JPS5936898B2 - Production method of methyl diasmonate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing methyl diasmonate represented by the following formula (1), which is useful as a perfume and pharmaceutical intermediate, mainly in the field of perfumery.

In particular, the methyl diasmonate of the above formula (1), which is related to a method for producing the above formula (1) in high yield and in a short process, is a compound isolated from a natural source of diasmine essential oil [Helv. Chim. Acta. 45,675 (19
62)] is one of the important aroma components of essential oils, and is highly valuable as a base material for perfume formulations, as it significantly enhances aroma. Conventionally, various proposals have been made regarding the synthesis of methyl diasmonate, but no industrially satisfactory proposal has been known to date.For example, Helv. Ollm
．． Acta. , 45, 692 (1962) has the following formula,
Accordingly, a process for the preparation of methyl diasmonate from diethyl dihydromuconate is described.

Furthermore, J. O. C. , 34, 266l (1969) describes a method for synthesizing methyl diasmonate from 2-methoxycarbonylmethylcyclopentanone through a transfer step according to the following formula.

Furthermore, J. O. C. , Main Article, 2021 (1971) describes a method for synthesizing methyl diasmonate from dihydroresorcinol through multiple steps according to the following formula or according to the following formula.

Moreover, J. O. C. , 4O, 462 (1975) describes a method for synthesizing methyl diasmonate from tetrahydroindanone through multiple steps according to the following formula.

These synthetic methods have the disadvantage that the synthesis of starting materials is difficult and expensive, and also have the disadvantage that they require complicated operations and multiple steps that are not suitable for industrial use.Furthermore, they produce by-products. Many have the disadvantage of poor yield. The present inventors have overcome the disadvantages and defects of the conventional proposals as described above, and have provided a method for industrially advantageously producing methyl diasmonate represented by the formula (1) in a shortened process. As a result of research, we found that R is a lower alkyl group, preferably a C, to C4 alkyl group, or -SiR (
Here, R' represents a lower alkyl group, preferably a methyl group), and a 2-epidiasmonic acid ester represented by the following formula (3), where M is an alkali metal atom such as Li, Na. In addition to epimerizing the side chain by reacting with methanol in the presence of a metal alcoholade represented by K, etc., and R″″″ represents a lower alkyl group, preferably a methyl group, at the same time, as R, It was discovered that when a compound of formula (2) having an alkyl group other than a methyl group is used, a transesterification reaction occurs, and methyl diasmonate of formula (1) can be formed with good yield and selectivity. did.

Among the compounds of formula (2) above, compounds in which R is other than a methyl group are compounds that have not been described in any literature.

Including these undocumented compounds, the 2Y compound is a system represented by the following formula (4), where R has the same meaning as defined in the above formula (2). 1-2,3-di-substituted cyclopentanone is represented by the following formula (5), where R'' is the same or different, and is a group selected from the group consisting of a phenyl group and an alkyl group, such as a C1 to ClO anoyl group. It has been found that it can be easily produced with good yield and selectivity by reacting with the Witstec reagent represented by

Furthermore, among the compounds of formula (4) above, compounds in which R is other than a methyl group are also compounds that have not been described in any literature.

Then, the formula (4
) The compound of formula (4) has a good yield by a method completely different from that of the known compound in which R is a methyl group,
It has been discovered that it can be easily produced in a two-step reaction using easily available publicly known compounds of formulas (7) and (8) described below as starting materials. Accordingly, an object of the present invention is to provide a new method for producing methyl diasmonate of the formula (1) with a shortened process and a good yield in an industrially advantageous manner.

The above objects and many other objects and advantages of the present invention include:
This will become clearer from the description below.

In order to facilitate understanding, a process diagram for producing the compound of formula (1) from the compounds 7) and (8) above can be shown as follows. R in Hayashi style (6) to (8)
Also mentioned above? It has the same meaning as stated in 2). The above formula (7
) and 2-substituted butadiene of formula (8), i.e., 2-alkoxy- or 2-trialkylsilyloxybutadiene, to 6- of formula (6) above.
Alkoxy or 6-trialkylsilyloxy-4
, 5,8,9-tetrahydroindanone- is carried out by converting a compound of formula (7) and a compound of formula (
8) It can be easily carried out by subjecting the compound to a Diels-Alda reaction. The reaction is, for example, about 80
The heating is preferably carried out at a temperature of about 180°C or higher, more preferably at a temperature of about 180°C or higher, for example, about 1800°C or higher.
Temperatures on the order of about 400°C, more preferably about 200 to about 300°C, are most often employed. The reaction can be carried out under atmospheric or pressurized conditions, for example in a pressure vessel under naturally occurring pressure conditions. 2 of the above formula (8)
Specific examples of -alkoxy-butadiene include, for example, 2
-methoxy-butadiene, 2-ethoxy-butadiene,
2-n-propoxybutadiene, 2-1s0-propoxybutadiene, 2-n-butoxybutadiene, 2
-1s0 butoxybutadiene, 2-Tert-butoxybutadiene, etc., and specific examples of 2-trialkylsilyloxybutadiene include, for example, trimethylsilyloxybutadiene. Further, as the above-mentioned solvent, an inert organic solvent can be used, such as benzene, toluene, xylene, n-hexane, n-heptane,
Hydrocarbon solvents such as These solvents may be used alone or in a mixture of two or more. After the completion of the Diels-Alda reaction, the reaction mixture is distilled, for example, under reduced pressure to obtain a 6-monosubstituted tetrahydroindanone of formula (6), i.e., 6-alkoxy- or 6-trialkylsilyloxy-4,5,8,9 −
Tetrahydrointanone 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-mentioned Diels-Alda reaction include 2-alkoxy- or 2-trianolekyl, which is mentioned as a specific example of the compound of formula (8) as the starting material. Examples include 6-alkoxy or 6-trialkylsilyloxy which is an adduct of silyloxyitadiene and 2-cyclopentynon of formula (7). In the present invention, in order to produce the cis-2,3-disubstituted cyclopentanone of the formula (4) from the 6-monosubstituted tetrahydrointanone of the formula (6), various oxidation methods exhibiting the mildest possible oxidation action can be used. agents are available.

(4) Ozone oxidation is preferred for easily producing compounds with good selectivity. For example, ozone gas is passed through the compound of formula (6) dissolved in an inert organic solvent at low temperature to form ozonide, and then a reducing agent is added without isolation to obtain the desired product (4
) can be obtained with high purity and high yield. The use of a reducing agent can be omitted in the case of using other oxidizing agents that are as mild as possible. The reaction is preferably carried out at as low a temperature as possible, preferably at room temperature or lower.

For example, when using ozone, room temperature to about -100°C,
More preferably, ozonation is performed at a low temperature of about 100°C to about -100°C, particularly about -20°C to about -80°C. For reduction with a reducing agent, higher temperatures can be employed, preferably from about -10°C to room temperature, and more preferably, the solvent used is an inert organic solvent that is liquid at the reaction temperature, such as methanol, ethanol, acetic acid. Examples include alcohols such as ethyl and methylene chloride, esters, and halogenated hydrocarbons, and these can be used alone or in combination. As the reducing agent, for example, zinc powder-acetic acid, phosphite, trivalent phosphorus compounds such as triphenylphosphine, dimethyl sulfide, etc. can be used. Alternatively, catalytic hydrogen reduction can be performed using Pd-CsPt and other various reduction catalysts. After the completion of the reaction, if an insoluble solid reducing agent remains in the reaction solution, it is removed, washed with water, and the oil phase is collected to obtain the compound of formula (4). The compound of formula (4) can also be obtained by extracting with methylene and removing the solvent. If desired, further purification can be achieved by distillation or other means. Specific examples of the compound of formula (4) above 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-J
iodine P-cyclopentanone, 2,3-cis-3-carboIsO-propoxymethyl-2-formylmethyl-1-
Cyclopentanone 2,3-cis-3-carbon-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-
Examples include carbotrimethylsiloxymethyl-2-formylmethyl-1-cyclopentanone.

From the cis-2,3-disubstituted cyclopentanone of the formula (4) obtained as described above, the compound of the formula (
2) The production of 2-Epidiasmonic acid ester is carried out using the formula (
4) The compound is represented by the following formula (5). In the formula, R″″ has the same meaning as described above.

can be easily obtained with high yield and good selectivity.

The phosphorane compound of formula (5) (Witstetsug reagent) is
For example, it can be obtained by reacting the following formula (5), where R'''' has the same meaning as above and X represents a halogen, preferably Cl, Br or I, with a base.

Examples of the base used include, for example, butyllithium, 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 it is best to use them in an approximately equivalent amount or a slightly smaller amount relative to the compound of the above formula (5Y).The reaction is carried out in a solvent under an inert gas atmosphere. The reaction is preferably carried out using an inert gas such as nitrogen or arygon.The reaction is preferably carried out at a temperature of about 0°C or higher, for example, a temperature of about 0°C to about 50°C is used. can.
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 dimethylformamide, dimethoxyethane, diglyme, and the like. 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. ) compound and formula (5)
This can be carried out by contacting the compound with the compound.

Examples of the solvent include the same organic solvents as those exemplified for the formation of the compound of formula (5Y).Selection of the solvent may be different even if the same solvent used for the formation of the compound of formula (5Y) is selected. There is no problem in selecting an aqueous solvent. It is preferable to use an anhydrous solvent as much as possible. The reaction proceeds well even at room temperature, so there is no need for particular heating or cooling, but such methods may be used if desired. For example,
Examples of temperatures include about 0° C. to 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 (compound) into the other. For example, about 1 to about 2
Amounts on the order of two times the molar amount, more preferably on the order of about 1 to about 1.5 times the molar amount, are 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 and methylene chloride, or diluted hydrochloric acid is added to deactivate excess phosphorane and the above solvent is extracted. After extraction and recovery of the solvent, it can be purified by distillation or column chromatography.

Representative examples of the 2-EP Diasmonate of formula (2) obtained as described above include methyl 2-EP Diasmonate, ethynole 2-EP Diasmonate, n-propyl 2-EP Diasmonate, and isopropyl 2-EP Diasmonate. , 2-epdiasmonic acid n
-butyl, isobutyl 2-epidiasmonate, tert-butyl 2-epidiasmonate, irimethylsilyl 2-epidiasmonate, and the like.

According to the method of the present invention, the 2-Epidiasmonic acid ester of the formula (2) obtained as described above is converted to
3) In the presence of a metal alcoholade of MOR'''' (wherein M represents an alkali metal atom such as LisNasK, and R'' represents a lower alkyl group, preferably a methyl group),
React with methanol. Methanol can also be utilized in the form of methanol-containing organic solvents. Examples of organic solvents include hydrocarbon solvents such as benzene, toluene, xylene, n-hexane, n-heptane, and the like. 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 epimerization of the side chain and converts the side chain of the five-membered ring get in 2) from cis to trans, and at the same time, a transesterification reaction occurs, and in formula (2), R Even in the case of the compound (2) in which R is other than methyl, R is converted to a methyl group, and methyl diasmonate is obtained as shown in the following formula as an example. In the above reaction, the amount of the metal alcoholade of formula (3) to be used can be selected as appropriate, and a catalytic amount is sufficient.

For example, the amount used may be about 5 to about 20% by weight based on the 2-Epidia yasmonic acid ester of formula (2). More preferably, it is about 5 to about 15% by weight. The amount of methanol to be used can be selected as appropriate, but it is usually about 50
It is best to use about twice (weight) or more, about 100 to about 2
The use of amounts on the order of 0.00 times often gives more favorable results. After the reaction, the metal alcoholade is neutralized, for example, with dilute hydrochloric acid, and then extracted with an organic solvent such as methylene chloride, hexane, ether, etc., and the solvent is distilled off under reduced pressure to obtain the formula (1). of methyl diasmonate 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,
16.0f of 2-cyclopentynon and 57.0i of 2-ethoxybutadiene are sealed and reacted at 240-250°C for 5 minutes.

After cooling the reaction product, the target product 6 is obtained by rectifying it under reduced pressure.
- Ethoxytetrahydroindanone in 72% yield of 24
．． 57 was obtained. Reference Example 2 Production of 6-trimethylsilyloxy-4,5,8,9-tetrahydroindanone [Formula (6)] In a quartz tube, 2.4t of 2-cyclopentynon and 11.0t of 2-trimethylsilyloxybutadiene were added. Prepare 47, seal the tube, 230-240
Incubate for 10 minutes at ℃.

After cooling the reaction product, the target product 6 is obtained by rectifying it under reduced pressure.
3.2 tons of -trimethylsilyloxytetrahydrointanone was obtained with a yield of 65%. Reference example 36-methoxy-4,
Process for producing 5,8,9-tetrahydroindanone [formula (6)] and 6-n-butoxy-4,5,8,9-tetrahydroindanone [formula (6)] 2-cyclopentynone and 2-
By reacting methoxybutadiene or 2-n-butoxybutadiene in the same manner as in Reference Example 2 and rectifying it, the target product 6-methoxytetrahydroindanone (yield 66
8%, B. p. 8O~83℃/0.5TmHg), or 6-n-butoxytetrahydroindanone (yield 62
%, B. p. 82~90℃/0.17! LlLHg) was obtained.

Reference example 4 Production method 6 of 2,3-cis-2-formylmethyl-3-carboethoxymethyl-1-cyclopentanone [formula (4)]
A predetermined amount of ozone is passed through a solution of 10.0 f of -ethoxytetrahydroindanone in 200 rr of methylene chloride at -70 to -78°C.

Next, this reaction solution was mixed with 51.0 f of zinc powder and 130 d of acetic acid.
It is added to the suspension solution and subjected to a reduction reaction at -10 to 4°C for 2 hours. The reaction product was poured into water, extracted with methylene chloride, the organic layer was washed with heavy sodium chloride, washed with water, dried with sodium sulfate, and the solvent was removed.
The target product, 2,3-cis-2-formylmethyl-3-carboethoxymethyl-1-, was obtained by distilling the residue under reduced pressure.
9.6 tons of cyclopentanone was obtained with a yield of 82.1%.
Reference Example 5 Production method of 2,3-cis-2-formyl-3-carbotrimethylsilyloxymethyl-1-cyclopentanone [Formula (4)] 6-Trimethylsilyloxytetrahydroindanone 5.0t in methanol 100ml solution A predetermined amount of ozone is passed through at -70 to -78°C, then -10°C to 0°C.
Add 7.07 ne of dimethyl sulfide and react for 2 hours.

By rectifying the reaction product under reduced pressure, the target product 2,3-
4.6V of cis-2-formylmethyl-3-carbotrimethylsilyloxymethyl-1-cyclopentanone was obtained with a yield of 78%. Reference example 62,3-cis-2-formylmethyl-3-carbomethoxymethyl-1-cyclopentanone [Formula (4) and 2,3-cis-2-formylmethyl-3-carbo-n-butoxymethyl- Method for producing 1-cyclopentanone [Formula (4)] From 6-methoxytetrahydroindanone and 6-n-butoxytetrahydroindanone, the target product 2,3-cis-12-formyl was produced in the same manner as in Reference Example 5. Methyl-3-carbomethoxymethyl 1-cyclopentanone (yield 85%, B.p.ll 2-114°C
/0.01WILHg) and 2,3-cis-2-formylmethyl-3-carbo-n-butoxymethyl-1-cyclopentanone (yield 74%, B.p.l 36-140°C
/0.005wrmHg) was obtained.

Reference Example 7 Production method of ethyl 2-Epidiasmonate [G2)] and n-butyl 2-Epidiayasmonate [Formula (2)] Separately produced from triphenyl n-propylphosphonium bromide was placed in a sufficiently dried and nitrogen-purged container. Add 180 me of a dimethoxyethane solution of triphenyl n-propylphosphorane equivalent to 0.05 mol, and add 180 me of a solution of triphenyl n-propylphosphorane in dimethoxyethane,
．． 1f of 2,3-cis-2-formylmethyl-3-carboethoxymethyl-1-cyclopentanone in the same solvent 1
00 Mamoru 1-4 Misery H7?珈)] A～yトν
;▲Meal νHira--i^^'1 Shrine 1qr==r▲-.

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 the desired ethyl 2-Epidiasmonate (9.
1Ii7 obtained in a yield of 80.2%. IR (liquid film) 1
745,1653crn-1 NMR (CCl4) 5.8
0 to 5.05 (2H, m) 3.85 (2H, q)
1.07 (3H,t) Boiling point 60 (~65°C/0.15-Hg In the above example, instead of 2,3-cis-2-formylmethyl-3-carboethoxymethyl-1-cyclopentanone, Reference 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-epdiasmonate was obtained in a yield of 78%. Obtained.

Boiling point 72° to 76°C/0.01-HgO Reference example 8 Trimethylsilyl 2-Epidiasmonate [Formula (2)]
By the same operation as in Reference Example 7, 2,3-cis-2-
After reacting formylmethyl-3-carbotrimethylsilicoxymethyl-1-cyclopentanone, sufficiently cooled water was added, extracted with methylene chloride, dried over magnesium sulfate, and rectified under reduced pressure. Trimethylsilyl 2-Epidiasmonate (yield 60%, B.p. 9
3-96°C/0.2-Hg).

Example 1 Method for producing methyl diasmonate 2-Epi Ethyl diasmonate 24V was dissolved in 100 g of anhydrous methanol, the inside of the container was purged with nitrogen, and 10 g of methanol containing 0.56 V of sodium methoxide was added.
Heat to reflux for 8 hours.

After neutralizing the reaction solution with diluted hydrochloric acid, it was extracted with methylene chloride.
After drying the solvent with magnesium sulfate, the solvent is recovered,
By rectifying under reduced pressure, the desired methyl diasmonate is obtained as 21y with a yield of 92.3%. IR [liquid film]
:1741,1650cm-1NMRCC14]5.
60-5.12 (2H, m) 4.60 (3H, s)
2.52-1.33 (12H, m) 1.0 (3H, t) B. p. 92℃/0.02TWLHg By the same Ω operation, the yield was 82.4% from trimethylsilyl 2-Epdiayasmonate, the yield was 80% from n-butyl 2-Epdiayasmonate, and the yield was 90% from methyl 2-Epdiayasmonate. Methyl diasmonate is obtained.

Claims (1)

[Claims] 1 The following formula (2), ▲There are mathematical formulas, chemical formulas, tables, etc.▼(2) However, in the formula, R
is a lower alkyl group or 2-epi-diasmonic acid ester represented by -SiR'_3 (where R' is a lower alkyl group), represented by the following formula (3) MOR''' (3) where, in the formula, M There are the following formulas (1), ▲ mathematical formulas, chemical formulas, tables, etc., which are characterized by reacting with methanol in the presence of a metal alcoholade, where R'' represents an alkali metal atom and R″′ represents a lower alkyl group. ▼Production method of methyl diasmonate represented by (1). 2 The following formula (4), ▲There are mathematical formulas, chemical formulas, tables, etc.▼(4) However, in the formula, R
is a lower alkyl group or -SiR_3' (where,
cis-2,3-disubstituted cyclopentanone represented by R' is a lower alkyl group is represented by the following formula (5).
, R_3″P=CHCH_2CH_3 (5) However, in the formula,
R'' is the same or different and represents a group selected from the group consisting of a phenyl group and an alkyl group.
▲There are mathematical formulas, chemical formulas, tables, etc.▼(2) However, in the formula, R
is the same as above, and 2-epi-diasmonic acid ester represented by the following formula (3) MOR''' (3) where M represents an alkali metal atom and R'' represents a lower alkyl group A method for producing methyl diasmonate represented by the following formula (1), ▲ mathematical formula, chemical formula, table, etc. ▼ (1), which is characterized by reacting with methanol in the presence of a metal alcoholade represented by .