JPH04279536A - Production of (s)-(-)-alpha-damascone and its new intermediate - Google Patents

Abstract

PURPOSE:To provide a new method for producing (S)-(-)-alpha-damascone, having fruity or floral aroma and flavor and useful as a material for compound perfumes used in foods or cosmetics and a new intermediate (S)-(-)-dehydro-alpha- damascol useful for producing the aforementioned compound. CONSTITUTION:New (R)-(+)-2,4,4-trimethyl-2-cyclohexen-1-ol expressed by formula I is selected as a starting raw material to synthesize (S)-(-)-alpha-damascone expressed by formula II in high yield and optical purity by carrying out reaction in 6 steps.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to a novel (s)-(-)-α-damascone which has a fruit-like or flower-like aroma and is useful as a material for mixed fragrances for food or cosmetics. Regarding the manufacturing method. Furthermore, the present invention provides (s)
-(-)-A novel intermediate useful for the production of α-damascone (
Also relates to s)-(-)-dehydro-α-damaskol.

0002

BACKGROUND OF THE INVENTION Conventionally, as far as the present inventors know, a method for producing (s)-(-)-α-damascone represented by formula (1) below has been disclosed in J. Am. Chem. Soc.
, Vol. 110, No. 20, 1988. Furthermore, the racemic form of the compound of formula (3) below, which is useful for the synthesis of the compound of formula (1) below, is known, but the substance specified for the compound of formula (3) has not been found in conventional literature. This is a new compound that has not been found before. In addition, in recent years, Ohloff et al. have confirmed that the absolute configuration of α-damascone in black tea is (S)-configuration.
It has been reported that the (S)-isomer has a significantly stronger aroma than the (R)-isomer ([Tetrahedron
22, 7003 (1989)].

0003

[Problems to be Solved by the Invention] However, although the reaction proposed above is complicated, the resulting products are (R)-(+)-α-damascone and (S)-( -)-α-damascone, and it is necessary to repeat recrystallization to increase the optical purity of each, and even with such operations, the optical purity is not necessarily satisfactory. Therefore, the following formula (1
) It is desired to establish a method for selectively producing only (S)-(-)-α-damascone represented by (S)-(-)-α-damascone.

0004

[Means for Solving the Problems] Therefore, the present inventors have conducted extensive research in order to solve the above problems. the result,
Novel (R)-(+)-2,4 represented by formula (7) below
, 4-trimethyl-2-cyclohexen-1-ol as a raw material, the following formulas (6), (5), (4), (3),
Through step (2), we succeeded in selectively synthesizing (S)-(-)-α-damascone of the present invention, represented by formula (1) below, with high optical purity. Therefore, the object of the present invention is to satisfy the following formula (1)
The present invention provides a novel method for producing the compound of formula (1) and a compound of the novel intermediate (3) useful for the synthesis of the compound of formula (1).

The method for producing the compound of formula (1) of the present invention can be represented by the reaction formula (A) shown below.

[0006]

embedded image In the formula, Bu represents a butyl group, and DMSO represents dimethyl sulfoxide.

The method for producing the compound of formula (1) according to the above reaction formula A will be explained in detail. First, to synthesize the compound of formula (6) from the compound of formula (7), the compound of formula (7) is reacted with tributylstannyl methyl iodide in an organic solvent in the presence of potassium hydride. This is done by letting

The compound of formula (7) used in this reaction is an invention entitled "Optically active 2,4,4-trimethyl-2-cyclohexen-1-ol and its production method" by the same applicant and filed on the same date. It can be easily synthesized by the method described in the specification of . Its outline can be shown, for example, by Reaction Formula B below.

[0009]

[Chemical formula 10]

In the formula, Ac2O represents acetic anhydride, and DMAP represents dimethylaminopyridine. That is, 2,4,4-trimethyl-2-cyclohexene represented by the formula (a) is obtained from ethyl vinyl ketone and isobutyraldehyde.
1-one is synthesized, this is reduced to lead to racemic 2,4,4-trimethyl-2-cyclohexen-1-ol represented by formula (b), and the racemic alcohol is converted to the conventionally known By adopting the acetate esterification reaction, the formula (
c) (±)-2,4,4-trimethyl-2-
It can be easily converted to cyclohexenyl acetate.

The racemic acetate thus obtained is asymmetrically hydrolyzed using an ester degrading enzyme such as porcine liver esterase or porcine pancreatic lipase.
Further purification by silica gel chromatography etc. gives 100% e. e. (enantio e
xcess: optical yield) of (R)-(+)-2,4,4
-trimethyl-cyclohexen-1-ol [formula (7)
compound] can be easily obtained.

In the reaction formula (A), the reaction for forming the compound of formula (6) is preferably carried out at a low temperature, usually in the range of, for example, about -10°C to +10°C. Although the reaction time can be selected as appropriate, about 3 to 5 hours is appropriate, for example.

The amount of potassium hydride used is, for example, about 1 to 1 mole of tributylstannyl methyl iodide.
It can be about 2 moles. It is convenient to use approximately 20% Nujol suspension, which is generally commercially available, as the potassium hydride. The appropriate amount of trimethylstannyl methyl iodide is, for example, about 1 to 2 moles per mole of the compound of formula (7). The organic solvent used in this reaction is often dimethyl sulfoxide, tetrahydrofuran, etc.
Any ordinary organic solvent can be used without being limited thereto. These solvents are used in an amount of, for example, about 5 to 20 times the weight of the compound of formula (7). After the reaction is complete, extract the product with a solvent such as ether,
It is concentrated and, if desired, purified by means such as column chromatography to obtain the compound of formula (6) in high yield and purity.

To synthesize the compound of formula (5) from the compound of formula (6) obtained as described above, the compound of formula (6) is reacted with n-butyllithium in an organic solvent. It can be done by This reaction, for example, is about -
The process is carried out at a temperature of about 20° C. to about -78° C. for about 1 to about 2 hours. The organic solvent used in this reaction is preferably, for example, tetrahydrofuran, and the amount used is not particularly limited, but for example, it is about 5 to 20 times the weight of the compound of formula (6) above. commonly used. In addition, the amount of n-butyllithium used is determined by the above formula (
The amount can be about 1 to 2 mol per 1 mol of the compound 6). After the reaction is completed, the reaction solution is poured into an aqueous ammonium chloride solution, the product is extracted with an organic solvent such as ether, concentrated, and optionally purified by column chromatography, etc. to obtain the above formula (5). The compound is obtained with high purity and good yield.

Next, to synthesize the compound of formula (4) above, the compound of formula (5) obtained above is mixed in an organic solvent,
This is carried out by oxidation reaction with dimethyl sulfoxide in the presence of oxalyl chloride. This reaction is preferably carried out at a low temperature of, for example, about -50°C to -78°C.
It takes about a minute. Oxalyl chloride has the above formula (5
) is used, for example, in an amount of about 1 to 3 mol per 1 mol of the compound. In addition, dimethyl sulfoxide has the above formula (5
) is used, for example, in an amount of about 1 to 10 moles per mole of the compound. Further, the organic solvent is preferably a solvent such as dichloromethane, and the amount used is often about 2 to 10 times the weight of the compound of formula (5) above. After the reaction is complete, an appropriate amount of alkali such as triethylamine is added to the reaction solution, the reaction product is extracted with an organic solvent such as ether, concentrated, and if desired purified by means such as column chromatography. , the compound of formula (4) above can be obtained with high purity and high yield.

To synthesize the compound of formula (3) from the compound of formula (4) obtained as described above, the compound of formula (4) is mixed with separately prepared propargyl magnesium halide in an organic solvent. This is done through a Grignard reaction. This reaction is carried out at about room temperature, for example, for about 1 to 2 hours. Tetrahydrofuran is used as the organic solvent, but any other organic solvent commonly used in Grignard reactions can be used. The amount of this solvent to be used is appropriately selected and used, but for example, a suitable range is about 1 to 10 times the weight of the compound of formula (4) above. Also,
Propargyl magnesium halide is used in an amount of, for example, about 1 to 10 mol per mol of the compound of formula (4). As propargyl magnesium halide,
Propargyl magnesium iodide is more preferred, but other halides may also be used. After the reaction is complete, pour the reaction solution into an aqueous ammonium chloride solution according to the usual method.
The compound of formula (3) is obtained with high purity and high yield by performing extraction, concentration and, if desired, purification by means such as column chromatography.

The above formula (2) from the compound of the above formula (3)
The synthesis of the compound of the above formula (
This is carried out by subjecting the compound of 3) to a hydrogenation reaction with a reducing agent in an organic solvent. The reducing agent used in this reaction is more preferably lithium aluminum hydride, but for example, R
ed-Al[Sodium bis(2-metho
xyethoxy)aluminumhydrox
Other reducing agents can also be used, such as IDE] (ALDRICH). The amount of these reducing agents to be used is, for example, about 1 to 10 to 1 mole of the compound of formula (3) above.
The range can be on the order of moles. The organic solvent is preferably tetrahydrofuran, but other organic solvents can also be used. It is more preferable to add an alkali such as sodium methoxide to the reaction system because the reaction is accelerated. The amount of such alkali to be used is determined by the above formula (3
), for example, about 1 to about 3 mol per mol of the compound. The reaction temperature and reaction time can be in the range of about 10 to 30 hours at about room temperature, for example. After the reaction is complete, the product is extracted with a solvent such as ether,
It is concentrated and optionally purified by means such as column chromatography to obtain the compound of formula (2) in high yield and purity.

The compound of formula (1) of the present invention is synthesized by subjecting the compound of formula (2) obtained above to an oxidation reaction in an organic solvent in the presence of an oxidizing agent. This oxidation reaction is usually carried out at a temperature of about 0 to about 50° C. for about 5 to 100 hours, although it depends on the type of oxidizing agent used. As the oxidizing agent, activated manganese dioxide is usually used, but other oxidizing agents such as PDC can also be used.
(Pyridium dichromate) etc. are also used. Acetone, methylene chloride, n-pentane, etc. are often used as organic solvents, and the amount of these solvents used is, for example, in a range of about 5 to about 20 times the weight of the compound of formula (2) above. Can be done. After the reaction is completed, the solvent is concentrated and
For example, by purifying by means such as column chromatography, the compound of the above formula (1) of the present invention can be purified to a high purity.
Obtained in high yield.

Hereinafter, several aspects of the present invention will be explained in more detail with reference to Reference Examples and Examples.

[Reference Example 1] Synthesis of 2,4,4-trimethyl-2-cyclohexen-1-one [compound of formula (a)] 75.0 g (892 mmol) of ethyl vinyl ketone and 96.4 g (1.34 mol) of isobutyraldehyde ) while keeping the mixture below 50°C and adding 2.25 m of concentrated sulfuric acid while stirring.
1 was added little by little. After stirring the mixture at room temperature for 5 hours, a Dean-Stark trap was attached and the reaction was carried out under reflux conditions for 16 hours. Distill the residue under reduced pressure, b
．． p. 86.2 g of 2,4,4-trimethyl-2-cyclohexen-1-one was obtained at 54-55° C./5 Torr.

[0020]

[Reference Example 2] Synthesis of (±)-2,4,4-trimethyl-2-cyclohexen-1-ol [compound of formula (b)] 18.5 g (486 mmol) of lithium aluminum hydride was dissolved in 800 ml of ether. This solution was cooled to 0°C while stirring, and 67.1 g (486 mmol) of the ketone body obtained in Reference Example 1 was added to 300 ml of ether.
was added dropwise. After stirring at 0° C. for 1 hour, water was added little by little to decompose the lithium aluminum hydride. After filtering and washing the solid matter, the filtrate is concentrated and the residue is distilled under reduced pressure; b. p. ,89~90℃/19Torr (±)-
62.8 g of 2,4,4-trimethyl-2-cyclohexen-1-ol was obtained.

[0021]

[Reference Example 3] Synthesis of (±)-2,4,4-trimethyl-2-cyclohexenyl acetate [compound of formula (c)] 61.5 g of racemic alcohol obtained in Reference Example 2
(439 mmol), acetic anhydride 67.3 g (659 mmol),
ol) and 77 ml of pyridine was cooled to 0°C while stirring, and 4.3 g of DMAP (35.2 mm
ol) was added little by little. After further stirring at 0°C for 1 hour, the reaction solution was poured into ice water and extracted with ether. The extract was washed with an aqueous copper sulfate solution, an aqueous sodium carbonate solution and a saline solution, dried over magnesium sulfate, the ether was recovered, and the residue was distilled under reduced pressure to obtain b. p. 82-84℃/10
．． (±)-2,4,4-trimethyl-2- at 5 Torr
75.7 g of cyclohexenyl acetate was obtained.

[0022]

[Reference Example 4] Synthesis of (R)-(+)-2,4,4-trimethyl-2-cyclohexen-1-ol [compound of formula (7)] 26.3 g (145 mmol) of compound of formula (c) was dispersed in 1.1 L of 0.1M phosphate buffer (ion-exchanged water: methanol = 8:2; pH 7.5), cooled to -10°C with vigorous stirring, and 50250 units of pig liver esterase (manufactured by Sigma) was dispersed. In addition, enzymatic degradation was performed for 65 hours. The reaction solution was saturated with common salt and ammonium chloride, and extracted three times with ether. The extract was washed with sodium carbonate and brine, dried over magnesium carbonate, ether was collected, and 27.5 g of the residue was purified by silica gel chromatography. As a result, 5.32 g of the compound of formula (7) (R)-(+)-2,4,4-trimethyl-2-cyclohexen-1-ol was obtained. The physical properties of this compound are b. p. 63-64℃/3Torr; [
α]D=+95.7°(21℃)(C=1.13, Me
OH); 100%e. e. Met.

[0023]

[Example 1]
,,(R)-(+)-2,4,4
,-trimethyl-2-cyclohexen-1-yl-tributyl stannyl methyl ether [compound (6)] 14.9 g of 20% KH (74.3 mmo
l), prepare 190 ml of THF and 48 ml of DMF,
This mixed solution was cooled with ice water, and (R)-(+)-2,4,4-trimethyl- of formula (7) was heated at 0°C while stirring.
8 g of 2-cyclohexen-1-ol (57.1 mmo
A solution of 1) dissolved in 57 ml of THF is added dropwise. 0℃
After stirring for 1 hour at the same temperature, Bu3SnCH2I32
．． Add 7 g (76 mmol) and react at room temperature for 2 hours with stirring. The reaction solution was poured into ice water and extracted with ether. After washing the ether layer with brine, it was dried over magnesium sulfate, the solution was concentrated using an evaporator, and the residue was purified by silica gel chromatography to obtain 19.5 g of the ether compound of formula (6).

[0024]

[Example 2] Synthesis of (S)-(-)-α-cyclogeraniol [compound of formula (5)] 19.5 g of the ether obtained in Example 1 was dissolved in THF.
Dissolve in 280 ml and cool the solution to -78°C. There, 36 ml of n-BuLi with a concentration of 1.66 M (57 m
mol) was added dropwise while maintaining the temperature at -78°C, and after stirring at the same temperature for 1 hour, the temperature was gradually raised to -20°C over a further 1 hour. The reaction solution was poured into an aqueous ammonium chloride solution and extracted with ether. After washing the extract, dry and concentrate.
The residue was purified by silica gel chromatography to obtain (S)-(-)-α-cyclogeraniol of formula (5)3.
89g was obtained (Y=57%). Its physical property values were as follows. b. p. 56-60℃/4Torr; [α]
D=-116.0° (21°C).

[0025]

[Example 3] (S)-(-)-α-cyclocitral [
Synthesis of compound of formula (4) 0.8 oxalyl chloride in 23 ml of methylene chloride
5 ml (9.7 mmol) was dissolved, cooled to -78°C, and DMSO1 dissolved in 2.3 ml of methylene chloride was added thereto.
．． 04 ml (14.6 mmol) was added dropwise. -78℃
After stirring for 5 minutes, a solution of 1.0 g (6.5 mmol) of the alcohol of formula (5) obtained in Example 2 dissolved in 7 ml of methylene chloride was added dropwise at the same temperature, and the solution was stirred at -78°C for 15 minutes.
Stir for a minute. Then, 4.07 m of triethylamine
1 (29.2 mmol), stirred at -78°C for 10 minutes, and then heated to 0°C. Add ice water and extract with ether. The ether layer was washed, dried and concentrated to give the crude formula (
4) (S)-(-)-α-cyclocitral 0.95
g (Y=97%).

[0026]

[Example 4] Synthesis of (S)-(-)-dehydro-α-damaskol [compound of formula (3)] 650 mg of the aldehyde of formula (4) obtained in Example 3 (
Propargyl magnesium bromide (0.5 mmol) was dissolved in 7 ml of THF at room temperature.
43 ml (21 mmol) of MinTHF was added dropwise. After stirring at room temperature for 1 hour, the mixture was poured into an aqueous ammonium chloride solution and extracted with ether. The ether layer was washed, dried and concentrated, and the residue was purified by silica gel chromatography to obtain 645 mg of (S)-(-)-dehydro-α-damascol of formula (3). The physical properties of the new compound were as follows. b. p. 95-100℃/Torr
;1H-NMR (90MHz, CDCl3) δ=0.
88 (s, 3H), 1.03 (s, 3H), 1.1-2
．． 2 (m, 6H), 1.83 (d, 3H), 1.98 (
s, 3H), 4.62 (d, 1H), 5.72 (m, 1
H).

[0027]

[Example 5] (S)-(-)-Damascall [Formula (2)
Synthesis of the compound of formula (3) obtained in Example 4 was dissolved in THF10
269 mg of lithium aluminum hydride (LAH) dissolved in 7 ml of THF (7.08 m
mol) and sodium methylate 227 mg (3.5
4 mmol) and stirred at room temperature for about 20 hours to carry out the reaction. The reaction solution is cooled with ice water and a small amount of water is added to decompose excess LAH. After filtering off the solid matter and washing with ether, the filtrate and washing liquid were combined and concentrated, and the residue was purified by silica gel chromatography to obtain the alcohol compound 26 of formula (2).
2 mg was obtained.

[0028]

[Example 6] Synthesis of (S)-(-)-damascone [formula (1) compound] Alcohol compound of formula (2) obtained in Example 5 170
mg (0.88 mmol) was dissolved in 9 ml of acetone,
2 g of activated manganese dioxide is added and the reaction is stirred at room temperature for 70 hours. Filter off the manganese dioxide and wash with acetone. The filtrate and washing liquid were combined and concentrated, and the residue was purified by silica gel chromatography to obtain 112 mg of (S)-(-)-damascone of formula (1) (Y = 6
7%). This was crystallized from hexane to obtain 86 mg of crystals. m. p. 17-18°C; [α]D=-501.
5° (21°C) (C=1.2, CHCl3).

[0028]

Effects of the Invention According to the present invention, a novel compound (R)-(+)-2,4,4-trimethyl-2 having high optical purity
By using -cyclohexen-1-ol as a starting material, (S)-(-)-damascone, which is useful as a fragrance substance, can be produced industrially very advantageously and with high optical purity. In addition, the novel intermediate (S)-(-)-dehydro-α-damascol obtained by the method of the present invention is extremely useful as a synthetic intermediate for optically active fragrance compounds.

Claims (2)

[Claims] [Claim 1] (S)-(-)-dehydro-α-damascol represented by the following formula (3): [Image Omitted] [Claim 2] (R)-(+)-2,4,4-trimethyl- represented by the following formula (7) [Chemical formula 2]
2-Cyclohexen-1-ol is reacted with tributyl stannyl methyl iodide in the presence of potassium hydride to obtain the following formula (6) [Chemical formula 3] where Bu represents a butyl group. (R)-(+
)-2,4,4-trimethyl-2-cyclohexene-1
-yl-tributylstannyl methyl ether is formed, and the compound of formula (6) is reacted with n-butyllithium to form (s)-(-)-α of the following formula (5). -cyclogeraniol is formed, and the compound of formula (5) is oxidized with dimethyl sulfoxide in the presence of oxalyl chloride to form (s)-(-)- of the following formula (4) [Chemical formula 5] α-cyclocitral is formed, and the compound of formula (4) is subjected to a Grignard reaction with propargyl magnesium halide to form (s)-(-)-dehydro-α- represented by the following formula (3) [Chemical 6] Damascol is formed, and the compound of formula (3) is hydrogenated in the presence of a reducing agent to form (s)-(-)-α-damascol represented by the following formula (2) [Chemical 7] A method for producing (s)-(-)-α-damascone represented by the following formula (1): .