JPS597183A - Naphthacenequinone derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R is H or lower alkoxy; one of R<1> and R<2> is H, and the other is lower alkylenedioxy; R<3> is H or lower alkanoyloxy). EXAMPLE:2, 2-Ethylenedioxy-6-hydroxy-1, 2, 3, 4-tetrahydro-5, 12-naphthacenequinone. USE:An intermediate for synthesizing 4-demethoxydaunomycin or daunomycin useful as a carcinostatic agent. PROCESS:A homophthalic anhydride shown by the formula II is reacted with a quinone derivative shown by the formula III (R<4> is halogen) in the presence of a base such as a lithium dialkylamide, etc. at 70-250 deg.C, preferably at 100- 200 deg.C, to give a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel naphthacenone derivatives and methods of production.

The naphthacenone derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (1).

[In the formula, R represents a hydrogen atom or a lower alkoxy group.

One of R1 and R2 represents a hydrogen atom, the other represents a lower alkyl atom, and 7=:/an alkyl group. R3 represents a hydrogen atom or a lower alkanoyl group. ] The compound of the present invention has the general formula (14) useful as an anticancer agent as shown below.
) It is a compound useful as an intermediate for synthesizing 4-demet bovine sitaunomycin or taunomycin.

In the present specification, examples of the lower alkyl-di-di--di------------------------------------------------------ Examples of the lower alkoxy group include meth+shi, etoshishi, zuDposhi, isozurobogyushi, zutogyushi, tart-butoshishi, peshyloshi, heshishiruoh+shi, etc. can be mentioned.

Examples of lower alkanoyl groups include acetyl groups, progonyl groups, dichloro groups, isodyl groups, pentanoyl groups, tert-butylcarbonyl groups, and hesyl groups. etc. can be mentioned.

The compound represented by the above general formula (1) can be manufactured by various methods, for example, according to the method shown in the following reaction scheme-1.

Reaction scheme-1 +2+ (Iα) [in the formula R4
indicates a hero atom. R1, R2 and R are the same as above. ] The reaction between the compound of general formula (2) and the compound of general formula (3) may be carried out by reacting the two in an appropriate solvent in the presence or absence of a basic compound or an acidic compound, for example. The ratio of the compound of general formula (2) and the compound of general formula (3) to be used is not particularly limited and can be appropriately selected from a wide range, but usually the latter is used in at least an equal amount of the former,
It is preferable to use an equal amount of 1.5 times as much. As the basic compound, a wide range of conventionally known compounds can be used.
Specifically, carbonates such as sodium carbonate, potassium carbonate, and sodium hydrogen carbonate; metal hydroxides such as sodium hydroxide and potassium hydroxide; metal alcoholades such as sodium methylate and sodium ethylate; Lithium sialamide, viridis, such as lithium diethylamide, lithium dimethylamide, etc.
Examples include organic basic compounds such as triethylamisi and N,N-dimethylanilishi. The amount of such a basic compound to be used is not particularly limited and can be appropriately selected within a wide range, but in the case of basic compounds other than lithium sialamide, it is usually 1/10 with respect to the compound of general formula (2).
It is preferable to use 0 to equimolar amount, preferably 1/20 to 1/2 times molar amount. The solvent used in this case is
A wide range of substances can be used that do not have a negative effect on the reaction.
Jiku D Lubeshi+! Aromatic hydrocarbons such as Shi, Zurombe Shizeshi, ethers such as diethyl ether, Dioshisashi, Tetra Shidorofuraji, saturated hydrocarbons such as Ruhe+Sashi, Rouheputashi, Schif D Hejusashi, dichloromethane, Examples include aliphatic hydrogenated hydrocarbons such as dichloroethane, chloroform, and carbon tetrachloride, polar solvents such as dimethylformamide, dimethylformamide, and hesicylic acid triamide, and ethyl acetate. The reaction is usually carried out at a temperature of about 70 to 250°C, preferably 100 to 20°C.
The reaction proceeds suitably at 0°C and is generally completed in about 0.5 to 10 hours. In addition, when lithium sialamide is used as the basic compound, the amount of the compound to be used is at least equimolar to the compound of general formula (2), preferably equal to 1.5 times It is best to use about 1. As the solvent used, for example, ethers such as diethyl ether, dioxic acid, tetrahydrofuran, and dimethic acid, and saturated hydrocarbons such as sulfuric acid, dimethic acid, and cyclohydric acid are used. is preferred.

The reaction is usually carried out at -78°C to 50°C, preferably at 8°C.
The reaction is carried out at ~room temperature, and generally completes in about 0.1 to 5 hours.

Specific examples of acidic compounds include Lewis acids such as aluminum chloride, ferric chloride, aluminum bromide, zinc chloride, titanium tetrachloride, and boron trifluoride. The usage ratio is usually 0.01 to the compound of general formula (2).
~5 times the molar amount, preferably 0.05 to the equivalent molar amount tThe reaction temperature is usually -20 to 100°C, preferably 0°C
~ around room temperature.

When lithium sialamides are used as the basic compound, the compound of general formula (1α) can be produced with high yield and high purity through simple operations.

The compound of general formula (2) used as a starting material in the above reaction scheme -1 is the following reaction scheme -2 and -3.
Manufactured according to the method shown in

Reaction scheme-2 i4) (e) (2α) [In the formula, X is 80] f, 7 atoms, R5 is a lower alkyl group,
R1' represents a lower alkyl group. R4 is the same as above. ] The reaction between the compound of general formula (4) and the compound of general formula (5) is generally called Diels-Alter reaction. For this reaction, a wide variety of reaction conditions for the usual Diels-Alter reaction can be applied, for example, the two may be reacted in a suitable solvent. As the solvent, the general formula (2)
Any solvent used in the reaction between the compound of formula (3) and the compound of general formula (3) can be used. The ratio of the compound of general formula (4) and the compound of general formula (5) to be used is not particularly limited and can be appropriately selected from within a wide range. Preferably, it is used in an amount of 7 to 1.5 times the amount. The reaction is usually carried out at room temperature to about 150°C, preferably 40 to 10.0°C, and is generally completed 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 range of known solvents can be used as long as it does not adversely affect the reaction, such as the aromatic hydrocarbon water ices, the ethers, the saturated hydrocarbons, the polar aprotic solvents, etc. .

Examples of the catalyst include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as p-toluethysulfosic acid, preferably hydrochloric acid. The amount of such a catalyst used is not particularly limited, but is usually from /100 to the compound of general formula (6).
Examples of the ketalizing agent include ethylene glycol, methylene glycol, l-rimethylene glycol, alcohols such as methanol, ethanol, isodurobanol, and ruditanol. The amount of such a ketalizing agent to be used is not particularly limited, but it is usually at least an equivalent molar amount, preferably an equivalent to 2 times the molar amount of the compound of general formula (6). The reaction is usually carried out at room temperature to about 100°C, preferably around room temperature, and the reaction is generally carried out at a temperature of 1 to 2
It took about 0 hours.

The dehydrohalogenation reaction of the compound of general formula (7) is carried out in a suitable solvent in the presence of a basic compound. As the basic compound, the compound of the general formula (2) and the general formula (
Any basic compound used in the reaction with the compound in 3) can be used. 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 (2) and the compound of general formula (3), 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 (2(L)) is produced.

Reaction scheme-3 (g) (91 (2h) [In the formula, R2' represents a lower alkyl group. Ra
, X and R5 are the same as above. ] Reaction of the compound of the general formula (8) with the compound of the general formula (6), ketalization of the compound of the general formula (9), and reaction of the compound of the general formula (10)
) Dehydrohalogenation of the metal compound includes the reaction of the compound of the general formula (4) with the compound of the general formula (5), the ketalization of the compound of the general formula (6), and the compound of the general formula (7), respectively. It can be carried out under the same reaction conditions as for dehydrohalogenation. In this way, a compound of general formula (2h) is produced.

When the compound of general formula (2) thus obtained is used as a starting material, the target compound of the present invention can be obtained in a short process and with a simple operation in high yield and high purity.

Further, the compound of the general formula (Il) can be produced by the method shown in the following reaction scheme-4.

Reaction Scheme-4 0HO (lα) 0HO (1b) [In the formula, R, R1 and R2 are the same as above. R3' represents a lower alkanoyl group. ] Acylosiloxification of the compound of general formula (lα) can be carried out, for example, in the presence of an acylosiloxinating agent in a suitable solvent. Examples of the oxidizing agent used here include Pb (OCOCH3), TtCOCOCH3>3
, Ibar0COCH3)2, etc. The amount of the acyl oscinating agent to be used is not particularly limited and can be appropriately selected from a wide range, but it is usually expressed by the general formula (2).
It is preferable to use at least an equivalent amount, preferably an equivalent amount to 3 times the amount of the compound.

Examples of solvents include aromatic hydrocarbons such as beshizeshi, tornidi, and bokshiren, hydrocarbons such as jig00methacrylate, jig0loethane, chloroform, and carbon tetrachloride, diethyl ether, geobeef san, and tetrachloride. Examples include ethers such as dolphradi, acetic acid, and mixed solvents thereof.

The reaction is usually carried out at room temperature to about 100°C, preferably around room temperature, and is generally completed in about 1 to 30 hours. When the acyl oxidation reaction is used, the general formula (lα)
When R is a hydrogen atom in the compound, the acyl-oxygen group is selectively introduced only at the 11th position, and when R is a lower alkyl group, the acyloxy group is selectively introduced only at the 12th position.

The naphtasecinone derivative represented by the above general formula (Ih) is induced into 4-demeth+cytaunomycin or taunomycin represented by the general formula (I4), which is useful as an anticancer agent, according to the method shown in Reactivity Formula-5 below.

Reaction Scheme-5 R00H (12 04) [In the formula, R is the same as above. ] Hydrolysis of the compound of general formula (1h) is carried out, for example, in a suitable solvent in the presence of an acid. Examples of solvents that can be used include water, alcohols such as methanol, ethanol, and iso''50 panol, ethers such as dioxane and tetrahydroflag, and mixed solvents thereof. Examples of acids include, for example, hydrochloric acid. 1. Mineral acids such as sulfuric acid and hydrobromic acid; 1. Organic acids such as trifluoroacetic acid and paratoluethysulfosic acid.The amount of such acids used is based on 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 completed in about 1 to 10 hours.

The compound of the general formula (1α) is acylated to form a compound of the general formula (I).
By using the method of preparing the compound of h) and hydrolyzing it, the compound of general formula (11) can be obtained in high yield and purity.

The reaction of inducing 4-dimethoxytaunomycin or taunomycin represented by the general formula (+4) from the compound of the general formula (Kawa) through the compound of the general formula (12) and the compound of the general formula (+3) is known, for example, tetra Hedrocillator CF, FαrirLa arLti P, Pra
Do,? , TetrantcLroaLetters
, 477 (1979) :), Journal Saizu
Chemical Society CD, N.Gupta
ancLN, Khan.

J,Chem,5oty,PerkirL I,6
89 (1981)], Journal of Organic Chemistry CF, F.

Lee, A.P., Martizez, J.H., Smlt.
N and D, F.

Henry, J. Org. Chem., 41
, 2296 (1976)], Tetrahet O,y Letter [J, AlaxaneLer and L,A.

Mitrher, Tetrahedron, Let
ters, 3403 (1978)], Journal of the American Chemical Society CF,
A, J, Kerdezky arbd M, P
, Cava, J.

A77L, Cham, Soc, 400, 36
35 (1978)) and tetrahedrociretar [A
, S., Kgndg., D., P., Cu, rra.
rb.

Y, Tsay and J, E, Mills,
Tetrahgclron Letters.

3537 ('+977 > ), Journal of the American Chemical Society II: A,
S, Kerbum.

Y-, g, T,? a, y, J, E, MiLl
,? , J. Am. Chem. Soc., 98
゜1967 (+976 > ), U.S. Patent No. 404
The method described in the specification of No. 6878 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 thin layer O-mography.

Reference examples and examples are listed below.

Reference Example 1 Under a nitrogen atmosphere, 990 μl of 2,6-cyclobenzene and 800 μl of 2-trimethylsilyloxypylamide
Warm the J Zecip 10 solution at 50-60°C for an hour.

The solvent was distilled off under reduced pressure to give syrupy 2,8αβ-dichloro-6-dolimethylsilyl-4Z,5,8.8α-
Tetrahydro-1,4-naphthyl oxide: 71.639 is obtained. Identification from IR spectrum and NMR spectrum.

IRνCH”3 (cm 1): l 585.16
70.1690, 72O NMRδ (CDC13); 0. +7 (9H, s=)
, 2.2 to 3.8 (5, H, m), 4.65 to 4.8 (Hz, m) Reference Example 2 Beef sea 4α, 5. ．． 8,8α-tetrahydro-1,4-naphthonione 1.63 F and ethylene glycol 1.05 F in an ether solution was added with concentrated hydrochloric acid 2
Add ~3 drops and stir at room temperature for 16 hours. After drying with sodium sulfate, the solvent was distilled off to give 2,8αβ-dichloroO-6,6-ethylenic acid 4α,5,8,8α-
Tetra and draw 1.4-naft beef 1.42 are obtained.

Identification is made by JR spectrum and NMR spectrum.

IRv ””'3 (m 1); 1590.165
5.167ONMRδ(CDC13); 1.84(
2H, t, J=6H1), 2.55-3.0 (4H, m
), 3.99 (4H, s), 3.85-4.2 (II, m), 6.88 (IH, s) Reference example 3 2.8αβ-dichloro-6,6-nithylene dioxidase 4
50 ml of ether of α, 5.8.8α-tetrahydron[]-]1.4-naphthonone 1.63! 565 μl of triethylamine is gradually added dropwise to the solution. After the addition, the mixture was stirred for 3 hours, water was added, and the organic layer was separated. Further remove the water layer.
! Extract twice with 50 ml of water and wash with water together with the previous organic layer. After drying over sodium sulfate, the solvent is distilled off, and the residue is then purified by silica gel column chromatography (eluent: Riloform). Recrystallized from benzene to give 2-
Chloro-6,6-ethylenic acid 5,6,7.8-
Tetra and draw 1,4-naft beef non 918■ is obtained.

mp 139.5-140℃ I Rl/CH”3 (crn-1): I 59
0.1655.1670mαX NMRδ (CDCl2); 1.86 (2H2t, J=7
H2), 2.5-2.9C4H,m), 4.00 (4H,!), 6-82 (lH,s) Elemental analysis value (C□2H1101, as Ct) CHCL calculated value (%) 56. 60 4.35 13.9
2 Actual value (%> 56.60 4.27 14.
08 Reference example 4 2.2-Ethylene dihydric acid 6-Sydroxylic acid 11-Acetylated Oxylic acid 1.2,3.4-Tetrahydric acid 5.
12-naphthalate 10% trifluoroacetic acid 1r
Add 0.5 d of water dropwise to the Ll solution and heat at 50° C. for 3 hours. Next, the solvent was distilled off under reduced pressure, water was added, extracted with chloroform, washed with water, dried, and the solvent was distilled off.The resulting residue was subjected to silica gel column chromatography (eluent:
Purify with form:ethyl acetate=9:l). Recrystallize with methanol to obtain 6.5 trq of 2-Ogyuso 5.12-
．． ;
11- Obtain Naftaseshi + Noshi.

mp296-298°C IRv CIf0L3 (m-1): I 710.
161O11580m, αX NMRδ (CDC1,); 13.48 (IH, s),
13.37 (IH, -?), 8.2-8.4 (2H, rn), 7.65-7.85 (2H, 7Fl), 3.76 (2
H,,r), 3.40 (2E, t, J=7.5Hz), 2
-64C2H,t, J=7.5Hz) Reference example 5 4-methoxycyc 5-silicon 9,9-ethylenedioxycyc 12-acet+cy 7.8.9. Add 0.5 ml of water dropwise to a 1 vtl solution of trifluoroacetic acid of IO-tetra-dronaphtase 6,11-dios 12, and heat at 50°C.
Heat for 6 hours. Thereafter, the solvent is distilled off, water is added and extracted with dichloromethane, washed with saturated brine, and dried over sodium sulfate. The solvent is distilled off, and the resulting residue is purified by silica gel chromatography (eluent: ethyl ether = lO:l). Recrystallize with acetic acid,
8 ■ 4-methoxycy 6.11-dihydro medium cy 7.8
,9.10-tetra-dronaftase-5,9,12-
1- Obtain Riosi.

mp252-256℃ (decomposition) IRv CIICL3 (cm-1); ] 715
, +615.1590ar NMRδ(CDCl2): 2-63 (2H, t
, J=6.5Hz), 3.26 (2H,t,
J=6.5H'z), 3-60 (2H,,r)
, 4.07 (3E', ffi'), 7.20-8
．． 10 (3j7.-m), 13.38 (IH,S)
, 13.89 (IH,r) Reference Example 6 A benzene 3-solution of 300 μl of 2,5-dichlorobesidy and 300 μl of 2-, trimethylsiliruo cyptadiene was heated at 80 to 90°C for 3 hours under a nitrogen stream. do. The solvent was distilled off under reduced pressure to give 2.4a, β-dimethylsilyl-4α, 5°8.8α-tetrahydro
-1.4-naphth + no, j 540■ is obtained. Identification from JR spectrum and NMR spectrum.

IRνuu Z3 (m-1); 1585.1665.1
69°NMRδ (CDCl2); 0.21 (9H
, s), 2.41-3.27 (4H, m), 3.6
7 (IH, t, J=8Hz), 4.72-4.
87 (IH, m), 7.01 (IB,,?) Reference Example 7 2,4αβ-dicyclo[10-7-
Dolimethylsiliruo Nakashi 4α, 5, 8. Two drops of concentrated hydrochloric acid were added to an ethereal solution of 'aα-tetrahydro-0-1.4-naphtho+nosi 540 cape and ethylecylicol 137 cm, and the mixture was stirred at room temperature for 16 hours.

After drying using sodium sulfate, the solvent was distilled off to give 2.4α
β-dichlorophyll, 7-dichlorophyll, 4α, 5,
8,8α-tetrahuman O-1,4-naphtho+Nosi 490
■ Get. Identification is made by IR spectrum and NMR spectrum.

IRν”” (m 1); I 590.1650.
1690ηiαX NMRδ(cDct3); 2.44-4.20(1
1H,y+t), 6.93 (IH,!) Reference example 8 2.4αβ-dichloro0-7.7-ethyresidic 4
α, 5,8,8α-tetrahydro-1,4-naphthyl-49 (Iv ether 15 m/solution to triethyl acetate
? Drop /172■. 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 liters of water, 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). It is recrystallized from Beshizeshiruheshisan to obtain 2-OO-7,7-ethylethyl-5,6°7.8-tetrahytone0-1.4-naphtho + noshi241.

mP98~98.5℃ IRJ/""3 (m-1); I 600.16
50 doors αX NMRδ(CI)C1s'); I , 82 (2
H-t, J = 6 Hz), 2.58-2.80 (
4H, m), 4.00 (4H, -?), 6.89 (IH,,t) Elemental analysis value (as 0□2H□104C2) CHCt Calculated value (%) 56.60 4.35 13.
92 Actual value (%) 56.61 4.27 1
4.05 Reference example 9 3.3-acetyl 6-hydro 11-acetyl 1,2.3.4-tetrahydro 0-5.1
2-naphtacetic acid 1, 71oW9 trifluoroacetic acid 1
Add 0.5 ml of water dropwise to the N solution and heat at 50° C. for 3 hours. Thereafter, the solvent was distilled off under reduced pressure, water was added to the residue, extracted with chloroform (IOmA!x3), the extract was washed with water, and dried over sodium sulfate.

Silica gel column chromatography (eluent, RI00
Purify with form:ethyl acetate=92I).

Recrystallize with methanol to obtain 5.5■ 2-Saiko 5.
12-,; human 0 in C 1.2,3.4-tetrahuman 0
-6.11- Obtain naphtaseshi noshi.

mp296-298℃ Example l Phophthalic anhydride 41+Hi, 2-Rio O-6,6
= A 2d solution of toluene containing 5,6,7,8-tetra, 1.4-naphtho, 765Ilv and 13cm of triethylamide in a sealed tube! Purify with 40 to 150 tel:benzene = 1:4). Recrystallized from Oo form to obtain 28 Misaki's 2.2-Ethyresidiocy 6- Shidoroushishi 1,2.3.4-Tetrahytone 0-5.12-
Obtain Naphthacenshi Non.

mp229-230.5℃ IRI/C1,1C13(α-1); 1605.163
0.1655ar NMRδ (CDCl2): l, 92 (2H
, t-1=6-5 Hz), 2.80-3.05
(4H, m), 4.02 (4E, !), 7.50-7.95 (3H, m), 8.01 (lH, S”), 8.35-8.55 (IH, m) .

14.06 (IH,,t) Elemental analysis value (C2oH engineering, as 05) CH Calculated value (%) 71.42 4.80 Actual value (CH) 71.00 4.73 Example 2 Phoheptapthalic anhydride thing 50■, 2-900-7.7-ethile, 7. ;O medium sea 5,6,7.8-tetra and draw 1
．． 4-naphthojuno, 770v and triethyl amici 13
1 ng of Tornizi 2d solution is heated in a sealed tube at 140-150° C. for 1 hour. Thereafter, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: benythyl:benzene=I:4). Please recrystallize Oaform! 8 capes of 3,3-ethylene di+, 6-hydro, 1,2,3,4-tetra, and 5.12-naphthacene are obtained.

mP214-216℃ IRv ""3 (Crn-1); I 605.1
630.1655 Door αX NMRδ (CDCI-3); I, 92 (2H-
t-7=6-5 Hz), 2.80-3.05 (
4H, m), 4.02 (4H, S), 7.750-7.95 (3H, m'), 8.01
(IH, -r), 8.35 to 8.55 (IH, m), 13.97 (IH, S) Example 3 8-Methobovine heptaphthalic anhydride 40■, 2-Crow 6 .6-Nythilene Dioxide 5.6,7.8-Tetrahydrogen(]-]1.4-Naphthalene 58.5"'jO Mbeshize 1.Qml solution was heated at around 110°C for 30 minutes under a nitrogen atmosphere. Heat. Next, the solvent is distilled off, and the residue is subjected to silica gel column chromatography (eluent, Beshizene:
; Ethyl ether=IO:]). Jig 00 Meta Sea Recrystallized from methanol to obtain 12 Cape Imaichi Meto Naka Sea 5- Doro Naka Sea 9.9- Echire'J Geo Gyu Sea 7.
8,9.10-tetra-dronaftase, :/-6.11
- Obtain dione.

mp252-254℃ IRv CM0L3 (crn-1); I 575
．． 1600.1630, ax 65O NMRδ (CDCl2); I, 89 (2H, t-
/ = 6.5 Hz), 2.76~3.00 (4H
, m), 4.00 ('7H,bz), 6.91-7.70 (3H, specialized), 7.93 (lJ7.#), 15.11 (]H,#) Elemental analysis value (C2 □H1806) CH Calculated value (%) 68.84 4.95 Actual value (%) 68.61 4.86 Example 4 Under nitrogen flow, at 0°C, diisozu 0 pilua three sieve 0.29 m
0.29 mmol of lithium diisochloride is produced.

The reaction mixture is cooled to -78° C. and 1.5 m/ml of tetrahydrofuradi is added. To this reaction mixture was added 48 μm of dihomophthalic anhydride in 3-methane and 0.5 μm of tetrahedral phthalate υ2.
QmA! Solution, 2-[1-6,6-ethylenic acid 5,6,7.8-tetrahydro-1.4-naphthylone 63.5] Add the Qml solution dropwise in this order. After the addition, the reaction mixture was heated at -78°C for 2
Stir for 0 minutes and gradually return to room temperature. After stirring for 1 hour at room temperature, saturated acinanium chloride solution is added, extracted with dichloromethane, and dried over sodium sulfate. After evaporating the solvent, the resulting residue was purified by silica gel chromatography (eluent, vesi:diethyl ether=IO:I) and recrystallized from dichloromethane-methanol.
Tq in 4-metallic acid 5-hydro+cy9,9-ethylenic acid 7.8.9. to-tetra doronaftat
C6.11-diol is obtained.

mP252-254°C Example 5 Under a nitrogen stream at 0°C, DiynezuO Hirua Sanshi 0.56
Lithium diisopropylamide is produced from 0.56 mmol of lithium diisopropylamide.

The reaction mixture is cooled to -78°C and 2.0 ml of tetrahydrofuran is added. To this reaction mixture, a solution of 3.0 ml of homophthalic anhydride 81~ in tetrahydrofuradi, 2
-Chloro-6,6-nitilendio+C5.6,7.8
- 3.0 ml of a solution of 1,4-naphthinoshinoshi 127 ml of tetrahydroflage was added dropwise in this order. After the addition, the reaction mixture was stirred at -78° C. for 20 minutes and gradually warmed to room temperature. After stirring at room temperature for 1 hour, saturated acinanium chloride solution is added and extracted with dichloromethane. The organic layer was washed successively with IO% HC1° water and saturated brine, and dried over sodium sulfate. The solvent was distilled off and recrystallized from OO form to give 158■2,2-ethyle:J;
- Shi Draw Shishi 1.2, 3.4 - Tetra Shi Draw 5.1
Obtain 2-naphthacene boar.

mp 229-230.5°C In the same manner as in Example 5, the compound of Example 2 is obtained using appropriate starting materials.

Example 6 2.2-Ethyresidic C6-Hydro+C1.2,
3.4-tetrahydro-5,12-naftasecy+no'',
/22 ■ and lead tetraacetate 60 ■ dichloromethane acetate = 2
: Dissolved in 4.51 rLll of a mixed solvent of 1 and dissolved at room temperature.
Stir for an hour. After the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with OOform. The residue obtained after distilling off the chloroform is purified by silica gel column chromatography (eluent: chloroform:ethyl acetate=30:I). 2,2-ethylenic acid 6-hydrohydric acid 1.2,3,4-tetrahydric acid which is the starting material for 11~
-5.12-naphtase and 8 2,2-ethyle, 7 dioxygen 6-hydro+cy 1.2.3.4-tetrahydro-5,12-naphtase obtain.

mp2I5-217℃ (recrystallization solvent methanol) IRv
CH”3 (crn-1); I 760.166
5.1630ax NMRδ(cnct3); 13.56(IH,
r), 7.90-8.20 (2H, m), 7.40
~7.70 (2H, m), 3.98 (411, s
), 3.02 (2H, t, J=7Hz), 2.83
(2H, s), 2.47 (3H,, p), 1.95 (2H, t, J=7Hz) Example 7 3.3-Ethylene dioxic 6-Hydroxycyan 1.2,
3.4-tetrahuman [1-5,12-naphthacene],
742 rng and lead tetraacetate + 10W were dissolved in 4.5 ml of a mixed solvent of acetic acid:,;
Stir for 6 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:ethyl acetate-30:l). 8.5■ 3,3-ethylenic acid 6-hydro +
Sea 1, 2. 3. 4 - Tetrahythro 5, 12 - Naftaseshi Tsun and 35■ 3.3 - Echireshishioshi Sea 6 -
Shidoro+C11-acetylo+C1,2.3.4-
Tetra and draw 5.12 - Naftaseshi + Noshi is obtained.

ml 226-228℃ (recrystallization solvent methanol) I
Rv CRC'3 (cTn-'); l 760.
1665.163ONMRδ(CI)C13); 1
3.57 (IH, s), 8.05-8.35 (2H,
m), 7.55-7.80 (2H, m), 4.0
2 (4H, bs), 3.00 (2E', s), 2.8] (2H, t, J = 7.5Hz),
2.48 (3H1S), 1.93 (2H, t, J=7.5Hz)Example 8 4-Methogyushi 5-Doroshishi 9,9-Ethirejishishishi 7.8.9.10- Tetra Dronaftaseshi 6
．． 11-dio, 728η and 85μ of lead tetraacetate were dissolved in 12ml 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, water was added to the residue, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (eluent, benzene, 7:diethyl ether, 10
:1) and recrystallized from dichloromethane methanol to obtain 19.7cm of 4-metallic acid 9+ 9-ethy, 7-year-old ``i-12-7''.
'Sechiruoshi 7.8.9. IO-tetrahydronaphthasecy-6,11-diol is obtained.

77LP 244.5-246°C iRν0HCL3 (cm-”): ] 590.
1630.1660, ax 76O NMRδ (CDC1,); 1.93 (2H,t, J
=6.5H2), 2.46 (3H, z), 2.84 (2H, bs), 3.04 (2H, t, J=6.5Hz), 4.
03 (4H, z), 4.04 (3H, /n, 7.20-7.90 (3H, m'), 13.84 (I
H,s) Elemental analysis value (as C23H2o08) ('
H Calculated value (%) 65.09 4.75 Actual value (%
) 65.07 4.59 (or more) -'t

Claims (1)

[Claims] ■ General formula [In the formula, R represents a hydrogen atom or a lower alkoxy group. R1
and R2, one of which represents a hydrogen atom and the other represents a lower alkyl group; R3 represents a hydrogen atom or a lower alkanoyl group. Natsuta Goinsonongin 4 books. ■ Phthalic anhydride represented by the general formula [in the formula, R represents a hydrogen atom or a lower alkoxy group] and the general formula [in the formula, R1 and R2 are one represents a hydrogen atom, and the other represents a lower alkyl didio+thi group. R1'' represents a halogen atom. ] is reacted with a +nosyl derivative represented by the following formula in the presence of ruamide in lithium sial, and then, if necessary, the obtained general formula [wherein R, R1 and R2 are the same as above] is obtained. ] The naphthacenone derivative represented by the above formula is converted into acyloxysilane to form a compound of the general formula [wherein R3' represents a lower alkanoyloxy group]. R, R' and R2 are the same as above. ] A method for producing a naphthacene derivative, which comprises obtaining a naphthacene derivative represented by: