JPS6338019B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to dihydropolyprenylnitrile. More specifically, the present invention relates to the general formula (In the formula, [formula] represents a trans isoprene unit,
[Formula] represents a cis isoprene unit, and n represents an integer from 11 to 19. ) is related to a novel dihydropolyprenyl nitrile. The dihydropolyprenylnitrile represented by the general formula () provided by the present invention is a substance useful as a raw material for medicines, cosmetics, etc., and is particularly useful as a synthetic intermediate for mammalian dolichols. Dolichols were first isolated from pig liver etc. by JFPennock et al. in 1960 [see Nature (London), 186 , 470 (1960)], and were later given the general formula (A). [In the formula, [formula] represents a trans isoprene unit,
[Formula] represents a cis isoprene unit. The same shall apply hereinafter in this specification. ] A mixture of polyprenol homologs having the structure shown in formula (A), where j representing the number of cis isoprene units generally ranges from 12 to 18, and j
It was revealed that the three homologues =14, 15 and 16 were the main constituents [RWKeenan et al.
al., Biochemical Journal, 165 , 505 (1977)]. Dolichols are widely distributed not only in the liver of pigs but also in the bodies of mammals, and are known to play extremely important functions in maintaining the life of living organisms. For example, JB Harford et al. conducted an in vitro study using the white medulla of calves and pigs' brains, and found that exogenous dolichol promotes the incorporation of sugar components such as mannose into lipids, which are important for maintaining the life of living organisms. [Biochemical
and Biophysical Research Communication,
76, 1036 (1977)]. The effect of dolichols on promoting the incorporation of sugar components into lipids is more pronounced in already mature animals than in growing organisms, so the role of dolichols in preventing aging is attracting attention. Also, RW
Keenan et al. state that it is important for rapidly growing organisms, such as those in childhood, to ingest dolichol from outside and supplement the dolichol obtained by biosynthesis within the body [Archives of
Biochemistry and Biophysics, 179 , 634
(1977)]. Furthermore, Akamatsu et al. quantified dolicolic acid ester in the regenerated liver of rats and found that the amount was significantly lower than in the normal liver, indicating that the glycoprotein synthesis function in the liver tissue was significantly reduced. We found that this function was improved by adding dolicolic acid ester from the outside [presented at the 54th Annual Meeting of the Japanese Biochemical Society (1981)]. As mentioned above, dolichols are substances that control extremely important functions for living organisms, and are useful as pharmaceuticals or intermediates thereof. Only 0.6 g of dolichol can be obtained through this process [J. Burgos et al., Biochemical
Journal, 88 , 470 (1963)]. Total synthesis of dolichols is extremely difficult using current organic synthesis techniques, as is clear from their complex and unique molecular structures. It would be advantageous if dolichols could be obtained by relying on natural products as synthetic intermediates and adding simple synthetic chemical treatments to them, but such convenient substances have not been found so far. Conventionally, the following general formula (B) [However, it is known that polyprenols represented by k = 4 to 6 (these are called betulaprenols) can be collected from silver birch ( Betula verrucosa ), but from these polyprenols, cis-isoprene units It is almost impossible to synthesize dolichols mainly containing 14, 15, and 16 molecules using current organic synthesis techniques. Also
K. Hannus et al .
reported that a polyprenyl component was isolated from leaves of S. sylvestris at a yield of 1% on a dry weight basis, and that this component was a polyprenyl acetate mixture containing 10 to 19 isoprene units primarily in the cis configuration. Phytochemistry, 13 , 2563 (1974)], their report does not elucidate the details of the trans and cis configurations in the polyprenylacetate. Furthermore, DFZinkel et al. reported the presence of C ₉₀ polyprenols with 18 isoprene units or an average number of isoprene units in extracts of pine strobus ( Pinus strobus ) leaves. [Phytochemistry,
11, 3387 (1972)], this report does not provide a detailed analysis of the trans and cis configurations of the polyprenol. Some of the present inventors and their co-researchers first hydrolyzed the extracts extracted from Japanese staghorn and Himalayan cedar using organic solvents, if necessary, and then used chromatography, fractional dissolution, and other methods. By processing by suitable separation methods, 14
A polyprenyl fraction consisting of a polyprenol and/or a mixture of its acetate homologues having ~22 isoprene units in exactly the same trans, cis configuration as mammalian dolichols is obtained; In comparison, the polyprenyl fraction exhibits a distribution of polyprenyl congeners very similar to that in mammalian dolichols, with only the absence of α-terminal saturated isoprene units, of which the polyprenyl fraction is optionally a constituent. It can be relatively easily separated into individual polyprenyl analogues (with a uniform number of isoprene units), and therefore the polyprenyl fraction and each polyprenyl analogue separated therefrom can be used as synthetic intermediates for mammalian dolichols. I found it to be very suitable. In order to efficiently produce mammalian dolichols using the above-mentioned polyprenyl compounds, the present inventors have intensively investigated a method of introducing a saturated isoprene unit into the α-terminus of the polyprenyl chain of the polyprenyl compound, and have found that such a method The present invention was completed by creating a dihydropolyprenyl nitrile represented by the general formula () which is useful as an intermediate in the following. The dihydropolyprenyl nitrile of the present invention represented by the general formula () [hereinafter referred to as dihydropolyprenyl nitrile ()]. ] is a general formula (In the formula, X represents a halogen atom, and n is as defined above.) Polyprenyl halide [hereinafter referred to as polyprenyl halide ()]. ] in the presence of a basic compound. (In the formula, R ¹ represents a lower alkyl group.) Acetoacetate [hereinafter referred to as acetoacetate ()]. ] General formula () obtained by reacting with (In the formula, R ¹ and n are as defined above.) Polyprenylketocarboxylic acid ester [hereinafter referred to as polyprenylketocarboxylic acid ester ()]. ] is hydrolyzed and decarboxylated to form the general formula (In the formula, n is as defined above.) Polyprenylacetone [hereinafter referred to as polyprenylacetone ()]. ] and then convert it to the general formula () in the presence of a base and/or acid. (In the formula, R ² represents a lower alkyl group.) Cyanoacetic acid lower alkyl ester [hereinafter referred to as cyanoacetic acid ester ()]. ] to form the general formula () (In the formula, R ² and n are as defined above.) Polyprenylcyanocarboxylic acid ester [hereinafter referred to as polyprenylcyanocarboxylic acid ester ()]. ], and the polyprenylcyanocarboxylic acid ester () is selectively reduced to give the general formula () (In the formula, R ² and n are as defined above.) Dihydropolyprenylcyanocarboxylic acid ester [hereinafter referred to as dihydropolyprenylcyanocarboxylic acid ester ()]. ] and can be produced by hydrolyzing and decarboxylating it. As mentioned above, polyprenyl halide () has the general formula that can be obtained directly or through hydrolysis from extracts of Japanese yam or Himalayan cedar. (In the formula, n is as defined above.) Polyprenol or a mixture thereof is treated with a halogenating agent such as phosphorus trihalide such as PCl ₃ or PBr ₃ , or thionyl halide such as SOCl ₂ or SOBr ₂ to generate a halogen. It can be easily obtained by This halogenation reaction is usually carried out by dissolving the above-mentioned polyprenol in a suitable solvent such as hexane or diethyl ether, and heating the solution at about -20°C in the presence or absence of a base such as triethylamine or pyridine. This is done by adding a halogenating agent at a temperature of ~+50°C. The reaction between polyprenyl halide () and acetoacetate () is preferably carried out in a solvent. Suitable solvents include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane. The amount of the solvent used is not critical, but it is 2 to 100 times (by weight), preferably 5 to 80 times (by weight), more preferably 10 to 50 times (by weight) relative to the polyprenyl halide (). It is preferable to use a sufficiently dried solvent in order for the desired reaction to proceed smoothly. In order to carry out this reaction, it is essential to have a basic compound present.
The basic compounds used include alkali metal hydrides such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium t-butoxide, potassium t-butoxide, sodium methoxide, and sodium ethoxide;
Hydroxides or alkoxides, n-butyllithium, methyllithium, etc. are suitable. The basic compound is generally about 0.1 to 5.0 mol, preferably 0.5 to 3.0 mol per mol of acetoacetate ().
It is used in a molar ratio, more preferably 0.7 to 1.5 molar. In a preferred embodiment, the basic compound is first added to a solution or dispersion of the basic compound by adding the acetoacetate () or conversely to a solution of the acetoacetate () by gradually adding the basic compound all at once or in small portions. An anion of acetoacetate () is formed, and then polyprenyl halide () is added thereto and reacted. The ratio of acetoacetate () and polyprenyl halide () to be used is not critical, but the molar ratio of acetoacetate ()/polyprenyl halide () is from 1/2 to
The ratio is 20/1, preferably 4/5 to 10/1, and more preferably 1/1 to 5/1. When forming the anion of acetoacetate (), the temperature is -30°C ~ under an inert gas atmosphere such as nitrogen gas or argon.
It is desirable to carry out the reaction at a temperature of +100°C, preferably -10°C to +80°C, so that the desired anion can be smoothly formed while suppressing side reactions. The time required for this anion formation varies depending on the reaction temperature used, but usually about 10 minutes to 5 hours is sufficient. Polyprenyl halide () is added to the anionic solution of acetoacetate () prepared in this manner and reacted. Depending on the reaction conditions used, the reaction may be allowed to proceed smoothly by adding polyprenyl halide (2) in small portions or in a dropwise manner rather than adding the entire amount at once. The temperature within the reaction system during the time of addition of polyprenyl halide () and thereafter until completion of the reaction is not critical, but is preferably within the range of -10°C to the boiling point of the solvent used. If the reaction temperature is too low, the reaction progresses slowly and takes too much time to complete the reaction. On the other hand, if the reaction temperature is too high, undesirable side reactions will proceed. From this point of view, it is preferable to employ a reaction temperature within the range of 0°C to 80°C. Polyprenyl halide ()
In order to complete the reaction after adding , it is necessary to continue stirring the reaction mixture at the above reaction temperature, and the time required for this varies depending on the reaction temperature used, but is usually about 30 minutes to 24 hours. It is. In order to confirm the progress of the reaction, it is convenient and preferable to monitor the decrease in the raw material polyprenyl halide () by thin layer chromatography. After the reaction, isolation of the polyprenylketocarboxylic acid ester () from the reaction mixture can be easily accomplished by applying isolation methods used in conventionally known synthetic reactions. Chromatography is particularly conveniently used. Adsorbents that can be used for chromatography include silica gel, alumina,
Examples include activated carbon and cellulose. Among these, silica gel is particularly preferably used. As the developing solvent, it is preferable to use a mixture of a small amount of a polar solvent such as diethyl ether, chloroform, ethyl acetate, or ethyl alcohol with a hydrocarbon solvent such as hexane, pentane, petroleum ether, or benzene. In addition, this isolation step is omitted and the next step, the synthesis reaction of polyprenylacetone (), is carried out directly.
It is also possible to carry out a purification step thereafter. Polyprenylketocarboxylic acid ester () can be saponified by applying the method conventionally used for the saponification reaction of higher fatty acid esters. For example, the objective can be achieved by stirring polyprenylketocarboxylic acid ester () with sodium hydroxide or potassium hydroxide in aqueous methanol, aqueous ethanol or aqueous isopropanol. The amount of sodium hydroxide or potassium hydroxide used is approximately
It is desirable that the amount is 1.0 to 20.0 molar equivalents, preferably 1.5 to 10.0 molar equivalents. Hydrous alcohols such as those mentioned above are suitable as reaction solvents, but hexane, pentane, benzene,
It is also preferable to add a small amount of a hydrocarbon solvent such as toluene. In order to allow the saponification reaction to proceed smoothly, it is desirable to adopt a reaction temperature ranging from 0°C to the boiling point of the solvent used, preferably within the range of 25 to 65°C. The time required for the reaction to complete varies depending on the temperature conditions employed, but
Usually within the range of about 0.5 to 24 hours. After carrying out the saponification reaction as described above,
Neutralize the reaction solution with a mineral acid such as hydrochloric acid or sulfuric acid, preferably under room temperature conditions or ice-cooled conditions, and then make the reaction solution acidic to a pH of about 1 to 3, and the decarboxylation reaction will occur automatically. and polyprenylacetone () is formed. After the decarboxylation reaction is completed,
The reaction solution is extracted with hexane, benzene, diethyl ether, etc., washed thoroughly with water, the organic layer is dried, and the solvent is distilled off to obtain crude polyprenylacetone (). Chromatography is preferably employed to purify this product. Adsorbents used in this chromatography include silica gel, alumina, activated carbon, and cellulose, with silica gel being particularly suitable. As the developing solvent, it is preferable to use a mixture of a hydrocarbon solvent such as hexane, pentane, petroleum ether, benzene, or toluene with a small amount of a polar solvent such as diethyl ether, diisopropyl ether, chloroform, ethyl acetate, or methyl acetate. be. Polyprenylacetone () synthesized as described above and cyanoacetate () are reacted in the presence of a base and/or acid to produce polyprenylcyanocarboxylic acid ester ().
is obtained. Examples of the cyanoacetic ester () that are preferably used include [Formula] [Formula] [Formula] [Formula] and the like. The amount of cyanoacetate () used is 0.5 to 10.0 molar equivalent to polyprenylacetone ().
Preferably 0.7 to 1.5 molar equivalent, more preferably 0.8
~1.0 equivalent. The reaction between polyprenylacetone () and cyanoacetate () is preferably carried out in a solvent inert to this reaction. Examples of solvents that can be suitably used include hexane, heptane, benzene, toluene, xylene, and chloroform. The amount of solvent used is not critical, but it is 5 to 200 times the weight of polyprenylacetone ().
More preferably, it is 10 to 100 times the weight. When proceeding with the reaction between polyprenylacetone () and cyanoacetic acid ester (), it is necessary to have a base and/or an acid present.
Examples of bases and/or acids that can be suitably used include ammonium acetate-acetic acid, acetamide-acetic acid, pyridine-acetic acid, piperidine, ε-
Examples include amino-n-caproic acid. The amount of the base and/or acid used is 0.01 to 10.0 molar equivalent, more preferably 0.1 to 1.0 molar equivalent, relative to polyprenylacetone (). The reaction can be carried out by dissolving polyprenylacetone (), cyanoacetate (), the above base and/or acid in the above solvent and stirring under heating conditions, but in order to complete the reaction, It is preferable to remove by-product water.
A simple method for removing water is to azeotrope it together with the solvent used and distill it out of the system. Therefore, the reaction temperature is preferably the boiling temperature of the solvent, and the reaction can be completed by reacting for 1 to 24 hours, preferably 2 to 10 hours under these reaction conditions. The obtained polyprenyl cyanocarboxylic acid ester () can be purified by applying conventionally known separation and purification techniques. Chromatography is particularly preferred because it is simple. As the adsorbent and developing solvent for this chromatography, the adsorbent and developing solvent described above for the purification of polyprenylacetone () can be similarly used. Polyprenylcyanocarboxylic acid ester ()
A mild reducing agent such as sodium borohydride, lithium borohydride, cyanosodium borohydride, etc. can be used as a reducing agent for reducing borohydride to dihydropolyprenylcyanocarboxylic acid ester (). Sodium is most preferably used. The amount of reducing agent used depends on the reducing agent used, but it is generally 0.5 to 10% of the amount of polyprenyl cyanocarboxylic acid ester ().
The equivalent amount is preferably 1 to 5 equivalents. This reduction reaction is carried out in a suitable solvent. Examples of preferably used solvents include ethanol and isopropanol. The temperature of the reduction reaction is usually room temperature, but if necessary, a temperature other than room temperature within the range of -20°C to +80°C can be used. Approximately 5 minutes under this temperature condition
The reaction can be completed by stirring for 10 hours. After the reaction is completed, dihydropolyprenylcyanocarboxylic acid ester (2) can be easily purified by chromatography in the same manner as polyprenylcyanocarboxylic acid ester (201). The hydrolysis reaction of dihydropolyprenylcyanocarboxylic acid ester () can be carried out by applying the method conventionally used for the hydrolysis reaction of higher fatty acid esters. For example, achieving the objective by stirring dihydropolyprenylcyanocarboxylic acid ester () together with sodium hydroxide or potassium hydroxide in an alcoholic solvent such as methanol, ethanol, isopropanol, ethylene glycol, propylene glycol, etc. Can be done. The amount of sodium hydroxide or potassium hydroxide used is approximately
It is desirable that the amount is 1.0 to 20.0 molar equivalents, preferably 1.5 to 10.0 molar equivalents. The above-mentioned alcohols are suitable as reaction solvents, but a small amount of hydrocarbon solvents such as hexane, pentane, benzene, toluene, etc. may be added to increase the solubility of dihydropolyprenylcyanocarboxylic acid ester (). preferable. In order to allow the above-mentioned hydrolysis reaction to proceed smoothly and to prevent the cyano group from being hydrolyzed, it is desirable to maintain the reaction temperature within the range of 0°C to 30°C. The time required for the reaction to complete varies depending on the temperature conditions employed, but is usually approximately
Within the range of 0.5 to 24 hours. After carrying out the hydrolysis reaction as described above, the reaction solution is acidified to a pH of about 1 to 4 using a mineral acid such as hydrochloric acid or sulfuric acid, preferably under room temperature conditions or ice-cooled conditions, and then hexane and benzene are added. , diethyl ether, ethyl acetate, etc., and the solvent is distilled off to obtain dihydropolyprenylcyanocarboxylic acid, which corresponds to a compound in the general formula () in which R is a hydrogen atom. To decarboxylate this, 5
It is preferable to dissolve it in ~100 times the weight of pyridine and heat under reflux for 1 to 5 hours together with 0.01 to 1.0 times the weight of copper powder. The copper powder is separated, the liquid is concentrated, dissolved in a solvent such as hexane or diethyl ether, washed with water, dried, and then the solvent is distilled off to obtain a crude product of dihydropolyprenylnitrile (). Chromatography is preferably employed to purify this product. Adsorbents used in this chromatography include silica gel, alumina, activated carbon, and cellulose, with silica gel being particularly preferred. As the developing solvent, a mixture of a small amount of a polar solvent such as diethyl ether, diisopropyl ether, chloroform, or ethyl acetate with a hydrocarbon solvent such as hexane, pentane, petroleum ether, or benzene is suitable. Mammalian dolichols can be synthesized from dihydropolyprenylnitrile () synthesized by the above method, for example, by the synthetic route shown below. However, in the above formula, PP is the formula (In the formula, n is as defined above.) In the reaction, dihydropolyprenylnitrile () is hydrolyzed to obtain a dihydropolyprenylcarboxylic acid represented by the general formula (X), and then a reduction reaction (reaction) with lithium aluminum hydride or the like is performed to obtain the dihydropolyprenylcarboxylic acid represented by the general formula (XI). Polyprenyl alcohols, ie mammalian dolichols, can be synthesized. Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples. In addition, IR analysis in Examples and Reference Examples was measured using a liquid film, and NMR analysis was performed using TMS.
was measured as an internal standard. The FD-MASS analysis values are values corrected as ¹ H, ¹² C, ¹⁴ N, ¹⁶ O, and ⁷⁹ Br. Reference example 1 Separation of polyprenol 10 kg of fig leaves collected in Kurashiki city at the end of October
(Undried weight) After drying with hot air at about 40°C for 24 hours, it was extracted by immersing it in chloroform 80 at room temperature (about 15°C) for one week. Petroleum ether 5 was added to the concentrate obtained by distilling off chloroform from this extract to separate insoluble components, and after concentrating the liquid, it was separated using a silica gel column using chloroform as a developing solvent to obtain about 37 g of an oily substance. Obtained. Approximately 400 ml of acetone was added to this oil to dissolve the acetone-soluble components, the resulting mixture was filtered, the liquid was concentrated, and the resulting oil was mixed with 400 ml of methanol, 40 ml of water, and 20 g of sodium hydroxide for 2 hours. After heating to 65°C, methanol was distilled off, diethyl ether (500 ml) was added to the residue for extraction, the ether layer was washed with approximately 100 ml of water five times, dried over anhydrous sodium sulfate, and the solvent was distilled off. 24.2 g of oil was obtained. Next, this oil was mixed with n-hexane/isopropyl ether = 90/10 using about 1 kg of silica gel.
(volume ratio) of the mixed solution to obtain 21.8 g of oil. This oil is a polyprenol with a purity of 95% or more, and it is used on a semi-preparative high-performance liquid chromatography column (LiChrosorb) manufactured by Merck & Co., Ltd.
Using RP18-10 (C ₁₈ type), use a mixed solvent of acetone/methanol = 90/10 (volume ratio) as the eluent.
High performance liquid chromatography analysis was performed using a differential refractometer as a detector, and the area ratio of each peak in the obtained chromatogram was determined, and the results were as follows. [Table] Using this high-performance liquid chromatography, each component was separated from the above oily substance and analyzed by mass spectrometry, infrared absorption spectrum, ¹ H-NMR spectrum, and ¹³ C
- NMR spectra confirmed that these components were polyprenol with the structure shown by the general formula (). For each component, field ionization mass spectrometry (FD-
Table 1 shows the results of MASS) and the δ value of ¹ H-NMR.
The δ values of ¹³ C-NMR are summarized in Table 2. [Table] [Table] Reference Example 2 Synthesis of polyprenyl bromide Polyprenol of general formula () where n=15
12.4 g and 1 ml of pyridine were added to 200 ml of n-hexane, and 2.0 g of phosphorus tribromide was added dropwise to the resulting solution at room temperature (approximately 20°C) under a nitrogen gas atmosphere.
After completion of the dropwise addition, the mixture was stirred overnight at room temperature under a nitrogen gas atmosphere. Next, this n-hexane solution was placed in a separating funnel, washed three times with about 50 ml of water, dried over anhydrous magnesium sulfate, and the n-hexane was distilled off to obtain 12.0 g of a slightly yellow liquid. When NMR analysis was performed on this product, the signal (d, δ = 4.08) attributed to the -C H ₂ OH group of the raw material polyprenol disappeared and a new -C H ₂ Br
A signal (d, δ = 3.91) assigned to . Further, when this liquid material was analyzed by FD-MASS, it was found that m/e = 1304. These analysis results confirmed that the above product was a polyprenyl bromide having the general formula () where n=15 and X= _Br . By similar operations, polyprenyl bromides with n other than 15 and polyprenyl bromide mixtures with n arbitrarily distributed between 11 and 19 were also synthesized. Example 1 30 ml of anhydrous tetrahydrofuran in a three-necked flask
and 640 ml of 50% sodium hydride were added thereto, and 1.57 g of ethyl acetoacetate was added dropwise while stirring at room temperature. After the intense generation of hydrogen gas became calm, the temperature in the flask was gradually raised while purging the inside of the flask with nitrogen gas, and stirring was continued for 1 hour under the condition of refluxing the solvent. Then, after cooling the reaction system to room temperature, polyprenyl bromide synthesized according to Reference Example 2 and having the general formula () where n=15 and X=B _r was added to the reaction system.
A solution of 4.30 g in tetrahydrofuran (10 ml) was added dropwise, and the mixture was stirred at room temperature overnight. After distilling off the solvent from the reaction mixture using a rotary evaporator, the residue was poured into about 20 ml of water, extracted with diethyl ether, and the obtained diethyl ether layer was washed successively with water, diluted hydrochloric acid, water, and sodium bicarbonate. , dried over anhydrous magnesium sulfate,
Diethyl ether was distilled off using a rotary evaporator to obtain a yellow liquid. This yellow liquid was heated under a reduced pressure of 1 mmHg.
The low-boiling components were distilled off by heating at 150°C for 30 minutes, and the residue was purified by silica gel column chromatography [using hexane/ethyl acetate = 98/2 (volume ratio) as the developing solution] to give a slightly yellow color. 2.48g liquid
I got it. The analysis results of this product are shown below. IR analysis: 1740, 1715, 1660, 830 cm ^{-1 1} H-NMR analysis: δ ^ppm _Ccl4 1.21 (3H, t, -CO ₂ C
H ₃ ), 3.21 (1H, t,
[Formula]), 4.11 (2H, q, - CO ₂ C H ₂ CH ₃ ) FD-MASS analysis: m/e = 1354 Based on the above analysis results, this slightly yellow liquid has n = 15 in the general formula (). , was confirmed to be ethyl polyprenylketocarboxylate in which R ¹ =C ₂ H ₅ . Next, ethyl polyprenylketocarboxylate was added to a solution of 0.5 g of sodium hydroxide, 20 ml of ethanol, and 5 ml of water, and after stirring for 3 hours under reflux conditions, most of the ethanol was distilled off using a rotary evaporator to form a residue. The mixture was poured into about 20 ml of water, concentrated hydrochloric acid was added little by little to make it acidic to a pH of about 2, and then extracted with hexane. The hexane layer was thoroughly washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a yellow viscous liquid. This product was purified by silica gel column chromatography [hexane/ethyl acetate = 98/2 (volume ratio) was used as the developing solution] to obtain 1.98 g of slightly yellow viscous liquid.
I got it. The analysis results of this product are shown below. IR analysis: 1715, 1660, 830cm ^{-1 1} H-NMR analysis: δ ^ppm _Ccl4 1.53 (s, 9H), 1.62
(s, 48H), 1.7-2.4 (m, 75H), 5.05
(br, 18H) FD-MASS analysis: m/e=1282 The above analysis results confirmed that this slightly yellow liquid was polyprenylacetone, where n=15 in the general formula (). Next, in a three-necked flask, add 50 ml of benzene, 173 mg of ethyl cyanoacetate, 35 mg of ammonium acetate, and acetic acid.
35 mg and 1.96 g of polyprenylacetone () synthesized earlier were charged, and at the boiling temperature of the solution, by-produced water was azeotroped with benzene and distilled out of the system.
The reaction was allowed to proceed for 10 hours. The reaction solution was then cooled to room temperature, washed with water in a separatory funnel, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a yellow liquid. This was subjected to silica gel column chromatography [hexane/ethyl acetate = 98/2 (volume ratio)]
was used as a developing solution] to obtain 1.42 g of a colorless liquid. The following analysis results confirmed that this liquid was a polyprenylcyanocarboxylic acid ester having the general formula () where n= ₁₅ and ^R2 = _C2H5 . IR analysis: 2220, 1725, 1660, 1600, 1440,
1370, 1275, 1220, 1060, 830cm ^{-1 1} H-NMR analysis: δ ^ppm _Ccl4 1.30 (t, 3H), 1.53
(s, 9H), 1.62 (s, 48H), 1.7~2.5 (m,
75H), 4.20 (q, 2H), 5.06 (br, 18H) FD-MASS analysis: m/e = 1377 Next, 1.40 g of this polyprenylcyanocarboxylic acid ester and 20 ml of isopropanol were placed in a three-necked flask and stirred at room temperature. While stirring, about 50 mg of sodium borohydride was added, and stirring was continued for 1 hour at the same temperature, then poured into about 50 ml of saturated ammonium chloride aqueous solution, and extracted with hexane. The hexane layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 1.35 g of a colorless liquid. According to the analysis results below, this product has n=15 and R ² in the general formula ().
It was confirmed that it was _a dihydropolyprenylcyanocarboxylic acid ester where = _C2H5 . IR analysis: 2245, 1740, 1660, 1440, 1370,
1295, 1240, 1185, 1175, 1020, 830cm ^{-1 1} H-NMR analysis: δ ^ppm _Ccl4 1.04 (dd, 3H), 1.30
(t, 3H), 3.36 (dd, 1H), 4.22 (q,
2H), 5.05 (br, 18H) FD-MASS analysis: m/e = 1379 Next, a mixture of 30 ml of ethanol, 3 ml of water, and 0.3 g of sodium hydroxide was added to this liquid, and after stirring at room temperature for 1 hour, 100 ml of water was added. After the addition, 6N-hydrochloric acid was added little by little to adjust the pH to 2, and the mixture was extracted three times with ether. The organic layers were combined, washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 1.22 g of a liquid product. Next, this liquid material was dissolved in 20 ml of pyridine, 0.1 g of copper powder was added, and the mixture was heated under reflux for 2 hours. The copper powder was then separated and washed with hexane. The liquid and washing liquid were combined, most of the solvent was removed using a rotary evaporator, the residue was dissolved in hexane, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a yellow liquid. Obtained. This liquid was subjected to silica gel column chromatography [hexane/ethyl acetate = 98/2
(volume ratio) was used as a developing solution].
1.01 g of colorless liquid was obtained. The following analysis results confirmed that this product was dihydropolyprenyl nitrile in which n=15 in the general formula (). IR analysis: 2245, 1660, 1440, 1375, 830cm ^{-1 1} H-NMR analysis: δ ^ppm _Ccl4 1.00 (d, 3H), 1.1 ~ 1.5
(m, 2H), 1.53 (s, 9H), 1.62 (s,
48H) 1.7-2.5 (m, 73H), 5.05 (br, 18H) FD-MASS analysis: m/e = 1307 Examples 2-9 By the same operation as Example 1, in the general formula (), X = B _r n is 11, 12, 13, 14, 16, 17, 18
And from each polyprenyl bromide which is 19, in the corresponding general formula (), n is 11, 12, 13, 14,
Dihydropolyprenyl nitriles 16, 17, 18 and 19 were synthesized. The yields of each of these synthetic reactions were approximately the same as in Example 1. In addition, the characteristic absorption of the infrared absorption spectrum and the characteristic signal of the ¹ H-NMR spectrum of each dihydropolyprenyl nitrile are substantially the same as those of the dihydropolyprenyl nitrile with n=15 in the general formula () synthesized in Example 1 at that position. It was a perfect match. Moreover, the values of FD-MASS analysis were as follows. [Table] Example 10 A polyprenol mixture obtained in the same manner as in Reference Example 1, in which n is distributed from 11 to 19 in the general formula () and whose composition is substantially the same as that described in Reference Example 1, was used as a reference example. A polyprenyl bromide mixture was prepared by reacting it with phosphorus tribromide according to the method of 2, and 4.30 g of the polyprenyl bromide mixture was converted into 4.30 g of polyprenyl bromide in which n=15 in the general formula ( ) of Example 1.
The same procedure as in Example 1 was carried out except that 0.97 g of a colorless viscous liquid was obtained as the final product. The IR and ¹ H-NMR analysis results of this product were substantially the same as those obtained for the dihydropolyprenyl nitrile of Example 1 in terms of characteristic absorption and position of characteristic signals.

Claims (1)

[Claims] 1. General formula (In the formula, [formula] represents a trans isoprene unit,
[Formula] represents a cis isoprene unit, and n represents an integer from 11 to 19. ) dihydropolyprenylnitrile.