CN105646484A - Crystal form B and preparation method - Google Patents
Crystal form B and preparation method Download PDFInfo
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- CN105646484A CN105646484A CN201610114026.8A CN201610114026A CN105646484A CN 105646484 A CN105646484 A CN 105646484A CN 201610114026 A CN201610114026 A CN 201610114026A CN 105646484 A CN105646484 A CN 105646484A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a crystal form B. The crystal form B is characterized in that Cu-K alpha radiation is used, X-RPD (X-ray powder diffraction) indicated by the 2 theta angle has diffraction peaks at 6.4+/-0.2 degrees, 7.9+/-0.2 degrees, 8.7+/-0.2 degrees, 9.8+/-0.2 degrees, 10.0+/-0.2 degrees and 17.0+/-0.2 degrees. The crystal form B can be prepared on a large scale safely and purified, can be stored stably, does not have moisture absorption, is very suitable for preparation of an inhalable preparation and has good compatibility with excipients such as lactose, starch and the like.
Description
Technical field
The present invention relates to medicinal chemistry art, specifically, the present invention relates to N-[3-tert-butyl-1-(3-chloro-4-hydroxyl phenyl)-1H-pyrazoles-5-base]-N '-{ 2-[(3-{2-[(2-ethoxy) sulfenyl] phenyl } [1,2,4] triazol [4,3-a] pyridine-6-base) sulfenyl] benzyl } the novel crystal forms B of urea, and the preparation method of crystal formation and purposes.
Background technology
N-[3-tert-butyl-1-(3-chloro-4-hydroxyl phenyl)-1H-pyrazoles-5-base]-N '-2-[(3-{2-[(2-ethoxy) sulfenyl] phenyl } [1,2,4] triazol [4,3-a] pyridine-6-base) sulfenyl] benzyl } urea is the noval chemical compound of the anaphylaxis and nonallergic airway disorders for treating such as chronic obstructive pulmonary disease (COPD) of up-to-date research and development, for a compounds of p 38 map kinase inhibitor. But when this compound stores, stability is not good, and has hygroscopicity, is unsuitable for the dry powder formulations of the suction that will develop.
Summary of the invention
For above-mentioned prior art Problems existing, the present invention provides a kind of N-[3-tert-butyl-1-(3-chloro-4-hydroxyl phenyl)-1H-pyrazoles-5-base]-N '-{ 2-[(3-{2-[(2-ethoxy) sulfenyl] phenyl } [1,2,4] triazol [4,3-a] pyridine-6-base) sulfenyl] benzyl } the novel crystal forms B of urea, good stability, does not have hygroscopicity.
Crystal form B of the present invention, it is characterised in that use Cu-K �� radiation, the X-ray powder diffraction (X-RPD) represented with 2 �� angles at 6.4 �� 0.2 ��, 7.9 �� 0.2 ��, 8.7 �� 0.2 ��, 9.8 �� 0.2 ��, 10.0 �� 0.2 ��, there is diffraction maximum at 17.0 �� 0.2 �� of places.
Further, described crystal form B, use Cu-K �� radiation, the X-ray powder diffraction represented with 2 �� angles is at 4.0 �� 0.2 ��, 6.0 �� 0.2 ��, 6.4 �� 0.2 ��, 7.9 �� 0.2 ��, 8.7 �� 0.2 ��, 9.8 �� 0.2 ��, 10.0 �� 0.2 ��, 12.3 �� 0.2 ��, 12.6 �� 0.2 ��, 14.8 �� 0.2 ��, 15.0 �� 0.2 ��, 17.0 �� 0.2 ��, 23.8 �� 0.2 ��, 24.6 �� 0.2 ��, 25.2 �� 0.2 ��, 25.5 �� 0.2 ��, 26.4 �� 0.2 ��, 27.6 �� 0.2 ��, 27.8 �� 0.2 ��, 28.2 �� 0.2 ��, 29.0 �� 0.2 ��, 33.1 there is diffraction maximum at �� 0.2 �� of place.
The preparation method of described crystal form B: N-[3-tert-butyl-1-(3-chloro-4-hydroxyl phenyl)-1H-pyrazoles-5-base]-N '-2-[(3-{2-[(2-ethoxy) sulfenyl] phenyl } [1,2,4] triazol [4,3-a] pyridine-6-base) sulfenyl] benzyl } urea refluxes in ethyl acetate, heating, to 40 DEG C, adds solvent t-butyl methyl ether, is cooled to zero degree with the speed of 2 DEG C/min, filtering, vacuum drying obtains crystal B.
Described N-[3-tert-butyl-1-(3-chloro-4-hydroxyl phenyl)-1H-pyrazoles-5-base]-N '-2-[(3-{2-[(2-ethoxy) sulfenyl] phenyl } [1,2,4] triazol [4,3-a] pyridine-6-base) sulfenyl] benzyl } ratio of urea and ethyl acetate is 1g:10ml.It is identical with ethyl acetate that described t-butyl methyl ether adds volume.
The present invention also provides for a kind of pharmaceutical composition, including described crystal form B and pharmaceutically acceptable excipient.
The present invention also provides for a kind of pharmaceutical composition, including the combination of described crystal form B and the second pharmacological active substance.
Crystal form B of the present invention can be prepared and purification safely on a large scale, and stable storing, does not have hygroscopicity, is highly suitable for preparing imbedibility preparation, good with the compatibility of the excipient such as breast sugar and starch. Additionally, the solvent involved by its preparation process is cheap, mild condition, simple to operate, there is good controllability and reproducibility, and the crystal formation prepared has fabulous stability, HPLC high purity more than 99%, do not have and turn brilliant phenomenon.
Accompanying drawing explanation
Fig. 1 is the X-RPD collection of illustrative plates of crystal form B of the present invention.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is expanded on further. Should be understood that these embodiments are merely to illustrate the present invention rather than restriction the scope of the present invention. The experimental technique of unreceipted actual conditions in the following example, generally conventionally condition. Experiment material used in following example and reagent all can obtain from commercially available channel if no special instructions.
Embodiment 1
10gN-[3-tert-butyl-1-(3-chloro-4-hydroxyl phenyl)-1H-pyrazoles-5-base]-N '-2-[(3-{2-[(2-ethoxy) sulfenyl] phenyl } [1,2,4] triazol [4,3-a] pyridine-6-base) sulfenyl] benzyl } urea refluxes in 100ml ethyl acetate, heating, to 40 DEG C, adds 100ml solvent t-butyl methyl ether, is cooled to zero degree with the speed of 2 DEG C/min, filtering, vacuum drying obtains crystal B. Using Cu-K �� radiation, the X-ray powder diffraction represented with 2 �� angles is as it is shown in figure 1, HPLC purity is for 99.92%.
Mensuration about the crystal formation of embodiment 1 preparation:
1. stability test
When the crystal B sample that Example 1 prepares is placed on 35 DEG C, investigating in the stability placing 1 month, 3 months, 6 months, result of the test is in Table 1. (method of concrete study on the stability is referred to the method for 2010 editions second annex XIXC of Chinese Pharmacopoeia; Purity detecting HPLC method, it is possible to reference to the method for 2010 editions second annex VD of Chinese Pharmacopoeia)
Table 1 replaces the stability test result of Buddhist nun's crystal form B according to Shandong
| Purity % | Crystal formation | |
| 1 month | 99.92 | Same Fig. 1 |
| 3 months | 99.92 | Same Fig. 1 |
| 6 months | 99.91 | Same Fig. 1 |
2. wettability test
Weigh B0.5 gram of crystal obtained by embodiment 1 and be laid in weighing botle, weigh, load weighted weighing botle opening is positioned over exsiccator (the using saturated ammonium chloride solution control) middle part that humidity is 80%, and covers exsiccator sealing lid; Place 24 hours, take out the weight again weighing weighing botle, and calculate percentage weight increase with this. Result crystal form B weightening finish 0.10%, illustrates that crystal form B of the present invention has the agent of low hygroscopicity being highly profitable.
Claims (7)
1. crystal form B, it is characterised in that use Cu-K �� radiation, the X-ray powder diffraction (X-RPD) represented with 2 �� angles at 6.4 �� 0.2 ��, 7.9 �� 0.2 ��, 8.7 �� 0.2 ��, 9.8 �� 0.2 ��, 10.0 �� 0.2 ��, there is diffraction maximum at 17.0 �� 0.2 �� of places.
2. the crystal form B according to Shandong for Buddhist nun according to claim 1, it is characterized in that, use Cu-K �� radiation, the X-ray powder diffraction represented with 2 �� angles is at 4.0 �� 0.2 ��, 6.0 �� 0.2 ��, 6.4 �� 0.2 ��, 7.9 �� 0.2 ��, 8.7 �� 0.2 ��, 9.8 �� 0.2 ��, 10.0 �� 0.2 ��, 12.3 �� 0.2 ��, 12.6 �� 0.2 ��, 14.8 �� 0.2 ��, 15.0 �� 0.2 ��, 17.0 �� 0.2 ��, 23.8 �� 0.2 ��, 24.6 �� 0.2 ��, 25.2 �� 0.2 ��, 25.5 �� 0.2 ��, 26.4 �� 0.2 ��, 27.6 �� 0.2 ��, 27.8 �� 0.2 ��, 28.2 �� 0.2 ��, 29.0 �� 0.2 ��, 33.1 �� 0.2 �� of place has diffraction maximum place to have diffraction maximum.
3. the preparation method of crystal form B, it is characterized in that, N-[3-tert-butyl-1-(3-chloro-4-hydroxyl phenyl)-1H-pyrazoles-5-base]-N '-2-[(3-{2-[(2-ethoxy) sulfenyl] phenyl } [1,2,4] triazol [4,3-a] pyridine-6-base) sulfenyl] benzyl } urea refluxes in ethyl acetate, heating, to 40 DEG C, adds solvent t-butyl methyl ether, is cooled to zero degree with the speed of 2 DEG C/min, filtering, vacuum drying obtains crystal B.
4. method according to claim 3, it is characterized in that, described N-[3-tert-butyl-1-(3-chloro-4-hydroxyl phenyl)-1H-pyrazoles-5-base]-N '-2-[(3-{2-[(2-ethoxy) sulfenyl] phenyl } [1,2,4] triazol [4,3-a] pyridine-6-base) sulfenyl] benzyl } ratio of urea and ethyl acetate is 1g:10ml.
5. method according to claim 3, it is characterised in that it is identical with ethyl acetate that described t-butyl methyl ether adds volume.
6. a pharmaceutical composition, including crystal form B described in claim 1 and pharmaceutically acceptable excipient.
7. a pharmaceutical composition, including the combination of crystal form B described in claim 1 and the second pharmacological active substance.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201610114026.8A CN105646484A (en) | 2016-03-01 | 2016-03-01 | Crystal form B and preparation method |
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| CN201610114026.8A CN105646484A (en) | 2016-03-01 | 2016-03-01 | Crystal form B and preparation method |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117214A (en) * | 2016-06-29 | 2016-11-16 | 上海创诺医药集团有限公司 | According to Shandong for Buddhist nun's novel crystal forms and preparation method thereof |
| US9828383B1 (en) | 2012-06-04 | 2017-11-28 | Pharmacyclic s LLC | Crystalline forms of a bruton's tyrosine kinase inhibitor |
| US20180028537A1 (en) | 2014-08-07 | 2018-02-01 | Pharmacyclics Llc | Novel Formulations of a Bruton's Tyrosine Kinase Inhibitor |
| US10010507B1 (en) | 2015-03-03 | 2018-07-03 | Pharmacyclics Llc | Pharmaceutical formulations of a bruton's tyrosine kinase inhibitor |
| US10183024B2 (en) | 2016-12-02 | 2019-01-22 | Apotex Inc. | Crystalline forms of ibrutinib |
| EP3575300A1 (en) | 2018-05-31 | 2019-12-04 | Apotex Inc. | Novel crystalline forms of ibrutinib |
| US10688050B1 (en) | 2018-12-21 | 2020-06-23 | Synthon B.V. | Pharmaceutical composition comprising ibrutinib |
| EP3669867A1 (en) | 2018-12-21 | 2020-06-24 | Synthon B.V. | Pharmaceutical composition comprising ibrutinib |
| WO2023242384A1 (en) | 2022-06-17 | 2023-12-21 | Krka, D.D., Novo Mesto | Crystalline form of ibrutinib |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101006087A (en) * | 2004-08-12 | 2007-07-25 | 辉瑞大药厂 | Triazolopyridinylsulfanyl derivatives as p38 MAP kinase inhibitors |
| EP2303267B1 (en) * | 2008-02-04 | 2013-07-03 | Pfizer Limited | Polymorphic form of a [1, 2, 4] triazolo [4, 3-a]pyridine derivative for treating inflammatory diseases |
-
2016
- 2016-03-01 CN CN201610114026.8A patent/CN105646484A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101006087A (en) * | 2004-08-12 | 2007-07-25 | 辉瑞大药厂 | Triazolopyridinylsulfanyl derivatives as p38 MAP kinase inhibitors |
| EP2303267B1 (en) * | 2008-02-04 | 2013-07-03 | Pfizer Limited | Polymorphic form of a [1, 2, 4] triazolo [4, 3-a]pyridine derivative for treating inflammatory diseases |
Cited By (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10294232B2 (en) | 2012-06-04 | 2019-05-21 | Pharmacyclics Llc | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
| US10294231B2 (en) | 2012-06-04 | 2019-05-21 | Pharmacyclics Llc | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
| US10961251B1 (en) | 2012-06-04 | 2021-03-30 | Pharmacyclics Llc | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
| US10065968B2 (en) | 2012-06-04 | 2018-09-04 | Pharmacyclics Llc | Crystalline forms of a bruton's tyrosine kinase inhibitor |
| US10106548B2 (en) | 2012-06-04 | 2018-10-23 | Pharmacyclics Llc | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
| US10125140B1 (en) | 2012-06-04 | 2018-11-13 | Pharmacyclics Llc | Crystalline forms of a bruton's tyrosine kinase inhibitor |
| US10266540B2 (en) | 2012-06-04 | 2019-04-23 | Pharmacyclics Llc | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
| US10752634B2 (en) | 2012-06-04 | 2020-08-25 | Pharmacyclics Llc | Crystalline forms of a brutons tyrosine kinase inhibitor |
| US9828383B1 (en) | 2012-06-04 | 2017-11-28 | Pharmacyclic s LLC | Crystalline forms of a bruton's tyrosine kinase inhibitor |
| US20180028537A1 (en) | 2014-08-07 | 2018-02-01 | Pharmacyclics Llc | Novel Formulations of a Bruton's Tyrosine Kinase Inhibitor |
| US10828259B2 (en) | 2015-03-03 | 2020-11-10 | Pharmacyclics Llc | Pharmaceutical formulations of a Bruton's tyrosine kinase inhibitor |
| US10010507B1 (en) | 2015-03-03 | 2018-07-03 | Pharmacyclics Llc | Pharmaceutical formulations of a bruton's tyrosine kinase inhibitor |
| US10213386B2 (en) | 2015-03-03 | 2019-02-26 | Pharmacyclics Llc | Pharmaceutical formulations of a Bruton's tyrosine kinase inhibitor |
| CN106117214A (en) * | 2016-06-29 | 2016-11-16 | 上海创诺医药集团有限公司 | According to Shandong for Buddhist nun's novel crystal forms and preparation method thereof |
| US10183024B2 (en) | 2016-12-02 | 2019-01-22 | Apotex Inc. | Crystalline forms of ibrutinib |
| EP3575300A1 (en) | 2018-05-31 | 2019-12-04 | Apotex Inc. | Novel crystalline forms of ibrutinib |
| US10688050B1 (en) | 2018-12-21 | 2020-06-23 | Synthon B.V. | Pharmaceutical composition comprising ibrutinib |
| EP3669867A1 (en) | 2018-12-21 | 2020-06-24 | Synthon B.V. | Pharmaceutical composition comprising ibrutinib |
| WO2020127912A1 (en) | 2018-12-21 | 2020-06-25 | Synthon B.V. | Pharmaceutical composition comprising ibrutinib |
| WO2023242384A1 (en) | 2022-06-17 | 2023-12-21 | Krka, D.D., Novo Mesto | Crystalline form of ibrutinib |
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Application publication date: 20160608 |