example 1.
The product obtained in example 5 was subjected to PXRD test, and it was found that: the diffraction angle 2 theta indicates that the diffraction grating has characteristic peaks at 5.6 degrees, 7.4 degrees, 9.6 degrees, 10.6 degrees, 12.3 degrees, 13.1 degrees, 13.8 degrees, 14.8 degrees, 16.8 degrees, 17.1 degrees, 18.7 degrees, 19.4 degrees, 20.1 degrees, 20.4 degrees, 21.4 degrees, 21.9 degrees, 22.7 degrees, 24.1 degrees, 25.6 degrees, 27.2 degrees and 29.1 degrees.
The DSC test of example 5 revealed that: the product has an endothermic peak at 144.7 ℃.
The following performance tests were carried out by using the same method as in example 1 for the product obtained in example 5:
(1) And (3) conventional performance test:
the purity of the product obtained in example 5 was 99.2%, the yield of the product was 91.8%, and the crystal habit of the product was bulk.
(2) Moisture wicking test:
the product prepared in example 5 had a water content varying from only 0.01% to 0.55%, whereas the dimethylamine sphaelactone fumarate (CN 111303097 a) had a water content varying from 0.01% to 4.3%, as indicated by the comparison: the product obtained in example 5 has a low hygroscopicity.
(3) And (3) stability testing:
and (3) stability test I:
after the water adsorption experiment is finished, the X-ray powder diffraction pattern of the sample does not have a new diffraction peak compared with that in fig. 1, which indicates that the sample does not have crystal form transformation before and after the dynamic water adsorption experiment, and shows that the dimethylamine michelia lactone-p-hydroxybenzoate disclosed by the invention has good stability.
After the water adsorption experiment is finished, new characteristic peaks appear at 7.8 degrees, 10.7 degrees, 11.3 degrees and 12.8 degrees in the michelia dimpled lactone fumarate (CN 111303097A), and the X-ray powder diffraction pattern of a sample is obviously changed.
In conclusion, the michelia lactone-p-hydroxybenzoate prepared in the embodiment 5 can well overcome the defect of poor hygroscopicity and high stability of the michelia lactone fumarate, and the controllability and the safety of the quality of the medicine are improved.
And (5) testing the stability:
the PXRD pattern, the weight loss of TGA and the melting point on DSC of the michelia lactone-p-hydroxybenzoate sample prepared in example 5 do not change significantly, which proves that the michelia lactone-p-hydroxybenzoate does not undergo crystal transformation and has good stability.
And (3) testing the stability:
the solid sample of the michelia figo lactone-p-hydroxybenzoate prepared in the embodiment 5 has no obvious change, but the PXRD patterns of the solid samples corresponding to the michelia figo lactone (CN 102234259B) and the michelia figo lactone fumarate (CN 111303097 a) have obvious new diffraction peaks, which indicates that a new phase is generated, and the difficulties of poor stability and easy degradation of the michelia figo lactone are proved to be solved by the michelia figo lactone-p-hydroxybenzoate, and the obstacle that the product quality is difficult to control due to the fact that the michelia figo lactone fumarate is easy to generate crystal transformation is overcome.
Example 6
Adding 1g of michelia lactone dimethylamine solid, 1.037g of p-hydroxybenzoic acid solid and 20mL of isopropanol into a penicillin bottle, heating to 60 ℃, and stirring for 10min to fully react the raw materials. Cooling to 0 ℃ at the speed of 5 ℃/h, filtering the obtained product, and then drying at 30 ℃ for 3h under normal pressure to obtain the dimethylamine michelia lactone-p-hydroxybenzoate.
The product obtained in example 6 was subjected to the crystallographic test, the test results being the same as in example 1.
The product obtained in example 6 was subjected to PXRD test, which revealed that: the diffraction angle 2 theta indicates that the diffraction grating has characteristic peaks at 5.5 degrees, 7.3 degrees, 9.6 degrees, 10.7 degrees, 12.5 degrees, 13.1 degrees, 13.8 degrees, 14.8 degrees, 16.7 degrees, 17.3 degrees, 18.9 degrees, 19.6 degrees, 20.2 degrees, 20.5 degrees, 21.5 degrees, 22.0 degrees, 22.8 degrees, 24.2 degrees, 25.7 degrees, 27.2 degrees and 29.1 degrees.
The DSC test of example 6 revealed that: the product has an endothermic peak at 145.3 ℃.
The following performance tests were carried out by using the same method as in example 1 for the product obtained in example 6:
(1) And (3) conventional performance test:
example 6 the purity of the product was 99.2%, the yield of the product was 93.6%, and the crystal habit of the product was bulk.
(2) Moisture wicking test:
the water content of the product prepared in example 6 varied from only 0.01% to 0.56%, whereas the water content of minocycline fumarate (CN 111303097 a) varied from 0.01% to 4.7%, as indicated by comparison: the product obtained in example 6 has a low hygroscopicity.
(3) And (3) stability testing:
and (3) stability testing:
after the water adsorption experiment is finished, the X-ray powder diffraction pattern of the sample does not have a new diffraction peak compared with that in fig. 1, which indicates that the sample does not have crystal form transformation before and after the dynamic water adsorption experiment, and shows that the michelia lactone-p-hydroxybenzoate dimethylamine prepared in the embodiment of the invention has good stability.
After the water adsorption experiment is finished, new characteristic peaks appear at 7.7 degrees, 10.6 degrees, 11.1 degrees and 12.6 degrees in the michelia dimpled lactone fumarate (CN 111303097A), and the X-ray powder diffraction pattern of a sample is obviously changed.
In conclusion, the michelia lactone-p-hydroxybenzoate prepared in the embodiment 6 can well overcome the defect of poor hygroscopicity and high stability of the michelia lactone fumarate, and the controllability and the safety of the quality of the medicine are improved.
And (5) testing the stability:
the PXRD pattern, the weight loss of TGA and the melting point on DSC of the michelia lactone-p-hydroxybenzoate sample prepared in example 6 did not change significantly, which proves that the michelia lactone-p-hydroxybenzoate has no crystal transformation and good stability.
And (3) testing the stability:
the solid sample of the michelia figo lactone-p-hydroxybenzoate prepared in the embodiment 6 has no obvious change, but PXRD patterns of the solid samples corresponding to the michelia figo lactone (CN 102234259B) and the michelia figo lactone fumarate (CN 111303097 a) have obvious new diffraction peaks, which indicates that a new phase is generated, and the problem that the michelia figo lactone-p-hydroxybenzoate of dimethylamine has poor stability and is easy to degrade is solved, and meanwhile, the obstacle that the product quality is difficult to control due to the fact that the michelia lactone fumarate is easy to generate crystal form conversion is overcome.
Claims (7)
1. The michelia lactone-p-hydroxybenzoate salt is characterized in that the molecular formula of the michelia lactone-p-hydroxybenzoate salt is C 31 H 39 NO 9 ；
The crystallography characteristics of the michelia lactone-P-hydroxybenzoate salt of dimethylamine comprise that the space group is P2 1 2 1 2 1 The cell parameters are a =12.8851 (6), b =14.4609 (6) a, c =30.5942 (16) a, α =90 °, β =90 °, γ =90 °, and the cell volume is 5700.6 (5) a 3 ；
In an X-ray powder diffraction spectrogram of the michelia lactone-p-hydroxybenzoate, characteristic peaks exist at 2 theta diffraction angles of 5.5 +/-0.2 degrees, 7.3 +/-0.2 degrees, 9.5 +/-0.2 degrees, 10.7 +/-0.2 degrees, 12.4 +/-0.2 degrees, 13.2 +/-0.2 degrees, 13.9 +/-0.2 degrees, 14.9 +/-0.2 degrees, 16.9 +/-0.2 degrees, 17.2 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.5 +/-0.2 degrees, 20.0 +/-0.2 degrees, 20.5 +/-0.2 degrees, 21.5 +/-0.2 degrees, 22.0 +/-0.2 degrees, 22.8 +/-0.2 degrees, 24.2 +/-0.2 degrees, 25.7 +/-0.2 degrees, 27.3 +/-0.2 degrees and 29.3 +/-0.2 degrees.
2. The michelia lactone-p-hydroxybenzoate as claimed in claim 1, wherein said michelia lactone-p-hydroxybenzoate has a differential scanning calorimetry analysis spectrum with a characteristic melting peak at 145 ± 2 ℃.
3. A method for preparing michelia lactone-p-hydroxybenzoate as claimed in claim 1 or claim 2, wherein the method comprises the steps of:
(1) Reacting michelia lactone dimethylamine with p-hydroxybenzoic acid to obtain a michelia lactone-p-hydroxybenzoate crude product;
(2) Cooling and crystallizing the crude product of michelia lactone-p-hydroxybenzoate of dimethylamine obtained in the step (1) to obtain the michelia lactone-p-hydroxybenzoate of dimethylamine;
the molar ratio of the michelia lactone to the p-hydroxybenzoic acid in the step (1) is 1;
the reaction temperature is 40-60 ℃, and the reaction time is 10-30min;
the reaction in the step (1) is carried out in an organic solvent;
the organic solvent is selected from any one of methanol, ethanol, isopropanol, acetone, acetonitrile or isopropyl acetate;
the addition amount of the michelia lactone dimethylamine is 20-100mg, and the addition amount of the organic solvent is 1mL;
the cooling rate of the cooling crystallization in the step (2) is 2-5 ℃/h;
the temperature of the cooling crystallization in the step (2) is-10 to 15 ℃.
4. The preparation method according to claim 3, wherein the step (2) further comprises subjecting the mixture obtained by cooling crystallization to solid-liquid separation, washing and drying in this order.
5. The method according to claim 4, wherein the solid-liquid separation is performed by filtration.
6. The method according to claim 4, wherein the drying is carried out at 25 to 40 ℃ for 1 to 3 hours under normal pressure.
7. Use of the michelia lactone-p-hydroxybenzoate as defined in claim 1 or 2, in the manufacture of an anti-rheumatic medicament.
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