WO2019130229A1 - Procédés et intermédiaires pouvant être utilisés pour la préparation de rucaparib - Google Patents

Procédés et intermédiaires pouvant être utilisés pour la préparation de rucaparib Download PDF

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WO2019130229A1
WO2019130229A1 PCT/IB2018/060640 IB2018060640W WO2019130229A1 WO 2019130229 A1 WO2019130229 A1 WO 2019130229A1 IB 2018060640 W IB2018060640 W IB 2018060640W WO 2019130229 A1 WO2019130229 A1 WO 2019130229A1
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formula
compound
group
rucaparib
recited
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PCT/IB2018/060640
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English (en)
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Sureshbabu JAYACHANDRA
Madhuresh Sethi
Vipin Kumar Kaushik
Vijaya Krishna RAVI
Bhaskar Kumar TELAGAMSETTY
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Mylan Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/04—Esters of boric acids

Definitions

  • the present invention relates to a process for the preparation of rucaparib and its pharmaceutically acceptable salts.
  • Rucaparib is an inhibitor of the mammalian polyadenosine 5’-diphosphoribose polymerase (PARP) enzyme. Rucaparib is chemically known as 8-fluoro-l, 3,4,5- tetrahydro-2-[4-[(methylamino)methyl]phenyl]-6H-pyrrolo[4,3,2-ef][2]benzazepin-6-one and its chemical structure is shown below.
  • PARP polyadenosine 5’-diphosphoribose polymerase
  • Rucaparib is marketed in the United States under the tradename RUBRACA ® by Clovis Oncology.
  • RUBRACA ® contains the camsylate salt of rucaparib, which has a chemical name of 8-fhioro-2- ⁇ 4-[(methylamino)methyl]phenyl ⁇ - 1,3,4, 5-tetrahydro-6H- azepino[5,4,3-cd]indol-6-one ((lS,4R)-7,7-dimethyl-2-oxobicyclo[2.2.l]hept-l- yl)methanesulfonate.
  • the chemical formula of rucaparib camsylate is Ci 9 Hi 8 FN 3 0*CioHi 6 0 4 S and the chemical structural shown below.
  • Rucaparib and process for its preparation are disclosed in U.S. Patent Nos. 6,495,541 and 7,323,562, and in Adam T. Gillmore, et al.,“ Multkilogram Scale-Up of a Reductive Alkylation Route to a Novel PARP Inhibitor. Organic Process Research & Development. 16 (12), 1897-1904 (2012). Rucaparib camsylate is disclosed in U.S. Patent No.
  • the present invention provides a process for the preparation of rucaparib.
  • rucaparib may be prepared by a process that includes the steps of:
  • Each“R” is independently selected from the group consisting of hydrogen (H) and an alkyl moiety, or together the“R” moieties form a cyclic ring, optionally containing one or more of O or N and optionally substituted with an alkyl moiety.
  • the compounds of Formula- A, Formula-B, and/or rucaparib may be complexed with a salt.
  • the leaving group L may be a halogen, for example, -F, -Cl, -Br, or -I.
  • the leaving group L is -Br and the protecting group P is methyl carbamate.
  • R is either H in each instance, or together the “R” moieties combine to form a heterocyclic ring.
  • rucaparib may be prepared by a process that includes the steps of:
  • Each“R” is independently selected from the group consisting of hydrogen (H) and an alkyl moiety, or together the“R” moieties form a cyclic ring, optionally containing one or more of O or N and optionally substituted with an alkyl moiety.
  • the compound of Formula-B may be optionally converted to an acid addition salt and the deprotecting step yields the acid addition salt of rucaparib.
  • “R” is H.
  • the present invention provides a process for the preparation of a compound of Formula-E.
  • the compound of Formula-E may be prepared by a process that includes the steps of:
  • L is a leaving group and “P” is an amine protecting group.
  • the protecting group is methyl carbamate.
  • Leaving groups (“L”) are well known to those skilled in the art and may be, for example, a halogen, an alkyl sulfonyloxy group, or an aryl sulfonyloxy group. Suitable halogens include -F, -Cl, -Br, and -I.
  • One suitable alkyl sulfonyloxy group includes, but is not limited to a methylsulfonyloxy group.
  • One suitable aryl sulfonyl group includes, but is not limited to, a p-toluene sulfonyloxy group.
  • One of skill in the art would recognize many other suitable leaving groups similar to those named above.
  • the compound of Formula-E may be further converted into rucaparib or a pharmaceutically acceptable salt thereof.
  • the present invention provides a process for the preparation a compound of Formula-C 1.
  • the compound of Formula-Cl may be prepared by a process that includes the steps of:
  • the amine protecting group is methyl chloroformate.
  • the solvent may be, for example, l,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dichloromethane, toluene, acetone, dimethyl formamide, or mixtures thereof.
  • the solvent is dichloromethane.
  • the compound of Formula-Cl may be further converted into rucaparib or a pharmaceutically acceptable salt thereof.
  • the compound of Formula-Cl may be prepared by a process that includes the steps of:
  • the amine protecting group is methyl chloroformate.
  • the solvent may be an ether solvent, a polar aprotic solvent, or mixtures thereof.
  • Suitable ether solvents include, but are not limited to, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, or mixtures thereof.
  • polar aprotic solvents include, but are not limited to, acetonitrile, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidine, and mixtures thereof.
  • the compound of Formula-Cl may be further converted into rucaparib or a pharmaceutically acceptable salt thereof.
  • the present invention provides a process for the preparation of a compound of Formula-M.
  • the compound of Formula-M may be prepared by a process that includes the steps of:
  • suitable solvents include, but are not limited to, methanol, ethanol, propanol, butanol, ethyl acetate, isopropyl acetate, tetrahydrofiiran, 2-methyl tetrahydrofuran, toluene, diisopropyl ether, methyl t-butyl ether, isopropyl ether, isopropanol, dichloromethane, chloroform, or mixtures thereof.
  • the present invention provides a process of preparing a compound of Formula-D.
  • the compound of Formula-D may be prepared by a process that includes the step of treating a compound of Formula-A with a suitable reagent in the presence of a base and a solvent
  • each“R” is independently selected from the group consisting of hydrogen (H) and an alkyl moiety, or together the“R” moieties form a cyclic ring, optionally containing one or more of O or N and optionally substituted with an alkyl moiety.
  • Suitable reagents include, but are not limited to, trimethyl borane, sequential trimethyl borane and diethanolamine, bis(pinacolato)diborane, and trialkylborates.
  • suitable trialkylborates include, but are not limited to, triisopropyl borate, trimethyl borate, or triethyl borate.
  • the compound of Formula-D may be converted to rucaparib or a pharmaceutically acceptable salt thereof.
  • the present invention provides novel compounds of Formula-Cl, Formula-C2, Formula-C3, Formula-D 1, Formula-D2, Formula-D3, and Formula-F. Each of these compounds may be useful in the preparation of rucaparib.
  • the present invention provides processes for the preparation of rucaparib, intermediates thereof, and pharmaceutically acceptable salts of rucaparib.
  • the intermediates utilized in the reaction schemes disclosed herein contain moieties that are interchangeable in different embodiments, for example, leaving groups, protecting groups, and moieties designated (and well understood in the art) as“R”.
  • each“R” may be, independently, a hydrogen (H) or an alkyl moiety, or together the “R” moieties form a cyclic ring, optionally containing one or more of O or N and optionally substituted with an alkyl moiety.
  • Leaving groups are well known to those skilled in the art and may be, for example, a halogen, an alkyl sulfonyloxy group, or an aryl sulfonyloxy group.
  • Suitable halogens include -F, -Cl, -Br, and -I.
  • One suitable alkyl sulfonyloxy group includes, but is not limited to a methylsulfonyloxy group.
  • One suitable aryl sulfonyl group includes, but is not limited to, a p-toluene sulfonyloxy group.
  • One of skill in the art would recognize many other suitable leaving groups similar to those named above.
  • Amine protecting groups are well known to those skilled in the art. Examples of suitable amine protecting groups, as well as suitable conditions for protecting and deprotecting can be found in prior art, such as J.F.W. McOmie (Ed.), Protective Groups in Organic Chemistry. Plenum Press, London (1973) and Greene's Protective Groups in Organic Synthesis. 5th Edition. Peter G. M. Wuts, John Wiley & Sons, Inc., Hoboken, New Jersey (2014), which are incorporated herein by reference in their entirety.
  • suitable protecting groups include, but are not limited to, carbonyls (e.g., methyl carbamate, 9- fluorenylmethyoxycarbonyl (Fmoc), trichloroethoxycarbonyl (Troc), tert- butyloxycarbonyl (BOC), 2-trimethylsilylethyloxycarbonyl (Teoc), allyloxycarbonyl (Alloc), p-methoxybenzyl carbonyl (Moz), and carboxybenzyl (Cbz)), sulfonyls (e.g., p- toluenesufonyl (Ts), trimethylsilylethanesulfoyl (Ses), tert-butylsulfonyl (Bus), 4- methoxyphenylsulfonyl, 4- nitrobenzene sulfonyl (nosyl)), trityl (trt), benzyl (
  • rucaparib may be prepared by a process that includes the steps of: a) reacting a compound of Formula-A with a compound of Formula-C to give a compound of Formula-B:
  • c) optionally converting rucaparib into its pharmaceutically acceptable salts Contemplated as within the scope of this embodiment is the use of pharmaceutically acceptable salts of Formula-A. In such instances, the salt complex would be carried through the reaction, creating the salt of Formula-B and the salt of rucaparib.
  • the salt may be, but is not limited to, hydrochloride, sulfuric, phosphorous, hydrobromide, oxalate, maleate, fumarate, malate, tartrate, citrate, benzoate, sulfonate, or camsylate.
  • a compound of Formula-A (or its salt) may be reacted with a compound of formula-C to yield a compound of Formula-B (or its salt).
  • This conversion may be carried out in the presence of a catalyst and a suitable solvent.
  • the catalyst may be, for example, l,l-bis(diphenylphosphino)ferrocene palladium (II) chloride, bis(dibenzylideneacetone)palladium(0) (“Pd(dba)2”), tris(dibenzylidenaeetone)palladium(0) (“Pd(dba)3”), 1, 1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (“Pd(dppp)2Ch”), tetrakis(triphenylphosphine)palladium(0) (“Pd(PPh3)4”), Palladium(II) acetate (“Pd(OAc)2”), or bis(triphenylphosphine)palladium(II) dichloride (“Pd(PPh3) 2 Ch”).
  • Pd(dba)2 bis(dibenzylideneacetone)palladium(0)
  • the solvent may be, for example, dimethyl formamide, dimethyl acetamide, l,4-dioxane, toluene, ethyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, monoglyme, diglyme, water, or mixtures thereof.
  • the compound of Formula-B may be optionally purified by forming an acid addition salt.
  • Suitable acid addition salts include, but are not limited to, hydrochloride, sulfuric, phosphorous, hydrobromide, oxalate, maleate, fumarate, malate, tartrate, citrate, benzoate, and sulfonate salts.
  • the compound of Formula-B may be converted into rucaparib by methods known in the art, for example, by the processes disclosed in U.S. Patent No. 7,323,562, which is hereby incorporated by reference.
  • Rucaparib may further converted into a pharmaceutically acceptable salts by methods well known in the art, for example, per the processes disclosed in U.S. Patent No. 9,045,487, which is hereby incorporated by reference.
  • both“R” moieties may be H and the protecting group may be methyl carbamate. This embodiment is shown below as Formula-C2.
  • the leaving group may be bromine. This embodiment is shown below as Formula-Al .
  • the compound of Formula-B l may be formed by reacting a compound of Formula-Al with a compound of Formula-C2, shown below.
  • An example of the preparation of the compound of Formula-Bl by this route is shown in Example 8.
  • Formula-Al may be prepared by methods known in the art, for example, by processes disclosed in U.S. Patent No. 6,495,541 and Chinese Patent No. 106008530, both which are hereby incorporated by reference.
  • the protecting group may be methyl carbamate and the“R” moieties may form a heterocyclic ring, shown below as Formula-C3.
  • Formula-C3 Formula-B l may be formed by reacting a compound of Formula-Al with a compound of Formula-C3, shown below.
  • An example of the preparation of the compound of Formula- B l by this route is shown in Example 9.
  • rucaparib may be prepared by a process that includes the steps of:
  • a compound of Formula-D may be reacted with a compound of Formula-E to result in a compound of Formula-B.
  • This may be carried out in the presence of a catalyst in a suitable solvent.
  • suitable solvents include, but are not limited to, dimethyl formamide, dimethyl acetamide, l,4-dioxane, toluene, ethyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, monoglyme, diglyme, water, or mixtures thereof.
  • Suitable catalyst include 1, 1- bis(diphenylphosphino)ferrocene palladium (II) chloride, bis(dibenzylideneacetone)palladium(0) (“Pd(dba)2”), tris(dibenzylidenaeetone)palladium(0) (“Pd(dba)3”), 1, 1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (“Pd(dppp)2Ch”), tetrakis(triphenylphosphine)palladium(0) (“Pd(PPh3)4”), Palladium(II) acetate (“Pd(OAc)2”), or bis(triphenylphosphine)palladium(II) dichloride (“Pd(PPh 3 )2Cl 2 ”).
  • the compound of Formula-B may purified, for example, by forming an acid addition salt.
  • Suitable salts include hydrochloride, sulfuric, phosphorous, hydrobromide, oxalate, maleate, fumarate, malate, tartarate, citrate, benzoate, sulfonate, and camsylate salts.
  • deprotecting of the salt of Formula-B will result in a salt of rucaparib.
  • Formula-B may be deprotected into rucaparib by methods known in the art, for example, by the processes disclosed in U.S. Patent No. 7,323,562, which is hereby incorporated by reference, or by any common methods well-known in the art.
  • Rucaparib may further converted into a pharmaceutically acceptable salts by methods well known in the art, for example, per the processes disclosed in U.S. Patent No. 9,045,487, which is hereby incorporated by reference
  • each“R” moiety may be H. This embodiment is shown below as Formula- Dl .
  • the leaving group may be bromine (-Br) and the protecting group may be a methyl carbamate group. This embodiment is shown below as Formula-El.
  • a compound of Formula-Dl may be reacted with a compound of Formula-El to result in the compound of Formula-B 1 as shown below.
  • An example of this reaction can be found in Example 10.
  • the “R” moieties may form a heterocyclic ring as shown below as Formula-D2.
  • a compound of Formula-D2 may be reacted with a compound of Formula-El to result in the compound of Formula-B 1.
  • An example of this reaction is disclosed in Example 11.
  • the“R” moieties may form a heterocyclic ring substituted with methyl groups, shown below as Formula-D3.
  • a compound of Formula-D3 may be reacted with a compound of Formula-El to result in the compound of Formula-B 1.
  • An example of this reaction is disclosed in Example 12.
  • the present invention provides a method for preparing a compound of Formula-D.
  • a compound of Formula-D may prepared by reacting a compound of Formula-A or an acid addition salt thereof with suitable reagent in the presence of a base and a solvent to give a compound of Formula-D.
  • a compound of Formula-A or an acid addition salt thereof may be converted to a compound of Formula-D.
  • suitable reagent in the presence of a base in a suitable solvent.
  • the suitable base includes, but is not limited to, n-butyl lithium.
  • Suitable solvents include, but are not limited to, tetrahydrofuran, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, l,4-dioxane, dimethyl formamide, dimethyl acetamide, toluene, ethyl acetate, 2- methyl tetrahydrofuran, monoglyme, diglyme, water, or mixtures thereof.
  • tetrahydrofuran is used.
  • Suitable acid addition salts of Formula-A include, but are not limited to, hydrochloride, sulfuric, phosphorous, hydrobromide, oxalate, maleate, fumarate, malate, tartarate, citrate, benzoate, sulfonate, or camsylate salts.
  • Suitable reagents may be chosen based on the desired identity of the“R” moieties.
  • the reagent may be trimethyl borane, sequential trimethyl borane and diethanolamine, bis(pinacolato)diborane, and trialkylborates.
  • suitable trialkyl borates include, but are not limited to, triisopropyl borate, trimethyl borate, or trimethyl borate.
  • the suitable reagent is trimethyl borane and the reaction results in the formation of a compound of Formula-D 1 , shown below.
  • An example of the preparation of a compound of Formula-Dl is shown in Example 6.
  • a compound of Formula-Dl may be further reacted with diethanolamine to result in the formation of a compound of Formula-D2, shown below.
  • An example of the preparation of a compound of Formula-D2 is shown in Example 7.
  • the suitable reagent is bis(pinacolato)diborane and results in the formation of a compound of Formula-D3, shown below.
  • An example of preparation of a compound of Formula-D3 is shown in Example 5.
  • the present invention provides a method for preparing a compound of Formula-E.
  • a compound of Formula-E may be prepared by a process that includes the steps of:
  • a compound of Formula-F may be subjected to reductive amination to give a compound of Formula-G.
  • This may be carried out, for example, by reacting a compound of Formula-E with methylamine followed by addition of suitable reducing agent.
  • suitable reducing agents include, but are not limited to, sodium cyanoborohydride, potassium cyanoborohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride, Raney-Ni, Pd/C, or trichlorosilane.
  • the compound of Formula-G may then be protected with a suitable amine protecting group to give a compound of Formula-E. Any suitable conditions for the protecting step may be used, e.g., J.F.W.
  • a compound of Formula-E wherein“P” is an alkoxy carbonyl group may be formed by reacting the compound of Formula-G with an alkyl halo formate in the presence of a suitable base and solvent.
  • the alkyl halo formate may be, for example, methyl chloroformate.
  • Suitable bases include, but are not limited to, inorganic bases such as alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali amines, alkali alkoxides, and organic bases such as pyridine, triethylamine, and N,N- diisopropylethylamine, morpholine, and N-methyl morpholine.
  • triethylamine is used.
  • suitable solvents include l,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dichloromethane, toluene, acetone, dimethyl formamide, or mixtures thereof.
  • the solvent is dichloromethane.
  • the present invention provides a method for the preparation of a compound of Formula-C.
  • a compound of Formula-C may be prepared by a process that includes the steps of:
  • a compound of Formula-H may be subjected to reductive amination to yield a compound of Formula-I. This may be carried out, for example, by reacting a compound of Formula-H with methylamine and adding a suitable reducing agent.
  • suitable reducing agents include, but are not limited to sodium cyanoborohydride, potassium cyanoborohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride, Raney-nickel, palladium on carbon (Pd/C), or trichlorosilane.
  • the compound of Formula-I may then be protected with a suitable amine protecting group to yield a compound of Formula-C 1.
  • Amine protecting groups (“P”) are as defined above.
  • the“P” in Formula-Cl may be an alkoxy carbonyl group and may be formed by reacting a compound of Formula-I with an alkyl halo formate in the presence of a suitable base and solvent.
  • Suitable bases include, but are not limited to, inorganic bases such as alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali amines, alkali alkoxides, and organic bases such as pyridine, triethylamine, and N,N- diisopropylethylamine, morpholine, and N-methyl morpholine. In particularly useful embodiments, triethylamine is used.
  • solvents examples include l,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dichloromethane, toluene, acetone, dimethyl formamide, or mixtures thereof.
  • the solvent is dichloromethane.
  • the alkyl halo formate may be methyl chloroformate and the compound of Formula-I may be converted to a compound of Formula-C2.
  • a compound of Formula-Cl may be prepared a process that includes the steps of:
  • a compound of Formula-J may be reacted with methylamine in the presence of a suitable solvent.
  • suitable solvents include, but are not limited to, ethers, polar aprotic solvents, and mixtures thereof.
  • suitable ethers include, but are not limited to, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, or mixtures thereof.
  • suitable polar aprotic solvents include, but are not limited to, acetonitrile, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidine, or mixtures thereof.
  • a compound of Formula-I wherein“P” is an alkoxy carbonyl group may be formed by reacting the compound of Formula-I with an alkyl halo formate in the presence of a suitable base and solvent.
  • the alkyl halo formate may be, for example, methyl chloroformate, in which case, a compound of Formula-C2 would be formed.
  • Suitable bases include, but are not limited to, inorganic bases such as alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali amines, alkali alkoxides, and organic bases such as pyridine, triethylamine, and N,N-diisopropylethylamine, morpholine, and N-methyl morpholine. In particularly useful embodiments, triethylamine is used.
  • solvents examples include l,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dichloromethane, toluene, acetone, dimethyl formamide, or mixtures thereof.
  • the solvent is dichloromethane.
  • the present invention provides a process for the preparation of a compound of Formula-M.
  • a compound of Formula-M may be prepared by a process that includes the steps of:
  • a compound of Formula-H may be reacted with diethanolamine to yield a compound of Formula-K.
  • a solvent for example, methanol, ethanol, propanol, butanol, ethyl acetate, isopropyl acetate, tetrahydrofiiran, 2-methyl tetrahydrofuran, toluene, diisopropyl ether, methyl t-butyl ether, isopropyl ether, isopropanol, dichloromethane, chloroform, or mixtures thereof.
  • the compound of Formula-K may then be reacted with methylamine followed by addition of a suitable reducing agent to give a compound of Formula-L.
  • suitable reducing agents include, but are not limited to sodium cyanoborohydride, potassium cyanoborohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride, Raney-Ni, Pd/C, or trichlorosilane.
  • Amine protecting groups (“P”) are well known to those skilled in the art and as defined above.
  • “P” may be an alkoxy carbonyl group in the compound of Formula-M and may be formed by reacting the compound of Formula-L with an alkyl halo formate in the presence of a suitable base and solvent.
  • suitable bases include, but are not limited to, inorganic bases such as alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali amines, alkali alkoxides, and organic bases such as pyridine, triethylamine, and N,N-diisopropylethylamine, morpholine, and N-methyl morpholine.
  • solvents examples include l,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofiiran, dichloromethane, toluene, acetone, dimethyl formamide, 2-methyl tetrahydrofiiran, monoglyme, diglyme, or mixtures thereof.
  • the solvent is dichloromethane.
  • the alkyl halo formate is methyl chloroformate
  • the compound of Formula-L may be converted to a compound of Formula-C3, as shown below:
  • the present invention provides novel intermediates of Formula-Cl, Formula-C2, Formula-C3, Formula-Dl, Formula-D2, Formula-D3, and Formula-L.
  • each intermediate shown above may be converted into rucaparib or a pharmaceutically acceptable salt thereof.
  • rucaparib or pharmaceutically acceptable salts thereof with a high purity may be prepared.
  • Rucaparib including pharmaceutically acceptable salts thereof, prepared by methods disclosed herein, may be useful for incorporating into pharmaceutical dosage forms.
  • the dosage forms may be oral dosage forms such as capsules or tablets.
  • Dosage forms may include pharmaceutically acceptable excipients such as microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol, talc, and any combination thereof. Artificial coloring and flavoring may also be incorporated.
  • Tablets or capsules may contain an effective dose of about 200 mg to about 300 mg of rucaparib, including 200 mg, 250 mg, and 300 mg.
  • rucaparib is incorporated into a dosage form as the camsylate salt.
  • Tablets or capsules may be useful in the treatment of recurrent epithelial ovarian, fallopian tube, prostate, bladder, or primary peritoneal cancer in patients who are in a complete or partial response to platinum-based chemotherapy or in the treatment of deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies. Tablets or capsules may be useful in monotherapy, or in combination with other anti -cancer agents.

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Abstract

La présente invention concerne un procédé de préparation de rucaparib ou des sels pharmaceutiquement acceptables de celui-ci. L'invention concerne également de nouveaux intermédiaires qui peuvent être convertis en rucaparib ou des sels pharmaceutiquement acceptables de celui-ci.
PCT/IB2018/060640 2017-12-28 2018-12-27 Procédés et intermédiaires pouvant être utilisés pour la préparation de rucaparib WO2019130229A1 (fr)

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CN114437085B (zh) * 2020-11-03 2023-06-23 烟台弘邦医药科技有限公司 一种瑞卡帕布中间体的制备方法

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CN111004244A (zh) * 2019-12-27 2020-04-14 重庆市碚圣医药科技股份有限公司 一种瑞卡帕布樟脑磺酸盐的合成方法
CN114437085B (zh) * 2020-11-03 2023-06-23 烟台弘邦医药科技有限公司 一种瑞卡帕布中间体的制备方法

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