JPH0631202B2 - Solanofuran manufacturing method - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel method for producing a known compound, solanofuran, which is useful as a perfume substance, particularly as a tobacco perfume.

More specifically, the present invention has been isolated and identified as an aroma component of tobacco [(Helv. Chim. Acta., 951.
(1973)], the following formula (1) that plays a major role as an aroma component of tobacco The present invention relates to a new method for producing solanofuran.

(Prior Art) Conventionally, as a method for synthesizing solanofuran represented by the above formula (1), for example, a method represented by the following reaction formula A is known [Helv. Chim. Acta. , 265-2
71 (1973)].

The above method uses a solanone of the above formula (6) synthesized through multiple steps as a starting material to subject the compound of the above formula (6) to a photooxidation reaction to synthesize a cyclic peroxide of the above formula (7). A method of synthesizing the solanofuran of the formula (1) by subjecting the compound of the formula (7) to a heat transfer reaction.

However, the solanone of the formula (6), which is the starting material in the above-mentioned method, is a trace amount of natural aroma component in tobacco, and its synthesis requires a large number of steps, which makes it practically difficult to provide and is easy to obtain. There is a problem that it cannot be obtained.

(Problems to be Solved by the Invention) It is an object of the present invention to provide an efficient and novel method for producing solanofuran represented by the above formula (1), which solves the problems of the conventional production methods.

(Means for Solving Problems) The present inventors have conducted extensive studies to solve the above-mentioned disadvantages and drawbacks of the conventional methods.

As a result, by using 5-isopropyl-6-heptin-2-one [the following formula (5)], which can be easily synthesized in two steps from commercially available piperiton, as a starting material, the above formula of the present invention can be obtained. The present invention has been completed by finding that the compound of (1) can be advantageously synthesized with high purity and high yield and by industrially simple operation.

Therefore, according to the present invention, a) the following formula (5) 5- (S) -isopropyl-6-heptin-
The following formula (4) in which a 2-one is acetalized to protect an oxo group 5-isopropyl-2-ethylenedioxy-represented by
6-heptin is synthesized, b) the compound of the formula (4) is condensed with chloroacetone, and c) the following formula (3) is obtained. 5-isopropyl-8-methyl-2-ethylenedioxy-8,9-epoxy-6-nonine represented by the following formula (2) Synthesizing 5-isopropyl-8-methyl-8,9-dihydroxy-6-nonin-2-one represented by: d) reacting the compound of formula (2) in the presence of cuprous chloride The present invention provides a novel method for producing the solanofuran of the formula (1) of the present invention.

The reaction method of the present invention is novel, and its reaction formula can be represented as follows, for example.

The method for producing the solanofuran of the above formula (1) of the present invention will be described in more detail below according to the above reaction formula B.

First, the reaction for synthesizing the compound of the above formula (4) from the compound of the above formula (5) in step a) can be easily carried out by subjecting the compound of the above formula (5) to a ketalization reaction with ethylene glycol in the presence of an acid catalyst. It can be carried out. The reaction proceeds in a solvent or in the absence of a solvent, and may be appropriately selected if necessary.

The amount of ethylene glycol used in this reaction is not particularly limited and may be used in a large excess. Usually, it is used within a range of about 1 to 5 mol per 1 mol of the compound of the formula (5). It is more preferable that the amount is in the range of about 1 to 2 mol. Further, the reaction proceeds regardless of whether the acid catalyst is an organic acid or an inorganic acid. Specific examples of these acid catalysts are as follows. And inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; and organic acids such as P-toluenesulfonic acid. There is no particular limitation on the amount of these acid catalysts to be used, and it is usually sufficient to use a catalytic amount, but if the suitable amount of the acid catalyst is specifically shown, it is about 0. It is within the range of 01 to about 0.1 mol. When a solvent is used, specific examples of the solvent include solvents such as benzene, toluene, hexane and xylene. The amount of these solvents to be used is also not particularly limited and may be appropriately selected, and for example, a range of about 1 to 10 times the weight of the compound of the formula (5) can be preferably exemplified.

The reaction temperature in the above reaction varies depending on the type of the acid catalyst used or the type of the solvent used, but is generally suitable in the range of about 70 ° C to 150 ° C. Further, the reaction time may be appropriately selected depending on the progress of the reaction, and is usually carried out, for example, by reacting for about 0.5 to 2 hours. After completion of the reaction, the compound of formula (4) can be obtained by washing the reaction solution with an alkaline aqueous solution and concentrating it according to a conventional method. The compound of formula (4) that can be synthesized in this manner can be used as a raw material for the next step without purification, but if necessary, it may be separated and purified by column chromatography, distillation or the like. It can also be purified and used in the next step.

Then, in step b), the compound of formula (4) obtained in step a) above is converted to a lithium salt or a halomagnesium salt with an alkyllithium such as butyllithium or a Clinard reagent, and then condensed with chloroacetone. The compound of formula (3) can be easily synthesized.

The above reaction is preferably carried out at a low temperature, for example about -80.
C. to about + 50.degree. C., more preferably about -60.degree.
An example is within the range of about 0 ° C. The reaction time is the total of the above-mentioned lithium salt or halomagnesium salt forming reaction and the condensation reaction described later, and is usually about 2
The time can be within the range of about 20 hours.

The amount of the alkyllithium such as butyllithium or Grignard reagent that can be used for the above-mentioned lithium salt or halomagnesium salt formation reaction is not strictly limited, but it may be 1 mol of the compound of the formula (4), Generally, it can be in the range of about 1 to 1.5 mol, more preferably in the range of about 1 to 1.3 mol. The amount of chloroacetone used in the condensation reaction is generally about 1 to about 3 with respect to 1 mol of the compound of the formula (4).
The molar range is suitable, and the more preferred range is from about 1 to about 2 mol.

The above reaction proceeds in the presence or absence of a solvent, but it is preferable to use a solvent. As the solvent, for example, dimethyl ether, diethyl ether, tetrahydrone, dioxane and the like are preferably used. After completion of the reaction, an appropriate amount of water is added and the mixture is stirred at a temperature of about room temperature for about 0.5 to 1 hour.

Thereafter, according to a conventional method, for example, an ammonium chloride aqueous solution is poured, solvent extraction, water washing are performed, and the solution is concentrated to obtain the compound of the formula (3).
The compound of can be easily obtained. The compound of the formula (3) obtained here can be used as a raw material for the next step without purification, but may be used after being purified by means such as column chromatography and distillation.

The compound of the formula (3) obtained in the step b) of the compound of the above formula (2) is then treated with an acid to give the compound of the above formula (2).
Can be easily synthesized [step c)].
The treatment at this time does not particularly require a solvent because it easily proceeds in a solvent or without a solvent, but when used, a water-soluble solvent such as acetone, methanol, ethanol, or tetrahydrofuran is preferably used. It The amount of these solvents to be used is not particularly limited and can be selected within a wide range, but for example, a range of about 2 to 20 times by weight with respect to the compound of the formula (3) can be preferably exemplified. The reaction temperature when the compound of the formula (3) is treated with an acid can be exemplified generally in the range of about 0 ° C to 80 ° C, preferably in the range of about 0 ° C to 30 ° C. The reaction time is not particularly limited and can be appropriately selected, but generally, for example, about 1 to 10
A time range is appropriate.

The acid used to treat the compound of formula (3) may be either an organic acid or an inorganic acid, such as sulfuric acid,
Examples thereof include inorganic acids such as hydrochloric acid and phosphoric acid; and organic acids such as P-toluenesulfonic acid and methanesulfonic acid. The amount of these acids used is about the amount of a catalyst, and for example, about 1 to 1 is used for the compound of formula (3).
The amount used may be in the range of 10% by weight. After completion of the reaction, the reaction product can be washed with an alkaline aqueous solution such as sodium bicarbonate, extracted with a solvent such as ether, and then concentrated to obtain the compound of the formula (2) according to a conventional method. This crude compound of formula (2) can be purified by means such as column chromatography and distillation.

In step d), a solanofuran of formula (1) above is formed from a compound of formula (2) that can be synthesized as described above. This formation reaction is carried out by heating the compound of formula (2) in the presence of cuprous chloride. Although the reaction proceeds even without solvent, it is generally preferred to carry out in a solvent. Further, the reaction is usually carried out in an atmosphere of an inert gas such as argon, nitrogen or helium. The heating temperature can be usually in the range of about 50 ° C to 200 ° C, more preferably in the range of about 100 ° C to 150 ° C. The reaction time may be appropriately selected, but a preferable range is about 1 to 3 hours.

The amount of cuprous chloride used in the above reaction does not work particularly favorably for the reaction even if used in a large amount, and therefore it is generally about 0.1 mol or less relative to the compound of formula (2). The usage amount of is adopted. Further, as the solvent, for example, 4-t
Solvents such as butyltoluene, xylene, mesitylene, toluene and the like can be mentioned. The amount of the solvent used is not particularly limited and can be appropriately selected and used.
For example, it can be used within a range of about 2 to 20 times by weight of the compound of the formula (2).

After completion of the reaction, the solvent is distilled off and purification by means such as column chromatography and distillation makes it possible to easily synthesize the target compound of the formula (1) in good yield and good purity.

(Examples) Hereinafter, embodiments of the present invention will be described in more detail with reference to Examples.

Example 1 Synthesis of 5-isopropyl-2-ethylenedioxy-6-heptin [Formula (4)] In a flask, 10.4 g (0.068 mol) of 5-isopropyl-6-heptin-2-one and ethylene glycol 6 were added. 0.4 g (3 mol), 50 m of benzene and 100 mg of p-toluenesulfonic acid are charged, and the resulting water is heated under reflux for 1.5 hours while distilling out the water out of the reaction system. Then, the reaction solution was washed with an aqueous solution of sodium bicarbonate and an aqueous solution of saturated saline, dried over magnesium sulfate, and then concentrated to obtain 10.8 g of a crude compound of the formula (4). Silica gel column chromatography (hexane: ethyl acetate = 9)
5: 5) to obtain 9.8 g of the compound of formula (4). Yield: 73.5% Boiling point: 73 ° C to 74 ° C / 2 mmHg.

Example 2 Synthesis of 5-isopropyl-8-methyl-2-ethylenedioxy-8,9-epoxy-6-nonine [formula (3)] 5-isopropyl-2-ethylenedioxy of formula (4) in a flask. Charge 9.3 g (0.047 mol) of -6-heptin and 100 m of ether and cool to -60 ° C.
In this, n-butyllithium hexane solution 60.6 m
(0.048 mol) was added dropwise over 10 minutes, and the mixture was stirred at -49 ° C for 1 hour.
Stir for hours. Then, a mixed solution of 7.6 m of chloroacetone and 20 m of ether was added dropwise over 10 minutes (-
60 ° C). Then, the mixture was stirred at −60 ° C. for 2 hours and then at room temperature for 1.
Stir for 5 hours. Then, 40 m of water is added, and the mixture is stirred overnight at room temperature. Pour the reaction solution into an aqueous solution of ammonium chloride,
The mixture was extracted with ether, the ether layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated to obtain 9.4 g of a crude compound of the formula (3). This is silica gel 1
Using 50 g, column chromatography (hexane:
Ethyl acetate = 95: 5) for purification and compound of formula (3) 5.
06 g was obtained. Yield: 58.9%.

NMR (60 MHZ); 0.96 (6H, d), 1.2
7 (3H, S), 1.51 (3H, S), 1.50
2.60 (6H, m), 2.67 (1H, d), 2.9
0 (1H, d), 3.88 (4H, S).

Example 3 Synthesis of 5-Isopropyl-8-methyl-8,9-dihydroxy-6-nonin-2-one [Formula (2)] 5-Isopropyl-8-methyl- of Formula (3) was added to a flask.
2-Ethylenedioxy-8,9-epoxy-6-nonine 400 mg, 10% hydrochloric acid 0.4 m and acetone 4 m were charged and reacted at room temperature (20 ° C.) for 4 hours. After completion of the reaction, the mixture was neutralized with sodium bicarbonate powder, extracted with ether, dried over magnesium sulfate, and concentrated to give a crude compound of the formula (2) 40%.
0 mg was obtained. This was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the formula (2).
330 mg of the compound of

Yield: 90.5%.

IRvmaxcm = 2965,1710.

Example 4 Synthesis of Solanofuran [Formula (1)] 607 mg (2.68) of 5-isopropyl-8-methyl-8,9-dihydroxy-6-nonin-2-one of formula (2)
6 mmol), 60 mg of cuprous chloride and 12 m of 4-t-butyltoluene were charged into a flask and reacted at 190 ° C. for 7.5 hours under an argon atmosphere. After completion of the reaction, 4-t-butyltoluene was recovered under reduced pressure (2 mmHg), and the obtained crude oil was purified by silica gel column chromatography (hexane: ethyl acetate = 97.5: 2.5). Yield of 534 mg of the compound of formula (1); 98%.

IRνmaxcm = 2950, 1715, 1540, 1
360.

PMR (60 MHZ); 0.80 (3H, d), 0.9
2 (3H, d), 200 (3H, S), 2.07 (3
H, S), 2.31 (2H, t), 5.86 (1H,
S), 7.07 (1H, S).

(Effect of the Invention) According to the present invention, the following formula (1) useful as a flavoring agent for tobacco is provided. The solanofuran represented by can be industrially advantageously synthesized with a good yield and a simple operation as compared with the conventional method.

Claims (2)

[Claims] 1. The following formula (2) The following formula (1) is characterized in that 5-isopropyl-8-methyl-8,9-dihydroxy-6-nonin-2-one represented by the formula is reacted in the presence of cuprous chloride. Solanofuran manufacturing method represented by. 2. The following formula (5) 5-isopropyl-6-heptin-2-one represented by the following formula is reacted with ethylene glycol in the presence of an acid catalyst,
Formula (4) below 5-isopropyl-2-ethylenedioxy-represented by
6-Heptin is formed and the compound of formula (4) is reacted with chloroacetone in the presence of butyllithium to give the compound of formula (3) 5-isopropyl-8-methyl-2-ethylenedioxy-8,9-epoxy-6-nonine represented by the following formula is formed, and the compound of the formula (3) is reacted with an acid to give a compound of the following formula (2 ) 5-isopropyl-8-methyl-8,9-dihydroxy-6-nonin-2-one represented by the following formula is formed, and the compound of the formula (2) is reacted in the presence of cuprous chloride. The following formula (1) Solanofuran manufacturing method represented by.