JPH0495052A - Extraction and production of terpene derivative - Google Patents

Abstract

NEW MATERIAL:A terpene derivative shown by the formula, namely (2s)-8- benzoyloxy-2,6-(1-methylethylidene)-5-cyclodecane-1. USE:A drug such as anti-inflammatory drug. PREPARATION:Zedoariae Rhizoma is immersed in an organic solvent, the extracted solution is concentrated to give essence. The essence is treated by column chromatography and high performance liquid chromatography, then dehydrourdione fractionated and crystallized with an organic solvent is reduced to give a solution of (2s)-8-hydroxy-2,6-dimethyl-9-(1-methylethylidene)-5- cyclodecen-1-one in pyridine, which is mixed with benzoyl chloride and stirred. Then the resulting material is extracted with ethyl acetate, the solvent is distilled away under reduced pressure to give a crude substance. The substance is separated and purified by high performance liquid chromatography to give a terpene derivative shown by the formula.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel terpene derivative (2S)-8-ben represented by the following structural formula (1).
zoyloxy-2,6(1-+*eLhylethy
lidene)-5-cyclodecane-1.

Conventional technology Herbal medicine gajutsu
ecloariae Rhizoma), Zingiberaceae] has been used as an aromatic stomachic for digestive system diseases since ancient times, and its ingredients include essential oils including cineole, sesquiterpene alcohol, camphuene, etc., as well as other fatty oils,
Contains starchy, sticky, rubbery, etc.
For example, it is described in Jikai No. 57163373.

In addition, a sesquiterpenoid derivative named furanogermenone has been isolated from zeju as a herbal medicine and has been found to have antihepatitis effects, and these facts are also shown in the above-mentioned publication, Furthermore, it is described in JP-A No. 61-227523 that it has an anti-ulcer effect.

Further, (4S,5S)-(÷)-germacrone 4.5 epoxide was isolated from Gejutsu, and it is described in Japanese Patent No. RFF461-227575 that this also has anti-ulcer effect.

In addition, Chem, Pharm, Bull 20 (
5) 987 (+972) H9 The existence of a sexterpenoid derivative named dehydroclodione by Ilikino et al. is known.

Problems to be Solved by the Invention Until now, the means to be solved by the derivative invention of the structural formula (1) shown on the right The present invention has solved the above-mentioned problems.
) provides a terpene derivative represented by structural formula (1).

In addition, the extract obtained by leaching zejutsu into an organic solvent and concentrating the extract was separated by column chromatography and high performance liquid chromatography, and the crystallized dehydrocurdione was reduced to a pyridine solution of the resulting fS substance. Add benzoyl, stir, and extract with ethyl acetate.

Provided is a method for extracting and producing a terpene derivative, characterized in that a compound represented by the above structural formula (1) is obtained by separating and purifying the crude product obtained by distilling off the solvent under reduced pressure using liquid chromatography. It is something to do.

The terpene derivative of the above structural formula (1) is obtained by distributing the extract obtained from the organic solvent extract of Gajutu with methanol and hexane, and separating the hexane layer by column chromatography. Benzoyl chloride is added to a pyridine solution of the substance obtained by reduction with sodium boronate, and after stirring, the mixture is extracted with ethyl acetate.

The obtained organic layer is washed with an aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution. After drying with magnesium sulfate, the solvent is distilled off under reduced pressure, and the resulting crude product is separated and purified using high performance liquid chromatography to obtain the derivative (1) above.

However, a pyridine solution is added to the reducing substance of dehydrocludione, but other organic bases may also be used.

Further, after stirring, extraction is performed with ethyl acetate, but this can also be done with other organic solvents. After extraction, it is preferable to use high performance liquid chromatography and column chromatography to separate and purify the crude product.

However, in all cases, silica gel was used as the carrier and a mixed solvent of n-hexane and ethyl acetate was mixed at a mixing ratio of 20=1, but the mixing ratio is not limited to this.

The physicochemical properties of the above-isolated derivative of structural formula (1) are as described below.

■It has no odor and is a colorless oil.

■Elemental analysis value: c22112go) Calculated value C near 7.6HH: 8.29$ Actual m value C near 7
．． 49$ ll: 8.171■(α)%'-149
It has a specific optical rotation of ° (C=1.03, rioo form).

■Circular dichroism spectrum (methanol): [θ)2.2-
270.74 (neH, Mato ax :c=o)(0
)zz+-753,55 (neg, wux).

■The ultraviolet absorption spectrum is (methanol, nm (
logε)): 228 (29262, 4, 47> 273 (1917, 3, 28) 281 (1519, 3, 18).

■Infrared absorption spectrum: Chloroform, cm-
'):1708 GC=0).

■Hydrogen nuclear magnetic resonance spectrum (90MHz, CDCL)
, , (ppm) 1.10 (3H, d, J near Hz
,2-He)1.75.1.79.1.97(3H,e
+sch, alls) 3.13.3.44 (2B, ^B
q, J: 17Hz, 1O-Hz5.12. (IHt, J
=7Hz, 5-H2) 6.10 (IH, dd, J:6.
6Hz 8-41) 7.3-7.6 (30, m, 3'4
1.4'-H2S"-11) 7.9-8.3 (211,
2'-H, 6'-H).

Effects of the Invention As explained in the previous section, according to the present invention, a novel terpene derivative that has not been seen before can be produced, so that it can be provided as a pharmaceutical such as an anti-inflammatory agent.

In addition, this new derivative can be easily obtained because it can use crude drugs as raw materials, and the manufacturing method is also easy because conventional separation and purification means can be used.

Example Details will be explained below based on examples.

Dried thin pieces (10.8 kg) of ginger, an herbal medicine, were extracted by digestion (water bath, 50° C.) with methanol (201) for 7 hours.

The same operation was repeated 9 times, the methanol extracts were combined, the solvent was distilled off under reduced pressure, and the methanol extract (YK-1
Yield: 1.12 kg, Yield from crude drug: 10.
4$).

Dissolve YK-1 (20 (Ig)) in methanol (600 liters) and extract 3[i] with hexane (31).

A portion of the remaining YK-1 (>800 g) is similarly partitioned and extracted with methanol-hexane.

The methanol layers were combined and the solvent was distilled off under reduced pressure to obtain a methanol layer extract (YK-2, 680 g, 7.1).

The hexane layers were combined and the solvent was distilled off under reduced pressure to obtain a hexane layer extract (YK 3.310 g, 3.2 g).

YK-3 (100g) was subjected to silica gel column chromatography [silica gel 3.0kg (MERCK, Ki
eselgel 60)), elution solvent: (1) hexane/ethyl acetate system (hexane:ethyl acetate, 50:1.20
:1.15:1.10:1゜8:l, each 20/)
, (2) Chloroform-methanol system (chloroform:
Methanol = 10:1. Fractionate into Y-4 to 8) using 8N) in the order of O:100.

That is, the solvent of the eluate from the elution solvent of hexane:ethyl acetate 20:1 was distilled off under reduced pressure to obtain the fourth fraction YK-4 (
23.3g, 0.75$) was obtained.

Similarly, hexane: ethyl acetate = 15:1.10:1.8
:5th fraction from the elution area with each elution solvent of 1 (YK-
5,14,3g, 0.46$), 6th fraction (YK-6
, 11.8g, 0.38$), 7th fraction (YK-7,
6.5g, 0.211), chloroform:methanol=
8th fraction from the 10:1 elution area (YK-8, 22.9 g.

0.74$) were obtained, respectively.

The solvent of YK-5 was distilled off under reduced pressure to obtain a sesquiterpenoid compound (dehydrocludione) in the form of colorless plate-like crystals.

methanol (
Cerium chloride, heptahydrate (477,7
mg) and sodium borohydride (48.5 mg>) were added and stirred at room temperature for 30 minutes.

After neutralization with a dilute aqueous sulfuric acid solution, the mixture is extracted three times with ethyl acetate, and the resulting organic layer is washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. After drying with magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product (275, hg).
is obtained. This crude product was separated and purified by silica gel column chromatography (S, Ox 2Bg, hexane: ethyl acetate = 5:1), and (2S)-8-hydrox
y-2,6-dimethyl-9-(1-methy
ethyl idene)-5-eyclodec
n-1-one (216sg, 711) is obtained.

Pyridine of this terpene derivative (35,9-g) <3.
5d) Benzoyl salt (0,1d) was added to the solution, and after stirring at room temperature for 30 minutes, it was poured into ice water for hydrolysis of the reagent, and extracted three times with ethyl acetate. The obtained organic layer was mixed with 51 aqueous hydrochloric acid solution (3 times) and saturated aqueous sodium hydrogen carbonate solution (2 times).
Washed with saturated aqueous sodium chloride solution (twice).

[After drying with magnesium magnesium, the solvent was distilled off under reduced pressure to obtain a crude product (118.3 mg).

The crude product was purified by high performance liquid chromatography (column: ZO
RBAXSIL 9.4X 250s-hexane:ethyl acetate 20:1) to separate and purify (2S)-8-ben
zoyfoxy-2,6-dimethyl-9-(1
-sethylethyl 1cliene) -5-e
yelodeeen-1-one (37.5mg, 73
1) was obtained. The physical and chemical properties of the terpene derivative thus obtained were as described above.

Claims (2)

[Claims] (1) Terpene derivative represented by the following structural formula (1) ▲
Contains mathematical formulas, chemical formulas, tables, etc.▼ (2) The extract obtained by leaching zejutsu into an organic solvent and concentrating the extract was obtained by column chromatography and high performance liquid chromatography, and then by reduction of dehydrocludion, which was fractionally crystallized from the organic solvent. The obtained (2S)-8-hydroxy-2,6-dim
ethyl-9-(l-methylethylidi
Benzoyl chloride was added to a pyridine solution of ene)-5-cyclodecen-1-one, stirred, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The crude product was separated and purified by high performance liquid chromatography to obtain the following structural formula. A production method characterized by obtaining the terpene derivative represented by (1). ▲Contains mathematical formulas, chemical formulas, tables, etc.▼