JPH06192161A - Production of optically active muscone - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as perfumery in high optical purity in a mass by the asymmetric hydrogenation of 3-methyl-2- cyclopentadecen-1-one using a ruthenium-optically active phosphine complex. CONSTITUTION:An optically active muscone is produced by hydrogenating 3-methyl-2-cyclopentadecen-1-one using a ruthenium-optically active phosphine complex as a catalyst in a solvent (e.g. methanol) under hydrogen pressure of 5-100 atm at 10-120 deg.C for 5-72hr. There are (R)-isomer and (S)-isomer in the rutheniumoptically active phosphine complex. The (S)-isomer is used in the case of using the (E)-isomer of 3-methyl-2-cyclopentadecenl-1-one to obtain (R)-(-)-muscone and, conversely, the (R)-isomer of the ruthenium-optically active phosphine complex is used in the case of using the (Z)-isomer of 3-methyl-2- cyclopentadecen-1-one.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing an optically active muscone such as (R)-(-)-muscon which is useful as a fragrance. Characterized by 3-
The present invention relates to a method for producing an optically active muscone from methyl-2-cyclopentadecen-1-one.

[0002]

2. Description of the Related Art Muscon is an important aroma component of an expensive and valuable musk, and various synthetic methods have been reported (H.
Suginome et al., Tetrahedron Let
T., 28, 1987 p3963-3966; RW.
Thies et al., J. Org. Chem., 52, 19
87 p3798-3806), and synthetic racemic muscone has been commercially available.

On the other hand, it is an optically active substance of Muscon (R)
Both the-(-)-form and the (S)-(+)-form are useful as perfumes, while the (R)-(-)-form is (S)-(+)-.
It has a stronger and richer musk aroma than the body, for example, the threshold of (S)-(+)-body is 223 ppb.
On the other hand, the threshold of the (R)-(−)-body is 61 pp.
b, the (R)-(-)-form is reported to be superior (W. Pickenhage).
n et al., ACS Symposium SER.388Flavor
Chemistry, 1989 p151).

Therefore, when Muscon is used as a raw material for perfume, the demand for optically active Muscon such as (R)-(−)-form Muscon is higher than that of racemic Muscon, but the optically active naturally obtained. The body is limited, and the reality is that there is no realistic method for synthesizing the optically active substance Muscon. That is, the currently known (R)-
As a method for synthesizing (−)-muscon, a method using an optically active substance as a starting material, for example, a method using (S) -hydroxyisobutyric acid (Q. Blanca et al., Helv.
Chim. Acta., Volume 60, 1977 p925-925.
944), a method using (+)-citronellal or (R) -citronellol (VR Mamdapur
Et al., Tetrahedron, Volume 20, 1964 p2
601-2604 and K. Utimoto et al., Tet.
rahedron Lett., 26, 1978 p.
2301-2304), a method using (S) -4-bromo-3-methylbutanenitrile (Zhuo-Feng
Xie et al., J. Chem. Soc., Chem. Comm.
un., 1988 p1638-1639), (R)-
Method using (+)-3-methyl-N-phenylglutamic acid (D. Terunuma et al., J. Org. Che
m., vol. 52, 1987 p1630-1632) and the like, but all of them required a large number of steps and it was difficult to synthesize a large amount.

Further, (E) -2-cyclopentadecene-
Method for introducing a methyl group by asymmetric Michael reaction of 1-one in the presence of a catalyst (K. Tanaka et al., J. Che
m.Soc., Chem. Commun., 1990 p7
95-797, ibid 1991 p101-102, ibid 19
91 p1632-1634, J. Chem. Soc.,
Perkin Trans, 1991 p1445-14
52, 1992 p1193 to 1194). However, also in this method, the amount of the optically active compound used as a catalyst is about twice the molar amount of 2-cyclopentadecen-1-one which is the starting material, and the synthesis of this optically active compound is complicated. However, there are still problems in industrialization such as a low temperature reaction of −78 ° C.

On the other hand, some asymmetric hydrogenation reactions of enone compounds using a ruthenium-optically active phosphine complex are known, and it is also assumed that the (R)-(-)-form muscone is synthesized using this. Is possible. For example, a method of asymmetrically hydrogenating 2-alkylidenecyclopentanone to synthesize an optically active 2-alkylcyclopentanone (Te
trahedron Lett., Volume 33, 1992 p.
635-638) and a method for asymmetric hydrogenation of a 2-alkylidene cyclic ketone to synthesize an optically active cyclic ketone (JP-A-3-48634). However, in each of these reactions, the substrate is an exo-type olefin, while in the α, β-unsaturated ketone, the type in which the double bond to be reduced is in the ring (endo type) is conventionally satisfactory. No results were obtained.

For example, in the case of isophorone (3,5,5-trimethyl-2-cyclohexene-1-one), optical purity is 62% ee, 3-methyl-2-cyclohexene-1-
When on, 22% ee, when 2-methyl-2-cyclohexen-1-one, 26% ee, 3-methyl-2-
In the case of cyclopenten-1-one, only optical purity of 4.5% ee was obtained (V. Massonne.
au et al., Tetra-hedron Lett., 27.
Vol., 1986 p5497-5498).

[0008]

Therefore, it has been desired to develop a method capable of practically synthesizing a large amount of optically active muscone having a high optical purity by a simple operation.

[0009]

Under such circumstances, the present inventors have conducted earnest research on a method for producing an optically active muscone using a ruthenium-optically active phosphine complex as a catalyst, and as a result, have found that a macrocycle as a starting material is used. 3-methyl-2-cyclopentadecene, which is an endo-type unsaturated ketone
The present invention has been completed by finding that the above problems can be solved by adopting 1-one and performing asymmetric hydrogenation using a ruthenium-optically active phosphine complex as a catalyst.

That is, the present invention is a method for producing an optically active muscone, which comprises asymmetric hydrogenation of 3-methyl-2-cyclopentadecen-1-one using a ruthenium-optically active phosphine complex as a catalyst.

The starting material of the present invention, 3-methyl-2-
Cyclopentadecen-1-one has a (E) -form or a (Z) -form, and either of them may be used in the present invention, and for example, it can be synthesized as follows.

3-methyl-2-cyclopentadecene-1
The synthesis of -one is carried out, for example, by condensation of 1,10-dibromodecane and acetylacetic acid ester, decarboxylation reaction, or by electrolysis of 8-oxononanoic acid to obtain 2,15-hexadecadione. It can be obtained by subjecting this to an intramolecular Aldol reaction to obtain 3-hydroxy-3-methylcyclohexadecanone and then dehydrating it (Helv. Chim. Acta,
1947 p2019-2023, Bull. Chem.
Soc. Jpn, Volume 53, 1980 p1417-14.
20, JP-A-55-85536, JP-A-59-1
No. 57047, JP-A-3-81242).

Ruthenium used as a catalyst in the present invention
Examples of the optically active phosphine complex include those represented by the following general formula (I) and general formula (II). ^{_{Ru 2 Cl 4 (R 1 -BINAP}} ) 2 (NEt 3) (I) Ru (R 1 -BINAP) (OAc) 2 (II) [ wherein, Et represents an ethyl group, Ac represents an acetyl group,
R ¹ -BINAP is the following formula

[Chemical 2] (Wherein R ¹ represents a hydrogen atom, a methyl group or a tert-butyl group) and represents an optically active tertiary phosphine compound]

Among the above-mentioned ruthenium-optically active phosphine complexes, those represented by the general formula (I) are described in, for example, J.
Chem. Soc., Chem. Commun., 19
85p922-944 and the method described in JP-A No. 61-63690. That is, [RuCl ₂ (COD)] _n obtained by reacting ruthenium chloride with cycloocta-1,5-diene (hereinafter referred to as COD) in an ethanol solvent.
And R ¹ -BINAP can be produced by reacting by heating in the presence of triethylamine in a solvent such as toluene or ethanol.

Examples of the ruthenium-optically active phosphine complex represented by the general formula (I) include the following. _{Ru 2 Cl 4 (BINAP) 2} (NEt 3) ( wherein, BINAP represents 2,2'-bis (diphenylphosphino) _{-1,1'-binaphthyl) Ru 2 Cl 4 (Tol-} BINAP) 2 ( NEt ₃₎ (wherein, Tol-BINAP is 2,2'-bis (di -p
- tolylphosphino) -1,1'-binaphthyl shows _{a) Ru 2 Cl 4 (t-} Bu-BINAP) 2 (NEt 3) ( wherein, t-Bu-BINAP is 2,2'-bis (di -
p-tert-butylphenylphosphino) -1,1′-
Shows binaphthyl)

The ruthenium-optically active phosphine complex represented by the general formula (II) can be prepared, for example, by the method of Noyori et al. (Modern Synthetic Method).
s, 5, 1989 p136). That is, the ruthenium-optically active phosphine complex represented by the general formula (I) is added to anhydrous sodium acetate and tert-
It can be produced by heating the reaction in a solvent of butanol.

Examples of the ruthenium-optically active phosphine complex represented by the general formula (II) include the following. Ru (BINAP) (OAc) ₂ (where BINAP represents 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl) Ru (Tol-BINAP) (OAc) ₂ (where Tol -BINAP is 2,2'-bis (di-p
-Tolylphosphino) -1,1'-binaphthyl) Ru (t-Bu-BINAP) (OAc) ₂ (where t-Bu-BINAP is 2,2'-bis (di-
p-tert-butylphenylphosphino) -1,1′-
Shows binaphthyl)

The ruthenium-optically active phosphine complex as described above has (R) -form and (S) -form.
Therefore, to obtain (R)-(-)-muscon, 3-methyl-2-cyclopentadecene-1- as a starting material
When the on (E) -form is used, the ruthenium-optically active phosphine complex may be the (S) -form. On the contrary, when the (Z) -form of 3-methyl-2-cyclopentadecen-1-one is used as the starting material, the (R) -form may be used as the ruthenium-optically active phosphine complex.

In order to carry out the method of the present invention, a catalyst, ruthenium-, is added to an autoclave previously substituted with nitrogen.
Optically active phosphine complex, on the other hand, 50-50,
000-fold molar amount, preferably 100-20,000-fold molar amount of 3-methyl-2-cyclopentadecen-1-one and the solvent are taken to make a homogeneous solvent, and then hydrogen pressure is 5-100 atm.
m, preferably 10 to 50 atm.

Examples of the solvent include alcohols such as methanol and halogenated hydrocarbons such as methylene chloride, which may be used alone or as a mixture. This hydrogenation can be performed by reacting at a reaction temperature of 10 to 120 ° C., preferably 25 to 80 ° C. for 5 to 72 hours, preferably 8 to 36 hours.

[0021]

INDUSTRIAL APPLICABILITY According to the method of the present invention, it becomes possible to synthesize a large amount of optically active muscone such as (R)-(-)-muscone with high optical purity. Moreover, not only that, the optically active muscone can be synthesized by a simple operation without requiring complicated steps. Therefore,
The method of the present invention is a very advantageous method capable of industrially producing optically active muscone such as (R)-(-)-muscone useful as a fragrance.

[0022]

The present invention will be described in more detail with reference to Reference Examples and Examples, but the present invention is not limited to these.

Reference Example 1 Synthesis of 2,15-hexadecanedione: Capacitor,
In a 1 liter 4-necked flask equipped with a thermometer, a dropping funnel and a stirrer, 31.7 g of sodium hydride (1.
32 mol) and tetrahydrofuran (THF) 50
0 ml was added. While stirring this, 172 g (1.32 mol) of ethyl acetoacetate was added dropwise over 3 hours.

Then, 100 g (0.33 mol) of 1,10-dibromodecane was added dropwise under reflux over 4 hours, and then the reaction was completed by stirring for 12 hours. The reaction solution was cooled to room temperature, 400 ml of a 5% hydrochloric acid solution was added, and the organic layer and the aqueous layer were separated. The obtained organic layer was washed twice with saturated brine and liquid separation was performed, and THF was distilled off from the organic layer under reduced pressure with an evaporator to obtain 160 g of a concentrated oil.

160 g of this concentrated oil and 528 g of a 10% aqueous sodium hydroxide solution were placed in a flask equipped with a condenser,
Stir at room temperature. After stirring for 8 hours at the same temperature, 50%
129 g of a sulfuric acid solution was added and the mixture was refluxed. The reaction was completed by stirring for 3 hours, and the reaction solution was brought to room temperature. The reaction solution was filtered through a Buchner funnel to obtain 40 g of crude crystals. The crude crystals were recrystallized with ethanol to obtain 38 g (0.15 mol) of 2,15-hexadecanedione in a yield of 45% of the theoretical amount. The melting point of this material was 83-84 ° C.

Reference Example 2 Synthesis of (E)-and (Z) -3-methyl-cyclopentadecen-1-one: Condenser, Thermometer, Dropping Ro
A 2-liter 4-necked flask equipped with a stirrer and a stirrer was purged with nitrogen, 400 mL of THF and 8.2 g (88 mmol) of phenol were added, and the mixture was cooled to 0 ° C., and then 1M diisobutylaluminum hydride hexane was added. 80 ml (80 mmol) of the solution was added dropwise. After the dropping, the temperature was raised to room temperature, and 7.6 g (96 mmol) of pyridine and 1.6 liter of n-hexane were added, and then 6
The temperature was raised to 5 ° C. and the mixture was refluxed.

Next, 5 g (20 mmol) of THF, 40 g of 2,15-hexadecanedione obtained in Reference Example 1 was used.
A mixed solution of 0 ml and 400 ml of n-hexane was added dropwise under reflux over 11 hours, and after completion of the addition, the mixture was further stirred for 2 hours. After completion of the reaction, return to room temperature,
After 3N-hydrochloric acid was added to separate the organic layer and the aqueous layer, the organic layer was washed with a 5% aqueous sodium hydroxide solution and washed twice with saturated saline, and the obtained organic layer was evaporated under reduced pressure. THF was distilled off with a tap to obtain a concentrated oil.

When this concentrated oil was purified by silica gel column chromatography, 3-methyl-cyclopentadecen-1-one, (E)-and (Z) -3-methyl-
Aldol mixture of cyclopentadecen-1-one 2.
7 g (11.4 mmol) was obtained. The aldehyde mixture was further purified by silica gel column chromatography to obtain (E) -3-methyl-cyclopentadecen-1-one (0.7 g, 3.0 mmol). Also,
Purification by column chromatography on silica gel coated with silver nitrate gave 0.5 g (2.1 mmol) of (Z) -3-methyl-cyclopentadecen-1-one.

Example 1 Synthesis of (R)-(-)-muscon (1): (E) -3 obtained by the method of Reference Example 2 after substituting 100 ml of autoclave with nitrogen. -Methyl-2-cyclopentadecen-1-one 2.3 g (9.7 mmol), R
_{u 2 Cl 4 [(S)} -Tol-BINAP] 2 NEt 3 9
mg (0.005 mmol) and 10 ml of methanol were added, and the reaction was carried out at a hydrogen pressure of 50 atm and 25 ° C. for 24 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography.
(Hexane: ethyl acetate = 20: 1 (volume ratio)) for purification, and 2.2 g of (R)-(-)-muscon (yield 95
%)Obtained.

The specific rotation of the obtained (R)-(-)-muscone is [α] _D ²⁵ -12.0 ° (C = 1.20, methano-
It was). Literature description (Helv. Chim. Ac
ta, 60 volumes, 1977 p925) (R)-(-)-
The specific rotation of Muscon is [α] -11.7 ° (C = 0.8
It is understood that the optical purity of the synthesized (R)-(−)-muscon is very high since it is 0, methanol).

Example 2 Synthesis of (R)-(-)-muscon (2): (Z) -3 obtained by the method of Reference Example 2 after substituting 100 ml of autoclave with nitrogen. -Methyl-2-cyclopentadecen-1-one 2.3 g (9.7 mmol), R
_{u 2 Cl 4 [(R)} -Tol-BINAP] 2 NEt 3 9
mg (0.005 mmol) and 10 ml of methanol were added, and the reaction was carried out at a hydrogen pressure of 50 atm and 25 ° C. for 24 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography.
(Hexane: ethyl acetate = 20: 1 (volume ratio)) for purification, and 2.2 g of (R)-(-)-muscon (yield 95
%)Obtained. The specific optical rotation of the obtained (R)-(-)-muscon is
[Α] _D ²⁵ -11.9 ° (C = 1.10, methanol).

Example 3 Synthesis of (R)-(-)-muscon (3): (Z) -3 obtained by the method of Reference Example 2 after substituting 100 ml of autoclave with nitrogen. -Methyl-2-cyclopentadecen-1-one 2.3 g (9.7 mmol), R
u ₂ Cl ₄ [(R) -BINAP] ₂ NEt ₃ 0.9 mg
(0.0005 mmol) and 10 ml of methanol were added, and the reaction was carried out at a hydrogen pressure of 50 atm and 75 ° C. for 30 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 (volume ratio)) to obtain (R)-(-)- 2.2 g of muscon (yield 95
%)Obtained. The specific optical rotation of the obtained (R)-(-)-muscon is
^{_{[Α] D 25 -11.7 ° (}} C = 1.10, methanol - Le) was.

Example 4 Synthesis of (R)-(-)-muscone (4): (Z) -3 obtained by the method of Reference Example 2 after substituting 100 ml of autoclave with nitrogen. -Methyl-2-cyclopentadecen-1-one 2.3 g (9.7 mmol), R
u (OAc) ₂ [(R) -BINAP] 0.8 mg (.0.
(0009 mmol) and methylene chloride (10 ml) were added, and the mixture was reacted at a hydrogen pressure of 30 atm and 50 ° C. for 36 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 (volume ratio)).
2.1 g (yield 91%) of (R)-(-)-muscon was obtained. The specific optical rotation of the obtained (R)-(-)-muscon is
^{_{[Α] D 25 -8.6 ° (}} C = 1.20, methanol - Le) was.

Example 5 Synthesis of (R)-(-)-muscon (5): (E) -3 obtained by the method of Reference Example 2 after substituting 100 ml of autoclave with nitrogen. -Methyl-2-cyclopentadecen-1-one 2.3 g (9.7 mmol), Ru
(OAc) ₂ [(S) -Tol-BINAP] 8.4 mg
(0.0094 mmol) and 10 ml of methanol were added, and the reaction was carried out at a hydrogen pressure of 50 atm and 25 ° C. for 24 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 (volume ratio)) to obtain (R)-(-)- 2.2 g of muscon (yield 95
%)Obtained. The specific optical rotation of the obtained (R)-(-)-muscon was [α] _D ²⁵ -9.8 ° (C = 1.15, methano-
It was). that's all

Claims (4)

[Claims] 1. 3-Methyl-2-cyclopentadecene-
A method for producing an optically active muscone, which comprises asymmetrically hydrogenating 1-one using a ruthenium-optically active phosphine complex as a catalyst. 2. A ruthenium-optically active phosphine complex having the following general formula (I) or (II) Ru ₂ Cl ₄ (R ¹ -BINAP) ₂ (NEt ₃ ) (I) Ru (R ¹ -BINAP) (OAc). ) ₂ (II) [In the formula, Et represents an ethyl group, Ac represents an acetyl group,
R ¹ -BINAP is represented by the following formula: (Wherein R ¹ represents a hydrogen atom, a methyl group or a tert-butyl group), which is an optically active tertiary phosphine compound]. 3. The (R)-(−)-muscon, wherein the ruthenium-optically active phosphine complex is the (S) -form and 3-methyl-2-cyclopentadecen-1-one is the (E) -form. Manufacturing method. 4. A (R)-(−)-muscon wherein the ruthenium-optically active phosphine complex is the (R) -form and 3-methyl-2-cyclopentadecen-1-one is the (Z) -form. Manufacturing method.