JPH0447660B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel process for the preparation of akravinones, known as aglycones of aclacinomycin. More specifically, the present invention discloses the novel compound 4-[1'-tert-butyldimethylsilyloxy-4'-hydroxy-5'-alkoxy-3'-(5'-oxoalkanoyl)naphtho-
The present invention relates to a method for producing akravinones by simple operations using a 2'-yl]-2-butenoic acid derivative as a starting material.

Aclacinomycin, known as an anti-cancer drug, has the formula It is a glycoside of akravinone shown as Several methods have been proposed to date to produce akravinone, but all of them require multiple steps and are complicated to operate, and are not necessarily satisfactory for industrial implementation. However, I could not say that.

As a result of intensive research to develop a method for efficiently producing akravinone or its analogues, the present inventors discovered that the general formula (In the formula, R ₁ is an alkyl group having 1 to 3 carbon atoms, R ₂ is an alkoxy group having 1 to 3 carbon atoms, and R ₃ is an alkyl group having 1 to 3 carbon atoms.
The present inventors have discovered that the object can be achieved by using a silyloxynaphthyl brenoate derivative represented by (6) as a starting material, and have completed the present invention.

That is, the present invention provides the general formula (In the formula, R ₁ , R ₂ and R ₃ are the same as above) A compound represented by the formula is treated with an alkali in a hydrophilic solvent, and the general formula (R ₁ , R ₂ and R ₃ in the formula are the same as above) and then desilylated and oxidized to give the general formula (In the formula, R ₁ , R ₂ and R ₃ are the same as above.) Next, this is treated with a Lewis acid to dealkylate it, and then treated with a base to form deoxyaclavinones. , further characterized by oxidizing this, the general formula (In the formula, R ₂ and R ₃ are the same as above.) The present invention provides a method for producing (±)aclavinones represented by the following formula.

The compound of general formula () used as a starting material in the method of the present invention is a new compound that has not been described in any literature, and can be easily produced, for example, according to the following reaction formula.

(R ₁ , R ₂ and R ₃ in the formula have the same meanings as above) That is, 1-methoxy-3-acetyl-5-
The alkoxynaphthalene [formula ()] is treated with sodium hydride in a polar solvent such as dimethylformamide and then reacted with chlorodimethyl ether to produce a compound of general formula (), which is then added to the compound in tetrahydrofuran. A compound of general formula () is obtained by reacting lithium diisopropylamine and further reacting with 3-ethyleneoxyalkanaldehyde. Then,
This compound was hydrogenated in tetrahydrofuran using a palladium catalyst to produce 3-(5'-ethylenedioxyalkanoyl)-1-methoxy-5-alkoxy-4-methoxymethoxynaphthalene, followed by p-toluene. By adding sulfonic acid and heating, a compound of the general formula () is obtained. This is demethylated using Seric ammonium nitrate to convert it into a compound of the general formula (). In the presence of a Lewis acid, 2 The ester of -dimethylphenylsilyl-3-butenoic acid is reacted to obtain a compound of general formula (). In this compound,
Reaction of tert-butyldimethylsilyl chloride in dimethylformamide gives the desired compound of general formula ().

The thus obtained compound of the general formula (), for example, methyl 4-[1'-tert-butyldimethylsilyloxy-4'-hydroxy-5'-methoxy-3'-
(5″-oxoheptanoyl)naphtho-2′-yl]-
2-Butenoate is usually a pale yellow crystal with a melting point around 110°C.

In the present invention, this compound is normally used as a starting material without any particular purification, but if desired, it may be used after being purified by conventional methods such as column chromatography or recrystallization. You can also do that.

The first step of the method of the present invention is carried out by dissolving the starting material of general formula () in a hydrophilic solvent and treating it with an alkali. Preferred hydrophilic solvents in this case are tetrahydrofuran, dioxane, and acetonitrile. Further, as the alkali, an alcoholic solution of potassium carbonate or sodium carbonate is suitable. This alkali is
It is used in an excess amount, preferably 15 to 30 times the molar amount, relative to the starting material. This reaction is carried out at a temperature from -80°C to room temperature, preferably around -75°C, and is usually completed in 1 to 5 hours, often about 2 hours.

Next, in the second step, the compound of general formula () obtained in the first step is first dissolved in a suitable solvent,
Treat with mineral acid to desilylate. The solvent in this case is preferably a mixed solvent of tetrahydrofuran, dioxane, etc., and water, acetic acid, etc.

Further, as the mineral acid, an excess amount of hydrochloric acid or hydrofluoric acid is used. This desilylation reaction takes place between 10 and 50
C., preferably around room temperature, for 5 to 20 hours, preferably about 12 hours.

After desilylation, oxidation treatment is subsequently performed, and bromine is used as the oxidizing agent in this case, and the amount used is equal to or more than the same molar amount, preferably 1 to 1.5 times the molar amount. This treatment is carried out in a halogenated carbon solvent such as carbon tetrachloride, chloroform, or methylene chloride using triethylamine or azobisisobutyronitrile as a catalyst. The reaction proceeds at a temperature from room temperature to the boiling point of the solvent, and
Complete in 24 hours. In this way, a compound of general formula () is obtained.

Next, in the third step, the compound of general formula () obtained as described above is dissolved in a solvent such as methylene chloride, chloroform, carbon tetrachloride, etc., and a Lewis acid is added to dealkylate it. This Lewis acid includes aluminum chloride, tin chloride,
Zinc chloride or the like is used in excess molar amount, preferably 10 to 15 times the molar amount, relative to the compound of general formula (). This reaction is carried out at a temperature of 10-50°C, preferably around room temperature, for a period of 5-15 hours, preferably 8-10 hours. Through this treatment, the methoxy group in the compound of general formula () is changed to a hydroxyl group, and the general formula (In the formula, R ₂ and R ₃ are the same as above.) A compound represented by the following is obtained.

This compound is then dissolved in a suitable solvent and treated with a base, resulting in cyclization, giving the general formula (In the formula, R ₂ and R ₃ are the same as above.) Deoxyaclavinones represented by the following are obtained.
Dioxane, tetrahydrofuran, etc. are used as the solvent in this case, and potassium carbonate, sodium carbonate, etc. are used as the base. The amount of the base to be used is an excess molar amount, preferably 15 to 25 times the molar amount, relative to the compound of general formula ()'. This reaction is completed at a temperature of 10 to 50°C, preferably around room temperature, in about 1 to 5 hours, usually about 2 hours.

When the deoxyaclavinones thus obtained are separated using high performance liquid chromatography, equal amounts of two stereoisomers, namely deoxyaclavinone and 10-epideoxyaclavinone, can be obtained.

In the final step of the present invention, the desired akravinones are produced by reacting the deoxyaclavinones obtained as described above with an oxidizing agent. Bromine is used as the oxidizing agent in this case, and carbon tetrachloride, chloroform, methylene chloride, etc. are used as the reaction solvent. The oxidizing agent is at least equimolar to deoxyaclavinones,
Preferably, 1 to 1.5 times the molar amount is used. The reaction is carried out at a temperature ranging from room temperature to 100°C, usually at the boiling point of the solvent, for 30 minutes to 5 hours, preferably 1 hour. In this case, it is advantageous to add triethylamine or azobisisobutyronitrile as a catalyst.

This final step is performed using deoxyaclavinone or 10-
When applied to epideoxyaclavinone, the general formula (±) Aclavinone or general formula represented by (±)10-epiaclavinone is obtained.

Next, the present invention will be further explained by examples.

Example Methyl 4-[1'-tert-butyldimethylsilyloxy-4'-hydroxy-5'-methoxy-3'-(5'-
oxoheptanoyl)naphtho-2'-yl]-2-
320 mg (0.61 mmol) of butenoate is dissolved in 5 ml of tetrahydrofuran and added dropwise at -78°C into an alkaline solution prepared by dissolving 2 mmol of potassium carbonate in 50 ml of methanol. At this time, the solution gradually turns yellow and begins to emit fluorescence. After reacting for 2 hours, the reaction solution was poured into an aqueous ammonium chloride solution and then extracted with methylene chloride. The methylene chloride extract is washed with brine, dried, and the solvent is removed by evaporation. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ ) to give the formula 198 mg (yield 62%) of the compound represented by is obtained as a light-colored oil.

303 mg (0.57 m
mol) in a mixed solvent of 10 ml of tetrahydrofuran, 2 ml of water, and 6 ml of acetic acid, and 5 ml of 47% hydrofluoric acid.
Add and stir at room temperature for 12 hours to react. Next, an aqueous sodium bicarbonate solution was added to the reaction solution, followed by extraction with ether, and the extract was washed with brine and concentrated, resulting in the corresponding desilylated product 239
mg is obtained. This crude product was dissolved in an equal mixture of carbon tetrachloride and chloroform and 0.63 mmol of bromine was added.
and reflux for 1 hour. After replacing the solvent of this reaction solution with methylene chloride, 1 ml of triethylamine was added and stirring continued overnight. The mixture is then acidified with 5% hydrochloric acid and extracted with methylene chloride. When this extract is washed and the solvent is distilled off, the formula 72 mg (0.176 mmol, yield 14%) of the compound shown by
is obtained as yellow needles with a melting point of 181-182°C.

Dissolve 77 mg (0.176 mmol) of the above compound in 10 ml of dry methylene chloride and add aluminum chloride.
Add 267 mg (2 mmol) and stir at room temperature for 9 hours to react. At this time, the color of the solution changes from yellow to purple.

Next, water and methylene chloride are added to this reaction solution, and 5% hydrochloric acid is added until the aqueous layer becomes almost colorless to separate the layers. The aqueous layer is extracted with methylene chloride and combined with the organic layer, washed, dried and concentrated. Purification of the residue by silica gel chromatography (CH ₂ Cl ₂ ) gives the formula 49 mg (0.124 mmol, yield 70%) of the compound shown by
is obtained as yellow needles with a melting point of 181-185°C.

22 mg of this compound is dissolved in 5 ml of tetrahydrofuran and mixed with a solution of 138 mg of sodium carbonate in 20 ml of methanol. After stirring at room temperature for 2 hours, water and methylene chloride were added, and
% hydrochloric acid to make the aqueous layer transparent. After separation, the pure layer is extracted with methylene chloride, and the organic layers are combined and washed. When this is dried and concentrated, 22 mg of light-colored crystals are obtained. When this was separated using thin layer chromatography, it was found that (±) akravinone and (±)
It was found to be a 1:1 diastereomeric mixture of 10-epiaclavinone.

Decomposed (±)aclavinone has a melting point of 195-224
℃ (decomposition) with light yellow crystals, as follows:
NMR and IR are shown.

NMR (CDCl ₃ ); δ=1.08 (t, 3H, J=7
Hz), 1.60 (q, 2H, J=7Hz), 2.27 (d,
H ₈ ax, J = 16Hz), 2.52 (dd, H ₈ eq, J = 16,
4Hz), 2.4-3.2 (with OH), 3.70 (s, 3H), 4.09
(s, H ₁₀ ), 5.37 (d, H ₇ , J=4Hz), 7.30
(m, 1H), 7.55-7.90 (m, 3H), 11.94 (s,
1H), 12.70 (s, 1H).

IR (KBr); 3400, 1720, 1665, 1620 cm ^-1 or (±) 10-epiaclavinone has a melting point of 192-195
℃ light yellow powder, NMR and IR as follows
showed that.

NMR (CDCl ₃ ); δ=1.03 (t, 3H, J=7
Hz), 1.62 (q, 2H, J=7Hz), 1.86 (dd,
H ₈ ax, J = 14.7Hz), 2.61 (dd, H ₈ eq, J = 6
Hz), 3.89 (s, 3H), 4.00 (s, H ₁₀ ), 5.39 (t,
H ₇ , J = 7Hz), 7.28 (m, 1H), 7.51 (s,
1H), 7.55-7.85 (m, 2H), 11.94 (s, 1H),
12.84 (s, 1H).

IR (KBr); 3400, 1715, 1655, 1610 ^{cm -1} .

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ is an alkyl group having 1 to 3 carbon atoms, R ₂ is an alkoxy group having 1 to 3 carbon atoms, and R ₃ is an alkyl group having 1 to 3 carbon atoms.
6) is treated with an alkali in a hydrophilic solvent to obtain the general formula (R ₁ , R ₂ and R ₃ in the formula are the same as above) and then desilylated and oxidized to give the general formula (In the formula, R ₁ , R ₂ and R ₃ are the same as above.) Next, this is treated with a Lewis acid to dealkylate it, and then treated with a base to form deoxyaclavinones. , further characterized by oxidizing this, the general formula (In the formula, R ₂ and R ₃ are the same as above.) A method for producing (±) akravinones represented by the following.