JPS6365052B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing bisabolol, specifically 3,7,11-trimethyldodeca-1,6,10
- When trien-3-ol (nerolidol) is cyclized in the presence of formic acid and then the product is hydrolyzed to produce bisabolol, the cyclization reaction is inhibited in the presence of a nonpolar solvent with a dielectric constant of 3.0 or less. The present invention relates to a method for producing bisabolol, which is characterized by carrying out the following steps.

Bisabolol is a monocyclic unsaturated tertiary sesquiterbene alcohol that is present in chamomile oil, lavender oil, etc., and has anti-inflammatory and antibacterial properties, and can be used in skin treatment products such as ointments, creams, lotions, or toothpaste. It is not only used in oral hygiene products such as gargles, but also as a preservative for mixed fragrances due to its fragrance-retaining properties.

A known method for synthesizing bisabolol is to cyclize nerolidol or farnesol in the presence of formic acid, and then hydrolyze the product. Regarding the cyclization reaction in this method, CD
GUTSCHE et. We examined the effects on the composition and found that (1) nerolidol cyclizes faster than farnesol; (2) the reaction rate is highest when 100% pure formic acid is used, and as the water content of formic acid increases, (3) When using 100% pure formic acid, the reaction is extremely fast at a reaction temperature of 30°C, and bisabolol,
The production amount of monocyclic products such as pisabolene is the maximum, and the production amount decreases with the passage of time, and the production amount of bisabolol and/or its formate ester decreases accordingly; (4) trans When trans-farnesol is reacted in the presence of 100% pure formic acid, at a reaction temperature of 0°C, the amount of bisabolol and/or its formate ester produced reaches the maximum amount after about 5 minutes, and then decreases, but the amount of produced It has been reported that the total concentration of monocyclic products such as bisabolol and bisabolene in the product increases rapidly and reaches the maximum after about 10 minutes [Tetrahedron, Vol. 24, pp. 859-876 (1968 )reference〕. In addition, the present inventors investigated this conventional method under various reaction conditions and found that when nerolidol was cyclized using formic acid with a purity of 75% (water content 25% by weight), the conversion rate was 20%. It was found that the reaction hardly progresses at a certain level. As described above, the conventional method described above is difficult to control the reaction, requires highly pure formic acid, and furthermore, when performing this cyclization reaction, there is a dehydration reaction as a side reaction and the separation of the bisabolol and formic acid produced. Since the production of water due to the esterification reaction of It has problems that make it difficult to adopt as an industrial production method, such as the need for a strict dehydration and purification process.

The present inventors have conducted intensive research to improve the conventional method of producing bisabolol by cyclizing nerolidol in the presence of formic acid and then hydrolyzing the product into an industrially applicable production method. If the cyclization reaction is carried out in the presence of a nonpolar solvent with a dielectric constant of 3.0 or less measured at 20°C, it is possible to use formic acid with a water content of up to about 30% by weight, and the reaction can be controlled. They found that bisabolol can be obtained easily and in good yield, leading to the completion of the present invention.

Examples of nonpolar solvents with a dielectric constant of 3.0 or less used in the present invention include pentane, hexane, heptane, octane, nonane, decane, hexadecane,
Aliphatic saturated hydrocarbons having 5 to 30 carbon atoms such as icosane and squalane; cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane, ethylcyclohexane, cycloheptane,
Alicyclic saturated hydrocarbons such as cyclooctane; halogenated hydrocarbons such as dichloromethane, dichloroethane, tetrachlorethylene, carbon tetrachloride; benzene, toluene, xylene, ethylbenzene,
Examples include aromatic hydrocarbons such as propylbenzene and dichlorobenzene, among which hexane,
Preferred are heptane, cyclopentane, cyclohexane, ethylcyclohexane, benzene, toluene, xylene, and the like. These solvents may be used alone or in combination.
It can be used in mixtures of more than one species. The amount of solvent used is approximately 0.5 to 10 times the weight of nerolidol.
Preferably it is about 1 to 4 times the weight.

If the cyclization reaction of nerolidol according to the method of the present invention is carried out at a temperature range of about 0 to 50°C, the excessive reaction rate can be suppressed, and the formation of falnetucel, bisabolene, etc. due to dehydration reaction can be suppressed, resulting in a good yield. A formate of bisabolol or a mixture of formate of bisabolol and bisabolol is obtained. In addition, when the cyclization reaction is carried out in the presence of hydrated formic acid with a water content of up to about 30% by weight, the formic acid ester of bisabolol or its and bisabolol can be obtained in good yield. The amount of formic acid used is preferably about 5 to 20 times the molar amount of nerolidol. Most of the bisabolol produced by this cyclization reaction is usually converted into an ester by reacting with formic acid.

After the cyclization reaction, for example, by separating an organic layer containing bisabolol formate or a mixture of this and bisabolol from the reaction mixture, washing with water as necessary, and then distilling off the solvent from this organic layer. A crude product of the formate ester of bisabolol or a mixture thereof with bisabolol can be obtained. This crude product or the above organic layer is subjected to the next hydrolysis reaction.

Bisabolol can be obtained by hydrolyzing the formic acid ester of bisabolol obtained by the cyclization reaction according to a conventional method. This hydrolysis reaction is carried out at room temperature or in the presence of an aqueous solution of a basic substance such as sodium hydroxide, potassium hydroxide, barium hydroxide, or sodium carbonate, if necessary, in the same solvent used in the cyclization reaction. The reaction is carried out at a temperature up to the boiling point of the solvent. When carrying out the hydrolysis reaction in the presence of the same solvent as used in the cyclization reaction, benzyltrimethylammonium chloride, tetrapentylammonium chloride, lauryltrimethyl chloride,
lauryldimethylethylammonium chloride,
Quaternary salts such as cetyltrimethylammonium bromide, benzylcetyldimethylammonium chloride, stearyltrimethylammonium chloride, stearyldimethylethylammonium bromide, etc.
grade ammonium salt; tetra n-butylphosphonium bromide, methyltri n-butylphosphonium bromide, ethyltri n-butylphosphonium bromide, benzyltri n-butylphosphonium chloride, lauryltri n-butylphosphonium bromide, cetyltri n-butylphosphonium bromide, stearyltri n-butylphosphonium bromide A phase transfer catalyst such as a quaternary phosphonium salt such as butylphosphonium bromide was applied to the formate ester of bisabolol at approximately
Preferably, it is used in an amount of 0.01 to 10 mol%. After completion of the reaction, for example, the reaction mixture is separated, the organic layer containing bisabolol is washed with water, dried, and if necessary, the solvent is distilled off from this organic layer to obtain an oil containing bisabolol. Bisabolol can be separated and obtained from this oil by a commonly used separation method such as distillation.

Hereinafter, the present invention will be specifically explained with reference to Examples.

Example 1 11.2 g of nerolidol, 28.7 g of 80% pure formic acid, and 19.7 g of n-hexane were placed in a 100 ml three-necked flask equipped with a thermometer, condenser, and stirrer, and heated to 50°C in a water bath. Stirred for 3 hours. After the reaction was completed, the reaction mixture was separated, and the upper layer was washed twice with an equal volume of water, then charged into the same reaction apparatus, and 15.5 g of a 30% aqueous sodium hydroxide solution and 0.09 g of benzyltrimethylammonium chloride were added. The mixture was stirred at 70°C for 2 hours. After the reaction was completed, the reaction mixture was separated, and the upper layer was washed with water, and anhydrous sodium sulfate was added thereto, and the mixture was left overnight to dry. N-hexane was distilled off from the liquid obtained by passing through a drying agent to obtain 11.0 g of a residue. When this product was analyzed by GLC using paranitrotoluene as an internal standard, it was found that 3.6 g of bisabolol and 2.9 g of fuarnesol were found.
g, bisabolene 1.5 g, farnetsen 0.4 g, and unreacted nerolidol 0.11 g. The yield of bisabolol was 32.5% based on the reacted nerolidol.

Comparative Example 1 In the same reaction apparatus as in Example 1, 11.2 g of nerolidol and 25.5 g of formic acid with a purity of 90% were charged.
Stirred at room temperature for 7 hours. After the reaction was completed, the reaction mixture was separated, and the upper layer was washed twice with an equal volume of water, then charged into the same reactor, and 15.5 g of a 30% aqueous sodium hydroxide solution was added, followed by stirring at 70°C for 2 hours. . After the reaction was completed, the reaction mixture was separated, and the lower layer was extracted with 20 ml of diethyl ether three times in a total of 60 ml.
After mixing the ether layer and the upper layer, anhydrous sodium sulfate was added to the mixture, and the mixture was left overnight to dry. Ether was distilled off from the liquid obtained by passing through a desiccant to obtain 11.1 g of a residue. GLC analysis of this product in the same manner as in Example 1 revealed that it contained 2.8 g of bisabolol, 2.4 g of falnesol, 0.95 g of bisabolene, 0.36 g of falnetsen, and 0.35 g of unreacted nerolidol. The yield of bisabolol is based on the reacted nerolidol.
It was 25.8%.

Example 2 Into the same reactor as in Example 1 were added 11.2 g of nerolidol, 23.5 g of 98% pure formic acid, and toluene.
22.4 g was charged and stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was separated and the upper layer was washed twice with an equal volume of water, and then charged into the same reactor, with a concentration of 40%
Add 6.7g of sodium hydroxide aqueous solution and 0.09g of benzyltrimethylammonium chloride, and 70℃
After heating to , the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was separated, and the organic layer was treated in the same manner as in Example 1, and then the toluene was distilled off to obtain 10.8 g of a residue. When this product was analyzed by GLC in the same manner as in Example 1, it was found that 4.27 g of bisabolol, 3.61 g of falnesol, and 3.61 g of bisabolene were found.
It contained 0.57 g, 0.34 g of farnetsen, and 1.21 g of unreacted nerolidol. The yield of bisabolol is 43.2 based on the reacted nerolidol.
It was %.

Example 3 In the same reaction apparatus as in Example 1, 11.2 g of nerolidol, 23.5 g of formic acid with a purity of 98%, and 33.2 g of carbon tetrachloride were charged, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was separated, and the organic layer (lower layer) was washed twice with an equal volume of water, and then carbon tetrachloride was distilled off from it using an evaporator. This residue was added to the above reactor using a 30% aqueous sodium hydroxide solution.
The mixture was charged with 15.5 g of the liquid and stirred for 2 hours while heating to 70°C. After the reaction is complete, separate the reaction mixture,
After washing the organic layer (upper layer) with water, it was dried in the same manner as in Example 1. After drying, this organic layer was prepared in Example 1.
GLC analysis was performed in the same manner as above. Bisabolol 4.20g, Falnesol 3.70g, Bizabolene 1.10g, Falnetsen 1.10g and unreacted nerolidol 1.22g
was included. The yield of bisabolol was 42.3% based on the reacted nerolidol.

Example 4 11.2 g of nerolidol, 28.7 g of formic acid with a purity of 80%, and 33 g of cyclohexane were charged into the same reactor as in Example 1, and stirred for 3 hours while heating to 50°C. After the reaction is completed, the reaction mixture is separated, and the upper layer is washed twice with an equal volume of water, then charged into the same reaction apparatus, and further added with a 30% aqueous sodium hydroxide solution.
15.5 g and 0.09 g of benzyltrimethylammonium chloride were added, and the mixture was stirred at 70°C for 2 hours. After the reaction was completed, the reaction mixture was separated and the upper layer was washed with water, and anhydrous sodium sulfate was added thereto, followed by drying by standing overnight. Cyclohexane was distilled off from the liquid obtained by passing through a desiccant, and the residue was subjected to GLC analysis in the same manner as in Example 1. It contained 4.51 g of bisabolol, 3.91 g of falnesol, 0.63 g of bisabolene, 0.36 g of farnetsen, and 0.33 g of unreacted nerolidol. The yield of bisabolol is based on the reacted nerolidol.
It was 41.9%.

Example 5 11.2 g of nerolidol, 23.5 g of formic acid with a purity of 98%, and 26 g of squalane were charged into the same reactor as in Example 1, and the mixture was stirred at room temperature for 0.5 hour. After the reaction was completed, the reaction mixture was separated, and the upper layer was washed twice with an equal volume of water, then charged into the same reactor, and 15.5 g of a 30% aqueous sodium hydroxide solution was added.
The mixture was stirred for 2 hours while heating to 70°C. After the reaction was completed, the reaction mixture was separated and the upper layer was washed with water.
It was dried with anhydrous sodium sulfate. Squalane was distilled off from the liquid obtained by passing through a desiccant, and the residue was subjected to GLC analysis in the same manner as in Example 1. It contained 3.56 g of bisabolol, 2.73 g of farnesol, 0.2 g of bisabolene, 0.32 g of farnetsen, and 0.25 g of unreacted nerolidol. The yield of bisabolol is based on the reacted nerolidol.
It was 32.1%.

Example 6 In the same reaction apparatus as in Example 1, 11.2 g of nerolidol, 23.5 g of formic acid with a purity of 98%, and 21 g of tetrachlorethylene were charged and stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was separated, and the organic layer (lower layer) was washed twice with an equal volume of water, and then tetrachlorethylene was distilled off using an evaporator. This residue and 30% sodium hydroxide aqueous solution
15.5 g was charged into the same reactor and stirred for 2 hours while heating to 70°C. After the reaction was completed, the reaction mixture was separated, and the organic layer (upper layer) was washed with water and then dried in the same manner as in Example 1. After drying, this organic layer was subjected to GLC analysis in the same manner as in Example 1. bisabolol
4.35g, Falnesol 3.45g, Bisabolene 0.58
g, 0.39 g of farnetsen and 0.58 g of unreacted nerolidol. The conversion rate of nerolidol and the yield of bisabolol based on the reacted nerolidol were 94.8% and 38.8%, respectively.

Comparative Example 2 Into the same reactor as in Example 1, 11.2 g of nerolidol and 27.09 g of formic acid with a purity of 85% were charged.
Stirred at room temperature for 5 hours. After the reaction was completed, the reaction mixture was separated, and the upper layer was treated in the same manner as in Comparative Example 1, and then subjected to a hydrolysis reaction. The resulting reaction mixture was treated in the same manner as in Comparative Example 1, and then subjected to GLC analysis.
It contained 2.74 g of bisabolol, 2.15 g of falnesol, 0.31 g of bisabolene, 0.28 g of falnetsen, and 4.39 g of unreacted nerolidol. The conversion rate of nerolidol and the yield of bisabolol based on the reacted nerolidol were 60.8%, respectively.
It was 24.7%.

Comparative Example 3 Into the same reactor as in Example 1, 11.2 g of nerolidol and 25.5 g of formic acid with a purity of 90% were charged.
The mixture was stirred for 1.5 hours while heating to 50°C. After the reaction was completed, the reaction mixture was separated, and the upper layer was treated in the same manner as in Comparative Example 1, and then subjected to a hydrolysis reaction. After treating the obtained reaction mixture in the same manner as in Comparative Example 1,
GLC analysis was performed. It contained 0.88 g of bisabolol and 3.23 g of bisabolene. Falnesol and unreacted nerolidol were not contained. The conversion rate of nerolidol and the yield of bisabolol were 100% and 7.85%, respectively.

Comparative Example 4 In the same reaction apparatus as in Example, 11.2 g of nerolidol, 23.5 g of formic acid with a purity of 98% and 20 ml of chloroform (inductivity: 5.05) were charged and stirred at room temperature for 5 hours.

After the reaction was completed, the reaction mixture was separated and the lower layer was washed twice with an equal volume of water, and then chloroform was distilled off using an evaporator to obtain 11.0 g of a residue. This product was charged into the same reactor and subjected to a hydrolysis reaction in the same manner as in Comparative Example 1. The resulting reaction mixture was treated in the same manner as in Comparative Example 1 and then subjected to GLC analysis.

Bisabolol 2.42g, Falnesol 2.11g,
It contained 0.45 g of bisabolene, 0.43 g of farnetsen, and 4.6 g of unreacted nerolidol. The conversion rate of nerolidol and the yield of bisabolol were 58.5% and 21.6%, respectively.

Claims (1)

[Claims] 1 3,7,11-trimethyldodeca-1,6,10
- cyclizing trien-3-ol in the presence of formic acid and then hydrolyzing the product to produce bisabolol, carrying out the cyclization reaction in the presence of a nonpolar solvent with a dielectric constant of 3.0 or less; A method for producing bisabolol, characterized by: