JPS5819659B2 - Method for producing γ-damascenone - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing γ-damascenone.

Although γ-damascenone has not been confirmed as a natural ζ, it is known as a synthetic fragrance that is important as a single fragrance in formulations because it imparts an extremely elegant, deep aroma.

Conventionally, only the following three methods have been known for synthesizing γ-damascenone.

That is, one method is the method described in Japanese Patent Publication No. 50-69048, in which α-tamascone (
1) is reacted with NBS (N-bromsuccinimide) to bromine the allyl position, and then treated with dimethylaniline to perform dehydrobromination to obtain γ-damascenone. According to this method, pure γ- Damascenone was not obtained, γ-damascenone (2) and β-damascenone (3)
) resulting in a 1:1 to 3:1 mixture.

Another method is Get, off, 2,240,311
,C.

A79 5052j (1973), He1v, chim
.

Acta, XXXIII 1746 (1950), using the starting material ethyl trimethylcyclohexenonecarboxylate (1) and converting it to ethyl trimethylcyclohexenolcarboxylate (3) according to the following formula B).
), then this compound (3) is dehydrated to obtain the compound (4), furthermore, a side chain at the allyl position is generated to obtain the compound (7), and then isomerized to obtain γ-damascenone (8). However, during the production of compound (4), compounds (5) and (6) are also generated as by-products, and these (4) and (5)
, (6) is used as a raw material, pure γ-damascenone cannot be obtained, and this method yields a mixture of damascenone.

In addition, the following abbreviations were used in formula B) to simplify the explanation.

Me: methyl group Et: ethyl group B u +butyl group On the other hand, the present invention aims to obtain the pure γ form of damascenone by a novel method.

That is, the present invention can be obtained by halogenating a dimedone carboxylic acid ester represented by (However, R represents an alkyl group or an aryl group, and the same applies to R in the following general formula) The same applies to X in the general formula below, which represents a halogen atom) After the enol halide represented by is formed into a halogen ester represented by by Witzteig reaction, this halogen ester is dehalogenated to form a γ-saffronate ester represented by Alternatively, the enol halide represented by the general formula (2) is dehalogenated to form a β-keto ester represented by the formula (2), and then this β-keto ester is subjected to a Witzteig reaction to form the β-keto ester represented by the general formula (4).
) and then reacted this γ-saffronate with an allyl compound to obtain 2-methylene-3,4-dehydro-6,6-dimethylcyclohexane-1-(3- buten-1-one),
The present invention relates to a method for producing γ-damascenone, which is characterized in that γ-damascenone is obtained by isomerizing this.

Next, in order to facilitate understanding of the production method of the present invention, a reaction formula showing an embodiment of the present invention is schematically illustrated.

Next, the manufacturing method of the present invention will be explained in more detail.

Dimedone carboxylic acid ester (1) used in the production method of the present invention can be easily obtained, for example, according to a method.

Enol halide (2) used in the production method of the present invention
is obtained by halogenating the above dimedone carboxylic acid ester (1), and this reaction can be carried out according to a known method (N, 5teiner B).

Willhelm: He1v, Chim, Act
a XXXV.

1752 (1952)].

In the method of the present invention, this enol halide (2) may be formed into a halogen ester (3) by Witteigh reaction, and then this halogen ester (3) may be dehalogenated to obtain a γ-saffronate ester (4). , or after dehalogenating enol halide (2) to form β-ketoester (2)′, this β-ketoester (2)
)' can also be subjected to the Wittich reaction to obtain γ-saffronic acid ester (4).

In this case, the former method provides a higher yield of γ-saffronate (4) than the latter method.

・The above Wittig reaction (an example of the Wittig reagent used in this case is Wittig reagent of methylene ylide represented by the following general formula).
There is a ttig reagent.

General formula (R') 3P=CH2 (wherein R' represents an aryl group such as a phenyl group, a P-1-ruyl group, or a P-methoxyphenyl group).

), : complete fu* ℃=individual and methylenetriphenylphosphine ylide prepared from sodium amide NaNH2.

The Wittig reagent used in the present invention is preferably prepared in a solvent such as benzene.

That is, when the Wittig reagent is prepared in a solvent such as dimethyl sulfoxide (DMSO), salts and bases are dissolved in addition to the ylide, making it impossible to obtain a solution containing only pure ylide.

Therefore, the yield is also poor.

For example, when benzene is used as an extraction solvent for ylide, a pure solution of ylide is obtained, and when the supernatant liquid is used, halogen ester (3) or γ-saffronate ester (4) can be obtained in high yield.

In the former method, when dehalogenating the halogen ester (3) to obtain the γ-saffronate ester (4), dehalogenation is carried out using, for example, a LiAIH(OCH3)3 tetrahydrofuran system to obtain the γ-sulfuric acid ester with a yield of 80% or more. A saffronic acid ester (4) is obtained.

In the latter method O, when enol halide (2) is dehalogenated to give β-ketoester (2)', the dehalogenation method is R, L, Frank, H,
K., Hall, J., Org.

Chem, 72.1645 (1950) as a dehalogenating agent, such as Zn
-KI is used to obtain β-ketoester (2)' in good yield.

The γ-saffronate (4) is synthesized in this manner, and this γ-saffronate is valuable as a new single product.

To synthesize the target product γ-damascenone (6) from γ-saffronate (4), first, γ-saffronate is reacted with an allyl compound to form a side button of an allyl keto group, and then 2-methylene-3 is synthesized. ,4-dehydro-6,6-dimethylcyclohexane-1-(3-buten-1-one)
(5), and then this (5) is isomerized.

As an allyl compound, allyl lithium CH2=CH-C
)l,,Li), allylmagnesium halide (CH2
=CH-CH2=CH, however, X represents a gen atom)
is exemplified.

A typical example of the catalyst used for isomerization is Kot-Bu (Bu represents a butyl group).

This allows quantitative isomerization to γ-damascenone (6).

Regarding the synthesis of γ-damascenone (6) from γ-saffronate ester (4), a small amount of compound (7) is produced as a by-product.

However, this compound (7) can be easily converted into the compound (5) by thermal decomposition, and can also be easily separated by distillation.

In this way, the method of the present invention uses dimedone carboxylic acid ester (
Using 1) as a raw material, γ-saffronic acid ester (4)
This novel method involves preparing γ-damascenone (6), reacting it with an allyl compound, and then isomerizing it to obtain pure γ-damascenone (6).

Next, examples of the present invention will be shown.

Example [1] Ethyl-4-lytetra-6,6-dimethyl-2-oxo-3-cyclohexene-1-carboxylate (2
) Synthesis of 15 phosphorus trichloride was added to a mixture of 61.1 (0.29 mol) of ethyl dimedonecarboxylate (1) and 170 g of chloroform.
．． 5 g (0.11 mol) was slowly added dropwise with stirring.

After that, the mixture was refluxed for 3 hours in a fume hood, the chloroform was distilled off as it was, and the contents were then poured into ice-water and extracted with ether, neutralized with aqueous soda carbonate, washed with water, and dried.
After removing the ether, distill it under reduced pressure.

b, pH 9-123°C/4mmHg portion 34.5.
! Get 9.

This is (2) with a yield of 52% and 1. R, 1732, 167
5°161s (crrL-t), NMR: 1.10
(s, 3H): 1.13 (s, 3H): 1.26
(t, 3H): 2.0-2.9 (m, 2H): 3.
00 (s', IH): 4.12 (q, 2H); 6
．． 13 (br, s, IH) in δ (ppm) [2] Synthesis of ethyl-6,6-dimethyl-2-oxo-3-cyclohexene-1-carboxylate <21 Enol chloride (2) above 87 g (0, 38 moles) and 2oo of zinc! 7 (3,06 moles) potassium iodide 1009 (0,6 moles) were mixed with 600 ml of ethanol, stirred vigorously at room temperature for 24 hours, and the reaction mixture was passed through the mouth to distill off the ethanol and extracted with ether. % hydrochloric acid, further washed with water, dried with sodium sulfate, distilled off the ether, and then distilled under reduced pressure.

b, p 30 g of a portion of 95-110°C/3°Hg is obtained.

Yield '41%, which is almost pure (2').

■R; 1730.1680 (C111-1), NMR;
1.07 (S, 3H); 1.13 (S, 3H); 1
．． 27(t, 3H): 1.96-2.73(m, 2
'H): 4.2 (q, 2H): 5.87~6
．． 10 (m, IH); 6.7:3-6.97 (m
, IH) in δ (ppm) [3] ethyl-4-chloro-
Synthesis of 6,6-dimethyl-2-methylene-3-cyclohexene-1-carboxylate (3) triphenylphosphine methylioside ph3p'P
CH31o22.2 & (0,055mo/L/)
The supernatant liquid of ylide prepared from 2.0 i (0,053 mol) of sodium amide and 100 ml of dry benzene was taken out with a 67 ml pump under nitrogen atmosphere, and 4.6 g (0,02 mol) of enol chloride (2) was extracted. Add 200 ml of dry benzene to the mixture and reflux for 6 hours.

This was post-treated in accordance with a conventional method and distilled under reduced pressure, page 15.
A portion of 2.3 g is obtained at 8-9°C/lmmHg.

50% yield, which is almost pure (3).

TR; 1730°1635, 890 (clrL-1
), NMR; 0.95 (s.

3H): 1.03 (s, 3H): 1.23(t
, 3H) 2.0 (d, IH); 2.87 (s, IH:)
:4.1(q, 2H) :4.98(br,s,
2H) ; 6.25 (br, s-I H) in
δ (ppm) [4] Ethyl-γ-safranate (4) (
Synthesis of ethyl-6-methylene-2,2-dimethyl-3-cyclohexene-1-carboxylate) 4-1°((
2)'→Synthesis of (4)] Triphenylphosphine methylene ylide (pbs,.

H3□02.2.9(.,.3-E/L/) and NaNH
2i, 2 jj (0,03 mol), dry benzene 5
β-ketoester (2') 2.9 (0,0
A Wittig reaction was carried out by adding 901 rLl of dry benzene to a solution of 1 mol) and 10 ml of dry benzene, followed by refluxing for 6 hours.

A composition is obtained by post-treatment according to a conventional method and distilling off benzene.

This is separated by column chromatography and the hexane fraction is a) 0
．． 2g, 10-20% benzene + hexane distillate)
We get 0.9.

b) is the spectrum component 4-2. [Synthesis of (3) → (4)] In a round bottom flask equipped with a nitrogen inlet tube, a rubber cap, a thermometer, a reflux tube with calcium chloride, and a magnetic stirrer.
Add 3.1 rd of + AlH4T HF solution through the mule cap with a nitrogen syringe.

Bring the temperature to 0°C and add with a syringe through the mule cap while stirring.

Bring the temperature to O'C and add 2.5 g (7.92 mlJ mol) of methanol via syringe while stirring.

This results in INL 1A13 H(OMe) 3T
An HF solution was obtained.

Next, prepare another similar flask and add dry THF5.
TL11 2.51 g (13.2 mmol) of copper iodide is added, and the temperature is lowered to 0° C. without stirring under a steady atmosphere, and all of the IN LiAlH(OMe)3-THF is slowly added dropwise.

Thereafter, 1.5 g (6.5 mmol) of chloroester (3) are added while maintaining the temperature at 0°C.

Stir for a further 30 minutes at 0°C and then for 24 hours at room temperature.

Post-treatment involves decomposition with saturated ammonium chloride solution, extraction with ether, washing with sodium bicarbonate water, further washing with cold water, and drying with sodium sulfate.

After distilling off the ether, the raw material is obtained.

This is 50% ethyl safranate (4) and 5 unreacted raw materials.
0% mixture.

IR of ethyl safranate (4); 1738°1640
．． 1601.890 (1-1), NMR; 0.90 (s
, 3H): 0.96(s, 3H); 1.20(
t, 3H): 1.5-2.6(m, 2H): 2
．． 84 (s, LH); 4.02 (q, 2H); 4.77
~4.97 (m, 2H); 5.5~6.1 (m
, 2H) in δ (ppm) [5] 2-methylene-3,4-dehydro-6,6-dimethylcyclohexane-1-(3-buten-1-one) (
5) Synthesis of dry THF2077211 lithium 0.6.9 (0,
1 mole) biphenyl small amount of triallylphenyl ether2.
3! A -THF-ether solution of allyllithium prepared from a mixture of 51 rll of dry THF and 1.1.9 (6.7 mmol) of γ-safranate (4) was reacted.

The reaction product was post-treated according to a conventional method to obtain a composition.

This includes (5) and (7) in a ratio of approximately 50:50.

This was directly used as a raw material for the next isomerization operation.

NMR of (5): 0.86 (s, 3H): 0
．． 96 (s.

3H); 1.6-1.9 (m, LH) 2.37-2
．． 72 (m, IH); 3.07 (s, IH);
3.18 (tX t, 2H): 4.93 (b
r, s, IJI): 5.0 (br, s, IH)
: 5.03-5.23 (m, 2H): 5.6:
3-6.20 (m, 3H) inδ(ppm
) (7) NMR: 0.89 (s, 3H); 1
．． 26 (s.

3H): 1.56 (s r I H): 1.
3-2.5 (m.

2H): 1.92-2.42 (m, 5H)
: 4.69-5.12 (m, 6H); 5.
42-6.16 (m.

4H) in δ (ppm) [6] Isomerization to γ-damascenone (6) (5) above,,! = About 1.5 g of the composition (7) is
BuOH (10 m) was added to the rice grains at room temperature, and then some metal potassium was added to the rice grains, left to stand for 1 hour with stirring, and then post-treated in a conventional manner to obtain (6) almost quantitatively.

NMR of (6): 0.90 (s, 3H); 0.9
6 (S.

3H); ], 5-2.6 (m, 2H): 1.88 (dX
d, 3H); 3.11 (s, IH):
4.88 (br, s, 1)-]); 5.0
0(br, s, LH): 5.53-5.93(
m, IH): 6.0-6.26 (m.

IH); 6.50-7.0 (m, IH) in δ (pp
m).

Claims (1)

[Claims] 1 A compound obtained by chlorinating a dimedone carboxylic acid ester represented by the general formula (wherein R represents an alkyl group or an aryl group, and the same applies to R in the following formula) with phosphorus trichloride. The enol chloride represented by is formed into the chloroester represented by by Witzteig reaction, and then this chloroester is dechlorinated with a tetrahydrofuran solution of cupric iodide monotrimethoxylithium aluminum hydrand to form γ-saffron represented by After obtaining the acid ester or dechlorinating the enol chloride represented by the general formula (2) with zinc-potassium iodide to form the β-keto ester, the β-keto ester is subjected to the Witzteich reaction. 2-methylene-3, by reacting this γ-saffronate with an allyl compound.
4-dehydro-6,6-dimethylcyclohexane-1-
(3-buten-1-one), which is isomerized to give γ-
A method for producing γ-damascenone, characterized by obtaining damascenone.