JPH1053586A - Production of 9-hydroxyellipticine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To profitably obtain the subject compound useful as an antitumor agent or an intermediate for synthesizing medicines, etc., by reacting a 3- formyl-6-acyloxycarbazole compound with aminoacetoaldehyde (acetal) and subsequently treating the reaction product with an acid. SOLUTION: A carbazole derivative acetal of formula I [R<1> is an alkyl, an aryl; R<2> is a lower alkyl, an aryl; R<3> , R<4> are each a (substituted) lower alkyl, or R<3> , R<4> are combinesd with each other at their ends to form a (substituted) lower alkylene] or its aldehyde conversion compound is treated with an acid to obtain the 9-hydroxyllipticine having a 5,11-dimethyl-6H- pyrido[4,3-b]carbazole structure of formula II in one process. If desired, the 9-hydroxyellipticine is converted into its salt. Thus, the objective 9- hydroxyellipticine useful as an antitumor agent or an intermediate for synthesizing medicinal compounds can effectively be obtained in a good yield.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing 9-hydroxyellipticine useful as an intermediate for synthesizing an antitumor agent or a pharmaceutical compound.

[0002]

2. Description of the Related Art Pyridocarbazole alkaloids such as ellipticine and 9-methoxyellipticine are alkaloids which have been known for a long time and are contained in apocynaceae plants. It is known that these compounds having a pyridocarbazole skeleton have antitumor activity. For example, elliptinium acetate (chemical name: 2-methyl-9-hydroxyellipticinium acetate) is used as a therapeutic agent for breast cancer. It is commercially available, and it is known that ellipticine and 9-hydroxy ellipticine also have antitumor activity.

[0003] Further, 9-hydroxy ellipticine is a synthetic intermediate of elliptinium acetate, or
It is known that it is also useful as a synthetic intermediate of the 9-acyloxyellipticine derivative described in JP-A-279441. The method for producing 9-hydroxyellipticine is described in Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 18, p. 755 (1975).
), There is a method by 9-methoxy ellipticine demethylation. However, since this method is performed at a high temperature using pyridine hydrochloride, there are many by-products such as dimers, and the generated 9-hydroxy ellipticine has poor solubility in a solvent. There is a problem that purification by the conventional technique is difficult.

[0004] The 9-methoxy ellipticine used as a raw material can be obtained from natural sources, for example, Australian
According to the method described in Journal of Chemistry (Aust. J. Chem), vol. 20, p. 2715 (1967), 3-methoxy-1,4-dimethylcarbazole
Is obtained by reacting the resulting compound with an acetal of aminoacetaldehyde, and then heating and cyclizing the obtained azomethine in the presence of orthophosphoric acid. Since it is carried out at a high temperature using phosphoric acid and phosphorus pentoxide, it is unsuitable as an industrial production method, and the reaction conditions are severe and many by-products are produced.

As another method for producing 9-hydroxyellipticine, there is a method described in JP-B-59-51956. In this method, 9-hydroxy ellipticine is converted to 6-hydroxy ellipticine.
Demethoxylation of methoxy-1,4-dimethylcarbazole, benzoylation of the resulting easily oxidized and unstable hydroxyl group of 6-hydroxy-1,4-dimethylcarbazole, followed by formyl substitution at the 3-position The obtained compound is reacted with an acetal of aminoacetaldehyde, and the obtained azomethine is cyclized in the presence of phosphoric acid or the like to produce 9-benzoyloxyellipticine. Finally, the benzoyl group is hydrolyzed with hydrochloric acid. Are obtained. However, in this method, 6-hydroxy-1,4-dimethylcarbazole, which is easily oxidized and unstable, is provided as a synthetic intermediate, and the method described in Australian Journal of Chemistry (Aust. J. Chem.), 20 volumes, 2
Since the method includes a ring-closing step similar to the method described on page 715 (1967), many by-products are produced and the yield is low.
In addition, there is a drawback that it is difficult to separate and purify 9-hydroxyellipticine, which is the target substance.

[0006] Separately, as a method for producing 8,9-dimethoxyellipticine, Journal of Medicinal Chemistry (J. Med. Chem.), Vol.
There is a method described on page 755 (1975).
According to this, azomethine is obtained through formylation of the 3-position of 6,7-dimethoxy-1,4-dimethylcarbazole and reaction of aminoacetaldehyde with an acetal.
This is reduced to an amine, the amino group is p-toluenesulfonylated, and the ring is closed with hydrochloric acid to give 8,9-dimethoxy ellipticine.

A method for converting an alkyl-alkyl ether into an ester by treating it with an acyl halide and sodium iodide is disclosed in Tet. Lett., Vol. 23, p. 681 (1982). There is a method described. According to this method,
For example, by treating β-cholestanyl methyl ether with sodium iodide and pivaloyl chloride,
-Pivaloyloxycholestan can be produced.
However, there is no description of conversion of alkyl-aryl ethers to esters.

[0008]

SUMMARY OF THE INVENTION The present invention provides a novel method for efficiently producing 9-hydroxyellipticine, which is easily oxidized, is unstable, and is difficult to purify, with good yield.

Further, the present invention provides a 6-lower alkoxy-
6- (Alkanoyloxy or arylcarbonyloxy) -1,4- which is a synthetic intermediate of 9-hydroxyellipticine in one step from 1,4-dimethylcarbazole
It is intended to provide a method for producing dimethylcarbazole.

[0010]

According to the present invention, 9-hydroxyellipticine or a salt thereof has the general formula [I]

[0011]

Embedded image

Wherein R ¹ is an alkyl or aryl group, R ² is a lower alkyl or aryl group, R ³ and R ⁴
Represents a lower alkyl group which may be the same or different and may have a substituent, or represents a lower alkylene group which may have a substituent bonded to each other at the terminal. )) Or an aldehyde-converted product thereof is treated with an acid to give 9-hydroxyellipticine in one step and, if desired, the product into a salt thereof.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, in R ¹ of the acetal represented by the general formula [I], the alkyl group is a linear or branched alkyl group having 1 to 21 carbon atoms, or an alkyl group having 3 to 21 carbon atoms. And 6 cyclic alkyl groups. In addition, examples of the aryl group include a substituted or unsubstituted phenyl group. Examples of the substituent on the phenyl group include a linear or branched alkyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group and the like. Specific examples of the linear or branched alkyl group having 1 to 21 carbon atoms include a methyl group, an ethyl group, and n
-Propyl, i-propyl, n-butyl, t-butyl, pentyl, hexyl, octyl, dodecyl, docosyl and the like. Examples of the cyclic alkyl group having 3 to 6 carbon atoms include a cyclopropyl group and a cyclohexyl group. Further, specific examples of the substituted or unsubstituted phenyl group include a phenyl group, a 2- or 4-tolyl group, a xylyl group, a 2- or 4-anisyl group, a 4-chlorophenyl group, and a 4-nitrophenyl group. it can. As the alkyl group, a lower alkyl group is preferable, and specifically, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-
A linear or branched alkyl group having 1 to 6 carbon atoms such as butyl group, t-butyl group, pentyl group and hexyl group; or a cyclic alkyl group having 3 to 6 carbon atoms such as cyclopropyl group and cyclohexyl group. be able to. As R ¹ , a group that can be easily removed as R ¹ CO— by hydrolysis using an acid can be suitably used. Examples of such a group include a methyl group, an ethyl group and a t-group.
-Butyl group, phenyl group, 4-chlorophenyl group, 4-
Examples include a nitrophenyl group.

As R ² , a linear or branched alkyl group having 1 to 6 carbon atoms or a substituted or unsubstituted phenyl group can be exemplified. 1 to 6 carbon atoms
Specific examples of the linear or branched alkyl group of
Examples include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a t-butyl group, a pentyl group, and a hexyl group. Further, specific examples of the substituted or unsubstituted phenyl group include a phenyl group, a tolyl group, a methoxyphenyl group and the like. R ²
Examples of preferred groups include a methyl group, a phenyl group, a p-tolyl group, a p-methoxyphenyl group and the like.

In R ³ and R ⁴ , the lower alkyl group may be a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and the lower alkylene group may be a straight-chain or branched alkyl group having 2 to 6 carbon atoms. And branched alkylene groups. Specific examples of the linear or branched alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a t-butyl group, a pentyl group, Hexyl groups and the like can be mentioned.
Examples of the linear or branched alkylene group having 2 to 6 carbon atoms include an ethylene group and a trimethylene group. Further, as a substituent of the lower alkyl group and the lower alkylene group, a lower alkoxy group such as a methoxy group and an ethoxy group can be suitably used.

The reaction of the present invention can be suitably carried out in a solvent in the presence of an acid. Examples of the acid include mineral acids (for example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid,
Any of perchloric acid) and organic acids (for example, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, and benzenesulfonic acid) can be used, but it is preferable to use a mineral acid, especially hydrochloric acid and hydrogen bromide. Acids and sulfuric acids can be suitably used.

The amount of the acid to be used is not particularly limited, and is usually about 10 to 2,000 mol%, preferably about 100 to 1200 mol%, based on the compound [I].

The solvent used in the present invention is not limited as long as it does not hinder the reaction.
Water, halogenated aliphatic hydrocarbon solvents such as chloroform and dichloromethane, ketone solvents such as acetone and methyl ethyl ketone, ether solvents such as dioxane and tetrahydrofuran, nitrile solvents such as acetonitrile, and halogenated solvents such as chlorobenzene and toluene. Examples thereof include aromatic hydrocarbon solvents, organic acids such as acetic acid and trifluoroacetic acid, and ether solvents such as tetrahydrofuran and dioxane, and ketone solvents such as acetone.

These solvents may be used alone,
If necessary, two or more kinds may be mixed in an appropriate ratio and used in a single-phase or two-phase form.

This reaction is carried out in a solvent used in a range of 25 to 200.
° C, preferably 50-120 ° C, especially 60-70 ° C
It is preferable to carry out.

The thus obtained 9-hydroxy ellipticine may be treated with an acid, if necessary, to form a salt with a mineral acid (eg, hydrochloride, sulfate, phosphate, hydrobromide). ), Salts with organic acids (e.g., methanesulfonate, acetate, fumarate, maleate, oxalate, benzenesulfonate, p-toluenesulfonate).

The acetal represented by the general formula [I] or an aldehyde-converted product thereof is a novel compound.
(1) General formula [IV]

[0023]

Embedded image

(Wherein R ⁵ represents a lower alkyl group). The dealkylation, alkanoylation or arylcarbonylation of the 6-substituent of the 6-lower alkoxycarbazole derivative represented by the formula [I
II]

[0025]

Embedded image

(Wherein the symbols have the same meanings as described above),
(2) Formula [II] obtained by formylating the 3-position of compound [III]

[0027]

Embedded image

(Wherein the symbols have the same meanings as described above), after converting the formyl group of the 3-formylcarbazole derivative into a formylmethylaminomethyl group which may be acetalized, and further converting the amino group. It can be produced by lower alkylsulfonylation or arylsulfonylation.

In the above step (1), compound [IV]
In a reaction in which dealkylation of the 6-position lower alkoxy group and alkanoylation or arylcarbonylation of compound [IV] are carried out in a solvent, the presence or absence of an alkali metal iodide or an alkaline earth metal iodide in a solvent under,
It can be carried out by reacting with a reactive derivative of an alkylcarboxylic acid or an arylcarboxylic acid.

As a reactive derivative of an alkylcarboxylic acid or an arylcarboxylic acid, an alkanoyl halide or an arylcarbonyl halide can be preferably used, and a lower alkanoyl halide can be more preferably used.

As the alkanoyl halide, a compound having 2 carbon atoms
To 22 straight-chain or branched-chain alkanoyl halides or cyclic alkane carboxylic acid halides having 4 to 7 carbon atoms. Specific examples include acetyl halide, propionyl halide, pivaloyl halide, cyclopropanecarbonyl halide, and cyclohexane. Examples include carbonyl halide, dodecanoyl halide, docosanoyl halide and the like. Preferably, a straight-chain or branched-chain alkanoyl halide having 2 to 7 carbon atoms (eg, acetyl halide, propionyl halide, pivaloyl halide) or a cyclic alkanecarboxylic acid halide having 4 to 7 carbon atoms (eg, cyclopropanecarbonyl halide, Examples thereof include a chain or cyclic lower alkanoyl halide such as cyclohexanecarbonyl halide), and it is particularly preferable to use acetyl halide, pivaloyl halide or the like.

Examples of the arylcarbonyl halide include a substituted or unsubstituted benzoyl halide, and specifically, benzoyl halide, 4-chlorobenzoyl halide, 4-nitrobenzoyl halide, 2-nitrobenzoyl halide,
Alternatively, there may be mentioned 4-toluoyl halide, xyloyl halide, 2- or 4-anisoyl halide and the like. In particular, it is preferable to use benzoyl halide or the like.

Examples of the alkali metal iodide include lithium iodide, sodium iodide and potassium iodide, and examples of the alkaline earth metal iodide include calcium iodide. Preferably, an alkali metal iodide such as sodium iodide or potassium iodide is used. When alkanoyl iodide or arylcarbonyl iodide is used as the alkanoyl halide or arylcarbonyl halide, the addition of the alkali metal iodide can be omitted.

The solvent is not limited as long as it does not interfere with the reaction. Examples thereof include nitriles such as acetonitrile, halogenated aliphatic hydrocarbon solvents such as chloroform, dichloromethane and dichloroethane, and N, N-dimethyl. Amides such as acetamide and 1,3-dimethyl-2-imidazolidinone can be used.

The reaction is carried out at a temperature of 0 to 150 ° C., preferably 40 to 150 ° C.
It is preferably carried out at 100 ° C, especially at 70 to 90 ° C.

In the above step (2), the compound [II
The reaction for formylating the 3-position of I] is carried out by the compound [III]
In a solvent with a formylating agent.

As the formylating agent, an ordinary formylating agent for formylating a benzene ring can be used. Specifically, N-methylformanilide and phosphorus oxychloride, dichloromethyl methyl ether and titanium tetrachloride,
Hexamethylenetetramine and acetic acid can be mentioned. In particular, it is preferable to use N-methylformanilide, phosphorus oxychloride, dichloromethyl methyl ether, titanium tetrachloride, or the like.

The solvent is not limited as long as it does not interfere with the reaction. Examples of the solvent include benzene, toluene,
Use of aromatic hydrocarbon solvents which may be halogenated such as chlorobenzene and orthodichlorobenzene, halogenated aliphatic hydrocarbon solvents such as dichloroethane and dichloropropane, and organic acids such as acetic acid and trifluoroacetic acid. Can be.

The reaction is carried out at 40 to 180 ° C., preferably at 70
It is preferably carried out at a temperature of from 130 to 130C, especially from 100 to 120C.

After converting the formyl group of the compound [II] to a formylmethylaminomethyl group which may be acetalized, the amino group is further subjected to lower alkylsulfonylation or arylsulfonylation by the reaction (i) of the compound [II] Is reacted with an aminoacetaldehyde lower alkyl acetal (or lower alkylene acetal) in a solvent or without solvent to reduce the generated azomethine, and, if desired, to convert the acetal to an aldehyde. (Ii) The reaction can be carried out by reacting the obtained compound with a lower alkylsulfonyl halide or an arylsulfonyl halide in the presence or absence of an acid agent.

In the above step (i), compound [II]
The reaction between the compound and the aminoacetaldehyde lower alkyl acetal (or lower alkylene acetal) can be carried out according to a usual imination method. The solvent is not limited as long as it does not hinder the reaction.Examples include chloroform, halogenated aliphatic hydrocarbon solvents such as dichloromethane, benzene, aromatic hydrocarbon solvents such as toluene, diisopropyl ether, and the like. Ether solvents such as tetrahydrofuran and dioxane can be used.

This reaction is carried out at 20 to 150 ° C., preferably at 50
It is preferable to carry out at a temperature of from 110 to 110C, especially from 50 to 70C.

The reduction can be carried out by catalytic reduction in a suitable solvent under a hydrogen atmosphere using a catalyst, or by using a metal hydride in a suitable solvent.

In the catalytic reduction, palladium-carbon, platinum-carbon, platinum oxide, Raney nickel and the like can be suitably used as a catalyst.

The solvent is not limited as long as it does not hinder the reaction. Examples of the solvent include water, alcohol solvents such as methanol and ethanol, aromatic hydrocarbon solvents such as benzene and toluene, ethyl acetate, and acetic acid. Ester solvents such as butyl and ether solvents such as tetrahydrofuran and dioxane can be used.

The reaction is carried out at a temperature of from 0 to 100 ° C., preferably from 10 to 100 ° C.
It is better to carry out at 40 ° C.

The metal hydride used for the reduction is not limited as long as it can reduce imine and does not affect the substituent at the 6-position. For example, sodium borohydride, borohydride Lithium, sodium cyanoborohydride and the like can be suitably used.

The solvent is not limited as long as it does not hinder the reaction. Examples of the solvent include water, alcohol solvents such as methanol and ethanol, halogenated aliphatic hydrocarbon solvents such as chloroform and dichloromethane, benzene, and the like. Aromatic hydrocarbon solvents such as toluene, ether solvents such as diisopropyl ether, tetrahydrofuran and dioxane can be used.

The reaction is carried out at -20 to 70 ° C., preferably at 0 to 70 ° C.
It is preferably carried out at 30 ° C.

The step of converting an acetal into an aldehyde, which is a desired step, can be carried out according to a conventional method, for example, by treating with an acid in a solvent or without a solvent. The solvent is not limited as long as it does not hinder the reaction, and examples thereof include ketone solvents such as acetone, ether solvents such as tetrahydrofuran and dioxane, and alcohol solvents such as methanol. As the acid, mineral acids such as hydrochloric acid, sulfuric acid, and nitric acid, and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid can be used. This conversion step may be performed after step (ii).

As the lower alkylsulfonyl halide used in the above step (ii), there can be mentioned a straight-chain or branched-chain alkylsulfonyl halide having 1 to 6 carbon atoms, specifically, methanesulfonyl halide, ethanesulfonyl halide and the like. Can be given. In particular, it is preferable to use methanesulfonyl halide or the like.

Examples of the arylsulfonyl halide include a substituted or unsubstituted benzenesulfonyl halide, and specific examples include benzenesulfonyl halide, p-toluenesulfonyl halide, and p-methoxybenzenesulfonyl halide. In particular, it is preferable to use benzenesulfonyl halide, p-toluenesulfonyl halide, or the like.

As the deoxidizing agent, inorganic bases and organic bases can be used. Examples of the inorganic bases include alkali metal carbonates such as potassium carbonate and sodium carbonate, and alkali metal bicarbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate. Or the like can be used. Preferably, alkali metal carbonates such as potassium carbonate and sodium carbonate are used. Organic bases include triethylamine, diisopropylethylamine, N, N-dimethylaniline,
Examples thereof include amines such as 4-N, N-dimethylaminopyridine and pyridine. Preferably, triethylamine, diisopropylethylamine, or the like is used.

The solvent is not limited as long as it does not hinder the reaction. Examples thereof include water, ketone solvents such as acetone and methyl ethyl ketone, ester solvents such as ethyl acetate, and ether solvents such as dioxane and tetrahydrofuran. Examples of the solvent include nitrile solvents such as acetonitrile and the like, and halogenated aliphatic hydrocarbon solvents such as chloroform and dichloromethane. Among them, solvents such as halogenated aliphatic hydrocarbon solvents such as chloroform are particularly preferable.

Although these solvents may be used alone,
If necessary, two or more kinds may be mixed in an appropriate ratio and used in a single-phase or two-phase form.

This reaction is carried out at 0 to 100 ° C., preferably at 20 to 100 ° C.
It is preferably carried out at 60 ° C.

If desired, the acetal can be converted to an aldehyde after lower alkylsulfonylation or arylsulfonylation. This conversion step can be performed according to the method described in step (i).

Further, the compound [III] obtained by the method of the present invention is subjected to a step according to the prior art to give 9
-Hydroxyellipticine can be produced.

For example, 9-hydroxy ellipticine or a salt thereof can be obtained by subjecting compound [III] obtained by the method of the present invention to a step according to the method described in JP-B-59-51956. . That is, after formylation of the 3-position of the compound [III], the obtained product is reacted with an acetal of aminoacetaldehyde, the obtained acetal is cyclized, and the obtained ellipticine derivative is hydrolyzed to give 9-hydroxyl. By preparing ellipticine and, if desired, converting it into a salt thereof, 9-
Hydroxylipepticin or a salt thereof can be produced.

As the conditions and reagents required for the reaction, the reaction conditions and reagents described in JP-B-59-51956 can be used. Reacting compound [III] with a formylating agent that introduces a formyl group into the aromatic ring (eg, N-methylformanilide and phosphorus oxychloride),
A 3-formylcarbazole derivative is produced, the resulting product is reacted with an acetal of aminoacetaldehyde (for example, aminoacetaldehyde dimethyl acetal), and the thus obtained acetal is reacted with a mixture of phosphoric anhydride and phosphoric acid. Cyclization to produce 9-lower alkanoyloxy ellipticine or 9-arylcarbonyloxy ellipticine, and hydrolyzing the resulting 9-acyloxy ellipticine derivative with an acid or alkali to give 9-hydroxy ellipticine 9-hydroxy ellipticine or a salt thereof can be produced by preparing the compound and, if desired, further converting the salt thereof.

The 9-hydroxyellipticine or a salt thereof obtained by the method of the present invention can be prepared by a known method according to the general formula [V].

[0062]

Embedded image

(Wherein, R ⁶ represents a lower alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, or a heteromonocyclic group) It can be a derivative and, if desired, a pharmacologically acceptable salt thereof.

That is, for example, Japanese Patent Application Laid-Open No. 6-279441
According to the method described in JP, the 9-hydroxy ellipticine or its salt of the general formula R ⁶¹ COOH (wherein, R ⁶¹ is optionally substituted lower alkyl group, substituted And when the substituent has an amino group, a carboxyl group or a hydroxyl group, they may be protected.), A salt thereof, Alternatively, compound [V] can be produced by reacting with a reactive derivative thereof, removing a protecting group if necessary, and further converting the product into a pharmaceutically acceptable salt thereof, if desired.

Such pharmaceutically acceptable salts include salts with mineral acids (eg, hydrochloride, sulfate, phosphate, hydrobromide) or salts with organic acids (eg, methanesulfonic acid) Salt, acetate, fumarate, maleate, oxalate, benzenesulfonate, p-toluenesulfonate).

In the above process for producing compound [V], R ⁶ is a lower alkoxy-substituted lower alkyl group or a carboxyl-substituted lower alkyl group which may be protected, or is protected as R ⁶ CO—. A group that forms a residue of an amino acid that may be preferable,
R ⁶ is preferably a carboxyl-substituted lower alkyl group such as a 3-carboxypropyl group. As the carboxyl-protecting group, a conventional protecting group such as a benzyl group can be used.

Further, 9-hydroxyellipticine or a salt thereof obtained by the method of the present invention can be prepared by a known method according to the general formula [VI].

[0068]

Embedded image

(Wherein, R ⁷ represents a lower alkyl group, and A ⁽⁻⁾ represents a pharmacologically acceptable anion). A 2-alkyl-9-hydroxy ellipticine derivative represented by the following formula:

That is, for example, according to the method described in JP-B-59-51956, 9-hydroxy ellipticine is reacted with a lower alkyl halide to introduce a lower alkyl group at the 2-position of 9-hydroxy ellipticine. Can convert halogen ions to other pharmacologically acceptable anions.

Examples of such pharmacologically acceptable anions include conjugate bases of inorganic acids and organic acids, and specific examples include halogen ions such as chloride ion and bromide ion, sulfate ion, phosphate ion, methane sulfone ion. Acid ion, acetate ion, fumarate ion, maleate ion,
Oxalate ions, benzenesulfonate ions, p-toluenesulfonate ions and the like are mentioned.

Particularly, R ⁷ is preferably a methyl group, and A ⁽⁻⁾ is preferably an acetate ion.

The starting compound [IV] can be produced, for example, according to the method described in JP-A-2-279671.

In the present specification, the alkyl group includes
A linear or branched alkyl group having 1 to 21 carbon atoms or a cyclic alkyl group having 3 to 6 carbon atoms is a lower alkyl group. And 3 to 6 cyclic alkyl groups. As the lower alkoxy group, a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms or a 3 to 6 carbon atoms.
Cyclic alkoxy group. Examples of the lower alkylene group include a linear or branched alkylene group having 2 to 6 carbon atoms. As the alkanoyl group, a linear or branched alkanoyl group having 2 to 22 carbon atoms or a cyclic alkanecarbonyl group having 4 to 7 carbon atoms, and as the lower alkanoyl group, a linear or branched alkanoyl group having 2 to 7 carbon atoms is used. Examples include a branched alkanoyl group or a cyclic alkanecarbonyl group having 4 to 7 carbon atoms. As halogen,
Examples include a chlorine atom, a bromine atom, a fluorine atom, an iodine atom and the like. Examples of the aryl group include a substituted or unsubstituted phenyl group, and examples of the heteromonocyclic group include 1 to 3 hetero atoms selected from nitrogen and sulfur such as thiazolyl, isothiazolyl, and thiazolidinyl. And a 5- or 6-membered heterocyclic group.

Ellipticine is 5,11-dimethyl-6H-pyrido [4,3-b] carbazole and has the following structure.

[0076]

Embedded image

Hereinafter, the present invention will be described more specifically with reference to examples.
The present invention is not limited by these.

[0078]

【Example】

Example 1 (1) 6-methoxy-1,4-dimethylcarbazole 2
6.0 kg and 34.6 kg of sodium iodide are added to 103 kg of acetonitrile. Further pivaloyl chloride 2
0.9 kg are added and the reaction mixture is heated to reflux for about 1 hour. After cooling the reaction solution, ethyl acetate is added and stirred. After the organic layer is washed with water, an aqueous solution of sodium thiosulfate is added, washed with water and stirred, and the organic layer is separated. The organic layer is washed with an aqueous sodium hydrogen carbonate solution and a saturated saline solution, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solution of isopropanol and water to give 6-pivaloyloxy-1,4-dimethylcarbazole (30.0%).
Gain kg.

IR (Nujol): 3400, 1740
(Cm ^-1 ) MS (m / z): 295 (M ⁺ ) ¹ H-NMR (CDCl ₃ , δ): 1.43 (9H,
s), 2.49 (3H, s), 2.74 (3H, s),
6.88 (1H, d, J = 7 Hz), 7.04 (1H,
dd, J = 2.9 Hz), 7.10 (1H, d, J = 7)
Hz), 7.34 (1H, d, J = 9 Hz), 7.72
(1H, d, J = 2 Hz), 8.05 (1H, br
s).

(2) While stirring with 22.6 kg of toluene, 17.8 kg of N-methylformanilide and 20.2 kg of phosphorus oxychloride are added, and the mixture is stirred at 25 to 35 ° C. for about 1 hour. To the reaction solution, 313 kg of toluene and 26.0 k of 6-pivaloyloxy-1,4-dimethylcarbazole were added.
After adding g, the mixture is refluxed for about 6 hours. Toluene was distilled off from the reaction solution under reduced pressure, and the residue was recrystallized from a mixture of acetone and water to give 3-formyl-6-pivaloyloxy-.
28.0 kg of 1,4-dimethylcarbazole are obtained.

IR (Nujol): 1750, 1680
(Cm ^-1 ) MS (m / z): 323 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ , δ): 1.37 (9H,
s), 2.56 (3H, s), 3.08 (3H, s),
7.18 (1H, dd, J = 2.9 Hz), 7.59
(1H, d, J = 9 Hz), 7.69 (1H, s),
7.90 (1H, d, J = 2 Hz), 10.36 (1
H, s), 11.80 (1H, s).

(3) While stirring in 201 kg of chloroform, 3-formyl-6-pivaloyloxy-1,4-
27.0 kg of dimethylcarbazole and 12.2 kg of aminoacetaldehyde diethyl acetal were added, and about 1
Heat to reflux for hours. After cooling, 31.6 kg of methanol are added. While the reaction solution is cooled, 1.6 kg of sodium borohydride is added while maintaining the temperature at 20 ° C. or lower. 15-20
After stirring at 30 ° C. for 30 minutes, chloroform and water are added to the reaction solution, the organic layer is separated, and the aqueous layer is further extracted with chloroform. The organic layers are combined, and after adding 136 kg of water, 17.4 kg of anhydrous potassium carbonate and 16.7 kg of p-toluenesulfonyl chloride, the mixture is stirred at 40 to 50 ° C. for about 1 hour. The reaction solution is cooled, and the organic layer is separated. After concentrating the organic layer, toluene was added to the residue, and the precipitated crystals were centrifuged to give 3- [N-tosyl-N- (2,2-diethoxyethyl) aminomethyl] -6-pivaloyloxy-1,4.
42.2 kg of dimethylcarbazole are obtained.

FAB-MS (+ NaCl) (m / z):
617 ([M + Na] ⁺ ) ¹ H-NMR (CDCl ₃ , δ): 1.06 (6H, t,
J = 7 Hz), 1.43 (9H, s), 2.37 (3
H, s), 2.39 (3H, s), 2.71 (3H,
s), 3.19 (2H, d, J = 6 Hz), 3.3-
3.5 (4H, m), 4.43 (1H, t, J = 6H
z), 4.65 (2H, s), 6.96 (1H, s),
7.05 (1H, dd, J = 2.9 Hz), 7.26
(2H, d, J = 8 Hz), 7.35 (1H, d, J =
9 Hz), 7.73 (2H, d, J = 8 Hz), 7.7
6 (1H, d, J = 2 Hz), 8.07 (1H, s).

(4) While stirring 196 kg of tetrahydrofuran, 3- [N-tosyl-N- (2,2-diethoxyethyl) aminomethyl] -6-pivaloyloxy-
30.0 kg of 1,4-dimethylcarbazole and 63.1 kg of concentrated hydrochloric acid are added. The reaction solution was heated to reflux for about 9 hours, cooled, added with 174 kg of acetone, centrifuged, and treated with 11.0 kg of 9-hydroxy ellipticine hydrochloride.
Get.

IR (Nujol): 3200 (cm ^-1 ) MS (m / z): 262 (M ⁺ ) ¹ H-NMR (DMSO-d ₆ , δ): 2.73 (3H,
s), 3.17 (3H, s), 7.13 (1H, dd,
J = 2.9 Hz, 7.45 (1H, d, J = 9H)
z), 7.75 (1H, d, J = 2 Hz), 8.29
(1H, d, J = 7 Hz), 8.34 (1H, d, J =
7 Hz), 9.45 (1H, brs), 9.80 (1
H, s), 11.93 (1H, s).

Reference Example 1 (1) 1.31 g of 9-hydroxyellipticine and 6.9 g of anhydrous potassium carbonate were added to 80 ml of acetone, and 815 mg of methoxyacetic chloride was added dropwise with stirring. After stirring at room temperature for 5 hours, 20 ml of dimethylformamide is added, and the mixture is stirred, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform-methanol) to obtain 823 mg of 9-methoxyacetoxyellipticine.

(2) 823 mg of this product was dissolved in 100 ml of a chloroform-methanol (1: 1) mixed solution, 260 mg of methanesulfonic acid was added, the mixture was stirred for 10 minutes, the solvent was distilled off under reduced pressure, and ether was added to the residue. The precipitated powder is collected by filtration, washed and dried to obtain 988 mg of methanesulfonate of 9-methoxyacetoxyellipticine.

FAB-MS (m / z): 335 (M
H ⁺ ) ¹ H-NMR (DMSO-d ₆ , δ): 2.40 (3H,
s), 2.79 (3H, s), 3.21 (3H, s),
3.48 (3H, s) 4.45 (2H, s), 7.43
(1H, dd, J = 2.0, 8.8 Hz), 7.63
(1H, d, J = 8.8 Hz), 8.18 (1H, d,
J = 2 Hz), 8.39 (2H, m), 9.84 (1
H, s), 11.81 (1H, NH), 15.1 (1
H, brs).

Reference Example 2 (1) To 60 ml of dimethylformamide were added 500 mg of 2-methoxypropionic acid, 648 mg of 1-hydroxybenzotriazole and 1.19 g of dicyclohexylcarbodiimide, and the mixture was stirred at room temperature for 4 hours. Then 9-
1.20 g of hydroxyellipticine hydrochloride and 486 mg of triethylamine are added, and the mixture is stirred overnight at room temperature. 300 ml of ethyl acetate is added to the reaction solution, and after stirring, insolubles are removed by filtration. The filtrate is washed with a 2% aqueous solution of potassium carbonate and saturated saline, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent: chloroform-methanol) to obtain 960 mg of 9- (2-methoxypropionyloxy) ellipticine.

(2) Using 960 mg of this product and 264 mg of methanesulfonic acid, a reaction treatment was carried out in the same manner as in Reference Example 1- (2) to give 1178 mg of methanesulfonic acid salt of 9- (2-methoxypropionyloxy) ellipticine. obtain.

FAB-MS (m / z): 349 (M
H ⁺ ) ¹ H-NMR (DMSO-d ₆ , δ): 1.56 (3H,
d, J = 6.8 Hz), 2.39 (3H, s), 2.7
8 (3H, s), 3.21 (3H, s), 3.48 (3
H, s), 4.31 (1H, q, J = 6.8 Hz),
7.41 (1H, dd, J = 2.2, 8.6 Hz),
7.63 (1H, d, J = 8.6 Hz), 8.13 (1
H, d, J = 2.2 Hz), 8.36 (1H, d, J =
7.1 Hz), 8.42 (1H, d, J = 7.1H)
z), 9.90 (1H, s), 12.11 (1H, N
H).

Reference Example 3 (1) To 140 ml of dimethylformamide were added 2.14 g of glutaric acid monobenzyl ester, 1.30 g of 1-hydroxybenzotriazole and 2.38 g of dicyclohexylcarbodiimide, and the mixture was stirred at room temperature for 4 hours. Then, 2.10 g of 9-hydroxy ellipticine is added, and the mixture is stirred at room temperature overnight. Thereafter, the same treatment as in Reference Example 2- (1) is performed to obtain 2.25 g of 9- [4- (benzyloxycarbonyl) butyryloxy] ellipticine.

FAB-MS (m / z): 467 (M
H ⁺ ) ¹ H-NMR (DMSO-d ₆ , 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), 7.2
9 (1H, dd, J = 2.1, 8.6 Hz), 7.39
(5H, m), 7.56 (1H, d, J = 8.6H
z), 7.93 (1H, d, J = 6.0 Hz), 8.1
1 (1H, d, J = 2.1 Hz), 8.44 (1H,
d, J = 6.0 Hz), 9.7 (1H, s).

(2) 1.18 g of this product and 243 mg of methanesulfonic acid are dissolved in 70 ml of a 50% aqueous methanol solution, 1 g of 10% palladium on carbon is added, and catalytic reduction is performed at normal temperature and normal pressure. The reaction solution is filtered, the filtrate is concentrated under reduced pressure, and ethanol-acetone (1:10) is added to the residue. The precipitated powder is collected by filtration and dried to give 9-
592 mg of (4-carboxybutyryloxy) ellipticine methanesulfonate are obtained.

FAB-MS (m / z): 377 (M
H ⁺ ) ¹ H-NMR (DMSO-d ₆ , δ): 1.95 (2H,
m), 2.39 (3H, s), 2.43 (2H, m),
2.74 (2H, m), 2.77 (3H, s), 3.1
9 (3H, s), 7.38 (1H, dd, J = 2.0,
8.8 Hz), 7.60 (1H, d, J = 8.8H)
z), 8.11 (1H, d, J = 2.0 Hz), 8.3
4 (1H, t, J = 7 Hz), 8.40 (1H, d, J
= 7 Hz), 9.87 (1H, s), 12.07 (1
H, s), 15.0 (2H, brs).

Reference Example 4 (1) N- (t-butoxycarbonyl) sarcosine 91
8 mg and 918 mg of 9-hydroxyellipticine are treated in the same manner as in Reference Example 3- (1) to obtain 1.05 g of 9- (Nt-butoxycarbonyl-N-methylaminoacetoxy) ellipticine.

FAB-MS (m / z): 434 (M
H ⁺ ) ¹ H-NMR (DMSO-d ₆ , δ): 1.46 (9H,
s), 2.79 (3H, s), 2.98 (3H, m),
3.21 (3H, s), 4.32 (2H, m), 7.3
1 (1H, m), 7.60 (1H, m), 7.93 (1
H, d, J = 6.0 Hz), 8.09 (1H, m),
8.44 (1H, d, J = 6.0 Hz), 9.7 (1
H, s), 11.5 (1H, brs).

(2) 1.00 g of this product was added to 10 m of dioxane.
and 15 ml of a 15% hydrochloric acid-dioxane solution under ice-cooling and stirring. After stirring the reaction solution at room temperature for 3 hours, 100 ml of ether is added, insolubles are collected by filtration, washed and dried to obtain 851 mg of 9-methylaminoacetoxyellipticine dihydrochloride.

FAB-MS (m / z): 334 (M
H ⁺ ) ¹ H-NMR (DMSO-d ₆ , δ): 1.88 (3H,
s), 2.01 (3H, s), 2.99 (3H, s),
4.38 (2H, s), 6.57 (1H, d, J = 8.
8 Hz), 6.79 (1H, dd, J = 2.0, 8.8)
Hz), 7.02 (1H, d, J = 2.0 Hz), 7.0.
35 (1H, d, J = 6.8 Hz), 7.57 (1H,
d, J = 6.8 Hz), 8.44 (1H, s).

[0100]

According to the process of the present invention, the acetal [I] in which the hydroxyl group at the 6-position is protected with an acyl group or an aldehyde-converted product thereof is treated with an acid to remove the protecting group and close the ring in a single operation. Thus, 9-hydroxy ellipticine, which is easily oxidized, unstable, and difficult to purify, can be efficiently produced with high yield.

According to the present invention, a 6- (alkanoyloxy or arylcarbonyloxy) carbazole derivative which is a synthetic intermediate of 9-hydroxyellipticine can be produced from a 6-lower alkoxycarbazole derivative in one step. it can.

Further, according to the present invention, 9-hydroxyellipticine can be obtained from a 6-lower alkoxycarbazole derivative in a short step at a high yield.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Kazuhiko Kondo 3-81-810 Utajima, Nishiyodogawa-ku, Osaka-shi, Osaka (72) Inventor Hiroshi Fujii 4-2-2 Higashi-Kamidai, Konan-ku, Ube-shi, Yamaguchi Prefecture No. 6

Claims (16)

[Claims] 1. A compound of the general formula [I] (Wherein, 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 may have a substituent, or a lower alkyl group; or Represents that they are bonded to each other at their terminals to form a lower alkylene group which may have a substituent.)
9-hydroxy ellipticine or a salt thereof, wherein 9-hydroxy ellipticine is produced in one step by treating the acetal represented by Recipe. 2. A compound of the general formula [IV] (Wherein, R ⁵ represents a lower alkyl group), wherein the 6-substituent of the 6-lower alkoxycarbazole derivative represented by the general formula (1) is subjected to dealkylation and alkanoylation or arylcarbonylation in one step. Formula [II
I] embedded image (In the formula, R ¹ represents an alkyl group or an aryl group.)
A method for producing a carbazole derivative represented by the formula: 3. The general formula [III] obtained by the method according to claim 2. (In the formula, R ¹ represents an alkyl group or an aryl group.)
Is formylated at the 3-position of the carbazole derivative represented by
The resulting general formula [II] (Wherein the symbols have the same meanings as described above), after converting the formyl group of the 3-formylcarbazole derivative into a formylmethylaminomethyl group which may be acetalized, and further converting the amino group to a lower alkylsulfonyl group. General formula [I] obtained by the conversion or arylsulfonylation (In the formula, R ² is a lower alkyl group or an aryl group, R ³ and R ⁴ are the same or different and may be a lower alkyl group which may have a substituent, or are bonded to each other at a terminal to form a substituent. And the other symbols have the same meanings as described above), or the aldehyde-converted product thereof is treated with an acid to give 9 -A method for producing 9-hydroxyellipticine or a salt thereof, which comprises producing hydroxyellipticine and, if desired, a salt thereof. 4. The method according to claim 1, wherein the acid is a mineral acid. 5. The method according to claim 4, wherein the acid is hydrochloric acid, hydrobromic acid or sulfuric acid. 6. The method according to claim 1, wherein the solvent used when treating the acetal compound [I] or its aldehyde conversion product with an acid is an ether solvent or a ketone solvent. 7. R ¹ is a lower alkyl group, R ³ and R
^{4. The method according} to claim 1, wherein ^4, is a lower alkyl group.
The described method. 8. The method according to claim 2, wherein R ¹ is a lower alkyl group. 9. A compound of the general formula [III] obtained by the method according to claim 2. (In the formula, R ¹ represents an alkyl group or an aryl group.)
After formylating the 3-position of the carbazole derivative represented by the formula, the obtained product is reacted with an acetal of aminoacetaldehyde, the obtained acetal compound is cyclized, and the obtained ellipticine derivative is hydrolyzed to 9-hydroxy A method for producing 9-hydroxyellipticine or a salt thereof, which comprises preparing ellipticine and further converting it into a salt thereof, if desired. 10. A method according to claim 1, 3, 4, 5, 6 or 7, wherein 9-hydroxyellipticine or a salt thereof is represented by the general formula [V]: (Wherein, R ⁶ represents a lower alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, or a heteromonocyclic group) or, if desired, A process for producing an ellipticine derivative or a pharmaceutically acceptable salt thereof, which is converted into a pharmaceutically acceptable salt thereof. 11. The method according to claim 10, wherein R ⁶ is a carboxyl-substituted lower alkyl group which may be protected or a group which forms an amino acid residue which may be protected as R ⁶ CO—. . 12. The method according to claim 11, wherein R ⁶ is a carboxyl-substituted lower alkyl group. 13. The method according to claim 12, wherein R ⁶ is a 3-carboxypropyl group. 14. A method according to claim 1, 3, 4, 5, 6 or 7, wherein 9-hydroxyellipticine or a salt thereof is converted to a compound of the general formula [VI] according to a known method. (Wherein, R ⁷ represents a lower alkyl group, and A ⁽⁻⁾ represents a pharmacologically acceptable anion). A process for producing an ellipticine derivative, comprising: 15. A compound of the general formula [I] (Wherein, 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 may have a substituent, or a lower alkyl group; or Represents that they are bonded to each other at their terminals to form a lower alkylene group which may have a substituent.)
Or an aldehyde-converted product thereof. 16. The compound according to claim 15, wherein R ¹ is a lower alkyl group, and R ³ and R ⁴ are lower alkyl groups.