CN106831620A - Crystal formation of Lei Xina get and preparation method thereof - Google Patents
Crystal formation of Lei Xina get and preparation method thereof Download PDFInfo
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- CN106831620A CN106831620A CN201710129665.6A CN201710129665A CN106831620A CN 106831620 A CN106831620 A CN 106831620A CN 201710129665 A CN201710129665 A CN 201710129665A CN 106831620 A CN106831620 A CN 106831620A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The present invention relates to a kind of crystal formation of 2 ((base of 4 cyclopropyl naphthalene 1) 1,2,4 triazoles of the 4H 3 base sulfenyl of 5 bromine 4) acetic acid (Lei Xina get) and preparation method thereof.The invention provides the crystal formation IX, crystal formation X, crystal formation XII, crystal formation XIII, crystal formation XIV of 2 ((base of 4 cyclopropyl naphthalene 1) 1,2,4 triazoles of the 4H 3 base sulfenyl of 5 bromine 4) acetic acid, and the preparation method of these crystal formations is simple and easy to control.
Description
Technical field
The invention belongs to chemical medicine, and in particular to a kind of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,
2,4- triazole -3- bases sulfenyl) acetic acid crystal formation and preparation method thereof.
Background technology
2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid (Lei Xina get,
Lesinurad), researched and developed by AstraZeneca (AstraZeneca), be a kind of uricosuric excretion oral medicine, it is closely bent by suppressing kidney
The sub- URAT1 of uric acid transporter of tubule and treat the patient with gout of hyperuricemia, its structural formula is：
US8003681B2 and CN101817793B disclose a kind of S- triazolyls α as hiv reverse transcriptase inhibitor-
Mercapto-acetanil, but the crystal form of its undisclosed compound；US8546436B2 and CN103298796A disclose Lei Xi
The Crystalline polymorphic forms formula 1 and form 2 received；CN104557748A discloses the crystal formation α and crystal formation β of Lei Xina get；
CN104447590A discloses crystal formation III, crystal formation IV, crystal formation V, the crystal formation VI of Lei Xina get, wherein, the preparation method of crystal formation III
It is that 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl) acetic acid powder is dissolved in acetonitrile solvent
In, settled solution is filtrated to get, the sample bottle that will be equipped with the settled solution seals up the sealed membrane for pricking hole, at ambient temperature slowly
Solid precipitation is evaporated into, solid is collected and is obtained final product crystal formation III.
The content of the invention
The technical problems to be solved by the invention are to provide 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- three
Azoles -3- bases sulfenyl) acetic acid novel crystal forms and preparation method thereof.Crystal formation of the present invention has beneficial property.The helpfulness
Matter includes that preparation process is simple, and easy to operate, the crystal formation for obtaining has preferable refining effect, and great Simplified flowsheet step is simultaneously
Efficiency is improved, and with excellent stability, is easily preserved in the process of circulation is produced, convenient transport, is that (5- is bromo- containing 2-
4- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl) acetic acid pharmaceutical preparation preparation there is provided new more preferable
Selection, had very important significance for drug development.
The present invention is adopted the following technical scheme that：
The present invention provides a kind of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl) acetic acid
Crystal formation Ⅸ, its X-ray powder diffraction figure 2theta values be 21.2 ° ± 0.2 °, 18.4 ° ± 0.2 °, 27.2 ° ± 0.2 ° at tool
There is characteristic peak.
Further, its X-ray powder diffraction figure is 25.1 ° ± 0.2 °, 23.9 ° ± 0.2 °, 13.1 ° also in 2theta values
There is characteristic peak at ± 0.2 °.
Further, its X-ray powder diffraction figure also 2theta values be 15.9 ° ± 0.2 °, 17.8 ° ± 0.2 °,
There is characteristic peak at 11.0 ° ± 0.2 °.
According to the present invention, the X-ray powder diffraction figure of described crystal formation IX is substantially consistent with Fig. 1.
According to the present invention, the differential scanning calorimetric analysis curve (DSC) of described crystal formation Ⅸ be displayed in be heated to 89 DEG C it is attached
Start first endothermic peak occur when near, start second endothermic peak occur when near 137 DEG C.Preferably, the DSC of crystal formation Ⅸ
Figure is substantially as shown in Figure 2.
According to the present invention, described crystal formation Ⅸ, when being heated to 120 DEG C, with about 5.1% mass loss, its thermogravimetric is divided
Analysis curve (TGA) figure is substantially as shown in Figure 3.
In the present invention, the crystalline substance of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
Type Ⅸ can be solvate or hydrate.
The present invention also provides a kind of described 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases
Sulfenyl) acetic acid crystal formation Ⅸ preparation method, by 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases
Sulfenyl) during acetic acid raw material adds the mixed solvent of ether solvent and water, it is then agitated, filter, be dried to obtain described 2- (5-
Bromo- 4- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl) acetic acid crystal formation Ⅸ.
Preferably, described 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
Raw material is the crystal formation III of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl) acetic acid.
Preferably, described ether solvent and the volume ratio that feeds intake of described water are 1:1~5.
It is further preferred that described ether solvent is 1 with the volume ratio that feeds intake of described water:2.
It is further preferred that described ether solvent is glycol dimethyl ether.
Preferably, described stirring is carried out at 5~30 DEG C.
It is further preferred that carrying out described stirring at 25 DEG C.
The present invention also provides a kind of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl) second
Acid crystal formation Ⅹ, its X-ray powder diffraction figure 2theta values be 21.9 ° ± 0.2 °, 26.8 ° ± 0.2 °, at 19.9 ° ± 0.2 °
With characteristic peak.
Further, its X-ray powder diffraction figure is 21.1 ° ± 0.2 °, 15.8 ° ± 0.2 °, 16.9 ° also in 2theta values
There is characteristic peak at ± 0.2 °.
Further, its X-ray powder diffraction figure also 2theta values be 24.2 ° ± 0.2 °, 23.1 ° ± 0.2 °,
There is characteristic peak at 29.1 ° ± 0.2 °.
According to the present invention, the X-ray powder diffraction figure of described crystal formation X is substantially consistent with Fig. 4.
According to the present invention, the differential scanning calorimetric analysis curve (DSC) of described crystal formation Ⅹ be displayed in be heated to 76 DEG C it is attached
Start first endothermic peak occur when near, start second endothermic peak occur when near 92 DEG C.Preferably, the DSC of crystal formation Ⅹ
Figure is substantially as shown in Figure 5.
According to the present invention, described crystal formation Ⅹ, when being heated to 110 DEG C, with about 5.0% mass loss, its thermogravimetric is divided
Analysis curve (TGA) figure is substantially as shown in Figure 6.
In the present invention, the crystalline substance of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
Type Ⅸ can be solvate or hydrate.
The present invention also provides a kind of described 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases
Sulfenyl) acetic acid crystal formation X preparation method, by 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- base sulphur
Base) acetic acid raw material adds the mixed solvent or alcohols solvent of alcohols solvent and water and the mixed solvent of aromatic hydrocarbon solvent
In, it is then agitated, filter, be dried to obtain described 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3-
Base sulfenyl) acetic acid crystal formation X.
Preferably, described 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
Raw material is the crystal formation III of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl) acetic acid.
Preferably, described alcohols solvent and the volume ratio that feeds intake of described water are 0.05~5:1；Described alcohols solvent
The volume ratio that feeds intake with described aromatic hydrocarbon solvent is 0.05~5:1.
It is further preferred that described alcohols solvent is 4 with the volume ratio that feeds intake of described water:1；Described alcohols solvent
The volume ratio that feeds intake with described aromatic hydrocarbon solvent is 4:1
It is further preferred that described alcohols solvent is methyl alcohol, described aromatic hydrocarbon solvent is toluene.
Preferably, described stirring is carried out at 5~30 DEG C.
It is further preferred that carrying out described stirring at 25 DEG C.
The present invention provides a kind of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
Crystal formation XII, its X-ray powder diffraction figure also 2theta values be 7.7 ° ± 0.2 °, 21.4 ° ± 0.2 °, at 26.5 ° ± 0.2 °
There is characteristic peak.
Further, its X-ray powder diffraction figure is 8.8 ° ± 0.2 °, 22.2 ° ± 0.2 °, 23.4 ° also in 2theta values
There is characteristic peak at ± 0.2 °.
Further, its X-ray powder diffraction figure also 2theta values be 16.9 ° ± 0.2 °, 19.7 ° ± 0.2 °,
There is characteristic peak at 28.1 ° ± 0.2 °.
According to the present invention, the X-ray powder diffraction figure of described crystal formation XII is substantially consistent with Fig. 7.
According to the present invention, the differential scanning calorimetric analysis curve (DSC) of described crystal formation XII be displayed in be heated to 57 DEG C it is attached
Start first endothermic peak occur when near.Preferably, the DSC figures of crystal formation XII are substantially as shown in Figure 8.
The present invention also provides a kind of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- base sulphur
Base) acetic acid crystal formation XII preparation method, including：During Lei Xina get added into the mixed solvent system of cyclic ethers class and water, one
Determine to stir a period of time at temperature, obtain suspension, filtration drying obtains white solid.
Preferably, the cyclic ethers class includes but is not limited to Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, hexamethylene ether etc.；It is highly preferred that
The cyclic ethers class is Isosorbide-5-Nitrae-dioxane, tetrahydrofuran；Most preferably 1,4- dioxane.
Further, the volume ratio of the cyclic ethers class that is used in methods described and the mixed solvent system of water for 9/1~
1/9, preferably 5/1-1/5, are more preferably 3/1-1/3, also preferably 1/3, most preferably 1/2.
Further, the temperature for being used in methods described is 5~30 DEG C, and preferably 20-25, also preferably 25-30 are optimal
Elect 25 DEG C as.
The present invention provides a kind of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
Crystal formation XIII, its X-ray powder diffraction figure also 2theta values be 9.7 ° ± 0.2 °, 24.8 ° ± 0.2 °, 26.4 ° ± 0.2 °
There is characteristic peak at place.
Further, its X-ray powder diffraction figure is 20.3 ° ± 0.2 °, 22.1 ° ± 0.2 °, 23.5 ° also in 2theta values
There is characteristic peak at ± 0.2 °.
Further, its X-ray powder diffraction figure also 2theta values be 16.8 ° ± 0.2 °, 19.7 ° ± 0.2 °,
There is characteristic peak at 25.4 ° ± 0.2 °.
According to the present invention, the X-ray powder diffraction figure of described crystal formation XIII is substantially consistent with Figure 11.
According to the present invention, the differential scanning calorimetric analysis curve (DSC) of described crystal formation XIII is displayed in and is heated to 52 DEG C
Start first endothermic peak occur when nearby, start second endothermic peak occur when near 73 DEG C.Preferably, crystal formation Ⅹ
DSC figures are substantially as shown in figure 12.
The present invention also provides a kind of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- base sulphur
Base) acetic acid crystal formation XIII preparation method, including：By in Lei Xina get addition alcohols solvents, one is stirred at a certain temperature
The section time, suspension is obtained, filtration drying obtains white solid.
Further, the alcohols includes but is not limited to methyl alcohol, ethanol, isopropanol, normal propyl alcohol, n-butanol, tert-butyl alcohol etc.；
Preferably methyl alcohol, ethanol, most preferably isopropanol, isopropanol.
Further, the temperature for being used in described method is 5~30 DEG C, preferably 20-25 DEG C, also preferably 25-30
DEG C, most preferably 25 DEG C.
The present invention provides a kind of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
Crystal formation XIV, its X-ray powder diffraction figure also 2theta values be 7.8 ° ± 0.2 °, 21.1 ° ± 0.2 °, 26.7 ° ± 0.2 °,
There is characteristic peak at place.
Further, its X-ray powder diffraction figure is 9.8 ° ± 0.2 °, 15.8 ° ± 0.2 °, 24.4 ° also in 2theta values
There is characteristic peak at ± 0.2 °.
Further, its X-ray powder diffraction figure also 2theta values be 10.6 ° ± 0.2 °, 21.1 ° ± 0.2 °,
25.1 ° ± 0.2 °, there is characteristic peak at 28.7 ° ± 0.2 °.
According to the present invention, the X-ray powder diffraction figure of described crystal formation XIV is substantially consistent with Figure 15.
According to the present invention, the differential scanning calorimetric analysis curve (DSC) of described crystal formation XIV be displayed in be heated to 52 DEG C it is attached
Start first endothermic peak occur when near, start second endothermic peak occur when near 55 DEG C.Preferably, the DSC of crystal formation Ⅹ
Figure is substantially as shown in figure 16.
The present invention also provides a kind of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl) second
The preparation method of the crystal formation XIIV of acid, including：During Lei Xina get added into the mixed solvent system of nitrile and water, in uniform temperature
Lower stirring a period of time, suspension is obtained, filtration drying obtains white solid.
Further, the nitrile includes but is not limited to acetonitrile, propionitrile, succinonitrile etc..Preferably acetonitrile, propionitrile is optimal
Elect acetonitrile as.
Further, the volume ratio of the mixed solvent system for being used in methods described is 5/1~1/5, preferably 4/
1-1/4, also preferably 2/1-1/2, are more preferably 1/2, most preferably 1/4.
Further, the temperature for being used in methods described is 5~30 DEG C, preferably 20-25 DEG C, also preferably 25-30 DEG C,
Most preferably 25 DEG C.
The present invention also provides a kind of pharmaceutical composition, and described pharmaceutical composition includes active component and pharmaceutically acceptable
Carrier, described active component includes described 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases
Sulfenyl) acetic acid crystal formation Ⅸ, crystal formation Ⅹ, crystal formation XII, crystal formation XIII, crystal formation XIV in one or more.
The present invention also provides described 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl)
Preparing treatment antihyperuricemic one or more in crystal formation Ⅸ, crystal formation Ⅹ, crystal formation XII, crystal formation XIII, the crystal formation XIV of acetic acid
Purposes in the pharmaceutical preparation of disease.
In the present invention, above-mentioned 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
Crystal formation III be obtained by known method, for example, can be obtained using the method described in embodiment 1 in CN104447590A.
Due to the utilization of above-mentioned technical proposal, the present invention has the following advantages that compared with prior art：
Present inventors have unexpectedly found that 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl) second
The novel crystal forms of acid, these crystal formation preparation process are simple, and easy to operate, the crystal formation for obtaining has preferable refining effect, greatly
Simplified flowsheet step simultaneously improves efficiency, and with excellent stability, is easily preserved in the process of circulation is produced, convenient fortune
It is defeated, it is the system of the pharmaceutical preparation containing 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
It is standby to provide new more preferable selection, had very important significance for drug development.
Brief description of the drawings
Fig. 1 is 2- obtained in embodiment 1 (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl)
The XRPD figures of the crystal formation Ⅸ of acetic acid；
Fig. 2 is 2- obtained in embodiment 1 (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl)
The DSC figures of the crystal formation Ⅸ of acetic acid；
Fig. 3 is 2- obtained in embodiment 1 (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl)
The TGA figures of the crystal formation Ⅸ of acetic acid；
Fig. 4 is 2- obtained in embodiment 4 (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl)
The XRPD figures of the crystal formation Ⅹ of acetic acid；
Fig. 5 is 2- obtained in embodiment 4 (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl)
The DSC figures of the crystal formation Ⅹ of acetic acid；
Fig. 6 is 2- obtained in embodiment 4 (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl)
The TGA figures of the crystal formation Ⅹ of acetic acid；
Fig. 7 is 2- obtained in embodiment 6 (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl)
The XRPD figures of the crystal formation XII of acetic acid；
Fig. 8 is 2- obtained in embodiment 6 (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl)
The DSC figures of the crystal formation XII of acetic acid；
Fig. 9 is 2- obtained in embodiment 6 (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyl)
The TGA figures of the crystal formation XII of acetic acid；
Figure 10 is (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- the bases) -4H-1,2,4- triazole -3- base sulphur of 2- obtained in embodiment 6
Base) acetic acid crystal formation XII1H-NMR (proton nmr spectra) figure；
Figure 11 is (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- the bases) -4H-1,2,4- triazole -3- base sulphur of 2- obtained in embodiment 8
Base) acetic acid crystal formation XIII XRPD figure；
Figure 12 is (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- the bases) -4H-1,2,4- triazole -3- base sulphur of 2- obtained in embodiment 8
Base) acetic acid crystal formation XIII DSC figure；
Figure 13 is (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- the bases) -4H-1,2,4- triazole -3- base sulphur of 2- obtained in embodiment 8
Base) acetic acid crystal formation XIII TGA figure；
Figure 14 is (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- the bases) -4H-1,2,4- triazole -3- base sulphur of 2- obtained in embodiment 8
Base) acetic acid crystal formation XIII1H-NMR (proton nmr spectra) figure；
Figure 15 is (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- the bases) -4H-1,2,4- triazole -3- base sulphur of 2- obtained in embodiment 10
Base) acetic acid crystal formation XIV XRPD figure；
Figure 16 is (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- the bases) -4H-1,2,4- triazole -3- base sulphur of 2- obtained in embodiment 10
Base) acetic acid crystal formation XIV DSC figure；
Figure 17 is (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- the bases) -4H-1,2,4- triazole -3- base sulphur of 2- obtained in embodiment 10
Base) acetic acid crystal formation XIV TGA figure；
Figure 18 is (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- the bases) -4H-1,2,4- triazole -3- base sulphur of 2- obtained in embodiment 10
Base) acetic acid crystal formation XIV1H-NMR (proton nmr spectra) figure；
Specific embodiment
The present invention is described in further details below in conjunction with specific embodiment.It should be understood that these embodiments are for saying
The bright basic principles, principal features and advantages of the present invention, and the present invention is not limited by the following examples.Used in embodiment
Implementation condition can do further adjustment according to specific requirement, and unreceipted implementation condition is usually the condition in normal experiment.
Used abbreviation is explained as follows in the present invention：
XRPD：X-ray powder diffraction
DSC：Differential scanning calorimetric analysis
TGA：Thermogravimetric analysis
X-ray powder diffraction figure of the present invention is adopted on Panalytical Empyrean x-ray powder diffraction instruments
Collection, test temperature uses ordinary temperature, such as 25 DEG C.The method parameter of X-ray powder diffraction of the present invention is as follows：
X ray reflection parameter：Cu,Kα
1.540598；1.544426
The intensities of K α 2/K α 1：0.50
Voltage：45 KVs (kV)
Electric current：40 milliamperes (mA)
Sweep limits：From 3.0 to 40.0 degree
Differential scanning calorimetric analysis (DSC) figure of the present invention is gathered on TA Q200.Differential of the present invention is swept
The method parameter for retouching thermometric analysis (DSC) is as follows：
Sweep speed：10℃/min；
Protective gas：Nitrogen.
Thermogravimetric analysis (TGA) figure of the present invention is gathered on TA Q5000.Thermogravimetric analysis (TGA) of the present invention
Method parameter it is as follows：
Sweep speed：10℃/min；
Protective gas：Nitrogen.
Hydrogen nuclear magnetic resonance modal data (1H-NMR) is picked up from Bruker Avance II DMX 400M HZ nuclear magnetic resonance ripples
Spectrometer.1-5mg samples are weighed, with 0.5mL deuterated dimethyl sulfoxides or deuterated water dissolves, the solution of 2-10mg/mL is made into.
Embodiment 1
The Lesinurad crystal formations III for weighing 49.8mg are put into the vial of 1.5mL, add the glycol dinitrate of 0.3mL
Ether dissolves it, then under low rate mixing (<The water of 0.6mL 100r/min) is added dropwise over, at room temperature (about 25 DEG C) stirrings 4
Hour, centrifugation is vacuum dried 12 hours.After testing, the solid that the present embodiment is obtained is crystal formation Ⅸ.
The X-ray powder diffraction data of the crystal formation Ⅸ that the present embodiment is obtained are as shown in table 1.Its XRPD figure such as Fig. 1, its DSC
Figure such as Fig. 2, its TGA figure such as Fig. 3.
Table 1
Embodiment 2
The Lesinurad crystal formations III for weighing 17.4mg are put into the vial of 1.5mL, add the glycol dinitrate of 0.2mL
Ether dissolves it, then under low rate mixing (<The water of 0.4mL 100r/min) is added dropwise over, at room temperature (about 25 DEG C) stirrings 4
Hour, drying at room temperature is centrifuged.After testing, the solid that the present embodiment is obtained is crystal formation Ⅸ.
The X-ray powder diffraction data of the crystal formation Ⅸ that the present embodiment is obtained are as shown in table 2.
Table 2
| 2theta | D is spaced | Intensity % |
| 11.09 | 7.98 | 17.66 |
| 13.09 | 6.76 | 22.96 |
| 15.92 | 5.57 | 26.93 |
| 17.86 | 4.97 | 27.41 |
| 18.35 | 4.83 | 44.70 |
| 19.44 | 4.57 | 24.08 |
| 19.88 | .47 | 30.13 |
| 21.3 | 418 | 100.00 |
| 22.83 | 3.89 | 51.59 |
| 23.96 | 3.71 | 40.17 |
| 24.31 | 3.66 | 35.67 |
| 25.04 | .56 | 59.94 |
| 26.11 | 3.41 | 36.45 |
| 27.21 | 3.28 | 45.06 |
| 27.57 | 3.24 | 56.40 |
| 28.46 | 3.14 | 31.17 |
| 31.03 | 2.88 | 10.37 |
| 32.13 | 2.79 | 36.51 |
| 34.51 | 2.60 | 22.06 |
Embodiment 3
The Lesinurad crystal formations III for weighing 17.3mg are put into the vial of 1.5mL, add the glycol dinitrate of 0.2mL
Ether dissolves it, then under low rate mixing (<The water of 0.4mL 100r/min) is added dropwise over, at room temperature (about 25 DEG C) stirrings 4
Hour, drying at room temperature is centrifuged.After testing, the solid that the present embodiment is obtained is crystal formation Ⅸ.
The X-ray powder diffraction data of the crystal formation Ⅸ that the present embodiment is obtained are as shown in table 3.
Table 3
Embodiment 4
The Lesinurad crystal formations III for weighing 300.2mg are put into the vial of 3mL, add 1.5mL methanol/water it is mixed
(methyl alcohol is 4 to the volume ratio of water to close solution:1) in, (about 25 DEG C) are stirred 4 hours at room temperature, centrifugation.After testing, this reality
It is crystal formation X to apply the solid that example obtains.
The X-ray powder diffraction data of the crystal formation X that the present embodiment is obtained are as shown in table 4.Its XRPD figures such as Fig. 4, its DSC figures
Such as Fig. 5, its TGA figure such as Fig. 6.
Table 4
Embodiment 5
The Lesinurad crystal formations III for weighing 50.2mg are put into the vial of 3mL, add the mixing of the methanol/water of 1mL molten
(methyl alcohol is 4 to the volume ratio of water to liquid:1) in, (about 25 DEG C) are stirred 1 day at room temperature, and drying at room temperature is centrifuged.After testing, originally
The solid that embodiment is obtained is crystal formation X.
The X-ray powder diffraction data of the crystal formation X that the present embodiment is obtained are as shown in table 5.
Table 5
Embodiment 6
The Lesinurad solid powders for weighing 13.6mg are put into the vial of 1.5mL, add the Isosorbide-5-Nitrae-dioxy of 0.25mL
(1,4- dioxane is 1 to the volume ratio of water to the mixed solution of six rings/water:2) in, (about 25 DEG C) stirrings 4 are small at room temperature
When, centrifugation, room temperature in vacuo is dried 12 hours.After testing, the product that the present embodiment is obtained is crystal formation XII.The X-ray of crystal formation XII
Powder diagram is as shown in fig. 7, its X-ray powder diffraction data is as shown in table 6.
Table 6
The DSC of the crystal formation XII of embodiment 6 schemes, TGA schemes,1H-NMR figures difference is as seen in figs. 8-10.
The crystal formation XII of embodiment 6 is being heated to starting first endothermic peak occur near 57 DEG C, and its DSC is as shown in Figure 8.
Crystal formation XII is when being heated to 90 DEG C for embodiment 6, and with about 9.2% mass loss, its TGA is as shown in Figure 9.
The crystal formation XII of embodiment 6 has singlet at 3.57, corresponding to the hydrogen chemical shifts of Isosorbide-5-Nitrae-dioxane, its1H-
NMR is as shown in Figure 10.
Embodiment 7
The Lesinurad solid powders for weighing 19.2mg are put into the vial of 1.5mL, add the Isosorbide-5-Nitrae-dioxy of 0.3mL
(1,4- dioxane is 1 to the volume ratio of water to the mixed solution of six rings/water:2) in, (about 25 DEG C) stirrings 20 are small at room temperature
When, centrifugation, room temperature in vacuo is dried 19 hours.After testing, the product that the present embodiment is obtained is crystal formation XII.Its X-ray powder diffraction
Data are as shown in table 7.
Table 7
Embodiment 8
The Lesinurad solid powders for weighing 20.4mg are put into the vial of 1.5mL, add the isopropanol of 0.25mL
In, (about 25 DEG C) are stirred 4 hours at room temperature, and centrifugation, room temperature in vacuo is dried 5 hours.After testing, the product that the present embodiment is obtained
Thing is crystal formation XIII.The X-ray powder diffraction figure of crystal formation XIII is as shown in figure 11, its X-ray powder diffraction data such as institute of table 8
Show.
Table 8
The DSC of the crystal formation XIII of embodiment 8 schemes, TGA schemes,1H-NMR figures difference is as shown in figs. 12-14.
The crystal formation XIII of embodiment 8 is being heated to starting first endothermic peak occur near 52 DEG C, starts near 73 DEG C
Existing second endothermic peak, its DSC is as shown in Figure 12.
Crystal formation XIII is when being heated to 72 DEG C for embodiment 8, with about 2.6% mass loss, continues to be heated to 135 DEG C
When, with about 8.1% mass loss, its TGA is as shown in Figure 13.
The crystal formation XIII of embodiment 8 has multiplet at 1.04 and 3.78, corresponding to the chemical shift of the hydrogen-like of isopropanol two,
Its1H-NMR is as shown in Figure 14.
Embodiment 9
The Lesinurad solid powders for weighing 19.3mg are put into the vial of 1.5mL, in the isopropanol of addition 0.2mL,
(about 25 DEG C) are stirred 20 hours at room temperature, and centrifugation, room temperature in vacuo is dried 19 hours.After testing, the product that the present embodiment is obtained
Thing is crystal formation XIII.Its X-ray powder diffraction data is as shown in table 9.
Table 9
Embodiment 10
The Lesinurad solid powders for weighing 10.0mg are put into the vial of 1.5mL, add the acetonitrile/water of 0.2mL
(acetonitrile is 1 to the volume ratio of water to mixed solution:4) in, (about 25 DEG C) are stirred 4 hours at room temperature, and centrifugation, room temperature in vacuo is done
Dry 12 hours.After testing, the product that the present embodiment is obtained is crystal formation XIV.The X-ray powder diffraction figure of crystal formation XIV such as Figure 15 institutes
Show, its X-ray powder diffraction data is as shown in table 10.
Table 10
The DSC of the crystal formation XIV of embodiment 10 schemes, TGA schemes,1H-NMR figures difference is as shown in figs. 16-18.
The crystal formation XIV of embodiment 10 is being heated to starting first endothermic peak occur near 52 DEG C, starts near 55 DEG C
Existing second endothermic peak, its DSC is as shown in Figure 16.
Crystal formation XIV is when being heated to 102 DEG C for embodiment 10, with about 9.6% mass loss gradient, its TGA such as accompanying drawings
Shown in 17.
The crystal formation XIV of embodiment 8 is having singlet at 2.07, corresponding to the hydrogen chemical shifts of acetonitrile, its1H-NMR is for example attached
Shown in Figure 18.
Embodiment 11
The Lesinurad solid powders for weighing 10.0mg are put into the vial of 1.5mL, add the acetonitrile/water of 0.2mL
(acetonitrile is 1 to the volume ratio of water to mixed solution:2) in, (about 25 DEG C) are stirred 4 hours at room temperature, and centrifugation, room temperature in vacuo is done
Dry 12 hours.After testing, the product that the present embodiment is obtained is crystal formation XIV.Its X-ray powder diffraction data is as shown in table 11.
Table 11
The above embodiments merely illustrate the technical concept and features of the present invention, its object is to allow person skilled in the art
Scholar will appreciate that present disclosure and implement according to this that it is not intended to limit the scope of the present invention.It is all according to the present invention
The equivalent change or modification that Spirit Essence is made, should all be included within the scope of the present invention.
Claims (7)
1. a kind of crystal formation Ⅸ of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid, its
It is characterised by：Its X-ray powder diffraction figure is 21.2 ° ± 0.2 ° in 2theta values, 18.4 ° ± 0.2 °, is had at 27.2 ° ± 0.2 °
There is characteristic peak；Its X-ray powder diffraction figure also 2theta values be 25.1 ° ± 0.2 °, 23.9 ° ± 0.2 °, at 13.1 ° ± 0.2 °
With characteristic peak.
2. a kind of crystal formation Ⅹ of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid, its
It is characterised by：Its X-ray powder diffraction figure is 21.9 ° ± 0.2 ° in 2theta values, 26.8 ° ± 0.2 °, is had at 19.9 ° ± 0.2 °
There is characteristic peak；Its X-ray powder diffraction figure also 2theta values be 21.1 ° ± 0.2 °, 15.8 ° ± 0.2 °, at 16.9 ° ± 0.2 °
With characteristic peak.
3. a kind of crystal formation XII of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid, its
It is characterised by：Its X-ray powder diffraction figure is 7.7 ° ± 0.2 ° in 2theta values, 21.4 ° ± 0.2 °, is had at 26.5 ° ± 0.2 °
There is characteristic peak；Its X-ray powder diffraction figure also 2theta values be 8.8 ° ± 0.2 °, 22.2 ° ± 0.2 °, at 23.4 ° ± 0.2 °
With characteristic peak.
4. a kind of crystal formation XIII of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid,
It is characterized in that：Its X-ray powder diffraction figure 2theta values be 9.7 ° ± 0.2 °, 24.8 ° ± 0.2 °, at 26.4 ° ± 0.2 °
With characteristic peak；Its X-ray powder diffraction figure is 20.3 ° ± 0.2 °, 22.1 ° ± 0.2 °, 23.5 ° ± 0.2 ° also in 2theta values
Place has characteristic peak.
5. a kind of crystal formation XIV of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid, its
It is characterised by：Its X-ray powder diffraction figure is 7.8 ° ± 0.2 ° in 2theta values, 21.1 ° ± 0.2 °, is had at 26.7 ° ± 0.2 °
There is characteristic peak；Its X-ray powder diffraction figure also 2theta values be 9.8 ° ± 0.2 °, 15.8 ° ± 0.2 °, at 24.4 ° ± 0.2 °
With characteristic peak.
6. a kind of pharmaceutical composition, described pharmaceutical composition includes active component and pharmaceutically acceptable carrier, its feature
It is：Described active component includes crystal formation IX, the crystal formation described in claim 2, claim 3 institute described in claim 1
One or more in crystal formation XIII, the crystal formation XIV described in claim 5 described in the crystal formation XII that states, claim 4.
7. the crystal formation IX described in claim 1, the crystal formation described in claim 2, the crystal formation XII described in claim 3, right will
Seek the crystal formation XIII described in 4, prepare treatment hyperuricemia one or more in the crystal formation XIV described in claim 5
Purposes in pharmaceutical preparation.
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| CN201610140242 | 2016-03-11 | ||
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018085932A1 (en) * | 2016-11-10 | 2018-05-17 | Apotex Inc. | Novel crystalline forms of lesinurad |
| WO2019001325A1 (en) * | 2017-06-28 | 2019-01-03 | 苏州科睿思制药有限公司 | Crystal form xv of lesinurad and preparation method therefor |
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2017
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018085932A1 (en) * | 2016-11-10 | 2018-05-17 | Apotex Inc. | Novel crystalline forms of lesinurad |
| US10513500B2 (en) | 2016-11-10 | 2019-12-24 | Apotex Inc. | Crystalline forms of Lesinurad |
| WO2019001325A1 (en) * | 2017-06-28 | 2019-01-03 | 苏州科睿思制药有限公司 | Crystal form xv of lesinurad and preparation method therefor |
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