JPS6299343A - Homophthalic acid derivative and acid anhydride thereof - Google Patents

Abstract

NEW MATERIAL:A homophthalic acid derivative shown by the formula I (R<1> is H or lower alkoxy; R<2> is lower alkanoyl) or its acid anhydride. EXAMPLE:2'-Acetoxyhomophthalic acid. USE:An intermediate for synthesizing daunomycin and adriamycin. PREPARATION:For example, a compound shown by the formula II is reacted with a compound shown by the formula III in a proper inert solvent in the presence of a basic compound at -80 deg.C-about room temperature to give a compound shown by formula IV. Then this compound shown by the formula IV is oxidized in a proper inert solvent in the presence of an oxidizing agent such as lead tetraacetate, etc., at about room temperature, to give a compound shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel homophthalic acid derivatives and their acid anhydrides.

BACKGROUND ART Conventionally, synthetic intermediates of daunomycin and adriamycin (compounds represented by the following general formula (1)) have already been reported in Tetrahedron, Sei Ω, 4539 (1984).

[In the formula, R1 represents a hydrogen atom or a lower alkoxy group, and R2 represents a lower alkanoyl group. ] However, in the method described in the above literature, the general formula (1
) cannot be produced in good yield and is not industrially satisfactory.

Means for Solving the Problems The present inventors have conducted extensive research to produce the compound of the above general formula (1), which is a synthetic intermediate for downmycin and adriamycin, in a high yield, and as a result, the following general formula ( It has been found that the desired effect of the present invention can be achieved through the homophthalic acid derivative represented by 2) and its acid anhydride. The present invention has been completed based on this knowledge.

The homophthalic acid 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 (2).

(In the formula, R1 represents a hydrogen atom or a lower alkoxy group, and R2 represents a lower alkanoyl group.) The acid anhydride of the above homophthalic acid derivative is also a new compound that has not been described in any literature, and is represented by the following general formula (3). % Formula % [In the formula, R1 and R2 are the same as above. ] In this specification, lower alkyl groups include straight chain or carbon alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, and n-hexyl groups. Branched alkyl groups can be mentioned.

Examples of the lower alkanoyl group include straight or branched alkanoyl groups having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, pentanoyl, and hexanoyl groups.

Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-
Examples include straight-chain or branched alkoxy groups having 1 to 6 carbon atoms such as butoxy, pentyloxy, and hexyloxy groups.

The compounds of the present invention represented by the above general formulas (2) and (3) are produced, for example, by the method shown in the following reaction scheme-1.

Reaction Scheme-1 In formula C, R' and R2 are the same as above. R3 and R' each represent a lower alkyl group, R5 represents a hydrogen atom, a lower alkyl group or a tri(lower alkyl)silyl group, and X represents a halogen atom such as a chlorine atom or a bromine atom. ] According to Reaction Scheme-1, a compound represented by general formula (6) is produced by reacting a known compound represented by general formula (4) with a known compound represented by general formula (5). Then, by oxidizing the compound (6), the compound of the present invention represented by the general formula (2) is produced, and by further reacting the compound (2) with the compound represented by the general formula (7), the compound of the present invention is produced by oxidizing the compound (6). A compound of the present invention represented by formula (3) is produced.

The reaction between compound (4) and compound (5) is carried out in a suitable inert solvent in the presence of a strong basic compound at a temperature of about -80'C to room temperature for about 30 minutes to 4 hours. Ru. The inert solvent used is not particularly limited, and a wide variety of common solvents that do not adversely affect the reaction can be used, and examples include ethers such as tetrahydrofuran, dioxane, and diethyl ethyl. The strong basic compound is not particularly limited, and examples include alkali metals such as lower alkyl lithium such as n-butyllithium, alkali metal hydrides such as sodium hydride, and ordinary strong basic compounds such as lithium diisopropylamide. Examples include basic compounds. The amounts of compound (5) and strong basic compound used are as follows: Compound (4)
Usually at least 3 times the molar amount, preferably 3
It is preferable to set the amount to about 4 times the molar amount.

The oxidation reaction of compound (6) is carried out in a suitable inert solvent in the presence of an oxidizing agent at a temperature of about 0 to 70'C, preferably room temperature, for about 1 to 6 hours. The inert solvent used is not particularly limited, and a wide variety of ordinary solvents that do not adversely affect the reaction can be used, such as ethers such as tetrahydrofuran, dioxane, and diethyl ether, and aromatic hydrocarbons such as benzene. There are many examples of this. As the oxidizing agent, a wide variety of conventionally known oxidizing agents can be used as long as it can add a lower alkanoyl group, such as lead tetra(lower alkanoate) such as lead tetraacetate,
Examples include manganese tri(lower alkanoate) such as manganese triacetate. The amount of oxidizing agent used may vary depending on the compound (
It is usually at least an equimolar amount, preferably an equimolar amount to about twice the molar amount of 6). In this way, the compound of the present invention having the general formula (2) is produced.

The reaction between the compound of general formula (2) and the compound of general formula (7) is carried out in a suitable inert solvent at a temperature of about 0 to 80°C, preferably around room temperature, for about 5 minutes to 12 hours. be done. The inert solvent used is not particularly limited, and a wide variety of ordinary solvents that do not adversely affect the reaction can be used, such as chloroform, methylene chloride, 1,
Examples include halogenated hydrocarbons such as 2-dichloroethane, ethers such as tetrahydrofuran, dioxane and diethyl ether, aromatic hydrocarbons such as benzene, and esters such as ethyl acetate. The amount of compound (7) to be used is usually at least equimolar to compound (2), preferably equimolar to twice the molar amount. In this way, the compound of the present invention of general formula (3) is produced.

The thus-produced compound of the present invention of general formula (3) can be induced to a compound of general formula (1) by the method shown in reaction scheme-2 below.

Reaction Scheme-2 [In the formula, R1 and R2 are the same as above. Y represents a halogen atom such as a chlorine atom, a bromine atom, an iodine atom, or a hydrogen atom.

] The reaction between compound (3) and the compound represented by the known general formula (8) is carried out in a suitable inert solvent in the presence of a strong basic compound at about -80 to 50'C, preferably at around air temperature. for about 10 minutes to 6 hours, preferably 15 to 30
It takes about a minute.

The inert solvent used is not particularly limited, and a wide range of ordinary solvents that do not adversely affect the reaction can be used, such as ethers such as tetrahydrofuran, dioxane, and diethyl ether, and saturated carbonized solvents such as hexane and cyclohexane. Hydrogens, aromatic hydrocarbons such as benzene, etc. can be mentioned. Strong basic compounds are not particularly limited, and include, for example, lower alkyl lithium such as n-butyl lithium, alkali metals such as lithium, sodium, and potassium, sodium hydride, potassium hydride, lithium hydride, etc. alkali metal hydride,
Examples include common strong basic compounds such as lithium diisopropylamide. The amount of compound (8) used is usually at least about equimolar amount to compound (3),
Preferably, the amount is about equimolar to 1.5 times the molar amount, and the amount of the strong basic compound is usually at least about the same molar amount, preferably 1 to 2 times the molar amount of compound (3). It is better to set it as a degree.

By the methods shown in the above reaction schemes -1 and -2, compound (1) is industrially advantageously produced in good yield by simple operations from compound (4) through compounds (2) and (3) of the present invention. It is possible.

Furthermore, the compound represented by the following general formula (9) is known as a synthetic intermediate for daunomycin and adriamycin [Journal of the American Chemical Society, 98.1967 (1976), Journal of
See The Chemical Society Perkin Transactions I, 1981.689].

[In the formula, R+/ represents a lower alkoxy group. However, the method described in the above-mentioned document cannot produce the compound of general formula (9) in good yield, and is not industrially satisfactory.

The present inventors have also discovered that the compound represented by the above general formula (9) can be produced in good yield when using a novel compound represented by the following general formula (10).

[In the formula, R1/ is the same as above. R6 represents a lower alkyl group. ] The compound of the above general formula (10) is, for example, reaction scheme-3
It can be produced on an industrial scale in good yield from the compound of general formula (1a) (the compound of general formula (1) in which R' is a lower alkoxy group) by the method shown in .

Reaction scheme-3 (la) αη [in the formula, R1',
R2 and R6 are the same as above. ] Hydrolysis of the compound of general formula (1a) is carried out, for example, in the presence of an acid in a suitable solvent. As the solvent used, a wide variety of common solvents can be used, and examples include water, alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane and tetrahydrofuran, and mixed solvents thereof. The acid is not particularly limited, and a wide variety of conventionally known acids can be used, such as mineral acids such as hydrochloric acid, 5fft acid, and hydrobromic acid, and organic acids such as trifluoroacetic acid and p-toluenesulfonic acid. It will be done. The amount of such acid used is usually in large excess relative to the compound (1a).The above reaction is usually carried out at air temperature to about 100'C, preferably at air temperature to about 80'C. The reaction is generally completed in about 1 to 10 hours.

The reaction between compound (11) and compound (12) obtained in this way is carried out in an appropriate inert solvent at about -80'C-air temperature,
Preferably, it is carried out at a temperature of -80 to -50°C for about 1 to 6 hours.

The inert solvent used is not particularly limited, and a wide range of ordinary solvents that do not adversely affect the reaction can be used, such as ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, etc. can be mentioned. The amount of compound (12) used is:
Usually at least about an equimolar amount relative to compound (11),
Preferably, it is about 5 to 20 times the molar amount.

The hydrolysis reaction and/or desilylation reaction of compound (10) is carried out in a suitable inert solvent in the presence of a catalyst and an acid. As the solvent, a wide range of common solvents can be used, including ethers such as tetrahydrofuran, dioxane, diethyl ether, and dimethoxyethylene glycol, saturated hydrocarbons such as hexane and cyclohexane, and aromatic hydrocarbons such as benzene. I can do it.

Further, as a catalyst, a wide range of known catalysts commonly used in this type of reaction can be used, such as mercury oxide (HQO).
etc. The acid is not particularly limited, and a wide variety of conventionally known acids can be used, including sulfuric acid, hydrochloric acid, and the like. The concentration of such acid is preferably around 20%, and the amount of acid used is preferably in large excess relative to compound (10). The amount of catalyst used is
Usually at least about an equimolar amount relative to compound (10),
Preferably, the amount is about 1 to 5 times the mole. The above reaction is usually carried out at about 0 to 100'C, preferably from 50 to 70'C.
The reaction is generally completed in about 1 to 2 hours in the morning.

The target compounds obtained in each of the above steps are easily isolated and purified from the reaction mixture by conventional separation means. Such separation means include, for example, solvent extraction method, solvent dilution method,
Examples include a recrystallization method, column chromatography, prevariative thin layer chromatography, and the like.

Effects of the Invention The compound of the present invention is a compound useful as an intermediate for synthesizing compound (1). By using the compound of the present invention, compound (1) can be produced on an industrial scale in good yield and with high purity.

Examples Examples and reference examples are listed below, but the present invention is not limited thereto.

Example 1 1180 mg of homophthalate in tetrahydrofuran (THF)
>8mQ solution was reacted with 342m() of lithium diisopropylamide at -78°C for 30 minutes.

Then add 0.75% of trimethylsilyl chloride to this solution.
Peng was reacted at -78° C. for 1.5 hours and at room temperature for 30 minutes. Next, this solution was reacted with lead tetraacetate (90%>550 mc+ solution of dried benzene 4rrIQ) at room temperature for 2 hours to quantitatively obtain 2'-acetoxyhomophthalic acid.

Yield: 232 mg (yield 100%) ” H-NMR (acetone-d6): δ2.12 (3
H, s, OCOCH3) 6.8 (2H, brs, C0
0Hx2>7.18 (IH, s, CH) 7.2~7.8 (3H, m, ArH>7.9~8.1
5 (1H, m, ArH>IR(KCQ) cm-
': 3070.3020,2920,2850°2630,
1755.1720, 1675.1600.1580 Example 2 2'-acetoxy-6-medoxyhomophthalic acid was quantitatively obtained from 210 mg of 6-medoxyhomophthalic acid in the same manner as in Example 1.

Yield: 261 m (J (yield 97%) + H-NMR (acetone-d6): δ2.09 (3
H,5SOCOCH3)3.87 (3HSS,OCH
3) 6.21 (1H, 5SCH> 6.30 (2H, brs, C00HX2>6.95~
7.55 (3H,m,ArH)IR(CHCQ3)
cm-': 3300-2800.1760-1710 Example 3 180mc+ of 2'-7 setoxyhomophthal and 65mc+ of trimethylsilylethoxyacetylene were reacted in 1.5ml of methylene chloride at air temperature for 4 hours to quantitatively give 4.
-Acetoxyhomophthalic anhydride was obtained.

Yield near 4 mg (yield 100%) 'H-NMR (CDCIQ3): δ2.31 (3
H, S, 0COCH3) 6.53 (1H, s, CH) 7.3~7.9 <3H, m1Art-1>8.05~
8.3 (1H, m, ArH>IR(CHCQ3)cm
-': 1805.1765.1600 Example 4 2'-acetoxy-6-medoxyhomophthalic acid 80 mg
4-acetoxy-8-methoxyhomophthalic anhydride was obtained in the same manner as in Example 3.

Yield near 4 mg (yield 99%) 'HNMR (CDCQ3 >: δ 2.32 (3H,S, OCOCH3) 4.00 (3
HS S, OCH3) 6.51 (1H,s, CH) 6.9~7.2 (2H,m, ArH>7.70 (I
H, t, ArH>IR(CHCQ3) cm-': 1815.
1765.1600 Reference Example 1 4-acetoxy-8-methoxyhomophthalic anhydride 86
2-chloro-6,6-nithylenedioxy-5.6,7.8-tetrahydro-1,4 was treated with 17 mq of sodium hydride in THF4N12 for 15 minutes at room temperature and then at air temperature for about 20 hours. 11-acetoxy-2,2-ethylenedioxy-6-hydroxy-
7-methoxy-1,2,3,4-tetrahydro-5,1
90mc+ of 2-naphthacenequinone was obtained.

Yield 62%, melting point 248-253°C Reference example 2 11-acetoxy-2,2-ethylenedioxy-6-hydroxy-7-methoxy-1,2,3°4-tetrahydro-5,12-naphthacenequinone 40m (2 mQ of water was added dropwise to 4 mf2 solution of trifluoroacetic acid, and
heated for an hour. After cooling, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent; benzene:ethyl ether = 10:1). Recrystallized from acetic acid to give 5,12-dihydroxy-2-oxo-7
-Medoxy 1.2,3.4-tetrahydro-6,11
-28 mg of naphthacenequinone was obtained.

Yield 88%, melting point 252-256°C Reference Example 3 101 mg of 2-trimethylsilylethynyl lithium and 370 mg of cerous chloride were reacted for 3 hours at -78 in 5 mQ of THF to synthesize trimedylsilylethynyl cerium chloride in advance. .

22,111 g of 5,12-dipidroxy-2-oxo-7-medoxy 1,2,3,4-tetrahydro-6゜11-naphthacenequinone was treated with trimethylsilylethynylcerium chloride and recrystallized from chloroform to give 4-
Methoxy-6,9,11-trihydroxy-9-trimethylsilylethynyl-7,8,9,10-tetrahydro-5,12-naphthacenequinone'19.5m! ;1 was obtained.

Yield 69%, melting point 262-264.5°C' HNMR
(CDCQ3): δ 0.16 (9H,s, (CH3) 33!)2.
13 (2H, brt, C8CH2) 3.02 (2H,
brt, Cy-CH2) 3.15 (2H, brs,
C+ o CH2>4.10 (3H,S,OCH3
) 7.38 (1H, dd, C3H) 7.76 (1H, t, C2H) 8.04 (1H, dd, C+ -H) 13.48
(IH, s, 0H) 13.85 (1H, s, OH> IR (CHC9t3) cm-': 1605.1580 Reference example 4 4-methoxy-6,9,11-trihydroxy-9-trimethylsilylethynyl-7 ,8,9゜10-tetrahydro-5,12-naphthacenequinone 8.8m (11 is T
It was hydrolyzed in HF11+1Q at 70°C for 1.5 hours using 13m0 of mercury oxide as a catalyst and 0.3111Q of 20% sulfuric acid, and recrystallized from ethyl acetate-THE.
6.6 mg of ±)-7-dioxydaunomycin was obtained.

Yield 86%, melting point 229-233.5°C (above)

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is a hydrogen atom or a lower alkoxy group, R^
2 represents a lower alkanoyl group. ] A homophthalic acid derivative or its acid anhydride represented by: