JP3413853B2 - Novel 15-membered cyclic compound and method for producing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

This invention relates to a compound of formula (IV) having a musky aroma.

[0002]

[Chemical 4]

The present invention relates to a novel 15-membered cyclic compound useful as a synthetic intermediate for muscone and a method for producing the same.

[0004]

BACKGROUND OF THE INVENTION Musk, which has been called orchid musk for a long time along with orchids, is a glandular secretion in the musk stalks of male musk deer, and is a very expensive and rare natural animal. It is a fragrance substance. The aromatic component of this musk is 19
L. in 26. It has been discovered by Ruzikka that it is a muscone represented by formula (IV).

Since this discovery, many attempts have been made to synthesize Muscon by a chemical method. For example,
A method of introducing a methyl group later by using exalton as a raw material (Ruzicka, Helv. Chim. Act.
a. , 17, 1308 (1934)) or a method of deriving a 12-membered cyclic ketone with a compound having a carbon number of 4 and then deriving a 15-membered ring structure (Eschenmoser, He.
lv. Chim. Acta. , 54, 2896 (197)
1); Trost, J .; Am. Chem. Soc. , 1
02,5683 (1980)), and a method of sequentially bonding compounds having 2, 12 and 1 carbon atoms to a compound having 12 carbon atoms (Stork, J. Am. Che).
m. Soc. , 97, 1264 (1975)) and the like have been proposed.

[0006]

However, in the case of synthesizing muscone by these conventional methods, each method has a large number of steps, the total yield is low, and more often expensive raw materials and reagents are required. There was a problem.

The present invention is intended to solve such a problem of the prior art, and an object thereof is to enable efficient production of the muscone represented by the formula (IV) at low cost.

[0008]

The above-mentioned object of the present invention is achieved by using the following novel 15-membered cyclic compounds as synthetic intermediates for muscone.

That is, the present invention has the formula (I)

[0010]

[Chemical 5]

There is provided a 15-membered cyclic compound represented by the formula: wherein A is —CH ₂ CH ₂ CH═CH—.

The present invention also provides a method for producing a 15-membered cyclic compound of formula (I), which comprises

[0013]

[Chemical 6]

[0014] (wherein, A is _{-CH 2 CH 2 CH = CH-,} R is alkoxide Shiechiru unsubstituted, X is a leaving group) The compound represented by the basic conditions Ring closure under formula (III)

[0015]

[Chemical 7]

There is provided a production method characterized by forming a compound represented by the formula (wherein A and R are as described above) and further hydrolyzing the compound.

Hereinafter, the present invention will be described in detail along with the process of totally synthesizing Muscon.

A) A in the formula (I) is -CH ₂ CH ₂ CH =
When CH-, the total synthesis of Muscon can be carried out as shown in Scheme 1.

[0019]

First, the 7-octenal of the formula (1) is subjected to an acetalization reaction in order to protect the aldehyde group, and is converted to 1,1-dialkoxy-7-octene of the formula (2). The starting material 7-octenal can be easily obtained from the hydrated dimer of butadiene. The acetalization reaction can be carried out according to a conventional method, for example, by refluxing 7-octenal and orthoformate with an acid catalyst such as p-toluenesulfonic acid.

Next, the compound of formula (2) is subjected to a hydroformylation reaction in which CO and H ₂ are reacted with each other in the presence of a Co or Rh catalyst such as Rh (acac) (CO) ₂ . It is converted to a saturated aldehyde compound of formula (3) having one more carbon atom in a form in which hydrogen and —CHO are added to the double bond.

Further, for the compound of formula (3), Horn
er-Emmonos reaction is performed to convert the terminal aldehyde group into an α, β-unsaturated carboxylic acid ester body having two more carbon atoms, and the acetal group is hydrolyzed with a mineral acid aqueous solution such as hydrochloric acid to give the compound represented by the formula (4). It is converted to the aldehyde / ester form of. The reagents used in the Horner-Emmonos reaction include Horner-Emmonos ph.
A reagent known as osphonate can be used, and for example, ethyldiethylphosphonoacetate [(EtO) ₂ P (O) CH ₂ COOEt] can be preferably used. This reagent is reacted with a strong base such as sodium hydride in a solvent such as THF to be converted into a phosphonate derivative, and then reacted with a compound of formula (3).

Next, the aldehyde group of the compound of formula (4) is reduced to a hydroxyl group and converted to the compound of formula (5). As this reduction reaction, it is necessary to select a reduction reaction condition that does not act on the α, β-unsaturated carboxylic acid ester group, and it is preferable to act sodium borohydride in a lower alcohol, for example.

Further, the terminal hydroxyl group of the compound of formula (5) is converted to a compound of formula (6) by substituting a group which will be a leaving group when the compound of formula (IIa) described below is ring-closed. To do. Examples of such a leaving group include a halogen atom such as chlorine, bromine and iodine, or an —OR ₃ group (in the formula, R ₃ is a substituted or unsubstituted arylsulfonyl group, for example, a benzenesulfonyl group, p-toluenesulfonyl group). Group, or a substituted or unsubstituted alkylsulfonyl group, for example, a methanesulfonyl group), etc., but from the viewpoints of compound stability, reactivity upon ring closure, etc., methanesulfonyl chloride, triethylamine and lithium bromide. Bromine introduced by and is preferred.

Next, only the ester portion of the α, β-unsaturated carboxylic acid ester group of the compound of formula (6) is reduced to give the corresponding unsaturated alcohol (11-halogeno-2-undecene) of formula (7). -1-all). For such a reduction reaction, it is necessary to select a reducing condition capable of selectively reducing only the ester portion, and for example, diisobutylaluminum hydride (DIB) in a hydrocarbon solvent.
It is preferable to act AL).

Next, the compound of the formula (7) is treated with an alcohol which is produced in the presence of an acetal of a lower alcohol of the senecionaldehyde of the formula (8), for example, senecionaldehyde dimethyl acetal and an acid catalyst such as terephthalic acid. It is converted into an α, β-unsaturated aldehyde compound of the formula (9) which has been carbonized with 5 carbons by reacting with heating and stirring while removing.

Furthermore, a catalyst obtained by adding trimethylsilyl cyanide to the compound of formula (9) and then complexing the phase transfer catalyst with KCN, for example, dicyclohexano-18-crown-6 / KCN represented by the following structure: Complex catalyst

[0028]

[Chemical 9]

## STR1 ## The reaction is carried out by adding a dilute mineral acid, for example, a 1N HCl aqueous solution to give cyanohydrin, and the crude cyanohydrin is further added with an alkyl vinyl ether in the presence of an acid catalyst such as p-toluenesulfonic acid. For example, it is converted into a compound of formula (IIa) by reacting with ethyl vinyl ether.

The compound of formula (IIa) can be converted into a 15-membered cyclic compound of formula (IIIa) by ring closure by the action of a base in a solvent. As the base used for the ring-closing reaction, metal amides such as lithium tetramethyldisilazane, sodium tetramethyldisilazane and lithium diisopropylamide, and metal hydrides such as sodium hydride and potassium hydride can be used.

The ring-closing reaction is carried out by using benzene, toluene,
Hydrocarbons such as hexane, diisopropyl ether, T
It is preferably carried out in a solvent such as ethers such as HF and 1,4-dioxane. The solvent is the compound (IIa).
It is preferred that the concentration of is about 0.05 to 0.5 mol / l.

The reaction temperature varies depending on the type of solvent and base used, but is generally in the range of about 20 to 100 ° C, preferably 65 to 80 ° C. The reaction time also varies depending on the type of solvent and base used, reaction temperature, etc., and is usually 10 minutes to 3 hours, preferably 30 minutes to 1.5 hours.

The ring-closing reaction is preferably carried out in an atmosphere of an inert gas such as nitrogen or argon.

The compound of formula (IIIa) thus obtained can be converted into the 15-membered cyclic compound of the invention of formula (Ia) by hydrolysis. This hydrolysis is
In the presence of an acid such as hydrochloric acid, acetic acid, p-toluenesulfonic acid, benzenesulfonic acid, pyridinium p-toluenesulfonate, acidic ion exchange resin, etc., preferably p-toluenesulfonic acid or pyridinium p-toluenesulfonate, the compound of formula (IIIa A lower alcohol solution of the compound of 1) such as methanol and ethanol is stirred and reacted at a temperature in the range of -10 ° C to room temperature for 10 minutes to 3 hours, and then reacted at a temperature in the range of 0 ° C to room temperature. , For example, dilute NaO
The reaction can be carried out by adding an aqueous solution of H to neutralize and further treating with an aqueous solution of ammonium chloride, an aqueous solution of sodium hydrogen carbonate, triethylamine and the like.

The 15-membered cyclic compound of the present invention represented by the formula (Ia) is 1-membered in an organic solvent such as methanol or ethyl acetate in the presence of a transition metal catalyst such as palladium carbon or platinum oxide.
It can be converted to the muscone of the formula (IV) by contacting with 100 atm of hydrogen gas for reduction.

[0036]

The novel 15-membered cyclic compound of the present invention can be produced from a compound that is inexpensive and easily available by a simple operation. Further, by subjecting it to a general catalytic hydrogenation reaction, the aromatic component of musk It can be converted to Muscon.
Therefore, it becomes possible to efficiently manufacture the Muscon at low cost.

[0037]

The present invention will be described in more detail with reference to the following examples.

Example 1 (Preparation of compound of formula (Ia))

[0039]

[Chemical 10]

Step (a) Preparation of compound of formula (2a)

[0041]

[Chemical 11]

7-octenal (50 g, 0.40 mo
1) and p-toluenesulfonic acid (0.1 g) were dissolved in methanol (200 ml) and cooled to 0 ° C. Methyl orthoformate (47.7 ml, 0.44 mo) was added to this solution.
1) was gradually added dropwise. After completion of the dropping, stirring was continued at 0 ° C. for 1 hour.

Triethylamine (1 ml) was added to the reaction solution to neutralize it, and the reaction solution was concentrated under reduced pressure to give a residue (69.5).
57.1 g (yield 83
%) Of the compound of formula (2a). Table 1 shows the NMR data of the compound of formula (2a).

[0044]

[Table 1]

Step (b) Preparation of compound of formula (3a)

[0046]

[Chemical 12]

Compound of formula (2a) obtained in step (a) (17.2 g, 0.10 mol), Rh (acac)
(CO) ₂ (26 mg, 0.01 mmol) and triphenylphosphine (2.6 g, 1 mmol) were dissolved in benzene (100 ml), and the solution was placed in a 300 ml stainless autoclave and carbon monoxide at 3 to 9 atmospheres. -The reaction was carried out by stirring at 60 to 70 ° C under a hydrogen mixed gas atmosphere. After reacting for 5 hours, the reaction solution was cooled, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. By distilling the obtained residue under reduced pressure, the compound of formula (2
The compound of a) is recovered and the regioisomer of the formula (3a) [(CH ₃ CH (CHO) (CH ₂ ) ₅ CH (OC
H ₃ ) ₂ ] was separated to obtain 13.1 g (yield 65%) of the compound of formula (3a). Table 2 shows the NMR data of the compound of formula (3a).

[0048]

[Table 2]

Step (c) Preparation of compound of formula (4a)

[0050]

[Chemical 13]

55% sodium hydride (9.6 g, 0.
22 mol) was suspended in tetrahydrofuran (300 ml). The suspension was cooled to 0 ° C. and into it ethyl diethylphosphonoacetate (53.8 g, 0.24 mo)
A solution of 1) in tetrahydrafuran (100 ml) was added dropwise. After the dropping was completed, the temperature was raised to room temperature and the mixture was stirred for 1 hour. In this state, the reaction solution became transparent.

The reaction solution was cooled again to 0 ° C., to which the compound of formula (3a) obtained in step (b) (40 g, 0.2
(mol) in tetrahydrofuran (100 ml) was added dropwise. After the dropping was completed, the reaction solution was stirred at room temperature for 3 hours. Thereafter, 100 ml of 3N hydrochloric acid was added, and the mixture was stirred at room temperature for 4 hours. Then, about 350 ml of tetrahydrofuran was distilled off under reduced pressure, the residual liquid was extracted twice with diisopropyl ether (200 ml), and the separated organic layer was saturated aqueous sodium hydrogen carbonate solution (100 ml), followed by saturated saline solution ( It was washed with 100 ml). The solvent was distilled off to obtain 52.1 g of the crude compound of the formula (4a).

Step (d) Preparation of compound of formula (5a)

[0054]

[Chemical 14]

The crude compound of formula (4a) (52.1 g, 0.2 mol) obtained in step (c) was added to methanol (300
ml) and cooled to 0 ° C. Sodium borohydride (2.28 g, 0.06 mol) was gradually added to this solution. About 200 ml of methanol was distilled off under reduced pressure, and the residual liquid was diluted with diisopropyl ether (300 ml). This solution was washed with 1N hydrochloric acid, the aqueous layer was extracted with diisopropyl ether (100 ml), and the organic layer was combined and washed with saturated aqueous sodium hydrogen carbonate solution (100 ml) and saturated brine (100 ml). The solvent was distilled off under reduced pressure to obtain 56.0 g of the crude compound of the formula (5a).

Step (e) Preparation of compound of formula (6a)

[0057]

[Chemical 15]

The crude compound of formula (5a) obtained in step (d) (56.0 g, 0.2 mol) and 24.2 g (0.2
4 mol) of triethylamine was dissolved in tetrahydrofuran (400 ml) and cooled to 0 ° C. Methanesulfonyl chloride (25.2 g, 0.2
(2 mol) was added dropwise, and after completion of the addition, the mixture was stirred for 30 minutes.

Furthermore, lithium bromide monohydrate (6
(3.0 g, 0.6 mol) was added and heated to about 4 under reflux.
Reacted for hours. After cooling, the reaction solution was diluted with 1N hydrochloric acid (200
ml) and diisopropyl ether (300 m
1, 200 ml) twice. The obtained organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution (200 ml) and subsequently with a saturated saline solution (200 ml). The solvent was distilled off under reduced pressure to obtain 65.0 g of the crude compound of the formula (6a).

Step (f) Preparation of compound of formula (7a)

[0061]

[Chemical 16]

The crude compound of formula (6a) (65.0 g, 0.2 mol) obtained in step (d) was added to toluene (500 m).
It was dissolved in l) and cooled to 0 ° C. A hexane solution (220 ml, 0.44 mol) of 2N diisobutylaluminum hydride (DIBAL) was added dropwise to this solution.
After the dropping was completed, 3N hydrochloric acid was gradually added to the reaction solution, and the reaction solution was diluted with diisopropyl ether (300 ml, 200 ml).
It was extracted twice with. The obtained organic layer was saturated aqueous sodium hydrogen carbonate solution (100 ml) and then saturated brine (100 ml).
ml). The solvent was distilled off under reduced pressure to give the compound of formula (7a)
The crude compound (53.3 g) of was obtained. The crude compound was purified by distillation under high vacuum to obtain 38.5 g of the compound of formula (7a) as colorless oil. The total yield of steps (c) to (f) is 77%. Table 3 shows the NMR data of the compound of formula (7a).

[0063]

[Table 3]

Step (g) Preparation of compound of formula (9a)

[0065]

[Chemical 17]

Allyl bromide alcohol compound of formula (7a) obtained in step (f) (25 g, 0.1 mol) and senecionaldehyde dimethyl acetal (39 g, 0.3
mol) and terephthalic acid (250 mg) while gradually removing methanol produced under an argon stream.
The mixture was heated and stirred on an oil bath at 0 ° C to 200 ° C for about 1 hour.

Thereafter, the reaction solution was cooled to room temperature, diluted with hexane (300 ml), saturated aqueous sodium hydrogen carbonate solution (100 ml), and then saturated saline solution (100 ml).
It was washed with and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 32.4 g of a crude compound of the formula (9a). Column chromatography of this crude compound (support Si
O2, eluting solvent: hexane / ethyl acetate = 15/1 (volume ratio)) and purified to give 25.9 g of a compound of formula (9a) in the form of a pale yellow oil (cis isomer / trans isomer = about 2/1,
Yield 82%). Table 4 shows the NMR of the compound of formula (9a)
Show the data.

[0068]

[Table 4]

The compound of formula (9a) can be used as a crude product in the reaction of the next step without column chromatography.

Step (h) Preparation of compound of formula (IIa ′)

[0071]

[Chemical 18]

Α and β of the equation (9a) obtained in the step (g)
-Unsaturated aldehyde compound (16.9 g, 53.6 mm
ol) and trimethylsilyl cyanide (8.56 ml, 6
(4.3 mmol) was mixed and stirred at about 5 ° C. To this mixture was added dicyclohexano-18-crown-6 / KCN.
The complex (about 100 mg) was added, and stirring was continued at 5 ° C. to room temperature for about 3 hours.

Then, tetrahydrofuran (8
0 ml) to dilute, then 1N hydrochloric acid (2 ml)
Was added and stirred for several minutes to remove the silyl group. The reaction mixture was diluted with diisopropyl ether (300 ml), washed with saturated brine (50 ml), and dried over anhydrous magnesium sulfate. By removing the solvent, an intermediate cyanohydrin compound was obtained as a residue.

The obtained cyanohydrin compound was dissolved in benzene (200 ml), and p-toluenesulfonic acid (50 mg) was further added to acidify the solution, which was then cooled to 5 ° C. Then ethyl vinyl ether (6.16 ml,
64.3 mmol) is gradually added dropwise, and about 1 after the addition is completed.
Stirring was continued for hours. Then, the reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate, the aqueous layer was extracted with diisopropyl ether, the organic layers were combined, washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 29.3 g of the compound of formula (IIa ′). This compound was subjected to column chromatography treatment (carrier S
iO ₂ , elution solvent: hexane / ethyl acetate = 15/1
(Volume ratio)), but the crude product can be used in the reaction of the next step. Table 5 shows the NMR data of the compound of formula (IIa ').

[0075]

[Table 5]

Step (i) Preparation of compound of formula (IIIa ')

[0077]

[Chemical 19]

Sodium amide (3.12 g, 80 mm
ol) was suspended in tetrahydrofuran (350 ml). This suspension was cooled to 0 ° C., hexamethyldisilazane (21.0 ml, 100 mmol) was added thereto, and 0
The mixture was stirred at ℃ ~ room temperature for 1 hour.

Then, the reaction solution is heated to reflux and the compound of formula (IIa ′) (11.8) obtained in step (h) is obtained.
g, 27.3 mmol) to tetrahydrofuran (150
The solution dissolved in (ml) was added dropwise over about 4 hours. After completion of dropping, the reaction solution was cooled to room temperature, and a saturated aqueous solution of ammonium chloride (100 ml) was added. About 350 ml of tetrahydrofuran was distilled off from the reaction solution under reduced pressure, and the mixture was diluted with diisopropyl ether (300 ml). This was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and then saturated brine, and dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, the compound of formula (III
The crude compound of a ') was obtained.

Step (j) Preparation of Compound of Formula (Ia)

[0081]

[Chemical 20]

The total amount of the crude compound of formula (IIIa ') obtained in step (i) was dissolved in methanol (200 ml),
Further p-toluenesulfonic acid was added until the solution was acidified. The solution was stirred at room temperature for 30 minutes for reaction, methanol was distilled off under reduced pressure, and the residual liquid was diluted with diisopropyl ether (200 ml). To this solution was added 2% by weight aqueous sodium hydroxide solution (100 ml) to give 5
Shake for minutes, then saturate ammonium chloride solution,
Then, it was washed with saturated saline and dried over anhydrous magnesium sulfate. 5. By distilling off the solvent under reduced pressure.
7 g of compound of formula (Ia) were obtained. NMR of this compound
The data are shown in Table 6.

[0083]

[Table 6]

Although the compound of formula (Ia) can be purified by column chromatography or distillation, it can be used as a raw material for Muscon synthesis in the form of a crude product.

Reference Example 1 (Production of dl-muscon of the formula (IV))

[0086]

[Chemical 21]

The compound of Example 1 of the formula (1a) (6.7
g), Pd / C catalyst (0.64 g) and methanol (5
(0 ml) and 200 ml pressure resistant container, and store at room temperature for 3
It was made to react with hydrogen gas of 50 atm for a time. The catalyst was filtered off from the reaction solution, methanol was distilled off from the filtrate under reduced pressure, the residual liquid was diluted with diisopropyl ether (200 ml), washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and purified by column chromatography to obtain 6.2 g of dl-muscon. Table 7 shows the NMR data of dl-muscon.

[0088]

[Table 7]

[0089]

Industrial Applicability According to the present invention, a novel 15-membered cyclic compound useful for efficiently and inexpensively producing Muscon, which is a compound useful as an aromatic component of musk, and a method for producing the same are provided.

─────────────────────────────────────────────────── --Continued front page (56) References JP-A-59-29687 (JP, A) Tetrahedron Letters, 1983, Vol. 24, No. 19, P 2005-2008 Tetrahedron Letters, 1983, Vol. 24, No. 33, P 3485-3488 Tetrahedron Letters, 1983, Vol. 24, No. 33, P 3489-3492 Tetrahedron Letters, 1983, Vol. 24, No. 43, P 4695-4698 (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07C 49/587 C07C 45/44 C07B 61/00 300 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. Formula (I): (In the formula, A is —CH ₂ CH ₂ CH═CH—). 2. The method for producing a 15-membered cyclic compound according to claim 1, wherein the compound of formula (II): (Wherein, A is _{-CH 2 CH 2 CH = CH-,} R is alkoxide Shiechiru non <br/> substituted, X is a leaving group) The compound represented by basic The ring is closed under the condition of formula (II
I) [Chemical Formula 3] (Wherein A and R are as described above), and the compound is further hydrolyzed.