JPH1149774A - Demethylation of podophyllotoxin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently obtain 4'-demethyl-4-epipodophyllotoxin as a main raw material for antitumor agents without the need of using any toxic halogen-based solvent, by demethylating a podophyllotoxin with hydrogen bromide in a nonhalogen-based organic solvent followed by hydrolysis of the resultant intermediate. SOLUTION: A podophyllotoxin of formula I is demethylated with hydrogen bromide in a nonhalogen-based solvent to form an intermediate of formula II, which, in turn, is hydrolyzed to obtain the objective compound of formula III, wherein the above solvent is pref. a mixed solvent composed of a nonhalogen-based aliphatic solvent (pref. methyl ethyl ketone or 2-pentanone, or the like) and a nonhalogen-based aromatic solvent (pref. touluene or xylene, or the like) in a volume ratio of (1:9) to (6:4), and it is recommended that the amount of the solvent to be used is 1.5-7 pts.vol. per pt.wt. of the compound of formula I and that of the hydrogen bromide 0.2-0.6 pt.wt. per pt.vol. of the solvent, and the reaction is carried out at -5 to 20 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to 4'-demethyl-4 which is a main raw material of 4'-demethyl-4-epipodophyllotoxin-β-D-ethylidene glucoside (generic name etoposide) widely used as an antitumor agent. The present invention relates to a method for producing epipodophyllotoxin.

[0002]

2. Description of the Related Art A podophyllotoxin represented by the following formula (1) is eliminated with hydrogen bromide to remove the methyl group at the 4'-position, and then hydrolyzed to give a 4'-demethyl-4- represented by the following formula (3). In the method for obtaining epipodophyllotoxin, a halogen-based solvent such as dichloroethane is preferably used as a solvent used in the treatment with hydrogen bromide. (Japanese Patent Publication No. 43-6469)

[0003]

In recent years, conversion of halogen-based solvents to non-halogen-based organic solvents has been desired because of their carcinogenicity to humans and harm to the environment. However, in the case of this reaction, it was thought that it was necessary to use a halogen-based solvent in order to stably dissolve hydrogen bromide at a high concentration and to allow the reaction to proceed smoothly.

[0004]

As a result of various studies on the reaction with a non-halogen organic solvent instead of a halogen solvent as a solvent used in the reaction, the present inventors have found that non-halogen aliphatic solvents such as ketone compounds and the like. It has been found that a mixed solvent of benzene and a non-halogenated aromatic solvent is particularly excellent, and it is possible to carry out the reaction even in a non-halogenated organic solvent, thereby completing the present invention.

That is, the present invention relates to the following (1) to (9). (1) Equation (1)

[0006]

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The podophyllotoxin represented by the formula (2) is demethylated with hydrogen bromide in a non-halogen organic solvent to obtain a compound of the formula (2)

[0008]

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A reaction intermediate represented by the formula (3) is obtained by hydrolyzing it:

[0010]

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A method for producing 4'-demethyl-4-epipodophyllotoxin represented by the formula:

(2) The process according to (1), wherein the non-halogen organic solvent is a mixed solvent of a non-halogen aliphatic solvent and a non-halogen aromatic solvent.

(3) The process according to (2), wherein the non-halogenated aliphatic solvent is a ketone compound.

(4) The process according to (3), wherein the ketone compound is a ketone compound having an alkyl group having 1 to 5 carbon atoms on both sides of the carbonyl group.

(5) The non-halogenated aromatic solvent is benzene which may have 1 to 3 alkyl groups having 1 to 4 carbon atoms and / or 1 to 3 nitro groups as a substituent (2), (3) ) Or (4).

(6) The mixing ratio (volume ratio) between the non-halogenated aliphatic solvent and the non-halogenated aromatic solvent is 0.5: 9.5.
To (8): (2), (3), (4) or (5).

(7) The mixed solvent of a non-halogenated aliphatic solvent and a non-halogenated aromatic solvent is used in an amount of 1 to 9 parts by volume per 1 part by weight of the compound represented by the formula (1). The production method according to (2), (3), (4), (5) or (6).

(8) The amount of hydrogen bromide used is in the range of 0.1 to 1.0 part by weight based on 1 part by volume of the solvent.
(2), (3), (4), (5), (6) or (7).

(9) The process according to (1), wherein the reaction intermediate represented by the formula (2) is hydrolyzed with an aqueous solution of an alkali metal or alkaline earth metal hydrogen carbonate or carbonate.

(10) A process comprising the step of demethylating a compound of the formula (1) with hydrogen bromide in a non-halogenated organic solvent to obtain a reaction intermediate represented by the formula (2): The method for producing 4'-demethyl-4-epipodophyllotoxin shown in 3).

[0021]

BEST MODE FOR CARRYING OUT THE INVENTION The reaction of the present invention is greatly inhibited by water in the system. Since the compound represented by the formula (1) usually contains several percent of water, it is preferable to use the compound after being sufficiently dehydrated in advance. For example, 100 ° C to 105 ° C
It is preferable to use the compound which has been sufficiently dehydrated by the above. The non-halogenated organic solvent is not particularly limited as long as it is excellent in solubility of hydrogen bromide, but a mixed solvent of a non-halogenated aliphatic solvent and a non-halogenated aromatic solvent is preferable.

The non-halogenated aliphatic solvent is preferably a ketone compound, and particularly preferably one in which the aliphatic hydrocarbon residue on both sides of the carbonyl group is an alkyl group having 1 to 5 carbon atoms, for example, acetone, methyl ethyl ketone, methyl propyl Examples thereof include ketone (2-pentanone), methyl isopropyl ketone, 3-pentanone, methyl isobutyl ketone, methyl butyl ketone (2-hexanone), and 3-hexanone. The non-halogenated aromatic solvent may be unsubstituted benzene or a compound having 1 carbon atom as a substituent.
Benzene having from 1 to 4 alkyl groups and / or 1 to 3 nitro groups, such as benzene, toluene,
Xylene, ethylbenzene, propylbenzene, butylbenzenes, trimethylbenzenes, nitrobenzene,
And nitrotoluenes. Among the above reaction solvents, particularly preferably, the non-halogenated aliphatic solvent is a solvent selected from the group consisting of methyl ethyl ketone, 2-pentanone, methyl isopropyl ketone, 3-pentanone, methyl isobutyl ketone, 2-hexanone and 3-hexanone. The aromatic solvent is a solvent selected from the group consisting of toluene, xylene, ethylbenzene and nitrobenzene.

Here, the ketone compound is a solvent that dissolves hydrogen bromide in an extremely large amount. The carbonyl group of the ketone compound and hydrogen bromide form an adduct, which is considered to be a good solvent for hydrogen bromide. However, when a large amount of a ketone compound is used, a large amount of hydrogen bromide is consumed due to the formation of the adduct, so that an extremely large amount of hydrogen bromide is required for the reaction to proceed smoothly. Therefore, it is desirable to use as little ketone compound as possible. On the other hand, the reaction solvent needs to have a certain volume and solubility for the reactants in order to smoothly carry out the reaction operation. Non-halogenated aromatic compounds are excellent as diluting solvents that satisfy these conditions by utilizing the solubility of hydrogen bromide in ketone compounds.

The mixing ratio (volume ratio) of the non-halogenated aliphatic solvent to the non-halogenated aromatic solvent is preferably in the range of 0.5: 9.5 to 8: 2 from the viewpoint of reactivity and solubility of the reactants. Particularly preferred is 1: 9 to 6: 4. The use amount of the solvent is preferably higher because the higher the concentration of hydrogen bromide, the higher the reaction rate. Therefore, the smaller the amount, the smaller the use amount of hydrogen bromide, which is preferable. 1 to 9 parts by volume per 1 part by weight of the compound to be used is preferable,
Particularly, 1.5 to 7 parts by volume is preferable. The compound of the formula (1) is suspended in a mixed solvent of a non-halogenated aliphatic solvent such as a ketone compound and a non-halogenated aromatic solvent. When hydrogen bromide gas is introduced therein, the contents are dissolved and the reaction proceeds. As the reaction proceeds, the compound of formula (2) precipitates as crystals, so that side reactions can be prevented.

The amount of hydrogen bromide used depends on the type of solvent, the amount used,
Although it depends on the mixing ratio (volume ratio) and the reaction temperature, it is usually preferably 0.1 to 1.0 part by weight, particularly preferably 0.2 to 0.6 part by weight, per part by volume of the solvent. The reaction temperature is usually -15 ° C to 40 ° C, preferably -10 ° C.
C. to 30.degree. C., more preferably -5.degree. C. to 20.degree. The target compound represented by the formula (3) is obtained by hydrolyzing the reaction intermediate represented by the formula (2) obtained by demethylating the compound represented by the formula (1). The hydrolysis is performed by a usual method. For example, a water-soluble solvent such as acetone is added to a reaction solution obtained by demethylating the compound represented by the formula (1), and a carbonate such as sodium carbonate, calcium carbonate, barium carbonate, potassium bicarbonate, hydrogen bicarbonate is added. It is easily hydrolyzed by adding an aqueous solution of a bicarbonate such as sodium and heating.

[0026]

Next, the present invention will be described more specifically with reference to examples. Example 1 1.00 g of podophyllotoxin [compound of the formula (1)] was suspended in a mixed solvent of 5 ml of toluene and 1 ml of methyl ethyl ketone, and the reactor was immersed in an ice bath. 2.12 g of hydrogen bromide was introduced into the reactor through a gas introduction tube. After the completion of blowing, the mixture was reacted in an ice bath for 8 hours. As a result of analyzing the reaction solution by high performance liquid chromatography, a demethylated product of the formula (2) was produced in a yield of 60.4% (liquid crystal plane specific purity). The desired product of 4′-demethyl-4-epipodophyllotoxin [compound of formula (3)] can be obtained by using this and conducting in the same manner as in Example 4.

Example 2 Podophyllotoxin [compound of the formula (1)] (1.00 g) was dissolved in 3.0 ml of toluene and methyl isobutyl ketone (2.0 g).
The suspension was suspended in 0 ml of the mixed solvent, and the reactor was immersed in an ice bath.
2.21 g of hydrogen bromide was introduced into the reactor through a gas inlet tube. After the completion of the blowing, the reaction was performed in an ice bath for 9 hours. As a result of analyzing the reaction solution by high performance liquid chromatography, a demethylated product of the formula (2) was produced in a yield of 73.0% (liquid chromatographic surface specific purity). The desired product of 4′-demethyl-4-epipodophyllotoxin [compound of formula (3)] can be obtained by using this and conducting in the same manner as in Example 4.

Example 3 Podophyllotoxin [compound of the formula (1)] (2.00 g) in toluene (4.2 ml) and methyl isobutyl ketone (1.
The mixture was suspended in 8 ml of the mixed solvent, and the temperature of the reactor was set to 15 ° C. 1.69 g of hydrogen bromide was introduced into the reactor through a gas introduction tube. After the completion of the blowing, the reaction solution was kept at 15 ° C. and reacted for 8 hours. As a result of analyzing the reaction solution by high performance liquid chromatography, a demethylated product of the formula (2) was produced in a yield of 65.3% (liquid crystal surface specific purity). The desired product of 4′-demethyl-4-epipodophyllotoxin [compound of formula (3)] can be obtained by using this and conducting in the same manner as in Example 4.

Example 4 Podophyllotoxin [compound of the formula (1)] (2.00 g) in toluene (4.2 ml) and methyl isobutyl ketone (1.
The suspension was suspended in 8 ml of the mixed solvent, and the reactor was immersed in an ice bath.
2.70 g of hydrogen bromide was introduced into the reactor through a gas inlet tube. The reaction was continued for 8 hours after the completion of the blowing. As a result of analyzing the reaction solution by high performance liquid chromatography, the demethylated product of the formula (2) was produced in a yield of 70.8%. The reactor was placed in a refrigerator, and the next day, the reaction solution was analyzed by high performance liquid chromatography.
It was produced in a yield of 6.8% (liquid crystal surface specific purity). 5 ml of acetone was added to the reaction solution, 20 ml of a 10% aqueous sodium carbonate solution was added dropwise, the mixture was hydrolyzed at 40 ° C. for 3 hours, and the reaction product was filtered to obtain 4′-demethyl-4-epipodophyllotoxin [formula (3)]. Compound 1.02)
g was obtained. Purity: 88.5%, content of target product: 0.83
g (44.5% yield).

[0030]

Industrial Applicability According to the present invention, 4'-demethyl-4 which is a raw material of etoposide without using a harmful halogen solvent is used.
-Epipodophyllotoxin can be obtained in a high purity and a high yield with a lower content of side reaction products as compared with known methods.

Claims (10)

[Claims] (1) Formula (1) Is demethylated with hydrogen bromide in a non-halogen organic solvent in a non-halogenated organic solvent to obtain a compound represented by the formula (2). A reaction intermediate represented by the following formula is obtained and hydrolyzed: A method for producing 4'-demethyl-4-epipodophyllotoxin represented by the formula: 2. The process according to claim 1, wherein the non-halogen organic solvent is a mixed solvent of a non-halogen aliphatic solvent and a non-halogen aromatic solvent. 3. The method according to claim 2, wherein the non-halogenated aliphatic solvent is a ketone compound. 4. The process according to claim 3, wherein the ketone compound is a ketone compound having an alkyl group having 1 to 5 carbon atoms on both sides of a carbonyl group. 5. A non-halogenated aromatic solvent comprising an alkyl group having 1 to 4 carbon atoms and / or a nitro group as a substituent.
2. A benzene which may have from 3 to 3.
5. The production method according to 3 or 4. 6. The mixing ratio (volume ratio) of the non-halogenated aliphatic solvent and the non-halogenated aromatic solvent is in the range of 0.5: 9.5 to 8: 2. Or the production method according to 5. 7. The amount of the mixed solvent of the non-halogenated aliphatic solvent and the non-halogenated aromatic solvent used is in the range of 1 to 9 parts by volume per 1 part by weight of the compound represented by the formula (1). The method according to claim 2, 3, 4, 5, or 6. 8. The method according to claim 1, wherein the amount of hydrogen bromide used is in the range of 0.1 to 1.0 part by weight per 1 part by volume of the solvent.
The production method according to 3, 4, 5, 6 or 7. 9. The process according to claim 1, wherein the reaction intermediate represented by the formula (2) is hydrolyzed with an aqueous solution of a bicarbonate or carbonate of an alkali metal or alkaline earth metal. 10. A compound of the formula (3) comprising a step of demethylating the compound of the formula (1) with hydrogen bromide in a non-halogenated organic solvent to obtain a reaction intermediate of the formula (2). The method for producing 4′-demethyl-4-epipodophyllotoxin represented by).