JPH0337532B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method for producing naphthacenequinone derivatives,
For more details, please refer to the formula This invention relates to a method for producing a naphthacenequinone derivative represented by:

The compound represented by the above formula (1) is a 4-
It is a compound useful as an intermediate for the synthesis of demethoxydaunomycin.

Conventional methods for producing the naphthacenequinone derivative represented by formula (1) include the method of Gupta et al. [DN
Gupta and N.Khan, J.Chem.Soc.Perkin I.689
(1981)] is known. However, this method requires a long reaction process and is complicated to operate.
It is desired to develop a new method for producing the naphthacenequinone derivative represented by formula (1) in place of the above method.

In view of the current situation, the present inventors have conducted extensive research in order to develop a new method for producing the naphthacenequinone derivative represented by formula (1), which does not have the above-mentioned drawbacks. In the course of this research, we synthesized a new compound, a naphthacenequinone derivative represented by the following general formula (2). A patent application has already been filed for this compound. The present inventors continued their research for the above purpose and found that when the compound of general formula (2) is acyloxylated, 11 of the compound of general formula (2)
It has been found that the desired compound of general formula (1) can be obtained in high yield and purity by selectively introducing an acyloxy group only into the position and then hydrolyzing the resulting compound in the presence of an acid. . The present invention was completed based on this knowledge.

That is, the present invention is based on the general formula [In the formula, one of R ¹ and R ² represents a hydrogen atom,
The other one represents a lower alkylenedioxy group. ] The naphthacenequinone derivative represented by is acyloxylated, and then the general formula obtained is [In the formula, R ³ represents a lower alkanoyl group. R ¹ and R ² are the same as above. ] The naphthacenequinone derivative represented by is hydrolyzed in the presence of an acid to form the formula The present invention relates to a method for producing a naphthacenequinone derivative, which is characterized by obtaining a naphthacenequinone derivative represented by:

According to the method of the present invention, high yield with simple operation,
Compounds of formula (1) can be produced in high purity.

In this specification, examples of lower alkylenedioxy groups include methylenedioxy, ethylenedioxy, and trimethylenedioxy groups, and examples of lower alkanoyl groups include acetyl, propionyl, butyryl, isobutyryl,
Examples include pentanoyl, tert-butylcarbonyl, and hexanoyl groups.

Acyloxylation of the compound of general formula (2) can be carried out, for example, in the presence of an acyloxylating agent in a suitable solvent. Examples of the acyloxylating agent used here include Pb(OCOCH ₃ ) ₄ , Tl
Examples include (OCOCH ₃ ) ₃ and Hg (OCOCH ₃ ) ₂ . The amount of the acyloxylating agent to be used is not particularly limited and can be appropriately selected within a wide range, but it is usually at least an equimolar amount, preferably an equimolar to 3 times the molar amount of the compound of general formula (2). Good to use. Examples of solvents include aromatic hydrocarbons such as benzene, toluene, and xylene;
Examples include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, ethers such as diethyl ether, dioxane, and tetrahydrofuran, acetic acid, and mixed solvents thereof. The reaction is usually carried out at room temperature to about 100°C, preferably around room temperature, and generally at 1
The reaction completes in about 30 hours.

Hydrolysis of the compound of general formula (3) is carried out, for example, in the presence of an acid in a suitable solvent. Examples of solvents used include water, alcohols such as methanol, ethanol, and isopropanol, dioxane,
Examples include ethers such as tetrahydrofuran, mixed solvents thereof, and the like. Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, and organic acids such as trifluoroacetic acid and para-toluenesulfonic acid. The amount of such acid to be used is usually in large excess relative to the compound of general formula (3). The reaction is usually carried out at room temperature to about 100°C, preferably room temperature to 80°C, and is generally carried out at a temperature of 1 to 10°C.
The reaction is completed in about an hour. In this way, the desired compound of formula (1) can be produced.

The compound of general formula (2) used as a starting material in the present invention is a new compound, and is produced, for example, by the methods shown in reaction schemes-1 to 3 below.

[In the formula, X and X ¹ represent a halogen atom, R ⁴ represents a lower alkyl group, and R ¹ ' represents a lower alkylenedioxy group. ] The reaction between the compound of general formula (4) and the compound of general formula (5) is generally called Diels-Alder reaction. For this reaction, a wide variety of reaction conditions for the usual Diels-Alder reaction can be applied, for example, the two may be reacted in a suitable solvent. As the solvent used here, a wide range of solvents can be used that do not adversely affect the reaction, and specifically, benzene,
Aromatic hydrocarbons such as toluene, xylene, chlorobenzene, dichlorobenzene, ethers such as diethyl ether, dioxane, tetrahydrofuran, saturated hydrocarbons such as n-hexane, n-heptane, cyclohexane, dichloromethane, dichloroethane, chloroform , aliphatic halogenated hydrocarbons such as carbon tetrachloride, polar aprotic solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, and ethyl acetate. Compounds of general formula (4) and general formula (5)
The proportion of the compound to be used is not particularly limited and can be appropriately selected from within a wide range, but it is usually advisable to use the latter in at least an equimolar amount, preferably an equimolar to 1.5 times the molar amount of the former. .
The reaction is usually carried out at room temperature to about 150°C, preferably from 40 to 150°C.
The reaction is carried out at 100°C and generally completes in about 1 to 48 hours.

The ketalization reaction of the compound of general formula (6) is carried out, for example, by reacting the compound of general formula (6) with a ketalization agent in the presence of a catalyst in a suitable solvent. As the solvent, a wide variety of known solvents can be used as long as it does not adversely affect the reaction, and for example, the aromatic hydrocarbons, ethers, saturated hydrocarbons, polar aprotic solvents, etc. can be used. Examples of the catalyst include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as para-toluenesulfonic acid, preferably hydrochloric acid. The amount of such catalyst to be used is not particularly limited, but usually the general formula
It is preferable to use 1/100 to 1/3 times the molar amount, preferably 1/20 to 1/5 times the molar amount of the compound (6). Examples of ketalizing agents include ethylene glycol,
methylene glycol, trimethylene glycol,
methanol, ethanol, isopropanol, n
-Alcohols such as butanol can be mentioned. The amount of such a ketalizing agent to be used is not particularly limited, but it is usually at least an equimolar amount, preferably an equimolar amount to the compound of general formula (6).
It is preferable to use twice the molar amount. The reaction is usually carried out at room temperature
It is carried out at about 100℃, preferably around room temperature,
The reaction is generally completed in about 1 to 20 hours.

The dehydrohalogenation reaction of the compound of general formula (7) is
This is carried out in a suitable solvent in the presence of a basic compound. As the basic compound, a wide range of conventionally known ones can be used, and specifically, carbonates such as sodium carbonate, potassium carbonate, and sodium bicarbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium methylate, Examples include metal alcoholates such as sodium ethylate, organic basic compounds such as pyridine, triethylamine, and N,N-dimethylaniline. The amount of the basic compound to be used is not particularly limited and can be appropriately selected within a wide range, but it is usually at least 0.1 to 1.5 times the molar amount, preferably 0.3 to 0.7 times the molar amount of the compound of general formula (7). Good to use. Further, as the solvent, any solvent that does not adversely affect the reaction, such as the solvent used in the reaction between the compound of general formula (4) and the compound of general formula (5), can be used. The reaction normally proceeds suitably at about 0 to 50°C, preferably around room temperature, and is generally completed in about 1 minute to 5 hours. In this way, a compound of general formula (8a) is produced.

[In the formula, R ² ' represents a lower alkylenedioxy group.
X, X ¹ and R ⁴ are the same as above. ] The reaction of the compound of the general formula (9) with the compound of the general formula (5), the ketalization of the compound of the general formula (10), and the dehydrohalogenation of the compound of the general formula (11) can be carried out using the above-mentioned general formula ( It can be carried out under the same reaction conditions as the reaction of the compound of 4) with the compound of general formula (5), the ketalization of the compound of general formula (6), and the dehydrohalogenation of the compound of general formula (7). . In this way, a compound of general formula (8b) is produced.

[In the formula, R ¹ , R ² and X are the same as above. ] The reaction between the compound of general formula (8) and the compound of general formula (12) is generally called Diels-Alder reaction. A wide range of reaction conditions for the usual Diels-Alder reaction can be applied to this reaction, for example, the two may be reacted in an appropriate solvent in the presence or absence of a basic compound. The ratio of the compound of general formula (8) and the compound of general formula (12) to be used is not particularly limited and can be appropriately selected within a wide range, but usually the latter is used in at least an equimolar amount, preferably an equal molar amount, to the former. It is preferable to use a molar to 1.5 times molar amount. As the basic compound, any compound used in the dehydrohalogenation reaction of the compound of general formula (7) can be used. The amount of the basic compound to be used is not particularly limited, but is usually 1/100 to equimolar amount, preferably 1/20 to 1/20 to the equivalent molar amount of the compound of general formula (1).
It is preferable to use 1/2 times the molar amount. In addition, as a solvent,
Any solvent used in the reaction between the compound of general formula (4) and the compound of general formula (5) can be used. The reaction is usually carried out at about 70 to 250°C, preferably 100 to 200°C.
The reaction proceeds suitably and is generally completed in about 1 to 10 hours.

The naphthacenequinone derivative represented by the above general formula (1) is induced into 4-demethoxydaunomycin represented by the formula (15), which is useful as an anticancer agent, according to the method shown in the following reaction scheme-4.

From the compound of formula (1) to the compound of formula (13) and formula (14)
The reaction of inducing 4-demethoxydaunomycin represented by formula (15) through a compound of
and P. Prados, Tetrahedron Letters, 477
(1979)], Journal of Chemical Society (DNGupta and N.Khan, J.Chem.
Soc. Perkin I.689 (1981)], Journal of
Organic Chemistry [WWLee, AP
Martizez, J.H. Smith and D.W.Henry, J.Org.
Chem.41, 2296 (1976)], Tetrahedron Letter [J.Alexander and LAMitsher, Tetrahedron
Letters, 3403 (1978)], Journal of American Chemical Society [FAJ
Kerdesky and MPCava, J.Am.Chem.Soe.
100, 3635 (1978)] and the Tetrahedron Letter [ASKende, DPCurran, Y.Tsay and JE
Mills, Tetrahedron Letters, 3537 (1977)], US Pat. No. 4,046,878, etc. may be followed.

The target compounds obtained in each of the above steps are easily isolated and purified from the reaction mixture by conventional separation means. Examples of such separation means include solvent extraction, solvent dilution, recrystallization, column chromatography, and preparative thin layer chromatography.

Reference examples and examples are listed below.

Reference example 1 2,6-dichlorobenzoquinone 990 under nitrogen stream
mg and 2-trimethylsilyloxybutadiene
A solution of 800 mg of benzene in 10 ml is heated at 50-60°C for 4 hours. The solvent was distilled off under reduced pressure to obtain syrupy 2,
8aβ-dichloro-6-trimethylsilyloxy-
1.63 g of 4a,5,8,8a-tetrahydro-1,4-naphthoquinone are obtained. IR spectrum and NMR
Identification from spectrum.

IR ν ^CHCl3 _nax (cm ^-1 ); 1585, 1670, 1690, 1720 NMR δ (CDCl ₃ ); 0.17 (9H, s), 2.2-3.8 (5H,
m), 4.65-4.8 (1H, m), 6.89 (1H, s) Reference example 2 2,5-dichlorobenzoquinone 300 under nitrogen stream
mg and 2-trimethylsilyloxybutadiene
A solution of 300 mg of benzene in 3 ml is heated at 80-90°C for 3 hours. The solvent was distilled off under reduced pressure, and 2,4aβ-dichloro-7-trimethylsilyloxy-4a,5,8,
8a-tetrahydro-1,4-naphthoquinone 540mg
get. Identification is based on IR spectrum and NMR spectrum.

IR ν ^CHCl3 _nax (cm ^-1 ); 1585, 1665, 1690 NMR δ (CDCl ₃ ); 0.21 (9H, s), 2.41-3.27
(4H, m), 3.67 (1H, t, J=8Hz), 4.72
~4.87 (1H, m) 7.01 (1H, s) Reference Example 3 2,8aβ-dichloro- obtained in Reference Example 1 above
6-trimethylsilyloxy-4a,5,8,8a
2-3 drops of concentrated hydrochloric acid are added to a solution of 1.63 g of -tetrahydro-1,4-naphthoquinone and 1.05 g of ethylene glycol in 10 ml of ether, and the mixture is stirred at room temperature for 16 hours. After drying with sodium sulfate, the solvent was distilled off to give 2,8aβ-dichloro-6,6-ethylenedioxy-4a,5,8,8a-tetrahydro-1,4-
1.4 g of naphthoquinone is obtained. IR spectrum and
Identification by NMR spectrum.

IR ν ^CHCl3 _nax (cm ^-1 ); 1590, 1655, 1670 NMR δ (CDCl ₃ ); 1.84 (2H, t, J=6Hz)
2.55~3.0 (4H, m), 3.99 (4H, s), 3.85~
4.2 (1H, m), 6.88 (1H, s) Reference Example 4 2,4aβ-dichloro-7 obtained in Reference Example 2 above
-trimethylsilyloxy-4a,5,8,8a-
Two drops of concentrated hydrochloric acid are added to a solution of 540 mg of tetrahydro-1,4-naphthoquinone and 137 mg of ethylene glycol in 5 ml of ether, and the mixture is stirred at room temperature for 16 hours. After drying using sodium sulfate, the solvent was distilled off.
4aβ-dichloro-7,7-ethylenedioxy-
490 mg of 4a,5,8,8a-tetrahydro-1,4-naphthoquinone are obtained. IR spectrum and NMR
Identification by spectrum.

IR ν ^CHCl3 _nax (cm ^-1 ); 1590, 1650, 1690 NMR δ (CDCl ₃ ); 2.44-4.20 (11H, m),
6.93 (1H, s) Reference example 5 Homophthalic anhydride 41 mg, 2-chloro-6,6
- A solution of 65 mg of ethylenedioxy-5,6,7,8-tetrahydro-1,4-naphthoquinone and 13 mg of triethylamine in 2 ml of toluene was added at 140 to 150 mL in a sealed tube.
Heat at ℃ for 1 hour. After cooling, the solvent is distilled off, and the residue is purified by silica gel column chromatography (eluent: ether: benzene = 1:4). Recrystallization from chloroform yields 28 mg of 2,2-ethylenedioxy-6-hydroxy-1,2,3,4-tetrahydro-5,12-naphthacenequinone.

mp 229-230.5℃ IR ν ^CHCl3 _nax (cm ^-1 ); 1605, 1630, 1655 NMR δ (CDCl ₃ ); 1.92 (2H, t, J = 6.5Hz),
2.80~3.05 (4H, m), 4.02 (4H, s), 7.50~
7.95 (3H, m), 8.01 (1H, s), 8.35-8.55
(1H, m), 14.06 (1H, s) Reference example 6 Homophthalic anhydride 50mg, 2-chloro-7,7
- A solution of 70 mg of ethylenedioxy-5,6,7,8-tetrahydro-1,4-naphthoquinone and 13 mg of triethylamine in 2 ml of toluene was added at 140 to 150 mL in a sealed tube.
Heat at ℃ for 1 hour. After cooling, the solvent is distilled off, and the residue is purified by silica gel column chromatography (eluent: ether: benzene = 1:4). Recrystallization from chloroform yields 18 mg of 3,3-ethylenedioxy-6-hydroxy-1,2,3,4-tetrahydro-5,12-naphthacenequinone.

mp 214-216℃ IR ν ^CHCl3 _nax (cm ^-1 ); 1605, 1630, 1655 NMR δ (CDCl ₃ ); 1.92 (2H, t, J = 6.5Hz),
2.80~3.05 (4H, m), 4.02 (4H, s), 7.50~
7.95 (3H, m), 8.01 (1H, s), 8.35-8.55
(1H, m), 13.97 (1H, s) Reference example 7 2,8aβ-dichloro-6,6-ethylenedioxy-4a,5,8,8a-tetrahydro-1,4-
565 mg of triethylamine is gradually added dropwise to a solution of 1.63 g of naphthoquinone in 50 ml of ether. After the addition, the mixture was stirred for 3 hours, water was added, and the organic layer was separated. Furthermore, the aqueous layer is extracted twice with 50 ml of benzene, combined with the organic layer, and washed with water. After drying over sodium sulfate, the solvent is distilled off, and the residue is then purified by silica gel column chromatography (eluent: chloroform). Recrystallized from benzene to give 2-chloro-6,6
918 mg of -ethylenedioxy-5,6,7,8-tetrahydro-1,4-naphthoquinone are obtained.

mp 139.5-140℃ IR ν ^CHCl3 _nax (cm ^-1 ); 1590, 1655, 1670 NMR δ (CDCl ₃ ); 1.86 (2H, t, J = 7Hz),
2.5-2.9 (4H, m), 4.00 (4H, s), 6.82
(1H, s) Elemental analysis value (as C ₁₂ H ₁₁ O ₄ Cl) C H Cl Calculated value (%) 56.60 4.35 13.92 Actual value (%) 56.60 4.27 14.08 Reference example 8 2,4aβ-dichloro-7,7- Ethylenedioxy-4a,5,8,8a-tetrahydro-1,4-
172 mg of triethylamine is added dropwise to a solution of 490 mg of naphthoquinone in 15 ml of ether. After the addition, the mixture was stirred for 3 hours, water was added, and the organic layer was separated. Furthermore, the aqueous layer is extracted twice with 15 ml of benzene, and combined with the organic layer, washed with water and saturated saline. After drying over magnesium sulfate, the solvent is distilled off, and the residue is then purified by silica gel column chromatography (eluent: chloroform). Recrystallization from benzene-n-hexane yields 241 mg of 2-chloro-7,7-ethylenedioxy-5,6,7,8-tetrahydro-1,4-naphthoquinone.

mp 98-98.5℃ IR ν ^CHCl3 _nax (cm ^-1 ); 1600, 1650 NMR δ (CDCl ₃ ); 1.82 (2H, t, J = 6Hz),
2.58-2.80 (4H, m), 4.00 (4H, s), 6.89
(1H, s) Elemental analysis value (as C ₁₂ H ₁₁ O ₄ Cl) C H Cl Calculated value (%) 56.60 4.35 13.92 Actual value (%) 56.61 4.27 14.05 Example 1 2,2-ethylenedioxy-6- Hydroxy-
22 mg of 1,2,3,4-tetrahydro-5,12-naphthacenequinone and 60 mg of lead tetraacetate are dissolved in 4.5 ml of a mixed solvent of acetic acid: dichloromethane = 2:1, and stirred at room temperature for 16 hours. After the reaction, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: chloroform:ethyl acetate = 30:1). 11 mg of starting material 2,2-ethylenedioxy-6-hydroxy-1,2,3,4-tetrahydro-5,12-naphthacenequinone and 8 mg of 2,
2-ethylenedioxy-6-hydroxy-11-acetyloxy-1,2,3,4-tetrahydro-
5,12-naphthacenequinone is obtained.

mp 215~217℃ (methanol) IR ν ^CHCl3 _nax (cm ^-1 ): 1760, 1665, 1630 NMR δ (CDCl ₃ ): 13.49 (1H, s), 7.90~
8.20 (2H, m), 7.40-7.70 (2H, m), 3.98
(4H, s), 3.02 (2H, t, J=7Hz), 2.82
(2H, s), 2.47 (3H, s), 1.95 (2H, t,
J=7Hz) Example 2 3,3-ethylenedioxy-6-hydroxy-
42 mg of 1,2,3,4-tetrahydro-5,12-naphthacenequinone and 110 mg of lead tetraacetate are dissolved in 4.5 ml of a mixed solvent of acetic acid: dichloromethane = 2:1, and stirred at room temperature for 16 hours. After the reaction, the solvent was distilled off under reduced pressure,
The residue is purified by silica gel column chromatography (eluent: chloroform:ethyl acetate = 30:1). 8.5 mg of starting material 3,3-ethylenedioxy-6-hydroxy-1,2,3,4-tetrahydro-5,12-naphthahinquinone and 35 mg of 3,3-ethylenedioxy-6-hydroxy-11
-Acetyloxy-1,2,3,4-tetrahydro-5,12-naphthahinquinone is obtained.

mp 226~228℃ (methanol) IR ν ^CHCl3 _nax (cm ^-1 ); 1760, 1665, 1630 NMR δ (CDCl ₃ ): 13.57 (1H, s), 8.05~
8.35 (2H, m), 7.55-7.80 (2H, m), 4.02
(4H, bs), 3.00 (2H, s), 2.81 (2H, t,
J=7.5Hz), 2.48 (3H, s), 1.93 (2H, t,
J=7.5Hz) Example 3 2,2-ethylenedioxy-6-hydroxy-
0.5 ml of water was added dropwise to a solution of 10 mg of 11-acetyloxy-1,2,3,4-tetrahydro-5,12-naphthacenequinone in 1 ml of trifluoroacetic acid, and the
Heat for an hour. After cooling, the solvent is distilled off under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent: chloroform:ethyl acetate = 9:1). Recrystallize with methanol to obtain 6.5 mg of 2-
Oxo-5,12-dihydroxy-1,2,3,4
-Tetrahydro-6,11-naphthacenequinone is obtained.

mp 269-298℃ IR ν ^CHCl3 _nax (cm ^-1 ); 1710, 1610, 1580 NMR δ (CDCl ₃ ); 13.48 (1H, s), 13.37
(1H, s), 8.2~8.4 (2H, m) 7.65~7.85 (2H,
m), 3.76 (2H, s), 3.40 (2H, t, J=7.5Hz),
2.64 (2H, t, J = 7.5Hz) Example 4 3,3-ethylenedioxy-6-hydroxy-
0.5 ml of water is added dropwise to a solution of 10 mg of 11-acetyloxy-1,2,3,4-tetrahydro-5,12-naphthacenequinone in 1 ml of trifluoroacetic acid, and the mixture is heated at 50°C for 3 hours. After cooling, the solvent was distilled off under reduced pressure, water was added to the residue, and extracted with chloroform (10 ml x 3).
Then, the extract is washed with water and dried over sodium sulfate. Purify by silica gel column chromatography (eluent: chloroform:ethyl acetate = 9:1). Recrystallization from methanol yields 5.5 mg of 2-oxo-5,12-dihydroxy-1,2,3,4-tetrahydro-6,11-naphthacenequinone.

mp 296~298℃

Claims (1)

[Claims] 1. General formula [In the formula, one of R ¹ and R ² represents a hydrogen atom,
The other one represents a lower alkylenedioxy group. ] The naphthacenequinone derivative represented by is acyloxylated, and then the general formula obtained is [In the formula, R ³ represents a lower alkanoyl group. R ¹ and R ² are the same as above. ] The naphthacenequinone derivative represented by is hydrolyzed in the presence of an acid to form the formula 1. A method for producing a naphthacenequinone derivative, which comprises obtaining a naphthacenequinone derivative represented by: