CN106008529A - Ibrutinib solvate and preparation method thereof - Google Patents
Ibrutinib solvate and preparation method thereof Download PDFInfo
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- CN106008529A CN106008529A CN201610642276.9A CN201610642276A CN106008529A CN 106008529 A CN106008529 A CN 106008529A CN 201610642276 A CN201610642276 A CN 201610642276A CN 106008529 A CN106008529 A CN 106008529A
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- shandong
- solvate
- buddhist nun
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- ibrutinib
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
The invention discloses an ibrutinib solvate and a preparation method thereof. The ibrutinib solvate is an anisole solvate of ibrutinib and has a chemical structural formula shown in the formula I. In the formula I, n is selected from 0.1-1. The preparation method comprises dissolving the raw material ibrutinib in anisole to obtain a clear solution, cooling the solution to a temperature of 0-20 DEG C, carrying out thermal insulation stirring for crystallization, filtering the crystals and drying the crystals to obtain the ibrutinib solvate. The ibrutinib solvate provided by the invention has advantages of low toxicity, easy preparation process, easy realization of large scale production and significant industrial application value.
Description
Technical field
The present invention relates to one according to Shandong for Buddhist nun's solvate and preparation method thereof, belong to field of pharmaceutical chemistry technology.
Background technology
According to Shandong for Buddhist nun (Ibrutinib, trade name: Imbruvica, former name: PCI-32765), entitled 1 [3 (R) 3 of chemistry
[4 amino 3 (4 Phenoxyphenyl) 1H pyrazolo [3,4 d] pyrimidine 1 base] 1 piperidyl] 2 propylene 1 ketone,
Its chemical structural formula is as follows:
Buddhist nun is replaced to be little molecule bruton's tyrosine kinase (BTK) inhibitor that the first generation is administered orally according to Shandong.In November, 2013
The approval listing of 13 Huo FDA (Food and Drug Adminstration)s (FDA), has been applied to the malignant tumor of multiple B cell type
Treatment, such as lymphoma mantle cell (MCL), chronic lymphocytic leukemia (is called for short slow pouring, CLL), primary macroglobulinemia
Disease (WM) etc..
In international patent application WO2013184572, disclose according to Shandong for the crystal formation A of Buddhist nun, crystal formation B, crystal formation C, crystalline substance
Type D, crystal formation E, crystal formation F and preparation method thereof, wherein: crystal formation A, crystal formation B, crystal formation C are anhydrides, crystal formation D
Being methyl isobutyl ketone solvent compound, crystal formation E is toluene solvate, and crystal formation F is Methanol Solvate, owing to methyl is different
Butyl ketone has strong local irritation and toxicity, toluene and methanol and broadly falls into Equations of The Second Kind solvent, has certain toxicity, therefore,
Crystal formation D, crystal formation E, crystal formation F all discomforts are cooperated in medicinal crystal-form.And study and show: only crystal formation A in six kinds of crystal formations
Applicable pharmaceutical formulation, but the preparation method complex operation of the crystal formation A disclosed in patent, the longest, yield is low, unfavorable
In industrial-scale production.
In Chinese patent CN104327085A, disclose another crystal formation A (hereinafter referred to as crystal formation A ') and preparation thereof
Method, but the preparation method of this crystal formation A ', wayward, poor reproducibility, it is not suitable for industrially scalable raw the most yet
Produce.
From above-mentioned prior art: there is multiple crystal formation according to Shandong for Buddhist nun, but above-mentioned crystal formation or belong to solvate, molten
Agent has toxicity discomfort and cooperates in medicinal crystal-form, or is exactly that preparation technology operates complexity, it is impossible to for industrial-scale production,
Therefore, it is badly in need of at present finding one not only safety and low toxicity, is suitable for pharmaceutical formulation but also the simple crystal formation of preparation technology, be suitable for system
The preparation of industrialization of agent and meet the various performance requirements of preparation.
Summary of the invention
The problems referred to above existed for prior art, it is an object of the invention to provide a kind of simple to operate, safety and low toxicity according to Shandong
For Buddhist nun's solvate and preparation method thereof, it is suitable for the preparation of industrialization of preparation and meets the various performance requirements of preparation.
For achieving the above object, the technical solution used in the present invention is as follows:
Of the present invention according to Shandong for Buddhist nun's solvate, for according to Shandong for the anisol solvate of Buddhist nun, its chemical structural formula such as formula
Shown in I:
Wherein, n (is according to Shandong for Buddhist nun's selected from 0.1～1
0.1～1 molecule anisole solvate).
Furtherly, of the present invention according to Shandong for Buddhist nun's solvate, wherein to be 0.5 (be according to Shandong for 0.5 molecule of Buddhist nun n
Anisol solvate), molecular formula is 2 (C25H24N6O2)·C7H8O。
Furtherly, of the present invention according to Shandong for Buddhist nun's solvate, under X-ray powder diffraction, at angle of diffraction 2 θ
Be 6.6 ° ± 0.1 °, 12.6 ° ± 0.1 °, 20.1 ° ± 0.1 °, 26.2 ° ± 0.1 °, 28.6 ° ± 0.1 °, there is characteristic peak at 29.0 ° ± 0.1 °.
Furtherly, of the present invention according to Shandong for Buddhist nun's solvate, there is the X-ray powder diffraction spectrogram shown in Fig. 1.
Furtherly, of the present invention according to Shandong for Buddhist nun's solvate, its Differential Scanning Calorimetry at 117～122 DEG C and
Feature endothermic peak is had respectively at 135～138 DEG C.
Furtherly, of the present invention according to Shandong for Buddhist nun's solvate, its crystal structural data is: anorthic system, and P1 is empty
Between group, cell parameter:α=93.961 (3) °,
β=101.001 (4) °, γ=116.217 (4) °, unit cell volumeZ=1.
Furtherly, of the present invention according to Shandong for Buddhist nun's solvate, in its Fourier's infared spectrum, characteristic peak positions is
1334cm-1、1306cm-1、1118cm-1、1077cm-1、1037cm-1、862cm-1。
A kind of prepare of the present invention according to Shandong for the method for Buddhist nun's solvate, comprise the steps:
1) at 0～60 DEG C (preferably 25～50 DEG C), will mix with methyl phenyl ethers anisole for Buddhist nun's raw material according to Shandong, obtain suspension；
2) insulated and stirred 1～24 hours (preferably 2～5 hours)；
3) filter, collect crystal, be dried (baking temperature preferably 40 DEG C), obtain described according to Shandong for Buddhist nun's solvate.
In step a) gained suspension, Buddhist nun's raw material is replaced to be 1:(5～15 with the solid-liquid ratio of methyl phenyl ethers anisole according to Shandong) g/mL.
A kind of prepare of the present invention according to Shandong for the method for Buddhist nun's solvate, comprise the steps:
A) will replace Buddhist nun's material dissolution in methyl phenyl ethers anisole according to Shandong, solution temperature is 50～60 DEG C, obtains the solution of clarification；
B) being cooled to 0～20 DEG C, insulated and stirred makes crystallize；
C) crystal of precipitation is collected by filtration, is dried, obtain described according to Shandong for Buddhist nun's solvate.
In step a) gained solution, Buddhist nun's raw material is replaced to be 1:(8～15 with the solid-liquid ratio of methyl phenyl ethers anisole according to Shandong) g/mL.
Described do not limit for the crystal formation of Buddhist nun's raw material according to Shandong, can be any one crystal formation unformed or known or their mixture.
Compared with prior art, the present invention has a following significance beneficial effect:
The result of study of the present invention shows: of the present invention is the methyl phenyl ethers anisole solvation replacing Buddhist nun according to Shandong for Buddhist nun's solvate according to Shandong
Thing, according to solvent grade scale, methyl phenyl ethers anisole belongs to the 3rd kind solvent, less to health and environmental hazard, therefore this
Bright according to Shandong for Buddhist nun's solvate, compared to known various solvates (according to Shandong for the methyl iso-butyl ketone (MIBK) of Buddhist nun, toluene,
Methanol Solvate), safety low-poison, it is suitable for the raw material crystal formation of pharmaceutical formulation；Especially, of the present invention according to Shandong for Buddhist nun
The preparation technology of solvate is simple, workable, and productivity is high, and steady quality is with short production cycle；In a word, the present invention
Relative to prior art, it is easy to accomplish scale, there is significant industrial application value.
Accompanying drawing explanation
Fig. 1 is the XRD spectra replacing Buddhist nun's anisol solvate according to Shandong of the present invention；
Fig. 2 is the FT-IR spectrogram replacing Buddhist nun's anisol solvate according to Shandong of the present invention；
Fig. 3 is the DSC/TGA spectrogram replacing Buddhist nun's anisol solvate according to Shandong of the present invention；
Fig. 4 is the hot ellipsoid figure replacing Buddhist nun's anisol solvate mono-crystalline structures according to Shandong.
Detailed description of the invention
Below in conjunction with specific embodiments and the drawings, the present invention is expanded on further.Should be understood that these embodiments are merely to illustrate this
Invention rather than restriction the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally according to often
Rule condition or according to the condition proposed by manufacturer.
Used in embodiment is commercially available prod according to Shandong for Buddhist nun's raw material, buys from peace profit medical sci-tech (Suzhou) company limited.
Embodiment 1
At 25 DEG C, 0.82g is mixed with 10ml methyl phenyl ethers anisole for Buddhist nun's raw material (no matter which kind of kenel) according to Shandong, obtains suspension；
Insulated and stirred 3 hours；Filtering, 40 DEG C are vacuum dried 12 hours, obtain 0.64g crystal；Productivity is 78%.
Fig. 1 is the XRD spectra of gained crystal, as seen from Figure 1: this crystal is under X-ray powder diffraction, in the angle of diffraction
Spend 2 θ be 6.6 ° ± 0.1 °, 12.6 ° ± 0.1 °, 20.1 ° ± 0.1 °, 26.2 ° ± 0.1 °, 28.6 ° ± 0.1 °, there is feature at 29.0 ° ± 0.1 °
Peak.
Fig. 2 is the FT-IR spectrogram of gained crystal, as seen from Figure 2: this crystal is at 1334cm-1、1306cm-1、1118cm-1、
1077cm-1、1037cm-1、862cm-1There is characteristic peak.
Fig. 3 is the DSC/TGA spectrogram of gained crystal, as seen from Figure 3: in means of differential scanning calorimetry spectrogram (DSC spectrogram), should
Crystal has feature endothermic peak at 117～122 DEG C and 135～138 DEG C respectively；In thermogravimetric analysis spectrogram (TGA spectrogram), this crystalline substance
Body, 60～120 DEG C of weightlessness 10.12%, illustrates that gained crystal is the 0.5 molecule anisole solvate replacing Buddhist nun according to Shandong.
Fig. 4 is the hot ellipsoid figure of gained crystal, as seen from Figure 4: this crystal is two and replaces Buddhist nun's molecule and a methyl phenyl ethers anisole according to Shandong
The basic structural unit of molecular composition crystalline solid, its crystal structural data is: anorthic system, P1 space group, cell parameter: α=93.961 (3) °, β=101.001 (4) °, γ=
116.217 (4) °, unit cell volumeZ=1.
To sum up analyze visible: this embodiment gained crystal be the present invention according to Shandong replace Buddhist nun's solvate.
Embodiment 2
At 50 DEG C, 1.53g is mixed with 8ml methyl phenyl ethers anisole for Buddhist nun's raw material (no matter which kind of kenel) according to Shandong, obtains suspension；
Insulated and stirred 2 hours；Filtering, 40 DEG C are vacuum dried 12 hours, obtain 1.22g crystal；Productivity is 80%.
Analyze after measured, gained crystal have the FT-IR chromatogram characteristic shown in the XRD spectra feature shown in Fig. 1, Fig. 2,
Hot ellipsoid graph structure feature shown in DSC/TGA chromatogram characteristic shown in Fig. 3 and Fig. 4, illustrates the present embodiment gained crystal also
For the present invention according to Shandong for Buddhist nun's solvate.
Embodiment 3
At 50 DEG C, 1.0g is dissolved in 8ml methyl phenyl ethers anisole for Buddhist nun's raw material (no matter which kind of kenel) according to Shandong, obtains clarification
Solution；Being cooled to 0 DEG C, insulated and stirred makes crystallize 1 hour；Filtering, 40 DEG C are vacuum dried 24 hours, obtain 0.89g brilliant
Body；Productivity is 89%.
Analyze after measured, gained crystal have the FT-IR chromatogram characteristic shown in the XRD spectra feature shown in Fig. 1, Fig. 2,
Hot ellipsoid graph structure feature shown in DSC/TGA chromatogram characteristic shown in Fig. 3 and Fig. 4, illustrates the present embodiment gained crystal also
For the present invention according to Shandong for Buddhist nun's solvate.
In sum: the present invention replaces Buddhist nun's solvate to be the anisol solvate replacing Buddhist nun according to Shandong according to Shandong, is solid for Buddhist nun according to Shandong
A kind of new solvate in volume morphing, has widened the solid forms ken replacing Buddhist nun according to Shandong further；And the present invention
Simple for Buddhist nun's solvate safety and low toxicity, preparation technology according to Shandong, it is easy to accomplish scale, there is significant industrial application value.
Finally need it is pointed out here that: be the most only the part preferred embodiment of the present invention, it is impossible to be interpreted as to the present invention protect
Protect the restriction of scope, some nonessential improvement and adjustment that those skilled in the art makes according to the foregoing of the present invention
Belong to protection scope of the present invention.
Claims (8)
1. one kind is replaced Buddhist nun's solvate according to Shandong, it is characterised in that: for replacing the anisol solvate of Buddhist nun, its chemical constitution according to Shandong
Formula is as shown in formula I:
Wherein, n is selected from 0.1～1.
The most according to claim 1 according to Shandong for Buddhist nun's solvate, it is characterised in that: wherein n is 0.5, and molecular formula is
2(C25H24N6O2)·C7H8O。
The most according to claim 2 according to Shandong for Buddhist nun's solvate, it is characterised in that: under X-ray powder diffraction,
Angle of diffraction 2 θ is 6.6 ° ± 0.1 °, 12.6 ° ± 0.1 °, 20.1 ° ± 0.1 °, 26.2 ° ± 0.1 °, 28.6 ° ± 0.1 °, have at 29.0 ° ± 0.1 °
There is characteristic peak.
The most according to claim 2 according to Shandong for Buddhist nun's solvate, it is characterised in that: its Differential Scanning Calorimetry exists
Feature endothermic peak is had respectively at 117～122 DEG C and 135～138 DEG C.
5. the method replacing Buddhist nun's solvate according to Shandong prepared described in claim 1, it is characterised in that: comprise the steps:
1) at 0～60 DEG C, will mix with methyl phenyl ethers anisole for Buddhist nun's raw material according to Shandong, obtain suspension；
2) insulated and stirred 1～24 hours；
3) filter, collect crystal, be dried, obtain described according to Shandong for Buddhist nun's solvate.
Method the most according to claim 5, it is characterised in that: step 1) in gained suspension, according to Shandong for Buddhist nun's raw material with
The solid-liquid ratio of methyl phenyl ethers anisole is 1:(5～15) g/mL.
7. the method replacing Buddhist nun's solvate according to Shandong prepared described in claim 1, it is characterised in that: comprise the steps:
A) will replace Buddhist nun's material dissolution in methyl phenyl ethers anisole according to Shandong, solution temperature is 50～60 DEG C, obtains the solution of clarification；
B) being cooled to 0～20 DEG C, insulated and stirred makes crystallize；
C) crystal of precipitation is collected by filtration, is dried, obtain described according to Shandong for Buddhist nun's solvate.
Method the most according to claim 7, it is characterised in that: in step a) gained solution, according to Shandong for Buddhist nun's raw material and benzene
The solid-liquid ratio of methyl ether is 1:(8～15) g/mL.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108727387A (en) * | 2018-07-25 | 2018-11-02 | 天津大学 | According to Shandong for Buddhist nun's isopropyl acetate solvent compound and preparation method thereof |
| CN109053738A (en) * | 2018-08-29 | 2018-12-21 | 浙江工业大学 | A kind of solvate and preparation method thereof replacing Buddhist nun according to Shandong |
| 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 |
| WO2024083164A1 (en) * | 2022-10-21 | 2024-04-25 | 长春金赛药业有限责任公司 | Solvate of indoline spiro compound, and crystal form thereof, preparation method therefor and use thereof |
| WO2024083160A1 (en) * | 2022-10-21 | 2024-04-25 | 长春金赛药业有限责任公司 | Crystal form and amorphous substance of indoline spiro compound, and preparation method therefor and use thereof |
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| CN104327085A (en) * | 2013-11-27 | 2015-02-04 | 苏州晶云药物科技有限公司 | PCI-32765 crystal form A and preparation method thereof |
| WO2015145415A2 (en) * | 2014-03-27 | 2015-10-01 | Perrigo Api Ltd. | Ibrutinib solid forms and production process therefor |
| WO2016025720A1 (en) * | 2014-08-14 | 2016-02-18 | Assia Chemical Industries Ltd. | Solid state forms of ibrutinib |
| WO2016079216A1 (en) * | 2014-11-20 | 2016-05-26 | Sandoz Ag | Physical forms of ibrutinib, a bruton's kinase inhibitor |
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2016
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104327085A (en) * | 2013-11-27 | 2015-02-04 | 苏州晶云药物科技有限公司 | PCI-32765 crystal form A and preparation method thereof |
| WO2015145415A2 (en) * | 2014-03-27 | 2015-10-01 | Perrigo Api Ltd. | Ibrutinib solid forms and production process therefor |
| WO2016025720A1 (en) * | 2014-08-14 | 2016-02-18 | Assia Chemical Industries Ltd. | Solid state forms of ibrutinib |
| WO2016079216A1 (en) * | 2014-11-20 | 2016-05-26 | Sandoz Ag | Physical forms of ibrutinib, a bruton's kinase inhibitor |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN108727387A (en) * | 2018-07-25 | 2018-11-02 | 天津大学 | According to Shandong for Buddhist nun's isopropyl acetate solvent compound and preparation method thereof |
| CN108727387B (en) * | 2018-07-25 | 2021-03-16 | 天津大学 | Ibrutinib isopropyl acetate solvent compound and preparation method thereof |
| CN109053738A (en) * | 2018-08-29 | 2018-12-21 | 浙江工业大学 | A kind of solvate and preparation method thereof replacing Buddhist nun according to Shandong |
| WO2024083164A1 (en) * | 2022-10-21 | 2024-04-25 | 长春金赛药业有限责任公司 | Solvate of indoline spiro compound, and crystal form thereof, preparation method therefor and use thereof |
| WO2024083160A1 (en) * | 2022-10-21 | 2024-04-25 | 长春金赛药业有限责任公司 | Crystal form and amorphous substance of indoline spiro compound, and preparation method therefor and use thereof |
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Application publication date: 20161012 |