JPS6056994A - Tocopherol derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula (R1 is glucose, galactose, cellobiose residue or acetylated derivative residue of it; R2 and R3 are H, or CH3). EXAMPLE:Dl-alpha-Tocopherylglucoside. USE:An antisterility vitamin, or an antioxidant. PREPARATION:Tocopherol is reacted with peracetylated saccharide (e.g., beta-D- glucopyranose pentaacetate, etc.) in a solvent (e.g., ethylene glycol diacetate, etc.) in the presence of p-toluenesulfonic acid as a catalyst at 80-100 deg.C for 3-7hr, to give a compound where R1 of the formula is acetylated saccharide residue. This compound is heated under reflux in anhydrous methanol in the presence of NaOCH3, treated with an ion exchange resin, deacetylated, to give a compound such as the example compound, etc. having the corresponding saccharide residue.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel tocopherol derivatives, and more particularly to tocopheryl glycosides.

Tocopherol has traditionally been used as an anti-inflammatory vitamin (pitamine E).
) (!: Also known as an antioxidant,
In recent years, it has come to be frequently used as a variety of medicines because it has various pharmacological actions such as peripheral vasodilatory action. However, tocopherol is a very unstable compound, and because it is a fat-soluble substance, it suffers from poor absorption from the intestinal tract and skin61.
It has been proposed to use derivatives such as esters of carboxylic acids and the like.

The present invention provides novel tocopheryl glycosides useful as such tocopherol derivatives, and the tocopheryl glycosides of the present invention have the following formula: [wherein R is a glucose residue, a galactose residue, or a cellobiose residue] Acetylated derivative residues of glucose, galactose or cellobiose.

and 8 are the same or different, and each means hydrogen or methyl.] It has a structure in which a sugar residue or an acetylated sugar residue is introduced into the hydroxyl group at the 6-position of tocopherol.

In formula (I), -C+eH33 at the 2-position of the 3,4-dihydrobenzopyran ring is 4°8. of the 2-position side chain of tocopherol.
12-) Represents a trimethyltridecyl group. In addition, isomers exist in tocopherol and the sugar introduced into the 6-position hydroxyl group, but in this specification, all of these are represented by formula (1), including isomer mixtures and isolated isomers.
Let it be expressed as

Preferably, R2 and - are both methyl or both hydrogen, ie α- or δ-tocopheryl glycoside.

Representative compounds of formula (1) include dl-α-tocopheryl glucoside, dl-α-tocopheryl galactoside, (117α-tocopheryl cellobioside, d-δ-tocopheryl galactoside, 6-o- (β-2,3,4,6-tetraacetylglucohyranosyl)-aX-α-tocopherol, 5-0-(
β-2,3,4,6-tetraacetylgalactobyranosyl)-d'1-a-1 copherol, 6-O-(4-0
-β-a -2,s', 4.6-tetraacetylglucopyranosyl-2.3.6-dolacetylgelcohylanosyl)-dl-α-tocopherol, 6-o-(β-2
, 3,4,6-tetraacetylgalactopyranosyl)-
Examples include d-δ-tocopherol.

Among the compounds of formula CI), those with glucose, galactose or cellobiose residues are useful as derivatives with improved stability and absorption of tocopherol, and those with acetylated sugar residues as is useful as an intermediate for its production.

The compound of formula (1) can be produced according to the known method for synthesizing aryl glycosides.

That is, by reacting tocopherol and a desired peracetylated sugar in an appropriate solvent at a high temperature, e.g., 80 to 100°C, for, for example, 3 to 7 hours, the tocopherol is reacted with the acetylated sugar residue of formula CI). A compound is obtained. As a solvent,
It has been found that this reaction proceeds favorably when ethylene glycol diacetate or nitrobenzene is used and p-toluenesulfonic acid is added as a catalyst.

The tocopherol used as a starting material is (1-1β-1
Either r- or δ-tocopherol may be used;
Peracetylated sugars are known or can be produced by acetylating the desired sugar by known acetylation methods.

The obtained compound of formula (1) in which R is an acetylated sugar residue is heated to reflux in an ordinary manner, for example, in anhydrous methanol in the presence of sodium methoxide, and then Amberlite IR-120 (H' Deacetylation by treatment with ion-exchange resins, such as (type), allows the bird to deacetylate glucose, galactose or cellobiose residues with the formula (
The compound 1) is obtained. This compound is obtained as stable crystals that are soluble in organic solvents such as alcohol, chloroform, and benzene, and poorly soluble in water, and can be further purified by conventional methods such as recrystallization.

Since the tocopheryl glycoside thus obtained contains a sugar component, which is a water-soluble molecule, it is expected to improve the fat solubility of tocopherol and, by extension, its absorption. It can be hydrolyzed to produce free tocopherol and express its activity.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 6-0-(β-2,3,4,6-tetraacetylglucopyranosyl)-(11-α-tocopherol d1-α-
Tocopherol 2. 9 (5.30 mmol) and 186 Ing (1.08 mmol) of p-)luenesulfonic acid are heated and dissolved in 6 ml of ethylene glycol diacetate. 20 g (5.12 mmol) of this dissolved IKβ-D-glucobylanose pentaacetate is added and reacted for 4 hours in a boiling water bath under a reduced pressure of 6011% while distilling off the acetic acid produced. Then, add 300ml of water to the reaction mixture.
ft and extracted three times with 50 m of benzene each. The benocene extracts were combined, dried, and the solvent was distilled off under reduced pressure to obtain 3.45 g of a black-purple oil.

3.45 g of the obtained oil was subjected to column chromatography on 180 g of silica gel (LIY x 500 mm) at a pressure of 5 to 9/d, eluted with a benzene-ethyl acetate gradient, and the solvent was removed. Removal gives 0.59 g of the title compound as a yellow oil.

Silica gel thin layer chromatography (Merck Art)
, 7749, Rf in developing solvent: chloroform)
= 0.37 (single spot).

UV: λ-OHnm (log g) = 223
(2,69ax), 2B2 (2,15).

[α) 24=+1.0° (c'=l, O, M, eOH
,), IR: 1776 (C=0)ci'.

MS: m/e760 (M+), 761 (Mj4-1)
, 430 (M-330, tocopherol), 331 (M
+-429, sugar).

Example 2 dl-α-tocopheryl glucoside 6-o-(β-2,3,4,6-tetraacetylglucopyranosyl)-dl-α-tocopherol obtained in Example 1 0.599C0,77 mmol) was dissolved in dry methanol 8-. IN sodium methoxide 2m6
Add t and heat to reflux in a boiling water bath.

After 5 minutes, the reaction mixture was cooled and added to Amberlite E-1.
Neutralize with 5 ml of 20(H"m). The resulting methanol solution is evaporated under reduced pressure to obtain 0.40.1 of the crude title compound in the form of white crystals (yield: 87.0%).

Melting point: 133-137°C.

Obtained crude crystal f: At 50°C, water-ethanol (
0.28 of the title compound purified by recrystallization from 1:1)
．． yield of 71%).

Melting point: 140-141°C.

UV 2'A”all nm(10g c)=293
(2°6ax 8), 210 (3,28).

(a) A+=45° (C=1.0, Mean)
.

ILL: 3390 (On), 2915 (C-■), 12
50(δ-CH)cIrLo M S: m/e 592 ('), 430 (
M-06H+.

05) Elemental analysis As C3sH6oOy Calculated value (%): 0,70.91; J 10.20 Actual value (support)): C, 70,28; H, 10,48 Example 3 6-0- (β-2,3,4,6-tetraacetylgalactobyranosyl)-d'1-tz-)coferol d1-
α-tocopherol: 2.82.16.55 mmol)
and CF p -)luenesulfonic acid 188.5 mg
(1,10 mmol) of ethylene glycol diacetate 4f
Warm and dissolve in rIl. Add 317 g of β-ri-galactobylanose bentaacetate (8,12
mmol) in an oil bath at 100°C, 70IIIH
The reaction is allowed to proceed for 4 hours under a reduced pressure of 1.5 g while distilling off the acetic acid produced. Next, 15μ4 of water was added to the reaction mixture, and the mixture was extracted three times with 50μ of ethyl acetate each. The ethyl acetate extracts were combined, dehydrated, and the solvent was distilled off under reduced pressure to obtain a black-purple oil 6.
Obtain 33g.

The resulting oil 6.33.9 was placed on a medium pressure ram (3201111X5QQim) of 180 g of silica gel,
The product was subjected to column chromatography at a pressure of d and eluted with a benzene-ethyl acetate gradient.

Removal of the solvent from the eluate yielded the title compound 084 as an orange oil.
get g.

Silica gel thin layer chromatography (Merck Art)
, 7749, developing solvent: benzene-methanol (6:1
)) = 08 (single spot).

UV:J:? ”nm(log t)-223C2,69
), 282 (2,19).

[α), ;'=+1.6° (c = 1.0, Me
an).

■几：I766　(C=0　)cIIL-'.

MS: m/e 760 (M+), 43o (
M+-330, tocopherol), 331 (M+-42
9. Sugar).

Example 4 dl-α-tocopheryl galactoside 6-0-(β-2,3,4,6-tetraacetylgalactobyranosyl dl-/Z-tocopherol 0.83 g (1, 1 mmol) undissolved in 8 parts of methanol, added 0.IN sodium methoxide 2-, and heated to reflux in a boiling water bath.After 5 minutes, the reaction mixture was cooled and dissolved in R-120 (H+ form). )5
- Neutralize. The resulting methanol solution was evaporated under reduced pressure to give the crude title compound as white crystals in 0.54.1 yield of 8.
3%).

The obtained crude crystals were mixed with water-ethanol (3
: 0.38 of the title compound purified by recrystallization from 7)
p (yield 70%).

Melting point: 176-177°C0 UV: λM8(:Mnm(log E) = 210 (
3,30ax), 293(2,70).

[α = +10.1° (c = l, O, MeOH)
.

MS: m/e 592 (M'), 430 (M
+-06M+.

Os)・Elemental analysis, Css HioOr, calculated value (a):
0,70.91; H,10,20 actual value (%)
: C,70,93;H,IO,26Example 5 5-o-(4-o-β-21314[6'-tetraacetylglucopyranosyl-2,3,6-)lyacetyl Glucopyranosyl)-al-α-tocopherol Following the method of Example 1, dl-α-tocopherol and octaacetyl cellobiose are reacted to give the title compound as an oil.

UV: 'AMeOHnm(1ogt)-207(3,
50ax), 292 (20,72).

(α)”=+2.3°(c”1.0, MeOH
).

Example 6 dl-α-Tocopheryl Cellobioside The product of Example 5 is deacetylated according to the method of Example 2 to obtain crystals of the title compound.

Melting point: >300°C.

UV: 1”OHnm (log e) = 206 (
3,30), aX 290 (2,48).

[α) A4-10a, 1° (c -1,0, MeOH
).

Example 7 6-o-(β-2,3,4,6-tetraacetylgalactopyranosyl)-d-δ-tocopherol d-δ-tocopherol 5.2.112.9 mmol) and p-)
Luenesulfonic acid 76m! ? (0.44 mmol) is warmed and dissolved in nitrobenzene 5-. Then, β
-galactopyranose pentaacetate) 3.3. ! i'
(8.50 mmol) in an oil bath, 201111H
g(7) React for 4 hours while distilling off the acetic acid produced under reduced pressure. Then, 300 frLe of water was added to the reaction mixture, and the mixture was extracted three times with 50 m of chloroform each time. The chloroform extracts are combined, dried and the solvent is evaporated under reduced pressure to give a dark purple oil 10I.

5 g of the obtained oil was placed on a medium pressure ram (3201111 x 1500 mm) containing 360 g of silica gel at 5 kg/(
The product was subjected to column chromatography at a pressure of 100 g and eluted with a benzene-ethyl acetate gradient.

Removal of the solvent from the eluate yielded the title compound as a yellow oil 4.0
get g.

Silica gel thin layer chromatography (Merck Art)
, 7749, developing solvent: benzene-ethyl acetate (9:1
Bf-0,6 (single spot) in )).

MS: m/e 402 (M+-330, δ
-tocopherol), 331 (M+-399, sugar).

Example 8 d-δ-Tocopheryl Galactoside 3.8 g (5.2 mm!j'mol) of the product of Example 7 are dissolved in dry methanol Iofne, 0,IN sodium methoxide 2- is added and boiled. Heat to reflux in a water bath.

After 5 minutes, the reaction mixture was cooled and Amberlite IR-1
201'' type) 5-, and the resulting methanol solution was evaporated under reduced pressure to give 25 g of the crude title compound as white crystals.
(yield 875%).

The obtained crude crystals were mixed with water-ethanol (
1.8 g of the title compound purified by recrystallization from 2:3)
get.

Melting point: 140°C0 UV, λCt(3a(nm(10gε)=206(1,
9aX 99), 282 (1,498).

(α)20=-11,0°(C=1.0, MeO
H).

MS: m/e 564 (M+), 402 (M
+-162).

The dl-α-tocopheryl galactoside and d-δ-tocopheryl galactoside obtained in the above example were
When β-galactosidase was allowed to act in a t-butanol-water system at 37°C and the progress of hydrolysis was investigated, dl-α-tocopheryl galactoside was reduced to approximately 40% of its original content 8 hours after the start of β-galactosidase action. is hydrolyzed, and approximately 50% of d-δ-tocopheryl galactoside is hydrolyzed after approximately 15 minutes, and approximately 70% of d-δ-tocopheryl galactoside is hydrolyzed after approximately 30 minutes, resulting in the corresponding free a- or δ-tocopherol, respectively. occurred.

Patent applicant Sunstar Co., Ltd. Representative patent attorney Aoyama Iwa) 2 people

Claims (9)

[Claims] (1) Formula: [In the formula, Kawa is a glucose residue, a galactose residue, a cellobiose residue, or an acetylated derivative residue of glucose, galactose or cellobiose (2), and
the same or different, each meaning hydrogen or methyl] Compounds represented by the following. (2) The compound of item (1) above, which is (11-α-tocopheryl glucoside). (3) The compound according to item (1) above, which is al-α-tocopheryl galactoside. (4) The compound of item (1) above, which is dl-α-tocopheryl cellobioside. (5) The compound of item (1) above, which is d-δ-tocopheryl galactoside. (6) The compound of item (1) above, which is 6-0-(β-2,3,4,6-tetraacetylglucopyranosyl)-+11-α-tocopherol. (7) The compound of item (1) above, which is 6-0-(β-2,3,4,6-tetraacetylgalactopyranosyl)-til-α-tocopherol. (8) 6-0- (4-0-β-d -2':, 3:4
: 6'-tetraacetylglucopyranosyl-2,3,
The compound according to item (1) above, which is 6-dryacetylgelcohylanosyl)-a:i-α-tocopherol. (9) The compound of item (1) above, which is 6-0-(β-2,3,4,6-tetraacetylgalactopyranosyl)-d-δ-tocopherol. ′