CN111909135A - AZD9291 deutero-mesylate new salt form and preparation method thereof - Google Patents
AZD9291 deutero-mesylate new salt form and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a novel AZD9291 deutero mesylate salt and a preparation method thereof. The novel salt form of AZD9291 deutero mesylate has a characteristic endothermic peak at 243 +/-3 ℃. Dissolving methanesulfonic acid in an ethanol-ethyl acetate mixed solvent, heating to 60-80 ℃, adding AZD9291 deuterated methanesulfonate while stirring, stirring the obtained mixture for 2-4 hours, collecting solids by filtering, and drying to obtain a new salt form of AZD9291 deuterated methanesulfonate. The method has the advantages of simple process, mild conditions and good repeatability. The solvent has small usage amount and toxicity, is convenient for industrial production, and obviously improves the solubility. Compared with AZD9291 deuterated methanesulfonate, the solubility of the new salt form of AZD9291 deuterated methanesulfonate is improved by 3 times at 25 ℃. The properties were stable at high temperature (60 ℃ C., unlimited humidity) and 40 ℃ C., RH 75%.
Description
Technical Field
The invention belongs to the technical field of medical crystallization, and particularly relates to a novel salt form of an osetinib deuterodine mesylate and a preparation method thereof.
Background
Oseltamiib (AZD9291) is the earliest lung cancer therapeutic drug developed by astrazen (sweden) limited, and is mainly applied to the lung cancer type non-small cell lung cancer that is the most difficult to effectively treat. The medicine has obvious treatment effect after the medicine is resistant to an epidermal growth factor receptor tyrosine kinase (EGFR) inhibitor of a late lung cancer patient taking a domestic Kernel, gefitinib (Iressa) hydrochloric acid erlotinib (Tarceva) and the drug resistance of the T790M mutation of a gatekeeper residue. AZD9291 has more favorable physical properties (e.g., higher aqueous solubility, higher permeability, and/or lower plasma protein binding) and/or favorable toxicity profiles and/or favorable metabolic profiles compared to first generation EGFR inhibitors (e.g., erlotinib, gefitinib, and erlotinib) and second generation EGFR inhibitors (e.g., lenatinib, afatinib, and dacatinib).
Ostinib (AZD9291) with chemical name of N- (2- { 2-dimethylaminoethyl-methylamino } -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide with a molecular weight of 499.61 and a molecular formula of C28H33N7O2The chemical structure formula is as follows:
however, demethylated metabolites of AZD9291 at the indole position produce toxic metabolites with higher affinity for wild-type EGFR and cause severe side effects during treatment. Such high affinity for wild-type EGFR poses serious safety problems and significantly limits the overall effectiveness of oseltamiib in treating cancer patients. In addition, the metabolites also increase IGF1R potency which can lead to hyperglycemia in human therapy. Thus, there is a need to develop safer, more effective, less toxic products. Deuterium substitution at critical positions has become a solution to the above problem.
As disclosed in patent CN108779102A, patent CN108779102, deuterated compounds of the methyl group at the indole position significantly inhibit the metabolic pathway of demethylation and ultimately improve the toxicological properties of the molecule. Deuteration at the vinyl group affects the molecular binding and distribution properties and reactivity of the molecules, enhancing the reactivity of the target and reducing steric hindrance can overcome drug resistance to some extent. Deuterons optimize the reactivity of the target while enhancing or maintaining the non-covalent binding ability of the compound is a way to improve efficacy and reduce toxicity.
The AZD9291 deuterated compound structure is deuterium-substituted on the AZD9291 structure, namely R1, R2, R3, R4, R5, R6, R7, R8 and R9 positions in FIG. 1 are each independently selected from hydrogen (H) and deuterium (D), and at least one of R1, R2, R3, R4, R5, R6, R7, R8 and R9 is D.
At present, the AZD9291 deuteron is obtained by taking 3- (2-chloropyrimidin-4-yl) -1H-indole as a raw material through a multistep halogen substitution reaction and a reduction reaction. The AZD9291 deuterium substitute directly obtained by the route has low water solubility, low blood concentration and brain concentration, and is not beneficial to the dissolution and absorption of the medicament in a body. Therefore, the AZD9291 deuterogen needs to be further reacted with methanesulfonic acid to obtain AZD9291 deuterogen mesylate with high solubility, high bioavailability and stable physicochemical properties.
Patent WO2018214886a1 and CN201810495698.7 propose deuterated AZD9291 mesylate obtained by crystallization using acetonitrile, acetone or water mixture as solvent, and the characteristic peaks of X-ray diffraction pattern are 7.1, 8.5, 9.4, 10.3, 15.1, 16.3, 18.7, 22.0, 25.6, 2.26(2 theta). The solubility of the product is slightly improved, but not much improved; and the preparation process uses acetonitrile and acetone which are harmful to human health, so that the environment protection and the human health are not facilitated.
Disclosure of Invention
In order to further improve the solubility of AZD9291 deuterated methanesulfonate and reduce the use amount of toxic and harmful solvents, the invention provides a novel AZD9291 deuterated methanesulfonate salt and a preparation method thereof.
The invention provides a novel AZD9291 deutero mesylate salt, wherein the X-ray powder diffraction pattern of the novel AZD9291 deutero mesylate salt is shown in figure 1. The new salt form has characteristic peaks at 5.3 + -0.1, 6.2 + -0.1, 9.9 + -0.1, 10.8 + -0.1, 11.4 + -0.1, 11.7 + -0.1, 12.23 + -0.1, 13.2 + -0.1, 14.0 + -0.1, 15.4 + -1, 15.7 + -0.1, 16.3 + -0.1, 17.6 + -0.1, 18.1 + -0.1, 19.0 + -0.1, 20.0 + -0.1, 20.6 + -0.1, 20.8 + -0.1, 22.0 + -0.1, 22.5 + -0.1, 22.7 + -0.1, 23.2 + -0.1, 23.9 + -0.1, 25.7 + -0.1, 26.2 + -0.1, 27.0 + -0.1 degree by X-ray powder diffraction 2 theta.
A differential scanning calorimetry DSC chart of the novel salt form of AZD9291 deutero mesylate is shown in figure 2. The novel salt form of AZD9291 deutero mesylate has a characteristic endothermic peak at 243 +/-3 ℃.
The invention provides a preparation method of a novel AZD9291 deuterated mesylate salt, which comprises the steps of dissolving methanesulfonic acid in an ethanol-ethyl acetate mixed solvent, heating to 60-80 ℃, adding AZD9291 deuterated mesylate while stirring, stirring the obtained mixture for 2-4 hours, collecting solid through filtration, and drying to obtain the novel AZD9291 deuterated mesylate salt.
The molar weight of the methanesulfonic acid is 1-1.5 times of that of AZD9291 deuterated methanesulfonate.
The ratio of the methanesulfonic acid to the mixed solvent is 10mg/ml to 20 mg/ml.
The volume ratio of the solvent ethanol to the ethyl acetate is 1: 0.5-1: 2; preferably 1: 1.
The drying condition is vacuum drying at the temperature of 60-90 ℃, and the drying time is 6-8 h.
AZD9291 deuterated methanesulfonate can be obtained from WO2018214886a1 and CN201810495698.7, or any commercially available product can be used.
The method has the advantages of simple process, mild conditions and good repeatability. The solvent has small usage amount and toxicity, is convenient for industrial production, and obviously improves the solubility. Compared with AZD9291 deuterated methanesulfonate, the solubility of the new salt form of AZD9291 deuterated methanesulfonate is improved by 3 times at 25 ℃. The properties were stable at high temperature (60 ℃ C., unlimited humidity) and 40 ℃ C., RH 75%.
Drawings
FIG. 1 is an X-ray diffraction diagram of a novel salt form of AZD9291 deuteron according to the invention.
FIG. 2 is a differential scanning calorimetry DSC of the new salt form of AZD9291 deuterogen of the present invention.
FIG. 3 is a comparison of accelerated stability test patterns of new salts of AZD9291 deuteron according to the present invention, wherein the patterns are from bottom to top 0 days of crystalline product, 5 days and 10 days of XRD pattern.
Detailed Description
The following are specific implementation examples of the new salt form of the AZD9291 deuteron, but it should not be understood that the scope of the above subject matter of the present invention is limited to the following implementation examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
AZD9291 deutero mesylate in the raw material is prepared by adopting the preparation methods of WO2018214886A1 and CN 201810495698.7.
Dissolving methanesulfonic acid in ethanol-ethyl acetate mixed solvent, heating to 60-80 deg.C, adding AZD9291 deutero mesylate while stirring (patent WO2018214886A1 and CN 201810495698.7). And stirring the obtained mixture for 2-4 hours, filtering, washing and drying crystal slurry to obtain the new AZD9291 deuterated mesylate salt.
Example 1
100.34mg of methanesulfonic acid are dissolved in 3ml of ethanol and 3ml of ethyl acetate, heated to 70 ℃ and 506.94mg of the starting AZD9291 deuterated methanesulfonate are added with stirring. The resulting mixture was stirred for 3 hours, the solid was collected by filtration and dried under vacuum at 60 ℃ for 6h to give the new salt form of AZD9291 deuterated mesylate. The powder X-ray diffraction pattern of the product is consistent with that of figure 1, and the new salt form has the characteristic peaks expressed by X-ray powder diffraction 2 theta at 5.3 + -0.1, 6.2 + -0.1, 9.9 + -0.1, 10.8 + -0.1, 11.4 + -0.1, 11.7 + -0.1, 12.23 + -0.1, 13.2 + -0.1, 14.0 + -0.1, 15.4 + -1, 15.7 + -0.1, 16.3 + -0.1, 17.6 + -0.1, 18.1 + -0.1, 19.0 + -0.1, 20.0 + -0.1, 20.6 + -0.1, 20.8 + -0.1, 22.0 + -0.1, 22.5 + -0.1, 22.7 + -0.1, 23.2 + -0.1, 23.9 + -0.1, 25.7 + -0.1, 26.2 + -0.1 and 27.1 degrees. The DSC spectrum is shown in figure 2, and the novel AZD9291 deutero mesylate salt has a characteristic endothermic peak at 243 +/-3 ℃.
Crystal form solubility investigation
In consideration of the stability of the new AZD9291 deuterated salt of example 1, the solubility of AZD9291 deuterated methanesulfonate, AZD9291 deuterated methanesulfonate (patent WO2018214886a1 and CN201810495698.7) of the present invention was compared and tested according to the four exemplary (fifteen) method of chinese pharmacopoeia 2015, the results are shown in the following table:
TABLE AZD9291 deuteron free base and mesylate Water solubility contrast
The solubility of the novel AZD9291 deuterated mesylate salt is improved by 3 times compared with the solubility of AZD9291 deuterated mesylate (patent WO2018214886A1 and CN201810495698.7) at 25 ℃.
Study of Crystal form stability
The stability of the new salt form of the AZD9291 deuteron in example 1 is examined, the AZD9291 deuteron crystal form product is respectively put under the conditions of high temperature (60 ℃, unlimited humidity) and 40 ℃ and RH 75% for acceleration test, samples are respectively taken for 5 days and 10 days for XRD detection, and the change of the appearance color, the product purity, the crystal form conversion and the like is examined by comparing with the result of the day 0. See table below.
Stability test result of new salt form of epidiazd 9291 deuteron
The specific spectrum of the accelerated stability test at 40 ℃ and RH 75% is shown in figure 3, and the result shows that the crystal form transformation of the new salt form of the AZD9291 deuteron does not occur.
The experiments show that the appearance, color and crystal form of the new AZD9291 deuteron salt prepared by the invention have no change under high temperature and accelerated conditions, and the stability of the product is good as shown in figure 3.
Example 2
100.34mg of methanesulfonic acid are dissolved in 3ml of ethanol and 1.5ml of ethyl acetate, heated to 60 ℃ and stirred, 506.94mg of the starting AZD9291 deuterated methanesulfonate are added. The resulting mixture was stirred for 4 hours, the solid was collected by filtration and dried under vacuum at 80 ℃ for 7h to give the new salt form of AZD9291 deuterated mesylate. The powder X-ray diffraction pattern of the product has characteristic peaks at 5.34, 6.26, 9.923, 10.85, 11.44, 12.28, 13.28, 14.15, 15.52, 15.84, 16.44, 15.52, 15.84, 16.45, 17.61, 18.14, 19.00, 19.73, 20.07, 20.85, 22.04, 22.48, 22.80, 23.30, 25.74 and 26.30 degrees, and DSC shows that the melting point is 242 ℃. The product of the embodiment can keep stable crystal form under the conditions of high temperature (60 ℃, unlimited humidity) and 40 ℃ and RH 75%, and the water solubility at 25 ℃ is 47.8 g/L.
Example 3
100.34mg of methanesulfonic acid are dissolved in 1.5ml of ethanol and 3ml of ethyl acetate, heated to 80 ℃ and stirred, 506.94mg of the starting AZD9291 deuterated methanesulfonate are added. The resulting mixture was stirred for 2 hours, the solid was collected by filtration and dried under vacuum at 70 ℃ for 8h to give the new salt form of AZD9291 deuterated mesylate. The product has a powder X-ray diffraction pattern with characteristic peaks at 5.36, 6.26, 9.96, 10.87, 11.51, 11.85, 12.34, 13.29, 14.1, 15.48, 15.80, 16.44, 17.12, 17.61, 18.25, 19.06, 19.72, 20.1, 20.68, 20.82, 22.08, 22.52, 22.83, 23.29, 24.96, 25.76, 26.28, 27.06, 27.69, 28.27, 29.430.38 and 35.38 degrees, and DSC shows that the melting point is 243 ℃. The product of the example can keep stable crystal form under the conditions of high temperature (60 ℃, unlimited humidity) and 40 ℃ and RH 75%, and the water solubility at 25 ℃ is 47.9 g/L.
Example 4
8.9mg of methanesulfonic acid are dissolved in 0.4ml of ethanol and 0.4ml of ethyl acetate, heated to 70 ℃ and 50mg of the starting AZD9291 deuterated methanesulfonate are added with stirring. The resulting mixture was stirred for 4 hours, the solid was collected by filtration and dried under vacuum at 60 ℃ for 6h to give the new salt form of AZD9291 deuterated mesylate. The powder X-ray diffraction pattern of the product has characteristic peaks at 5.12, 6.03, 9.70, 11.225, 12.08, 13.06, 15.22, 16.19, 16.88, 17.36, 17.98, 18.84, 19.49, 20.39, 20.56, 21.76, 22.58, 23.04, 25.56, 26.05 and 26.84 degrees, and DSC shows that the melting point is 244 ℃. The product of the embodiment can keep stable crystal form under the conditions of high temperature (60 ℃, unlimited humidity) and 40 ℃ and RH 75%, and the water solubility at 25 ℃ is 47.9 g/L.
Example 5
9mg of methanesulfonic acid are dissolved in 0.5ml of ethanol and 0.5ml of ethyl acetate, heated to 70 ℃ and 50mg of the starting AZD9291 deuterated methanesulfonate are added with stirring. The resulting mixture was stirred for 4 hours, the solid was collected by filtration and dried under vacuum at 60 ℃ for 7h to give the new salt form of AZD9291 deuterated mesylate. The powder X-ray diffraction pattern of the product has characteristic peaks at 5.20, 9.81, 11.32, 12.11, 13.08, 15.28, 16.24, 17.40, 18.05, 18.90, 19.52, 20.64, 22.34, 23.08, 25.65, 26.20 and 16.94 degrees, and DSC shows that the melting point is 243 ℃. The product of the embodiment can keep stable crystal form under the conditions of high temperature (60 ℃, unlimited humidity) and 40 ℃ and RH 75%, and the water solubility at 25 ℃ is 47.8 g/L.
Example 6
9.5mg of methanesulfonic acid are dissolved in 0.5ml of ethanol and 0.5ml of ethyl acetate, heated to 70 ℃ and 50mg of the starting AZD9291 deuterated methanesulfonate are added with stirring. The resulting mixture was stirred for 3 hours, the solid was collected by filtration and dried under vacuum at 60 ℃ for 8h to give the new salt form of AZD9291 deuterated mesylate. The powder X-ray diffraction pattern of the product has characteristic peaks at 5.31, 6.28, 9.94, 10.89, 11.48, 11.828, 12.28, 13.33, 14.08, 15.45, 15.80, 16.44, 17.15, 17.59, 18.18, 19.09, 19.75, 20.07, 20.56, 22.02, 22.48, 22.78, 23.30, 23.95, 25.73, 26.3, 27.08 and 28.20 degrees, and DSC shows that the melting point is 244 ℃. The product of the embodiment can keep stable crystal form under the conditions of high temperature (60 ℃, unlimited humidity) and 40 ℃ and RH 75%, and the water solubility at 25 ℃ is 47.9 g/L.
The experimental apparatus and the test conditions adopted in the application are as follows:
x-ray powder diffractometer XRPD
The model is as follows: BRUKER D8 DISCOVER from Bruker, Germany
The method comprises the following steps: cu target Ka, voltage 40KV, current 40mA, test angle 3-45 degrees, step size 0.02, exposure time 0.2S, light pipe slit width 1mm, detector slit width 2.7 mm.
Differential calorimetric scanner DSC
The model is as follows: TA instruments Inc. of USA TA 250
The method comprises the following steps: the heating rate is 10 ℃/min
TGA (thermal gravimetric analysis) instrument
The model is as follows: TA instruments Inc. TA 550
The method comprises the following steps: the heating rate is 10 ℃/min
Dynamic moisture adsorption instrument DVS
The model is as follows: UK SMS company DVS inrinsic
The method comprises the following steps: 25 ℃, 10% humidity of each step, and 10min under the judgment standard of less than 0.002%
Electric heating constant temperature drying box
The model is as follows: DHG-9011A (Shanghai essence macro laboratory equipment Co., Ltd.)
Programmable medicine stable constant temperature and humidity testing machine
The model is as follows: CMA-100C (Shanghai break precision equipment Limited)
Precision balance
The model is as follows: XSE105 (mettleltopol).
Although the method and the manufacturing technique of the present invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that modifications or rearrangements of the method and the technical procedures set forth herein can be made to achieve the final manufacturing technique without departing from the spirit and scope of the invention. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and content of the invention.
Claims (9)
1. A novel crystal form of AZD9291 deuteron mesylate is characterized in that an X-ray powder diffraction pattern expressed by 2 theta has peaks at 5.3 +/-0.1, 6.2 +/-0.1, 9.9 +/-0.1, 10.8 +/-0.1, 11.4 +/-0.1, 11.7 +/-0.1, 12.23 +/-0.1, 13.2 +/-0.1, 14.0 +/-0.1, 15.4 +/-1, 15.7 +/-0.1, 16.3 +/-0.1, 17.6 +/-0.1, 18.1 +/-0.1, 19.0 +/-0.1, 20.0 +/-0.1, 20.6 +/-0.1, 20.8 +/-0.1, 22.0 +/-0.1, 22.5 +/-0.1, 22.7 +/-0.1, 23.2 +/-0.1, 23.9 +/-0.1, 25.7 +/-0.1, 26.0.1 and 27.0 +/-0.1 degrees.
2. The crystalline form of claim 1, characterized by a DSC profile with a characteristic endothermic peak at 243 ± 3 ℃.
3. A preparation method of a novel AZD9291 deuterated mesylate crystal form is characterized by dissolving methanesulfonic acid in an ethanol-ethyl acetate mixed solvent, heating to 60-80 ℃, adding AZD9291 deuterated mesylate while stirring, stirring the obtained mixture for 2-4 hours, filtering to collect solids, and drying to obtain the novel AZD9291 deuterated mesylate salt form.
4. The method as claimed in claim 3, wherein the molar amount of methanesulfonic acid is 1 to 1.5 times that of AZD9291 deuterated methanesulfonate.
5. The method according to claim 3, wherein the ratio of the methanesulfonic acid to the mixed solvent is 10 to 20 mg/ml.
6. The method according to claim 3, wherein the volume of the solvent ethanol and ethyl acetate is 1:0.5 to 1: 2.
7. The method according to claim 3, wherein the volume of the solvents ethanol and ethyl acetate is 1: 1.
8. The method according to claim 3, wherein the reaction temperature is 60 to 80 ℃ and the reaction time is 2 to 4 hours.
9. The method as claimed in claim 3, wherein the drying is carried out under vacuum at 60-90 ℃ for 6-8 h.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104140418A (en) * | 2014-08-15 | 2014-11-12 | 朱孝云 | Novel 2-(2, 4, 5-subsituted aniline) pyrimidine derivatives and use thereof |
CN105153122A (en) * | 2015-08-27 | 2015-12-16 | 上海圣考医药科技有限公司 | [(indole-3-yl)pyrimidine-2-yl]aminophenylpropyl-2-eneamide derivative and its salt, preparation method of derivative, and application of derivative and salt |
CN108558835A (en) * | 2017-05-24 | 2018-09-21 | 浙江同源康医药股份有限公司 | A kind of crystal form, the Preparation method and use of deuterated AZD9291 |
CN111285852A (en) * | 2020-04-02 | 2020-06-16 | 广州博济医药生物技术股份有限公司 | Crystal form of deuterated oxitinib medicinal salt and preparation method thereof |
-
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104140418A (en) * | 2014-08-15 | 2014-11-12 | 朱孝云 | Novel 2-(2, 4, 5-subsituted aniline) pyrimidine derivatives and use thereof |
CN105153122A (en) * | 2015-08-27 | 2015-12-16 | 上海圣考医药科技有限公司 | [(indole-3-yl)pyrimidine-2-yl]aminophenylpropyl-2-eneamide derivative and its salt, preparation method of derivative, and application of derivative and salt |
CN108558835A (en) * | 2017-05-24 | 2018-09-21 | 浙江同源康医药股份有限公司 | A kind of crystal form, the Preparation method and use of deuterated AZD9291 |
CN111285852A (en) * | 2020-04-02 | 2020-06-16 | 广州博济医药生物技术股份有限公司 | Crystal form of deuterated oxitinib medicinal salt and preparation method thereof |
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