JPS6048517B2 - Diterpene-based polyepoxy alcohol derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel diterpene-based polyepoxycol derivative and a method for producing the same. The diterpene-based polyepoxyalco derivative of the present invention is represented by the following general formula [1]. [In the formula, R represents a lower alkyl group. Also AC. The ditertapene system of the present invention represented by the above general formula [1] shows a double bond between the carbon atoms at the 7th and 8th positions, or forms an epoxy ring with the carbon atoms at the 7th and 8th positions. The derivatives have anti-leukemic activity and anti-tumor activity and are useful as therapeutic agents for these diseases. The diterpene derivative of the present invention can be synthesized using, for example, a diterpene dienone derivative represented by the following general formula [2] as a starting material. o [In the formula, R is the same as above] Compounds in which R is a methyl group in the diterpene dienone derivatives represented by the above general formula [2] are as follows: It is publicly known 5 according to the present inventor's announcement, and for example, it can be derived through the reaction route shown below using levopimaric acid represented by the following formula [3] contained in pine resin as a starting material. The above reaction to obtain chlorohydrin [5] from levobimaric acid [3] via biseboxide [4] is described by Hertz et al. [W. J. Herzetal]. Org. Ch
em. , 35, 3338 (1970).
Just follow the law. Synthesis of chloroketone [6] from chlorohydrin [5] is carried out by Johns oxidation, and the thus obtained chlorketone [6] is then synthesized with dimethylformamide (DM
F) Medium LiCl and Ll. C.O. By reacting with 100℃ for 2 hours, the conjugated non-isomers [7] and [8]
can lead to This conjugated non[7] is also an allyl alcohol obtained by treating bisepoxide [4] with a catalytic amount of dry HCI in ether at -20°C.

It can also be advantageously synthesized by Dionez oxidation of [9]. The resulting conjugated non-[7] can then be converted to 7,11-dibromide [10] by bromination with 2 equivalents of NBS under reflux of carbon tetrachloride, resulting in the desired diterpene-based dienone derivative in which R is a methyl group. [2] can be obtained by vigorously stirring the above 7,11-dibromide [10] with zinc powder in tetrahydrofuran (THF) under reflux. The diterpene dienone derivative [2] in which R is other than a methyl group can be synthesized according to the above method. The compound of the present invention can be produced using the thus obtained diterpene dienone derivative [2] as a starting material, for example, according to the following reaction route. [In the formula, R is the same as above] In the above, first, the diterpene dienone [2] is reacted with an oxidizing agent to obtain a diepoxye derivative [11] in which the double bond between the 9,11 atoms is epoxidized. This reaction is stable because the carbon-carbon double bonds at the 7 and 8 positions of the raw material [2] are conjugated with the adjacent ton group, so for example, 0 to
This can be easily carried out preferably under temperature conditions around room temperature. There are no particular restrictions on the oxidizing agent used, but peracetic acid, perbenzoic acid, and methachlorobenzoic acid may be used. Organic peracids such as perbutyric acid are preferred. The above oxidation. There is no limit to the amount used, but usually raw material compounds [
2] is preferably used in an equimolar amount or in excess. Further, in the above reaction, a weak alkaline substance such as dibasic dibasic phosphate or dipotassium phosphate may be present in order to prevent the reaction between the organic acid produced as a by-product and the epoxy group. The fact that the configuration of the newly introduced epoxy rings at positions 9 and 11 of the diepoxyenone derivative [11] thus obtained is β type means that various compounds derived from the derivative [11] are as follows. Confirmed by measuring the physical and chemical properties of 1 When derivative [11] is hydrogenated in the presence of palladium-carbon in ethanol, alcohol form [14] [PMR (proton magnetic resonance spectroscopy, same hereinafter): δ = 4.
89 ppm (Br, d, J=83 Hz)] and an ethyl ether compound [15] are obtained. When the alcohol [14] is acetylated, the acetate [16] [IR: 1740c77z-1, 1640
cTn-'', 1620C771-'', PMR: δ=3.
53ppm (IH, d, J = 2Hz), = 6.26pp
m(IH, brs)] is obtained. Alcohol [1]
4] with methanesulfonic acid chloride in the presence of triethylamine at 0°C in methylene chloride [17] is reacted with tetraethylammonium acetate in acetone at reflux temperature to form the acetate [18] [ IR:1730c! n-1, 1
675 cm-1, 1620) C7Ft-1, PMR: δ
=3.74ppm (IH, d, J=4Hz), =5.7
6 ppm (IH, m)] is obtained. The acetate [
18] was hydrolyzed in ethanol at room temperature in the presence of sodium carbon to give the alcohol [19] [PMR: δ=3
．． 76ppm (IH, d, J=5Hz), 4.56pp
m(IH, dd, J=5,10Hz)] is obtained. In the above, the chemical shift of the proton of the methyl group at the ■ position of the alcohol [14] (PMR: δ = 1.30 ppm
) is that of alcohol [19] (PMR: δ = 1.1
6 ppm). In PMR obtained by adding 2 European trisdipivaloylmethane (Eu (Dpm)), the chemical shift of the proton of the methyl group at the ■ position of alcohol [14] is larger than that of alcohol [19]. In the method of the present invention, the diepoxyenone derivative [11) obtained above is then reduced to convert the ketone group at position 14 into a hydroxyl group. As a result, the desired isomers [12] and [12'] of the diepoxy alcohol derivative are obtained as a mixture of equal amounts.
j The above ring element reaction proceeds by using a lower alcohol such as methanol or ethanol as a reaction solvent and allowing a boron-based reducing agent to act on the diepoxyenone derivative [11] at a temperature of 20°C or less. Specific examples of the reducing agent used in the above include lithium borohydride, sodium borohydride, and potassium borohydride. Although the amount used is not limited, it is preferable to use an excess amount (more than the equivalent amount). The reason why the hydroxyl group at the 14th position of the diepoxy alcohol derivative [12] obtained by the above reaction is β is because the proton at the 14th position and the proton of the hydroxyl group are sterically fixed by a hydrogen bond. Tsupring [PMR: δ2.92ppm (I
H, d, J=12Hz)]. 2 Two isomers of diterpene triepoxy alcohol derivatives [13] and [13] which are other target compounds of the present invention
'] is the diepoxy alcohol derivative obtained above [
12]. This oxidation reaction is carried out from compound [2] 3 to compound [1].
It can also be carried out using an organic peracid in the same way as the reaction to obtain 1). For example, diketones such as biacetyl and benzyl can be used as photosensitizers, and sunlight or While irradiating ultraviolet rays 3. This can also be easily carried out by bringing the poxyalcohol derivative [12] into contact with oxygen gas or air. Examples of the production of the compounds of the present invention are listed below as examples. 4t Example 1 457719 of the diterpene dienone derivative [2] (R=CH3) represented by the general formula [2] was dissolved in 4.57 nι of anhydrous methylene chloride, and 33 mg of 70% pure methachloroperbenzoic acid was added at room temperature. 2. Let's stir the gap. After the reaction, ether was added, and the mixture was washed in the following order: 10% sodium sulfite aqueous solution, 10% sodium carbonate aqueous solution, and brine.
The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 58 m9 of oil are thus obtained. This was purified by silica gel column chromatography (benzene ethyl diacetate 20:1) to obtain a diepoxyenone derivative (R=Cll.) represented by the general formula [11].
Get mg. J yield 74% IR analysis result: νki174=
1710cm-1, 1640cm-1NMR (CDCI
. ) Analysis result: δ = 3.82 ppm (D, J = 3 Hz) = 4.08 ppm (D, J = 3 Hz) = 6.76 ppm (m) High mass spectrum analysis result: C2lH28O5, m/1 = 360.1980 ( M゛)
Next, the diepoxyenone derivative [11) (R
=CH3) was dissolved in 3mι of methanol,
Add 45 mg of sodium borohydride at 0°C and stir for 3 minutes. The activity of excess reducing agent is stopped by adding 50% aqueous acetic acid solution, and the mixture is extracted with ether. Subsequently, the ether layer was washed successively with a saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 30 m9 of crystals. This was purified by silica gel column chromatography (benzene ethyl diacetate 10:1) to obtain the general formula [12] (R=CHa).
Crystal 13m of diepoxy alcohol derivative represented by
9 (yield 40%) and general formula [12'] (R=CH3)
Oily substance 11 of diepoxy alcohol derivative represented by
m9 (yield 34%) is obtained. Diepoxy alcohol derivative [12] Melting point: 162-165°C NMR (CDCl3) analysis result: δ = 2.92 ppm (D, J = 12 Hz) 3.51 pp
m (D, J = 3 Hz) 3.95 ppm (D, J = 3 Hz) 4.30 ppm (D, J = 12 Hz) 6.00 ppm (m) Elemental analysis results: Calculated value (%) C69.588H8.342 Actual value (%)
C69.688H8.472 Diepoxy alcohol derivative [12'] NMR (CDCI.) analysis results: δ = 3.45 ppm (D, J = 3 Hz) = 3.73 ppm (D, J = 3 Hz) = 4.67 ppm (Dd , J=8.3Hz)=6. I1
ppm (m) Example 2 Diepoxy alcohol derivative obtained in Example 1 above [12
] (R=CH3) was converted into 20% of anhydrous methylene chloride.
ml, add 350ml of methachloroperbenzoic acid and 500mg of disodium phosphate, and stir at room temperature for 2 weeks. After the reaction, water is added to dissolve the solid matter and extraction with ether is performed. 10% sodium bisulfite, 10% ether layer
After washing with sodium carbonate and brine in that order, and drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 224 m9 of assembled crystals.
get. This was purified twice by silica gel column chromatography (benzene-ethyl diacetate 20:1) to give 38 mg of crystals of the diterpene triepoxy alcohol derivative (R=CH) represented by the general formula [13] (yield: 38
%) and a crystal of a diterpene triepoxy alcohol derivative (R=CH.) represented by the general formula [13'] 7m
g (yield 3%). In addition, 4 mg (2%) of the dieboxy alcohol derivative [12] used as the raw material was recovered.
Diterpene triepoxy alcohol derivative [13] Melting point: 185.5-187.5°C NMR (CDCl3) analysis result: δ = 2.95 ppm (D, J = 12 Hz) = 3.32 p
m (m) = 3.56 ppm (D, J = 3 Hz) = 3.72 ppm (D, J = 12 Hz) = 3.89 ppm (D, J = 3 Hz) Diterpene triepoxy alcohol derivative [13']
Melting point: 179.5-181.5° CNMR (CDCe3
) Analysis result δ = 2.77ppm (D, J = 11Hz) = 3.23p
pm (D, J = 5 Hz) = 3.36 ppm (D, J = 11 Hz) = 3.50 ppm (D, J = 4 Hz) = 4.04 ppm (D, J = 4 Hz) Example 3 Diepoxy alcohol derivative [12 ] (R=CH3) and 1 mL of biacetyl in 80 mι of anhydrous benzene.
and internally irradiated with a high-pressure mercury lamp (100 V, 400 W) for 4 hours at 20° C. in a quartz container while passing oxygen.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R represents a lower alkyl group. Further, A indicates an ethylenic double bond between the carbon atoms at the 7th and 8th positions, or indicates that an epoxy ring is formed together with the carbon atoms at the 7th and 8th positions. A diterpene-based polyepoxy alcohol derivative represented by ]. 2. A diterpene dienone derivative represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R represents a lower alkyl group] is reacted with an oxidizing agent to form a 9,11-β-epoxy compound, and then General formula ▲Mathematical formula characterized by the action of a reducing agent on this,
There are chemical formulas, tables, etc. ▼ [In the formula, R is the same as above] A method for producing a diterpene diepoxy alcohol derivative represented by the following. 3 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R represents a lower alkyl group] General formula characterized by oxidizing the diterpene diepoxy alcohol derivative represented by ▲ Numerical formulas, chemical formulas, tables, etc. There are ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In each formula, R is the same as above] A method for producing a diterpene-based triepoxy alcohol derivative.