JPS587638B2 - Shinki Hosetsu Kagobutsu no Seizouhou - Google Patents

Description

[Detailed description of the invention] The present invention relates to a novel method for producing clathrate compounds.

More specifically, the present invention relates to a method for producing a novel clathrate compound by reacting a cyclohexene derivative or a benzene derivative having an inbrenoid carbon side chain having 7 to 15 carbon atoms or a side chain similar thereto with a cyclodextrin.

First, bisaborane (2-p-methylcyclohexyl-6
-Methylhebutane) Since it was discovered that the sesquiterpenoids Juvabion and Dehydrodiyuvabion have physiological activity in insects, a large number of their analogs have been synthesized in anticipation of their use as insect repellents and other uses. It became so.

Among these compounds are cyclohexene derivatives or benzene derivatives having an imprenoid side chain consisting of 7 to 15 carbon atoms.

Compounds with side chains corresponding to structures in which part of the carbon side chain is replaced with ether bond oxygen or sulfur bonds have also been synthesized.

These compounds contain many physiologically active substances and are expected to find a wide range of uses in the future.

However, among these compounds, some with particularly high physiological activity have unstable bonds such as double bonds and epoxy rings in their molecules, making them susceptible to the effects of light, heat, oxygen, etc. Some compounds are physically unstable.

Therefore, when these compounds are used for deworming or other purposes, they rapidly lose their activity and have the disadvantage that sufficient effects cannot be obtained.

As a result of intensive research to improve this drawback, the present inventor found that these compounds form clathrate compounds with cyclodextrin, and that these clathrate compounds have almost no physiological activity compared to the original substance. We have discovered that it is extremely stable without any changes, and have arrived at the present invention.

That is, the present invention provides a cyclohexene derivative or a benzene conductor having an imprenoid carbon side chain having 7 to 15 carbon atoms or a side chain in which some carbons of the carbon side chain are substituted with oxygen or sulfur. }This is a method for producing a novel clathrate compound characterized by reacting it with phosphorus.

Examples of the cyclohexene derivatives having an inbrenoid side chain used in the present invention include jubavione, dehydrodubavione, 4-(1-methylene-57-methyl-
Examples include 4'-hexenyl)-1-carbomethoxycyclohexene 1.

Furthermore, the benzene derivative having an isoprenoid side chain used in the present invention is p-(1,5-dimethyl-3
-oxohexyl)methylbenzoate, p-(1.5-
Methyl dimethyl-1,2-4,5-diepoxyhexyl)benzoate, methyl p-(1,5-dimethyl-1,5-dichlorohexyl)benzoate, p-(5-methyl-3-
Oxohexyl) methyl benzoate, etc.

Furthermore, as a compound having a structure in which a part of the isoprenoid carbon chain is substituted with oxygen (ether bonded oxygen) used in the present invention, 3.4-methylenedioxyphenyl-6/,7/monoepoxygeranyl ether , 3.4-methylenedioxyphenyl-6',7'-epoxy-3,
'7'-dimethyl-2'-nonenyl ether, 3,4-
Methylenedioxyphenyl-7',s/monoepoxy-4
,'8'-dimethyl-3'-decenyl ether, 7-hydroxy-3,7-dimethyl-2-octenyl-p-nitrophenyl ether, 7-ethoxy-3,7-dimethyl-2-octenyl-p-nitrophenyl ether Examples include phenyl ether.

In addition, compounds in which part of the imprenoid carbon chain is substituted with sulfur (sulfur bond, i.e., sulfide, sulfone, etc.) used in the present invention include 7-ethoxy-3,7-dimethyl-2-octenyl-p-nitrophene. Nyl sulfide, 7-ethoxy-3,7-dimethyl-2-octenyl-p-nitrophenyl sulfone, and the like.

In the present invention, the compound used to form an inclusion compound with cyclodextrin has an isobrenoid side chain consisting of 7 to 15 carbon atoms as exemplified above, but the number of double bonds in the side chain and the position of cis It can be used regardless of trans isomerism.

Further, a hydroxyl group, an alkoxyl group, a halogen, etc. may be substituted at an appropriate position on the skeleton, and the atoms constituting the carbon chain may be carbonyl carbons.

Alternatively, one or two methyl groups may be bonded to appropriate positions on the isoprene skeleton.

Three types of cyclodextrins are known: α, β, and γ, and any of them can be used in the present invention, or a mixture thereof can also be used.

In particular, β-cyclodextrin is preferably used.

The clathrate compound of the present invention can be produced by, for example, dissolving the substance to be included in a water-soluble organic solvent, adding the cyclodextrin to water or a water-soluble organic solvent solution,
This is done by separating the precipitated clathrate compounds.

Although heating may be performed during mixing, it is preferable to carry out the reaction at a temperature of 50° C. or lower since some substances have poor thermal stability.

The ratio of organic solvent and water used during production can be appropriately adjusted depending on the solubility of the product and raw materials.

Elemental analysis revealed that the composition of the clathrate compound thus obtained varies depending on the manufacturing conditions, and usually contains about 1 to 20 parts (by weight) of cyclohexene derivatives or benzene derivatives.

It was confirmed through heating tests and ultraviolet irradiation tests that these clathrate compounds are more stable than the original cyclohexene derivatives and benzene derivatives.

That is, p-(1.5-dimethyl-1.2-4.5-diepoxyhexyl)benzoic acid methyl ester (I) and its β
- Cyclodextrin clathrate compound <1o. 2% (1)
Table 1 shows the results of heating each of these (including 100% and 100%) at 130°C and determining their weight changes.

Table 1 Heating test of methyl p-(1.5-dimethyl-1.2-4.5-diepoxyhexyl)benzoate and cyclodextrin clathrate (retained weight) Compound (I) remained after 24 hours The material turned yellowish brown and polymerized.

Furthermore, when Juvavion and its β-cyclodextrin clathrate compound (containing 6.9% Juvavion) were each irradiated with ultraviolet rays, Juvavion changed color and polymerized after 100 hours, but the clathrate compound There was almost no change in the spectrum.

In this way, inclusion compounds of cyclohexene derivatives and benzene derivatives with cyclodextrin, which have highly physiologically active terbenoid side chains, have increased stability compared to their constituent cyclohexene derivatives and benzene derivatives themselves, so their efficacy can be reduced. Not only can it be maintained for a long period of time, but the exemplified compounds are usually liquids, whereas the clathrate compounds are powders, so they are easy to handle and form formulations, making them extremely useful in practice.

The present invention will be explained in more detail below using Examples.

Example 1 1.50 g of β-cyclodextrin was heated and dissolved in 4 Qcc of water, kept at 40°C, and without stirring, p-(1,5-
A solution of 0.18 g of dimethyl-1.2-4.5-diepoxyhexyl)benzoic acid methyl ester dissolved in 2 cc of methanol was added dropwise over 15 minutes.

After stirring for 30 minutes, the precipitate was cooled on ice and separated with P, washed with petroleum ether and dried under reduced pressure to obtain the clathrate compound 1.089.
I got it.

Elemental analysis value C: 44.75, H; 6. ss%t2(C
42H70035) Calculated value C as C16H2004・8H20: 44.64 ratio 9Hj 6.59 ratio, that is, the content of methyl p-(1.5-dimethyl-1.2-4.5-diepoxyhexyl)benzoate in the product is 1 o. It was 2%.

Example 2 β-Cyclodextrin 1.52.9 was heated and dissolved in 40 cc of water, and after cooling to room temperature, Juvavion 0.18
A solution of 0.5 cc of methanol was added thereto, stirred, left overnight, filtered through P, washed with a small amount of 50% methanol, and dried under reduced pressure to obtain 0.0.83 g of the clathrate compound.

Calculated from the elemental analysis value, the content of Juvavion is 6.9
He was in charge.

Example 3 1.45 g of β-cyclodextrin was dissolved in 40 cc of water, kept at 45°C and stirred, and then 0.189 g of 3,4-methylenedioxyphenylgeranyl ether was dissolved in 2 c of methanol.
The solution dissolved in c was added dropwise over a period of 15 minutes.

The mixture was treated in the same manner as in Example 1 to obtain 1.09 g of the clathrate compound.

Calculated from elemental analysis values, the content of geranyl ether is 1
It was Section 3.2.

Example 4 1.509 β-cyclodextrin was dissolved in 40 cc of water, kept at 45°C, and while stirring, a solution of 0.18 g of geranyl p-nitrophenyl ether dissolved in 2 cc of methanol was added dropwise over 10 minutes. After stirring for a minute, the precipitate was cooled on ice, separated, washed with 50% methanol, and dried under reduced pressure to obtain 0.95 g of the clathrate compound.

The content of geranyl p-nitrophenyl ether calculated from elemental analysis was 10.4%.

Example 5 β-Cyclodextrin 1.51,9 was dissolved in 4Qcc of water, kept at 40°C and stirred, and then 7-ethoxy-3,7-
A solution of 0.21 g of dimethyl 2-octenyl-p-nitrophenyl sulfide dissolved in 1.5 cc of ethanol was added dropwise over 10 minutes, stirred for 40 minutes, cooled on ice, separated the precipitate, and dissolved in a small amount of 50 ml. After washing with ethanol and drying under reduced pressure, 1.16 g of the clathrate compound was obtained.

The content of 7-ethoxy-3,7-dimethyl-2-octenyl p-nitrophenyl sulfide calculated from elemental analysis was 11.5%.

Claims (1)

[Claims] 1. A cyclohexene derivative or a benzene derivative having a structure in which an inbrenoid carbon side chain having 7 to 15 carbon atoms or a part of the carbon in the carbon side chain is replaced with oxygen or sulfur is reacted with cyclodextrin. Characteristic method for producing novel clathrate compounds.