JPS6045193B2 - Method for producing spiro[5-isopropylbicyclo[3,1,0]hexane-2,2'-oxirane] - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is an important synthetic intermediate for useful compounds such as trans-sabinene hydrate, which is used as an accentuator for spearmint and peppermint peppers, and is also used as a fragrance agent (perhumum, flavor, etc.). ), and also relates to a method for producing a new substance spiro[5-isopropylbicyclo[3.1.0]hexane-2.τ-oxirane] which is useful as a material for mixed fragrances.

First, the present inventors discovered the new substance spiro[5-isopropylbicyclo[3.1.0]hexane-2.2'-oxirane], more specifically, the chemical structural formula (1) --- (1 ) trans-spiro[5-isopropylbicyclo[3.1.0]hexane-2.7-oxirane] represented by A, and cis-spiro[5-isopropylbicyclo[3.1. 0]Hexane-2・2″-
5-isopropylbicyclo[3・1.0] Hexane-2-one (hereinafter referred to as "Zabina Ketozo 5").

) was proposed for the production of the spiro compound by reacting sulfonium methylide or sulfoxonium methylide (Japanese Patent Application No. 1983-391 (1983)).
Special Publication No. 55-139551)). However, in the method for producing this spiro compound, the starting material zabinaketone (chemical structural formula (6)) is converted into 3-isopropyl-2-cyclopenten-1-one (3-isopropyl-2-cyclopenten-1-one) (
Chemical structural formula (3)) is used as a raw material, which is reduced with lithium aluminum hydride in ether to produce 3-isopropyl-2-cyclopenten-1-ol (chemical structural formula (3)).
4)), and then reacted with methylene iodide in ether in the presence of a zinc-copper catalyst to obtain 5-isopropylbicyclo[3.1.0]hexane-2-ol (chemical structural formula (5) ) and then oxidizing it with chromic acid [US Pat. No. 3,591,643; W. I. Fanta et al. J
．． Org. Chem. 33, 1656 (1968)],
In this way, the synthesis of zabinaketone requires relatively many steps, and since zabinaketone can only be obtained in a yield of about 57% from 3-isopropyl-2-cyclopenten-1-one, 3-isopropyl-2-cyclopenten-1-one -1-
When the spiro compound is obtained using ion as a raw material, the total yield will decrease.

In view of this, the present inventors continued their intensive research and found that by using 3-isopropyl-2-cyclopenten-1-one as a starting material and reacting it with sulfoxonium methylide, it was possible to directly produce trans- and cis-spiropropylene. [5-isopropylbicyclo[3.1.0]hexane-2.2″-
Oxirane] is synthesized, and the target spiro compound can be easily obtained in just one step without the need for multiple steps as mentioned above, and the yield is high, with almost no by-products. Not only that, but the reaction is particularly high temperature,
The reaction proceeds under mild conditions without the need for harsh high-pressure conditions, and does not require expensive reagents, dangerous chromic acid compounds, or special equipment, so spiro compounds can be produced efficiently and inexpensively. We have found that it is very effective in industrial production, and have completed the present invention. That is, the present invention allows 3-isopropyl-2-cyclopenten-1-one to react with sulfoxonium methylide,
Spiro [5-
Isopropylbicyclo[3.1.0]hexane-2.2
The present invention provides a method for producing ``-oxirane''.

The present invention will be explained in detail below.

As shown in formula (B), the present invention provides 3-isopropyl-2-cyclopentene l-1 represented by chemical structural formula (3).
-one with sulfoxonium methylide, usually at a ratio of 2 to 5 moles of the latter to 1 mole of the former,
-isopropyl-2-cyclopenten-1-one directly from trans- and cis-spiro[5-isopropylbicyclo[3●1.0
[Hexane-2,7-oxirane] is synthesized.

In this case, 3-isopropyl-2-cyclopentene-1
-one can be synthesized, for example, by reacting 6-methyl-2,5-heptanedione with a base (US Pat. No. 3,591,643).

Furthermore, sulfoxonium methylide can be obtained by reacting a methylsulfoxonium salt represented by general formula (7) with a base. However, in formula (7), R1,
R2 is a methyl group, a t-butyl group, a phenyl group,
These include substituted phenyl groups, naphthyl groups, diethylamino groups, etc., and any combination of these can be used.
Further, R3 is usually a methyl group, but a methyl group in which the hydrogen group is substituted with silicon, sulfur, a hydrogen atom (group), etc. can also be used. That is, in the present invention, the methylsulfoxonium salt refers to a salt in the above formula (7) in which R3 is a methyl group or a substituted methyl group. Furthermore, sulfoxonium methylide refers to a compound represented by the general formula or a compound in which the hydrogen group of the -UH2 group is substituted with silicon, sulfur, halogen atom (group), etc.

In addition, when the methylide obtained by using a methylsulfoxonium salt in which R3 is a substituted methyl group in formula (7) is reacted with 3-isopropyl-2-cyclopenten-1-one, the substituted methyl group is removed from the product. It is necessary to remove atoms (groups), and by removing them, the desired spiro compound can be obtained. Furthermore, in formula (7), X- is a normal anion, such as a halogen ion, a fluoroborate ion, a chlorate ion, a perchlorate ion, an antimony hexachloride ion, a picrate ion, a sulfonate ion,
These include sulfate ions, sulfate ester ions, nitrate ions, tetraphenylboron ions, etc., and halogen ions and borofluoride ions are usually used. In addition, examples of the base to be reacted with the methylsulfoxonium salt include metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, metal carbonates such as sodium carbonate and potassium carbonate, sodium acetate, potassium acetate, etc. fatty acid metal salts of
Metal oxides such as silver oxide and calcium oxide; metal hydrides such as sodium hydride, potassium hydride, and calcium hydride; alcoholates such as sodium ethoxide and potassium t-butoxide;
Dimsil potassium, alkyl lithium, aryl lithium, phenyl potassium, trityl sodium, naphthalene sodium, sodium amide, lithium amide, metallic lithium, metallic sodium, metallic potassium, amines, quaternary ammonium, etc. are used. Ru.

Note that metal hydroxides, metal hydrides, and alkyl lithiums are preferably used. When the above-mentioned methylsulfoxonium salt and base are reacted, the reaction temperature is -80 to 100°C, usually -20 to 80°C in the solvent described below.
The reaction time is 1 to 2 minutes to 1 day.

Therefore, 3-isopropyl-2-cyclopentene-1-
When synthesizing the target substance by reacting methyl sulfoxonium salt with sulfoxonium methylide, after reacting methyl sulfoxonium salt with a base to synthesize sulfoxonium methylide,
The reaction product can be purified by removing impurities, and the purified sulfoxonium methylide and 3-isopropyl-2-cyclopenten-1-one can be reacted in an appropriate solvent, but in general, sulfoxonium Since methylide is unstable, it is recommended to react the methylsulfoxonium salt with a base in an appropriate solvent and then directly add 3-isopropyl-2-cyclopenten-1-one to the reaction mixture. , or methyl sulfoxonium salt and base and 3
-isopropyl-2-cyclopenten-1-one are preferably mixed in a suitable solvent and reacted simultaneously.

The solvent used for the reaction of the methyl sulfoxonium salt and the base and the solvent used for the reaction of the sulfoxonium methylide obtained thereby and 3-isopropyl-2-cyclopenten-1-one may be the same or different. Examples of solvents include dimethyl sulfoxide, N●N-dimethylformamide, acetonitrile, pyridine, triethylamine, water, alcohol, tetrahydrofuran, dioxane, ether, petroleum ether, hexane, benzene,
Tor. Ene, xylene, etc. can be used alone or in appropriate combinations. Also, 3-isopropyl-2-
When cyclopenten-1-one is reacted with sulfoxonium methylide, the reaction temperature is preferably around -80°C to 100°C, usually 0 to 80°C, and the reaction time is several minutes to 2 days. (This is determined by the reaction temperature, the molar ratio of 3-isopropyl-2-cyclopenten-1-one and sulfoxonium methylide, etc.)

) In this case, it is also possible to first react at a low temperature for a predetermined period of time, and then raise the temperature and further react for a predetermined period of time. The molar ratio of sulfoxonium methylide is stoichiometrically 3.
It is sufficient to use twice the mole of -isopropyl-2-cyclopenten-1-one, and in practice, it is sufficient to use about 2.2 moles per mole of 3-isopropyl-2-cyclopenten-1-one. Additionally, sulfoxonium methylide can be used in excess to speed up the time to completion of the reaction.

However, 3-isopropyl-2-cyclopentene-1-
If only a small amount of sulfoxonium methylide is added to ion, 3-isopropyl-2-cyclopentene-1
It is not preferable to add less than 2 moles of sulfoxonium methylide, as the -one does not completely react to the spiro compound and the yield of the spiro compound decreases; therefore, the sulfoxonium methylide is isopropyl 2
-Usually 2 to 5 per mole of cyclopentene-1-one
The mixing ratio is expressed as molar ratio.

The reaction solution obtained by reacting 3-isopropyl-2-cyclopenten-1-one and sulfoxonium methylide in a suitable solvent is poured into water, extracted with a solvent such as ether, and then extracted with a solvent such as ether. is distilled off to collect the reaction product.

This reaction product contains trans- and cis-spiro[5-isopropylbicyclo[3.1.0]hexane-2.2''
-oxirane] and contains almost no other by-products, it is not necessary to purify the obtained reaction product, and the above reaction product can be used as it is for various purposes. be able to. Furthermore, when the above-mentioned trans isomer and cis isomer are to be isolated, they can be separated from each other by thin layer chromatography, column chromatography, fractional distillation using a highly efficient fractionation column, or the like. Note that the yield of total spiro[5-isopropylbicyclo[3.1.O]hexane-2.7-oxirane] containing trans and cis isomers is usually 58 to 78%, and when using the method of the present invention, The trans isomer is preferentially produced.

In this case, the spiro compound can also be obtained by using sulfonium methylide instead of sulfoxonium methylide and reacting it with 3-isopropyl-2-cyclopenten-1-one, but the yield is is around 3%, so the use of sulfonium methylide is not suitable as a method for synthesizing the spiro compound. The trans- and cis-biro[5-isopropylbicyclo[3●1.0]hexane-2.2''-oxirane] obtained by the above method can be used as a synthetic intermediate for the pinene hydrate and the like.

That is, when synthesizing trans-zabinene hydrate using the above-mentioned trans-spiro compound, isolated trans-spiro[5-isopropylbicyclo[3.1.
0]hexane-2.)2''-oxirane] is reduced by reacting it with a reducing agent such as lithium aluminum hydride in an appropriate solvent such as tetrahydrofuran, and the resulting reaction product is treated with water, ether, sodium hydroxide, etc. are added sequentially to form a precipitate, and the precipitate is treated and the solvent is distilled off from the bottom liquid obtained. As a result, transusabinene hydrate is obtained with a yield of 90% or more. In addition, aluminum lithium hydride or the like is directly added to the reaction solution obtained by reacting the above 3-isopropyl-2-cyclopenten-1-one with sulfoxonium methylide to form trans- and cis-zabinene. A hydrate mixture may be produced and transusabinene hydrate isolated thereby.

Furthermore, cis-sabinene hydrate can also be synthesized in the same manner as above.

Therefore, using trans-spiro[5-isopropylbicyclo[3.1.0]hexane-2.2''-oxirane] as an intermediate, 3-isopropyl-2-cyclopenten-1-one can be prepared in just two steps. Moreover, as described above, according to the method of the present invention, trans-spiro compounds are produced in a higher proportion than cis-spiro compounds, so trans-spiro compounds are synthesized in high yields, and trans-spiro compounds are produced in a higher proportion than cis-spiro compounds. Cis-susabinene hydrate, which is useful as a fragrance ingredient, can be easily obtained.

That is, trans- and cis-sabinene hydrate are
Conventionally, 3-isopropyl-2
-It is synthesized by synthesizing zabinaketone from cyclopenten-1-one and reacting it with the addition of a methyl Grignard reagent or a methyl metal compound (US Pat. No. 3,591,643), which leads to the synthesis of zabinene hydrate. In addition to requiring a considerable amount of time and effort, in this method the production ratio of trans isomer to cis isomer is usually 1:8.5, which is a very low production ratio of trans isomer.

Therefore, when obtaining trans-zabinene hydrate (chemical structural formula (11)), as shown in formula (C), zabinaketone is reacted with methylene triphenyl phosfluoran to obtain zabinene (chemical structural formula (8)). was synthesized and then reacted with potassium t-butoxide using dimethyl sulfoxide as a solvent to obtain a-thuene (chemical structural formula (9)).
was synthesized, and further photooxygenated a-tsene to form trans-2
- After synthesizing tzen-4-ol (chemical structural formula),
This must be subjected to a hydrogenation reaction using a metal catalyst to obtain transusabinene hydrate. Therefore, conventionally, the synthesis of trans- and cis-zabinene hydrates was very troublesome and the yield was low, but by using the present invention for synthesizing spiro compounds, it is easy. Furthermore, trans- and cis-zabinene hydrates can be synthesized in high yields, and the above spiro compounds are extremely useful as intermediates. Furthermore, both the trans-spiro compound and the cis-spiro compound are liquid at room temperature, and the trans-spiro compound has a fresh, refreshing, light green aroma, and the aroma of the cis-spiro is a Costas-like woody aroma. It has a refreshing, slightly camphor scent.

Therefore, since each has its own unique aroma, trans- and cis-spiro [5-isopropylbicyclo[3.1●0]hexane-2●7-oxirane] are each used as a flavoring agent, and are also used in blended fragrances. Used as a material. As explained above, according to the present invention, 3-isopropyl-2-cyclopenten-1-one can be directly converted into trans- and cis-spiro[5-isopropylbicyclo[3.1.O]hexane-2.7-oxirane in just one step. ] can be synthesized in high yield with almost no by-products, and the reaction does not require particularly harsh conditions such as high temperature and pressure, and the reaction proceeds under mild conditions, and is not expensive. Spiro compounds can be obtained efficiently and economically without the need for reagents or special equipment, which is very effective in industrial production, and the present invention can be effectively used in the synthesis of zabinen hydrate, etc. can.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples.

In the following Examples, 3-isopropyl-2-cyclopenten-1-one is abbreviated as 6℃P''.Example 1 1.08y (45Tr!.M) of sodium hydride was mixed with dimethyl sulfoxide (hereinafter, ゜゜DMS0). It is called ゛.

) 50ml, trimethylsulfoxonium iodide 10.
12y467TLM) and stirred at room temperature for 30 minutes, CP2.48f (207 nM) was added dropwise over 3 minutes. Next, the mixture was stirred at room temperature for an hour to react, and then the reaction solution was poured into ice water and extracted three times with ether. This extract was washed once with water, dried over magnesium sulfate, and the ether was distilled off to obtain a crude product 2.58y (yield: 85%). As a result of quantifying this by gas chromatography, trans- and cis-spiro[5-isopropylbicyclo[3.1.0]hexane-2.2''-oxirane] (hereinafter simply referred to as ゜゜trans form゛ and ゜"cis form", respectively) .

) yields were 48% and 30%, respectively. Further, the above-mentioned trans isomer and cis isomer were isolated by preparative gas chromatography, and their physical properties were measured. The results were as follows.

Trans-isomer boiling point: 48~phase °C/27n! NHg Elemental analysis value: ClOHl6O calculated value C78.89%, HlO. 59% Actual value C78.6O%, HlO. 66% NMR (CCl,, TMS) δ: 0.39 (M..2H), 0.94 (Q,.6H), 1
．． 15~2.07 (M..5H) 283 (Q..2H)
, 380 (M.lH) MS. sm/e: 152, 137
, 123, 1211109, 81, 67GC (PEG2
OMllO%, 2m11200C): Rt=6.5rr
11n cis boiling point: 57-59nC/4w! NHg elemental analysis value: QOHl6O calculated value C78.89%, HlO. 59% Actual value C78.55%, HlO. 74% NMR (CCl4TMS) δ: 0.42 (M..2H), 095 (Q..6H), 1.
20-2.05 (M..5H) 285 (Q,.2H),
383(MllH)MS. ．． m/e: 152, 137,
123, 121, 109, 81, 67GC (PEG2O
MllO%, 2m. , 1200C) Rt=7.7min
Reference Example Synthesis of Zabinen Hydrate 1.06f (77T1.M) of trans-spiro[5-isopropylbicyclo[3.1.0]hexane-2.7-oxirane] synthesized in Example 1 was added to 30ml of tetrahydrofuran (THF). 0.57y (157nM) of lithium aluminum hydride was added little by little.

After heating under reflux for 1 hour, cool with ice and add 25 ml of water.
, ether 10ml 110% sodium hydroxide aqueous solution 1
．． 8 ml of the mixture was added one after another, and the resulting precipitate was filtered out.

After drying the extract with magnesium sulfate and distilling off the solvent, 0.99y of transusabinene hydrate (yield 92%) was obtained.
)was gotten. As a result of identification by gas chromatography, mass spectrum, and NMR spectrum, it was confirmed that the obtained product matched the standard product. In addition, by the same operation as above, cis-spiro[5-isopropylbicyclo[3,1,0]hexanes-2,7-oxirane]
From this, cis-zabinene hydrate was obtained with a yield of 90%.

Example 2 N-N in 0.53y (22TrLM) of sodium hydride
- 24ml of dimethylformamide and 5.06y of trimethylsulfoxonium iodide (23mM) were added, and after stirring at room temperature for 1 hour, CPl. A solution of 24y (10TrLM) dissolved in 6 mL of N·N-dimethyl sulfoxide was added dropwise over 3 minutes, and then reacted at room temperature for 3 hours.

Hereinafter, the same treatment as in Example 1 was carried out to obtain a crude product of 1.09
f (yield 72%) was obtained. The yields of trans isomer and cis isomer were 48% and 16%, respectively. Example 3 Sodium hydride 0.72y (307T1.M) T824ml
, trimethylsulfoxonium iodide 6.82f (31
7TLM) and reacted for 6 hours under THF reflux, then CPl. A solution of 24y dissolved in 6ml of THF was
Dropwise for 3 minutes, then heated to 50℃ for 3? It was allowed to react for a while.

Hereinafter, the same treatment as in Example 1 was carried out, and the crude product 1.26
f (yield 83%) was obtained. What is the yield of trans isomer and cis isomer? % and 21%. Example 4 Trimethylsulfoxonium chloride 12.85f (1007
n, M) and 50 ml of THF1 were added thereto, and the mixture was heated under reflux for 4 hours with stirring.

Next, this reaction product was cooled, and by-produced sodium chloride was separated by using Celite as a filtering agent to obtain a THF solution of dimethylsulfoxonium methylide. This was further added with L positive to make 200 mL, and stored in a refrigerator under a nitrogen atmosphere. 30ml of THF solution of this dimethylsulfoxonium methylide (15mM)
was placed in a reaction vessel, and CPO. 62y(5rr1,
Add a solution of M) dissolved in 3 ml of THF, and incubate at 50°C for 3 ml.
The reaction was carried out by stirring for C@.

Hereinafter, the same treatment as in Example 1 was carried out to obtain 0.63f of crude product (
A yield of 83%) was obtained. The yields of trans isomer and cis isomer were 55% and 22%, respectively. Example 5 n-butyllithium (15% n-hexane solution) 6.7
mt (11mM), n-hexane 5m11 trimethylsulfoxonium iodide 2.53y (237T1,M),
DMSOlOml was added and stirred for 35 minutes.

C.P.O. A solution of 62y (5TrLM) dissolved in 5 mL of DMSO was added dropwise over 5 minutes, and the reaction was allowed to proceed for 2'3If at room temperature.
(yield: 62%). The yields of trans isomer and cis isomer were 47% and 11%, respectively. Example 6 D to potassium t-butoxy 1.57f (14Tn,M)
MSOlOml, trimethylsulfoxonium iodide 3
．． 19y (14.5rn, M) was added, and after stirring the two powders at room temperature, CPO. 62y (5wLM) was added dropwise over 1 minute, and then DMSOlOml was added and reacted at room temperature for 24 hours.

Hereinafter, the same treatment as in Example 1 was carried out to obtain a crude product of 0.51f (
A yield of 67% was obtained. The yields of trans isomer and cis isomer were 40% and 21%, respectively. Example 7 DMSO2OnL in 0.26y (117n, M) of sodium hydride
Add 2.72y (11.5rr1.M) of l(diethylamino)dimethylsulfoxonium fluoroborate,
Stir at room temperature for 25 minutes, then add CPO. 62y (57r
1,M) was added dropwise over 5 minutes and reacted at 50°C for 2 hours, followed by the same treatment as in Example 1, resulting in a crude product of 0.59f.
(yield 78%).

Claims (1)

[Scope of Claims] 1 Spiro [5] characterized in that sulfoxonium methylide is reacted at a ratio of 2 to 5 moles per mole of 3-isopropyl-2-cyclopenten-1-one.
-isopropylbicyclo[3.1.0]hexane-2.
2'-oxirane] production method. 2. Reacting a base with a methylsulfoxonium salt to produce sulfoxonium methylide, purifying this, and then reacting the purified methylide with 3-isopropyl-2-cyclopenten-1-one. A method for producing spiro[5-isopropylbicyclo[3.1.0]hexane-2.2'-oxirane] according to item 1. 3 After reacting the base with methylsulfoxonium salt,
Spiro[5-isopropylbicyclo[3.1.0]hexane-2.2'-oxirane] according to claim 1, in which this reaction solution is directly reacted with 3-isopropyl-2-cyclopenten-1-one. manufacturing method. 4. Spiro[5-isopropylbicyclo[3.1.0]hexane-2 according to claim 1, in which a base, a methylsulfoxonium salt, and 3-isopropyl-2-cyclopenten-1-one are reacted simultaneously.・Production method of 2'-oxirane].