CN107365315A - A kind of pyrazole compound, its crystal formation and preparation method thereof - Google Patents
A kind of pyrazole compound, its crystal formation and preparation method thereof Download PDFInfo
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a kind of pyrazole compound, its crystal formation and preparation method thereof.The pyrazole compound is two [dihydrofuran of 1 (base of 5 hydroxyl, 3 methyl, 1 phenyl 1H pyrazoles 4) 6 methyl 1,3 simultaneously the alcohol of [3,4 c] pyridine 7] tri hydrochloride monohydrates.The two TM2002 tri hydrochlorides monohydrate and its crystal formation, stability is good, during bulk drug and preparation production preserve, advantageously reduces the generation of impurity, improves the quality of product.The preparation method of the present invention is simple, quick, and preparation condition is gentle, stable yield, is adapted to large-scale production.
Description
Technical field
The present invention relates to a kind of pyrazole compound, its crystal formation and preparation method thereof.
Background technology
1- (5- hydroxy-3-methyl -1- phenyl -1H- pyrazoles -4- bases) -6- methyl isophthalic acids, 3- dihydrofuran simultaneously [3,4-c] pyrrole
Pyridine -7- alcohol hydrochlorides (hereinafter referred TM2002 hydrochlorides), are a kind of protein modified formation inhibitors, its structural formula is as indicated with 1：
TM2002 hydrochlorides are as protein modifier production inhibitor, without other protein modifier production inhibitors
The side effect (such as pyridoxine deficiency) of (such as Edaravone), while kidney is played a protective role.
It is well known that stability of the crystal formation to bulk drug and preparation, dissolubility influence is particularly significant, but TM2002 hydrochlorides
Crystal formation there are no at present pertinent literature report.In patent document WO2005054205, using methanol and 2N hydrochloric acid methanol knots
Crystalline substance, and add ethanol concentration, crystalline TM2002 hydrochloric acid salt powder is obtained, but do not report its XRPD data.
The content of the invention
The technical problems to be solved by the invention are the provision of a kind of pyrazole compound, its crystal formation and its preparation side
Method, specifically, that is, it there is provided a kind of two TM2002 tri hydrochloride monohydrates, its crystal formation and preparation method thereof.This two
TM2002 tri hydrochlorides monohydrate and its crystal formation, stability is preferable, during bulk drug and preparation production preserve, is advantageous to
The generation of impurity is reduced, improves the quality of product.The preparation method of the present invention is simple, quick, and preparation condition is gentle, and yield is steady
It is fixed, it is adapted to large-scale production.
The present inventor has found during compound TM2002 hydrochlorides are studied, when with methanol and methanol hydrochloride solution
When (i.e. crystallization condition in WO2005054205), ethanol and hydrochloric acid, or isopropanol crystallize with hydrochloric acid to TM2002, institute
It is identical (hereinafter referred crystal formation I) to obtain crystal formation, 2 θ characteristic absorption peaks, interplanar distance and the relative intensity of its X-ray powder diffraction figure
It is as shown in table 1 below：
Table 1
The DCO analysis shows of the crystal formation I, the crystal formation I are a TM2002 hydrochloride.
The present inventor is found that a kind of novel crystal forms (the hereinafter referred crystal formation of TM2002 hydrochlorides in further research
Ⅲ).For crystal formation I, crystal formation III has more preferable stability, especially high-temperature stability, is given birth in bulk drug and preparation
During production preserves, the generation of impurity is advantageously reduced, improves product quality.
The present invention solves above-mentioned technical problem by the following technical programs.
The invention provides a kind of pyrazole compound, its be two [1- (5- hydroxy-3-methyl -1- phenyl -1H- pyrazoles -
4- yls) -6- methyl isophthalic acids, 3- dihydrofuran simultaneously [3,4-c] pyridine -7- alcohol] tri hydrochloride monohydrate.
The structural formula of the pyrazole compound is as shown in Equation 2：
The invention provides a kind of 1- (5- hydroxy-3-methyl -1- phenyl -1H- pyrazoles -4- bases) -6- methyl isophthalic acids, 3- dihydros
The crystal formation III of furans simultaneously [3,4-c] pyridine -7- alcohol hydrochlorides, 2 θ characteristic absorptions of the X-ray powder diffraction figure of the crystal formation III
Peak is：6.48±0.2、12.68±0.2、12.96±0.2、13.20±0.2、13.46±0.2、14.68±0.2、15.34±
0.2、16.16±0.2、16.77±0.2、18.33±0.2、19.24±0.2、19.61±0.2、21.17±0.2、21.41±
0.2、21.59±0.2、23.12±0.2、23.60±0.2、24.21±0.2、25.90±0.2、26.50±0.2、27.25±
0.2、28.39±0.2、29.16±0.2、29.68±0.2、30.61±0.2、31.05±0.2、31.55±0.2、32.12±
0.2nd, 32.64 ± 0.2,33.58 ± 0.2,34.83 ± 0.2,36.03 ± 0.2 and 36.72 ± 0.2；
The crystal formation III is two [1- (5- hydroxy-3-methyl -1- phenyl -1H- pyrazoles -4- bases) -6- methyl isophthalic acids, 3- dihydros
Furans simultaneously [3,4-c] pyridine -7- alcohol] tri hydrochloride monohydrate.
It is preferred that the data of the X-ray powder diffraction figure of the crystal formation III are as shown in table 2 below：
Table 2
More preferably, the X-ray powder diffraction figure of the crystal formation III is substantially as shown in Figure 7.
In the better embodiment of the present invention, described crystal formation III is monocrystalline, and the crystal formation III belongs to anorthic system, empty
Between group P-1, cell parameter：α=106.70 °, β
=102.35 °, γ=99.08 °, unit cell volumeAsymmetry unit number Z=2, crystalline density are in structure cell
1.430g/cm3。
In the present invention, it is preferred that the crystal formation III differential scanning calorimetry (DSC) detect at 144~145 DEG C and
There is endothermic peak at 224~225 DEG C.More preferably, the DSC figures of the crystal formation III are substantially as shown in Figure 8.
In the present invention, the infrared spectrum of the crystal formation III is at least in 3038.7cm-1, 2652.3cm-1, 1546.4cm-1,
1419.8cm-1, 1305.6cm-1, 1038.5cm-1And 701.7cm-1There is absworption peak at place.More preferably, the infrared light of the crystal formation III
Spectrum is substantially as shown in Figure 9.
Present invention also offers a kind of 1- (5- hydroxy-3-methyl -1- phenyl -1H- pyrazoles -4- bases) -6- methyl isophthalic acids,
The preparation method of the 3- dihydrofuran simultaneously crystal formation III of [3,4-c] pyridine -7- alcohol hydrochlorides, it comprises the steps：By 1- (5- hydroxyls
Base -3- methyl isophthalic acids-phenyl -1H- pyrazoles -4- bases) -6- methyl isophthalic acids, 3- dihydrofuran simultaneously [3,4-c] pyridine -7- alcohol be dissolved in it is molten
In agent, cooling crystallization, produce；The solvent includes hydrochloric acid and water；The initial temperature of the crystallization is below 40 DEG C.
Wherein, 1- (5- hydroxy-3-methyl -1- phenyl -1H- pyrazoles -4- bases) -6- methyl isophthalic acids, 3- dihydrofuran simultaneously [3,4-
C] pyridine -7- alcohol is also known as TM2002.
Wherein, in the solvent, in addition to hydrochloric acid and water, alcohol and/or ethyl acetate can also be contained.The alcohol can be
One or more in alcohol commonly used in the art, preferably methanol, ethanol and isopropanol.
In the solvent, the concentration of the hydrochloric acid is preferably 1~11mol/L, is more preferably 6~9mol/L.
In the solvent, the volumetric concentration of the alcohol is preferably 20%~90%, is more preferably 33%~65%.
In the solvent, the volumetric concentration of the ethyl acetate is preferably 20%~80%, more preferably for 50%~
71%.
By common sense in the field, activated carbon can be added with except thermal source, before " cooling crystallization " after " being dissolved in solvent "
Filter out the activated carbon.
Wherein, the method for the dissolving and condition can be this area conventional method and condition, the temperature of the dissolving compared with
It is 40~100 DEG C goodly.
Wherein, the method for the cooling crystallization and condition can be this area conventional method and condition, the cooling crystallization
Target temperature be preferably 0~40 DEG C, be more preferably 0~10 DEG C.The initial temperature of the crystallization is preferably 15~40 DEG C.
In the present invention, after the cooling crystallization, can also be filtered and/or dry operation.It is described filtering and/or
Dry method and condition can be this area conventional method and condition, and the temperature of the drying is preferably 30~50 DEG C.
In the preferred embodiment of the present invention, before the cooling crystallization, crystal seed III is added.The crystal seed III is warp
XRPD detects the solid particle for being defined as crystal formation III.
Present invention also offers a kind of preparation method of the pyrazole compound, its step with foregoing 1- (5- hydroxyls-
3- methyl isophthalic acids-phenyl -1H- pyrazoles -4- bases) -6- methyl isophthalic acids, the crystal formation of 3- dihydrofuran simultaneously [3,4-c] pyridine -7- alcohol hydrochlorides
II preparation method.Its preferable operating condition is also the same as those described above.Obtained is two [1- (5- hydroxy-3-methyl -1- benzene
Base -1H- pyrazoles -4- bases) -6- methyl isophthalic acids, 3- dihydrofuran simultaneously [3,4-c] pyridine -7- alcohol] tri hydrochloride monohydrate.
It on the basis of common sense in the field is met, above-mentioned each optimum condition, can be combined, it is each preferably real to produce the present invention
Example.
Agents useful for same and raw material of the present invention are commercially available.
In the present invention, the X-ray powder diffraction figure is to use Bruker D8ADVANCE type powder x-ray diffractions
Collection, under the test condition of 40kV/40mA (pipe pressure/pipe stream), with what is determined under the K α spectral lines of Cu targets, 2 θ values scopes are from 3 degree
To 45 degree, with 0.02 °/step-length, from 3 ° to 45 °, continuous scanning, 8.0 °/min of sweep speed, reproducible θ ± 0.20 ° of scope 2 are (excellent
Select 2 θ ± 0.10 °).
In the present invention, differential scanning calorimetry (DSC) gathers on NETZSCH DSC 204F1, crucible type：Aluminium crucible
(acupuncture perforation), purge gass：High Purity Nitrogen；20mL/min, protect gas：High Purity Nitrogen；60mL/min, programming rate：10℃/min.
In the present invention, infrared test instrument is NICOLET 670-FTIR, using pressing potassium bromide troche.
In the present invention, described ambient temperature is the conventional ambient temperature in this area, generally 10~30 DEG C.
The positive effect of the present invention is：
The stability of the TM2002 hydrochloride Forms III of the present invention is preferable, and especially high-temperature stability is good, in bulk drug and
During preparation production preserves, the generation of impurity is advantageously reduced, improves product quality.The preparation method of the present invention is simple, fast
Victory, preparation condition is gentle, stable yield, is adapted to large-scale production.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction figure of the TM2002 hydrochloride Forms I of comparative example 1.
Fig. 2 is the DSC figures of the TM2002 hydrochloride Forms I of comparative example 1.
Fig. 3 is the IR figures of the TM2002 hydrochloride Forms I of comparative example 1.
Fig. 4 is the TGA figures of the TM2002 hydrochloride Forms I of comparative example 1.
Fig. 5 is the molecule stereo structure perspective view of the monocrystalline I of comparative example 2.
Fig. 6 is that the structure cell of the monocrystalline I of comparative example 2 accumulates perspective view.
Fig. 7 is the X-ray powder diffraction figure of the TM2002 hydrochloride Forms III of embodiment 1.
Fig. 8 is the DSC figures of the TM2002 hydrochloride Forms III of embodiment 1.
Fig. 9 is the IR figures of the TM2002 hydrochloride Forms III of embodiment 1.
Figure 10 is the TGA figures of the TM2002 hydrochloride Forms III of embodiment 1.
Figure 11 is the molecule stereo structure perspective view of the monocrystalline III of embodiment 2.
Figure 12 is that the structure cell of the monocrystalline III of embodiment 2 accumulates perspective view.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Apply among a scope.The experimental method of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product specification selects.
Assay method used in following embodiments and comparative example is as described below：
X-ray powder diffraction figure is gathered using Bruker D8ADVANCE types powder x-ray diffraction, in 40kV/
Under 40mA (pipe pressure/pipe stream) test condition, with what is determined under the K α spectral lines of Cu targets, 2 θ values scopes from 3 degree to 45 degree, with
The continuous scanning from 3 ° to 45 ° of 0.02 °/step-length, sweep speed 8.0 °/min, reproducible θ ± 0.20 ° of scope 2 (preferably 2 θ ±
0.10°)。
Differential scanning calorimetry (DSC) gathers on NETZSCH DSC 204F1, crucible type：Aluminium crucible (needle-penetration
Hole), purge gass：High Purity Nitrogen；20mL/min, protect gas：High Purity Nitrogen；60mL/min, programming rate：10℃/min.
Infrared test instrument is NICOLET 670-FTIR, using pressing potassium bromide troche.
Thermogravimetric analysis instrument is to be gathered on NETZSCH TG 209F1, crucible type：Alumina crucible, purge gass：It is high-purity
Nitrogen；20mL/min, protect gas：High Purity Nitrogen；10mL/min, programming rate：10℃/min.
In embodiment and comparative example, the concentration of used concentrated hydrochloric acid is 12mol/L.
Comparative example 1
TM2002 hydrochlorides are prepared by WO2005054205 methods.Crystal I is designated as, corresponding crystal formation is crystal formation I.
Specific method is as follows：By TM2002 crude products (5g) plus 2mol/L methanol hydrochloride solution (15ml), add methanol
(250ml), is heated to complete molten, is concentrated under reduced pressure, and when being concentrated into crystallization and starting, adds ethanol (100ml), replaces solvent and simultaneously concentrate,
Repeat 2 times, be concentrated into about 50ml, cooling places (4 DEG C) of refrigerator overnight, filtering, ethanol filter wash cake, dries to obtain TM2002 salt
Hydrochlorate 4.5g, purity 98.6%.The powder X-ray diffraction collection of illustrative plates of the crystal I is as shown in figure 1, specific data see the table below 3.The crystal I
DSC, IR and TGA test result respectively as shown in Figure 2, Figure 3 and Figure 4.
Table 3
Comparative example 2
The crystal I as made from literature method carries out single crystal cultivation, obtains monocrystalline, and specific preparation method is as follows：
TM2002 crude products 1g is added to 4mol/L hydrogen chloride methanol solution (5ml), adds methanol (30ml), is heated to all molten
Solution, adds ethanol (30ml), is stored at room temperature overnight precipitation solid, the monocrystalline for taking bulk crystalline to be crystal formation I, is denoted as monocrystalline I.
The monocrystalline I of acquisition is subjected to Advances in crystal X-ray diffraction experiment, it is as a result as follows：
One diffraction experiment
This crystal is in water white transparency column, and diffraction experiment crystal size is 0.11 × 0.13 × 0.19mm, and category three is tiltedly brilliant
System, space group P-1, cell parameter：A=7.0972 (14), b=9.6880 (19),α=104.89
γ=96.80 (3) °, β=97.70 (3) °, °, (3) unit cell volumeAsymmetry unit number Z=in structure cell
2。
Diffracted intensity data are collected with Bruker SMART APEX-II diffractometers, CuK α radiation, graphite monochromator, are singly led
Pipe diameter ф=0.50mm, crystal and ccd detector distance d=60.3mm, pipe press 40kV, pipe stream 30mA, scan mode：
Scanning, it is 10621 to collect total diffraction points, and independent diffraction points are 3734, observable points (| F | 2 >=2 σ | F | 2) be
2596.
Two structure elucidations
Crystal structure is parsed using direct method (Shelxs97), all 25 non-hydrogen atom positions are obtained from E figures, are used
Least square refinement structural parameters and differentiation atomic species, use geometric calculation and difference Fourier method to obtain whole hydrogen
Atom site, and final Reliability factor R1=0.0468, wR2=0.1288 (w=1/ σ | F | 2), S=1.026.It is final to determine chemistry
Metering-type is C18H17N3O3HCl, it is 359.80 to calculate molecular weight, calculates crystalline density 1.456g/cm3。
The compound of molecule relative configuration figure corresponding 1 of the monocrystalline I, Fig. 5 are that the molecule stereo structure of the monocrystalline I projects
Figure, Fig. 6 are that structure cell of the monocrystalline I along a direction of principal axis accumulates perspective view, and table 4 is the atomic coordinates parameter value of non-hydrogen atom.
Table 4
As a result show：Molecules align belongs to the second space-like group under crystalline state, therefore sample should not have optically active, it may be determined that brilliant
The relative configuration of compound is as shown in Equation 1 in body.Intermolecular under crystalline state hydrogen bond contact to be present, molecule is tieed up with Van der Waals force and hydrogen bond
It is its stable alignment in space.
Embodiment 1
TM2002 crude products 1g is dissolved in 6mol/L aqueous hydrochloric acid solution (20mL), being heated to 90 DEG C makes TM2002 crude products complete
Portion dissolves, and adds 0.2g activated carbons, and flow back 15min, filters while hot, and filtrate cooling separates out solid, and the initial temperature of crystallization is 35
DEG C, 0~5 DEG C of ice-water bath is incubated 1.5h, filtering, TM2002 hydrochlorides 0.6g is dried to obtain at 50 DEG C.After testing, purity ﹥
99.0%, yield 60%.
In the present embodiment, the MS and NMR data of product are as follows：
EMS-MS m/z:324.1[M+H]+。
1H-NMR(400MHz,CDCl3+CF3COOH)δ：2.35(s,3H,CH3),2.68(s,3H,CH3),5.32-5.43
(m,2H,CH2),6.64(s,1H,CH),7.26-7.51(m,7H),8.10(s,1H)。
Tested through XRPD and DSC, as shown in Figure 7 and Figure 8, specific XRPD data are shown in Table 5 to test result.By the institute of embodiment 1
Obtained TM2002 hydrochlorides are designated as crystal III, and corresponding crystal formation is crystal formation III.IR the and TGA test results of the crystal III are respectively such as
Shown in Fig. 9 and Figure 10.
Table 5
Embodiment 2
Single crystal cultivation is carried out to crystal III, obtains monocrystalline, specific preparation method is as follows：
TM2002 crude products 1g is dissolved in the in the mixed solvent of 6ml concentrated hydrochloric acids, 2mL water and 4mL ethanol, being heated to 80 DEG C makes
TM2002 crude products all dissolve, and are cooled to 35 DEG C of addition crystal seeds III, are stored at room temperature overnight precipitation solid, it is this to take bulk crystalline
The monocrystalline of invention crystal, it is determined as crystal formation III through XRPD, is denoted as monocrystalline III.
The monocrystalline III of acquisition is subjected to Advances in crystal X-ray diffraction experiment, it is as a result as follows：
One diffraction experiment
Crystal of the present invention is block in water white transparency, and diffraction experiment crystal size is 0.20 × 0.23 × 0.31mm, category three
Oblique system, space group P-1, cell parameter：A=9.4217 (19), b=14.1143 (3),α=
106.70 (3), β=102.35 (3), γ=99.08 (3) °, unit cell volumeAsymmetry unit in structure cell
Number Z=2.
Diffracted intensity data are collected with Bruker SMART APEX-II diffractometers, CuK α radiation, graphite monochromator, are singly led
Pipe diameter ф=0.50mm, crystal and ccd detector distance d=60.3mm, pipe press 40kV, pipe stream 30mA, scan mode：
Scanning, it is 21719 to collect total diffraction points, and independent diffraction points are 8037, observable points (| F | 2 >=2 σ | F | 2) be
6584.
Two structure elucidations
Crystal structure is parsed using direct method (Shelxs97), all 52 non-hydrogen atom positions are obtained from E figures, are used
Least square refinement structural parameters and differentiation atomic species, use geometric calculation and difference Fourier method to obtain whole hydrogen
Atom site, final Reliability factor R1=0.1352, wR2=0.4615 (w=1/ σ | F |2), S=1.118.It is final to determine chemistry
Metering-type is 2 (C18H17N3O3)·3HCl·H2O, it is 773.07 to calculate molecular weight, calculates crystalline density 1.430g/cm3。
The molecule relative configuration figure of the monocrystalline III corresponds to the compound of formula 2, and Figure 11 is the molecule stereo structure of the monocrystalline III
Perspective view, Figure 12 are that structure cell of the monocrystalline III along a direction of principal axis accumulates perspective view, and table 6 is the atomic coordinates parameter value of non-hydrogen atom.
Table 6
As a result show：Molecules align belongs to the second space-like group under crystalline state, therefore sample should not have optically active, it may be determined that brilliant
The relative configuration of compound such as formula 2 in body.Intermolecular under crystalline state hydrogen bond contact to be present, molecule maintains it with Van der Waals force and hydrogen bond
Stable alignment in space.
Embodiment 3
TM2002 crude products 1g is added to the in the mixed solvent of 4mL concentrated hydrochloric acids, 4mL water and 20mL ethyl acetate, is heated to 80 DEG C
All dissolved to TM2002 crude products, cooling separates out solid, and crystallization initial temperature is 40 DEG C, ice-water bath insulation 1h, filtering, acetic acid second
Ester washs filter cake, and TM2002 hydrochlorides 0.66g is dried to obtain in 30 DEG C.After testing, purity 99.9%, single miscellaneous ＜ 0.1% are obtained
TM2002 hydrochlorides through XRPD determine it is identical with the sample of embodiment 1, it be two TM2002 tri hydrochloride monohydrates, correspondence crystalline substance
Type is crystal formation III.
Embodiment 4
TM2002 crude products 129g is dissolved in the in the mixed solvent of 780mL concentrated hydrochloric acids, 250mL water and 500mL ethanol, is heated to
90 DEG C all dissolve to TM2002 crude products, add activated carbon 1g, and flow back 15min, filters while hot, filtrate cooling, are added at 35 DEG C
Crystal seed III, the crystal seed III are that the solid particle for determining that crystal formation is crystal formation III is tested through XRPD, separate out solid, and ice-water bath is incubated 1h,
Filtering, ethanol washing filter cake, dries to obtain TM2002 hydrochlorides 113.5g in 50 DEG C.After testing, purity 99.9%, single miscellaneous ＜
0.1%, obtained TM2002 hydrochlorides are identical with the sample of embodiment 1 through XRPD measure, and it is two TM2002 tri hydrochlorides one
Hydrate, corresponding crystal formation is crystal formation III.
Embodiment 5
By TM2002 hydrochlorides are prepared the step of embodiment 4, differ only in, in solvent：Concentration of hydrochloric acid is 1mol/L, first
The volumetric concentration of alcohol is 90%.Obtained TM2002 hydrochlorides are identical with the sample of embodiment 1 through XRPD measure, and it is two
TM2002 tri hydrochloride monohydrates, corresponding crystal formation is crystal formation III.
Embodiment 6
By TM2002 hydrochlorides are prepared the step of embodiment 4, differ only in, in solvent：Concentration of hydrochloric acid is 8mol/L, different
The volumetric concentration of propyl alcohol alcohol is 20%.Obtained TM2002 hydrochlorides are identical with the sample of embodiment 1 through XRPD measure, and it is two
TM2002 tri hydrochloride monohydrates, corresponding crystal formation is crystal formation III.
Embodiment 7
By TM2002 hydrochlorides are prepared the step of embodiment 1, differ only in, in solvent：Concentration of hydrochloric acid is 11mol/L,
Initial recrystallization temperature is 15 DEG C.Obtained TM2002 hydrochlorides are identical with the sample of embodiment 1 through XRPD measure, and it is two
TM2002 tri hydrochloride monohydrates, corresponding crystal formation is crystal formation III.
Embodiment 8
By TM2002 hydrochlorides are prepared the step of embodiment 3, differ only in, in solvent：Concentration of hydrochloric acid is 4mol/L, second
The volumetric concentration of acetoacetic ester is 50%.Obtained TM2002 hydrochlorides are identical with the sample of embodiment 1 through XRPD measure, and it is two
TM2002 tri hydrochloride monohydrates, corresponding crystal formation is crystal formation III.
Effect example
Stability contrast is carried out (at 60 DEG C to the crystal obtained by embodiment 1 and comparative example 1 using HPLC analytic approach
Place 10 days), it is as a result as shown in table 7 below.
Table 7
Wherein, impurity A is TM2002 caused impurity in preparation process.As a result show：Crystal formation III is steady at high temperature
Qualitative good, the impurity of crystal formation III increases only 10%, and the impurity of crystal formation I increases by 58%.
Claims (10)
1. a kind of pyrazole compound, it is characterised in that it is two [1- (5- hydroxy-3-methyl -1- phenyl -1H- pyrazoles -4-
Base) -6- methyl isophthalic acids, 3- dihydrofuran simultaneously [3,4-c] pyridine -7- alcohol] tri hydrochloride monohydrate.
2. a kind of 1- (5- hydroxy-3-methyl -1- phenyl -1H- pyrazoles -4- bases) -6- methyl isophthalic acids, 3- dihydrofuran is simultaneously [3,4-c]
The crystal formation III of pyridine -7- alcohol hydrochlorides, it is characterised in that 2 θ characteristic absorption peaks of the X-ray powder diffraction figure of the crystal formation III
For：6.48±0.2、12.68±0.2、12.96±0.2、13.20±0.2、13.46±0.2、14.68±0.2、15.34±
0.2、16.16±0.2、16.77±0.2、18.33±0.2、19.24±0.2、19.61±0.2、21.17±0.2、21.41±
0.2、21.59±0.2、23.12±0.2、23.60±0.2、24.21±0.2、25.90±0.2、26.50±0.2、27.25±
0.2、28.39±0.2、29.16±0.2、29.68±0.2、30.61±0.2、31.05±0.2、31.55±0.2、32.12±
0.2nd, 32.64 ± 0.2,33.58 ± 0.2,34.83 ± 0.2,36.03 ± 0.2 and 36.72 ± 0.2；
The crystal formation III is two [1- (5- hydroxy-3-methyl -1- phenyl -1H- pyrazoles -4- bases) -6- methyl isophthalic acids, 3- dihydrofuran
And [3,4-c] pyridine -7- alcohol] tri hydrochloride monohydrate.
3. crystal formation III as claimed in claim 2, it is characterised in that the data of the X-ray powder diffraction figure of the crystal formation III are such as
Shown in following table：
The X-ray powder diffraction figure of the crystal formation III is preferably substantially as shown in Figure 7.
4. crystal formation III as claimed in claim 2 or claim 3, it is characterised in that described crystal formation III is monocrystalline, the category of crystal formation III three
Oblique system, space group P-1, cell parameter： α
=106.70 °, β=102.35 °, γ=99.08 °, unit cell volumeAsymmetry unit number Z=2 in structure cell,
Crystalline density is 1.430g/cm3。
5. crystal formation III as claimed in claim 2 or claim 3, it is characterised in that the differential scanning calorimetry detection of the crystal formation III exists
There is endothermic peak at 144~145 DEG C and 224~225 DEG C；
And/or the infrared spectrum of the crystal formation III is at least in 3038.7cm-1, 2652.3cm-1, 1546.4cm-1, 1419.8cm-1,
1305.6cm-1, 1038.5cm-1And 701.7cm-1There is absworption peak at place.
6. crystal formation III as claimed in claim 5, it is characterised in that the differential scanning calorimetry figure of the crystal formation II is substantially such as
Shown in Fig. 8；
And/or the infrared spectrum of the crystal formation II is substantially as shown in Figure 9.
7. one kind 1- (5- hydroxy-3-methyl -1- phenyl -1H- pyrazoles -4- bases) -6- first as described in any one of claim 2~6
The preparation method of base -1,3- dihydrofuran simultaneously crystal formation III of [3,4-c] pyridine -7- alcohol hydrochlorides, it is characterised in that under it includes
State step：By 1- (5- hydroxy-3-methyl -1- phenyl -1H- pyrazoles -4- bases) -6- methyl isophthalic acids, 3- dihydrofuran simultaneously [3,4-c] pyrrole
Pyridine -7- alcohol is dissolved in solvent, cooling crystallization, is produced；The solvent includes hydrochloric acid and water；The initial temperature of the crystallization is 40
Below DEG C.
8. preparation method as claimed in claim 7, it is characterised in that in the solvent, the concentration of the hydrochloric acid for 1~
11mol/L, preferably 6~9mol/L；
And/or also contain alcohol and/or ethyl acetate in the solvent；The alcohol is preferably in methanol, ethanol and isopropanol
It is one or more；The volumetric concentration of the alcohol is preferably 20%~90%, is more preferably 33%~65%；The ethyl acetate
Volumetric concentration be preferably 20%~80%, be more preferably 50%~71%.
9. preparation method as claimed in claim 7 or 8, it is characterised in that after " being dissolved in solvent ", activated carbon is added,
The activated carbon is filtered out before " cooling crystallization "；
And/or the temperature of the dissolving is 40~100 DEG C；
And/or the target temperature of the cooling crystallization is 0~40 DEG C, preferably 0~10 DEG C；
And/or the initial temperature of the crystallization is 15~40 DEG C；
And/or after the cooling crystallization, filtered and/or dry operation；The temperature of the drying is preferably 30~
50℃。
10. preparation method as claimed in claim 7 or 8, it is characterised in that before the cooling crystallization, add crystal seed III, institute
It is the solid particle for being defined as crystal formation III through XRPD detections to state crystal seed III.
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| WO2003024446A1 (en) * | 2001-09-11 | 2003-03-27 | Mitsubishi Pharma Corporation | Oxidation stress inhibitor and method of measuring oxidation stress |
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| WO2003024446A1 (en) * | 2001-09-11 | 2003-03-27 | Mitsubishi Pharma Corporation | Oxidation stress inhibitor and method of measuring oxidation stress |
| WO2005054205A1 (en) * | 2003-12-05 | 2005-06-16 | Tokai University Educational System | Protein modifier production inhibitor |
| CN103260622A (en) * | 2010-12-20 | 2013-08-21 | 辉瑞大药厂 | Novel fused pyridine compounds as casein kinase inhibitors |
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