JPH0320233A - Polyprenyl composition and its production - Google Patents

Abstract

PURPOSE:To obtain the subject composition extremely suitable as a synthetic intermediate for mammal dolichols by extracting leaves of ginkgo or cedar with lipophilic organic solvent and separating the resultant extract by chromatography, etc. CONSTITUTION:Leaves of ginkgo or ceder are extracted with a lipophilic organic solvent and the extract is optionally hydrolyzed and then subjected to separation process comprising chromatography, fractional dissolution, fractional freeze-precipitation, molecular distillation or their combination to obtain the objective polyprenyl composition composed of a mixture of plural kinds of the compounds of formula I (A1 is OH or acetyloxy; group of formula II is trans-unit; group of formula III is cis-unit; (n) is 11-19) and containing >=70wt.% (in total) of the compounds of (n)=14, (n)=15 and (n)=16 as essential components. Preferably, the contents of the compounds of (n)=14, (n)=15 and (n)=16 are 20-35wt.%, 30-50wt.% and 10-25wt.%, respectively.

Description

[Detailed description of the invention]

The present invention relates to a novel polyprenyl composition or compound,
For more information, please refer to Ginkgo biloba (Ginkgobilo)
ba) or Himalayan cedar (Cedrus deodara)
), novel polyprenyl compounds derived from the polyprenyl analogs, methods for producing these polyprenyl compounds or compounds, and mammals. The present invention relates to the use of such compositions or compounds in the synthesis of dolichols. Dolichols were published in 1960 by J. F. Pennoc
[N
ature (London), 186, 470 (19
60)], and later they described the dolichols using the following general formula {CH! C-C CH*X-CHt-CH C
H* CHx OHJ ---------- (A) CH. 1 In the formula, one CHt C- C CH! 1 represents a trans-isodiH prene unit, -Cl, -C-C-C
I! - represents a cis isoprene unit; the same applies hereinafter. A mixture of polyprenol analogues having the structure represented by It was revealed that [R. W. Keenan etal, Bioch
chemical Journal, 1 6 5 + 4
05 (1977)]. Furthermore, dolichols are widely distributed not only in the liver of pigs but also in the bodies of chewing mammals, and are known to play extremely important functions in maintaining the life of living organisms. For example, J. B. Harfor
d et al. In vitro tests using the white medulla of cows and pigs have shown that exogenous dolichol promotes the incorporation of carbohydrates such as mannose into lipids, and as a result, the formation of glycoproteins, which are important for sustaining the life of living organisms, is increased. [Biochemical
al and BiophysicalResearch
h Communication 7 6 + 1
0 3 6 (1 977)]. The effect of dolichols on promoting the incorporation of sugars into lipids is more pronounced in already mature animals than in growing organisms, and the role of dolichols in preventing aging is attracting attention. Also, R. L Keenan
[Archives of Bioche+mist
ry and Biophysics,! 7 9.
6 3 4 (see 1 9 7 7)]. Akamatsu et al. quantified dolichol in the regenerated liver of mice and found that the amount was significantly reduced compared to the normal amount in the liver, indicating that the synthesis and function of glycoproteins in the liver tissue was greatly reduced and that external factors were involved. It was discovered that the function was improved by adding sex dolichols (presented at the 1981 annual meeting of the Japanese Biochemical Society). As described above, dolichols are extremely important substances for living organisms, and there is a strong desire to develop applications for them in pharmaceuticals, their derivatives, cosmetics, and the like. However, the reality is that it has not been possible to conduct sufficient research on Dolichols because they are difficult to obtain. For example, only about 0.6 g of dolichol can be obtained from 10 kg of pig liver after a complicated separation procedure [J. Burgos et al. Bioche
mical Journal, 8 8 e 4 7
0 (1963)]. On the other hand, it is extremely difficult to completely synthesize dolichols using current synthetic organic chemistry techniques, as evidenced by their complex and unique molecular structures. Therefore, it would be advantageous if dolichols could be obtained by relying on natural products and applying simple synthetic chemical treatments, but such convenient substances have not been found so far. Not served. It has been known that polyprenol compounds can be collected from various plants, and the following polyprenols have been collected. (1) Soranenol (2) Aicaprenol (3) Betulaprenol Betulaprenol is the same as Dolichol. -It has a structure in which two trans isoprene units are connected to a terminal isoprene unit, and this is followed by a cis-type inprene unit, but the betulaprenols known so far have a number of cis-type isoprene units as described above. There are only six isoprene units at most, and in order to control dolichols, which mainly have 14, 15, and 16 cis-isoprene units, eight or more isoprene units must be restricted to cis-type. Extension is necessary, which is almost impossible with current organic synthesis technology. Also, recently, K. Hannus et al. isolated a polyisoprenyl fraction of approximately 1% dry weight from the leaves of Pinus sylvestris, and found that the seven fractions were predominantly cis-10-19.
reported that it consists of polyisogrenyl acetate with isoprene units. However, the main components of the pinoprenol 7-lactone are homologues with 15 and 16 isoprene units, and homologs with 19 isoprene units of 17, 18 and 19, which are the main components of mammalian dolichols. The body contains only trace amounts [Phyt
ochemistry, 13.2563 (1974)
Reference] o K. Although the trans and cis configurations in the above pinoprenol analogues are not elucidated in detail in the literature of Hannus et al., if the binoprenol analogues are
Even if the fraction has the same trans and cis configuration as the mammalian dolichols, in order to derive the mammalian dolichols from it, at least two isoprene units must be regulated and elongated in the cis form, and then roughly a It is clear that a saturated isoprene unit must be bonded to one end, which poses great difficulties in assembly. Furthermore, D. F. Zinkal et al.
C, . reported the presence of polyprenols [Phytochsmist
ry, soil yu. 3387 (1972)]. but,
The analysis they are conducting is extremely crude due to the NMR, and according to the results of a follow-up test by the present inventors, the polyprenol 7-lactate extracted from Stroop pine needles contains 17 isogrene units. It was found that the homologue with Therefore, in order to synthesize mammalian dolichols from the polyprenyl fraction isolated from the needles of pine strobes, it is necessary to synthesize mammalian dolichols if the polyprenyl fraction has the same trans and cis configuration as mammalian dolichols. Even if it were, it would still be necessary to introduce at least one isoprene unit while controlling it to be in the cis form, which would still pose great difficulties in synthesis. Therefore, the present inventors have the same number of isoprene units and trans and cis configurations as mammalian dolichols, and therefore carried out a difficult operation in organic synthesis to introduce isoprene units while keeping them regulated in the cis configuration. As a result of analyzing extracts from various plants in search of plant sources for polyprenyl compounds that are not needed, we surprisingly found that polyprenyl fractions extracted from ginkgo biloba and Malayan cedar (
or composites) show a distribution of polyprenyl homologues that is very similar to that in mammalian dolichols, except that the saturated isoprene unit at the a-terminus is absent compared to mammalian dolichols. That, therefore,
It has been found that it is very suitable as an intermediate for the synthesis of mammalian dolichols. Thus, according to one aspect of the invention, the general formula CH3C=CH-CH! {CH! -C-C CJ
Te'1 H −+CHz-C=C-CHD-1A, (
1) n In the formula, AI is a hydroxyl group or acetyl group. Represents a butyoxy group, i-CH, -C-C-CI
, 1 represents a trans { H trans-type isoprene unit; C H CHz - C- C- Cut represents a cis-type inprene unit; n is an integer from 11 to 19; and n is l4; A compound of formula (I), where n is 15
and at least three compounds of formula (I) where n is 16 in substantial amounts, and the total content of these three compounds is such that the mixture contains A novel polyprenyl composition (fraction) is provided, characterized in that it is at least 70% by weight. According to another aspect of the invention, the novel polyprenyl composition (or fraction) is composed of Ginkgo biloba (Ginko biloba).
kgo biloba) or Himalayan cedar (Cedrus)
Deodara) leaves are extracted with an oil-soluble organic solvent, and the resulting extract is hydrolyzed if necessary, and then subjected to chromatography, fractional dissolution, fractional cryoprecipitation, molecular distillation, or any of these methods. For separation methods consisting of two or more combinations, Merck TLC
plate silicagel 5QF z@n
Thin layer chromatography (1001
1 development), the Rf value of solanesyl acetate as a standard substance is 0.40 to 0.45.
It can be produced by a method characterized by isolating and collecting a fraction exhibiting an Rf value within the range of 8 to 0.25 and/or 0.50 to 0.55. Hereinafter, the polyprenyl composition of the present invention and the method for producing the same will be explained in more detail. The ginkgo biloba used as a raw material for the extraction of the polyprenyl composition of the present invention is a plant belonging to the order Ginkgoda of the phylum Gymnosperms, subphylum Gymnosperms, which is mainly distributed in East Asia, especially Japan, China, and Korea. are plants that belong to the order Conifera, subfamily Gymnosperma, subfamily Conifera, which is widely distributed in temperate and cold regions, and the leaves of these plants are used as raw materials in the present invention. Ginkgo biloba or Himalayan cedar leaves that can be used as raw materials may be from young green leaves to completely yellow leaves, or leaves at any stage after defoliation, and these leaves may be subjected to the treatment according to the present invention after drying. It may be applied or used undried. However, dried leaves are generally preferred, and the degree of drying is advantageously such that the moisture content is generally less than about 30%, preferably less than 10%, based on the weight of the dry leaves. Furthermore, it is preferable to extract the leaves after crushing them, thereby increasing the contact area with the extraction solvent and increasing the extraction efficiency. The polyprenyl analog represented by the formula (I) is generally contained in leaves of ginkgo or Himalayan cedar in a fairly high concentration in the form of free alcohol and/or acetate ester, and the polyprenyl analog can be extracted from the leaves. In order to effectively extract the polyprenyl analogue, an oil-soluble organic solvent that well dissolves the polyprenyl analogue is preferably used. Such oil-soluble organic solvents generally have a dielectric constant (ε
) is 32.7 or less, preferably 25.0 or less, more preferably 20.7 or less. Specifically, the following solvents may be used alone or in a mixture of two or more. (a) Hydrocarbons: for example petroleum ether, pentane, hexane, heptane, benzene, toluene, xylene, etc. (b) Halogenated hydrocarbons: For example, chloroform, methylene chloride, carbon tetrachloride, ethane tetrachloride, verchlorethylene, trichlorethylene, etc. (C) Esters: For example, methyl acetate, ethyl acetate, ethyl propionate, etc. (d) Ethers: For example, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc. (e) Ketones: For example, acetone, methyl ethyl ketone, diethyl ketone, diimpropyl ketone, etc. Cf) Alcohols: For example, methyl alcohol, ethyl alcohol, proyl alcohol, butyl alcohol, etc. When selecting the solvent to be used, the desired formula (
Selectively extracting the polyprenyl compound of I) with high efficiency,
It is desirable that other substances are not extracted as much as possible, and from this point of view, in the above solvent, hydrocarbons, halogenated hydrocarbons, esters, diethyl ether,
Particularly preferred are less polar ethers and ketones such as diisopropyl ether. The amount of extraction solvent used is not critical and can be varied widely depending on the type of solvent used, the type and condition of the leaves to be extracted, etc., but in general, the amount of ginkgo or Himalayan cedar sugar (dry about 1 to about 100 parts by weight, preferably 5 to 50 parts by weight, more preferably 1O
It is advantageous to use within the range 30 parts by weight. Extraction can be carried out by immersing the leaves in the above solvent and stirring continuously or intermittently as necessary. The temperature during extraction is also not critical and can be varied over a wide range depending on conditions such as the type and amount of solvent used.
Generally, temperatures from about 0° C. to the reflux temperature of the solvent can be used, and room temperature is usually sufficient. It is advantageous to carry out the extraction under such conditions, usually for 1 to 10 days. The immersion liquid after the extraction process is made into a concentrated liquid by removing the leaves and other solids and then removing the solvent as necessary. The extract thus obtained is then subjected to a separation step consisting of a chromatography method, a fractional dissolution method, a fractional cryoprecipitation method, a molecular distillation method, or a combination of any two or more of these methods, Target polyprenyl 7
ration can be collected. Confirmation of the fraction containing the polyprenyl compound in the above separation step is carried out using TLC p manufactured by Merck & Co.
late Silicage1 6 0 F *sa
precoated. Using a layer thickness of 0.25+am and n
- Thin layer chromatography using a mixed solvent of hexane and ethyl acetate at a volume ratio of 9:1 as the developing solvent.
development), the Rl value of solanesyl acetate as a standard substance is 0.40 to 0.45.
8 to 0.25 (when A1 represents a hydroxyl group in the above formula (I)) and/or 0.50 to 0.55 (when A1 represents an acetyloxy group in the above formula (1)). This can be done based on whether or not a spot exists at the Rf value. Therefore, when referring to the Ri value of thin layer chromatography 7E in the following explanation, unless otherwise specified,
It should be understood that values measured under the above conditions are meant. The operations of the chromatography method, fractional dissolution method, fractional cryoprecipitation method, and molecular distillation method that can be used in the above extract separation step are known per se, and the present invention also uses known methods. It can be done according to
Details of each method will be explained with reference to literature, and only points to be particularly noted will be described here. (A) Chromatography method [H. Heftma
n“Chromatography”Reinhold
Publish Co. , New York (1
9 6 1) Reference 1 Thin layer chromatography and liquid chromatography are suitable when the amount of extract is small, but column chromatography is suitable when processing a large amount of extract. be. Examples of carriers for chromatography that can be used include silica gel, alumina, florisil, celite, activated carbon, and cellulose, with silica gel being preferred. Examples of developing solvents when performing a separation operation using a silica gel ram include hexane/ethyl acetate (volume ratio 95:5 to 80:20), hexane/isopropyl ether (volume ratio 95:5 to 80: 20), petroleum ether/methyl acetate (volume ratio 95:5-80:20), petroleum ether/isopropyl alcohol (volume ratio 99:l-9
0:1O), benzene/ethyl ether (volume ratio 95:
5-80:20), benzene/ethyl acetate (volume ratio 98
:2 to 80:20) or chloroform. CB) Fractional dissolution method [L. C. Craig″Te
chn iqueof Organic Chemis
try” Vol. 3. Interscie
nce, (1951)] The polyprenyl compound of the formula (I) is easily soluble in non-polar solvents such as pentane and hexane, but poorly soluble in polar solvents such as methanol and water. It can be purified by a fractional dissolution method using the difference in sex, for example, by dissolving a crude product such as an extract concentrate in the above non-polar solvent,
Next, by washing with a polar solvent that is immiscible with the non-polar solvent, impurities that are easily soluble in the polar solvent can be largely removed. Examples of non-polar solvents suitably used in this method include hydrocarbon solvents such as petroleum ether, pentane, hexane, heptane, petroleum benzyl, benzene, and toluene, and halogenated hydrocarbon solvents such as methylene chloride and chloroform. is suitable. Further, as a polar solvent immiscible with such a non-polar solvent, water or methanol is suitable, for example. (C) Fractional cryoprecipitation method [E. W. Berg”Ph
ysicaland Chemical Method
ds of Separation"Chapter1
4. 15, McGravHill, N. Y
．． (1963)] The polyprenyl compound of formula (I) solidifies at about 10° C. or less. Therefore, the extract is allowed to cool to below -10°C, preferably from about -15 to about -30°C, and after solidifying the target product, impurities that do not solidify at such temperatures are purified by solid-liquid separation. be able to. however,
The polyprenyl compound does not have very good crystallinity,
Since it becomes a waxy solid, it is difficult to completely purify it by this method, so it is preferable to perform it in combination with other purification methods. (D) Molecular distillation method (G. Durrows, “Mo.
regular Distillation” Clar
Endon Press, Oxford (19
60)] Since the compound of formula (I) has a large molecular weight, low molecular weight impurities can be removed by using a molecular distillation method. For example, 10-"~10-'omHg
Molecular distillation is carried out under heating conditions of 100 to 250° C. in a vacuum degree of 100° C., and the fraction is divided into a low molecular fraction and a high molecular fraction. At this time, the target substance is retained in the high molecular fraction, and low molecular weight impurities can be largely removed. If a sufficiently pure polyprenyl fraction cannot be obtained by each of the above separation methods, a combination of two or more of these separation methods can also be used. For example, chromatography method and fractional dissolution method: chromatography method and fractional cryoprecipitation method and fractional dissolution method; chromatography method and fractional cryoprecipitation method and fractional dissolution method and molecular distillation method; chromatography method and molecular distillation method Combinations such as chromatography method and molecular distillation method; molecular distillation method and fractional dissolution method; molecular distillation method, fractional dissolution method, and fractional cryoprecipitation method can be used. Thus, the Rf value in thin layer chromatography is 0.
．． 18-0.25 and/or 0.50-0.55 fractions are isolated and collected. Rf value is 0. l8~0.2
The 7 fraction of 5 consists essentially of a mixture of homologues when A, in the formula (I) represents a hydroxyl group, while the fraction with Rf values of 0.50 to 0.55 consists of the fraction of the formula (I) A.I) represents an acetyloxy group, consisting essentially of a mixture of homologs. The 7 fractions thus obtained can be further subjected to, for example, partition-type high performance liquid chromatography to isolate individual homolog fractions. In the above separation step, before the extract is subjected to the above separation operation, the extract is hydrolyzed to remove A. represents an acetyloxy group, the corresponding A. It is possible to convert beforehand into homologs in which represents a hydroxyl group. This may simplify the subsequent separation operation. However, such hydrolysis is of course limited to R after the separation operation.
It is also possible to perform this on a fraction containing a fraction with an i value of 0.50 to 0.55. This hydrolysis can be carried out using any conventional method known for hydrolyzing fatty acid esters, such as sodium hydroxide or hydroxide in hydrous methanol or ethanol. About 5 to 50 parts by weight of the above extract or fraction per 100 parts by weight of a solution in which potassium is dissolved (the alkali metal hydroxide concentration can preferably be about 0.1 to 30% by weight). in addition to approximately 2
What is necessary is just to make it react at 5-90 degreeC for about 0.5-5 hours. Polyprenyl isolated and recovered by the method described above.
In the fraction, the fraction with R [value of 0.18 to 0.25 is A. represents a hydroxyl group and consists essentially of a mixture of a plurality of polyprenol congeners where
5 is the A.7 ratio in the above formula (1). represents an acetyloxy group, consisting essentially of a mixture of a plurality of polyprenylacetate analogues. The ratio of the former to the latter in the extract is approximately 1:20 to 1.
:5, and the distribution state (pattern) of polyglenol or polyprenylacetate homologues in each fraction is roughly the same, and the distribution state (pattern) is within the range of the type of plant used as the raw material (Ginkgo biloba or Himalayan cedar), it remains almost constant regardless of factors such as the youth of the leaves, the time of collection, and the region. The fractions thus generally include compounds of formula (I) where n is 14 (hereinafter referred to as polyprene-14), compounds of formula (I) where n is 15 (hereinafter referred to as polyprene-15) and n is 16. The fraction contains at least three compounds of formula (I) (hereinafter referred to as polyprene-16) in substantial amounts, and the total content of these three compounds is at least 70% based on the weight of the fraction. % by weight, preferably at least 75% by weight. Generally, the fraction contains a maximum content of polyprene-15, usually from 30 to 50% by weight, more typically 32% by weight, based on the weight of the fraction.
~47% by weight. Additionally, the fraction is generally polyprene-14;
! Riprene-15 and polyprene-16t - They are contained in a unique quantitative relationship, and when their respective contents are expressed as a%b and C weight%, the quantitative relationship is usually b) a) c. . Furthermore, the 7-raction generally converts voriprene=14 into 2
0 to 35% by weight, more typically 23 to 32% by weight, and polyprene-16 generally at a content of 10 to 25%, more typically 11 to 20% by weight (based on the weight of said 7 lacs). Contains. As mentioned above, the polyprenyl composition (or fraction) provided by the present invention has a distribution pattern of mammalian dolichols and polyprenol congeners, that is, n in the above formula (!) and the above formula (A). It is distinctive in that the distribution pattern of j in is extremely similar, and the distribution state can be compared to the Petat-Dolichol distribution pattern 1! (Human dolichol also shows almost the same distribution as pig dolichol) The comparison is as follows. The numbers in brackets indicate more typical ranges. Table 1 Values of n in formula (I) and j in formula (A) Content (wt%) Polyprenyl composition of the present invention 0-3 (0-2) 0.1-6 (0.1- 6) 4-17 (5-14) 20-35 (23-32) 30-50 (32-47) 1O-25 (11-20) 2-1O (2-6) 0.1-5 (0. 1-2) 0'-3 (0-1.5) 0.43 0.60 4.38 25.59 46.01 18.79 3.4l O. 72 0.06 The polyprenyl compositions provided by the present invention are shown in Table 1 above.
It does not substantially contain any constituents other than the polyprenyl analog of formula CI), and the average value of n in the composition is usually within the range of 14.25 to 15.25. As is clear from the distribution state of polyprenyl homologs shown in Table 1 above and the comparison between formula (1) and formula (A), the polyprenyl composition provided by the present invention has a By bonding one saturated isoprene unit to the C-terminus of a polyprenyl compound, mammalian dolichol can be derived. In particular, there is no problem with the cis or trans configuration of the saturated imprene units to be bonded, and there is no difficulty in the reaction operation when bonding the saturated imprene units. Therefore, it can be said that the polyprenyl composition provided by the present invention is an extremely important substance as an intermediate for synthesis of mammalian dolichol. When the polyprenyl composition according to the present invention is induced into mammalian dolichol, the composition may be used as it is, or, if necessary, after isolation of each polyprenyl compound constituting the composition. It can also be reacted. Therefore, in the following description, the reaction will be explained as a reaction to the polyprenyl compound of formula (I), but it is of course understood that the polyprenyl compound can be directly replaced with a polyprenyl composition having the above-mentioned distribution pattern. Should. When deriving the polyprenyl compound of formula (1) to dolichol of formula (A), the compound of formula (I) may be used as is or A1 in formula (1) may be substituted with another highly reactive leaving atom or group. Thereafter, it can be reacted with a saturated isoprene unit introduction reagent. Thus, according to yet another aspect of the invention, the general formula CHs C=CH CH*-{-CHz-C-C-
A polyprenyl compound represented by CH*TE'IH is reacted with a compound represented by the general formula CHI 8 Y-CH, -CH-CH, -Z (IV) to form the following formula CHs C-CH CHzfcHt-C-C- ct
t, ter direct H In the above formulas (III) to (V), X represents a leaving atom or group; Y represents MgHaI or a lithium atom, where Hal is a halogen atom; 2 is a formula - c.
Represents a uton group or its functional precursor group; CH, spring-CH! -Cow- represents the unit of trans isoprene; 1Cut-C-CCut-
represents a cis isoprene unit; n represents an integer from 11 to 19, and when 2 represents a functional precursor group, the group is then optionally converted to -CH,OR
Provided is a method for producing the mammalian dolichol of formula (V) or its precursor, which is characterized by changing the formula (V) to In the above formula (III), the leaving atom or group X includes a hydroxyl group and an acetyloxy group, as well as the bonding of Any atom or thick group having the property of causing a substitution reaction with the carbon to which Y was bonded on the carbon to which Y was bonded can be mentioned, and the following groups are preferable, namely, halogen atoms and formula 10C.
OR r, -OR,, - OPO(OR*)*, -
selected from the groups SORs, -SOJi, OCOORs, R, -S'''R3 ・Hal, where R
, is a hydrogen atom, a methyl group substituted with 1 to 3 fluorine or chlorine atoms, an alkyl or alkenyl group having 2 to 18 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an aryl group having 7 to 10 carbon atoms. represents N1 aralkyl groups,
Rt is a lower alkyl group, a lower alkenyl group, an aryl group having 6 to 10 carbon atoms, a pyridyl group, a thiazolyl group,
represents a thiazolinyl group or an oxazolyl group, R represents a lower alkyl group, an aryl group having 6 to 10 carbon atoms, or an aralkyl group having 7 to 11 carbon atoms, Q represents oxygen or a sulfur atom, and Hal represents It is a halogen atom. As used herein, the term "lower" means that the group or compound to which this term is attached contains up to 8 carbon atoms, preferably up to 4 carbon atoms. In the above definition, "methyl group substituted with 1 to 3 fluorine or chlorine atoms" includes -CHJ, -CHF
*, -CF,, -CHICI, -CHCI! and -C.C.
h, among others -CH, F, -CF, and -C
H. CI is preferred. Further, the alkyl group and alkenyl group may be linear, branched or cyclic, and examples of the alkyl group include methyl, ethyl, n-probyl, inglovir, n-butyl, sec- Butyl, isobutyl, tert-butyl, n-bentyl, isoamyl,
Examples include n-hexyl, n-octyl, n-decyl, n-dodecyl, n-undecyl, stearyl, cyclopentyl, cyclohexyl, cycloheptyl, and alkenyl groups include, for example, 3-butenyl, 3-pentenyl, 4-pentenyl. , geranyl, farnesyl, oleyl, and the like. Therefore, particularly preferred among the "alkyl or alkenyl groups having 2 to 18 carbon atoms" represented by % Rl are alkyl groups having 2 to 6 carbon atoms and alkenyl groups having 4 to 6 carbon atoms. , and a "lower alkyl group" represented by R1 and R,
As the "lower alkenyl group", methyl, ethyl, n-propyl, i-propyl, butyl, vinyl, and 3-butenyl are particularly preferred. On the other hand, "aryl groups having 6 to 10 carbon atoms" include phenyl groups and 7-enyl groups in which the benzene nucleus is substituted with 1 to 3 lower alkyl groups, such as tolyl, xylyl groups, and naphthyl groups. ``Number of carbon atoms 7~
Examples of the "11 aralkyl group" include lower alkyl groups substituted with substituted or unsubstituted 7-enyl groups, such as penzyl, phenethyl, methylbenzyl, dimethylbenzyl, σ- or β-naphthylmethyl, and the like. In addition to the hydroxyl group and the acetyloxy group, preferred specific examples of the leaving atom or group represented by X in the formula (III) include the following. (a) Halogen atoms, such as chlorine, bromine or iodine atoms. Cb) Formula -OCOR. groups, such as formyl group, heptano7-fluoroacetyloxy group, trifluoroacetyloxy group, monochloroacetyloxy group, propionyloxy group, butyryloxy group, stearoyloxy group, penzoyloxy group, 3,5-dimethylbenzoyloxy group , 4-ethylbenzoyloxy group, etc. (C) Formula -OR. groups, such as methoxy group, ethoxy group, phenoxy group, 2-biridyloxy group, 2-penzothiazolyloxy group, 2-benzoxazolinoleoxy group, trimethynoresilyloxy group, dimethyl-t -butylsilyloxy group, methylthio group, ethylthio group, 7
enylthio group, tolylthio group, 2-thiazolinylthio group, 2-penzothiazolylthio group, 2-penzoxazolylthio group, 2-biridylthio group, etc. (d) Formula -OPO(OR s )! groups, such as dimethylphosphonooxy group, diethylphosphonooxy group, diphenylphosphonooxy group, etc. (e) a group of the formula -SOR, such as a methylsul7ynyl group, an ethylsul7ynyl group, a clobylsulfinyl group,
phenylsulfinyl group, 4-tolylsulfynyl group, etc. Cf) Formula-So,R. groups, such as methylsulfonyl, ethylsulfonyl, probylsulfonyl, 7enylsulfonyl, 4-tolylsulfonyl, and the like. (g) a group of the formula -OCO,R'', such as a methoxycarbonyloxy group, an ethoxyluponyloxy group, a propoxycarbonyloxy group, a phenoxycarbonyloxy group, a 4-triloxycarbonyloxy group, etc.; a lucanorebamoinoleoxy group; , N,N-diethyl-rubamoyloxy group, N,N-dibrobylcarbamoyloxy group, N,N-diphenyl-rubamoyloxy group%N-
7enyl-N-ethyl group, rubamoyloxy group, etc. Ammonium bromide group, triethylammonium iodide group, diphenylethylammonium bromide group, etc. Sulfonium bromide group, diethylsulfonium iodide group, dipropylsulfonium bromide group, 7enylethylsulfonium bromide group, etc. When the compound of the above formula (III) is used in isolated form, one in which n is 15 is particularly suitable. On the other hand, in the compound of formula (rV) which is reacted with the compound of formula (III), 2 represents a group of formula 100, OH or a functional precursor group thereof; Includes hydroxymethyl and aldehyde groups protected with protecting groups that can be easily removed by treatments such as decomposition or hydrogenolysis; the latter aldehyde group, after deprotection,
It can be converted to a hydroxymethyl group under mild reducing conditions, such as reduction with complex metal hydride reducing agents such as sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium aluminum hydride, and the like. Specific examples of such functional precursor groups include the following. (1) Formula -CH,O-R. In the group formula, R4 is a lower alkyl group, an aralkyl group having 7 to 11 carbon atoms, an aliphatic or alicyclic ether residue having 1 to 8 carbon atoms, or R@r, RsR and R. each represents a lower alkyl group, 7-enyl, tolyl or xylyl group. Examples include -CH,OCR3, -CH20C,H,, -
CHOOC. H,,-CI! QC,H,,-CH,
O.C. H. ．． , -CH,OCH. OCH3, CHx
OCHxOC*Hs, CH*OC*HaOCHn, -C
H20C. H, oC, Its, -CH*OCsHsOC
Hs, -CHzOCsHsOCJs, -CH,QC!
H, QC, H40CH3, CH 3 0CH! Q
C z H 4 0CH s, OCR, represents a lower alkylene group. For example, OCR, CHzOSi(CHs)i, CHzOSiCHs(
CJiXCs}Iy), CHIOSI(CH3)2C4
H1 Ls CH20Si(t-CJs)(Ca
Hs)z, CH20S1(CsHs)s, etc. In the formula, Qs and Q2 each represent an oxygen or sulfur atom; R. ．． and R. 2 each represents a lower alkyl group, or may be taken together. Most of the compounds of formula (IV) are known, and new ones can be easily produced according to known compounds. The reaction between the compound of formula (I [[) and the compound of formula (IV)] can be carried out by a method known per se. For example, it is generally desirable to carry out the reaction in an inert organic solvent. As the solvent used, ether solvents such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, dimethoxyethane, and diethylene glycol dimethyl ether are mainly used. It is also possible to partially blend hydrocarbons such as hexane and bezene, hexamethylphosphoramide, etc. into this and use it as a mixed solvent. Among these, a particularly preferred solvent is tetrahydrofuran. Furthermore, the ratio of 1:1 of the compound of formula 1) to the compound of formula (III) is not critical and can be varied widely depending on the type of compound of formula (III) and/or formula (IV) used. However, in general, the compound of formula (IV) can be used in the range of 0.5 to 10 mol, preferably 1 to 6 mol, more preferably 1.5 to 4 mol, per mol of compound of formula (III). It is preferable to use The reaction can be carried out in the absence or presence of a catalyst. If no catalyst is used, the reaction is generally carried out between about 0°C and the reflux temperature of the reaction mixture, preferably between about 0°C and about 80°C.
Advantageously, it is carried out at temperatures between
), in particular, X is a halogen atom, OP
Preference is given to using compounds of the formula (II[) in which O(ORs)x represents an oxazolyloxy or biridyloxy group, in which R is as defined above. On the other hand, when carrying out the reaction in the presence of a catalyst, examples of catalysts that can be used include copper, nickel and palladium catalysts, with copper catalysts specifically including CuCls CuBr
, Cut, CuOAc and other copper CI) compounds; Li.
CuClICuClx1CuBr,, Cult, Cu(
OAc),,Cu(CH s COCHCOCH
s)! Examples of nickel catalysts include copper (I[) compounds such as nickel complexes; NtClt,
NiBrl, Nil. , Ni(NOs)z, Ni(CH
Nickel (II) compounds such as sCOCHCOCHs)t can be used, and as palladium catalysts, for example, palladium complexes; PdCl, Pd(OAc
),, Pd(NOs)g, Pd(CHsCOCHCOC
Palladium (If) compounds such as Hs)x and the like are included. Among these catalysts, when using a compound of formula (IV) in which Y represents MgHa 1 as a starting material, copper (1)
or (II) catalysts are suitable; on the other hand, when using compounds of formula (TV) in which Y represents lithium, copper(I)
Catalysts are preferred. In the former case, the amount of such copper catalyst used is generally 0.001-1.
0 equivalent, preferably 0.001 to 0.1 equivalent, and in the latter case 1 to 1 mole of compound of formula 1).
The proportion can be 5 equivalents, preferably 1.2 to 3 equivalents. a compound of formula (III) and formula (IV) in the presence of the above catalyst;
The reaction temperature when reacting compounds is generally -30℃
A range of ~+30°C, preferably a range of -20'C~+20°C is appropriate, and preferable groups of X in the starting material compound of formula (I[[) include acetyloxy group, -0CORt, - 0COOR,, R, and pyridyloxy groups, where R
．． , R, and Hal are as defined above. In addition, when using a too large amount of catalyst and/or reacting at too high a temperature, the following formula CH s −
C - CH - CHx { CHz C - C
-CI! Terr1H? Since isomers of the compound of the following formula (V) represented by H■-CH-CH2-Z 1 CH, where Z and n are as defined above, may be produced as by-products, such isomers may be It is important to choose conditions that will cause as little damage as possible. In this way, a compound represented by the following formula, in which 2 and n are as defined above, is obtained in good yield. Separation and purification of the present compound from the reaction mixture can be carried out using methods known per se, such as chromatography using silica gel or alumina, fractional dissolution, molecular distillation, and the like. The protective group can be removed from the compound of formula (V) by subjecting the compound to hydrolysis or hydrogenolysis according to a method known per se. For example, Z is the formula 1CH, -0-R. and when R4 represents a lower alkyl group, the formula (
The compound of V) can be deprotected by treatment with trimethyl iodide in a solvent such as tetrahydrofuran, chloroform, methylene chloride, etc. at room temperature,
Further, when R4 in the group of the above formula represents an aralkyl group, a tetrahydro7rane solution of the compound of formula (V) is dropped into a solution of lithium dissolved in ethylamine,
After the reaction is complete, excess lithium can be deprotected by decomposing it with a saturated aqueous ammonium chloride solution, for example.
When R4 in the group of the above formula represents an ether residue, the compound of formula (V) can be used, for example, in hexane/ethanol.

[
After dissolving in a mixed solvent of about 18% (volume ratio), pyridine paratoluenesulfonate (preferably about 0%) is added to the solution.
1 to 0.2 equivalents) and allowed to react at a temperature of about 50 to 60°C for several hours, and after the reaction is complete, deprotection can be carried out by neutralizing the reaction mixture with sodium carbonate or the like.
When R in the group of the above formula represents a silyl group,
Deprotection can be achieved by adding tetra-n-butylammonium fluoride (preferably about 2 equivalents) to a tetrahydrofuran solution of the compound of formula (v) and stirring overnight at room temperature. And Q. and Q do not simultaneously represent a sulfur atom, by treating the compound of formula (V) with, for example, dilute hydrochloric acid (preferably at a concentration of about 10%) in a solvent such as tetrahydrofuran or ingropanol. 2 can be changed to an aldehyde group (-CHO), and
When Q and Q in the group of the above formula simultaneously represent a sulfur atom, an equivalent or more amount of HgC1 and CdCO and a small amount of water are added to a seven-ton solution of the compound of formula (V) and reacted at room temperature for several hours. The group can be converted into an aldehyde group by The aldehyde group thus converted can be reduced under mild reducing conditions using rust metal hydrides such as sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium aluminum hydride, etc. By reducing the hydroxymethyl group-
It can be changed to (CH,OH). The reduction can be carried out according to a method known per se. For example, when sodium borohydride is used, it is preferable to carry out the reduction reaction in a solvent such as alcohol, tetrahydrofuran, ether, etc. at about 0°C to room temperature. In addition, when using lithium borohydride, lithium aluminum hydride or sodium aluminum hydride, about -3
It is advantageous to carry out the reduction reaction at 0° C. to room temperature. After the reduction reaction is completed, the reaction mixture is treated with water, alcohol, ethyl acetate, etc. to decompose the excess reducing agent, and then separated and purified according to a conventional method to obtain the target alcohol [where Z in the formula (V) is A compound representing a hydroxymethyl group] can be obtained in high yield. As mentioned above, the dairy dolichol synthesized as described above is useful as a valuable physiologically active compound in the fields of pharmaceuticals, cosmetics, and the like. In addition, in the compound of the formula (III), when X represents a leaving atom or group other than a hydroxyl group and an acetyloxy group, that is, in the following formula, A is a halogen atom, or the formula OCOR+, QRz, -0PO(ORx)t, -S
OR, represents a ralkyl group, R2 is a lower alkyl group,
Represents a lower alkenyl group, an aryl group having 6 to 10 carbon atoms, a pyridyl group, a thiazolyl group, a thiazolinyl group, or an oxazolyl group, and R is a lower alkyl group, an aryl group having 6 to 10 carbon atoms, or an aryl group having 6 to 10 carbon atoms. represents 7 to 11 aralkyl groups, Q represents an oxygen or sulfur atom, and Hal is a norogen atom,
CI3- CH, - C=
C-CI,- represents a trans-type grave H R, group, where R1 is a hydrogen atom, a methyl group substituted with 1 to 3 heptad atoms or chlorine atoms, a carbon atom number of 2
~18 alkyl or alkenyl group, 6 to 10 carbon atoms aryl group, or 7 to 11 carbon atoms cttz-C2C-CH,- represents a cis isoprene unit; n is l A polyprenyl compound represented by the following, which is an integer from 1 to 19, is a novel compound that has not been described in conventional literature. From the compound of the formula (1), the formula (
The conversion of If) into a compound, that is, the method of changing A in formula (I) to A, is known per se, and can be carried out, for example, as follows. (i) Compounds of formula (II) when A2 represents a halogen atom: A. It can be obtained by halogenating a compound of formula (I) where represents a hydroxyl group with a halogenating agent such as phosphorus trihalide, thionyl halide, etc. The halogenation can be carried out, for example, by dropping the above-mentioned halogenating agent in a solvent such as hexane or diethyl ether in the presence or absence of a base such as pyridine or triethylamine at a temperature of about -20°C to +50°C. This can be done by (2) A, is -OCOR. The formula (II
) Compound of A. It can be produced by esterification or transesterification of a compound of formula (I) where represents a hydroxyl group. For example, esterification may convert the compound of formula (1) to about 1-10
the desired acid anhydride or acid halide (preferably about 1 to 5 equivalents) in the presence of an equivalent of pyridine and about -3000 to +50
This can be carried out by reacting at a temperature of °C. (3) Formula (II
) Compound: The compound of formula (II) produced as described in the above (1), in which A represents a halogen atom, is treated with an alcohol or thiol of the formula R2QH in the presence of a base. It can be obtained by making it act. Furthermore, a compound in which Q represents an oxygen atom can also be synthesized by reacting a halide of the formula RIHal (here, Hal represents a halogen atom) with a compound of formula (I) in which A+ represents a hydroxyl group. be able to. The above reaction is generally carried out by adding the raw material compound to the alcohol or compound described above in a solvent such as dimethylformamide or tetrahydrofuran in the presence of a base such as sodium hydride or n-butyllithium at room temperature or (4) (5) under cooling. This can be done by treatment with thiol or halide. Formula (II) when A, represents -OPO(ORs)z
Compound: This compound has the formula (I
) of the formula CIOPO (OR
3) It can be obtained by reacting with phosphorochloridate represented by z. Compound of formula (II) when A, represents -SOR 3: The present compound is A, which is produced as described in the previous section (3).
It can be produced by oxidizing the compound of formula (II), represented by -SR, with a small excess of an oxidizing agent, such as sodium periodate or aqueous hydrogen peroxide. The oxidation can be carried out in aqueous methanol, aqueous acetone, etc., usually at room temperature. (6) Compound of formula (II) when l represents -SO,R: This compound is produced by A
, represents a halogen atom, in a solvent such as dimethylformamide or tetrahydrofuran at a temperature of room temperature to about 70°C. S.O.
It can be obtained by reacting with Na. (7) p. The formula when t is represented by -OCOzRs (
Compound of formula 11): This compound is prepared by converting a compound of formula CI) in which A1 represents a hydroxyloxy group to H in the presence of a base such as pyridine.
It can be obtained by reacting with a halocarbonate represented by alCO,R. Compound of A. represents a hydroxyl group, the formula (1
) with about 0 moyl halide in the presence of a base such as butyllithium in a suitable solvent. R, compound of formula (It): The present compound is A, which is produced as described in the previous section (1).
represents a halogen atom (Hat), the compound of formula (II) is generally treated at room temperature with a large excess of amine R,
and reaction R. -N-R, can be obtained by The two compounds of (I[) are A, which is produced as described in the previous section (3),
represents -SR, and the compound of formula (n) has the formula R. H
Al is reacted with alkyl halide or before (1
) When A2 represents a halogen atom, the compound of formula (I[) produced as described in section ) has the formula R, -S-R. It can be produced by reacting with sulfide. Next, the present invention will be explained in more detail with reference to Examples. In the examples, IR analysis was performed using a liquid film for oily substances, and KBr tablets were used for solids, and NMR analysis was performed using TMS as an internal standard. FD-MASS analysis is 'H,”
C,”N,”0,F1215 i, 31p, 12
S, 3% (value corrected as 1.71Br. Example 1 5 kg (undried weight) of yellowed ginkgo leaves collected in Tokyo from late autumn to early winter were crushed into small pieces using a mixer, and then placed in a room m (approximately 20 ℃) for 7 days using a mixed solvent (100N) of petroleum ether/acetone-471 (volume ratio).The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to give about 100g of A residue was obtained. N-hexane 11 was added to this to dissolve the n-hexane soluble fraction, filtered, and the filtrate was concentrated using a silica gel ram to dissolve n-hexane/diethyl ether 95/
n-hexane/ethyl acetate with a mixed solvent of 5 (volume ratio)
Silica gel thin layer chromatography using a mixed solvent of 9/l (volume ratio) (TLC plate manufactured by Merck & Co.)
silicagel 60 Fz. precoa
ted, locn development using a layer thickness of 0.25III1), the fraction with Rf-0.52 was separated to obtain about 17 g of oil. In this thin layer chromatography, solanesyl acetate showed an Rf value of 0.41. Mix this oil with methanol 200 + A, water 20
ml and 65°C for 2 hours with 10 g of sodium hydroxide.
After heating to , methanol was distilled off, the residue was extracted by adding diethyl ether (300 sml), the ether layer was washed five times with about 50 ml of water, dried over anhydrous sodium sulfate, and the solvent was distilled off. IO.3 g of oil was obtained, which is a polybrenol with a purity of more than 95%, for which p-Bondapak-
C+a (silica gel surface treated with Cra hydrocarbon compound) is used as a filler, a mixed solvent of acetone/methanol-90/10 (volume ratio) is used as a developing agent,
The area ratio of each peak in a chromatogram obtained by high performance liquid chromatography using a differential spectrometer as a detector was determined and summarized in Table 5 below. In addition, Merck's semi-preparative high performance liquid chromatography ram (
C+a type) Using RD18-10, each fraction was separated from the above oil (polyprenol content 95% or more) by using a mixed solvent of acetone/methanol-90/10 (volume ratio) as a developing agent. mass spectrometry, infrared absorption spectrum, 'H-NMR spectrum and "C-
It was confirmed by NMR spectrum that these fractions were polyprenol having a structure represented by general formula (1). Field electrochemical mass spectrometry (FD-MA S
The results of S) and the H-NMR δ values are shown in Table 2.
The C-NMR δ values are summarized in the third table. IH-NM
In the data of R, (b) means a wide signal, (d) means a doublet signal, and (t) means a triplet signal. Example 2 10 kg (undried weight) of non-yellowing ginkgo leaves collected in Kurashiki City at the end of October were dried with hot air at about 40°C for 24 hours, and then soaked in chloroform 801 at room temperature (about 15°C) for 7 days. Soaked and extracted. Petroleum ether 51 was added to the concentrate obtained by distilling off chloroform from this oil extract, and insoluble fractions were filtered out. After concentrating the filtrate, it was applied to a silica gel column using chloroform as a developing solvent. Rf-0.50 and 0. Fraction 19 was separated to yield about 37 g of oil. Approximately 40% of acetone is added to this oil to dissolve the acetone-soluble fraction, the resulting mixture is filtered, the filtrate is concentrated, and the resulting oil is mixed with 400% of methanol, 40% of water, and sodium hydroxide. After heating at 65°C for 2 hours with 20g of methanol, the methanol was distilled off and diethyl ether (500+
Add ++j2) and extract, and extract about 100ml of the ether layer.
After washing with water 5 times, drying with anhydrous sodium sulfate,
The solvent was distilled off to obtain 24.2 g of oil. This oil was then purified using approximately 1 kg of silica gel.
Rf-
A fraction of 0.19 was separated to give 21.8 g of oil. This oil is a polyprenol with a purity of 95% or more, and the molecular weight distribution of this oil was measured in the same manner as in Example 1 and is shown in Table 5 below. Example 3 5 kg of ginkgo leaves collected in Kurashiki City in mid-June C
undried weight) according to the method of Example 1 but without saponification reaction with sodium hydroxide to give 8.
．． 7 g of oil was obtained. This product is polygrenyl acetate with a purity of 90% or more, and the same high-performance liquid chromatography method as in Example 1 was performed on this product.

【however,
A mixed solution of acetone/methanol-70/30 (volume ratio) was used as a developing agent] to determine the area ratio of each peak, which is shown in Table 5 below. Similarly to Example 1, a high-performance liquid chromatography ram for semi-separation was used [however, a mixed solvent of acetone/methanol = 7% (volume ratio) was used as the developing agent.
D-MASS% IR,'H-NMR and "C-NM
R analysis was conducted to confirm that these components were polyprenylacetate represented by general formula (1). The area ratio of each peak determined by high performance liquid chromatography is shown in Table 5 below, and the FD-MASS analysis values of these precipitates are shown in the table below. 1 11 2 12 3 13 4 14 5 15 6 16 7 17 8 18 9 19 1012 1012 1080 1080 1148 1148 1216 1216 1284 1284 1352 1352 1420 1420 1488 1 488 1556 1556 Example 4 Ginkgo biloba collected in Kurashiki City at the end of October Leaves at about 60℃
After drying with hot air for 65 hours, each portion was divided into 100 g portions, immersed in the solvent li shown in the table, and kept at room temperature (approximately 25 g) for 7 days.
Extraction was performed at The weight of the concentrate obtained by distilling off the extraction solvent from these extracts was measured and summarized in the table as the total amount of extract. These concentrates were dissolved in 200-h of hexane, and the solution was made into a mixed solution of methanol/water = 9/l (volume ratio) about f
After washing with 3 times of water, the mixture was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain an oily substance. This oil was heated to 65°C for 2 hours with methanol 50- and potassium hydroxide 1 g, then the methanol was distilled off, and the residue was extracted with diethyl ether (100-). After washing with brine three times, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain an oil. This oil was separated using 100 g of silica gel with a mixture of n-hexane/ethyl acetate-971 (by volume) to disperse the polyprenol mixture. The weight of the polyprenol at this time is summarized in Table 4 as the polyprenol content. The composition of the obtained polyprenol mixture was substantially the same as that of the polyprenol mixture obtained in Example 2, regardless of the type of solvent used. Table 4: Results of extraction and separation of 100 g of dried ginkgo leaves In the table, the numerical ratios for miscible solvents mean volume ratios. Example 5 10 kg of Himalayan cedar leaves collected in Kurashiki City in late May
The same operation as shown in Example 2 was carried out to obtain 22.1 g of oil. Table 5 shows the molecular weight distribution of this oil, which was measured in the same manner as in Example 1. Table 5 Beak Na. Value of n 1 11 2 12 3 13 4 14 515 6 16 717 8 18 9 19 Average value of n Example 123 1.8 0.3 1.2 3.1 1.1 4.5 9.4 5.9 14.4 31.1 25-6 28.1 35.2 39.4 33.4 12.7 19.2 13.0 3.8 5.9 3.8 1.7 1.8 1.2 1. 2 0.8 0.4 14.6 15.0 14.5 5 0.76 2.06 7.00 24.32 38.54 19.22 5.19 1.39 0.54 ■4.8 Example 6 Polyprenylacetate general precept n=15,X
=OH, a polyprenol of general formula (III) l. 2
1.2 g of acetic anhydride was added dropwise at room temperature to a solution of 4 g of pyridine and 1.0 g of pyridine dissolved in dry diethyl ether, and after the addition was completed, the mixture was stirred overnight at room temperature. The resulting reaction mixture was washed with saturated brine, then dried over anhydrous sodium sulfate, diethyl ether was distilled off, and a pale yellow viscous liquid was obtained. This product was purified by silica gel column chromatography (using hexane/ethyl acetate as a developing solution) to obtain 1.08 g of a pale yellow liquid. When this product was analyzed by IR, the result was approximately 3.300.Sur absorption caused by the OH group of the raw material polyprenol disappeared, and -0CO
1745 caused by CH3 (!I1-' and 1255c
m-' absorption appeared. In addition, when NMR analysis was performed, the signal (double, δ-4.08) attributed to -CH20H of the raw material polyprenol disappeared, and a new signal (double, δ4.08) attributed to CH*OCOCHs disappeared. 55) was observed. -CH20COCH, the signal to be assigned to CHI 1 -CH. Signal assigned to -C- (δ-2.04)
It was observed to overlap with Moreover, m/e=1284 was obtained by FD-MASS analysis. From the above, this liquid is n
General formula (III) where = 15, X - OCOCR,
was confirmed to be polyprenylacetate. n
polyprenylacetate other than 15 and n is 11-
A polyprenylacetate mixture arbitrarily distributed in No. 19 was also synthesized by a similar procedure. Example 7 Synthesis of polyprenyl bromide, n=15, X-
12.4 g of polyprenol of general formula (m), which is OH, and pyridine were added to 200 g of n-hexane, and the resulting solution was diluted with 2
．． 0 g of phosphorus tribromide was added dropwise, and after the addition was completed, 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 10 times with approximately 50-hexane water, dried over anhydrous magnesium sulfate, and 12.0 g of a slightly yellow liquid was obtained by distilling off the n-hexane. Obtained. When NMR analysis was performed on this product, a signal (
doublet, δ4.08) disappears and a new −(
! ! ．． Signal attributed to Br (double, δ
-3.91) appeared. Further, when this liquid material was analyzed by FD-MASS, it was m/e-1304. Based on these analysis results,
In the general formula [1 [], n = 1 5
,A! - Br was confirmed to be polyprenyl bromide. Polyprenyl bromides with n other than 15 and polyprenyl bromide mixtures with n arbitrarily distributed between 11 and 19 were also synthesized by similar operations. The above polyprenyl bromide (n=15) 0.66
g in dimethylformamide lO-, and to this was added anhydrous sodium acetate l. After adding about 50 g of Og and stirring overnight at about 50 g, about 50 g of diethyl ether was added and filtered. The filtrate was washed with water about 20 times, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
g of a pale yellow liquid was obtained. This product was compared with the polyprenylacetate (n=15) obtained in Example 6 by NMR
The spectra and m/e values by FD-MASS analysis match, n = 15, X-OCOCR. It was confirmed that it was a polyprenylacetate of the general formula [11]. Example 8 Synthesis of polyprenyl chloride n = 1 5
* 12.4 g of polyprenol of general formula (III) where x = on and 1.0 mg of pyridine were mixed with 200-
was added to 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 Example 7 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. In addition, NMR analysis revealed that the raw material polyprenol was 1C! ! , OH disappears, and a new signal assigned to CH, CI (double, a = 3.95
) appeared. ? FD-MASS analysis gave m/e-1260. From the above, it can be concluded that the above raw material is n-15. A ■
It was confirmed that it was a polyprenyl chloride of the general formula [I[], which is 101. Polyprenyl chlorides with n other than 15 and polyprenyl chloride mixtures with n arbitrarily distributed between 11 and 19 were also synthesized by the same operation. Example 9 Synthesis of polyprenyl formate 0.8-Sulfuric anhydride and 2-99% formic acid were mixed under ice cooling and stirred at room temperature for 2 hours.
1.24 g of polyprenol of the general formula [I[1] was added, and the mixture was stirred for 1 hour under water cooling. The reaction mixture was then poured into water, stirred for 30 minutes, and then extracted with diethyl ether. The obtained ether layer was thoroughly washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and the ether was distilled off to obtain 0.48 g of a yellow liquid. This product is very unstable, but when IR analysis was performed, the absorption caused by the OH group of the raw material polyprenol disappeared, and 172
Absorption due to the 10 COH group appeared at 5 cm-' and 1160 (to)-2. Further, upon NMR analysis, a signal (singlet, δ-7.90) attributed to the 10COH group was observed. From the above, it was confirmed that this liquid was a compound having the general formula [11, where n=l5, A,=-OCOH. Polyprenyl formate other than n-15 and n is 11
-19 polyprenyl formate mixtures randomly distributed were also synthesized by a similar operation. Example lO Synthesis of polyprenyl tri7-fluoroacetate n=15. 1.24 g of polyprenol of the general formula [1[] which is X-OH and 1.24 g of pyridine. Og to methylene chloride
OmJ! After 0.5 g of tri7fluoroacetic anhydride was added dropwise to the solution at 0 to 5° C., the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then poured into water and extracted with diethyl ether. The resulting ether layer was washed successively with diluted hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give a yellow color. 0.83 g of liquid was obtained. About this stuff! As a result of R analysis, the absorption caused by the OH group of the raw material polyprenol disappeared and the temperature was 1790 cm-'.
Absorption due to triple oacetate appeared at approximately 1210 cm-'' and 1140 cm-''(J-'). NMR analysis revealed that -CH of the raw material polyprenol
, OH disappears, and -CH! Q.C.O.
A new signal (double
t. δ-4.72) was observed. Also FD-MASS
Analysis gave m/e=1338. From the above,
This liquid is n m l 5 1 A, -ococF,
It was confirmed to be a compound of the general formula [111]. Polyprenyl tri7-fluoroacetates with n other than 15 and polyprenyl trifluoroacetate mixtures with n arbitrarily distributed between 11 and 19 were also combined by a similar operation. Example 11 Synthesis of polyprenyl monochrome acetate 1.24 g of polyprenol of the general formula [1 [[] with n''15,X+mOH and 1.0 g of pyridine are dissolved in methylene chloride 10- After 0.4 g of monochloroacetic anhydride was added dropwise at 5°C, the mixture was stirred at room temperature overnight.The reaction mixture was then worked up in the same manner as in Example 1O to obtain 1.30 g of a pale yellow liquid, which was further added to Purification was performed by silica gel column chromatography (using hexane/ethyl acetate as a developing solution) to obtain 1.25 g of liquid. IR analysis of this material revealed that the absorption caused by the OH groups of the raw material polyprenol had disappeared, and approx. 1 7
．． Absorption due to C--O appeared at 50 cm-'. NMR analysis revealed -CH* of the raw material polyprenol.
The signal assigned to OH disappears, and a new -CH.
OCOCH! Signals attributed to CI (double
t. a-4-57) and 100OCR, signal attributed to CI (singlet, δ3.93)
appeared. Also, according to FD-MASS analysis, m/e=1
318 was obtained. From the above, this liquid has n = 1
5, A * = OCOCH * Cl, the general formula [
It was confirmed that it was a compound of No. 1 []. Polyprenyl monochloroacetates with n other than 15 and polyprenyl monochloroacetate mixtures with n arbitrarily distributed between 11 and 19 were also synthesized by the same operation. Example 12 Synthesis of polyprenylprobionate The same operation as in Example 6 was carried out except that 1.53 g of propionic anhydride was used instead of acetic anhydride, and slightly yellow liquid 1 was prepared.
．． 0.2 g was obtained. When this was analyzed by IR, the absorption caused by the OH group of the raw material polyprenol disappeared, and -0
C.O.C., H. l740am-' and 1250 due to
m-' absorption appeared. When NMR analysis was performed, it was found that -CH. of the raw material polyprenol. The signal assigned to OH disappears, and -CH. A signal (double, δm4.56) assigned to OCoc*tts was observed. Moreover, m/e=1298 by FD-MASS analysis
I got it. From the above, this liquid is n −” l 5
．． AI-10COC! It was confirmed to be a compound of general formula [11] which is Hl. Polyprenyl propionates with n other than 15 and polyprenyl propionate mixtures with n arbitrarily distributed between 11 and 19 were also combined by a similar operation. Example 13 Synthesis of polyprenyl oleate (i)n
= 1 5,
It was heated at 0° C. for 24 hours under a nitrogen gas atmosphere. After the reaction solution was cooled to room temperature, it was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a yellow liquid. Silica gel power ram chromatograph 7
Purification by E (using hexane/ethyl acetate as a developing solution) gave 0.48 g of a colorless viscous liquid. IR analysis of this liquid revealed that the absorption caused by the OH groups of the raw material polyprenol had disappeared. Moreover, m/e=1506 was given by FD-MASS analysis. From the above, this formula has the general formula [111, n = "l 5 # A
! ” -OCO{CHrhCH-CH<CH z'n
It was confirmed that the compound was ``-CH s. (■) 1.17 g of polyprenol of the general formula [111, where n = 1 4, XmOH, 0.3 g of methyl oleate, and 0.05 g of potassium hydroxide. was dissolved in toluene 50, heated at 110°C for 8 hours under a nitrogen gas atmosphere,
After the reaction was completed, the reaction mixture was cooled to room temperature, washed with water, dried, and the solvent was distilled off to obtain 1.2 g of a pale yellow liquid. As a result of the same analysis as above, this product was found to have the general formula [111 with n-1 4 . A s- - OCOeCHz
It was confirmed that the compound is }-CH-Cl{CHz and CHs. Example 14 In the general formula [I[1], n- 1 5, When polyprenol of X-OH and methylene stearate were transesterified, 12 g of a pale yellow liquid was obtained. When this product was analyzed by FD-MASS, it was found that this product has A! gave m/e-1508 indicating that it is a polyprenyl compound where is a CHs(CHg)tscOo group and n-15. Example 15 Synthesis of polyprenyl penzoate 0.28 g of penzoyl chloride is added at room temperature to a mixture of 1.24 g of polyprenol of the general formula [[I] with n = 15, X = OH and pyridine lO-2, Stir overnight at room temperature. The reaction mixture was then poured into approximately 150 mN water, extracted with diethyl ether, and the resulting ether layer was mixed with saturated brine, diluted hydrochloric acid, water, saturated sodium bicarbonate,
After washing with saturated brine again, it was dried over anhydrous magnesium sulfate, and the ether was distilled off to obtain a yellow liquid. This was purified using silica gel chromatography (using hexane/ethyl acetate as a developing solvent) to a 0.00% concentration.
92g of slightly yellow liquid was obtained. When this product was subjected to IR analysis, the absorption caused by the OH group of the raw polyprenol disappeared, and the absorption caused by the ester bond appeared at 1715 am-'' and 1270 cm-''. Also FD-MA
SS analysis gave m/e"1346. From the above, this liquid substance has n in the general formula [1[]
-15, A*=OCOCsHs. By similar operations, polyprenyl benzoates with n other than 15 and polyprenyl benzoate mixtures with n randomly distributed between 11 and 19 were also synthesized. Example 16A Synthesis of Polyprenyl Methyl Ether Polyprenol 1. of the general formula [11[] where n=15,X-OH. 24 g of anhydrous diethyl ether-hexane (1:1 (volume ratio)) was dissolved, and 0.1 g of n-butyllithium (1.6M hexane solution) was dissolved.
69 sJ (1.1 mmol) was added dropwise at 0° C., and after stirring for 10 minutes, 156 mg (1.1 mmol) of methyl iodide was added. After reacting for 30 minutes, the mixture was poured into water and extracted with hexane. The hexane layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a yellow liquid. This product was purified by silica gel column chromatography (using hexane/ethyl acetate as a developing solvent/medium) to obtain 1.14 g of a pale yellow liquid. This thing! As a result of R analysis, the absorption caused by the OH group of the raw material polyprenol disappeared, and the result was 1120 cm-' 1100 am.
-' 1080 cm-' Absorption due to ether bonds appeared. In NMR analysis, a signal assigned to -0CH3 appeared at 8-3.27. FD-MA
The ss analysis gave m/e=1256. From the above, it can be seen that this liquid substance has the general formula [nl, n=15, A,
1-OCR. It was confirmed that the compound was In addition, by similar operations, polyprenyl methyl ethers with n=15 and polyprenyl methyl ether mixtures with n arbitrarily distributed between 11 and 19 were also synthesized. Implementation N16B Synthesis of polyprenylphenyl ether 168 mg of finely ground potassium hydroxide and 310 mg of phenol were dissolved in 30 mg of dimethoxyethane warmed to about 60°C, and n = 1 5 * A! =Br
Polyprenyl bromide of the general formula [nll] 1.30
g was added thereto, and the mixture was heated under reflux for 6 hours. After cooling the reaction mixture, it was poured into water and extracted with diethyl ether. The obtained ether layer was diluted with 5% aqueous sodium hydroxide solution.
After washing twice, it was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting yellow liquid was purified by silica gel column chromatography (using hexane as a developing solvent) to obtain 0.42 g of a slightly yellow liquid. IR analysis of this product revealed 1600cII-' 1580c caused by phenyl ether.
Absorption at m-' and 1220 cm-' was observed. N
MR analysis showed that the raw material polyprenyl bromide was 1CH. Br
Signal attributed to (double, δ-3.91
) disappears, and a signal (doublest, a = 4 .) newly assigned to -CHx-O CsHm appears.
39) appeared. Further, FD-MA SS analysis gave m/e-1318. From the above, this liquid has n=15, Az − − OC
It was confirmed to be a compound of the general formula [111], which is Js. In addition, by the same operation, polyprenylphenyl ethers having n=15 and polyprenylphenyl ether mixtures in which n was arbitrarily mixed with ll-19 were synthesized. 50% sodium hydride (0.5 g) was added to anhydrous dimethylformamide (25+J) and stirred at room temperature for 1 hour, during which n=” l 5.X in general formula (II) was added.
A solution of polyprenol (12.4 g), which is -OH, dissolved in anhydrous dimethylformamide (10 m!) was added dropwise, and after the addition was completed, the mixture was stirred for an additional hour. Then 2-chloropyridine (1.1Ta1) was added and stirred overnight at room temperature.
After 17N, the reaction solution was poured into about 100ml of water, extracted with diethyl ether, washed with water, dried, and concentrated to obtain a yellow liquid. This liquid was subjected to silica gel column chromatography (using hexane/ethyl acetate as a developing solution) to obtain 9.9 g of a pale yellow liquid. NMR analysis of this product revealed that -CM,O of the raw material voriprenol.
Signal assigned to H (double, δ-4.0
8) disappears, and a new one G! ! , O- (double, δ-4.71) and δ
-6.50-6.7 2. multiplet. a
=7.3 multiplet of 0 to 7.52, δ-8
．． 00-8.08) appeared. Also, use this liquid as an FD.
-MASS analysis gave m/e=1319. From the above, it can be seen that in general formula (II), n
=15. It was confirmed that it was polyprenyl (2-pyridyl) ether, which is an Az-2-pyridyloxy group. By similar operations, polyprenyl (2-pyridyl) ethers in which n is other than 15 and polyprenyl (2-pyridyl) ether mixtures in which n is arbitrarily distributed between 11 and 19 were synthesized. After washing 50% sodium hydride (528+ag) with dry hexane several times under nitrogen gas atmosphere, anhydrous tetrahydrofuran (50a+J) and anhydrous dimethylformamide (
50mj) was added and stirred, and in general formula (III), n
-15. Polyprenol (12.4g) which is X-OH
and stirred at 10°C for 1 hour. Next, 2-chlorobenzothiazole (1.3d) was added dropwise, and after the dropwise addition was completed, it was kept at 10°C for 2 hours, stirred overnight at room temperature, poured into about 200 TaIl water, extracted with diethyl ether, washed with water, dried, and concentrated. 12.5 g of yellow liquid was obtained. This compound showed one spot on thin layer chromatography 7E, no side reactions were observed, the yield was almost quantitative, and no further purification was required. Furthermore, when purification was attempted using a silica gel column, it was found that partial decomposition occurred. When this liquid was analyzed by NMR, a signal attributed to raw material polyprenol 100, OR (
double. δ-4.08) disappears, and a signal (double,
δ is assigned to one; one signal (multiplet,
a-6-9 7-7.62) appeared. Also,
When this liquid was analyzed by FD-MASS, m/! -1
375 was given. From the above, it was confirmed that this liquid substance was recrenyl (2-penzothiazolyl) ether represented by general formula (II). By similar operations, polyprenyl (2-penzothiazolyl) ethers in which n is other than 15 and polyprenyl (2-penzothiazolyl) ether mixtures in which n is arbitrarily distributed from 11 to 19 were synthesized. Polyprenol (1.24 g), which is n-15,X-OH in general formula (III), was added to methylene chloride (10
), add triethynoleamine (202 mg), dimethyl t-butylsilyl chloride (151 mg), and 4-dimethynoleaminopyridine (5 mg), and stir at room temperature overnight. The reaction mixture was poured into water and extracted with ether. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting liquid was subjected to column chromatography using Mallinckrodt's silica gel CC-7 (hexane was used as the developing solution). ) and purified by 1. 30 g of liquid was obtained. When this material was analyzed by IR, the absorption caused by the OH group of the raw material polyprenol at about 3300 cm-' disappeared, and NMR analysis revealed that it was 10 SilJe! The signal attributed to tBu is (si
nglet, δ-0.85) was observed. Also FD-M
ASS analysis gave m/e = 1356. From the above, this liquid is n − in the general formula (n).
15*A, OsiMe, tBu was confirmed to be polyprenyldimethyl t-butylsilyl ether. Polyprenyl dimethyl with n other than 15 by the same operation

[-butylsilyl ether and n is 1
A mixture of polyprenyldimethyl t-butylsilyl ethers randomly distributed in 1-19 was synthesized. Example 20 Combination of polyprenylmethylsul7ide or n-15+A2-B of general formula (II)
1. Polyprenyl bromide (1.30 g) which is r.
A 15% methylmercabutan sodium solution (3 mJ2) and benzyltriethylammonium chloride (50 mg) were added to the mixture dissolved in benzene, and the mixture was stirred vigorously at 40°C overnight. After cooling, the mixture is extracted with ether, and the ether layer is washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The yellow liquid obtained by distilling off the ether was purified by silica gel column chromatography (using hexane as a developing solution) to obtain 0.40 g of liquid. NMR analysis of this product revealed that it was S-C! ! The signal assigned to 3 (stnglet, δ-1 .9 5) and -Cl! S
Signal assigned to CH, (d01blet, δ-2
．． 96) was observed. Moreover, m/e=1272 was obtained by FD-MASS analysis. From the above, this liquid has n1 5 . of general formula (U). A! =SC
It was confirmed that it was H1. Polyprenyl methyl sulfides in which n is other than 15 and polyprenyl methyl sulfide mixtures in which n is arbitrarily distributed between 11 and 19 were also synthesized by similar operations. Example 21 Synthesis of foliprenyl phenyl sul7ide Thiophenol (2.2 g) 8 and potassium carbonate (2.
8 g) was added to dimethynolephonolemamide (50 mj!) and while stirring at room temperature (approximately 20° C.) polyprenyl bromide (13. 0 g) was added dropwise. After the dropwise addition was completed, stirring was continued at room temperature overnight, and the reaction solution was diluted with water (
(approximately 100 J) and extracted with hexane. Next, the hexane layer was washed with 1O% aqueous sodium hydroxide solution, washed with water,
Thereafter, it was dried over anhydrous magnesium sulfate and hexane was distilled off to obtain a yellow liquid. This yellow liquid was purified by silica gel column chromatography (using methylene chloride as a developing solution) to obtain 8.6 g of a slightly yellow liquid. NMR analysis of this product revealed a signal (do
ublet, δ-3.91) disappears, and newly -CH
, S- (double, a
m3.47) and -SCaHs (multiplet, δ-7.05-7.32) appeared. Further, when this liquid was analyzed by FD-MASS, m/e-1334 was given. From the above, it can be seen that in the general formula (If), n
It was confirmed to be polyprenylphenyl sulf7ide, which is l5+Ax--SCsH@. Polyprenylphenyl sulfur containing n other than 15 was prepared by a similar operation. Polyprenylphenyl sulfide mixtures were synthesized in which hydride and n were optionally mixed from 11 to 19. 2-Mercagutthiazoline (1.35 g) and 50% sodium hydride (0.48 g) were added to dimethylformamide (15mj!) and stirred at room temperature for 1 hour.
In general formula (II), n-15. A solution of polyprenyl bromide (6.5 g), which is Al-Br, dissolved in dimethylformamide (5 m0) was added dropwise, and after the addition was completed, the mixture was stirred overnight at room temperature.Then, the reaction solution was poured into about 50 yd of water and extracted with diethyl ether. , washed with water, dried, and concentrated to obtain a yellow liquid. This liquid was purified by silica gel column chromatography 7E (using hexane/ethyl acetate as a developing solution) to obtain 2.8 g of a slightly yellow liquid. NMR analysis of this product revealed a signal (double
* δ-3.91) disappears, and a signal (double. δ-3.91) newly assigned to -CH,S (double.
eL, a-3. 3 2 and triplet
, δ 4.16) appeared. In addition, this liquid is FD-
MASS analysis gave m/e=1343. From the above, it can be seen that this compound has two compounds in general formula (II) (
It was confirmed to be 2-thiazolinyl) sul7ide. By similar operation, polyprenyl other than n-15 (2-
Thiazolinyl) sul7ide and any mixed polyprenyl(2-thiazolinyl) 7ide mixture of n-11 to 194 were combined. 2-Menolecaptopyridine (1.llg) and 50% sodium hydride (0.48 g) were dissolved in dimethylformamide (25m7) and stirred at room temperature for 1 hour.
In general formula (II), n-15. A! -Br polyprenyl bromide (6.5 g) was added, and after stirring at room temperature overnight, the reaction solution was poured into about 50 aei of water and extracted with diethyl ether. Next, the diethyl ether layer was washed with water, dried over anhydrous magnesium sulfate, and the ether was distilled off to obtain a yellow liquid. This liquid was purified by silica gel column chromatography (using hexane/ethyl acetate as a developing solution) to obtain 3.9 g of a slightly yellow liquid. NMR analysis of this product revealed a signal (double, δ) attributed to 10H2Br of the raw material polyprenyl bromide.
-3.91) disappears, and a new signal (double, δ=3.78) assigned to one CH,S and -S-C. Signals attributed to H, N (multipl
et, δ-6.75-8.35) appeared. In addition, when this liquid was analyzed by FD-MASS, m/e = 133
I gave it a 5. From the above, it can be seen that in general formula (II), n
= 1 5, A! - - It was confirmed to be polyprenyl (2-pyridyl) sulfide, which is SCsHtN. By similar operation, polyprenyl (2-pyridyl) sulfide other than n=15 and nm l1
-19, optionally mixed polyprenyl (2-pyridyl) sulfide was combined. Example 24 Synthesis of polyprenyl diethyl phosphate Polygrenol (1.24 g) which is n-15,X-OH in the general formula (III) and pyridine (0.16+J
) in methylene chloride, and a solution of diethyl phosphorochloridate (181 mg) in methylene chloride (2-) was added dropwise at 0°C under a nitrogen atmosphere. After stirring at 0° C. for 1 hour, stirring was continued at room temperature overnight. Water was added to the reaction mixture and then extracted with ether. The ether layer was sequentially washed with dilute hydrochloric acid, water, saturated sodium bicarbonate, and saturated brine, dried over anhydrous magnesium sulfate, and the ether was distilled off to give a pale yellow liquid (1.3
5g) was obtained. This compound showed one spot on I-layer chromatography 7E, no side reactions were observed, the yield was almost quantitative, and no further purification was required. In IR analysis, the absorption at 1260 cm-' caused by P-0 and P-0
A broad absorption at 1050 940 cm-' due to -C alkyl appeared. In NMR analysis, a signal attributed to OI1-CH, OP(OEt), (double doublet
Signals assigned to δ 4.38) and 0 appeared. Further, FD-MASS analysis gave m/e=1378. From the above, this liquid has n = 1 5,
It was confirmed that it was a compound represented by the general formula (II) of Az-OP(OXOEt)z. In addition, by similar operations, polyprenyl diethyl phosphate heptaates with n=15 and polyprenyl diethyl phosphate mixtures with n arbitrarily distributed between 11 and 19 were combined. Practical example 25 Synthesis of polyprenylphenyl sulfoxide In general formula (II), n − 1 5 + A, −S
C. H. Polyprenyl 7-enylsulfuryl F (1.
Sodium metaperiodate (257 mg) was dissolved in MeOH (1 O aj!) and dissolved in water (5 mj!).
) and stir overnight at room temperature. Brine was added and extracted with ether. The ether layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the ether was distilled off to obtain a yellow liquid. This was purified by silica gel column chromatography (using hexane/ether as a developing solution). 0 6 g of liquid was obtained. When this product was subjected to IR analysis, strong absorption due to sulfoxide appeared in 1035c theory-1, which had no absorption in raw material polyprenyl 7enyl sulfide. NMR analysis revealed that the raw material polyprenylphenyl sulfide was mono-CHi.
Signals attributed to SCaHs (double,
δ-3.47) disappeared, and a signal (doubleL, δ-3.35) attributed to -CH2SOCJs appeared. Further, FD-MASS analysis gave m/e-1350. From the above, it was confirmed that this product was a polyprenylphenyl sulfoxide having the general formula (II) of n-15+Az--SOC,H. By the same operation, polyprenyl 7-enyl sulfoxides in which n is other than 15 and polyprenylphenyl sulfoxide mixtures in which n is 11-19 and optionally mixed were synthesized. Example 26 Synthesis of polyprenylphenyl sulfone In general formula (II), n = 1 5 + A z =
= IBr polyprenyl bromide (1.30 g)
was dissolved in a mixed solution of N,N-dimethylformamide (LOMJD and tetrahydrofuran (10-)), sodium phenylsulfinate (0.33 g) was added, and the mixture was stirred at room temperature for 17 hours and then at 50°C for 1 hour. The solvent was removed in an evaporator, water was added, and benzene was extracted. The benzene layer was washed with water and dried over anhydrous magnesium sulfate. Removal of the solvent gave a yellow liquid. This was subjected to silica gel column chromatography (hexane). /using ethyl acetate as a developing solution), 0-9
4 g of pale yellow liquid was obtained. IH-NMR analysis of this product revealed a signal (do
ublet. a = 3. 9 1) disappeared,
Newly - Signal assigned to CHzSOtCJs (
doublet, δ=3.77) and -So,C,H
, signal assigned to (multiplet, δ-7
．． 31-7.93) appeared. Also, FD-MASS
Analysis gave m/e=1366. From the above, this liquid is n ''' l 5 , At-SO
It was confirmed that it was a compound represented by the general formula (II) of ICJs. In addition, by the same operation, polyprenyl 7-enyl sulfones in which n was other than 15 and polyprenylphenyl sulfone mixtures in which n was arbitrarily mixed with 11-19 were synthesized. Actual calculation example 27 In the synthesis general formula (III) of polyprenylethyl carbonate, n=1 5. Polyprenol (12.4 g) where X=OH was dissolved in anhydrous pyridine (50-
β) and ethyl chlorocarbonate (β) with stirring at room temperature.
4.8 J) was added dropwise, and then stirring was continued at room temperature overnight. The mixture was then poured into about 300 mJ of water, extracted with ether, and the ether layer was washed with water, diluted hydrochloric acid, and water in that order, dried, and concentrated to obtain a yellow liquid. This liquid was subjected to silica gel column chromatography (using hexane/ethyl acetate as a developing solution) to obtain 7.21 g of a pale yellow liquid. NMR analysis of this liquid revealed a signal (do
ublet, δ-4.08) disappeared, and one new CH,
Signal assigned to 0 (double, δ-4.4
5) and -0-C-QC,H, the signal I1 0 (triplet, 8 = 1.2 0 and qu
Attet, δ=4.05) appeared. In addition, when this liquid was analyzed by FD-MASS, m/e-1314 was found.
gave. From the above, it can be seen that this liquid has n in the general formula (II).
It was confirmed to be polyprenyl 110 ethyl carbonate with = 15, A2--OCOEt. By similar operations, polyprenylethyl carbonates in which n is other than 15 and polyprenylethyl carbonate mixtures in which n is arbitrarily distributed from 11 to 19 were synthesized. Example 28 Polyprenyldimethylcarbamate General formula CI[) where n=1 5. Polyprenol (2.48 g), which is
-) was added. Next, under the same temperature conditions, dimethyl rubamoyl chloride (0.2-) was added and the mixture was heated at 0°C for 30 minutes.
After stirring at room temperature for 2 hours, the mixture was poured into about 20 mL of water, extracted with diethyl ether, washed with water, dried, and concentrated to obtain a yellow liquid. This liquid was subjected to silica gel column chromatography (hexane/ethyl acetate was used as a developing solution) to obtain 2.16 g of a pale yellow liquid. NMR analysis of this liquid revealed a signal attributed to -CI,OH of the raw material polyprenol (do seven blet).
, δ-4.08) disappeared, and new signals (double, δ-4.42) and 2.80) assigned to one CH, O- appeared. Also, use this liquid as FD-MA.
SS analysis gave m/e=1313. From the above, it was confirmed that this liquid was O 2 dimethyl carbamate in general formula (II). Polyprenyl dimethyl carbamates with n other than 15 and polyprenyl dimethyl carbamates a with n arbitrarily distributed between 11 and 19 were synthesized by similar operations. Polyprenyl bromide (2.6 g), which is n-15, As-Br in the general formula (II), was added to anhydrous triethylamine (loeijl) and left overnight at room temperature to precipitate a pale yellow waxy substance. This precipitate was separated, thoroughly washed with anhydrous ether, and then the solvent was removed under reduced pressure to obtain 2.35 g of a pale yellow waxy substance. NMR this thing
Analysis (DMSO-dS), -CH. Signal attributed to Br (dou
bullet. δ-3.91) disappeared, and the signal assigned to -CI,H (double, a = 3.7
7) and the signals assigned to one N(CJs)s (triplet.δ-1.14 and quartet
, δ-3.22) appeared. This waxy material was extremely hygroscopic and elemental analysis and IR analysis were impossible. Moreover, FD-MASS analysis was also impossible because it was an ammonium salt. However, according to NMR analysis, this product has n-15+A*-No(CJs)s in the target general formula (If).
It was confirmed that it was polyprenyltriethylammonium bromide, which is Bre. By the same operation, polyprenyltriethylammonium bromide in which n is other than 15 and a polyprenyltriethylammonium bromide mixture in which n is arbitrarily distributed from 11 to 19 were synthesized. In general formula (II), n-1 5 + A z-B
Polyprenyl bromide (2.6 g) as r was added to dimethylsul7ide (10-) and left overnight at room temperature. A yellow waxy substance precipitated, which was separated, thoroughly washed with anhydrous ether, and then the solvent was removed under reduced pressure to obtain a yellow waxy substance 1. 27 g was obtained. N this thing
MR analysis revealed that 1CH of raw material polyprenyl bromide
Signal attributed to 2Br (double, δ-3
．． 91) disappeared, and the signal (double, δ-4.15) and -S(
CHs) Signal (singlet, δ) assigned to x
-2.88) appeared. This substance has high hygroscopicity and cannot be analyzed for elemental analysis, and FD-MASS analysis is also impossible because it is a sulfonium salt. However, based on the NMR analysis results, the general formula (1 [) n-15. A2--S(C
It was confirmed to be polyprenyldimethylsulfonium bromide, which is H3) Jre. By similar operations, polyprenyldimethylsulfonium bromides with n other than 15 and polyprenyldimethylsulfonium bromide mixtures with n arbitrarily distributed between 11 and 19 were synthesized. Example 3l Magnesium strips (0.316 g, 13 ma+oj!), anhydrous tetrahydrofuran (0.5 d) and 1,2-dipromoethane (0.08 mj!) were placed in an argon-substituted three-necked flask. This was then heated with a hair dryer until it bubbled violently. A solution of 2-[4-promo-3-methylbutoxy]-tetrahydro-2H-pyran (2.51 g, l Ommol) in anhydrous tetrahydro7rane (3.0-j!) was then added to this activated product. The solvent was added dropwise to the magnesium at a rate that just brought the solvent to a boil. After the addition was completed, the mixture was stirred at 70° C. for 15 minutes. Anhydrous tetrahydrofuran (60 aml) was added to this to prepare a Grignard solution. Separately, in a three-necked flask purged with argon, a mixture of general formula (III) was prepared in the same manner as in Example 6.
= 1 5 ,
Anhydrous tetrahydro 7 run solution of la (0.1 molar solution,
2.01) was added. The previously prepared Grignard solution was added dropwise to this at 0°C over 1 hour, and stirring was continued at 0°C for 2 hours. Thereafter, saturated ammonium chloride water was added to the reaction mixture for hydrolysis, followed by extraction with ether. The ether layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off using a rotary evaporator to give 7
．． 95 g of pale yellow liquid was obtained. This product was subjected to silica gel thin layer chromatography (hexane/ethyl acetate-97
/3 (volume ratio) was used as the developing solution) to give R{-0.
It mainly had spots in 35. In addition, when this pale yellow liquid was analyzed by FD-MASS, m/e = 1284, which indicates the presence of raw material polyprenylacetate, was not detected at all, and n = 15, 2-tetrahydro-2H-bilar in general formula (V). m/e=1396, which indicates the target compound which is a nyloxymethyl group, was detected as a main peak. Next, this pale yellow liquid was dissolved in hexane (40 ml), and p-toluenesulfonic acid pyridine (0-1
3gx 0.5mmmoj! ) and ethanol (20d)
added. This solution was heated and stirred at 55° C. for 3 hours. After cooling, sodium R acid (0.21 g) was added to neutralize the mixture, and the solvent was distilled off using a rotary evaporator. The obtained concentrate was dissolved in ether, washed with saturated aqueous sodium bicarbonate, then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed on a rotary evaporator and the remaining oil was transferred to Q. 5 Torr. , and heated at 150° C. for 30 minutes to remove low-boiling components. The remaining liquid was subjected to silica gel chromatography (
A colorless and transparent liquid (5.64 g) was obtained by using hexane/ethyl acetate (9/l as a developing solution). This product is silica gel thin layer chromatography (hexane/ethyl acetate - 9/1 (volume ratio) is used as the developing solution)
gave a single spot at Rf-0.19. Also,
The analysis results shown below confirmed that this liquid was the target compound of general formula (V), where n=15 and z - - cH,on. FD-MASS analysis m/e = 1312 (calculated value 1312)! R analysis (el1-'). 830. 1060.
1376. 1440.2850. 2920. 33
20th C-NMR analysis (ppm/intensity) 135.365
/430,135.229/3567. 135.00
5/349, 134.937/290, 131.2
10/213, 125.071/5242.124.
993/499, 124.448/505, 124
．． 282/463, 124.214/445,
61.241/554. 4 (LO29/541.3
9.757/683.37.548/582.32.2
45/5500. 32.021/456. 2L31
6/528.26.825/492. 26.699
/548, 26.436/5166.25.677
/542,25.308/567.23.430/63
30, 19.5.57/548.17.679/353
, 16.006/640'H-NMR analysis (ppm
*Signal shape, proton ratio) 5.10 (b, 18H
), 3.66 (also 2H), 2.03 (b.70H)
, 1.68 (s.48H), 1.60 (s,9H)
, 1.80- 1.10(-,5H), 0.91
(d.3H) In addition, IR analysis showing the presence of the isomerized product mentioned above showed 907 aa1'', and 'H-NMR analysis showed δ = 5.78 ppm (double d
oublet) was not detected at all. The 2-

[4-Bromo-3-methylptoxy]-tetrahydro-2H-bilane was synthesized as follows. 4-bromo 3-methylbutanol 16.7gt-20
Dihydropyran io. is dissolved in anhydrous methylene chloride and cooled with water. Og was added dropwise. After the addition was completed, the solvent was stirred at room temperature for 2 hours, the solvent was distilled off, and 16.2 g of 2-

[4-Bromo 3
-Methylptoxy 1-tetrahydro-2H-bilane was obtained. The NMR spectrum of this product was as shown below. δl. 0 0 (double.3H), 1.2
0-2.2 0 (multiplet. 9H)
, 3.2 0-3. 9 0 (multiplet, 6
H), 4. 5 3 (broad, lH). Examples 32-34 Polyprenyl compounds shown in Table 6 (n=15) in place of the polyprenyl acetate used in Example 3l
The same operation was performed using The results are shown in Table 6. Example 35 4 was used in place of 2-[4-bromo-3-methylptoxy]-tetrahydro-2H-pyran used in Example 3l.
-bromo using 3-methylbutylbenzyl ether and using CuBr instead of LizCuCl.
The operations up to the reaction with pyridine monotoluenesulfonate were performed. 0.0% of the liquid obtained so far. 5 Tor
r. The mixture was heated at 130°C for 30 minutes and a low boiling point was distilled off to obtain 6.75 g of a pale yellow liquid. Next, this liquid was purified by silica gel column chromatography (hexane/isopropylether-97/3 (volume ratio) was used as a developing solution) to obtain 5.33 g of a slightly yellow liquid. This gave a single spot at Rf-0.59 by silica gel thin layer chromatography (hexane/isopropylether-95/5 (volume ratio) was used as a developing solution). The following analysis results confirmed that this compound was a compound of general formula (V) with n-15 and Z=CHtOCHtCaHi. FD-MASS analysis; m/e-1402IR analysis (cm
-'); 698. 735, 840. 1100
．． 1387. 1450. 1662. 2g40.
2930. 2970'H-NMR analysis (δppII
1 signal shape, proton number ratio); 7.2B (s
．． 5H), 5.07 (b.18H). 4.42
(s, 28). 3.45 (t, 2H), 2.04 and 2.00 (s.70H). 1.62 (s, 48H)
．． 1.50 (s.9H). 1.22(b,5H
). 0.80 (b.3H). Next, a three-necked flask purged with argon was cooled with ice water, and anhydrous ethylamine (10 md) was added thereto, and lithium (0-10 g, 15 B-atm) was added thereto, followed by stirring at 0°C for 10 minutes. Anhydrous tetrahydrofuran solution of the above-mentioned liquid material was added dropwise into the resulting blue solution over 10 minutes. After further stirring at O'C for 30 minutes, diethyl ether and saturated ammonium chloride aqueous solution were added for hydrolysis, and the ether layer was washed with 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, and dried over anhydrous magnesium sulfate. After that, the solvent was distilled off and the remaining liquid was purified by silica gel column chromatography (hexane/ethyl acetate = 9/l (volume ratio) was used as the developing solution) to obtain 4.80 g of a colorless and transparent liquid. Ta. Rf value of silica gel thin layer chromatography of this liquid and FD-
MAS'S, IR, eye C-NMR. 'H-NMR analysis results were the same as those of the liquid obtained in Example 3l. IR analysis 907cm-' also indicates the presence of isomerized metabolites.
'H-NMR analysis Absorption at δ-5.78 ppm was not detected at all. Examples 36-44 The same operation was performed using other polyprenyl compounds (n=15) in place of the polyprenyl acetate used in Example 35. The results are shown in Table 6. In Examples 42 and 43, 907cI1 in Summer R analysis
−'． 'a-5.78p in H-NMR analysis
A weak absorption of pm was detected, confirming the presence of a small amount of isomerized metabolite. Examples 45-48 The same operation was carried out using other metal compounds in place of the copper bromide used in Example 35. The results are shown in Table 6. Example 49 Magnesium strips (
0.474 g, l9-5n+mol), anhydrous tetrahydrofuran (0.5ml and 1,2-dibromoethane (0.08+J)) were heated with a dryer until it foamed violently.Next, 4-promo3 -Methylbutylbenzyl ether (3.86 g).
15 m+aoi) of anhydrous tetrahydrofuran (4.5
+al) solution was added dropwise to the activated magnesium at such a rate that the solvent just boiled. After the addition was completed, the mixture was stirred at 70° C. for 30 minutes. Anhydrous tetrahydrofuran (25 mj!) was added to this to form a Grignard solution. Separately, in a three-necked flask purged with argon, anhydrous iodide
Copper (1-43 gs 7.5 mnoj!) and anhydrous tetrahydrofuran (40-) were added, and this was cooled to -30°C in a dry ice-acetone bath. The previously prepared Grignard solution was added dropwise to this suspension at -30°C, and after the dropwise addition was completed, the mixture was further stirred at -30°C for 20 minutes. In the general formula (III), n-15, X-O
COCI, polyprenyl acetate (6.4 2
g15ma+ol) of anhydrous tetrahydrofuran (10
-) The solution was added dropwise at -30°C. The reaction mixture was gradually warmed to room temperature, and stirring was continued at room temperature for an additional 10 hours. Then, add saturated ammonium chloride water to hydrolyze it,
Extracted with ether. The ether layer was washed with saturated ammonium chloride water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained pale yellow liquid substance was 0.0%. 5 Torr
．． , 13 Heated at 0°C for 30 minutes to remove low-boiling fractions, and purified the residue by silica gel column chromatography (using hexane/isopropylether 97/3 (volume ratio) as the developing solution). 4-63g of slightly yellow liquid was obtained. This liquid was obtained by silica gel thin layer chromatography 7E (hexane/imbrovir ether-95/5).
(volume ratio) was used as the developing solution) to give a single spot on Rf-0.59. In addition, m/e = 1402 was given by FD-MASS analysis, and these analysis results indicate that n = 15 in the general formula (V) obtained in Example 35,
It was identical to that of the compound Z-CHxOCHzCaHs. Next, this liquid was subjected to a debenzylation reaction in the same manner as in Example 35. As a result, purification using silica gel column chromatography (hexane/ethyl acetate-9
/l (volume ratio) used as developing solution) 4.15g
A colorless transparent liquid was obtained. Silica gel thin layer chromatography of this (hexane/ethyl acetate - 9/l (volume ratio)
(used as developing solution), Rf value, FD-MASS
The analytical m/e value was the same as that of the compound of general formula (V), n=15, Z-CI,OH obtained in Example 3l. However, in IR analysis, it was 90'7cm-''.
Further, in 'H-NMR analysis, weak absorption was observed at δ-5.78 ppm. Examples 50-5l The same operation was carried out using another polyprenyl compound (n=15) in place of the polygrenyl acetate used in Example 49. The results are shown in Table 6. In both Examples 50 and 51, it was confirmed by IR analysis and NMR analysis that a small amount of isomerized product was present. Example 52 Polyprenyl bromide (n = 1 to 5) was used in place of the polyprenyl acetate used in Example 35, and steel bromide was not used, and the temperature was 0°C for 2 hours after the completion of dropping the Grignard reagent. Instead, the reaction was carried out for 9 hours at the reflux temperature of tetrahydrofuran. The results are shown in Table 6. Examples 53 to 55 In Example 52, the reaction was performed using other polyprenyl compounds (n=15) in place of polyprenyl bromide. The results are shown in Table 6. Example 56 Lithium (1.7 g
, O-25 gram atoms) and anhydrous ether (40-
0 0 mmoj! ) in anhydrous ether (20 aml), confirm that heat is generated, and then reduce the temperature to 0°C.
The mixture was cooled to 100 mL and the remainder was added dropwise. After the addition was completed, stirring was continued for 2 hours at 10°C. Separately, in a three-necked flask purged with argon, put anhydrous Daiichi Steel Iodide (990.6eeg, 5.2m+aoj!) and anhydrous ether (20d), and add the previously prepared lithium reagent solution (10+ mo / equivalent) to lO
The mixture was added dropwise over several minutes, and the mixture was further stirred at this temperature for 15 minutes. In general formula [11I], nml5, X-OC
OCH, polygrenyl acetate (3.2 1
gs2. 5 m+moj! ) of anhydrous ether (15-β) was added dropwise at −10° C. over 20 minutes, and the mixture was further stirred at this temperature for 1 hour. After that, saturated ammonium chloride water was added to this reaction mixture for hydrolysis.
Extracted with ether. Wash the ether layer with saturated saline,
After drying over anhydrous magnesium sulfate, the solvent was removed using a rotary evaporator to obtain 5.09 g of a pale yellow liquid. This product had a main spot at Rf-0.35 using silica gel thin layer chromatography 7E (hexane/ethyl acetate-97/3 (volume ratio) was used as a developing solution). Moreover, m/e=1396 was given by FD-MASS analysis. This liquid was reacted with pyridine p-toluenesulfonate in the same manner as in Example 3l, and the same procedure was repeated to obtain 2.12 g of a colorless and transparent liquid. This is silica gel thin layer chromatography, FD-MASS
．． Both IR11H-NMR analyzes gave the same results as in Example 3l. Example 57 In place of the polyprenylacetate used in Example 56, a reaction was performed using polyprenylphenyl sulfoxide with n-15, X-S(0)C,H,
．． 15 g of a colorless transparent liquid was obtained. This liquid had the same results as obtained in Example 56 in silica gel thin layer chromatography and FD-MASS analysis. Example 58 In place of the polyprenylacetate used in Example 56, n=15, X − S(0)*C. 1.3 by performing a reaction using polyprenylphenyl sulfone, which is Hs.
8 g of a colorless transparent liquid was obtained. This liquid had the same results obtained in Example 56 in silica gel thin layer chromatography and FD-MASS analysis. Example 59 Lithium (1.7 g
, 0.25 grams. atom) and anhydrous ether (40-), and add 2-[4-promo 3-methylbutoxy J
-Tetrahydro-2H-pyran (2 5.2 gs
First, add a small amount of anhydrous ether (20-) solution of
The mixture was cooled to 100 mL, and the remainder was added dropwise. After the addition was completed, the mixture was stirred at 10° C. for 2 hours. Separately, in a three-necked flask purged with argon, the general formula (II
In I), polyprenyl bromide (3.80 g, 2.5 mol) which is n-15, The corresponding amount) was added dropwise over 10 minutes, and the mixture was further stirred at room temperature for 10 hours. Thereafter, saturated ammonium chloride water was added for hydrolysis, followed by extraction with ether. The ether layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was removed using a rotary evaporator to obtain 5.46 g of a pale yellow liquid. This liquid was reacted with pyridine p-toluenesulfonate in the same manner as in Example 3l, and the same procedure was repeated to obtain 0.44 g of a colorless transparent liquid. This product had the same results as Example 3l in silica gel thin layer chromatography and FD-MASS analysis. Example 60 (A) Lithium (1.7 g, (L2 5 gram atom)) and anhydrous ether (
2-[4-bromo-3-methylbutoxy]-tetrahydro-28-bilane (25-
First, a small amount of anhydrous ether (20a+J) solution of 1 gs l 0 0 m+++ oji was added, and after confirming that heat generation occurred, the mixture was cooled to 0° C. and the remainder was added dropwise. After completion of the dropwise addition, stirring was continued at 10° C. for 2 hours. (B) Separately, in a 3-necked 7 flask purged with argon, polyprenol (3.l l gs 2.5++++soj!
) and anhydrous ether (5-) solution of methyllithium (1.3+moi/1, 1
．． 9-, 2-5+amoj! ) was dropped, and after the dropping was completed, the temperature was 0°C.
The mixture was stirred for 20 minutes. Next, put anhydrous cuprous iodide (0.48 g, 2.5 m 01) and anhydrous tetrahydro-7rane (6-) into a three-necked flask that was replaced with argon, and add to this the ether solution prepared in (B). was added dropwise at room temperature, and after the addition was completed, the mixture was stirred at room temperature for 30 minutes, and then cooled to -65°C in a dry ice-acetone bath. This was added to the lithium reagent solution prepared in (A) (lOmII
Iol equivalent) was added dropwise at this temperature, followed by N iodide,
N-methyl7enylaminotriphenylphosphonium (
1 -2 4 g, 2.5mn+oj! ) anhydrous N,
N-dimethylformamide (13-) solution was added dropwise. After the dropwise addition was completed, the mixture was stirred at -65°C for 1 hour, gradually warmed to room temperature, and further stirred at room temperature for 2 hours. Thereafter, saturated ammonium chloride water was added for hydrolysis, followed by extraction with ether. Wash the ether layer with 0.2N hydrochloric acid,
Dry over anhydrous magnesium sulfate. The solvent was removed on a rotary evaporator, the residue was mixed with 50 mA of hexane, and the precipitated triphenylphosphine oxide was then filtered off.
The filtrate was concentrated to obtain 3.49 g of a pale yellow liquid. This liquid was reacted with p-toluenesulfonic acid pyridine in the same manner as in Example 3l, and the same procedure was repeated in 2.1.
0 g of a colorless transparent liquid was obtained. Silica gel thin layer chromatography of this, FD-MASS, IR, 'H-
The NMR and C-NMR analyzes were the same as those of Example 3l. Example 6l Magnesium strips (
0.3 1 6 gs 1 3 mmoj! ), anhydrous tetrahydrofura (0.5-) and 1,2-dibromoethane (0.08a+N) were added and heated with a dryer until it bubbled vigorously. Next, 4-(di72nyl-1-butylsilyloxy)-2-methylbutyl bromide (4
．． A solution of 0 5 gs l Ommojl ) in anhydrous tetrahydro7rane (5.0 mj2) was added dropwise to the activated magnesium at such a rate that the solvent just boiled. After the addition was completed, the mixture was stirred at 70° C. for 30 minutes. Anhydrous tetrahydro-7rane (60d) was added to this to prepare a Grignard solution. Separately, the general formula (I[I
), a solution of polyprenyl acetate (6.42 g, 5 mmol), n-15, CuC
l. Anhydrous tetrahydro 7 run solution (0.1 molar solution,
2.0 mN). The previously prepared Grignard solution was added dropwise to this at 0°C over 1 hour, and stirring was continued at 0°C for 2 hours. Thereafter, saturated ammonium chloride water was added to the reaction mixture for hydrolysis, followed by extraction with ether. The ether layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off using a rotary evaporator to obtain an oily substance with a concentration of 0.0%. 5 Torr. ．． 1 3 0
After heating at °C for 30 minutes to remove low-boiling components, the mixture was purified by silica gel column chromatography (using hexane/ethyl acetate as a developing solution) to obtain 4.27 g of a colorless transparent liquid. FD-MASS analysis of this product gave m/e=1550. Next, this liquid was dissolved in tetrahydrofuran (30 mjQ, and while stirring at room temperature, tetra-n-butylammonium heptafluoride (5 g) was added little by little, followed by stirring at room temperature for 2 hours. Tetrahydrofuran was distilled off, and approximately 50 mjQ of ether was added. was added, washed with saturated brine, dried over anhydrous magnesium sulfate, and the liquid obtained by distilling off the ether was subjected to silica gel column chromatography (hexane/ethyl acetate - 9/1 (volume ratio)).
was used as a developing solution) to obtain 3.82 g of a colorless transparent liquid. This product gave the same Rf value as the compound obtained in Example 3l by silica gel thin layer chromatography 7E (hexane/ethyl acetate - 9/l (volume ratio) was used as the developing solution). Also FD-MASS, IR%'H
-NMR and C-NMR analysis results are also the same, so this liquid substance is n-15, 2-C in general formula (V).
It was confirmed that it was a compound of I,OH. The 4-(diphenyl-t-butylsilyloxy)-2-methylbutyl bromide used above was synthesized as follows. 4-promo-3-methylbutanol (16.7 g)
Triethylamine (2 g) and 4-dimethylaminopyridine (50 g) were dissolved in anhydrous methylene chloride.
After adding t-butyldiphenylsilyl chloride (33.0 g) at room temperature, the mixture was stirred overnight at room temperature, poured into water, and extracted with ether. The ether layer was thoroughly washed with saturated brine, dried over anhydrous magnesium sulfate, and the ether was distilled off to obtain an oil. This material is manufactured by Mallinckrodt's silica gel CG-
The product was purified by column chromatography (using hexane/ethyl ether as a developing solution) using 700 ml to obtain 38.1 g of a colorless transparent liquid. When IR analysis was performed on this, the absorption derived from the raw material OH group near 3,300c+o-'' had disappeared.In addition, NMR analysis showed that 80.90
(3H, double), 1. 0 2 (9
H, singlet), ■. 1-1. 7
(2H, mulLiplet), 1.7-2.
2(lH, muHiplet), 3. 2 2
(double, 2 H), 3. 6 3 (2
H, triplet), 7.1-7.4 (5H
．． 7.4 7.
8 (5H, multiplet) signal was observed, and it was confirmed that it was the target 4-(diphenyl-t-butylsilyloxy)-2-methylbutyl bromide. Example 62 Magnesium strips (0-3 16 gs 13 mmol), anhydrous tetrahydrofuran (0.5 mj2) and 1.2-
Dibromoethane (0.08 mJ) was added and heated with a hair dryer until it bubbled vigorously. Next, 4-methoxy 2-methylbutyl bromide (1.81 g, 10 mmoj
! ) in anhydrous tetrahydrofuran (3.0+1),
The solvent was added dropwise to the activated magnesium at a rate just enough to bring it to a boil. After the addition was completed, the mixture was stirred at 70° C. for 15 minutes. This is added to anhydrous tetrahydro 7 run (
60-) was added to prepare a Grignard solution. Separately, put the general formula (ml) into a three-necked flask purged with argon.
Polyprenyl acetate (6.4 2 g, 5 mmol) which is n-15, X--OCOCHS in
Anhydrous tetrahydrofuran (15-) solution and Li2Cu
C1. A 7-run solution of anhydrous tetrahydride (0.1 molar solution, 2.0 g+1) was added. The previously prepared Grignard solution was added dropwise to this at 0°C over 1 hour, and the mixture was roughly stirred at 0°C for 2 hours. Thereafter, saturated ammonium chloride water was added to the reaction mixture for hydrolysis, followed by extraction with ether. The ether layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off using a rotary evaporator to give a 0. 5 Torr. , 1
After heating at 30°C for 30 minutes to distill off low-boiling components,
It was purified by silica gel column chromatography (using hexane/ethyl acetate as a developing solution) to obtain 4.72 g of a colorless transparent liquid. When this was analyzed by FD-MASS, a peak was detected at m/e = 1326, and this liquid was n-15 in general formula (V), Z = CH20CH3
It was confirmed that this was the target compound. Next, dissolve this liquid in anhydrous methylene chloride (10d),
trimethylsilane iodide (1.0%) at room temperature under argon.
30 gs 6. 5mmoI! ) was added thereto, and the mixture was further stirred at room temperature for 10 hours. Thereafter, methanol (l) was added, and after stirring for 20 minutes, the solvent was removed using a rotary evaporator. The remaining liquid was dissolved in ether, washed with an aqueous sodium bisulfite solution, an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The liquid obtained by distilling off the solvent was subjected to silica gel column chromatography (hexane/ethyl acetate = 9/l).
(volume ratio) was used as a developing solution) and purified by 3.2
8 g of a colorless transparent liquid was obtained. Silica gel thin layer chromatography of this liquid (7E (hexane/ethyl acetate-9/l)
Ri value of (volume ratio) used as developing solution), FD-MAS
m/e value of S, also IR, 'H-NMR, l''c-NM
The analysis results for R were consistent with those of the compound of general formula (V)+: n-15, 2-CH,OH obtained in Example 31. In addition, 4-methoxy 2-methylbutyl bromide used above was synthesized as follows. 50% sodium hydride (30.7g) was dissolved in THF (40%
A solution of 3-methyl-3-buten-ol (50.0 g) in THF (50 d) was added, and 2
After heating under reflux for an hour, a solution of methyl iodide (90.8 g) in THF (50 mjl) was added dropwise under water cooling, and the mixture was stirred overnight at room temperature. Pour into water, extract with ether, wash the ether layer with water,
Wash with saturated brine and dry over anhydrous magnesium sulfate. After carefully distilling off the solvent, fractional distillation was carried out under normal pressure.
66.5 g of liquid was obtained as a fraction at 102°C. When this liquid was subjected to IR analysis, the absorption caused by the 10H group of the raw alcohol at about 3.300 cs&-' disappeared. N
According to MR analysis, 81.69 (s, 3H), 2.23
(t, 2H), 3.26 (s, 3H), 3.57
(t.2H), 4. 7 1 (broad singing
let, 2 H) was observed. GC-MASS analysis gave m/e = lOO. The above analysis confirmed that this liquid was 3-methyl-3-butenyl methyl ether. Sodium borohydride (2-5 g) was dissolved in THF (320
sj! ), and the above methyl ether (20
．． 0 g) was added dropwise, and the boron trisulfide complex (lo
．． lmA) was added dropwise at 25°C, stirring was continued for 1 hour, then cooled to 0°C and a methanol solution of bromine (42.56 g) and sodium methoxide (28 wt%, 64 wt%) was added dropwise at 25°C.
．． 0g) was added dropwise from a different dropping funnel at below 5°C. After stirring the reaction mixture for another 20 minutes at room temperature, a saturated aqueous sodium bicarbonate solution (100 mj2) was added, and then water was added until the white precipitate disappeared. The organic layer is separated, the aqueous layer is extracted with ether, and the combined organic layers are washed successively with a saturated aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, distill it under reduced pressure at 60°0/5m■
22.5 g of a colorless transparent liquid was obtained as a Hg fraction. NMR analysis of this liquid revealed that it was 80. 9 6 (
double. 3 H), 1.38-2.1 0
(multiplex, 3H) , 3.3 1(si
nglet, 3H), 3. 3 5 ~ 3. 6
0 (multiplet, 4H) was observed. This confirmed that this liquid was the target compound. Example 63 Magnesium strips (
0.3 1 6 g, 1 3 mmoj! ), anhydrous tetrahydro 7 run (0.5-) and 1,2-dibromoethane (0.08aiJ) were added and heated with a dryer until it foamed violently. Then 4,4-dimethoxy-
2-methylbutyl bromide (2.11 g, 10mm
A solution of o1) in anhydrous tetrahydro7rane (3.On+J) was added dropwise to the activated magnesium at such a rate that the solvent just boiled. After completing the dropwise addition, the mixture was heated to 70°C.
The mixture was stirred for 30 minutes. To this was added 7 runs of anhydrous tetrahydride (60 mJl) to form a Grignard solution. Separately, in a three-necked flask purged with argon, the general formula (Ill
) is n-15, X-OCOCH, polyprenylacetate (6-42 g s 5
A 7-run solution (0.1 molar solution, 2.0 d) of LiICuCl4 and LiICuCl4 in anhydrous tetrahydride was added. The previously prepared Grignard solution was added dropwise to this at 0°C over 1 hour, and stirring was continued at 0°C for 2 hours. Thereafter, saturated ammonium chloride water was added to the reaction mixture for hydrolysis and extraction with ether. The ether layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off using a rotary evaporator to obtain 7.67 g of a pale yellow liquid. When this liquid was analyzed by FD-MASS, only a very weak peak was detected at m/e = 1284, which indicates the presence of raw material polyprenylacetate, and in general formula [V], n = 15, Z = CI (OCH3)! m/e = 1 3 5 6 indicating the target compound was detected as the main peak. Then, the above pale yellow liquid was diluted with tetrahydrofuran (30mj
2) and 1O% aqueous hydrochloric acid (10m+j) and stirred at room temperature for 5 hours. Tetrahydrofuran was distilled off from this reaction solution using a rotary evaporator, and the residue was extracted with ether. The ether layer was washed with saturated brine, saturated sodium bicarbonate water, and saturated brine, dried over anhydrous magnesium sulfate, and ether distilled off using a rotary evaporator to obtain 7.29 g of a pale yellow liquid. When this liquid was analyzed by FD-MASS, m/e=1310 was detected as a main peak, and it was confirmed that n-15, Z-CHO in general formula (v). Next, add this liquid to hexane (20s+jl). ! : Dissolved in a mixed solvent of ethanol (10d), added sodium borohydride (1.0g) at room temperature, and stirred for 1 hour. Thereafter, the solvent was distilled off using a rotary evaporator, about 50% of ether was added, the mixture was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed on a rotary evaporator and the remaining oil was heated to 0.5 Torr. , and heated at 150° C. for 30 minutes to remove low-boiling components. The remaining oily substance was purified by silica gel column chromatography (using hexane/ethyl acetate - 9/l (volume ratio) as a developing solvent) to obtain a colorless and transparent liquid 4.25
I got g. IR, 'H-NMR, mouth C-NM of this
The R, FD-MASS analysis results are for general formula (V) obtained in Example 3l, n = 15, Z - CI! It was the same as the compound that was OR. The 4,4-dimethoxy-2-methylbutyl bromide used above was synthesized as follows. 4-promo 3-methylbutyric acid ethyl ester (20.9
g) in anhydrous toluene (400I61) and heated to -78°C.
The mixture was cooled and stirred, and diimptylaluminium hydride (1 molar solution, 120 mA) was gradually added dropwise under a nitrogen atmosphere, and stirring was continued for an additional 30 minutes at -78°C. Next, methanol was carefully added to decompose the excess reducing reagent, and the mixture was diluted with ether (400 mJ), 100% of water was added, and the mixture was stirred at room temperature for 2 hours. After filtering this solution through Celite, the aqueous layer was extracted with ether. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 8 g of crude oil. IR analysis of this material revealed that - 282 due to CHO group
A weak absorption at 0.2720m-'' and a strong absorption at 1720e!a-' were observed. Also, in NMR analysis, δ-9.60
A signal assigned to −〇〇〇 was observed. The above oil was dissolved in methanol (300 g), p-}luenesulfonic acid (500 g) was added, and the mixture was stirred at room temperature for 2 hours. After neutralizing by adding sodium bicarbonate, it was concentrated under reduced pressure, the residue was poured into water, extracted with ether, the ether layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the ether was distilled off. 18 g of crude oil was obtained. This product was purified by silica gel column chromatography (using hexane/ether as a developing solution) to 17.2 g (7
;) A colorless and transparent liquid was obtained. IR analysis of this liquid revealed that it was 2820 ats-
".2720c theory-1 and 1720cm-' characteristic absorption derived from aldehyde disappears, and 1200~l
0 0 0 (J-"), several acetal-derived absorption lines appeared. Also, in NMR analysis, Zj 1.00 (3H,
double),? -1 ” 1 -7 (2
H, multiplet), 1.7-2.0 (l H
, multiplet), 3. 2 2 ( 6
H, singlet), 3.3 1 (2H,
multiplet) , 4-3 2 (l H,t
A r ipleO signal was observed. Also GC-M
ASS analysis gave m/e = 210. This confirmed that this liquid was 4,4-dimethoxy-2-methylbutyl bromide. Example 64 In a three-necked flask purged with argon, magnesium strips (0.316 g, 13 mmol), anhydrous tetrahydro7rane (0.5-) and 1.2-dipromoethane (0.08-1) were added. and heated it with a hair dryer until it bubbled violently. Then 4,4-dimethylthio-
2-Methylbutyl bromide (2.43 gs l O
A solution of 1 mmol) in anhydrous tetrahydro7rane (3.1 J) was added dropwise to the activated magnesium at a rate such that the solvent just boiled. After the addition was completed, the mixture was stirred at 70° C. for 15 minutes. Anhydrous tetrahydro 7 run (60+J) was added to this to prepare a Grignard solution. Separately, the general formula (nl) was added to a three-necked flask purged with argon.
Polyprenyl acetate (6.4 2 g, 5 mmoj!) with n-15, x -10 COCR,
Seven runs of anhydrous tetrahydride (15 ml solution and LiCuC
1 g of anhydrous tetrahydrofuran solution (0.1 molar solution,
2.0-) was added. The previously prepared Grignard solution was added dropwise to this at 0°C over 1 hour, and stirring was continued at 0°C for 2 hours. Thereafter, saturated ammonium chloride water was added to the reaction mixture for hydrolysis, followed by extraction with ether. The ether layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off using a rotary evaporator to obtain an oily substance with a concentration of 0.0%. 3 Torr. ．． 150℃
The mixture was heated for 30 minutes to distill off some of the low boiling point. FD-MASS analysis of the remaining yellow liquid revealed that n=15,7,-CH(SCHs)g in general formula (V).
A peak was detected at /e-1388. This oil was then dissolved in acetone (20 sj!) and to this were added water (1-), mercuric chloride (0.25 g) and cadmium carbonate (0.25 g). The mixture was heated at room temperature for 25 minutes.
After stirring for an hour, mercuric chloride (0.10 g
) and cadmium carbonate (0.10 g) were added, and stirring was continued for 20 hours. After removing the precipitate by filtration and distilling off the acetone, the remaining liquid was dissolved in ether, and the ether solution was washed with water, 10% potassium iodide aqueous solution, water, and saturated sodium chloride water, and dried over anhydrous magnesium sulfate. . The solvent was distilled off, the residue was dissolved in a mixed solvent of hexane (20-) and ethanol (LOMJL), and sodium borohydride (1.0 g) was added at room temperature, followed by stirring for 1 hour. Thereafter, the solvent was distilled off, ether and saturated ammonium chloride water were added to the residue, and the aqueous layer was extracted with ether. The ether layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off and the remaining oil was reduced to 0. 5
Torr. , 130°C for 30 minutes to remove the low boiling point. The residue was purified by silica gel chromatography (using hexane/ethyl acetate = 9/l (volume ratio) as the developing solution) to give a colorless and transparent liquid (3.0
7 g) was obtained. Silica gel thin layer chromatography of this liquid (hexane/ethyl acetate - 9/l (volume ratio)
was used as a developing solution) R [value, m/ of FD-MASS
e single value, and IR, 'H-NMR, and C-NMR analysis results show that n=15 in the general formula (V) obtained in Example 3l.
, Z-CH. It was consistent with that of the OH compound. The 4,4-dimethylthio-2-methylbutyl bromide used above was synthesized as follows. The crude aldehyde (14.8 g) obtained by reducing 4-bromo 3-methylbutyric acid ethyl ester (20.9 g) with diisobutylaluminum hydride in anhydrous toluene at -78°C
) was dissolved in anhydrous ether (200 mβ), methylthiotrimethylsilane (21.6 g) was added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. After adding water, extract with ether. After washing the ether layer with saturated brine and drying over anhydrous magnesium sulfate, the ether was distilled off and the resulting liquid was purified by silica gel column chromatography (using hexane/ether as a developing solution) to yield 17.4 g. A colorless and transparent liquid was obtained. When this material was subjected to IR analysis, no absorption due to the raw material aldehyde of 2820.2720 and 1720ca+-' was observed, and in NMR analysis (singlet, δ2
．． 08) was measured. Further, GC-MASS analysis gave m/e = 242. Example 65 The same operation as in Example 35 was performed using anhydrous diethyl ether instead of anhydrous tetrahydrofuran, and 4.5
2 g of a colorless transparent liquid was obtained. This liquid was subjected to silica gel thin layer chromatography (hexane/ethyl acetate-9/l (
R [value, FD-MAS
The m/e value of S was the same as that of the compound of n-15, Z-CH,OH in general formula (V) obtained in Example 35. In addition, weak absorption was observed at 907 cm-' in IR analysis. Example 66 (S)-4-bromo 3- was used in place of 4-bromo 3-methylbutylpenzyl ether used in Example 35.
Methyl butyl benzyl ether ([el M- +6
-05', c-1-10. C! Example 2 using HIOH) and replacing polyprenylacetate with n=15
The same operation was carried out using the polyprenol mixture in which n was distributed in the range of 11-19 obtained in Example 6 and made into a polyprenylacetate mixture, and 4-72g was obtained.
A colorless and transparent liquid was obtained. This liquid was collected using Merck's semi-preparative high performance liquid chromatography ram LiChrosorb.
Nine main peaks were detected using high-performance liquid chromatography using RPI 8-IO (C. type) with a mixed solvent of acetone/methanol-90/10 (volume ratio) as the eluent and a differential refractometer as the detector. It was confirmed. The abundance ratio was determined from the area ratio of this chromatodarum and is shown below. Peak No. Value of n Abundance ratio FD-MASS
1 11 0.3 10402
12 1.0 11083
13 5.9 11764
14 25.7 12445
15 39.6 13126
16 19.3 13807
17 5.7 14488 1
8 1.7 15169 19
0.8 1584 Separate into each fraction using the same liquid chromatography 7E and perform FD-MA
SS analysis was performed and each peak was confirmed to be of n=l-19. Also, I R. for each peak separated. '}I-NMR, "C-NMR
and the objective is n=1 1-19, z-cttzou
It was confirmed that it was a compound of general formula (V). The compound in which n=15 in beak head 5 gave exactly the same analytical values as the compound obtained in Example 3l. Regarding other peaks, IR, 'H-NMR, and 'C-NMR all had absorption signals at the same position, and the intensity ratios were only slightly different. When measuring the light intensity of [glV-+0.51°(
neat) It happened. Example 67 Following the method described at the end of Example 3l, replacing the 2-[4-bromo 3-methylbutoxy J-tetrahydro-2H-bilane used in Example 3l, (R)-4-
Synthesized using bromo-3-methylbutanol (R)
-2-[4-bromo-3-methylbutoxy]-tetrahydro-2H-bilane ([al'fl-3-6
1” c-4.0, CHCIs) and n
The same operation was carried out using the polyprenyl acetate mixture used in Example 66 instead of the polyprenyl acetate of =15 to obtain 5-52 g of a colorless and transparent liquid. When this was subjected to high performance liquid chromatography 7E analysis under the same conditions as in Example 66, the same results as in Example 66 were obtained. Also, FD-MASS, IR, 'H-NMR, C-NMR
The analysis also gave the same results as Example 66. In addition, when measuring the light intensity of this liquid, [g]
W--0.5 1 (neat) There was.

Claims (1)

[Claims] 1. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) In the formula, A_1 represents a hydroxyl group or an acetyloxy group; ▲ Numerical formula, There are chemical formulas, tables, etc. ▼ represents a trans isoprene unit; ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ represents a cis isoprene unit; n is an integer from 11 to 19. A plurality of polyprenyl compounds represented by consisting essentially of a mixture of species and comprising at least three compounds of formula (I) where n is 14, a compound of formula (I) where n is 15 and a compound of formula (I) where n is 16; Each of these three compounds is contained in a substantial amount as an essential component, and the total content of these three compounds is at least 7% based on the weight of the mixture.
A polyprenyl composition characterized in that it contains 0% by weight. 2. A composition according to claim 1 containing the highest content of a compound of formula (I) in which n is 15. 3. A composition according to claim 1, containing a compound of formula (I) in which n is 15 in an amount ranging from 30 to 50% by weight, based on the weight of the mixture. 4. The content of the compound of formula (I) where n is 14, the compound where n is 15 and the compound where n is 16 is determined as a
, b and c in weight%, the following quantitative relationship: b>a
The composition according to claim 1, which satisfies >c. 5, based on the weight of the mixture, the formula (where n is 14)
Claim 1 containing a compound of formula (I) in an amount ranging from 20 to 35% by weight and a compound of formula (I) in which n is 16 in an amount ranging from 10 to 25% by weight. Compositions as described. 6. The total content of the compound of formula (I) where n is 14, the compound of formula (I) where n is 15 and the compound of formula (I) where n is 16 is at least 75% by weight of a composition according to claim 1. 7. The mixture contains multiple types of compounds of formula (I) as follows: 172-10 180.1-5 190-3. 8. The composition according to claim 1, wherein the average value of n is 14.25 to 15.25. 9. Extract Ginkgobiloba leaves with an oil-soluble organic solvent, hydrolyze the resulting extract if necessary, and then apply chromatography, fractional dissolution, fractional cryoprecipitation, molecular distillation, or any of these methods. When subjected to a separation method consisting of a combination of two or more of the following methods, TLC platel silica gel manufactured by Merck
60F_2_5_4pre-coated, layer thickness 0.2
In thin layer chromatography (10 cm development) using 5 mm and a mixed solvent of n-hexane and ethyl acetate at a volume ratio of 9:1 as the developing solvent, the R_f value of solanesyl acetate as a standard substance was 0.40. ~0.45 under conditions of 0.18-0.25 and/or 0.50-0
．． The method for producing a polyprenyl composition according to claim 1, characterized in that a fraction exhibiting an R_f value within the range of 55 is isolated and collected. 10. The method according to claim 9, wherein the organic solvent is selected from hydrocarbons, halogenated hydrocarbons, esters, ethers, alcohols, and ketones.