CN102030745A - Dasatinib solvate and preparation method thereof - Google Patents
Dasatinib solvate and preparation method thereof Download PDFInfo
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- CN102030745A CN102030745A CN 201010561241 CN201010561241A CN102030745A CN 102030745 A CN102030745 A CN 102030745A CN 201010561241 CN201010561241 CN 201010561241 CN 201010561241 A CN201010561241 A CN 201010561241A CN 102030745 A CN102030745 A CN 102030745A
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- isopropyl ether
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Abstract
The invention discloses a crystalline solvate YE of Dasatinib and isopropyl ether, belonging to the field of chemical synthesis. The molar ratio of crystalline to isopropyl ether in the solvate is 1:0.5. The solvate shows an XRPD (X Ray Powder Diffraction) pattern having characteristic peaks at 2 theta angles of 5.9, 11.86, 14.94, 15.72, 16.54, 17.44, 17.84, 18.20, 18.9, 21.42, 24, 26.12 and the like. The invention also provides a preparation method of Dasatinib crystalline solvate, which comprises the following steps of: mixing Dasatinib with methanol, dissolving at 60 to 80 DEG C, adding isopropyl ether, cooling to room temperature, and filtering to obtain the isopropyl ether solvate.
Description
Technical field
The present invention relates to the synthetic field of medicine, more specifically for relating to a kind of Dasatinib solvate and preparation method thereof.
Background technology
Dasatinib, chemical name is N-(2-chloro-6-aminomethyl phenyl)-2-{[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidyl] amino }-the 5-thiazole carboxamides, its structural formula as shown in Equation 1, it is the antitumour drug of U.S. Bristol-Myers Squibb company exploitation, go on the market in the U.S. in February, 2006, commodity are called Sprycel, clinical each stage chronic myeloid leukemia of adult that is used for previously treatment failure or does not tolerate also can be used for treating to other therapies resistance or the positive acute lymphoblastic leukemia adult patients of Philadelphia chromosome that do not tolerate.
According to the pertinent literature report, Dasatinib has many crystallized forms.CN200580011916 has announced H1-7, T1H1-7, N-6, BU-2 and E2-15 kind crystallized form, WO2009053854A2 has then announced more than 60 kind of crystallized forms such as AA, AB, AC, in addition, WO2010067374A2 has announced Form I crystallized form, and WO2010062715A2 has then announced BN, BR and 3 kinds of crystallized forms of BS.Wherein H1-7 is a monohydrate, and T1H1-7, Form 1 are the non-solvent compound with N-6, and remaining is solvate.
Summary of the invention
The solvate that the purpose of this invention is to provide a kind of Dasatinib and isopropyl ether, promptly be appointed as N-(2-chloro-6-aminomethyl phenyl)-2-{[6-[4-(2-the hydroxyethyl)-1-piperazinyl of DasatinibYE crystal formation in embodiment]-2-methyl-4-pyrimidyl] amino }-solvate of 5-thiazole carboxamides and isopropyl ether, wherein the mol ratio of Dasatinib and isopropyl ether is 1: 0.5.
Solvate of the present invention uses Cu-K α radiation,
The X-ray powder diffraction of representing with 2 θ angles as shown in Figure 2, spectral signature is as follows:
| 2θ | I/I 0％ | 2θ | I/I 0％ |
| 5.900 | 94 | 24.000 | 40 |
| 11.860 | 100 | 24.520 | 42 |
| 13.500 | 11 | 24.860 | 15 |
| 14.940 | 80 | 25.680 | 11 |
| 15.720 | 13 | 26.120 | 21 |
| 16.540 | 21 | 27.300 | 14 |
| 17.440 | 11 | 27.540 | 14 |
| 17.840 | 16 | 28.100 | 18 |
| 18.200 | 19 | 30.200 | 8 |
| 18.900 | 15 | 31.920 | 7 |
| 21.120 | 24 | 33.600 | 7 |
| 21.420 | 44 | 36.680 | 7 |
| 22.640 | 27 | 38.460 | 7 |
It is 5.9,11.86, and 14.94,15.72,16.54,17.44,17.84,18.20,18.9,21.42,24,26.12 2 θ angles such as grade show characteristic peak.
Solvate to described Dasatinib and isopropyl ether carries out magnetic resonance detection, and the result is:
1H?NMR(d
6-DMSO，500MHz)：11.42(s，1H)，9.84(s，1H)，8.21(s，1H)，7.40，7.38(d，J＝10Hz，1H)，7.23-7.29(m，2H)，6.05(s，1H)，4.40(t，J＝5Hz，1H)，3.58(m，1H)，3.51(m，6H)，3.29(s，4H)，2.49(m，3H)，2.43(t，J＝6.3Hz，2H)，2.40(s，3H)，2.24(S，3H)，1.03(d，J＝6Hz，5H)。
From above result as can be known, Dasatinib in the Dasatinib isopropyl ether solvate: the ratio of isopropyl ether is 1: 0.5.
The present invention further discloses N-(2-chloro-6-aminomethyl phenyl)-2-{[6-[4-(2-the hydroxyethyl)-1-piperazinyl that is designated as YE]-2-methyl-4-pyrimidyl] amino }-preparation method of 5-thiazole carboxamides crystal type solvate.
The concrete scheme of this method is as follows:
With Dasatinib and methanol mixed, after 60 ℃～80 ℃ dissolvings, add isopropyl ether, be cooled to room temperature, filter, obtain Dasatinib and isopropyl ether crystal type solvate.
Further, solvent temperature is preferably 75 ℃.
Further, the quality ratio of used methyl alcohol and Dasatinib is preferably 20～30.
Further, the quality ratio of used isopropyl ether and methyl alcohol is preferably 1～2.
Further, described preparation method also comprises 20～40 ℃ of drying step behind filtration step
Further, drying is to carry out under vacuum environment.
Disclose among the CN200580011916.6 Dasatinib monohydrate thermal dehydration has been produced non-solvent compound T1H1-7, therefore mention the crystal type solvate YE of described Dasatinib and isopropyl ether for the present invention, the solvent isopropyl ether boiling point that it comprises is 68.5 degrees centigrade, less than 100 degrees centigrade of the boiling points of water, therefore easier desolventizing prepares the non-solvent compound of Dasatinib.
The present invention successfully prepares Dasatinib crystal type solvate, and used solvent isopropyl ether boiling point low (68.5 ℃) is easy to carry out the desolvation of solvate, has significant values for producing Dasatinib non-solvent compound; In addition, preparation method's cost of the present invention is low, and process is controlled, and favorable reproducibility and stable is fit to suitability for industrialized production, has important economic value.
Description of drawings:
What Fig. 1 represented is the HNMR collection of illustrative plates of Dasatinib YE crystal formation of the present invention;
What Fig. 2 represented is the XRPD collection of illustrative plates of Dasatinib YE crystal formation of the present invention.
Embodiment:
The invention discloses a kind of Dasatinib crystal formation and preparation method thereof, those skilled in the art can use for reference this paper content, suitably improve processing parameter and realize.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are regarded as being included in the present invention.Method of the present invention and application are described by preferred embodiment, the related personnel obviously can change or suitably change and combination methods and applications as herein described in not breaking away from content of the present invention, spirit and scope, realizes and use the technology of the present invention.
Below in conjunction with embodiment, further set forth the present invention.
The preparation of embodiment 1:Dasatinib YE crystal formation
Take by weighing Dasatinib (487mg, 1mmol), join then in the reaction flask, add 10mL methyl alcohol, controlled temperature is at 75 ℃, magnetic agitation, molten clear back adds the 10mL isopropyl ether, slowly reduces to room temperature, filter, (3 * 2mL) washings obtain Dasatinib YE crystal formation 440mg, yield 90.1% with isopropyl ether.
The preparation of embodiment 2:Dasatinib YE crystal formation
(487mg 1mmol), joins in the reaction flask then to take by weighing Dasatinib, add 10mL methyl alcohol, controlled temperature is at 80 ℃, magnetic agitation, and molten clear back adds the 10mL isopropyl ether, slowly reduce to room temperature, filter, with isopropyl ether (3 * 2mL) washings, 40 ℃ of vacuum-dryings, obtain Dasatinib YE crystal formation 440mg, yield 90.5%.
The preparation of embodiment 3:Dasatinib YE crystal formation
(487mg 1mmol), joins in the reaction flask then to take by weighing Dasatinib, add 10mL methyl alcohol, controlled temperature is at 60 ℃, magnetic agitation, and molten clear back adds the 10mL isopropyl ether, slowly reduce to room temperature, filter, with isopropyl ether (3 * 2mL) washings, 20 ℃ of vacuum-dryings, obtain Dasatinib YE crystal formation 440mg, yield 90.3%.
The magnetic resonance detection of embodiment 4:Dasatinib YE crystal formation
The Dasatinib YE crystal formation that embodiment 1-3 is obtained carries out magnetic resonance detection, sees Fig. 1, and the result is as follows:
1H?MR(d
6-DMSO，500MHz)：11.42(s，1H)，9.84(s，1H)，8.21(s，1H)，7.40，7.38(d，J＝10Hz，1H)，7.23-7.29(m，2H)，6.05(s，1H)，4.40(t，J＝5Hz，1H)，3.58(m，1H)，3.51(m，6H)，3.29(s，4H)，2.49(m，3H)，2.43(t，J＝6.3Hz，2H)，2.40(s，3H)，2.24(S，3H)，1.03(d，J＝6Hz，5H)。
Dasatinib in the prepared Dasatinib YE crystal formation: the ratio of isopropyl ether is 1: 0.5.
The X-ray powder diffraction of embodiment 5:Dasatinib YE crystal formation is analyzed
The Dasatinib YE crystal formation that embodiment 1-3 is obtained carries out the analysis of X-ray powder diffraction, uses Cu-K α radiation,
The X-ray powder diffraction of representing with 2 θ angles as shown in Figure 2, spectral signature is as follows:
| 2θ | I/I 0％ | 2θ | I/I 0％ |
| 5.900 | 94 | 24.000 | 40 |
| 11.860 | 100 | 24.520 | 42 |
| 13.500 | 11 | 24.860 | 15 |
| 14.940 | 80 | 25.680 | 11 |
| 15.720 | 13 | 26.120 | 21 |
| 16.540 | 21 | 27.300 | 14 |
| 17.440 | 11 | 27.540 | 14 |
| 17.840 | 16 | 28.100 | 18 |
| 18.200 | 19 | 30.200 | 8 |
| 18.900 | 15 | 31.920 | 7 |
| 21.120 | 24 | 33.600 | 7 |
| 21.420 | 44 | 36.680 | 7 |
| 22.640 | 27 | 38.460 | 7 |
The above only is a preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (8)
1. the solvate of Dasatinib and isopropyl ether, it is characterized in that: wherein the mol ratio of Dasatinib and isopropyl ether is 1: 0.5.
2. the described solvate of claim 1 is characterized in that, uses Cu-K α radiation,
The X-ray powder diffraction spectral signature of representing with 2 θ angles is as follows:
3. according to the preparation method of claim 1 or 2 described solvates, it is characterized in that, may further comprise the steps: Dasatinib and methanol mixed, after 60 ℃～80 ℃ dissolvings, add isopropyl ether, be cooled to room temperature, filter, obtain the solvate of Dasatinib and isopropyl ether.
4. preparation method according to claim 3 is characterized in that, the quality ratio of methyl alcohol and Dasatinib is 20～30: 1.
5. preparation method according to claim 3 is characterized in that, the quality ratio of isopropyl ether and Dasatinib is
6. preparation method according to claim 3 is characterized in that, the quality ratio of isopropyl ether and methyl alcohol is 1～2.
7. preparation method according to claim 3 is characterized in that, also comprises 20～40 ℃ of drying step after the filtration.
8. preparation method according to claim 7 is characterized in that described drying is carried out under vacuum environment.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105030778A (en) * | 2015-09-22 | 2015-11-11 | 青岛华之草医药科技有限公司 | Dasatinib composition granule serving as medicine for treating leukemia |
| WO2016001025A1 (en) | 2014-06-30 | 2016-01-07 | Basf Se | Multicomponent crystals of dasatinib with menthol or vanillin |
| US9340536B2 (en) | 2012-06-15 | 2016-05-17 | Basf Se | Multicomponent crystals comprising dasatinib and selected co-crystal formers |
| US9556164B2 (en) | 2013-07-25 | 2017-01-31 | Basf Se | Salts of Dasatinib in crystalline form |
| US9884857B2 (en) | 2013-07-25 | 2018-02-06 | Basf Se | Salts of dasatinib in amorphous form |
| US11059813B2 (en) | 2017-07-07 | 2021-07-13 | Biocon Limited | Polymorphic forms of Dasatinib |
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| WO2009053854A2 (en) * | 2007-10-23 | 2009-04-30 | Teva Pharmaceutical Industries Ltd. | Polymorphs of dasatinib and process for preparation thereof |
| WO2010062715A2 (en) * | 2008-11-03 | 2010-06-03 | Teva Pharmaceutical Industries Ltd. | Polymorphs of dasatinib and process for preparation thereof |
| WO2010067374A2 (en) * | 2008-12-08 | 2010-06-17 | Hetero Research Foundation | Polymorphs of dasatinib |
| 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 |
| CN102040596A (en) * | 2009-10-10 | 2011-05-04 | 上海希迪制药有限公司 | Dasatinib polymorph and preparation method thereof |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1980909A (en) * | 2004-02-06 | 2007-06-13 | 布里斯托尔-迈尔斯·斯奎布公司 | 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 |
| WO2010062715A2 (en) * | 2008-11-03 | 2010-06-03 | Teva Pharmaceutical Industries Ltd. | Polymorphs of dasatinib and process for preparation thereof |
| WO2010067374A2 (en) * | 2008-12-08 | 2010-06-17 | Hetero Research Foundation | Polymorphs of dasatinib |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9340536B2 (en) | 2012-06-15 | 2016-05-17 | Basf Se | Multicomponent crystals comprising dasatinib and selected co-crystal formers |
| US9556164B2 (en) | 2013-07-25 | 2017-01-31 | Basf Se | Salts of Dasatinib in crystalline form |
| US9884857B2 (en) | 2013-07-25 | 2018-02-06 | Basf Se | Salts of dasatinib in amorphous form |
| WO2016001025A1 (en) | 2014-06-30 | 2016-01-07 | Basf Se | Multicomponent crystals of dasatinib with menthol or vanillin |
| CN105030778A (en) * | 2015-09-22 | 2015-11-11 | 青岛华之草医药科技有限公司 | Dasatinib composition granule serving as medicine for treating leukemia |
| US11059813B2 (en) | 2017-07-07 | 2021-07-13 | Biocon Limited | Polymorphic forms of Dasatinib |
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| CN102030745B (en) | 2012-05-09 |
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