CN105646494A - Ponatinib compound - Google Patents
Ponatinib compound Download PDFInfo
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- CN105646494A CN105646494A CN201410633842.0A CN201410633842A CN105646494A CN 105646494 A CN105646494 A CN 105646494A CN 201410633842 A CN201410633842 A CN 201410633842A CN 105646494 A CN105646494 A CN 105646494A
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- ponatinib
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Abstract
The present invention belongs to the technical field of medicine, and particularly relates to a ponatinib compound and a preparation method thereof, wherein ponatinib is subjected to heating dissolving in ethanol-acetic acid-aqueous solution, and cooling in stages is performed to obtain the ponatinib compound. According to the present invention, the new crystal form of ponatinib is obtained and has advantages of high purity and good stability, wherein the maximum impurity is less than 0.1%. The present invention further relates to applications of the ponatinib compound having the new crystal form in manufacture of leukemia treatment drugs.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to Ponatinib novel crystal forms and preparation method thereof, the invention also relates to treat the application in leukemia by this Ponatinib compositions.
Background technology
Ponatinib is the third generation tyrosine kinase inhibitor of U.S. Ali Ya De (Ariad) drugmaker research and development. Also not there is because of this compound the Chinese translation of standard, therefore its transliteration is " Ponatinib " at this by the applicant. This medicine of in December, 2012 obtains the listing approval of FDA (Food and Drug Adminstration) (FDA), and commodity are called Iclusig. For treating two kinds of rare leukemia, i.e. acute lymphoblastic leukemia (Ph+ALL) adult patients of chronic myelocytic leukemia (CML) and Philadelphia Chromosome Positive. The chemistry of Ponatinib (Ponatinib) is called: 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-[(4-(4-methylpiperazine-1-yl)-methyl)-3-(trifluoromethyl) phenyl] Benzoylamide, its structural formula is:
In research process, the method repeating prior art, the Ponatinib impurity number obtained is more, and total impurities is higher. The Ponatinib that the present invention obtains, has the advantage that: purity is high, and maximum contaminant is less than 1 ��; Good stability.
Summary of the invention
One object of the present invention, discloses a kind of Ponatinib compound crystal.
Another object of the present invention, the preparation method disclosing Ponatinib compound crystal.
Another purpose of the present invention, discloses the pharmaceutical composition of Ponatinib.
The invention also discloses the compound crystal of Ponatinib and manufacture the application treated in leukemic medicine.
In conjunction with the purpose of the present invention, present invention is specifically described.
The invention provides a kind of Ponatinib compound, this Ponatinib compound crystal, adopt D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: CuKa target, tube voltage 40KV, tube current 100mA. X-ray powder diffraction characteristic absorption peak (2 ��) and D value are as follows,
In the present invention, the mensuration of 2 �� values uses light source, and precision is �� 0.2 ��, therefore represents above-mentioned taken value and has allowed certain reasonably range of error, and its range of error is �� 0.2 ��.
Another object of the present invention, the preparation method disclosing Ponatinib compound crystal,
Bibliographical information, Ponatinib has multiple preparation method, and because its process for purification is different, fusing point has relatively big difference; Quantity and the total amount of impurity are bigger. The present inventor is by substantial amounts of experiment, explore the relationship between quality of refining solvent and the Ponatinib crystal obtained, by Ponatinib is dissolved in alcohol, acetic acid heated in water solution, it is subsequently adding and lowers the temperature stage by stage, the preparation method obtaining Ponatinib compound crystal of the present invention.Astoundingly, this Ponatinib compound crystal has the advantage that: purity is high, and maximum contaminant is less than 1 ��; Good stability.
This preparation method screens from substantial amounts of single or mixed solvent, it does not have method can be instructed and be drawn. The partial solvent tested has, water; Methanol, ethanol, propanol, isopropanol, butanol, isobutanol, propylene glycol etc.; The ketone reagent such as acetone; The ethers reagent such as ether and diisopropyl ether; Esters, such as ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, ethyl n-butyrate., methyl butyrate etc.; Acetonitrile; Dichloromethane, chloroform, hexane, heptane, toluene, oxolane, DMF etc. Using the single of them or mixed solvent, mixed solvent can be two kinds, and three kinds or four kinds of solvent mixing, in mixed solvent, the ratio of various solvents is different.
Specifically include the following step: Ponatinib adds in the mixed liquor of 6-8 times of (w/v) alcohol, acetic acid water=5-9:0.5-1:1-2, heating is to 50 DEG C-55 DEG C, filtered while hot, filtrate 30 DEG C-35 DEG C is incubated 3-4 hour, 10 DEG C-15 DEG C, then it is incubated 3-4 hour, crystallization, filtering, namely drying obtains above-mentioned Ponatinib compound crystal.
Ponatinib used, according to the method synthesis that existing document provides, the chemical constitution of the Ponatinib of synthesis is through proton nmr spectra, elementary analysis, it was demonstrated that chemical constitution is correct.
Another purpose of the present invention, it is provided that comprise the compositions of Ponatinib compound crystal and the Ponatinib of one or more pharmaceutically acceptable carriers composition.
The pharmaceutical composition preparation of the present invention is as follows: use standard and conventional technology; make the compounds of this invention acceptable solid or liquid-carrier on galenic pharmacy be combined, and so as at random acceptable adjuvant and excipient are combined and prepare into microgranule or microsphere on galenic pharmacy. Said composition is used for preparing oral formulations.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, amount or the concentration of compound used regulate in a wider scope, and the weight range of reactive compound is 1%��50%(weight of compositions).
Present invention also offers Ponatinib compound crystal and manufacture the application treated in leukemic medicine.
Stability test
The chemical stability of the Ponatinib compound crystal of the present invention has been studied by inventor, investigation condition is high temperature (60 DEG C �� 2 DEG C), strong illumination (4500Lx �� 500lx), high humidity (92.5%, RH) inspection target is outward appearance, content and have related substance (optical isomer).
Outward appearance, content is without change.
Result: from 0 10 days under high light, high temperature, super-humid conditions, outward appearance, optical isomer, content do not change, and illustrate that chemical stability is good, are suitable for manufacture and the long term storage of pharmaceutical preparation.
Detailed description of the invention:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field be better understood from the present invention. Embodiment is only indicative, is in no way to be construed as the scope that it is intended to limit the present invention in any manner.
Embodiment 1
Equipped with stirring, thermometer, condenser 3000ml reaction bulb in, adding Ethanol-Acetic Acid-water (5:0.5:1) mixed liquor of 200 grams of Ponatinib and 1200ml, start stirring, heat temperature raising heats to 50 DEG C-55 DEG C, filtered while hot, filtrate 30 DEG C-35 DEG C is incubated 3 hours, 10 DEG C-15 DEG C, then is incubated 3 hours, crystallization, filtering, namely drying obtains above-mentioned Ponatinib compound crystal, 172.6 grams.Purity 99.94%.
Embodiment 2
Equipped with stirring, thermometer, condenser 3000ml reaction bulb in, adding Ethanol-Acetic Acid-water (8:1:2) mixed liquor of 200 grams of Ponatinib and 1600ml, start stirring, heat temperature raising heats to 50 DEG C-55 DEG C, filtered while hot, filtrate 30 DEG C-35 DEG C is incubated 3 hours, 10 DEG C-15 DEG C, then is incubated 3 hours, crystallization, filtering, namely drying obtains above-mentioned Ponatinib compound crystal, 173 grams. Purity 99.99%.
Claims (6)
1. Ponatinib compound shown in formula I,
(I)
The crystal of described Ponatinib compound, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has the following 2 �� angles of diffraction and D value,
The error of the 2 �� angles of diffraction is �� 0.2.
2. the preparation method of Ponatinib compound crystal described in claim 1, by Ponatinib being dissolved in alcohol, acetic acid heated in water solution, then cooling obtains stage by stage.
3. the preparation method of Ponatinib compound crystal described in claim 2, it is characterized in that comprising the following steps: in the mixed liquor that Ponatinib adds 6-8 times of (w/v) alcohol, acetic acid water=5-9:0.5-1:1-2, heating is to 50 DEG C-55 DEG C, filtered while hot, filtrate 30 DEG C-35 DEG C is incubated 3-4 hour, 10 DEG C-15 DEG C, it is incubated 3-4 hour again, crystallization, filters, and namely drying obtains above-mentioned Ponatinib compound crystal.
4. the compositions containing Ponatinib compound crystal described in claim 1 with the Ponatinib of one or more pharmaceutically acceptable carriers composition.
5. the compositions described in claim 4, it is characterised in that said composition is used for preparing oral formulations.
6. Ponatinib compound described in claim 1 is manufacturing the application treated in leukemic medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410633842.0A CN105646494A (en) | 2014-11-12 | 2014-11-12 | Ponatinib compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410633842.0A CN105646494A (en) | 2014-11-12 | 2014-11-12 | Ponatinib compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105646494A true CN105646494A (en) | 2016-06-08 |
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ID=56483919
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410633842.0A Pending CN105646494A (en) | 2014-11-12 | 2014-11-12 | Ponatinib compound |
Country Status (1)
| Country | Link |
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| CN (1) | CN105646494A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20210094961A1 (en) * | 2018-06-22 | 2021-04-01 | Johnson Matthey Public Limited Company | Form of ponatinib |
-
2014
- 2014-11-12 CN CN201410633842.0A patent/CN105646494A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20210094961A1 (en) * | 2018-06-22 | 2021-04-01 | Johnson Matthey Public Limited Company | Form of ponatinib |
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| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160608 |
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| WD01 | Invention patent application deemed withdrawn after publication |