CN106117214A - According to Shandong for Buddhist nun's novel crystal forms and preparation method thereof - Google Patents
According to Shandong for Buddhist nun's novel crystal forms and preparation method thereof Download PDFInfo
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- CN106117214A CN106117214A CN201610497395.XA CN201610497395A CN106117214A CN 106117214 A CN106117214 A CN 106117214A CN 201610497395 A CN201610497395 A CN 201610497395A CN 106117214 A CN106117214 A CN 106117214A
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- shandong
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- alkane
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- MUGJDDLNIGASQR-GOSISDBHSA-N C=CC(N1C[C@H](C[n](c2ncnc(N)c22)nc2-c(cc2)ccc2Oc2ccccc2)CCC1)=O Chemical compound C=CC(N1C[C@H](C[n](c2ncnc(N)c22)nc2-c(cc2)ccc2Oc2ccccc2)CCC1)=O MUGJDDLNIGASQR-GOSISDBHSA-N 0.000 description 1
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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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- 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 present invention provides a kind of and replaces Buddhist nun's novel crystal forms and preparation method thereof according to Shandong.Specifically, the invention provides according to Shandong for Buddhist nun crystal formation III and preparation method thereof.What preparation method provided by the present invention prepared has good heat stability according to Shandong for Buddhist nun crystal formation III, and stable storing under normal condition is suitable for industrial applications.
Description
Technical field
The present invention relates to medicinal chemistry art, in particular it relates to 1-[(3R)-3-[4-amino-3-(4-phenoxy group
Phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base]-piperidino] the novel crystal forms III of-2-propylene-1-ketone, and novel crystal forms
Preparation method and purposes.
Background technology
According to Shandong for Buddhist nun (Ibrutinib) by Pharmacyclics company of the U.S. and Johson & Johnson's joint research and development, trade name
Imbruvica, its chemical name is: [[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] is phonetic for (3R)-3-for 1-
Pyridine-1-base]-piperidino]-2-propylene-1-ketone, structural formula X is as follows:
The pioneering new drug of a kind of oral bruton's tyrosine kinase (BTK) inhibitor according to Shandong for Buddhist nun, this medicine by with
Target protein Btk activity site cysteine residue (Cys-481) optionally covalent bond, irreversibility ground suppression BTK, thus
Tumor is effectively stoped to move to be adapted to the lymphoid tissue of tumor growth environment from B cell.In November, 2013, U.S. food medicine
Product management board (FDA) ratifies its listing, for treating a kind of rare aggressive leukemia lymphoma mantle cell (MCL), and 2014
July in year, FDA ratified its treatment for chronic lymphocytic leukemia (CLL).
Patent WO2013/184572 of Pharmacyclics company of U.S. application in 2013 discloses according to Shandong for the six of Buddhist nun
Planting crystal formation, wherein crystal formation D is methyl isobutyl ketone solvent compound, and crystal formation E is toluene solvate, and crystal formation F is methanol solvate
Thing, is all not suitable for pharmaceutical formulation.In its excess-three kind crystal formation, report crystal formation B hygroscopicity according to WO2013/184572 and compare
Greatly, crystal formation A is not easy moisture absorption by contrast, does not report stability and the solubility data of crystal formation C.
According to WO2013/184572 disclosure, in six kinds of crystal formations, only crystal formation A is suitable for pharmaceutical formulation, its report
Crystal formation A has three kinds of preparation methoies: method one is will to be suspended in the organic solvent of 10 times of volumes for Buddhist nun's amorphous substance according to Shandong, shaking
Swing and device be heated to 50 DEG C, vibrate 1 hour, add the organic solvent of 30 times of volumes, be again heated to 50 DEG C and vibrate 1 hour,
Then being cooled to 0 DEG C with the speed of 0.1 DEG C/min, filter, the solid obtained is crystal formation A, and filtrate is by pin hole slow evaporation also
Obtain crystal formation A.This kind of method complex operation, and because consumption of organic solvent is 40 times, so the product being filtrated to get for the first time
Product yield is low, although and from filtrate, also can obtain product, but the most oversize；Method two is will to suspend for Buddhist nun's amorphous substance according to Shandong
In the organic solvent of 1-10 times of volume, then seal reaction bulb, seal 5 days in curing chamber, be filtrated to get crystal formation A.This kind
Method is the most long and it needs to special installation；Method three be by according to Shandong for Buddhist nun's heating for dissolving in the methanol of 10 times of volumes,
Adding water under insulation, then heat up, be then cooled to room temperature and continue to stir 16 hours, obtaining crystal formation A, yield is 80%.This kind
The complex operation of method, has liter gentleness cooling repeatedly, the bad control of production process in operation.
Suzhou crystalline substance cloud CN104327085A discloses another crystal formation A (hereinafter referred to as crystal formation A '), the preparation of its report
Method has three kinds: method one, by according to Shandong for Buddhist nun's dissolving crude product in the mixed solution of isopropanol and normal heptane, at room temperature with often
The speed stirring of minutes 750 turns obtains crystal formation A ', and such high-revolving stirring industrializing implementation is highly difficult；Method two, will be according to Shandong
For Buddhist nun's dissolving crude product in the mixed solvent of isopropanol and normal heptane, and drop to 5 DEG C with the cooling rate of 0.1 DEG C/min from 50 DEG C
Obtaining crystal formation A, so accurate cooling rate is difficult to control；Method three, will replace Buddhist nun's dissolving crude product in acetone according to Shandong, more slowly
Adding normal heptane, and stirring obtains crystal formation A in 1 day under the rotating speed of 1000 turns per minute, what this method ratio method one required turns
Speed is higher, and industrialization is more difficult to realize.Inventor, when repeating these methods, finds poor reproducibility, somewhat controls bad will obtain
To crystal formation A disclosed in WO2013/184572.
WO2015145415A discloses it and replaces Buddhist nun crystal formation III, IV, V, VI, VII, VIII, IX totally 6 kinds from name according to Shandong
Crystal formation, the most only crystal formation VI are non-solvent compound crystal formations, and crystal formation VI is being strict controlled in temperature 40 DEG C, relatively by crystal formation IV
In the environment of humidity 75%, placing the sufficiently long time, can to convert crystal formation be VI, and the method is readily obtained crystal formation IV and crystal formation VI
Mixed crystal, especially industrialized great production transfer crystalline substance effect can be worse.The metastable crystal formation of WO2015145415A report has two
Kind, one is crystal formation VII, and for anisol solvate, another kind is crystal formation VIII, for chlorobenzene solvent compound, is all not suitable for
Pharmaceutical formulation.
WO2016025720A discloses the acetic acid solvate crystal formation G and anisol solvate crystal formation J replacing Buddhist nun according to Shandong,
The most all be not suitable for further formulation development.
Therefore, it is simple that this area needs exploitation preparation method badly, Heat stability is good, is suitable for the most brilliant for Buddhist nun according to Shandong of formulation development
Type.
Summary of the invention
It is an object of the invention to provide a kind of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo
[3,4-d] pyrimidine-1-base]-piperidino] the crystal formation III of-2-propylene-1-ketone, and the preparation method of novel crystal forms and purposes.
First aspect present invention, it is provided that the crystal formation III of a kind of structure compound represented by a formula X, described crystal formation is high steady
Crystal qualitatively,
In another preference, described " high stability " refers to place 10 days described crystal formation III at 60 DEG C of lower open mouths, or
Place 10 days at relative humidity 92%, room temperature 25 DEG C, or place after 10 days under the illumination of room temperature 4500xl, stable crystal form.
In another preference, optical purity >=98% of described crystal formation III, preferably >=99%, most preferably >=
99.5%.
In another preference, chemical purity >=95% of described crystal formation III, preferably >=97%, most preferably >=99%.
In another preference, the X-ray powder diffraction pattern of described crystal formation III includes 3 or more than 3 selected from lower group
2 θ values: 5.11 ° ± 0.2 °, 6.47 ° ± 0.2 °, 11.13 ° ± 0.2 °, 13.42 ° ± 0.2 °, 17.05 ° ± 0.2 °, 19.13 °
±0.2°。
In another preference, the X-ray powder diffraction pattern of described crystal formation III includes 5 or more than 5 selected from lower group
2 θ values: 5.11 ° ± 0.2 °, 6.47 ° ± 0.2 °, 6.63 ° ± 0.2 °, 11.13 ° ± 0.2 °, 13.42 ° ± 0.2 °, 17.05 ° ±
0.2°、17.92°±0.2°、19.13°±0.2°、20.03°±0.2°、20.61°±0.2°、23.70°±0.2°。
In another preference, the X-ray powder diffraction pattern of described crystal formation III characterizes such as Fig. 1 substantially.
In another preference, the differential scanning calorimetry of described crystal formation III is analyzed collection of illustrative plates and is had in the range of 185 ± 5 DEG C
There is characteristic peak.
In another preference, the differential scanning calorimetry of described crystal formation III analyzes collection of illustrative plates substantially as Fig. 2 characterizes.
In another preference, the thermogravimetric analysis collection of illustrative plates of described crystal formation III characterizes such as Fig. 3 substantially.
In another preference, the infrared Fourier transform spectrum of described crystal formation III includes that 3 or more than 3 are selected from down
The characteristic absorption peak of group: 1681cm-1、1646cm-1、1610cm-1、1518cm-1、1487cm-1、1436cm-1、1372cm-1、
1235cm-1、1142cm-1、1100cm-1±2cm-1。
In another preference, the infrared Fourier transform spectrum of described crystal formation III is substantially as shown in Figure shown in 4.
Second aspect present invention, it is provided that a kind of side replacing Buddhist nun crystal formation III according to Shandong prepared as described in the first aspect of the invention
Method, including step:
I () will be dissolved in organic solvent for Buddhist nun crude product I according to Shandong, wherein, according to Shandong for Buddhist nun crude product I and the weight of organic solvent
Volume ratio is 1:1-1:30g/ml；
(ii) crystallize at-10 DEG C to 90 DEG C, thus obtain described crystal formation III；
Wherein, described according to Shandong for Buddhist nun crude product I selected from lower group: according to Shandong for Buddhist nun crystal formation C, according to Shandong for Buddhist nun's amorphous substance, according to Shandong
For Buddhist nun crystal formation A or a combination thereof.
In another preference, in described step (i), described organic solvent is selected from lower group: alcohols solvent, esters are molten
Agent, ketones solvent, alkane or a combination thereof, preferably alcohols solvent are mixed with alkane with the mixed solvent of alkane, esters solvent
The mixed solvent of bonding solvent, ketones solvent and alkane or a combination thereof.
In another preference, in the mixed solvent of described alcohols solvent and alkane, described alcohols and the volume ratio of alkane
For 1-10:1.
In another preference, described esters solvent is with the mixed solvent of alkane, and described esters with alkane volume ratio is
1-10:1.
In another preference, in the mixed solvent of described ketones solvent and alkane, described ketone and the volume ratio of alkane
For 1-10:1.
In another preference, in described step (i), described alcohols solvent is selected from lower group: methanol, ethanol, normal propyl alcohol, different
Propanol, n-butyl alcohol, isobutanol, the tert-butyl alcohol, n-amyl alcohol or a combination thereof.
In another preference, in described step (i), described esters solvent is selected from lower group: ethyl acetate, isopropyl acetate
Ester, methyl acetate, Ethyl formate, butyl acetate or a combination thereof.
In another preference, in described step (i), described ketones solvent is selected from lower group: acetone, 2-butanone, methyl are different
Butyl ketone, Ketohexamethylene or a combination thereof.
In another preference, in described step (i), described alkane is selected from lower group: pentane, normal hexane, hexamethylene, just
Heptane or a combination thereof.
Third aspect present invention, it is provided that a kind of medical composition, described compositions comprises (a) first aspect present invention institute
That states replaces Buddhist nun crystal formation III, and (b) pharmaceutically acceptable carrier according to Shandong.
Fourth aspect present invention, it is provided that medicine described in one crystal formation III as described in the first aspect of the invention or the third aspect
The purposes of compositions, for preparing prevention and/or the medicine for the treatment of cancer or for preparing the medicine of suppression tumor cell.
In another preference, described tumor includes lymphoma.
In another preference, described tumor cell includes lymphoma cell.
In should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and having in below (eg embodiment)
Can be combined with each other between each technical characteristic that body describes, thus constitute new or preferred technical scheme.As space is limited, exist
This repeats the most one by one.
Accompanying drawing explanation
Fig. 1 shows the X-ray powder diffractogram (XRPD) replacing Buddhist nun crystal formation III according to Shandong of the present invention.
Fig. 2 shows the differential scanning calorimetric analysis spectrogram (DSC) replacing Buddhist nun crystal formation III according to Shandong of the present invention.
Fig. 3 shows the thermogravimetic analysis (TGA) spectrogram (TGA) replacing Buddhist nun crystal formation III according to Shandong of the present invention.
Fig. 4 shows the infrared Fourier transform spectrogram (FT-IR) replacing Buddhist nun crystal formation III according to Shandong of the present invention.
Fig. 5 show the present invention according to Shandong, (a is original spectrogram, and b is relative for Buddhist nun's crystal formation III stability XRPD comparison diagram
Humidity 92%, room temperature 25 DEG C place 10 days spectrograms, and c is 60 DEG C and places 10 days spectrograms, and d is room temperature, 10 days spectrums of 4500xl illumination
Figure).
Detailed description of the invention
The present inventor, by extensively in-depth study, develops a kind of 1-[(3R)-3-[4-amino-3-(4-benzene first
Phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base]-piperidino] the crystal formation i.e. crystal formation III of-2-propylene-1-ketone, its
Possess good heat stability and non-hygroscopic, and preparation technology is simply efficient, reproducible, large-scale industrial can be realized raw
Produce.On this basis, the present invention is completed.
Term explanation
Unless otherwise defined, whole technology the most used herein and scientific terminology are respectively provided with such as art of the present invention
The identical meanings that is generally understood that of those of ordinary skill.
As used herein, when using in mentioning the numerical value specifically enumerated, term " about " means that this value can be from enumerating
Value variation is not more than 1%.Such as, as used herein, statement " about 100 " include 99 and 101 and between whole values (such as,
99.1,99.2,99.3,99.4 etc.).
As used herein, term " contains " or " including (comprising) " can be open, semi-enclosed and enclosed.Change
Yan Zhi, described term also include " substantially by ... constitute " or " by ... constitute ".Term " 3 or more than 3 ", " 5 or 5
Include above " technical scheme with whole numerical value.
Polymorph
As used in the present invention, " crystal formation III ", " 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo
[3,4-d] pyrimidine-1-base]-piperidino] the crystal formation III of-2-propylene-1-ketone ", " according to Shandong for Buddhist nun crystal formation III " is interchangeable makes
With.
Preparation method
The present invention also provides for the preparation method of described crystal III, including step:
I () will be dissolved in organic solvent for Buddhist nun crude product I according to Shandong, w/v is 1:1-1:30g/ml；
(ii) crystallize at-10 DEG C to 90 DEG C, thus obtain described crystal formation III；
Wherein, described according to Shandong for Buddhist nun crude product I selected from lower group: according to Shandong for Buddhist nun crystal formation C, according to Shandong for Buddhist nun's amorphous substance, according to Shandong
For Buddhist nun crystal formation A or a combination thereof.
In another preference, in described step (i), described organic solvent is selected from lower group: alcohols solvent, esters are molten
Agent, ketones solvent, alkane or a combination thereof, preferably alcohols solvent are mixed with alkane with the mixed solvent of alkane, esters solvent
The mixed solvent of bonding solvent, ketones solvent and alkane or a combination thereof.
As used herein, described each alcohols solvent, esters solvent, ketones solvent, the carbon atom number range of alkane are 1-10.
Additionally, in the preparation method of the present invention, mother solution is carried out one or many recovery, merge and reclaim circulation profit
With.
Pharmaceutical composition
Present invention also offers a kind of pharmaceutical composition, described pharmaceutical composition comprises the activity in the range of safe and effective amount
Composition, and pharmaceutically acceptable carrier.
" active component " of the present invention refer to of the present invention according to Shandong for Buddhist nun crystal formation III.
" active component " of the present invention and pharmaceutical composition for prepare prevention and/or treatment cancer medicine or
For preparing the medicine of suppression tumor cell.
" safe and effective amount " refers to: the amount of active component be enough to be obviously improved the state of an illness, and is unlikely to produce serious pair
Effect.Generally, pharmaceutical composition contains 1-2000mg active component/agent, more preferably, containing 10-200mg active component/agent.Relatively
Goodly, described " potion " is a tablet.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solid or liquid filler or gelatinous mass,
They are suitable for people and use and it is necessary to have enough purity and of a sufficiently low toxicity." compatibility " referred to herein as compositions
Middle each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the drug effect of compound.Pharmacy
Upper acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethyl cellulose, ethyl cellulose sodium, fiber
Element acetas etc.), gelatin, Talcum, kollag (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil is (such as Oleum Glycines, Semen Sesami
Oil, Oleum Arachidis hypogaeae semen, olive oil etc.), polyhydric alcohol (such as propylene glycol, glycerol, mannitol, sorbitol etc.), emulsifying agent (as), profit
Humectant (such as sodium lauryl sulphate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, apirogen water etc..
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited.The active component of the present invention or medicine
The method of application of compositions is not particularly limited, and representational method of application includes (but being not limited to): in oral, tumor, rectum,
Parenteral (intravenous, intramuscular or subcutaneous) etc..The compounds of this invention can be individually dosed, or pharmaceutically acceptable with other
Compound administering drug combinations.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.
In these solid dosage formss, active component mixes, such as Fructus Citri Limoniae with at least one conventional inert excipients (or carrier)
Acid sodium or dicalcium phosphate, or mix with following compositions: (a) filler or bulking agent, such as, starch, lactose, sucrose, glucose, sweet
Dew alcohol and silicic acid；(b) binding agent, such as, hydroxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and Ah
Draw primary glue；(c) wetting agent, such as, glycerol；(d) disintegrating agent, such as, agar, calcium carbonate, potato starch or tapioca, algae
Acid, some composition silicate and sodium carbonate；(e) retarding solvent, such as paraffin；F () absorbs accelerator, such as, quaternary ammonium compound；
(g) wetting agent, such as spermol and glyceryl monostearate；(h) adsorbent, such as, Kaolin；(i) lubricant, such as,
Talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.Capsule, tablet and ball
In agent, dosage form also can comprise buffer agent.
Described solid dosage forms also can use coating and shell material to prepare, such as casing and other material well known in the art.It
Can comprise opacifying agent, and, in this compositions, the release of active component can certain in digestive tract in a delayed fashion
A part discharges.The example of adoptable embedding component is polymeric material and Wax.
Liquid formulation for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.
In addition to active component, liquid dosage form can comprise the conventional inert diluent used in this area, such as water or other solvent, solubilising
Agent and emulsifying agent, example knows, ethanol, isopropanol etc..In addition to these inert diluents, compositions also can comprise auxiliary agent, such as moistening
Agent, emulsifying agent and suspending agent, sweeting agent, correctives and spice.
In addition to active component, suspension can comprise suspending agent, such as, ethoxylation isooctadecane alcohol, polyoxyethylene mountain
Pears alcohol and Isosorbide Dinitrate, microcrystalline Cellulose, aluminium methoxide and agar or the mixture etc. of these materials.
Compositions for parenteral injection can comprise physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or emulsion, and for being again dissolved into the sterilized powder of aseptic Injectable solution or dispersion liquid.Suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethanol, polyhydric alcohol and suitable mixture thereof.
The compounds of this invention can be individually dosed, or with other treatment medicine (such as chemotherapeutic) administering drug combinations.
When making pharmaceutical composition, it it is the mammal that the compounds of this invention of safe and effective amount is applicable to treatment
(such as people), when wherein using, dosage is the effective dosage pharmaceutically thought, for the people of 60kg body weight, day is to medicament
Amount is usually 1～2000mg, preferably 20～500mg.Certainly, concrete dosage is it is also contemplated that route of administration, patient health situation etc.
Factor, within the scope of these are all skilled practitioners technical ability.
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 according to conventional strip
Part, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage ratio and number are percentage by weight and weight
Number.
Raw material and universal method
Raw materials used in embodiment prepare with reference to WO2013/184572 for Buddhist nun crystal formation C, crystal formation A according to Shandong, according to Shandong for Buddhist nun without fixed
Shape thing is prepared with reference to WO2008/039218.
XRD figure spectrum assay method
X-ray powder diffraction instrument: Dedye～Scherrer INEL CPS～120X-ray powder diffractometer；Radiation
Source:Strength ratio α 1/ α 2 is 0.5；Generator (Generator) kv:40kv；Occur
Device (Generator) mA:30mA；Initial 2 θ: 2.000 °, sweep limits: 2.0000～50.000 °.
DSC collection of illustrative plates assay method
Differential scanning calorimetry (DSC) instrument: the Q2000 type of TA company of the U.S., in the range of 20～450 DEG C, the rate of heat addition
10 DEG C/min, nitrogen flow rate 50ml/min.
TGA collection of illustrative plates assay method
Thermogravimetric analysis (TGA) instrument: the SDT Q600 type of TA company of the U.S., in the range of 20～450 DEG C, the rate of heat addition 10
DEG C/min, nitrogen flow rate 100ml/min.
FTIR collection of illustrative plates assay method
Infrared spectrophotometer (FTIR) instrument: PE Spectrum Two, tests temperature 23 DEG C, relative humidity 54%, adopts
Use pellet technique.
Main advantages of the present invention are:
(1) the crystal formation III of the present invention has good heat stability and agent of low hygroscopicity.
(2) preparation method of the crystal formation III of the present invention is simple, is suitable for large-scale industrial production.
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 according to conventional strip
Part, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage ratio and number are percentage by weight and weight
Number.
Experiment material used in following example and reagent the most all can obtain from commercially available channel.
Embodiment 1 replaces the preparation of Buddhist nun crystal formation III according to Shandong
To add in 50ml normal propyl alcohol for Buddhist nun's amorphous substance (5.0g) according to Shandong, and be heated to backflow and make dissolving.Treat molten the most follow-up
Continuous stirring 30 minutes.Stop heating, lower the temperature with the speed of about 1 DEG C/min, be cooled to 50 DEG C, have solid to separate out, insulated and stirred 2
Hour, to filter, filtrate uses ethyl acetate drip washing, and filter cake is vacuum dried to obtain 3.2g product in 50 DEG C.
Result: the x-ray diffractogram of powder of gained solid such as Fig. 1 is characterized, differential scanning spectrogram is as in figure 2 it is shown, thermogravimetric
Analyze as it is shown on figure 3, infrared Fourier transform spectrum as shown in Figure 4.
Embodiment 2 replaces the preparation of Buddhist nun crystal formation III according to Shandong
To add in 75ml isopropanol for Buddhist nun crystal formation C (5.0g) according to Shandong, stirred overnight at room temperature, the suspended matter mistake that will obtain
Filter, 50 DEG C are dried under vacuum to constant weight, obtain 3.9g white solid.
Result: the x-ray diffractogram of powder of gained solid is identical with embodiment 1 gained crystal formation.
Embodiment 3 is prepared for Buddhist nun crystal formation III according to Shandong
To add in 300ml ethyl acetate for Buddhist nun's amorphous substance (50.0g) according to Shandong, and be heated to 70 DEG C and make dissolving, treat molten clearly
After, stop heating, mixture is cooled to rapidly 50 DEG C.Insulated and stirred 2 hours, filters.Filter cake 15ml ethyl acetate drip washing,
26.2g white solid it is vacuum dried to obtain at 50 DEG C.
Result: the x-ray diffractogram of powder of gained solid is identical with embodiment 1 gained crystal formation.
Embodiment 4 is prepared for Buddhist nun crystal formation III according to Shandong
To add in the 20ml isopropanol mixed solvent with 10ml normal hexane for Buddhist nun crystal formation A (3.0g) according to Shandong, be heated to 50
DEG C make dissolving, until molten clear after, stop heating, mixture cooled to rapidly 0～5 DEG C.Insulated and stirred 2 hours, filters.Filter cake is used
2ml isopropanol and the mixed solvent drip washing of 1ml normal hexane, be vacuum dried to obtain 2.5g white solid at 50 DEG C.
Result: the x-ray diffractogram of powder of gained solid is identical with embodiment 1 gained crystal formation.
Embodiment 5 is prepared for Buddhist nun crystal formation III according to Shandong
To add in 50ml 2-butanone for Buddhist nun crystal formation C (5.0g) according to Shandong, stirring and dissolving, it is heated to 70 DEG C, insulated and stirred 2
Hour, the suspended matter filtered while hot that will obtain, filter cake 3ml 2-butanone drip washing, 50 DEG C are dried under vacuum to constant weight, obtain 2.5g
White solid.
Result: the x-ray diffractogram of powder of gained solid is identical with embodiment 1 gained crystal formation.
Mother solution in above-described embodiment can merge recovery.
Embodiment 6 stability test
Obtained by Example 1-5 according to Shandong for Buddhist nun crystal formation III, be divided into identical three groups, place at 60 DEG C of lower open mouths respectively
10 days；Place 10 days at relative humidity is 92% room temperature 25 DEG C；Under room temperature after 4500xl illumination 10 days, the XRPD of above-mentioned three groups
Comparison collection of illustrative plates is as shown in Figure 5.
From figure 5 it can be seen that the crystal formation III stability of crystal form that the present invention obtains is fine.
Embodiment 7 wettability test
Weigh being laid in weighing botle for each 0.5 gram of Buddhist nun crystal formation III according to Shandong obtained by embodiment 1-5 respectively, weigh, will
Load weighted weighing botle opening is positioned over exsiccator (the using saturated ammonium chloride solution control) middle part that humidity is 80%, and covers dry
Dry device seals lid；Place 24 hours, take out and again weigh the weight of weighing botle, and calculate percentage weight increase with this and be about 0.5%.
The above embodiment of the present invention shows, crystal formation III not only preparation technology is simple, and have high stability and
The agent of low hygroscopicity being highly profitable.
The all documents mentioned in the present invention are incorporated as reference the most in this application, just as each document by individually
It is incorporated as with reference to like that.In addition, it is to be understood that after the above-mentioned teachings having read the present invention, those skilled in the art can
To make various changes or modifications the present invention, these equivalent form of values fall within the model that the application appended claims is limited equally
Enclose.
Claims (10)
1. the crystal formation III of structure compound represented by a formula X, it is characterised in that described crystal formation is the crystal of high stability,
2. crystal formation III as claimed in claim 1, it is characterised in that it is one or more that described crystal formation III has selected from lower group
Feature:
(1) X-ray powder diffraction pattern of described crystal formation III includes 3 or more than 3 selected from the 2 θ values of lower group: 5.11 ° ±
0.2°、6.47°±0.2°、11.13°±0.2°、13.42°±0.2°、17.05°±0.2°、19.13°±0.2°；
(2) X-ray powder diffraction pattern of described crystal formation III includes 5 or more than 5 selected from the 2 θ values of lower group: 5.11 ° ±
0.2°、6.47°±0.2°、6.63°±0.2°、11.13°±0.2°、13.42°±0.2°、17.05°±0.2°、17.92°±
0.2°、19.13°±0.2°、20.03°±0.2°、20.61°±0.2°、23.70°±0.2°；
(3) X-ray powder diffraction pattern of described crystal formation III characterizes such as Fig. 1 substantially；And/or
(4) the thermogravimetric analysis collection of illustrative plates of described crystal formation III characterizes such as Fig. 3 substantially.
3. crystal formation III as claimed in claim 1, it is characterised in that the differential scanning calorimetry of described crystal formation III analyzes collection of illustrative plates
In the range of 185 ± 5 DEG C, there is characteristic peak；And/or
The differential scanning calorimetry of described crystal formation III analyzes collection of illustrative plates substantially as Fig. 2 characterizes.
4. crystal formation III as claimed in claim 1, it is characterised in that the infrared Fourier transform spectrum of described crystal formation III includes
3 or more than 3 characteristic absorption peak being selected from lower group: 1681cm-1、1646cm-1、1610cm-1、1518cm-1、1487cm-1、
1436cm-1、1372cm-1、1235cm-1、1142cm-1、1100cm-1±2cm-1；And/or
The infrared Fourier transform spectrum of described crystal formation III is substantially as shown in Figure shown in 4.
5. prepare the method replacing Buddhist nun crystal formation III according to Shandong as claimed in claim 1, including step:
I () will be dissolved in organic solvent for Buddhist nun crude product I according to Shandong, wherein, according to Shandong for Buddhist nun crude product I and the bulking value of organic solvent
Ratio is 1:1-1:30g/ml；
(ii) crystallize at-10 DEG C to 90 DEG C, thus obtain described crystal formation III；
Wherein, described according to Shandong for Buddhist nun crude product I selected from lower group: according to Shandong for Buddhist nun crystal formation C, according to Shandong for Buddhist nun's amorphous substance, according to Shandong for Buddhist nun
Crystal formation A or a combination thereof.
6. method as claimed in claim 5, it is characterised in that in described step (i), described organic solvent is selected from lower group:
Alcohols solvent, esters solvent, ketones solvent, alkane or a combination thereof, preferably alcohols solvent and the mixed solvent of alkane, ester
Kind solvent and the mixed solvent of alkane, the mixed solvent of ketones solvent and alkane or a combination thereof.
7. method as claimed in claim 6, it is characterised in that in the mixed solvent of described alcohols solvent and alkane, described alcohol
Class is 1-10:1 with the volume ratio of alkane；And/or
Described esters solvent is with the mixed solvent of alkane, and described esters and alkane volume ratio are 1-10:1；And/or
Described ketones solvent is with the mixed solvent of alkane, and described ketone is 1-10:1 with the volume ratio of alkane.
8. method as claimed in claim 5, it is characterised in that in described step (i), described alcohols solvent is selected from lower group: first
Alcohol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, isobutanol, the tert-butyl alcohol, n-amyl alcohol or a combination thereof.
9. method as claimed in claim 5, it is characterised in that in described step (i), described esters solvent is selected from lower group: second
Acetoacetic ester, isopropyl acetate, methyl acetate, Ethyl formate, butyl acetate or a combination thereof.
10. a medical composition, it is characterised in that it is brilliant for Buddhist nun according to Shandong that described compositions comprises described in (a) claim 1
Type III, and (b) pharmaceutically acceptable carrier.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018000250A1 (en) * | 2016-06-29 | 2018-01-04 | 上海创诺医药集团有限公司 | New ibrutinib crystal form and preparation method therefor |
| 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 |
| 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 |
Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102887900A (en) * | 2006-09-22 | 2013-01-23 | 药品循环公司 | Inhibitors of bruton's tyrosine kinase |
| CN103121999A (en) * | 2012-08-29 | 2013-05-29 | 苏州迪飞医药科技有限公司 | Method for synthesizing tyrosine kinase inhibitor PCI-32765 |
| CN103626774A (en) * | 2013-11-20 | 2014-03-12 | 苏州明锐医药科技有限公司 | Preparation method of Ibrutinib |
| CN103923084A (en) * | 2014-01-29 | 2014-07-16 | 苏州晶云药物科技有限公司 | Several new crystal forms and preparation methods thereof |
| 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 |
| CN104736178A (en) * | 2012-06-04 | 2015-06-24 | 药品循环公司 | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
| 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 |
| CN105646484A (en) * | 2016-03-01 | 2016-06-08 | 孙霖 | Crystal form B and preparation method |
| CN105646499A (en) * | 2016-03-01 | 2016-06-08 | 孙霖 | Crystal form G of ibrutinib and preparation method |
| CN105646498A (en) * | 2016-03-01 | 2016-06-08 | 孙霖 | Crystal form F of ibrutinib and preparation method |
| CN105693716A (en) * | 2016-03-01 | 2016-06-22 | 孙霖 | Crystal form A and preparing method |
-
2016
- 2016-06-29 CN CN201610497395.XA patent/CN106117214A/en active Pending
Patent Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102887900A (en) * | 2006-09-22 | 2013-01-23 | 药品循环公司 | Inhibitors of bruton's tyrosine kinase |
| CN104736178A (en) * | 2012-06-04 | 2015-06-24 | 药品循环公司 | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
| CN103121999A (en) * | 2012-08-29 | 2013-05-29 | 苏州迪飞医药科技有限公司 | Method for synthesizing tyrosine kinase inhibitor PCI-32765 |
| CN103626774A (en) * | 2013-11-20 | 2014-03-12 | 苏州明锐医药科技有限公司 | Preparation method of Ibrutinib |
| 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 |
| CN103923084A (en) * | 2014-01-29 | 2014-07-16 | 苏州晶云药物科技有限公司 | Several new crystal forms and preparation methods 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 |
| CN105646484A (en) * | 2016-03-01 | 2016-06-08 | 孙霖 | Crystal form B and preparation method |
| CN105646499A (en) * | 2016-03-01 | 2016-06-08 | 孙霖 | Crystal form G of ibrutinib and preparation method |
| CN105646498A (en) * | 2016-03-01 | 2016-06-08 | 孙霖 | Crystal form F of ibrutinib and preparation method |
| CN105693716A (en) * | 2016-03-01 | 2016-06-22 | 孙霖 | Crystal form A and preparing method |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018000250A1 (en) * | 2016-06-29 | 2018-01-04 | 上海创诺医药集团有限公司 | New ibrutinib crystal form and preparation method therefor |
| 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 |
| 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 |
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