CN107162965A - A kind of toluene fulfonate amorphous forms of Sorafenib half and preparation method thereof - Google Patents
A kind of toluene fulfonate amorphous forms of Sorafenib half and preparation method thereof Download PDFInfo
- Publication number
- CN107162965A CN107162965A CN201610127172.4A CN201610127172A CN107162965A CN 107162965 A CN107162965 A CN 107162965A CN 201610127172 A CN201610127172 A CN 201610127172A CN 107162965 A CN107162965 A CN 107162965A
- Authority
- CN
- China
- Prior art keywords
- amorphous forms
- cancer
- sorafenib
- toluene fulfonate
- temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of toluene fulfonate amorphous forms of Sorafenib half and preparation method thereof, the application containing its pharmaceutical composition and its in cancer therapy drug.
Description
Technical field
The present invention relates to new 4- { 4- [({ [4- chloro- 3- (trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-N- picolines
Toluene fulfonate amorphous forms of -2- formamides half and preparation method thereof, belong to field of pharmaceutical chemistry technology.
Background technology
WO2000/42012A discloses diphenyl urea compounds 4- { 4- [({ [the chloro- 3- of 4- (trifluoromethyl) of a class ω-carboxyl aryl substitution
Phenyl] amino } carbonyl) amino] phenoxy group }-N- picoline -2- formamides, i.e. Sorafenib, shown in its structural formula such as formula (I)：
WO2000/42012A also discloses the compound and its salt, such as tosilate, i.e. Sorafenib Tosylate,
Such as structure formula (II), it can be used for suppressing the mediated cancerous cell growth of Raf kinases institute.
Disease (the example that WO2003/068228A more particularly to formula (II) compound are mediated in treatment VEGF signal transduction pathways
Such as tumour) application, available for abnormal vascular generation or high osmosis illness.WO2003/0475979A discloses formula (II)
Compound combines the disease kinase mediated for treating Raf with cell toxicant or cytostatic compound, such as cancer, such as lung cancer,
Cancer of pancreas, thyroid cancer, kidney, intestinal cancer or growth of cancer cells.
Formula (I) compound or its salt can be prepared in the method described in WO2000/42012A or WO2000/41698.
WO2006/034797A discloses 3 kinds of non-solvent compounds (being referred to as polymorphic I, II, III) of formula (II) compound, 2
Solvate (Methanol Solvate, an alcohol solvent compound) is planted, wherein：Polymorphic I is Thermodynamically stable type, in
223~231 DEG C fusing decompose, and polymorphic I even handled by suspension after be still storage-stable；Polymorphic II metastable states,
With 194 DEG C of transition point；Polymorphic III, in 187~190 DEG C of thawings.WO2009092070A is related to formula (II) compound
2 kinds of solvates, i.e. DMSO solvates polymorph b, nmp solvent compound polymorphic C.WO2009/106825A
It is related to unformed formula (I) and (II) compound.WO2010/142678A is related to the unformed of formula (II) compound, crystallization
Formula (I) compound hydrochloride or its hydrate, mesylate, benzene sulfonate, half benzene sulfonate monohydrate eutectic and Malaysia
Hydrochlorate.WO2010/079498A is related to the non-solvent compound (polymorphic II) of formula (II) compound, its PXRD collection of illustrative plates 9.7,
11.2nd, there is diffraction maximum, DSC collection of illustrative plates shows it at 181.25 DEG C at 13.1,17.7,18.4,21.4,22.7 and 24.6 ± 2theta
Start to melt, have endothermic peak at 184.61 DEG C.WO2014/138905A is related to the half DMSO solvents of formula (II) compound
Compound.CN104761492A is related to 2 kinds of non-solvent compounds (polymorph b, C) of formula (II) compound, wherein, polymorphic
C has exothermic peak at 169.78 DEG C~179.94 DEG C, has endothermic peak at 232.95 DEG C~238.66 DEG C.WO2009/092070A is further related to
1 kind of toluenesulfonic acid (1 of Sorafenib half：0.5) and its polymorphic (polymorphic A), wherein, the PXRD of the polymorphic A
Collection of illustrative plates has diffraction at 6.6,9.0,9.6,13.4,14.0,17.2,18.3,20.4,22.8,24.9,27.1 ± 0.2theta
Peak.
The content of the invention
The invention provides a kind of amorphous forms of the toluene fulfonate of Sorafenib half.
Further, X-ray powder diffraction collection such as Fig. 1 of the amorphous forms of the toluene fulfonate of Sorafenib half of the invention
It is shown.
Yet further, the DSC collection of illustrative plates of the amorphous forms of the toluene fulfonate of Sorafenib half of the invention is as shown in Figure 2.
Present invention also offers a kind of method of the amorphous forms prepared described in claim 1, it is characterised in that including as follows
Step：Sorafenib Tosylate I crystal is suspended in ethanol or ethanol, stirred, 25~100 DEG C are warming up to, temperature control is added dropwise
Water, Quan Rong, cool crystallization, dries, produces at 130~135 DEG C of temperature.In some embodiments of the present invention, suspend
It can be substituted with etoh solvent with methanol.In some embodiments of the present invention, preferred 75-80 DEG C of the warming temperature, more preferably
80℃。
Present invention also offers a kind of pharmaceutical composition, the toluene fulfonate of Sorafenib half that it contains dose therapeutically effective is unformed
Form, and pharmaceutically acceptable auxiliary material.
It is too high in preparation treatment abnormal vascular generation or permeability that the present invention also provides the toluene fulfonate amorphous forms of Sorafenib half
Application in lesion associated conditions or the medicine of cancer, wherein, the cancer be selected from leukaemia, lung cancer, cancer of pancreas, thyroid cancer,
The growth of kidney, intestinal cancer or cancer cell.
Present invention also offers a kind of combination medicine, comprising the toluene fulfonate amorphous forms of Sorafenib half and it is one or more its
His medicine, wherein one or more other drugs are cell toxicity medicament, signal transduction inhibitor, anticarcinogen or antiemetic.
Brief description of the drawings
Fig. 1 is the PXRD collection of illustrative plates of the amorphous forms of the toluene fulfonate of Sorafenib half of the present invention.
Fig. 2 is the TG-DSC collection of illustrative plates of the amorphous forms of the toluene fulfonate of Sorafenib half of the present invention.
Specific embodiment
It is explained further below by example and illustrates the present invention, but the invention is not limited in any way.It is any type of etc.
Protection scope of the present invention is each fallen within substituting.
Characterizing method
The tester of X-ray powder diffraction (PXRD) collection of illustrative plates is Bruker D8 ADVANCE type X-ray diffractometers, test
Condition is Cu targets, K α lines, 40kV, 40mA, and step-length is 0.02 °, and sweep speed is 8 °/min, and scanning range is 3 °~45 °.
The tester of thermogravimetric (TG-DSC) collection of illustrative plates is synchronous solving, numbering：Q20 SB-432, test content：DSC
And TGA, test condition be from room temperature 25 DEG C start to warm up, 5 DEG C/min of speed, 25 DEG C~250 DEG C of Range of measuring temp.
Embodiment 1 Sorafenib, half toluene fulfonate is unformed to be prepared
It is many that method according to CN101065360A (WO2006/034797A patent families) prepares Sorafenib Tosylate
Crystal formation I.
6.3g4- { 4- [({ [4- chloro- 3- (trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-N- picoline -2- formamides is outstanding
Float in ethanol and stir, add 0.91g p-methyl benzenesulfonic acid monohydrates, reaction solution is warming up to 74 DEG C under stirring, by other one
Part 2.2g p-methyl benzenesulfonic acid monohydrate is added dropwise in above-mentioned solution with having after ethanol dissolving, after completion of dropping, temperature control reaction
2 hours, preferably 2 hours.Be cooled to 3 ± 2 DEG C at 2 hours, then temperature control and continue stirring 1 hour, suction filtration, forced air drying
Obtain 8.08g Sorafenib Tosylate polymorphics I.
5g Sorafenib Tosylate polymorphics I is suspended in 25ml ethanol, 80 DEG C are heated under stirring, then 8g is purified
Water is slowly added dropwise in above-mentioned suspension, treats complete molten, the lower Temperature fall crystallization of stirring 5 hours, separates out a large amount of solids, suction filtration is obtained
To faint yellow solid, dried 3 hours at 130~135 DEG C of temperature, you can.
Structural characterization
PXRD the and TG-DSC collection of illustrative plates of the product of testing example 1, is shown in Fig. 1 and Fig. 2 respectively.
Claims (9)
1. a kind of amorphous forms of the toluene fulfonate of Sorafenib half.
2. amorphous forms according to claim 1, it is characterised in that its X-ray powder diffraction collection is as shown in Figure 1.
3. amorphous forms according to claim 1, it is characterised in that its DSC collection of illustrative plates is as shown in Figure 2.
4. a kind of method of the amorphous forms prepared described in claim 1, it is characterised in that comprise the following steps：Sorafenib Tosylate I crystal is suspended in ethanol or ethanol, stirs, is warming up to 25~100 DEG C, temperature control is added dropwise water, Quan Rong, and cool crystallization, dries, produces at 130~135 DEG C of temperature.
5. a kind of method of the amorphous forms prepared described in claim 1, it is characterised in that the warming temperature is 75-80 DEG C.
6. a kind of method of the amorphous forms prepared described in claim 1, it is characterised in that the warming temperature is 80 DEG C.
7. a kind of pharmaceutical composition, it is characterised in that the amorphous forms of the claim 1 containing dose therapeutically effective, and pharmaceutically acceptable auxiliary material.
8. application of the amorphous forms of claim 1 in the generation for the treatment of abnormal vascular or hyperpermeability processes associated conditions or the medicine of cancer is prepared, wherein, the cancer is selected from the growth of leukaemia, lung cancer, cancer of pancreas, thyroid cancer, kidney, intestinal cancer or cancer cell.
9. a kind of combination medicine, the amorphous forms comprising claim 1 and one or more other drugs, wherein one or more other drugs are cell toxicity medicament, signal transduction inhibitor, anticarcinogen or antiemetic.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610127172.4A CN107162965A (en) | 2016-03-07 | 2016-03-07 | A kind of toluene fulfonate amorphous forms of Sorafenib half and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610127172.4A CN107162965A (en) | 2016-03-07 | 2016-03-07 | A kind of toluene fulfonate amorphous forms of Sorafenib half and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107162965A true CN107162965A (en) | 2017-09-15 |
Family
ID=59848459
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610127172.4A Pending CN107162965A (en) | 2016-03-07 | 2016-03-07 | A kind of toluene fulfonate amorphous forms of Sorafenib half and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107162965A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2766288C2 (en) * | 2020-03-30 | 2022-03-11 | Общество с ограниченной ответственностью "АКСЕЛЬФАРМ" | Amorphous form of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)-amino]phenoxy}-n-methylpyridine-2-carboxamide tosylate (versions), method for production and use thereof for treatment of oncological diseases |
-
2016
- 2016-03-07 CN CN201610127172.4A patent/CN107162965A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2766288C2 (en) * | 2020-03-30 | 2022-03-11 | Общество с ограниченной ответственностью "АКСЕЛЬФАРМ" | Amorphous form of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)-amino]phenoxy}-n-methylpyridine-2-carboxamide tosylate (versions), method for production and use thereof for treatment of oncological diseases |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10519176B2 (en) | Crystalline forms | |
| AU2014239995B2 (en) | Salt of omecamtiv mecarbil and process for preparing salt | |
| WO2011095059A1 (en) | Polymorphs of dasatinib, preparation methods and pharmaceutical compositions thereof | |
| JP6158811B2 (en) | Crystalline polymorph of 4- [5- (pyridin-4-yl) -1H-1,2,4-triazol-3-yl] pyridine-2-carbonitrile and process for producing the same | |
| CN113795490A (en) | Novel crystalline forms of N- (3- (2- (2-hydroxyethoxy) -6-morpholinopyridin-4-yl) -4-methylphenyl) -2 (trifluoromethyl) isonicotinamide as Raf inhibitors for the treatment of cancer | |
| CN101983195A (en) | Novel polymorphs and processes for their preparation | |
| JP2007520546A (en) | A stable amorphous form of Montelukast sodium | |
| KR20130008050A (en) | Method and process for preparation and production of deuterated ω-diphenylurea | |
| WO2011086541A1 (en) | Novel polymorph of nilotinib monohydrochloride monohydrate | |
| WO2012070062A2 (en) | Novel polymorph of nilotinib hydrochloride | |
| CN102070618B (en) | Compound and crystals thereof | |
| KR20240000540A (en) | (S)-N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3- Solid state forms of (2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and salts thereof | |
| EP2542548A1 (en) | Process for preparation of polymorphic form and new polymorphic form of imatinib mesylate isolated in that process | |
| CN102197035A (en) | Novel crystalline form and processes for its preparation | |
| TW202200594A (en) | Crystalline form a of GLP-1 receptor agonist and preparation method therefor | |
| CN107162965A (en) | A kind of toluene fulfonate amorphous forms of Sorafenib half and preparation method thereof | |
| JP2022535870A (en) | Crystal polymorph of CDK9 inhibitor, method for producing the same, and use thereof | |
| WO2016151304A1 (en) | Novel polymorphic form x of nilotinib dihydrochloride hydrate | |
| CN108069891B (en) | A crystal form of methyl methylamine hydrochloride, preparation and application thereof | |
| CN113840605B (en) | Crystalline forms of N- (5- ((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-indazol-5-yl) pyrimidin-2-amine hydrochloride and uses thereof | |
| JP6072908B2 (en) | Deuterated ω-dimethylurea or polymorph of its salt | |
| CN105503715A (en) | Sorafenib semi-tosylate polymorphism and preparing method thereof | |
| CN104211682A (en) | pyridine compounds and applications thereof | |
| CN102197034A (en) | Novel polymorphs of sunitinib and processes for their preparation | |
| JP2018518515A (en) | Polymorphs of phenylaminopyrimidine compounds or salts thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170915 |
|
| WD01 | Invention patent application deemed withdrawn after publication |