CN104478815B - Various salt, their 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 and preparation method thereof - Google Patents
Various salt, their 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 and preparation method thereof Download PDFInfo
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- CN104478815B CN104478815B CN201410783347.8A CN201410783347A CN104478815B CN 104478815 B CN104478815 B CN 104478815B CN 201410783347 A CN201410783347 A CN 201410783347A CN 104478815 B CN104478815 B CN 104478815B
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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
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
Novel crystal forms of salt the present invention relates to 2 ((base of 4 cyclopropyl naphthalene 1) 1,2,4 triazoles of the 4H 3 base sulfenyl of 5 bromine 4) acetic acid (formula (I) compound) and preparation method thereof.The novel crystal forms of the salt include：Calcium salt crystal formation A, sylvite crystal formation A, hydrochloride Form A, hydrochloride Form B, esilate crystal formation A, Mesylate Form A, Mesylate Form B, ethanedisulphonate crystal formation A, ethanedisulphonate crystal formation B, isethionate crystal formation A, arginine salt crystal formation A.
Description
Technical field
The present invention relates to chemical medicine, more particularly to 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,
4- triazole -3- bases sulfenyl) acetic acid various salt, their 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 (Lesinurad) is
A kind of uricosuric drains oral medicine, and hyperuricemia is treated by the sub- URAT1 of the uric acid transporter for suppressing kidney proximal tubule
Patient with gout.Shown in the structure of the medicine such as formula (I)：
The drug molecule of nearly half is all exist in a salt form and be administered.Some are undesirable can to improve medicine into salt
Physical chemistry or biopharmaceutical properties, the solubility or dissolution rate, reduction for such as changing medicine are drawn moist, raising stability, are changed
Fusing point, improvement grind performance, are easy to prepare purifying, improve permeability etc., and the suitable salt form of selection extremely has for drug development
It is necessary.Meanwhile, a kind of salt form there may be polymorphic.Different crystal forms have different fusing points, solubility, dissolving out capability, chemistry
Stability, mechanical stability etc., these physical and chemical performances directly influence the validity and processing characteristics of medicine sometimes.Cause
This, carries out comprehensive and systematic salt form screening and crystal formation screening in medicament research and development, selection is best suitable for the salt form and its crystal formation of exploitation, is
One of very important important research content.
The report of the existing sodium salt of formula (I) compound and its crystal formation.Yuan Yan companies disclose 2- (5- in WO2011085009A2
Bromo- 4- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) sodium acetate crystalline polymorphs and solid interphase
Type, is respectively designated as polymorphic A, polymorph b, polymorph b ', polymorphic C, polymorphic D, polymorphic E and solid interphase 1,
Solid interphase 2, solid interphase 3.Polymorph b in the patent, polymorph b ', polymorphic C, polymorphic D and polymorphic E
It is obtained by starting material of polymorphic A；Middle facies pattern crystallinity is not high, has mixed amorphous, amorphous thermodynamic instability, after
Continuous process has the risk of crystal transfer.
Based on above mentioned problem, screen and select it is more with advantageous property 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -
4H-1,2,4- triazole -3- bases sulfenyls) acetic acid salt form and its crystal formation, for the industrialized production of the medicine provides new selection tool
It is significant.
The content of the invention
The present invention is based on comprehensive salt form screening and crystal formation screening, there is provided various salt of compound shown in formula (I) and they
Novel crystal forms.
Further, the salt of formula (I) compound that the present invention is provided, shown in its structural formula such as formula (II)：
Wherein, X is independently calcium, potassium, hydrochloric acid, ethyl sulfonic acid, methanesulfonic acid, ethionic acid, ethylenehydrinsulfonic acid and arginine.
The salt of compound shown in the formula (I) that the present invention is provided, it is characterised in that described salt is crystal salt.
The salt of compound is readily available shown in the formula (I) that the present invention is provided, it is only necessary to by formula (I) compound formula (I)
The solution of compound and calcium hydroxide, potassium hydroxide, hydrochloric acid, ethyl sulfonic acid, methanesulfonic acid, ethionic acid, ethylenehydrinsulfonic acid, arginine
Mixed crystallization in a suitable solvent, you can be readily derived the salt form of stabilization.Described suitable solvent, can be acetic acid second
Ester, acetonitrile, tetrahydrofuran, methyl alcohol, acetone or other organic solvents, or organic solvent and water mixed solvent.
The salt of compound shown in the formula (I) that the present invention is provided can be used to prepare the purposes in gout medicine.
Pharmaceutical composition, be the salt with compound shown in formula (I) as active component, addition medicine often with auxiliary material prepare and
Into.
Further, the crystal form of the salt of formula (I) compound that the present invention is provided includes following several：Calcium salt crystal formation
A, sylvite crystal formation A, hydrochloride Form A, hydrochloride Form B, esilate crystal formation A, Mesylate Form A, Mesylate Form
B, ethanedisulphonate crystal formation A, ethanedisulphonate crystal formation B, isethionate crystal formation A, arginine salt crystal formation A.
Further, the crystal form of the salt of formula (I) compound that the present invention is provided, it is characterised in that each is brilliant
There is characteristic peak at the X-ray powder diffraction figure of type peak value shown in the following table.
Principal character peak in the X-ray powder diffraction figure of table 1 formula (I) various salt of compound
| The type of salt | The crystal form of salt | Angle (° 2 θ) |
| Calcium salt | Crystal formation A | 8.5 °, 4.2 °, 17.1 ° |
| Sylvite | Crystal formation A | 23.8 °, 11.8 °, 23.1 ° |
| Hydrochloride | Crystal formation A | 10.6 °, 20.2 °, 9.2 ° |
| Hydrochloride | Crystal formation B | 23.8 °, 21.4 °, 23.0 ° |
| Esilate | Crystal formation A | 21.8 °, 21.6 °, 18.8 ° |
| Mesylate | Crystal formation A | 23.8 °, 18.6 °, 6.1 ° |
| Mesylate | Crystal formation B | 7.2 °, 22.4 °, 5.7 ° |
| Ethanedisulphonate | Crystal formation A | 21.9 °, 9.4 °, 15.7 ° |
| Ethanedisulphonate | Crystal formation B | 17.6 °, 11.8 °, 21.5 ° |
| Isethionate | Crystal formation A | 6.0 °, 18.2 °, 23.4 ° |
| Arginine salt | Crystal formation A | 8.9 °, 17.3 °, 5.9 ° |
Wherein 2 θ values are ± 0.2 °.
Further, the crystal form of the salt of formula (I) compound that the present invention is provided, is further characterized in that, each
The X-ray powder diffraction figure of crystal formation also has characteristic peak in addition to the characteristic peak shown in table 1 at following peak value.
Secondary feature peak in the X-ray powder diffraction figure of table 2 formula (I) various salt of compound
| The type of salt | The crystal form of salt | Angle (° 2 θ) |
| Calcium salt | Crystal formation A | 19.9 °, 20.5 °, 21.4 °, 23.8 °, 25.1 °, 25.8 °, 29.0 ° |
| Sylvite | Crystal formation A | 17.2 °, 26.1 °, 25.0 °, 21.8 °, 26.8 °, 7.3 °, 27.6 ° |
| Hydrochloride | Crystal formation A | 23.0 °, 25.9 °, 25.4 °, 22.2 °, 6.9 °, 17.9 °, 24.5 ° |
| Hydrochloride | Crystal formation B | 26.7 °, 23.4 °, 10.5 °, 18.4 °, 24.6 °, 30.0 °, 31.1 ° |
| Esilate | Crystal formation A | 5.7 °, 25.5 °, 19.7 °, 8.7 °, 14.9 °, 24.1 °, 29.5 ° |
| Mesylate | Crystal formation A | 23.3 °, 9.4 °, 24.3 °, 12.5 °, 17.5 °, 18.8 °, 22.3 ° |
| Mesylate | Crystal formation B | 8.9 °, 23.7 °, 17.2 °, 17.9 °, 15.8 °, 19.6 °, 26.2 ° |
| Ethanedisulphonate | Crystal formation A | 18.6 °, 19.1 °, 20.9 °, 29.5 °, 5.1 °, 23.9 °, 26.8 ° |
| Ethanedisulphonate | Crystal formation B | 22.7 °, 5.8 °, 21.8 °, 23.5 °, 25.2 °, 27.1 °, 28.7 ° |
| Isethionate | Crystal formation A | 22.8 °, 24.4 °, 23.8 °, 12.4 °, 21.8 °, 15.0 °, 25.7 ° |
| Arginine salt | Crystal formation A | 24.5 °, 22.9 °, 23.5 °, 21.5 °, 19.3 °, 14.6 °, 26.9 ° |
Wherein 2 θ values are ± 0.2 °.
Heretofore described calcium salt crystal formation A, its X-ray powder diffraction figure is as shown in Figure 1.
Further, heretofore described calcium salt crystal formation A, it is characterised in that its differential scanning calorimetry (DSC) point
Analysis starts endothermic peak occur near 115.1 DEG C, as shown in Figure 2.
Further, heretofore described calcium salt crystal formation A, it is characterised in that when being heated to 110.0 DEG C, have
About 11.4% weight loss gradient, its thermogravimetric analysis figure (TGA) is as shown in Figure 3.
The calcium salt crystal formation A that the present invention is provided has excellent property, good stability, also, with Yuan Yan companies in patent
Sodium salt crystal formation A disclosed in WO2011085009A2 is compared, and draws moist with extremely low, is hardly influenceed by high humility and damp
Solution, is conducive to the exploitation and storage of the medicine.
Heretofore described sylvite crystal formation A, its X-ray powder diffraction figure is as shown in Figure 4.
Further, heretofore described sylvite crystal formation A, it is characterised in that its differential scanning calorimetry (DSC) point
Analysis starts endothermic peak occur respectively near 72.7 DEG C and 135.0 DEG C, as shown in Figure 5.
Further, heretofore described sylvite crystal formation A, it is characterised in that when being heated to 130.0 DEG C, have
About 6.0% weight loss gradient, its thermogravimetric analysis figure (TGA) is as shown in Figure 6.
Heretofore described hydrochloride Form A, its X-ray powder diffraction figure is as shown in Figure 7.
Further, heretofore described hydrochloride Form A, it is characterised in that its differential scanning calorimetry (DSC)
Analysis starts endothermic peak occur respectively near 122.4 DEG C and 153.5 DEG C, as shown in Figure 8.
Further, heretofore described hydrochloride Form A, it is characterised in that when being heated to 153.0 DEG C, tool
There is about 18.2% weight loss gradient, its thermogravimetric analysis figure (TGA) is as shown in Figure 9.
Heretofore described hydrochloride Form B, its X-ray powder diffraction figure is as shown in Figure 10.
Further, heretofore described hydrochloride Form B, it is characterised in that its differential scanning calorimetry (DSC)
Analysis starts endothermic peak occur respectively near 94.1 DEG C, 109.7 DEG C, 155.3 DEG C and 166.5 DEG C, as shown in figure 11.
Further, heretofore described hydrochloride Form B, it is characterised in that when being heated to 140.0 DEG C, tool
There is about 8.2% weight loss gradient, its thermogravimetric analysis figure (TGA) is as shown in figure 12.
Heretofore described esilate crystal formation A, its X-ray powder diffraction figure is as shown in figure 13.
Further, heretofore described esilate crystal formation A, it is characterised in that its differential scanning calorimetry
(DSC) analysis starts endothermic peak occur near 177.3 DEG C, as shown in figure 14.
Further, heretofore described esilate crystal formation A, it is characterised in that when being heated to 140.0 DEG C,
With about 0.9% weight loss gradient, its thermogravimetric analysis figure (TGA) is as shown in figure 15.
Heretofore described Mesylate Form A, its X-ray powder diffraction figure is as shown in figure 16.
Further, heretofore described Mesylate Form A, it is characterised in that its differential scanning calorimetry
(DSC) analysis starts endothermic peak occur near 173.2 DEG C, as shown in figure 17.
Further, heretofore described Mesylate Form A, it is characterised in that when being heated to 150.0 DEG C,
With about 0.4% weight loss gradient, its thermogravimetric analysis figure (TGA) is as shown in figure 18.
Heretofore described Mesylate Form B, its X-ray powder diffraction figure is as shown in figure 19.
Further, heretofore described Mesylate Form B, it is characterised in that its differential scanning calorimetry
(DSC) analysis starts endothermic peak occur near 171.7 DEG C, as shown in figure 20.
Further, heretofore described Mesylate Form B, it is characterised in that when being heated to 150.0 DEG C,
With about 0.9% weight loss gradient, its thermogravimetric analysis figure (TGA) is as shown in figure 21.
Heretofore described ethanedisulphonate crystal formation A, its X-ray powder diffraction figure is as shown in figure 22.
Further, heretofore described ethanedisulphonate crystal formation A, it is characterised in that its differential scanning calorimetry
(DSC) analysis starts endothermic peak occur near 190.6 DEG C, as shown in figure 23.
Further, heretofore described ethanedisulphonate crystal formation A, it is characterised in that be heated to 150.0 DEG C
When, with about 1.6% weight loss gradient, its thermogravimetric analysis figure (TGA) is as shown in figure 24.
Heretofore described ethanedisulphonate crystal formation B, its X-ray powder diffraction figure is as shown in figure 25.
Further, heretofore described ethanedisulphonate crystal formation B, it is characterised in that its differential scanning calorimetry
(DSC) analysis starts endothermic peak occur near 194.2 DEG C, as shown in figure 26.
Further, heretofore described ethanedisulphonate crystal formation B, it is characterised in that be heated to 160.0 DEG C
When, with about 0.5% weight loss gradient, its thermogravimetric analysis figure (TGA) is as shown in figure 27.
Heretofore described isethionate crystal formation A, its X-ray powder diffraction figure is as shown in figure 28.
Further, heretofore described isethionate crystal formation A, it is characterised in that its means of differential scanning calorimetry
Method (DSC) analysis starts endothermic peak occur near 135.8 DEG C, as shown in figure 29.
Further, heretofore described isethionate crystal formation A, it is characterised in that be heated to 110.0 DEG C
When, with about 1.9% weight loss gradient, its thermogravimetric analysis figure (TGA) is as shown in figure 30.
Heretofore described arginine salt crystal formation A, its X-ray powder diffraction figure is as shown in figure 31.
Further, heretofore described arginine salt crystal formation A, it is characterised in that its differential scanning calorimetry
(DSC) analysis starts endothermic peak occur respectively near 50.2 DEG C and 182.2 DEG C, as shown in figure 32.
Further, heretofore described arginine salt crystal formation A, it is characterised in that when being heated to 150.0 DEG C,
With about 2.5% weight loss gradient, its thermogravimetric analysis figure (TGA) is as shown in figure 33.
The present invention relates to 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
(Lesinurad), i.e. formula (I) compound and calcium hydroxide, potassium hydroxide, hydrochloric acid, ethyl sulfonic acid, methanesulfonic acid, ethionic acid, hydroxyl
The crystal formation of the salt that ethyl sulfonic acid, arginine are formed, it is characterised in that its preparation method comprises the following steps：
A) by 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
(Lesinurad) powder dissolving in a suitable solvent, is made into solution A；
B) it is 1 by mol ratio：1 or 2：The formation body of the salt of 1 (the formation body of lesinurad/ salt) adds above-mentioned solution A
In；
C) solution at room temperature in whipping step b) more than 24 hours, preferably 24 hours or 40 hours；
D) solid obtained in centrifugation step c), after testing, the crystal formation that above-mentioned salt is formed is respectively：Calcium salt crystal formation A, sylvite
Crystal formation A, hydrochloride Form A, hydrochloride Form B, esilate crystal formation A, Mesylate Form A, Mesylate Form B, second two
Sulfonate crystal formation A, ethanedisulphonate crystal formation B, isethionate crystal formation A and arginine salt crystal formation A.
Wherein, described suitable solvent, can be ethyl acetate, acetonitrile, tetrahydrofuran, methyl alcohol, acetone or other have
Machine solvent, or organic solvent and water mixed solvent.
Brief description of the drawings
Fig. 1 is brilliant for the calcium salt of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The XRPD figures of type A.
Fig. 2 is brilliant for the calcium salt of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The DSC figures of type A.
Fig. 3 is brilliant for the calcium salt of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The TGA figures of type A.
Fig. 4 is brilliant for the sylvite of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The XRPD figures of type A.
Fig. 5 is brilliant for the sylvite of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The DSC figures of type A.
Fig. 6 is brilliant for the sylvite of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The TGA figures of type A.
Fig. 7 is the hydrochloride of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The XRPD figures of crystal formation A.
Fig. 8 is the hydrochloride of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The DSC figures of crystal formation A.
Fig. 9 is the hydrochloride of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The TGA figures of crystal formation A.
Figure 10 is the hydrochloride of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The XRPD figures of crystal formation B.
Figure 11 is the hydrochloride of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The DSC figures of crystal formation B.
Figure 12 is the hydrochloride of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The TGA figures of crystal formation B.
Figure 13 is the ethyl sulfonic acid of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The XRPD figures of salt crystal formation A.
Figure 14 is the ethyl sulfonic acid of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The DSC figures of salt crystal formation A.
Figure 15 is the ethyl sulfonic acid of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The TGA figures of salt crystal formation A.
Figure 16 is the methanesulfonic acid of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The XRPD figures of salt crystal formation A.
Figure 17 is the methanesulfonic acid of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The DSC figures of salt crystal formation A.
Figure 18 is the methanesulfonic acid of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The TGA figures of salt crystal formation A.
Figure 19 is the methanesulfonic acid of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The XRPD figures of salt crystal formation B.
Figure 20 is the methanesulfonic acid of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The DSC figures of salt crystal formation B.
Figure 21 is the methanesulfonic acid of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The TGA figures of salt crystal formation B.
Figure 22 is the sulphur of second two of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The XRPD figures of hydrochlorate crystal formation A.
Figure 23 is the sulphur of second two of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The DSC figures of hydrochlorate crystal formation A.
Figure 24 is the sulphur of second two of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The TGA figures of hydrochlorate crystal formation A.
Figure 25 is the sulphur of second two of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The XRPD figures of hydrochlorate crystal formation B.
Figure 26 is the sulphur of second two of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The DSC figures of hydrochlorate crystal formation B.
Figure 27 is the sulphur of second two of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The TGA figures of hydrochlorate crystal formation B.
Figure 28 is the hydroxyl second of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The XRPD figures of sulfonate crystal formation A.
Figure 29 is the hydroxyl second of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The DSC figures of sulfonate crystal formation A.
Figure 30 is the hydroxyl second of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The TGA figures of sulfonate crystal formation A.
Figure 31 is the arginine of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The XRPD figures of salt crystal formation A.
Figure 32 is the arginine of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The DSC figures of salt crystal formation A.
Figure 33 is the arginine of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The TGA figures of salt crystal formation A.
Figure 34 is brilliant for the calcium salt of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
(a schemes the stability test contrast XRPD figures of type A for the XRPD of calcium salt crystal formation A, and b is placed on 25 DEG C/60%RH for calcium salt crystal formation A
Under the conditions of XRPD figures after 2 weeks, c is that calcium salt crystal formation A is placed under the conditions of 40 DEG C/75%RH the figures of the XRPD after 2 weeks).
Figure 35 is brilliant for the calcium salt of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The DVS figures of type A.
Specific embodiment
Used abbreviation is explained as follows in the present invention：
XRPD：X-ray powder diffraction
DSC：Differential scanning calorimetric analysis
TGA：Thermogravimetric analysis
DVS：Dynamic water is adsorbed
Hereinafter the present invention, but the protection domain being not intended to limit the invention will be expanded on further by specific embodiment.
Those skilled in the art can be made improvements to preparation method and using instrument within the scope of the claims, and these improvement also should be regarded as
Protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
In following embodiments, unless otherwise indicated, described test method is generally built according to normal condition or manufacturer
The condition of view is implemented；Shown raw material, reagent can be obtained by way of commercially available purchase.
X-ray powder diffraction figure of the present invention is on Panalytical Empyrean x-ray powder diffraction instruments
Collection.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)
Divergent slit：Automatically
Scan pattern：Continuously
Sweep limits：From 3.0 to 40.0 degree
Sampling step length：0.013 degree
Differential scanning calorimetric thermogram of the present invention is gathered on TAQ2000 differential scanning calorimeters.Institute of the present invention
The method parameter of the differential scanning calorimetric analysis stated is as follows：
Sweep speed/DEG C/min:10 DEG C/min
Protective gas：Nitrogen
Thermogravimetric analysis figure of the present invention is gathered on TAQ500 thermogravimetric analyzers.Thermogravimetric analysis of the present invention
Method parameter is as follows：
Sweep speed/DEG C/min:10 DEG C/min
Protective gas：Nitrogen
Dynamic water of the present invention adsorbs (DVS) figure by SMS companies (Surface Measurement Systems
Ltd.) gathered on the Intrinsic dynamic water adsorption instruments of production.The method parameter of described dynamic water adsorption instrument is as follows：
Temperature：25℃
Carrier gas, flow velocity：N2, 200 ml/mins
Unit interval mass change：0.002%/minute
RH range：0%RH-95%RH
Embodiment 1
The calcium salt crystal formation A's of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
Prepare：
By 151.1mg 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
(Lesinurad) powder is dissolved in 2.0mL tetrahydrofurans：Water=19:1(v:V) in mixed solvent, then by 14.2mg
Calcium hydroxide add the solution, stirred 24 hours under room temperature condition, the solid as calcium salt crystal formation A that centrifugation is obtained.Its
XRPD figures are as shown in Figure 1.
Embodiment 2
The sylvite crystal formation A's of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
Prepare：
By 10.0mg 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
(Lesinurad) powder is dissolved in 0.6mL ethyl acetate, then the potassium hydroxide of 1.9mg added into the solution, room temperature condition
Lower stirring 40 hours, the solid as sylvite crystal formation A that centrifugation is obtained.Its XRPD figures are as shown in Figure 4.
Embodiment 3
The hydrochloride Form A of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
Preparation：
By 10.0mg 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
(Lesinurad) powder is dissolved in 0.6mL ethyl acetate, then the 36.5% of 2.5 μ L hydrochloric acid added into the solution, room temperature
Under the conditions of stir 40 hours, the solid as hydrochloride Form A that obtains of centrifugation.Its XRPD figures are as shown in Figure 7.
Embodiment 4
The hydrochloride Form B of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
Preparation：
By 149.9mg 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
(Lesinurad) powder is dissolved in 1.1mL ethyl acetate, then the 36.5% of 37.7mg hydrochloric acid added into the solution, room
Stirred 40 hours under the conditions of temperature, the solid as hydrochloride Form B that centrifugation is obtained.Its XRPD figures are as shown in Figure 10.
Embodiment 5
The esilate crystal formation of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The preparation of A：
By 150.5mg 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
(Lesinurad) powder is dissolved in 2.5mL ethyl acetate, then the ethyl sulfonic acid of 40.5mg added into the solution, room temperature condition
Lower stirring 24 hours, the solid as esilate crystal formation A that centrifugation is obtained.Its XRPD figures are as shown in figure 13.
Embodiment 6
The Mesylate Form of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The preparation of A：
By 150.1mg 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
(Lesinurad) powder is dissolved in 2.5mL acetonitriles, then the methanesulfonic acid of 36.7mg added into the solution, is stirred under room temperature condition
Mix 24 hours, the solid as Mesylate Form A that centrifugation is obtained.Its XRPD figures are as shown in figure 16.
Embodiment 7
The Mesylate Form of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The preparation of B：
By 10.0mg 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
(Lesinurad) powder is dissolved in 0.6mL ethyl acetate, then the methanesulfonic acid of 3.1mg added into the solution, under room temperature condition
Stirring 24 hours, the solid as Mesylate Form B that centrifugation is obtained.Its XRPD figures are as shown in figure 19.
Embodiment 8
The ethanedisulphonate of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid is brilliant
The preparation of type A：
By 10.0mg 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
(Lesinurad) powder is dissolved in 0.4mL acetonitriles, then 1, the 2- ethionic acids of 4.5mg are added into the solution, room temperature condition
Lower stirring 24 hours, the solid as ethanedisulphonate crystal formation A that centrifugation is obtained.Its XRPD figures are as shown in figure 22.
Embodiment 9
The ethanedisulphonate of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid is brilliant
The preparation of type B：
By 10.0mg 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
(Lesinurad) powder is dissolved in 0.6mL ethyl acetate, then 1, the 2- ethionic acids of 4.6mg are added into the solution, room temperature
Under the conditions of stir 24 hours, the solid as ethanedisulphonate crystal formation B that obtains of centrifugation.Its XRPD figures are as shown in figure 25.
Embodiment 10
The isethionate of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The preparation of crystal formation A：
By 10.0mg 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
(Lesinurad) powder is dissolved in 0.6mL ethyl acetate, adds the 80% of 3.9mg ethylenehydrinsulfonic acid, then room temperature bar
Stirred 24 hours under part, the solid as isethionate crystal formation A that centrifugation is obtained.Its XRPD figures are as shown in figure 28.
Embodiment 11
The arginine salt crystal formation of 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
The preparation of A：
By 10.0mg 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) acetic acid
(Lesinurad) powder is dissolved in 0.4mL acetonitriles, adds the arginine of 4.3mg, and then stirring 24 is small under room temperature condition
When, the solid as arginine salt crystal formation A that centrifugation is obtained.Its XRPD figures are as shown in figure 31.
Embodiment 12
Calcium salt crystal formation A stability studies：
Calcium salt crystal formation A is respectively placed under the conditions of 25 DEG C/60%RH and 40 DEG C/75%RH, solid is taken out after 2 weeks and is surveyed
Examination XRPD, as a result shows that calcium salt crystal formation A keeps constant, as a result such as table 3:
The calcium salt crystal formation A stability studies of table 3
Calcium salt crystal formation A places 2 weeks crystal formations and protects under the conditions of 25 DEG C/60%RH and 40 DEG C/75%RH, two kinds of accelerated stabilities
Hold constant, above-mentioned result of the test shows, calcium salt crystal formation A has good stability.
Embodiment 13
Calcium salt crystal formation A and sodium salt crystal formation A disclosed in WO2011085009A2 draws moist comparative study：
About 10mg calcium salt crystal formation A of the invention and sodium salt crystal formation A disclosed in WO2011085009A2 is taken respectively enters Mobile state
Water adsorption (DVS) is tested.Result such as table 4.
The calcium salt crystal formation A of table 4 and sodium salt crystal formation A disclosed in WO2011085009A2 draws moist comparative study (DVS
Such as Figure 35)
On draw the description of moist feature with draw moist weightening define that (Chinese Pharmacopoeia version annex XIX J medicines in 2010 draw
Moist test direction principle)：
Deliquescence：Absorb enough moisture and form liquid
It is great to draw moist：Draw wet weightening not less than 15%
Have and draw moist：Draw wet weightening less than 15% but not less than 2%
Slightly draw moist：Draw wet weightening less than 2% but not less than 0.2%
Nothing is moist almost without drawing：Draw wet weightening less than 0.2%
Result shows, calcium salt crystal formation A of the invention increases weight 0.15% after being balanced under 80% relative humidity, belong to without or it is several
Nothing draws moist；And sodium salt crystal formation A disclosed in WO2011085009A2 increases weight 25.11% after balancing under 80% relative humidity,
Belong to great and draw moist.Compared with prior art, calcium salt crystal formation A have it is extremely low draw moist, hardly influenceed by high humility and
Deliquescence.
Claims (2)
1. compound 2- (the bromo- 4- of 5- (4- cyclopropyl naphthalene -1- bases) -4H-1,2,4- triazole -3- bases sulfenyls) second shown in formula (I)
The calcium salt crystal formation A of acid,
Characterized in that, the X-ray powder diffraction figure of the calcium salt crystal formation A 2 θ values be 8.5 ° ± 0.2 °, 4.2 ° ± 0.2 °,
17.1 ° ± 0.2 °, 19.9 ° ± 0.2 °, 20.5 ° ± 0.2 °, 21.4 ° ± 0.2 °, 23.8 ° ± 0.2 °, 25.1 ° ± 0.2 °, 25.8 °
± 0.2 °, there is characteristic peak at 29.0 ° ± 0.2 °.
2. calcium salt crystal formation A according to claim 1, its preparation method is included formula (I) compound and calcium hydroxide four
The process of mixed crystallization in the mixed system of hydrogen furans and water.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410783347.8A CN104478815B (en) | 2013-12-23 | 2014-12-17 | Various salt, their 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 and preparation method thereof |
| US15/106,361 US9969701B2 (en) | 2013-12-20 | 2014-12-19 | Salts and co-crystals of lesinurad |
| PCT/US2014/071501 WO2015095703A1 (en) | 2013-12-20 | 2014-12-19 | Novel salts and co-crystals of lesinurad |
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|---|---|---|---|
| CN2013107137890 | 2013-12-23 | ||
| CN201310713789.0A CN103755651A (en) | 2013-12-23 | 2013-12-23 | Novel crystal form of salt of 2-(5-bromine-4-(4-cyclopropyl naphthalene-1-yl)-4H-1,2,4-triazole-3-yl-sulfenyl) acetic acid and preparation method of novel crystal form |
| CN201410783347.8A CN104478815B (en) | 2013-12-23 | 2014-12-17 | Various salt, their 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 and preparation method thereof |
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| CN201410783347.8A Expired - Fee Related CN104478815B (en) | 2013-12-20 | 2014-12-17 | Various salt, their 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 and preparation method thereof |
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| CN105294585B (en) * | 2014-07-02 | 2019-02-12 | 成都海创药业有限公司 | A kind of compound for treating gout |
| EP3281941B1 (en) | 2016-08-11 | 2019-07-24 | Zentiva K.S. | Process for preparing 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4h-1,2,4-triazol-3-ylthio)acetic acid |
| WO2018150335A1 (en) * | 2017-02-14 | 2018-08-23 | Lupin Limited | Novel cocrystal of lesinurad and process for the preparation thereof |
| 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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| AU2011203708B2 (en) * | 2010-01-08 | 2013-08-01 | Ardea Biosciences, Inc. | Polymorphic, crystalline and mesophase forms of sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, and uses thereof |
| PT2582683T (en) * | 2010-06-15 | 2018-05-25 | Ardea Biosciences Inc | Treatment of gout and hyperuricemia |
| CA2813555C (en) * | 2010-10-15 | 2014-11-25 | Ardea Biosciences, Inc. | Methods for treating hyperuricemia and related diseases |
| EA022301B1 (en) * | 2010-12-30 | 2015-12-30 | Ардеа Биосайнсиз, Инк. | Polymorphic forms of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4h-1,2,4-triazol-3-ylthio)acetic acid and uses thereof |
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Address after: 215123 Biological Park B4-101, No. 218 Xing Hu Street, Suzhou Industrial Park, Jiangsu Co-patentee after: SUZHOU PENGXU PHARMATECH Co.,Ltd. Patentee after: CRYSTAL PHARMATECH Co.,Ltd. Address before: 215123 Biological Park B4-101, No. 218 Xing Hu Street, Suzhou Industrial Park, Jiangsu Co-patentee before: SUZHOU PENGXU PHARMATECH Co.,Ltd. Patentee before: Crystal Pharmatech Co.,Ltd. |
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Granted publication date: 20170627 Termination date: 20211217 |