[go: up one dir, main page]

WO2015075749A1 - Nouveaux procédés de préparation de vemurafenib - Google Patents

Nouveaux procédés de préparation de vemurafenib Download PDF

Info

Publication number
WO2015075749A1
WO2015075749A1 PCT/IN2014/000733 IN2014000733W WO2015075749A1 WO 2015075749 A1 WO2015075749 A1 WO 2015075749A1 IN 2014000733 W IN2014000733 W IN 2014000733W WO 2015075749 A1 WO2015075749 A1 WO 2015075749A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
group
acid
vemurafenib
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.)
Ceased
Application number
PCT/IN2014/000733
Other languages
English (en)
Inventor
Satyanarayana Chava
Seeta Rama Anjaneyulu GORANTLA
Venkata Sunil Kumar Indukuri
Venkata Rama Krishna Murthy MOTURU
Srivardhana Rao JAMJANAM
Anil Kumar Reddy SHAMAKURA
Siva Kumar GUNAPARTHI
Veera Venkata Suresh Kumar NEKKANTI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laurus Labs Pvt Ltd
Original Assignee
Laurus Labs Pvt Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Laurus Labs Pvt Ltd filed Critical Laurus Labs Pvt Ltd
Priority claimed from IN5395CH2013 external-priority patent/IN2013CH05395A/en
Publication of WO2015075749A1 publication Critical patent/WO2015075749A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention generally relates to novel processes for the preparation of Vemurafenib or a pharmaceutically acceptable salt thereof using novel intermediates.
  • Vemurafenib also known as propane- 1 -sulfonic acid ⁇ 3-[-(4-chlorophenyl)-lH- pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4difluoro-phenyl ⁇ -amide, is represented by the following structure of Formula I:
  • Vemurafenib is marketed by Hoffmann La Roche under the trade name ZELBORAF is a kinase inhibitor and indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.
  • U.S. Patent No. 7,504,509 (“the '509 patent”), 7,863,288 (“the '288 patent”) and 8,143,271 (“the '271 patent”) discloses a variety of pyrrolo-pyridine and their derivatives such as vemurafenib.
  • the '288 patent discloses a process for preparation of vemurafenib by condensation of 5-(4-chloro-phenyl)-azaindole and (2,4- difluoro-3-formyl-phenyl)-amide in presence of potassium hydroxide and methanol.
  • the process disclosed * in the '288 patent is schematically represented as follows:
  • the disadvantage associated with the '288 patent disclosed process involves formation of substantial amounts of biphenyl impurity of Formula A, which is formed due to use of acetonitrile as solvent for coupling of 5-bromo- azaindole and p-chlorophenyl boronic acid.
  • Use of acetonitrile as solvent in this step requires higher temperature and extended time to complete reaction leads to formation of substantial amounts of biphenyl impurity of Formula A.
  • the biphenyl impurity of Formula A which is further proceeded to form compound of Formula B as impurity in the final vemurafenib, which is very difficult to remove from the final product and extensive multiple purification procedures are required to remove the same from the final API.
  • the '288 patent disclosed process involves tedious chromatographic purifications makes the process not viable for large scale manufacturing.
  • U.S. Patent No. 8,329,724 discloses a process for the preparation of vemurafenib by acylation of 5-bromo-7-azaindole with 2,6-difluoro-3- [(propylsulfonyl)amino]benzoyl chloride in presence of aluminium trichloride, in a solvent like methylene chloride, the obtained azaindole intermediate amine was protected with 2,6-dichloro benzoyl chloride.
  • the obtained protected compound was subjected to Suzuki-coupling in presence of 4-chlorophenyl boronic acid to obtain amine protected vemurafenib, finally deprotecting the obtained compound in presence of ammonia to obtain vemurafenib.
  • the process disclosed in the '724 patent is schematically represented as follows:
  • U.S. Patent No. 8,779,150 discloses a process for the preparation of vemurafenib by involving azaindole cyclisation.
  • the process disclosed in the ⁇ 50 application is schematically represented as follows:
  • Patent Publication No. WO2012/109075 discloses a process for preparation of vemurafenib analogous.
  • the process disclosed in the ⁇ 75 publication is schematically represented as follows:
  • Patent Publication No. WO 2013/181415 discloses a process for preparation of vemurafenib.
  • the process disclosed in the '415 publication is schematically represented as follows:
  • Jason R Buck et al discloses a process for preparation of vemurafenib in Tetrahedron Letters 53 (2012) 4161-4165 & Tetrahedron Letters 55 (2014) 169-173 by rapid microwave-assisted organic synthesis.
  • the process disclosed by Jason R Buck et al is schematically represented as follows:
  • the process disclosed by Jason R Buck et al includes all reaction steps are carried out by microwave-assisted organic synthesis, which is not suitable for large scale production.
  • present inventors focused research to simplify the process for the preparation of vemurafenib with fewer steps, greater yield, and higher purity by using novel intermediates to obviate the problems associated with the reported processes.
  • the present invention provides novel processes for the preparation of vemurafenib using novel intermediates.
  • the present invention provides a novel process for the preparation of vemurafenib of Formula I or a pharmaceutically acceptable salt thereof:
  • the present invention provides a novel process for the preparation of vemurafenib or a pharmaceutically acceptable salt thereof, comprising:
  • the present invention provides a novel process for the preparation of vemurafenib or a pharmaceutically acceptable salt thereof, comprising:
  • the present invention provides a novel process for the preparation of vemurafenib or a pharmaceutically acceptable salt thereof, comprising:
  • the present invention provides a novel process for the preparation of vemurafenib or a pharmaceutically acceptable salt thereof of Formula I:
  • the present invention provides a compound of Formula II or a pharmaceutically acceptable salt thereof.
  • R] and R 2 independently represents an alkyl, or R ⁇ and R 2 taken together form an optionally substituted alkylene ring.
  • the present invention provides a compound of Formula II or a pharmaceutically acceptable salt thereof.
  • Rt and R 2 independently represents an alkyl; or Rt and R 2 taken together form an optionally substituted alkylene ring; wherein the alkyl is selected from the group consisting of methyl, ethyl, propyl, butyl and the like; alkylene is selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene and the like.
  • the present invention provides a compound of Formula Ila or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of Formula lib or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of Formula III or a pharmaceutically acceptable salt thereof.
  • Ri and R 2 independently represents an alkyl, or Ri and R 2 taken together form an optionally substituted alkylene ring.
  • the present invention provides a compound of Formula III or a pharmaceutically acceptable salt thereof.
  • and R 2 independently represents an alkyl; or Ri and R 2 taken together form an optionally substituted alkylene ring; wherein the alkyl is selected from the group consisting of methyl, ethyl, propyl, butyl and the like; alkylene is selected from the group consisting of methylene, ethylene, propylene, butylene. pentylene and the like.
  • the present invention provides a compound of Formula Ilia or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of Formula Illb or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of Formula V; wherein
  • R 2 taken together form an optiona y su st tute a y ene ng.
  • the present invention provides a compound of Formula V or a pharmaceutically acceptable salt thereof;
  • R ⁇ and R 2 independently represents an alkyl; or R
  • the present invention provides a compound of Formula Va or a pharmaceutically acceptable salt thereof;
  • the present invention provides a compound of Formula Vb or a pharmaceutically acceptable salt thereof;
  • the present invention provides a process for preparation of vemurafenib of Formula I or a pharmaceutically acceptable salt thereof, comprising:
  • Formula VII Formula VIII Formula EX b) converting the compound of Formula IX in to vemurafenib or a pharmaceutically acceptable salt thereof.
  • the present invention provides a process for preparation of vemurafenib of Formula I or a pharmaceutically acceptable salt thereof, comprising:
  • the present invention provides a process for purification of compound of Formula IX, comprising:
  • the present invention provides a process for the preparation of vemurafenib of Formula I or a pharmaceutically acceptable salt thereof, comprising:
  • the present invention provides a process for the preparation of vemurafenib of Formula I or a pharmaceutically acceptable salt thereof; comprising:
  • the present invention provides a compound of Formula IX having less than 0.02% as measured by HPLC of Formula A:
  • the present invention provides vemurafenib having less than 0.02% as measured by HPLC each of compound of Formula A or Formula B:
  • the present invention provides a novel process for the preparation of vemurafenib or a pharmaceutically acceptable salt thereof of Formula I: comprising:
  • the present invention provides a process for the preparation of a compo in 'X' represents halo
  • the present invention provides a novel process for the preparation of vemurafenib or a pharmaceutically acceptable salt thereof of Formula I: comprising:
  • Formula XIII Formula VII Formula XIV b) nitro reduction of the compound of Formula XIV with a suitable reducing agent to obtain a compound of Formula XI, wherein 'X' represents halo;
  • the present invention provides a novel process for the preparation of vemurafenib or a pharmaceutically acceptable salt thereof of Formula I: comprising: reacting a compound of Formula XII with a compound of Formula IV, wherein 'X' represents suitable leaving group; in presence of a base to obtain vemurafenib.
  • the present invention provides a compound of Formula XII or a pharmaceutically acceptable salt thereof.
  • the present invention provides a process for the preparation of compound of Formula XII or a pharmaceutically acceptable salt thereof:
  • the present invention provides a process for purification of vemurafenib or a pharmaceutically acceptable salt thereof, comprising:
  • the present invention provides a pharmaceutical composition, comprising vemurafenib or a pharmaceutically acceptable salt thereof prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
  • the present invention provides novel processes for the preparation of vemurafenib using novel intermediates.
  • the present invention provides a novel process for the preparation of vemurafenib of Formula I or a pharmaceutically acceptable salt thereof:
  • alkyl used herein the specification represents Ci to C 5 alkyl and is selected from but not limited to methyl, ethyl, propyl, isopropyl, butyl and the like.
  • alkylene ring used herein the specification represents methylene, ethylene, propylene, butylene, pentylene and the like, optionally substituted with Ci to C 5 alkyl.
  • suitable leaving group used herein the specification represents a halo group such as CI, Br, I; OTf (inflate); OTs (tosylate) and the like.
  • 2,6-difluoro-3-nitro benzaldehyde, 5-halo7-azaindole of Formula VII are known in the art and can be prepared by any known method, for example 2,6-difluoro-3-nitro benzaldehyde may be synthesized as disclosed in PCT Publication No. 2010/003025, compound of Formula VII may be synthesized as disclosed in Heterocycles vol. 50, nb. 2, (1999), page 1065 - 1080.
  • the step a) of reacting 2,6-difluoro-3-nitro benzaldehyde with a suitable protecting group is carried out in presence of suitable dehydrating agent to obtain a compound of Formula II; wherein Ri and R 2 independently represents an alkyl as defined as above; preferably methyl, or Ri and R 2 taken together form an optionally substituted alkylene ring as defined as above, preferably ethylene ring.
  • the suitable protecting group includes but is not limited to trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, tributyl orthoformate, tripentyl orthoformate, methylene glycol, ethylene glycol, propylene glycol, butylene glycol, pentylene glycol and the like; preferably trimethyl orthoformate or ethylene glycol.
  • the suitable dehydrating agent includes but is not limited to p-toluenesulfonic acid (PTSA), camphorsulfonic acid (CSA), pyridinium p-toluenesulfonate (PPTS), sulfonic acid exchange resins (Amberlyst, Dowex), sulfuric acid, nitric acid and the like and mixtures thereof; preferably p-toluenesulfonic acid or sulfuric acid.
  • PTSA p-toluenesulfonic acid
  • CSA camphorsulfonic acid
  • PPTS pyridinium p-toluenesulfonate
  • sulfonic acid exchange resins Amberlyst, Dowex
  • the reaction of 2,6-difluoro-3-nitro benzaldehyde with a suitable protecting group and a dehydrating agent may be carried out in a suitable solvent.
  • the suitable solvent includes but is not limited to alcohols, ethers, esters, halogenated solvents, aromatic hydrocarbons, cyclic hydrocarbons, amides, nitriles, water and mixtures thereof.
  • alcohols include, but are not limited to methanol, ethanol, propanol, isopropanol and the like;
  • Ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1 ,4-dioxane and the like;
  • esters include, but are not limited to methyl acetate, ethyl acetate, isopropyl acetate and the like;
  • halogenated solvents include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like;
  • aromatic hydrocarbons include, but are not limited to toluene, xylene and the like;
  • cyclic hydrocarbons include, but are not limited to hexane, cyclohexane, heptane and the like;
  • amides include, but are not limited to dimethyl formamide, dimethylsulfoxide,
  • reaction of 2,6-difluoro-3-nitro benzaldehyde with a suitable protecting group and a dehydrating agent is carried out at a temperature of about 25°C to reflux temperature; preferably at about 60°C to about 1 10°C.
  • the step b) of nitro reduction process of the aforementioned process involves reduction of the nitro group in the compound of Formula II; wherein R ⁇ and R 2 are defined as above; in presence of a suitable reducing agent in an organic solvent to obtain a compound of Formula III, wherein R ⁇ and R 2 are defined as above.
  • the suitable reducing agent used herein is selected from the group consisting of Palladium on carbon, Raney nickel, Platinum oxide, Sodium hydrosulfite, Zinc and the like; preferably Palladium on carbon.
  • the organic solvent for nitro reduction is used herein is selected from the group consisting of alcohols, ethers, aromatic hydrocarbons and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, propanol, isopropanol and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1 ,4-dioxane and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixtures thereof; preferably methanol, ethanol, tetrahydrofuran and mixtures thereof.
  • the nitro reduction is carried out at a temperature of about 25°C to about reflux. After completion of the reaction, the reaction mass is subjected to filtration and the resultant reaction mass may be concentrated under vacuum to obtain a compound of Formula III as residue; wherein R ⁇ and R 2 are defined as above.
  • step c) of the aforementioned process involves reaction of compound of Formula III; wherein Ri and R 2 are defined as above; with a compound of Formula IV; wherein 'X' represents halo; in presence of a base to obtain a compound of Formula V; wherein Ri and R 2 are defined as above.
  • the base used herein for the reaction of compound of Formula III and compound of Formula IV; wherein Ri and R 2 are defined as above; include but is not limited to inorganic bases selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; and organic bases selected from the group consisting of triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N- methyl morpholine, piperidine, pyridine and the like and mixtures thereof; preferably pyridine, triethylamine, potassium carbonate and mixtures
  • the reaction of compound of Formula III and Formula IV; wherein Ri and R 2 are defined as above; may be carried out in a suitable solvent.
  • suitable solvent include but is not limited to esters, ketones, amides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons and mixtures thereof.
  • the esters include, but are not limited to methyl acetate, ethyl acetate, isopropyl acetate and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1 ,4-dioxane and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform, carbon tetrachloride and the like; aromatic hydrocarbons include, but are not limited to toluen
  • the reaction of compound of Formula III and Formula IV; wherein Ri and R 2 are defined as above; is carried out at a temperature of about 0°C to reflux temperature; preferably at about 25°C to about 35°C.
  • the step d) of deprotecting the compound of Formula V; wherein Ri and R 2 are defined as above; is carried out in presence of a suitable deprotecting agent to obtain a compound of Formula VI.
  • the suitable deprotecting agent used herein is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoro acetic acid, trichloro acetic acid, methane sulfonic acid and the like and mixture thereof; preferably hydrochloric acid.
  • the source of acid may be in the form of an aqueous, anhydrous or gas form, for example aqueous hydrochloric acid or solvent containing hydrochloric acid or hydrochloric acid gas.
  • the deprotection of compound of Formula V; wherein Ri and R 2 are defined as above; may be carried out in a suitable organic solvent.
  • the suitable organic solvent includes but is not limited to esters, ketones, nitriles, ethers, halogenated hydrocarbons and mixtures thereof.
  • the esters include, but are not limited to methyl acetate, ethyl acetate, isopropyl acetate and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1 ,4- dioxane and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform, carbon tetrachloride and the like; preferably tetrahydrofuran, acetonitrile, methylene chloride or mixture thereof.
  • the deprotection of Formula V is carried out at a temperature of about 25°C to reflux temperature; preferably at about 60°C to about 70°C.
  • the compound of Formula VI thus obtained may be converted in to vemurafenib of Formula I by reacting the compound of Formula VI with a compound of Formula IX in presence of a suitable base to obtain a compound of Formula X; and converting the compound of Formula X into vemurafenib or a pharmaceutically acceptable salt thereof.
  • Formula VI Formula IX Formula X
  • the step of reacting the compound of Formula VI with a compound of Formula ⁇ can be carried out according to processes known in the art, for example the reaction is carried out in presence of a suitable base in a suitable solvent at a temperature of about 25°C to reflux temperature to obtain a compound of Formula X, which is then converted into vemurafenib as procedure known in the art.
  • the present invention provides a process for the preparation of vemurafenib of Formula I or a pharmaceutically acceptable salt thereof, comprising: a) reacting a compound of Formula VI with a compound of Formula IX in presence of a suitable base in a non-alcoholic solvent to obtain a compound of Formula X; and
  • the '288 patent discloses a process for preparation of vemurafenib, which involves formation of methoxy intermediate, which is formed due to the presence of alcoholic solvent such as methanol in the reaction of compound of Formula VI and Formula IX.
  • the methoxy compound is converted in to vemurafenib through deprotection of methyl moiety.
  • the additional process steps such as formation of methoxy compound and, then deprotection to remove methyl moiety, which process involves prolonged period of reaction time of about 72 hours for formation of methoxy compound and about 12 hours for deprotection reaction; which process leads to an increase in the manufacturing cycle time and decrease in the product yield and quality.
  • non alcoholic solvent in the reaction of compound of Formula VI with a compound of Formula IX avoids the formation of such alkyl derivatives, which eliminates the additional process steps to remove alkyl moiety, thereby the process substantially decreases the reaction time cycle and improves the product yield.
  • the non-alcoholic solvent used herein in the reaction of compound of Formula VI and compound of Formula IX includes but is not limited to ethers, amides, nitriles, water and mixtures thereof.
  • Ethers include, but are not limited to tetrahydrofuran, 1 ,4-dioxane and the like; amides such as dimethyl formamide, dimethylsulfoxide, dimethyl acetamide, N- methyl pyrrolidinone and the like; nitriles such as acetonitrile, propionitrile and the like and mixtures thereof; preferably tetrahydrofuran, dimethyl formamide, acetonitrile, water or mixture thereof.
  • the suitable base used herein for the reaction of compound of Formula VI and compound of Formula IX include but is not limited to inorganic bases selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; and organic bases selected from the group consisting of triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and the like; guanidine bases such as 1 ,1 ,3,3-Tetramethylguanidine (TMG) and the like and mixtures thereof
  • reaction of compound of Formula VI and compound of Formula FX is carried out at a temperature of about 25°C to reflux temperature; preferably at about 25°C to about 35°C.
  • the compound of Formula X thus obtained by the processes described as above may be optionally purified and converting it into vemurafenib by the processes known in the art.
  • the purification step of compound of Formula X may be carried out by dissolving it in a suitable solvent.
  • the suitable solvent may be selected from the group comprising halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform, carbon tetrachloride and the like; ethers such as methyl tertiary butyl ether, diethyl ether, diisopropyl ether and the like and mixtures thereof; preferably methylene chloride.
  • Further step of heating to obtain a solution at a temperature of from about ambient temperature to about reflux temperature; then, the reaction solution may be cooled at a temperature from about 20°C or less such that the compound of Formula X can be isolated by conventional techniques.
  • the conversion of the compound of Formula X in to vemurafenib is carried out by the process known in the art for e.g., as process described in the '288 patent or in presence of suitable oxidising agent such as 2,3-Dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), potassium dichromate, pyridinium chloro chromate, hydrogen peroxide and in a suitable solvent to obtain vemurafenib.
  • suitable oxidising agent such as 2,3-Dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), potassium dichromate, pyridinium chloro chromate, hydrogen peroxide and in a suitable solvent to obtain vemurafenib.
  • the present invention provides a process for the preparation of vemurafenib of Formula I or a pharmaceutically acceptable salt thereof, comprising: a) reacting a compound of Formula VII; wherein 'X' represents halo with 4- chlorophenyl boronic acid of Formula VIII in presence of a suitable palladium catalyst and a base in a suitable solvent selected from the group consisting of ketones, ethers, amides, aromatic hydrocarbons, water or mixture thereof, to obtain a compound of Formula IX; and
  • Formula VII Formula VIII Formula IX b) converting the compound of Formula IX in to vemurafenib or a pharmaceutically acceptable salt thereof.
  • the reported literatures for example, the '288 patent discloses preparation of compound of Formula IX by coupling of 5-bromo-azaindole of Formula VII and p-chlorophenyl boronic acid in presence of acetonitrile and water at a temperature of about 170°C for extended periods and silica-gel column purification with ethyl acetate/hexane. This process has certain drawbacks as it involves formation of substantial amounts of biphenyl impurity of Formula A, which is formed due to the presence of acetonitrile as solvent.
  • the compound of Formula IX contains the biphenyl impurity of Formula A as an impurity, which readily produces Formula B as an impurity during the formation of final vemurafenib API.
  • the said impurity of Formula B is very difficult to remove from the vemurafenib product; it requires multiple . purification procedures to remove such impurity, which process is not viable for large scale manufacturing.
  • control of Formula A during the reaction between Formula VII and Formula VIII itself is advantageous.
  • use of other than acetonitrile as reaction solvent during the reaction of Formula VII and Formula VIII substantially reduces the formation of Formula A as an impurity; which eliminates the additional purification steps, thereby the process substantially decreases the reaction time cycle and improves the product yield.
  • halo such as bromo, chloro, or iodo
  • the suitable palladium catalyst used herein is selected from the group consisting of tetrakis (triphenylphosphine) palladium(O), tetrakis(tri(otolyl) phosphine) palladium(O), Pd 2 (dba) 3 , [l , Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)2Cl 2 ), Palladium(II)acetate and the like and mixtures thereof; preferably tetrakis (triphenylphosphine) palladium.
  • the base used herein for the reaction of a compound of Formula VII and a compound of Formula VIII include but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert- tyutoxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; and organic bases such as triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N- methyl morpholine, piperidine, pyridine and the like and their mixtures thereof; preferably sodium methoxide, potassium carbonate, potassium tert-butoxide or sodium tert-butoxide; more preferably
  • the suitable solvent for reaction of a compound of Formula VII and a compound of Formula VIII include but is not limit to ketones, ethers, amides, aromatic hydrocarbons, water and mixtures thereof.
  • the ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like;
  • ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1 ,4-dioxane, 1 ,2-domethoxy ethane, and the like;
  • amides include, but are not limited to dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, N-methyl pyrrohdinone and the like;
  • aromatic hydrocarbons include, but are not limited to toluene, xylene and the like; water and mixture thereof; preferably 1,4
  • the reaction of a compound of Formula VII and a compound of Formula VIII is advantageously carried out at a temperature of about 25°C to reflux temperature; preferably at about 65°C to 95°C, more preferably at about 80°C to 90°C.
  • the obtained reaction mass may be separated off and the obtained product containing organic layer may be cooled to about 0°C to 5°C to precipitate out the compound IX.
  • the present invention provides a compound of Formula IX prepared by the process described as above having a purity of at least about 97%, as measured by HPLC, preferably at least about 98% as measured by HPLC, and more preferably at least about 99.5%, as measured by HPLC; and content of Formula A is less than about 0.1%, as measured by HPLC, more preferably less than about 0.05% as measured by HPLC.
  • compound of Formula FX thus obtained may be purified by treating the compound of Formula IX in a suitable solvent.
  • the present invention provides a process for purification of compound of Formula IX, comprising:
  • the suitable solvent used herein for purification of compound of Formula IX include but is not limited to alcohols, ethers, esters, amides, nitriles, ketones, halogenated hydrocarbons, aromatic hydrocarbons, water and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, isopropanol, n-propanol, t-butanol and the like;
  • ethers include, but are not limited to tetrahydrofuran, methyl tertiary butyl ether, diethyl ether and the like;
  • esters include, but are not limited to methyl acetate, ethyl acetate, isopropyl acetate and the like;
  • amides include, but are not limited to dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide and the like;
  • nitriles include, but are not limited to acetonitrile, propionitrile and the like;
  • the solution may be heated to dissolve the compound of Formula IX.
  • the temperature suitable for dissolving compound of Formula IX depends on the solvent used and .the amount of compound of Formula IX in the solution.
  • the solution is heated at a temperature of at least about 30°C to about reflux; preferably at about 60°C to about 65°C.
  • the resultant reaction solution may be cooled at a temperature from about 20°C or less such that the compound of Formula IX can be isolated by conventional techniques. for example filtration.
  • the temperature during stirring can range from about - 10°C to about +20°C, preferably at about -10 to about + 10°C, more preferably at temperature between 0°C to 5°C.
  • the present invention provides a compound of Formula IX prepared by the purification as described above having a purity of at least about 97%, as measured by HPLC, preferably at least about 98% as measured by HPLC, and more preferably at least about 99.8%, as measured by HPLC; and content of Formula A is less than about 0.05%, as measured by HPLC, more preferably less than about 0.02% as measured by HPLC.
  • the present invention provides a process for the preparation of vemurafenib or a pharmaceutically acceptable salt thereof, comprising providing a compound of Formula IX as obtained by the process described above, as a starting material or as an intermediate by the process known in the art, for example as per the '288 patent, where the purity of the vemurafenib having at least about 98% as measured by HPLC, preferably at least about 99.8% as measured by HPLC and substantially free of impurity of Formula A or Formula B; wherein the word "substantially free” refers to vemurafenib having less than about 0.15% of Formula A or Formula B as measured by HPLC, preferably less than about 0.1% of Formula A or Formula B as measured by HPLC; more preferably less than about 0.05% of Formula A or Formula B as measured by HPLC; still more preferably less than about 0.02% of Formula A or Formula B as measured by HPLC.
  • the present invention provides a compound of Formula IX having less than 0.02% of Formula A:
  • the present invention provides vemurafenib having less than 0.02% each of compound of Formula A or Formula B:
  • the present invention provides a compound of Formula II or a pharmaceutically acceptable salt thereof;
  • Ri and R 2 independently represents an alkyl, or Ri and R 2 taken together form an optionally substituted alkylene ring.
  • the present invention provides a compound of Formula II or a pharmaceutically acceptable salt t
  • R] and R 2 independently represents an alkyl; or R ⁇ and R 2 taken together form an optionally substituted alkylene ring; wherein the alkyl is selected from the group consisting of methyl, ethyl, propyl, butyl and the like; alkylene is selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene and the like.
  • the present invention provides a compound of Formula Ila or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of Formula lib or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of Formula III or a pharmaceutically acceptable salt th
  • R 2 independently represents an alkyl, or Ri and R 2 taken together form an optionally substituted alkylene ring.
  • the present invention provides a compound of Formula III or a pharmaceutically acceptable salt thereof;
  • Ri and R 2 independently represents an alkyl; or Ri and R 2 taken together form an optionally substituted alkylene ring; wherein the alkyl is selected from the group consisting of methyl, ethyl, propyl, butyl and the like; alkylene is selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene and the like.
  • the present invention provides a compound of Formula Ilia or a pharmaceutically acceptable salt thereo
  • the present invention provides a compound of Formula Illb or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of Formula V or a pharmaceutically acceptable salt thereof;
  • Ri and R 2 independently represents an alkyl, or Ri and R 2 taken together form an optionally substituted alkylene ring.
  • the present invention provides a compound of Formula V or a pharmaceutically acceptable salt th
  • Ri and R 2 independently represents an alkyl; or Ri and R 2 taken together form an optionally substituted alkylene ring; wherein the alkyl is selected from the group consisting of methyl, ethyl, propyl, butyl and the like; alkylene is selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene and the like.
  • the present invention provides a compound of Formula Va or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of Formula Vb or a pharmaceutically acceptable salt thereof.
  • the present invention provides a process for the preparation of vemurafenib of Formula I or a pharmaceutically acceptable salt thereof; comprising: a) reacting 2,6-difluoro-3-nitro benzaldehyde with trimethyl orthoformate or ethylene glycol in presence of a dehydrating agent such as PTSA or sulfuric acid to obtain a compound of Formula Ila or Formula lib;
  • the present invention provides a process for purification of vemurafenib or a pharmaceutically acceptable salt thereof, comprising:
  • vemurafenib isolating the vemurafenib.
  • the starting material of vemurafenib may be prepared by the processes of the present invention described above or by the process known in the art can be used for purification process.
  • the step a) process involves providing dissolving or suspending vemurafenib in a suitable water immiscible solvent and water at a temperature of about 25-35°C.
  • the suitable water immiscible solvent used herein for purification of vemurafenib include but is not limited to methyl tertiary butyl ether, diethyl ether, ethyl acetate, methylene chloride, chloroform toluene, xylene and the like and mixtures thereof; preferably methylene chloride, ethyl acetate or toluene.
  • the base used herein for step b) is selected from the group consisting of ammonia, sodium hydroxide, potassium hydroxide and the like; preferably sodium hydroxide.
  • separating the organic and aqueous layers and the aqueous layer may be optionally treated with the water immiscible solvent.
  • the resultant aqueous layer containing product may be treating with an acid to precipitating out the product.
  • the acid may be selected from the group comprising hydrochloric acid, sulfuric acid, acetic acid and the like; preferably hydrochloric acid.
  • the acid may be added at a temperature of less than about 20°C, preferably less than 10°C.
  • the precipitated vemurafenib can be recovered by any conventional techniques known in the art, for example filtration.
  • the temperature during stirring can range from about 0°C to about 15°C, preferably at about 5°C to about 10°C.
  • vemurafenib obtained by the processes described as above, having purity of at least about 98% as measured by HPLC, preferably at least about 99.8% as measured by HPLC and substantially free of impurity of Formula A or Formula B; wherein the word "substantially free” refers to vemurafenib having less than about 0.15% of Formula A or Formula B as measured by HPLC, preferably less than about 0.1% of Formula A or Formula B as measured by HPLC; more preferably less than about 0.05% of Formula A or Formula B as measured by HPLC; still more preferably less than about 0.02% of Formula A or Formula B as measured by HPLC.
  • the pharmaceutical acceptable salts include acid addition salts formed with inorganic acids or with organic acids.
  • the inorganic acids may be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, sulfamic acid, and the like; organic acids may be selected from acetic acid, oxalic acid, fumaric acid, citric acid, succinic acid, tartaric acid, salicylic acid, benzoic acid, glycolic acid, methane sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lactic acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, mandelic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid, chlorogenic acid, caftaric acid, coutaric acid, p-hydroxy benzoic acid, vanillic acid,
  • the present invention provides a novel process for the preparation of vemurafenib or a pharmaceutically acceptable salt thereof of Formula I:
  • Formula XIII Formula VII Formula XIV b) nitro reduction of the compound of Formula XIV with a suitable reducing agent to obtain a compound of Formula XI, wherein 'X' represents halo;
  • the starting material of compound of Formula XIII or a reactive derivative, preferably chloro derivative and Formula XIII are known in the art and can be prepared by any known method, for example starting compound of Formula XIII and Formula VII may be synthesized as disclosed in PCT Publication No. 2012/109075.
  • the reaction of 2,6-difluoro-3-nitrobenzoic acid or a reactive derivative of Formula XIII, preferably its chloro derivative with 5-halo-7-azaindole of Formula VII; wherein 'X' represents halo; preferably bromo is carried out in presence of a Lewis acid catalyst and in a suitable solvent to obtain a compound of Formula XIV, wherein 'X' is bromo.
  • the reactive derivative of 2,6-difluoro-3-nitrobenzoic acid of Formula XIII may be prepared by reacting compound of Formula XIII with source of chlorine like oxalyl chloride or thionyl chloride and in a chlorinated solvent like methylene chloride to obtain acid chloride of compound of Formula XIII a.
  • the suitable Lewis acid catalyst for the reaction of compound of Formula XIII and Formula VII is selected from the group consisting of aluminum chloride, aluminum bromide, ferric chloride, tin chloride, stannic chloride and the like; preferably aluminum chloride.
  • the compound of Formula XIII and Formula VII may be reacted in a suitable solvent.
  • the suitable solvent includes but is not limited to ethers, halogenated hydrocarbons, aromatic hydrocarbons and mixtures thereof, ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4- dioxane and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform, carbon tetrachloride and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like; preferably methylene chloride.
  • reaction of compound of Formula XIII and Formula VII is carried out at a temperature of about 0°C to about reflux temperature; preferably at about 5°C to about 40°C.
  • the nitro reduction process of the aforementioned process involves reduction of the nitro group in the compound of Formula XIV in presence of a suitable reducing agent and in an organic solvent to obtain a compound of Formula XI, wherein the 'X' is bromo.
  • the suitable reducing agent for nitro reduction is selected from the group consisting of Fe HCl, Fe NRtCl, SnCl 2 and the like; preferably the suitable reducing agent is Fe HCl.
  • the organic solvent for nitro reduction of compound of Formula XIV includes but is not limited to alcohols, ethers, aromatic hydrocarbons and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, propanol, isopropanol and the like;
  • ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1 ,4-dioxane and the like;
  • aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixtures thereof; preferably the solvent mixture for reduction is tetrahydrofuran, ethanol and mixtures thereof.
  • the nitro reduction is carried out at a temperature of about 30°C to about reflux; preferably at about 60°C to about 80°C.
  • the reaction mass is subjected to filtration and the resultant reaction mass may be concentrated under vacuum to obtain residue.
  • the compound of Formula XI, wherein 'X' is bromo is isolated from the residue so obtained by methods known in the art, for example solvent crystallization, solvent slurry and the like.
  • the present invention provides a process for the preparation of vemerafenib of Formula I, comprising reacting a compound of Formula XI, wherein 'X' represents bromo; as obtained by the process described above or may be obtained by any known process, as a starting material or as an intermediate with 4-chlorophenyl boronic acid of Formula VIII in presence of a suitable palladium catalyst and a base to obtain a compound of Formula XII and converting the compound of Formula XII into vemurafenib or a pharmaceutically acceptable salts thereof according step c) and d) of the above.
  • the palladium catalyst for coupling of compound of Formula XI and Compound of Formula VIII include but are not limit to tetrakis (triphenylphosphine) palladium (0), tetrakis(tri(otolyl)phosphine)palladium(0),Pd 2 (dba)3,[ 1 , 1 'Bis(diphenylphosphino)ferroce ne]dichloropalladium(II) (Pd(dppf) 2 CH 2 Cl 2 ), Palladium(II)acetate and mixtures thereof; preferably mixture of Pd(dppf) 2 CH 2 Cl 2 and Palladium(II)acetate.
  • the base for coupling of compound of Formula XI and Compound of Formula VIII include inorganic bases selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the Jike; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; and alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate and the like; and organic bases such as triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and the like and their mixtures thereof; preferable potassium carbonate.
  • the base can be added either as solution in water or it may be added as solid to the solution of reaction mixture.
  • the reaction of compound of Formula XI and Formula VIII is advantageously carried out in a suitable solvent.
  • suitable solvents include but are not limit to ketones, amides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons, water and mixtures thereof.
  • acetone Preferably acetone, methyl isobutyl ketone, methyl ethyl ketone, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone , acetonitrile, propionitrile, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, methylene chloride, ethylene chloride, chloroform, toluene, xylene; water and mixture thereof; preferably acetone, 1,4-dioxane, tetrahydrofuran, dimethyl formamide and mixtures thereof; more preferably 1 ,4-dioxane.
  • the coupling reaction of compound of Formula XI and Formula VIII is advantageously carried out at a temperature of about 30°C to 120°C; preferably at about 40°C to about 90°C.
  • the present invention provides a process for the preparation of vemerafenib of Formula I, comprising reacting a compound of Formula XII as obtained by the process described above, as a starting material or as an intermediate with a compound of Formula IV, wherein 'X' represents suitable leaving group; preferably chloro, according to step d) of the above.
  • the suitable base used herein for the reaction of compound of Formula XII and compound of Formula IV include but is not limited to inorganic bases selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; and alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate and the like; and organic bases selected from the group consisting of triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N- methyl morpholine, piperidine, pyridine and the like and their mixtures thereof; preferably pyridine, triethylamine or potassium carbonate; more preferably pyridine.
  • the reaction of compound of Formula XII and Formula IV is advantageously carried out in a suitable solvent.
  • suitable solvent include but is not limited to esters, ketones, amides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons and mixtures thereof.
  • reaction of compound of Formula XII and Formula IV is carried out at a temperature of about 0°C to reflux temperature; preferably at about 25°C to about 65°C.
  • the resultant product may be isolated by known methods, for example one or more solvent extractions followed by solvent evaporation.
  • the present invention provides a compound of Formula XII or a pharmaceutically acceptable salt thereof.
  • the present invention provides vemurafenib or a pharmaceutically acceptable salt thereof and its intermediates, obtained by the above process, as analyzed using high performance liquid chromatography (“HPLC”) with the conditions are tabulated below:
  • the present invention provides a pharmaceutical composition, comprising vemurafenib or a pharmaceutically acceptable salt thereof prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
  • Such pharmaceutical composition may be administered to a mammalian patient in any dosage form, e.g., solid, liquid, powder, injectable solution, etc.
  • reaction mass was concentrated under vacuum at 40°C to 42°C and charged ethyl acetate (100ml), IN HC1 at room temperature.
  • Organic layer and aqueous layers was separated, aqueous layer was back extracted with ethyl acetate (50ml).
  • Combined organic layer was successively washed with water (100ml), brine (100ml), dryed over anhydrous sodium sulphate and concentrated under vacuum to obtain residue of compound of Formula Va.
  • reaction mass was concentrated under vacuum at 40°C to 42°C and charged ethyl acetate (100ml), IN HC1 at room temperature.
  • Organic layer and aqueous layers was separated, aqueous layer was back extracted with ethyl acetate (50ml), combined organic layer was successively washed with water (100ml), brine (100ml), dryed over anhydrous sodium sulphate and concentrated under vacuum to obtain residue of compound of Formula Vb.
  • EXAMPLE 12 Preparation of Vemurafenib A 250 ml round bottom flask fitted with a mechanical stirrer, thermometer socket was charged Propane- 1 -sulfonic acid (3- ⁇ [5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3- yl]-hydroxy-methyl ⁇ -2,4-difluoro-phenyl)-amide of Formula X (lOgm), 2,3-Dichloro- 5,6-dicyano-l ,4-benzoquinone (6gm) in 1 ,4-dioxane (80ml), water (3.5ml) at room temperature and stirred for 3hr.
  • Propane- 1 -sulfonic acid (3- ⁇ [5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3- yl]-hydroxy-methyl ⁇ -2,4-difluoro-phenyl)
  • the solid was isolated by filtration and washed with methanol (10ml) to obtain crude compound.
  • the crude compound was further purified from tetrahydrofuran and n-heptane to obtain title compound as a cream color solid.
  • the solid obtained was taken in 50 mL of water and adjusted to pH 13.0 with IN NaOH and reaction mass washed with 50 mL of methylene chloride twice and aqueous layer pH was adjusted to 6.0 with IN HC1 to precipitate solids. Filtered the obtained solids and washed with water (2 ⁇ 20 mL), dried under vacuum at 60-65 °C for 5 hr to obtain the title compound as an off-white color solid.
  • reaction mass cooled to 30-35°C, filtered the reaction mass and washed with tetrahydrofuran (30 ml).
  • the obtained solvent was concentrated and charged water (300 ml) at 30-35°C and stirred for 1 hr.
  • the obtained solids were filtered and washed with purified water (50 ml), dryed at 40-45°C to obtain title compound. Yield: 7.0 gm.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux intermédiaires de vemurafenib ou de son sel pharmaceutiquement acceptable, et leurs procédés de préparation. L'invention porte en outre sur de nouveaux procédés de préparation de vemurafenib ou de son sel pharmaceutiquement acceptable au moyen des nouveaux intermédiaires.
PCT/IN2014/000733 2013-11-22 2014-11-24 Nouveaux procédés de préparation de vemurafenib Ceased WO2015075749A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN5395/CHE/2013 2013-11-22
IN3113/CHE/2014 2014-06-26
IN3113CH2014 2014-06-26
IN5395CH2013 IN2013CH05395A (fr) 2013-11-22 2014-11-24

Publications (1)

Publication Number Publication Date
WO2015075749A1 true WO2015075749A1 (fr) 2015-05-28

Family

ID=53179069

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2014/000733 Ceased WO2015075749A1 (fr) 2013-11-22 2014-11-24 Nouveaux procédés de préparation de vemurafenib

Country Status (1)

Country Link
WO (1) WO2015075749A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109970733A (zh) * 2017-12-28 2019-07-05 新发药业有限公司 一种维罗非尼及其类似物的简便制备方法
US10407427B2 (en) 2016-07-01 2019-09-10 Fermion Oy Processes for the preparation of Vemurafenib
US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008079909A1 (fr) * 2006-12-21 2008-07-03 Plexxikon, Inc. Composés et méthodes de modulation des kinases, et indications connexes
WO2008079906A1 (fr) * 2006-12-21 2008-07-03 Plexxikon, Inc. Composés et méthodes pour moduler une kinase et indications associées
WO2010129570A1 (fr) * 2009-05-06 2010-11-11 Plexxikon, Inc. Formes solides de sulfonamides et d'acides aminés
US7863288B2 (en) * 2005-06-22 2011-01-04 Plexxikon, Inc. Compounds and methods for kinase modulation, and indications therefor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7863288B2 (en) * 2005-06-22 2011-01-04 Plexxikon, Inc. Compounds and methods for kinase modulation, and indications therefor
WO2008079909A1 (fr) * 2006-12-21 2008-07-03 Plexxikon, Inc. Composés et méthodes de modulation des kinases, et indications connexes
WO2008079906A1 (fr) * 2006-12-21 2008-07-03 Plexxikon, Inc. Composés et méthodes pour moduler une kinase et indications associées
WO2010129570A1 (fr) * 2009-05-06 2010-11-11 Plexxikon, Inc. Formes solides de sulfonamides et d'acides aminés

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10407427B2 (en) 2016-07-01 2019-09-10 Fermion Oy Processes for the preparation of Vemurafenib
US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
CN109970733A (zh) * 2017-12-28 2019-07-05 新发药业有限公司 一种维罗非尼及其类似物的简便制备方法
CN109970733B (zh) * 2017-12-28 2020-05-08 新发药业有限公司 一种维罗非尼及其类似物的简便制备方法

Similar Documents

Publication Publication Date Title
JP6985367B2 (ja) 新規化合物および方法
CN111386272B (zh) 一种改进的瑞博西尼及其盐的制备方法
CN113227045B (zh) 取代的杂环稠合的γ-咔啉的合成
TW201210990A (en) Manufacturing method for compounds having HIV integrase inhibitory activities
CN106946917A (zh) 一种jak抑制剂巴瑞替尼及其中间体的新合成方法
CN105503867A (zh) 用于制备取代的5-氟-1h-吡唑并吡啶类化合物的方法
WO2023109968A2 (fr) Procédé de synthèse de finérénone et d'un intermédiaire de celle-ci
JP7347852B2 (ja) 重水素化大環状化合物の調製方法
JP6694109B2 (ja) 改善された５ｒ−ベンジルオキシアミノピペリジン−２ｓ−ギ酸エステル及びそのシュウ酸塩の調製方法
CN113195450B (zh) 取代的杂环稠合的γ-咔啉的合成
KR102266680B1 (ko) 벨리노스테트의 다형태 및 이의 제조 방법
RU2621725C2 (ru) Способ получения 1-([1,3]диоксолан-4-илметил)-1н-пиразол-3-иламина
WO2023109802A1 (fr) Inhibiteur double de pde3/4 hétérocyclique fusionné tricyclique et son utilisation
CA2719526A1 (fr) Conversion du tryptophane en derives de .beta.-carboline
WO2015075749A1 (fr) Nouveaux procédés de préparation de vemurafenib
CN103664816B (zh) Hiv逆转录酶抑制剂依法韦伦类化合物的一锅法不对称合成工艺
CN107118215B (zh) 一种治疗乳腺癌药物瑞博西尼中间体的制备方法
CN114560859B (zh) 一种吲哚并喹啉衍生物及其制备方法和应用
WO2020134212A1 (fr) Procédés de synthèse d'une halofuginone et d'un intermédiaire de celle-ci
CN113336703B (zh) 1,3,4,5-四取代1h-吡唑衍生物的合成
WO2015085827A1 (fr) Procédé pour la préparation de silodosine et intermédiaire correspondant
WO2024017150A1 (fr) Procédé de synthèse de deucravacitinib
WO2014008639A1 (fr) Procédé de préparation d'indacatérol
CN107400083A (zh) 一种3‑[2‑(3‑氯苯基)乙基]‑2‑吡啶甲腈的制备方法
WO2010049500A2 (fr) Procédé de préparation du tadalafil

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14864596

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14864596

Country of ref document: EP

Kind code of ref document: A1