WO2009111061A1 - Process for the preparation of sorafenib and salts thereof - Google Patents
Process for the preparation of sorafenib and salts thereof Download PDFInfo
- Publication number
- WO2009111061A1 WO2009111061A1 PCT/US2009/001448 US2009001448W WO2009111061A1 WO 2009111061 A1 WO2009111061 A1 WO 2009111061A1 US 2009001448 W US2009001448 W US 2009001448W WO 2009111061 A1 WO2009111061 A1 WO 2009111061A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- imidazole
- chloro
- trifluoromethyl
- compound
- Prior art date
Links
- 0 **(*c1C(F)(F)F)ccc1Cl Chemical compound **(*c1C(F)(F)F)ccc1Cl 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
-
- 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
Definitions
- the present invention relates to intermediates of sorafenib base, their preparation and conversion to sorafenib base and salts thereof.
- Sorafenib base 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino] phenoxy]-N-methyl-pyridine-2-carboxamide of the following formula:
- sorafenib salts such as sorafenib tosylate of the following formula.
- Sorafenib tosylate is marketed as Nexavar® by Bayer for the treatment of advanced renal cell carcinoma. It is a small molecular inhibitor of Raf kinase, PDGF (platelet-derived growth factor), VEGF (vascular endothelial growth factor) receptor 2 and 3 kinases, and c-Kit (the cytokine receptor for stem cell factor).
- N-(2-methoxy-5-(trifiuoromethyl)phenyl)-N'-(4-(2-(N- methylcarbamoyl)-4-pyridyloxy)phenyl)urea which is a dechlorinated analogue of sorafenib
- 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline of formula 2, 5-(trifluoromethyl)-2-methoxyaniline and l,l'-carbonyldiimidazole (“CDI”) as illustrated by the following scheme: H-,
- sorafenib base which is obtained as an off-white solid in US 7,235,576 or as colorless to slightly brownish crystals in WO 2006/034796.
- sorafenib is prepared by coupling between 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline of formula 2 and 4-chloro-3-(trifiuoromethyl)phenyl isocyanate of formula 1, as illustrated by the following scheme: 1 sorafenib
- the isocyanate of formula 1 which is a reactive derivative of carbonic acid, can be prepared, according to US 2,745,874, from its corresponding aniline derivative.
- This patent also describes the reaction between the isocyanate and an aminobenzene compound, such as aniline, to provide derivatives of diphenyl urea such as l,3-Bis-(4-choloro-3-trifluoromethyl-phenyl)-urea of the following formula:
- C p 0741 1 ,3- B is- ( ⁇ c h lor o-3-tr if Iu o ro m ethyl- p h eny l> ur e a
- Bankston et ⁇ l. (Organic Process Research & Development 2002 Vol. 6 p. 777-781) relates to the two processes in scheme 1 and 2, and to the urea impurities that are formed in them.
- the present invention encompasses the compound of formula 4 of the following structure
- n is either 0 or 1.
- n is either 1 or 0, and HA is an acid, preferably p-toluenesulfonic acid (“PTSA").
- PTSA p-toluenesulfonic acid
- the present invention encompasses a process for preparing sorafenib base comprising reacting the compound of formula 4:
- the present invention encompasses a process for preparing sorafenib salt comprising preparing sorafenib base according to a process of the present invention, and converting it to sorafenib salt.
- the salt is PTSA salt.
- the present invention encompasses a process for preparing imidazole complex of imidazole- 1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of formula 4a of the following structure:
- CDI carbonyldiimidazole
- the present invention encompasses a process for preparing imidazole- 1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of formula 4b of the following structure:
- the present invention encompasses a process for preparing sorafenib and salt thereof comprising preparing the compounds of formula 4a or 4b according to a processes of the present invention, and converting either of them to sorafenib and salt thereof.
- the present invention relates to intermediates of sorafenib base, their preparation and conversion to sorafenib base and salts thereof.
- sorafenib is relatively not soluble in many solvents and thus purifying it is a challenge., i.e., trials to reduce the levels of impurities such as those mentioned I n the prior art were unsuccessful, thus provided sorafenib contaminated with about 10% of urea impurities.
- the present invention offers a process via two novel intermediates that are isolated.
- the isolation of these intermediates allows to purify the intermediate, especially from the urea impurities, thus leading to highly pure sorafenib in high yields that is obtained without any additional purification, but by simply precipitating it from the reaction mixture. Since sorafenib can be produced by this process in high yields and purity avoiding time consuming purification processes, this process is advantageous for industrial scale.
- the present invention encompasses the compound of formula 4 of the following structure:
- n is either 0 or 1.
- n is 1.
- above compound of formula 4 is provided in an isolated form.
- the isolated compound of formula 4 is solid, more preferably it is crystalline.
- the term isolated in reference to the compound of formula 4 corresponds to a compound of formula 4 that is physically separated from the reaction mixture, where it is formed.
- the separation can be done by filtering the precipitated compound of formula 4.
- the compound of formula 4 is separated from l,3-bis-(4-choloro-3-trifluoromethyl-phenyl)urea.
- the presence of l,3-bis-(4-choloro-3-trifluoromethyl-phenyl)urea can be detected by TLC.
- the compound of formula 4 is an imidazole complex of imidazole- 1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of formula 4a, having the following structure:
- the isolated an imidazole complex of imidazole- 1-carboxylic acid 4-chloro-3- (trifluoromethyl)phenyl amide of formula 4a can be used as an advantageous intermediate in the preparation of sorafenib, due to the removal of excess of carbonyldiimidazole (CDI) when isolating the compound of formula 4a.
- CDI carbonyldiimidazole
- CDI If CDI is not removed, it reacts with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline of formula 2 in the process for preparing Sorafenib base, to further provide l,3-bis-[4-(2-(N- methylcarbamoyl)-4-pyridyloxy)phenyl]urea, which contaminates Sorafenib and is difficult to purify from.
- the above compound of formula 4a can be characterized by a 1 H-NMR (300 MHz) spectrum in CDCl 3 having chemical shifts at 7.07, 7.12, 7.46, 7.67, 7.77, 7.83, 7.92, 8.45 and 10.7 ppm.
- n 0
- the compound of formula 4 is imidazole-1- carboxylic acid (4-chloro-3-trifluoromethylphenyl) amide of formula 4b, having the following structure:
- the compound of formula 4 can be used for the preparation of sorafenib and salts thereof having the following structure:
- n is either 0 or 1
- HA is an acid, preferably, p-toluenesulfonic acid (“PTSA”), i.e., sorafenib tosylate.
- PTSA p-toluenesulfonic acid
- the above compound refers to sorafenib base, and when n is 1 the above compound refers to a sorafenib salt, preferably, sorafenib tosylate.
- the process comprises reacting the compound of formula 4 of the following structure:
- sorafenib base wherein n is either 0 or 1.
- the starting material is the compound of formula 4a, i.e., n is 1
- the imidazole complex of imidazole- 1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of formula 4a can be prepared by a process comprising reacting 4-chloro-3- (trifluoromethyl) aniline of formula 3 with carbonyldiimidazole (CDI) of formula 5, as shown in the following scheme:
- the solvent is a halogenated hydrocarbon.
- the halogenated hydrocarbon is a Ci-C 6 halogenated hydrocarbon, most preferably, the Ci -C 6 halogenated hydrocarbon is dichloromethane, dichloroethane or chlorobenzene.
- CDI is added in an amount of about 1 mole equivalent to about 1.2 mole equivalent per mole equivalent of 4-chloro-3-(trifluoromethyl)aniline of formula 3, more preferably about 1 mole equivalent per mole equivalent of 4-chloro-3- (trifluoromethyl)aniline of formula 3.
- the mixture is then maintained to obtain a solution.
- the mixture is maintained at a temperature of about 2O 0 C to about 40 0 C, preferably 2O 0 C to about 35°C, more preferably 20 0 C to about 30 0 C.
- the mixture is maintained at a temperature of about 3O 0 C.
- the solution is stirred; preferably for a period of about 8 hours to about 24 hours, more preferably 10 hours to about 20 and most preferably 16 hours to about 24, especially about 16 hours.
- the stirring is done at a temperature of about 0 0 C to about 30 0 C, more preferably at about 5°C to about 15°C, during which time the compound of formula 4a precipitates.
- the precipitated imidazole complex of imidazole- 1-carboxylic acid 4-chloro- 3-(trifluoromethyl)phenyl amide of formula 4a is then recovered.
- the recovery may be done, for example, by filtering, washing, and drying under vacuum; preferably, drying is done at a temperature of about 18°C to about 3O 0 C, preferably about 2O 0 C to about 22°C. Preferably, drying is done for a period of about 4 hours to about 16 hours, more preferably about 12 hours to about 16 hours.
- the imidazole- 1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of formula 4b can be prepared by a process comprising reacting 4-chloro-3-(trifluoromethyl)phenyl isocyanate of formula 1 and imidazole or salt thereof of formula 6, wherein M is hydrogen, sodium or potassium.
- the process can be illustrated by the following scheme:
- M may be hydrogen, sodium, or potassium, and is preferably hydrogen.
- the solvent is a halogenated hydrocarbon, preferably a chlorinated hydrocarbon. More preferably, the halogenated hydrocarbon is a C 1 -C 6 halogenated hydrocarbon and preferably a Ci-C 6 chlorinated hydrocarbon, most preferably, the Ci-C 6 halogenated hydrocarbon is chloroform.
- the amount of imidazole is about 1 mole equivalent to about 1.2 mole equivalent per mole equivalent of 4-chloro-3-(trifluoromethyl)phenyl isocyanate of formula 1 , more preferably about 1 mole equivalent per mole equivalent of 4- chloro-3-(trifluoromethyl)phenyl isocyanate of formula 1.
- the solution is then maintained to obtain a suspension, thus providing a precipitate of imidazole- 1-carboxylic acid 4-chloro-3- (trifluoromethyl)phenyl amide of formula 4b.
- the suspension is maintained at a temperature of about 15 0 C to about 25°C,more preferably at a temperature of about 20 0 C to about 22 0 C.
- it is maintained for a period of about 0.5 hour to about 2 hours, more preferably for a period of about 1 hour.
- the suspension is then cooled, prior to recovering imidazole- 1- carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of formula 4b.
- cooling is to a temperature of about 10° to about -5°, more preferably to about 0 0 C.
- the suspension is further maintained at such temperature for a period of about 0.5 hour to about 2 hours , more preferably of about 1 hour.
- the precipitated imidazole- 1-carboxylic acid (4-chloro-3-trifluoromethyl- phenyl)-amide of formula 4b is then be recovered.
- the recovery may be done, for example, by filtering, washing, and drying under vacuum.
- washing is done with chloroform.
- drying is done at a temperature of about 35°C to about 45 0 C, more preferably about 40 0 C.
- drying is done for a period of about 12 hours to about 20 hours, more preferably 16 hours.
- the recovered imidazole complex of imidazole- 1-carboxylic acid 4-chloro-3- (trifluoromethyl)phenyl amide of formula 4a, and imidazole- 1-carboxylic acid 4- chloro-3-(trifluoromethyl)phenyl amide of formula 4b can then be converted to sorafenib and salts thereof.
- the conversion can be done by a process comprising reacting either the compound of formula 4a or the compound of formula 4b with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline of formula 2 to obtain sorafenib base.
- a solution of the compound of formula 4a or the compound of formula 4b is formed in a solvent selected from the group consisting of: halogenated hydrocarbons and preferably chlorinated hydrocarbins, esters, and mixtures thereof.
- the halogenated hydrocarbon is a Ci-C 6 halogenated hydrocarbon and more preferably a Ci- C 6 chlorinated hydrocarbon.
- the Ci- C 6 halogenated hydrocarbon is 1 ,2-dichloroethane, chlorobenzene or chloroform.
- the ester is C 2 -C 6 ester.
- the C 2 -C 6 ester is ethyl acetate, ethyl formate, ethyl propionate, or methyl acetate. More preferably, the C 2 -C 6 ester is ethyl acetate.
- the solution is preferably heated prior to the reaction with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline of formula 2.
- the heating is to a temperature of about 3O 0 C to about 80 0 C, depending on the solvent used.
- heating is to a temperature of about 60 0 C to about 70 0 C
- methyl acetate or ethyl formate heating is to a temperature of about 30 0 C to about 50 0 C
- chlorobenzene heating is to a temperature of about 60 0 C to about 70 0 C.
- the mixture is kept , preferably under stirring, to allow the formation of sorafenib base, which precipitates.
- the mixture is kept at a temperature of about 20 0 C to about 80 0 C, more preferably about 50 0 C to about 70 0 C.
- the mixture is kept for a period of about 15 minutes to obtain a suspension comprising the said precipitate of sorafenib base.
- precipitation can be followed by cooling the suspension.
- the cooling is to a temperature of about 30 0 C to about 10 0 C, more preferably to a temperature of about 20 0 C to about 1O 0 C.
- the suspension can be further maintained at the above temperatures for about 1 hour to about 20 hours, preferably about 10 hours to about 18 hours and most preferably 16 hours.
- the obtained sorafenib base can then be recovered.
- the recovery process of sorafenib base may comprise filtering off the precipitated sorafenib base, washing, and drying. Preferably, drying is done at a temperature of about 50 0 C to about 60 0 C; preferably for overnight.
- the recovered sorafenib is obtained as a white powder having a purity of at least about 99.7% area by HPLC.
- the obtained sorafenib base can then be converted to its salts.
- the conversion can be done by reacting sorafenib base with an acid.
- the acid is p-toluenesulfonic acid and the obtained salt is the corresponding tosylate salt.
- the conversion to the tosylate salt can be done, for example, according to any of the processes described in WO2006/034796.
- Example 1 Preparation of sorafenib intermediate imidazole complex of imidazole- 1- carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of formula 4a.
- Example 3 Preparation of sorafenib intermediate imidazole- 1-carboxylic acid (4- chloro-3-trifluorornethyl-phenyl)-amide of formula 4b.
- Example 5 Preparation of sorafenib tosylate as described in Method 5c of WO 2006/034796.
- Example 6 Preparation of sorafenib base according to WO 2006/034796.
- 4-(4-Aminophenoxy)-N-methyl-2-pyridinecarboxamide (5.23 g, 21.5 mmol) was suspended in ethyl acetate (14.6 g) and the suspension was heated to 40°C.
- 4- chloro-3-trifluoromethylphenylisocyanate (5 g, 22.6 mmol)
- ethyl acetate 5.8 g
- the mixture was stirred for a further 30 min and the product was filtered off. After washing with ethyl acetate (3 g), the product was dried under reduced pressure at 50°C.
- the title product was obtained as a brownish powder (9.45 g, 94.5% yield).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Methods for the synthesis of the N-carbamoyl imidazole Formulae (I), (II) and its 1 :1 adduct with imidazole are provided. Methods for the preparation of these crystalline intermediates in a high state of purity are also provided. These intermediates react cleanly under mild conditions to produce sorafenib in high yield and purity, without generating difficult-to-remove impurities.
Description
PROCESS FOR THE PREPARATION OF SORAFENIB AND SALTS
THEREOF
FIELD OF INVENTION
The present invention relates to intermediates of sorafenib base, their preparation and conversion to sorafenib base and salts thereof.
BACKGROUND
Sorafenib base, 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino] phenoxy]-N-methyl-pyridine-2-carboxamide of the following formula:
Sorafenib tosylate is marketed as Nexavar® by Bayer for the treatment of advanced renal cell carcinoma. It is a small molecular inhibitor of Raf kinase, PDGF (platelet-derived growth factor), VEGF (vascular endothelial growth factor) receptor 2 and 3 kinases, and c-Kit (the cytokine receptor for stem cell factor).
US 7,235,576 discloses processes for preparation of sorafenib base and analogues thereof
According to one process, N-(2-methoxy-5-(trifiuoromethyl)phenyl)-N'-(4-(2-(N- methylcarbamoyl)-4-pyridyloxy)phenyl)urea, which is a dechlorinated analogue of sorafenib, is prepared by coupling 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline of formula 2, 5-(trifluoromethyl)-2-methoxyaniline and l,l'-carbonyldiimidazole ("CDI"), as illustrated by the following scheme:
H-,
5-(tn fluoromethyl)- 2-πiEthoxyaniline 4 -Q. <N-methyl caibamoyl)-4-pyn dyloxy)aniline
N- (2 - m ethαx y-5 - (trifluor cm ethyl)ρhenyl)-N '- (4- (2-(N -m ethylc βib amoyl)- 4- pyn dyl ox jζ| phe ryl)w e a
Scheme 1
and purifying the obtained product by column chromatography. This patent also reports that the reaction of an aniline derivative, such as 4-(2-(N-methylcarbamoyl)- 4-pyridyloxy)aniline of formula 2, with l,l'-carbonyldiimidazole ("CDI"), leads also to the formation of symmetrical urea impurities, such as l,3-bis-[4-(2-(N- methylcarbamoyl)-4-pyridyloxy)phenyl]urea of the following formula:
H3
C p θ740 1 ,3- B s- [4-(2- (N ■ m ethy lea rb a moyl> 4- pyri dy loxy)p h e nyl]- u r ea without describing how to purify from them.
US 7,235,576 and WO 2006/034796 also report a process for preparation of sorafenib base, which is obtained as an off-white solid in US 7,235,576 or as colorless to slightly brownish crystals in WO 2006/034796. hi this process, sorafenib is prepared by coupling between 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline of formula 2 and 4-chloro-3-(trifiuoromethyl)phenyl isocyanate of formula 1, as illustrated by the following scheme: 1
sorafenib
Scheme 2
The isocyanate of formula 1 , which is a reactive derivative of carbonic acid, can be prepared, according to US 2,745,874, from its corresponding aniline derivative. This patent also describes the reaction between the isocyanate and an aminobenzene compound, such as aniline, to provide derivatives of diphenyl urea such as l,3-Bis-(4-choloro-3-trifluoromethyl-phenyl)-urea of the following formula:
C p 0741 1 ,3- B is- (Φ c h lor o-3-tr if Iu o ro m ethyl- p h eny l> ur e a
Bankston et αl. (Organic Process Research & Development 2002 Vol. 6 p. 777-781) relates to the two processes in scheme 1 and 2, and to the urea impurities that are formed in them.
Thus, there is a need in the art for a new process that provides sorafenib in high yield and purity.
SUMMARY OF INVENTION
In one embodiment, the present invention encompasses the compound of formula 4 of the following structure;
wherein n is either 0 or 1. hi another embodiment the present invention provides the use of the compound formula 4:
to prepare sorafenib and salts thereof of the following formula:
wherein n is either 1 or 0, and HA is an acid, preferably p-toluenesulfonic acid ("PTSA").
In another embodiment, the present invention encompasses a process for preparing sorafenib base comprising reacting the compound of formula 4:
with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline of formula 2: HCHj
to obtain sorafenib base, wherein n is either 1 or 0.
In yet another embodiment, the present invention encompasses a process for preparing sorafenib salt comprising preparing sorafenib base according to a process of the present invention, and converting it to sorafenib salt. Preferably, the salt is PTSA salt.
In one embodiment, the present invention encompasses a process for preparing imidazole complex of imidazole- 1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of formula 4a of the following structure:
4a comprising reacting 4-chloro-3-(trifluoromethyl)aniline of the following formula 3:
with carbonyldiimidazole (CDI) of formula 5 having the following structure;
to obtain an imidazole complex of imidazole- 1-carboxylic acid 4-chloro-3- (trifiuoromethyl)phenyl amide of formula 4a.
In another embodiment, the present invention encompasses a process for preparing imidazole- 1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of formula 4b of the following structure:
4b comprising reacting 4-chloro-3-(trifluoromethyl) phenyl isocyanate of formula 1 :
with imidazole or a salt thereof of formula 6:
6 wherein M is hydrogen, sodium or potassium; to obtain imidazole- 1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of formula 4b.
In another embodiment, the present invention encompasses a process for preparing sorafenib and salt thereof comprising preparing the compounds of formula 4a or 4b according to a processes of the present invention, and converting either of them to sorafenib and salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to intermediates of sorafenib base, their preparation and conversion to sorafenib base and salts thereof.
The processes of the prior art lead directly to the formation of sorafenib without an intermediate step. Hence, the urea impurities which are formed during the
process are not removed and thus contaminate sorafenib. Sorafenib is relatively not soluble in many solvents and thus purifying it is a challenge., i.e., trials to reduce the levels of impurities such as those mentioned I n the prior art were unsuccessful, thus provided sorafenib contaminated with about 10% of urea impurities.
The present invention offers a process via two novel intermediates that are isolated. The isolation of these intermediates allows to purify the intermediate, especially from the urea impurities, thus leading to highly pure sorafenib in high yields that is obtained without any additional purification, but by simply precipitating it from the reaction mixture. Since sorafenib can be produced by this process in high yields and purity avoiding time consuming purification processes, this process is advantageous for industrial scale.
A skilled in the art would appreciate that the process of the present invention can also be adapted for the preparation of other aryl urea derivatives in high yield and purity.
In one embodiment, the present invention encompasses the compound of formula 4 of the following structure:
4 wherein n is either 0 or 1. Preferably, n is 1.
In a preferred embodiment, above compound of formula 4 is provided in an isolated form. Preferably, the isolated compound of formula 4 is solid, more preferably it is crystalline.
As used herein, the term isolated in reference to the compound of formula 4 corresponds to a compound of formula 4 that is physically separated from the reaction mixture, where it is formed. For example, the separation can be done by filtering the
precipitated compound of formula 4. More preferably, the compound of formula 4 is separated from l,3-bis-(4-choloro-3-trifluoromethyl-phenyl)urea. The presence of l,3-bis-(4-choloro-3-trifluoromethyl-phenyl)urea can be detected by TLC.
When n is i, the compound of formula 4 is an imidazole complex of imidazole- 1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of formula 4a, having the following structure:
4a
The isolated an imidazole complex of imidazole- 1-carboxylic acid 4-chloro-3- (trifluoromethyl)phenyl amide of formula 4a can be used as an advantageous intermediate in the preparation of sorafenib, due to the removal of excess of carbonyldiimidazole (CDI) when isolating the compound of formula 4a. If CDI is not removed, it reacts with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline of formula 2 in the process for preparing Sorafenib base, to further provide l,3-bis-[4-(2-(N- methylcarbamoyl)-4-pyridyloxy)phenyl]urea, which contaminates Sorafenib and is difficult to purify from.
The above compound of formula 4a can be characterized by a 1H-NMR (300 MHz) spectrum in CDCl3 having chemical shifts at 7.07, 7.12, 7.46, 7.67, 7.77, 7.83, 7.92, 8.45 and 10.7 ppm. When n is 0, the compound of formula 4 is imidazole-1- carboxylic acid (4-chloro-3-trifluoromethylphenyl) amide of formula 4b, having the following structure:
4b
The above compound of formula 4b can be characterized by data selected from the group consisting of: a 1H-NMR (300 MHz) spectrum in CDCl3 having chemical shifts at about 7.913, 7.836, 7.480, 8.418, 7.725 and 7.097 ppm; MS-ESI spectrum of [M+H]+ = m/z 290/292; and combinations thereof.
The compound of formula 4 can be used for the preparation of sorafenib and salts thereof having the following structure:
as described below, wherein n is either 0 or 1 , and HA is an acid, preferably, p-toluenesulfonic acid ("PTSA"), i.e., sorafenib tosylate.
When n is 0, the above compound refers to sorafenib base, and when n is 1 the above compound refers to a sorafenib salt, preferably, sorafenib tosylate.
The process comprises reacting the compound of formula 4 of the following structure:
and 4-(2-(N-methylcarbamoyi)-4-pyridyloxy)anilme of formula 2 of the following structure:
to obtain sorafenib base, wherein n is either 0 or 1.
When the starting material is the compound of formula 4a, i.e., n is 1, the imidazole complex of imidazole- 1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of formula 4a can be prepared by a process comprising reacting 4-chloro-3- (trifluoromethyl) aniline of formula 3 with carbonyldiimidazole (CDI) of formula 5, as shown in the following scheme:
Scheme 3
First, a solution of 4-chloro-3-(trifluoromethyl)aniline of formula 3 is provided. Preferably, the solvent is a halogenated hydrocarbon. More preferably, the halogenated hydrocarbon is a Ci-C6 halogenated hydrocarbon, most preferably, the Ci -C6 halogenated hydrocarbon is dichloromethane, dichloroethane or chlorobenzene.
Then, 1,1 ' -carbonyldiimidazole ("CDI")of formula 5 is added to obtain a mixture.
Preferably, CDI is added in an amount of about 1 mole equivalent to about 1.2 mole equivalent per mole equivalent of 4-chloro-3-(trifluoromethyl)aniline of formula 3, more preferably about 1 mole equivalent per mole equivalent of 4-chloro-3- (trifluoromethyl)aniline of formula 3.
Preferably, the mixture is then maintained to obtain a solution. Preferably, the mixture is maintained at a temperature of about 2O0C to about 400C, preferably 2O0C to about 35°C, more preferably 200C to about 300C. Most preferably, the mixture is maintained at a temperature of about 3O0C.
The solution is stirred; preferably for a period of about 8 hours to about 24 hours, more preferably 10 hours to about 20 and most preferably 16 hours to about 24, especially about 16 hours. Preferably, the stirring is done at a temperature of about 00C to about 300C, more preferably at about 5°C to about 15°C, during which time the compound of formula 4a precipitates.
The precipitated imidazole complex of imidazole- 1-carboxylic acid 4-chloro- 3-(trifluoromethyl)phenyl amide of formula 4a is then recovered. The recovery may
be done, for example, by filtering, washing, and drying under vacuum; preferably, drying is done at a temperature of about 18°C to about 3O0C, preferably about 2O0C to about 22°C. Preferably, drying is done for a period of about 4 hours to about 16 hours, more preferably about 12 hours to about 16 hours.
When the starting material is the compound of formula 4b, i.e., n is 0, the imidazole- 1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of formula 4b can be prepared by a process comprising reacting 4-chloro-3-(trifluoromethyl)phenyl isocyanate of formula 1 and imidazole or salt thereof of formula 6, wherein M is hydrogen, sodium or potassium. The process can be illustrated by the following scheme:
Scheme 4
First, a solution of imidazole or a salt thereof of formula 6 is provided. M may be hydrogen, sodium, or potassium, and is preferably hydrogen. Preferably, the solvent is a halogenated hydrocarbon, preferably a chlorinated hydrocarbon. More preferably, the halogenated hydrocarbon is a C1-C6 halogenated hydrocarbon and preferably a Ci-C6 chlorinated hydrocarbon, most preferably, the Ci-C6 halogenated hydrocarbon is chloroform.
Then, 4-chloro-3-(trifluoromethyl)phenyl isocyanate of formula 1 is added to the solution.
Preferably, the amount of imidazole is about 1 mole equivalent to about 1.2 mole equivalent per mole equivalent of 4-chloro-3-(trifluoromethyl)phenyl isocyanate of formula 1 , more preferably about 1 mole equivalent per mole equivalent of 4- chloro-3-(trifluoromethyl)phenyl isocyanate of formula 1.
Preferably, the solution is then maintained to obtain a suspension, thus providing a precipitate of imidazole- 1-carboxylic acid 4-chloro-3- (trifluoromethyl)phenyl amide of formula 4b. Preferably the suspension is maintained
at a temperature of about 150C to about 25°C,more preferably at a temperature of about 200C to about 220C. Preferably, it is maintained for a period of about 0.5 hour to about 2 hours, more preferably for a period of about 1 hour.
Preferably the suspension is then cooled, prior to recovering imidazole- 1- carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of formula 4b. Preferably, cooling is to a temperature of about 10° to about -5°, more preferably to about 00C. Preferably, the suspension is further maintained at such temperature for a period of about 0.5 hour to about 2 hours , more preferably of about 1 hour.
The precipitated imidazole- 1-carboxylic acid (4-chloro-3-trifluoromethyl- phenyl)-amide of formula 4b is then be recovered. The recovery may be done, for example, by filtering, washing, and drying under vacuum. Preferably, washing is done with chloroform. Preferably, drying is done at a temperature of about 35°C to about 450C, more preferably about 400C. Preferably, drying is done for a period of about 12 hours to about 20 hours, more preferably 16 hours.
The recovered imidazole complex of imidazole- 1-carboxylic acid 4-chloro-3- (trifluoromethyl)phenyl amide of formula 4a, and imidazole- 1-carboxylic acid 4- chloro-3-(trifluoromethyl)phenyl amide of formula 4b can then be converted to sorafenib and salts thereof.
The conversion can be done by a process comprising reacting either the compound of formula 4a or the compound of formula 4b with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline of formula 2 to obtain sorafenib base.
Initially, a solution of the compound of formula 4a or the compound of formula 4b is formed in a solvent selected from the group consisting of: halogenated hydrocarbons and preferably chlorinated hydrocarbins, esters, and mixtures thereof. Preferably, the halogenated hydrocarbon is a Ci-C6 halogenated hydrocarbon and more preferably a Ci- C6 chlorinated hydrocarbon. Preferably, the Ci- C6 halogenated hydrocarbon is 1 ,2-dichloroethane, chlorobenzene or chloroform. Preferably, the ester is C2-C6 ester. Preferably, the C2-C6 ester is ethyl acetate, ethyl formate, ethyl propionate, or methyl acetate. More preferably, the C2-C6 ester is ethyl acetate.
The solution is preferably heated prior to the reaction with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline of formula 2. Preferably, the
heating is to a temperature of about 3O0C to about 800C, depending on the solvent used. For example, when using dichloroethane, ethyl propionate or ethyl acetate, heating is to a temperature of about 600C to about 700C, when using methyl acetate or ethyl formate heating is to a temperature of about 300C to about 500C and when using chlorobenzene heating is to a temperature of about 600C to about 700C.
Then, 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline of formula 2 is added to the heated solution to obtain a mixture.
The mixture is kept , preferably under stirring, to allow the formation of sorafenib base, which precipitates. Preferably, the mixture is kept at a temperature of about 200C to about 800C, more preferably about 500C to about 700C. Preferably, the mixture is kept for a period of about 15 minutes to obtain a suspension comprising the said precipitate of sorafenib base.
Typically, to increase the yield of the precipitated sorafenib base, precipitation can be followed by cooling the suspension. Preferably, the cooling is to a temperature of about 300C to about 100C, more preferably to a temperature of about 200C to about 1O0C. Optionally, to increase the yield even more, the suspension can be further maintained at the above temperatures for about 1 hour to about 20 hours, preferably about 10 hours to about 18 hours and most preferably 16 hours.
The obtained sorafenib base can then be recovered. The recovery process of sorafenib base may comprise filtering off the precipitated sorafenib base, washing, and drying. Preferably, drying is done at a temperature of about 500C to about 600C; preferably for overnight.
The recovered sorafenib is obtained as a white powder having a purity of at least about 99.7% area by HPLC.
The obtained sorafenib base can then be converted to its salts. The conversion can be done by reacting sorafenib base with an acid. Preferably, the acid is p-toluenesulfonic acid and the obtained salt is the corresponding tosylate salt. The conversion to the tosylate salt can be done, for example, according to any of the processes described in WO2006/034796.
EXAMPLES
Experimental:
NMR:
NMR Instrument: Varian Mercury-300, Frequency:, 300.07 MHz , solvent: CDCl3
MH analysis:
Instrument: Finnigan LCQ (ion-trap)
Method: ESI, positive ion mode
Conditions: Source Voltage (kV) 3.49, Source Current (μA) 2.98, Capillary Voltage
(V) 17.86, Capillary Temp (°C): 190.5. Mobile phase 70 % aqueous methanol containing 5 mM ammonium formate. Direct inlet, samples 1 mg/ml in dichloromethane.
Example 1 : Preparation of sorafenib intermediate imidazole complex of imidazole- 1- carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of formula 4a.
To a solution of 4-chloro-3-(trifluoromethyl)aniline of formula 3 (15 g) in 1,2- dichloroethane (150 g) under nitrogen atmosphere, CDI (12.4 g; 1.0 eq) was added. The reaction mixture was warmed and maintained at 30°C until the suspension had dissolved, then stirred for 16 hours at 20-22°C. The precipitate was collected, rinsed with dichloroethane, and dried at 20-22°C overnight under vacuum. Sorafenib intermediate 4a was obtained as a colorless powder (20.8 g, 76% yield). 1H-NMR (300 MHz) spectrum in CDCl3: chemical shifts at about 7.46, 7.83, 10.7, 8.45, 7.07, 7.77, 7.67 and 7.12.
Elemental analysis: Theoretical C, 47.01; H, 3.10; Cl, 9.91 ; F, 15.93; N, 19.58; O, 4.47. Experimental C, 46.7; H, 3.13; N 19.60
Example 2: Preparation of sorafenib base.
To a solution of the imidazole complex of imidazole- 1-carboxylic acid 4- chloro-3-(trifluoromethyl)phenyl amide of formula 4a (8.5 g) in 1,2-dichloroethane (60 g) at 60°C, 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide (4.5 g) was added, and the mixture was kept under stirring at 60-650C for 15 minutes until a
precipitate formed. The suspension was allowed to cool slowly to 20°C, and then stirred for 16 hours. The precipitate was filtered off, washed with 1 ,2-dichloroethane and dried at 50°C under vacuum overnight. Sorafenib base was obtained as a colorless powder (8 g, 93% yield, 99.9% purity).
Example 3: Preparation of sorafenib intermediate imidazole- 1-carboxylic acid (4- chloro-3-trifluorornethyl-phenyl)-amide of formula 4b.
4-Chloro-3-(trifluoromethyl)phenyl isocyanate (15.0 g) was added to a solution of imidazole (4.6 g) in CHCl3 (150 g) at room temperature. The initial solution was stirred at room temperature for Ih, obtaining a suspension which was cooled to 0°C and kept under stirring for 1 h. The solid was filtered off, washed with CHCl3 and dried at 40°C under reduced pressure for 16 h, to yield 19.2 g (98%) of intermediate 4b.
1H-NMR (300 MHz) spectrum in CDCl3: chemical shifts at about 7.913 (1 H, d, J=2.7), 7.836 (1 H, dd, J=8.7, 2.7 Hz), 7.480 (1 H, d, J=8.7 Hz), 8.418 (1 H, dd, J=I .4, 0.9 Hz), 7.725 (1 H, dd, J=I.6, 1.4 Hz), 7.097 (1 H, dd, J=I .6, 0.9 Hz). MS-ESI spectrum: TM+H1+ m/z 290/292
Example 4: Preparation of Sorafenib base.
To a solution of imidazole- 1-carboxylic acid 4-chloro-3-(trifluoromethyl)- phenyl amide of formula 4b (12.5 g 1.0 eq) in chlorobenzene (150 g) at 70-75°C, 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide (10 g) was added and the mixture was kept under stirring at 70-75°C for 15 minutes until a precipitate formed. The suspension was then cooled to 10°C and the precipitate was filtered off, washed with chlorobenzene, water and dried at 60°C under vacuum overnight. Sorafenib was obtained as a colorless powder (18.5 g, 95% yield, 99.7% purity).
Example 5: Preparation of sorafenib tosylate as described in Method 5c of WO 2006/034796.
4-{4-[({[4-Chloro-3-(trifluoromethyl) phenyl]amino}carbonyl)amino]phenoxy}-N- methylpyridine-2-carboxamide (50 g, 0.1076 mol) is suspended in ethyl acetate (500 g) and water (10 g). The mixture is heated to 69°C within 0.5 h, and a filtered solution of p-toluenesulfonic acid monohydrate (3.26 g, 0.017 mol) in a mixture of water (0.65 g) and ethyl acetate (7.2 g) is added. After filtration a filtered solution of
p-toluenesulfonic acid monohydrate (22 g, 0.11 mol) in a mixture of ethyl acetate (48 g) and water (4.34 g) is added. The mixture is cooled to 23°C within 2 h. The product is filtered off, washed twice with ethyl acetate (92.5 g each time) and dried under reduced pressure. The title compound (65.5 g, 96% of theory) is obtained as colorless to slightly brownish crystals.
Example 6: Preparation of sorafenib base according to WO 2006/034796. 4-(4-Aminophenoxy)-N-methyl-2-pyridinecarboxamide (5.23 g, 21.5 mmol) was suspended in ethyl acetate (14.6 g) and the suspension was heated to 40°C. Then 4- chloro-3-trifluoromethylphenylisocyanate (5 g, 22.6 mmol), dissolved in ethyl acetate (5.8 g) was added to such a degree that the temperature is kept below 60°C. After cooling to 20°C within 1 hour, the mixture was stirred for a further 30 min and the product was filtered off. After washing with ethyl acetate (3 g), the product was dried under reduced pressure at 50°C. The title product was obtained as a brownish powder (9.45 g, 94.5% yield).
Claims
We claim:
1. A compound of the following formula:
Formula 4 wherein n is either 0 or 1.
2. The compound of claim 1, wherein the compound is isolated.
3. The compound of claim 1 or claim 2, wherein n=l, corresponding to an imidazole complex of imidazole- 1-carboxylic acid 4-chloro-3- (trifluoromethyl)phenyl amide having the following formula:
Formula 4a
4. The compound of claim 3 characterized by a 1H-NMR (300 MHz) spectrum in CDCl3 having chemical shifts at 7.07, 7.12, 7.46, 7.67, 7.77, 7.83, 7.92, 8.45 and 10.7.
5. The compound of claim 1 or claim 2, wherein n=0, corresponding to imidazole- 1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide having the following formula:
Formula 4b
The compound of claim 5, characterized by data selected from the group consisting of: a 1H-NMR (300 MHz) spectrum in CDCl3 having chemical shifts at about 7.913, 7.836, 7.480, 8.418, 7.725 and 7.097; a mass spectrum of MS-ESI [M+H]+ = m/z 290/292; and combinations thereof.
A process for preparing Sorafenib base comprising reacting the compound of formula 4 of the following formula:
Formula 4 with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline of formula 2:
Formula 2 wherein n is either 1 or 0.
8. The process of claim 7, wherein said process comprises a) dissolving the compound of formula 4 to obtain a solution; b) adding the compound of formula 2 to obtain a mixture, and c) precipitating Sorafenib base.
9. The process of claim 8, wherein the solvent in the solution of step (a) is selected from the group consisting of: halogenated hydrocarbons, esters, and mixtures thereof.
10. The process of claim 9, wherein the solvent is selected from the group consisting of: CpC6 halogenated hydrocarbon, C2-C6 ester, and mixtures thereof.
11. The process of claim 10, wherein the solvent is selected from the group consisting of: 1 ,2-dichloroethane, chlorobenzene, chloroform, ethyl acetate, ethyl formate, ethyl propionate, methyl acetate, and mixtures thereof.
12. The process of any one of claims 7-11, further comprising recovering Sorafenib base.
13. The process of any one of claims 7-12, further comprising converting Sorafenib base to Sorafenib salt.
14. The process of claim 13, wherein the salt is p-toluenesulfonic acid ("PTSA") salt.
15. The process of any one of claims 7-14, wherein:
(a) n is i, and the compound of formula 4 is prepared by a process comprising reacting 4-chloro-3-(trifiuoromethyl)aniline of formula 3 and carbonyldiimidazole (CDI); or
(b) n is 0, and the compound of formula 4 is prepared by a process comprising reacting 4-chloro-3-(trifluoromethyl)phenyl isocyanate of formula 1 and imidazole of formula 6.
16. A process for preparing an imidazole complex of imidazole- 1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of the following formula:
Formula 4a comprising reacting 4-chloro-3-(trifluoromethyl)aniline of the following formula:
Formula 3 with carbonyldiimidazole (CDI) of formula 5 having the following structure;
17. The process of claim 16, comprising (a) providing a solution of 4-chloro-3- (trifluoromethyl)aniline of formula 3; and (b) adding carbonyldiimidazole (CDI) of formula 5 to obtain a suspension comprising the imidazole complex of imidazole- 1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of formula 4a.
18. The process of claim 17, wherein the solvent in the solution of step (a) is halogenated hydrocarbon.
19. The process of claim 18, wherein the halogenated hydrocarbon is a C]-C6 halogenated hydrocarbon.
20. The process of claim 19, wherein the Ci-C6 halogenated hydrocarbon is dichloromethane, chlorobenzene or chloroform.
21. The process of any one of claims 16-20, further comprising recovering the imidazole complex of imidazole- 1-carboxylic acid 4-chloro-3- (trifluoromethyl)phenyl amide of formula 4a.
22. A process for preparing imidazole- 1 -carboxylic acid 4-chloro-3- (trifluoromethyl)phenyl amide of the following formula:
Formula 4b comprising reacting 4-chloro-3-(trifluoromethyl)phenyl isocyanate of the following formula: O
1 with imidazole or a salt thereof of formula 6:
Formula 6 wherein M is hydrogen, sodium or potassium.
23. The process of claim 22, comprising (a) providing a solution of imidazole of formula 6, and (b) adding 4-chloro-3-(trifiuoromethyl)phenyl isocyanate of formula 1 to obtain a suspension comprising imidazole- 1-carboxylic acid 4- chloro-3-(trifluoromethyl)phenyl amide of formula 4b.
24. The process of claim 23, wherein the solvent in the solution of step (a) is a halogenated hydrocarbon.
25. The process of claim 24, wherein the halogenated hydrocarbon is a CpC6 halogenated hydrocarbon.
26. The process of claim 24, wherein the Ci-C6 halogenated hydrocarbon is chloroform.
27. The process of any one of claims 22-26, further comprising recovering imidazole- 1-carboxylic acid 4-chloro-3-(trifluoromethyi)phenyl amide of formula 4b.
28. A process for preparing Sorafenib or a salt thereof of the following formula:
comprising preparing the compounds of formula 4a or 4b according claims 16 or 22 and converting either of them to Sorafenib or a salt thereof; wherein n is either 0 or 1 , and HA is an acid.
29. The process of claim 28, wherein the acid is p-toluenesulfonic acid ("PTSA").
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP09718066A EP2142507A1 (en) | 2008-03-06 | 2009-03-05 | Process for the preparation of sorafenib and salts thereof |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US6847808P | 2008-03-06 | 2008-03-06 | |
US61/068,478 | 2008-03-06 | ||
US15016909P | 2009-02-05 | 2009-02-05 | |
US61/150,169 | 2009-02-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2009111061A1 true WO2009111061A1 (en) | 2009-09-11 |
Family
ID=40584732
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2009/001448 WO2009111061A1 (en) | 2008-03-06 | 2009-03-05 | Process for the preparation of sorafenib and salts thereof |
Country Status (3)
Country | Link |
---|---|
US (1) | US20090253913A1 (en) |
EP (1) | EP2142507A1 (en) |
WO (1) | WO2009111061A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011092663A2 (en) | 2010-01-29 | 2011-08-04 | Ranbaxy Laboratories Limited | 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-n2-methylpyridine-2-carboxamide dimethyl sulphoxide solvate |
CN103724259A (en) * | 2013-12-12 | 2014-04-16 | 江苏集贤绿色化学科技研究院有限公司 | Synthesis method for sorafenib |
WO2015031604A1 (en) | 2013-08-28 | 2015-03-05 | Crown Bioscience, Inc. | Gene expression signatures predictive of subject response to a multi-kinase inhibitor and methods of using the same |
RU2568638C1 (en) * | 2015-02-26 | 2015-11-20 | Индивидуальный предприниматель Михайлов Олег Ростиславович | CRYSTALLINE β-MODIFICATION OF 4-[4-({[4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL]CARBAMOYL}AMINO)PHENOXY]-N-METHYL-PYRIDINE-2-CARBOXAMIDE OF p-TOLUENE SULPHONATE, METHOD FOR PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITION BASED THEREON |
CN105585523A (en) * | 2015-12-29 | 2016-05-18 | 上海北卡医药技术有限公司 | Novel sorafenib TsOH crystal form as well as preparation method and application thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006034796A1 (en) * | 2004-09-29 | 2006-04-06 | Bayer Healthcare Ag | Process for the preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-n-methylpyridine-2-carboxamide |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2745874A (en) * | 1953-06-18 | 1956-05-15 | Geigy Ag J R | Insecticidal derivatives of diphenyl urea |
US7235576B1 (en) * | 2001-01-12 | 2007-06-26 | Bayer Pharmaceuticals Corporation | Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
-
2009
- 2009-03-05 US US12/381,000 patent/US20090253913A1/en not_active Abandoned
- 2009-03-05 WO PCT/US2009/001448 patent/WO2009111061A1/en active Application Filing
- 2009-03-05 EP EP09718066A patent/EP2142507A1/en not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006034796A1 (en) * | 2004-09-29 | 2006-04-06 | Bayer Healthcare Ag | Process for the preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-n-methylpyridine-2-carboxamide |
Non-Patent Citations (2)
Title |
---|
BANKSTON D ET AL: "A Scalable Synthesis of BAY 43-9006: A Potent Raf Kinase Inhibitor for the Treatment of Cancer", ORGANIC PROCESS RESEARCH & DEVELOPMENT,, vol. 6, no. 6, 1 January 2002 (2002-01-01), pages 777 - 781, XP002523918 * |
PAPADOPOULOS E P: "Reactions of imidazoles with isocyanates at elevated temperature", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, EASTON.; US, vol. 42, no. 24, 25 November 1977 (1977-11-25), pages 3925 - 3929, XP002378857, ISSN: 0022-3263 * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011092663A2 (en) | 2010-01-29 | 2011-08-04 | Ranbaxy Laboratories Limited | 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-n2-methylpyridine-2-carboxamide dimethyl sulphoxide solvate |
WO2011092663A3 (en) * | 2010-01-29 | 2011-12-29 | Ranbaxy Laboratories Limited | Sorafenib dimethyl sulphoxide solvate |
US8618305B2 (en) | 2010-01-29 | 2013-12-31 | Ranbaxy Laboratories Limited | Sorafenib dimethyl sulphoxide solvate |
AU2011210326B2 (en) * | 2010-01-29 | 2014-10-09 | Sun Pharmaceutical Industries Limited | Sorafenib dimethyl sulphoxide solvate |
WO2015031604A1 (en) | 2013-08-28 | 2015-03-05 | Crown Bioscience, Inc. | Gene expression signatures predictive of subject response to a multi-kinase inhibitor and methods of using the same |
CN103724259A (en) * | 2013-12-12 | 2014-04-16 | 江苏集贤绿色化学科技研究院有限公司 | Synthesis method for sorafenib |
RU2568638C1 (en) * | 2015-02-26 | 2015-11-20 | Индивидуальный предприниматель Михайлов Олег Ростиславович | CRYSTALLINE β-MODIFICATION OF 4-[4-({[4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL]CARBAMOYL}AMINO)PHENOXY]-N-METHYL-PYRIDINE-2-CARBOXAMIDE OF p-TOLUENE SULPHONATE, METHOD FOR PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITION BASED THEREON |
CN105585523A (en) * | 2015-12-29 | 2016-05-18 | 上海北卡医药技术有限公司 | Novel sorafenib TsOH crystal form as well as preparation method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
EP2142507A1 (en) | 2010-01-13 |
US20090253913A1 (en) | 2009-10-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2005289099B2 (en) | Process for the preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide | |
JP6061158B2 (en) | Synthesis intermediate of 6- (7-((1-aminocyclopropyl) methoxy) -6-methoxyquinolin-4-yloxy) -N-methyl-1-naphthamide, or a pharmaceutically acceptable salt thereof, and its use | |
CA2796238C (en) | Process for the preparation of 4-{4-[({[4-chloro-3-trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-n-methylpyridine-2-carboxamide, its salts and monoydyrate | |
AU2010299483B2 (en) | Process for the preparation of sorafenib tosylate | |
PL195808B1 (en) | Inhibition of raf kinase using symmetrical and dissymmetrical substituted dimethylureas | |
WO2009111061A1 (en) | Process for the preparation of sorafenib and salts thereof | |
EP2470182B1 (en) | Synthesis of a neurostimulative piperazine | |
CZ20023395A3 (en) | Novel preparation process of torsemide intermediate | |
JP6891131B2 (en) | A novel method for preparing enzalutamide | |
KR20190049883A (en) | Method for producing phenylalanine compound | |
CS207750B2 (en) | Method of making the n'-cyano-n'-alcyl-n-2-/5-methyl-1h-imidazol-4-yl/methyl thicethyl guanidines | |
US20110040097A1 (en) | Process for preparing lercanidipine hydrochloride | |
JP5078211B2 (en) | Method for producing heterocyclic compound | |
JP3884063B2 (en) | Cefcapene pivoxil methanesulfonate | |
CN106083822B (en) | A kind of preparation method of dabigatran etexilate methanesulfonate intermediate | |
CN110078674B (en) | Preparation method of 2-alkyl amino pyrimidone | |
JP2006193480A (en) | Method for producing 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid | |
JP2010083888A (en) | Method for preparing azelnidipine crystal | |
KR20230032513A (en) | Method for preparing Camostat mesylate | |
JPH0558985A (en) | Production of cyanoguanidine derivative | |
JP2019131532A (en) | Acid anhydride, and method for producing l-carnosine with the acid anhydride | |
TW202342451A (en) | Synthesis of a kif18a inhibitor | |
KR100247730B1 (en) | Process for the preparation of fusidic acid sodium salt | |
HU213116B (en) | A new process for producing n``-cyano-n`-(4-pyridyl)-n-(1,2,2-trimethyl-propyl)-guanidine | |
CN113045491A (en) | Preparation method of Lunvatinib and intermediate |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 2009718066 Country of ref document: EP |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09718066 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |