WO1997046559A1

WO1997046559A1 - Process for preparing 9-hydroxyellipticine

Info

Publication number: WO1997046559A1
Application number: PCT/JP1997/001825
Authority: WO
Inventors: Kenji Tsujihara; Naoyuki Harada; Tomiki Hashiyama; Kazuhiko Kondo; Hiroshi Fujii
Original assignee: Tanabe Seiyaku Co., Ltd.
Priority date: 1996-06-04
Filing date: 1997-05-29
Publication date: 1997-12-11
Also published as: AU2976497A; ID17750A

Abstract

A process for preparing 9-hydroxyellipticine, or salt thereof, which comprises treating acetal compound (I): wherein R1 is alkyl or aryl, R2 is lower alkyl or aryl, R?3 and R4¿ are the same or different and each are substituted or unsubstituted lower alkyl, or both may combine each other at their termini to form substituted or unsubstituted lower alkylene, or a corresponding aldehyde thereof, with an acid, to give 9-hydroxyellipticine in a single step, and if necessary, converting the resulting 9-hydroxyellipticine into a salt thereof. These compounds are useful as an antitumor agent or an intermediate for preparing other medicaments.

Description

D E S C R I P T I O N

PROCESS FOR PREPARING 9-HYDROXYELLIPTICINE

TECHNICAL FIELD

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. BACKGROUND ART 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.

Moreover, 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. However, 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. Furthermore, 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.

Further, 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. However, 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. In the process, 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. However, 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.

Alternatively, J. Med. Chem., 18, 755 (1975) discloses another process for preparing 8,9-dimethoxyellipticine. In this process, 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, β-cholestanyl methyl ether can be converted into β-pivaloyloxycholestane by treating it with sodium iodide and pivaloyl chloride. However, this literature never discloses a process for converting an alkyl-aryl ether into an ester thereof. DISCLOSURE OF INVENTION

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.

According to the present invention, 9-hydroxyellipticine or a salt thereof can be prepared in a single step by treating an acetal compound of the formula (I):

wherein R¹ is an alkyl group or an aryl group, R² is a lower alkyl group or an

aryl group, R³ and R⁴ 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 R¹ 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. The group R¹

may preferably be a group which can be easily removed in the form of RⁱCO- by hydrolysis using an acid, and include, for example, methyl, ethyl, t-butyl, phenyl, 4-chlorophenyl and 4-nitrophenyl.

The group for R² 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 R² is methyl, phenyl, p-tolyl and p- methoxyphenyl.

The lower alkyl group for R³ and R⁴ 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). Among these acids, 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.

These 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.

Thus obtained 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).

The acetal compound of the formula (I) or a corresponding aldehyde thereof is novel compounds, and can be prepared by the following steps:

(1) de-alkylating and alkanoylating or arylcarbonylating a substituent at the 6-position of a 6-lower alkoxycarbazole derivative of the formula (IV):

wherein R⁵ is a lower alkyl group, in a single step,

(2) formylating the 3-position of the resulting carbazole derivative of the formula (III):

wherein R¹ is an alkyl group or an aryl group, to give a 3-formylcarbazole derivative of the formula (II):

(π)

wherein R¹ 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. In the above step (1), 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. Among these compounds, 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. When an alkanoyl iodide or an arylcarbonyl iodide is used as an alkanoyl halide or an arylcarbonyl halide, the reaction may be carried out without using an alkali metal iodide.

As the solvent, there may be used any solvent which does not disturb the reaction. Such 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.

In the above step (2), 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. As the 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. Especially, a combination of N-methylformanilide and phosphorus oxychloride, or a combination of dichloromethyl methyl ether and titanium tetrachloride are preferable.

As the solvent, there may be used any solvent which does not disturb the reaction. Such 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).

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:

(i) reacting the compound (II) with an aminoacetaldehyde-lower alkyl acetal (or lower alkylene acetal) in a suitable solvent or without a solvent, reducing the resulting azomethine compound, and if necessary, converting the resulting acetal into an aldehyde; then (ii) reacting the product with a lower alkylsulfonyl halide or an arylsulfonyl halide in the presence or absence of an acid scavenger in a solvent.

In the above step (i), 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. As 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.

As the solvent, there may be used any solvent which does not disturb the reaction. Such 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.

As the solvent, there may be used any solvent which does not disturb the reaction. Such 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. As the solvent, there may be used any solvent which does not disturb the reaction. Such 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

(ϋ).

In the above step (ii), 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). Especially, 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. Especially, triethylamine and diisopropylethylamine are preferable.

As the solvent, there may be used any solvent which does not disturb the reaction. Such 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.

These 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

100°C, preferably at a temperature between 20°C and 60°C.

If necessary, 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

(III), which is prepared according to the present invention in a conventional manner.

For example, 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^'ellipticine, and if necessary, followed by converting it into a salt thereof.

9-Hydroxyellipticine prepared according to the present invention, or a salt thereof, can be converted into an ellipticine derivative of the formula (V):

wherein R⁶ 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.

That is, according to the method disclosed in JP-A-6-279441 , 9- hydroxyellipticine or a salt thereof is reacted with a compound of the formula:

R⁶¹COOH

wherein R⁶¹ 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).

In the above-mentioned process for preparing the compound (V), the process wherein R⁶ is a lower alkyl group which is substituted by a protected or

unprotected carboxyl or a group which constitutes in the form of R⁶CO- a protected or unprotected amino acid residue is preferred, and the process wherein R⁶ is a carboxy-substituted lower alkyl group such as 3-carboxypropyl is more prefer red.

Alternatively, 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):

wherein R⁷ is a lower alkyl group and A⁽-⁾ is a pharmaceutically acceptable anion, by a conventional method.

That is, according to the method disclosed in JP-B-59-51956, 9-hydroxy- ellipticine is reacted with a lower alkyl halide to introduce a lower alkyl group onto the 2-position of 9-hydroxyellipticine, and if necessary, the halogen ion of the product thus obtained is converted into another pharmaceutically acceptable anion, to give the compound (VI).

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.

Especially, R⁷ is preferably methyl, and A^ is preferably acetate ion.

The compound (VI) may be prepared by the method disclosed in JP-A-2- 279671. Throughout the present description and claims, 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.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is illustrated in more detail by the following

Examples and Reference Examples, but should not be construed to be limited thereto.

Example 1

(1) To acetonitrile (103 kg) are added with stirring 6-methoxy-l ,4- dimethylcarbazole (26.0 kg), sodium iodide (34.6 kg), and pivaloyl chloride

(20.9 kg). The mixture is heated at reflux for one hour. The reaction mixture is cooled, and thereto is added ethyl acetate. The mixture is washed successively with water, aqueous sodium thiosulfate, water, aqueous sodium hydrogen¬ carbonate and saturated aqueous sodium chloride. The organic layer is dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting residue is recrystallized from a mixture of isopropanol and water to give 6-pivaloyloxy-l ,4-dimethylcarbazole (30.0 kg).

IR (nujol): 3400, 1740 (cm"¹)

MS (m/z): 295 (M⁺)

'H-NMR (CDCI₃, 6): 1.43 (9H, s), 2.49 (3H, s), 2.74 (3H, s), 6.88 (IH, d,

J=7 Hz), 7.04 (IH, dd, J=2, 9 Hz), 7.10 (IH, d, J=7 Hz), 7.34 (IH, d, J=9 Hz), 7.72 (IH, d, J=2 Hz), 8.05 (1 H, brs)

(2) To toluene (22.6 kg) are added with stirring N-methylformanilide (17.8 kg) and phosphorus oxychloride (20.2 kg), and the mixture is stirred at 25-35°C for one hour. To the reaction mixture are added toluene (313 kg) and 6-pivaloyloxy- 1 ,4-dimethylcarbazole (26.0 kg), and then the mixture is heated at reflux for six hours. The reaction mixture is concentrated under reduced pressure to remove the toluene, and the residue is recrystallized from a mixture of acetone and water to give 3-formyl-6-pivaloyloxy-l ,4-dimethylcarbazole (28.0 kg). IR (nujol): 1750, 1680 (cm-*)

MS (m/z): 323 (M+)

'H-NMR (DMSO-dg, δ): 1.37 (9H, s), 2.56 (3H, s), 3.08 (3H, s), 7.18 (IH,

dd, J=2, 9 Hz), 7.59 (IH, d, J=9 Hz), 7.69 (IH, s), 7.90 (IH, d. J=2 Hz). 10.36 (IH, s), 11.80 (1 H, s)

(3) To chloroform (201 kg) are added with stirring 3-formyl-6-pivaloyl- oxy-l ,4-dimethylcarbazole (27.0 kg) and aminoacetaldehyde diethyl acetal (12.2 kg), and the mixture is heated at reflux for one hour. After cooling, methanol (31.6 kg) is added to the reaction mixture. Then sodium borohydride (1.6 kg) is added to the mixture below 20°C. The mixture is stirred at 15-20°C for 30 minutes, and thereto are added chloroform and water. The organic layer is separated, and the aqueous layer is extracted with chloroform. The organic layers are combined, and thereto are added water (136 kg), anhydrous potassium carbonate (17.4 kg) and p-toluenesulfonyl chloride (16.7 kg), and the mixture is stirred at 40-50°C for one hour. The reaction mixture is cooled, and the organic layer is separated and concentrated. The resulting residue is crystallized from toluene, and the precipitated crystals are collected by centrifugation to give 3-[N-tosyl-N-(2,2-diethoxyethyl)aminomethyl]-6- pivaloyloxy-l ,4-dirnethylcarbazole (42.2 kg). FAB-MS (+NaCl) (m/z): 617 ([M+Na]⁺)

¹ H-NMR (CDC1₃, δ): 1.06 (6H, t, J=7 Hz), 1.43 (9H, s), 2.37 (3H, s), 2.39

(3H, s), 2.71 (3H, s), 3.19 (2H, d, J=6 Hz), 3.3-3.5 (4H, m), 4.43 (IH, t, J=6 Hz), 4.65 (2H, s), 6.96 (IH, s), 7.05 (IH, dd, J=2, 9 Hz), 7.26 (2H, d, J=8 Hz), 7.35 (IH, d, J=9 Hz), 7.73 (2H, d, J=8 Hz), 7.76 (IH, d, J=2 Hz), 8.07 (IH, s)

(4) To tetrahydrofuran (196 kg) are added 3-[N-tosyl-N-(2,2-diethoxy- ethyl)aminomethyl]-6-pivaloyloxy-l ,4-dimethylcarbazole (30.0 kg) and cone, hydrochloric acid (63.1 kg). The mixture is heated at reflux for 9 hours, and cooled. To the mixture is added acetone ( 174 kg), and the resulting crystals are collected by centrifugation to give 9-hydroxyellipticine hydrochloride (1 1.0 kg).

IR (nujol): 3200 (cm-¹)

MS (m/z): 262 (M+)

¹H-NMR (DMSO-d₆, δ): 2.73 (3H, s), 3.17 (3H, s), 7.13 (IH, dd, J=2, 9 Hz),

7.45 (IH, d, J=9 Hz), 7.75 (IH, d, J=2 Hz), 8.29 (IH, d, J=7 Hz), 8.34 (IH, d, J=7 Hz), 9.45 (IH, brs), 9.80 (IH, s), 11.93 (IH, s) Reference Example 1

(1) To acetone (80 ml) are added 9-hydroxyellipticine (1.31 g) and anhydrous potassium carbonate (6.9 g), and thereto is added dropwise with stirring methoxyacetyl chloride (815 mg). The mixture is stirred at room temperature for 5 hours, and thereto is added dimethylformamide (20 ml). The mixture is stirred, and filtered, and the filtrate is concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform-methanol) to give 9-methoxyacetoxy- ellipticine (823 mg).

(2) The above product (823 mg) is dissolved in a mixture of chloro¬ form-methanol (1 : 1) (100 ml), and thereto is added methanesulfonic acid (260 mg). The mixture is stirred for 10 minutes, and concentrated under reduced pressure to remove the solvent. To the residue is added ether, and the precipitated powder is collected by filtration, washed with ether, and dried to give 9-methoxyacetoxyellipticine methanesulfonate (988 mg). FAB-MS (m/z): 335 (MH+) ⁱ H-NMR (DMSO-d₆, δ): 2.40 (3H, s), 2.79 (3H, s), 3.21 (3H, s), 3.48 (3H,

s), 4.45 (2H, s), 7.43 (IH, dd, J=2.0, 8.8 Hz), 7.63 (IH, d, J=8.8 Hz), 8.18 (IH, d, J=2 Hz), 8.39 (2H, m), 9.84 (IH, s), 11.81 (IH, NH), 15.1 (IH, brs) Reference Example 2 (1) To dimethylformamide (60 ml) are added 2-methoxypropionic acid

(500 mg), 1 -hydroxybenzotriazole (648 mg) and dicyclohexylcarbodiimide (1.19 g), and the mixture is stirred at room temperature for four hours. To the mixture are added 9-hydroxyellipticine hydrochloride (1.20 g) and triethylamine (486 mg), and the mixture is stirred at room temperature overnight. To the reaction mixture is added ethyl acetate (300 ml), and the mixture is stirred, and the insoluble materials are removed by filtration. The filtrate is washed successively with 2 % aqueous potassium carbonate and saturated aqueous sodium chloride. The organic layer is dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform- methanol) to give 9-(2-methoxypropionyloxy)ellipticine (960 mg).

(2) The above product (960 mg) and methanesulfonic acid (264 mg) are treated in the same manner as in Reference Example 1 -(2) to give 9-(2- methoxypropionyloxy)ellipticine methanesulfonate (1 178 mg). FAB -MS (m/z): 349 (MH+)

Η-NMR (DMSO-α δ): 1.56 (3H, d, J=6.8 Hz), 2.39 (3H, s), 2.78 (3H, s),

3.21 (3H, s), 3.48 (3H, s), 4.31 (IH, q, J=6.8 Hz), 7.41 (IH, dd, J=2.2, 8.6 Hz), 7.63 (I H, d, J=8.6 Hz), 8.13 (IH, d, J=2.2 Hz), 8.36 (IH, d, J=7.1 Hz), 8.42 (IH, d, J=7.1 Hz), 9.90 (IH, s), 12.11 (1H, NH) Reference Example 3

(1) To dimethylformamide (140 ml) are added monobenzyl glutarate (2.14 g), 1 -hydroxybenzotriazole (1.30 g) and dicyclohexylcarbodiimide (2.38 g), and the mixture is stirred at room temperature for four hours. To the mixture is added 9-hydroxyellipticine (2.10 g), and the mixture is stirred at room temperature overnight. The mixture is treated in the same manner as in Reference Example 2-(l ) to give 9-[4-(benzyloxycarbonyl)butyryloxy]- ellipticine (2.25 g).

FAB-MS (m/z): 467 (MH+)

^JH-NMR (DMSO-d₆, δ): 1.99 (2H, m), 2.56 (2H, t, J=7 Hz), 2.72 (2H, t, J=7

Hz), 2.79 (3H, s), 3.21 (3H, s), 5.14 (2H, s), 7.29 (IH, dd, J=2.1 , 8.6 Hz), 7.39 (5H, m), 7.56 (IH, d, J=8.6 Hz), 7.93 (IH, d, J=6.0 Hz), 8.11 (IH, d, J=2.1 Hz), 8.44 (IH, d, J=6.0 Hz), 9.7 (lH, s)

(2) The above product (1.18 g) and methanesulfonic acid (243 mg) are dissolved in 50 % aqueous methanol (70 ml), and thereto is added 10 % palladium-carbon (1 g), and the mixture is subjected to catalytic hydrogenation at room temperature under atmospheric pressure. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. To the residue is added ethanol-acetone (1 : 10), and the precipitated powder is collected by filtration, and dried to give 9-(4-carboxybutyryloxy)ellipticine methane¬ sulfonate (592 mg).

FAB-MS (m/z): 377 (MH+)

¹ H-NMR (DMSO-d₆, δ): 1.95 (2H, m), 2.39 (3H, s), 2.43 (2H, m), 2.74 (2H, m), 2.77 (3H, s), 3.19 (3H, s), 7.38 (IH, dd, J=2.0, 8.8 Hz), 7.60 (IH, d, J=8.8 Hz), 8.11 (IH, d, J=2.0 Hz), 8.34 (IH, t, J=7 Hz), 8.40 (I H, d, J=7 Hz), 9.87 (IH, s), 12.07 (lH, s), 15.0 (2H, brs) Reference Example 4 (1) N-(t-Butoxycarbonyl)sarcosine (918 mg) and 9-hydroxyellipticine

(918 mg) are treated in the same manner as in Reference Example 3-(l ) to give 9-(N-t-butoxycarbonyl-N-methylaminoacetoxy)ellipticine (1.05 g).

FAB-MS (m/z): 434 (MH+)

^!H-NMR (DMSO-dg, δ): 1.46 (9H, s), 2.79 (3H, s), 2.98 (3H, m), 3.21 (3H,

s), 4.32 (2H, m), 7.31 (IH, m), 7.60 (IH, m), 7.93 (IH, d, J=6.0 Hz), 8.09 (IH, m), 8.44 (IH, d, J=6.0 Hz), 9.70 (IH, s), 11.5 (IH, brs)

(2) The above product (1.00 g) is added to dioxane (10 ml), and thereto is added with stirring 15 % hydrochloric acid-dioxane solution (5 ml) under ice-cooling. The mixture is stirred at room temperature for three hours, and thereto is added ether (100 ml). The insoluble materials are removed by filtration, washed with ether, and dried to give 9-methylaminoacetoxyellipticine dihydrochloride (851 mg).

FAB-MS (m/z): 334 (MH+)

¹ H-NMR (DMSO-d₆, δ): 1.88 (3H, s), 2.01 (3H, s), 2.99 (3H, s), 4.38 (2H, s),

6.57 (IH, d, J=8.8 Hz), 6.79 (IH, dd, J=2.0, 8.8 Hz), 7.02 (I H, d, J=2.0 Hz), 7.35 (IH, d, J=6.8 Hz), 7.57 (IH, d, J=6.8 Hz), 8.44 (IH, s) INDUSTRIAL APPLICAΗON

According to the present invention, 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.

Besides, according to the present invention, a 6-(alkanoyloxy or aryl¬ carbonyioxy )carbazole derivative, which is an intermediate for preparing 9- hydroxyellipticine, can be prepared in a single step from a 6-lower alkoxy¬ carbazole derivative. Furthermore, according to the present invention, 9-hydroxyellipticine can be prepared by a short procedure and in a high yield from a 6-lower alkoxy¬ carbazole derivative.

Claims

C L A I M S

1. A process for preparing 9-hydroxy ellipticine, or a salt thereof, which comprises treating an acetal compound of the formula (I):

aryl group, R³ an R⁴ 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, to give 9-hydroxyellipticine in a single step, and if necessary, converting the resulting 9-hydroxyellipticine into a salt thereof.

2. A process for preparing a carbazole derivative of the formula (III):

wherein R¹ is an alkyl group or an aryl group, which comprises de-alkylating and alkanoylating or arylcarbonylating a substituent at the 6-position of a 6- lower alkoxycarbazole derivative of the formula (IV):

wherein R⁵ is a lower alkyl group, in a single step.

3. A process for preparing 9-hydroxyellipticine or a salt thereof, which comprises

(i) formylating the 3-position of a carbazole derivative of the formula OH):

wherein R¹ is an alkyl group or an aryl group, which is obtained in the process of claim 2,

(ii) converting the formyl group of the resulting 3-formylcarbazole derivative of the formula (II):

wherein R^] is the same as defined above, into a formylmethylaminomethyl group which may optionally be in the form of an acetal,

(ϋi) lower-alkylsulfonylating or arylsulfonylating the amino group of the product to give an acetal compound of the formula (I):

wherein R¹ is the same as defined above, R² is a lower alkyl group or an aryl

group, R³ an R⁴ 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,

(iv) treating the compound (I) or a corresponding aldehyde thereof with an acid, to give 9-hydroxyellipticine in a single step, and

(v) if necessary, converting the resulting 9-hydroxyellipticine into a salt thereof.

4. The process according to any one of claims 1 and 3, wherein the acid is a mineral acid.

5. The process according to claim 4, wherein the mineral acid is hydrochloric acid, hydrobromic acid or sulfuric acid.

6. The process according to any one of claims 1 , 3, 4 and 5, wherein the solvent used in the acid treatment of an acetal compound (I) or a corresponding aldehyde thereof is ethers or ketones.

7. The process according to any one of claims 1 , 3, 4, 5 and 6, wherein R¹ is a lower alkyl group, and R³ and R⁴ are a lower alkyl group.

8. The process according to claim 2, wherein R¹ is a lower alkyl group.

9. A process for preparing 9-hydroxy ellipticine or a salt thereof, which comprises

(i) formylating the 3-position of the carbazole derivative of the formula (HI):

wherein R¹ is an alkyl group or an aryl group, which is obtained in claim 2, (ii) reacting the product with an acetal of aminoacetaldehyde, (iii) subjecting the resulting acetal compound to cyclization reaction, (iv) subjecting the resulting ellipticine derivative to hydrolysis to give 9-hydroxyellipticine, and (v) if necessary, converting it into a salt thereof.

10. A process for preparing an ellipticine derivative of the formula (V):

wherein R⁶ is a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxy group, or a heteromonocyclic group, or a pharmaceutically acceptable salt thereof, which comprises converting 9- hydroxyellipticine or a salt thereof prepared according to any one of clai s 1 , 3, 4, 5, 6 and 7, into the ellipticine derivative of the formula (V) or a pharmaceutically acceptable salt thereof, by a conventional method.

11. The process according to claim 10, wherein R⁶ is a lower alkyl group which is substituted by a protected or unprotected carboxyl group or a group which constitutes in the form of R⁶CO- a protected or unprotected amino acid residue.

12. The process according to claim 11, wherein R⁶ is a carboxyl- substituted lower alkyl group.

13. The process according to claim 12, wherein R⁶ is 3-carboxypropyl.

14. A process for preparing an ellipticine derivative of the formula (VI):

wherein R⁷ is a lower alkyl group and A⁽-⁾ is a pharmaceutically acceptable anion, which comprises converting 9-hydroxyellipticine or a salt thereof prepared according to any one of claims 1 , 3, 4, 5, 6 and 7, into the ellipticine derivative of the formula (VI) or a pharmaceutically acceptable salt thereof, by a conventional method.

15. An acetal compound of the formula (I):

aryl group, R³ an R⁴ 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.

16. The compound according to claim 15, wherein R¹ is a lower alkyl

group, and R³ and R⁴ are a lower alkyl group.