CN106632344A - Pyrrolopyrazine compound crystal forms and preparation method thereof - Google Patents
Pyrrolopyrazine compound crystal forms and preparation method thereof Download PDFInfo
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- CN106632344A CN106632344A CN201510711697.8A CN201510711697A CN106632344A CN 106632344 A CN106632344 A CN 106632344A CN 201510711697 A CN201510711697 A CN 201510711697A CN 106632344 A CN106632344 A CN 106632344A
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- 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
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Abstract
The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to ten new crystal forms of an anti-cancer compound 3-((1H-pyrrolo[2,3-b]pyrazin-5-yl)ethynyl)-4-methyl-N-[4-(4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide hydrochloride, and a preparation method thereof, compositions containing the crystal forms, and uses of the crystal forms or the compositions containing the crystal forms in drug preparation. According to the present invention, the ten crystal forms have advantages of good physical and chemical stability, good solubility and good bioavailability, and are suitable for preparation development.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to compound 3- ((the 1H- pyrrolo-es with antitumaous effect
[2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzene
Ten kinds of novel crystal forms of carboxamide hydrochloride, its preparation method, the composition comprising the crystal formation, and the crystalline substance
The purposes of type or the composition comprising the crystal formation in medicine preparation.
Background technology
Protein tyrosine kinase (PTKs) is that a class can be catalyzed γ-phosphoric acid on ATP and be transferred to protein-tyrosine residue
On kinases, by be catalyzed multiple protein tyrosine residue on phenolic hydroxyl group occur phosphorylation, and then activate function
The protein enzyme system of albumen effect.Occupy in protein tyrosine kinase (PTKs) signal transduction pathway in the cell
Highly important status, a series of physiological and biochemical procedures such as cell growth, differentiation, death are adjusted.Albumen junket
The unconventionality expression of histidine kinase can cause cell propagation regulation to get muddled, and then lead oncogenic generation.This
Outward, the unconventionality expression of protein tyrosine kinase also with the invasion and attack and transfer of tumour, tumor neovasculature generation,
The chemotherapy resistance to the action of a drug of tumour is closely related.Tyrosine kinase inhibitor can be used as atriphos (ATP) and junket ammonia
The competitive inhibitor that acid kinase is combined, competitive binding EGFR-TK blocks the activity of EGFR-TK,
Suppress cell propagation, there are several tyrosine protein kinase inhibitors to be successfully obtained exploitation.
In chronic myelocytic leukemia (CML) patient, No. 22 chromosome long arm transpositions to No. 9 chromosomes are formed
Philadelphia chromosome, and cause BCR genes and abl gene to merge to form BCR-ABL fusions, express
BCR-ABL protein EGFR-TK, by the effect such as phosphorylation in cell signalling and conversion, promotes
The unlimited hyperplasia of CML maturation granulocytes.BCR-ABL is not expressed in normal cell, has become treatment
The ideal medicament target of CML.At present, BCR-ABL tyrosine kinase has become most of chronic
The first-line treatment medicine of granulocytic leukemia.
Compound 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] benzamide hydrochloride salt is a known compound, the structure with following formula 1：
The compound is disclosed in WO2014082578, and the document is hereby incorporated by with entire contents
With reference to.WO2014082578 reports 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamides have good to various cancer cells
Inhibitory activity, can be used for treatment and/or prevention of tumor.But, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases)
Acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt
Crystal formation have no any report.
This area knows, the difference of drug crystal forms, can cause the difference of various physicochemical properties, such as solubility, molten
Go out speed, mobility, density, hardness, optical and electrical properties etc..These differences can be reflected in thermodynamic stability
On, such as stable type, metastable type and instability mode；Also can be reflected on physical and chemical stability, such as hygroscopicity,
Crystal transfer, sample degradation etc..These differences directly affect prescription preparation process, storage method, the body of medicine
In interior medicine generation, moves performance etc., and then has influence on Drug safety and validity.
Therefore, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines are studied
- 1- bases) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt polymorphism and select in clinical treatment
It is upper meaningful and stablize controllable crystal formation there is highly important meaning.
The content of the invention
To 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] benzamide hydrochloride salt crystal formation research in, the present inventor is found that altogether
Tens kinds of crystal formations, in the numerous crystal formations for obtaining, wherein ten kinds of crystal formations have good physical and chemical stability,
Solubility and bioavilability, are adapted to formulation development.
With during X-ray diffraction measure crystallization of the invention, due to the impact of the condition of the instrument or measure of measure,
For there is the relative intensity of certain measure error, particularly x-ray diffraction pattern with examination in measured summit
Test the change of condition and change.For example, the evaluated error of 2 θ values is for about ± 0.2 ° sometimes, the survey of relative intensity
It is ± 20% to determine error sometimes.Therefore, it is determined that during every kind of crystalline texture, it should which this error is taken into account.
Can be understood as any having the crystal formation of essentially identical or similar x-ray diffraction pattern equal to the crystal formation of the application
Belong within scope of the present application.
In a first aspect, the present invention provides 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl
Ten kinds of crystal formations of-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt and its
Preparation method.
It is an object of the present invention to provide compound 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetylene
Base) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt one
The crystal formation for being named as F crystal formations is planted, the crystal formation has good physical and chemical stability.
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt F crystal formations, radiated using Cu-Ka, its
X- powder x ray diffraction the θ of the angle of diffraction 2 be 10.1 ° ± 0.2 °, 12.5 ° ± 0.2 °, 20.2 ° ± 0.2 °, 22.1 ° ± 0.2 °,
Characteristic diffraction peak is shown at 25.1 ° ± 0.2 °.
Specifically, the present invention provides 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4-
Methylpiperazine-1-yl) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt F crystal formations, using Cu-Ka spokes
Penetrate, its X-ray powder diffraction the θ of the angle of diffraction 2 be 10.1 ° ± 0.2 °, 12.5 ° ± 0.2 °, 16.8 ° ± 0.2 °,
17.4°±0.2°、18.1°±0.2°、20.2°±0.2°、22.1°±0.2°、23.9°±0.2°、25.1°±0.2°、29.2°±0.2°
Place shows characteristic diffraction peak.
More specifically, the present invention provides 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl
The F crystal formations of-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt, use
Cu-Ka radiate, its X-ray powder diffraction the θ of the angle of diffraction 2 be 5.4 ° ± 0.2 °, 10.1 ° ± 0.2 °, 12.5 ° ± 0.2 °,
16.8°±0.2°、17.4°±0.2°、18.1°±0.2°、20.2°±0.2°、22.1°±0.2°、23.9°±0.2°、25.1°±0.2°、
Characteristic diffraction peak is shown at 29.2 ° ± 0.2 °.
Further specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt F crystal formations have accompanying drawing
X-ray diffraction pattern described in 1.Its peak value is shown in Table 1, wherein the error of 2 θ values is for about ± 0.2 °.Peak strength
Depending on sample morphology and granularity, and it is varied from, wherein low-intensity peak value (intensity is less than 10%) is in some feelings
Do not exist under condition.
Table 1
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt F crystal formations have differential as described in Figure 2
Scanning calorimetric (DSC) curve, the curve shows endothermic peak, at about 171.9 DEG C suction is shown at about 128.0 DEG C
Thermal spike, at about 200.6 DEG C exothermic peak is shown, at about 235.7 DEG C endothermic peak is shown.
To realize the present invention, the present invention provides the preparation method of the F crystal formations, and the method is easy to operate, reappears
Property is good.Methods described includes anti-solvent additive process, the slow volatility process of room temperature, high polymer revulsion, gas-solid infiltration
Method and suspension paddling process etc..
In one approach, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) second is prepared using anti-solvent adding method
Alkynyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt F
Crystal formation, including with good solvent tetrahydrofuran 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl is processed
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt, adds after being completely dissolved
Enter anti-solvent ethyl acetate or methyl tertiary butyl ether(MTBE), about 5 DEG C of stirrings are then demultiplex out the precipitation for separating out.E.g., from about
1.2mL tetrahydrofurans, process 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4-
Methylpiperazine-1-yl) methyl) -3- trifluoromethyls] benzamide hydrochloride salt sample, e.g., from about 15mg, solid
After being completely dissolved, ethyl acetate e.g., from about 1.4mL is slowly added dropwise, isolates the precipitation of precipitation.
In another approach, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetylene is prepared using suspension paddling process
Base) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt F is brilliant
Type, including with tetrahydrofuran 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- are processed
Methylpiperazine-1-yl) methyl) -3- trifluoromethyls] the prepared suspension of benzamide hydrochloride salt A crystal formations, stirring
After separate solid.Whipping temp be room temperature to 50 DEG C, preferably room temperature or 50 DEG C.For example use about 0.5mL tetra-
Hydrogen treatment of furans 15mg3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
Piperazine -1- bases) methyl) -3- trifluoromethyls] the prepared suspension of benzamide hydrochloride salt A crystal formations, magnetic force under room temperature
Stir about 6 days, centrifugation solid.
3- used ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- first in the present invention
Base piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt A crystal formations, radiated using Cu-Ka,
Its X-ray powder diffraction the θ of the angle of diffraction 2 be 6.6 ° ± 0.2 °, 11.2 ° ± 0.2 °, 13.5 ° ± 0.2 °, 18.0 ° ± 0.2 °,
19.9 ° ± 0.2 °, have characteristic peak at 20.3 ° ± 0.2 °；Preferably, radiated using Cu-Ka, its X-ray powder
Diffraction the θ of the angle of diffraction 2 be 6.3 ° ± 0.2 °, 6.6 ° ± 0.2 °, 11.2 ° ± 0.2 °, 13.5 ° ± 0.2 °, 16.1 ° ± 0.2 °,
17.2 ° ± 0.2 °, 18.0 ° ± 0.2 °, 19.9 ° ± 0.2 °, 20.3 ° ± 0.2 °, 22.4 ° ± 0.2 °, have feature at 26.3 ± 0.2 °
Peak, it is further preferred that radiated using Cu-Ka, its X-ray powder diffraction the θ of the angle of diffraction 2 be 6.3 ° ± 0.2 °,
6.6°±0.2°、11.2°±0.2°、13.5°±0.2°、16.1°±0.2°、17.2°±0.2°、18.0°±0.2°、19.9°±0.2°、
20.3°±0.2°、20.7°±0.2°、22.4°±0.2°、23.5°±0.2°、23.8°±0.2°、25.6°±0.2°、26.3°±0.2°、
26.9 ° ± 0.2 °, 28.4 ° ± 0.2 °, have characteristic peak at 29.2 ° ± 0.2 °.For example, in a specific embodiment,
A crystal formations have x-ray diffraction pattern as shown in figure 21, with means of differential scanning calorimetry (DSC) as described in Figure 22
Curve, the curve shows endothermic peak at about 80 DEG C, and at about 120 DEG C endothermic peak is shown.
3- used ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- first in the present invention
Base piperazine -1- bases) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt A crystal formations preparation method include it is following
Method：
(1) 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl is prepared using suspension stirring means
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt A crystal formations, including use
Solvent processes 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] the prepared suspension of benzamide hydrochloride salt, solid is separated after stirring, described is molten
Agent is selected from concentrated hydrochloric acid, dichloromethane, chloroform and tetrahydrofuran water mixed solvent, it is preferable that described solvent choosing
It is for about 1 from concentrated hydrochloric acid, dichloromethane, chloroform and the volume ratio that pH is for about 2-5:2 tetrahydrofuran water mixing
Solvent.For example, in a specific embodiment, the method for preparing A crystal formations is included with about 0.5mL
Dichloromethane processes about 15mg3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- first
Base piperazine -1- bases) methyl) -3- trifluoromethyls] the prepared suspension of benzamide hydrochloride salt, magnetic force is stirred under room temperature
About 6 days are mixed, centrifugation solid.
(2) 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- first is prepared using anti-solvent adding method
Base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt A crystal formations, including
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines are processed with good solvent
- 1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt, anti-solvent, Ran Houfen are added after being completely dissolved
The precipitation of precipitation is separated out, wherein the good solvent is acetic acid or DMA, the anti-solvent is
Normal heptane or toluene, when the good solvent is acetic acid, the anti-solvent is normal heptane；When the good solvent is
During DMA, the anti-solvent is toluene.
(3) 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- is prepared using high polymer induction crystallisation
Methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt A crystal formations, bag
Include and dissolve 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- first with ethanol water
Base piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt, add to gained settled solution and mix
It is sufficiently stirred for after high polymer, slowly volatilizees under room temperature condition, is then demultiplex out the precipitation for separating out.Described ethanol
It is for about 4 that the aqueous solution is preferably volume ratio:1 ethanol water.Described mixing high polymer is selected from mixing high polymer
A (etc. quality polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hypromellose
Element and methylcellulose uniformly mix) and mixing high polymer B (etc. the PCL of quality, polyethylene glycol, gather
Methyl methacrylate, sodium alginate and hydroxyethyl cellulose uniformly mix).For example use about 1.0mL volume ratios
For about 4:1 ethanol water dissolving 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt sample, e.g., from about
10mg, mixing high polymer is added in gained settled solution, is sufficiently stirred for slowly being volatilized under rear room temperature, is separated
Go out the precipitation of precipitation.
(4) 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl is prepared using gas-solid osmosis
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt A crystal formations, including by
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3-
Trifluoromethyl] benzamide hydrochloride salt is placed in the obturator equipped with solvent, places under room temperature, then
Take out solid.Preferably, described solvent is selected from water, dichloromethane, chloroform and ethyl acetate.For example will
15mg 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) first
Base) -3- trifluoromethyls] benzamide hydrochloride salt is placed in the 20mL vials equipped with about 2mL water, room
Temperature is lower to place about 5 days, then takes out solid.
(5) 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl is prepared using recrystallization method
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt A crystal formations, including step
It is rapid as follows：A) by 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
- 1- bases) methyl) -3- trifluoromethyls] aqueous acetone solution is added in benzamide hydrochloride salt, flow back；b)0-5℃
Lower cooling crystallization；Acetone is selected from about 2.5 with the volume ratio of water in described aqueous acetone solution:1-10:1；Described
The usage amount of aqueous acetone solution is every gram of 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloric acid mixes molten using acetone water
Liquid about 5-15mL.
In another approach, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- are prepared using high polymer induction crystallisation
Base) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloric acid
Salt F crystal formations, including with tetrahydrofuran 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl is dissolved
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt, clarifies molten to gained
Liquid add mixing high polymer (etc. quality polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, poly- acetic acid second
Alkene ester, Hydroxypropyl methylcellulose and methylcellulose uniformly mix) after be sufficiently stirred for, slowly volatilize under room temperature condition,
It is then demultiplex out the precipitation for separating out.For example process 3- ((1H- pyrrolo-es [2,3-b] with about 1.0mL tetrahydrofuran solutions
Pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzoyl
Amine hydrochlorate sample, e.g., from about 10mg, add in gained settled solution and mix high polymer, e.g., from about 2mg,
It is sufficiently stirred for slowly being volatilized under rear room temperature, isolates the precipitation of precipitation.
In another approach, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) is prepared using the slow volatility process of room temperature
Acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt F
Crystal formation, including with solvents tetrahydrofurane 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl is processed
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt, is configured to about
The settled solution of 10mg/mL, slowly volatilizees under room temperature condition, is then demultiplex out the precipitation for separating out.For example,
Measure 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that 1.0mL concentration is 10mg/mL
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt tetrahydrofuran solution,
Slow volatilization 2 days, isolate the precipitation of precipitation under room temperature.
Further object is that providing compound 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetylene
Base) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt one
The crystal formation for being named as L crystal formations is planted, the crystal formation has good physical and chemical stability.
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt L crystal formations, radiated using Cu-Ka, its
X- powder x ray diffraction the θ of the angle of diffraction 2 be 11.7 ° ± 0.2 °, 16.0 ° ± 0.2 °, 17.6 ° ± 0.2 °, 18.6 ° ± 0.2 °,
25.5 ° ± 0.2 °, show characteristic diffraction peak at 26.6 ° ± 0.2 °.
Specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt L crystal formations, use
Cu-Ka radiate, its X- powder diffraction the θ of the angle of diffraction 2 be 11.7 ° ± 0.2 °, 13.3 ° ± 0.2 °, 16.0 ° ± 0.2 °,
17.6 ° ± 0.2 °, 18.6 ° ± 0.2 °, 25.5 ° ± 0.2 °, show characteristic diffraction peak at 26.6 ° ± 0.2 °.
More specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt L crystal formations have accompanying drawing
X-ray diffraction pattern described in 3.Its peak value is shown in Table 2, wherein the error of 2 θ values is for about ± 0.2 °.Peak strength
Depending on sample morphology and granularity, and it is varied from, wherein low-intensity peak value (intensity is less than 10%) is in some feelings
Do not exist under condition.
Table 2
| 2 θ angles (°) | Intensity (%) | 2 θ angles (°) | Intensity (%) |
| 11.7 | 18.5 | 13.3 | 7.1 |
| 16.0 | 19.7 | 17.6 | 9.6 |
| 18.6 | 10.7 | 21.9 | 3.8 |
| 25.5 | 100 | 26.6 | 41.6 |
| 28.4 | 7.9。 |
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt L crystal formations have differential as described in Figure 4
Scanning calorimetric (DSC) curve, the curve shows exothermic peak, at about 231.0 DEG C suction is shown at about 96.5 DEG C
Thermal spike, at about 264.3 DEG C endothermic peak is shown.
To realize the present invention, the present invention provides the preparation method of the L crystal formations, such as anti-solvent additive process, bag
Include and process 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl with good solvent tetrahydrofuran
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt, adds after being completely dissolved
Enter anti-solvent normal heptane, 5 DEG C of stirrings are then demultiplex out the precipitation for separating out.Such as 1.2mL tetrahydrofurans, are processed
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3-
Trifluoromethyl] benzamide hydrochloride salt sample, such as 15mg after solid is completely dissolved, is slowly added dropwise just
Heptane such as 1.0mL, isolates the precipitation of precipitation.
Further object is that providing compound 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetylene
Base) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt one
The crystal formation for being named as M crystal formations is planted, the crystal formation has good physical and chemical stability.
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt M crystal formations, radiated using Cu-Ka, its
X- powder x ray diffraction the θ of the angle of diffraction 2 be 7.6 ° ± 0.2 °, 9.0 ° ± 0.2 °, 14.1 ° ± 0.2 °, 15.3 ° ± 0.2 °,
16.2 ° ± 0.2 °, 21.8 ° ± 0.2 °, 24.6 ° ± 0.2 °, show characteristic diffraction peak at 24.9 ° ± 0.2 °.
Specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt M crystal formations, use
Cu-Ka radiate, its X- powder diffraction the θ of the angle of diffraction 2 be 7.6 ° ± 0.2 °, 9.0 ° ± 0.2 °, 11.9 ° ± 0.2 °,
14.1°±0.2°、15.3°±0.2°、15.5°±0.2°、16.2°±0.2°、18.0°±0.2°、20.3°±0.2°、20.8°±0.2°、
21.8 ° ± 0.2 °, 24.6 ° ± 0.2 °, show characteristic diffraction peak at 24.9 ° ± 0.2 °.
More specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt M crystal formations have accompanying drawing
X-ray diffraction pattern described in 5.Its peak value is shown in Table 3, wherein the error of 2 θ values is for about ± 0.2 °.Peak strength
Depending on sample morphology and granularity, and it is varied from, wherein low-intensity peak value (intensity is less than 20%) is in some feelings
Do not exist under condition.
Table 3
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt M crystal formations have differential as described in Figure 6
Scanning calorimetric (DSC) curve, the curve shows endothermic peak, at about 231.0 DEG C suction is shown at about 103.6 DEG C
Thermal spike, at about 261.3 DEG C endothermic peak is shown.
To realize the present invention, the present invention provides the preparation method of the M crystal formations, including the slow volatility process of room temperature
With gas-liquid osmosis etc..
In one approach, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) second is prepared using the slow volatility process of room temperature
Alkynyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt M
Crystal formation, including by concentration for 10mg/mL 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt ethanol solution, room temperature
Under the conditions of slowly volatilize, be then demultiplex out separate out precipitation.Such as 1.0mL concentration is the 3- ((1H- of 10mg/mL
Pyrrolo- [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- fluoroforms
Base phenyl] benzamide hydrochloride salt ethanol solution, slow volatilization 11 days, isolate the precipitation of precipitation under room temperature.
In another approach, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetylene is prepared using gas-liquid osmosis
Base) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt M is brilliant
Type, including with ethanol 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl is dissolved
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt, it is open to be placed in equipped with methyl tertiary butyl ether(MTBE)
Vial in, place under the conditions of closed rear room temperature, centrifugation goes out the precipitation of precipitation.For example use 1.0mL
Ethanol dissolves 10mg 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
- 1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt, it is positioned over resulting solution is open equipped with 4mL
In the 20mL vials of methyl tertiary butyl ether(MTBE), place 10 days under the conditions of closed rear room temperature, centrifugation goes out analysis
The precipitation for going out.
Further object is that providing compound 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetylene
Base) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt one
The crystal formation for being named as N crystal form is planted, the crystal formation has good physical and chemical stability.
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt N crystal form, radiated using Cu-Ka, its
X- powder x ray diffraction the θ of the angle of diffraction 2 be 16.0 ° ± 0.2 °, 16.9 ° ± 0.2 °, 18.2 ° ± 0.2 °, 19.8 ° ± 0.2 °,
21.5 ° ± 0.2 °, 23.6 ° ± 0.2 °, show characteristic diffraction peak at 23.7 ° ± 0.2 °.
Specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt N crystal form, uses
Cu-Ka radiate, its X-ray diffraction the θ of the angle of diffraction 2 be 10.7 ° ± 0.2 °, 11.2 ° ± 0.2 °, 11.8 ° ± 0.2 °,
16.0°±0.2°、16.9°±0.2°、18.2°±0.2°、19.8°±0.2°、20.7°±0.2°、21.5°±0.2°、23.6°±0.2°、
Characteristic diffraction peak is shown at 23.7 ° ± 0.2 °.
More specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt N crystal form has accompanying drawing
X-ray diffraction pattern described in 7.Its peak value is shown in Table 4, wherein the error of 2 θ values is for about ± 0.2 °.Peak strength
Depending on sample morphology and granularity, and it is varied from, wherein low-intensity peak value (intensity is less than 10%) is in some feelings
Do not exist under condition.
Table 4
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt N crystal form has differential as described in Figure 8
Scanning calorimetric (DSC) curve, the curve shows endothermic peak at about 180.3 DEG C.
To realize the present invention, the present invention provides the preparation method of the N crystal form, including gas-solid osmosis, outstanding
Floating paddling process etc..
In one approach, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetylene is prepared using gas-solid osmosis
Base) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt N is brilliant
Type, including by 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] benzamide hydrochloride salt A crystal formations are placed in equipped with the closed of 1,4- dioxane
In device, place under room temperature, then take out solid.For example by 15mg 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5-
Base) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloric acid
Salt A crystal formations are placed in the 20mL vials equipped with 2mL Isosorbide-5-Nitraes-dioxane, placement 5 days under room temperature, then
Take out solid.
In another approach, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) second is prepared using suspension stirring means
Alkynyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt N
Crystal formation, including with Isosorbide-5-Nitrae-dioxane 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl is processed
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt A crystal formations are obtained and suspend
Liquid, after stirring at 50 DEG C solid is separated.For example process 15mg3- ((1H- pyrrolo-es with 0.3mL1,4- dioxane
[2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls]
Benzamide hydrochloride salt A crystal formations are obtained suspension, and then 50 DEG C are stirred 6 days, centrifugation solid.
Further object is that providing compound 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetylene
Base) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt one
The crystal formation for being named as P crystal formations is planted, the crystal formation has good physical and chemical stability.
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt P crystal formations, radiated using Cu-Ka, its
X- powder x ray diffraction the θ of the angle of diffraction 2 be 12.6 ° ± 0.2 °, 16.4 ° ± 0.2 °, 19.4 ° ± 0.2 °, 20.8 ° ± 0.2 °,
22.6 ° ± 0.2 °, 24.5 ° ± 0.2 °, 26.6 ° ± 0.2 °, show characteristic diffraction peak at 27.4 ° ± 0.2 °.
Specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt P crystal formations, use
Cu-Ka radiate, its X-ray diffraction the θ of the angle of diffraction 2 be 8.8 ° ± 0.2 °, 12.6 ° ± 0.2 °, 16.4 ° ± 0.2 °,
17.0°±0.2°、18.2°±0.2°、19.1°±0.2°、19.4°±0.2°、19.8°±0.2°、20.8°±0.2°、22.6°±0.2°、
24.0 ° ± 0.2 °, 24.5 ° ± 0.2 °, 26.6 ° ± 0.2 °, show characteristic diffraction peak at 27.4 ° ± 0.2 °.
More specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt P crystal formations, use
Cu-Ka radiate, its X-ray diffraction the θ of the angle of diffraction 2 be 5.6 ° ± 0.2 °, 7.8 ° ± 0.2 °, 8.8 ° ± 0.2 °,
11.3°±0.2°、12.6°±0.2°、16.4°±0.2°、17.0°±0.2°、18.2°±0.2°、19.1°±0.2°、19.4°±0.2°、
19.8°±0.2°、20.8°±0.2°、22.6°±0.2°、23.6°±0.2°、24.0°±0.2°、24.5°±0.2°、26.6°±0.2°、
Characteristic diffraction peak is shown at 27.4 ° ± 0.2 °.
Further specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt P crystal formations have accompanying drawing
X-ray diffraction pattern described in 9.Its peak value is shown in Table 5, wherein the error of 2 θ values is for about ± 0.2 °.Peak strength
Depending on sample morphology and granularity, and it is varied from, wherein low-intensity peak value (intensity is less than 10%) is in some feelings
Do not exist under condition.
Table 5
| 2 θ angles (°) | Intensity (%) | 2 θ angles (°) | Intensity (%) |
| 5.6 | 8.8 | 7.8 | 9.3 |
| 8.8 | 15.1 | 11.3 | 11.3 |
| 11.8 | 8.1 | 12.6 | 26.9 |
| 13.5 | 6.2 | 15.1 | 6.6 |
| 16.4 | 28.2 | 17.0 | 18.1 |
| 18.2 | 22.0 | 19.1 | 40.4 |
| 19.4 | 58.9 | 19.8 | 34.3 |
| 20.8 | 100 | 22.6 | 47.7 |
| 23.6 | 14.1 | 24.0 | 27.1 |
| 24.5 | 41.1 | 25.2 | 9.4 |
| 25.7 | 7.8 | 26.5 | 50.4 |
| 27.4 | 41.8 | 29.6 | 4.8 |
| 30.6 | 6.6 | 31.9 | 6.0。 |
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt P crystal formations have differential as described in Figure 10
Scanning calorimetric (DSC) curve, the curve shows endothermic peak, at about 182.2 DEG C suction is shown at about 158.7 DEG C
Thermal spike.
To realize the present invention, the present invention provides the preparation method of the P crystal formations, such as suspension paddling process.
Specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- is prepared using suspension stirring means
Methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt P crystal formations, bag
Include and process 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- with 1,4- dioxane
Methylpiperazine-1-yl) methyl) -3- trifluoromethyls] the prepared suspension of benzamide hydrochloride salt A crystal formations, stirring
After separate solid.For example process 15mg3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- with 0.5mL1,4- dioxane
Base) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloric acid
Salt A crystal formations obtain suspension, magnetic agitation 6 days under room temperature, centrifugation solid.
Further object is that providing compound 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetylene
Base) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt one
The crystal formation for being named as Q crystal formations is planted, the crystal formation has good physical and chemical stability.
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt Q crystal formations, radiated using Cu-Ka, its
X- powder x ray diffraction the θ of the angle of diffraction 2 be 8.5 ° ± 0.2 °, 12.5 ° ± 0.2 °, 14.8 ° ± 0.2 °, 17.7 ° ± 0.2 °,
23.5 ° ± 0.2 °, show characteristic diffraction peak at 24.5 ° ± 0.2 °.
Specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt Q crystal formations, use
Cu-Ka radiate, its X- powder x ray diffraction the θ of the angle of diffraction 2 be 6.6 ° ± 0.2 °, 8.5 ° ± 0.2 °, 10.7 ° ± 0.2 °,
11.3°±0.2°、12.5°±0.2°、14.8°±0.2°、17.8°±0.2°、18.1°±0.2°、18.9°±0.2°、20.0°±0.2°、
20.4 ° ± 0.2 °, 23.1 ° ± 0.2 °, 23.5 ° ± 0.2 °, 23.9 ° ± 0.2 °, 24.5 ° ± 0.2 °, show spy at 28.5 ° ± 0.2 °
Levy diffraction maximum.
Further specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt Q crystal formations have accompanying drawing
X-ray diffraction pattern described in 11.Its peak value is shown in Table 6, wherein the error of 2 θ values is for about ± 0.2 °.Peak strength
Depending on sample morphology and granularity, and it is varied from, wherein low-intensity peak value (intensity is less than 10%) is in some feelings
Do not exist under condition.
Table 5
| 2 θ angles (°) | Intensity (%) | 2 θ angles (°) | Intensity (%) |
| 6.6 | 12.2 | 8.5 | 26.7 |
| 10.7 | 11.5 | 11.3 | 15.4 |
| 12.3 | 25.1 | 12.5 | 33.3 |
| 13.6 | 10.7 | 14.8 | 24.8 |
| 16.4 | 14.9 | 17.7 | 90.2 |
| 18.1 | 20.1 | 19.0 | 11.2 |
| 20.0 | 12.9 | 20.4 | 14.1 |
| 21.4 | 3.0 | 23.1 | 26.5 |
| 23.5 | 31.0 | 23.9 | 27.7 |
| 24.5 | 100 | 28.5 | 17.5 |
| 29.9 | 13.6 | 32.0 | 1.8。 |
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt Q crystal formations have differential as described in Figure 12
Scanning calorimetric (DSC) curve, the curve shows endothermic peak, at about 114.3 DEG C heat absorption is shown at about 70.4 DEG C
Peak, at about 174.5 DEG C endothermic peak is shown.
To realize the present invention, the present invention provides the preparation method of the Q crystal formations, such as suspension paddling process.
Specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- is prepared using suspension stirring means
Methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt Q crystal formations, bag
Include and process 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl with 2- methyltetrahydrofurans
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt A crystal formations are obtained and suspend
Liquid, separates solid after stirring.For example process 15mg3- ((1H- pyrrolo-es [2,3-b] with 0.5mL2- methyltetrahydrofurans
Pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzoyl
Amine hydrochlorate A crystal formations are obtained suspension, magnetic agitation 6 days under room temperature, centrifugation solid.
Further object is that providing compound 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetylene
Base) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt one
The crystal formation for being named as R crystal formations is planted, the crystal formation has good physical and chemical stability.
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt R crystal formations, radiated using Cu-Ka, its
X- powder x ray diffraction the θ of the angle of diffraction 2 be 9.7 ° ± 0.2 °, 10.8 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.2 ° ± 0.2 °,
13.9 ° ± 0.2 °, 23.5 ° ± 0.2 °, show characteristic diffraction peak at 24.4 ° ± 0.2 °.
Specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt R crystal formations, use
Cu-Ka radiate, its X- powder x ray diffraction the θ of the angle of diffraction 2 be 9.7 ° ± 0.2 °, 10.8 ° ± 0.2 °, 12.5 ° ± 0.2 °,
13.2 ° ± 0.2 °, 13.9 ° ± 0.2 °, 17.8 ° ± 0.2 °, 19.5 ° ± 0.2 °, 23.5 ° ± 0.2 °, show spy at 24.4 ° ± 0.2 °
Levy diffraction maximum.
More specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt R crystal formations have accompanying drawing
X-ray diffraction pattern described in 13.Its peak value is shown in Table 7, wherein the error of 2 θ values is for about ± 0.2 °.Peak strength
Depending on sample morphology and granularity, and it is varied from, wherein low-intensity peak value (intensity is less than 10%) is in some feelings
Do not exist under condition.
Table 7
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt R crystal formations have differential as described in Figure 14
Scanning calorimetric (DSC) curve, the curve shows endothermic peak, at about 203.0 DEG C suction is shown at about 126.1 DEG C
Thermal spike, at about 229.3 DEG C exothermic peak is shown, at about 257.8 DEG C endothermic peak is shown.
To realize the present invention, the present invention provides the preparation method of the R crystal formations, such as suspension paddling process.
Specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- is prepared using suspension stirring means
Methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt R crystal formations, bag
Include and process 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines with isopropanol
Piperazine -1- bases) methyl) -3- trifluoromethyls] the prepared suspension of benzamide hydrochloride salt A crystal formations, separate after stirring
Solid.For example process 15mg3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- with 0.5mL isopropanols
Methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt A crystal formations are obtained
Suspension, magnetic agitation 6 days under room temperature, centrifugation solid.
Further object is that providing compound 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetylene
Base) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt one
The crystal formation for being named as T crystal formations is planted, the crystal formation has good physical and chemical stability.
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt T crystal formations, radiated using Cu-Ka, its
X- powder x ray diffraction the θ of the angle of diffraction 2 be 8.1 ° ± 0.2 °, 8.6 ° ± 0.2 °, 13.5 ° ± 0.2 °, 15.8 ° ± 0.2 °,
18.7 ° ± 0.2 °, 20.3 ° ± 0.2 °, 21.9 ° ± 0.2 °, show characteristic diffraction peak at 23.8 ° ± 0.2 °.
Specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt T crystal formations, use
Cu-Ka radiate, its X- powder x ray diffraction the θ of the angle of diffraction 2 be 8.1 ° ± 0.2 °, 8.6 ° ± 0.2 °, 13.5 ° ± 0.2 °,
14.5°±0.2°、15.0°±0.2°、15.8°±0.2°、17.3°±0.2°、18.7°±0.2°、20.3°±0.2°、21.9°±0.2°、
23.1 ° ± 0.2 °, show characteristic diffraction peak at 23.8 ° ± 0.2 °.
More specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt T crystal formations, use
Cu-Ka radiate, its X- powder x ray diffraction the θ of the angle of diffraction 2 be 8.1 ° ± 0.2 °, 8.6 ° ± 0.2 °, 11.3 ° ± 0.2 °,
12.2°±0.2°、13.5°±0.2°、14.5°±0.2°、15.0°±0.2°、15.8°±0.2°、17.3°±0.2°、18.7°±0.2°、
20.3 ° ± 0.2 °, 21.9 ° ± 0.2 °, 23.1 ° ± 0.2 °, show characteristic diffraction peak at 23.8 ° ± 0.2 °.
Further specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt T crystal formations have accompanying drawing
X-ray diffraction pattern described in 15.Its peak value is shown in Table 8, wherein the error of 2 θ values is for about ± 0.2 °.Peak strength
Depending on sample morphology and granularity, and it is varied from, wherein low-intensity peak value (intensity is less than 10%) is in some feelings
Do not exist under condition.
Table 8
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt T crystal formations have differential as described in Figure 16
Scanning calorimetric (DSC) curve, the curve shows endothermic peak, at about 229.7 DEG C suction is shown at about 143.2 DEG C
Thermal spike, at about 263.9 DEG C endothermic peak is shown.
To realize the present invention, the present invention provides the preparation method of the T crystal formations, such as gas-solid osmosis.
Specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl is prepared using gas-solid osmosis
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt T crystal formations, including by
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3-
Trifluoromethyl] benzamide hydrochloride salt A crystal formations are placed in the obturator equipped with isopropanol, room temperature decentralization
Put, then take out solid.For example by 15mg 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt A crystal formations are placed in and are equipped with
In the 20mL vials of 2mL isopropanols, place 5 days under room temperature, then take out solid.
Further object is that providing compound 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetylene
Base) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt one
The crystal formation for being named as V crystal formations is planted, the crystal formation has good physical and chemical stability.
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt V crystal formations, radiated using Cu-Ka, its
X- powder x ray diffraction the θ of the angle of diffraction 2 be 8.0 ° ± 0.2 °, 8.3 ° ± 0.2 °, 14.0 ° ± 0.2 °, 14.7 ° ± 0.2 °,
17.8 ° ± 0.2 °, 20.8 ° ± 0.2 °, 23.7 ° ± 0.2 °, 24.7 ° ± 0.2 °, show characteristic diffraction peak at 26.3 ° ± 0.2 °.
Specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt V crystal formations, use
Cu-Ka radiate, its X- powder x ray diffraction the θ of the angle of diffraction 2 be 8.0 ° ± 0.2 °, 8.3 ° ± 0.2 °, 14.0 ° ± 0.2 °,
14.7°±0.2°、17.8°±0.2°、19.9°±0.2°、20.8°±0.2°、21.3°±0.2°、22.3°±0.2°、22.9°±0.2°、
23.7 ° ± 0.2 °, 24.7 ° ± 0.2 °, 25.7 ° ± 0.2 °, 26.3 ° ± 0.2 °, show characteristic diffraction peak at 27.5 ° ± 0.2 °.
More specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt V crystal formations, use
Cu-Ka radiate, its X- powder x ray diffraction the θ of the angle of diffraction 2 be 8.0 ° ± 0.2 °, 8.3 ° ± 0.2 °, 10.8 ° ± 0.2 °,
14.0°±0.2°、14.7°±0.2°、17.8°±0.2°、18.1°±0.2°、19.9°±0.2°、20.8°±0.2°、21.3°±0.2°、
22.3°±0.2°、22.9°±0.2°、23.7°±0.2°、24.7°±0.2°、25.7°±0.2°、26.3°±0.2°、27.5°±0.2°
Place shows characteristic diffraction peak.
Further specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt V crystal formations have accompanying drawing
X-ray diffraction pattern described in 17.Its peak value is shown in Table 9, wherein the error of 2 θ values is for about ± 0.2 °.Peak strength
Depending on sample morphology and granularity, and it is varied from, wherein low-intensity peak value (intensity is less than 10%) is in some feelings
Do not exist under condition.
Table 9
| 2 θ angles (°) | Intensity (%) | 2 θ angles (°) | Intensity (%) |
| 8.0 | 25.0 | 8.3 | 25.6 |
| 10.8 | 14.7 | 14.0 | 55.8 |
| 14.7 | 69.8 | 15.4 | 6.8 |
| 17.8 | 37.5 | 18.1 | 18.7 |
| 18.6 | 10.6 | 19.0 | 14.1 |
| 19.9 | 18.5 | 20.8 | 83.7 |
| 21.3 | 39.6 | 22.3 | 30.3 |
| 22.9 | 27.3 | 23.3 | 18.2 |
| 23.7 | 64.3 | 24.3 | 11.3 |
| 24.7 | 100 | 25.7 | 27.2 |
| 26.3 | 53.9 | 27.5 | 28.2 |
| 28.4 | 11.0 | 29.5 | 14.4 |
| 30.1 | 7.6 | 31.0 | 13.2。 |
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt V crystal formations have differential as described in Figure 18
Scanning calorimetric (DSC) curve, the curve shows endothermic peak, at about 153.8 DEG C suction is shown at about 146.8 DEG C
Thermal spike, at about 170.7 DEG C exothermic peak is shown, at about 265.3 DEG C endothermic peak is shown.
To realize the present invention, the present invention provides the preparation method of the V crystal formations, such as gas-solid osmosis.
Specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl is prepared using gas-solid osmosis
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt V crystal formations, including by
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3-
Trifluoromethyl] benzamide hydrochloride salt A crystal formations are placed in the obturator equipped with DMF, room temperature decentralization
Put, then take out solid.For example by 15mg 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt A crystal formations are placed in and are equipped with
In the 20mL vials of 2mLDMF, place 5 days under room temperature, then take out solid.
Further object is that providing compound 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetylene
Base) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt one
The crystal formation for being named as X crystal formations is planted, the crystal formation has good physical and chemical stability.
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt X crystal formations, radiated using Cu-Ka, its
X- powder x ray diffraction the θ of the angle of diffraction 2 be 5.4 ° ± 0.2 °, 10.0 ° ± 0.2 °, 15.8 ° ± 0.2 °, 20.0 ° ± 0.2 °,
Characteristic diffraction peak is shown at 21.1 ° ± 0.2 °.
Specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- methyl that the present invention is provided
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt X crystal formations have accompanying drawing
X-ray diffraction pattern described in 19.Its peak value is shown in Table 10, wherein the error of 2 θ values is for about ± 0.2 °.Peak value is strong
Degree depends on sample morphology and granularity, and is varied from, and wherein low-intensity peak value (intensity is less than 5%) is at some
In the case of do not exist.
Table 10
| 2 θ angles (°) | Intensity (%) | 2 θ angles (°) | Intensity (%) |
| 5.4 | 8.0 | 10.0 | 6.0 |
| 15.8 | 100 | 17.3 | 2.9 |
| 20.0 | 9.7 | 21.1 | 26.9 |
| 22.2 | 3.3 | 24.6 | 4.0 |
| 25.0 | 2.0 | 26.4 | 1.0 |
| 29.8 | 1.2 | 31.9 | 1.2。 |
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl that the present invention is provided
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt X crystal formations have differential as described in Figure 20
Scanning calorimetric (DSC) curve, the curve shows endothermic peak, at about 261.5 DEG C suction is shown at about 135.2 DEG C
Thermal spike.
To realize the present invention, the present invention provides the preparation method of the X crystal formations, such as anti-solvent additive process.
Specifically, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- is prepared using anti-solvent additive process
Methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt X crystal formations, bag
Include and process 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- with good solvent DMSO
Methylpiperazine-1-yl) methyl) -3- trifluoromethyls] benzamide hydrochloride salt, anti-solvent is added after being completely dissolved
Methyl iso-butyl ketone (MIBK), 5 DEG C of stirrings are then demultiplex out the precipitation for separating out.Such as process 3- ((1H- with 0.2mL DMSO
Pyrrolo- [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- fluoroforms
Base phenyl] benzamide hydrochloride salt, such as 15mg, addition 15.0mL methyl iso-butyl ketone (MIBK)s after being completely dissolved, 5 DEG C
The precipitation of precipitation is isolated in stirring after 2 days.
Second aspect, the present invention provides pharmaceutical composition, and it includes 3- ((the 1H- pyrrolo-es [2,3-b] of the present invention
Pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzoyl
Any one or a few and pharmaceutically acceptable carrier of ten kinds of crystal formations of amine hydrochlorate.By 3- ((1H- pyrrolo-es
[2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls]
Any one or a few of ten kinds of crystal formations of benzamide hydrochloride salt is prepared by mixing into pharmaceutically acceptable carrier
Pharmaceutical preparation, to be suitable for oral or parenteral.Medication include, but are not limited to intracutaneous, intramuscular,
Intraperitoneal, intravenous, subcutaneous, intranasal and peroral route.The preparation can be applied by any approach, example
Such as by being transfused or injecting, the approach absorbed by transepithelial or mucocutaneous (such as oral mucosa or rectum etc.)
Apply.Administration can be whole body or local.The example of oral administration preparation includes solid or liquid dosage form,
Specifically, including tablet, pill, granula, pulvis, capsule, syrup, emulsion, supensoid agent etc..Institute
Stating preparation can be prepared by methods known in the art, and comprising the conventional use of carrier of field of pharmaceutical preparations.
The third aspect, the present invention provides 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] ten kinds of crystal formations of benzamide hydrochloride salt are arbitrarily
One or more or 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
- 1- bases) methyl) -3- trifluoromethyls] and ten kinds of crystal formations of benzamide hydrochloride salt any one or a few medicine
Composition is used for the method for the treatment of and/or prevention of tumor and prevents and/or treat in the medicine of tumour in preparation
Using including 3- ((1H- pyrrolo-es [2, the 3-b] pyrazine -5- that crowd or the tumor patient administration present invention are easily sent out to tumour
Base) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloric acid
Any one or a few or 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl of ten kinds of crystal formations of salt
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] ten kinds of crystal formations of benzamide hydrochloride salt are arbitrarily
The pharmaceutical composition of one or more, effectively to reduce Tumor incidence, extend tumor patient life.
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((the 4- methyl piperazines of the present invention
- 1- bases) methyl) -3- trifluoromethyls] ten kinds of crystal formations of benzamide hydrochloride salt are respectively provided with good stability, fit
Share in making pharmaceutical preparation.
Description of the drawings
Fig. 1 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt F crystal formations x-ray diffraction pattern.
Fig. 2 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt F crystal formations DSC figure.
Fig. 3 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt L crystal formations x-ray diffraction pattern.
Fig. 4 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt L crystal formations DSC figure.
Fig. 5 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt M crystal formations x-ray diffraction pattern.
Fig. 6 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt M crystal formations DSC figure.
Fig. 7 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt N crystal form x-ray diffraction pattern.
Fig. 8 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt N crystal form DSC figure.
Fig. 9 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt P crystal formations x-ray diffraction pattern.
Figure 10 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt P crystal formations DSC figure.
Figure 11 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt Q crystal formations x-ray diffraction pattern.
Figure 12 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt Q crystal formations DSC figure.
Figure 13 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt R crystal formations x-ray diffraction pattern.
Figure 14 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt R crystal formations DSC figure.
Figure 15 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt T crystal formations x-ray diffraction pattern.
Figure 16 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt T crystal formations DSC figure.
Figure 17 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt V crystal formations x-ray diffraction pattern.
Figure 18 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt V crystal formations DSC figure.
Figure 19 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt X crystal formations x-ray diffraction pattern.
Figure 20 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt X crystal formations DSC figure.
Figure 21 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt A crystal formations x-ray diffraction pattern.
Figure 22 is 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt A crystal formations DSC figure.
Specific embodiment
Underneath with 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
Piperazine -1- bases) methyl) -3- trifluoromethyls] and benzamide starting material be referred to WO2014082578 description side
It is prepared by method.
The 3- of embodiment 1 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt preparation
By 985g3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazine -1-
Base) methyl) -3- trifluoromethyls] benzamide and 15L absolute ethyl alcohols be added in the glass kettle of 30L, heat
50 DEG C are cooled to after flowing back, are maintained at 50 DEG C and are slowly added dropwise the ethanol solution containing 215g hydrochloric acid
(35.47%), after completion of dropping, crystallization of lowering the temperature.Filter, (0 DEG C) washing of ethanol, 50 DEG C of forced air drying 2h,
Obtain 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) first
Base) -3- trifluoromethyls] benzamide hydrochloride salt.
The 3- of embodiment 2 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] benzamide hydrochloride salt A crystal formations preparation
Weigh 22.72g 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
Piperazine -1- bases) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt in reaction bulb, add 227mL acetone,
45-60 DEG C is cooled to after temperature rising reflux 30min, 22.7mL water is added, is stirred at room temperature after 2h and is filtered, by institute
Obtain forced air drying 2h at 50 DEG C of solid and obtain 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt A crystal formations.
A crystal formations obtained in embodiment 2 have x-ray diffraction pattern as shown in figure 21 and as shown in figure 22
DSC schemes.
The 3- of embodiment 3 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
- 1- bases) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt F crystal formations preparation
Weigh 15mg3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
- 1- bases) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt in 20mL vials, add 1.2mL tetra-
Hydrogen furans dissolves, and is slowly added dropwise 1.4mL ethyl acetate, and 5 DEG C of stirring 1h are centrifugally separating to obtain 3- ((1H- pyrroles
And [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethylbenzenes
Base] benzamide hydrochloride salt F crystal formations.
The 3- of embodiment 4 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] benzamide hydrochloride salt F crystal formations preparation
Weigh 15mg 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
- 1- bases) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt in 20mL vials, add 1.2mL tetra-
Hydrogen furans dissolves, and is slowly added dropwise 1.0mL methyl tertiary butyl ether(MTBE)s, and 5 DEG C of stirring 1h are centrifugally separating to obtain 3- ((1H-
Pyrrolo- [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- fluoroforms
Base phenyl] benzamide hydrochloride salt F crystal formations.
The 3- of embodiment 5 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] benzamide hydrochloride salt F crystal formations preparation
Measure 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- first that 1.0mL concentration is 10mg/mL
Base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt tetrahydrofuran solution,
Slow volatilization 2 days, are centrifugally separating to obtain 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- under room temperature
Methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt F crystal formations.
The 3- of embodiment 6 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] benzamide hydrochloride salt F crystal formations preparation
Weigh 10mg 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
- 1- bases) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt in 3mL vials, add 1.0mL tetra-
Hydrogen furans dissolve, continuously add 2mg mixing high polymer A (etc. quality polyvinylpyrrolidone, polyethylene
Alcohol, polyvinyl chloride, polyvinyl acetate, Hydroxypropyl methylcellulose and methylcellulose uniformly mix), fully stir
Slow volatilization 2 days under the conditions of rear room temperature are mixed, centrifugal filtration obtains 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) second
Alkynyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt F
Crystal formation.
The 3- of embodiment 7 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] benzamide hydrochloride salt F crystal formations preparation
Weigh 15mg 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
- 1- bases) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt A crystal formations in 1.5mL single port bottles, add
0.5mL tetrahydrofurans, magnetic agitation 6 days under room temperature, centrifugation obtains 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5-
Base) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloric acid
Salt F crystal formations.
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl prepared by above example 3-7
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt F crystal formations, Jing measurements
With essentially identical X ray diffracting spectrum.
The 3- of embodiment 8 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] benzamide hydrochloride salt L crystal formations preparation
Weigh 15mg 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
- 1- bases) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt in 20mL vials, add 1.2mL tetra-
Hydrogen furans obtains settled solution, is slowly added dropwise 1.0mL normal heptanes, and at 5 DEG C 48h is stirred, and is filtrated to get 3- ((1H-
Pyrrolo- [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- fluoroforms
Base phenyl] benzamide hydrochloride salt L crystal formations.
The 3- of embodiment 9 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] benzamide hydrochloride salt M crystal formations preparation
Measure 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- first that 1.0mL concentration is 10mg/mL
Base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt ethanol solution, room
The lower slow volatilization of temperature 11 days, obtains 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt M crystal formations.
The 3- of embodiment 10 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] benzamide hydrochloride salt M crystal formations preparation
Measure 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) the acetenyl) -4- first that 1.0mL concentration is 10mg/mL
Base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt ethanol normal heptane is mixed
(volume ratio is 1 to close solution:1), slow volatilization 2 days under room temperature, obtain 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5-
Base) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloric acid
Salt M crystal formations.
The 3- of embodiment 11 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] benzamide hydrochloride salt N crystal form preparation
Weigh 15mg3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
- 1- bases) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt A crystal formations in 1.5mL single port bottles, add
0.3mL1,4- dioxane, magnetic agitation 6 days at 50 DEG C, centrifugation obtains 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5-
Base) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloric acid
Salt N crystal form.
The 3- of embodiment 12 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] benzamide hydrochloride salt P crystal formations preparation
Weigh 15mg3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
- 1- bases) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt A crystal formations in 1.5mL single port bottles, add
0.5mL1,4- dioxane, magnetic agitation 6 days under room temperature, centrifugation obtains 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5-
Base) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloric acid
Salt P crystal formations.
The 3- of embodiment 13 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] benzamide hydrochloride salt Q crystal formations preparation
Weigh 15mg3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
- 1- bases) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt A crystal formations in 1.5mL single port bottles, add
0.5mL2- methyltetrahydrofurans, magnetic agitation 6 days under room temperature, centrifugation obtains 3- ((1H- pyrrolo-es [2,3-b] pyrroles
Piperazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
Hydrochloride Q crystal formations.
The 3- of embodiment 14 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] benzamide hydrochloride salt R crystal formations preparation
Weigh 15mg3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
- 1- bases) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt A crystal formations in 1.5mL single port bottles, add
0.5mL isopropanols, magnetic agitation 6 days under room temperature, centrifugation obtains 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases)
Acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt
R crystal formations.
The 3- of embodiment 15 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] benzamide hydrochloride salt T crystal formations preparation
Weigh 15mg 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
- 1- bases) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt A crystal formations in 1.5mL single port bottles, add
0.5mL dichloromethane, magnetic agitation 6 days under room temperature weigh the solid 15mg that centrifugal filtration obtains and are placed in 3mL
Vial in, it is open to be positioned in the vial of the 20mL equipped with 2mL isopropanols, it is close under room temperature condition
Placement 5 days is closed, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines are obtained
Piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt T crystal formations.
The 3- of embodiment 16 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] benzamide hydrochloride salt V crystal formations preparation
Weigh 15mg 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
- 1- bases) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt A crystal formations in 1.5mL single port bottles, add
0.5mL dichloromethane, magnetic agitation 6 days under room temperature weigh the solid 15mg that centrifugal filtration obtains and are placed in 3mL
Vial in, it is open to be positioned in the vial of the 20mL equipped with 2mLDMF, it is closed under room temperature condition
Place 5 days, obtain 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
- 1- bases) methyl) -3- trifluoromethyls] benzamide hydrochloride salt V crystal formations.
The 3- of embodiment 17 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] benzamide hydrochloride salt X crystal formations preparation
Weigh 15mg 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methyl piperazines
- 1- bases) methyl) -3- trifluoromethyls] and benzamide hydrochloride salt in 20mL vials, add 0.2mL
DMSO obtains settled solution, is slowly added dropwise 15.0mL methyl iso-butyl ketone (MIBK)s, and at 5 DEG C 1h is stirred, and filters
To 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) first
Base) -3- trifluoromethyls] benzamide hydrochloride salt X crystal formations.
The 3- of embodiment 18 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] ten kinds of crystal formations of benzamide hydrochloride salt X-ray powder diffraction measurement
X-ray powder diffraction pattern (XRPD) is in PANalytical Empyrean X-ray powder diffractions point
Gather in analyzer, typical XRPD parameters are shown in Table 11.
Table 11
The 3- of embodiment 19 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] ten kinds of crystal formations of benzamide hydrochloride salt heat analysis
DSC figures are gathered on TA Q200/2000 differential scanning calorimetries and TA Q500/5000 thermogravimetric analyzers
Spectrum, typical test parameters is shown in Table 12.
Table 12
| DSC | |
| Sample disc | Aluminium dish, gland |
| Temperature range/DEG C | 25-300℃ |
| Sweep speed/DEG C/min | 10 |
| Protective gas | Nitrogen |
The 3- of embodiment 20 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] benzamide hydrochloride salt crystal formation stability test
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) first
Base) -3- trifluoromethyls] the M crystal formations of benzamide hydrochloride salt, R crystal formations, T crystal formations, F crystal formations and L be brilliant
Type respectively weighs 3 parts of 0.5g opening and is laid in measuring cup, respectively it is open be positioned over 25 DEG C/60% relative humidity (RH),
7 days in 40 DEG C/75% relative humidity (RH) and 90 DEG C of air dry ovens, content and crystal formation situation of change are investigated,
The results are shown in Table 13.
The crystal formation content of table 13 and crystal formation change
1Relative purity refers to that the sample purity placed 7 days compares the ratio for placing front initial purity, in theory such as
Fruit purity is not changed in, and relative purity is exactly 100%, reflects sample chemically stable disposition under test conditions
Condition.
2 is initial concentration.
Above-mentioned experimental result shows, 3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl
- N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide hydrochloride salt M crystal formations, R crystal formations,
T crystal formations, F crystal formations and L crystal formations have good chemical stability and physical stability.
The 3- of embodiment 21 ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls)
Methyl) -3- trifluoromethyls] benzamide hydrochloride salt crystal formation dissolubility test
3- ((1H- pyrrolo-es [2,3-b] pyrazine -5- bases) acetenyl) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) first
Base) -3- trifluoromethyls] the M crystal formations of benzamide hydrochloride salt, R crystal formations, T crystal formations respectively weigh 3 parts of 0.5g
In 50mL vials, water, methyl alcohol and ethanol are separately added into, observe dissolving situation, result of the test shows M
Crystal formation easily dissolves in water, methyl alcohol and ethanol, and R crystal formations are readily soluble in water, easily molten in methyl alcohol and ethanol
Solution, T crystal formations are readily soluble in water, easily dissolve in methyl alcohol and ethanol.
Although being below described in detail to the present invention, however it is understood by skilled practitioners that without departing from
On the premise of the spirit and scope of the present invention various modifications and changes can be carried out to the present invention.The right of the present invention
Scope is not limited to the detailed description made above, and should belong to claims.
Claims (20)
1. F crystal formations of the compound of formula 1, it is characterised in that radiated using Cu-Ka, its x-ray diffraction pattern,
With spend 2 θ that represent 10.1 ° ± 0.2 °, 12.5 ° ± 0.2 °, 16.8 ° ± 0.2 °, 17.4 ° ± 0.2 °, 18.1 ° ± 0.2 °,
20.2 ° ± 0.2 °, 22.1 ° ± 0.2 °, 23.9 ° ± 0.2 °, 25.1 ° ± 0.2 °, show characteristic diffraction peak at 29.2 ° ± 0.2 °,
2. F crystal formations of the compound of formula as claimed in claim 11, its x-ray diffraction pattern is as shown in Figure 1.
3. L crystal formations of the compound of formula 1, it is characterised in that radiated using Cu-Ka, its x-ray diffraction pattern,
With spend 2 θ that represent 11.7 ° ± 0.2 °, 13.3 ° ± 0.2 °, 16.0 ° ± 0.2 °, 17.6 ° ± 0.2 °, 18.6 ° ± 0.2 °,
25.5 ° ± 0.2 °, show characteristic diffraction peak at 26.6 ° ± 0.2 °,
4. L crystal formations of the compound of formula as claimed in claim 31, its x-ray diffraction pattern is as shown in Figure 3.
5. M crystal formations of the compound of formula 1, it is characterised in that radiated using Cu-Ka, its x-ray diffraction pattern,
With spend 2 θ that represent 7.6 ° ± 0.2 °, 9.0 ° ± 0.2 °, 11.9 ° ± 0.2 °, 14.1 ° ± 0.2 °, 15.3 ° ± 0.2 °,
15.5°±0.2°、16.2°±0.2°、18.0°±0.2°、20.3°±0.2°、20.8°±0.2°、21.8°±0.2°、24.6°±0.2°、
Characteristic diffraction peak is shown at 24.9 ° ± 0.2 °,
6. M crystal formations of the compound of formula as claimed in claim 51, its x-ray diffraction pattern is as shown in Figure 5.
7. the N crystal form of the compound of formula 1, it is characterised in that radiated using Cu-Ka, its x-ray diffraction pattern,
With spend 2 θ that represent 10.7 ° ± 0.2 °, 11.2 ° ± 0.2 °, 11.8 ° ± 0.2 °, 16.0 ° ± 0.2 °, 16.9 ° ± 0.2 °,
18.2 ° ± 0.2 °, 19.8 ° ± 0.2 °, 20.7 ° ± 0.2 °, 21.5 ° ± 0.2 °, 23.6 ° ± 0.2 °, show spy at 23.7 ° ± 0.2 °
Levy diffraction maximum,
8. the N crystal form of the compound of formula as claimed in claim 71, its x-ray diffraction pattern is as shown in Figure 7.
9. P crystal formations of the compound of formula 1, it is characterised in that radiated using Cu-Ka, its x-ray diffraction pattern,
With spend 2 θ that represent 8.8 ° ± 0.2 °, 12.6 ° ± 0.2 °, 16.4 ° ± 0.2 °, 17.0 ° ± 0.2 °, 18.2 ° ± 0.2 °,
19.1°±0.2°、19.4°±0.2°、19.8°±0.2°、20.8°±0.2°、22.6°±0.2°、24.0°±0.2°、24.5°±0.2°、
26.6 ° ± 0.2 °, show characteristic diffraction peak at 27.4 ° ± 0.2 °,
10. P crystal formations of the compound of formula as claimed in claim 91, its x-ray diffraction pattern such as Fig. 9 institutes
Show.
The Q crystal formations of the compound of 11. formula 1, it is characterised in that radiated using Cu-Ka, its x-ray diffraction pattern,
With spend 2 θ that represent 6.6 ° ± 0.2 °, 8.5 ° ± 0.2 °, 10.7 ° ± 0.2 °, 11.3 ° ± 0.2 °, 12.5 ° ± 0.2 °,
14.8°±0.2°、17.8°±0.2°、18.1°±0.2°、18.9°±0.2°、20.0°±0.2°、20.4°±0.2°、23.1°±0.2°、
23.5 ° ± 0.2 °, 23.9 ° ± 0.2 °, 24.5 ° ± 0.2 °, show characteristic diffraction peak at 28.5 ° ± 0.2 °,
The Q crystal formations of the compound of 12. formula as claimed in claim 11 1, its x-ray diffraction pattern such as Figure 11
It is shown.
The R crystal formations of the compound of 13. formula 1, it is characterised in that radiated using Cu-Ka, its x-ray diffraction pattern,
With spend 2 θ that represent 9.7 ° ± 0.2 °, 10.8 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.2 ° ± 0.2 °, 13.9 ° ± 0.2 °,
17.8 ° ± 0.2 °, 19.5 ° ± 0.2 °, 23.5 ° ± 0.2 °, show characteristic diffraction peak at 24.4 ° ± 0.2 °,
The R crystal formations of the compound of 14. formula as claimed in claim 13 1, its x-ray diffraction pattern such as Figure 13
It is shown.
The T crystal formations of the compound of 15. formula 1, it is characterised in that radiated using Cu-Ka, its x-ray diffraction pattern,
With spend 2 θ that represent 8.1 ° ± 0.2 °, 8.6 ° ± 0.2 °, 13.5 ° ± 0.2 °, 14.5 ° ± 0.2 °, 15.0 ° ± 0.2 °,
15.8°±0.2°、17.3°±0.2°、18.7°±0.2°、20.3°±0.2°、21.9°±0.2°、23.1°±0.2°、23.8°±0.2°
Place shows characteristic diffraction peak,
The T crystal formations of the compound of 16. formula as claimed in claim 15 1, its x-ray diffraction pattern such as Figure 15
It is shown.
The V crystal formations of the compound of 17. formula 1, it is characterised in that radiated using Cu-Ka, its x-ray diffraction pattern,
With spend 2 θ that represent 8.0 ° ± 0.2 °, 8.3 ° ± 0.2 °, 14.0 ° ± 0.2 °, 14.7 ° ± 0.2 °, 17.8 ° ± 0.2 °,
19.9°±0.2°、20.8°±0.2°、21.3°±0.2°、22.3°±0.2°、22.9°±0.2°、23.7°±0.2°、24.7°±0.2°、
25.7 ° ± 0.2 °, 26.3 ° ± 0.2 °, show characteristic diffraction peak at 27.5 ° ± 0.2 °,
The V crystal formations of the compound of 18. formula as claimed in claim 17 1, its x-ray diffraction pattern such as Figure 17
It is shown.
The X crystal formations of the compound of 19. formula 1, it is characterised in that radiated using Cu-Ka, its x-ray diffraction pattern,
Shown at 5.4 ° ± 0.2 °, 10.0 ° ± 0.2 °, 15.8 ° ± 0.2 °, 20.0 ° ± 0.2 °, 21.1 ° ± 0.2 ° with spending 2 θ for representing
Show characteristic diffraction peak,
The X crystal formations of the compound of 20. formula as claimed in claim 19 1, its x-ray diffraction pattern such as Figure 19
It is shown.
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