DE2242237A1 - MENTHOL GLYCOSIDES, THE PROCESS FOR THEIR PRODUCTION, THEIR USE FOR THE DEVELOPMENT OF PEPPERMINT TASTE AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

TOYO HAKKA KOGYO KABUSHIKI KAISHA
Satosho Machi, Japan

"Menthol glycosides, process for their preparation, their use to develop peppermint flavor and these compounds containing medicinal products "

Priority: 2 ?. August 1971, Japan, nos. 65 616 and 65 617

The invention relates to new menthol glycosides and processes for their Manufacture, their use zuj? Development of peppermint flavor as well as medicaments containing these compounds.

Menthol is popular because of its refreshing peppermint taste in medicinal preparations, foodstuffs and cachous such as toothpaste, used * Since menthol is swiftly soluble in water, however its use mower is limited to the following:

(a) Mixing the menthol in solid form with a material, which is to be mixed with menthol;

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(b) making a suspension using an emulsifying agent or

(c) Dissolving the menthol in an organic solvent such as Ethanol.

For this reason, the use of menthol has so far been restricted by necessity »And there was a need for highly soluble menthol derivatives.

In its free form, menthol develops the peculiar peppermint taste and loses its pharmacological effect but these properties when mixed with other compounds.

The object of the invention was accordingly to make available water-soluble menthol derivatives that are mixed with others Compounds are compatible and which develop the characteristic peppermint taste on hydrolysis. The task is achieved by the invention.

The invention thus relates to the general menthol glycosides Formula I.

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in which R denotes the remainder of a monosaccharide or oligosaccharide Specific examples of monosaccharides that form the radical R are glucose, galactose, mannose, maltose, arabinose, Cellobiose, fructose, xylose and ribose. A preferred oligosaccharide is sucrose.

The invention also relates to a process for the preparation of the menthol glycosides of the general formula I, which is characterized is that you get a menthol.

(a) with either a monosaccharide or oligosaccharide, if appropriate condensed in the presence of a catalyst or

(b) with an acylated monosaccharide or oligosaccharide or

(c) an acyl halo monosaccharide. or oligosaccharide brings to implementation and saponified the menthol acyl glycoside obtained according to (b) or (c) to form menthol glycoside. Under menthol are 1-menthol and dl-menthol and their isomers, such as neomenthol, to understand. The process according to the invention can be carried out by methods known per se for the preparation of glycosides will; See Ullmanns Encyklopadie der technischen Chemie, 3rd edition, Vol. 8 (1957), pp. 220-221.

In the case of procedure (a) according to the following reaction scheme

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in which R has the above meaning, ongoing reaction of menthol with a monosaccharide or oligosaccharide (hereinafter referred to as saccharide), preferably both starting compounds are dissolved in a solvent such as dimethyl sulfoxide, the resulting solution is heated and, if necessary, a catalyst or a condensing agent is added. The reaction can also be carried out at room temperature. Preferably the reaction is carried out for about 3 to 8 hours at temperatures of 50 to 130 ⁰ C and the reflux temperature of the solvent used.

In process variant (b) or (c), which has a menthol acyl glycoside runs, a saccharide is first acylated in order to prevent the decomposition of the saccharide during the reaction and to facilitate crystallization. The acylated saccharide obtained is according to the following reaction scheme with a converted to a menthol acyl glycoside:

0-R (0- ■ ·· ^CarbOn -

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In the general formulas, acyl denotes the corresponding radical of an aliphatic carboxylic acid, preferably acetic acid or Propionic acid, R the saccharide residue, η is an integer with a value of at least 3 · In a second reaction step the Mentholacylglykosid obtained according to the following Reaktipnsschema

0-R (0-acylL η + ^.

Jl ** "X II * ·.

^H 5

0-R +

Carboxylic acid

_z hydrolyzed to Mentholglykosid.

According to procedure (c), the reaction proceeds according to the following

Reaction scheme OH RX % CH

* Acyl)

n-X

CH,

CH,

0-R (0 - acyl)

A-X

HX

CH ₅
3 09812/1238

X denotes a chlorine, bromine or iodine atom, preferably a bromine atom, and R, acyl and η have the above meanings. The menthol acyl glycoside is then saponified to give the corresponding menthol glycoside. Procedures (b) and (c) are preferred because of the higher overall yields.

In the process of the invention, hydrogen chloride, sulfuric acid, phosphoric acid, polyphosphoric acid, p-toluenesulfonic acid or cation exchange resins in the H ⁺ -iOrm, various carbonates, such as silver carbonate or lead carbonate, or silver oxide, zinc oxide, zinc acetate or mercury (H) acetate as condensing agents, can be used as catalysts and dimethyl sulfoxide, dimethylformamide, ether, benzene or toluene can be used as the solvent. The compounds of the invention do not have the peppermint flavor typical of menthol. You will, however, according to the following reaction slip

♦ ROH OH "

CH, CH

in which R has the above meaning, under the action of various carbohydrases or acids to menthol and the hydrolyzed corresponding sugars.

The invention therefore also relates to the use of compounds

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gene of the general formula I for the development of peppermint taste .

It is known that carbohydrases are widespread in nature are. For example, maltase, lactase, emulsin and amylase occur in human saliva. These enzymes are able to To cleave glycoside bonds. Likewise is the glycoside-splitting one Known effects of acids. ·

It was found that a glycoside called menthol called aglycone contains, develops the peppermint taste of the aglycon without losing the water solubility when the glycoside bond is cleaved under the action of enzymes or acids. The rate of hydrolysis of menthol glycosides under action of carbohydrases or acids depends on the type and amount of the glycoside. For example, developed 1-menthyl glucoside the peppermint taste in the mouth in a short time and retains it Effect much longer than simple 1-menthol. As a result Menthol glycosides are, for example, valuable additives to gargles.

A particularly rapid release of the peppermint flavor is achieved you, if you add an enzyme to the menthol glycoside beforehand clogs. However, it must be ensured that the enzyme does not react with the menthol glycoside. Another possibility consists in keeping the enzyme separated from the menthol glycoside and only adding it when it is used. To (increase the

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For enzymatic activity, an enzyme activator can be added to all carbohydrases that are capable of binding glycosides cleavage of a menthol glycoside can be used. So you are not on the enzymes present in the human body limited. All inorganic or organic acids which cleave menthol glycoside bonds can be used as acids are suitable and not harmful to the human body.

■ The hydrolysis products of the compounds of the invention, menthol and saccharide, can be used by the human body and are non-toxic. In addition, menthol is used as a disinfectant for the mouth and throat and as a remedy for itchy skin, vomiting, diarrhea, facial pain, insect bites and Suitable for burns.

The invention therefore also relates to medicinal preparations consisting of at least one menthol glycoside of the invention and customary carriers and / or diluents and / or auxiliaries.

The examples illustrate the invention.

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example 1

A mixture of 5 S 1-menthol and 7 S glucose is dissolved in 10 ml of dimethyl sulfoxide and reacted at 100 ^° C. for 5 hours with stirring. The resulting mixture is extracted several times with chloroform. The combined chloroform extracts are evaporated to dryness under reduced pressure. A highly viscous material is obtained. After recrystallization from V / ater remain 0, A g 1-Menthylglucosid (4% of theory), melting at 73 to 75 ⁰ C [a] ^ ⁸ -91.47 ° (c = 1.957; CHCl _3).

C ₁₆ H ₅₀ O ₆ (MW 318.4) £ _% H_%

calc .: 60.35 9.50

Found: 60.18 9.64

Example 2

10 g of glucose are suspended in 30 g of 1-menthol with gentle heating. 10 g of a cation exchange resin in the H ⁺ form (Amberlite IR-120) are added to this suspension while stirring and the mixture is reacted for 25 hours. After extraction and recrystallization according to Example 1, 0.8 g (1.5% of theory) 1-menthyl glucoside is obtained.

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-ίο- 22A2237

Example 3

A mixture of 5 g of 1-menthol and 10 g of acetyl glucose is dissolved with heating. A few drops of sulfuric acid are added while stirring. After three hours of reaction at 90 ^° C., the reaction mixture is extracted with diethyl ether. The extract is evaporated to dryness. A highly viscous material is obtained. After crystallization from ethanol, 3 g (20% of theory) of 1-Menthylacetylglucosid, mp 130 ⁰ C. [a] J ⁷ -53.69 ° (c - 1.016, CHCl _x).

8 ° 10 (MG 486) C. JS H Jk ^C 24 ^H 3 ber .: 59 , 24 7th , 87 found: 59 , 23 8th , 01

3 g of the compound obtained are suspended in 20 ml of V / water and 7 g of barium hydroxide are added while stirring. The mixture is stirred at room temperature for one hour. The barium carbonate and barium acetate are then separated off and the mother liquor evaporated. 1.95 g (98% of theory) 1-menthyl glucoside are obtained.

The saponification can also be carried out as follows: 3 g of the compound obtained are in a solution of ammonia dissolved in methanol and left to stand in the refrigerator for 16 to 18 hours. The solution is then evaporated. It remains behind the 1-menthyl glucoside. The acctylglucose is produced in a known manner from glucose by reaction with acetic anhydride sodium acetate manufactured.

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Example 4-

A mixture of 5 g of neomenthol and 10 g of acetyl glucose is dissolved in 10 ml of benzene and a few drops of polyphosphoric acid are added while heating and stirring.After working up the reaction mixture according to Example 3, 6.7 g of neomenthylacetyl glucoside with a melting point of 136.5 are obtained to 137.5 ⁰ C [a] | ° + 1.85 ° (c = 0.918;. CHCl -) * the yield of Neomenthylglucosid after the saponification is 4.35 g (44-% of theory).

Example 5

10 g! -Menthol and 20 g acetobromoglucose are mixed and dissolved with heating. The solution is mixed with 5 g of anhydrous silicon excess carbonate. After two hours of reaction at 80 ° C. in a reaction vessel equipped with a stirrer and a condenser closed by a calcium chloride tube, the reaction mixture is filtered off from the silver bromide and extracted with dietary ether. After evaporation of the extract, a viscous material is obtained. After working up according to Example 3, 15 g of 1-Henthylacetylglucosid and after saponification 9.75 g (4-9 % of theory) of 1-Menthylglucosid.

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Example 6

10 g of neomenthol and 20 g of acetobromo glucose are mixed and converted according to Example 5 to 15 g of neomenthylacetyl glucoside. After the saponification according to Example 3, the neomenthyl glucoside is obtained in a yield of about 49 % of theory.

Example 7

10 g dl-menthol, and 20 g of acetobromoglucose are mixed and reacted as in Example 5 to 15 g dl-Menthylacetylglucosid from P. 165-168 ⁰ C. [α] · η + 0 °. According to Example 3, dl-menthyl glucoside is obtained from this compound in a yield of about 50% of theory.

Example 8

5 g of 1-menthol and 10 g acetobromogalactose are mixed and reacted as in Example 5 to 6 g of 1-Henthylacetylgalactosid, mp 117-118 ⁰ C. [a] ^ ° + 23.55 ° (c = 4.990; CHCl ₅ ). The yield is 40% of theory. 1-Menthylgalactosid is obtained from this compound according to Example 3 in a yield of about 48% of theory.

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- Example 9

5 g of l-menthol and 10 g of acetobromosucrose are converted according to Example 5 to 3 g of l-menthylacetyl glucoside. The yield is 20 % of theory. According to Example -3, 1-menthyl glucoside is obtained on saponification.

Example 10

5 g of l-menthol and 10 g of acetobromolactose are reacted according to Example 5. There v / ground 2 g (8% of theory) of 1-Menthylacetyllactosid, mp 86-87 ⁰ C was obtained [αΐψ -3.82 ° (c = 5,099; CHCl ^). The compound is saponified according to Example 3 to give 1-menthyllactoside.

Example 11

10 mg of 1-menthyl glucoside are dissolved in 1 ml of water. The solution is mixed with 1 ml of 0.05 M acetate buffer with a pH of 5.25 and then mixed with 1 ml ß-glucosidase solution (emulsin; 20 mg / ml). The mixture is then brought to a total volume of 5 ml with water. The reaction is carried out at 36 to 37 ° C with stirring carried out. The cleavage reaction is carried out by thin layer chromatography tracked. The hydrolysis is almost complete after one minute. The amount of 1-menthol released is for gas chromatographic determination 4.7 mg (calculated 4.9 mg)

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Example 12

1 ml of a 1 percent menthyl glucoside solution is placed in a test tube given and mixed with 0.5 ml of a 10 percent hydrochloric acid solution. The test tube is closed with a stopper and heated in a boiling water bath for 15 minutes.

The hydrolysis reaction is investigated according to Example 10. 4.6 mg of 1-menthol are found (calculated 4.9 mg).

Example 13

By mixing 30 g of ethanol, 1.2 g of a surfactant A 0.1 percent 1-menthol solution is prepared using 145.65 g of distilled water and 0.15 g of 1-menthol. For the production a comparison solution, this solution is made up to twice the volume with distilled water. To make a Test solution is 0.15 g of 1-menthyl glucoside in 100 g of distilled Dissolved in water.

Taste tests are carried out on five randomly selected people carried out. After rinsing their mouths with tap water, each test person takes 5 ml of the test solution for 5 minutes in the mouth and then spits it out again. The peppermint flavor was rated "imperceptible (-)", "perceptible (+)", "strongly perceptible (++)" and "rvery strongly perceptible (+4 +)". In addition · .. · rden the initial perception, the maximum and determines the duration of the peppermint flavor. The results

are shown in the following table.

30981 2 / T 238 öAD

CaJ Ό CO 00

is)

32 a

Attempt
person \ 5
SOC. 10 15th 20th 25th I. ₊ + 30th 35 I. + ⁺ - 45 50 55
¹ i
1
min. t * ι ++ 2 3 - I.
5 1
6th ¹ α. ^: A test
solution + H- + + H-l t ι +
⁺ I _{+ +} i ⁺⁺ _{+ +} + + + ⁺ H- ++ * +++ ++ .- .. - - B. Comparative
solution -r + t - ++ - - + "t * H- + ■ -t- H- ⁺ + ++ m 7th Test-
solution - - trt - - + • I- ₊ + ++ ₊₊ ++ 4th Comparison
solution - l ++ ++ + JL. JL. + ++ + ρ D. Test-
solution - + +++ - + +
■ ++ +++ ■ H- - + A. Comparison
solution +++ ⁺ A * * ^ ^{+ +} -H- j Ξ test
solution - - H- H- + +
t + H- + ⁺ * Comparison
solution + ■! - + - Η- ' ^{+ +} - I ⁺ -H- "Γ test
solution ** Comparative
1 solution I -r

^ s>

ro GO

Attempt
person D. Test- '
solution I.
IA 15th ί ♦ _ 36 17th 38 19- 1 + 20th I. j • ä- ■ r 21 22nd I. ■ i · Ί I. ₊ I.
23 I. I. 24 25th I. - I. - - Comparison 4- , - I.
-1- ί W.
BAD OHiGI solution I.
I.
- NAU test I. solution ₊ ⁺ . _ - U)
ο Β
co Comparison - - 00 solution '. _. NJ - - ■■■■ - Test-
solution -r ■ TO Comparison solution 1 •1· - Test-
solution Y- Comparison solution Te st-
solution Comparison solution

From this table it can be seen that the refreshing effect of the compounds of the invention as potent as that of 1-menthol is. The development of the peppermint taste begins after 10 to 30 seconds and the maximum is reached after 3 to 4 minutes. The duration of action is about 20 minutes.

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Claims (4)

Claims (D in which R is the remainder of a monosaccharide or oligosaccharide means. 2. Process for the preparation of the menthol glycosides according to claim 1, characterized in that a menthol is used in a known manner (a) with either a monosaccharide or an oligosaccharide optionally condensed in the presence of a catalyst or (b) with an acylated monosaccharide or oligosaccharide or (c) an acyl halo monosaccharide or oligosaccharide brings to implementation and saponified the menthol acyl glycoside obtained according to (b) or (c) to give menthol glycoside. 3 · Use of the compounds according to claim 1 for development of peppermint flavor. 309812/1238 4. Medicinal preparations consisting of at least one compound according to. Claim 1 and usual carriers and or or Diluents and / or * or auxiliaries. 309812/1238