WO2016199020A1 - Procédé de préparation de céritinib - Google Patents

Procédé de préparation de céritinib Download PDF

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Publication number
WO2016199020A1
WO2016199020A1 PCT/IB2016/053339 IB2016053339W WO2016199020A1 WO 2016199020 A1 WO2016199020 A1 WO 2016199020A1 IB 2016053339 W IB2016053339 W IB 2016053339W WO 2016199020 A1 WO2016199020 A1 WO 2016199020A1
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WIPO (PCT)
Prior art keywords
compound
formula
ceritinib
acid
group
Prior art date
Application number
PCT/IB2016/053339
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English (en)
Inventor
Veerender Murki
Sridhar Vasam
Shravan Kumar Komati
Nageshwar Gunda
Venkata Rao Badisa
V Ramana Rao R
Srinivas ORUGANTI
Rakesh GANORKAR
Vilas Hareshwar Dahanukar
Srinivas Katkam
Poornachander THATIPALLI
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Dr. Reddy's Laboratories Limited
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Publication of WO2016199020A1 publication Critical patent/WO2016199020A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom

Definitions

  • One aspect of the present application relates to processes for preparation of ceritinib and intermediates thereof.
  • Ceritinib is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.
  • Ceritinib is chemically known as 5-chloro-N4-[2- [(lmethylethyl)sulfonyl]phenyl]-N2-[5-methyl-2-(l-methylethoxy)-4-(4-piperidinyl) phenyl]- 2,4-pyrimidinediamine
  • US patent number, US8039479B2 discloses ceritinib and a process for preparation thereof.
  • the process involves the use of platinum oxide as a reagent for reduction of 4-(5-isopropoxy-2-methyl-4-nitrophenyl)pyridine to afford corresponding piperidine derivative.
  • the corresponding piperidine derivative requires column chromatography for purification. Hence, the process is not suitable for commercial production of ceritinib.
  • CN104447515A discloses a process for the preparation of Ceritinib, which involves the reduction of 4-(5-isopropoxy-2-methyl-4- nitrophenyl)pyridine in four separate stages.
  • the first stage involves the formation of 4-(5- isopropoxy-2-methyl-4-nitrophenyl)- 1 -benzyl-pyridinium bromide by treating 4-(5-isopropoxy- 2-methyl-4-nitrophenyl)pyridine with benzyl bromide;
  • the second stage involves treating the product of first stage with sodium borohydride to provide 2-isopropoxy-5-methyl-4-(l-benzyl- l,2,3,6-tetrahydro-pyridin-4-yl)-benzyl amine;
  • the third stage involves preparation of hydrochloride salt of second stage product; and the fourth stage involves hydrogenation of third stage product in presence of hydrogen.
  • CN'515 application discloses preparation of ceritinib by reacting 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride with 2,5- dichloro-N-(2-(isopropylsulfonyl)-phenyl)pyrimidin-4-amine in isopropanol at refluxing temperature to afford ceritinib dihycrochloride, which is further treated with sodium hydroxide to produce ceritinib.
  • the process of CN'515 application involves too many conversions which affect the overall yield of ceritinib and hence makes the process unsuitable for commercial production of ceritinib.
  • One aspect of the present application relates to a process for preparation of ceritinib or acid- addition salt thereof comprising reacting a compound of formula (I) with a compound of formula (II) or an acid
  • Ri is a leaving group selected from a group of halogen, -SO 2 R 2 ;
  • R 2 may be a linear or branched alkyl having 1-6 carbon atoms and an aromatic group having 6-12 carbon atoms optionally having one or more substituents selected from a group of halogen and alkyl having 1 - 6 carbon atoms.
  • Another aspect of the present application relates to a process for the preparation of ceritinib or acid-addition salt thereof comprising the steps of:
  • Ri is a leaving group selected from a group of halogen, -SO 2 R 2 ;
  • R 2 may be a linear or branched alkyl having 1-6 carbon atoms and an aromatic group having 6-12 carbon atoms optionally having one or more substituents selected from a group of halogen and alkyl having 1 - 6 carbon atoms.
  • One aspect of the present application relates to a process for preparation of ceritinib or acid- addition salt thereof comprising reacting a compound of formula (I) with a compound of formula (II) or an acid-addition salt thereof
  • Ri is a leaving group selected from a group of halogen, -SO 2 R 2 ;
  • R 2 may be a linear or branched alkyl having 1-6 carbon atoms and an aromatic group having 6-12 carbon atoms optionally having one or more substituents selected from a group of halogen and alkyl having 1 - 6 carbon atoms.
  • One specific aspect of the present application relates to a process for preparation of ceritinib or acid-addition salt thereof comprising reacting a compound of formula (IA) with a compound of formula ( ⁇ ) or an acid-addition salt thereof
  • Another specific aspect of the present application relates to a process for preparation of ceritinib or acid-addition salt thereof comprising reacting a compound of formula (IB) with a compound of formula (II) or an acid-addition salt thereof
  • the reaction of compound of formula (I) and compound of formula (II) or an acid-addition salt thereof may be carried out in an inert organic solvent including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; ether such as tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, isopropanol and the like.
  • the solvent may be aromatic hydrocarbon solvent such as toluene; alcoholic solvent such as isopropanol.
  • the reaction may be carried out in isopropanol.
  • the reaction may be carried out in presence of an acid.
  • the acid may be an organic acid such as p-toulene sulfonic acid, propionic acid, trifluoroacetic acid and the like; or an inorganic acid such as hydrochloric acid, nitric acid and the like.
  • the acid may be p-toulene sulfonic acid.
  • the acid-addition salt of the compound of formula (II) includes but not limited to hydrochloric acid salt of compound of formula (II), sulfuric acid salt of compound of formula (II), malic acid salt of compound of formula (II), p-toluene sulfonic acid salt of compound of formula (II), trifluoroacetic acid salt of compound of formula (II) and the like.
  • compound of formula (II) may be in the form of hydrochloric acid salt or trifluoroacetic acid salt.
  • the reaction may be carried out at a temperature of about 20 °C to about boiling point of the solvent. Specifically, the reaction is carried out in an autoclave at about 100 °C to about 200 °C. Acid addition salt of ceritinib may result after reaction, which may optionally be converted to ceritinib by addition of suitable base.
  • Another aspect of the present application relates to a process for the preparation of compound of formula (IA) comprising la (IX)
  • the oxidizing agent may be meta- chloroperbenzoic acid.
  • Another aspect of the present application relates to a process for the preparation of compound of formula (IX) comprising reacting a compound of formula (VII) with a compound of formula (VIII)
  • the reaction between compound of formula (VII) and the compound of formula (VIII) may be carried out in an inert organic solvent including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; ether such as tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, isopropanol and the like.
  • the solvent may be selected from a group of DMF, DMSO and mixture thereof.
  • reaction between compound of formula (VII) and the compound of formula (VIII) may be carried out in presence of a base including but not limited to an amide base such as lithium diisopropylamide and the like; organic base such as triethylamine and the like; hydride base such as sodium hydride and the like.
  • a base including but not limited to an amide base such as lithium diisopropylamide and the like; organic base such as triethylamine and the like; hydride base such as sodium hydride and the like.
  • Compound of formula (VII), compound of formula (VIII) and compound of formula (IB) may be prepared by following the processes known in the art.
  • the present application relates to conversion of compound of formula (IX) to ceritinib by a process as described in the present application,
  • the present application also relates to use of compound of formula (IX) as an intermediate for the preparation of ceritinib.
  • the present application also relates to compound of formula (IA)
  • the present application relates to conversion of compound of formula (IA) to ceritinib by a process as described in the present application.
  • the present application also relates to use of compound of formula (IA) as an intermediate for the preparation of ceritinib.
  • Another aspect of the present application relates to a process for the preparation of ceritinib or acid-addition salt thereof comprising the steps of:
  • Pi and P 2 are independently -H or an amino protecting group or together with nitrogen atom forms nitro group and P3 is an amino protecting group and X is halogen;
  • Ri is a leaving group selected from a group of halogen, -SO 2 R 2 ;
  • R 2 may be a linear or branched alkyl having 1-6 carbon atoms and an aromatic group having 6-12 carbon atoms optionally having one or more substituents selected from a group of halogen and alkyl having 1 - 6 carbon atoms.
  • the reaction of compound of formula (III) with a compound of formula (IV) to afford compound of formula (V) may be carried out in an inert organic solvent in presence of a palladium catalyst.
  • the inert organic solvent for the reaction including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; ether such as tetrahydrofuran, 1,4-dioxane and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like.
  • the solvent may be aromatic hydrocarbon solvent such as toluene; ether such as tetrahydrofuran, 1,4-dioxane and the like. More specifically, reaction of compound of formula (III) and compound of formula (IV) may be carried out in an ether solvent such as 1,4-dioxane. Any known palladium catalyst may be used in the reaction; specifically Tris(dibenzylideneacetone)dipalladium(0) may be used in the reaction. Further, the reaction medium may comprise 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), tosyl- hydrazine and a base.
  • Xphos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
  • the base may include but not limited to organic base such as triethylamine, diisopropylethyl amine, pyridine and the like; alkoxide base such as sodium methoxide, sodium tert-butoxide, lithium tert-butoxide and the like; hydride base such as sodium hydride, potassium hydride and the like.
  • organic base such as triethylamine, diisopropylethyl amine, pyridine and the like
  • alkoxide base such as sodium methoxide, sodium tert-butoxide, lithium tert-butoxide and the like
  • hydride base such as sodium hydride, potassium hydride and the like.
  • an alkoxide base such as sodium methoxide, sodium tert-butoxide, lithium tert-butoxide may be used in the reaction. More specifically, lithium tert-butoxide may be used as a base.
  • Compound of formula (V) may be hydrogenated by any known methods in the art to afford compound of formula (VI). Specifically, the compound of formula (V) may be hydrogenated in presence of a heterogenous catalyst like palladium/charcoal.
  • the protecting groups of compound of formula (VI) may be removed by any known methods in the art to afford compound of formula (II) or an acid-addition salt thereof.
  • the skilled person would understand that when Pi, P 2 and P 3 are all benzyl or hydrogen or Pi and P 2 together with nitrogen atom forms nitro group, the hydrogenation step (b) would result into compound of formula (II) or an acid-addition salt thereof.
  • step (c) is performed to afford compound of formula (II) or an acid- addition salt thereof.
  • acid-addition salt of ceritinib prepared by the process of the present application, may be purified by crystallization.
  • the crystallized acid-addition salt of ceritinib may be further recrystallized to enhance the purity of acid-addition salt of ceritinib.
  • the crystallization or recrystallization of acid-addition salt of ceritinib may be performed in suitable organic solvent, water and mixture thereof.
  • acid-addition salt of ceritinib may be purified by crystallization in alcoholic solvent such as methanol, isopropanol and the like; water or mixture thereof.
  • Acid-addition salt of ceritinib may be converted to ceritinib by treating acid-addition salt of ceritinib with a base selected from the group consisting of triethylamine, diisopropyl ethylamine, tromethamine, sodium carbonate, potassium carbonate and cesium carbonate.
  • acid- addition salt of ceritinib may be converted to crystalline form A of ceritinib by treating acid- addition salt of ceritinib with a base selected from the group consisting of triethylamine, diisopropyl ethylamine, tromethamine, sodium carbonate, potassium carbonate and cesium carbonate.
  • ceritinib dihydrochloride may be converted to crystalline form A of ceritinib by treating ceritinib dihydrochloride with a base selected from the group consisting of triethylamine, diisopropyl ethylamine, tromethamine, sodium carbonate, potassium carbonate and cesium carbonate.
  • a base selected from the group consisting of triethylamine, diisopropyl ethylamine, tromethamine, sodium carbonate, potassium carbonate and cesium carbonate.
  • the solvent used for converting acid-addition salt of ceritinib to ceritinib may include but not limited to alcoholic solvent such as methanol, isopropanol and the like; ketone solvent such as acetone, methyl ethyl ketone and the like; ether solvent such as tetrahydrofuran, 1,4-dioxane, diethyl ether and the like; ester solvent such as ethyl acetate, n-butyl acetate and the like; water; polar aprotic solvent such as dimethyl formamide and the like; nitrile solvent such as acetonitrile and the like; or mixture thereof. Ceritinib or crystalline form A of ceritinib may be isolated from the reaction mass by a process known in the art. Specifically, crystalline form A of ceritinib may be isolated from the reaction mass by filtration.
  • the amino protecting group may be any group known in the art. Specifically, the amino protecting group may be selected from a group of benzyl and tert -butyl carbamate. Alternatively, the amino protecting group may be an acyl group. Specifically, the amino protecting group may be acetyl group.
  • the present application relates to conversion of compound of formula (III) to ceritinib by a process as described in the present application.
  • the present application also relates to use of compound of formula (III) as an intermediate for the preparation of ceritinib.
  • the present application relates to conversion of compound of formula (IIIA) to ceritinib by a process as described in the present application.
  • the present application also relates to use of compound of formula (IIIA) as an intermediate for the preparation of ceritinib.
  • the present application relates to conversion of compound of formula (IIIB) to ceritinib by a process as described in the present application.
  • the present application also relates to use of compound of formula (IIIB) as an intermediate for the preparation of ceritinib.
  • the present application relates to conversion of compound of formula (IIIC) to ceritinib by a process as described in the present application.
  • the present application also relates to use of compound of formula (IIIC) as an intermediate for the preparation of ceritinib.
  • the present application relates to conversion of compound of formula (HID) to ceritinib by a process as described in the present application.
  • the present application also relates to use of compound of formula (HID) as an intermediate for the preparation of ceritinib.
  • the amino protecting group may be any group known in the art. Specifically, the amino protecting group may be selected from a group of benzyl and tert-butyl carbamate. Alternatively, the amino protecting group may be an acyl group. Specifically, the amino protecting group may be acetyl group.
  • the present application relates to conversion of compound of formula (VA) to ceritinib by a process as described in the present application.
  • the present application also relates to use of compound of formula (VA) as an intermediate for the preparation of ceritinib.
  • the present application relates to conversion of compound of formula (VB) to ceritinib by a process as described in the present application.
  • the present application also relates to use of compound of formula (VB) as an intermediate for the preparation of ceritinib.
  • the present application relates to conversion of compound of formula (VC) to ceritinib by a process as described in the present application.
  • the present application also relates to use of compound of formula (VC) as an intermediate for the preparation of ceritinib.
  • Still another specific aspect of the present application relates to compound of formula (VI)
  • Pi and P 2 are independently -H or an amino protecting group or together with nitrogen atom forms nitro group and P 3 is an amino protecting group.
  • the present application relates to conversion of compound of formula (VI) to ceritinib by a process as described in the present application.
  • the present application also relates to use of compound of formula (VI) as an intermediate for the preparation of ceritinib.
  • Still another specific aspect of the present application relates to compound of formula (VIA)
  • the present application relates to conversion of compound of formula (VIA) to ceritinib by a process as described in the present application.
  • the present application also relates to use of compound of formula (VIA) as an intermediate for the preparation of ceritinib.
  • step (c) is not needed to perform since the hydrogenation of corresponding compound of formula (VA) or compound of formula (VB) at step (b) would result into compound of formula (II).
  • step (c) is needed to perform since the hydrogenation of corresponding compound of formula (VC) would result compound of formula (VIA) which would result into compound of formula (II) following deprotection of acetyl group.
  • the present application also relates to a process for the preparation of compound of formula (IIIA)
  • the present application further relates to a process for the preparation of compound of formula (IIIA) comprising reacting a compound of formula (XB)
  • the solvent used for the reaction of compound of formula (XA) or (XB) with a suitable halogenating agent includes but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; ether such as tetrahydrofuran, 1,4-dioxane and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; chlorinated solvent such as chloroform and the like.
  • the halogenating agent used in the reaction may be any halogenating agent known in the art.
  • the halogenating agent may be selected from N-bromosuccinamide, N- chlorosuccinamide.
  • the present application also relates to a process for the preparation of compound of formula (IIIB) comprising reacting a compound of formula (XB) with N-bromosuccinamide
  • the present application relates to a process for the preparation of compound of formula (IIIB) comprising
  • the present application further relates to a process for the preparation of compound of formula (IIIC) comprising reacting a compound of formula (XC) with N-bromosuccinamid
  • the present application also relates to a process for the preparation of compound of formula (HID) comprising reacting a compound of formula (XD) with N-bromosuccinamide
  • the present application relates to a process for the preparation of compound of formula (HID) comprising
  • the solvent used for the reaction of compound of formula (XA) or compound of formula (XB) or compound of formula (XC) or compound of formula (XD) with N-bromosuccinamide includes but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; ether such as tetrahydrofuran, 1,4-dioxane and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; chlorinated solvent such as chloroform and the like.
  • polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like
  • ether such as tetrahydrofuran, 1,4-dioxane and the like
  • aliphatic hydrocarbon solvent such as hexane, heptane and the like
  • the present application relates to a process for the preparation of compound of formula (V) comprising reacting compound of formula (III) with N-protected pyrrolidone of formula (IV)
  • Pi and P 2 are independently -H or an amino protecting group or together with nitrogen atom forms nitro group and P3 is an amino protecting group and X is halogen.
  • the present application relates to a process for the preparation of compound of formula (VA) comprising reacting compound of formula (IIIB) with N-protected pyrrolidone of formula (IVA)
  • the present application further relates to a process for the preparation of compound of formula (VB) comprising reacting compound of formula (IIIC) with N-protected pyrrolidone of formula (IVA)
  • the present application relates to a process for the preparation of compound of formula (VC) comprising reacting compound of formula (HID) with N-protected pyrrolidone of formula (IVA)
  • Another aspect of the present application relates to a process for the preparation of compound of formula (VI) comprising the steps of:
  • Pi and P 2 are independently -H or an amino protecting group or together with nitrogen atom forms nitro group and P 3 is an amino protecting group and X is halogen.
  • One specific aspect of the present application relates to a process for preparation of ceritinib or acid-addition salt thereof comprising the steps of:
  • Ri is a leaving group selected from a group of halogen, -SO 2 R 2 ;
  • R 2 may be a linear or branched alkyl having 1-6 carbon atoms and an aromatic group having 6-12 carbon atoms optionally having one or more substituents selected from a group of halogen and alkyl having 1 - 6 carbon atoms.
  • Another specific aspect of the present application relates to a process for preparation of ceritinib or acid-addition salt thereof comprising the steps of:
  • Ri is a leaving group selected from a group of halogen, -SO 2 R 2 ;
  • R 2 may be a linear or branched alkyl having 1-6 carbon atoms and an aromatic group having 6-12 carbon atoms optionally having one or more substituents selected from a group of halogen and alkyl having 1 - 6 carbon atoms.
  • Another specific aspect of the present application relates to a process for preparation of ceritinib or acid-addition salt thereof comprising the steps of:
  • Ri is a leaving group selected from a group of halogen, -SO 2 R 2 ;
  • R 2 may be a linear or branched alkyl having 1-6 carbon atoms and an aromatic group having 6-12 carbon atoms optionally having one or more substituents selected from a group of halogen and alkyl having 1 - 6 carbon atoms.
  • Another specific aspect of the present application relates to a process for preparation of ceritinib or acid-addition salt thereof comprising the steps of:
  • Ri is a leaving group selected from a group of halogen, -SO 2 R 2 ;
  • R 2 may be a linear or branched alkyl having 1-6 carbon atoms and an aromatic group having 6-12 carbon atoms optionally having one or more substituents selected from a group of halogen and alkyl having 1 - 6 carbon atoms.
  • One aspect of the present application relates to a process for the preparation of compound of formula (II) or acid-addition salt thereof comprising the steps of
  • Pi and P 2 are independently -H or an amino protecting group or together with nitrogen atom forms nitro group and P 3 is an amino protecting group and X is halogen;
  • One specific aspect of the present application relates to a process for the preparation of compound of formula (II) or an acid-addition salt thereof comprising the steps of:
  • Another specific aspect of the present application relates to a process for the preparation of compound of formula (II) or an acid-addition salt thereof comprising the steps of:
  • Still another specific aspect of the present application relates to a process for preparation of ceritinib or acid-addition salt thereof comprising the steps of:
  • compound of formula (VC) may be deprotected to provide a compound of formula (VI') or an acid-addition salt thereof
  • compound of formula (VI') or an acid-addition salt thereof may be hydrogenated to provide compound of formula (II) or an acid addition salt thereof
  • Another aspect of the present application relates to a process for the preparati compound of formula (II) or acid-addition salt thereof comprising the steps of:
  • Pi and P 2 are independently -H or an amino protecting group or together with nitrogen atom forms nitro group and P3 is an amino protecting group and X is halogen;
  • Another aspect of the present application relates to a process for the preparati compound of formula (II) or acid addition salt thereof comprising the steps of:
  • Another aspect of the present application relates to a process for the preparati compound of formula (II) or acid addition salt thereof comprising the steps of:
  • Still another specific aspect of the present application relates to a process for preparation of compound of formula (II) or acid-addition salt thereof comprising the steps of: (a) hydrogenation of compound of formula (VC) to provide compound of formula (VIA)
  • Another specific aspect of the present application relates to a process for preparation of compound of formula (II) or acid-addition salt thereof comprising the steps of:
  • Still another specific aspect of the present application relates to a process for preparation of compound of formula (II) or acid-addition salt thereof comprising deprotection of protecting group of c
  • Another aspect of the present application relates to acid-addition salt of ceritinib, wherein the salt is not dihydrochloride salt.
  • the present application relates to diacetate salt of ceritinib, dicitrate salt of ceritinib, dioxalate salt of ceritinib, diformate salt of ceritinib, dimesylate salt of ceritinib, dimaleate salt of ceritinib, ditosylate salt of ceritinib, dibenzoyl tartarate salt of ceritinib, diphosphate salt of ceritinib.
  • Yet another aspect of the present application relates to a process for preparation of acid- addition salt of ceritinib comprising reacting acid-addition salt of compound of formula (II) with compound of formula (I)
  • Ri is a leaving group selected from a group of halogen, -SO 2 R 2 ;
  • R 2 may be a linear or branched alkyl having 1-6 carbon atoms and an aromatic group having 6-12 carbon atoms optionally having one or more substituents selected from a group of halogen and alkyl having 1 - 6 carbon atoms and wherein acid-addition salt is selected from a group of diacetate salt, dicitrate salt, dioxalate salt, diformate salt, dimesylate salt, dimaleate salt, ditosylate salt, dibenzoyl tartarate salt, diphosphate salt.
  • Still another aspect of the present application relates to a process for preparation of ceritinib comprising the steps of:
  • Ri is a leaving group selected from a group of halogen, -SO 2 R 2 ;
  • R 2 may be a linear or branched alkyl having 1-6 carbon atoms and an aromatic group having 6-12 carbon atoms optionally having one or more substituents selected from a group of halogen and alkyl having 1 - 6 carbon atoms;
  • the base is selected from a group of triethylamine, diisopropyl ethylamine, tromethamine, sodium carbonate, potassium carbonate and cesium carbonate and wherein acid-addition salt is selected from a group of diacetate salt, dicitrate salt, dioxalate salt, diformate salt, dimesylate salt, dimaleate salt, ditosylate salt, dibenzoyl tartarate salt, diphosphate salt.
  • Another aspect of the present application relates to a process for preparation of acid-addition salt of ceritinib comprising reacting acid-addition salt of compound of formula (II) with compound of formula (IB)
  • acid-addition salt is selected from a group of diacetate salt, dicitrate salt, dioxalate salt, diformate salt, dimesylate salt, dimaleate salt, ditosylate salt, dibenzoyl tartarate salt, diphosphate salt.
  • Still another aspect of the present application relates to a process for preparation of ceritinib comprising the steps of:
  • base is selected from a group of triethylamine, diisopropyl ethylamine, tromethamine, sodium carbonate, potassium carbonate and cesium carbonate and wherein acid- addition salt is selected from a group of diacetate salt, dicitrate salt, dioxalate salt, diformate salt, dimesylate salt, dimaleate salt, ditosylate salt, dibenzoyl tartarate salt, diphosphate salt.
  • Another aspect of the present application relates to process for preparation of a salt of ceritinib comprising the steps of:
  • the acid is selected from a group of acetic acid, citric acid, oxalic acid, formic acid, methane sulfonic acid, maleic acid, p-toluene sulfonic acid, dibenzoyl tartaric acid and o- phosphoric acid.
  • the suitable solvent of step (a) includes but not limited to alcoholic solvent such as methanol, ethanol, isopropanol and the like; ketone solvent such as acetone, methyl ethyl ketone and the like; ester solvent such as ethyl acetate, n-butyl acetate and the like; nitrile solvent such as acetonitrile and the like and mixtures thereof.
  • the solvent is an ester solvent. More specifically, the solvent is ethyl acetate.
  • any physical form of ceritinib may be utilized, which may be crystalline or amorphous, for providing the mixture of ceritinib in a suitable solvent or mixtures thereof.
  • any physical form of ceritinib may be utilized, which may be anhydrous or hydrate, for providing the mixture of ceritinib in suitable solvent or mixtures thereof.
  • the acid selected from a group of acetic acid, citric acid, oxalic acid, formic acid, methane sulfonic acid, maleic acid, p-toluene sulfonic acid, dibenzoyl tartaric acid and o- phosphoric acid may be added to the mixture of step (a) or may be dissolved in a suitable solvent and the solution may be added to the mixture of step (a).
  • the suitable solvent for dissolving the acid in step (b) includes but not limited to alcoholic solvent such as methanol, ethanol, isopropanol and the like; ketone solvent such as acetone, methyl ethyl ketone and the like; ester solvent such as ethyl acetate, n-butyl acetate and the like; nitrile solvent such as acetonitrile and the like and mixtures thereof.
  • the solvent is an alcoholic solvent. More specifically, the solvent is methanol.
  • the reaction mixture may be stirred for about 15 minutes to about 5 hours at a temperature of about 0 °C to about boiling point of the solvent.
  • the reaction mixture may be stirred for about 30 minutes to about 3 hours at a temperature of about 0 °C to about 40 °C.
  • the product may be precipitated by adding a suitable anti-solvent to the reaction mass.
  • the suitable anti-solvent includes but not limited to aromatic hydrocarbons such as toluene, xylene and the like; aliphatic hydrocarbons such as heptane, n-hexane and the like.
  • the anti-solvent is an aliphatic hydrocarbon. More specifically, the anti-solvent is n-hexane.
  • the product may be isolated from the reaction mass by any technique known in the art. Specifically, the product, diphosphate salt of ceritinib, may be isolated from the reaction mass by filtration. Optionally, the resultant product may be dried at any suitable conditions.
  • Another aspect of the present application relates to a process for the preparation of ceritinib or an acid-addition salt thereof comprising the steps of:
  • Ri is as designated above.
  • the reaction between compound of formula (III) and compound of formula (IV) in step (a) may be carried out in presence of a Grignard reagent including but not limited to isopropyl magnesium chloride.
  • the reaction may be carried out in an inert organic solvent including but not limited to an ether such as tetrahydrofuran, 1,4-dioxane and the like; aromatic hydrocarbon such as toluene, xylene and the like.
  • the reaction may be performed in tetrahydrofuran.
  • Dehydration of compound of formula (XI) may be carried out in presence of a suitable dehydrating agent to afford compound of formula (V).
  • the dehydrating agent include but not limited to aluminium phosphate, calcium oxide, ⁇ , ⁇ '-dicyclohexylcarbodiimide, orthoformic acid, phosphorus pentoxide, phosphoryl chloride, sulfuric acid, p-toluene sulfonic acid and the like.
  • the dehydration of compound of formula (XI) may be carried out in presence of p-toluene sulfonic acid to afford compound of formula (V).
  • the remaining reactions of the above aspect may be performed substantially similar to one or more reactions described in the previous embodiments.
  • the present application relates to conversion of compound of formula (XI) to ceritinib by a process as described in the present application.
  • the present application also relates to use of compound of formula (XI) as an intermediate for the preparation of ceritinib.
  • the present application relates to conversion of compound of formula (XIA) to ceritinib by a process as described in the present application.
  • the present application also relates to use of compound of formula (XIA) as an intermediate for the preparation of ceritinib.
  • the present application also relates to a process for the preparation of compound of formula (XI) comprising reacting a compound of formula (III) with a compound of formula (IV) in presence of a Grignard reagent to afford compound of formula (XI)
  • the present application also relates to a process for the preparation of compound of formula (XIA) comprising reacting a compound of formula (IIIB) with a compound of formula (IV A) in presence of a Grignard reagent
  • the present application also relates to a process for the preparation of compound of formula (V) comprising dehydrating compound of formula (XI) with a suitable dehydrating agent
  • the present application relates to a process for the preparation of compound of formula (VA) comprising dehydrating compound of formula (XIA) with a suitable dehydrating agent
  • Halogen is defined as non-metallic elements found in group VII of the periodic table and is selected from fluorine, bromine, chlorine and iodine.
  • a reaction vessel was charged with 4-methyl-2-nitrophenol (50 g) and dissolved in DMF (500 mL). To the reaction mass, 2-bromopropane (80.3 g) was added and the reaction mass was heated to 80 °C for 16 hours. After the completion of the reaction, the reaction mass was cooled to about 20-25 °C and methyl tert-butyl ether (500 mL) was added. The reaction mass was washed with water (3 x 500 mL) and then with brine (500 mL). The organic layer was dried over sodium sulfate and distilled completely to afford the desired product.
  • Benzyl bromide (84.1 g) and potassium carbonate (101 g) was added to a solution of 4-bromo-2- isopropoxy-5-methylaniline (30 g) in acetonitrile (300 mL).
  • the reaction mass was heated to 80 °C for 12 hours and cooled to 20-25 °C.
  • the reaction mass was filtered through celite pad which was washed with ethyl acetate (50 mL).
  • the solvent was distilled to afford to crude product.
  • the crude product was diluted with ethyl acetate (300 mL) and washed with water (2 x 300 mL), followed by brine (300 mL).
  • the organic layer was dried over sodium sulfate and distilled to afford the crude product.
  • the crude product was purified by silica gel column chromatography (5% ethyl acetate in hexane) to obtain the title compound.
  • N,N-dibenzyl-4-bromo-2-isopropoxy-5- methylaniline 13 g was added to the reaction mass and the reaction mass was heated to 110 °C for 16 hours.
  • the reaction mass was cooled to 20-25 °C, diluted with dichloromethane (200 mL) and filtered through celite pad. The celite pad was washed with dichloromethane (50 mL). The organic layer was ditilled to afford the crude product. Water (200 mL) was added to the product and the compound was extracted from the aqueous layer with dichloromethane (2 x 150 mL). The organic layer was washed with brine (100 mL) and dried over sodium sulfate. The solvent was distilled to afford the crude product. The crude product was purified by silica gel column chromatography to provide the desired compound.
  • the crude product was dissolved in dichloromethane (200 mL) and washed with saturated solution of sodium bicarbonate (2 x 50 mL), followed by brine (2 x 50 mL). The organic layer was dried over sodium sulfate and distilled to afford the crude product.
  • the crude product was purified by silica gel column chromatography using methanol-dichloromethane (Methanol:Dichloromethane::2:98 to 10:90) as eluent to provide the desired compound.
  • the combined organic layer was washed with brine (100 mL) and dried over sodium sulfate.
  • the organic layer was distilled under reduced pressure to afford the crude compound.
  • the crude product was dissolved in ethyl acetate (50 mL) and cooled to 10 °C. To this solution, hexane (300 mL) was added and stirred for 10 minutes. The precipitated solid was filtered. The mother liquor was again treated as above with ethyl acetate (20 mL) and hexane (100 mL) to afford the second crop.
  • reaction mass was quenched with saturated solution of ammonium chloride (50 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was dried over sodium sulfate and distilled under reduced pressure to provide the crude product. The crude product was purified by silica gel column chromatography to afford the title compound.
  • the reaction mass was cooled to 20-25 °C and filtered through celite pad.
  • the celite pad was washed with ethyl acetate (500 mL).
  • the organic layer was ditilled under vacuum to afford the crude product.
  • the crude product was dissolved in ethyl acetate (1 L) and washed with aqueous solution of sodium bicarbonate (7%, 1 L).
  • the organic layer was separated and stirred with aqueous solution of hydrochloric acid (0.5 N, 1 L).
  • Aqueous hydrochloric acid solution (10 N, 250 mL) was added to the isolated aqueous layer containing hydrochloride salt of N-(4-(l-benzyl-l,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5- methylphenyl)acetamide.
  • the reaction mass was stirred for 60-70 °C for about 4 hours.
  • Ethyl acetate (1 L) was added to the reaction mass.
  • the pH of the reaction mass was adjusted to 7-8 by the addition of solid sodium bicarbonate under stirring.
  • the ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate (1 x 300 mL).
  • the solvent was evaporated completely under vacuum.
  • the residue was dissolved in methanol (50 mL) and palladium-charcoal (10 %, 5 g) was added to it.
  • the reaction mass was stirred with 8-10 Kg pressure of hydrogen gas at 25-35 °C for about 16 hours. .
  • the reaction mass was filtered over celite bed. The bed was washed with methanol (2 x 20 mL). The solvent was evaporated completely under vacuum to provide the title compound.
  • the reaction mass was filtered through hyflow and washed with methanol (25 mL). The methanol layer was concentrated completely under vacuum.
  • Heptane (50 mL) was added to the residue and stirred for 10-15 min at 20-30 °C.
  • the solid was filtered and washed with heptane (30 mL).
  • the solid was dried in vacuum tray drier for 5 hours at 45 °C to provide the title compound.
  • Example 28B Purification of 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline A mixture of 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline (500 mg), as prepared in Example 27 and isopropanol (5 mL) was heated at 55-60 °C for 10 minutes. Another lot of isopropanol (5 mL) was added to the mixture at 55-60 °C. The reaction mass was further heated for 2 hours and filtered at hot condition. The solid was dried at 50 °C to provide pure title compound.
  • Lithium tert-butoxide (100 g) was added slowly to a solution of 2-(isopropylsulfonyl)aniline (100 g) in dimethyl acetamide (800 mL) at about 19-26 °C.
  • a solution of 2,4,5 - trichloropyrimidine (161 g) in dimethyl acetamide (100 mL) was added to the above solution slowly in a period of about 2 hours.
  • the temperature of the reaction mass was observed to rise to 45 °C.
  • the reaction mass was allowed to cool to 25-30 °C.
  • the reaction mass was quenched by the addition of aqueous solution of ammonium chloride (10 %, 3 L). The reaction mass was stirred for 1 hour and the filtered to provide crude title compound.
  • Ceritinib dihydrochloride (1 g), as prepared in Example 31 was mixed with isopropanol (20 mL) and methanol (2 mL). The mixture was heated for about 1 hour at about 55-60 °C. The solid was filtered at hot condition and washed with isopropanol (5 mL). The solid was dried at 45 °C in vacuum oven for 1-2 hours to provide pure ceritinib dihydrochloride.
  • Ceritinib dihydrochloride 13 g, as prepared in Example 31 was mixed with isopropanol (50 mL) and methanol (5 mL). The mixture was heated for about 20 minutes at about 55-65 °C. The reaction mass was allowed to cool to 25-30 °C and stirred for 30 minutes. The solid was filtered and washed with isopropanol (10 mL). The solid was dried at 45 °C in vacuum oven for 1-2 hours to provide pure ceritinib dihydrochloride.
  • Ceritinib dihydrochloride (17 g), as prepared in Example 31 was mixed with isopropanol (340 mL) and methanol (30 mL). The mixture was heated for about 35 minutes at about 55-65 °C. The reaction mass was allowed to cool to 25-30 °C and stirred for 30 minutes. The solid was filtered at hot condition and washed with isopropanol (30 mL). The solid was dried at 45 °C in vacuum oven for 1-2 hours to provide pure ceritinib dihydrochloride.
  • Example 34A Purification of ceritinib dihydrochloride A mixture of ceritinib dihydrochloride (500 mg), as prepared in Example 33, dimethyl formamide (5 mL) and acetonitrile (10 mL) was heated for 30 minutes at 65-75 °C. The solid was filtered at the hot condition and washed with acetonitrile (5 mL). The compound was dried in vacuum oven at 45 °C for 1-2 hours to provide pure title compound.
  • the reaction mass was cooled to 25- 30 °C and filtered through celite pad.
  • the celite pad was washed with ethyl acetate (1.5 L).
  • the organic layer was distilled under vacuum to afford the crude product.
  • the crude product was dissolved in ethyl acetate (2.5 L) and washed with water (1 L) and saturated aqueous solution of sodium bicarbonate (2.5 L).
  • the organic layer was separated and stirred with aqueous solution of hydrochloric acid (0.5 N, 2.5 L).
  • the reaction mass was cooled to 25- 30 °C and filtered through celite pad.
  • the celite pad was washed with ethyl acetate (1.5 L).
  • the organic layer was distilled under vacuum to afford the crude product.
  • the crude product was dissolved in ethyl acetate (2.5 L) and washed with water (1 L) and saturated aqueous solution of sodium bicarbonate (2.5 L).
  • the organic layer was separated and stirred with aqueous solution of hydrochloric acid (0.5 N, 2.5 L).
  • the crude compound was dissolved in acetone (1.5 L).
  • a solution of oxalic acid (180 g) in acetone (1.5 L) was added to the above solution drop wise at about 25 °C in a period of about 2 hours.
  • Another lot of acetone (1 L) was added to the reaction mass.
  • the reaction mass was heated at 50-60 °C and stirred for about 1 hour.
  • the solid was filtered under hot condition and washed with acetone (1 L). The solid was dried at 45 °C under vacuum to provide the title compound.

Abstract

La présente demande concerne un procédé de préparation de céritinib et de ses intermédiaires. Plus spécifiquement, la présente demande concerne un procédé de préparation de N-(4- (1-benzyl-1,2,3,6-tétrahydropyridin-4-yl)-2-isopropoxy-5-méthylphényl)acétamide (VC) comprenant le traitement d'un N-(4-(bromométhyl)-2-isopropoxy-5-méthylphényl)acétamide (IIID) avec une 1-benzylpipéridin-4-one (IVA). Un procédé de conversion du N-(4-(1-benzyl- 1,2,3,6-tétrahydropyridin-4-yl)-2-isopropoxy-5-méthylphényl)acétamide (VC) en céritinib ou en un sel d'addition d'acide de celui-ci est en outre décrit.
PCT/IB2016/053339 2015-06-08 2016-06-08 Procédé de préparation de céritinib WO2016199020A1 (fr)

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IN2858CH2015 2015-06-08
IN2858/CHE/2015 2015-06-08
IN201641009375 2016-03-17
IN201641009375 2016-03-17

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CN106854182A (zh) * 2016-12-19 2017-06-16 山东轩德医药科技有限公司 一种2,5‑二氯‑n‑(2‑(异丙基磺酰基)苯基)嘧啶‑4‑胺的制备方法
CN110143947A (zh) * 2019-05-29 2019-08-20 华东师范大学 一种色瑞替尼类似物的制备方法
CN111410649A (zh) * 2019-01-04 2020-07-14 南京海润医药有限公司 一种塞瑞替尼的制备方法
CN115215788A (zh) * 2022-08-24 2022-10-21 苏州凯瑞医药科技有限公司 一种色瑞替尼关键中间体的制备方法

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CN104447515A (zh) * 2014-11-07 2015-03-25 药源药物化学（上海）有限公司 制备色瑞替尼的新中间体及其制备方法

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CN106854182A (zh) * 2016-12-19 2017-06-16 山东轩德医药科技有限公司 一种2,5‑二氯‑n‑(2‑(异丙基磺酰基)苯基)嘧啶‑4‑胺的制备方法
CN106854182B (zh) * 2016-12-19 2020-02-07 山东轩德医药科技有限公司 一种2,5-二氯-n-(2-(异丙基磺酰基)苯基)嘧啶-4-胺的制备方法
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CN111410649B (zh) * 2019-01-04 2022-09-02 南京海润医药有限公司 一种塞瑞替尼的制备方法
CN110143947A (zh) * 2019-05-29 2019-08-20 华东师范大学 一种色瑞替尼类似物的制备方法
CN110143947B (zh) * 2019-05-29 2021-10-15 华东师范大学 一种色瑞替尼类似物的制备方法
CN115215788A (zh) * 2022-08-24 2022-10-21 苏州凯瑞医药科技有限公司 一种色瑞替尼关键中间体的制备方法
CN115215788B (zh) * 2022-08-24 2023-09-22 苏州凯瑞医药科技有限公司 一种色瑞替尼关键中间体的制备方法

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