JP2001081097A - Hinokition acetoglucoside and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new hinokitiol D-glucose glucoside which has a high antioxidative action and is useful in the fields of medicines, foods and cosmetics. SOLUTION: 4 or 6-Isopropyltropolone-2-O-β-D-glucoide tetra-O-acetate (abbreviated name: H-GAa or H-GAb). The compound: H-GAa has the structure of the formula, and is obtained by (A) a bromination process comprising reacting penta-O-acetyl-β-D-glucose with HBr-acetic acid to produce tetra-O-acetyl-β-D- glucopyranosyl bromide (abbreviated name: TAGB) and them adding an organic solvent to the reaction mixture to transfer the product TAGB to the organic solvent side, and (B) an acetylation process comprising reacting the TAGB with hinokitiol in the presence of a silver catalyst (for example, a silver carbonate catalyst carried on celite) in an organic solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel compound, hinokitiol acetoglucoside, and to a method for producing the compound by synthesis. The invention also relates to a method for producing hinokitiol glucoside from this compound.

[0002]

BACKGROUND OF THE INVENTION Hinokitiol, ie, 4-isopropyltropolone-1-one-2-ol, is an essential oil component of trees such as Taiwan cypress and Aomori hiba, and has many properties such as antibacterial, antifungal, antiseptic, and hair growth promotion. The effect has been recognized, and a wide range of uses such as medicines, agricultural chemicals, hair products and food preservatives are being developed.

[0003] However, hinokitiol is poorly soluble in water, and the hinokitiol preparation is limited in dosage form, so that its use range is also limited. As one means for overcoming this problem, attempts have been made to use hinokitiol as a glycoside. For example, JP-A-7-17993 proposes that hinokitiol be combined with D-glucose and used as an antibacterial agent. The present inventors have utilized cultured cells derived from tissue pieces of plants of the genus Eucalyptus,
Invented a method for advantageously producing hinokitiol glycosides,
This has already been disclosed in JP-A-7-82288.

After that, the inventor made various studies to develop a method for producing hinokitiol glycosides by chemical synthesis. To form tetra-O-acetyl-β-D-glucopyranosyl bromide (hereinafter abbreviated as “TAGB”), which is reacted with hinokitiol in the presence of a silver salt catalyst to give 4- or 6- -Isopropyltropolone-2-O-β-D-glucoside tetra-O-acetate (hereinafter the former is referred to as “HG
Aa ", the latter being abbreviated as" H-GAb "). H-GAa and H-GAb are both novel compounds and have been found to have high antioxidant activity. Furthermore, it was confirmed that H-Ga and H-Gb can be obtained by deacetylation of H-GAa and H-GAb.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide novel compounds, H-GAa and H-GAb, and a method for producing them, utilizing the above-mentioned new knowledge obtained by the inventor. Another object of the present invention is to provide a method for producing -Ga and H-Gb.

[0006]

The novel compound 4- of the present invention
Isopropyltropolone-2-O-β-D-glucoside tetra-O-acetate (abbreviation “H-GAa”) and 6-isopropyltropolone-2-O-β-D-glucoside tetra-O-acetate (abbreviation “H-GAa”) GAb ")
Have the following structures, respectively.

[0007]

Embedded image

DETAILED DESCRIPTION OF THE INVENTION The process according to the invention for preparing the novel compound H-GAa or H-GAb described above comprises the following steps: (A) Penta-O-acetyl-β-D-glucose with H
By reacting Br-acetic acid, tetra-O-acetyl-β-D-glucopyranosyl bromide (abbreviation “TA”)
GB "), and adding an organic solvent to the reaction mixture to transfer the product TAGB to the organic solvent side; and (B) combining TAGB and hinokitiol in an organic solvent in the presence of a silver salt catalyst. H-GAa and H-GAb
And the catalyst is separated, and the organic solvent is removed to remove HG
Acetylation step to obtain Aa and H-GAb.

The H-GAa or H-GA thus obtained
The process of the present invention for producing H-Ga or H-Gb from GAb comprises following steps (A) and (B) followed by the following step (C): (C) H- An acetyl group is eliminated by adding an alkaline substance to GAa or H-GAb in a lower alcohol solvent, neutralized with a cation exchange resin, and then the solvent is removed to obtain H-Ga or H-Gb. Process.

[0009]

EXAMPLE A) Bromination Step A 300 ml eggplant-shaped flask was charged with 20 g of penta-O-acetyl-β-D-glucose (abbreviated as “PAG”) and 100 ml of HBr-acetic acid, and the atmosphere in the flask was replaced with nitrogen gas. Then, the mixture was stirred and reacted at room temperature for 24 hours. Thereafter, 200 ml of chloroform was added and the mixture was stirred for a while, and the reaction mixture was poured into a 500 ml Erlenmeyer flask containing 200 ml of ice water, and was strongly stirred with a magnetic stirrer so that the aqueous layer and the organic layer were mixed well. After 5 minutes, the stirring was stopped and the aqueous layer was removed. The operation of adding 300 ml of a saturated saline solution to the remainder and stirring and removing the aqueous layer was repeated three times.
After adding a saturated saline solution for the fourth time and stirring, only the organic layer was taken out with a separating funnel. The organic layer was dried by adding anhydrous sodium sulfate.

The desiccant was removed by filtration, and the dried organic layer was placed in a 300 ml eggplant-shaped flask, and the solvent was removed by evaporation using a rotary evaporator. The operation of adding 100 ml of n-hexane to the concentrate and removing the solvent was repeated three times to obtain 19.3 g of a white powder of TAGB. Yield is PA
91% based on G standards. Since the obtained compound TAGB is unstable, each operation was performed at a temperature as low as possible, and the obtained product was stored in a freezer.

B) Acetylation step The TAG obtained in the above step A is placed in a 300 ml eggplant-shaped flask.
B, 19 g of hinokitiol, 20.0 g of a celite-supported silver carbonate catalyst, and dried ether 150
ml was added and stirred for a short time to dissolve. 5 in a water bath
While maintaining the temperature at 0 ° C., the mixture was stirred for 8 hours while heating and refluxing with a cooling tube attached. Thereafter, ice was placed in a water bath to lower the temperature below room temperature, and the cooling tube was removed. 150 ml of ethyl acetate was added to the reaction mixture, stirred for 2 to 3 minutes, and the catalyst was separated by filtration. The catalyst was washed several times with ethyl acetate, the washings were put together with the filtrate in a 500 ml eggplant-shaped flask, and the solvent was evaporated by a rotary evaporator.
150 ml of ether was added, n-hexane was further added until a precipitate was formed, and the mixture was heated and dissolved in a water bath and allowed to stand for a while. 10.1 g of white crude crystals were obtained. The yield based on TAGB was 45%.

The crude crystals were subjected to HPLC analysis under the following conditions. Column: SUPERCOSIL LC-F 4.6 × 2
50 mm Eluent: CH ₃ CN / H ₂ O (45/55) Flow rate: 1.0 ml / min. Detection: UV 245 nm Two peaks were obtained as shown in FIG. 1: Peak No. 1 H-GAb t _R (. min): 10.93 peak _{No.2 H-GAa t R (min} .): 12.01

Recrystallization was repeated from the compound of peak No. 1 to obtain white needle-like crystals. Melting point: 151-152 ° C MS (El positive) m / Z 494 [M ⁺ ] The mother liquor obtained by recrystallization of H-GAb was repeatedly purified using silica gel chromatography to obtain H-GA
a white powder was obtained. MS (El positive) m / Z 494 [M ⁺ ] NMR spectrum data of H-GAa and H-GAb are shown in comparison below.

¹ H-NMR (CDCl ₃ ) δ ppm J (Hz) Product H-GAa H-GAb 123 7.20 (1H, d, J = 1.5) 7.10 (1H, br, s) 4 5 6.85 (1H , ddd, J = 8.5,1.5,1.0) ┌6.88 (2H, m) 6 7.15 (1H, dd, J = 12.4,8.5) ７7 7.05 (1H, dd, J = 12.0,1.0) 7.07 (1H, dd) , J = 5.5,5.0) 8 2.79 (1H, m, J = 7.0) 2.75 (1H, m) 9 1.22 (3H, d, J = 7.0) 1.21 (3H, d, J = 7.0) 10 1.22 (3H, d, J = 7.0) 1.21 (3H, d, J = 7.0) Glc 1 '5.42 (1H, d, J = 7.6) 5.43 (1H, d, J = 7.5) 2' 5.25 (1H, dd, J = 9.2) , 7.6) 5.24 (1H, dd, J = 9.0,7.5) 3 '5.31 (1H, dd, J = 9.5,9.2) 5.28 (1H, dd, J = 9.0,9.0) 4' 5.12 (1H, dd, J = 10.0,9.5) 5.13 (1H, dd, J = 10.0,9.0) 5 '3.74 (1H, ddd, J = 10.0,5.0,2.5) 3.75 (1H, ddd, J = 10.0,5.0,2.5) 6'a 4.11 (1H, dd, J = 12.5,2.5) 4.10 (1H, dd, J = 12.5,2.5) 6'b 4.20 (1H, dd, J = 12.5,5.0) 4.24 (1H, dd, J = 12.5,5.0) ) Ac 2.10 (3H, s) 2.08 (3H, s) 2.03 (3H, s) 2.04 (3H, s) 2.02 (3H, s) 2.02 (3H, s) 2.02 (3H, s) 2.02 (3H, s)

¹³ C-NMR (CDCl ₃ ) δ ppm product H-GAa H-GAb product H-GAa H-GAb 1 180.3 160.8 Glc 1 ′ 98.1 98.0 2 160.5 180.4 2 ′ 71.2 71.3 3 127.6 136.8 3 ′ 72.5 72.5 4 153.6 157.1 4 '68.4 68.3 5 128.2 133.4 5' 72.1 72.1 6 136.6 130.9 6 '61.9 61.7 7 137.9 124.0 Ac 170.4 170.5 8 38.3 38.3 170.0 170.1 9 23.0 22.8 169.8 169.7 10 23.0 22.9 169.4 169.4 20.8 20.7 20.6 20.6 20.6 20.6 20.6 20.6

C) Deacetylation step 1 of H-GA (mixture of H-GAa and H-GAb)
0.0 g was dissolved in 200 ml of methanol, a saturated methanol solution of potassium carbonate was added dropwise while stirring the solution, and the reaction was followed by TLC. When the H-GA spot completely disappeared, an appropriate amount of ion-exchange resin “Amberlite IRC-50” was added to neutralize, and the resin was separated by filtration. The solvent was removed from the obtained filtrate using a rotary evaporator. A methanol / ethyl acetate (1/4) mixed solution was added to the concentrate, and the solvent was evaporated once again, whereby a white powder of HG (a mixture of H-Ga and H-Gb) was obtained. The yield was 6.1 g, 91% in yield.
%Met.

[0017]

The novel compound H- provided by the present invention
GAa and H-GAb have high antioxidant activity and are useful substances in the fields of medicine, food, and cosmetics. The process of the present invention for producing the same comprises starting from a compound TAGB, which has no particular difficulty in its own synthesis, and linking it with hinokitiol, so that the intermediate bromide is unstable and low temperature. Except that it is necessary to keep the reaction, the reaction can proceed without any particular problem, and the yield is high, so that it can be carried out sufficiently economically.
The H-GAa and H-GAb can be converted to H-GAa by a simple method.
It can be converted to D-glucose glycosides of Ga and H-Gb, ie hinokitiol. These hinokitiol D-glucose glycosides are substances whose usefulness has already been confirmed.

[Brief description of the drawings]

FIG. 1 shows H-GAa /
Chart of HPLC analysis of H-GAb.

Claims (4)

[Claims] (1) 4-isopropyltropolone-2-O-
β-D-glucoside tetra-O-acetate (abbreviation “H
-GAa "). 2. 6-isopropyltropolone-2-O-
β-D-glucoside tetra-O-acetate (abbreviation “H
-GAb "). 3. A method for producing H-GAa or H-GAb comprising the following steps: (A) penta-O-acetyl-β-D-glucose
By reacting Br-acetic acid, tetra-O-acetyl-β-D-glucopyranosyl bromide (abbreviation “TA”)
GB "), and adding an organic solvent to the reaction mixture to transfer the product TAGB to the organic solvent side; and (B) combining TAGB and hinokitiol in an organic solvent in the presence of a silver salt catalyst. H-GAa and H-GAb
And the catalyst is separated, and the organic solvent is removed to remove HG
Acetylation step to obtain Aa and H-GAb. 4. The method according to claim 3, comprising performing the following steps following the steps (A) and (B) according to claim 3.
-Isopropyltropolone-2-O-β-D-glucoside (abbreviation “H-Ga”) or 6-isopropyltropolone-2-O-β-D-glucoside (abbreviation “HG”)
b)) Production method: (C) An alkaline substance is added to H-GAa or H-GAb in a lower alcohol solvent to eliminate an acetyl group, neutralized with a cation exchange resin, and then the solvent is removed. Deacetylation step for obtaining H-Ga or H-Gb.