JPH0139414B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to polyprenylketocarboxylic acid esters. More specifically, the invention relates to the general formula (In the formula, [Formula] represents a trans-type isoprene unit, [Formula] represents a cis-type isoprene unit, n represents an integer from 11 to 19, and R represents a lower alkyl group.) Relating to prenylketocarboxylic acid esters. The polyprenylketocarboxylic acid ester represented by the general formula () provided by the present invention can be used as a pharmaceutical,
It is a useful substance as a raw material for 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-type isoprene unit, and [Formula] represents a cis-type isoprene unit. The same shall apply hereinafter in this specification. ] is a mixture of polyprenol analogues having the structure shown in formula (A), where j representing the number of cis isoprene units is generally distributed from 12 to 18, and 3 where j = 14, 15 and 16. It was revealed that species congeners are the main species [RW Keenan et 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, J.B.
Harford et al. used the white medulla of calves and pigs.
Vitro tests have revealed that exogenous dolichol promotes the incorporation of sugar components such as mannose into lipids, and as a result, has the effect of increasing the formation of glycoproteins, which are important for sustaining 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. In addition, RWKeenan and colleagues state that it is important for organisms that are rapidly growing, such as during childhood, to ingest dolichol from outside and supplement the dolichol that is biosynthesized within the body. [Archives of Biochemistry and Biophysics,
179, 634 (1977)]. Furthermore, Akamatsu et al. quantified dolichol phosphate ester in the regenerated liver of rats and found that the amount was significantly reduced compared to that in the normal liver, indicating that the glycoprotein synthesis function in the liver tissue was greatly reduced. We found that the function was improved by externally adding dolichol phosphate [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)]. It is extremely difficult to completely synthesize dolichols using current organic synthesis techniques, as evidenced by 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 white birch (Betula verrucosa); It is almost impossible to synthesize dolichols mainly containing 14, 15, and 16 molecules using current organic synthesis technology. 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 _C90 polyprenols with an average number of 18 isoprene units or cis isoprene units in extracts from leaves of Pinus strobus. However, this report does not provide a detailed analysis of the trans and cis configurations of the polyprenol [see Phytochemistry, 11 , 3387 (1972)]. 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 polyprenylketocarboxylic acid ester represented by the general formula (), which is useful as an intermediate in the following. According to the invention, the 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 is as defined above.) Acetoacetate [hereinafter referred to as acetoacetate ()]. ] By reacting with polyprenylketocarboxylic acid ester represented by the general formula () [hereinafter referred to as polyprenylketocarboxylic acid ester (). ] can be obtained. In general formulas () and (), R is preferably a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-
It is an alkyl group having 1 to 4 carbon atoms such as a butyl group, but may also be an alkyl group having 5 to 8 carbon atoms. 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.) A polyprenol represented by the formula 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 is 2 to 100 times (by weight), preferably 5 to 80 times (by weight), and more preferably 10 to 50 times (by weight) to the polyprenyl halide (). . It is preferable to use a sufficiently dried solvent in order to allow the intended reaction to proceed smoothly. In order to carry out this reaction, the presence of a basic compound is essential. 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 anionic reaction 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. In particular, chromatography is conveniently used. Adsorbents that can be used in chromatography include silica gel, alumina, activated carbon, and cellulose. Among these, silica gel is particularly preferably used. As the developing solvent, 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 is suitable. Polyprenylketocarboxylic acid ester (), which can be synthesized as described above, is a new compound that has not been described in any literature, and mammalian dolichols can be synthesized from this compound, for example, by the following reaction route. However, in the above formula, PP − is the formula (In the formula, n is as defined above.), R and R' represent a lower alkyl group, and M represents an alkali metal. The reaction is a saponification reaction of polyprenylketocarboxylic acid ester (), and this reaction is carried out, for example, in a solution in which sodium hydroxide is dissolved in an amount of 1 to 5 times the mole of polyprenylketocarboxylic acid ester () in ethanol. It is carried out by treating polyprenylketocarboxylic acid ester (). The reaction is a decarboxylation reaction, and this reaction is carried out without or after isolation of the polyprenyl ketocarboxylate () obtained in the reaction by treating it with a strong acid such as hydrochloric acid or sulfuric acid. . Polyprenylcarboxylic acid ester () can be obtained by performing a Wittig reaction (reaction) on the polyprenylacetone () obtained by the reaction using a reagent such as [Formula] or [Formula]. After hydrolyzing this polyprenylcarboxylic acid ester (), the α-terminal isoprene unit portion is selectively hydrogenated (reacted) in the presence of a palladium, nickel, or rhodium catalyst, and the resulting α-terminal portion is saturated isoprene. Alcohol (IX), that is, mammalian dolichols, can be synthesized by reducing polyprenylcarboxylic acid () having the unit with, for example, lithium aluminum hydride. 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, ¹⁶ O, ³⁵ Cl, 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) was dried with hot air at about 40°C for 24 hours, and then 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 is added to this oil to dissolve the acetone-soluble components, the resulting mixture is filtered, and the liquid is concentrated.
The obtained oil was heated at 65°C for 2 hours with 400 ml of methanol, 40 ml of water, and 20 g of sodium hydroxide, then the methanol was distilled off, and the residue was extracted with diethyl ether (500 ml), and the ether layer was extracted with about 100 ml. After washing with water 5 times, it was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 24.2 g of an oily substance. 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 oily substance is polyprenol with a purity of 95% or more, and it is processed using a semi-preparative high-performance liquid chromatography column manufactured by Merck & Co., Ltd.
High performance liquid chromatography analysis was performed using LiChrosorbRP18-10 (C ₁₈ type) using a mixed solution of acetone/methanol = 90/10 (volume ratio) as the eluent and a differential refractometer as a detector. The results of determining the area ratio of each peak in the chromatogram were as follows. [Table] [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 (). Field ionization mass spectrometry (FD-) for each component
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. Reference Example 3 Synthesis of polyprenyl chloride Polyprenol of general formula () where n=15
12.4 g and 1.0 ml of pyridine were added to 200 ml of n-hexane, and 1.5 g of thionyl chloride was added dropwise to the resulting solution at room temperature under a nitrogen gas atmosphere, and after the dropwise addition was completed, the mixture was further stirred at room temperature for 2 hours. This reaction mixture was then post-treated in the same manner as in Reference Example 2 to obtain 11.2 g of a pale yellow liquid. When this product was subjected to IR analysis, it was found that the absorption caused by the OH groups of the raw material polyprenol had disappeared. Also
When NMR analysis was performed, the signal attributed to -C H ₂ OH of the raw material polyprenol disappeared.
Signals newly assigned to -C H ₂ Cl (d, δ
= 3.95) appeared. Moreover, m/e=1260 was given by FD-MASS analysis. From the above, the above product has the general formula () where n=15 and X=Cl
was confirmed to be polyprenyl chloride. Polyprenyl chlorides with n other than 15 and polyprenyl chloride mixtures with n arbitrarily analyzed between 11 and 19 were also synthesized by similar operations. Example 1 30 ml of anhydrous tetrahydrofuran in a three-necked flask
and 640 mg 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. After cooling the reaction system to room temperature, polyprenyl bromide synthesized according to Reference Example 2 and having general formula () where n=15 and X=Br 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 resulting 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, 830cm ^{-1 1} H-NMR analysis: δ ^pppm _CCl4 1.21 (3H, t, -
CO ₂ CH 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=C ₂ H ₅ . By similar operation, n in general formula () is
From each polyprenyl bromide having a value other than 15 between 11 and 19, in the corresponding general formula (), R=
C ₂ H ₅ , n is 11, 12, 13, 14, 16, 17, 18 and
Each polyprenylketocarboxylate ethyl compound No. 19 was synthesized. Their yields were approximately the same as those obtained when ethyl polyprenylketocarboxylate with n=15 was synthesized. Further, the characteristic absorption of their infrared absorption spectrum and the characteristic signal of their ¹ H-NMR spectrum coincided with those of the above-mentioned ethyl polyprenylketocarboxylate with n=15 at that position. Example 2 Methyl acetoacetate instead of ethyl acetoacetate
The same operation as in Example 1 was performed except that 1.40 g was used, and 2.26 g of a slightly yellow liquid was obtained. of this
MNR analysis, IR analysis and FD-MASS analysis gave the following results, confirming that this is methyl polyprenylketocarboxylate with the general formula () where n=15 and R= _CH3 . It was done. IR analysis: 1740, 1720, 1660, 830cm ^{-1 1} H-NMR analysis: δ ^ppm _CCl4 3.25 (1H, t,
[Formula]), 3.78 (3H, s, - CO ₂ C H ₃ ) FD-MASS analysis: m/e = 1340 By the same operation, polyprenyl ketones where n is a value other than 15 between 11 and 19 A mixture of methyl carboxylate and polyprenylketocarboxylate in which n is arbitrarily distributed between 11 and 19 could also be synthesized. Example 3 The same operation as in Example 1 was carried out, except that 1.91 g of t-butyl acetoacetate was used instead of ethyl acetoacetate, to obtain 2.28 g of a slightly yellow liquid. of this
MNR analysis, IR analysis and _FD -MASS analysis gave the following results, and this is _a polyprenylketocarboxylic acid t- It was confirmed to be butyl. IR analysis: 1740, 1715, 1660, 830 cm ^{-1 1} H-NMR analysis: δ ^ppm _CCl4 1.50 (9H, s, CO ₂ C ( CH
₃ ) ₃ 3.22 (1H, t, [Formula]) FD-MASS analysis: m/e = 1382 By similar operation, t-butyl polyprenylketocarboxylate where n is a value between 11 and 19 other than 15 It was also possible to synthesize a t-butyl polyprenylketocarboxylate mixture in which n is arbitrarily distributed between 11 and 19. Example 4 General formula () instead of polyprenyl bromide
The same operation as in Example 1 was carried out except that 4.00 g of polyprenyl chloride with n=15 and X=Cl was used, and in the general formula (), n=15 and R=
Ethyl polyprenylketocarboxylate _that is _C2H5
Obtained 2.20g. Reference Example 4 In the general formula () synthesized in Example 1, n=
15, 2.48 g of ethyl polyprenylketocarboxylate with R=C ₂ H ₅ was added to a solution of 0.5 g of sodium hydroxide, 20 ml of ethanol, and 5 ml of water, stirred for 3 hours under reflux conditions, and then heated in a rotary evaporator. The residue was poured into about 20 ml of water, and concentrated hydrochloric acid was added little by little to acidify the solution to a pH of about 2, followed by extraction 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 (using hexane/ethyl acetate = 98/2 (volume ratio) as a developing solution) to obtain 1.98 g of a slightly yellow viscous liquid. 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 From the above analysis results, it was confirmed that this slightly yellow liquid was polyprenylacetone, where n=15 in the above formula (). 40 ml of anhydrous tetrahydrofuran in a three-necked flask
and 220 mg of 50% sodium hydride were added thereto, and a solution of 1.0 g of ethyl diethylphosphonoacetate [formula] dissolved in 10 ml of anhydrous tetrahydrofuran was added dropwise while stirring at room temperature.
After the dropwise addition was completed, stirring was continued for an additional hour at room temperature, and then a solution of 1.92 g of the above polyprenylacetone dissolved in 10 ml of anhydrous tetrahydrofuran was added dropwise at room temperature. 3
Stir for hours. After cooling to room temperature and adding about 1 ml of water, the solvent was distilled off using a rotary evaporator. About 50 ml of water was added to the residue and extracted with hexane. The hexane layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the hexane was distilled off to obtain a yellow liquid. This liquid was subjected to silica gel column chromatography (hexane/ethyl acetate = 98/
2 volume ratio was used as developing solution) and purified to 1.62g.
A colorless liquid was obtained. The following analysis results confirmed that this product was polyprenylcarboxylic acid ethyl having n=15 and R'=C ₂ H ₅ in the formula (). IR analysis: 1715, 1640, 1440, 1385, 1210, 1135,
830, 790cm ^{-1 1} H-NMR analysis: δ ^ppm _CCl4 1.20 (t, 3H), 1.53 (s,
9H), 1.62 (s, 48H), 1.7~2.4 (m,
75H), 4.06 (q, 2H), 5.06 (br, 18H),
5.56 (br, 1H) FD-MASS analysis: m/e = 1352 Then the above polyprenylcarboxylic acid ethyl 1.62
g was added to a solution of 0.3 g of sodium hydroxide, 3 ml of water, and 20 ml of ethanol, stirred under reflux conditions for 5 hours, then most of the ethanol was distilled off using a rotary evaporator, 10 ml of water was added, and diluted with dilute hydrochloric acid. After adjusting the pH to about 5, the mixture was extracted with hexane. The hexane layer was washed with saturated saline, dried over anhydrous magnesium sulfate,
The solvent was distilled off to obtain a yellow liquid. This material was subjected to silica gel column chromatography [hexane/
Using ethyl acetate = 90/10 (volume ratio) as a developing solution], 1.42 g of a colorless liquid was obtained.
This is based on the following analysis results. (In the formula, PP is as defined above.) It was confirmed that it was a polyprenylcarboxylic acid in which n=15. IR analysis: 3600~2900 (WeaK), 2800~2400
(WeaK), 1690, 1660, 1630, 1440,
1375, 830cm ^{-1 1} H-NMR analysis: (δ ^ppm _CCl4 ): 1.53 (s, 9H), 1.62
(s, 48H), 1.7-2.4 (m, 75H), 5.06
(br, 18H) 5.56 (br, 1H), ~11.5 (br,
1H). Next, 1.42 g of this polyprenylcarboxylic acid was selectively hydrogenated by the method shown below. μ,
0.7 mg of μ'-dichlorobis(1,5-cyclooctadiene) rhodium () and 7.3 mg of neomenthyl diphenylphosphine were placed in a pressure bottle, degassed while stirring with a magnetic stirrer, and then replaced with argon. 5 ml of distilled absolute ethanol were added and the resulting yellow solution was stirred for 30 minutes under 3 atmospheres of hydrogen pressure. Apart from this, 1.42g of polyprenylcarboxylic acid and 17mg of sodium methoxide
A solution of was dissolved in 4 ml of absolute ethanol was stirred under an argon atmosphere. The catalyst solution and polyprenylcarboxylic acid solution prepared in this way were passed through an exhaust pipe into an autoclave that had been previously degassed and replaced with argon, and a hydrogen pressure of 2.5 atm was applied to carry out a hydrogenation reaction at room temperature for 24 hours. Summer. The solution after the reaction was concentrated using a rotary evaporator, diluted hydrochloric acid was added to the residue, extracted with hexane, dried over magnesium sulfate, and the solvent was distilled off to obtain 1.40 g of a yellow liquid. This was subjected to silica gel column chromatography [hexane/ethyl acetate = 90:10 (volume ratio)]
was used as a developing solution] to obtain 1.25 g of a colorless viscous liquid. This product was confirmed to be dihydropolyprenylcarboxylic acid, where n=15 in the formula (), based on the following analysis results. IR analysis: 3600-2900 (Weak), 2800-2400
(Weak), 1705, 1660, 1440, 1375, 830
cm ^{-1 1} H-NMR analysis: (δ ^ppm _CCl4 ): 1.53 (s, 9H), 1.62
(s.48H), 1.7-2.5 (m, 76H), 5.06 (br,
18H), ~10.0 (br, 1H) [δ5.56 (br, 1H) present in the raw material unsaturated polyprenyl carboxylic acid disappears] FD-MASS analysis; m/e = 1328 Anhydrous tetrahydrofuran in a three-necked flask 10ml
After adding 100 mg of lithium aluminum hydride and cooling to 0°C under nitrogen atmosphere, 1.20 g of the above dihydropolyprenylcarboxylic acid was added with 55 g of anhydrous tetrahydrofuran.
ml solution was added dropwise while stirring. After the dropwise addition was completed, the mixture was stirred at 0° C. for 1 hour and at room temperature for an additional 5 hours, and then poured little by little into diluted hydrochloric acid and thoroughly stirred. Hexane was added to separate the layers, and the aqueous layer was further extracted twice with hexane. The organic layers were combined, washed with water, sodium bicarbonate, and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 1.12 g of an anhydrous liquid. This product was purified by silica gel column chromatography (using hexane/ethyl acetate = 90:10 (volume ratio) as a developing solution) to obtain 1.04 g of a colorless liquid. This product was confirmed to be dolichol, where n=15 in the formula () above, based on the following analysis results. IR analysis: 3320, 2920, 2850, 1440, 1376, 1060,
830cm ^{-1 1} H-NMR analysis (δ ^ppm _CCl4 ): 1.91 (d, 3H), 1.60
(s, 9H), 1.68 (s, 48H), 1.10~1.80
(m, 5H), 2.03 (b, 70H), 3.66 (m,
2H), 5.10 (b, 18H) ¹³ C-NMR (ppm/intensity): 16.006/640,
17.679/353, 19.557/548, 23.430/6330,
25.308/567, 25.677/542, 26.436/5166,
26.699/548, 26.825/492, 29.316/528,
32.021/456, 32.245/5500, 37.548/582,
39.757/683, 40.029/541, 61.241/551,
124.214/445, 124.282/463, 124.448/
505, 124.993/499, 125.071/5242,
131.210/213, 134.937/290, 135.005/
349, 135.229/3567, 135.365/430. FD-MASS analysis: m/e=1312

Claims (1)

[Claims] 1. General formula (In the formula, [Formula] represents a trans-type isoprene unit, [Formula] represents a cis-type isoprene unit, n represents an integer from 11 to 19, and R represents a lower alkyl group.) Carboxylic acid ester.