CN104341410A - New Dasatinib crystal form and preparation method thereof - Google Patents
New Dasatinib crystal form and preparation method thereof Download PDFInfo
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- CN104341410A CN104341410A CN201310347301.7A CN201310347301A CN104341410A CN 104341410 A CN104341410 A CN 104341410A CN 201310347301 A CN201310347301 A CN 201310347301A CN 104341410 A CN104341410 A CN 104341410A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention relates to a new Dasatinib crystal form and a preparation method thereof. The new Dasatinib crystal form is named as a crystal form V and has characteristic peaks at 6.02 degrees, 6.91 degrees, 8.55 degrees, 12.44 degrees, 13.30 degrees, 13.84 degrees, 16.83 degrees, 24.41 degrees and 24.96 degrees (2theta) in an X ray powder diffraction spectrum obtained by means of Cu-Ka radiation detection. The invention also provides a method for preparing the new Dasatinib crystal form V. The method is simple, convenient and good in reproducibility, and the obtained new Dasatinib crystal form V is high in purity, good in stability and applicable to industrial production.
Description
Technical field
The present invention relates to Dasatinib (N-(the chloro-6-aminomethyl phenyl of 2-)-2-[[6-[4-(2-hydroxyethyl)-1-piperazine
Base]-2-methyl-4-pyrimidyl] amino]-5-thiazole carboxamides) new crystal and preparation method thereof.
Technical background
Dasatinib chemistry N-(the chloro-6-aminomethyl phenyl of 2-)-2-by name [[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidyl] is amino]-5-thiazole carboxamides, structural formula is as shown in the formula shown in I:
Formula I
Dasatinib, commodity are called Shi Dasai (Sprycel), the many tyrosine kinase inhibitors of the one researched and developed by Bristol Myers Squibb, be mainly used in treatment Adult chronic's myelogenous leukemia (CML), the acute lymphoblastic leukemia adult patient to other therapy resistances or not tolerant Philadelphia Chromosome Positive can also be treated.
Patent US6596746 discloses the compounds process for production thereof of formula I, uses 80%EtOH-H
2the ethanol heating for dissolving of O, gained solution again dilute with water is cooled to room temperature, and gained solid is stable Dasatinib monohydrate, this patent is also with having opened another kind of preparation method, be elutriant with 10%MeOH-EtOAc, by purification by column chromatography, obtain the amorphous of Dasatinib.
Patent US20050215795 discloses patent CN100404032C and discloses Dasatinib monohydrate (Form H1-7), butanols solvated compounds (Form BU-2), di-alcohol solvated compounds (Form E2-1), anhydride N-6, anhydride T1H1-7 and preparation method thereof.Wherein Dasatinib monohydrate (Form H1-7), its X-ray diffraction figure is at [2theta(θ) number of degrees] about 4.6,11.2,13.8,15.2,17.9,18.0 (climaxs), 18.4,19.2,19.6,21.2,23.2,23.6,24.5,25.9, there is characteristic peak at 28.0 places, Dasatinib monohydrate good stability, are the crystal formations of listing.
Patent WO2009053854 discloses the polymorphic of 42 kinds of Dasatinibs, but major part is all solvated compounds, does not have actual using value.
In addition patent CN102086195 also discloses a kind of polymorphic of Dasatinib, substantially identical with a water thing crystal formation, does not have novelty.
In recent years, the polymorphism of drug molecule more and more causes the attention of scientist.Due to different polycrystalline kenels in stability, liberation degree, bioavailability is first-class very large difference; therefore be necessary to carry out polymorphic research as much as possible to drug molecule; to guarantee to obtain best crystalline form; thus obtain higher stability, liberation degree, bioavailability etc., thus produce higher biological activity.
Summary of the invention
The invention discloses a kind of good stability, favorable reproducibility, Dasatinib New crystal form I that purity is high and preparation method thereof.
Dasatinib new crystal V of the present invention, uses in the X-ray powder diffraction pattern of Cu-K α radiation detection, has following characteristics peak, its 2 θ angle value and relative intensity as shown in the table:
| 2θ | Relative intensity |
| 6.02 | 100.00 |
| 6.91 | 58.64 |
| 8.55 | 2.31 |
| 12.44 | 7.89 |
| 13.30 | 53.64 |
| 13.84 | 12.55 |
| 16.83 | 2.94 |
| 24.41 | 3.76 |
| 24.96 | 3.22 |
Dasatinib new crystal V of the present invention has X powder diffraction collection of illustrative plates as shown in Figure 1.
Dasatinib new crystal V of the present invention, is characterized in that this crystal formation has 3.74% thermal weight loss, and dsc is analyzed collection of illustrative plates and is presented at about 284 ~ 287 DEG C of place's meltings, occurs endotherm(ic)peak.
Dasatinib new crystal V of the present invention has thermogravimetric analysis collection of illustrative plates as shown in Figure 2 and dsc analyzes collection of illustrative plates.
The present invention provides a kind of method preparing Dasatinib new crystal V simultaneously, and the method comprises:
Dasatinib is dissolved in one or both large polar solvents under (a) room temperature, is configured to suspension;
B the suspension described in () to (a) adds a kind of strong acid solution makes its salify, and heated and stirred is to dissolving completely and filtering;
C add another kind of solvent in the filtrate of () to (b), then adjust PH to be neutral to a kind of strong base solution of mixed solution and dripping, continuing stirring has solid to separate out, and filtration, washing, drying obtain Dasatinib new crystal V.
Preparation method of the present invention, the solvent that step (a) uses comprises methyl alcohol, ethanol, Virahol, first alcohol and water, second alcohol and water, isopropyl alcohol and water, particular methanol.
Preparation method of the present invention, the strong acid solution that step (b) uses comprises hydrochloric acid, sulfuric acid, phosphoric acid, preferred hydrochloric acid.
Preparation method of the present invention, the amount of the strong acid that step (b) uses and the molar mass of bulk drug than being 1:1 ~ 2:1, preferred 1:1 ~ 1.2:1.
Preparation method of the present invention, the solvent that step (c) uses comprises acetonitrile, tetrahydrofuran (THF), dioxane, ethyl acetate, propyl acetate, isopropyl acetate, preferred acetonitrile.
Preparation method of the present invention, the quantity of solvent that step (c) uses and the quantity of solvent volume ratio that step (a) uses are 0.5:1 ~ 1:0.5, preferred 1:1 ~ 1:0.5.
Preparation method of the present invention, the highly basic that step (c) uses comprises sodium hydroxide, potassium hydroxide, triethylamine, preferred sodium hydroxide.
Preparation method of the present invention, the amount of the highly basic that step (c) uses and the molar mass of bulk drug than being 1:1 ~ 2:1, preferred 1:1 ~ 1.2:1.
The method preparing Dasatinib new crystal V provided by the present invention, simple to operate, favorable reproducibility, obtains that new crystal V purity is high, good stability, can meet large-scale industrial production.
Accompanying drawing explanation
X-ray powder diffraction (XRPD) collection of illustrative plates of the Dasatinib new crystal V that accompanying drawing 1 obtains according to the embodiment of the present invention 1.
The thermogravimetric analysis of the Dasatinib new crystal V that accompanying drawing 2 obtains according to the embodiment of the present invention 1 and dsc analyze collection of illustrative plates (TGA-DSC).
Embodiment
Following embodiment is to describe the present invention in detail, and unrestricted the present invention.
Analyzing and testing condition of the present invention is as follows:
1, X-ray powder diffraction data uses X ' Pert Pro MPD (Multi-Purpose Diffractometer) to measure, light pipe type: Empyrean XRD tube Cu LFF HR; Electric current and voltage: 45kV, 40mA; The vertical goniometer of goniometer: PW3050/60, radius 240mm; Slit: DS=2 °, SS=1/2 °, mask=15mm, RS=5.0mm; The super detector of detector: X ' Celerator; Scan pattern: continuous sweep; Sweep limit: 3 ° of-40 ° of 2 θ; Often walk gate time: 20s; Scanning total time: 6min.
2, DSC-TGA is measured by the SDT Q600 of TA company of the U.S., and test condition is 120ml/min N2, heat-up rate 10 DEG C/min.
Embodiment 1
Under room temperature, take 200mg Dasatinib free alkali, join in 4ml methanol solution, stirring lower Dasatinib is suspended in solution system, the methanol hydrochloride solution of 1ml0.5M is dripped to suspension, continue to be stirred to Dasatinib to dissolve completely, filter liquor is for subsequent use, to the acetonitrile of filtrate added drop-wise 6ml, after dripping off, solution is still clarified, the methyl alcohol 1ml containing 20mg sodium hydroxide is dripped again in solution, have solid to separate out after stirring 5min, continue to stir 10h, filtration, drying obtain Dasatinib new crystal V.
Embodiment 2
Under room temperature, take 200mg Dasatinib free alkali, join in 4ml ethanolic soln, stirring lower Dasatinib is suspended in solution system, the ethanol solution hydrochloride of 1ml0.5M is dripped to suspension, continue to be stirred to Dasatinib to dissolve completely, filter liquor is for subsequent use, to the acetonitrile of filtrate added drop-wise 6ml, after dripping off, solution is still clarified, the ethanol 1ml containing 20mg sodium hydroxide is dripped again in solution, have solid to separate out after stirring 5min, continue to stir 10h, filtration, drying obtain Dasatinib new crystal V.
Embodiment 3
Under room temperature, take 200mg Dasatinib free alkali, join 5ml Virahol, stirring lower Dasatinib is suspended in solution system, the hydrochloric acid aqueous isopropanol of 1ml0.5M is dripped to suspension, continue to be stirred to Dasatinib to dissolve completely, filter liquor is for subsequent use, to the ethyl acetate of filtrate added drop-wise 6ml, after dripping off, solution is still clarified, the Virahol 1ml containing 20mg sodium hydroxide is dripped again in solution, have solid to separate out after stirring 5min, continue to stir 10h, filtration, drying obtain Dasatinib new crystal V.
Embodiment 4
Under room temperature, take 200mg Dasatinib free alkali, join in the mixing solutions of 4ml ethanol and 1ml water, stirring lower Dasatinib is suspended in solution system, the ethanol solution hydrochloride of 1ml0.5M is dripped to suspension, continue to be stirred to Dasatinib to dissolve completely, filter liquor is for subsequent use, to the acetonitrile of filtrate added drop-wise 6ml, after dripping off, solution is still clarified, the ethanol 1ml containing 30mg potassium hydroxide is dripped again in solution, have solid to separate out after stirring 5min, continue to stir 10h, filtration, drying obtain Dasatinib new crystal V.
Claims (10)
1. the crystalline form V of a Dasatinib compound (formula I), it is characterized in that the X-ray powder diffraction pattern of described crystalline form V comprises the characteristic peak shown in following 2 θ angles: 6.02 °, 6.91 °, 8.55 °, 12.44 °, 13.30 °, 13.84 °, 16.83 °, 24.41 °, 24.96 °.
2. Dasatinib new crystal V as claimed in claim 1, is characterized in that described crystalline form V has 3.74% thermal weight loss, and dsc is analyzed collection of illustrative plates and is presented at about 284 ~ 287 DEG C of place's meltings, occurs endotherm(ic)peak.
3. prepare a method for formula described in claim 1 (I) compound new crystal V, comprising: following steps
Under (a) room temperature by Dasatinib and polar solvent miscible in, be configured to suspension;
B add strong acid solution in the suspension described in () to (a) and make its salify, heated and stirred is to dissolving completely and filtering;
C add little polar solvent in the filtrate of () to (b), then be neutral to its dropping strong base solution to pH, continuing stirring has solid to separate out, and filtration drying obtains Dasatinib new crystal V.
4. method as claimed in claim 3, the polar solvent described in step (a) is selected from: methyl alcohol, ethanol, Virahol, first alcohol and water, second alcohol and water, isopropyl alcohol and water.
5. method as claimed in claim 3, the strong acid solution described in step (b) comprises hydrochloric acid, sulfuric acid, phosphoric acid.
6. method as claimed in claim 3, the amount of the strong acid described in step (b) and the molar mass of Dasatinib are than being 1:1 ~ 2:1, preferred 1:1 ~ 1.2:1.
7. method as claimed in claim 4, the solvent described in step (c) is selected from acetonitrile, tetrahydrofuran (THF), dioxane, ethyl acetate, propyl acetate, isopropyl acetate.
8. method as claimed in claim 4, the quantity of solvent that step (c) uses and the quantity of solvent volume ratio that step (a) uses are 0.5:1 ~ 1:0.5, preferred 1:1 ~ 1:0.5.
9. method as claimed in claim 4, the highly basic described in step (c) is selected from sodium hydroxide, potassium hydroxide.
10. method as claimed in claim 4, the amount of the highly basic that step (c) uses and the molar mass of Dasatinib than being 1:1 ~ 2:1, preferred 1:1 ~ 1.2:1.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310347301.7A CN104341410A (en) | 2013-08-09 | 2013-08-09 | New Dasatinib crystal form and preparation method thereof |
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| CN201310347301.7A CN104341410A (en) | 2013-08-09 | 2013-08-09 | New Dasatinib crystal form and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107033137A (en) * | 2016-02-03 | 2017-08-11 | 正大天晴药业集团股份有限公司 | A kind of crystal formation of Dasatinib and preparation method thereof |
| WO2019209908A1 (en) | 2018-04-25 | 2019-10-31 | Johnson Matthey Public Limited Company | Crystalline forms of dasatinib |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005077945A2 (en) * | 2004-02-06 | 2005-08-25 | Bristol-Myers Squibb Company | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
| WO2009053854A2 (en) * | 2007-10-23 | 2009-04-30 | Teva Pharmaceutical Industries Ltd. | Polymorphs of dasatinib and process for preparation thereof |
| CN101891738A (en) * | 2010-02-08 | 2010-11-24 | 南京卡文迪许生物工程技术有限公司 | Dasatinib polymorph and preparation method and medical composite thereof |
| WO2010139980A1 (en) * | 2009-06-03 | 2010-12-09 | Generics [Uk] Limited | Process for preparing crystalline dasatinib monohydrate |
| CN102010407A (en) * | 2010-11-16 | 2011-04-13 | 上海科胜药物研发有限公司 | New method for synthesizing dasatinib |
| CN102408423A (en) * | 2011-11-29 | 2012-04-11 | 上海希迪制药有限公司 | Method for preparing large particle size dasatinib |
-
2013
- 2013-08-09 CN CN201310347301.7A patent/CN104341410A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005077945A2 (en) * | 2004-02-06 | 2005-08-25 | Bristol-Myers Squibb Company | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
| WO2009053854A2 (en) * | 2007-10-23 | 2009-04-30 | Teva Pharmaceutical Industries Ltd. | Polymorphs of dasatinib and process for preparation thereof |
| WO2010139980A1 (en) * | 2009-06-03 | 2010-12-09 | Generics [Uk] Limited | Process for preparing crystalline dasatinib monohydrate |
| CN101891738A (en) * | 2010-02-08 | 2010-11-24 | 南京卡文迪许生物工程技术有限公司 | Dasatinib polymorph and preparation method and medical composite thereof |
| CN102010407A (en) * | 2010-11-16 | 2011-04-13 | 上海科胜药物研发有限公司 | New method for synthesizing dasatinib |
| CN102408423A (en) * | 2011-11-29 | 2012-04-11 | 上海希迪制药有限公司 | Method for preparing large particle size dasatinib |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107033137A (en) * | 2016-02-03 | 2017-08-11 | 正大天晴药业集团股份有限公司 | A kind of crystal formation of Dasatinib and preparation method thereof |
| WO2019209908A1 (en) | 2018-04-25 | 2019-10-31 | Johnson Matthey Public Limited Company | Crystalline forms of dasatinib |
| US11440908B2 (en) | 2018-04-25 | 2022-09-13 | Johnson Matthey Public Limited Company | Crystalline forms of dasatinib |
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Inventor after: Si Yongxing Inventor after: Fang Gan Inventor after: Xu Wei Inventor after: Gu Hong Inventor before: Si Yongxing Inventor before: Fang Gan Inventor before: Xu Wei Inventor before: Wu Wenju Inventor before: Zhang Xini |
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Application publication date: 20150211 |