JPH0317823B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing polyprenylacetoxime derivatives. The polyprenylacetoxime derivative in the present invention has the general formula: (In the formula, R means hydrogen or a lower alkyl group,
n means an integer from 2 to 9. ) (hereinafter referred to as a compound). It is known that conventionally known oxime compounds similar to this are hydrolyzed into carbonyl compounds in the presence of acids, oxidizing agents, or reducing agents. The compound according to the present invention can also be hydrolyzed in the same way as known compounds, resulting in the following formula: (In the formula, n means an integer of 2 to 9.) Polyprenylacetone represented by the following can be easily obtained in high yield. Furthermore, the compound polyprenylacetone can be produced by the general formula (In the formula, n means an integer of 2 to 9.) It is known that polyprenyl alcohol represented by the following can be easily obtained in high yield. These polyprenyl alcohols are well known as fragrances present in natural essential oils such as linalool and nerolidol, and are also important compounds as part of the side chains of vitamin E, vitamin K ₂ and coenzyme Q. Therefore, a method for synthesizing polyprenylacetone, which is a precursor of these polyprenyl alcohols, in good yield is of great industrial value. Traditionally, the typical method for producing this type of polyprenylacetone is Metal&
The method of condensing acetone and polyprenyl halide in the presence of an alkali developed by Thermit [Brit.Pat.851, 658] and its improved method, or after condensing acetoacetate and polyprenyl halide under basic conditions. The method of O. Isler et al. [Helv. Chim. Acta, 37 , 225 (1954)] can be used to obtain polyprenylacetone by hydrolysis and decarboxylation. However, the former method has a yield of only 60
~70%, and by-products include dialkylation products or aldol reactions of acetone itself, and its applications are limited to halogen compounds with relatively short side chains. On the other hand, the latter method is
Applicable to various polyprenyl halides,
Although there are few by-products in each step, the steps are long and the overall yield is low at 60-70%. Therefore, both methods are not satisfactory in terms of yield, and considering that these halogen compounds are expensive, especially when using long-chain polyprenyl halides, simpler and better-yielding synthesis methods are needed. Law is required. As a result of extensive studies, the present inventors have completed a method for producing a new compound that is extremely useful for producing polyprenylacetone, a useful precursor of polyprenyl alcohol, in a high yield and easily. It's ivy. The method for producing a compound according to the specific invention of the present invention includes:
General formula: (In the formula, R means hydrogen or an alkyl group.) An acetoxime derivative represented by the general formula: (In the formula, X means a reactive derivative of a halogen or a hydroxyl group, and n means an integer of 2 to 9.) A condensation reaction is performed with a polyprenyl alcohol derivative represented by the following in the presence of a basic substance, and the general formula : This method is characterized by obtaining the above-mentioned compound represented by, ie, a polyprenylacetoxime derivative. The compound represented by the above general formula (hereinafter referred to as a compound) can be easily synthesized by a condensation reaction of acetone and various primary hydroxylamines. On the other hand, the compound represented by the above general formula (hereinafter referred to as a compound) is obtained by reacting polyprenyl alcohol with a halogenating agent such as thionyl chloride or phosphorus tribromide, or methanesulfonyl chloride or paratoluenesulfonyl chloride under basic conditions. This allows easy synthesis with high yield. One of the characteristics of the condensation reaction with these compounds is that it is carried out in the presence of a basic substance, and by using these compounds, the compounds can be obtained. As the basic substance used in the condensation reaction, alkyllithium such as n-butyllithium, phenyllithium, lithium amide such as lithium diisopropylamide, and a hydrogen abstracting agent such as Grignard reagent can be used. Furthermore, an alkali metal, an alkali metal hydride, etc. may be used in combination. The amount of these basic substances to be used is when R of the compound is hydrogen, that is, when it is acetoxime.
More than twice the molar amount of acetoxime is required. When R in the compound is other than hydrogen, that is, when it is an acetoxime derivative, the basic substance is required in an equimolar or more amount. Although the basic substance may be used in excess, it is usually sufficient to use it in an amount of 1.0 to 1.3 equivalents of the molar ratio required for the reaction. The reaction is carried out in a solvent, and any substance that does not react with either the raw material compound, the basic substance, or the product can be used, but generally ether solvents such as tetrahydrofuran and diethyl ether, and even hexane are used. Hydrocarbon solvents such as benzene can also be used. Furthermore, the reaction can be carried out at low temperatures (-80
C) to high temperature (+80 C), but it is preferable to carry out the process at a temperature between about -50 C and about 10 C, since it varies depending on the type of raw material or hydrogen abstracting agent used. It is possible to obtain the target compound in good yield under the above conditions, but as mentioned above, the obtained compound can be hydrolyzed in the presence of an acid, an oxidizing agent, or a reducing agent to form a polymer. It can be easily converted to prenylacetone in high yield. Examples of acids used in the hydrolysis reaction include mineral acids such as hydrochloric acid and oxalic acid, and organic acids such as acetic acid and oxalic acid. Examples of the oxidizing agent include cerium ammonium nitrate, benzene selenic anhydride, chlorochromic acid pyridine salt, and hydrogen monoperoxide. Further, examples of the reducing agent include disodium dithionite, vanadium dichloride, titanium trichloride, chromium dichloride, molybdenum trichloride, and the like. However, when R of the compound is H, the hydrolysis reaction by acid does not proceed. The reaction is carried out in a mixed solvent of water and an organic solvent. In this case, the organic solvent used can be any substance that does not react with compounds, acids, oxidizing agents, or reducing agents, but preferably tetrahydrofuran is highly soluble in water. , acetone or lower alcohols are preferable, and the reaction time can be shortened by using these solvents. Further, although the reaction generally proceeds at a relatively low temperature, it may be preferable to heat or cool the reaction depending on the type of oxidizing agent or reducing agent or solvent used. Under the above conditions, polyprenylacetone can be obtained in high yield, and as mentioned above,
It is an important precursor of polyprenyl alcohol, which is a useful intermediate for various natural products, and by using these reactions, polyprenylacetoxime derivatives and polyprenylacetone can be obtained easily and in high yields. . EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited to these Examples. Example 1 6,10-dimethyl-5,9-undecadiene-
2-one-2-oxime (compound: n=
2. Synthesis of R=H) Acetoxime 3.82 as a compound under nitrogen stream
g (52 mmol) was added to 40 ml of dry tetrahydrofuran, dissolved, and cooled to -32° to -28°C.
1.50mmol/ml, 93mmol). At this time n
- When 31 ml of butyl lithium was added, the reaction solution became milky and cloudy, but when the remaining 31 ml was added, it became a pale yellow, transparent solution. After stirring for 30 minutes, 8.1 g (37.3 mmol) of geranyl bromide was added as a compound.
Stir for an additional 120 minutes. The temperature was gradually raised over 60 minutes, and when it reached 5°C, water and diethyl ether were added to wash, extract, and separate the liquids. The organic layer is dried over anhydrous magnesium sulfate. The organic layer was filtered and concentrated under reduced pressure to obtain 7.7 g of an oily residue. This residue was purified by silica gel column chromatography,
6.8 g (yield 87.1%) of a colorless transparent oil was obtained. The identification data of this product is shown in the attached table (the same applies to the following examples). Example 2 Synthesis of 6,10,14-trimethyl-5,9,13-pentadecatrien-2-one-2-oxime (compound; n=3, R=H) Acetoxime 2.19 as a compound under nitrogen stream
g (30 mmol) was added to 20 ml of dry tetrahydrofuran, dissolved, and cooled to -27° to -22°C. 0.70 g (30.4 mmol) of metallic sodium was added and stirred until the metallic sodium disappeared. Furthermore, 20 ml of n-butyllithium (n-hexane solution, concentration 1.50 mmol/ml,
30 mmol). After stirring for 60 minutes, add 7.4 g (26 (mmol)) of phanerucyl bromide as a compound and stir for an additional 120 minutes.The temperature was gradually raised over 60 minutes, and when it reached 5°C, water and diethyl ether were added. The organic layer was added, washed, extracted, and separated. The organic layer was dried over anhydrous sodium sulfate. The organic layer was filtered and concentrated under reduced pressure to obtain 6.9 g of an oily residue.
This residue was purified by silica gel column chromatography to obtain 6.0 g of a colorless transparent oil (yield:
83.5%) obtained. Example 3 6,10,14,18,22,26,30,34,38-nonamethyl-5,9,13,17,21,25,29,33,37-
Synthesis of nonatriacontanonaen-2-one-2-hydroxime (compound: n=9, R=H) Acetoxime 0.95 as a compound under nitrogen stream
g (13 mmol) was added to 20 ml of dry tetrahydrofuran, dissolved, cooled to -25° to -20°C, added with 0.32 g (13.3 mmol) of sodium hydride, and stirred until no hydrogen generation was observed. Furthermore, 8.7 ml of n-butyllithium (n-hexane solution, concentration 1.50 mmol/
ml, 13.1 mmol). After stirring for 60 minutes, 7.4 g of solanesyl bromide (purity 94.1%,
A solution of 10 mmol) dissolved in 20 ml of dry tetrahydrofuran was added and stirred for an additional 120 minutes. The temperature was gradually increased over 60 minutes, and when it reached 5°C, water and n-hexane were added for washing, extraction, and liquid separation. The organic layer is dried over anhydrous sodium sulfate. Filter the organic layer and concentrate under reduced pressure to obtain 7.2 g of amorphous crystalline residue.
I got it. This residue was purified by silica gel column chromatography to obtain 5.9 g of amorphous white crystals.
(yield 86.0%). Example 4 6,10-dimethyl-5,9-undecadiene-2
Synthesis of -one-2-0-methyloxime (compound: n=2, R=CH ₃ ) Under a nitrogen atmosphere, 1.66 g (19.1 mmol) of o-methylacetoxime was added to 20 ml of dry tetrahydrofuran and dissolved at -35°. Cool to ~-28℃,
12.7ml of n-butyllithium (n-hexane solution,
Add a concentration of 1.50 mmol/ml, 19.1 mmol). After stirring for 30 minutes, 4.0 g of geranyl bromide was added as a compound.
(18.4 mmol) and stir for an additional 120 minutes. The temperature was gradually raised over 60 minutes, and when it reached 5°C, water and diethyl ether were added to wash, extract, and separate the liquids. The organic layer is dried over anhydrous magnesium sulfate. The organic layer was filtered and the solvent was distilled off under reduced pressure to obtain an oily residue of 5.1 g.
I got it. This residue is distilled under reduced pressure to obtain the main fraction (boiling point
105°C, 1 mmHg) 4.36g (yield 82.7%) was obtained. Example 5 6,10,14,18,22,30,34,38-nonamethyl-5,9,13,17,21,25,29,33,37-nonatriacontanonaen-2-one-2 -0-methyloxime (compound: n=9, R=CH ₃ )
Synthesis Under a nitrogen atmosphere, add 0.97 g (11.1 mmol) of 0-methylacetoxime to 10 ml of dry tetrahydrofuran and dissolve, then cool to -32° to -24°C.
7.4ml of n-butyllithium (n-hexane solution,
Add a concentration of 1.50 mmol/ml, 11.1 mmol). After stirring for 30 minutes, 6.27 g of solanesyl bromide was obtained as a compound.
A solution of (purity 94.1%, 8.5 mmol) dissolved in 20 ml of dry tetrahydrofuran was added, and the mixture was further stirred for 120 minutes. It took 60 minutes to gradually raise the temperature to 5℃.
When the temperature reaches 1, water and n-hexane are added to wash, extract, and separate the liquids. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to form an amorphous crystalline residue.
5.98g was obtained. This residue was purified by silica gel column chromatography to obtain amorphous white crystals.
5.66g (yield 89.5%) was obtained. Next, the properties, physical properties, etc. of typical compounds obtained by the method of the present invention will be listed.

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Claims (1)

[Claims] 1. General formula: (In the formula, R means hydrogen or a lower alkyl group.) An acetoxime derivative represented by the general formula: (In the formula, X means a halogen or a reactive derivative of a hydroxyl group, and n means an integer from 2 to 9.)
The general formula consists of condensing with a polyprenyl alcohol derivative represented by: A method for producing a polyprenylacetoxime derivative represented by the formula (wherein R and n have the meanings described above). 2. The production method according to claim 1, wherein the condensation reaction is carried out in the presence of a basic substance. 3. The production method according to claim 2, wherein the basic substance is an alkyllithium, phenyllithium, lithium amide, or a Grignard reagent. 4. The manufacturing method according to claim 3, in which an alkali metal or an alkali metal hydride is used in combination.