CN113200949B - Dimethylamine michelia lactone-salicylate and preparation method and application thereof - Google Patents

Abstract

The present invention relates to a kind of dimethylamine microlide-salicylate and its preparation method and application, the molecular formula of the dimethylamine microlide-salicylate is C ₂₄ H ₃₃ NO ₆ , the dimethylamine The crystallographic properties of amine michelolactone-salicylate include the space group P2 ₁ 2 ₁ 2 ₁ and the unit cell parameters of

α=90°, β=90°, γ=90°, the unit cell volume is

Compared with dimethylaminomildolide fumarate and dimethylaminomildolide hydrochloride, the dimethylaminemimicrolide salicylate provided by the invention has better hygroscopicity and stability. The method is prepared by a solvent-assisted grinding method or a cooling crystallization method, and has simple operation, mild conditions, good repeatability, environmental protection, low toxicity and safety, and is suitable for large-scale production.

Description

A kind of dimethylamine michelolactone-salicylate and its preparation method and application

technical field

The invention belongs to the technical field of pharmaceutical crystallization, and in particular relates to a dimethylaminomimicrolactone-salicylate and a preparation method and application thereof.

Background technique

Sesquiterpenoids are mainly composed of 3 isoprene units and contain 15 carbon atoms. They are typical NF-kB inhibitors and have extensive significance in cancer treatment. It is known from in vivo and in vitro experiments Such compounds have good therapeutic effects on liver cancer, lung cancer, pancreatic cancer, breast cancer, glioma, acute lymphoblastic leukemia and other diseases, and can selectively kill tumor cells without damaging normal cells. At the same time, the compounds are widely distributed, can reduce costs, and improve the quality of life of cancer patients.

Dimethylamine michelolide, which belongs to sesquiterpene lactone compounds, has a molecular formula of C ₁₇ H ₂₇ NO ₃ , and its English name is Dimethylaminocheliolide (DMAMCL). It is a white powdery solid with poor water solubility and will degrade when placed for a long time , these problems have largely affected the development of pharmaceutical products, the design of technological processes, and the prospect of therapeutic efficacy.

WO2015006893A1 discloses the use of sesquiterpene lactone compounds and their derivatives including dimethylamine michelolactone in treating rheumatoid arthritis, inhibiting cancer stem cells and then treating cancer. The preparation method of amine michelolactone hydrochloride and fumarate. Wherein, dimethylamine michelolactone is dissolved in dichloromethane, and dilute hydrochloric acid solution is added while stirring. During the stirring process, the pH in the solution should be monitored in real time. When the pH of the solution is controlled at 4-5, stop adding dilute hydrochloric acid dropwise. The solution was collected and freeze-dried to obtain dimethylamine michelolactone hydrochloride; and dimethylamine michelolactone fumarate was obtained by dissolving dimethylamine michelolactone in dichloromethane and adding fumarolactone to the solution. Acid, obtained by concentration and drying. Dichloromethane belongs to the second class of organic solvents. It has certain toxicity and carcinogenicity. Its boiling point is extremely low. The vapor is narcotic. If inhaled in large quantities, it will cause acute poisoning, symptoms such as headache, vomiting, and impaired hematopoietic function. It is widely used in industrial mass production. bring certain security risks.

CN104876899A points out that although dimethylamine michelolactone hydrochloride can improve water solubility, it causes serious moisture, and in high temperature and high humidity tests, it is found that the color of the powder product changes from white to gray and dark brown, and the content of active substances decreases from 99% To 60%, it shows that the degradation of dimethylaminomildolide hydrochloride is serious. The defects of high hygroscopicity and poor physical and chemical stability further limit the research and development of dimethylaminomildolide hydrochloride drug. Compared with dimethylaminomildolide hydrochloride, although dimethylaminomicrolactone fumarate has improved the hygroscopicity to a certain extent, it still does not solve the problem that the product is prone to degradation and deterioration.

A series of patents such as CN103724307B, CN111303097A, CN111303100A, CN111303098A and CN111303099A have successively disclosed six different crystal forms of dimethylamine michelactone fumarate and their preparation methods. The existence of polymorphic forms makes it difficult to control the quality stability of dimethylamine migna lactone fumarate in the production process, because experimental studies have found that different crystal forms of dimethylamine migna lactone fumarate will be in a certain solvent , temperature, humidity and other conditions of mutual transformation. Different crystal forms of the same drug will have significant differences in solubility, melting point, dissolution behavior, fluidity, bioavailability, etc., which will affect the stability, bioavailability and efficacy of the drug. The crystal form has an important impact on the properties and use of pharmaceutical products, and a stable preparation process with high reproducibility is urgently needed to ensure the effective crystal form of the product.

In summary, the currently disclosed dimethylaminomildolide hydrochloride and dimethylaminomicrolide fumarate do not have obvious advantages in terms of hygroscopicity, physical and chemical stability, product quality controllability, etc., but These properties are crucial for drug discovery and scale-up.

Therefore, the development of a new salt type of dimethylamine michelolactone makes it have more excellent characteristics, including production safety, product stability, good post-processing performance, low moisture absorption, etc. Effective application is very important.

Contents of the invention

In order to solve the problems existing in the existing dimethylamine mincrolactone salt type and its preparation method, such as high hygroscopicity, poor stability, easy mutual conversion of crystal forms, complicated process, strong toxicity of solvents used, poor controllability of process and product quality, etc. To solve many technical problems, the present invention provides a kind of dimethylaminomildolide-salicylate and its preparation method and application. The dimethylamine michelolactone salicylate provided by the invention not only has low hygroscopicity, high physical and chemical stability, but also has a safe and low-toxicity preparation process, less solvents used, good repeatability, strong operability, and mild conditions, which is beneficial to Industrial production and subsequent drug development.

One of the objectives of the present invention is to provide a dimethylaminomildolide-salicylate, the molecular formula of which is C ₂₄ H ₃₃ NO ₆ , and has the following structure :

α＝90°，β＝90°，γ＝90°，晶胞体积为

The crystallographic characteristics of the dimethylamine michelolactone-salicylate include that the space group is P2 ₁ 2 ₁ 2 ₁ , and the unit cell parameters are

α=90°, β=90°, γ=90°, the unit cell volume is

In the present invention, in the X-ray powder diffraction spectrum of the dimethylamine michelolactone-salicylate, the 2θ diffraction angles are 7.6±0.2°, 10.2±0.2°, 11.4±0.2°, 11.9±0.2 °, 12.5±0.2°, 13.2±0.2°, 14.9±0.2°, 16.0±0.2°, 16.5±0.2°, 17.8±0.2°, 18.8±0.2°, 19.6±0.2°, 20.2±0.2°, 21.7±0.2 °, 22.1±0.2°, 22.4±0.2°, 23.0±0.2°, 24.0±0.2°, 24.7±0.2°, 25.1±0.2°, 27.4±0.2° have characteristic peaks.

In the present invention, the differential scanning calorimetry spectrum of the dimethylamine michelolactone-salicylate has a characteristic melting peak at 172±2°C.

The product purity of the dimethylamine michelactone salicylate provided by the invention can reach more than 99%, the product yield is more than 90%, and the block crystal habit is formed.

The water content of the dimethylamine michelactone salicylate sample provided by the invention is only 0.6%±0.03% when the ambient temperature is 25° C. and the relative humidity reaches 95%. Control temperature is 40 ℃, and humidity is 75% in the accelerated stability test of up to 12 weeks, the melting point of the dimethylamine michelolactone salicylate sample provided by the invention has no obvious change compared with the initial sample, and the melting point before decomposition The weight loss is less than 0.1%, indicating that the dimethylaminomildolide salicylate sample provided by the present invention has higher stability and lower hygroscopicity. In the buffer solution of pH=6.8 simulating human intestinal fluid, the dimethylaminomildolide salicylate sample provided by the present invention did not undergo crystal transformation or degradation during the 5-hour suspension experiment.

Two of the purpose of the present invention is to provide a kind of preparation method of dimethylaminomildolide-salicylate as described in one of purpose, described preparation method comprises the following steps:

Grinding and mixing dimethylamine michelolactone and salicylic acid to obtain the dimethylamine michelolactone-salicylate.

Compared with other preparation processes, the solvent-assisted grinding method of dimethylamine michelolactone salicylate provided by the present invention has simple operation, mild conditions, easy preparation, good repeatability, and the selected solvents are three types of solvents, which are green and environmentally friendly. , low toxicity and safety, suitable for large-scale production.

In the present invention, the molar ratio of dimethylamine michelolactone and salicylic acid is 1:(0.8-1.2), such as 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, etc. .

In the present invention, the grinding equipment includes a ball mill or an agate mortar.

In the present invention, the grinding is carried out in a solvent. Based on the amount of dimethylaminomildolide added as 1 mg, the added volume of the solvent is 0.512-0.853 μL, such as 0.512 μL, 0.55 μL, 0.6 μL, 0.65μL, 0.7μL, 0.75μL, 0.8μL, 0.853μL, etc.

In the present invention, the solvent includes any one or a combination of at least two of methanol, ethanol, n-propanol, acetone, acetonitrile, 1,4-dioxane, ethyl acetate or isopropyl acetate.

In the present invention, the grinding frequency is 15-30Hz, such as 15Hz, 18Hz, 20Hz, 22Hz, 25Hz, 28Hz, 30Hz, etc., and the grinding time is 5-60min, such as 5min, 10min, 15min, 20min, 25min, 30min, 35min, 40min, 45min, 50min, 55min, 60min, etc.

The third object of the present invention is to provide a kind of preparation method of dimethylaminomildolide-salicylate as described in one of the objects, the preparation method comprises the following steps:

(1) reacting dimethylaminomildolide and salicylic acid in an organic solvent to obtain a mixture;

(2) cooling and crystallizing the reaction mixture obtained in step (1) to obtain the dimethylamine michelolactone-salicylate.

Compared with other preparation processes, the cooling crystallization preparation method of dimethylamine michelolactone salicylate provided by the present invention has simple operation, mild conditions, easy preparation, good repeatability, and the selected solvents are three types of solvents, which are green and environmentally friendly. , low toxicity and safety, suitable for large-scale production.

In the present invention, the molar ratio of dimethylaminomildolide and salicylic acid in step (1) is 1:(0.9-1.5), such as 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.

In the present invention, the added amount of dimethylamine michelolactone is 15-60 mg (such as 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, etc.), the step (1) The amount of organic solvent added was 1 mL.

In the present invention, the organic solvent in step (1) includes any one or a combination of at least two of ethanol, acetone, acetonitrile, 1,4-dioxane, ethyl acetate or isopropyl acetate.

In the present invention, the reaction temperature in step (1) is 40-60°C, such as 40°C, 42°C, 45°C, 47°C, 50°C, 52°C, 55°C, 57°C, 60°C, etc., the reaction The time is 30-60min, such as 30min, 35min, 40min, 45min, 50min, 55min, 60min, etc.

In the present invention, the cooling crystallization rate in step (2) is 5-10°C/h, such as 5°C/h, 6°C/h, 7°C/h, 8°C/h, 9°C/h, 10℃/h etc.

In the present invention, the end point of cooling crystallization in step (2) is 10-20°C, such as 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, etc.

In the present invention, the step (2) further includes sequentially performing solid-liquid separation, washing and drying on the crystals obtained after cooling and crystallization.

In the present invention, the method of solid-liquid separation is filtration.

In the present invention, the drying is carried out under normal pressure conditions, and the drying temperature is 25-40°C, such as 25°C, 28°C, 30°C, 32°C, 35°C, 37°C, 40°C, etc. , the drying time is 3-6h, such as 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, etc.

The fourth object of the present invention is to provide an application of dimethylaminomildolide-salicylate as described in the first object in antirheumatic drugs or anticancer drugs.

Compared with the prior art, the present invention has the following beneficial effects:

The dimethylamine michelolactone-salicylate provided by the invention has lower hygroscopicity and higher physical and chemical stability, and is easy to store and transport; the preparation method of dimethylamine michelactone-salicylate is simple , the raw material is easy to obtain, low in price, safe and low in toxicity, easy to implement, and convenient for industrialized large-scale production and application; the dimethylamine michelolactone-salicylate provides a new option for the preparation of medicaments, and is of great importance to the development of drugs Significance, so that it can be better used in clinical treatment.

Description of drawings

Fig. 1 is the crystal structure figure of the dimethylamino michelactone salicylate prepared in Example 1.

Fig. 2 is the X-ray diffractogram (PXRD) of the dimethylaminomildolide salicylate prepared in Example 1.

Fig. 3 is the differential scanning calorimetry (DSC) of the dimethylaminomildolide salicylate prepared in Example 1.

Fig. 4 is the dynamic moisture adsorption figure of the dimethylamino michelactone salicylate prepared in Example 1.

Fig. 5 is the dynamic moisture adsorption diagram of dimethylamine michelolactone fumarate.

Fig. 6 is the X-ray diffraction pattern of dimethylaminomildolide salicylate prepared in Example 1 before and after dynamic moisture adsorption.

Fig. 7 is the X-ray diffraction pattern of dimethylamine michelolactone fumarate before and after dynamic moisture adsorption.

Fig. 8 is the comparison of the stability test spectrum of the dimethylaminomildolide salicylate prepared in Example 1, wherein from bottom to top are 0 day, 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks PXRD spectrum.

Fig. 9 is the suspension of dimethylaminosigrolactone salicylate, dimethylaminosigrolactone fumarate, and dimethylaminosigrolactone prepared in Example 1 in a phosphate buffer solution of pH=6.8 for 5 h Comparison of PXRD patterns, wherein from bottom to top is the PXRD pattern of dimethylaminomilactone salicylate before suspension, the PXRD pattern of dimethylaminomilactone salicylate after suspension, and the PXRD pattern of dimethylaminomilactone salicylate before suspension. The PXRD pattern of amine migna lactone fumarate, the PXRD pattern of dimethylamine migna lactone fumarate after suspension, the PXRD pattern of dimethylamine migna lactone before suspension, and the PXRD pattern of dimethylamine migna lactone after suspension PXRD patterns of esters.

Detailed ways

The above-mentioned content of the present invention will be further described in detail below through specific implementation in the form of examples, but it should not be understood that the scope of the above-mentioned subject of the present invention is limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

It should be noted that in the X-ray powder diffraction spectrum, the diffraction pattern obtained from crystalline compounds is often characteristic for a specific crystal form, and the relative intensity of the characteristic peaks may vary due to crystallization conditions, particle size and other measurement conditions. The dominance orientation effect produced by differences in Therefore, the relative intensity of the diffraction peaks is not characteristic for the crystalline form in question. When judging whether it is identical to a known crystalline form, more attention should be paid to the relative positions of peaks rather than their relative intensities. In addition, for any given crystalline compound, the position of the peak may have certain deviations due to equipment and operating conditions, and the characteristic peaks within the error range can be regarded as the same characteristic peak, which is also well known in the field of crystallography. For example, due to temperature changes, sample movement, or instrument calibration when analyzing samples, the position of the peak can move, and the measurement error of the 2θ 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 their PXRD spectra are similar on the whole, and the relative intensity error may be large.

(1) PXRD testing instrument: X-ray powder diffractometer

Instrument model: Japan Rigaku D/max-2500;

电压40kV，电流100mA，测试角度2-40°，步长8°/min，曝光时间0.2s，测试温度为室温(25℃)，光管狭缝宽度1mm，探测器狭缝宽度2.7mm。Test method: Copper target Cu-Kα ray

The voltage is 40kV, the current is 100mA, the test angle is 2-40°, the step size is 8°/min, the exposure time is 0.2s, the test temperature is room temperature (25°C), the light pipe slit width is 1mm, and the detector slit width is 2.7mm.

(2) DSC test equipment: differential calorimetry scanner

Instrument model: Mettler Toledo DSC1/500 from Mettler Toledo;

Test method: sample size 5-10mg, heating rate 10°C/min, flow rate of protective gas nitrogen 50mL/min.

(3) SCXRD test instrument: single crystal X-ray diffractometer

Instrument model: Japan Rigaku Saturn 70 single crystal diffractometer;

采集温度113K。Test method: CCD detector (graphite monochromator), molybdenum target Mo-Kα ray

The collection temperature is 113K.

(4) DVS dynamic water adsorption instrument: dynamic steam adsorption instrument

Instrument model: VTI-SA+ dynamic moisture adsorption instrument (TA Instruments, USA);

Test method: the sample size is 5-20mg, the temperature is kept constant at 25°C, and the relative humidity is from 1%-95%.

Example 1

Weigh 29.3 mg of dimethylaminomilactone solid and 13.8 mg of salicylic acid solid, add 20 μL of methanol, ball mill at a frequency of 30 Hz for 30 minutes, and dry at room temperature to obtain a solid sample of dimethylaminomilactone salicylate.

α＝90°，β＝90°，γ＝90°，晶胞体积为

Fig. 1 is the crystallographic feature of the product prepared in Example 1, as can be seen from Fig. 1, the crystallographic feature is: the space group is P2 ₁ 2 ₁ 2 ₁ , and the unit cell parameter is

α=90°, β=90°, γ=90°, the unit cell volume is

Fig. 2 is the powder X-ray diffraction pattern that embodiment 1 prepares and obtains the product, as can be seen from Fig. 2, is represented at 7.6 °, 10.2 °, 11.4 °, 11.9 °, 12.5 °, 13.2 °, 14.9 °, 14.9 °, There are characteristic peaks at 16.0°, 16.5°, 17.8°, 18.8°, 19.6°, 20.2°, 21.7°, 22.1°, 22.4°, 23.0°, 24.0°, 24.7°, 25.1°, 27.4°.

Figure 3 is the DSC spectrum of the product prepared in Example 1. It can be seen from Figure 3 that the product has a characteristic melting peak at 172°C.

Carry out following performance test by the product that embodiment 1 obtains:

(1) Routine performance test:

The purity (HPLC) of the product obtained in embodiment 1 is 99.5%, the yield of the product is 96%, and the crystal habit (scanning electron microscope) of the product is block crystal habit.

(2) Humidity test:

Test object: the product that embodiment 1 obtains and dimethylaminomilactone fumarate (CN111303097A);

Test instrument: VTI-SA ⁺ dynamic moisture adsorption instrument (TA Instruments, USA);

Test method: take a 5mg sample and place it in a moisture adsorption instrument, keep the temperature at 25°C, and the relative humidity from 1% to 95%, and observe the change of the water content of the sample;

Test result: the water content of the product prepared by embodiment 1 only changes from 0.01% to 0.61% (see Figure 4), while the water content of dimethylamine michelolactone fumarate (CN111303097A) changes from 0.01% to 4.3% ( See Fig. 5), illustrate by contrast: the product that embodiment 1 obtains has lower hygroscopicity.

(3) Stability test:

Stability test one:

Test object: the product obtained in embodiment 1 and dimethylamine michelolactone fumarate (CN111303097A) after the hygroscopicity experiment finishes;

Test instrument: X-ray diffractometer;

Test result: after the dimethylaminomildolide-salicylate prepared in embodiment 1 finished the water adsorption experiment, no new diffraction peaks appeared in the X-ray powder diffraction pattern of the sample compared with Fig. 2 (see Fig. 6 ), indicating that the crystal form transition did not occur in the sample before and after the dynamic moisture adsorption experiment, indicating that the stability of dimethylamine mimilactone-salicylate of the present invention is better.

Dimethylamine michelolactone fumarate (CN111303097A) after finishing water adsorption experiment, new characteristic peak (seeing Fig. 7) appears at 7.8 °, 10.5 °, 11.1 °, 12.6 °, the X-ray powder diffraction of sample The spectrum has changed significantly, and further analysis shows that the sample changes from anhydrous crystal form to hydrate crystal form under high humidity conditions, and then shows that the stability of dimethylamine michelolactone fumarate is poor, and it is affected by the environmental humidity. The impact is obvious, the storage conditions are harsh, and improper preservation is easy to deteriorate.

In summary, the dimethylaminomildolide-salicylate prepared in Example 1 can well solve the problems of high hygroscopicity and poor stability in dimethylaminomicrolide fumarate, and improve the Drug quality controllability and safety.

Stability test two:

Test object: the product prepared in embodiment 1;

Test method: Dimethylamine michelolactone-salicylate samples are evenly distributed in an open petri dish, the thickness of the sample is less than 5mm, sealed and placed in a desiccator for 12 weeks, the temperature is controlled at 40 ° C, and the humidity is 75 %, then PXRD, TGA, and DSC were performed on the samples placed for 1 week, 2 weeks, 4 weeks, 8 weeks, and 12 weeks, and compared with the test results on the 0th day;

Test results: See Figure 8 for the PXRD spectrum, and Table 1 for the specific data of TGA and DSC;

Table 1

day 0 week 1 week 2 week 4 week 8 week 12 Weight loss before decomposition (%)TGA 0.02 0.03 0.05 0.06 0.08 0.07 T_onset(℃)DSC 172.05 172.03 172.06 172.05 172.11 172.08

It can be seen from Figure 8 and Table 1 that: the PXRD spectrum of the dimethylamine micholactone-salicylate sample, the weight loss of TGA and the melting point on the DSC did not change significantly, proving that the dimethylamine michelolactone-salicylate There is no crystal transformation, and the stability is good.

Stability test three:

Test object: the product prepared in Example 1, dimethylamine michelactone fumarate sample (CN111303097A), dimethylamine michelactone sample (CN102234259B);

Test method: Add the above three samples into three vials containing 15mL phosphate buffer solution (PH=6.8), place them on a constant temperature heating stirrer at 37°C, and conduct a suspension test at a stirring rate of 300r/min. After 5 hours, the suspension was centrifuged, filtered, and dried at room temperature for 3 hours to obtain the corresponding solid samples, and then the three groups of solid samples were characterized by PXRD;

Test result: the specific comparative collection of graphs of PXRD is shown in Fig. 9, as can be known by Fig. 9: only the solid sample of dimethylaminomildolide-salicylate of the present invention does not have significant change, and dimethylaminomildolide, dimethylamine The PXRD pattern of the solid sample corresponding to amine michelolactone fumarate has obvious new diffraction peaks, indicating that a new phase has been produced, which proves again that dimethylamine michelolactone-salicylate solves the problem of dimethylamine michelin Lactone is poorly stable and easy to degrade, and at the same time, it overcomes the obstacle that the product quality is difficult to control due to the easy crystal transformation of dimethylaminolactone fumarate.

Example 2

Weigh 58.6 mg of dimethylaminomildolide solid and 33.12 mg of salicylic acid solid, add 50 μL of acetone, ball mill at a frequency of 30 Hz for 40 minutes, and dry at room temperature to obtain a solid sample of dimethylaminomildolide salicylate.

The product that embodiment 2 obtains is carried out crystallographic test, and test result is the same as embodiment 1.

Carry out PXRD test to the product that embodiment 2 obtains, as can be known: with diffraction angle being 2θ, represent in 7.4 °, 10.0 °, 11.2 °, 11.7 °, 12.3 °, 13.0 °, 14.7 °, 15.8 °, 16.3 °, 17.6 °, There are characteristic peaks at 18.6°, 19.4°, 20.0°, 21.5°, 21.9°, 22.2°, 22.8°, 23.9°, 24.6°, 25.0°, 27.2°.

Carry out DSC test to embodiment 2, know: product has endothermic peak at 171.5 ℃.

Adopt the method identical with embodiment 1 to carry out following performance test by the product that embodiment 2 obtains:

(1) Routine performance test:

The purity of the product obtained in Example 2 is 99.2%, the yield of the product is 95%, and the crystal habit of the product is block crystal habit.

(2) Humidity test:

The water content of the product prepared in Example 2 only changes from 0.01% to 0.60%, while the water content of dimethylamine michelolactone fumarate (CN111303097A) changes from 0.01% to 4.5%, which is illustrated by comparison: Example 2 obtains The product has low hygroscopicity.

(3) Stability test:

Stability test one:

After the dimethylamine michelolactone-salicylate prepared in Example 2 finished the water adsorption experiment, no new diffraction peaks appeared in the X-ray powder diffraction pattern of the sample compared with Figure 2, indicating that in the dynamic moisture adsorption experiment There was no crystal form transition in the samples before and after, indicating that the dimethylaminomildolide-salicylate of the present invention has better stability.

Dimethylamine michelolactone fumarate (CN111303097A) after finishing the water adsorption experiment, new characteristic peaks appeared at 7.9 °, 10.6 °, 11.2 °, 12.7 °, and the X-ray powder diffraction pattern of the sample took place obvious Further analysis showed that the sample changed from anhydrous crystalline form to hydrate crystalline form under high humidity conditions, which further showed that the stability of dimethylamine michelolactone fumarate was poor and was significantly affected by environmental humidity. Storage conditions Harsh, improper preservation and perishable.

In summary, the dimethylamine mignalactone-salicylate prepared in Example 2 can well solve the problems of high hygroscopicity and poor stability of dimethylaminomimicrolide fumarate, and improve the Drug quality controllability and safety.

Stability test two:

The PXRD spectrum of the dimethylaminomildolide-salicylate sample prepared in Example 2, the weight loss of TGA and the melting point on the DSC did not change significantly, proving that the dimethylaminomildolide-salicylate did not occur Crystal transformation, good stability.

Stability test three:

The solid sample of the dimethylaminomildolide-salicylate prepared in embodiment 2 does not change significantly, while the dimethylaminemimicrolactone (CN102234259B) and the dimethylaminomildolide fumarate (CN111303097A) correspond to There are obvious new diffraction peaks in the PXRD pattern of the solid sample, indicating that a new phase has been produced, which proves once again that dimethylamine michelactone-salicylate solves the problem of poor stability and easy degradation of dimethylamine michelolactone At the same time, it overcomes the obstacle that the product quality is difficult to control due to the easy crystal transformation of dimethylamine michelolactone fumarate.

Example 3

Weigh 146.5 mg of dimethylamine micholactone solid and 55.2 mg of salicylic acid solid, add 100 μL of ethyl acetate, ball mill at a frequency of 20 Hz for 60 min, and dry at 40° C. to obtain dimethylamine michololactone salicylate solid sample.

The product that embodiment 3 obtains is carried out crystallographic test, and test result is the same as embodiment 1.

Carry out XRD test to the product that embodiment 3 obtains, as can be known: take diffraction angle as 2θ to represent that 2θ diffraction angle is 7.7°, 10.3°, 11.5°, 11.9°, 12.6°, 13.3°, 14.9°, 16.1°, 16.6° , 17.9°, 18.8°, 19.7°, 20.3°, 21.8°, 22.2°, 22.5°, 23.1°, 24.1°, 24.8°, 25.2°, 27.5° have characteristic peaks.

Carry out DSC test to embodiment 3, know: product has endothermic peak at 170.8 ℃.

Adopt the method identical with embodiment 1 to carry out following performance test by the product that embodiment 3 obtains:

(1) Routine performance test:

The purity of the product obtained in Example 3 is 99.2%, the yield of the product is 98%, and the crystal habit of the product is block crystal habit.

(2) Humidity test:

The water content of the product prepared in Example 3 only changes from 0.01% to 0.61%, while the water content of dimethylamine michelolactone fumarate (CN111303097A) changes from 0.01% to 4.4%, which is illustrated by comparison: Example 3 obtains The product has low hygroscopicity.

(3) Stability test:

Stability test one:

After the dimethylamine michelolactone-salicylate prepared in Example 3 finished the water adsorption experiment, no new diffraction peaks appeared in the X-ray powder diffraction pattern of the sample compared with Figure 2, indicating that in the dynamic moisture adsorption experiment There was no crystal form transition in the samples before and after, indicating that the dimethylaminomildolide-salicylate of the present invention has better stability.

Dimethylamine michelolactone fumarate (CN111303097A) after finishing the water adsorption experiment, new characteristic peaks appeared at 7.8 °, 10.5 °, 11.1 °, 12.6 °, and the X-ray powder diffraction pattern of the sample took place obvious Further analysis showed that the sample changed from anhydrous crystalline form to hydrate crystalline form under high humidity conditions, which further showed that the stability of dimethylamine michelolactone fumarate was poor and was significantly affected by environmental humidity. Storage conditions Harsh, improper preservation and perishable.

In summary, the dimethylaminomildolide-salicylate prepared in Example 3 can well solve the problems of high hygroscopicity and poor stability in dimethylaminomildolide fumarate, and improve the Drug quality controllability and safety.

Stability test two:

The PXRD spectrum of the dimethylaminomildolide-salicylate sample prepared in Example 3, the weight loss of TGA and the melting point on the DSC did not change significantly, proving that dimethylaminemimicrolide-salicylate did not occur Crystal transformation, good stability.

Stability test three:

The solid sample of the dimethylaminomildolide-salicylate prepared in embodiment 3 does not change significantly, while the dimethylaminomildolide (CN102234259B) and the dimethylaminomildolide fumarate (CN111303097A) correspond to There are obvious new diffraction peaks in the PXRD pattern of the solid sample, indicating that a new phase has been produced, which proves once again that dimethylamine michelactone-salicylate solves the problem of poor stability and easy degradation of dimethylamine michelolactone At the same time, it overcomes the obstacle that the product quality is difficult to control due to the easy crystal transformation of dimethylamine michelolactone fumarate.

Example 4

Weigh 29.3 mg of dimethylaminomilactone solid and 13.8 mg of salicylic acid solid into an agate mortar, add 20 μL of 1,4-dioxane, grind for 5 minutes, and dry at room temperature to obtain dimethylaminomilactone water Solid sample of sylate.

The crystallographic test is carried out to the product that embodiment 4 obtains, and test result is the same as embodiment 1.

Carry out XRD test to the product that embodiment 4 obtains, as can be known: with diffraction angle being 2θ, represent at 7.8 °, 10.4 °, 11.6 °, 12.0 °, 12.6 °, 13.4 °, 15.0 °, 16.2 °, 16.7 °, 17.9 °, There are characteristic peaks at 18.9°, 19.8°, 20.4°, 21.9°, 22.3°, 22.5°, 23.2°, 24.2°, 24.9°, 25.3°, 27.6°.

Carry out DSC test to embodiment 4, know: product has endothermic peak at 172.2 ℃.

Adopt the method identical with embodiment 1 to carry out following performance test by the product that embodiment 4 obtains:

(1) Routine performance test:

The purity of the product obtained in Example 4 is 99.2%, the yield of the product is 97%, and the crystal habit of the product is block crystal habit.

(2) Humidity test:

The water content of the product prepared in Example 4 only changes from 0.01% to 0.62%, while the water content of dimethylamine michelolactone fumarate (CN111303097A) changes from 0.01% to 4.7%, which is illustrated by comparison: Example 4 obtains The product has low hygroscopicity.

(3) Stability test:

Stability test one:

After the water adsorption experiment of the dimethylaminomildolide-salicylate prepared in Example 4, no new diffraction peaks appeared in the X-ray powder diffraction pattern of the sample compared with Figure 2, indicating that in the dynamic moisture adsorption experiment There was no crystal form transition in the samples before and after, indicating that the dimethylaminomildolide-salicylate of the present invention has better stability.

Dimethylamine michelolactone fumarate (CN111303097A) after finishing the water adsorption experiment, new characteristic peaks appeared at 7.8 °, 10.5 °, 11.1 °, 12.6 °, and the X-ray powder diffraction pattern of the sample took place obvious Further analysis showed that the sample changed from anhydrous crystalline form to hydrate crystalline form under high humidity conditions, which further showed that the stability of dimethylamine michelolactone fumarate was poor and was significantly affected by environmental humidity. Storage conditions Harsh, improper preservation and perishable.

In summary, the dimethylaminomildolide-salicylate prepared in Example 4 can well solve the problems of high hygroscopicity and poor stability in dimethylaminomicrolide fumarate, and improve the Drug quality controllability and safety.

Stability test two:

The PXRD spectrum of the dimethylaminomildolide-salicylate sample prepared in Example 4, the weight loss of TGA and the melting point on the DSC did not change significantly, proving that the dimethylaminomicrolide-salicylate did not occur Crystal transformation, good stability.

Stability test three:

The solid sample of dimethylaminomildolide-salicylate prepared in embodiment 4 does not change significantly, while dimethylaminemimicrolactone (CN102234259B) and dimethylaminemimicrolide fumarate (CN111303097A) correspond to There are obvious new diffraction peaks in the PXRD pattern of the solid sample, indicating that a new phase has been produced, which proves once again that dimethylamine michelactone-salicylate solves the problem of poor stability and easy degradation of dimethylamine michelolactone At the same time, it overcomes the obstacle that the product quality is difficult to control due to the easy crystal transformation of dimethylamine michelolactone fumarate.

Example 5

Weigh 58.6 mg of dimethylamine micholactone solid and 27.6 mg of salicylic acid solid, add 30 μL of acetonitrile, ball mill at a frequency of 15 Hz for 20 minutes, and dry at 40 ° C to obtain the solid of dimethylamine micholactone salicylate sample.

The crystallographic test is carried out to the product that embodiment 5 obtains, and test result is the same as embodiment 1.

Carry out XRD test to the product that embodiment 5 obtains, it can be known that: take diffraction angle as 2θ to represent in 7.7 °, 10.3 °, 11.5 °, 12.0 °, 12.5 °, 13.2 °, 14.9 °, 16.1 °, 16.6 °, 17.8 °, There are characteristic peaks at 19.0°, 19.6°, 20.3°, 21.8°, 22.3°, 22.5°, 23.2°, 24.1°, 24.8°, 25.3°, 27.5°.

Carry out DSC test to embodiment 5, know: product has endothermic peak at 173.1 ℃.

Adopt the method identical with embodiment 1 to carry out following performance test by the product that embodiment 5 obtains:

(1) Routine performance test:

The purity of the product obtained in Example 5 is 99.2%, the yield of the product is 96%, and the crystal habit of the product is block crystal habit.

(2) Humidity test:

The water content of the product prepared in Example 5 only changes from 0.01% to 0.58%, while the water content of dimethylamine michelolactone fumarate (CN111303097A) changes from 0.01% to 4.5%, which is illustrated by comparison: Example 5 obtains The product has low hygroscopicity.

(3) Stability test:

Stability test one:

After the water adsorption experiment of the dimethylaminomildolide-salicylate prepared in Example 5, no new diffraction peaks appeared in the X-ray powder diffraction pattern of the sample compared with Figure 2, indicating that in the dynamic moisture adsorption experiment There was no crystal form transition in the samples before and after, indicating that the dimethylaminomildolide-salicylate of the present invention has better stability.

Dimethylamine michelolactone fumarate (CN111303097A) after finishing the water adsorption experiment, new characteristic peaks appeared at 7.8 °, 10.5 °, 11.1 °, 12.6 °, and the X-ray powder diffraction pattern of the sample took place obvious Further analysis showed that the sample changed from anhydrous crystalline form to hydrate crystalline form under high humidity conditions, which further showed that the stability of dimethylamine michelolactone fumarate was poor and was significantly affected by environmental humidity. Storage conditions Harsh, improper preservation and perishable.

In summary, the dimethylamine microlactone-salicylate prepared in Example 5 can well solve the problems of high hygroscopicity and poor stability of dimethylaminomimicrolide fumarate, and improve the Drug quality controllability and safety.

Stability test two:

The PXRD spectrum of the dimethylaminomildolide-salicylate sample prepared in Example 5, the weight loss of TGA and the melting point on the DSC did not change significantly, proving that the dimethylaminomicrolide-salicylate did not occur Crystal transformation, good stability.

Stability test three:

The solid sample of the dimethylaminomildolide-salicylate prepared in Example 5 does not change significantly, while the dimethylaminemimicrolactone (CN102234259B) and the dimethylaminomildolide fumarate (CN111303097A) correspond to There are obvious new diffraction peaks in the PXRD pattern of the solid sample, indicating that a new phase has been produced, which proves once again that dimethylamine michelactone-salicylate solves the problem of poor stability and easy degradation of dimethylamine michelolactone At the same time, it overcomes the obstacle that the product quality is difficult to control due to the easy crystal transformation of dimethylamine michelolactone fumarate.

Example 6

Add 1.5g solid dimethylamine michelolactone, 0.706g solid salicylic acid, and 100mL ethyl acetate into the reaction flask, heat to 60°C, and stir for 60 minutes to fully react the raw materials. Cool to 10°C at a rate of 5°C/h, filter the obtained product, and then dry under normal pressure at 25°C for 6 hours to obtain dimethylaminomildolide salicylate.

The crystallographic test is carried out to the product that embodiment 6 obtains, and test result is the same as embodiment 1.

Carry out XRD test to the product that embodiment 6 obtains, it can be known that: take diffraction angle as 2θ to represent at 7.6 °, 10.2 °, 11.4 °, 11.9 °, 12.5 °, 13.2 °, 14.9 °, 16.0 °, 16.5 °, 17.8 °, There are characteristic peaks at 18.8°, 19.6°, 20.2°, 21.7°, 22.1°, 22.4°, 23.0°, 24.0°, 24.7°, 25.1°, 27.4°.

Carry out DSC test to embodiment 6, know: product has endothermic peak at 172.3 ℃.

Adopt the method identical with embodiment 1 to carry out following performance test by the product that embodiment 6 obtains:

(1) Routine performance test:

The purity of the product obtained in Example 6 is 99.2%, the yield of the product is 96.5%, and the crystal habit of the product is block crystal habit.

(2) Humidity test:

The water content of the product prepared in Example 6 only changes from 0.01% to 0.60%, while the water content of dimethylamine michelolactone fumarate (CN111303097A) changes from 0.01% to 4.3%, which is illustrated by comparison: Example 6 obtains The product has low hygroscopicity.

(3) Stability test:

Stability test one:

After the water adsorption experiment of the dimethylaminomildolide-salicylate prepared in Example 6, no new diffraction peaks appeared in the X-ray powder diffraction pattern of the sample compared with Figure 2, indicating that in the dynamic moisture adsorption experiment There was no crystal form transition in the samples before and after, indicating that the dimethylaminomildolide-salicylate of the present invention has better stability.

Dimethylamine michelolactone fumarate (CN111303097A) after finishing the water adsorption experiment, new characteristic peaks appeared at 7.8 °, 10.5 °, 11.1 °, 12.6 °, and the X-ray powder diffraction pattern of the sample took place obvious Further analysis showed that the sample changed from anhydrous crystalline form to hydrate crystalline form under high humidity conditions, which further showed that the stability of dimethylamine michelolactone fumarate was poor and was significantly affected by environmental humidity. Storage conditions Harsh, improper preservation and perishable.

In summary, the dimethylamine mignalactone-salicylate prepared in Example 6 can well solve the problems of high hygroscopicity and poor stability of dimethylaminomimicrolide fumarate, and improve the Drug quality controllability and safety.

Stability test two:

The PXRD spectrum of the dimethylaminemimilactone-salicylate sample prepared in Example 6, the weight loss of TGA and the melting point on the DSC did not change significantly, proving that dimethylaminomildolide-salicylate did not occur Crystal transformation, good stability.

Stability test three:

The solid sample of dimethylaminomildolide-salicylate prepared in Example 6 did not change significantly, while dimethylaminomildolide (CN102234259B) and dimethylaminomildolide fumarate (CN111303097A) corresponded There are obvious new diffraction peaks in the PXRD pattern of the solid sample, indicating that a new phase has been produced, which proves once again that dimethylamine michelactone-salicylate solves the problem of poor stability and easy degradation of dimethylamine michelolactone At the same time, it overcomes the obstacle that the product quality is difficult to control due to the easy crystal transformation of dimethylamine michelolactone fumarate.

Example 7

Add 3 g of dimethylamine michelactone solid, 2.119 g of salicylic acid solid, and 50 mL of ethanol into the reaction flask, heat to 40°C, and stir for 30 min to fully react the raw materials. Cool to 10°C at a rate of 10°C/h, filter the obtained product, and then dry under normal pressure at 30°C for 3 hours to obtain dimethylaminomildolide salicylate. The powder X-ray diffraction spectrum of the product is consistent with the accompanying drawing 1, and the DSC spectrum has an endothermic peak at 173.7°C.

The crystallographic test is carried out to the product that embodiment 7 obtains, and test result is the same as embodiment 1.

Carry out XRD test to the product that embodiment 7 obtains, as can be known: with diffraction angle being 2θ, represent at 7.5 °, 10.2 °, 11.3 °, 11.7 °, 12.4 °, 13.0 °, 14.7 °, 15.9 °, 16.4 °, 17.7 °, There are characteristic peaks at 18.6°, 19.4°, 20.1°, 21.6°, 22.0°, 22.3°, 22.9°, 23.8°, 24.5°, 24.9°, 27.2°.

Carry out DSC test to embodiment 7, know: product has endothermic peak at 173.7 ℃.

Adopt the method identical with embodiment 1 to carry out following performance test by the product that embodiment 7 obtains:

(1) Routine performance test:

The purity of the product obtained in Example 7 is 99.2%, the yield of the product is 93%, and the crystal habit of the product is block crystal habit.

(2) Humidity test:

The water content of the product prepared in Example 7 only changes from 0.01% to 0.61%, while the water content of dimethylamine michelolactone fumarate (CN111303097A) changes from 0.01% to 4.3%, which is illustrated by comparison: Example 7 obtains The product has low hygroscopicity.

(3) Stability test:

Stability test one:

After the water adsorption experiment of the dimethylaminomildolide-salicylate prepared in Example 7, no new diffraction peaks appeared in the X-ray powder diffraction pattern of the sample compared with Figure 2, indicating that in the dynamic moisture adsorption experiment There was no crystal form transition in the samples before and after, indicating that the dimethylaminomildolide-salicylate of the present invention has better stability.

Dimethylamine michelolactone fumarate (CN111303097A) after finishing the water adsorption experiment, new characteristic peaks appeared at 7.8 °, 10.5 °, 11.1 °, 12.6 °, and the X-ray powder diffraction pattern of the sample took place obvious Further analysis showed that the sample changed from anhydrous crystalline form to hydrate crystalline form under high humidity conditions, which further showed that the stability of dimethylamine michelolactone fumarate was poor and was significantly affected by environmental humidity. Storage conditions Harsh, improper preservation and perishable.

In summary, the dimethylamine mignalactone-salicylate prepared in Example 7 can well solve the problems of high hygroscopicity and poor stability of dimethylaminomimicrolide fumarate, and improve the Drug quality controllability and safety.

Stability test two:

The PXRD spectrum of the dimethylamine michelactone-salicylate sample prepared in Example 7, the weight loss of TGA and the melting point on the DSC did not change significantly, proving that dimethylamine michelactone-salicylate did not occur Crystal transformation, good stability.

Stability test three:

The solid sample of the dimethylaminomildolide-salicylate prepared in Example 7 does not change significantly, while the dimethylaminemimicrolactone (CN102234259B) and the dimethylaminemimicrolide fumarate (CN111303097A) correspond to There are obvious new diffraction peaks in the PXRD pattern of the solid sample, indicating that a new phase has been produced, which proves once again that dimethylamine michelactone-salicylate solves the problem of poor stability and easy degradation of dimethylamine michelolactone At the same time, it overcomes the obstacle that the product quality is difficult to control due to the easy crystal transformation of dimethylamine michelolactone fumarate.

Example 8

Add 6g of dimethylamine michelolactone solid, 2.543g of salicylic acid solid, and 120mL of acetonitrile into the reaction flask, heat to 50°C, and stir for 40min to fully react the raw materials. Cool to 20°C at a rate of 8°C/h, filter the obtained product, and then dry under normal pressure at 40°C for 5 hours to obtain dimethylaminomildolide salicylate.

The crystallographic test is carried out to the product that embodiment 8 obtains, and test result is the same as embodiment 1.

Carry out XRD test to the product that embodiment 8 obtains, as can be known: with diffraction angle being 2θ, represent at 7.6 °, 10.2 °, 11.4 °, 11.9 °, 12.5 °, 13.2 °, 14.9 °, 16.0 °, 16.5 °, 17.8 °, There are characteristic peaks at 18.8°, 19.6°, 20.2°, 21.7°, 22.1°, 22.4°, 23.0°, 24.0°, 24.7°, 25.1°, 27.4°.

Carry out DSC test to embodiment 8, know: product has endothermic peak at 173.2 ℃.

Adopt the method identical with embodiment 1 to carry out following performance test by the product that embodiment 8 obtains:

(1) Routine performance test:

The purity of the product obtained in Example 8 is 99.2%, the yield of the product is 93.5%, and the crystal habit of the product is block crystal habit.

(2) Humidity test:

The water content of the product prepared in Example 8 only changes from 0.01% to 0.60%, while the water content of dimethylamine michelolactone fumarate (CN111303097A) changes from 0.01% to 4.4%, which is illustrated by comparison: Example 8 obtains The product has low hygroscopicity.

(3) Stability test:

Stability test one:

After the water adsorption experiment of the dimethylamine michelolactone-salicylate prepared in Example 8, no new diffraction peaks appeared in the X-ray powder diffraction pattern of the sample compared with Figure 2, indicating that in the dynamic moisture adsorption experiment There is no crystal form transition in the samples before and after, indicating that the stability of the dimethylaminomildolide-salicylate of the present invention is better.

Dimethylamine michelolactone fumarate (CN111303097A) after finishing the water adsorption experiment, new characteristic peaks appeared at 7.8 °, 10.5 °, 11.1 °, 12.6 °, and the X-ray powder diffraction pattern of the sample took place obvious Further analysis showed that the sample changed from anhydrous crystalline form to hydrate crystalline form under high humidity conditions, which further showed that the stability of dimethylamine michelolactone fumarate was poor and was significantly affected by environmental humidity. Storage conditions Harsh, improper preservation and perishable.

In summary, the dimethylamine mignalactone-salicylate prepared in Example 8 can well solve the problems of high hygroscopicity and poor stability of dimethylaminomimicrolide fumarate, and improve the Drug quality controllability and safety.

Stability test two:

The PXRD spectrum of the dimethylamine michelactone-salicylate sample prepared in Example 8, the weight loss of TGA and the melting point on DSC did not change significantly, proving that dimethylamine michelactone-salicylate did not occur Crystal transformation, good stability.

Stability test three:

The solid sample of the dimethylaminomildolide-salicylate prepared in Example 8 did not change significantly, while the dimethylaminemimicrolactone (CN102234259B) and the dimethylaminomildolide fumarate (CN111303097A) corresponded There are obvious new diffraction peaks in the PXRD pattern of the solid sample, indicating that a new phase has been produced, which proves once again that dimethylamine michelactone-salicylate solves the problem of poor stability and easy degradation of dimethylamine michelolactone At the same time, it overcomes the obstacle that the product quality is difficult to control due to the easy crystal transformation of dimethylamine michelolactone fumarate.

Example 9

Add 3 g of dimethylamine michelactone solid, 1.412 g of salicylic acid solid, and 75 mL of acetone into the reaction flask, heat to 45°C, and stir for 40 min to fully react the raw materials. Cool to 10°C at a rate of 5°C/h, filter the obtained product, and then dry under normal pressure at 40°C for 3 hours to obtain dimethylaminomildolide salicylate.

The crystallographic test is carried out to the product that embodiment 9 obtains, and test result is the same as embodiment 1.

Carry out XRD test to the product that embodiment 9 obtains, as can be known: with diffraction angle being 2θ, represent at 7.7 °, 10.4 °, 11.5 °, 12.0 °, 12.6 °, 13.3 °, 15.0 °, 16.2 °, 16.6 °, 17.9 °, There are characteristic peaks at 19.0°, 19.8°, 20.4°, 21.8°, 22.3°, 22.5°, 23.2°, 24.1°, 24.8°, 25.2°, 27.5°.

Carry out DSC test to embodiment 9, know: product has endothermic peak at 172 ℃.

Adopt the method identical with embodiment 1 to carry out following performance test by the product that embodiment 9 obtains:

(1) Routine performance test:

The purity of the product obtained in Example 9 is 99.2%, the yield of the product is 94%, and the crystal habit of the product is block crystal habit.

(2) Humidity test:

The water content of the product prepared in Example 9 only changes from 0.01% to 0.57%, while the water content of dimethylamine michelolactone fumarate (CN111303097A) changes from 0.01% to 4.8%, which is illustrated by comparison: Example 9 obtains The product has low hygroscopicity. (3) Stability test:

Stability test one:

After the water adsorption experiment was finished for the dimethylamine michelolactone-salicylate prepared in Example 9, no new diffraction peaks appeared in the X-ray powder diffraction pattern of the sample compared with Figure 2, indicating that in the dynamic water adsorption experiment There is no crystal form transition in the samples before and after, indicating that the stability of the dimethylaminomildolide-salicylate of the present invention is better.

Dimethylamine michelolactone fumarate (CN111303097A) after finishing the water adsorption experiment, new characteristic peaks appeared at 7.8 °, 10.5 °, 11.1 °, 12.6 °, and the X-ray powder diffraction pattern of the sample took place obvious Further analysis showed that the sample changed from anhydrous crystalline form to hydrate crystalline form under high humidity conditions, which further showed that the stability of dimethylamine michelolactone fumarate was poor and was significantly affected by environmental humidity. Storage conditions Harsh, improper preservation and perishable.

In summary, the dimethylamine mignalactone-salicylate prepared in Example 9 can well solve the problems of high hygroscopicity and poor stability of dimethylaminomimicrolide fumarate, and improve the Drug quality controllability and safety.

Stability test two:

The PXRD spectrum of the dimethylamine micholactone-salicylate sample prepared in Example 9, the weight loss of TGA and the melting point on the DSC did not change significantly, proving that dimethylaminomildolide-salicylate did not occur Crystal transformation, good stability.

Stability test three:

The solid sample of the dimethylaminomildolide-salicylate prepared in Example 9 does not change significantly, while the dimethylaminemimicrolactone (CN102234259B) and the dimethylaminemimicrolide fumarate (CN111303097A) correspond to There are obvious new diffraction peaks in the PXRD pattern of the solid sample, indicating that a new phase has been produced, which proves once again that dimethylamine michelactone-salicylate solves the problem of poor stability and easy degradation of dimethylamine michelolactone At the same time, it overcomes the obstacle that the product quality is difficult to control due to the easy crystal transformation of dimethylamine michelolactone fumarate.

Example 10

Add 1.5g of dimethylaminomilanolide solid, 0.706g of salicylic acid solid, and 50mL of 1,4-dioxane into the reaction flask, heat to 55°C, and stir for 30 minutes to fully react the raw materials. Cool to 15°C at a rate of 8°C/h, filter the obtained product, and then dry under normal pressure at 30°C for 5 hours to obtain dimethylaminomildolide salicylate.

The crystallographic test is carried out to the product obtained in Example 10, and the test result is the same as in Example 1.

Carry out XRD test to the product that embodiment 10 obtains, as can be known: with diffraction angle being 2θ, represent at 7.8 °, 10.4 °, 11.6 °, 12.0 °, 12.7 °, 13.4 °, 15.1 °, 16.2 °, 16.7 °, 18.0 °, There are characteristic peaks at 19.0°, 19.8°, 20.4°, 21.9°, 22.3°, 22.6°, 23.2°, 24.2°, 24.9°, 25.3°, 27.6°.

Carry out DSC test to embodiment 10, know: product has endothermic peak at 171.8 ℃.

Adopt the method identical with embodiment 1 to carry out following performance test by the product that embodiment 10 obtains:

(1) Routine performance test:

The purity of the product obtained in Example 10 is 99.2%, the yield of the product is 94.5%, and the crystal habit of the product is block crystal habit.

(2) Humidity test:

The water content of the product prepared in Example 10 only changes from 0.01% to 0.6%, while the water content of dimethylamine michelolactone fumarate (CN111303097A) changes from 0.01% to 4.7%, which is illustrated by comparison: Example 10 obtains The product has low hygroscopicity. (3) Stability test:

Stability test one:

After the end of the water adsorption experiment of the dimethylaminomildolide-salicylate prepared in Example 10, no new diffraction peaks appeared in the X-ray powder diffraction pattern of the sample compared with Figure 2, indicating that in the dynamic moisture adsorption experiment There was no crystal form transition in the samples before and after, indicating that the dimethylaminomildolide-salicylate of the present invention has better stability.

Dimethylamine michelolactone fumarate (CN111303097A) after finishing the water adsorption experiment, new characteristic peaks appeared at 7.8 °, 10.5 °, 11.1 °, 12.6 °, and the X-ray powder diffraction pattern of the sample took place obvious Further analysis showed that the sample changed from anhydrous crystalline form to hydrate crystalline form under high humidity conditions, which further showed that the stability of dimethylamine michelolactone fumarate was poor and was significantly affected by environmental humidity. Storage conditions Harsh, improper preservation and perishable.

In summary, the dimethylamine mignalactone-salicylate prepared in Example 10 can well solve the problems of high hygroscopicity and poor stability of dimethylaminomimicrolide fumarate, and improve the Drug quality controllability and safety.

Stability test two:

The PXRD spectrum of the dimethylaminomildolide-salicylate sample prepared in Example 10, the weight loss of TGA and the melting point on the DSC did not change significantly, proving that dimethylaminemimicrolide-salicylate did not occur Crystal transformation, good stability.

Stability test three:

The solid sample of dimethylaminomildolide-salicylate prepared in Example 10 did not change significantly, while dimethylaminomildolide (CN102234259B) and dimethylaminomildolide fumarate (CN111303097A) corresponded There are obvious new diffraction peaks in the PXRD pattern of the solid sample, indicating that a new phase has been produced, which proves once again that dimethylamine michelactone-salicylate solves the problem of poor stability and easy degradation of dimethylamine michelolactone At the same time, it overcomes the obstacle that the product quality is difficult to control due to the easy crystal transformation of dimethylamine michelolactone fumarate.

The applicant declares that the above description is only a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto, and those skilled in the art should understand that any person skilled in the art should be aware of any disclosure in the present invention Within the technical scope, easily conceivable changes or substitutions all fall within the scope of protection and disclosure of the present invention.

Claims (8)

1. The michelia lactone-salicylate is characterized in that the molecular formula of the michelia lactone-salicylate is C ₂₄ H ₃₃ NO ₆ And has the following structure:

the crystallography characteristics of the michelia lactone salicylate of dimethylamine comprise that the space group is P2 ₁ 2 ₁ 2 ₁ With cell parameters of

α =90 °, β =90 °, γ =90 °, cell volume of

In an X-ray powder diffraction spectrogram of the michelia dimpled amine lactone-salicylate, characteristic peaks exist at 2 theta diffraction angles of 7.6 +/-0.2 degrees, 10.2 +/-0.2 degrees, 11.4 +/-0.2 degrees, 11.9 +/-0.2 degrees, 12.5 +/-0.2 degrees, 13.2 +/-0.2 degrees, 14.9 +/-0.2 degrees, 16.0 +/-0.2 degrees, 16.5 +/-0.2 degrees, 17.8 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.6 +/-0.2 degrees, 20.2 +/-0.2 degrees, 21.7 +/-0.2 degrees, 22.1 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.0 +/-0.2 degrees, 24.0 +/-0.2 degrees, 24.7 +/-0.2 degrees, 25.1 +/-0.2 degrees and 27.4 +/-0.2 degrees.

2. The michelia lactone-salicylate of dimethylamine of claim 1, wherein the differential scanning calorimetry analysis of the michelia lactone-salicylate of dimethylamine has a characteristic melting peak at 172 ± 2 ℃.

3. A method of producing michelia lactone-salicylate of dimethylamine according to claim 1 or 2, wherein the method comprises the steps of:

grinding and mixing michelia dimcta lactone and salicylic acid to obtain the michelia dimcta lactone-salicylate;

the molar ratio of the michelia lactone dimethylamine to the salicylic acid is 1.8-1.2;

the grinding equipment comprises a ball mill or an agate mortar;

the grinding is carried out in a solvent, and the adding volume of the solvent is 0.512-0.853 mu L, wherein the adding amount of the michelia lactone is 1 mg;

the solvent is selected from any one of methanol, acetone, acetonitrile, 1, 4-dioxane or ethyl acetate;

the grinding frequency is 15-30Hz, and the grinding time is 5-60min.

4. A method of producing michelia lactone-salicylate of dimethylamine according to claim 1 or 2, wherein the method comprises the steps of:

(1) Reacting michelia lactone dimethylamine with salicylic acid in an organic solvent to obtain a mixture;

(2) Cooling and crystallizing the mixture obtained by the reaction in the step (1) to obtain the michelia lactone-salicylate;

the molar ratio of the dimethylamine michelia lactone to the salicylic acid in the step (1) is 1;

the adding amount of the organic solvent in the step (1) is 1mL, wherein the adding amount of the michelia lactone dimethylamine is 15-60 mg;

the organic solvent in the step (1) is selected from any one of ethanol, acetone, acetonitrile, 1, 4-dioxane or ethyl acetate;

the reaction temperature in the step (1) is 40-60 ℃, and the reaction time is 30-60min;

the cooling rate of the cooling crystallization in the step (2) is 5-10 ℃/h;

and (3) the cooling end point of the cooling crystallization in the step (2) is 10-20 ℃.

5. The method according to claim 4, wherein the step (2) further comprises subjecting the crystalline material obtained after cooling crystallization to solid-liquid separation, washing and drying in this order.

6. The method according to claim 5, wherein the solid-liquid separation is performed by filtration.

7. The method according to claim 5, wherein the drying is carried out under atmospheric conditions at a temperature of 25-40 ℃ for a time of 3-6 hours.

8. Use of the minocycline-salicylate of claim 1 or 2 in the preparation of an anti-rheumatic medicament.

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