CN102250063B - Crystal form of imatinib mesylate and preparation method thereof - Google Patents
Crystal form of imatinib mesylate and preparation method thereof Download PDFInfo
- Publication number
- CN102250063B CN102250063B CN201010176726.2A CN201010176726A CN102250063B CN 102250063 B CN102250063 B CN 102250063B CN 201010176726 A CN201010176726 A CN 201010176726A CN 102250063 B CN102250063 B CN 102250063B
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- CN
- China
- Prior art keywords
- spectral line
- peak
- ray diffraction
- crystal form
- imatinib mesylate
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- 239000013078 crystal Substances 0.000 title claims abstract description 26
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 title abstract description 12
- 229960003685 imatinib mesylate Drugs 0.000 title abstract description 10
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 230000003595 spectral effect Effects 0.000 claims description 21
- 238000002441 X-ray diffraction Methods 0.000 claims description 19
- 230000015572 biosynthetic process Effects 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 229960002411 imatinib Drugs 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 2
- -1 compound imatinib mesylate Chemical class 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 229940080856 gleevec Drugs 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- ABOLPUDOABZSNW-UHFFFAOYSA-N N1CCNCC1.CC1=C(C=C(C(=O)O)C=C1)C(=O)O Chemical compound N1CCNCC1.CC1=C(C=C(C(=O)O)C=C1)C(=O)O ABOLPUDOABZSNW-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention relates to a crystal form of imatinib mesylate and a preparation method thereof, in particular to a crystal form of 4-[(4-methyl-1-piperazine) methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyridine] amino] phenyl]-aniline mesylate shown as a formula (I) and a preparation method thereof.
Description
Technical field
The present invention relates to imatinib mesylate 4-[(4-methyl isophthalic acid-piperazine) methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl] crystal formation and preparation method thereof of-aniline mesylate.
Background technology
Imatinib mesylate (Imatinib Mesilate, Gleevec, Glivec) is studied by Novartis company,, in the U.S., European Union and Japan and other countries listing, is used for the treatment of chronic myelogenous leukemia.
Imatinib mesylate has multiple crystal formation.Novartis A.-G. discloses Gleevec, the crystallization of β-variant, acicular α-crystal formation at 1998-07-16 for the first time at US6894051; WO2004106326 (Hetero Drugs Limited, India) has reported H1-crystal formation; WO2005077933 (Natco Pharma Limited, India) has reported α 2-crystal formation; WO2006048890 (Sun Pharmaceutical Industries Limited) has reported non-acicular α-crystal formation; WO2006054314 (NatcoPharma Limited, India) has reported I crystal formation and II crystal formation; WO2007023182 (novartis AG) has reported δ-crystal formation and ε-crystal formation; WO2007059963 (novartis AG) has reported crystal formation F, G, H, I, K; WO2007136510 (Teva) has reported that form IV is to crystal form X VI.
Summary of the invention
Describe in more detail the present invention by accompanying drawing and other auxiliary method below.
The object of the present invention is to provide structure is the new crystal of the imatinib of formula 1.
Wherein,
Formula (1) compound is crystal form A:
It is that (a) 18.3 °, (b) 19.8 °, (c) 21.6 °, (d) 22.3 ° locate to show X-ray diffraction peak at diffraction angle 2 θ;
It locates to show X-ray diffraction peak at diffraction angle 2 θ for (a) 18.3 °, and the spectral line relative intensity that described peak has is 100; In diffraction angle, 2 θ locate to show X-ray diffraction peak for (b) 19.8 °, and the spectral line relative intensity that described peak has is 60; In diffraction angle, 2 θ locate to show X-ray diffraction peak for (c) 21.6 °, and the spectral line relative intensity that described peak has is 76; In diffraction angle, 2 θ locate to show X-ray diffraction peak for (d) 22.3 °, and the spectral line relative intensity that described peak has is 63;
It shows that at diffraction angle 2 θ places having spectral line relative intensity is 50 or above X-ray diffraction spectral line (spectral line intensity provides in bracket): 18.3 ° (100), 19.8 ° (60), 21.6 ° (76), 22.3 ° (63);
It shows that at diffraction angle 2 θ places having spectral line relative intensity is 30 or above X-ray diffraction spectral line (spectral line intensity provides in bracket): 6.5 ° (31), 17.7 ° (34), 18.3 ° (100), 19.8 ° (60), 21.6 ° (76), 22.3 ° (63), 23.1 ° (35), 23.4 ° (49), 25.3 ° (33);
With related substance, the form more than 99.5% exists for it;
It has the x-ray diffraction pattern shown in accompanying drawing 1, and wherein the Relative Peak intensity at each peak does not depart from shown in accompanying drawing 1 in collection of illustrative plates Relative Peak intensity more than 20%;
It contains a part crystallization ethanol.
Or formula (1) compound is crystal form B:
It is that (a) 6.0 °, (b) 18.1 °, (c) 24.2 ° locate to show X-ray diffraction peak at diffraction angle 2 θ;
It locates to show X-ray diffraction peak at diffraction angle 2 θ for (a) 6.0 °, and the spectral line relative intensity that described peak has is 99; In diffraction angle, 2 θ locate to show X-ray diffraction peak for (b) 18.1 °, and the spectral line relative intensity that described peak has is 77; In diffraction angle, 2 θ locate to show X-ray diffraction peak for (c) 24.2 °, and the spectral line relative intensity that described peak has is 87;
It shows that at diffraction angle 2 θ places having spectral line relative intensity is 50 or above X-ray diffraction spectral line (relative intensity provides in bracket): 6.0 ° (99), 18.1 ° (77), 24.2 ° (87);
It shows that at diffraction angle 2 θ places having spectral line relative intensity is 20 or above X-ray diffraction spectral line (relative intensity provides in bracket): 6.0 ° (99), 15.9 ° (21), 17.1 ° (37), 18.1 ° (77), 18.7 ° (31), 19.1 ° (24), 19.8 ° (45), 20.9 ° (35), 23.8 ° (29), 24.2 ° (87), 25.2 ° (30);
With related substance, the form more than 99.5% exists for it;
It has the x-ray diffraction pattern shown in accompanying drawing 2, wherein not Relative Peak intensity more than 20% in collection of illustrative plates shown in slip chart 2 of the Relative Peak intensity at each peak.
Brief description of the drawings
Fig. 1: the x-ray diffraction pattern of the crystal form A of display type 1 compound imatinib mesylate, in the drawings, transverse axis is depicted as diffraction angle 2 θ, and the longitudinal axis is depicted as spectral line relative intensity.In x-ray diffraction pattern, diffraction angle 2 θ are 18.3 ° and locate, have 100% spectral line relative intensity.A crystal formation is characterised in that at diffraction angle 2 θ be 6.5 ° (31), 17.7 ° (34), 18.3 ° (100), 19.8 ° (60), 21.6 ° (76), 22.3 ° (63), 23.1 ° (35), 23.4 ° (49), 25.3 ° of diffraction that (33) place has.
Fig. 2: the x-ray diffraction pattern of the crystal form B of display type 1 compound imatinib mesylate is 6.0 ° (99), 15.9 ° (21), 17.1 ° (37), 18.1 ° (77), 18.7 ° (31), 19.1 ° (24), 19.8 ° (45), 20.9 ° (35), 23.8 ° (29), 24.2 ° (87), 25.2 ° of diffraction that (30) have at diffraction angle 2 θ.
Embodiment
Embodiment 1: use second alcohol and water to prepare the crystal form A of imatinib mesylate
By in compound 1 (460g, 0.78mol) suspension ethanol (5L), add purified water (70ml), reflux makes to dissolve, and then naturally cooling stirs 12h crystallization.Filter, ethanol filter cake for (300ml) washs, and at 65 DEG C of gained solids, drying under reduced pressure is to constant weight.Obtain target product (414g, off-white color solid), productive rate 90%.
Embodiment 2: use THF to prepare the crystal form B of imatinib mesylate
Imatinib alkali 10.0g is suspended in THF 200ml, controls temperature at 10-15 DEG C, drip methylsulfonic acid 1.85g, in 10 minutes, finish, then insulation continues to stir 30min.Solid filtering, filter cake washs 20ml × 2 with THF, and 60 DEG C of vacuum-drying 48h of solid, obtain yellow solid 11.4g.
Claims (2)
1. the crystal formation of formula (1) compound,
It is characterized by, be 6.5 °, 17.7 °, 18.3 °, 19.8 °, 21.6 °, 22.3 °, 23.1 °, 23.4 °, 25.3 ° at diffraction angle 2 θ and locate to show that having spectral line relative intensity is 30 or above X-ray diffraction spectral line.
2. crystal formation as claimed in claim 1, with related substance, the form more than 99.5% exists for it.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010176726.2A CN102250063B (en) | 2010-05-19 | 2010-05-19 | Crystal form of imatinib mesylate and preparation method thereof |
| CN201410026320.4A CN103864752B (en) | 2010-05-19 | 2010-05-19 | Crystal formation of imatinib mesylate and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010176726.2A CN102250063B (en) | 2010-05-19 | 2010-05-19 | Crystal form of imatinib mesylate and preparation method thereof |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410026320.4A Division CN103864752B (en) | 2010-05-19 | 2010-05-19 | Crystal formation of imatinib mesylate and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102250063A CN102250063A (en) | 2011-11-23 |
| CN102250063B true CN102250063B (en) | 2014-10-22 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201010176726.2A Expired - Fee Related CN102250063B (en) | 2010-05-19 | 2010-05-19 | Crystal form of imatinib mesylate and preparation method thereof |
| CN201410026320.4A Expired - Fee Related CN103864752B (en) | 2010-05-19 | 2010-05-19 | Crystal formation of imatinib mesylate and preparation method thereof |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201410026320.4A Expired - Fee Related CN103864752B (en) | 2010-05-19 | 2010-05-19 | Crystal formation of imatinib mesylate and preparation method thereof |
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| CN (2) | CN102250063B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104513227A (en) * | 2013-09-29 | 2015-04-15 | 山东新时代药业有限公司 | Production method for imatinib mesylate alpha crystal form |
| CN105566291B (en) * | 2016-02-02 | 2018-06-01 | 连云港恒运药业有限公司 | The method for preparing Crystal form of imatinib mesylate |
| CN114957206B (en) * | 2022-04-11 | 2024-02-27 | 中国药科大学 | Imatinib eutectic crystal and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101641345A (en) * | 2006-10-26 | 2010-02-03 | 西科尔公司 | Imatinib base, and imatinib mesylate and processes for preparation thereof |
| CN101735197A (en) * | 2009-12-18 | 2010-06-16 | 天津市炜杰科技有限公司 | Method for synthesizing Imatinib |
| CN102040587A (en) * | 2009-10-26 | 2011-05-04 | 韩南银 | Preparation method of imatinib mesylate |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2398565A (en) * | 2003-02-18 | 2004-08-25 | Cipla Ltd | Imatinib preparation and salts |
| AU2003232650A1 (en) * | 2003-05-06 | 2004-11-26 | Il Yang Pharm Co., Ltd. | N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof |
| WO2006054314A1 (en) * | 2004-11-17 | 2006-05-26 | Natco Pharma Limited | Polymorphic forms of imatinib mesylate |
| CN100451015C (en) * | 2007-02-14 | 2009-01-14 | 杭州盛美医药科技开发有限公司 | Preparing method of imatinib |
| US7550591B2 (en) * | 2007-05-02 | 2009-06-23 | Chemagis Ltd. | Imatinib production process |
-
2010
- 2010-05-19 CN CN201010176726.2A patent/CN102250063B/en not_active Expired - Fee Related
- 2010-05-19 CN CN201410026320.4A patent/CN103864752B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101641345A (en) * | 2006-10-26 | 2010-02-03 | 西科尔公司 | Imatinib base, and imatinib mesylate and processes for preparation thereof |
| CN102040587A (en) * | 2009-10-26 | 2011-05-04 | 韩南银 | Preparation method of imatinib mesylate |
| CN101735197A (en) * | 2009-12-18 | 2010-06-16 | 天津市炜杰科技有限公司 | Method for synthesizing Imatinib |
Non-Patent Citations (4)
| Title |
|---|
| 李铭东等.甲磺酸伊马替尼的合成.《中国药学杂志》.2008,第43卷(第3期),第228-229页. |
| 甲磺酸伊马替尼的合成;李铭东等;《中国药学杂志》;20080229;第43卷(第3期);第228-229页 * |
| 甲磺酸伊马替尼的合成;陈敖等;《精细与专用化学品》;20070421;第15卷(第8期);第23-25页 * |
| 陈敖等.甲磺酸伊马替尼的合成.《精细与专用化学品》.2007,第15卷(第8期),第23-25页. |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103864752B (en) | 2015-11-25 |
| CN102250063A (en) | 2011-11-23 |
| CN103864752A (en) | 2014-06-18 |
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Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee before: Jiangsu best Pharmaceutical Co.,Ltd. Patentee before: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee after: Jiangsu best Pharmaceutical Co.,Ltd. Patentee after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Patentee before: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. |
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