JPS60120828A - Production of bisabolol - Google Patents

Abstract

PURPOSE:To obtain industrially and advantageously the aimed compound, by carrying out cyclization reaction in a specific nonpolar solvent in producing bisabolol useful as an anti-inflammatory agent, etc., by cyclizing nerolidol in the presence of formic acid, and if necessary hydrolyzing the reaction product. CONSTITUTION:3,7,11-Trimethyldodeca-1,6,10-trien-3-ol (nerolidol) is cyclized in a nonpolar solvent, preferably hexane, heptane, cyclopentane, cyclohexane, ethylcyclohexane, benzene, toluene or xylene having <=3.0 dielectric constant measured at 20 deg.C in the presence of formic acid preferably at about 0-50 deg.C, and the resultant reaction product is if necessary hydrolyzed to afford the aimed bisabolol in high yield. According to the method, formic acid with up to about 30wt% moisture content can be used, and the formic acid after recovery can be reused. The reaction is easily controlled.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing bisabolol, and in detail, 3.
7.11-) Limethyldodecar 1.6.10-) Dien-5-ol (nerolidol) is cyclized in the presence of formic acid and then optionally hydrolyzed to produce bisabolol. , the cyclization reaction is carried out with a dielectric constant of 3.
The present invention relates to a method for producing bisabolol, characterized in that it is carried out in the presence of a non-polar solvent of 0 or less.

Bisabolol is a monocyclic unsaturated tertiary sesquiterpene 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, and lotions, or in toothpaste and gargles. It is not only used in oral hygiene products such as medicines, but also as a preservative for mixed fragrances because of 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, C, D.

GUTSCHE et al. used farnesol or nerolidol in a very dilute state of several percent by weight relative to formic acid, and found that differences in reaction time, reaction temperature, water content of formic acid, and starting alcohol were used to determine the rate of the cyclization reaction and the product yield. 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) Purity 1
When 00% formic acid is used, the reaction is very fast at a reaction temperature of 30°C, and the amount of monocyclic products such as bisabolol and bisabolene produced reaches its maximum in just 1 minute after the start of the reaction.
(4)) Lance, trans-
When 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.
After that, it decreases, but the total concentration of monocyclic products such as bisabolol and bisabolene in the product increases rapidly, reaching the maximum after about 10 minutes (Tet-
rahedron, Vol, 24. pp, 859
~876 (1968)].

In addition, the present inventors investigated this conventional method under various reaction conditions and found that when nepridol 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 temperature of about 4.

In this way, the above conventional methods have difficulties in controlling the reaction;
In addition, highly purified formic acid is required, and when performing this cyclization reaction, it is impossible to avoid the side reactions of dehydration and the production of water due to the esterification reaction between the bisabolol and formic acid produced. Since water and formic acid form an azeotropic composition, a rigorous dehydration and purification process is required in order to recover and reuse the formic acid that contains produced water and was used in large quantities in the reaction. This method has problems that make it difficult to adopt as a standard manufacturing method.

The present inventors cyclized nerolidol in the presence of formic acid,
Then, as a result of intensive research to improve the conventional method of producing bisabolol by hydrolyzing the product as needed into an industrially applicable production method, the cyclization reaction was carried out at 20°C.
When the reaction is carried out in the presence of a nonpolar solvent with a dielectric constant of 3.0 or less, it is possible to use formic acid with a water content of up to about 30%, and the reaction can be easily controlled. Moreover, they discovered that bisabolol can be obtained in good yield, and have completed 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, itane, cyclohexane, methylcyclohexane, ethylcyclohexane,
Alicyclic saturated hydrocarbons such as Schifkyohebutane and cyclooctane; aromatic hydrocarbons such as dichloromethluene, xylene, ethylbenzene, furobylbenzene, and dichlorobenzene; among them, hexane, heptanecyclopentane, Preferred are cyclohexane, ethylcyclohexane, benzene, toluene, and xylenato. These solvents can be used alone or in a mixture of two or more. The amount of solvent used is approximately 0.5 to nerolidol.
~10 times the weight, preferably about 1 to 4 times the weight.

The cyclization reaction of nepridol according to the method of the present invention is about 0 to 50
If carried out in the temperature range of °C, the excessive reaction rate can be suppressed, and the production of farnetsene, bisapolene, etc. due to dehydration reaction can be suppressed, and bisabolol formate or bisabolol formate and bisabolol can be combined in good yield. A mixture is obtained. In addition, the cyclization reaction is carried out at a water content of about 5
When carried out in the presence of up to 0% by weight of hydrated formic acid, bisabolol formate or a mixture of bisabolol and bisabolol can be produced in good yield in several tens of minutes to several hours without significantly reducing the reaction rate. Obtainable. 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, an organic layer containing bisabolol formate or a mixture of this and bisabolol is separated from the reaction mixture, washed with water as necessary, and then the solvent is distilled off from this organic layer. A crude product of the formate ester of yosibisabolol 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, tetrahentylammonium chloride, lauryltrimethylchloride, lauryldimethylethylammonium chloride, Cetyltrimethylammonium bromide, benzylcetyldimethylammonium chloride,
Quaternary ammonium salts such as stearyltrimethylammonium chloride 1, stearyldimethylethylammonium bromide; tetra n-butylphosphonium bromide, methyltri n-butylphosphonium bromide, ethyltri n-butylphosphonium bromide, benzylt IJ
n-Butylphosphonium chloride, lauryltri n-
A phase transfer catalyst such as a quaternary phosphonium salt such as butylphosphonium bromide, cetyltri n-butylphosphonium bromide, stearyltri n-butylphosphonium bromide, etc. is applied to the formate ester of bisabolol at about 0.0%.
It is preferable to use 0.01 to 10 mol. After the reaction is complete,
For example, the oil containing bisabolol can be obtained by separating the reaction mixture, washing the organic layer containing bisabolol with water, drying, and then distilling off the solvent from this organic layer, if necessary. 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 using Examples.

Example 1 Nerolidol 11.29. 28.79 g of formic acid with a purity of 80% and 19.7 g of n-hexane were charged, and the mixture was stirred for 3 hours while being heated to 50° C. in a water bath. After completion of the reaction, one reaction mixture was separated, and the upper layer was washed twice with equal volumes of water, then charged into the same reaction apparatus, and further added with 30% sodium hydroxide aqueous solution 15.54F and benzyltrimethylammonium chloride 0.099%. The mixture was added and 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 leaving overnight. N-hexa/ was distilled off from the p liquid obtained by filtration with a drying agent to obtain a residue of 11.09%.

This was analyzed by GLC using para-nitrotoluene as an internal standard.
As a result of analysis, bisabolol 5.6g, farnesol 2.99g. It contained 1.5 g of bisabolene, 0.49 g of farnetsene, and 0.11 g of unreacted nerolidol. The yield of bisabolol was 32.5 cm based on the reacted nerolidol.

Comparative Example 1 Nerolidol 11 was added to the same reactor as in Example 1.
．． Prepare 2.5.5g of formic acid with 21F and purity of 90%,
The mixture was 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 reaction apparatus, and further added with 4C 30% sodium hydroxide aqueous solution 15. ．． 51F was added and stirred at 70°C for 2 hours. After the reaction was completed, the reaction mixture was separated, and the lower layer was extracted with diethyl ether/L-20yrt 5 times in a total of 60 ml. After the ether layer and the upper layer were mixed, anhydrous sodium sulfate was added to the mixture. The mixture was added and left overnight to dry. Ether was distilled off from the filtrate obtained by filtering the desiccant, and residue 1
1.19 was obtained. This product was prepared in the same manner as in Example 1 and GL
C analysis revealed that it contained 2.8 g of bisabolol, 2.4 g of farnesol, 0.95 Q of bisabolene, 0.56 Q of farnesene, and 0.35 g of unreacted nerolidol. The yield of bisabolol was 25.8% based on the reacted nerolidol.

Example 2 Nerolidol 11 was added to the same reactor as in Example 1.
．． 2g, 98% pure formic acid 23.51F and toluene 2
2.49 was added 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 equal volumes of water, and then charged into the same reactor, and 6.7 g of aqueous sodium 40 thihydroxide solution and 0.099 of penzyltrimethylammonium chloride were added. After the mixture was added and heated to 70°C, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was separated into layers, and the organic layer was treated in the same manner as in Example 1, and then citoluene 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, bisabolol 4.27f, farnesol 3
．． 619, bisapolene 0.579, farnessen 0.
It contained 54 g and unreacted nerolidol 1.211F. The yield of bisabolol was 43.2% based on the reacted nerolidol.

Example 3 Nerolidol 11 was added to the same reactor as in Example 1.
．． 2 g, 98% pure formic acid 25.59 and carbon tetrachloride 5
5.29 and 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 the carbon tetrachloride was distilled off using an evaporator.

This residue was charged into the above reaction apparatus along with 15.5 g of a 50% aqueous sodium hydroxide solution, 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 subjected to GL treatment in the same manner as in Example 1.
C was analyzed. Bisabolol 4.20g, Farnesol 3.7Of, Bisabolene 1.1Of, Farnetsen 1
．． 109 and unreacted nerolidol 1.229. The yield of bisabolol was 42.3% based on the reacted nerolidol.

Example 4 Nerolidol 11 was added to the same reactor as in Example 1.
．． 2f, 28.79 g of formic acid with a purity of 80 g, and 3 q of cyclohexane were added, and the mixture was stirred for 3 hours while heating to 50°C. 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 further added with 15.51F of 30 sodium hydroxide aqueous solution and 0.099 of benzyltrimethylammonium chloride. The mixture was added and stirred at 70°C for 2 hours. After the reaction was completed, the reaction mixture was separated into layers, the upper layer was washed with water, anhydrous sodium sulfate was added thereto, and the mixture was dried by standing overnight. Dicyclohexane was distilled off from the furnace liquid obtained by adding a drying agent, and the residue was analyzed by GLC in the same manner as in Example 1. It contained 4.51f of bisabolol, 3.91f of farnesol, 0.659 of bisabolene, 0.369 of farnetsen, and 0.539 of unreacted nerolidol. The yield of bisabolol is 41% based on the reacted nerolidol. q
It was 'lr.

Example 5 Nerolidol 11 was added to the same reactor as in Example 1.
．． 21i1. 25.59 g of formic acid with a purity of 98% and 26 g of squalane were charged and stirred at room temperature for 0.5 hour. After the reaction was completed, one reaction mixture was separated, and the upper layer was washed twice with an equal volume of water, then charged into the same reactor, and 50% sodium hydroxide aqueous solution (15.59%) was added and heated to 70°C. While stirring, the mixture was stirred for 2 hours.

After the reaction was completed, the reaction mixture was separated, and the upper layer was washed with water and then dried over anhydrous sodium sulfate. Cisqualane was distilled off from the p liquid obtained by filtering the desiccant, and the residue was analyzed by GLC in the same manner as in Example 1.

Bisabolol 5.569, farnesol 2.73g,
It contained 0.2 f of bisabolene, 0.52 g of farnetusene, and 0.259 unreacted nerolidol.

The yield of bisabolol was 32.1% based on the reacted nerolidol.

Example 6 Nerolidol 11 was added to the same reactor as in Example 1.
．． 2 g, 23.59 g of formic acid with a purity of 98%, and 21 g of tetrachloroethylene were charged, and the mixture was stirred at room temperature for 5 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 15.59 g of an aqueous sodium 50 hydroxide solution were 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 analyzed by GLC in the same manner as in Example 1. Bisabolol 4.
55f, farnesol 3.45f, bisabolene 0.5
8f, farnetsen 0.59 Q and rJ unreacted nerolidol 0.589 were contained. The conversion rate of nerolidol and the yield of bisabolol based on the reacted nerolidol were 94.8% and 58.8%, respectively.

Comparative Example 2 Nerolidol 11 was added to the same reactor as in Example 1.
．． 29 and 27.099% of formic acid with a purity of 85% were charged, and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, one 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. bisabolol 2.749,
Farnesol 2.15f% bisabolene Q, 5j'l,
Farnetsen 0.289 and unreacted nerolidol 4
．． 399 were included. The conversion rate of nerolidol and the yield of bisabolol based on the reacted nerolidol were 6o, a%, and 24.7%, respectively.

Comparative Example 3 Nerolidol 11 was added to the same reactor as in Example 1.
．． Prepare 21F and 25.5f of formic acid with a purity of 90%,
The mixture was stirred for 1.5 hours while warming to 0°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 0.889 bisabolol and 5.239 bisabolene. Farnesol and unreacted nerolidol were not included. The conversion rate of nerolidol and the yield of bisabolol are each 100 Ti,
It was 7.85%.

Patent applicant Rishi Co., Ltd. Agent: Patent Attorney Ken Fuyo

Claims (1)

[Claims] 3.7.11-) Limethyldodecar 1.6.10-)
When dien-5-ol is cyclized in the presence of formic acid and then optionally hydrolyzed to produce bisabolol, the nuclear cyclization reaction is carried out in a non-polar solvent with a dielectric constant of 5.0 or less. A method for producing bisabolol, characterized by carrying out in the presence of bisabolol.