JPS628438B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to cis-2,3-disubstituted cyclopentanones, which are attracting attention as intermediates for the production of fragrances and pharmaceuticals, particularly methyl diasmonate useful in the fragrance field, and methods for producing them. .

More specifically, the present invention is based on the following formula (4)' However, in the formula, R' represents a lower alkyl group, and relates to a cis-2,3-disubstituted cyclopentanone represented by the following which has not been described in any literature. In addition, the following formula (6) useful for producing the following formula (4) compound, including the formula (4)′ compound, However, in the formula, R is a lower alkyl group, preferably C ₁
~C ₄ alkyl group or −SiR′ ₃ (where,
R' represents a lower alkyl group (preferably a C ₁ -C ₄ alkyl group).

The 6-substituted tetrahydroindanone represented by is also a compound that has not been described in any literature.

Furthermore, the present invention includes the compound of the above formula (4)', and the compound of the following formula (4), However, in the formula, R has the same meaning as above for formula (6), and relates to a method for producing a cis-2,3-disubstituted cyclopentanone represented by:

Conventionally, compounds in which R is a methyl group in the above formula (4) and their production methods have been known (J.
Org.Chem., Vol.40, No.4, 1975). According to this known method, the compound has the following process formula: It is produced by a complicated and multi-step reaction shown in

The present inventors conducted research to avoid such a complicated and industrially disadvantageous multi-step method and to produce the above compound. As a result, easily available formula (7) 2-cyclopentenone and formula (8) 2
Using -substituted butadiene as a starting material, the 6-substituted tetrahydroindanone of formula (6) above can be easily obtained with good yield and selectivity, and the compound of formula (6) can be
For example, by treatment with a mild oxidizing agent such as ozone, compounds of the formula (4)' can be
It has been discovered that cis-2,3-disubstituted cyclopentanone represented by (4) can be easily produced. Furthermore, methyl diasmonate, which is useful as a fragrance and a pharmaceutical intermediate, can be industrially advantageously produced from the compound of formula (4), and when a compound in which R is a group other than a methyl group is used as the compound of formula (4). It was also discovered that methyl diasmonate can be easily obtained.

Accordingly, an object of the present invention is to provide cis-2,3-di-substituted cyclopentanones useful in the perfume and pharmaceutical manufacturing fields and methods for their production.

The above objects and many other objects and advantages of the present invention will become more apparent from the following description.

According to the present invention, the cis-2,3-disubstituted cyclopentanone represented by the above formula (4) including the above formula (4)' compound, in the formula (6), where R is -SiR' ₃ (Here, R' represents a lower alkyl group) is a 6-substituted tetrahydroindanone represented by the above formula (6), which is an oxidizing agent having a mild oxidizing effect. It can be easily formed by processing. The 6-substituted tetrahydroindanone of formula (6) has the following formula (7), 2-cyclopentenone represented by and the following formula (8) However, in the formula, R can be obtained by reacting a 2-substituted butadiene having the same meaning as defined in the above formula (6). Cis-2,3 of formula (4) including the obtained compound of formula (4)' of the present invention
-Disubstituted cyclopentanone is, for example, the following formula
(5), R″ ₃ P=CHCH ₂ CH ₃ (5) where R″ is the same or different and represents a group selected from the group consisting of a phenyl group and an alkyl group, such as a C ₁ to _{C 10} alkyl group. By reacting with the Uitztetsug reagent represented by,
The following formula (2), However, in the formula, R is a lower alkyl group or -
SiR′ ₃ (wherein R′ represents a lower alkyl group) can be converted into a 2-epi-diasmonic acid ester represented by the following formula: (3), MOR (3) where M is an alkali metal atom such as Li,
By reacting with methyl alcohol in the presence of a metal alcoholate represented by Na, K, etc., where R is a lower alkyl group, preferably a methyl group, the following formula (1), It can be converted to methyl diasmonate represented by

In addition to the usage example of forming methyl diasmonate of formula (1) from the compound of formula (4), the compound of formula (4)' of the present invention is included from the 6-substituted tetrahydroindanone of formula (6) to form formula (4). ) The method for producing the compound and the production of the compound of formula (6) can be shown as shown in the process diagram below.

A 6-substituted tetrahydroindanone of formula (6), including the above-mentioned formula (4)' compound of the present invention, used for the production of a compound of formula (4), i.e., 6-alkoxy- or 6-trialkylsilyloxy-4 ,5,8,9-
Tetrahydroindanone is produced by combining 2-cyclopentenone of formula (7) above and 2-substituted butadiene of formula (8), that is, 2-alkoxy- or 2-trialkylsilyloxy-butadiene, in the presence of a solvent or in the absence of a solvent. It can be easily produced by carrying out a Diels-Alder reaction in the presence of The reaction is preferably carried out under heating conditions of, for example, about 80°C or higher, more preferably at a temperature of about 180°C or higher, for example, about 180° to about 400°C, more preferably about 200 to about 300°C. Temperatures of approximately The reaction can be carried out under atmospheric or pressurized conditions, for example in a pressure vessel under naturally occurring pressure conditions.

Specific examples of the 2-alkoxy-butadiene of the above formula (8) include, for example, 2-methoxy-butadiene,
2-ethoxy-butadiene, 2-n-propoxy-butadiene, 2-iso-propoxy-butadiene, 2-n-butoxy-butadiene, 2-iso-
Examples include butoxy-butadiene, 2-tert-butoxy-butadiene, and specific examples of 2-trialkylsilyloxybutadiene include, for example,
Trimethylsilyloxybutadiene is mentioned.

Further, as the above-mentioned solvent, an inert organic solvent can be used, such as benzene, toluene, xylene, n
- Hydrocarbon solvents such as hexane, n-peptane, etc. may be mentioned. These solvents may be used alone or in a mixture of two or more.

After the completion of the Diels-Alder reaction, the reaction mixture is distilled, for example, under reduced pressure to obtain a 6-substituted tetrahydroindanone of formula (6), i.e., 6-alkoxy- or 6-trialkylsilyloxy-
4,5,8,9-tetrahydroindanone can be obtained with high purity. If desired, it is also possible to further purify using a silica gel column or the like.

Specific examples of the compound of formula (6) that can be obtained by the above Diels-Alder reaction include, for example:
A 6-alkoxy compound or 6-alkoxy compound which is an adduct of 2-alkoxy- or 2-trialkylsilyloxy-butadiene and 2-cyclopentenone of formula (7) mentioned above as a specific example of the starting material formula (8) compound. -Trialkylsilyloxy derivatives can be mentioned.

In the present invention, the compound of the formula (4)′ is included.
(4) In order to produce cis-2,3-disubstituted cyclopentanone from 6-substituted tetrahydroindanone of formula (6), including the compound of formula (6)' above, various mildest oxidation methods can be used. Active oxidizing agents are available. formula
(4) Ozone oxidation is preferred for easily producing the compound with good selectivity. For example, ozone gas is dissolved in an inert organic solvent at low temperature to form ozonide, and then a reducing agent is added without isolation to produce the desired compound of formula (4) with high purity and high yield. You can get it at a high rate. In the case of using other oxidizing agents that are as mild as possible, the use of reducing agents can be omitted.

The reaction is preferably carried out at as low a temperature as possible, preferably at room temperature or lower. For example, when ozone is used, room temperature to about -100°C, more preferably about 10°C
Ozone oxidation under low temperature conditions of about -100°C, particularly about -20°C to -80°C is used. When reducing with a reducing agent, higher temperatures can be used,
Preferably from about -10°C to room temperature, more preferably about -
The temperature is about 10°C to about 20°C.

Examples of the solvent used include inert organic solvents that are liquid at the reaction temperature, such as alcohols such as methanol, ethanol, ethyl acetate, and methylene chloride, esters, and halogenated hydrocarbons. can be used alone or in combination. As the reducing agent, for example, zinc powder-acetic acid or phosphite, trivalent phosphorus compounds such as triphenylphosphine, dimethyl sulfide, etc. can be used. Or, Pd
Catalytic hydrogen reduction can also be carried out using -C, Pt and other various reduction catalysts. After the reaction, if an insoluble solid reducing agent remains in the reaction solution, it can be filtered, washed with water, and the oil phase can be collected to obtain the compound of formula (4). If desired, the compound of formula (4) can be obtained. The compound of formula (4) can also be obtained by extracting with water and removing the solvent. If desired, further purification can be achieved by distillation or other means. Specific examples of the target compound of the above formula (4) including the formula (4)' of the present invention thus obtained include 2,3-cis-3-carbomethoxymethyl-2-formylmethyl-1- Cyclopentanone, 2,3-cis-3-carboethoxymethyl-2
-Formylmethyl-1-cyclopentanone, 2,3-cis-3-carbo-n-propoxymethyl-2-formylmethyl-1-cyclopentanone, 2,3-cis-3-carboiso-propoxymethyl-2 -Formylmethyl-1-cyclopentanone, 2,3-cis-3-carbo-n-butoxymethyl-2-formylmethyl-1-cyclopentanone, 2,3-cis-3-carboiso-butoxymethyl-2 -Formylmethyl-1-cyclopentanone, 2,3-cis-3-carbotert-butoxymethyl-2-formylmethyl-1-cyclopentanone, 2,3-cis-3-carbotrimethylsilyloxymethyl-2 -formylmethyl-1-cyclopentanone and the like.

Hereinafter, the formula (4)′ of the present invention obtained as described above will be described.
As an example of the use of cis-2,3-disubstituted cyclopentanone of the formula (4) including the compound, the production of methyl diasmonate of the formula (1) from the compound will be explained.

The 2-epi-diasmonic acid ester of formula (2) can be produced by converting the compound of formula (4) into the following formula (5), R″ ₃ P=CHCH ₂ CH ₃ (5) where R″ is as described above. are synonymous.

It can be easily obtained with good yield and selectivity by reacting with the Witsteg reagent represented by: The phosphorane compound (Witstetsug reagent) of formula (5) is, for example, represented by the following formula (5)′, R″ ₃ PCHCH ₂ CH ₃ X (5)′ where R″ has the same meaning as above, and X It can be obtained by reacting a halogen, preferably Cl, Br or I, with a base. Examples of bases used include butyllithium,
Examples include phenyllithium, lithium diethylamide, sodium ethoxide, sodium hydride, sodium amide, potassium hydride, potassium amide, and the like. There are no particular restrictions on the amount of these bases used, but the above formula
(5) It is preferable to use the amount approximately equivalent to or slightly less than the compound. The reaction is preferably carried out in a solvent under an inert gas atmosphere, and examples thereof include inert gases such as nitrogen, helium, and argon. The reaction is preferably carried out at a temperature of about 0°C or higher; for example, temperatures on the order of about 0°C to about 50°C can be used. Further, the solvent is preferably as anhydrous as possible, and specific examples of the solvent include n-hexane, cyclohexane, pentane, benzene, toluene, diethyl ether, dioxane, tetrahydrofuran, dimethyl sulfoxide, N,N-
Examples include organic solvents such as dimethylformamide, dimethoxyethane, and diglyme. These can be used alone or in combination.

The Witsteg reagent of formula (5) which can be formed in this way and the cis-2,3-disubstituted cyclopentanone of formula (4), i.e. cis-2,3-2-formylmethyl-3-carbalkoxymethyl - or cis-2,3-2-formylmethyl-3-carbosilyloxymethyl-1-cyclopentanone is preferably reacted with the formula (4) in an organic solvent under an inert gas atmosphere as described above. ) and the compound of formula (5). Examples of the solvent include the same organic solvents as those exemplified for the formation of the compound of formula (5) above. Regarding the selection of the solvent, the same solvent as used for forming the compound of formula (5) or a different solvent may be selected. It is preferable to use an anhydrous solvent whenever possible. The reaction is
Since the process proceeds satisfactorily at room temperature, there is no particular need for heating or cooling, although such means can be employed if desired. For example, the temperature may be about 0° C. to about the reflux temperature of the solvent used. The reaction operation is preferably carried out while dropping either the compound of formula (4) or the compound of formula (5) into the other. The amount of the Witsteg reagent of formula (5) to be used for the compound of formula (4) can be selected as appropriate, for example, about 1
~about 2 times the molar amount, more preferably about 1~about
An amount on the order of 1.5 times the mole is most often employed.

After the reaction is completed, the reaction solution is directly concentrated and extracted with an organic solvent such as n-hexane, chloroform, methylene chloride, etc., or diluted hydrochloric acid is added to deactivate excess phosphorane, and then extracted with the above solvent. After extraction and recovery of the solvent, it can be purified by distillation or column chromatography.

Representative examples of the 2-epi-diasmonate of formula (2) obtained as described above include, for example, methyl 2-epi-diasmonate, 2-epi-diasmonate,
Ethyl diasmonate, 2-epi-diasmonate n
-propyl, 2-epi-diasmonate isopropyl, 2-epi-diasmonate n-butyl, 2-epi-diasmonate isobutyl, 2-epi-diasmonate tert-butyl, 2-epi-diasmonate trimethylsilyl ester, etc. be able to.

The 2-epi-diasmonic acid ester of the formula (2) obtained as described above is combined with the formula (3) MOR (where M represents an alkali metal atom such as Li, Na, or K, and R represents a lower The mixture is reacted with methanol in the presence of a metal alcoholate of an alkyl group (preferably a methyl group). Methanol can also be utilized in the form of methanol-containing organic solvents. Examples of organic solvents include benzene, toluene, xylene, n-
Mention may be made of hydrocarbon solvents such as hexane and n-heptane.

The reaction can be easily carried out by bringing the compound of formula (2) into contact with methanol in the presence of the compound of formula (3). Since the reaction proceeds at room temperature, there is no particular need for cooling or heating, although such conditions can be employed if desired. For example, a temperature of about 0°C to about 70°C can be exemplified. This reaction causes side chain epimerization, converting the side chain of the five-membered ring ketone in formula (2) from cis to trans, and at the same time, a transesterification reaction occurs, resulting in Even in compounds of formula (2) in which R is other than methyl, R is converted to a methyl group, yielding methyl diasmonate as exemplified by the following formula.

In the above reaction, the amount of the metal alcoholate of formula (3) to be used can be appropriately selected, and a catalytic amount is sufficient. For example, the amount used may be about 5 to about 20% by weight based on the 2-epi-diasmonic acid ester of formula (2). More preferably, it is about 5 to about 15% by weight. The amount of methanol used can be selected as appropriate, but it is usually about 50 times or more (by weight) relative to the 2-epi-diasmonic acid ester of formula (2), and about 100 to about 200 times. The use in
Often gives more favorable results.

After the reaction, the metal alcoholate is neutralized with, for example, dilute hydrochloric acid, extracted with an organic solvent such as methylene chloride, hexane, ether, etc., and the solvent is distilled off under reduced pressure to obtain the desired methyl diasmonate formula ( 1) can be obtained with high purity and high yield.
Moreover, if desired, it can be easily purified by column chromatography or other purification means.

Reference Example 1 Method for producing 6-ethoxy-4,5,8,9-tetrahydroindanone [formula (6)] In a 100 ml autoclave, 16.0 g of 2-cyclopentenone and 57.0 g of 2-ethoxybutadiene were sealed, and 240 Incubate for 5 minutes at ~250°C. After cooling the reaction product, the target product 6-
Ethoxytetrahydroindanone with a yield of 72%
24.5g was obtained.

Bp: 100-105℃/1.5mmHg IR (liquid film): 1738, 1655cm ^-1 NMR (CCl ₄ ): δ4.38 (1H, m), 3.60 (2H,
q), 1.22 (3H, t) Reference example 2 6-trimethylsilyloxy-4,5,8,9-
Method for producing tetrahydroindanone [formula (6)′] In a quartz tube, 2.4 g of 2-cyclopentenone and 2
- Charge 11.4 g of trimethylsilyloxybutadiene, seal the tube, and react at 230 to 240°C for 10 minutes. After the reaction product was cooled, it was rectified under reduced pressure to obtain 3.2 g of the target product, 6-trimethylsilyloxytetrahydroindanone, in a yield of 65%.

Bp: 92-96℃/1.0mmHg IR (liquid film): 1740, 1655cm ^-1 NMR (CCl ₄ ): δ4.70 (1H, m), 0.19 (9H,
s) Reference example 3 6-methoxy-4,5,8,9-tetrahydroindanone [formula (6)] and 6-n-butoxy 4,,5,8,9-tetrahydroindanone [formula (6)] Production method of 2-cyclopentenone and 2-methoxybutadiene or 2-n-butoxybutadiene in Reference Example 2
By reacting and rectifying in the same manner as above, the target product 6-methoxytetrahydroindanone (yield 68
%, bP80-83℃/0.5mmHg), or 6-n-butoxytetrahydroindanone (yield 62%, b.
p.82-90℃/0.1mmHg) was obtained.

Reference example 4 2,3-cis-2-formylmethyl-3-carboethoxymethyl-1-cyclopentanone [formula
(4)] A predetermined amount of ozone is passed into a solution of 10.0 g of 6-ethoxytetrahydroindanone in 200 ml of methylene chloride at -70 to -78°C. Next, this reaction solution was added to a suspension of 51.0 g of zinc powder in 130 ml of acetic acid, and
Perform the reduction reaction at ℃ for 2 hours. The reactant was poured into water, extracted with methylene chloride, and the organic layer was washed with heavy sodium chloride.
After washing with water and drying with Glauber's salt, the solvent was removed and the residue was distilled under reduced pressure to obtain the desired product, 2,3-cis-2-
Formylmethyl-3-carboethoxymethyl-1
-9.6 g of cyclopentanone was obtained with a yield of 82.1%.

Bp: 66-68℃/0.04mmHg IR (liquid film): 1741, 1730, 1722cm ^-1 NMR (CCl ₄ ): δ9.85, 4.10, 1.25 Example 1 2,3-cis-2-formylmethyl-3 -Production method of carbotrimethylsilyloxymethyl-1-cyclopentanone [formula (4)'] A predetermined amount of ozone is added to a solution of 5.0 g of 6-trimethylsilyloxytetrahydroindanone in 100 ml of methanol at -70 to -78°C. through, then -10℃~0
Add 70 ml of dimethyl sulfide at ℃ and react for 2 hours. By rectifying the reaction product under reduced pressure, 46 g of the target product, 2,3-cis-2-formylmethyl-3-carbotrimethylsilyloxymethyl-1-cyclopentanone, was obtained with a yield of 78%.

Bp: 140-143℃/0.1mmHg IR (liquid film): 1741, 1730, 1720cm ^-1 NMR (CCl ₄ ): 9.85 (1H, s), 0.15 (9H, s) Reference example 5 2,3-cis- 2-formylmethyl-3-carbomethoxymethyl-1-cyclopentanone [formula
(4)] and 2,3-cis-2-formylmethyl-
Process for producing 3-carbo-n-butoxymethyl-1-cyclopentanone [formula (4)] 6-methoxytetrahydroindanone and 6-
From n-butoxytetrahydroindanone, the desired product 2,3-cis-2 was obtained in the same manner as in Example 1.
-Formylmethyl-3-carbomethoxymethyl-
1-cyclopentanone (85% yield, bp112-114
°C/0.01mmHg) and 2,3-cis-2-formylmethyl-3-carbo-n-butoxymethyl-1
- Cyclopentanone (74% yield, bp 136-140
℃/0.005mmHg) was obtained.

Reference example 6 Ethyl 2-epi-diasmonate [formula (2)] and 2
-Production method of n-butyl epi-diasmonate [formula (2)]] In a sufficiently dried container purged with nitrogen, add 0.05 mol of triphenyl n-produced separately from triphenyl n-propylphosphonium bromide.
Dimethoxyethane solution of propylphosphorane
180 ml of the same solvent was added, and a solution of 10.1 g of 2,3-cis-2-formylmethyl-3-carboethoxymethyl-1-cyclopentanone dissolved in 100 ml of the same solvent was added dropwise while cooling on ice, and the mixture was reacted for 20 minutes at room temperature. let
After the reaction is completed, dilute hydrochloric acid is added to the reaction solution and extracted with methylene chloride. After recovering the solvent, the residue is rectified under reduced pressure to obtain 9.1 g of the desired ethyl 2-epi-diasmonate at a yield of 80.2%.

IR (liquid film) 1745, 1653 cm ^-1 NMR (CCl ₄ ) 5.80-5.05 (2H, m), 3.85 (2H,
q), 1.07 (3H, t) Boiling point 60° to 65°C/0.15 mmHg In the above example, in place of 2,3-cis-2-formylmethyl-3-carboethoxymethyl-1-cyclopentanone, Example 6 The same procedure was carried out except that 2,3-cis-2-formylmethyl-3-carbo-n-butoxymethyl-1-cyclopentanone obtained in 1 was used, and n-butyl 2-epi-diasmonate was obtained in a yield of 78. Obtained in %. Boiling point 72°~76°C/0.01
mmHg.

Reference Example 7 Trimethylsilyl 2-epi-diasmonate [Formula
(2)] After reacting 2,3-cis-formylmethyl-3-carbotrimethylsilyloxymethyl-1-cyclopentanone in the same manner as in Reference Example 6,
After adding sufficiently cooled water and extracting with methylene chloride, drying with magnesium sulfate and rectifying under reduced pressure, trimethylsilyl 2-epi-diasmonate (yield 60%, bp 93-96℃/0.2mmHg) was obtained. can get.

Reference Example 8 Method for producing methyl diasmonate Dissolve 24 g of ethyl 2-epi-diasmonate in 100 ml of anhydrous methanol, replace the inside of the container with nitrogen, and add methanol 10 containing 0.56 g of sodium methoxide.
ml and heated under reflux for 8 hours. After neutralizing the reaction solution with dilute hydrochloric acid, extracting with methylene chloride, drying the solvent with magnesium sulfate, and recovering the solvent.
By rectifying under reduced pressure, 21 g of the desired methyl diasmonate was obtained with a yield of 92.3%.

IR (liquid film) 1741, 1650cm ^-1 NMR (CCl ₄ ) 5.60-5.12 (2H, m) 4.60 (3H,
s), 2.52-1.33 (12H, m), 1.0 (3H,
t) bp92℃/0.02mmHg By the same operation, yield 82.4% from trimethylsilyl 2-epi-diasmonate, yield 80% from n-butyl 2-epi-diasmonate, 2-epi-
Methyl diasmonate can be obtained with a yield of 90% from methyl diasmonate.

Claims (1)

[Claims] 1 The following formula (4)' cis-2,3-disubstituted cyclopentanone, where R' represents a lower alkyl group. 2 The following formula (6) However, in the formula, R represents -SiR' ₃ (herein, R' represents a lower alkyl group), and the 6-substituted tetrahydroindanone represented by the following formula (4 )′ However, in the formula, R' has the same meaning as above, and the method for producing cis-2,3-disubstituted cyclopentanone represented by