JPS58110581A - Quinone derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formulaI(one of R<1> and R<2> is H and the other is lower alkylenedioxy; X is halogen). EXAMPLE:2-Chloro-6,6-ethylenedioxy-5,6,7.8-tetrahydro-1,4-naphthoquinone. USE:A synthetic intermediate of 4-demethoxydaunomycin useful as a carcinostatic agent. PROCESS:The compound of formlaIis prepared by (1) carrying out the Diels-Alder reaction of the compound of formula II or III (X<1> is halogen) with the compound of formula IV at a molar ratio of 1:1-1.5, (2) ketalizing the product and introducing a lower alkylene-dioxy group, and (3) subjecting the product to dehydrohalogenation reaction.

Description

[Detailed description of the invention] The present invention relates to novel quinone derivatives.

The quinone 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, one of R1 and R3 represents a hydrogen atom, and the other represents a lower alkylenedioxy group.

In addition, X represents a halogen atom.] The compound of the present invention is a compound useful as an intermediate for synthesizing 4-demethoxydaunomycin represented by the general formula (2), which is useful as an anticancer agent as shown below.

In this specification, examples of lower alkylenedioxy groups include methylenedioxy, ethylenedioxy, trimethylenedioxy groups, and examples of halogen atoms include chlorine atom, bromine atom, fluorine atom, iodine atom, etc. The compound represented by the above general formula (x>) can be produced by various methods, but for example, among the compounds of general formula (1), R
A compound in which 1 represents a lower alkylene dioxy group and R1 represents a hydrogen atom (i.e., a compound of general formula (1m)) is produced according to the method shown in the following reaction scheme-1, and the compound of general formula (1) is Among them, compounds in which R1 represents a hydrogen atom and R1 represents a lower alkylenedioxy group [i.e., a compound having the general formula (
Compound lb)] is produced according to the method shown in the following reaction scheme.

Reaction formula-1 [In the formula, x1 is a halogen atom, Rs is a lower alkyl group%
R'' represents a lower alkylenedioxy group.

X is the same as above.] The reaction between the compound of general formula (2) and the compound of general formula (3) is generally called Diels-Alder reaction. For this reaction, the reaction conditions of the usual Diels-Alder reaction can be widely applied (for example, the two may be reacted in a suitable solvent; the solvent used here is
We use a wide range of substances that do not have a negative effect on the reaction, specifically benzene, toluene, xylene, chlorobenzene,
Aromatic hydrocarbons such as dichlorobenzene, ethers such as diethyl ether, dioxane, and tetrahydrofuran, saturated hydrocarbons such as rhohexane, n-hebutane, and citalohexane, dichloromethane, dichloroethane, chloroform, tetrachloride, etc. aliphatic halogenated hydrocarbons, polar aprotic solvents such as dimethylform, dimethyl sulfoxide, and methyl chloride;
Let's take ethyl vinegar as an 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 selected as appropriate from a wide range, but usually the former is at least equal to 7% of the latter. The reaction is usually carried out at room temperature to about 150°C, preferably 40 to 100°C, and the reaction is generally completed in about 1 to 48 hours. do.

The ketalization reaction of the compound of general formula (4) is carried out, for example, by reacting the compound of general formula (4) 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 anti-I5, such as the aromatic hydrocarbons, ethers, saturated hydrocarbons, polar aprotic solvents, etc. .

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 a catalyst to be used is not particularly limited, but it is usually from 1/100 to 1/100 relative to the compound of general formula (4).
178 times the molar amount, preferably l/g.

It is preferable to use ~'15 times the molar amount. Examples of the ketalizing agent include alcohols such as ethylene glycol, methylene glycol, trimethylene glycol, methanol, ethanol, impropatol, and n-butanol.

The amount of the ketalizing agent to be used is not particularly limited, but it is usually at least an equimolar amount, preferably about twice the molar amount of the compound of general formula (4). The reaction is usually carried out at room temperature to about 100°C, preferably around room temperature, and the nuclear reaction is generally completed in 1 to 20 hours.

The dehydrohalogenation reaction of the compound of general formula (5) is carried out in a suitable solvent in the presence of a basic compound. Conventionally known basic compounds are widely used, specifically carbonates such as sodium carbonate, potassium carbonate, and sodium bicarbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, and sodium methylate. Examples include metal alcoholades 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 selected appropriately from a wide range, but it is usually at least 0.1 to 1.0% relative to the compound of general formula (5).
It is preferable to use 6 times the molar amount, preferably O] to 0.7 times the molar amount, and as a solvent, one that does not adversely affect the reaction, for example, the compound of the general formula (2) and the compound of the general formula (3). Any solvent used for anti-F)IC with metal compounds can be used. The reaction normally proceeds suitably at about 0 to 60"C, preferably around room temperature, and is generally completed in about 1 minute to 6 hours. In this way, a compound of general formula (1) is produced. .

Reaction formula-2 +e+ (7+ (81 (lb) [In the formula, R3' represents a lower alkylenedioxy group.

X%x1 and R3 are the same as above. ] The reaction of the compound of general formula (6) with the compound of general formula (3), the ketalization of the compound of general formula
) and a metal compound of the general formula (:()), ketalization of the compound of the general formula (4), and dehydrohalogenation of the compound of the general formula (5) can be carried out under the same reaction conditions. A compound of the general formula (lb) is produced.

According to the above reaction schemes -.1 and 2, the compound of general formula (1) can be produced with high yield and high purity through simple operations.

The quinone derivative represented by the above general formula (1) is induced into 4-demethoxydaunomycin represented by the general formula (2), which is useful as an anticancer agent, according to the method shown in the following reaction scheme-8.

Reaction formula-8 +1) α [υ υH (to) [In the formula, R1, R snow and X are the same as above. ] General formula (1)
The reaction between the compound of formula (9) and the compound of general formula (9) is generally called Diels-Alder reaction. For this reaction, a wide range of reaction conditions for the usual Diels-Alder reaction can be applied. For example, it is sufficient to react the two in an appropriate solvent in the presence or absence of a basic compound, and the general formula (1
The ratio of the compound of formula (9) to the compound of general formula (9) is not particularly limited and can be selected from a wide range, but usually the latter is used in at least a tenth molar amount, preferably an equimolar amount, relative to the former. It is preferable to use 1.6 times the molar amount. As the basic compound, any compound used in the dehydrohalogenation reaction of the compound of the general formula (5) can be used. The amount of the basic compound to be used is not particularly limited, but it is usually in an amount of 1/10 to 1/10 ml,
Preferably it 1/$! It is preferable to use O-t/2 times the molar amount. As the solvent, any 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 γO-$150°C, preferably from 100 to 200°C, and is generally completed in about 1 to 10 hours.

The oxidation reaction of the compound of general formula (-) is carried out in a suitable solvent in the presence of an oxidizing agent. Examples of the oxidizing agent that can be used include four-fold lead, viridinyl chloride,
Examples include chromium compounds such as Jean's reagent and Corinth's reagent.

The amount of the oxidizing agent to be used is not particularly limited, but it is usually at least equimolar or more based on the compound of the general formula αG,
Preferably, it is used in an equimolar amount to 1.6 times the molar amount. Examples of the solvent to be used include the aromatic aspect ratio hydrogens, the halogenated hydrocarbons, and the like.

The reaction is usually carried out at about -20°C to 100°C, preferably at room temperature to 70''C, and is generally completed for about 6 to 72 hours.

The reaction of inducing 4-demethoxydaunomycin represented by the general formula (to) from the compound of the general formula 〇 through the compound of the general formula @, the compound of the general formula υ, and the compound of the general formula (b) is known, and for example, Tetrahedron letter (F, F
aring and P, Prados, Tetr
ahedronLett@rs, 477 (1979
), Journal of Chemical Science (D.N., Gupta and N.Khan.

J, Chem, Soc, PerklnI, 689
(1981)), Journal of Organic Chemistry [w.

111, Lee, A,! ', Martlzez,
J,)1. Sm1th and D,! .

Henry, J. Org. Chem., 41.21
196 (1976)), Tetrahedron Letter (J,
Alexander an+S L, A.

Mltmher, Tetrahedron Lett
er@, 8408 (197B):), Journal of the American Chemical Society (F,
A., J., Kerdesky and M., P., Cav.
a.

J, Am, Chem, Soc,, Zoo, 86
85 (1978)) and Tetrahedron Letters (A, S
, Kend@, D.P., Currmn.

Y, Tsmy and J-E, Mlls, Tet.
ra+hadron Letters.

86B? (1977)), U.S. Patent No. 4,046,87
The method described in Specification No. 8 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 A solution of 990 ml of 2,6-cyclopenzoquinone and 800 mF of 2-trimethylsilyloxybutadiene in 10 ml of benzene is heated at 60 to 60° C. for 4 hours under a nitrogen stream. The solvent was distilled off under reduced pressure, and a syrup-like 2.8&β-dichloro-6-dolimethylsilyloxysilane was obtained.6.8.8
m-tetrahydro-1,4-naphthoquinone 1.68 p
get. Fixed from IR spectrum and NMR spectrum.

I Rν”” (cm-1) #1F186.1
670.1690°171(1 NMR#(CDCI!s); 0.17(9
H, s), 2.2-L8 (6H, m), 4.66--4.8 (IH, m), 6.89 (IH, s) Reference Example 2 2.5-dichlorobenzoquinone under nitrogen stream 800 mF and 2-trimethylsilyloxybutadiene 800 nf
A solution of I in 8 rnl of benzene is heated at 80-90°C for 8 hours. Remove the solvent under reduced pressure! ! , 811β-dichloro-7-trimethylsilyloxy-4m.

6.8.8 540 ml of a-tetrahydro-1,4-naphthoquinone are obtained. Fixed from IR spectrum and NMR spectrum F.

Noj Hatake -1.

IRI' (cm), 1585.166
6.169ONMRδ(CDCJ!'s); 0
．． 21 (9H, s), $! , 41-B, 27 (4H, m
), 8.67 (IH-t*J-8Hz), 4.72-4.87 (IH, m), 7.01 (IH, s) Reference Example 8 2,8aβ obtained in Reference Example 1 above -Dichloro-6-drimethylsilyloxy-4m, 5.8.8a-Tetrahydro-1,4-naphthoquinone L, 68F and ethylene glycol 1.059% in ether 10m/solution were added with 2 to 8 drops of chloric acid and heated to room temperature. Stir for 16 hours. After drying with sodium sulfate, the solvent was distilled off to give 2.8aβ-dichloro-6,6-ethylenedioxy-4-4, 5,8,8-tetrahydro-1,4-su7toquinone 1.411. It is identified by the obtained IR spectrum and NMR spectrum.

aIIoz Hatake” R' II@X (cm): 159
0.1666.167ONMRδ (CDC/31)
; 1.84 (1!H,t, J=6Hg)L5
5-B, 0 (4H, m), 8.99 (4H, s), 8.86-4.2 (IH, m), 6.88 (tH, s) Reference Example 4 Obtained in Reference Example 2 above Add 2 to 8 drops of concentrated hydrochloric acid to a solution of 540 nS' of 2,8aβ-dichloro-7-drimethylsilyloxy-4m,6,8,8a-tetrahydro-1,4-naphthoquinone and 7 mF of hyethylene glycol in 6 rats of ether, and leave at room temperature. Stir for 16 hours. After drying using sodium a-acid, the solvent was distilled off to obtain 2.8&β-cycloloaf, 7-nithylenedioxy-4a, 6.8*8m
-Tetrahydro-1,4-naphthoquinone 490 mF is obtained, identified by IR and NMR spectra.

I Ry """(cm'); 1590.16
5G, 169ONMRδ (CDCI!s); 2
．． 44-4JO (11H, m), 6.98 (IH, s) Reference Example 6 Homophthalic anhydride 41 mg, 2-chloro-6,6-nitylendioxy-5.6,7.8-tetrahydro-1,
4-naphthoquinone 65mF and triethylamine 18mF
A solution of F in 2 mj' of toluene is heated at 140 to 160° C. for 1 hour in a sealed tube. The solvent is distilled off in the cold, and the residue is purified by silica gel column chromatography (eluent: ether: benzene = 1:4). Recrystallization from chloroform yields 28 mf of 2,2-ethylenedioxy-6-hydroxy-1,2°3.4-tetrahydro-6,12-naphthacenequinone.

mp 229-280.5°C I Ry aIIo” (cm-”); 1605.
1680.16!55NMRa (CDC/31)
; 1.92 (2H, t, J-6,6Hz)
, 2.80-8.05 (4H, at), 4.02 (
4H,s), 7. '60-7.95 (8H, m), 8.01 (IH, s), 8.85-8. ! i 5 (IH, m),
14.06 (IH.

I) Reference Example 6 Homophthalic anhydride 50 mF% 2-chloro-7,7-nithylenedioxy-6.6.7.8-tetrahydro-1,
4-naphthoquinone 70mF and triethylamine 18mF
2 ml of toluene of F: Heat the solution in a sealed tube at 140-150° C. 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). Recrystallized from chloroform to 18 mF of 8.8-ethylenedioxy-6-hydroxy-1,2,8,4-tetrahydro-5,11! - Obtain naphthacenequinone.

mpS! 14~216°C I RW """(cm-"); 1606,1
680%1665NMRICCDCIs);1.
9S! (2H, t, J-6, 6Hz), 1! , 80-8
．． 05 (4H, m), 4.02 (4H, s), 7.50 - 7.95 (8H, m), 8.01 (IH, s), 8.85 - 8.55 (IH, m ), 18.97 (11°-) Reference example 7! ,! ! -ethylenedioxy-6-hydroxy-1°!
! , 8.4-tetrahydro-6,12-su7tarynquinone 80 mF of lead tetradenate was added to a dichloromethane 6 mR tel solution of 22 mW, and the mixture was stirred at room temperature under a nitrogen stream for 14 hours. Add 4 ml of water, separate the IS layer, extract the aqueous layer twice with 6 ml of chloroform, wash with the organic layer and dry with sodium a-sun. After evaporating the solvent, the residue was purified by preparative thin layer chromatography (silica gel, developing solution: lyaloform), and 4 mF of 2
．． 1! -ethylenedioxy-6,12-dihydrotei-1.2°3.4-tetrahydro-6,11-naphthacenequinone is obtained.

mp! 10-211 i°C Reference Example 8 2.2-ethylenedioxy-6-hydroxy-1°g,
a,4-tetrahydro-5,II-naphthacenequinone 1
4 mF dichloromethane/20 m l-methoxy-1-propenyloxytrimethylsilane under nitrogen flow in solution
1 and heated at 80 to 40°C for 20 minutes. After cooling D
Add CC10mF and stir at room temperature for 16 hours. Decant twice with ether and evaporate the solvent. Wl
The residue is purified by silica gel column chromatography (eluent: chloroform) to obtain 2 mF of 2,2-ethylenedioxy-6,12-dihydroxy-1,2,8,4-tetrahydro-6,11-naphthacenequinone.

mp 210-21g°C Example 1 2.8aβ-chloroH-6.6-nithylenedioxy-4
Triethylamine 5 (15 mF) was gradually added dropwise to a solution of 1.68 F of ether, 6.8.8a+-tetrahydro-1,4-naphthoquinone. To separate.

Furthermore, the water layer is benzene 50m1! Extract twice with water, combine with the organic layer, and wash with water. After drying over sodium sulfate, the solvent is distilled off, and the residue is purified by silica gel column chromatography (eluent: chloroform). Recrystallization from benzene yields 918 ml of 2-chloro-6,6-ditylenedioxy-5.6.7jl-tetra-1,4-naphthoquinone.

mp 189.5-140℃ I Ry """(cm-1); 1B9G, 1
665.167ONMR#(CDCZl); 1
．． 86 (2H, t, J to 7H tom), 25 to 2.9 (4
H, m), 4.00 (4H, s), 6.8! (IH,s) Elemental analysis value (as C1s Htt 04 Cl)C
) I (:/ Calculated value -66,6048518,9! Actual value e19 56.60 4.27 14.0
8 Example 2 2,8aβ-cycloloaf, 7-nithylenedioxy-4
15 ml of ether of m, 5,8.8 m-tetrahydro-1,4-naphthoquinone 490 snP! 172 mF of triethylamine solution is added dropwise. Stir for 8 hours after dropping,
Add water and separate the organic layer. Furthermore, the aqueous layer is mixed with benzene 1
Extract twice with rsml, combine with the previous organic layer, and wash 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). benzene-n
- recrystallized from hexane to produce 2-chloro-7,7-nithylenedioxy-5.6,7.8-tetrahydro-1,4-
241 mF of naphthoquinone is obtained.

mp 98~98J"O I Ry"""(cm-"); 1600.1
65ONMRa (CDCJP);
1.82 (!H,t, J=6Hz), L
6B-L80 (4H, m), 4.00 (4H, I), 6.89 < la es) Elemental analysis value (as C1 to H1to4C/)C
HC/ Calculated value -56,604,8518,9$1 Actual value f1
56.61 4.27 14.05 (and above) Procedural amendment (醋) 3. Person making the amendment 4. Voluntary action by the agent 6. Number of inventions increased by the amendment Among the amendments, Shunho On page 7 of the specification The chemical formula of the compound of general formula (7) described below is subject to numerous corrections.

(7)'' 2 The chemical formula of the compound of general formula (8) described on page 8 of the specification 1s is corrected as shown in the table below.

"(8)" 3 Specification page 14, line 16, page 15, line 13, 1
On page 6, line 12 and page 17, line 11, correct the words ``fixed'' to read ``rq fixed.''

4. On page 15 of the specification, lines 1 and 2, the text "2.2-2.8" should be corrected to "2.2-3.8."

5. In the specification, page 15, line 9, page 17, line 8, page 17, line 8, and page 23, line 2, ``rfr2.8aβ'' will be corrected to ``r2, 4aβ'', respectively.

6. The phrase "2 to 3 drops" on page 17, line 6 of the specification is corrected to "2 drops."

(that's all)

Claims (1)

[Claims] ■ General formula [In the formula, one of R1 and R1 represents a hydrogen atom and the other represents a lower alkylenedioxy group. X represents a halogen atom. ] A quinone derivative represented by