CN109053738A - A kind of solvate and preparation method thereof replacing Buddhist nun according to Shandong - Google Patents
A kind of solvate and preparation method thereof replacing Buddhist nun according to Shandong Download PDFInfo
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- CN109053738A CN109053738A CN201810997233.1A CN201810997233A CN109053738A CN 109053738 A CN109053738 A CN 109053738A CN 201810997233 A CN201810997233 A CN 201810997233A CN 109053738 A CN109053738 A CN 109053738A
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- shandong
- buddhist nun
- solvate
- isopropyl acetate
- crystal form
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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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
Abstract
The invention discloses a kind of solvates and preparation method thereof that Buddhist nun is replaced according to Shandong.The isopropyl acetate list solvate for replacing Buddhist nun according to Shandong for Buddhist nun's solvate according to Shandong, preparation method are as follows: will be added in suitable isopropyl acetate according to Shandong for Buddhist nun's raw material, and make it in suspension, and keep stirring at a certain temperature, filtering is drying to obtain according to Shandong for Buddhist nun's list solvate；Or will be dissolved in isopropyl acetate in a heated condition according to Shandong for Buddhist nun's raw material, acquired solution is then transferred to decrease temperature crystalline under cryogenic conditions, is filtered, solid is collected, is obtained after dry and replace Buddhist nun's list solvate according to Shandong.The new solvate that Buddhist nun is replaced according to Shandong provided by the invention, under the conditions of different pH, solubility is 2~4 times of medicinal crystal-form A, and stability is preferable, safety and low toxicity, and preparation process is simple, condition is easily controllable, yield is higher, to equipment without particular/special requirement, has the potentiality as medicinal crystal-form.
Description
Technical field
The invention belongs to field of medicine preparing technology, are related to the preparation of bulk pharmaceutical chemicals, and in particular to a kind of molten for Buddhist nun according to Shandong
Agent compound and preparation method thereof.
Background technique
Buddhist nun (Ibrutinib) is replaced according to Shandong, entitled 1- ((3R) -3- (4- amino -3- (4- the Phenoxyphenyl) -1H- pyrrole of chemistry
Azoles simultaneously [3,4-d] pyrimidine -1- base) -1- piperidyl) -2- propylene -1- ketone, trade name Imbruvica, chemical structural formula such as formula
(II) shown in:
Replacing Buddhist nun according to Shandong is by the target anticancer of Johnson Johnson company and Pharmacyclics company R & D Cooperation
Drug is a kind of inhibitor of small molecule bruton's tyrosine kinase (BTK), is suitable for treatment B cell non-Hodgkin lymphoma
(NHL) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).The medicine was November 13 in 2013
Huo U.S. Food and Drug Administration (FDA) approval listing.
In the international monopoly WO2013/184572A1 of Yuan Yan company application, six kinds of crystal forms that Buddhist nun is replaced according to Shandong are disclosed,
In there are three types of no hydrate, respectively crystal form A, crystal form B and crystal form C；In addition there are three types of solvates, respectively methylisobutylketone
Solvate crystal form D, toluene solvate crystal form E and Methanol Solvate crystal form F.Crystal form A is at present according to Shandong for the medicinal of Buddhist nun
Crystal form, in pH=8.0, solubility is 13.0 μ g/mL, there are problems that poor solubility, crystal form B solubility in pH=7.42
Only 9.6 μ g/mL, the problem of equally existing poor solubility；It is not mentioned in the stability and solubility data of crystal form the C patent
And；And in three kinds of solvates, have no the report of solubility properties, and either methylisobutylketone, toluene or methanol are equal
With toxicity, it is not suitable for medicinal crystal-form.
Periodical literature (Cryst.Growth Des., 2018,18:1315-1326.) is reported according to Shandong for Buddhist nun's crystal form A, crystalline substance
Type B and tri- kinds of crystal form C are without hydrate and preparation method.Crystal form A is by being slowly added to water into the methanol solution for replacing Buddhist nun according to Shandong
It is prepared as solvent resistant；Crystal form B for water is rapidly joined in the methanol solution of Buddhist nun to according to Shandong as solvent resistant by preparing；Crystal form C
Pass through the methanol solution cooling recrystallization preparation according to Shandong for Buddhist nun.The dissolution rate of crystal form B and crystal form C are 3 times or so of crystal form A.
The another kind for grinding patent different from original is disclosed in the patent WO2015/081180A1 of Suzhou crystalline substance cloud application to replace according to Shandong
By preparing according to Shandong for the method for Buddhist nun's solution decrease temperature crystalline, the stability of crystal form is good by Buddhist nun's crystal form I and preparation method thereof, crystal form I,
Almost no hygroscopicity, solubility raising are not obvious, about the 1.2 of crystal form A times.
Ratiopharm company application patent WO2016/050422A1 in disclose according to Shandong for Buddhist nun's hydrochloride form and
Preparation method.There is preferable solubility (solubility is 410 μ g/mL when pH=6.8), preparation method for Buddhist nun's hydrochloride according to Shandong
, to the organic solution that hydrogen chloride is added dropwise in Buddhist nun's solution is replaced according to Shandong, to be readily incorporated chemical structure such as in preparation process under cryogenic conditions
Impurity shown in formula (III).In the patent not about according to Shandong for the report in terms of Buddhist nun's hydrochloric acid salt-stable.
According to above-mentioned document, for Buddhist nun, there are a variety of crystal forms according to Shandong for anticancer drug, and wherein crystal form A is current medicinal crystalline substance
Type, poorly water-soluble, total bioavilability are only 3%；Crystal form B, crystal form C and crystal form I belong to metastable crystal form, and solubility is mentioned
It is high；Crystal form D, crystal form E and crystal form F belong to solvate, but used solvent has certain toxicity, is not suitable as medicinal
Crystal form；There is preferable solubility for Buddhist nun's hydrochloride according to Shandong, be conducive to improve bioavilability, but do not report the salt form in patent
Stability.Therefore, it is high and have the new for Buddhist nun according to Shandong of certain stability to need to develop a kind of safety and low toxicity, solubility for this field
Crystal form.
Summary of the invention
In order to overcome according to Shandong for solubility is low, stability is insufficient present in existing crystal form of Buddhist nun and preparation method thereof, reappears
Property it is poor, preparation process is cumbersome the disadvantages of, the purpose of the present invention is to provide it is a kind of according to Shandong for Buddhist nun solvate and its preparation
Method.The resulting solvate good stability according to Shandong for Buddhist nun, favorable reproducibility, improve 2~4 times relative to crystal form A solubility,
Relative to crystal form D, crystal form E and crystal form F, used solvent toxicity is low, and preparation process is simple, condition is easily controllable, yield
It is higher, to equipment without particular/special requirement, there are the potentiality as medicinal crystal-form.
A kind of solvate replacing Buddhist nun according to Shandong, it is characterised in that for the isopropyl acetate list solvation for replacing Buddhist nun according to Shandong
Object, shown in structural formula such as formula (I):
Replacing the mass ratio of the material of Buddhist nun and isopropyl acetate according to Shandong is 1:1.
The solvate that Buddhist nun is replaced according to Shandong, it is characterised in that described to be with angle of diffraction for the solvate of Buddhist nun according to Shandong
2 θ indicate X-ray powder diffraction (PXRD) map be shown in 7.44 ° ± 0.2 °, 7.91 ° ± 0.2 °, 9.05 ° ± 0.2 °,
10.32°±0.2°、14.39°±0.2°、14.69°±0.2°、15.73°±0.2°、18.27°±0.2°、18.97°±
0.2°、20.64°±0.2°、21.34°±0.2°、21.97°±0.2°、22.71°±0.2°、25.05°±0.2°、27.05°
There is characteristic peak at ± 0.2 °, 27.72 ° ± 0.2 °.
The solvate that Buddhist nun is replaced according to Shandong, it is characterised in that the X-ray powder diffraction (PXRD) indicated with 2 θ angles
Map is shown below position with characteristic peak and relative intensity:
The solvate that Buddhist nun is replaced according to Shandong, it is characterised in that the differential scanning amount of the solvate according to Shandong for Buddhist nun
Hot (DSC) curve is shown at 73~77 DEG C, 155~159 DEG C feature endothermic peak respectively, there is feature heat release at 77~82 DEG C
Peak；Thermogravimetric analysis (TGA) curve according to Shandong for the solvate of Buddhist nun is shown in 50~150 DEG C, weightless 18.0-18.9%；300
~500 DEG C, weightless 68.0-68.9%.
The solvate that Buddhist nun is replaced according to Shandong, it is characterised in that the Fourier of the solvate according to Shandong for Buddhist nun is infrared
Spectrum (FT-IR) map display characteristic peak positions are 3409cm in wave number-1、3115cm-1、1721cm-1、1637cm-1、1613cm-1、1519cm-1、1242cm-1、11367cm-1And 1069cm-1Place.
The preparation method of the solvate according to Shandong for Buddhist nun, it is characterised in that use magma method or lowering temperature crystallization.
The preparation method of the solvate according to Shandong for Buddhist nun, it is characterised in that included the following steps: using magma method
1) it will be mixed for Buddhist nun's raw material with isopropyl acetate solvent according to Shandong, and obtain suspension；
2) suspension of step 1) stirred under constant temperature conditions, filter, collect solid, drying, obtained according to Shandong for Buddhist nun's second
Isopropyl propionate list solvate.
The preparation method of the described solvate according to Shandong for Buddhist nun, it is characterised in that in step 1) is for Buddhist nun's raw material according to Shandong
Crystal form C；In the suspension, it is preferably 10~200mg:1mL that the solid-liquid ratio of Buddhist nun's raw material and isopropyl acetate solvent is replaced according to Shandong,
Preferably 50~100mg:1mL；
Constant temperature in step 2) is 0~50 DEG C, preferably 20~30 DEG C；Stirring rate is 100~1500 revs/min
Clock, preferably 500~1000 revs/min；Mixing time is 1~24 hour, preferably 5~12 hours.
The preparation method of the solvate according to Shandong for Buddhist nun, it is characterised in that lowering temperature crystallization includes the following steps:
1) it will be dissolved in isopropyl acetate solvent under condition of heating and stirring according to Shandong for Buddhist nun's raw material, and obtain solution；
2) filtration step 1 while hot) solution, filtrate is placed in cooling crystallization, filtering, drying in low temperature environment, obtains according to Shandong
For Buddhist nun's isopropyl acetate list solvate.
The preparation method of the described solvate according to Shandong for Buddhist nun, it is characterised in that in step 1) is for Buddhist nun's raw material according to Shandong
Crystal form A, crystal form B, crystal form C and unformed；Heating temperature is 50 DEG C~89 DEG C, preferably 70 DEG C~89 DEG C；
Low temperature environment in step 2) is -40~25 DEG C；Preferably -20~5 DEG C.
By using above-mentioned technology, the present invention obtains one kind according to Shandong for Buddhist nun's solvate, replaces Buddhist nun's novel crystal forms as according to Shandong, with
It is known compared according to Shandong for Buddhist nun's crystal form and technology of preparing have it is following significant the utility model has the advantages that
1) the isopropyl acetate list solvate of the present invention for replacing Buddhist nun according to Shandong for Buddhist nun's solvate according to Shandong, compared to
The medicinal crystal-form A of Buddhist nun is replaced according to Shandong, under the conditions of different pH, solubility improves 2~4 times；According to solvent grade scale, acetic acid
Isopropyl ester belongs to third class solvent, small to environmental and human health impacts harm, replaces Buddhist nun's methylisobutylketone, first according to Shandong compared to known
Benzene, Methanol Solvate, safety and low toxicity are particularly suited for the raw material crystal form of preparation, and the present invention only obtains one kind according to Shandong for Buddhist nun
Novel crystal forms do not influence its therapeutic effect, because being used for small molecule bruton's tyrosine kinase (BTK) as targeted anticancer medicine
Inhibitor, be equally applicable to treatment B cell non-Hodgkin lymphoma (NHL) chronic lymphocytic leukemia (CLL) and
Small lymphocytic lymphoma (SLL)；
2) of the present invention simple for Buddhist nun's solvate preparation process according to Shandong, condition is easily controllable, and yield is higher, to setting
For no particular/special requirement, industrialization easy to accomplish；
3) of the present invention to place 2 months stabilizations at room temperature according to Shandong for Buddhist nun's solvate, respectively at 25 DEG C,
Intensity of illumination be 4500 ± 500lx and relative humidity be 90 ± 5% under conditions of place 10 days and 25 DEG C, grind under the conditions of 20Hz
Mill 10 minutes, crystal form does not change, illustrates that its stability is preferable, is suitble to the production and storage of drug, has exploitation patent medicine
The potentiality of object preparation.
Detailed description of the invention
Fig. 1 is the PXRD map of the present invention that Buddhist nun's solvate is replaced according to Shandong；
Fig. 2 is the DSC curve of the present invention that Buddhist nun's solvate is replaced according to Shandong；
Fig. 3 is the TGA curve of the present invention that Buddhist nun's solvate is replaced according to Shandong；
Fig. 4 is the FT-IR map of the present invention that Buddhist nun's solvate is replaced according to Shandong；
Fig. 5 shows the PXRD map of the present invention that Buddhist nun's isopropyl acetate list solvate stability contrast is replaced according to Shandong
(a is the original figure spectrum that Buddhist nun's isopropyl acetate list solvate is replaced according to Shandong, and b is to exist according to Shandong for Buddhist nun's isopropyl acetate list solvate
25 DEG C, place 10 days under the conditions of 4500 ± 500lx intensity of illumination after map；C is to replace Buddhist nun's isopropyl acetate list solvation according to Shandong
Object placed 10 days under 25 DEG C, 90 ± 5% relative humidities after map；D is to replace Buddhist nun's isopropyl acetate list solvation according to Shandong
Object grinds map after ten minutes under the conditions of 25 DEG C, 20Hz).
Specific embodiment
Below in conjunction with embodiment, the invention will be further described, and professional and technical personnel in the field can be made more comprehensive
Understand the present invention, but do not limit the invention in any way range.
The present invention acquires instrument and method used in data:
Instrument used in X-ray powder diffraction pattern is Bruker D42 Advance diffractometer.Sample is in room temperature item
It is tested under part, testing conditions are as follows: 2 3~40 ° of θ angular ranges；0.02 ° of step-length/step；Speed 0.2s/ step.
Differential scanning calorimetric analysis data are collected in TA DSC 250.Detection process are as follows: take 1~10mg sample to be with 30 DEG C
Equilibrium temperature, the heating rate of 10 DEG C/min is under the protection of 200mL/min dry nitrogen atmosphere from 30 DEG C of heating samples to 200
℃。
Thermogravimetric analysis data is collected in TGA Q500.Detection process are as follows: 5~10mg sample is taken, in 40mL/min dry nitrogen
Under the protection that atmosphere is enclosed, with the heating rate of 20 DEG C/min from 30 DEG C of heating samples to 500 DEG C.
Infrared spectrogram is from Burker Tensor 27FT-IR.Test method are as follows: prepare sample tabletting and KBr is empty
White tabletting, is detected, and infrared spectrogram is obtained.
Dissolubility data is from UV-2550 ultraviolet specrophotometer, Detection wavelength 260nm, at this wavelength solvent
Isopropyl acetate solvent contained in compound does not interfere detection.
Embodiment 1
It weighs 1000mg and is added to the cillin bottle of 20mL according to Shandong for Buddhist nun's crystal form C raw material, then measure 10mL isopropyl acetate and add
Enter in the cillin bottle, 10 DEG C, stir 12 hours under 1000 revs/min of revolving speed, filters, filter cake is placed in room temperature condition and air-dries 24
Hour, it obtains according to Shandong for Buddhist nun's isopropyl acetate list solvate 1121mg, yield 91%.Pass through powder x-ray diffraction analysis
It can determine whether that raw material has turned brilliant to replace Buddhist nun's solvate according to Shandong completely, can determine whether that resulting solvate is acetic acid by TGA analysis
Isopropyl ester list solvate, gained have X-ray powder diffraction as shown in Figure 1 according to Shandong for Buddhist nun's isopropyl acetate list solvate
Figure, DSC curve are shown in that Fig. 2, TGA curve are shown in that Fig. 3, FT-IR map are shown in Fig. 4.
Embodiment 2
It weighs 500mg and is added to the cillin bottle of 20mL according to Shandong for Buddhist nun's crystal form C raw material, then measure the addition of 10mL isopropyl acetate
In the cillin bottle, 25 DEG C, stir 5 hours under 1000 revs/min of revolving speed, filters, filter cake is placed in room temperature condition vacuum drying 2
Hour, it obtains according to Shandong for Buddhist nun's isopropyl acetate list solvate 524mg, yield 85%.
Embodiment 3
It weighs 1000mg and is added in the cillin bottle of 20mL according to Shandong for Buddhist nun's crystal form C raw material, then measure 15mL isopropyl acetate
It is added in the cillin bottle, 30 DEG C, stir 10 hours under 500 revs/min of revolving speed, filters, filter cake is placed in room temperature environment very
Sky is 2 hours dry, obtains according to Shandong for Buddhist nun's isopropyl acetate list solvate 1059mg, yield 86%.
Embodiment 4
It weighs 1000mg and is added to the cillin bottle of 20mL according to Shandong for Buddhist nun's crystal form C raw material, then measure the addition of 7mL isopropyl acetate
It in the cillin bottle, 0 DEG C, stir 24 hours under 1200 revs/min of revolving speed, filters, filter cake is placed in room temperature condition, and to air-dry 24 small
When, it obtains according to Shandong for Buddhist nun's isopropyl acetate list solvate 1146mg, yield 93%.
Embodiment 5
It weighs 100mg and is added in the cillin bottle of 4mL according to Shandong for Buddhist nun's crystal form A raw material, then measure the addition of 3mL isopropyl acetate
In the cillin bottles, 89 DEG C are heated under stirring, is filtered while hot, filtrate is placed in decrease temperature crystalline 3 days in -20 DEG C of environment, obtain according to
Replace Buddhist nun's isopropyl acetate list solvate 100mg, yield 81% in Shandong.
Embodiment 6
It weighs 100mg and is added to the cillin bottle of 4mL according to Shandong for Buddhist nun's crystal form B raw material, then measuring the addition of 3mL isopropyl acetate should
In cillin bottle, it is heated to 80 DEG C under stirring, filters while hot, filtrate is placed in decrease temperature crystalline 5 days in -30 DEG C of environment, is obtained according to Shandong
For Buddhist nun isopropyl acetate list solvate 102mg, yield 83%.
Embodiment 7
It weighs 100mg and is added to the cillin bottle of 4mL according to Shandong for Buddhist nun's crystal form C raw material, then measuring the addition of 4mL isopropyl acetate should
In cillin bottle, it is heated to 50 DEG C under stirring, filters while hot, filtrate is placed in decrease temperature crystalline 7 days in -40 DEG C of environment, is obtained according to Shandong
For Buddhist nun isopropyl acetate list solvate 95mg, yield 77%.
Embodiment 8
It weighs 100mg and is added to the cillin bottle of 4mL according to Shandong for the unformed raw material of Buddhist nun, then measure the addition of 4mL isopropyl acetate
In the cillin bottle, it is heated to 80 DEG C under stirring, filters while hot, filtrate is placed in 0 DEG C of environment decrease temperature crystalline 3 days, is obtained according to Shandong
For Buddhist nun isopropyl acetate list solvate 97mg, yield 79%.
Embodiment 9
It weighs 100mg and is added to the cillin bottle of 4mL according to Shandong for Buddhist nun's crystal form A raw material, then measuring the addition of 2mL isopropyl acetate should
In cillin bottle, it is heated to 89 DEG C under stirring, filters while hot, filtrate is placed in 0 DEG C of environment decrease temperature crystalline 7 days, obtains replacing according to Shandong
Buddhist nun isopropyl acetate list solvate 106mg, yield 86%.
Embodiment 10
It weighs 100mg and is added to the cillin bottle of 20mL according to Shandong for Buddhist nun's crystal form C raw material, then measure the addition of 1mL isopropyl acetate
In the cillin bottle, it is heated to 89 DEG C under stirring, filters while hot, filtrate is placed in 25 DEG C of environment decrease temperature crystalline 7 days, is obtained according to Shandong
For Buddhist nun isopropyl acetate list solvate 108mg, yield 88%.
2~10 sample of embodiment have PXRD map same as Example 1 or similar, DSC curve, TGA curve and
FT-IR map；Illustrate that 2~10 sample of embodiment and 1 sample of embodiment are identical crystal forms.
It is of the present invention according to Shandong be for Buddhist nun's isopropyl acetate list solvate it is substantially pure, it is single, it is basic without mixed
Close other crystal forms or amorphous state.Heretofore described " crystal form " refers to be confirmed by shown X-ray powder diffraction collection.
Well known to those skilled in the art, experimental error therein depends on sample preparation, sample purity, instrument condition etc..PXRD map
In 2 θ angles would generally be different and slightly different with sample and instrument.The difference of 2 θ angle of diffraction maximum is not according to same
Product, different instruments etc. may differ 1 °, 0.8 °, 0.5 °, 0.3 °, 0.2 °, 0.1 ° etc., allow generally for error ± 0.2 °, so
2 θ angle of diffraction maximum cannot function as sole criterion.The relative intensity of diffraction maximum may be with sample size, sample preparation and other experiments
Condition and change, so the relative intensity of diffraction maximum cannot function as sole criterion.Thus, what those skilled in the art can consider
It is that any crystal form with the same or similar characteristic peak of X-ray powder diffraction collection of the present invention belongs to model of the invention
Farmland." single crystal form ", which refers to, is detected as single crystal form by X-ray powder diffraction.
Comparative example 1
Solubility experiment and stability reality are carried out for Buddhist nun's isopropyl acetate list solvate to according to Shandong for Buddhist nun's crystal form A and Yi Lu
It tests.
1. room temperature solubility is tested: the present invention being taken to replace Buddhist nun's crystal form A according to Shandong for Buddhist nun's isopropyl acetate list solvate and Yi Lu
Each 25mg is respectively placed in 20mL cillin bottle, is separately added into the 0.05M that pH value is 2.0,2.5,3.5,4.5,5.5,6.8 and 8.0
Phosphate buffered saline solution 15mL, after stirring 24 hours under 25 DEG C, 400rpm revs/min of revolving speed, filtering, filtrate carries out ultraviolet point
The detection of light photometer, the results are shown in Table 1.
Table 1 replaces the solubility of Buddhist nun's isopropyl acetate list solvate and crystal form A according to Shandong
Shown in the table 1 the result shows that, according to Shandong for Buddhist nun's isopropyl acetate list solvate different pH value phosphoric acid buffer
Solubility in solution improves 2~4 times than crystal form A.
2. stability experiment: the present invention being taken, for Buddhist nun's isopropyl acetate list solvate, to be uniformly split in open training according to Shandong
Support in ware, thickness of sample is less than 5mm, be individually positioned in 25 DEG C, intensity of illumination be 4500 ± 500lx and relative humidity be 90 ±
Under conditions of 5%, in the 0th day, the 5th day, sampling in the 10th day carried out PXRD detection, as a result as shown in table 2 and Fig. 5, replaced Buddhist nun according to Shandong
The crystal form of isopropyl acetate list solvate does not change.
Grinding stability experiment: take the present invention each for Buddhist nun's crystal form A for Buddhist nun's isopropyl acetate list solvate and Yi Lu according to Shandong
100mg is respectively placed in ball mill, is ground 10 minutes under the conditions of 25 DEG C, 20Hz, carry out PXRD detection, and with grinding before make
Control, as a result as shown in table 2 and Fig. 5.
Table 2 is tested according to Shandong for the stability of crystal form of Buddhist nun's isopropyl acetate list solvate
From table 2 and result shown in fig. 5 can be seen that the present invention it is resulting according to Shandong for Buddhist nun's isopropyl acetate list solvate
Crystal form do not change at different conditions.
Claims (10)
1. a kind of solvate for replacing Buddhist nun according to Shandong, it is characterised in that for the isopropyl acetate list solvate for replacing Buddhist nun according to Shandong, knot
Shown in structure formula such as formula (I):
Replacing the mass ratio of the material of Buddhist nun and isopropyl acetate according to Shandong is 1:1.
2. the solvate according to claim 1 for replacing Buddhist nun according to Shandong, it is characterised in that the solvate for replacing Buddhist nun according to Shandong
With angle of diffraction be the X-ray powder diffraction pattern that indicates of 2 θ be shown in 7.44 ° ± 0.2 °, 7.91 ° ± 0.2 °, 9.05 ° ±
0.2°、10.32°±0.2°、14.39°±0.2°、14.69°±0.2°、15.73°±0.2°、18.27°±0.2°、18.97°
±0.2°、20.64°±0.2°、21.34°±0.2°、21.97°±0.2°、22.71°±0.2°、25.05°±0.2°、
There is characteristic peak at 27.05 ° ± 0.2 °, 27.72 ° ± 0.2 °.
3. the solvate according to claim 1 for replacing Buddhist nun according to Shandong, it is characterised in that the x-ray powder indicated with 2 θ angles
Diffracting spectrum is shown below position with characteristic peak and relative intensity:
4. the solvate according to claim 1 for replacing Buddhist nun according to Shandong, it is characterised in that the solvate for replacing Buddhist nun according to Shandong
Differential scanning calorimetric curve be shown at 73~77 DEG C, 155~159 DEG C and have feature endothermic peak respectively, have at 77~82 DEG C
Feature exothermic peak；Thermal gravimetric analysis curve according to Shandong for the solvate of Buddhist nun is shown in 50~150 DEG C, weightless 18.0-18.9%；?
300~500 DEG C, weightless 68.0-68.9%.
5. the solvate according to claim 1 for replacing Buddhist nun according to Shandong, it is characterised in that the solvate for replacing Buddhist nun according to Shandong
FTIR spectrum map show characteristic peak positions wave number be 3409cm-1、3115cm-1、1721cm-1、1637cm-1、
1613cm-1、1519cm-1、1242cm-1、11367cm-1And 1069cm-1Place.
6. a kind of preparation method of -5 any solvates according to Shandong for Buddhist nun according to claim 1, it is characterised in that adopt
With magma method or lowering temperature crystallization.
7. the preparation method of the solvate according to claim 6 according to Shandong for Buddhist nun, it is characterised in that use magma method packet
Include following steps:
1) it will be mixed for Buddhist nun's raw material with isopropyl acetate solvent according to Shandong, and obtain suspension；
2) suspension of step 1) stirred under constant temperature conditions, filter, collect solid, drying, obtained different for Buddhist nun's acetic acid according to Shandong
Propyl ester list solvate.
8. it is according to claim 7 according to Shandong for Buddhist nun solvate preparation method, it is characterised in that in step 1) according to
Shandong is crystal form C for Buddhist nun's raw material；In the suspension, it is preferably 10 that the solid-liquid ratio of Buddhist nun's raw material and isopropyl acetate solvent is replaced according to Shandong
~200mg:1mL, preferably 50~100mg:1mL；
Constant temperature in step 2) is 0~50 DEG C, preferably 20~30 DEG C；Stirring rate is 100~1500 revs/min, excellent
It is selected as 500~1000 revs/min；Mixing time is 1~24 hour, preferably 5~12 hours.
9. the preparation method of the solvate according to claim 6 according to Shandong for Buddhist nun, it is characterised in that lowering temperature crystallization packet
Include following steps:
1) it will be dissolved in isopropyl acetate solvent under condition of heating and stirring according to Shandong for Buddhist nun's raw material, and obtain solution；
2) filtration step 1 while hot) solution, filtrate is placed in cooling crystallization, filtering, drying in low temperature environment, obtains according to Shandong for Buddhist nun
Isopropyl acetate list solvate.
10. it is according to claim 9 according to Shandong for Buddhist nun solvate preparation method, it is characterised in that in step 1) according to
Shandong is crystal form A, crystal form B, crystal form C and unformed for Buddhist nun's raw material；Heating temperature is 50 DEG C~89 DEG C, preferably 70 DEG C~89 DEG C；
Low temperature environment in step 2) is -40~25 DEG C；Preferably -20~5 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810997233.1A CN109053738B (en) | 2018-08-29 | 2018-08-29 | Solvate of ibrutinib and preparation method thereof |
Applications Claiming Priority (1)
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| 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 |
| CN113214261A (en) * | 2020-01-21 | 2021-08-06 | 尚科生物医药（上海）有限公司 | Purification method of ibrutinib crystal form A |
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| CN106008529A (en) * | 2016-08-08 | 2016-10-12 | 上海工程技术大学 | Ibrutinib solvate and preparation method thereof |
| CN106103462A (en) * | 2014-03-18 | 2016-11-09 | 赛利亚医药公司 | The new polymorphic forms of TCM B and New Solid |
| 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 |
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| CN106008529A (en) * | 2016-08-08 | 2016-10-12 | 上海工程技术大学 | Ibrutinib solvate and preparation method thereof |
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| 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 |
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| CN113214261A (en) * | 2020-01-21 | 2021-08-06 | 尚科生物医药（上海）有限公司 | Purification method of ibrutinib crystal form A |
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