JPS6033371B2 - Method for producing trans-p-menthane-2,3-diol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new method for producing trans-p-menthane-2,3-diol, and its purpose is to produce equatorial type trans-p-menthane-2, which has an excellent cooling effect.
- We aim to provide a new method for producing 3-diol.

Menthol, which is the main component of peppermint oil, has been known for a long time as a substance that gives a cooling effect.

The effect of menthol is not due to latent heat of vaporization, but is said to directly stimulate the cold receptors in the nerve endings of the skin and mucous membranes of the human body, causing a cooling and refreshing sensation, and it is used as a cooling agent. It is widely used as an additive in foods, beverages, toothpaste, gargles, cosmetics, cigarettes, etc. but,
Menthol has a characteristic strong minty odor and is quite volatile, which may limit its use.
In addition to menthol, many compounds that have a cooling effect are known.

Among them, p-menthane diols are described in Tokusekki No. 12790/1983, p-menthane-2,3-diol, p-menthane-2,5-diol, p-menthane-2
・6-diol, p-menthane-3,5-diol, p
It is described that -menthane-3,6-diol is odorless or has almost no odor and can be used as a cooling sensation agent. However, the differences in cooling effects due to structural differences between stereoisomers have not yet been elucidated. The present inventor aimed to provide a compound that is odorless, tasteless, and has a strong lining effect.
-We conducted intensive research on various isomers of menthanediol.

That is, first, p-menthane-1, which is relatively easily obtained,
・2-diol, p-menthane-1,3-diol, p
-menthane-2,3-diol, p-menthaso3,4
- When we investigated diols, we found that especially p-
We found that menthane-2,3-diol has an excellent cooling effect, and as a result of conducting further research on stereoisomers of this product, we found that in trans-p-menthane-2,3-diol, all the substituents are located in the equatorial position. That is, it has been found that the one represented by the following formula (1) has the strongest cooling effect and has no menthol odor. On the other hand, both the cis-diol compound (0), in which the hydroxyl group at position 2 is in the axial position, and the trans-diol compound (m), in which the hydroxyl group is in the axial position, have a lining effect similar to that of compound (1). It is inferior in comparison and has a bitter taste. Therefore, the present inventor focused on this trans-1P-menthane-2,3-diol and conducted research on a method for producing it industrially advantageously.

Conventionally, p-menthane-2,3-diol has been produced by hydroxylating menthene-2 with osmine tetrooxide and peracetic acid [J. Chem
．． Soc. 895 (1953)], a method in which diosphenol can be reduced with catalytic hydrogen using Raney nickel or with metallic sodium and ethanol [
J. Chem. Soc. 3512 (1953)], and a method in which piberitone is subjected to hydroboration by acting with diborane, and then treated with alkaline hydrogen peroxide [
Tetrahedron. vo124 5701 (19
68)] etc. have been reported.

However, in these methods, the raw materials used are expensive and the yields are not sufficient, and neither of these methods is satisfactory as an industrial method. Moreover, what is obtained by these methods is a mixture of stereoisomers, and it has been shown that in the above-mentioned Tegeahedron, which uses piberitone as a raw material, the production ratio of equatorial and axial forms is almost the same. , the equatorial type transformer which is the object of the present invention.
This is an unsuitable method for obtaining p-menthane-2,3-diol. In this situation, the present inventor tried various reactions using piberitol, which is available at low cost, as a raw material.
We succeeded in producing 3-diol.

The present invention is shown by the following reaction formula.

That is, in the present invention, piberitol (W) is reacted with an organic acid to form piberitol poxide (V), and this is heated with aluminum isopropoxide to produce p-menthene-2,3-diol (of ), which was then catalytically hydrogenated to give cis-p-menthane-2.
3-diol (blood) and further heat this with an alkali metal or alkali metal alcoholate to form a trans-diol.
This is a method for producing p-menthane-2,3-diol (skin).

In the method of the present invention, first, piberitol (W) is reacted with an organic peracid slightly in excess of the equivalent amount to produce piberitol epoxide (V).

Piberitol may be used in either the cis form, the trans form, or a mixture thereof. The organic peracid used here is
peracetic acid, perpropionic acid, benzoic acid, perphthalic acid,
Examples include p-nitroperbenzoic acid, and the use of peracetic acid is most preferred. The reaction is carried out in an organic solvent such as dichloromethane in the presence of an alkali salt such as sodium carbonate, from 0 to
The reaction is carried out by adding peracetic acid dropwise while cooling to 5° C., stirring the mixture for about 3 hours after the dropwise addition is complete, and then continuing to stir the mixture at room temperature to complete the reaction. In this process, piberitolepoxide (V) is obtained in a yield of 95% or more. From NMR analysis values and consideration of the reaction mechanism, it was confirmed that 80% or more of this product contained the following structure in which the epoxy group was in the cis position relative to the alcohol group. Next, in order to introduce this piberitol poxide (V) into a diol form, the present inventor tried various reactions. For example, this was directly hydrogenated using Raney nickel to perform a reduction reaction, but p-menthane- By-products such as 1,3-diol and further reduced menthol were produced, and satisfactory results could not be obtained.

As a result of further investigation, we found that if we first perform a ring-opening rearrangement of the epoxy ring and then reduce this, the diol form is approximately 8
It has been found that it can be obtained with a good yield of 0 to 85%. That is, by heating aluminum isopropoxide in a solvent such as piberitolepoxide (V),
2.3-diol (M). This is a mixture of 6mene and 1'7mene. In addition to aluminum isopropoxide, butyl lithium and the like can be used here, but it is preferable to use aluminum isopropoxide, which is industrially easily available, and the amount used is 0.4 molar ratio to piberitol poxide. The following is sufficient. The p-menthene-2,3-diol is then reduced by a conventional method. That is, by using Raney nickel in a solvent and reducing it with hydrogen under pressure, cis-p-menthane-2,3-diol (blood) can be obtained in good yield. Palladium-carbon may be used instead of Raney nickel, but Raney nickel is preferably used industrially. The thus obtained cis-p-menthane-2,3-diol (W) is isomerized into the trans form by heating with an alkali metal or alkali metal alcoholate. The use of an alkali metal or alkali metal alcoholate to isomerize the cis form of such diols into the trans form is a method discovered for the first time by the present inventor, and is a novel method not yet known in the literature. It is. In other words, cis-p-menthane-2 and 3
- Add an alkali metal or alkali metal alcoholate to diol (blood) and heat at high temperature, i.e. about 170 ml, in a nitrogen stream.
Heat the bait for about 5 to 1 hour around ~200:00. In this case, the isomerization reaction is completed and the cis form completely changes to the trans form. In addition, it was confirmed from instrumental analysis such as NMR and IR that trans-p-menthane-2,3-diol (blood), in which all substituents are located in equatorial positions, is the main product of 85% or more. Ta. As the alkali metal used here, sodium, potassium, and lithium are used, but sodium is preferred industrially, and as the alkali metal alcoholate, sodium methylate, sodium ethylate, chlorium methylate, and potassium ethylate are used. It will be done. After the reaction is complete, a solution such as toluene is added to the reaction solution, the organic layer is separated, the solvent is recovered, and the target product, trans-p-, is purified by distillation under reduced pressure.
Menthane-2,3-dioml can be obtained in a yield of about 80% or more based on the cis isomer. Moreover, the analytical values are consistent with the numerical values described in the above-mentioned literature. As described above, the present invention uses piberitol, which is easily available and inexpensive, as a starting material and is an excellent method for obtaining odorless equatorial trans-p-menthane-2,3-diol with excellent cooling effect in high yield. It's a method.

In addition, trans-p-menthane-2.3 obtained in the present invention
- Diol has an excellent cooling effect, so it can be used in foods, beverages, toothpaste, gargles, cosmetics, imitation lotions,
It can be widely used as an additive in medicines, cigarettes, etc., and its odorless property with no minty odor makes it possible to use it in a wide range of applications as a cooling agent. Next, the present invention will be explained by examples.

Example 1 {i} Piberitol epoxide: Transpiveritol 154 mol (lmol), sodium carbonate 10M (lmol) and dichloromethane 35
40% of
After 228 g (1.2 mol) of peracetic acid was added dropwise, the mixture was incubated at the same temperature for 3 hours and then at room temperature for 3 hours to complete the reaction.

Next, the reaction solution was poured into 500 g of water, and the organic layer was separated, and then washed twice with 500 g of a 5% ferrous ammonium sulfate aqueous solution. This is distilled under reduced pressure to first recover dichloromethane, and then further distilled under reduced pressure to obtain a boiling point of 68-7.
Obtained 146.3 nights of 800/2-4 ribs Hg. This product contained 82% cis isomer and 18% trans isomer. Furthermore, this product was precision distilled using a McMahon tower 2 staged distillation vessel to isolate the cis-isomer 110. 'ji
' p-menthene-2,3-diol: toluene 200
Yu and aluminum isopropoxide 74 Yu (0.37
mol) 170 lmol of the above-mentioned piberitol epoxide was added dropwise over 1 hour to the mixture, which was heated under reflux under a nitrogen stream.

The reaction was completed by continuing to reflux with light for another 2 hours. 30 minutes after cooling
Pour into cold 10% hydrochloric acid at 0.000 0.00000000000000000000000s0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000 to000000000000000
After washing with water and drying with anhydrous trinitrate, distillation is performed under reduced pressure to first recover toluene, which has a boiling point of 85~105oo/2~4.
144.5 ml of p-menthene-2,3-diol (a mixture of 60 and 1 (7)) diol was obtained.
iii) Cis-p-menthane-2,3-diol: 182 p-menthane-2,3-diol (1.0
7 mol) and isopropanol 882 and Raney Nickel NDT-650ll (manufactured by Ken Fine Chemicals) were placed in an autoclave, and the hydrogen pressure was 20 to 25 k9/s.
Hydrogenation was performed at a temperature of 90 to 100 qo.

After the reaction was completed in 4 hours, the catalyst was removed by filtration, and the isopropanol was recovered by distillation under reduced pressure.
O/176.5 cis-p-menthane-2.3-diol of 2-4 Yanagi Hg was obtained.

Trans-p-menthane-2,3-diol: cis-p-menthane-2,3-diol 170 m(
A 28% solution of sodium methylate (4M) was added to the solution (1 mol), and the temperature was raised to 18,000°C over 3 cycles under a nitrogen stream.

After distilling off methanol while increasing the temperature, 185~190oo
I watched the flies for 5 hours. Next, cool to 80℃ and add toluene 2
After adding 200 g of water to dissolve the reactants, 200 g of water was added and the mixture was allowed to stand for 30 minutes, and then the organic layer was separated and washed with 200 g of water. This organic layer was distilled under reduced pressure to first remove toluene, and then the boiling point was 85 to 95 qC/2.
144.5 of trans-p-menthane-2,3-diol with ~4 Hg was obtained. This product was 85% entirely equatorial and the remaining 15% was a mixture of other isomers.
Further, this was subjected to precision distillation using a distillation device equipped with 20 stages of mass-machining column to isolate 118 units of trans-p-menthane-2,3-diol, which was a total of 100 mol. The refractive index of this material is n-color ol. 4775, specific rotation is [Q] color. 11.0o, and the results of the infrared absorption spectrum are as shown in FIG. Example 2 To 170 lmol of cis-p-menthane-2,3-diol obtained in Example 1, 15 g of sodium ethylate was added, and the temperature was raised to 180°C over 30 minutes under a nitrogen stream. .

After distilling off ethanol while increasing the temperature, 185-190
I worshiped the flies for 5 hours at 00. Next, cool to 8,000 ℃, add 200 ml of toluene to dissolve the reactant, and add 20 ml of water to this.
After adding 0.0 ml of water and stirring for 3 hours, the organic layer was separated and washed with 200 ml of water. This product was distilled under reduced pressure to first remove toluene, and then the boiling point was 85 to 950.
0/2-4 skin Hg trans-p-menthane-2,3-
Diol 131 was obtained. This product was 85% entirely equatorial and the remaining 15% was a mixture of other isomers. Further, this was subjected to precision distillation in the same manner as in Example 1 to isolate 107 trans-p-menthane-2,3-diol, all of which were catalytic. The analytical value of this product is Example 1
It was similar to Example 3 10 pieces of metallic sodium were added to 170 lmol of cis-p-menthane-2,3-diol obtained in Example 1, and the temperature was gradually raised to 18,000 mol over 1 hour under a nitrogen stream. did.

In this case, a rapid reaction may occur, so care must be taken to avoid rapid heating. Furthermore 185-190q○
After reacting for 5 hours at
It took an hour to add the evening meal. Next, 250 μm of toluene was added to dissolve the reactant, and 250 μm of water was added to this to dissolve the reactant.
After drying and washing, the effective layer was separated and washed with 250 ml of water. Next, this was distilled under reduced pressure to first remove toluene, and then 130 g of trans-p-menthane-2,3-diol having a boiling point of 85 to 95 oo and 2 to 4 Hg was obtained. Further, this was subjected to precision distillation in the same manner as in Example 1 to isolate 101 units of trans-p-menthane-2,3-diol, all of which were in the precatorial form. The analytical values of this product were the same as in Example 1.

[Brief explanation of the drawing]

Figure 1 shows the total mechanical type transformer obtained in Example 1.
The infrared absorption spectrum of p-menthane-2,3-diol is shown. illustration ship

Claims (1)

[Scope of Claims] 1. A method for producing trans-p-menthane-2,3-diol, which comprises heating cis-p-menthane-2,3-diol with an alkali metal or an alkali metal alcoholate. 2. Piperitol is reacted with an organic peracid to form piperitol epoxide, which is then heated with aluminum isopropoxide to produce p-menthene-2,3-
diol, which is then catalytically hydrogenated to give cis-
A method for producing trans-p-menthane-2,3-diol, which comprises preparing p-menthane-2,3-diol and further heating this with an alkali metal or an alkali metal alcoholate.