WO2009054004A2 - Process for the preparation of sorafenib - Google Patents
Process for the preparation of sorafenib Download PDFInfo
- Publication number
- WO2009054004A2 WO2009054004A2 PCT/IN2008/000698 IN2008000698W WO2009054004A2 WO 2009054004 A2 WO2009054004 A2 WO 2009054004A2 IN 2008000698 W IN2008000698 W IN 2008000698W WO 2009054004 A2 WO2009054004 A2 WO 2009054004A2
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- Prior art keywords
- formula
- sorafenib
- compound
- reaction
- sodium
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- PLIKAWJENQZMHA-UHFFFAOYSA-N Nc(cc1)ccc1O Chemical compound Nc(cc1)ccc1O PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 1
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
Definitions
- Present invention relates to a novel and improved process for the preparation of sorafenib (4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide) of formula I involving a novel intermediate of formula II.
- Compound of formula II is a key intermediate used in the synthesis of sorafenib of formula I.
- Sorafenib is a multiple kinase inhibitor targeting both RAF kinase and receptor tyrosine kinase that promote angiogenesis. Clinical development of sorafenib is reviewed in Expert Opin. Pharmacother.., 7, 453-461 (2006). Sorafenib is available in the market as tosylate salt under the brand name Nexavar.
- Sorafenib and its pharmaceutically acceptable salts and solvates are reported for the first time in WO0041698 (corresponding US 03139605) by Bayer.
- WO0041698 corresponding US 03139605
- picolinic acid of formula III is reacted with thionyl chloride to give the 4-chloro derivative which on treatment
- a scalable process for the preparation of sorafenib is disclosed in WO2006034796.
- chemistry is used in making sorafenib of formula I.
- catalytic quantity. of DMF used in the prior art process is replaced with reagents like hydrogen bromide, thionyl bromide and sodium bromide. Yield of required product remained same without any advantages from newly introduced corrosive reagents.
- Process improvements like change of solvents, reagents, etc were applied in subsequent steps making the process scalable.
- Overall yield of sorafenib is increased to 74% from the prior art 63% yield. Purity of sorafenib is only 95% and was obtained as light brown colored solid.
- the main objective of the present invention is to provide an improved process for the preparation of sorafenib, which is commercially applicable.
- R C 1 -C 8 alkyl
- ester compound of formula X is reacted with ester derivative of formula XI in the presence of a base in a solvent medium to get novel esters of formula XII.
- Reaction of ester compound of formula XII with methylamine yielded the required sorafenib of formula I.
- process of the present invention provides a novel process for the preparation of sorafenib of formula I,
- the isocyanate of formula VIII is reacted with 4-aminophenol of formula IX or its acid addition salt in the presence of a solvent, inert towards isocyante at a temperature above 15°C.
- a neutralizing agent such as triethylamine, inert towards isocyanate is used to liberate the base.
- compound of formula X is reacted with compound of formula XI in a solvent such as DMF, DMAc, DMSO, THF, dioxane, toluene, cyclohexane, acetonitrile.
- Base used in the reaction is selected from sodium or potassium alcoholate or sodium or potassium hydroxide, carbonate, bicarbonate, sodium hydride, etc. Temperature of the reaction is in the range of 25-120°C.
- compound of formula VI is prepared from 2-picolinic acid of formula HL 2-Picolinic acid of formula III is reacted with thionyl chloride in the presence of catalytic amount of DMF and in a solvent medium at 60-80°C to get the acid chloride of formula IV.
- the acid chloride of formula IV thus obtained is reacted in situ with an alcohol to get the corresponding ester derivative of formula XI.
- the ester derivative of formula XI is reacted with methanolic methylamine to get the corresponding amide of formula VI.
- sorafenib base is produced in more than 80% yield with more than 99% purity by HPLC.
- Present invention provides novel compound of formula X.
- the crude compound (4.7 g) was dissolved in 10 ml of IPA and added 1.9 g of p- toluenesulfonic acid.
- the reaction mass was stirred at RT for 15 h and filtered.
- the wet solid was washed with 10 ml of IPA and dried at 50-60°C to get 3.4 g of title compound as off-white crystalline solid.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A novel and improved process for the preparation of sorafenib (4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide) of formula (I) involving a novel intermediate of formula (II) as key intermediate is disclosed. Sorafenib tosylate, available in the market as Nexavar is a multiple kinase inhibitor targeting both RAF kinase and receptor tyrosine kinase that promote angiogenesis.
Description
NOVEL PROCESS FOR THE PREPARATION OF SORAFENIB
FIELD OF INVENTION
Present invention relates to a novel and improved process for the preparation of sorafenib (4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide) of formula I involving a novel intermediate of formula II. Compound of formula II is a key intermediate used in the synthesis of sorafenib of formula I.
I Il
Sorafenib is a multiple kinase inhibitor targeting both RAF kinase and receptor tyrosine kinase that promote angiogenesis. Clinical development of sorafenib is reviewed in Expert Opin. Pharmacother.., 7, 453-461 (2006). Sorafenib is available in the market as tosylate salt under the brand name Nexavar.
BACKGROUND OF INVENTION Sorafenib and its pharmaceutically acceptable salts and solvates are reported for the first time in WO0041698 (corresponding US 03139605) by Bayer. In the literature only one route is disclosed for the preparation of sorafenib. According to this route (Scheme-I), picolinic acid of formula III is reacted with thionyl chloride to give the 4-chloro derivative which on treatment
VII
Scheme-I with methanol gave the methyl ester of formula V. Compound of formula V is reacted with methylamine to get the corresponding amide of formula VL Compound of formula VI is reacted with 4-aminophenol to get the ether derivative of formula VII. Compound of formula VII is reacted with 4-chloro-3-trifluoromethylphenylisocyante to get sorafenib base of formula I. Overall yield of sorafenib in this process is 10% from commercially available 2-picolinic acid of formula II. Main drawback in this process is chromatographic purification of the intermediates involved in the process and low yield at every step.
Donald Bankston's (Org. Proc. Res. Dev., 2002, 6, 777-781) development of an improved synthesis of the above basic route afforded sorafenib in an overall yield of 63% without involving any chromatographic purification. Process improvements like reduction of time in thionyl chloride reaction; avoid the isolation of intermediates of formulae IV and V5 reduction of base quantity in p-aminophenol reaction, etc lead to the simplification of process and improvement in yield of final compound of formula I.
Above mentioned improvements could not reduce the number of steps in making sorafenib of formula-I. In the first step all the raw materials are charged and heated to target temperature (72°C). Such a process on commercial scale will lead to sudden evolution of gas emissions such as sulfur dioxide and hydrogen chloride. Also, in the
aminophenol reaction two bases (potassium carbonate and potassium t-butoxide) were used in large excess to accomplish the required transformation.
A scalable process for the preparation of sorafenib is disclosed in WO2006034796. In this process also above mentioned chemistry is used in making sorafenib of formula I. In the first step, catalytic quantity. of DMF used in the prior art process is replaced with reagents like hydrogen bromide, thionyl bromide and sodium bromide. Yield of required product remained same without any advantages from newly introduced corrosive reagents. Process improvements like change of solvents, reagents, etc were applied in subsequent steps making the process scalable. Overall yield of sorafenib is increased to 74% from the prior art 63% yield. Purity of sorafenib is only 95% and was obtained as light brown colored solid.
Main drawbacks in this process are production of low quality sorafenib and requirement of corrosive and difficult to handle reagents such as thionyl bromide and hydrogen bromide. Also, there is no major improvement in the yield of sorafenib.
Keeping in view of the difficulties in commercialization of the above-mentioned process for the preparation of sorafenib, we aimed to develop a simple and economical process for commercial production of sorafenib.
We observed that a promising approach for a process for the preparation of sorafenib would be to (a) avoid the usage of costly and difficult to handle reagents like hydrogen bromide and thionyl bromide used in the first step of the process.
Accordingly, the main objective of the present invention is to provide an improved process for the preparation of sorafenib, which is commercially applicable.
Another objective of the present invention is to provide an improved process for the preparation of sorafenib avoiding the linear route with a shorter and convergent route.
Still another objective of the present invention is to provide an improved process for the preparation of sorafenib with >99% quality.
PROCESS OF THE PRESENT INVENTION The present invention has been developed based on our finding that the reaction of 4- chloro-3-trifluoromethylphenylisocyanate of formula VIII with of 4-aminophenol of formula IX produces exclusively the novel urea derivative (N-(4-chloro-3- trifluoromethylphenyl)(4-hydroxyphenyl)-carboxamide) of formula X without the formation of any carbamate (N-(4-chloro-3-trifluoromethyl-phenyl)(4- aminophenyl)carboxamide) derivative (Scheme-II). Reaction of this novel urea derivative with 4-chloro-N-methylpyridine-2-carboximde of formula VI in the presence of a base yielded the required sorafenib in high yield and purity.
VIII IX X
Xl
R = C1-C8 alkyl,
C3-C8 cycloalkyl, aryl, aralkyl
Scheme-II
Alternatively, compound of formula X is reacted with ester derivative of formula XI in the presence of a base in a solvent medium to get novel esters of formula XII. Reaction of ester compound of formula XII with methylamine yielded the required sorafenib of formula I.
Accordingly, process of the present invention provides a novel process for the preparation of sorafenib of formula I,
which comprises:
(i) Reaction of the isocyante of formula VIII,
VIII with 4-aminophenol of formula IX,
X (ii) Reaction of compound of formula X with compound of formula XIII,
XIII wherein X = NHCH3, 0-C1-C8 alkyl, O-C3-C8-cycloalkyl, O-aryl, O-alkylaryl or its acid addition salt in an organic solvent medium in the presence of a base at 25-120°C to get the compound of formula XIV5
XIV wherein X = as defined above
(iii) Reaction of compound of formula XIV (when X is not a methylamino group) with aqueous methylamine to get sorafenib of formula I
In a preferred embodiment of the present invention the isocyanate of formula VIII is reacted with 4-aminophenol of formula IX or its acid addition salt in the presence of a solvent, inert towards isocyante at a temperature above 15°C. hi case of acid addition salt of 4-aminophenol a neutralizing agent such as triethylamine, inert towards isocyanate is used to liberate the base.
In a preferred embodiment of the present invention compound of formula X is reacted with compound of formula XI in a solvent such as DMF, DMAc, DMSO, THF, dioxane, toluene, cyclohexane, acetonitrile. Base used in the reaction is selected from sodium or potassium alcoholate or sodium or potassium hydroxide, carbonate, bicarbonate, sodium hydride, etc. Temperature of the reaction is in the range of 25-120°C.
hi a preferred embodiment of the present invention compound of formula VI is prepared from 2-picolinic acid of formula HL 2-Picolinic acid of formula III is reacted with thionyl chloride in the presence of catalytic amount of DMF and in a solvent medium at 60-80°C to get the acid chloride of formula IV. The acid chloride of formula IV thus obtained is reacted in situ with an alcohol to get the corresponding ester derivative of formula XI. The ester derivative of formula XI is reacted with methanolic methylamine to get the corresponding amide of formula VI.
According to the present invention sorafenib base is produced in more than 80% yield with more than 99% purity by HPLC.
Present invention provides novel compound of formula X.
The details of the invention are given in the Examples given below which are provided to illustrate the invention only and therefore should not be construed to limit the scope of the present invention.
EXAMPLES
Example 1
Preparation of l-(4-chloro-3-(trifluoromethyl)phenyI)-3-(4-hydroxyphenyl)urea Into a 250 ml, four-necked RB flask was charged 1O g of 4-aminophenol and 100 ml of toluene. A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyante (20.4 g) in toluene (50 ml) was added to the reaction mass at 25-300C. The reaction mass was stirred at room temperature for 16 h. The reaction mass was filtered and washed the. solid with 50 ml of toluene. The wet material was dried in the oven at 50-60°C to get 29.8 g of title compound as white solid. M.P. is 218-222°C. IR (KBr): 3306, 1673, 1625, 1590, 1560, 1517, 1482, 1435, 1404, 1328, 1261, 1182, 1160, 1146, 1125, 1095, 1032, 884, 849, 832, 812, 766, 746, 724, 683, 539 and 434 cm"1.
Example 2 Preparation of sorafenib tosylate
Into a 100 ml, three-necked RB flask was charged 2.0 g of l-(4-chloro-3- (trifluoromethyl)-phenyl)-3-(4-hydroxyphenyl)urea and 10 ml of DMF. Potassium tert- butoxide (2.3 g) was added to the reaction mass and stirred for 45 min at RT. 4-Chlro-N- methylpicolinamide (1.14 g) and potassium carbonate (0.42 g) were added to the reaction mass and heated to 80°C. The reaction mass was maintained at 80-85°C for 8 h and cooled to 30°C. The reaction mass was poured into water and extracted with ethyl acetate. Ethyl acetate layer was washed with water, brine and dried over sodium sulphate. Solvent was distilled of under reduced pressure.
The crude compound (4.7 g) was dissolved in 10 ml of IPA and added 1.9 g of p- toluenesulfonic acid. The reaction mass was stirred at RT for 15 h and filtered. The wet
solid was washed with 10 ml of IPA and dried at 50-60°C to get 3.4 g of title compound as off-white crystalline solid.
Advantages of present invention: 1. Present process is shorter and simpler.
2. Present process produces sόrafenib in high yield (>80%) and high purity (>99%).
3. Present process uses a novel intermediate of formula-X.
4. Present process is economically and commercially viable.
Claims
1. A novel process for the preparation of sorafenib of formula I,
I which comprises: (i) Reaction of the isocyante of formula VIII,
VIII with 4-aminophenol of formula IX,
IX or its acid addition salt in the presence of a solvent, inert towards isocyante at a temperature above 15°C to get the compound of formula X,
X
(ϋ) Reaction of compound of formula X with compound of formula XIII,
XIIl wherein X = NHCH3, 0-C1-C8 alkyl, O-C3-C8-cycloalkyl, O-aryl, O-alkylaryl or its acid addition salt in an organic solvent medium in the presence of a base at 25-120°C to get the compound of formula XIV,
XIV wherein X = as defined above (iii) Reaction of compound of formula XIV (when X is not a methylamino group) with aqueous methylamine to get sorafenib of formula I
2. The process according to claim 1 wherein the inert solvent used in step (i) is selected from methylene chloride, chloroform, toluene, cyclohexane, heptane, acetonitrile, acetone, terahydrofuran, preferably methylene chloride, toluene or acetone.
3. The process according to claims 1 and 2 wherein the solvent used in step (ii) is selected from DMF, DMAc, DMSO, THF5 dioxane, toluene, cyclohexane, acetonitrile, preferably DMF or toluene or a mixture of both.
4. The process according to claims 1-3 wherein the base used in step (ii) is selected from sodium or potassium alcoholate, sodium or potassium hydroxide, carbonate, bicarbonate, sodium hydride, preferably sodium or potassium alcoholate with or without sodium or potassium carbonate.
5. The process according to claims 1-4 wherein the preferred temperature of reaction in step (ii) is 40-80°C.
6. The process according to claims 1-5 wherein the amount of methylamine used in step
(iii) is 1-6 molar equivalents, preferably 1-4 molar equivalents.
7. Pharmaceutical compositions comprising sorafenib prepared according to the present invention or its salts for the treatment of RAF kinase and receptor tyrosine kinase promoted angiogenesis.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2372CH2007 | 2007-10-22 | ||
| IN2372/CHE/2007 | 2007-10-22 |
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| WO2009054004A3 WO2009054004A3 (en) | 2009-07-02 |
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Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7838541B2 (en) | 2002-02-11 | 2010-11-23 | Bayer Healthcare, Llc | Aryl ureas with angiogenesis inhibiting activity |
| US7897623B2 (en) | 1999-01-13 | 2011-03-01 | Bayer Healthcare Llc | ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors |
| WO2011036647A1 (en) | 2009-09-24 | 2011-03-31 | Ranbaxy Laboratories Limited | Process for the preparation of sorafenib tosylate |
| WO2011036648A1 (en) | 2009-09-24 | 2011-03-31 | Ranbaxy Laboratories Limited | Polymorphs of sorafenib acid addition salts |
| WO2011058522A1 (en) | 2009-11-12 | 2011-05-19 | Ranbaxy Laboratories Limited | Sorafenib ethylsulfonate salt, process for preparation and use |
| 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 |
| WO2011113367A1 (en) * | 2010-03-18 | 2011-09-22 | 苏州泽璟生物制药有限公司 | Method and process for preparation and production of deuterated ω-diphenylurea |
| US8124630B2 (en) | 1999-01-13 | 2012-02-28 | Bayer Healthcare Llc | ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| CN103408488A (en) * | 2013-08-13 | 2013-11-27 | 张家港威胜生物医药有限公司 | Optimal synthetic method of sorafenib |
| US8796250B2 (en) | 2003-05-20 | 2014-08-05 | Bayer Healthcare Llc | Diaryl ureas for diseases mediated by PDGFR |
| CN104177292A (en) * | 2014-08-08 | 2014-12-03 | 亿腾药业（泰州）有限公司 | Method for industrial production of sorafenib tosylate polymorphic form I |
| 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 |
| CN104761492A (en) * | 2014-01-03 | 2015-07-08 | 正大天晴药业集团股份有限公司 | Crystal form of sorafenib tosylate, and preparation method thereof |
| CN105399668A (en) * | 2015-12-29 | 2016-03-16 | 开封制药(集团)有限公司 | Method for preparing sorafenib through one-pot process |
| CN105481764A (en) * | 2014-09-16 | 2016-04-13 | 重庆圣华曦药业股份有限公司 | Preparation method of sorafenib p-toluenesulfonate |
| CN105801475A (en) * | 2016-04-25 | 2016-07-27 | 华润双鹤利民药业（济南）有限公司 | Method for preparing sorafenib tosylate |
| CN109796400A (en) * | 2017-11-16 | 2019-05-24 | 四川科伦药物研究院有限公司 | A kind of toluenesulfonic acid Sorafenib crystal form and preparation method thereof |
| WO2020160453A1 (en) * | 2019-01-31 | 2020-08-06 | Ionis Pharmaceuticals, Inc. | Modulators of yap1 expression |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0848078A (en) * | 1994-08-05 | 1996-02-20 | Nippon Paper Ind Co Ltd | Heat-sensitive recorder |
| WO2000041698A1 (en) * | 1999-01-13 | 2000-07-20 | Bayer Corporation | φ-CARBOXY ARYL SUBSTITUTED DIPHENYL UREAS AS p38 KINASE INHIBITORS |
| WO2000042012A1 (en) * | 1999-01-13 | 2000-07-20 | Bayer Corporation | φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS |
| WO2003068228A1 (en) * | 2002-02-11 | 2003-08-21 | Bayer Pharmaceuticals Corporation | Aryl ureas with angiogenesis inhibiting activity |
| 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 |
| EP1683785A1 (en) * | 2003-11-11 | 2006-07-26 | Eisai Co., Ltd. | Urea derivative and process for producing the same |
-
2008
- 2008-10-22 WO PCT/IN2008/000698 patent/WO2009054004A2/en active Application Filing
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0848078A (en) * | 1994-08-05 | 1996-02-20 | Nippon Paper Ind Co Ltd | Heat-sensitive recorder |
| WO2000041698A1 (en) * | 1999-01-13 | 2000-07-20 | Bayer Corporation | φ-CARBOXY ARYL SUBSTITUTED DIPHENYL UREAS AS p38 KINASE INHIBITORS |
| WO2000042012A1 (en) * | 1999-01-13 | 2000-07-20 | Bayer Corporation | φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS |
| WO2003068228A1 (en) * | 2002-02-11 | 2003-08-21 | Bayer Pharmaceuticals Corporation | Aryl ureas with angiogenesis inhibiting activity |
| EP1683785A1 (en) * | 2003-11-11 | 2006-07-26 | Eisai Co., Ltd. | Urea derivative and process for producing the same |
| 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 |
|---|
| D. BANKSTON 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, 2002, pages 777-781, XP002523918 cited in the application * |
| PAN W ET AL: "Pyrimido-oxazepine as a versatile template for the development of inhibitors of specific kinases" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 15, no. 24, 15 December 2005 (2005-12-15), pages 5474-5477, XP025314229 ISSN: 0960-894X [retrieved on 2005-12-15] * |
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| US8124630B2 (en) | 1999-01-13 | 2012-02-28 | Bayer Healthcare Llc | ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| US7897623B2 (en) | 1999-01-13 | 2011-03-01 | Bayer Healthcare Llc | ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors |
| US8841330B2 (en) | 1999-01-13 | 2014-09-23 | Bayer Healthcare Llc | Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| US8618141B2 (en) | 2002-02-11 | 2013-12-31 | Bayer Healthcare Llc | Aryl ureas with angiogenesis inhibiting activity |
| US7838541B2 (en) | 2002-02-11 | 2010-11-23 | Bayer Healthcare, Llc | Aryl ureas with angiogenesis inhibiting activity |
| US8242147B2 (en) | 2002-02-11 | 2012-08-14 | Bayer Healthcare Llc | Aryl ureas with angiogenisis inhibiting activity |
| US8796250B2 (en) | 2003-05-20 | 2014-08-05 | Bayer Healthcare Llc | Diaryl ureas for diseases mediated by PDGFR |
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| US8609854B2 (en) | 2009-09-24 | 2013-12-17 | Ranbaxy Laboratories Limited | Process for the preparation of sorafenib tosylate |
| US8604208B2 (en) | 2009-09-24 | 2013-12-10 | Ranbaxy Laboratories Limited | Polymorphs of sorafenib acid addition salts |
| WO2011036648A1 (en) | 2009-09-24 | 2011-03-31 | Ranbaxy Laboratories Limited | Polymorphs of sorafenib acid addition salts |
| WO2011058522A1 (en) | 2009-11-12 | 2011-05-19 | Ranbaxy Laboratories Limited | Sorafenib ethylsulfonate salt, process for preparation and use |
| US8552197B2 (en) | 2009-11-12 | 2013-10-08 | Ranbaxy Laboratories Limited | Sorafenib ethylsulfonate salt, process for preparation and use |
| 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 |
| 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 |
| CN102803222A (en) * | 2010-03-18 | 2012-11-28 | 苏州泽璟生物制药有限公司 | Method and process for preparation and production of deuterated omega-diphenylurea |
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| JP2013522243A (en) * | 2010-03-18 | 2013-06-13 | ▲蘇▼州▲澤▼▲ジン▼生物制▲薬▼有限公司 | Methods and processes for the synthesis and production of deuterated ω-diphenylurea |
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| WO2011113367A1 (en) * | 2010-03-18 | 2011-09-22 | 苏州泽璟生物制药有限公司 | Method and process for preparation and production of deuterated ω-diphenylurea |
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| JP2015091845A (en) * | 2010-03-18 | 2015-05-14 | ▲蘇▼州▲澤▼▲ジン▼生物制▲薬▼有限公司 | P-TOLUENESULFONIC ACID SALT(CM4307.TsOH) OF 4-(4-(3-(4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL)UREIDO)-PHENOXY)-N-(1',1',1'-TRIDEUTEROMETHYL)PICOLINAMIDE, METHOD OF PRODUCING CM4307.TsOH AND MEDICAL COMPOSITION CONTAINING CM4307.TsOH |
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| CN105399668A (en) * | 2015-12-29 | 2016-03-16 | 开封制药(集团)有限公司 | Method for preparing sorafenib through one-pot process |
| CN105801475A (en) * | 2016-04-25 | 2016-07-27 | 华润双鹤利民药业（济南）有限公司 | Method for preparing sorafenib tosylate |
| CN105801475B (en) * | 2016-04-25 | 2018-01-12 | 华润双鹤利民药业（济南）有限公司 | A kind of preparation method of Sorafenib Tosylate |
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| CN109796400B (en) * | 2017-11-16 | 2022-07-29 | 四川科伦药物研究院有限公司 | Sorafenib tosylate crystal form and preparation method thereof |
| WO2020160453A1 (en) * | 2019-01-31 | 2020-08-06 | Ionis Pharmaceuticals, Inc. | Modulators of yap1 expression |
| US11214803B2 (en) | 2019-01-31 | 2022-01-04 | Ionis Pharmaceuticals, Inc. | Modulators of YAP1 expression |
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