CN116444525A - Preparation method of ponatinib hydrochloride A crystal form - Google Patents
Preparation method of ponatinib hydrochloride A crystal form Download PDFInfo
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- CN116444525A CN116444525A CN202310308725.6A CN202310308725A CN116444525A CN 116444525 A CN116444525 A CN 116444525A CN 202310308725 A CN202310308725 A CN 202310308725A CN 116444525 A CN116444525 A CN 116444525A
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- 239000013078 crystal Substances 0.000 title claims abstract description 31
- BWTNNZPNKQIADY-UHFFFAOYSA-N ponatinib hydrochloride Chemical compound Cl.C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 BWTNNZPNKQIADY-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 229960002183 ponatinib hydrochloride Drugs 0.000 title claims abstract description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 30
- PHXJVRSECIGDHY-UHFFFAOYSA-N ponatinib Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 PHXJVRSECIGDHY-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000002137 L01XE24 - Ponatinib Substances 0.000 claims abstract description 28
- 229960001131 ponatinib Drugs 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 20
- 239000012458 free base Substances 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 9
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 8
- 150000002576 ketones Chemical class 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 6
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical group COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- 229940093499 ethyl acetate Drugs 0.000 claims description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 3
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 3
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 3
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 3
- 229940090181 propyl acetate Drugs 0.000 claims description 3
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 238000007605 air drying Methods 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 230000008901 benefit Effects 0.000 abstract description 3
- 238000004090 dissolution Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 235000019441 ethanol Nutrition 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 6
- 238000002441 X-ray diffraction Methods 0.000 description 5
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 4
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000005611 electricity Effects 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 230000003068 static effect Effects 0.000 description 2
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 229940124290 BCR-ABL tyrosine kinase inhibitor Drugs 0.000 description 1
- 108091008794 FGF receptors Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- -1 T315I mutation) Chemical compound 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 206010057469 Vascular stenosis Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 210000004214 philadelphia chromosome Anatomy 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to the field of drug crystal forms, and particularly relates to a preparation method of a ponatinib A hydrochloride crystal form, which comprises the following steps: the method for preparing the crystal form A of the ponatinib hydrochloride has the advantages of high yield, simple process, good reproducibility and less dissolution residues, and can stably obtain the crystal form A of the ponatinib hydrochloride.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and in particular relates to a preparation method of a crystal form A of ponatinib hydrochloride
Background
Ponatinib hydrochloride (Ponatinib), chemical name: 3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methyl-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide, hydrochloride salt, having the following structural formula:
ponatinib tablet was first approved by the U.S. FDA for accelerated marketing at month 12 of 2012, but was suspended for sale at month 10 of 2013 due to the "risk of severe and fatal thrombosis and vascular stenosis". In 12 months 2013, the FDA has again approved its marketing under security monitoring after performing a risk benefit assessment on it. The european union and japan were successed to the collection of 7 months in 2013 and 9 months in 2016.
Ponatinib hydrochloride is currently approved by the U.S. FDA for use: (1) CP-CML (chronic stage chronic myelogenous leukemia) resistant or intolerant to at least two past kinase inhibitors (2) AP-CML (accelerated stage chronic myelogenous leukemia), BP-CML (acute stage chronic myelogenous leukemia), ph+ ALL (philadelphia chromosome positive acute lymphoblastic leukemia) without other kinase inhibitor indications. Ponatinib belongs to 3 rd generation BCR-ABL Tyrosine Kinase Inhibitor (TKI), can effectively inhibit wild type and mutant BCR-ABL (including T315I mutation), and can also widely inhibit VEGFR, PDGFR, FGFR, FLT, KIT and other tyrosine kinase families.
Patent CN105188701a discloses a preparation method of a crystal form a of ponatinib hydrochloride, the required starting material must be a specific free base of the crystal form a, ethanol is used as a solvent for salifying, and seed crystals are added to prepare the crystal form a of ponatinib hydrochloride, and the residual amount of ethanol is 0.85%. This method has the following disadvantages: (1) the crystallization mode is complex, and 5 steps of cooling evaporation, anti-solvent addition, grinding, pulping and steam diffusion are needed; (2) the method is to crystallize the A crystal form in ethanol to obtain the A crystal form; (3) the residual ethanol is difficult to control to below 0.5%; (4) the ponatinib free base is the specific form a desired.
Patent CN104496994 a discloses a preparation process of a crystal form of ponatinib hydrochloride, wherein acetonitrile is adopted for heating, hydrochloric acid is dropwise added into ethanol for stirring, and then the crystal form of ponatinib hydrochloride is prepared, the method adopts a second solvent acetonitrile which is not friendly to the environment and has high toxicity, and the preparation process of the patent is reproduced to find that: the Ponatinib free base has poor solubility in acetonitrile, the acetonitrile residue is seriously out of standard, and the obtained Ponatinib alpha crystal form has poor fluidity and larger static electricity, so that the Ponatinib free base is not suitable for medicinal use.
Disclosure of Invention
In order to overcome the defects of complex preparation process, high dissolution residual, poor fluidity and low yield of the crystal form A of the ponatinib hydrochloride in the prior art, the invention aims to provide the preparation method of the crystal form A of the ponatinib hydrochloride, which has the advantages of good reproducibility, good product quality, simple preparation process, environmental protection and high yield and is suitable for industrialized mass production.
The preparation method of the crystal form A of the ponatinib hydrochloride provided by the invention comprises the following steps:
s1: heating and dissolving the ponatinib free base in a ketone solvent or an ester solvent;
s2: dropwise adding hydrochloric acid to form salt;
s3: stirring, cooling, crystallizing, filtering or centrifuging, and drying to obtain the crystal form A of the ponatinib hydrochloride.
Further, the ketone solvent in S1 is selected from acetone or 2-butanone; the ester solvent is selected from methyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate or butyl acetate;
further, the ketone or ester solvent is selected from one or more of acetone, 2-butanone, methyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate or butyl acetate;
further preferably, the ketone solvent is selected from acetone; the ester solvent is selected from ethyl acetate;
further, the mass volume ratio of the ponatinib free base to the ketone solvent or the ester solvent in the S1 is 1:20-1:50 g/mL, preferably 1:20-1:30 g/mL, and more preferably 1:25g/mL.
The molar ratio of the ponatinib free base to the hydrochloric acid in the S2 is 1:0.8-1.1, preferably 1:0.98.
As a preferable scheme, an amide solvent, an alcohol solvent or water can be added in the step S2;
further, in the preferred embodiment of S2, the amide solvent is selected from N, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone; the alcohol solvent is selected from ethanol, methanol, n-propanol or isopropanol;
further, the mass volume ratio of the ponatinib free base to the amide solvent, the alcohol solvent or the water is 1:1-1:5 g/mL, preferably 1:1g/mL.
The salifying temperature in the S2 is 50-80 ℃, preferably 50-60 ℃, more preferably 50 ℃;
further, the crystallization time of S3 is 2+/-0.5 h.
Further, the drying mode is reduced pressure drying or forced air drying; the drying temperature is 65-95 ℃, preferably 65-75 ℃; drying time is 10-20 h.
Further, the drying mode is preferably reduced pressure drying, the vacuum degree is-0.080 to-0.095 MPa, the drying temperature is 75 ℃, and the drying time is 16 hours.
Further, the preparation method of the crystal form A of the ponatinib hydrochloride comprises the following steps:
dissolving the ponatinib free alkali in acetone or ethyl acetate by heating, then dropwise adding hydrochloric acid, stirring for 30 minutes, cooling to 50 ℃ for crystallization, stirring at 50 ℃ for 2 hours, cooling to room temperature, stirring at the temperature for 2 hours, filtering, and drying at the temperature of 75 ℃ in vacuum to obtain the ponatinib A hydrochloride crystal form.
The beneficial effects obtained by the invention are as follows:
(1) The invention has simple process, only needs to use the free base of the ponatinib and the hydrochloric acid to form salt, and can obtain the crystal form A of the ponatinib hydrochloride after cooling and crystallization, and the whole reaction can be completed in one step;
(2) The requirements on reaction equipment are not high, and the used solvent is safe and has low toxicity;
(3) The crystal form A of the ponatinib hydrochloride can be prepared without a specific crystal form or adding seed crystals, and the prepared crystal form A has high purity and low solvent residue, meets the medicinal standard, has the yield of more than 90 percent and is suitable for industrial production.
Drawings
Figure 1 is an XRD pattern of crystalline form a of ponatinib hydrochloride.
Detailed Description
The present invention is described in further detail below with reference to examples, but is not limited to the following examples, and any equivalents in the art, which are in accordance with the present disclosure, are intended to fall within the scope of the present invention.
XRD: powder diffraction by X-rays
The X-ray powder diffraction (XRD) test described herein was performed using a malvern-panaceae Empyrea powder diffractometer, with specific parameters as shown in the following table:
EXAMPLE 1 preparation of Ponatinib hydrochloride form A
5.0g of ponatinib free base is taken and dissolved in 125ml of acetone by heating, then 0.88g of hydrochloric acid is added dropwise, stirring is carried out for 30 minutes, then the temperature is reduced to 50 ℃ for crystallization, stirring is carried out at 50 ℃ for 2 hours, then the temperature is reduced to room temperature, stirring is carried out for 2 hours by heat preservation, filtration is carried out, and filter cakes are washed by acetone. Drying at 75℃under vacuum gave 4.95g of a yellow solid, 92.7% yield and 0.26% solvent residue of acetone, and the obtained immobilization was subjected to X-ray powder measurement using Cu-ka rays, the XRD pattern of which is shown in FIG. 1.
EXAMPLE 2 preparation of Ponatinib hydrochloride form A
5.0g of ponatinib free base is taken and dissolved in 125mL of ethyl acetate by heating, then 0.88g of hydrochloric acid is added dropwise, stirring is carried out for 30 minutes, cooling is carried out to 50 ℃ for crystallization, stirring is carried out at 50 ℃ for 2 hours, cooling is carried out to room temperature, stirring is carried out for 2 hours by heat preservation, filtering is carried out, and filter cake is washed by ethyl acetate. Drying at 75℃under vacuum gives 4.79g of a yellow solid, 90.7% yield, 0.25% solvent residue of ethyl acetate and an XRD pattern consistent with example 1.
EXAMPLE 3 preparation of Ponatinib hydrochloride form A
5.0g of ponatinib free base is taken and dissolved in 150mL of acetone by heating, then a mixed solution of 0.88g of hydrochloric acid and 3.5mL of N, N-dimethylformamide is added dropwise, the temperature is reduced to 50 ℃ for crystallization after stirring for 30 minutes, the temperature is reduced to room temperature after stirring for 2 hours at 50 ℃, the temperature is maintained and stirred for 2 hours, the filtration is carried out, and a filter cake is washed by acetone. Drying at 75℃under vacuum gives 4.61g of a yellow solid, 91.2% yield, 0.37% residual solvent for acetone, with an XRD pattern consistent with example 1.
EXAMPLE 4 preparation of Ponatinib hydrochloride form A
5.0g of Ponatinib free base is taken and dissolved in 150mL of ethyl acetate by heating, then 0.88g of hydrochloric acid and 3.5mL of N, N-dimethylformamide are added dropwise, the mixture is stirred for 30 minutes, then the temperature is reduced to 50 ℃ for crystallization, the mixture is stirred for 2 hours at 50 ℃, then the mixture is cooled to room temperature, the mixture is stirred for 2 hours at a constant temperature and then filtered, and filter cakes are washed by ethyl acetate. Drying at 75℃under vacuum gave 4.66g of a yellow solid in 91.5% yield with 0.34% ethyl acetate as residual solvent and an XRD pattern consistent with example 1.
Comparative example 1 preparation of Ponatinib hydrochloride form A
Synthetic route for preparing crystalline form of ponatinib α hydrochloride by reference to section [ 0058 ] of prior art CN104496994 a ]
Ponatinib (5.00 g) was taken at room temperature (about 24 ℃) and added to 100ml of acetonitrile, and the mixture was heated to 45℃and stirred for 1h, where the Ponatinib was insoluble; 1.04g of hydrochloric acid is diluted by 10ml of absolute ethyl alcohol and added into the mixture, and a large amount of solids are separated out after 1-2min of solid solution; after the mixture was stirred at 45℃for 30min, the mixture was cooled to 25℃and kept at 25℃for 2h, filtered and dried at 50℃under vacuum to give 4.1g of an off-white solid. The solvent residue of acetonitrile was 1.6%, well above the 0.041% acetonitrile residue specified in ICH Q3C.
Compared with the preparation process of the examples 1-4, acetonitrile is adopted as a solvent in the comparative example 1, the acetonitrile belongs to a class of solvents and is a limited-use solvent, and the solvent residue of the acetonitrile is 1.6 percent which is far higher than the prescribed acetonitrile residue in ICH Q3C by 0.041 percent; the residual amount of the solvent used in the application is lower than 0.5% specified in ICH Q3C; in addition, the crystal form A of the ponatinib hydrochloride obtained in the comparative example 1 has poor fluidity and large static electricity, and is not suitable for medicinal use.
Claims (9)
1. A method for preparing a crystal form a of ponatinib hydrochloride, which is characterized by comprising the following steps:
s1: heating and dissolving the ponatinib free base in a ketone solvent or an ester solvent;
s2: dropwise adding hydrochloric acid to form salt;
s3: stirring, cooling, crystallizing, filtering or centrifuging, and drying to obtain the crystal form A of the ponatinib hydrochloride.
2. The preparation method according to claim 1, wherein the ketone solvent in the step S1 is selected from acetone or 2-butanone; the ester solvent is selected from methyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate or butyl acetate; the mass volume ratio of the ponatinib free base to the ketone solvent or the ester solvent is 1:20-1:50 g/mL.
3. The method according to claim 1, wherein the molar ratio of the ponatinib free base to the hydrochloric acid in step S2 is 1:0.8 to 1.1.
4. The method according to claim 1, wherein the step S2 is further performed by adding an amide solvent, an alcohol solvent or water.
5. The process according to claim 4, wherein the amide-based solvent is selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone; the alcohol solvent is selected from ethanol, methanol, n-propanol or isopropanol.
6. The preparation method according to claim 4 or 5, wherein the mass-to-volume ratio of the ponatinib free base to the amide solvent, the alcohol solvent or the water in the S2 is 1:1-1:5 g/mL.
7. The method according to claim 1, wherein the salt forming temperature in S2 is 50 to 80 ℃.
8. The preparation method according to claim 1, wherein the drying mode in S3 is reduced pressure drying or air drying, the drying temperature is 65-95 ℃ and the drying time is 10-20 h.
9. The preparation method according to claim 1, characterized in that the preparation method comprises the steps of:
dissolving the ponatinib free alkali in acetone or ethyl acetate by heating, then dropwise adding hydrochloric acid, stirring for 30min, cooling to 50 ℃, stirring at 50 ℃ for 2h, cooling to room temperature, stirring at 50 ℃ for 2h, filtering, and drying at 75 ℃ in vacuum to obtain the ponatinib A hydrochloride crystal form.
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| CN202310308725.6A CN116444525A (en) | 2023-03-27 | 2023-03-27 | Preparation method of ponatinib hydrochloride A crystal form |
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| CN202310308725.6A CN116444525A (en) | 2023-03-27 | 2023-03-27 | Preparation method of ponatinib hydrochloride A crystal form |
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