[go: up one dir, main page]

WO1997046559A1 - Procede de preparation de 9-hydroxyellipticine - Google Patents

Procede de preparation de 9-hydroxyellipticine Download PDF

Info

Publication number
WO1997046559A1
WO1997046559A1 PCT/JP1997/001825 JP9701825W WO9746559A1 WO 1997046559 A1 WO1997046559 A1 WO 1997046559A1 JP 9701825 W JP9701825 W JP 9701825W WO 9746559 A1 WO9746559 A1 WO 9746559A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl group
group
lower alkyl
acid
hydroxyellipticine
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/JP1997/001825
Other languages
English (en)
Inventor
Kenji Tsujihara
Naoyuki Harada
Tomiki Hashiyama
Kazuhiko Kondo
Hiroshi Fujii
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.)
Mitsubishi Tanabe Pharma Corp
Original Assignee
Tanabe Seiyaku Co 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 Tanabe Seiyaku Co Ltd filed Critical Tanabe Seiyaku Co Ltd
Priority to AU29764/97A priority Critical patent/AU2976497A/en
Publication of WO1997046559A1 publication Critical patent/WO1997046559A1/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system

Definitions

  • the present invention relates to an improved novel process for preparing 9-hydroxyellipticine which is useful as an antitumor agent or an intermediate for preparing other medicaments.
  • Pyridocarbazole alkaloids such as ellipticine, 9-methoxyellipticine are well known alkaloids which exist in Apocynaceae. These compounds having a pyridocarbazole nucleus have been known to show anti-tumor activities, for example, elliptinium acetate (chemical name: 2-methyl-9-hydroxyellipticinium acetate) is commercialized as an agent for the treatment of breast cancer, and ellipticine and 9-hydroxyellipticine have been known to show potent anti ⁇ tumor activities.
  • 9-hydroxyellipticine has been known to be useful as an intermediate for preparing ellipticinium acetate or 9-acyloxyellipticine derivatives which are disclosed in JP-A-6-279441.
  • J. Med. Chem., 18, 755 (1975) discloses a process for preparing 9-hydroxyellipticine by de-methylating 9-methoxyellipticine.
  • this process is needed to be carried out at a high temperature with using pyridine hydrochloride, so that many undesirable by-products such as dimers are also produced.
  • 9-hydroxy- ellipticine is of poor solubility in solvents, so that the purification thereof by a conventional purification method such as recrystallization is very difficult.
  • the starting 9-methoxyellipticine is obtained from natural resources, or may be prepared by the method disclosed in Aust. J. Chem., 20, 2715 (1967), i.e., by formylating the 3-position of 6-methoxy-l ,4-dimethyl- carbazole, reacting the product with an acetal of aminoacetaldehyde, subjecting the resulting azomethine compound to cyclization in the presence of ortho- phosphoric acid.
  • the cyclization reaction is carried out with using phosphoric acid and phosphorus pentoxide at a high temperature, so that the process is not industrially suitable and there are produced many by-products under such severe reaction conditions.
  • JP-B-59-51956 discloses another process for preparing 9-hydroxy- ellipticine.
  • 9-hydroxyellipticine is prepared by de-methylating 6- methoxy-l ,4-dimethylcarbazole, benzoylating the hydroxy group of the resulting 6-hydroxy-l ,4-dimethylcarbazole which is unstable and readily oxidized, formylating the 3-position of the product, reacting the product with an acetal of aminoacetaldehyde, subjecting the resulting azomethine compound to cyclization in the presence of phosphoric acid, etc., and removing a benzoyl group from the resulting 9-benzoyloxyellipticine with using hydrochloric acid.
  • this process also has defects. That is, it consists the step of using 6- hydroxy- 1 ,4-dimethylcarbazole which is unstable and readily oxidized as an intermediate, and the step of the same cyclization reaction as in the method disclosed in the above-mentioned Aust. J. Chem., 20, 2715 (1967). Therefore, many undesirable by-products are also generated, so that the yield of 9-hydroxy- ellipticine is low, and it is very difficult to isolate and purify 9-hydroxyellipticine thus prepared.
  • J. Med. Chem., 18, 755 (1975) discloses another process for preparing 8,9-dimethoxyellipticine.
  • 8,9-dimethoxyellipticine is prepared by formylating the 3-position of 6,7-dimethoxy-l ,4-dimethylcarbazole, reacting the product with an acetal of aminoacetaldehyde, reducing the resulting azomethine compound to a corresponding amine compound, p-toluene- sulfonylating the amino group thereof, and then subjecting the product to cyclization with hydrochloric acid.
  • Tetrahedron Letters, 23, 681 (1982) discloses a process for converting an alkyl-alkyl ether into a corresponding ester thereof by treating it with an acyl halide and sodium iodide. According to the method, ⁇ -cholestanyl methyl ether can be converted into ⁇ -pivaloyloxycholestane by treating it with sodium iodide and pivaloyl chloride.
  • this literature never discloses a process for converting an alkyl-aryl ether into an ester thereof.
  • An object of the present invention is to provide an improved novel process for preparing 9-hydroxyellipticine which is unstable, readily oxidized and difficult to be purified, at high yield and with efficiency.
  • Another object of the present invention is to provide a process for preparing a 6-(alkanoyloxy or arylcarbonyioxy)- 1 ,4-dimethylcarbazole, which is an intermediate for preparing 9-hydroxyellipticine, from a 6-lower alkoxy- 1 ,4- dimethylcarbazole in a single step.
  • 9-hydroxyellipticine or a salt thereof can be prepared in a single step by treating an acetal compound of the formula (I):
  • R 1 is an alkyl group or an aryl group
  • R 2 is a lower alkyl group or an
  • aryl group, R 3 and R 4 are the same or different and each are a substituted or unsubstituted lower alkyl group, or both may combine each other at their termini to form a substituted or unsubstituted lower alkylene group, or a corresponding aldehyde thereof, with an acid, and if necessary, converting the resulting 9-hydroxyellipticine into a salt thereof.
  • the "alkyl group” for R 1 in the acetal compound of the formula (I) includes, for example, a straight chain or branched chain alkyl group having 1 to 21 carbon atoms, or a cyclic alkyl group having 3 to 6 carbon atoms.
  • the "aryl group” includes, for example, a substituted or unsubstituted phenyl group. Examples of the substituent on the phenyl group include a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, a halogen atom and a nitro group.
  • Suitable examples of the straight chain or branched chain alkyl group having 1 to 21 carbon atoms are methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, pentyl, hexyl, octyl, dodecyl and docosyl.
  • Suitable examples of the cyclic alkyl group having 3 to 6 carbon atoms are cyclopropyl and cyclohexyl.
  • Suitable examples of the substituted or unsubstituted phenyl group are phenyl, 2- or 4-tolyl, xylyl, 2- or 4-anisyl, 4-chlorophenyl and 4-nitrophenyl group.
  • the alkyl group may preferably be a lower alkyl group, for example, a straight chain or branched chain alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, pentyl and hexyl, or a cyclic alkyl group having 3 to 6 carbon atoms such as cyclopropyl and cyclohexyl.
  • R i CO- may preferably be a group which can be easily removed in the form of R i CO- by hydrolysis using an acid, and include, for example, methyl, ethyl, t-butyl, phenyl, 4-chlorophenyl and 4-nitrophenyl.
  • the group for R 2 may be a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted phenyl group.
  • the straight chain or branched chain alkyl group having 1 to 6 carbon atoms is, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, pentyl and hexyl.
  • the substituted or unsubstituted phenyl group is, for example, phenyl, tolyl, and methoxyphenyl.
  • the preferable group for R 2 is methyl, phenyl, p-tolyl and p- methoxyphenyl.
  • the lower alkyl group for R 3 and R 4 includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, pentyl and hexyl, and the lower alkylene group includes a straight chain or branched chain alkylene group having 2 to 6 carbon atoms, for example, ethylene and trimethylene.
  • the substituent on the lower alkyl group and/or the lower alkylene group is preferably a lower alkoxy group such as methoxy and ethoxy.
  • the conversion of an acetal compound of the formula (I) or a corresponding aldehyde thereof into 9-hydroxyellipticine is preferably carried out in the presence of an acid in a solvent.
  • the acid includes a mineral acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, perchloric acid) or an organic acid (e.g., trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid).
  • a mineral acid is preferable, and hydrochloric acid, hydrobromic acid, sulfuric acid are especially preferable.
  • the amount of the acid is not critical, and it is usually in the range of 10 to about 2000 mole %, more preferably in the range of 100 to about 1200 mole %, to the amount of the compound (I).
  • the solvent used in the present invention may be any solvent which does not disturb the reaction, for example, water, halogenated aliphatic hydrocarbons (e.g., chloroform, dichloromethane), ketones (e.g., acetone, methyl ethyl ketone), ethers (e.g., dioxane, tetrahydrofuran), nitriles (e.g., acetonitrile), halogenated or non-halogenated aromatic hydrocarbons (e.g., chlorobenzene, toluene) and organic acids (e.g., acetic acid, trifluoroacetic acid), and among these solvents, ethers such as tetrahydrofuran and dioxane, and ketones such as acetone are especially preferable.
  • halogenated aliphatic hydrocarbons e.g., chloroform, dichloromethane
  • ketones e.g., acetone, methyl e
  • solvents may be used alone, but if necessary, can be used in the form of a mixture of two or more solvents in a suitable ratio, in a single phase or two phases.
  • the reaction is preferably carried out at a temperature between 25°C and
  • 200°C preferably at a temperature between 50°C and 120°C, most preferably at a temperature between 60°C and 70°C.
  • 9-hydroxyellipticine can be converted into a salt thereof, if necessary, by treating it with an acid.
  • Such salt include, for example, a salt with a mineral acid (e.g., hydrochloride, sulfate, phosphate, hydrobromide), or a salt with an organic acid (e.g., methanesulfonate, acetate, fumarate, maleate, oxalate, benzenesulfonate, p-toluenesulfonate).
  • a mineral acid e.g., hydrochloride, sulfate, phosphate, hydrobromide
  • an organic acid e.g., methanesulfonate, acetate, fumarate, maleate, oxalate, benzenesulfonate, p-toluenesulfonate.
  • the acetal compound of the formula (I) or a corresponding aldehyde thereof is novel compounds, and can be prepared by the following steps:
  • R 5 is a lower alkyl group, in a single step
  • R 1 is an alkyl group or an aryl group, to give a 3-formylcarbazole derivative of the formula (II):
  • R 1 is the same as defined above, converting the formyl group of the compound (II) into a formylmethylaminomethyl group which may optionally be in the form of an acetal, followed by lower-alkylsulfonylating or aryl- sulfonylating the amino group of the product.
  • the de-alkylation of the 6-lower alkoxy group of the compound (IV) and alkanoylating or arylcarbonylating are carried out in a single step by reacting the compound (IV) with a reactive derivative of an alkylcarboxylic acid or arylcarboxylic acid in the presence or absence of an alkali metal iodide or an alkaline earth metal iodide in a solvent.
  • the reactive derivative of an alkylcarboxylic acid or arylcarboxylic acid may preferably be an alkanoyl halide or an arylcarbonyl halide, and a lower alkanoyl halide is especially preferable.
  • the alkanoyl halide includes, for example, a straight chain or branched chain alkanoyl halide having 2 to 22 carbon atoms, or a cyclic alkanecarbonyl halide having 4 to 7 carbon atoms, for example, acetyl halide, propionyl halide, pivaloyl halide, cyclopropanecarbonyl halide, cyclohexanecarbonyl halide, dodecanoyl halide and docosanoyl halide.
  • Preferable alkanoyl halides are, for example, a lower alkanoyl halide such as a straight chain or branched chain alkanoyl halide having 2 to 7 carbon atoms (e.g., acetyl halide, propionyl halide, pivaloyl halide) or a cyclic alkanecarbonyl halide having 4 to 7 carbon atoms (e.g., cyclopropanecarbonyl halide, cyclohexanecarbonyl halide).
  • Most preferable alkanoyl halides are acetyl halide and pivaloyl halide.
  • the arylcarbonyl halide includes a substituted or unsubstituted benzoyl halide, for example, benzoyl halide, 4-chlorobenzoyl halide, 4-nitrobenzoyl halide, 2- or 4-toluoyl halide, xyloyl halide, and 2- or 4-anisoyl halide.
  • benzoyl halide is more preferable.
  • the alkali metal iodide includes, for example, lithium iodide, sodium iodide, and potassium iodide.
  • the alkaline earth metal iodide is, for example, calcium iodide.
  • An alkali metal iodide such as sodium iodide and potassium iodide is more preferable.
  • the reaction may be carried out without using an alkali metal iodide.
  • solvent there may be used any solvent which does not disturb the reaction.
  • solvent includes, for example, nitriles (e.g., acetonitrile), halogenated aliphatic hydrocarbons (e.g., chloroform, dichloromethane, dichloroethane) and amides (e.g., N,N-dimethylacetamide, l,3-dimethyl-2- imidazolidinone).
  • the reaction is carried out at a temperature between 0°C and 150°C, preferably at a temperature between 40°C and 100°C, most preferably at a temperature between 70°C and 90°C.
  • the formylation of the 3-position of the compound (III) is carried out by treating the compound (III) with a formylating agent in a solvent.
  • a formylating agent there may be mentioned a conventional formylating agent which can formylate a benzene ring.
  • Such formylating agent includes, for example, a combination of N-methylformanilide and phosphorus oxychloride, a combination of dichloromethyl methyl ether and titanium tetrachloride, and a combination of hexamethylenetetramine and acetic acid.
  • a combination of N-methylformanilide and phosphorus oxychloride, or a combination of dichloromethyl methyl ether and titanium tetrachloride are preferable.
  • solvent there may be used any solvent which does not disturb the reaction.
  • solvent includes, for example, halogenated or non-halogenated aromatic hydrocarbons (e.g., benzene, toluene, chlorobenzene, orthodichloro- benzene), halogenated aliphatic hydrocarbons (e.g., dichloroethane, dichloro- propane), and organic acids (e.g., acetic acid, trifluoroacetic acid).
  • aromatic hydrocarbons e.g., benzene, toluene, chlorobenzene, orthodichloro- benzene
  • halogenated aliphatic hydrocarbons e.g., dichloroethane, dichloro- propane
  • organic acids e.g., acetic acid, trifluoroacetic acid
  • the reaction may be carried out at a temperature between 40°C and 180°C, preferably at a temperature between 70°C and 130°C, most preferably at a temperature between 100°C and 120°C.
  • the reactions of converting the formyl group of the compound (II) into a forrnylmethylaminomethyl group which may optionally be in the form of an acetal, and lower-alkylsulfonylating or arylsulfonylating the amino group of the product, can be carried out by the steps:
  • the reaction between the compound (II) and the aminoacetaldehyde-lower alkyl acetal (or a lower alkylene acetal) can be carried out by a conventional imine-forming reaction.
  • the solvent there may be used any solvent which does not disturb the reaction.
  • Such solvent includes, for example, halogenated aliphatic hydrocarbons (e.g., chloroform, dichloro ⁇ methane), aromatic hydrocarbons (e.g., benzene, toluene), and ethers (e.g., diisopropyl ether, tetrahydrofuran, dioxane).
  • the reaction may be carried out at a temperature between 20°C and
  • 150°C preferably at a temperature between 50°C and 110°C, most preferably at a temperature between 50°C and 70°C.
  • the reduction reaction is carried out by catalytic hydrogenation with using a catalyst under hydrogen atmosphere in a suitable solvent, or by using a metal hydride in a suitable solvent.
  • the catalyst used in the catalytic hydrogenation may be preferably palladium-carbon, platinum-carbon, platinum oxide, and Raney nickel.
  • solvent there may be used any solvent which does not disturb the reaction.
  • solvent includes, for example, water, alcohols (e.g., methanol, ethanol), aromatic hydrocarbons (e.g., benzene, toluene), esters (e.g., ethyl acetate, butyl acetate), ethers (e.g., tetrahydrofuran, dioxane).
  • the reaction is preferably carried out at a temperature between 0°C and 100°C, preferably at a temperature between 10°C and 40°C.
  • the metal hydride may be any one which can reduce an imine and does not influence the 6-substituent, and includes, for example, metal hydrides such as sodium borohydride, lithium borohydride, sodium cyanoborohydride.
  • solvent there may be used any solvent which does not disturb the reaction.
  • solvent includes, for example, water, alcohols (e.g., methanol, ethanol), halogenated aliphatic hydrocarbons (e.g., chloroform, dichloro- methane), aromatic hydrocarbons (e.g., benzene, toluene), and ethers (e.g., diisopropyl ether, tetrahydrofuran, dioxane).
  • the reaction is preferably carried out at a temperature between -20°C and 70°C, preferably at a temperature between 0°C and 30°C.
  • the desired step of converting the acetal into an aldehyde is carried out by a conventional method. For example, it can be carried out by treating with an acid in a solvent or without a solvent.
  • the solvent there may be used any solvent which does not disturb the reaction.
  • solvent includes, for example, ketones (e.g., acetone), ethers (e.g., tetrahydrofuran, dioxane), alcohols (e.g., methanol).
  • the acid may be a mineral acid (e.g., hydrochloric acid, sulfuric acid, nitric acid) and an organic acid (e.g., methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid).
  • the conversion step may be employed after the step
  • the lower alkylsulfonyl halide is a straight chain or branched chain alkylsulfonyl halide having 1 to 6 carbon atoms, and includes, for example, methanesulfonyl halide and ethanesulfonyl halide. Methane- sulfonyl halide is especially preferable.
  • the arylsulfonyl halide is a substituted or unsubstituted benzenesulfonyl halide, and includes, for example, benzenesulfonyl halide, p-toluenesulfonyl halide and p-methoxybenzenesulfonyl halide. Benzenesulfonyl halide and p- toluenesulfonyl halide are especially preferable.
  • the acid scavenger may be inorganic bases or organic bases.
  • the inorganic base includes, for example, an alkali metal carbonate (e.g., potassium carbonate, sodium carbonate), or an alkali metal hydrogencarbonate (e.g., sodium hydrogencarbonate, potassium hydrogencarbonate).
  • alkali metal carbonates such as potassium carbonate and sodium carbonate are preferable.
  • the organic base includes, for example, amines such as triethylamine, diisopropylethylamine, N,N-dimethylaniline, 4-(N,N-dimethylamino)pyridine and pyridine.
  • triethylamine and diisopropylethylamine are preferable.
  • solvent there may be used any solvent which does not disturb the reaction.
  • solvent includes, for example, water, ketones (e.g., acetone, methyl ethyl ketone), esters (e.g., ethyl acetate), ethers (e.g., dioxane, tetrahydro ⁇ furan), nitriles (e.g., acetonitrile) and halogenated aliphatic hydrocarbons (e.g., chloroform, dichloromethane). Especially, halogenated aliphatic hydrocarbons such as chloroform are preferable.
  • ketones e.g., acetone, methyl ethyl ketone
  • esters e.g., ethyl acetate
  • ethers e.g., dioxane, tetrahydro ⁇ furan
  • nitriles e.g., acetonitrile
  • solvents may be used alone, but if necessary, can be used in the form of a mixture of two or more solvents in a suitable ratio, in a single phase or two phases.
  • the reaction is usually carried out at a temperature between 0°C and
  • the acetal can be converted into an aldehyde after the lower alkylsulfonylation or arylsulfonylation, if necessary.
  • the conversion reaction can be carried out according to the above-mentioned step (i).
  • 9-Hydroxyellipticine may also be prepared by treating the compound
  • the compound (III) is treated by the method disclosed in JP- B-59-51956 to give 9-hydroxyellipticine or a salt thereof. That is, 9-hydroxy- ellipticine or a salt thereof is prepared by reacting the compound (III) with a formylating agent (e.g., N-methylformanilide and phosphorus oxychloride) which can introduce a formyl group onto the 3-position of the compound (III), reacting the resulting 3-formylcarbazole derivative with an acetal of aminoacetaldehyde (e.g., aminoacetaldehyde dimethyl acetal), subjecting the acetal compound to cyclization in the presence of a mixture of phosphoric anhydride and phosphoric acid to give a 9-lower alkanoyloxyellipticine or a 9- arylcarbonyloxyellipticine, and subjecting the resulting product to hydrolysis with an acid or a base to give 9-hydroxy ' elliptic
  • 9-Hydroxyellipticine prepared according to the present invention, or a salt thereof, can be converted into an ellipticine derivative of the formula (V):
  • R 6 is a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxy group, or a heteromonocyclic group, by a conventional method, and if necessary, followed by converting the compound (V) into a pharmaceutically acceptable salt thereof.
  • R 61 is a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxy group, or a heteromonocyclic group, and when these substituents have an amino group, a carboxyl group or a hydroxy group, then these groups may optionally be protected, or a salt thereof, or a reactive derivative thereof, if necessary, removing the protecting groups from the product, and further followed by converting the product into a pharmaceutically acceptable salt thereof, to give the compound (V).
  • the pharmaceutically acceptable salt includes, for example, a salt with a mineral acid (e.g., hydrochloride, sulfate, phosphate, hydrobromide), or a salt with an organic acid (e.g., methanesulfonate, acetate, fumarate, maleate, oxalate, benzenesulfonate, p-toluenesulfonate).
  • a mineral acid e.g., hydrochloride, sulfate, phosphate, hydrobromide
  • an organic acid e.g., methanesulfonate, acetate, fumarate, maleate, oxalate, benzenesulfonate, p-toluenesulfonate.
  • R 6 is a carboxy-substituted lower alkyl group such as 3-carboxypropyl is more prefer red.
  • 9-hydroxyellipticine or a salt thereof prepared according to the present invention can be converted into a 2-alkyl-9-hydroxyellipticine derivative of the formula (VI):
  • R 7 is a lower alkyl group and A ( - ) is a pharmaceutically acceptable anion, by a conventional method.
  • the pharmaceutically acceptable anion includes, for example, a conjugated base of an inorganic acid or organic acid, for example, a halogen ion (e.g., chloride ion, bromide ion), sulfate ion, phosphate ion, methanesulfonate ion, acetate ion, fumarate ion, maleate ion, oxalate ion, benzenesulfonate ion and p-toluenesulfonate ion.
  • a halogen ion e.g., chloride ion, bromide ion
  • sulfate ion e.g., phosphate ion, methanesulfonate ion
  • acetate ion e.g., fumarate ion
  • maleate ion oxalate ion
  • R 7 is preferably methyl, and A ⁇ is preferably acetate ion.
  • the compound (VI) may be prepared by the method disclosed in JP-A-2- 279671.
  • the "alkyl group” includes, for example, a straight chain or branched chain alkyl group having 1 to 21 carbon atoms, or a cyclic alkyl group having 3 to 6 carbon atoms.
  • the "lower alkyl group” includes, for example, a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, or a cyclic alkyl group having 3 to 6 carbon atoms.
  • the "lower alkoxy group” includes, for example, a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, or a cyclic alkoxy group having 3 to 6 carbon atoms.
  • the "lower alkylene group” includes, for example, a straight chain or branched chain alkylene group having 2 to 6 carbon atoms.
  • the "alkanoyl group” includes, for example, a straight chain or branched chain alkanoyl group having 2 to 22 carbon atoms, or a cyclic alkanecarbonyl group having 4 to 7 carbon atoms.
  • the "lower alkanoyl group” includes, for example, a straight chain or branched chain alkanoyl group having 2 to 7 carbon atoms, or a cyclic alkanecarbonyl group having 4 to 7 carbon atoms.
  • the "halogen atom” means chlorine atom, bromine atom, fluorine atom or iodine atom.
  • the "aryl group” includes, for example, a substituted or unsubstituted phenyl group, and the "heteromonocyclic group” includes a 5- or 6-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom and a sulfur atom, for example, thiazolyl group, isothiazolyl group, and thiazolidinyl group.
  • Ellipticine is 5,l l-dimethyl-6H-pyrido[4,3-b]carbazole, and has the following formula.
  • 9-hydroxyellipticine which is easily oxidized and unstable, and has difficulty in purification, can be prepared by treating the acetal compound (I) wherein the 6-hydroxy group is protected by an acyl group, or a corresponding aldehyde thereof, with an acid, so that the removal of the protecting group and the cyclization reaction can be carried out in a single step.
  • a 6-(alkanoyloxy or aryl ⁇ carbonyioxy )carbazole derivative which is an intermediate for preparing 9- hydroxyellipticine
  • a 6-(alkanoyloxy or aryl ⁇ carbonyioxy )carbazole derivative which is an intermediate for preparing 9- hydroxyellipticine
  • 9-hydroxyellipticine can be prepared by a short procedure and in a high yield from a 6-lower alkoxy ⁇ carbazole derivative.

Landscapes

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

Abstract

Cette invention concerne un procédé de préparation de 9-hydroxyellipticine, ou d'un de ses sels, lequel procédé consiste à traiter à l'aide d'un acide un composé acétal correspondant à la formule (I) où R1 représente alkyle ou aryle, et R2 représente aryle ou alkyle inférieur. R3 et R4 peuvent être identiques ou différents et représentent chacun un alkyle inférieur substitué ou non. R3 et R4 peuvent encore être combinés l'un à l'autre au niveau de leurs terminaisons de manière à former un alkylène substitué ou non ou, encore, un aldéhyde correspondant de ce dernier. Ce traitement permet d'obtenir du 9-hydroxyellipticine en une seule étape, le 9-hydroxyellipticine ainsi obtenu pouvant en cas de besoin être transformé en l'un de ses sels. Ces composés sont utiles en qualité d'agent antitumoral ou en qualité de produit intermédiaire dans la préparation d'autres médicaments.
PCT/JP1997/001825 1996-06-04 1997-05-29 Procede de preparation de 9-hydroxyellipticine Ceased WO1997046559A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU29764/97A AU2976497A (en) 1996-06-04 1997-05-29 Process for preparing 9-hydroxyellipticine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8/141214 1996-06-04
JP14121496 1996-06-04

Publications (1)

Publication Number Publication Date
WO1997046559A1 true WO1997046559A1 (fr) 1997-12-11

Family

ID=15286802

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1997/001825 Ceased WO1997046559A1 (fr) 1996-06-04 1997-05-29 Procede de preparation de 9-hydroxyellipticine

Country Status (3)

Country Link
AU (1) AU2976497A (fr)
ID (1) ID17750A (fr)
WO (1) WO1997046559A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0009445A1 (fr) * 1978-09-15 1980-04-02 ANVAR Agence Nationale de Valorisation de la Recherche Procédé de préparation d'hydroxy-9 ellipticine et de dérivés de celle-ci

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0009445A1 (fr) * 1978-09-15 1980-04-02 ANVAR Agence Nationale de Valorisation de la Recherche Procédé de préparation d'hydroxy-9 ellipticine et de dérivés de celle-ci

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MALCOLM SAINSBURY ET AL: "Chemistry of 6H-Pyrido[4,3-b]carbazoles.Part13.Syntheses of ring-A and ring-D-substituted ellipticines", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, 1988, LETCHWORTH GB, pages 2945 - 2954, XP002038195 *

Also Published As

Publication number Publication date
AU2976497A (en) 1998-01-05
ID17750A (id) 1998-01-22

Similar Documents

Publication Publication Date Title
US5367076A (en) Process for imidazo[4,5-C]quinolin-4-amines
KR100474496B1 (ko) S형2-치환히드록시-2-인돌리디닐부티르산에스테르화합물및이의제조방법
US6429315B1 (en) Process for preparing N6-substituted adenosine derivatives
EP0704445A1 (fr) Préparation des composés de guanine substitués sur la position 9
WO1999051607A2 (fr) Procede de purification d'un derive de cephalosporine
JP4094710B2 (ja) 新規なカンプトテシン誘導体
RU2147303C1 (ru) Промежуточные продукты и способ получения солей нафтиридонкарбоновой кислоты
US6559304B1 (en) Method for synthesizing caspase inhibitors
US6177565B1 (en) Process for synthesizing piperazic acid
WO1997046559A1 (fr) Procede de preparation de 9-hydroxyellipticine
HU194563B (en) Process for preparing beta-carboline derivatives
Ninomiya et al. Photocyclisation of enamides. Part 20. Photocyclisation ofN-naphthylacrylamides and synthesis of the basic indolo [4, 3-fg] quinoline nucleus of ergot alkaloids
US6482957B2 (en) Cyclopentenecarboxamide derivative, method for preparing the same and bicycloamide derivative used therein
US6426417B1 (en) Processes and intermediates useful to make antifolates
KR100797349B1 (ko) 비시클릭 화합물의 제조 방법 및 이 방법의인터루킨-1Ｓｇ(Ｂ) 전환 효소 (ＩＣＥ) 억제제를제조하기 위한 용도
JPH1053586A (ja) ９−ヒドロキシエリプチシンの製法
CN103664943B (zh) 嘌呤衍生物的制备方法及其中间体和应用
HK157996A (en) Process for the production of bissilylated 3-iodomethylcephalosporine derivatives
EP0054892B1 (fr) Synthèse d'indolines
Mimura et al. An efficient synthesis of a new class of DNA intercalating antitumor 7, 10-dihydroxy-6H-pyrazolo [4, 5, 1-de] acridin-6-ones
IL99535A (en) Preparation of 1-[(2s)-3-mercapto-methyl-1-oxopropyl]-l-proline and intermediate thereof
KR0161351B1 (ko) 신규 티아(디아)졸 초산의 반응성 포스페이트 유도체 및 그의 제조방법
JP2023120513A (ja) 縮合多環式化合物の調製方法
EP0695754A1 (fr) DERIVE D'INDOLO 2,3-b]QUINOXALINE

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH HU IL IS KE KG KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN YU AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA