Ethyl (1R,6S)-2,2,6-trimethylcyclohexanecarboxylate, aroma chemical composition containing the same and process of producing the same

Ethyl (1R,6S)-2,2,6-trimethylcyclohexanecarboxylate represented by formula (1) ##STR1## is disclosed. Also, an aroma chemical composition containing the same and a process of the production of the same are disclosed.

FIELD OF THE INVENTION 
The present invention relates to an aroma chemical composition to be used 
for perfuming cosmetics. Also, the present invention relates to a process 
of producing ethyl 2,2,6-trimethylcyclohexanecarboxylate useful as an 
aroma chemical. Furthermore, the present invention relates to a process of 
producing optically active ethyl 
(1R,6)-2,2,6-trimethylcyclohexanecarboxylate particularly useful as an 
aroma chemical. 
BACKGROUND OF THE INVENTION 
As components of living things in the earth, there are materials showing 
various characteristics caused by their asymmetric structures, and it is 
generally known that among physiologically active materials having an 
asymmetric structure, those useful for a human being are frequently of 
specific antipodes, such tendency is particularly remarkable in the fields 
of, for examples, medicaments, agricultural chemicals, pheromones, and 
food additives, and that when they are a racemic mixture, the effect is 
greatly reduced, or a negative function appears. For example, 
JP-A-63-44544 describes that: "In the present science, while there is no 
single theory which can elucidate the phenomenon of the sense of smell, it 
has frequently been experimentally clarified that only one optically 
active substance of a certain compound has desired odor properties and 
that while a racemate thereof has similar smell character characteristics, 
its aroma intensity is not more than a half thereof at the most" (the term 
"JP-A" as used herein means an "unexamined Japanese patent application"). 
This is not exceptional in the field of aroma chemicals. For example, for 
the odor of peppermint, L-menthol is useful, for the odor of cumin, 
d-carvone is useful, and for the odor of grapefruit, d-nootkatone is 
useful, respectively, but they each has a different odor from other 
optical antipodes, or the odor is stronger than other optical antipodes. 
As recent examples, such phenomena are observed in .alpha.-ionone, 
hydroxycitronellal, rose oxide, etc. (see, Kagaku Sosetsu, 14 (1976), "Aji 
To Nioi No Kagaku (Chapter 6). Therefore, the development of optically 
active aroma chemicals is significant for the development of new odors or 
effective optical antipodes like the development of new aroma chemicals. 
Ethyl 2,2,6-trimethylcyclohexanecarboxylate is a known compound already 
described in Chem. Ber., Vol. 102, 709-711 (1969), but its odor and value 
as an aroma chemical are not described therein. Also, since ethyl 
2,2,6-trimethylcyclohexanecarboxylate has asymmetric carbon atoms in the 
molecule, while it is expected that two mirror-image isomers of a (+) 
isomer and a (-) isomer exist, the ethyl 
2,2,6-trimethylcyclohexanecarboxylate described in the foregoing 
literature is a racemic mixture, and neither report regarding the 
individual synthesis of these isomers nor report about the properties of 
the isomers. 
Also, as an analogue of the 2,2,6-trimethylcyclohexanecarboxylic acid ester 
compound known as an aroma chemical, a mixture of ethyl 
2-ethyl-6,6-dimethylcyclohexanecarboxylate and ethyl 
2,3,6,6-tetramethylcyclohexanecarboxylate is disclosed in JP-B-2-62542 
(the term "JP-B" as used herein means an "examined published Japanese 
patent application"), but the properties of the individual compounds and 
the odor characteristics as a mixture are not shown therein. 
With respect to racemic 2,2,6-trimethylcyclohexanecarboxylic acid 
derivatives, investigations have been made about the production process of 
a violet odor [see, Helv. Chem. Acta, 31, 134 (1948)]. Also, ethyl 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylate according to the present 
invention (hereinafter sometimes referred to simply as "the compound of 
the present invention") is a very useful aroma chemical having a 
fruit-like and floral odor. 
The inventors carried out the process shown by the following reaction 
scheme for producing (1R,6S)-2,2,6-trimethylcyclohexanecarboxylic acid. 
That is, using optically active (3S)-7-methoxycitronellal as a raw 
material, enol acetate was first formed and cyclized to provide 
(1R,6S)-2,2,6-trimethylcyclohexanecarbaldehyde, which was then oxidized to 
provide (1R,6S)-2,2,6-trimethylcyclohexanecarboxylic acid, and this acid 
was esterified to synthesize the compound of the present invention, i.e., 
ethyl (1R,6S)-2,2,6-trimethylcyclohexanecarboxylate. 
##STR2## 
As an example of obtaining an optically active carboxylic acid by 
recrystallizing a carboxylic acid as a diastereomer salt of an asymmetric 
amine to undergo optical resolution, there are known a process of 
producing p-isopropyl .alpha.-methyldihydrocinnamate as described in 
JP-A-55-27166 and a process of producing p-tert-butyl 
.alpha.-methyldihydrocinnamate as described in JP-A-55-35459. 
Recently, with the diversity of various fragrance cosmetics and hygienic 
materials, a new demand which has not been known in conventional fragrance 
cosmetics and hygienic materials has been being increased; the development 
of aroma chemical substances having strong diffusibility, specific 
fragrance quality, high preference, long lasting, good stability, and high 
safety has been required; and in particular, aroma chemical materials 
having a floral and fruit-like odor, which can satisfy the aforesaid 
requirements, are insufficient. 
Accordingly, the present invention is aimed to provide an aroma chemical 
material or aroma chemical composition capable of satisfying the aforesaid 
requirements and giving a floral and fruit-like odor. 
In general, it is known that in aroma chemical compositions, even a slight 
difference in top note, etc. of a single aroma chemical sometimes changes 
the fragrance quality as a product. In particular, in a high-class 
perfume, etc., a delicate difference of a single aroma chemical determines 
the propriety as the perfume. In particular, in the case of a single aroma 
chemical giving a floral and fruit-like odor, delicate odor factors such 
as naturalness and freshness are important as a value of the aroma 
chemical. 
In regard to the relation of the steric structure and odor of the compound 
of the present invention, the inventors have recognized that in the 
geometric isomers (i.e., the cis-form and the trans-form), the trans-form 
is superior to the cis-form and that in the optical isomers of the 
trans-form [i.e., the (1R,6S)-form and the (1S,6R)-form], the (1R,6S)-form 
is superior to the (1S,6R)-form. In other words, the higher the ratio of 
the trans-form to the cis-form and the higher the optical purity, the more 
excellent the odor and the higher the value as an aroma chemical. 
However, in the component composition of ethyl 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylate which was obtained first by 
the inventors, the content of the (1R,6S)-form as the trans-form was about 
90%, and the content of the (1S,6S)-form as the cis-form was about 10%. 
Also, in regard to the optical purity, when not subjected to the optical 
resolution, while the optical purity of the product depends on the optical 
purity of a raw material, since commercially available 
(3S)-7-methoxyoitronellal as the raw material has an optical purity of 98% 
ee, the optical purity of the product is not higher than the foregoing 
optical purity. That is, there was a room for an improvement in the ethyl 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylate first obtained by the 
inventors. 
Accordingly, in the component composition of ethyl 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylate, it was important to develop 
a process of producing geometrically and optically pure ethyl 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylate. 
SUMMARY OF THE INVENTION 
An object of the present invention is to develop a novel aroma chemical 
component giving a floral and fruit-like odor and also to provide a 
process of producing the foregoing novel aroma chemical component, and 
particularly a process of producing geometrically and optically pure ethyl 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylate. 
Under the above-described circumstances, the inventors have made extensive 
investigations about the synthesis of 2,2,6-trimethylcyclohexanecarboxylic 
acid derivatives and odors thereof. As a result, it has been found that in 
regard to odor properties, ethyl 2,2,6-trimethylcyclohexanecarboxylate has 
strong diffusibility and a specific floral and fruit-like odor with high 
preference and that of the two kinds of the geometric isomers of ethyl 
2,2,6-trimethylcyclohexanecarboxylate, the trans-form particularly has the 
foregoing odor properties. 
Furthermore, as a result of syntheses of the optically active compounds of 
ethyl 2,2,6-trimethylcyclohexanecarboxylate, it has been discovered that 
of the four kinds of the optical isomers, the (1R,6S)-form particularly 
has the foregoing odor properties and is excellent in the odor intensity. 
Thus, as a result of testing the stability and safety for using as an 
aroma chemical material, it has been confirmed that the stability and 
safety of the (1R,6S)-form are very high. Moreover, as a result of 
perfuming testing, it has also been discovered that the (1R,6S)-form can 
become a useful aroma chemical. Thus, the present invention has been 
accomplished based on these discoveries 
That is, the present invention provides optically active ethyl 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylate represented by the following 
formula (1), a process of producing the same, and an aroma chemical 
composition containing the same.

DETAILED DESCRIPTION OF THE INVENTION 
Racemic ethyl 2,2,6-trimethylcyclohexanecarboxylate was investigated with 
respect to the fragrance quality using two kinds of synthesis processes of 
a synthesis process wherein the cis-form is a main component as shown in 
reaction scheme 1 and a synthesis process wherein the trans-form is a main 
component as shown in reaction scheme 2. 
##STR4## 
That is, in reaction scheme 1, commercially available .beta.-cyclocitral 
(3) was hydrogenated using a palladium catalyst, to obtain 
2,2,6-trimethylcyclohexanecarbaldehyde (4) having a composition comprising 
65% of the cis-form and 35% of the trans-form, which was then oxidized 
with nitric acid to provide a carboxylic acid (5). This acid (5) was 
reacted with ethyl bromide using an equimolar amount of sodium hydroxide 
and a catalytic amount of a quaternary ammonium salt, to obtain ethyl 
2,2,6-trimethylcyclohexanecarboxylate (2a) having a composition comprising 
68% of the cis-form and 32% of the trans-form. 
Also, in reaction scheme 2, commercially available 7-methoxycitronellal (6) 
was reacted with acetic anhydride to provide enol acetate (7), which was 
then subjected to a cyclization reaction using a phosphoric acid catalyst, 
without being purified, to obtain 2,2,6-trimethylcyclohexanecarbaldehyde 
(4) having a composition comprising 90% of the trans-form and 10% of the 
cis-form. This aldehyde (4) was oxidized and esterified in the same manner 
as in reaction scheme 1 described above, to obtain ethyl 
2,2,6-trimethylcyclohexanecarboxylate (2b) having a composition comprising 
90% of the trans-form and 10% of the cis-form. 
As a result of evaluating the odor about two kinds of the samples thus 
obtained, it was astonishingly found that the sample containing the 
trans-form as a main component synthesized by the process of reaction 
scheme 2 has a high fragrace character intensity, a specific floral and 
fruit-like odor, and high preference as compared with the sample 
synthesized by the process of reaction scheme 1. Thus, as a result of 
separating the product by the process of reaction scheme 2 into the 
cis-form and the trans-form and confirming the odors thereof, it was 
clarified that the cis-form has a weak and featureless floral odor, 
whereas the trans-form has the foregoing desired odor features. 
Then, as to the trans-form, according to the synthesis process of reaction 
scheme 2, ethyl (1S,6R) -2,2,6-trimethylcyclohexanecarboxylate (16) and 
ethyl (1R,6S)-2,2,6-trimethylcyclohexanecarboxylate (1) were respectively 
synthesized using commercially available optically active 
d-7-methoxycitronellal (12) and L-7-methoxycitronellal (8) as a raw 
material by the process showing in the following reaction scheme 3 and 
reaction scheme 4, and the fragrance quality of each product was 
evaluated. As a result, it was found that the odor intensity of the 
(1S,6R)-form (16) is about 1/3 of the odor intensity of the (1R,6S)-form 
(1) and fails in the diffusibility and feature of a specific fruit-like 
odor, whereas the (1R,6S)-form (1) has the foregoing excellent odor 
properties. 
##STR5## 
In addition, as the process of obtaining optically active 
2,2,6-trimethylcyclohexanecarboxylic acid (11) or (15) using 
trans-2,2,6-trimethylcyclohexanecarbaldehyde (10) or (14) in reaction 
scheme 3 or reaction scheme 4, there are a process of using sodium 
chlorite as described in, for example, Tetrahedron, 37, 2091 (1981), a 
process of using ruthenium chloride and hydrogen peroxide described in, 
for example, J. Org. Chem., 53, 3587 (1988), a process of using Caro's 
acid as described in, for example, J. Org. Chem., 33, 2525 (1968), a 
process of using a heteropoly acid and hydrogen peroxide as described in, 
for example, J. Org. Chem., 53, 3587 (1988), etc., in addition to the 
foregoing process of employing the nitric acid oxidation. Also, as the 
process of producing optically active ethyl 
2,2,6-trimethylcyclohexanecarboxylate (1) or (16) by ethyl esterification 
of optically active 2,2,6-trimethylcyclohexanecarboxylic acid (11) or 
(15), usually well-known processes of reacting the carboxylic acid (11) or 
(15) with ethanol using an acid catalyst can be also used. 
Furthermore, as the process of directly synthesizing optically active ethyl 
2,2,6-trimethylcyclohexanecarboxylate (1) or (16) from optically active 
trans-2,2,6-trimethylcyclohexanecarbaldehyde (10) or (14), a process of 
reacting sodium hypochlorite and ethanol as described in, for example, 
Tetrahedron, Lett., 23, 4647 (1982) can be used. 
Also, the inventors extensively investigated a novel process of producing 
ethyl (1R,6S)-2,2,6-trimethylcyclohexanecarboxylate. As a result, they 
have succeeded in obtaining geometrically and optically pure (1R,6S) 
-2,2,6-trimethylcyclohexanecarboxylic acid (11) by converting racemic or 
optically active 2,2,6-trimethylcyclohexanecarboxylic acid into a 
diastereomer salt using an asymmetric amine and recrystallizing the salt. 
By esterification of the product, geometrically and optically pure ethyl 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylate (1) can be easily produced, 
leading to accomplishment of the present invention. 
That is, the present invention also provides a process of producing 
geometrically and optically pure ethyl 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylate. 
As a result of testing the safety and stability, which are necessary 
conditions for the use of the thus obtained optically active ethyl 
2,2,6-trimethylcyclohexanecarboxylate (1) or (16) as an aroma chemical 
material, it was found that these compounds are almost safety in 
irritation and sensitivity to the human skin and, thus, have high safety. 
Also, it was found that these compounds show high stability in performing 
soaps, do not cause fading by the action of light, and are utterly stable 
at a pH of from 3 to 10. 
Thus, a specific floral and fruit-like odor-imparting agent or an 
odor-improving agent having strong diffusibility and high preference 
containing ethyl (1R,6S)-2,2,6-trimethylcyclohexanecarboxylate (1) of the 
present invention can be provided, and also fragrance cosmetics, hygienic 
materials, medical supplies, etc., containing the compound of the present 
invention as an odor component can be provided. That is, the commercial 
values of shampoos, rinses, perfumes, colognes, hair tonics, hair creams, 
bases for dressing the hair, such as pomade, etc., face powders, rouges, 
other dressing bases and dressing detergents, soaps, dishwashing 
detergents, detergents for laudry, softeners, disinfecting detergents, 
deodorizing detergents, room aromatic agents, furniture cares, 
disinfectants, insecticides, bleaching agents, other various kinds of 
hygienic detergents, tooth pastes, mouth washers, toilet papers, perfuming 
agents for facilitating the administration of medial supplies, etc., can 
be increased by compounding therewith the compound of the present 
invention in a proper amount capable of imparting a unique odor. 
Production Process of Raw Material Racemate 
In regard to the synthesis of 2,2,6-trimethylcyclohexanecarboxylic acid 
mainly composed of the transform of a racemate which becomes a raw 
material for the optical resolution, there are, for example, two kinds of 
synthetic processes shown in the reaction schemes described hereinbelow. 
In the 1st process, commercially available .beta.-cyclocitral (3) is 
hydrogenated using a hydrogenation catalyst such as palladium, to provide 
2,2,6-trimethylcyclohexanecarbaldehyde (4) mainly composed of the cisform, 
which is then isomerized using an acid catalyst such as phosphoric acid, 
to obtain 2,2,6-trimethylcyclohexanecarbaldehyde mainly composed of the 
trans-form (the trans-form content: 90 to 95%). Then, the aldehyde is 
oxidized in a usually well-known oxidation process, such as, for example, 
a nitric acid oxidation process, to obtain 
2,2,6-trimethylcyclohexanecarboxylic acid (5) mainly composed of the 
trans-form. 
In the 2nd process, as in foregoing reaction scheme 2, racemic 
7-methoxycitronellal (6) is reacted with acetic anhydride to provide enol 
acetate (7), which is then cyclized with phosphoric acid, etc., to obtain 
2,2,6-trimethylcyclohexanecarbaldehyde (4) mainly composed of the 
trans-form (the trans-form content: 88 to 93%). The aldehyde (4) is 
oxidized in a similar manner to obtain 
2,2,6-trimethylcyclohexanecarboxylic acid (5) mainly composed of the 
trans-form (the trans-form content: 88 to 93%). 
##STR6## 
Optical Resolution of Raw Material 
As an asymmetric amine which functions as a resolving agent for carrying 
out the optical resolution of racemic 2,2,6-trimethylcyclohexanecarboxylic 
acid, amines such as arylalkylamines [e.g., 1-phenylethylamine, 
1-phenyl-2-tolylethylamine, and 1-(1-naphthyl)ethylamine], natural 
alkaloids (e.g., guinine, brucine, and cinchonine), aminoalcohols, can be 
used, but primary amines represented by aryl group-containing ethylamines 
are preferably used. Of these amines, 1-phenylethylamine and 
1-(1-naphthyl)ethylamine are particularly preferable for obtaining a high 
optically pure product with good yield. 
There is no particular restriction on a recrystallizing solvent, and any 
solvent which dissolves a sparingly soluble or easily soluble diastereomer 
salt at a temperature of from room temperature to the boiling point 
thereof and precipitates the diastereomer salt at room temperature as it 
is or by cooling, concentrating, etc., may be used. For example, alcohols 
such as methanol and ethanol, esters such as ethyl acetate and methyl 
acetate, chlorinated hydrocarbons such as chloroform and methylene 
chloride, ethers such as diethyl ether and diisopropyl ether, hydrocarbons 
such as n-hexane and benzene, and water can be used singly or as a mixture 
thereof. A mixed solvent system of n-hexane and ethyl acetate or a single 
solvent system of diisopropyl ether is particularly preferable. 
The practical optical resolution is as follows. 
That is, after adding 2,2,6-trimethylcyclohexanecarboxylic acid (5) and an 
optically active amine in the foregoing solvent singly or mixed solvent at 
room temperature to form the salt, the solution is heated with stirring to 
uniformly dissolve the salt. The temperature of the solution is slowly 
lowered to room temperature to selectively crystallize the dissolved 
diastereomer salt, and the crystals are separated, whereby the optical 
resolution is carried out. 
In addition, at the crystallization, there is no particular need of adding 
seeds to the solution but for quickening the crystallization, it is 
effective to add a slight amount of the diastereomer salt as a seed for 
the crystallization. 
In regard to the amount of the resolving agent used, it is preferred to use 
the resolving agent in the range of from about 0.7 to 1.1 equivalents to 
2,2,6-trimethylcyclohexanecarboxylic acid. 
The diastereomer salt thus obtained is desalted by an ordinary method, to 
provide desired optically active 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylic acid (11) shown in the 
foregoing reaction schemes, and at the same time, the optically active 
amine is recovered. For example, a diluted aqueous hydrochloric acid 
solution and an organic solvent are added to the diastereomer salt, 
followed by shaking well the mixture to decompose the salt. After 
separating an organic layer containing 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylic acid (11) from an aqueous 
layer containing the optically active amine hydrochloride, the organic 
layer is washed with water and dehydrated, and the solvent is distilled 
off. Then, by distillation or silica gel column chromatography, optically 
active (1R,6S)-2,2,6-trimethylcyclohexanecarboxylic acid (11) can be 
obtained. The aqueous layer is made basic with a diluted aqueous potassium 
hydroxide solution and after shaking well the aqueous layer together with 
an organic solvent and separating the organic solvent layer from the 
aqueous layer, the optically active amine is recovered from the organic 
solvent layer. 
In addition, about both the optical antipodes of 
2,2,6-trimethylcyclohexanecarboxylic acid, after measuring the optical 
rotation thereof and convering into ethyl 
2,2,6-trimethylcyclohexanecarboxylate as a final product, gas 
chromatographic analysis by a capillary column carrying optically active 
cyclodextrin was carried out, and the difference in the areal percentages 
of both the enantiomers was used as the optical enatiometric excess (e.e.) 
or the optical purity (see, Hajime Nozaki, Hoshiimonodakeo Tsukuru Kagaku, 
page 236, 1983, published by Shokabo K. K.). 
Also, as a process of forming geometrically and optically pure ethyl 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylate (1) by esterification of 
geometrically and opticallypure 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylic acid (11) obtained, a process 
of reacting the carboxylic acid (11) and ethanol using an acid catalyst, 
and a process of reacting the carboxylic acid (11) in a system of sodium 
hydroxide (or potassium hydroxide) and ethyl bromide (or ethyl iodide) 
using a phase transfer catalyst are well known. 
Then, the present invention is further described in more detail by the 
following Synthesis Examples, Test Examples, and Examples, but these 
Examples are for illustrating the present invention but not to limit it in 
any way. 
SYNTHESIS EXAMPLE 1 
Synthesis of ethyl 2,2,6-trimethylcyclohexanecarboxylate (2a) containing 
the cis-form as main component 
1A): In a 500-ml autoclave, 200 g of .beta.-cyclocitral (3) (gas 
chromatographic purity: 94%) and 100 g of isopropyl alcohol were reacted 
using 5 g of a 5% palladium-alumina catalyst at a hydrogen pressure of 5 
kg/cm.sup.2 and at a reaction temperature of 25.degree. C. until a 
theoretical amount of hydrogen was consumed. Then, the catalyst was 
removed from the reaction mixture by filtration, and the isopropyl alcohol 
was recovered from the filtrate under reduced pressure by means of an 
evaporator, to provide 201 g of a concentrated oil. Then, 201 g of the 
concentrated oil was rectified by a 30-cm Helipack-packed still, to 
provide 168 g of 2,2,6-trimethylcyclohexanecarbaldehyde [boiling point: 
77.5.degree. to 79.5.degree. C./8 mm Hg, composition by gas chromatograph 
(type: HEWLETT KARD 5890, column: Carbo wax 20M (HP) 0.2 mm.times.25 m, 
conditions: 80.degree. C. to 220.degree. C., 5.degree. C./min.; 
hereinafter the same): trans-form content: 35%, cis-form content: 65%]. 
Analytical Data: MS (CI) M/e: 
(4)-Trans-form: 155 (M+, 14), 139 (9), 121 (16), 111 (20), 95 (16), 84 
(36), 69 (100), 55 (36), 41 (20) 
(4)-Cis-form: 155 (M+, 16), 139 (8), 121 (17), 111 (21), 96 (28), 85 (69), 
69 (100), 55 (42), 41 (27) 
1-B): In a 300-ml 4-necked flask equipped with a condenser, a thermometer, 
a dropping funnel, and a stirrer was placed 39 g of nitric acid (60% 
aqueous solution) and heated to 55.degree. C. To the solution was added 
dropwise 93 g (0.60 mole) of 2,2,6-trimethylcyclohexanecarbaldehyde (4) 
composed of 35% of the trans-form and 65% of the cis-form synthesized in 
Synthesis Example 1-A) described above over a period of 2 hours. 
Thereafter, the reaction was carried out for 3 hours at the same 
temperature. Then, 100 g of toluene and 100 g of water were added to the 
reaction mixture at room temperature to wash with water and form an 
organic layer and an aqueous layer separately. The organic layer was 
washed thrice with 100 g of a saturated aqueous sodium chloride solution, 
and the toluene was distilled off under reduced pressure by means of an 
evaporator, to provide 101 g of crude 2,2,6-trimethylcyclohexanecarboxylic 
acid (5) composed of 35% of the trans-form and 65% of the cis-form. 
Analytical Data: MS (CI) M/e 
(5)-Trans-form: 170 (M+, 7), 152 (35), 137 (4), 127 (7), 110 (100), 100 
(7), 87 (54), 69 (96), 56 (46), 41 (30), 29 (3) 
(5)-Cis-form: 170 (M+, 6), 152 (35), 137 (4), 127 (7), 110 (100), 100 (55), 
87 (55), 69 (91), 56 (44), 41 (30), 29 (1) 
1-C): In a 300-ml 4-necked flask equipped with a condenser, a thermometer, 
a dropping funnel, and a stirrer were placed 55 g (0.0135 mole) of 
tricaprylylmethylammonium chloride (trade name: Aliquat 336) as a phase 
transfer catalyst and 38.0 g (0.68 mole) of potassium hydroxide, and to 
the mixture was added dropwise a solution composed of 46 g (0.27 mole) of 
2,2,6-trimethylcyclohexanecarboxylic acid (5) synthesized in Synthesis 
Example 1-B) described above and 79 ml of toluene at a temperature of 
40.degree. C. or lower over a period of 30 minutes. After 20 minutes since 
then, 41.3 g (0.367 mole) of ethyl bromide was added dropwise to the 
mixture at a temperature of from 40.degree. C. to 45.degree. C. over a 
period of one hour. Furthermore, the mixture was stirred for 3 hours at 
the same temperature to finish the reaction. After washing the reaction 
mixture with water and separating an organic layer from an aqueous layer 
formed, the organic layer was washed with 100 ml of an aqueous 3% 
hydrochloric acid solution, and after further separating an organic layer 
from an aqueous layer, the organic layer was further washed twice with 100 
ml of an aqueous soda ash solution and a saturated aqueous sodium chloride 
solution. Then, the organic layer formed was separated from the aqueous 
layer and distilled under reduced pressure by an evaporator to distill off 
the toluene, whereby 54 g of a concentrated oil was obtained. Then, 54 g 
of the concentrated oil was rectified with a Widmer still, to provide 38 g 
of ethyl 2,2,6-trimethylcyclohexanecarboxylate (2a) (boiling point: 
98.degree. C./10 mm Hg; gas chromatic purity: 32% of the trans-form, 68% 
of the cis-form). 
Analytical Data: MS (CI) M/e 
(1)-Trans-form: 198 (M+, 8), 183 (4), 152 (87), 109 (86), 87 (53), 69 
(100), 55 (62), 41 (95), 29 (96) 
(1)-Cis-form: 198 (M+, 10), 183 (4), 152 (90), 129 (58), 110 (83), 87 (52), 
69 (100), 55 (48), 41 (80), 29 (62) 
SYNTHESIS EXAMPLE 2 
Synthesis of ethyl 2,2,6-trimethoxycyclohexanecarboxylate (2b) containing 
the trans-form as main component 
2-A): In a 2-liter 4-necked flask equipped with a condenser, a thermometer, 
a dropping funnel, and a stirrer were placed 305 g of acetic anhydride, 
9.5 g of sodium acetate, and 247 g of triethylamine in a nitrogen gas 
atmosphere, the mixture was heated to 75.degree. C. with stirring, and to 
the solution formed was added dropwise 350 g of commercially available 
racemic methoxycitranellal (6) (made by Takasago International 
Corporation) over a period of one hour. 
Thereafter, the reaction mixture was refluxed for 6 hours at a temperature 
of from 101.degree. C. to 117.degree. C., the reaction mixture was cooled 
to 5.degree. C. and washed with 200 g of water and 200 g of toluene, an 
organic layer was separated from an aqueous layer formed, 200 g of water 
was further added to the organic layer, and water washing and separation 
of the organic layer from the aqueous layer were carried out twice, to 
provide 590 g of a toluene solution of enol acetate (7). By measuring the 
solution with gas chromatography, it was confirmed that compound (7) has a 
composition composed of 29.5% of the cis-form, 62.7% of the trans-form, 
and 5.3% of diacetate (17). 
Spectral Data: MS (CI) M/e 
(7)-Trans-form: 229 (M+1, 1), 197 (70), 155 (42), 137 (100), 95 (12), 73 
(41) 
(7)-Cis-form: 229 (M+1, 3), 197 (100), 155 (88), 137 (98), 95 (24), 73 (82) 
Diacetate (17): 289 (M+1, 0.2), 197 (85), 155 (75), 137 (100), 103 (19), 73 
(33) 
The (7)-trans-form, the (7)-cis-form, and diacetate (17) are shown below. 
##STR7## 
Then, in a 2 liter 4-necked flask equipped with a condenser, a thermometer, 
a drainage means, and a stirrer were placed 590 g of a toluene solution of 
compound (7) obtained in the foregoing step, 210 g of 85% phosphoric acid, 
and 175 g of toluene, and the mixture was refluxed (the refluxing 
temperature: 70.degree. C. to 105.degree. C.) with stirring for 3 hours in 
a nitrogen gas atmosphere (the refluxing temperature was controlled by 
removing methanol formed together with toluene from the system). 
The reaction mixture was cooled to 5.degree. C., washed with 700 ml of cold 
water, an organic layer formed was separated from an aqueous layer, and 
after washing the organic layer once with 700 ml of water, 700 ml of an 
aqueous 5% soda ash solution, and then 700 ml of a saturated aqueous 
sodium chloride solution, followed by separating the organic layer from 
the aqueous layer. The toluene was distilled off under reduced pressure to 
provide 305 g of a concentrated oil. The concentrated oil thus obtained 
was rectified by a 30-cm Helipack-packed still, to provide 149 g of 
2,2,6-trimethylcyclohexanecarbaldehyde (4) [boiling point: 79.5.degree. C. 
to 80.5.degree. C./8 mm Hg, the composition by gas chromatography: 90% of 
the trans-form, 10% of the cis-form]. 
2-B): In a 300-ml 4-necked flask equipped with a condenser, a thermometer, 
a dropping funnel, and a stirrer was placed 40 g of nitric acid (60% 
aqueous solution) and heated to 55.degree. C. To the solution was added 
dropwise 95 g (0.62 mole) of 2,2,6-trimethylcyclohexanecarbaldehyde (4) 
composed of 90% of the trans-form and 10% of the cis-form synthesized in 
Synthesis Example 2-A) described above over a period of 2 hours. 
Thereafter, the reaction was carried out for 3 hours at the same 
temperature. Then, 100 g of toluene and 100 g of water were added to the 
reaction mixture at room temperature to wash with water and form an 
organic layer and an aqueous layer separately. The organic layer was 
washed thrice with 100 g of a saturated aqueous sodium chloride solution, 
and 80 ml of the toluene was distilled off under reduced pressure by means 
of an evaporator, to provide 104 g of crude 
2,2,6-trimethylcyclohexanecarboxylic acid (5) composed of 89% of the 
trans-form and 11% of the cis-form (boiling point: 44.degree. to 
54.degree. C.). The mass spectra of the cis- and trans-forms of the acid 
(5) were the same as those in Synthesis Example 1. 
2-C): In a 300-ml 4-necked flask equipped with a condenser, a thermometer, 
a dropping funnel, and a stirrer were placed 5.6 g (0.0137 mole) of 
tricaprylylammonium chloride (trade name: Aliquat 336) as a phase transfer 
catalyst and 38.9 g (0.69 mole) of potassium hydroxide, and a solution 
composed of 47.5 g (0.28 mole) of 2,2,6-trimethylcyclohexanecarboxylic 
acid (5) synthesized in Synthesis Example 2-B) described above and 80 ml 
of toluene was added dropwise to the mixture at a temperature of 
40.degree. C. or lower over a period of 30 minutes. After 20 minutes since 
then, 42.3 g (0.375 mole) of ethyl bromide was added dropwise to the 
mixture at a temperature of from 40.degree. C. to 45.degree. C. over a 
period of one hour. The mixture was further stirred for 3 hours at the 
same temperature to finish the reaction. After washing the reaction 
mixture with 200 ml of water and separating an organic layer from an 
aqueous layer formed, the organic layer was washed with 100 ml of an 
aqueous 3% hydrochloric acid solution, followed by separating the organic 
layer formed. The organic layer was washed twice with 100 ml of an aqueous 
5% soda ash solution and 100 ml of a saturated aqueous sodium chloride 
solution, followed by separating the organic layer formed. Then, the 
organic layer was distilled under reduced pressure by an evaporator to 
distill off the toluene, whereby 55 g of a concentrated oil was obtained. 
Then, 55 g of the concentrated oil was rectified by a 30-cm Widmer still, 
to provide 39 g of ethyl 2,2,6-trimethylcyclohexanecarboxylate (2a) 
[boiling point: 98.degree. C./10 mm Hg; gas chromatographic purity: 90% of 
the trans-form, 10% of the cis-form]. 
It was also confirmed that the mass spectrum of the compound (2a) was the 
same as that in Synthesis Example 1. 
SYNTHESIS EXAMPLE 3 
Synthesis of ethyl 2,2,6-trimethylcyclohexanecarboxylate (2a) directly from 
2,2,6-trimethylcyclohexanecarbaldehyde (4) 
In a one-liter 4-necked flask equipped with a condenser, a thermometer, a 
dropping funnel, and a stirrer were placed 57 g of 
2,2,6-trimethylcyclohexanecarbaldehyde (4) [gas chromatographic 
composition: 90% of the trans-form, 10% of the cis-form] synthesized in 
synthesis Example 2, 45 g of acetic acid, and 250 ml of ethanol. After 
stirring the mixture and cooling it to 10.degree. C., 600 g of a 
commercially available aqueous sodium hypochlorite solution (active 
chlorine content: 9.5%) was added dropwise thereto at the same temperature 
over a period of one hour. Thereafter, the mixture was returned to room 
temperature and stirred for one hour to finish the reaction. The 
composition of the reaction mixture by gas chromatography was comprised of 
62% of ethyl 2,2,6-trimethylcyclohexanecarboxylate (2a), 27% of 
2,2,6-trimethylcyclohexanecarboxylate, and 11% of other unknown 
components. 
Then, after adding 300 g of toluene to the reaction mixture, extracting the 
product, and separating a toluene layer from an aqueous layer, the toluene 
layer was washed with an aqueous 10% sodium hydroxide solution and 
separated from an aqueous layer to remove the acid (5). Then, the toluene 
was distilled off to provide 48 g of a concentrated oil. Then, 48 g of the 
concentrated oil was rectified by a 15-cm Helipack-packed still, to 
provide 28 g of ethyl 2,2,6-trimethylcyclohexanecarboxylate (1a) [boiling 
point: 96.5.degree. C. to 98.degree. C./10 mm Hg; gas chromatographic 
purity: 89% of the trans-form, 11% of the cis-form]. 
SYNTHESIS EXAMPLE 4 
Synthesis of ethyl (1R,6S)-2,2,6-trimethylcyclohexanecarboxylate (1) 
4-A): In a 5-liter 4-necked flask equipped with a condenser, a thermometer, 
a dropping funnel, and a stirrer were placed 871 g of acetic anhydride, 27 
g of sodium acetate, and 706 g of triethylamine in a nitrogen gas 
atmosphere, and after heating the mixture to 75.degree. C. with stirring, 
1 kg of commercially available L-methoxycitronellal (8) (made by Takasago 
International Corporation; [.alpha.].sub.D.sup.25 =-10.42.degree., optical 
purity=98% ee) was added dropwise thereto over a period of one hour. 
Thereafter, the reaction mixture was refluxed for 6 hours at a temperature 
of from 10.degree. C. to 15.degree. C. and cooled to 5.degree. C., the 
reaction mixture was washed with 500 g of water and 500 g of toluene, and 
the toluene layer was separated from an aqueous layer. Then, the toluene 
layer was washed twice with 500 g of water, followed by separating the 
toluene layer from an aqueous layer in each step to provide 1690 g of a 
toluene solution of enol acetate (9). When the solution was analyzed by 
gas chromatography, the cis-form was 29.0%, the trans-form was 62.9%, and 
diacetate (18) was 5.5%. 
The mass spectra of enol acetate and diacetate obtained in the reaction 
were the same as those of the (7)-trans-form, the (7)-cis-form, and 
diacetate (18) in Synthesis Example 2. 
The trans-form [(9)-trans-form], the cis-form [(9)-cis-form], and diacetate 
(18) are shown below. 
##STR8## 
Then, in a 5-liter 4-necked flask equipped with a condenser, a thermometer, 
a drainage means, and a stirrer were placed 1690 g of the toluene solution 
of compound (9) obtained above, 620 g of 85% phosphoric acid, and 500 g of 
toluene, and the mixture was refluxed (refluxing temperature: 71.degree. 
C. to 107.degree. C.) with stirring for 3 hours in a nitrogen gas 
atmosphere (the refluxing temperature was controlled by removing slowly 
methanol formed together with toluene). 
The reaction mixture obtained was cooled to 5.degree. C. and washed with 
2,000 ml of cold water, and an organic layer formed was separated from an 
aqueous layer. Furthermore, after washing once the organic layer with each 
of 2,000 ml of water, 2,000 ml of an aqueous 5% soda ash solution, and 
2,000 ml of a saturated aqueous sodium chloride solution, followed by 
separating the organic layer from an aqueous layer. The toluene was 
distilled off under reduced pressure to provide 872 g of a concentrated 
oil. Then, 872 g of the concentrated oil was rectified with a 1-m 
Helipack-packed still to provide 425 g of optically active 
2,2,6-trimethylcyclohexanecarbaldehyde (10) [boiling point: 80.degree. C. 
to 81.degree. C./8 mm Hg; [.alpha.].sub.D.sup.25 =-0.47.degree.; gas 
chromatographic purity: 90% of the trans-(1R,6S)-form, 10% of the 
cis-(1S,6S)-form]. 
The trans-(1R,6S)-form [(10)-trans-form] and the cis-(1S,6S)-form 
[(10)-cis-form] are shown below. 
##STR9## 
4-B): In a 300-ml 4-necked flask equipped with a condenser, a thermometer, 
a dropping funnel, and a stirrer was placed 42 g of nitric acid (aqueous 
60% solution), and the temperature was raised to 55.degree. C. by heating. 
To the solution was added dropwise 100 g (0.65 mole) of 
(1R,6S)-2,2,6-trimethylcyclohexanecarbaldehyde (10) [composition: 90% of 
the (1R,6S)-form, 10% of the (1S,6S)-form] synthesized in Synthetic 
Example 4-A) with stirring over a period of 2 hours. After carrying out 
the reaction for 3 hours at the same temperature, the reaction mixture was 
washed with water with 100 g of toluene and 100 g of water at room 
temperature, followed by separating an organic layer from an aqueous 
layer. The organic layer was washed thrice with 100 g of a saturated 
aqueous sodium chloride solution, followed by separating the organic layer 
from an aqueous layer. The toluene was distilled off from the organic 
layer by an evaporator under reduced pressure to provide 109 g of crude 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylic acid (11) [composition: 91% 
of the (1R,6S)-form, 9% of the (1S,6S)-form; melting point: 44.degree. C. 
to 54.degree. C.]. 
The product was recrystallized from methylene chloride as a solvent to 
provide 52 g of pure (1R,6S)-2,2,6-trimethylcyclohexanecarboxylic acid 
(11) (melting point: 67.degree. C. to 68.degree. C.; optical rotation 
[.alpha.].sub.D.sup.25 =+14.37.degree.). 
Analytical Data of Compound (11): 
.sup.1 H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.903 (d, 3H, J=5.94 Hz), 0.907 
(m, 1H), 0.99 (s, 1H), 1.010 (s, 1H), 1.18 (m, 1H), 1.42 (m, 1H), 1.50 (m, 
2H), 1.73 (m, 1H), 1.83 (m, 2H) 
MS m/e: 170 (M+, 7), 152 (35), 137 (4), 127 (7), 110 (100), 100 (7), 87 
(54), 69 (96), 56 (46), 41 (30), 29 (3) 
IR (cm.sup.-1): 3400-2500, 2950, 2926, 1700, 950 
4-C): In a 300-ml 4-necked flask equipped with a condenser, a thermometer, 
a dropping funnel, and a stirrer were placed 5.9 g (0.0145 mole) of 
tricaprylylmethylammonium chloride (trade name: Aliquat 336) as a phase 
transfer catalyst and 40.9 g (0.73 mole) of potassium hydroxide, and a 
solution composed of 50 g (0.29 mole) of 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylic acid (11) synthesized in step 
4-B) and 85 ml of toluene was added dropwise to the mixture at a 
temperature of 40.degree. C. or lower over a period of 30 minutes. After 
20 minutes since then, 44.5 g (0.395 mole) of ethyl bromide was added 
dropwise to the mixture at a temperature of from 40.degree. C. to 
45.degree. C. over a period of one hour, and the mixture was further 
stirred for 3 hours at the same temperature to finish the reaction. The 
reaction mixture was washed with 200 ml of water, followed by separating 
an organic layer from an aqueous layer. The organic layer was washed with 
100 ml of an aqueous 3% hydrochloric acid solution, followed by separating 
the organic layer from an aqueous layer. The organic layer was further 
washed twice with 100 ml of an aqueous 5% soda ash solution and 100 ml of 
a saturated aqueous sodium chloride solution, followed by separating the 
organic layer from an aqueous layer. The toluene was distilled off from 
the organic solvent solution obtained by an evaporator under reduced 
pressure to provide 58 g of a concentrated oil. Then, 58 g of the 
concentrated oil was rectified by a 30-cm Widmer still to provide 41 g of 
pure ethyl (1R,6S)-2,2,6-trimethylcyclohexanecarboxylate (1) [boiling 
point: 98.degree. C./10 mm Hg; optical rotation: [.alpha.].sub.D.sup.25 
=+14.14.degree., gas chromatographic purity: 99.9% or higher]. 
Analytical Data of Ethyl (1R,6S)-Trimethylcyclohexanecarboxylate (1): 
.sup.1 H-NMR (400 MHz, CDCl.sub.3) .delta.: 0.826 (d, 3H, J=6.0 Hz), 0.90 
(m, 1H), 0.936 (s, 3H), 0.970 (s, 3H), 1.15 (m, 1H), 1.26 (t, 3H, J=7.1 
Hz), 1.39 (m, 1H), 1.50 (m, 2H), 1.69 (m, 1H), 1.79 (d, 1H, J=11.4 Hz), 
1.85 (m, 1H), 4.14 (q, 2H, J=7.1 Hz) 
MS m/e: 198 (M+, 8), 183 (4), 152 (27), 109 (86), 87 (53), 69 (100), 55 
(62), 41 (95), 29 (96) 
IR (cm.sup.-1): 2925, 1740, 1460, 1385, 1240, 1195, 1040 
SYNTHESIS EXAMPLE 5 
Synthesis of ethyl (1S,6R)-trimethylcyclohexanecarboxylate (16) 
5-A): In a 2 liter 4-necked flask equipped with a condenser, a thermometer, 
a dropping funnel, and a stirrer were placed 280 g of acetic anhydride, 9 
g of sodium acetate, and 230 g of triethylamine in a nitrogen gas 
atmosphere, and while heating the mixture to 75.degree. C. with stirring, 
320 g of commercially available d-methoxycitronellal (12) (made by 
Takasago International Corporation, [.alpha.].sub.D.sup.25 
=+10.52.degree., optical purity: 98% ee) was added dropwise thereto over a 
period of one hour. 
After refluxing (100.degree. C. to 119.degree. C.) the reaction mixture for 
6 hours, the resulting reaction mixture was cooled to 5.degree. C., washed 
with 160 g of water and 160 g of toluene, followed by separating an 
organic layer formed from an aqueous layer. The organic layer was further 
washed twice with 160 g of water, followed by separating the organic 
solvent solution formed from an aqueous solution to provide 540 g of a 
toluene solution of enol acetate (13). The gas chromatographic composition 
of the compound (13) was composed of 30% of the cis-form (13), 63% of the 
trans-form (13), and 5.0% of diacetate (19) 
The mass spectra of enol acetate (13) were the same as those of the 
(7)-trans-form, the (7)-cis-form, and diacetate (19) in Synthesis Example 
2. 
The trans-form (13), the cis-form (13), and diacetate (19) formed are shown 
below. 
##STR10## 
Then, in a 2 liter 4-necked flask equipped with a condenser, a thermometer, 
a drainage means, and a stirrer were placed 540 g of the toluene solution 
of compound (13) obtained, 200 g of 85% phosphoric acid, and 160 g of 
toluene, and the mixture was refluxed (refluxing temperature: 80.degree. 
C. to 108.degree. C.) with stirring in a nitrogen gas atmosphere (the 
refluxing temperature was controlled by slowly removing methanol formed 
together with toluene). 
The reaction mixture was cooled to 5.degree. C. and washed with 640 ml of 
cold water, followed by separating an organic layer from an aqueous layer. 
The organic layer was washed once with 640 ml of water, 640 ml of an 
aqueous 5% soda ash solution, and 640 ml of a saturated aqueous sodium 
chloride solution, followed by separating the organic layer formed from an 
aqueous layer in each time to provide 280 g of a concentrated oil. The 
concentrated oil was rectified by a 30-cm Helipack-packed still to provide 
136 g of optically active 2,2,6-trimethylcyclohexanecarbaldehyde (14) 
[boiling point: 79.degree. C. to 81.degree. C./8 mm Hg; 
[.alpha.].sub.D.sup.25 =+0.49.degree.; gas chromatographic purity: 91% of 
the trans-(1S,6R)-form, 9% of the cis-(1R,6R)-form]. 
The trans-form [(14)-trans-form] and the cis-form [(14)-cis-form] formed 
are shown below. 
##STR11## 
5-B): In a 300-ml 4-necked flask equipped with a condenser, a thermometer, 
a dropping funnel, and a stirrer was placed 38 g of nitric acid (aqueous 
60% solution) and heated to 55.degree. C. Then, 90 g of 
(1S,6R)-2,2,6-trimethylcyclohexanecarbaldehyde (14) [composition: 91% of 
the (1S,6R)-form, 9% of the (1R,6R)-form] synthesized in Synthesis Example 
5-A) was added dropwise thereto with stirring over a period of 2 hours. 
After carrying out the reaction for 3 hours at the same temperature, the 
reaction mixture was washed with water with 90 g of toluene and 100 g of 
water at room temperature, followed by separating an organic layer formed 
from an aqueous layer. The organic layer was washed thrice with 100 g of a 
saturated aqueous sodium chloride solution, followed by separating the 
organic layer from an aqueous layer. The toluene was distilled off from an 
organic layer by an evaporator under reduced pressure to provide 98 g of 
crude (1S,6R)-2,2,6-trimethylcyclohexanecarboxylic acid (15) [composition: 
91% of the (1S,6R)-form, 9% of the (1R,6R)-form]. The product was 
recrystallized from methylene chloride as a solvent to provide 46 g of 
pure (1S,6R)-2,2,6-trimethylcyclohexanecarboxylic acid (15) [melting 
point: 67.degree. C. to 68.degree. C.; optical rotation; 
[.alpha.].sub.D.sup.25 =-14.40.degree.]. 
5-C): In a 300-ml 4-necked flask equipped with a condenser, a thermometer, 
a dropping funnel, and a stirrer were placed 5.3 g (0.013 mole) of 
tricaprylmethylammonium chloride (trade name: Aliquat 336) as a phase 
transfer catalyst and 37 g (0.65 mole) of potassium hydroxide, and a 
solution composed of 45 g (0.26 mole) of 
(1S,6R)-2,2,6-trimethylcyclohexanecarboxylic acid synthesized in Synthesis 
Example 5-B) described above and 80 ml of toluene was added dropwise 
thereto at a temperature of 40.degree. C. or lower over a period of 30 
minutes. After 20 minutes since then, 40 g (0.355 mole) of ethyl bromide 
was added dropwise thereto at a temperature of from 40.degree. C. to 
45.degree. C. over a period of one hour. The mixture was further stirred 
for 3 hours at the same temperature to finish the reaction. 
The reaction mixture obtained was washed with 200 ml of water, followed by 
separating an organic layer from an aqueous layer. The organic layer was 
washed with 100 ml of an aqueous 3% hydrochloric acid solution, followed 
by separating the organic layer from an aqueous layer. The organic layer 
was further washed twice with 100 ml of an aqueous 5% soda ash solution 
and 100 ml of a saturated aqueous sodium chloride solution, followed by 
separating the organic solvent solution. The toluene was distilled off 
from the organic layer by an evaporator under reduced pressure to provide 
52 g of a concentrated oil. Then, 52 g of the concentrated oil was 
rectified with a 30-cm Widmer still to provide 37 g of pure ethyl 
(1S,6R)-2,2,6-trimethylcyclohexanecarboxylate (16) [boiling point: 
98.degree. C./10 mm Hg; optical rotation: [.alpha.].sub.D.sup.25 
=-14.17.degree.; gas chromatographic purity: 99.9% or higher]. 
The compound (16) obtained is shown below. 
##STR12## 
TEST EXAMPLES 
1) Stability Test with Soap 
A soap was perfumed with ethyl 2,2,6-trimethylcyclohexanecarboxylate (2b) 
synthesized in Synthesis Example 2 and placed in a glass container, 
followed by closing tightly. The container was placed in a chamber kept at 
50.degree. C., whereby a stability test was carried out for 2 months. 
As a result of determining the change of the fragrance quality by 5 expert 
panelists, it was found that not only any odor by the decomposed products 
was observed, but neither change nor deterioration of the fragrance were 
confirmed and, hence, the compound (2b) was stable to the passage of time. 
Also, for determining the stability to the sun light, when the foregoing 
soap was placed under the sun light for one month at room temperature to 
carry out the tanning test, no tanning was observed at all. 
2) Stability Test with Acidic Solution 
An acetic acid-acidic solution (pH 3) of ethyl 
2,2,6-trimethylcyclohexanecarboxylate (2b) synthesized in Synthesis 
Example 2 having the following composition was prepared. 
______________________________________ 
Acetic Acid 1 g 
Triethyl Citrate 50 g 
Ethyl 2,2,6-Trimethylcyclohexane 
10 g 
carboxylate (2b) 
n-Dodecane (internal standard) 
1 g 
______________________________________ 
The solution was placed in a 100-ml glass container and after storing it in 
a chamber kept at 40.degree. C. for one month, the change of the 
composition was determined by gas chromatography. As a result, it was 
confirmed that no change was observed and, thus, ethyl 
2,2,6-trimethylcyclohexanecarboxylate was stable under the acetic 
acid-acid condition. 
3) Stability Test with Basic Solution 
A basic solution (pH 10) of ethyl 2,2,6-trimethylcyclohexanecarboxylate 
(2b) synthesized in Synthesis Example 2 having the following composition 
was prepared. 
______________________________________ 
Triethylamine 1 g 
Triethyl Citrate 50 g 
Ethyl 2,2,6-Trimethylcyclohexane- 
5 g 
carboxylate 
Water 0.5 g 
Methanol 10 g 
n-Dodecane (internal standard) 
1 g 
______________________________________ 
The solution was placed in a 100-ml glass container, and after storing the 
container in a chamber kept at 40.degree. C. for one month, the change of 
the composition was determined by gas chromatography. As a result, it was 
confirmed that no change was observed and, hence, ethyl 
2,2,6-trimethylcyclohexanecarboxylate (2b) was stable under the 
amine-basic condition (pH 10). 
4) Safety Test 
In regard to the safety of ethyl 2,2,6-trimethylcyclohexanecarboxylate (2b) 
synthesized in Synthesis Example 2, a sensitization test, a skin primary 
irritation test, a phytotoxicity test, and a mutation test were applied 
but all results were negative and hence the safety of the compound (2b) 
was very high. 
EXAMPLE 1 
An enzyme-containing bleaching agent composition having the following 
composition was prepared. 
______________________________________ 
(weight part) 
______________________________________ 
Sodium Percarbonate 93.7 
Enzyme (Alkalaze 29T, trade name, 
1.0 
made by Novo Industry Co.) 
Anhydrous Calcium Sulfate 
5.0 
Ethanol Solution of 50% Ethyl 
0.3 
2,2,6-Trimethylcyclohexanecarboxylate 
obtained in Synthesis Example 2 
Sum 100.0 
______________________________________ 
About the foregoing composition and compositions each containing ethyl 
2,2,6-trimethylcyclohexanecarboxylate (2a), wherein the cis-form was the 
main component, obtained in Synthesis Example 1 or optically active ethyl 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylate (1) obtained in Synthesis 
Example 4 in place of the ethyl 2,2,6-trimethylcyclohexanecarboxylate 
(2b), wherein the trans-form was the main component, (90% of the 
trans-form, 10% of the cis-form) obtained in Synthesis Example 2 in the 
foregoing composition, comparison tests were carried out in regard to 
masking properties of the enzyme odor. 
That is, each of the foregoing bleaching agent compositions was closed in a 
plastic bottle, the bottle was stored in a chamber kept at 40.degree. C. 
for 30 days, and the change of the enzyme odor was determined. The 
evaluated results by 10 expert panelists are shown in Table 1. 
TABLE 1 
______________________________________ 
Ethyl 2,2,6-Trimethyl- 
cyclohexanecarboxylate 
(A) (B) (C) 
______________________________________ 
Synthesis Example 4 
10 0 0 
Synthesis Example 2 
8 2 0 
Synthesis Example 1 
2 5 3 
______________________________________ 
(A)Number of panelists who did not smell the enzyme odor. 
(B)Number of panelists who smelled a little the enzyme odor. 
(C)Number of panelists who smelled considerably the enzyme odor. 
From the results shown above, it has been found that the bleaching agent 
using ethyl (1R,6S)-trimethylcyclohexanecarboxylate (1) obtained in 
Synthesis Example 4 completely masks the enzyme odor and that the 
bleaching agent using ethyl 2,2,6-trimethylcyclohexanecarboxylate (2b) 
mainly composed of the trans-form obtained in Synthesis Example 2 also 
satisfies the masking effect to the enzyme odor. Also, there was no change 
of the fragrance quality in both of these bleaching agents. 
EXAMPLE 2 
Using each of ethyl 2,2,6-trimethylcyclohexanecarboxylate (2b) (90% of the 
trans-form, 10% of the cis-form) mainly composed of the trans-form 
obtained in Synthesis Example 2, ethyl 
2,2,6-trimethylcyclohexanecarboxylate (2a) mainly composed of the cis-form 
obtained in Synthesis Example 1, and optically active ethyl 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylate (1) obtained in Synthesis 
Example 4, each of floral bouquet-like fragrances for ladies' use having 
the following formulations (compositions) was prepared, and the fondness 
was tested by 20 expert panelists. 
As a result, in regard to each of formulations 1 and 2 each using ethyl 
(1R,6S)-trimethylcyclohexanecarboxylate (1) obtained in Synthesis Example 
4 or ethyl 2,2,6-trimethylcyclohexanecarboxylate (2b) mainly composed of 
the trans-form obtained in Synthesis Example 2, all the panelists answered 
that they liked them since there was a settlement in top note as compared 
to the blank, and there was a tender floral smell. Also, in the case of 
formulation 3 using ethyl 2,2,6-trimethylhexanecarboxylate (2a) mainly 
composed of the cis-form obtained in Synthesis Example 1, the 5 panelists 
answered that formulation 3 was better than the blank, the 13 panelists 
answered that the effect of adding ethyl 
2,2,6-trimethylcyclohexanecarboxylate was not noticed, and further the 2 
panelists answered that the blank was better. In addition, in the 
comparison of formulation 1 with formulation 2, the 18 panelists answered 
that formulation 1 had a stronger diffusibility of top note and was better 
than formulation 2 since the formulation 1 had a fresh odor. 
______________________________________ 
Formula- 
Formula- Formula- 
tion 1 tion 2 tion 3 Blank 
______________________________________ 
.beta.-Ionone 80 80 80 80 
Benzyl Acetate 
60 60 60 60 
Benzyl Salicylate 
120 120 120 120 
Cis-2-hexenyl salicylate 
30 30 30 30 
L-Citronellol 34 34 34 34 
L-Hydroxyoitronellal 
50 50 50 50 
Eugenol 40 40 40 40 
Methyl Dihydro- 
20 20 20 20 
jasmonate 
Indole 1 1 1 1 
p-t-Butyl-.alpha.-methyldi- 
120 120 120 120 
hydrocinnaminc 
Aldehyde 
Linalool 80 80 80 80 
Ethylene Brassylatez 
80 80 80 80 
Rose Absolute 30 30 30 30 
Phenylethyl Alcohol 
50 50 50 50 
Vanillin 5 5 5 5 
Acetylcedrene 120 120 120 120 
Compound (1)* 10 -- -- -- 
Compound (2b)** 
0 10 0 0 
Compound (2a)*** 
-- -- 10 -- 
Sum 1000 1000 1000 990 
______________________________________ 
*Ethyl (1R,6S)2,2,6-trimethylcyclohexanecarboxylate (1) of Synthesis 
Example 4 
**Ethyl 2,2,6trimethylcyclohexanecarboxylate (2b) of Synthesis Example 2 
***Ethyl 2,2,6trimethylcyclohexanecarboxylate (2a) of Synthesis Example 1 
 
EXAMPLE 2 
A rose base having high preference of the following formulation was 
prepared using ethyl 2,2,6-trimethylcyclohexanecarboxylate (2b) mainly 
composed of the trans-form obtained in Synthesis Example 2. 
______________________________________ 
Formulation (weight part) 
______________________________________ 
Nonyl Aldehyde 2 
.beta.-Ionone 30 
Cis-3-hexenyl Acetate 3 
L-Citronellol 80 
L-Citronellyl Acetate 7 
Garaniol 110 
Phenylethyl aldehyde Dimethyl Acetal 
50 
Isocyclocitral 6 
L-Rose Oxide 10 
Cis-3-hexenol 7 
Methyleugenol 20 
Nerol 20 
Phenylethyl Acetate 65 
Phenylethyl Alcohol 560 
Compound (2b)* 30 
Sum 1000 
______________________________________ 
*Ethyl 2,2,6trimethylcyclohexanecarboxylate (2b) of Synthesis Example 2 
EXAMPLE 4 
A citrus-like fragrance having high preference of the following formulation 
was prepared using ethyl (1R,6S)-2,2,6-trimethylcyclohexanecarboxylate (1) 
obtained in Synthesis Example 4. 
______________________________________ 
Formulation (weight part) 
______________________________________ 
Benzyl Acetate 6 
Bergamot Oil 100 
Citral 30 
L-Citronellol 10 
Geranyl Acetate 60 
Grape Fruit Oil 50 
Methyl Dihydrojasmonate 
50 
Heliotropin 2 
Lemon Oil 250 
Lime Oil 30 
Linalool 50 
Linalyl Acetate 100 
Ethyl Brassylate 15 
Orange Oil 190 
Petigrain Citronia Oil 2 
Phenylethyl Alcohol 20 
Styrallyl Acetate 15 
4-(4-Methyl-3-pentenyl)-3-cyclohexane- 
5 
1-carbaldehyde 
Compound (1)* 15 
Sum 1000 
______________________________________ 
*Ethyl (1R,6S)2,2,6-trimethylcyclohexanecarboxylate (1) of Synthesis 
Exqample 4. 
SYNTHESIS EXAMPLE 6 
Synthesis of 2,2,6-trimethylcyclohexanecarboxylic acid (5) mainly composed 
of the racemic trans-form using cyclocitral (3) as raw material 
6-A): In a 500-ml autoclave, a mixture of 200 g of .beta.-cyclocitral (3) 
(gas chromatographic purity: 94%) and 100 g of isopropyl alcohol was 
subjected to hydrogenation reaction using 5 g of a 5% palladium-alumina 
catalyst at a hydrogen pressure of 5 kg/cm.sup.2 and at a reaction 
temperature of 25.degree. C. until a theoretical amount of hydrogen was 
consumed. Then, the catalyst was removed from the reaction mixture by 
filtration, and the isopropyl alcohol was recovered from the filtrated by 
an evaporator under reduced pressure to provide 201 g of a concentrated 
oil of crude 2,2,6-trimethylcyclohexanecarbaldehyde [the composition by 
gas chromatograph: 29% of the trans-form, 70% of the cis-form, and 0.3% of 
others]. 
After reacting 201 g of the concentrated oil and 20 g of p-toluenesulfonic 
acid using 800 ml of toluene at 80.degree. C. for 10 hours, the reaction 
mixture was washed with water and neutralized by an ordinary manner to 
provide 197 g of a concentrated oil of crude 
2,2,6-trimethylcyclohexanecarbaldehyde (4) mainly composed of the 
trans-form. 
Then, by rectifying 197 g of the concentrated oil with a 30-cm 
Helipack-packed still, 138 g of 2,2,6-trimethylcyclohexanecarbaldehyde (4) 
[boiling point: 78.6 to 80.6.degree. C./8 mm Hg; the composition by gas 
chromatography: 90.2% of the trans-form, 9.8% of the cis-form] was 
obtained. 
The structure of the trans-form and the cis-form are as follows. 
##STR13## 
6-B): In a 300-ml 4-necked flask equipped with a condenser, a thermometer, 
a dropping funnel, and a stirrer was placed 39 g of nitric acid (aqueous 
60% solution), and the temperature was raised to 55.degree. C. Then, 93 g 
(0.60 mole) of 2,2,6-trimethylcyclohexanecarbaldehyde [composition: 90.2% 
of the trans-form, 9.8% of the cis-form] synthesized in Synthesis Example 
6-A) was added dropwise thereto over a period of 2 hours. Thereafter, the 
reaction was carried out for 3 hours at the same temperature, and the 
reaction mixture obtained was washed with of 100 g of toluene and 100 g of 
water, followed by separating an organic layer from an aqueous layer. 
After further washing thrice the organic layer with 100 g of a saturated 
aqueous sodium chloride solution, the organic layer formed was separated 
from an aqueous layer. The toluene was distilled off from the organic 
layer by an evaporator under reduced pressure to provide 101 g of crude 
2,2,6-trimethylcyclohexanecarboxylic acid (5) [composition: 90.5% of the 
trans-form, 9.5% of the cis-form]. 
The structures of the trans-form and the cis-form of crude 
2,2,6-trimethylcyclohexanecarboxylic acid (5) obtained are shown below. 
##STR14## 
SYNTHESIS EXAMPLE 7 
Optical resolution of 2,2,6-trimethylcyclohexanecarboxylic acid using 
optically active .alpha.-naphthylethylamine 
To 10.800 ml of n-hexane was added 90.0 g (0.528 mole) of 
2,2,6-trimethylcyclohexanecarboxylic acid mainly composed of the racemate 
obtained in Synthesis Example 6 [90.5% of the trans-form, 9.5% of the 
cis-form] was added at room temperature, and 90.3 g of 
(R)-(+)-1-(1-naphthyl)ethylamine was further added thereto with stirring 
to form precipitates. To the reaction system containing the precipitates 
was added 810 ml of ethyl acetate, and the mixture was heated with 
stirring to dissolve the precipitates to form a homogenous solution. After 
stopping the heating, the solution was allowed to stand overnight as it 
was. The crystals thus formed were similarly recrystallized 4 times (5 
times in the sum total) to provide 20.4 g of a white acicular crystal of a 
(1R,6S)-trimethylcyclohexanecarboxylic 
acid-(R)-(+)-1-(1-naphthyl)ethylamine salt [melting point: 102.degree. C. 
to 105.degree. C., [.alpha.].sub.D.sup.24 =+27.6.degree. (c=0.51, EtOH)]. 
The percent yield for the product was 11.3%. 
Then, the salt obtained was stirred in a mixture of 300 ml of 10% 
hydrochloric acid and 900 ml of diethyl ether for 30 minutes at room 
temperature, followed by separating a diethyl ether layer formed from an 
aqueous layer. The diethyl ether layer was washed with 300 ml of a 
saturated aqueous sodium chloride solution, and after dehydrating over 
anhydrous sodium sulfate, the solvent was distilled off to provide 10.2 g 
of optically active (1R,6S)-2,2,6-trimethylcyclohexanecarboxylic acid (11) 
[melting point: 68.degree. C. to 69.degree. C., [.alpha.].sub.D.sup.24 
=+14.3.degree. (c=1.01, EtOH), gas chromatographic purity: 99.9% of the 
trans-form, 0.1% of the cis-form]. In addition, the aqueous layer was made 
basic (ph 10) with 48.8 g of sodium hydroxide and then extracted with 700 
ml of diethyl ether, whereby 9.3 g of (R)-(+)-1-(1-naphthyl)ethylamine was 
recovered. 
The optical purity of the recovered 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylic acid was determined as 
follows. That is, after converting the carboxylic acid into the optically 
active desired compound, i.e., ethyl 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylate by an ethylation method 
using toluene as a solvent as well as potassium hydroxide and ethyl 
bromide in the presence of a phase transfer catalyst, the analysis was 
carried out by an optically active capillary column (50 ml.times.0.25 mm) 
carrying CP-cyclodextrin-B-236-M-19 under a constant condition at 
85.degree. C., and from the difference of the areal percentage of two 
kinds of diastereomers obtained, the optical purity was determined to be 
97.5% ee. 
SYNTHESIS EXAMPLE 8 
Optical resolution of 2,2,6-trimethylcyclohexanecarboxylic acid using 
optically active .alpha.-phenylethylamine 
To 1,080 ml of diisopropyl ether was added 27.0 g (0.159 mole) of optically 
active 2,2,6-trimethylcyclohexanecarboxylic acid ([.alpha.].sub.D.sup.25 
=+14.37.degree.) having an optical purity of 98% ee obtained in Synthesis 
Example 4-B) at room temperature, and 19.2 g (0.159 mole) of 
(+)-1-phenylethylamine [hereinafter referred to as "(+)-PEA"] was further 
added thereto with stirring to form precipitates. The reaction system 
containing the precipitates was heated with stirring to dissolve the 
precipitates and form a homogenous solution, and the heating was stopped. 
The solution was allowed to stand overnight as it was. Crystals thus 
formed were recrystallized again (total twice) similarly, to provide 15.2 
g of a white acicular crystal of a (+)-PEA salt [melting point: 71.degree. 
C. to 73.degree. C., [.alpha.].sub.D.sup.24 =+21.0.degree. (c=0.99, 
EtOH)]. The percent yield for the product was 56.3%. 
The salt obtained was stirred in a mixture of 200 ml of 10% hydrochloric 
acid and 600 ml of diethyl ether for 30 minutes at room temperature. After 
separating a diethyl ether layer formed from an aqueous layer, the diethyl 
ether layer was washed with 200 ml of a saturated aqueous sodium chloride 
solution, followed by separating the diethyl ether layer formed from an 
aqueous layer. After dehydrating the diethyl ether layer over anhydrous 
sodium sulfate, the solvent was distilled off to provide 8.8 g of 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylic acid (11) [melting point: 
70.degree. C.; [.alpha.].sup.24 =+14.7.degree. (c=0.51, EtOH); gas 
chromatographic purity: 100%]. 
The structure of (1R,6S)-2,2,6-trimethylcyclohexanecarboxylic acid (11) 
[compound (11)] obtained is as follows. 
##STR15## 
In addition, after making the aqueous layer basic (pH 10) with 32.5 g of 
sodium hydroxide, the aqueous layer was extracted with 500 ml of diethyl 
ether to recover 5.7 g of (+)-PEA. 
The optical purity of the (1R,6S)-2,2,6-trimethylcyclohexanecarboxylic acid 
(11) was determined to be 99.99% ee by the method described in Synthesis 
Example 7. 
In addition, the esterification of the foregoing optically resolved 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylic acid (11) was carried out by 
the following manner. 
In a 100-ml 4-necked flask-equipped with a condenser, a thermometer, a 
dropping funnel, and a stirrer were placed 10.2 g (0.0025 mole) of 
tricaprylylmethyl ammonium chloride (trade name: Aliquat 336) as a phase 
transfer catalyst and 7.0 g (0.126 mole) of potassium hydroxide, and a 
solution composed of 8.5 g (0.05 mole) of 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylic acid (11) and 15 ml of 
toluene was added dropwise thereto at a temperature of 40.degree. C. or 
lower over a period of 30 minutes. After 20 minutes since then, 7.6 g 
(0.068 mole) of ethyl bromide was added dropwise to the mixture at a 
temperature of from 40.degree. C. to 45.degree. C. over a period of one 
hour. The mixture was further stirred for 3 hours at the same temperature 
to finish the reaction. 
The reaction mixture obtained was washed with 37 ml of water, followed by 
separating an organic layer formed from an aqueous layer. The organic 
layer was washed with 19 ml of an aqueous 3% hydrochloric acid solution, 
followed by separating the organic layer from an aqueous layer. The 
organic layer was further washed twice with 19 ml of an aqueous 5% soda 
ash solution and 19 ml of a saturated aqueous sodium chloride solution, 
followed by separating the organic layer. The toluene was distilled off 
from the organic layer by an evaporator under reduced pressure to provide 
10.0 g of a concentrated oil. Then, 10.0 g of the concentrated oil was 
rectified with a micro still to provide 6 g of ethyl 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylate (1) (boiling point: 
99.degree. C./10 mm Hg). 
The gas chromatographic purity of the product analyzed by gas 
chromatography was 100%, and the optical purity thereof analyzed by an 
optically active analysis column was 99.99% ee. [[.alpha.].sub.D.sup.24 
=+13.0.degree. (c=1.06, ethanol; n.sub.D.sup.22 =1.446] 
The product was used for the sample in the following example. 
EXAMPLE 5 
Using each of ethyl (1R,6S)-2,2,6-trimethylcyclohexanecarboxylate (1) 
having an optical purity of 100% obtained in Synthesis Example 7 and ethyl 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylate (1) having an optical purity 
of 98% ee obtained in Synthesis Example 4-C), each of floral bouquet-like 
fragrances for ladies' use having following formulations was prepared and 
the fondness was tested by 20 expert panelists. 
As a result, the 15 panelists answered that formulation 1 using the product 
obtained in Synthesis Example 7 was better since in this case, there was a 
settlement in top note, the fragrance was more fresh, and had a natural 
tender floral odor. Also, the 4 panelists answered that both the odors 
were almost the same as each other, and the one panelist answered that 
formulation 2 using the product obtained in Synthesis Example 4-C) was 
better. 
______________________________________ 
Formula- Formula- 
tion 1 tion 2 
______________________________________ 
.beta.-Ionone 80 80 
Benzyl Acetate 60 60 
Benzyl Salicylate 
120 120 
Cis-3-hexenyl Salicylate 
30 30 
L-Citronellol 34 34 
L-Hydroxycitronellal 
50 50 
Eugenol 40 40 
Methyl Dihydrojasmonate 
20 20 
Indol 1 1 
p-t-Butyl-.alpha.-methyldihydro- 
120 120 
cinnamic Aldehyde 
Linalool 80 80 
Ethylene Brassylate 
80 80 
Rose Absolute 30 30 
Phenylethyl Alcohol 
50 50 
Vanillin 5 5 
Acetyl cedrene 120 120 
Compound (1)* 10 -- 
Compound (1)** -- 10 
Sum 1000 1000 
______________________________________ 
*Ethyl (1R,6S)2,2,6-trimethylcyclohexanecarboxylate (1) (optical purity 
99.99% ee) synthesized in Synthesis Example 7 
**Ethyl (1R,6S)2,2,6-trimethylcyclohexanecarboxylate (1) (optical purity 
98% ee) synthesized in Synthesis Example 4C). 
The present invention provides an aroma chemical composition containing 
industrially useful ethyl 2,2,6-trimethylcyclohexanecarboxylate, in 
particular, the optically active form thereof. That is, ethyl 
(1R,6S)-2,2,6-trimethylcyclohexanecarboxylate obtained by the present 
invention is excellent in properties as an aroma chemical, and the aroma 
chemical composition containing the optically active form is used in wide 
fields such as various fragrance cosmetics, hygienic materials, medical 
supplies, coating compositions, etc. 
While the invention has been described in detail and with reference to 
specific embodiments thereof, it will be apparent to one skilled in the 
art that various changes and modifications can be made therein without 
departing from the spirit and scope thereof.