CN113929664A - AZD9291-3, 5-pyridine dicarboxylic acid salt and preparation method thereof - Google Patents

AZD9291-3, 5-pyridine dicarboxylic acid salt and preparation method thereof Download PDF

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CN113929664A
CN113929664A CN202010669002.5A CN202010669002A CN113929664A CN 113929664 A CN113929664 A CN 113929664A CN 202010669002 A CN202010669002 A CN 202010669002A CN 113929664 A CN113929664 A CN 113929664A
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azd9291
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dicarboxylic acid
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张纪云
翟立海
马超
董怀民
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Lunan Pharmaceutical Group Corp
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Abstract

The invention relates to the technical field of crystal form drug molecules, and particularly provides AZD9291-3, 5-pyridine dicarboxylic acid salt and a preparation method and application thereof, wherein the AZD 9291-3.5-pyridine dicarboxylic acid salt has characteristic peaks at 4.26 +/-0.2 degrees, 8.71 +/-0.2 degrees, 10.75 +/-0.2 degrees, and 26.04 +/-0.2 degrees by using Cu-Kalpha radiation and an X-ray diffraction spectrum expressed by 2 theta. The AZD9291-3, 5-pyridine dicarboxylic acid salt provided by the invention is simple and convenient in preparation method, the crystal form solubility of the prepared salt is remarkably improved, the stability is good, and the AZD9291-3, 5-pyridine dicarboxylic acid salt is suitable for being used as a pharmaceutical active ingredient.

Description

AZD9291-3, 5-pyridine dicarboxylic acid salt and preparation method thereof
Technical Field
The invention relates to the technical field of crystal form drug molecules, in particular to the technical field of AZD9291 crystal forms, and specifically relates to AZD9291-3, 5-pyridine dicarboxylic acid salts and a preparation method and application thereof.
Background
AZD9291(Osimertinib), chemical name: n- [2- [ [2- (dimethylamino) ethyl ] (methyl) amino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino ] phenyl ] prop-2-enamide, english name: n- (2- { [2- (dimethyllamino) ethyl ] (methyl) amino } -4-methoxy-5- { [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino } phenyl) acrylamide. CAS number: 1421373-65-0, the structural formula is shown as follows:
Figure BDA0002581536890000011
if the lung cancer patient has EGFR or ALK gene mutation, the targeted drug can obtain better survival benefit. However, the efficacy of these drugs is generally short-lived, and resistance occurs in months 9-11, which arises because cancer cells can evade the therapeutic activity of EGFR or ALK inhibitors by mutating and changing the growth pattern.
ADZ9291, developed by AstraZeneca (AstraZeneca), is a third generation oral, irreversible selective EGFR mutation inhibitor useful for activating and resistant mutant EGFR, i.e., 50% of acquired resistance to EGFR treatment for advanced non-small cell lung cancer patients is caused by the T790M mutation, and ADZ9291 can nullify this challenging mutation. ADZ9291 has better treatment effect on NSCLC patients with existing resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and T790M mutation.
Patent CN103702990A discloses the structure of ADZ9291 compound. Polymorphic forms of this compound and its mesylate salt are also disclosed in this patent, including form B of the ADZ9291 mesylate salt form A, ADZ9291 mesylate salt. Patent CN104961731A discloses ADZ9291 phosphate; patent CN106432231A discloses ADZ9291 pharmaceutically acceptable salts sulfate, p-toluenesulfonate, tartrate, acetate and citrate; patent CN107915725A patent discloses novel pharmaceutically acceptable salts of maleic acid, fumaric acid, gluconic acid, malonic acid, succinic acid and lactic acid.
The former company used the mesylate salt of AZD9291 for clinical studies. However, methanesulfonic acid is highly toxic and, in selective cases, unsuitable for pharmaceutical use. And the methanesulfonate has problems of high hygroscopicity and deliquescence due to high humidity. Therefore, it is necessary to develop other salts with high bioavailability, low toxicity and suitability for pharmaceutical use. Although the prior literature has disclosed numerous AZD9291 crystal forms, systematic studies on the crystal forms are still to be perfected.
Disclosure of Invention
In view of the defects of the prior art, the invention provides AZD9291-3, 5-pyridine dicarboxylic acid salt, which has excellent physicochemical properties and is suitable for being used as an active ingredient of medicaments.
The specific technical content of the invention is as follows:
the invention provides AZD9291-3, 5-pyridine dicarboxylic acid salt, which uses Cu-Kalpha radiation, and has characteristic peaks at 4.26 +/-0.2 degrees, 8.71 +/-0.2 degrees, 10.75 +/-0.2 degrees, 26.04 +/-0.2 degrees in an X-ray diffraction spectrum expressed by 2 theta.
Preferably, the AZD9291-3, 5-pyridinedicarboxylate has an X-ray diffraction pattern expressed in 2 theta using Cu-Ka radiation having characteristic peaks at 4.26 + -0.2 degrees, 8.71 + -0.2 degrees, 10.75 + -0.2 degrees, 12.75 + -0.2 degrees, 13.86 + -0.2 degrees, 17.03 + -0.2 degrees, 19.21 + -0.2 degrees, 21.53 + -0.2 degrees, 26.04 + -0.2 degrees.
Preferably, the AZD9291-3, 5-pyridinedicarboxylate has an X-ray diffraction pattern shown in FIG. 1 using Cu-Ka radiation.
Preferably, the AZD9291-3, 5-pyridinedicarboxylate has an endothermic peak at 176.15 ℃ in a Differential Scanning Calorimetry (DSC) curve.
The invention also provides a method for preparing AZD9291-3, 5-pyridine dicarboxylic acid salt, which comprises the following steps:
dissolving AZD9291 and 3, 5-pyridinedicarboxylic acid in an organic solvent, heating to reflux, cooling and crystallizing after the solution is clarified, filtering, and drying to obtain the product.
The organic solvent is selected from one or more mixed solvents of methanol, acetonitrile, ethanol and acetone.
Preferably, the organic solvent is selected from one or two of acetonitrile and methanol.
The molar ratio of the AZD9291 to the 3, 5-pyridinedicarboxylic acid is 1: 2.0-4.0; preferably, the molar ratio of AZD9291 to 3, 5-pyridinedicarboxylic acid is 1:2.0 to 3.0.
The mass-volume ratio of the AZD9291 to the organic solvent in the system is 5-15: 1, wherein the mass is in mg and the volume is in mL.
The cooling crystallization temperature is 0-30 ℃, and preferably, the cooling crystallization temperature is 5-20 ℃.
The crystallization time is 45-72 hours.
The drying temperature is 45-70 ℃, and the drying time is 8-12 hours.
Confirmation of crystal structure of AZD9291-3, 5-pyridinedicarboxylic acid salt
The X-ray crystal data of the invention is collected on a Japan X-talaBSynergy model instrument, the temperature is measured at 293(2) K, CuKa radiation is used, and data are collected in an omega scanning mode and are subjected to Lp correction. Analyzing the structure by a direct method, finding out all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and refining the structure by a least square method.
The X-ray powder diffraction test instrument and the test conditions of the invention are as follows: panalytical empyrean x-ray powder diffractometer; light source Cu target, flat sample stage, incident light path: BBHD, diffraction path: PIXCEL, voltage 45KV, current 40mA, divergence slit 1/4 degrees, anti-divergence slit 1 degree, cable-stayed slit 0.04rad degree, counting time of each step 0.5s, and scanning range 3-50 degrees.
The TGA/DSC thermal analysis tester and the test conditions in the invention are as follows: TGA/DSC thermogram METTLER TOLEDO TGA/DSC3 +; dynamic temperature section: 30-300 ℃; heating rate: 10 ℃/min; segment gas N2(ii) a Gas flow rate: 50 mL/min; crucible: an aluminum crucible of 40. mu.l.
The crystallographic data obtained by testing and analyzing the AZD9291-3, 5-pyridine dicarboxylic acid salt prepared by the invention (see Table 1) have the following crystallographic parameters: triclinic system, chiral space group is P-1; the unit cell parameters are:
Figure BDA0002581536890000031
Figure BDA0002581536890000032
a is 107.9250(10) °, β is 95.4710(10) °, γ is 97.2170(10) °, unit cell volume
Figure BDA0002581536890000033
The molecular formula is: c42H43N9O10Molecular weight ofThe method comprises the following steps: 833.85. the structural analysis picture of the AZD9291-3, 5-pyridinedicarboxylic acid salt of the invention shows that one molecule of oxitinib and two molecules of 3, 5-pyridinedicarboxylic acid exist in the crystal, as shown in the attached figure 3. The stack diagram of AZD9291-3, 5-pyridinedicarboxylate according to the invention is shown in FIG. 2.
TABLE 1 AZD9291-3, 5-pyridinedicarboxylate Primary crystallography data
Figure BDA0002581536890000034
Figure BDA0002581536890000041
According to the crystallographic data, the characteristic peaks in the X-ray powder diffraction pattern (Cu-K alpha) corresponding to the AZD9291-3, 5-pyridine dicarboxylic acid salt prepared by the invention are shown in the attached figure 1 and the table 2. The result of a Differential Scanning Calorimetry (DSC) curve of the AZD9291-3, 5-pyridine dicarboxylate is shown in figure 4, and the Differential Scanning Calorimetry (DSC) curve has an endothermic peak at 176.15 ℃; the thermogravimetric analysis (TGA) of the AZD9291-3, 5-pyridine dicarboxylate has only one weight loss step, and the structure is stable. The AZD9291-3, 5-pyridinedicarboxylate crystal has a DSC/TGA spectrum shown in figure 4.
TABLE 2 AZD9291-3, 5-pyridinedicarboxylate major PXRD peaks
Figure BDA0002581536890000042
Figure BDA0002581536890000051
All AZD9291-3, 5-pyridinedicarboxylate samples prepared according to the present invention had the same crystallographic parameters, X-ray powder diffraction pattern and DSC/TGA pattern as described above.
The invention also provides a pharmaceutical composition comprising the AZD9291-3, 5-pyridinedicarboxylate salt prepared as described above in combination with other active ingredients and/or pharmaceutically acceptable auxiliary components.
Preferably, the pharmaceutical composition can be prepared into spray, tablets, capsules, powder injections, liquid injections and the like by using standard or conventional technology.
The invention also provides application of the AZD9291-3, 5-pyridine dicarboxylic acid salt in preparing a medicament for treating lung cancer, in particular application in preparing a medicament for treating non-small cell lung cancer.
Compared with the prior art, the AZD9291-3, 5-pyridine dicarboxylic acid salt prepared by the invention has the advantages of remarkably improved solubility and good stability, and is suitable for preparing medicaments.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of AZD9291-3, 5-pyridinedicarboxylate;
FIG. 2 is a diagram of a stack of AZD9291-3, 5-pyridinedicarboxylate salts;
FIG. 3 is an ORTEP diagram of AZD9291-3, 5-pyridinedicarboxylate;
FIG. 4 is a TGA/DSC thermogram of AZD9291-3, 5-pyridinedicarboxylate.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
Example 1
Adding 1.0g of AZD9291 and 0.8g of 3, 5-pyridinedicarboxylic acid into 100mL of methanol, heating to reflux, clarifying the solution, slowly cooling to 5 ℃, standing for crystallization for 60 hours, filtering, washing a filter cake with methanol, and vacuum-drying at 65 ℃ for 10 hours to obtain AZD9291-3, 5-pyridinedicarboxylic acid salt, wherein the yield is 91.32 percent, and the purity is 99.97 percent.
Example 2
Adding 1.0g of AZD9291 and 1.0g of 3, 5-dipicolinic acid into 83mL of ethanol, heating to reflux, clarifying the solution, slowly cooling to 0 ℃, standing for crystallization for 65 hours, filtering, washing a filter cake with ethanol, and vacuum-drying at 50 ℃ for 11 hours to obtain AZD9291-3, 5-dipicolinate, wherein the yield is 91.16 percent and the purity is 99.96 percent.
Example 3
Adding 1.0g of AZD9291 and 0.7g of 3, 5-dipicolinic acid into 125mL of acetonitrile, heating to reflux, clarifying the solution, slowly cooling to 10 ℃, standing for crystallization for 50 hours, filtering, washing a filter cake with acetonitrile, and vacuum-drying at 60 ℃ for 12 hours to obtain AZD9291-3, 5-dipicolinate, wherein the yield is 87.83 percent and the purity is 99.94 percent.
Example 4
Adding 1.0g of AZD9291 and 1.2g of 3, 5-dipicolinic acid into a mixed solvent of 30mL of methanol and 36mL of acetone, heating to reflux, clarifying the solution, slowly cooling to 15 ℃, standing for 50 hours for crystallization, filtering, washing a filter cake with methanol, and performing vacuum drying at 60 ℃ for 12 hours to obtain AZD9291-3, 5-dipicolinate, wherein the yield is 77.16% and the purity is 99.92%.
Example 5
Adding 1.0g of AZD9291 and 1.3g of 3, 5-pyridinedicarboxylic acid into 200mL of acetone, heating to reflux, clarifying the solution, slowly cooling to 30 ℃, standing for crystallization for 45 hours, filtering, washing a filter cake with acetone, and drying in vacuum at 70 ℃ for 8 hours to obtain AZD9291-3, 5-pyridinedicarboxylic acid salt, wherein the yield is 63.16 percent, and the purity is 99.88 percent.
Example 6
Adding 1.0g of AZD9291 and 1.5g of 3, 5-dipicolinic acid into 167mL of methanol, heating to reflux, clarifying the solution, slowly cooling to 20 ℃, standing for crystallization for 72 hours, filtering, washing a filter cake with methanol, and drying in vacuum at 45 ℃ for 10 hours to obtain AZD9291-3, 5-dipicolinate, wherein the yield is 54.07 percent and the purity is 99.88 percent.
Verification test
(1) Stability test
The stability test was carried out on the AZD9291-3, 5-pyridinedicarboxylate prepared in examples 1 to 3 of the present invention. The specific stability test method is carried out according to the guidance method of stability investigation in the fourth part of the Chinese pharmacopoeia 2015 edition, the purity is detected by an HPLC method, and the specific test results are shown in Table 3.
TABLE 3 stability test results of AZD9291-3, 5-pyridinedicarboxylate under light, high temperature and high humidity conditions
Figure BDA0002581536890000061
Figure BDA0002581536890000071
As can be seen from table 3, the AZD9291-3, 5-pyridinedicarboxylic acid salts prepared in examples 1 to 3 of the present invention have no significant change in purity under the conditions of light, high temperature and high humidity, and it is seen that the AZD9291-3, 5-pyridinedicarboxylic acid salts prepared in the present invention have good stability.
(2) Solubility test
The solubility comparison study was carried out on the AZD9291-3, 5-pyridinedicarboxylate prepared in examples 1 to 3 of the present invention and the AZD9291 mesylate crystal form A, AZD9291 fumarate in the prior art. The method comprises the following steps: respectively measuring 10ml of medium (water, 0.1mol/LHCl solution and phosphate buffer solution with pH of 6.8) into a penicillin bottle, adding excessive samples to be detected, sealing the penicillin bottle, placing the penicillin bottle in a constant-temperature water bath at 25 ℃, stirring for 1 hour, filtering through a 0.45-micron filter membrane, and taking filtrate; the absorbance was measured at a wavelength of 210nm, and the solubility was calculated by measuring the absorbance of a standard control.
TABLE 4 solubility of the Oxitinib polymorphs in different media (mg/ml)
Figure BDA0002581536890000072
The test data show that the solubility of the crystal form prepared in the embodiments 1-3 of the invention is remarkably improved compared with the AZD9291 mesylate crystal form A, AZD9291 fumarate in the prior art, which indicates that the AZD9291-3, 5-pyridine dicarboxylic acid salt prepared in the invention has good solubility, and can be prepared into a pharmaceutical preparation which is beneficial to absorption by human bodies.

Claims (10)

1. An AZD9291-3, 5-pyridine dicarboxylate, which is characterized in that: the X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 4.26 +/-0.2 degrees, 8.71 +/-0.2 degrees, 10.75 +/-0.2 degrees and 26.04 +/-0.2 degrees by using Cu-Kalpha radiation.
2. AZD9291-3, 5-pyridinedicarboxylate according to claim 1, characterized in that: an X-ray diffraction spectrum expressed by 2 theta by using Cu-Kalpha radiation has characteristic peaks at 4.26 +/-0.2 degrees, 8.71 +/-0.2 degrees, 10.75 +/-0.2 degrees, 12.75 +/-0.2 degrees, 13.86 +/-0.2 degrees, 17.03 +/-0.2 degrees, 19.21 +/-0.2 degrees, 21.53 +/-0.2 degrees and 26.04 +/-0.2 degrees.
3. AZD9291-3, 5-pyridinedicarboxylate according to claim 1, characterized in that: the AZD9291-3, 5-pyridine dicarboxylate has an X-ray diffraction pattern shown in figure 1 by using Cu-Ka radiation.
4. AZD9291-3, 5-pyridinedicarboxylate according to claim 1, characterized in that: the AZD9291-3, 5-pyridine dicarboxylic acid salt has an endothermic peak at 176.15 ℃ in a differential scanning calorimetry curve.
5. A process for the preparation of AZD9291-3, 5-pyridinedicarboxylate according to any of claims 1 to 4, comprising the following steps:
dissolving AZD9291 and 3, 5-pyridinedicarboxylic acid in an organic solvent, heating to reflux, cooling and crystallizing after the solution is clarified, filtering, and drying to obtain the product.
6. The method of claim 5, wherein: the organic solvent is selected from one or more mixed solvents of methanol, acetonitrile, ethanol and acetone.
7. The method of claim 5, wherein: the molar ratio of the AZD9291 to the 3, 5-pyridinedicarboxylic acid is 1:2.0 to 4.0.
8. The method of claim 5, wherein: the mass-volume ratio of the AZD9291 to the organic solvent in the system is 5-15: 1, wherein the mass is in mg and the volume is in mL.
9. A pharmaceutical composition comprising AZD9291-3, 5-pyridinedicarboxylate according to any of claims 1 to 4 in combination with further active ingredients and/or pharmaceutically acceptable auxiliary components.
10. Use of an AZD9291-3, 5-pyridinedicarboxylate according to any of claims 1 to 4 for the preparation of a medicament for the treatment of lung cancer.
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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
CN110483486A (en) * 2019-09-17 2019-11-22 鲁南制药集团股份有限公司 A kind of western Tenylidone of Austria coughs up hydrochlorate crystal form and preparation method thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103702990A (en) * 2011-07-27 2014-04-02 阿斯利康(瑞典)有限公司 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer
CN104961731A (en) * 2015-02-05 2015-10-07 苏州晶云药物科技有限公司 Phosphate of epidermal growth factor receptor inhibitor, and crystal form and preparation method thereof
CN106674202A (en) * 2015-11-05 2017-05-17 惠州信立泰药业有限公司 Dimethyl sulfonate of compound A, crystal form of dimethyl sulfonate, and medicinal composition containing dimethyl sulfonate
CN106432231A (en) * 2016-09-09 2017-02-22 无锡佰翱得生物科学有限公司 AZD 9291 pharmaceutical salt and crystal form and preparation method thereof
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
CN107176954A (en) * 2017-06-02 2017-09-19 无锡双良生物科技有限公司 Pharmaceutical salts and its crystal formation, the preparation method and application of a kind of EGFR inhibitor
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CN110483486A (en) * 2019-09-17 2019-11-22 鲁南制药集团股份有限公司 A kind of western Tenylidone of Austria coughs up hydrochlorate crystal form and preparation method thereof

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