JP2002069026A - Method for manufacturing (e)-3-methyl-2- cyclopentadecenone - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for preparing 3-methyl-2-cyclopentadecenone (2) capable of producing an (E)-isomer, one of the geometric isomers at a high compositional ratio and having high positional selectivity in double bond-forming. SOLUTION: (E)-3-methyl-2-cyclopentadecenone expressed by the formula-1 is manufactured by subjecting 3-hydroxy-3-methylcyclopentadecanone to a dehydration reaction in the presence of an alkoxytitanium compound expressed by TiCln(OR)4-n, wherein R is a 1-4C alkyl; and n is 0, 1, 2 or 3.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a fragrance used in cosmetics, and more particularly to an optically active substance which is a key fragrance component of musk.
The present invention relates to a method for producing a synthetic intermediate of (R)-(-)-Muscone.

[0002]

2. Description of the Related Art In recent years, the Washington Treaty, which has negotiated the protection of endangered creatures, has banned the capture of musk deer, and musk, which has historically played a very important role as a fragrance, is becoming unavailable. There is an urgent need to develop alternatives. Therefore, development of a method for producing (R)-(-)-Muscone, which is a key aroma component of musk, has become an important issue, and many research reports have been made.

For example, JP-A-6-192161 discloses (R)-
A method for preparing (-)-Muscone is disclosed. That is, by using (Z)-or (E) -3-methyl-2-cyclopentadecenone (2) as a starting material, selecting an optically active ruthenium-phosphine complex which is an asymmetric hydrogenation catalyst, Of purity
A method for preparing (R)-(-)-Muscone is known (reaction formula-1). From this reaction formula-1, it can be understood that (R)-(-)-muscone having a purity corresponding to the purity of the (E)-or (Z) -form is prepared, and (E)-or (Z) -3-methyl
If 2-cyclopentadecenone (2) can be prepared, it can be said to be very advantageous.

[0004]

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[0005] In addition, many methods for preparing 3-methyl-2-cyclopentadecenone (2), which is a synthetic intermediate of (R)-(-)-Muscone, have been reported. As one of them, the following preparation method of 2,15-hexadecadione (3) by intramolecular aldol condensation reaction has been known. That is, a method using an aldol reagent of magnesium bromide-N-methylanilide (PhN (Me) MgBr 2) (Helv. Chim. Acta. 1947, p. 2,019-2,023),
A method using an isobutylaluminum hydride-pyridine aldol reagent (Tsuji et al., Bull. Chem. Soc. Jpn.
1980, volume 53, p.1,417-1,420, JP-B-61-11210), a method using propyl zinc chloride (PrZnCl)
(Japanese Unexamined Patent Publication No. 59-157047) and a reaction method by adding water at a high temperature in a titanium oxide-sodium oxide catalyst system (Michael Hulman, Japanese Unexamined Patent Publication No. 3-81242) and the like have been known. . However, in these reports, as shown in the reaction formula-2, the reaction product is a double bond regioisomer other than the target compound, 3-methyl-2-cyclopentadecenone {(E)-(2)}. However, there is a drawback that 3-methyl-3-cyclopentadecenone (4) and 3-methylenecyclopentadecanone (5) are produced as by-products.

[0006]

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Further, these reports do not particularly disclose the geometrical isomer composition of the target compound, 3-methyl-2-cyclopentadecenone (2). As a result of additional tests of these methods, it was found that the (E) -form or the (Z) -form was less than 70%. Even if R-(-)-Muscone is prepared by a conventional method using 3-methyl-2-cyclopentadecenone (2) having such a purity as a starting material, R-(-)-Muscone having high optical purity can be obtained. This is impossible, and in order to obtain a high-purity product, separation and purification such as column purification are required, which is not satisfactory as an industrial production method.

As a different method for preparing 3-methyl-2-cyclopentadecenone (2), which is a synthetic intermediate of (R)-(-)-Muscone, for example, Monatshefte fur Chemie 110, 245-247
(1979). There, 3-hydroxy-3-methylcyclopentadecanone (1) was converted to p-toluenesulfonic acid-1.
A dehydration reaction was carried out in the presence of a hydrate to prepare 3-methyl-2-cyclopentadecenone, and the (E) -form: (Z) -form was 4: 1.
It has been reported that 3-methyl-2-cyclopentadecenone was prepared. However, the method disclosed here has many steps and requires the use of expensive reagents, and thus has many problems in a practical industrial production method. Furthermore, the spectral data on which the numerical values for the (E) -form and the (Z) -form are based are inadequate, and as a result of additional testing based on the above report, the prepared target compound, 3-methyl- The ratio of (E) -form: (Z) -form of 2-cyclopentadecenone (2) was found to be 28:72. The structure of (E) -form or (Z) -form is determined by Tsuji et al.
1980, vol. 53, p. 1, 417-1, 420), the structure of (E) -form and (Z) -form was determined.

[0009]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a compound having a high composition ratio of the (E) -isomer, which is one of the geometric isomers, and a high selectivity for 3-methyl-2-position of a double bond. An object of the present invention is to provide a method for preparing cyclopentadecenone (2). Also,
Another object of the present invention is to provide a method for inexpensively producing a synthetic intermediate of (R)-(-)-Muscone. In addition, compared with the conventional preparation method, (R)-(-)-Muscone has few problems from an industrial point of view, and makes it possible to prepare inexpensively and economically.

[0010]

Means for Solving the Problems In view of the above circumstances, the present inventors have made intensive studies, and as a result, 3-hydroxy-3-methylcyclopentadecanone (1) is represented by TiCl _n (OR) _4-n. Wherein R represents 1 to 4 carbon atoms
Dehydration in the presence of an alkyl group, n represents any one of 0, 1, 2, and 3), whereby the double bond positional isomers {(4) and (5) } Without by-product, and the selective synthesis of 3-methyl-2-cyclopentadecenone {(E)-(2)}-form was successful in about 80% or more, and completed the present invention.

Further, 2,15-hexadecadione (3) is subjected to intramolecular aldol addition reaction to give 3-hydroxy-3
-Methylcyclopentadecanone (1) can be prepared, and by adopting this process, the price is particularly low,
Economically 3-hydroxy-3-methylcyclopentadecanone
(1) was successfully manufactured and the present invention was completed.

That is, the present invention relates to (1) an alkoxytitanium compound represented by TiCl _n (OR) _4-n , wherein R represents 1 to 4 carbon atoms.
Wherein n represents any one of 0, 1, 2, and 3), and a dehydration reaction is carried out in the presence of Formula-1
A method for producing (E) -3-methyl-2-cyclopentadecenone,

Formula-1 (2) 2,15- presence hexadecanol dione titanium tetrachloride and a trialkylamine, was carried out 3-hydroxy-3-methyl-cyclopentadecanone an intramolecular aldol addition reaction prepared, then TiCl _n of the compound (OR) The presence of an alkoxytitanium compound represented by _4-n (where R represents an alkyl group having 1 to 4 carbon atoms, and n represents any of 0, 1, 2, 3)
(E) -3-methyl- represented by the above formula-1, characterized in that the compound is subjected to a dehydration reaction in the presence of one or both of an alkoxytitanium compound represented by R) _{4 and} TiCl ₂ (OR) ₂ A method for producing 2-cyclopentadecenone, (3) a method for producing (E) -3-methyl-2-cyclopentadecenone, wherein the alkoxytitanium compound is a tetraalkoxytitanium compound represented by Ti (OR) ₄ , (4) (E) -3-methyl-2-in which 80% or more of (E) -form is present
A method for producing cyclopentadecenone.

The details of the present invention will be described below. 3-hydroxy-3-methyl-cyclopentadecanone used in the present invention (1)
It is already known per se. This compound can be prepared by a known method. In particular, when the following method is employed, the target compound can be prepared economically at low cost and is advantageous.
That is, as shown in Reaction formula-3, 2,15-hexadecadione
By subjecting (3) to intramolecular aldol addition reaction using titanium tetrachloride and a tertiary amine, 3-hydroxy-3-methylcyclopentadecanone (1) can be selectively prepared.

[0014]

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The preparation of the starting material 2,15-hexadecadione (3) can be carried out by the method described in JP-A-6-192161. That is, as described in Reaction Scheme-4, 1,
Using 10-dibromodecane as a raw material, two molecules of acetoacetate were reacted, and then the product was prepared by a method of hydrolysis and decarboxylation.

[0016]

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The reaction conditions for the intramolecular aldol addition reaction of 2,15-hexadecadione represented by Reaction Formula-5 are as follows.

[0018]

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Regarding the amount of titanium tetrachloride used, the substrate (3)
Is used in an amount of 100% to 400% by mol, preferably in the range of 200% to 280%. As the tertiary amine, those represented by the general formula R3N such as triethylamine and tri-n-butylamine are advantageously used for economic reasons.Of course, the general formula: R ¹ R ² R ³ N,
And those represented by R ¹ (R ² ) ₂ N can also be used. here,
R ¹ , R ² and R ³ each represent a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group and an n-butyl group. The use amount of these tertiary amines is preferably 50% to 200% by mol% based on titanium tetrachloride.
Preferably, it is 80% to 150%.

Examples of the solvent used include aliphatic hydrocarbon solvents such as heptane and hexane, alicyclic hydrocarbon solvents such as cyclohexane, aromatic hydrocarbon solvents such as toluene and xylene, and halogenated hydrocarbons such as methylene chloride. Solvents are preferably used. As the amount of solvent used,
In consideration of the reaction efficiency, usually, the ratio of the substrate (3) / solvent is preferably 1/100 to 1/1000 by weight / weight ratio, more preferably 1/300 to 1/600. .

The reaction can be usually carried out at a temperature of -30 ° C. to 80 ° C., but preferably under mild conditions near room temperature (15 ° C. to 30 ° C.). Can be achieved.

One of the features of the present invention is a compound that coexists during the dehydration reaction of 3-hydroxy-3-methyl-cyclopentadecanone (1). That is, an alkoxytitanium compound represented by TiCl _n (OR) _4-n (where R represents an alkyl group having 1 to 4 carbon atoms and n represents any of 0, 1, 2, 3) I do.
Here, R is preferably a methyl group, an ethyl group, an isopropyl group, a propyl group, a normal butyl group, an isobutyl group, or the like. Specific examples of the alkoxy titanium compound include Ti (O
R) ₄ , TiCl (OR) ₃ , TiCl ₂ (OR) _{2 and the} like. More preferred compounds are Ti (OR) ₄ and TiCl ₂ (OR) ₂ , and even more preferred compounds are Ti (OR) ₄ . These alkoxytitanium compounds may be used alone or in combination of two or more. These compounds are known. These compounds are used in an amount of 50% by mol% based on the substrate (1).
% To 1000% is used, preferably 100% to 300%.

As the solvent to be used, aromatic hydrocarbons such as toluene are preferably used. Other solvents include alicyclic hydrocarbon solvents such as hexane, halogenated hydrocarbon solvents such as methylene chloride, tetrahydrofuran, dioxane and dioxymethane. Oxygen hydrocarbon solvents are preferably used. The amount of the solvent used may be arbitrarily used, but is usually 5 to 100 by weight / weight ratio with respect to the substrate (3).
Double is used, preferably 10 to 100 times.

The reaction can be usually carried out at a temperature of -30 ° C to 80 ° C, but preferably under mild conditions around room temperature (15 to 30 ° C).

The 3-methyl-2- obtained by this dehydration reaction
As shown in Table 1, cyclopentadecenone (2) surprisingly did not produce a double bond regioisomer (4) at all, and the stereostructure of the target compound (2) was as follows: It was found that the (E) -isomer was obtained with a high selectivity of about 90%. (See example)

[0026]

[Table 1]

[0027]

According to the present invention, 3-methyl-2-cyclopentade has a large proportion of ((E) -isomer) among the geometric isomers of the target product and also has a large double bond regioselectivity. Made it possible to obtain senone. That is, according to the present invention, there is no by-product of the double bond regioisomer {(4) and (5)}, and the (E) -isomer has a high purity of (E) -3-methyl-2 of about 80% or more. -Cyclopentadecenone could be prepared. In addition, no particularly expensive chemical substance is used, and milder reaction conditions are employed. Using (E) -3-methyl-2-cyclopentadecenone obtained by the present invention as a raw material, it is economically possible to produce optically active (R)-(-)-muscone which is very important as a fragrance. became.

[0028]

The present invention will be described in more detail with reference to the following examples and reference examples, but the present invention is not limited to these examples. The analytical instruments used are as follows. NMR: Varian Unity-plus 300 IR: JASCO FT / IR-8000

[0029]

[Reference Example 1] Preparation of 3-hydroxy-3-methylcyclopentadecanone (1) A methylene chloride solvent (1200 ml) was previously placed in a two-liter two-necked flask under an argon stream, and the mixture was added at 23 to 27 ° C with 2,2. 15 A mixed solution of hexadecadione (3) (3.8 g, 15 mmol) and tri-n-butylamine (10.83 g, 58.5 mmol) in methylene chloride (132 ml) and titanium tetrachloride (5.43 ml, 49.
5 mmol) in methylene chloride (144 ml) was co-injected (simultaneously added) over a period of about one hour using a microfeeder. The mixture was further stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was stirred and concentrated under reduced pressure. The residue was extracted with ether, and the organic layer was washed with water, saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the crude product was subjected to silica gel column chromatography (hexane / ethyl acetate =
8: 1), 1.44 g of colorless and transparent 3-hydroxy-3-methylcyclopentadecanone (1) (yield: 38% wt)
I got The obtained spectrum data of (1) showed the following values.

IR (Neat, NaCl); 3484, 2930, 2855, 17
03, 1460, 1408, 1372 cm ^{-1 1} H NMR [300 MHz; δ (CDCl ₃ )]; 1.09-1.57 (20H, m), 1.1
7 (3H, s), 1.61-1.72 (1H.m), 1.72-1.84 (1H, m), 2.33-
2.40 (1H.m) 2.43 (1H, d J = 16.8Hz), 2.51 (0.5H, dd ,, J
= 16.4, 5.6Hz), 2.53 (0.5H, dd, J = 16.4,5.4Hz), 2.81
(1H, d, J = 17.1Hz ), 3.80-4.09 (1H, brs) 13 C NMR [75 MHz; δ (CDCl 3)]; 22.51, 23.68, 25.65,
26.11, 26.37, 26.50, 26.61, 26.67, 27.52, 27.70, 2
7.91, 41.17, 43.49, 50.70, 72.29, 213.94 ,.

[0031]

Example 1 (E) -3-methyl-2-cyclopentadecenone
Preparation of {(E)-(2)}-1 3-hydroxy-3-methylcyclopentadeca prepared in Reference Example-1 under a stream of argon in a 200 ml four-necked flask equipped with a thermometer, a condenser and a stirrer. Non (1) (1.28g, 5mmo
To a toluene solution of l) (50 ml) was added dropwise tetraisobutyl orthotitanate (13.8 ml, 40.0 mmol) at room temperature (20 to 25 ° C), and the mixture was stirred at the same temperature for 14 hours. The reaction mixture was poured into cold water and extracted with cooled ethyl acetate. After washing with a saturated saline solution similarly cooled, it was dried with anhydrous sodium sulfate. After evaporating the solvent, 1.2 g of product {(E)-(2): Z- (2)} = 91: 9) was obtained.
This product was purified by column chromatography, and the purified (E) -3-methyl-2-cyclopentadecenone {(E)-
The spectrum data of (2)} showed the following values.

¹ H NMR [300 MHz; δ (CDCl ₃ )]; 1.16-1.40
(15H, m), 1.44-1.70 (5H, m), 1.87 (3H.d, J = 1.5Hz),
2.34-2.43 (2H, m), 2.73-2.76 (2H.m), 6.08- 6.12 (1H,
m) ¹³ C NMR [75 MHz; δ (CDCl ₃ )]; 23.85 23.94 25.162
5.48 26.19 26.38 26.6326.80 26.95 26.99 27.05 31.7
6 43.60 125.02 158.63 202.06.

[0033]

Example 2 (E) -3-methyl-2-cyclopentadecenone
Preparation of {(E)-(2)}-2 The reaction was carried out in exactly the same manner as in Example-1, except that tetraisobutyl orthotitanate in Example-1 was replaced with tetraisopropyl orthotitanate, and the product {( E)-(2): Z-
(2)} = 88:12).

[0034]

[Test Example 1] 3-Methyl-2-cyclopentadecenone {(E)-
Preparation of mixture of isomer and (Z) -isomer} The title compound was prepared by the method described in Monatshefte fur Chemie 110, 245-247 (1979). To a solution of 3-hydroxy-3-methylcyclopentadecanone (42 mg, 0.17 mmol) in dichloromethane (0.5 ml) was added p-toluenesulfonic acid monohydrate (13 mg, 0.07 mmol) at room temperature, and the mixture was heated at the same temperature for 3 hours. Stirred.
The reaction mixture was added dropwise to cold water and extracted with cold ethyl acetate. After washing with a cooled saturated saline solution, the extract was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the product was purified by column chromatography (hexane / ethyl ether = 20: 1) to obtain the desired compound (13 mg, 85%). The target compound was (E) -form: Z-form = 28: 72. The spectrum data of the Z-form of the target compound showed the following values.

¹ H NMR [300 MHz; δ (CDCl ₃ )]; 1.16-1.40
(15H, m), 1.44-1.70 (5H, m), 2.14 (3H, d, J = 1.2Hz),
2.16-2.21 (2H, m), 2.34-2.43 (2H.m), 6.15 (1H, d, J =
1.2Hz) ¹³ C NMR [75 MHz; δ (CDCl ₃ )]; 25.16 25.47 25.64 2
6.36 26.55 26.67 26.7026.75 26.86 27.13 40.03 4
4.46 123.72 158.94 202.38

[0036]

[Reference Example 2] Preparation of (R)-(-)-muscon After replacing 100 ml of autoclave with argon, methanol (10 ml), RuCl4 {(S) -Tol-BINAP} 2NEt3 (10 mg. 0.0
056 mmol) and (E) -3-methyl-2- prepared in Example-1
Cyclopentadecenone {(E)-(2)} (0.6 g, 2.53 mmol) was added and reacted at 30 ° C. for 7 hours under a hydrogen pressure of 3,000 Kpa. After completion of the reaction, methanol was distilled off to obtain a target compound. The target compound obtained as necessary is purified by silica gel column chromatography {hexane: ethyl acetate = 10: 1 (V / V)}, and (R)-(−)-muscone (0.57 g: 99% ee) ) Got.

Claims (4)

[Claims] 1. An alkoxytitanium compound represented by the formula: TiCl _n (OR) _{4-n wherein} R is an alkyl group having 1 to 4 carbon atoms, and n is a 3-hydroxy-3-methylcyclopentadecanone.
0, 1, 2, or 3), wherein the dehydration reaction is carried out in the presence of (E) -3-methyl-2-cyclopentadecenone represented by the formula-1. [Formula 1] 2. An intramolecular aldol addition reaction of 2,15-hexadecadione in the presence of titanium tetrachloride and a trialkylamine to prepare 3-hydroxy-3-methylcyclopentadecanone. An alkoxytitanium compound represented by TiCl _n (OR) _4-n (where R represents 1 carbon atom)
To 4 alkyl groups, n represents any one of 0, 1, 2, and 3)
A process for producing (E) -3-methyl-2-cyclopentadecenone represented by the formula-1, characterized by carrying out a dehydration reaction in the presence of: Embedded image Formula-1 3. The (E) -3-methyl according to claim 1, wherein the alkoxytitanium compound is a compound represented by Ti (OR) _4.
A method for producing 2-cyclopentadecenone. 4. The composition according to claim 1, wherein the (E) -form is at least 80%.
The method for producing (E) -3-methyl-2-cyclopentadecenone according to claim 1, which is selected from the group consisting of: