JP2008100951A - Method for preparing 2-cyclopentadecenone - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a technique for preparing 2-cyclopentadecenone at a high yield using fewer reaction steps and under a mild preparation condition, and a method for preparing muscone from 2-cyclopentadecenone prepared by the above method. <P>SOLUTION: The method for preparing 2-cyclopentadecenone comprises a step of causing a 2-substituted cyclopentadecanone represented by formula 1 (wherein R represents -SO<SB>2</SB>R<SP>1</SP>, R<SP>1</SP>represents a methyl group or a tolyl group) to undergo an elimination reaction in the presence of an acid. A 2-4C organic acid that may contain a fluorine atom, a 1-3C alkanesulfonic acid that may contain a fluorine atom, or an arylsufonic acid is preferred as an organic acid to be used in the above reaction. A mineral acid such as sulfuric acid, hydrochloric acid and nitric acid is preferred as an inorganic acid to be used in the above reaction. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

（式中、Ｒは−ＳＯ_２Ｒ^１を示し、Ｒ^１はメチル基、トリル基を示す。） The present invention relates to a method for producing 2-cyclopentadecanone. More specifically, the present invention relates to a method for producing 2-cyclopentadecenone characterized by reacting a 2-substituted cyclopentadecanone represented by the following formula 1 in the presence of an acid, and the method: The present invention relates to a method for producing muscone from the obtained 2-cyclopentadecenone.
Formula 1

(In the formula, R represents —SO ₂ R ¹ , and R ¹ represents a methyl group and a tolyl group.)

  The incense-like fragrance component has been used for a long time, and it has been used extensively, probably because of its longing for its characteristic fragrance. In recent years, alternatives such as nitromusk, which have been consumed in large quantities as an aroma-like fragrance component, have been rigorously evaluated in terms of safety and environment, including use restrictions. As a result, combined with consumer-oriented expansion, the use of substances having a structure that is highly biodegradable, ie, macrocyclic ketones, has been rapidly promoted. In particular, an inexpensive supply of muscone, which is a naturally occurring and representative musk odorant, is desired.

Many attempts have been made so far to industrially produce Muscon. In particular, a process for producing muscone using 2-cyclopentadecenone as an intermediate has been studied for a long time, and the development of a simple and inexpensive method for synthesizing 2-cyclopentadecenone is important for the industrial production of muscone. Is extremely important.
As a production method of 2-cyclopentadecenone, for example, a production method in which a diesterified product of a linear alkanedioic acid is intramolecularly cyclized by an acyloin condensation reaction is known (Patent Documents 1 and 2). These methods have the disadvantages that the number of reaction steps is large and complicated.

  As a method for solving this problem, a technique for producing cycloalkenone by dehydrating 2-hydroxycycloalkanone using phosphoric acid or solid acid as an acid catalyst in a liquid phase has been reported (Patent Document 3). This method is advantageous in that the number of reaction steps is short, but it cannot be said that the production efficiency is so good, and further improvement measures are required.

JP 61-56146 A JP-A-5-155802 JP 2002-220361 A

  Under the circumstances as described above, an object of the present invention is to provide a technique for producing 2-cyclopentadecenone with a short number of reaction steps. Another object of the present invention is to provide a technique for producing 2-cyclopentadecenone with good yield under mild production conditions. Another object of the present invention is to provide a method for producing muscone based on 2-cyclopentadecenone obtained by the above method.

While the present inventors are diligently researching to achieve the above-mentioned object, paying attention to 2-methanesulfonyloxycyclopentadecanone, and surprisingly, the 2-methanesulfonyloxycyclopentadecanone is unexpectedly changed. It was found that when the elimination reaction was carried out in the presence of an acid, 2-cyclopentadecenone could be obtained with good yield even under mild reaction conditions, and could be obtained very selectively. Based on this knowledge, further research was conducted and the present invention was finally completed.
That is, the present invention includes the following inventions.

（式中、Ｒは−ＳＯ_２Ｒ^１を示し、Ｒ^１はメチル基、トリル基を示す。）
請求項２の発明は、請求項１の発明において、上記式１で表される２-置換シクロペンタデカノンを、シクロペンタデカノンからワンポットで合成することを特徴とし、請求項３の発明は、同じく、上記式１で表される２-置換シクロペンタデカノンを２−ヒドロキシシクロペンタデカノンからワンポットで合成することを特徴とする。なお、本発明は、シクロペンタデカノンからワンポットで上記式１で表される２-置換シクロペンタデカノンを製造する発明を包含する。 The invention according to claim 1 is a method for producing 2-cyclopentadecenone, wherein a 2-substituted cyclopentadecanone represented by the following formula 1 is subjected to elimination reaction in the presence of an acid.
Formula 1

(In the formula, R represents —SO ₂ R ¹ , and R ¹ represents a methyl group and a tolyl group.)
The invention of claim 2 is characterized in that, in the invention of claim 1, the 2-substituted cyclopentadecanone represented by the above formula 1 is synthesized in one pot from cyclopentadecanone. Similarly, the 2-substituted cyclopentadecanone represented by the above formula 1 is synthesized from 2-hydroxycyclopentadecanone in one pot. The present invention includes an invention for producing a 2-substituted cyclopentadecanone represented by the above formula 1 from cyclopentadecanone in one pot.

The invention of claim 4 is the invention of claim 3, wherein 2-hydroxycyclopentadecanone is obtained by condensing a dialkyl ester of pentadecanoic acid.
The invention according to claim 5 is a method for producing muscone, characterized in that 2-cyclopentadecenone obtained by the method according to any one of claims 1 to 4 is methylated. In addition, this invention also includes the invention which alkylates 2-cyclopentadecenone. Here, alkyl means an alkyl group having 1 to 4 carbon atoms.

The present invention will be described in detail below.
The 2-substituted cyclopentadecanone of the present invention is represented by the above formula 1.
In the formula, R represents —SO ₂ R ¹ , and R ¹ represents a methyl group or a tolyl group.
R is also a methanesulfonyl group or a toluenesulfonyl group.

  The present invention is characterized in that 2-cyclopentadecenone is obtained in one pot from the above-mentioned 2-substituted cyclopentadecanone. That is, the above-mentioned 2-substituted cyclopentadecanone is added to a reaction solvent containing an acid, reacted in the presence of an acid, the substituent of the above-mentioned 2-substituted cyclopentadecanone is eliminated, and 2-cyclopentadecenone is removed. Obtainable. Here, obtaining a chemical substance in one pot means that the target chemical substance can be prepared by adding and reacting the types and amounts of chemical substances necessary for the reaction including the starting materials in the reaction vessel.

The acid to be present is not particularly limited as long as it is an acid that can achieve the object of the present invention, but the organic acid may have a fluorine atom and may have a fluorine atom. Alkane sulfonic acids having 1 to 3 carbon atoms and aryl sulfonic acids are preferred. Among them, acetic acid which may have a fluorine atom, alkanesulfonic acid having 1 to 2 carbon atoms which may have a fluorine atom, and toluenesulfonic acid are more preferable. As the inorganic acid, mineral acids such as sulfuric acid, hydrochloric acid, phosphoric acid and nitric acid are preferable. As the Lewis acid, scandium trifluoromethanesulfonate (Sc (OTf) ₃ ), aluminum chloride, and boron trifluoride are preferable. More specifically, preferred acids include trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, acetic acid, Sc (OTf) ₃ and the like. From a general viewpoint. In particular, trifluoromethanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, and Sc (OTf) ₃ are preferable. A plurality of acids can also be used.
The amount of the coexisting acid is not particularly limited as long as the object of the present invention can be achieved, and cannot be defined unconditionally because it varies depending on the type and amount of 2-substituted cyclopentadecanone used and the type of acid used. However, as an example of the amount of the acid used, a preferable effect is obtained when the amount is 0.1 to 5 equivalents relative to 2-substituted cyclopentadecanone.

  In the present invention, the solvent to be used is not particularly limited as long as it can achieve the object of the present invention. Specifically, pentane, hexane, benzene, toluene, xylene, nitrobenzene, nitromethane, acetone, diethyl ether, diisopropyl ether. , Dicyclopentyl ether, cyclopentyl ethyl ether (CPME), dichloromethane, chloroform, dimethyl sulfoxide, and dimethylformamide (DMF). Among these, pentane, hexane, dichloromethane, DMF, and acetic acid are particularly preferable. A plurality of solvents can also be used.

In the present invention, at least the above-mentioned 2-substituted cyclopentadecanone, acid, and solvent are stirred in a container to produce 2-cyclopentadecenone in one pot. The order in which the acid and the solvent are added to the container is not particularly limited.
The temperature at the time of stirring is not particularly limited, but can be from room temperature to a temperature several degrees higher than the boiling point of the solvent used.
The reaction time varies depending on the type and amount of 2-substituted cyclopentadecanone, acid, and solvent to be used, but about 0.5 to 48 hours is usually sufficient.

By treating the reaction solution as it is by a conventional method, 2-cyclopentadecenone can be obtained in good yield. Moreover, you may perform the refinement | purification process of a conventional method as needed for the said reaction liquid.
The present invention is advantageous because 2-cyclopentadecenone can be obtained from the above-mentioned 2-substituted cyclopentadecanone in one pot, but the amount of by-products in 2-cyclopentadecenone is very small. This is also advantageous.

There are various methods for obtaining the 2-substituted cyclopentadecanone. For example, it can be synthesized from cyclopentadecanone in one pot.
That is, 2-substituted cyclopentadecanone can be obtained by reacting cyclopentadecanone with methanesulfonic acid or toluenesulfonic acid in a solvent.
The blending amount of methanesulfonic acid or toluenesulfonic acid is preferably approximately equivalent to that of cyclopentadecanone, but may be blended in a larger amount, for example, within 2.5 equivalents.

It is necessary that the other two types of compounds coexist in the solvent. The two types of compounds are halogenated benzene and organic peracids. Of the former, iodobenzene is particularly preferred. Examples of the latter include m-perbenzoic acid, perbenzoic acid, and peracetic acid, and m-perbenzoic acid is particularly preferable.
The reaction proceeds if the former compounding amount is within 0.05 to 0.4 equivalent, but is preferably 0.07 to 0.2 equivalent. The blending amount of iodobenzene is the same. The latter peracids are preferably within 1 to 2.5 equivalents, but may be added in a slightly larger amount.
Examples of the solvent to be used include dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, and CPME, and dichloromethane is particularly preferable.
Although the reaction conditions are not particularly limited, as an example, the reaction temperature may be between 0 ° C. and 40 ° C., preferably 10 to 25 ° C., and the reaction time is preferably about 1 to 10 hours.

A method for obtaining the above-mentioned 2-substituted cyclopentadecanone, which is a method different from the above, is a method of synthesizing from 2-hydroxycyclopentadecanone in one pot.
That is, 2-pentacyclopentadecanone can be obtained by reacting cyclopentadecanone with halogenated methanesulfonyl or halogenated toluenesulfonyl in a solvent containing a base. The blending amount of methanesulfonyl halide or toluenesulfonyl halide is preferably approximately equivalent to that of cyclopentadecanone, but may be blended slightly more, for example, within 1.5 equivalents.

The base and solvent to be used are not particularly limited. Specifically, the base to be used includes triethylamine, pyridine, collidine, and dimethylaminopyridine, and the solvent to be used is dichloromethane, chloroform, hexane, pentane, benzene, triethylamine, pyridine, Examples include DMF, acetonitrile, tetrahydrofuran, CPME, and diethyl ether, with dichloromethane, triethylamine, pyridine, acetonitrile, and benzene being particularly preferable.
The reaction conditions are not particularly limited. For example, it is desirable that the reaction temperature is 5 ° C. to 30 ° C. and the reaction time is about 1 to 6 hours.

It is a method for obtaining the above-mentioned 2-substituted cyclopentadecanone, and it can also be obtained by subjecting a dialkyl ester of pentadecanedioic acid to a cyclization reaction in a method different from the above.
For example, if the dialkyl ester is subjected to an acyloin cyclization reaction in the presence of sodium, a 2-substituted cyclopentadecanone can be easily obtained.
In this case, the yield is further improved by adding trimethylsilyl chloride.

  The dialkyl ester of pentadecanoic acid can be produced by diesterifying pentadecanoic acid by a known method. For example, pentadecanoic acid can be diesterified while removing water in methanol containing p-toluenesulfonic acid to produce dimethyl ester of pentadecanoic acid.

  Muscon can be produced using 2-cyclopentadecenone thus produced using a known reaction as a starting material. Since 2-cyclopentadecenone produced in the present invention is essentially pure (E) isomer, the operation of separating and purifying the (E) isomer and (Z) isomer is not particularly necessary, and can be easily performed. Advantageously (R) -muscon can be produced. For example, muscone can be produced by the Michael reaction in the presence of a copper reagent and a grinal reagent.

  According to the present invention, 2-cyclopentadecenone can be easily synthesized with a high yield in a short process. That is, 2-cyclopentadecenone can be produced in a single pot with an easily available acid and in good yield under mild conditions. Moreover, the produced 2-cyclopentadecenone is essentially pure (E) isomer, and according to the present invention, (R) muscone can be produced efficiently and inexpensively. Since 3-cyclopentadecenone, which is difficult to separate by the conventional elimination reaction, is produced as a by-product with a considerable production ratio, the present invention is a very practical invention.

Hereinafter, the present invention will be specifically described by way of examples. However, the present invention is not limited to these examples, and can be changed without departing from the scope of the present invention.
In the prescription described below, unless otherwise specified, “%” means “% by mass” and “part” means “mass part”.

Example 1 Preparation of 2-Cyclopentadecenone 160 mg (0.5 mmol: 1 eq.) Of 2-methanesulfonylcyclopentadecanone was dissolved in 1 mL of dichloromethane in a 5 mL vial to obtain a solution (0.5 M). Thereto was added 0.045 mL (0.5 mmol: 1 eq.) Of trifluoromethanesulfonic acid, and stirring was started at room temperature. After 1 hour, after confirming the disappearance of the raw material by thin layer chromatography (TLC), 3 mL of a saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction. The reaction solution was extracted with 3 mL of ethyl acetate. This operation was repeated twice. The collected organic layer was washed with 3 mL of water and 3 mL of saturated brine, and dried over anhydrous sodium sulfate. After the drying treatment, the solvent was distilled off after filtration with a suction cup to obtain a crude product. Silica gel filtration (SiO ₂ : 3 g, hexane / ethyl acetate = 70/30 volume ratio) was performed to obtain 103 mg (yield 92%) of a yellow liquid.
As a result of determining the structure by NMR, it was only (E) -2-cyclopentadecenone.
Analytical data of the prepared compound was as follows.

Examples 2 to 6 Preparation of 2-cyclopentadecenone Using the acids shown in Table 1 in the amounts shown in Table 1, the reaction was carried out for the times shown in Table 1, and otherwise the same operation as in Example 1 was carried out. Pentadecenone was obtained. The yield was as shown in Table 1.
As a result of determining the structure by NMR, it was only (E) -2-cyclopentadecenone.

Table 1

Examples 7 to 9 Preparation of 2-cyclopentadecenone Using the acids shown in Table 2 in the amounts shown in Table 2 and using the hexane solvent, the reaction was carried out for the times shown in Table 2, and otherwise the same operation as in Example 1 was performed. 2-cyclopentadecenone was obtained. The yield was as shown in Table 2.
As a result of determining the structure by NMR, it was only (E) -2-cyclopentadecenone.
Table 2

(Example 10) Preparation of 2-cyclopentadecenone In a 5 mL vial, 77 mg (0.2 mmol: 1 eq.) Of 2-toluenesulfonyloxycyclopentadecanone was dissolved in 0.4 mL of dichloromethane, and the solution (0.5 M) was dissolved. Obtained. Trifluoromethanesulfonic acid 0.01mL (0.2mmol: 1eq.) Was added there, and stirring was started at room temperature. Two hours later, after confirming that the raw materials had disappeared on TLC, 3 mL of a saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction. The reaction solution was extracted with 3 mL of ethyl acetate. This operation was repeated twice. The collected organic layer was washed with 3 mL of water and 3 mL of saturated brine, and dried over anhydrous sodium sulfate. After the drying treatment, the solvent was distilled off after filtration with a suction cup to obtain a crude product. Silica gel filtration (SiO ₂ : 3 g, hexane / ethyl acetate = 70/30 volume ratio) was performed to obtain yellow liquid (E) -2-cyclopentadecenone 36.7 mg (yield 55%)).

Examples 11 to 12 Preparation of 2-cyclopentadecenone The acids listed in Table 3 were used in the amounts shown in Table 3 and allowed to react for the times listed in Table 3. Otherwise, the same procedure as in Example 10 was followed. Pentadecenone was obtained. The yield was as shown in Table 3.
As a result of determining the structure by NMR, it was only E-form.
Table 3

(Comparative Example 1)
Under a nitrogen gas atmosphere, 155.4 mg (0.4880 mmol: 1.0 eq.) Of 2-methanesulfonyloxycyclopentadecanone was added to a 10 mL eggplant flask and dissolved in 1.0 mL (0.49 M) of o-xylene. Then, 0.21 mL (1.507 mmol: 3.1 eq.) Of triethylamine was added, and the reaction was started at reflux (144 ° C.) temperature. After 6 hours, it was confirmed that the reaction had progressed by TLC, and then cooled to room temperature. 0.5 mL of 5% aqueous hydrochloric acid was added, and 2 mL of ether was added for extraction treatment. This operation was repeated three times. The collected organic layer was washed with 3 mL of saturated saline and 3 mL of water and dried over anhydrous sodium sulfate. Suction filtration was performed, and the solvent was distilled off with an evaporator to obtain 146.8 mg of a crude product. Thereafter, the crude product was purified by column chromatography (SiO ₂ : 1.5 g, hexane / ethyl acetate = 95/5 volume ratio). As a result, a yellow liquid product ((E) -2-cyclopentadecenone, 99.4 mg of (E) -3-cyclopentadecenone, (Z) -3-cyclopentadecenone mixture) was obtained. According to gas chromatography of the product, 74.8 mg (yield 69%) of (E) -2-cyclopentadecenone and a mixture of (E) and (Z) isomers of 3-cyclopentadecenone 19.2 mg (Yield 18%) was obtained.

(Comparative Example 2)
Under a nitrogen gas atmosphere, 21.34 mg (0.6855 mmol: 1.0 eq.) Of 2-methanesulfonyloxycyclopentadecanone was added to a 10 mL eggplant flask, dissolved in 1.40 mL (0.49 M) of DMF, and then lithium carbonate. 157.9 mg (2.137 mmol: 3.1 eq.) Was added and the reaction was started at reflux (150 ° C.) temperature. After 2 hours, it was confirmed that the reaction had progressed by TLC, and then cooled to room temperature. 15 mL of 5% nitric acid aqueous solution was added, and 2 mL of ether was added for extraction treatment. After this operation, the same operation as in Comparative Example 1 was performed to obtain 195.8 mg of a crude product. Thereafter, the crude product was purified by column chromatography (SiO ₂ : 6 g, hexane / ethyl acetate = 95/5 volume ratio). As a result, 90.1 mg of a yellow liquid product was obtained. From a gas chromatography analysis of the product, 54.2 mg (yield 36%) of (E) -2-cyclopentadecenone and a mixture of (E) -form and (Z) -form of 3-cyclopentadecenone 31. 5 mg (yield 21%) was obtained.

(Comparative Example 3)
Under a nitrogen gas atmosphere, 1.39 g (4.58 mmol: 1 eq.) Of 2-bromocyclopentadecanone was dissolved in 9.2 mL of dimethylformamide (DMF) to obtain a solution (0.5 M). Thereto was added 854 mg (11.6 mmol: 2.5 eq.) Of lithium carbonate, and the reaction was started at reflux (150 ° C.) temperature. After 2.5 hours, it was confirmed that the raw material had disappeared on TLC, and then cooled to room temperature. The mixture was neutralized by adding 15 mL of 5% nitric acid aqueous solution and extracted by adding 3 mL of ethyl acetate. This operation was repeated three times. The collected organic layer was washed with 15 mL of water and 15 mL of saturated brine, and dried over anhydrous sodium sulfate. After drying, the solvent was distilled off after filtration through a suction cup to obtain 1.45 g of a crude product. As a result of isolation by column chromatography (SiO ₂ : 60 g, hexane / ethyl acetate = 98/2 volume ratio), 576 mg of 2-cyclopentadecenone (yield 56%) and (E) of 3-cyclopentadecenone 19.2 mg (yield 18%) of a mixture of the isomer and (Z) isomer was obtained.

ＮＭＲ

(Example 13) Preparation of Muscon 100 mg (0.5 wt / wt) of copper chloride was added to a 50 mL two-necked flask under a nitrogen atmosphere, and 3.6 mL (0.25 M) of ethyl ether was added. 9 mL (9 mmol: 1 eq.) Of methylmagnesium iodide was added, and stirring was started at 0 ° C. 200 mg (0.9 mmol: 1 eq.) Of 2-cyclopentadecenone dissolved in 9 mL (0.1 M) of ethyl ether was added dropwise over 4 hours using a dropping funnel. After 2 hours, 10 mL of a cooled 10% hydrochloric acid aqueous solution was added, and the mixture was extracted with 3 mL of ethyl ether. The ethyl ether extraction process was repeated twice. The collected organic layer was washed with 3 mL of water and 3 mL of saturated brine, and dried over anhydrous sodium sulfate. After drying, the solvent was distilled off after filtration through a suction cup to obtain 294 mg of a crude product. Column chromatography (SiO ₂ : 3 g, hexane / ethyl acetate = 70/30 volume ratio) was performed to obtain 172.9 mg (yield 81%) of colorless and transparent dl Muscon.
Analytical data of the prepared compound was as follows.

NMR

Example 14 Preparation of 2-methanesulfonyloxycyclopentadecanone Under an argon atmosphere, 91.1 mg (0.4060 mmol, 1 eq) of cyclopentadecanone was added to a 20 mL eggplant flask and 1.0 mL of dichloromethane (0.40M). ), Iodobenzene 0.009 mL (16.5 mg, 0.0807 mmol, 0.2 eq) and methanesulfonic acid 51.9 μL (76.9 mg, 0.7997 mmol, 2.0 eq) And m-chloroperbenzoic acid ( purity 73%) (201.5 mg, 0.8524 mmol, 2.1 eq) were added and stirred at room temperature. After 4 hours, it was confirmed by TLC that the reaction proceeded.
After adding 2 mL of saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with 2 mL of dichloromethane. This extraction operation was repeated twice. The collected organic phase was washed with 3 mL of saturated aqueous sodium hydrogen carbonate solution, 3 mL of saturated brine, and 3 mL of water, and dried over anhydrous sodium sulfate. Suction filtration was performed, and the solvent was distilled off with an evaporator to obtain 0.162 g of a crude product. Thereafter, the crude product was purified by column chromatography (SiO ₂ : 4.8 g, hexane: ethyl acetate = 95: 5 volume ratio). As a result, an odorless white liquid 2-methanesulfonyloxycyclopentadecanone 78.2 mg was obtained. (Yield 61%) and (E) -2-cyclopentadecenone 1.7 mg (yield 2%), 2-hydroxycyclopentadecanone 2.6 mg (yield 3%).
Analytical data of the prepared compound was as follows.

実施例１６ ２−メタンスルホニルオキシシクロペンタデカノンの調製(1mL, 0.5mL)
132mg. 0.5mmol,1eq)
１０ｍＬナスフラスコに２−ヒドロキシシクロペンタデカノン１３２ｍｇ、（０．５mmol，１ｅｑ、純度９１％）をジクロロメタン１ｍＬ（０．５Ｍ）溶液とした。ピリジン０．０８ｍＬ（１ｍmol１1 eq）、塩化メタンスルホニル０．１３ｍＬ（１ｍmol２ eq）を加え、攪拌を開始した。２０℃で５時間反応後、ＴＬＣ上でゲｂｂ量の消失を確認し、１０％塩酸水溶液（４ｍＬ）を加え、反応を停止した。
ジクロロメタン５ｍＬで抽出処理した。この抽出操作を２回繰り返した。集めた有機相を水５ｍＬ、飽和食塩水５ｍＬで洗浄し無水硫酸ナトリウムで乾燥した。これを、目皿吸引ろ過後、溶媒を留去、粗成生物１８６．７ｍｇを得た。カラムクロマトグラフィー（SiO_２：４．８ｇ、ヘキサン／酢酸エチル＝９５／５容量比）で単離した結果、白黄色固体２−メタンスルホニルオキシシクロペンタデカノン１２９ｍｇ（収率８１％）を得た。

Example 15 Aciloin condensation Under a nitrogen gas atmosphere, 360 mL of toluene was charged into a three-necked flask, 18.5 g (0.804 ml, 4.2 eq.) 400 mmol: 4.2 eq.) Of sodium metal was added, and heating was started. When metallic sodium melted at 100 ° C., stirring (251 rpm) was started carefully. When metallic sodium is dispersed, 57.62 g (0.192 mol) of dimethyl ester of pentadecanoic acid is dissolved in 100 mL of toluene, and 87.3 g (0.804 ml, 4.2 eq) of Me ₃ SiCl is mixed. It was added dropwise at an internal temperature of 100 over 5 hours. After completion of dropping, the mixture was aged for 2 hours, and disappearance of unreacted substances was confirmed by GC (unreacted 1.4%). Cool to 50 ° C. or less, add 5 mL of methanol to decompose metallic sodium, stir for 30 minutes, add 150 mL of water, 11 g of p-toluenesulfonic acid (0,058 mol, 0.3 eq.), And reflux for 2.5 hours Let The internal temperature at this time was about 70 ° C. If decomposition | disassembly was confirmed by GC, it cooled, added 100 mL of water, and liquid-separated at 50-60 degreeC. Next, it was washed with 100 mL of saturated aqueous sodium bicarbonate, and then with 200 mL and 100 mL of water. It was dehydrated and filtered with 20 g of anhydrous sodium sulfate, washed with cake (toluene 50 mL), and concentrated to dryness under reduced pressure. The obtained acyloin body was 42.52 g , and the GC purity was 91.11%. As a result, the extraction yield was 93.5%, and the extraction net yield was 85.2%.
2-hydroxycyclopentadecanone

Example 16 Preparation of 2-methanesulfonyloxycyclopentadecanone (1 mL, 0.5 mL)
132mg.0.5mmol, 1eq)
In a 10 mL eggplant flask, 132 mg of 2-hydroxycyclopentadecanone (0.5 mmol, 1 eq, purity 91%) was used as a solution of 1 mL (0.5 M) in dichloromethane. 0.08 mL (1 mmol 11 eq) of pyridine and 0.13 mL (1 mmol 2 eq) of methanesulfonyl chloride were added and stirring was started. After the reaction at 20 ° C. for 5 hours, the disappearance of the amount of Gebb was confirmed on TLC, and a 10% hydrochloric acid aqueous solution (4 mL) was added to stop the reaction.
Extraction was performed with 5 mL of dichloromethane. This extraction operation was repeated twice. The collected organic phase was washed with 5 mL of water and 5 mL of saturated brine and dried over anhydrous sodium sulfate. After this, the solvent was distilled off after filtration through a suction dish to obtain 186.7 mg of a crude product. As a result of isolation by column chromatography (SiO ₂ : 4.8 g, hexane / ethyl acetate = 95/5 volume ratio), 129 mg (yield 81%) of white-yellow solid 2-methanesulfonyloxycyclopentadecanone was obtained. .

Claims (5)

A process for producing 2-cyclopentadecenone, wherein a 2-substituted cyclopentadecanone represented by the following formula 1 is subjected to elimination reaction in the presence of an acid.
Formula 1

(In the formula, R represents —SO ₂ R ¹ , and R ¹ represents a methyl group and a tolyl group.) The method for producing 2-cyclopentadecenone according to claim 1, wherein the 2-substituted cyclopentadecanone represented by formula 1 according to claim 1 is synthesized from cyclopentadecanone in one pot. The method for producing 2-cyclopentadecenone according to claim 1, wherein the 2-substituted cyclopentadecanone represented by the formula 1 according to claim 1 is synthesized from 2-hydroxycyclopentadecanone in one pot. . The method for producing 2-cyclopentadecenone according to claim 3, wherein the 2-hydroxycyclopentadecanone according to claim 3 is obtained by condensing a dialkyl ester of pentadecanoic acid. A method for producing muscone, comprising methylating 2-cyclopentadecenone obtained by any one of claims 1 to 4.