JPS6136752B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on Demol et.al. [Helv.Chim.Acta.
55, 1866 (1972)], or the following formula useful as a flavoring substance found in Burley leaf tobacco by Fujimori et al.
(1), However, in the formula, 〓 indicates the presence of trans and cis isomer bonds, and the known compound 4-(2-butenylidene)-3,5,5-trimethyl-2 can exist in the form of four isomers represented by - Concerning the new compound of formula (2) below, which is useful for the production of cyclohexen-1-one, and its production method, it is possible to use inexpensive raw materials with easier reaction operations and a shortened synthetic route compared to conventionally proposed synthesis methods. The present invention relates to a compound of formula (2) useful for industrially advantageously obtaining the compound of formula (1) in high yield and purity, and a method for producing the same.

More specifically, in addition to being useful as a synthetic intermediate for the compound of formula (1), the present invention itself exhibits a sweet, musky, and powdery odor reminiscent of orris, and is capable of imparting or modulating a persistent odor. The following formula (2), which is also useful as an agent, The present invention relates to 4-(1-hydroxy-2-butenyl)-3,5,5-trimethyl-2-cyclohexen-1-one, which has not been described in any prior art literature, and its production method and utilization.

Furthermore, the present invention provides the following formula (3) useful for the synthesis of the above formula (2) compound: 3,5,5-, which is not described in the conventionally known literature, represented by
Trimethyl-1-trimethylsiloxy-1,3-
It also relates to cyclohexadiene and its production method.

Conventionally, for the production of the compound of formula (1) above, for example, a production method shown by the following formula has been proposed.

(i) USP No. 3268589: − (ii) Helv.Chim.Acta., 57, 2087 (1974): − (iii) Bull.Chem.Soc.Jap. 52 , 1233 (1979): − These conventional proposals require expensive and difficult-to-obtain starting materials, require reaction reagents that are disadvantageous in operation, require disadvantageous multiple steps and complicated operations, and have low yields and It is not suitable for industrial implementation due to the following drawbacks. For example, proposal (i) above requires several steps to synthesize dehydroionone, is expensive, and has drawbacks such as poor rearrangement reaction yield of alcohol;
Even in this proposal, several steps are required to produce the above starting material from isophorone, the use of reaction reagents that are disadvantageous in operation is required, and the product has the desired formula (1).
Containing three types of compounds other than the compound, there are drawbacks such as complicated separation and low yield of the target product.Furthermore, in the proposal (iii) above, the raw material dimedone is expensive and difficult to obtain. It has drawbacks such as the need for frequent use of reaction reagents, which is disadvantageous in operation.

The present inventors have developed the formula (1) 4-(2-butenyline)- which overcomes the defects and disadvantages of the conventional proposals.
3,5,5-trimethyl-2-cyclohexene-
Research was conducted to provide a method for producing 1-one.

As a result, the following formula (4) The compound 4-(1-hydroxy-2- Butenyl)-3,5,5-trimethyl-2-cyclohexen-1-one can be easily produced in a good yield, and the compound of formula (1) can be produced by dehydrating the compound of formula (2). It was discovered that it can be produced with high yield.

Moreover, the compound of formula (2) itself exhibits a sweet, whey, and powdery odor reminiscent of orris, and is persistent, and is unique and noteworthy in the prior art as a persistent aroma flavor imparting or modulating agent. It has been discovered that this compound, which has not yet been described, is useful in a wide range of fields including cosmetics, food and drink (including tobacco and other luxury goods), and health and hygiene/pharmaceuticals.

Furthermore, the compound of formula (2) is converted from isophorone to the compound of the formula
It can be easily produced via 3,5,5-trimethyl-1-trimethylsiloxy-1,3-cyclohexadiene shown in (3), which has not been described in the conventional literature, and is thus more effective than the conventional proposal. It has been found that the compound of formula (1) can be industrially advantageously produced with high yield and high purity from inexpensive and easily available raw materials through easy reaction operations and three shortened steps.

Therefore, an object of the present invention is to obtain a compound of formula (2)4 which is useful as an intermediate for a new method for producing the compound of formula (1) above, and which is itself useful as a long-lasting aroma imparting or flavor modulating agent. -(1-hydroxy-2-
An object of the present invention is to provide (butenyl)-3,5,5-trimethyl-2-cyclohexen-1-one and its production and use.

Still another object of the present invention is to provide 3,5,5-
Trimethyl-1-trimethylsiloxy-1,3-
The present invention provides cyclohexadiene and a method for producing the same.

The above objects and many other objects and advantages of the present invention will become more apparent from the following description.

Using the novel compound of formula (2) of the present invention, the following formula (2), By dehydrating 4-(1-hydroxy-2-butenyl)-3,5,5-trimethyl-2-cyclohexen-1-one represented by
The following formula (1), However, in the formula, 〓 indicates the presence of trans and cis isomer bonds, which may exist in the form of four isomers represented by 4-
(2-butenylidene)-3,5,5-trimethyl-
A method for producing 2-cyclohexen-1-one can be provided.

The formula (2) compound used in the above production method is, for example, the following formula (3), It can be formed by a condensation reaction between 3,5,5-trimethyl-1-trimethylsiloxy-1,3-cyclohexadiene and crotonaldehyde. This compound of formula (3) is also a compound that has not been described in any literature, and the compound (3) is
For example, the following formula (4), It can be obtained by isomerizing isophorone represented by and then subjecting it to a silylation reaction.

The production of a compound of formula (1) in a mode including the above mode of forming a compound of formula (2) from a compound of formula (4) above can be illustrated as follows.

In the above embodiment, the production of the compound of formula (3) from the compound of formula (4) is carried out, for example, by isomerizing isophorone of formula (4) by contacting it with an alkylmagnesium halide in the presence of a Lewis acid, and then, for example, This can be easily carried out by contacting trimethylhalosilane, such as trimethylchlorosilane, in the presence of a tertiary amine to carry out the silylation reaction.
This reaction may be carried out, for example, in the presence of a Lewis acid, preferably in an ethereal organic solvent, from about -80°C to about 50°C, more preferably from about -10°C to about 10°C.
Under temperature conditions such as °C for about 1 to 3 hours, formula (4)
This can be carried out by bringing isophorone and alkylmagnesium halide into contact, and then adding a tertiary amine, trimethylchlorosilane and an aprotic polar solvent under similar conditions, and allowing the mixture to come into contact for about 5 to about 48 hours. .

The amounts of alkylmagnesium halide and trimethylchlorosilane to be used relative to the isophorone can be selected as appropriate, but a preferred example is an amount of about 1 to about 2 moles relative to 1 mole of isophorone. Further, the amount of the tertiary amine to be used can be selected as appropriate, and a preferable example is about 0.1 to about 1 mole per mole of isophorone. Furthermore, the amount of the Lewis acid to be used is preferably about 0.01 to about 0.5 mol per 1 mol of isophorone.

Examples of the ether organic solvent used in the reaction include diethyl ether, dipropyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, and any combination thereof. Examples of the alkylmagnesium halides include methylmagnesium chloride, methylmagnesium bromide, methylmagnesium iodide, ethylmagnesium chloride,
Examples include ethylmagnesium bromide. Further, as an example of the Lewis acid, ferric chloride can be exemplified. Furthermore, examples of the above-mentioned tertiary amine include trimethylamine, triethylamine, tripropylamine, tributylamine, pyridine, N,N-dimethylaniline, etc., and examples of the above-mentioned aprotic polar solvent include: Examples include N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, and the like.

For example, the compound of formula (3), which is an oily substance with a boiling point of about 89 to 90°C/18 mmHg that has not been described in the literature, can be easily formed by a condensation reaction with crotonaldehyde. 4-(1-hydroxy-2-butenyl)- of the above formula (2)
3,5,5-trimethyl-2-cyclohexene-
It can be converted to 1-one.

This reaction is carried out, for example, in the presence of a Lewis acid, preferably in a halogenated organic solvent, for example at about -80
°C to about 50 °C, more preferably about -60 °C to about -40 °C
This can be carried out by bringing the compound of formula (3) into contact with crotonaldehyde under low temperature conditions such as. The reaction time can be selected appropriately, for example, about 10
The contact time can be exemplified from minutes to about 10 hours, more preferably about 1 to 2 hours. Further, the amount of crotonaldehyde to be used relative to the compound of formula (3) can be appropriately selected, for example, about 1 to about 5 mol, more preferably about 1 to about 5 mol, per 1 mol of the compound of formula (3).
An example of the amount used is about 1.5 mol.
Furthermore, the amount of the Lewis acid to be used can be selected as appropriate, and may be about 0.1 to about 3 mol, more preferably about 1 mol, per 1 mol of the compound of formula (3).

Examples of the halogenated organic solvent used in the reaction include monochloromethane, dichloromethane, chloroform, carbon tetrachloride, monochloroethane, 1,2-dichloroethane, and mixtures thereof. Further, examples of Lewis acids include titanium tetrachloride, tin tetrachloride, aluminum chloride, zinc chloride, boron trifluoride diethyl ether complex, boron trifluoride acetic acid complex, and the like. After distilling off the solvent, the reaction product can be purified by vacuum distillation, column chromatography, or the like, if desired.

For example, 4-(1-hydroxy-2-butenyl)- of the formula (2), which has a boiling point of about 126 to 140°C/0.9 mmHg and which has not been described in any prior literature, can be obtained as described above.
3,5,5-trimethyl-2-cyclohexene-
1-one can exist in the form of two isomers (threo and erythro), and these isomers can be separated and purified by the purification means exemplified above. IR and NMR of these isomers are shown in Examples below. Also, the production ratio of isomers is approximately 45/
It is about 55-35/65.

According to the method of the present invention, 4-(1-hydroxy-2-butenyl)-3,5,5-trimethyl-2-cyclohexen-1-one of the formula (2), which can be obtained as described above, for example. By dehydrating , 4-(2-butenylidene)-3,5,5-trimethyl-2-cyclohexen-1-one of the formula (1) can be easily obtained in high yield.

This dehydration reaction is carried out, for example, in the presence of a tertiary amine, from about -80°C to about 80°C, more preferably at about 0°C.
℃ to about 30℃, for example, about 30 minutes to
This can be carried out by contacting the compound of formula (2) with a dehydrating agent for about 48 hours, more preferably about 2 to about 4 hours.

When carrying out the above dehydration reaction, the amount of the dehydrating agent to be used can be selected as appropriate, but for example, about 1 to about 10 mol, more preferably about 2 mol, per 1 mol of the compound of formula (2).
An example of the amount used is about 3 mol to about 3 mol. Further, the amount of the tertiary amine used can be selected as appropriate, for example, about 1 to about 30 mol per 1 mol of the compound of formula (2),
More preferably, the amount used is about 5 to about 10 moles.

Examples of the dehydrating agent include phosphorus oxychloride, methanesulfonyl chloride, paratoluenesulfonyl chloride, N-methyl-2-fluoropyridinium paratoluenesulfonate, N-methyl-2-chloropyridinium iodide, and the like. can. Examples of the tertiary amine include trimethylamine, triethylamine, tripropylamine, triisopropylamine, tributylamine, pyridine, and N,N-dimethylaniline.

The reaction product obtained as described above can be distilled under reduced pressure to obtain the compound of formula (1), but the purity can be improved by further treating the reaction product with a base.
This is a preferable embodiment for carrying out the method of the present invention, since the yield can be further improved.

According to this preferred embodiment, the reaction product obtainable as described above is prepared, preferably in an aromatic solvent, in the presence of a metal halide, for example at about 50°C.
Further contact with the base can be carried out under temperature conditions such as from about 150°C to about 150°C, more preferably from about 70 to about 80°C, for example for about 10 minutes to about 12 hours, more preferably about 1 hour. At this time, the amount of the metal halide to be used with respect to the reaction crude product is, for example, according to the formula (2).
An example of the amount used is about 0.01 to about 10 mol, more preferably about 0.1 to about 1 mol, per mol of the compound. In addition, the amount of the above base to be used is based on the formula
(2) The amount used can be, for example, about 1 mol to about 50 mol, more preferably about 2 to about 5 mol, per 1 mol of the compound.

Further, examples of the aromatic solvent used in carrying out the above preferred embodiment include benzene, toluene,
Examples include xylene. Examples of metal halides include sodium iodide and potassium iodide. Examples of the bases include 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,
2] Octane, 1,5-diazabicyclo[5,
4,0] undec-5-entriethylamine,
Examples include tripropylamine and pyridine.

After the solvent is distilled off and recovered, the reaction product can be purified, if desired, by means such as vacuum distillation or column chromatography. The compound of formula (1) consists of isomers, and these four isomers can be separated and purified by the above-mentioned purification means. The production ratio of isomers, and is approximately 10:50:5:35 to 15:40:15:30.

The compound of formula (2) of the present invention can be used in a wide range of ways as a persistent aroma and flavor imparting or modulating agent.
2-butenyl)-3,5,5-trimethyl-2-
Foods and drinks, including tobacco and other luxury goods, characterized by containing cyclohexen-1-one as an aromatic flavor component; 4-(1-hydroxy-2-butenyl)-3,5 of the compound of formula (2) , 5-trimethyl-2-cyclohexen-1-one as a fragrance component; soaps, detergents, and cosmetics containing 4-(1-hydroxy-2
-butenyl)-3,5,5-trimethyl-2-cyclohexen-1-one as an aromatic flavor component can be provided. For example, luxury goods such as tobacco; beverages such as juices, fruit alcoholic beverages, milk drinks, lactic acid bacteria drinks, carbonated drinks; frozen desserts such as ice creams and ice candy;
It imparts its unique aroma and flavor to various foods, including Japanese and Western sweets; jams; bread; chewing gum, coffee, cocoa, black tea, and other favorite foods; and various instant beverages and foods. Foods and beverages can be provided in appropriate amounts. In addition, for example, cosmetics containing shampoos, hair rinses, hair creams, pomades, other hair cosmetic bases; cosmetic soaps and other makeup/facial cleansing bases are blended with an appropriate amount to impart the unique fragrance. Can be provided.

Furthermore, its unique fragrance can be used in various health and hygiene products such as laundry detergents, disinfectant detergents, deodorant cleaning products, and other health and hygiene products; various health and hygiene materials such as toothpaste, tissue paper, and toilet paper, as well as pharmaceuticals. It is possible to provide health, sanitary, and pharmaceutical products that are blended or applied in an appropriate amount to impart flavor.

Hereinafter, an example of implementing the method of the present invention will be explained in more detail with reference to Examples.

Example 3 Synthesis of 5,5-trimethyl-1-trimethylsiloxy-1,3-cyclohexadiene: - 0.8 mol (19.5 g) of magnesium, 0.8 methyl bromide
mole (76 g), and anhydrous diethyl ether 350
Prepare methylmagnesium bromide from -10℃
Below, add 2.0g of ferric chloride and add 0.6g of isophorone.
A solution of mol (83 g) and 70 g of anhydrous diethyl ether is added dropwise over 30 minutes and stirred for 1 hour. Below 0℃,
Triethylamine 60ml, trimethylchlorosilane
100ml, and hexamethylphosphate triamide 60
ml and stir for an additional 24 hours. The reaction solution was poured into ice water and extracted with hexane. The organic layer is washed with a 5% aqueous potassium hydrogen sulfate solution and further with a 5% aqueous sodium hydroxide solution, and then dried over anhydrous magnesium sulfate. The solvent was recovered and the residual liquid was distilled under reduced pressure to a boiling point of 89℃.
Oil as fraction at ~90℃/18mmHg 3, 5, 5
-trimethyl-1-trimethylsiloxy-1,3
-101 g of cyclohexadiene (yield 80%) was obtained. IR: 1655, 1595, 850cm ^-1 , NMR (δ
TMSppm, inCCl ₄ ); 0.13 (s, 9H), 0.90
(s, 6H), 1.56 (m, 3H), 1.90 (m, 2H),
4.75 (m, 2H) 4-(1-hydroxy-2-butenyl)-3,
5,5-trimethyl-2-cyclohexene-1
Synthesis of -one: - 400 g of dichloromethane, 0.5 g of crotonaldehyde
mol (42 g), and 3,5,5-trimethyl-
To a solution of 0.45 mol (95 g) of 1-trimethylsiloxy-1,3-cyclohexadiene was added 0.45 mol (64
g) is added dropwise over 1 hour. After stirring under the same conditions for 2 hours, the mixture was poured into a cooled 5% aqueous sodium hydrogen carbonate solution. The aqueous layer is extracted with dichloromethane. The organic layer is dried over anhydrous magnesium sulfate. Collect dichloromethane and subject the residual liquid to distillation under reduced pressure to reduce the boiling point to 126.
Oily substance 4-(1
-hydroxy-2-butenyl)-3,5,5-trimethyl-2-cyclohexen-1-one 73g
(yield 78%). The above compound obtained here contains two types of diastereomers, which can be separated by silica gel column chromatography. (SiO ₂ solvent diethyl ether: hexane =
1:1) 32 g of isomer and 41 g of isomer were obtained.

Isomers: IR; 3450, 1650, 970cm ^-1 , NMR
(δTMSppm, inCCl ₄ ): 1.00 (s, 3H), 1.13
(s, 3H), 1.66 (d, 3H), 1.80 (d, 1H),
2.08 (d, 3H), 2.22 (d, 1H), 2.40 (d,
1H), 3.40 (brs, 1H), 4.45 (dd, 1H), 5.50
(m, 2H), 5.82 (brs, 1H), isomer: IR; 3370, 1645, 985cm ^-1 , NMR
(δTMSppm, inCCl ₄ ): 0.98 (s, 3H), 1.15
(s, 3H), 1.70 (dd, 3H), 1.93 (d, 3H), 1.6
~2.0 (m, 2H), 2.68 (d, 1H), 3.52 (brs,
1H), 4.55 (brs, 1H), 5.55 (m, 2H), 5.75
(brs, 1H), Synthesis of 4-(2-butenylidene)-3,5,5-trimethyl-2-cyclohexen-1-one (reference example); - 0.29 mol (33 g) of methanesulfonyl chloride and 1.2 mol of pyridine ( 95g) of 4-(1
Add 0.1 mol (20 g) of -hydroxy-2-butenyl)-3,5,5-trimethyl-2-cyclohexen-1-one, stir at 20°C for 2 hours, and pour into cold dilute hydrochloric acid. Extraction is performed with diethyl ether, and the ether layer is washed with a 5% aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The residual liquid recovered from the ether was added to a solution of 200 ml of toluene, 0.1 mol (15 g) of sodium iodide, and 0.3 mol (46 g) of 1,5-diazabicyclo[5,4,0]undec-5-ene, and the mixture was heated at 80°C. , stir for 1 hour. After cooling, pour into cold dilute hydrochloric acid and extract the aqueous layer with toluene. The organic layer is washed with a 5% aqueous sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. The toluene was collected, and the residual liquid was distilled under reduced pressure to obtain an oily substance 4 as a fraction with a boiling point of 110-118℃/1.5mmHg.
-(2-Butenylidene)-3,5,5-trimethyl-2-cyclohexen-1-one 13 g (yield 70
%) was obtained.

Gas chromatography (PEG20M, 200℃,
H ₂ 1.0Kg/cm ² , N ₂ 1.0Kg/cm ² ), the isomer,
The production ratio of , and was 15:45:10:30, and the following data were obtained by separation and purification by gas chromatography preparative separation.

Isomer IR; 1665, 1630, 1590, 730 cm ^-1 , NMR (δ
TMSppm, _inCCl4 ): 1.22 (s, 6H), 1.82
(d, 3H), 2.20 (s, 2H), 2.23 (d, 3H),
5.65 (m, 1H), 5.80 (brs, 1H), 6.30 (m,
1H), 6.45 (m, 1H), MSm/e; 190 (M ⁺ ),
175, 148, 147, 133, 122, 119, 105, 91, 79,
77, 69, 55, 41, 39 isomer IR; 1665, 1635, 1595, 970 cm ^-1 , NMR (δ
TMSppm, _inCCl4 ): 1.19 (s, 6H), 1.85
(d, 3H), 2.20 (s, 2H), 2.25 (d, 3H),
5.80 (brs, 1H), 5.80 (m, 1H), 6.17 (d,
1H), 6.45 (m, 1H), MSm/e; 190 (M ⁺ ),
175, 148, 147, 133, 122, 119, 105, 91, 79,
77, 69, 55, 41, 39, isomer IR; 1665, 1582, 725 cm ^-1 , NMR (δ
TMSppm, _inCCl4 ): 1.33 (s, 6H), 1.83
(d, 3H), 2.10 (d, 3H), 2.25 (s, 2H),
5.73 (m, 1H), 5.82 (brs, 1H), 6.55 (m,
1H), 6.68 (m, 1H), MSm/e; 190 (M ⁺ ),
175, 148, 147, 133, 122, 119, 105, 91, 79,
77, 69, 55, 41, 39 isomer IR; 1670, 1630, 1585, 968 cm ^-1 , NMR (δ
TMSppm, _inCCl4 ): 1.35 (s, 6H), 1.90
(d, 3H), 2.08 (d, 3H), 2.26 (s, 2H),
5.82 (brs, 1H), 5.90 (m, 1H), 6.45 (d,
1H), 6.70 (m, 1H), MSm/e; 190 (M ⁺ ),
175, 148, 147, 133, 122, 119, 105, 91, 79,
77, 69, 55, 41, 39.

Claims (1)

[Claims] 1. The following formula (2), 4-(1-hydroxy-2-butenyl)-3,5,5-trimethyl-2-cyclohexen-1-one represented by: 2 The following formula (3), The following formula (2) is characterized by a condensation reaction between 3,5,5-trimethyl-1-trimethylsiloxy-1,3-cyclohexadiene and crotonaldehyde represented by A method for producing 4-(1-hydroxy-2-butenyl)-3,5,5-trimethyl-2-cyclohexen-1-one represented by