CN108707154A - A kind of drug solvent for the treatment of cancer closes object and preparation method thereof - Google Patents
A kind of drug solvent for the treatment of cancer closes object and preparation method thereof Download PDFInfo
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- CN108707154A CN108707154A CN201810753837.1A CN201810753837A CN108707154A CN 108707154 A CN108707154 A CN 108707154A CN 201810753837 A CN201810753837 A CN 201810753837A CN 108707154 A CN108707154 A CN 108707154A
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- buddhist nun
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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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Abstract
The invention belongs to pharmaceutical technology fields, the drug solvent for disclosing a kind for the treatment of cancer closes object and preparation method thereof, the X-ray powder diffraction collection disclosed by the invention indicated with the 2 θ ± 0.2 ° angles of diffraction for Buddhist nun's acetone solvate according to Shandong shows characteristic diffraction peak at 5.54 °, 10.47 °, 15.54 °, 16.37 °, 17.95 °, 19.71 °, 20.40 °, 24.13 °, 24.28 °, 26.05 ° and 27.22 °, entirely different with the prior art.The invention also discloses the preparation methods that Buddhist nun's acetone solvate is replaced according to Shandong, and the preparation method is simple to operation, and yield and purity are high, and reaction condition is mild, are suitble to large-scale production.
Description
Technical field
The invention belongs to pharmaceutical technology field, discloses a kind of drug solvent for the treatment of cancer and closes object and preparation method thereof,
More particularly to a kind of acetone solvate and preparation method thereof replacing Buddhist nun according to Shandong.
Background technology
Buddhist nun, the entitled 1-[ of chemistry are replaced according to Shandong;(3R)-3-[4- amino -3- (4- Phenoxyphenyls) -1H- Bi Zuobings [3,4-d]
Pyrimidine -1- Jis ]- 1- Pai Dingjis ]- 2- propylene -1- ketone, the entitled Ibrutinib of English, structural formula are shown in formula I：
It is found by Celera Genomics companies for Buddhist nun (Ibrutinib) according to Shandong.In April, 2006, Pharmacyclics
BTK inhibitor projects are bought from Celera Genomics companies by company, then select PCI-32765 (i.e. present to replace Buddhist nun according to Shandong
(Ibrutinib)) subsequent preclinical study is carried out.In December, 2011, Pharmacyclics companies and Janssen Pharmaceutica
(Janssen) cooperation joint development replaces Buddhist nun (Ibrutinib) and marketing according to Shandong.2 months 2013, Buddhist nun is replaced according to Shandong
(Ibrutinib) breakthrough medicine qualification is authorized by FDA, and is approved as covering respectively in November, 2013 and 2 months 2014
Cell lymphoma (mantle cell lymphoma, MCL) and chronic lymphocytic leukemia (chronic lymphocytic
Leukemia, CLL) medicine.
According to Shandong for Buddhist nun (Ibrutinib) be used as a kind of Michael receptors, optionally with bruton's tyrosine kinase
The cysteine residues (Cys-481) of (Bruton ' s tyrosine kinase, BTK) form covalent bond.The kinases is at least
The important medium of three kinds of key B- cells survival mechanism.This multiple action of bruton's tyrosine kinase can make it command B-
Cell malignancies carry out, into lymphoid tissue, tumour cell being enable to contact necessary microenvironment and existence.This is novel
Drug bring hope to the treatment of refractory neoplasm.
Preparation method in relation to Ibrutinib studies have reported that, patent US20140275126, US20150376193,
WO2015074464, CN104557945 and WO2016127915 etc. report the synthetic method of Ibrutinib and the like.
Crystal form patent US9296753, the U.S.Patent Application 20130338172 of Yuan Yan companies,
U.S.Patent Application 20140336203 and U.S.Patent Application 20150158871 display according to
Shandong has 3 kinds of anhydrous polymorphic type objects (A, B, C) and 3 kinds of solvates for Buddhist nun (Ibrutinib).Crystal form A has highest fusing point,
About 154 DEG C, crystal form B is melted at about 120 DEG C, and the fusing point of crystal form C is about 140 DEG C, shows that crystal form A is thermodynamicaHy most stable
Form.At room temperature, crystal form B and C is the metastable polymorphic type object formed under conditions of dynamics is controlled.Crystal form A is
Pharmacyclics companies select commercialized crystal form.Crystal form A in water have lower solubility (13mg/L, pH 8) and
Higher body outer osmotic belongs to 2 class compounds of BCS.Since the grain size of API is to the biology profit according to Shandong for Buddhist nun (Ibrutinib)
Expenditure is affected, and needs to be micronized API.
In fasted condition, the absolute oral bioavailbilty of crystal form A is only 2.9%.In a clinical research, work as food
After food rich in fat, bioavilability about increases by 2 times, shows there is significant food effect according to Shandong for Buddhist nun.In view of its life
Object availability is low and food effect is big, and free alkali is not ideal API forms.
US9296753 disclose according to Shandong replace Buddhist nun crystal form A, X-ray powder diffraction figure (2 θ) at 13.6 ± 0.1 °,
There are one when 16.1 ± 0.1 °, 18.9 ± 0.1 °, 21.3 ± 0.1 ° and 21.6 ± 0.1 ° existing characteristics peaks, DSC are shown in 157 DEG C
A endothermic peak, at 159 DEG C there are an exothermic peak, the stability of crystal form is good, it is solvent-free conjunction object after testing；
US9296753 also disclose according to Shandong replace Buddhist nun crystal form B, X-ray powder diffraction figure (2 θ) at 5.2 ± 1 °, 10.2 ± 1 °,
There are an endothermic peaks when 16.5 ± 1 °, 18.5 ± 0.1 ° and 20.8 ± 1 ° existing characteristics peaks, DSC are shown in 117 DEG C；
US9296753 also disclose according to Shandong replace Buddhist nun crystal form C, X-ray powder diffraction figure (2 θ) at 7.0 ± 1 °, 14.0 ± 1 °,
15.7 ± 1 °, 18.2 ± 0.1 °, 19.1 ± 0.1 ° of 2-Theta, 19.5 ± 0.1 °, 20.3 ± 0.1 °, 22.1 ± 0.1 ° and 22.9
There are an endothermic peaks when ± 0.1 ° of existing characteristics peak, DSC are shown in 138 DEG C.
Belong to insoluble drug for Buddhist nun according to Shandong, is usually prepared into solid pharmaceutical preparation administration, and for the solid system of crystal form drug
For agent, the stability and dissolution rate of preparation and the crystal form of bulk pharmaceutical chemicals have prodigious relationship, replace Buddhist nun in crystallization according to Shandong, if
Using different solvent and process conditions, then its molecule differs in the number of permutations of each crystal form structure cell and position and latticed form
Sample forms different crystal structures, can change its property, quality and drug effect according to Shandong for the polymorphous variation of Buddhist nun.Therefore, it is replaced according to Shandong
The stable crystalline of Buddhist nun is studied its pharmaceutical composition and clinical application, is had for further studying the physicochemical properties of the compound
It is of great significance.
Compound polymorphic is a kind of universal phenomenon, for excellent performances one such as the stability, hygroscopicity, dissolubility of crystal form
It is directly a kind of long-range pursuit.Invention finds that most of existing crystal form is from stability, hygroscopicity solution by a large amount of experimental study
The certainly stable problem of its preparation, and the dissolution of preparation then often passes through the addition of auxiliary material and the control of raw material crystal form in production process
System angularly solves.It is always the technological difficulties of this field to replace the slightly solubility of Buddhist nun's raw material according to Shandong, can not be broken through always.
The present invention passes through a large amount of experimental study, using new method for crystallising, obtained it is a kind of it is new replace Buddhist nun's crystal form according to Shandong,
It is acetone solvate after testing, provided by the invention good for Buddhist nun's acetone solvate purity height, stability according to Shandong.The present invention
The preparation method that Buddhist nun's acetone solvate is replaced according to Shandong is also disclosed, the preparation method is simple to operation, and reaction condition is mild, yield
And purity is high, is suitble to large-scale production.
Invention content
The present invention is intended to provide one kind is novel to replace Buddhist nun's acetone solvate and preparation method thereof according to Shandong.
In order to achieve the object of the present invention, the technical solution used for：A kind of drug solvent conjunction object for the treatment of cancer, this is molten
Agent closes object as, for Buddhist nun's acetone solvate, molecular formula is according to Shandong：C25H24N6O2DMSO, structural formula is following (Formula II),
The X-ray powder diffraction collection indicated with the 2 θ ± 0.2 ° angles of diffraction 5.54 °, 10.47 °, 15.54 °, 16.37 °, 17.95 °,
Characteristic diffraction peak is shown at 19.71 °, 20.40 °, 24.13 °, 24.28 °, 26.05 ° and 27.22 °.
It is provided by the invention that the X-ray powder diffraction that Buddhist nun's acetone solvate is obtained using Cu-K alpha ray measurements is replaced according to Shandong
Figure is as shown in Figure 1.
The present invention also provides it is a kind of according to Shandong replace Buddhist nun's acetone solvate preparation method, the specific steps are：
Step (1) takes replaces Buddhist nun's crude product according to Shandong, and the mixed solution of acetone/water is added, and heating stirring dissolves 1-20min, activity
Carbon decoloring filters；
Filtrate obtained by step (1) is down to 0-6 DEG C by step (2), and acetone is added dropwise, and continues the crystallization that cools down；
Step (3) insulated and stirred is complete to crystallization, growing the grain, filters, and washes, dry, obtains white crystalline powder.
Preferably, in the acetone/water mixed solution described in step (1), the volume ratio of acetone and water is 20：1.0~1.2：
1.0；Step (1) is described to replace the mass volume ratio of Buddhist nun's crude product and mixed solution for 1g according to Shandong:10ml~1g:30ml；Described stirs
It is 100-150 revs/min to mix speed.
It is further preferred that in acetone/water mixed solution described in step (1), the volume ratio of acetone and water is 15：1.0；
Step (1) is described to replace the mass volume ratio of Buddhist nun's crude product and mixed solution for 1g according to Shandong:20ml；The mixing speed be 130 turns/
Minute.
Preferably, step (3) described rearing crystal time is 1h~3h；Step (3) described drying temperature is 100 DEG C~150 DEG C.
In the present invention, it is described according to Shandong for Buddhist nun's crude product can be it is to be further purified according to Shandong for Buddhist nun's solid mixture according to Shandong
It may be marketable material for Buddhist nun's crude product or be prepared by art methods, the crystal form result of gained is in error range
It is interior, it is novel crystal forms of the present invention.
The formation mechenism of crystal is very complicated, and the acquisition of a new crystal also has prodigious contingency, and sometimes different is molten
Agent will produce identical crystal structure under different crystallization conditions.Certain specific crystal formations also can not necessarily obtain more added with
The physicochemical property of profit.The properties such as stability, hygroscopicity, dissolubility, bioactivity, the toxicity of drug can be produced because of the difference of crystal form
Raw huge difference.
Studies have shown that in X-ray powder diffraction pattern, the diffraction spectrogram that is obtained from novel crystal forms for specific crystal form toward
Toward being characteristic, wherein the relative intensity of bands of a spectrum (especially in low angle) may be because of crystallization condition, grain size and other
The difference of determination condition and the advantage orientation effect that generates and change.Therefore, the relative intensity of diffraction maximum is to targeted crystal form
Not characteristic, when judging whether identical as known crystal form, it should be noted that the relative position at peak rather than it
Relative intensity.
It is provided by the present invention to confirm the crystalline acetone containing a molecule, character according to Shandong for the crystallization of Buddhist nun's acetone solvate
For white crystalline powder, the loss of recrystallisation solvent will not occur under the conditions of air drying.And its x-ray diffractogram of powder is composed
There is the relative position at visibly different peak with the prior art, it is seen that it is a kind of novel crystal forms unlike the prior art.
Carry out explanation and illustration sheet below by provided by the invention studied for Buddhist nun's acetone solvate crystal form according to Shandong
Inventive technique scheme：
1, crystal form detects
Take the present invention be prepared according to Shandong replace Buddhist nun's acetone solvate, the X-ray obtained using Cu-K alpha ray measurements
Powder diagram as shown in Figure 1, its X-ray powder diffraction figure for being indicated with the 2 θ ± 0.2 ° angles of diffraction 5.54 °, 10.47 °,
Feature is shown at 15.54 °, 16.37 °, 17.95 °, 19.71 °, 20.40 °, 24.13 °, 24.28 °, 26.05 ° and 27.22 °
Peak.
2, differential thermal analysis and thermogravimetric analysis
Thermogravimetric and differential thermal analysis are carried out for Buddhist nun's acetone solvate according to Shandong to prepared by the present invention, as a result such as attached drawing 2 and attached
Shown in Fig. 3；The result shows that this product quickly loses the weight of about 1 acetone molecules at 140 DEG C or so；This product at about 134 DEG C and
There is endothermic peak at 170 DEG C, it is a kind of different crystal form to demonstrate it from side.
Compared with prior art, the invention has the advantages that：
(1) it is provided by the present invention according to Shandong for Buddhist nun's acetone solvate be a kind of novel crystal forms different from the prior art；This
Invention is provided simple to operation for the preparation method of Buddhist nun's acetone solvate according to Shandong, and reaction condition is mild, and yield is more than
99.0%, it is suitble to large-scale production.
(2) provided by the invention good for Buddhist nun's acetone solvate purity height, stability according to Shandong.
Description of the drawings
Fig. 1 is the X-ray powder diffraction pattern that Buddhist nun's acetone solvate is replaced according to Shandong prepared by the present invention.
Fig. 2 is the TGA collection of illustrative plates that Buddhist nun's acetone solvate is replaced according to Shandong prepared by the embodiment of the present invention 1.
Fig. 3 is the DSC collection of illustrative plates that Buddhist nun's acetone solvate is replaced according to Shandong prepared by the embodiment of the present invention 1.
Specific implementation mode
Technical scheme of the present invention is described in detail with embodiment below, it will help to technical scheme of the present invention
The advantages of, effect there is further understanding, embodiment not to limit protection scope of the present invention, protection scope of the present invention is by weighing
Profit requires to determine.
Embodiment：The preparation of Buddhist nun's acetone solvate is replaced according to Shandong
(1) it takes and replaces Buddhist nun crude product 100g according to Shandong, acetone/water (volume ratio 15 is added:1.0) mixed solution 2000ml, adds
(130 revs/min) dissolving 1-20min of thermal agitation, activated carbon decolorizing filter；
(2) step (1) filtrate is cooled to 0-6 DEG C, the acetone 500ml of precooling is added dropwise, continue to be cooled to -10 DEG C of crystallizations；
(3) insulated and stirred is complete to crystallization, growing the grain 2h, filters, and washing, 110 DEG C of dryings obtain white crystalline powder
99.90g yield 99.90%.
Obtained white crystalline powder is shown in Fig. 1 using the X-ray powder diffraction spectrogram that Cu-K alpha ray measurements obtain.
Claims (6)
1. a kind of drug solvent for the treatment of cancer closes object, which is characterized in that the solvate is molten for the acetone of Buddhist nun according to Shandong
Object is closed in agent, and molecular formula is：C25H24N6O2C3H6O, the X-ray powder diffraction figure indicated with the 2 θ ± 0.2 ° angles of diffraction
Spectrum at 5.54 °, 10.47 °, 15.54 °, 16.37 °, 17.95 °, 19.71 °, 20.40 °, 24.13 °, 24.28 °, 26.05 ° and
Characteristic diffraction peak is shown at 27.22 °.
2. a kind of drug solvent for the treatment of cancer as described in claim 1 closes object, which is characterized in that surveyed using Cu-K alpha rays
The X-ray powder diffraction figure measured is as shown in Figure 1.
3. a kind of drug solvent for the treatment of cancer as claimed in claim 1 or 2 closes the preparation method of object, it is characterised in that including
Following steps：
Step (1) takes replaces Buddhist nun's crude product according to Shandong, and the mixed solution of acetone/water is added, and heating stirring dissolves 1-2min, and activated carbon is de-
Color filters；
Filtrate obtained by step (1) is down to 0-6 DEG C by step (2), and acetone is added dropwise, and continues the crystallization that cools down；
Step (3) insulated and stirred is complete to crystallization, growing the grain, filters, and washes, dry, obtains white crystalline powder.
4. a kind of drug solvent for the treatment of cancer as claimed in claim 3 closes the preparation method of object, which is characterized in that step
(1) in the acetone/water mixed solution described in, the volume ratio of acetone and water is 20：1.0~1.2：1.0；Step (1) is described according to Shandong
It is 1g for the mass volume ratio of Buddhist nun's crude product and mixed solution:10ml~1g:30ml；The mixing speed is 100-150 revs/min
Clock.
5. a kind of drug solvent for the treatment of cancer as claimed in claim 4 closes the preparation method of object, which is characterized in that step
(1) in the acetone/water mixed solution described in, the volume ratio of acetone and water is 15：1.0；Step (1) it is described according to Shandong for Buddhist nun's crude product with
The mass volume ratio of mixed solution is 1g:20ml；The mixing speed is 130 revs/min.
6. a kind of drug solvent for the treatment of cancer as claimed in claim 4 closes the preparation method of object, which is characterized in that step
(3) rearing crystal time is 1h~3h；Step (3) described drying temperature is 100 DEG C~150 DEG C.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013157022A1 (en) * | 2012-04-20 | 2013-10-24 | Advinus Therapeutics Limited | Substituted hetero-bicyclic compounds, compositions and medicinal applications thereof |
| CN105085529A (en) * | 2014-05-15 | 2015-11-25 | 广东东阳光药业有限公司 | Novel crystal form of ibrutinib and preparation method thereof |
| CN105294696A (en) * | 2015-11-19 | 2016-02-03 | 上海创诺医药集团有限公司 | Novel crystal forms of ibrutinib and preparation method thereof |
| CN105440040A (en) * | 2015-12-23 | 2016-03-30 | 浙江京新药业股份有限公司 | Ibrutinib purification method |
| CN106008514A (en) * | 2014-01-29 | 2016-10-12 | 苏州晶云药物科技有限公司 | New crystal form of ibrutinib and preparation method of new crystal form |
| WO2017085628A1 (en) * | 2015-11-16 | 2017-05-26 | Olon S.P.A. | Process for the preparation of the amorphous form of ibrutinib and novel crystalline form |
| CN106905320A (en) * | 2015-12-23 | 2017-06-30 | 杭州容立医药科技有限公司 | It is a kind of to be adapted to medicinal replace Buddhist nun and its preparation according to Shandong |
| CN107530345A (en) * | 2015-03-03 | 2018-01-02 | 雷迪博士实验室有限公司 | The polymorph of Buddhist nun is replaced according to Shandong |
-
2018
- 2018-07-10 CN CN201810753837.1A patent/CN108707154A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013157022A1 (en) * | 2012-04-20 | 2013-10-24 | Advinus Therapeutics Limited | Substituted hetero-bicyclic compounds, compositions and medicinal applications thereof |
| CN106008514A (en) * | 2014-01-29 | 2016-10-12 | 苏州晶云药物科技有限公司 | New crystal form of ibrutinib and preparation method of new crystal form |
| CN105085529A (en) * | 2014-05-15 | 2015-11-25 | 广东东阳光药业有限公司 | Novel crystal form of ibrutinib and preparation method thereof |
| CN107530345A (en) * | 2015-03-03 | 2018-01-02 | 雷迪博士实验室有限公司 | The polymorph of Buddhist nun is replaced according to Shandong |
| WO2017085628A1 (en) * | 2015-11-16 | 2017-05-26 | Olon S.P.A. | Process for the preparation of the amorphous form of ibrutinib and novel crystalline form |
| CN105294696A (en) * | 2015-11-19 | 2016-02-03 | 上海创诺医药集团有限公司 | Novel crystal forms of ibrutinib and preparation method thereof |
| CN105440040A (en) * | 2015-12-23 | 2016-03-30 | 浙江京新药业股份有限公司 | Ibrutinib purification method |
| CN106905320A (en) * | 2015-12-23 | 2017-06-30 | 杭州容立医药科技有限公司 | It is a kind of to be adapted to medicinal replace Buddhist nun and its preparation according to Shandong |
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Application publication date: 20181026 |