JPS61194049A - Lambda-menthyl 3-hydroxybutyrate, production thereof, and chilling agent containing said compound as active component - Google Patents

Abstract

NEW MATERIAL:lambda-Menthyl 3-hydroxybutyrate of formula. USE:Chilling agent added to foods, drinks, cosmetics, pharmaceuticals, cigarettes, etc. It has long-acting excellent chilling effect, is colorless and odorless, free from unagreeable taste, has excellent safety, stability and solubility, etc., and can be produced from an inexpensive raw material in short step with simple operation in high yield. PREPARATION:The objective lambda-menthyl 3-hydroxybutyrate can be produced by reacting lambda-menthol with diketene in the presence of an alkaline catalyst, and reducing the resultant lambda-menthyl acetoacetate.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to l-menthyl 3-hydroxybutyrate, a method for producing the same, and a cooling agent containing the same as an active ingredient. l
- Menthyl 3-hydroxybutyrate can be added to foods and drinks, cosmetics, medicines, cigarettes, etc., and by imparting a cooling effect, the commercial value thereof can be increased.

[Conventional technology]

BACKGROUND ART Compounds that have a so-called cooling effect, which gives a physiologically cold sensation to the skin and mucous membranes of the human body, have been known for a long time, and a typical example is menthol, which is the main component of peppermint oil. The cooling effect of menthol is not due to the compound's latent heat of vaporization, but is said to act as a direct stimulus to the cold receptors in the nerve endings of the human body, stimulating the central nervous system and giving a cooling sensation. Menthol is used as a cooling agent in foods, drinks, cosmetics, and pharmaceuticals.

Although it is widely used in toothpaste, cigarettes, etc., it has a unique strong musty odor and is quite volatile, so its cooling effect is not sustainable and its use may be limited.

In addition to menthol, other compounds that have a cooling effect include:
3-Substituted-p-menthanes (JP-A-47-16647, JP-A-47-16649).

N-substituted-P-menthane-3-carbofusamides (JP-A-47-16648), p-menthanediols (JP-A-47-16650), N-substituted ureas (JP-A-47-16650),
0-142737), 3-menthoxypropane-1,
2-diol (JP-A-58-88334), tricyclic alcohols (JP-A-59-219208, JP-A-59)
-219243) etc. have been disclosed.

[Problem that the invention seeks to solve]

Menthol and conventionally disclosed cooling agents: ■ have a weak cooling effect; ■ have no long-lasting cooling effect; ■ have a strong odor.
■It has an unpleasant taste such as bitterness; ■It has safety issues; ■It has poor chemical properties such as stability and solubility; ■It has high manufacturing costs. , I still haven't found one that satisfies me. Therefore, it is desired to develop an ideal cooling agent that overcomes all of these problems.

[Means for solving problems]

As a result of repeated research to develop a cooling sensation agent that overcomes the above-mentioned problems, the present inventors discovered a new compound derived from l-menthol! - Discovered that menthyl 3-hydroxybutyrate has a sufficiently satisfactory cooling effect, and confirmed the cooling effect of this compound by applying it to foods and drinks, cosmetics, medicines, toothpaste, cigarettes, etc. and completed the present invention.

That is, the present invention is characterized in that l-menthol and diketene are reacted in the presence of β-menthyl 3-hydroxybutyrate (2) represented by an alkali catalyst to obtain l-menthyl acetoacetate, and this is reduced. The present invention provides a cooling sensation agent containing l-menthyl 3-hydroxybutyrate as an active ingredient, which is represented by the method for producing l-menthyl 3-hydroxybutyrate represented by the following formula.

The novel compound l-menthyl 3-hydroxybutyrate of the present invention is! -Menthol (formula ■) and diketene (formula ■)
It can be industrially produced using the following reaction formula as a raw material.

(n) (I[[) The reaction is a two-step process; first, l-menthol and diketene are formed through the first step esterification reaction! -Produce menthyl acetoacetate (2). The reaction in the first step is carried out in the presence of an alkali catalyst at 50-130°C, preferably at 90-130°C.
It is carried out at 10°C. Here, the alkali catalyst is sodium carbonate.

Although various substances such as potassium carbonate, sodium acetate, and sodium hydroxide can be used, potassium carbonate or sodium acetate is preferably used. To give a specific example of the first step, for example, 1 moj of l-menthol! (156g)
Add 0.05 to 0.1 g of an alkali catalyst such as potassium carbonate or sodium acetate to the solution, stir, and raise the temperature to 90 to 11
By dropping 1.05 to 1.10 mol of diketene while maintaining the temperature at 0°C, l-menthylacetoacetate can be obtained in high yield (95% or more) without a solvent. !
- Menthyl acetate is the usual method! -Although it can also be produced by transesterification of menthol and ethyl acetoacetate, the method of the present invention using diketene has a high yield and allows the next step of reduction reaction to be carried out without separating the product. Very advantageous.

The second step of reducing i-menthyl acetoacetate to l-menthyl 3-hydroxybutyrate can be carried out by a chemical reduction method or a catalytic hydrogenation method. In the chemical reduction method, it is preferable to use a soft type of reducing agent that does not act on ester groups and reduces only carbonyl groups, such as sodium borohydride, lithium borohydride, and t-butoxyaluminum hydride. Examples include lithium, among which sodium borohydride is preferably used. Chemical reduction method is -20℃~20℃,
Preferably at a temperature of -5°C to 5°C! - Carry out the reduction of menthyl acetoacetate. Here, if the reaction temperature is higher than 20°C, there is a risk that the ester group will be cleaved. To give a specific example of the chemical reduction method, for example, 10 to 13 g of sodium borohydride is added to 11 of isopropyl alcohol, stirred, and while maintaining the temperature at -5°C to 5°C, 1 moj! By dropping a solution of (240 g) of isopropyl alcohol (100 mj), the desired l-menthyl 3-hydroxybutyrate can be obtained in high yield (95% or more).

Next, when performing the second step by a catalytic hydrogenation method, l-menthyl acetoacetate is mixed with Raney nickel.

It is charged into a reaction vessel together with a reduction catalyst such as a copper chromium catalyst,
10-100kg/cd, preferably 60-80kg/cd
- hydrogen pressure, 60-120°C, preferably 90-100°C
The hydrogenation is carried out at a reaction temperature of °C.

If the reaction temperature is higher than 120° C., the ester group may be cleaved. To give a specific example of the catalytic hydrogenation method, for example, 1 moβ (240 g) of 1-menthyl acetoacetate and 2 to 2 Raney nickel catalysts are placed in an autoclave.
Charge 3g, hydrogen pressure 70kg/cd, reaction temperature 95~
I-menthyl 3-hydroxybutyrate can be obtained in a good yield (90%) by hydrogenating at 100° C. and absorbing a theoretical amount of hydrogen.

i-menthyl 3-hydroxybutyrate is a colorless and odorless liquid, and its solubility is that of food.

It is convenient for practical use because it dissolves freely in ethanol, propylene glycol, triethyl citrate, benzyl benzoate, dioctyl phthalate, etc., which are solvents commonly used in cosmetics, and about 23% dissolves in a 50% aqueous ethanol solution. Regarding stability, changes over time were investigated when the pH was changed at 43° C. in a 2% ethanol/water (1: lv/v) solution.

As a result, in the alkaline range of pH 11.0, hydrolysis gradually occurs and menthol is produced, but in the medium acidic range of pH 6.7 and pH 4.2, the decomposition is only about 1% even after 6 months, which is sufficient for practical use. It was confirmed that it has stability.

Regarding the safety of β-menthyl 3-hydroxybutyrate, the primary irritation test, phototoxicity test, and sensitization test of this compound using prickly-haired guinea pigs were all negative, the biodegradability test, Decomposition by microorganisms is observed in the samples, and Salmonella
t himurium TA 100rTA98
and TA1538) and Escherichia coli (E.
A microbial mutagenicity test using S. acoli WP-2) was negative, and the 50% lethal dose (LDso) when administered orally to male rats was 10,300 mg/
Judging from the fact that the weight was 1.5 kg, it was confirmed that there was no problem at all.

The l-menthyl 3-hydroxybutyrate of the present invention can be used alone as a cooling agent or in combination with alcohol.

Chewing gum, as a solution with propylene glycol, benzyl benzoate, etc., or as an emulsion mixed with an emulsifier, or as a powder adsorbed on starch, talc, etc., or as an aerosol propellant with a low-boiling hydrocarbon or a low-boiling halogen hydrocarbon; candy,
Food and beverages such as frozen desserts and soft drinks, cosmetics such as creams, lotions, powders, hair tonics, shampoos, and lipsticks, pharmaceuticals such as ointments, patches, oral preparations, and cough drops, as well as toothpaste, gargles, cigarettes, and tobacco products. It can be added to filters etc. to provide a cooling effect. In addition, this cooling sensation agent may contain other ingredients depending on the application, such as preservatives,
Antioxidants, fragrance, 2 colorants.

Surfactants and the like may also be appropriately blended and used. There is no particular limit to the amount of addition of this cooling agent, but when used, l-menthyl 3-hydroxybutyrate is added to o, ooi to 10
It is preferable to use it in a range of % by weight.

〔Example〕

The present invention will be described in detail below with reference to Examples, but the present invention is not limited to these Examples.

Production Example (2nd Section 7%/I Gomu , 0.5 g of sodium acetate was added, and the mixture was heated to 90° C. with stirring under a N2 gas stream.

To this, 582 g (6.94 woj) of diketene was added dropwise over 2 hours to carry out the reaction. Since this reaction is exothermic, the reaction temperature was kept at 90 to 110°C with occasional cooling.
I kept it.

After the dropwise addition, stirring was continued while maintaining the same temperature for another 2 hours to complete the reaction, and 1582 g of crude l-menthyl acetoacetate (purity about 95%) was obtained.

The obtained crude l-menthyl acetoacetate was used as a raw material for the second step (reduction) without being purified.

Example 1 After replacing the inside of a 31 flask with a stirrer with N2 gas in advance, 21 isopropyl alcohol and 25.2 g (0,667 moj!) of sodium borohydride were added, cooled in a dry ice-acetone bath, and left for 15 minutes. ℃. A solution of 505 g (2 mol) of crude l-menthylacetoacetate (purity approximately 95%) obtained in the production example in isopropyl alcohol (200 * 1) was added dropwise to this solution over 3 hours with stirring under a N2 gas stream to allow the reaction to occur. went. During this time, the reaction temperature was controlled at -5°C to 0°C. After the dropwise addition, stirring was continued while maintaining the same temperature for another hour to complete the reaction.

To this reaction-completed solution, 237 g of 10% hydrochloric acid water was added dropwise over about 1 hour while stirring and maintaining the temperature at 09 to 5°C to decompose excess sodium borohydride.

Next, after neutralizing with 10% sodium bicarbonate solution, vacuum distillation (distillation temperature: 40° C. or lower) was performed to recover isopropyl alcohol. Toluene 11 was added to the concentrated solution after isopropyl alcohol recovery, and the mixture was transferred to a separatory funnel, washed with saturated saline 1j2, and separated.

The organic layer was washed again with 11 saturated brine, separated, and the resulting organic layer was distilled under reduced pressure to recover toluene. −
495 g of menthyl 3-hydroxybutyrate concentrate was obtained. This product was distilled using a 30cm Windmar rectifier, and the fraction with a boiling point of 100' to 105°C and 10.4 mHg was collected to give 465 g of l-menthyl 3-hydroxybutyrate.
(1,92 mof) was obtained (theoretical yield 96.1%).

The characteristic values of this compound are as follows.

d:: :'0.9793. n",':
1.4603. (α) ”: −64
,9Uv:λIIIax -218na+ IRCNaC&'liquid film, cm-'): 3440
(v 0-H).

1700 (ν C=O”) (shown in Figure 1) M
S (m/e): 243 (M + 1
), 227,155,138,123°105.95(
P), 81, 71.57, 43.29 (shown in Figure 2).

) NMR<CDCl3, I) pm): 0.72-1.02 (IIH, 7-CH of menthane.

9 CHz, 10 CH3, and 5-H(ax), 6-(ax)) 1.22(
3H; d -CHoH-C hill) 1.02-2.28
(7H; l:/tough(7)2-ui, 1-H.

4 once, 8 once, 5-H (eq).

6-(eq) ) 2.21(2H; d -oco--cuney CHOH
-) 3.05 (IH; t, t ) ntan (D3-H)
4.74 (I H; t, q Chz C
HOHCH3) (shown in Figure 3) Example 2 505 g (2 mo.
) and 4.8 g of Raney Nickel W-7 (manufactured by Yoken Fine Chemicals ■), and hydrogen pressure was 70 kg/cI.
A. Hydrogenation was carried out at a reaction temperature of 95 to 100°C to absorb a theoretical amount of hydrogen. Next, the reaction solution after filtering off the catalyst using a glass filter was distilled using a 30 cm Widmer rectifier, and a fraction with a boiling point of 100' to 105'C10,4 flHg was collected to collect l-menthyl 3-hydroxybutyrate 436
g (1,80 moj) was obtained (theoretical yield 90.1%).
).

Example 3 Chewing gum Parts by weight Gum base 230 Powder Sugar
480 grape li
160 water candy
117 plasticizer
1 "Cola flavor" 10 (manufactured by Takasago International Corporation) l-menthyl 3-hydroxybutyrate 2ioo.

The formulation according to the above formulation was kneaded in a Nee-Goo to make chewing gum. When compared with a product that does not contain the compound of the present invention, good results were obtained in that the slightly harsh flavor of the cola flavor used became mellower, and a refreshing feeling without bitterness remained for a long time during the day. .

Example 4 Hard candy Weight part Granule W
600 starch syrup (20% moisture)
500 water 250
Blend the raw materials according to the above recipe, and add 150% at normal pressure using the usual method.
It was heated to ℃ to form a paste.

Before the paste was cooled and solidified, 0.1% of "Saigu Fragrance" (manufactured by Takasago International Corporation) and 0.5% of a 1% ethanol solution of l-menthyl 3-hydroxybutyrate were added and thoroughly kneaded.

When the hard candy obtained in this way is eaten,
Compared to the product without the addition of the compound of the present invention, the slightly sharp feeling of the Saigu flavor disappeared and the flavor became mellower, and the refreshing feeling accompanied by the image of foaming felt when drinking a sparkling drink like Saigu was noticeably observed. It was done.

Example 5 Sherbet Weight part: Upper white 1!
200 powdered starch syrup
40 stabilizer
3 caramel
Appropriate amount of “cola flavor”
1 (manufactured by Takasago International Corporation)! - Menthyl 3-hydroxybutyrate 51% ethanol solution in water 1-1 The above-mentioned formulation was placed in a freezer to make a sherbet. The taste of the flavor was milder than that of the product without the compound of the present invention, and the cooling effect on the mouth was noticeable even after relaxing after a meal.

Example 6 Average Ekuji Beverage Granulated Sugar 700g Quen tJ! 4
g “Saigu Fragrance” (manufactured by Takasago International Corporation) 5
g1-menthyl 3-hydroxybutyrate 10g1%
Ethanol solution □ (added water)
1000 ml of syrup was prepared according to the above recipe, 35 ml of syrup and 165 ml of carbonated water were each filled into a bottle, and sterilized at 70° C. for 10 minutes to obtain a Saigu beverage.

When this was cooled to 5° C. and drunk, it had a mellow flavor and was superior in its mild and refreshing taste compared to the drink without the compound of the present invention.

Example 7 Skin cream Part by weight Stearic acid monoglyceride 35 Stearic acid
47 cetyl alcohol
17 Light liquid paraffin
140 isopropyl myristate
30 Glycerin 80 Stearyl Alcohol 32 Butylparaben 0.5 Methylparaben 0.5 Triethanolamine 1 Fragrance
3 water
6041-Menthyl 3-Hydroxybutyre) 10 The above formulation, excluding glycerin, water and fragrance, was first blended, stirred and mixed thoroughly under heating at about 70°C, and then kept at that temperature to mix glycerin and water. The mixture was further stirred and mixed thoroughly. Thereafter, the mixture was cooled with gentle stirring, and when the temperature dropped to about 50° C., a fragrance was added, and the mixture was further cooled to room temperature while stirring to obtain a skin cream. When this was used on the skin, it was a skin cream with excellent cooling effects that did not cause any irritation and still felt refreshing even 30 minutes after use.

Example 8 Skin lotion Parts by weight Ethanol 200 Propylene glycol 50 Glycerin
42 methylparaben
1 fragrance 2 water
7001-menthyl 3-hydroxybutyrate
5 A skin lotion was prepared by blending each component according to the above recipe. When I used this on my skin, it was not irritating at all, and even after the cooling sensation caused by the evaporation of the alcohol had disappeared, I could still feel a distinct cooling sensation on my skin, and it lasted for a long time.

Example 9 Shishi and ticks once a week - Parts by weight Dimethylpolysiloxane 105 Squalane 155 Talc
325 Serisite
65 aluminum hydroxychloride 270 benzalkonium chloride
10 Citrus fragrance (Takasago Fragrance Industry ■
(manufactured by) 101-menthyl 3-hydroxybutyre)
60 The above formulation was stirred at room temperature to uniformly disperse it. After putting 1/10 volume of this into a pressure-resistant filling container, chlorofluorocarbon gas was injected into the filling container under pressure as a spray agent. The obtained antiperspirant is a spray antiperspirant powder that has a mild scent, and immediately after use, there is a strong cooling sensation due to the evaporation of the spray, and even after the spray has evaporated, there is a refreshing feeling The cold sensation persisted.

Example 10 Hair tonic Parts by weight Ethanol 520 Jojoba oil
4 Polyoxyethylene sorbitan laurate 12 Propylene glycol
12 triclosan
1 fragrance l water
445β-menthyl 3-hydroxybutyrate
5 The above formulation was mixed uniformly to make a hair tonic. When this hair tonic was applied to the scalp, there was a refreshing cooling sensation, and the cooling sensation continued even after the cooling effect due to evaporation of ethanol had ended.

Example 11 Shampoo Part by weight Sodium lauryl sulfate 100 Water
8501-
Menthyl 3-hydroxybutyrate 50DOO The above formulation was stirred at room temperature and uniformly dispersed to prepare a shampoo. When I washed my hair with this shampoo, I felt a gentle cool sensation on my scalp that lasted for a long time.

Example 12 0 Red Parts by weight Castor oil 450 Hexadecyl alcohol 250 Lanolin
40 beeswax
50 Osikelite
40 Kyan Deli La Row
70 carnauba wax
20 titanium oxide
20 Red No. 202 5 Red No. 204 25 Red 227
No. A Luki 151-menthyl 3-hydroxybutyrate 15 ioo.

The above formulation was heated and mixed, poured into a container, and cooled and molded. This lipstick gave a refreshing cool feeling to the lips after application.

Example 13 Ren 1 or 1 - Part by weight Calcium hydrogen phosphate 500 Carboxymethyl cellulose 10 Sodium lauryl sulfate 20 Glycerin
250 Satukarin
2 “Two Paste Flavor”
8 (manufactured by Takasago International Corporation)! -Menthyl 3-hydroxybutyrate 2 water
-m1 According to the above recipe, various ingredients were mixed with a blender to make a line drawing brush. When I used this product, I got good results that had a pleasant, refreshing feeling without bitterness that spread throughout the day and lasted for a long time.

Example 14 Left standing position, weight part dl-
Camphor 80 Methyl salicylate 20 Yellow petrolatum
8501-menthyl 3-hydroxybutyrate 50 The above formulation was thoroughly mixed to obtain an anti-itch ointment. When used, it had a pleasant cooling effect on the skin that lasted for a long time.

Example 15 Green blood dish fruit Digestive enzyme mixture 25 parts by weight Cinnamon powder
7 Chiyoji powder
2 end of gentian
1 Sodium bicarbonate
6.55 Magnesium carbonate
100 synthetic aluminum silicate
2001-menthyl 3-hydroxybutyrate
10(1oAX h/-le>94)1 n n
n Each component was thoroughly mixed according to the above prescription to prepare the drug for gastrointestinal administration. When I took this, I felt a refreshing swelling sensation, and a gentle cooling sensation spread from my mouth to my throat.

Example 16 1-! Parts by weight Tobacco 9801-menthyl 3-hydroxybutyrate 20 (1% ethanol solution)
Remove the contents of 1000 commercially available cigarettes (cherry) and use 1% l-menthyl 3-hydroxybutyrate.
After the ethanol solution was added by spraying, the ethanol was removed by air drying, and the product was wrapped again in paper to obtain a cigarette containing the compound of the present invention.

When I smoked this, I felt a mild cooling sensation that spread and lasted during the day.

Example 17 Remove a part of the filter from a commercially available cigarette (cherry) and
- impregnated with a 1% solution of menthyl 3-hydroxybutyrate in ethanol, a portion of the filter containing 0.05% of the compound;
included. After removing the ethanol with a hot air dryer, I connected it to a cigarette again and smoked it, and at the same time the smoking taste became mellower and at the same time the refreshing sensation spread throughout the day.

〔Effect of the invention〕

According to the present invention, it is possible to produce l-menthyl 3-hydroxybutyrate, a new compound, from inexpensive raw materials in a short process and in high yield without any operational difficulties, which is very advantageous industrially. It is. In addition, the cooling agent containing this new compound as an active ingredient exhibits an excellent cooling effect over a long period of time, is colorless, odorless, and has no unpleasant taste, and has excellent safety, stability, and solubility. Therefore, it can be widely used in various fields.

[Brief explanation of the drawing]

Figures 1 to 3 show IR, MS, and NMR spectra of l-menthyl 3-hydroxybutyrate, respectively.

Claims (3)

[Claims] (1) Formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) l-menthyl 3-hydroxybutyrate represented by (2) A formula characterized by reacting l-menthol and diketene in the presence of an alkali catalyst to obtain l-menthylacetoacetate, which is then reduced ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) The method for producing l-menthyl 3-hydroxybutyrate shown. (3) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) A cooling agent whose active ingredient is l-menthyl 3-hydroxybutyrate.