JPH0745488B2 - Method for producing tetrahydropyran derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention is an improvement of a 1-hydroxyphenoxytetrahydropyran derivative which is an industrial drug, a compound useful as a medicine, a derivative thereof, or a synthetic intermediate thereof. It relates to a manufacturing method.

[Conventional technology]

Conventionally, the following structural formula: Arbutin, which is represented by, is known to be a useful compound as a stabilizer for color photographic images, a diuretic, and a urinary tract agent [The Merck Index].
k Index) 10th edition, page 112, page 792 (1983)].

Conventionally, as a method for producing arbutin, 1-bromo-glucose tetraacetate is reacted with hydroquinone in the presence of sodium hydroxide, and then hydrolyzed in the presence of barium hydroxide (1), or β- D-glucose pentaacetate (2) a method of reacting hydroquinone in the presence of aluminum chloride, (3) a method of reacting p-benzoyloxyphenol in the presence of boron trifluoride, and then removing all acyl groups Or (4) a method of reacting p-benzyloxyphenol in the presence of phosphorus oxychloride, then removing the acetyl group with sodium and methanol, and finally hydrogenating, optionally in the presence of a charcoal-supported palladium catalyst. Etc. are known (see the above cited document).

[Problems to be solved by the invention]

The above-mentioned conventional methods have problems that the arbutin produced is impure, the yield is low, it is complicated due to the multistep process, and some raw materials are expensive.

An object of the present invention is to provide a method for producing arbutin or a related compound thereof with high yield and simple steps.

[Means for solving problems]

The present invention can be summarized by the following general formula I: A divalent phenol represented by the following general formula II: (In the formula, R is hydrogen or a lower alkyl group, R ^{1 to} R ³ are the same or different, hydrogen, a hydroxyl group, a lower alkoxy group, a lower acyloxy group or an aralkyloxy group, and R ⁴ is a hydrogen atom, a lower alkyl group or a hydroxymethyl group. , A lower alkoxymethyl group, a lower acyloxymethyl group or an aralkyloxymethyl group) is reacted with a 1-acyloxytetrahydropyran derivative represented by the formula (1) in the presence of a sulfonic acid and / or a triphenylmethane salt. The following general formula III: (In the formula, R ^{1 to} R ⁴ are the same as those in formula II) The present invention relates to a method for producing a 1-hydroxyphenoxytetrahydropyran derivative.

The divalent phenol represented by the general formula I includes hydroquinone, resorcin and catechol.

In the general formula II, examples of the lower alkyl group represented by R include methyl and ethyl. Also R ¹ ~
Examples of the group represented by R ³ include each group such as methoxy, setoxy, acetoxy, propionyloxy, benzyloxy and the like. Examples of the group represented by R ⁴ include methyl, ethyl, methoxymethyl, ethoxymethyl, acetoxymethyl, propionyloxymethyl and benzyloxymethyl groups. Of these, penta-lower acylate of glycopyranoside is preferable.

Among the catalysts, examples of sulfonic acids include methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and sulfonic acid group-containing ion exchange resins such as Amberlyst-15. On the other hand, an example of a triphenylmethane salt is the formula Ph ₃ C
X (wherein Ph is a phenyl group, X is an anion such as Cl
_{O 4, BF 4, SbCl 4} , PF 6, SnCl 5, F 3 CCOO- those represented by at shown) and the like.

Both of these may be used in combination.

These catalysts may be used in an amount of 0.01 to 1.0 mol% based on the raw materials.

The solvent may or may not be used. Examples of usable solvents are diethyl ether, ethers such as tetrahydrofuran and dioxane, hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and chlorobenzene, methyl ester and ethyl acetate. Esters such as esters may be mentioned.

The reaction temperature varies depending on the solvent used, but is generally 0.
It may be up to 200 ° C, preferably 20 to 120 ° C. The reaction time is 0.
It takes about 5 to 100 hours.

[Examples] Hereinafter, the present invention will be described in more detail with reference to Examples.
The present invention is not limited to these examples.

Example 1 4-hydroxyphenyltetra-0-acetyl-β-D
-Synthesis of glucopyranoside (1) Hydroquinone 1.1 g (10 mmol) and penta-0-acetyl-β-D-glucopyranoside (2) 3.9 g (10 mmol) were added to 10 ml of toluene and heated to reflux. At the same temperature, 9.6 mg (0.1 mmol) of methanesulfonic acid was added dropwise to 3
Reacted for hours. After completion of the reaction, neutralize the acid with NaHCO ₃ water,
Then, the organic matter was extracted with ethyl acetate. After concentrating the extract, the target product was isolated by column chromatography to obtain 2.9 g of compound (1).

Yield 60%, mp 130 to 133 ° C. Nuclear Magnetic Resonance Spectrum (in _{CDCl 3) 2.04 (3H, S} ) 2.05 (3H, s) 2.08 (6H, s) 3.80
(1H, m) 4.15 (1H, br.d., J = 12Hz) 4.34 (1H, d
₀ d., J = 12 Hz, 5 Hz) 4.9 to 5.3 (5H, m) 6.76 (2H,
d., J = 8 Hz) 6.92 (2H, d., J = 8 Hz) Examples 2-10 Hydroquinone 1.1 g (10 mmol) and compound (2) 3.9 g
The solvent shown in Table 1 below and 0.1 mmol of the catalyst were added to (10 mmol) and the reaction was carried out under the conditions shown in Table 1. After the reaction,
The compound (1) obtained by neutralizing the reaction mixture with aqueous NaHCO ₃ and then extracting with ethyl acetate was analyzed by gas chromatography. The results are also shown in Table 1.

Example 11 3-Hydroxyphenyltetra-0-acetyl-β-D
-Synthesis of glucopyranoside (3) Resorcinol (3.3 g, 30 mmol) and the compound (ml) were added and heated to reflux. At the same temperature, 290 mg (3 mmol) of methanesulfonic acid was added dropwise and reacted for 3 hours. After reaction, NaHC
The acid was neutralized with O ₃ water, and then the organic matter was extracted with ethyl acetate. After concentrating the extract, the target product was isolated by column chromatography to obtain 8.6 g of compound (3). Yield 65%,
Colorless oil Example 12 2-Hydroxyphenyl tetra-0-acetyl-β-D
-Synthesis of glucopyranoside (4) 3.3 g of catechol instead of resorcin in Example 11
By the same procedure as in Example 11 except that (30 mmol) was used, 80 g of compound (4) was obtained. Yield 61%, colorless oil [Effect of the invention] As described above, according to the method of the present invention, arbutin, a related compound thereof, or an intermediate thereof can be obtained in a high yield by a simpler method than conventional methods. There is a remarkable effect that can be obtained by.

Claims (1)

[Claims] 1. The following general formula I: A divalent phenol represented by the following general formula II: (In the formula, R is hydrogen or a lower alkyl group, R ^{1 to} R ³ are the same or different, hydrogen, a hydroxyl group, a lower alkoxy group, a lower acyloxy group or an aralkyloxy group, and R ⁴ is a hydrogen atom, a lower alkyl group or a hydroxymethyl group. , A lower alkoxymethyl group, a lower acyloxymethyl group or an aralkyloxymethyl group) is reacted with a 1-acyloxytetrahydropyran derivative represented by the formula (1) in the presence of a sulfonic acid and / or a triphenylmethane salt. The following general formula III: (Wherein R ^{1 to} R ⁴ have the same meanings as in formula II), and a method for producing a 1-hydroxyphenoxytetrahydropyran derivative.