JPH0493B2 - - Google Patents

Description

[Detailed description of the invention] The present invention provides novel polyprenyl compositions or compounds.
For more information, please visit Ginkgo
biloba) or Himalayan cedar (Cedrus deodara)
A mixture of multiple polyprenyl congeners extracted from
A novel polyprenyl composition comprising
Novel polyprenyls derived from renyl congeners
compounds, these polyprenyl compositions or compounds
Manufacturing method and mammalian dolichol
(dolichol) in the synthesis of such compositions or
Concerning the use of compounds. Dolichols were described by J.F. Pennock et al. in 1960.
It was first isolated from pig liver etc.
[Nature (London),186, 470 (1960)],
Later, they described the dolichols using the following general formula: In the formula, [formula] is a transformer type i. Represents the soprene unit, [formula] represents a cis isoprene unit;
The same applies below. A mixture of polyprenol congeners with the structure shown in
compound, and the cis isoprene unit in the above formula
The number j is generally distributed from 12 to 18, and j = 14, 15
and 16 are mainly composed of three homologues.
[R.W.Keenan et al,
Biochemical Journal,165, 405 (1977)].
In addition, dolichols are not only found in pig liver, but also in mammals.
Widely distributed in the mammalian body, supporting the life of living organisms
It is known that
It is. For example, J.B. Harford et al.
In an in vitro test using pig brain white medulla,
Exogenous dolichol is a fat containing sugar components such as mannose.
promotes the incorporation into the quality of life, and as a result,
An action that increases the formation of glycoproteins that are important for maintenance.
[Biochemical
and Biophysical Research Communication
76, 1036 (1977)]. Cause of dolichols
The effect of promoting the uptake of sugar components into lipids during the growth period is
in an animal that is already more mature than in a living body
Dolico has been shown to be effective in preventing aging.
The movement of the ball is attracting attention. Also, R.W.
Keenan et al.
For living organisms that ingest dolichol from outside,
Supplements dolichol obtained by biosynthesis in the own body
[Archives of
Biochemistry and Biophysics,179, 634 (1977)
reference]. Akamatsu et al. quantified dolichol in the regenerated liver of mice.
However, its amount is significantly reduced compared to normal liver content.
As a result, the glycoprotein synthesis function in the liver tissue is drastically reduced.
and the addition of exogenous dolichols
We found that this function was improved (Nippon Seika Co., Ltd.)
(Presented at the 1981 academic conference). In this way, dolichols are extremely important to living organisms.
Important substances, pharmaceuticals or their synthetic intermediates,
Development of applications in cosmetics, etc. is strongly desired.
Ru. However, conventional Dolicol products are difficult to obtain.
Therefore, it is not possible to conduct sufficient research.
That is the reality. For example, 10kg of pig liver.
After a complicated separation operation, about 0.6g of Dolico was obtained.
[J. Burgos et al.
Biochemical Journal,88, 470 (1963)]. On the other hand, total synthesis of dolichols is
As is evident from the complex and unique molecular structure of
This is extremely difficult with current synthetic organic chemistry technology.
be. Therefore, we relied on natural products as synthetic intermediates, and
By simply adding a simple synthetic chemical treatment to the
It would be advantageous if we could obtain the rules, but
Until now, no such convenient substance has been found.
stomach. Traditionally, polyprenol compounds have been extracted from various plants.
It is known that the following polyp can be collected.
Lenols are being collected. Betulaprenol, like dolichols,
-Two trans isoprenes in the terminal isoprene unit
A chain of rene units leads to cis isoprene.
It has a structure in which units are connected, but so far it has not been known.
Betulaprenol, which is commonly used in the
The number of type isoprene units is only 6 at most,
From these, the number of cis isoprene units is 14, 15 and
Synthesize dolichols mainly consisting of and 16
In order to
It is necessary to regulate and extend the
This is almost impossible with current organic synthesis technology. Also, recently, K. Hannus et al.
Approximately 1% dry extract from the leaves of Pinus sylvestris
Isolation of polyisoprenyl fraction by dry weight
However, the fraction mainly consists of 10 to 19 cis-type molecules.
Polyisoprenyl acetate with isoprene units of
It is reported that it consists of However, the pi
Noprenol fraction contains 15 and 16 iso
Congeners with prene units are the main components, and mammalian derivatives
17, 18 and 19 which are the main components of the recalled products
Congeners with isoprene units are present only in trace amounts.
[Phytochemistry,13, 2563 (1974)
reference]. In the literature of K. Hannus et al., the above-mentioned pinopreno
For more information on the trans and cis configurations in the
Although the details have not been resolved, if the Pinot Pireno
ole fraction is similar to mammalian dolichols.
as having similar trans and cis configurations.
Also, to induce mammalian dolichol from it
has at least two isoprene units in the cis form.
After regulating and elongating the α-terminus, a saturated
The prene units have to be combined, which requires a lot of synthetic effort.
It is clear that there are many difficulties involved. Furthermore, D.F. Zinkel et al.
strobus) leaf extract contains 18 isoprene monomers.
or a series of polyprenes with an average of 18 units.
C containing nol congeners₉₀Polyprenol is present
[Phytochemistry,11,
3387 (1972)]. But they are doing it
The analysis is extremely crude based on NMR, and is
According to the results of additional tests by the inventors, strobe pine
Polyprenol fraction extracted from leaves
is mainly composed of homologues with 17 isoprene units.
It turns out that there is something. However, this strobe
Polyprenyl fraccio isolated from pine needles
To synthesize mammalian dolichols from
If the polyprenyl fraction is mammalian
Trans and cis configuration similar to dolichols
Even if you have at least one item
Introducing the soprene unit while regulating it to cis type
and still pose major difficulties in synthesis.
Accompany. Therefore, the present inventors investigated mammalian dolichols and
Isoprene of the same number and trans and cis configuration
unit and therefore the isoprene unit in the cis form.
Difficult in terms of organic synthesis to introduce under regulated conditions
Polyprenyl compounds that do not require extensive manipulation
The results of analyzing extracts from various plants in search of the source of
Surprisingly, this time, we found that Japanese crocodile and Himala
Polyprenyl fraction extracted from Yasugi
(or composition) compared to mammalian dolichols.
Only the α-terminal saturated isoprene unit is absent.
polyprenyl in mammalian dolichols.
Polyprenyl congeners with very similar congener distribution
showing the distribution of the mammalian dolichols.
It has been found that it is very suitable as a synthetic intermediate for
I started it. However, according to one aspect of the invention, the general formula In the formula, A₁is a hydroxyl group or acetyl group
represents a cy group; [formula] is a tran represents an isoprene unit; [Formula] is cis isoprene unit represents; n is an integer from 11 to 19; A mixture of multiple types of polyprenyl compounds represented by
and n is 14 ()
compounds, n is 15 () and n is
16, at least three compounds of formula () are required.
Contains a substantial amount of each as an essential component, and
The total content of the three compounds is the weight of the mixture.
Characterized by at least 70% by weight based on
Novel polyprenyl compositions (fractions)
) will be provided. The above novel polyprenyl composition (or flux)
According to another aspect of the present invention,
Ginkgo biloba or Himalayan cedar
(Cedrus deodara) leaves are treated with an oil-soluble organic solvent.
The extract obtained is extracted with water and added with water if necessary.
After decomposition, chromatography method, fractional dissolution
method, fractional cryoprecipitation method, molecular distillation method, or these methods
A portion consisting of a combination of two or more types of laws
Silica for thin layer chromatography
Gel plate, e.g. TLC plate silicagel manufactured by Merck & Co.
60F₂₅₄pre-coated, layer thickness 0.25 mm and n-
Mixing hexane and ethyl acetate in a volume ratio of 9:1
Thin layer chromatography using a solvent as a developing solvent
Soranesi as a standard material in (10cm deployment)
Ruacetate R_fUnder the condition that the value is between 0.40 and 0.45
R in the range 0.18-0.25 and/or 0.50-0.55_fvalue
It is characterized by isolating and collecting fractions showing
It can be manufactured by a method. The above describes the polyprenyl composition of the present invention and its production.
The manufacturing method will be explained in more detail. When extracting the polyprenyl composition of the present invention,
Gypsophila, which is used as food, is mainly grown in East Asia.
A. Seed plants distributed especially in Japan, China and Korea
A plant that belongs to the phylum Gymnosperma, subphylum Gymnosperma, class Taxiformes.
Also, Himalayan cedars are grown in temperate and cold regions.
Seed plants, phylum Gymnosperms, subphylum Conifera, widely distributed in
It is a plant belonging to the order Conifera, and in the present invention
The leaves of these plants are used as raw materials. Gypsophila or Himalayan cedar that can be used as raw materials
The leaves range from young green leaves to completely yellow leaves.
Leaves at any stage up to or after falling
These leaves can also be treated according to the invention after drying.
or may be used undried.
can. However, in general, dried leaves are
is preferable, and the degree of drying in that case depends on the weight of the dry leaves.
Moisture content by standard is generally below about 30%, preferably 10%
% or less is advantageous. Additionally, the leaves are broken.
It is preferable to extract after crushing, and then
This increases the contact area with the extraction solvent and improves extraction efficiency.
can be given. Polyprenyl analog represented by the above formula ()
is commonly found in the leaves of Japanese yam or Himalayan cedar.
Free alcohol form and/or acetate form
It is contained in a fairly high concentration in the leaves, and the poly is extracted from the leaves.
In order to effectively extract prenyl congeners, the
Oil-soluble organic compound that dissolves polyprenyl congeners well
Solvents are preferably used. Such oil-soluble organic solvents generally include dielectric
Constant (ε) is 32.7 or less, preferably 25.0 or less,
More preferably, it is 20.7 or less, and
Specifically, the solvents listed below can be used alone or
can be used as a mixed solvent of two or more types.
Wear: (a) Hydrocarbons: e.g. petroleum ether, penta
hexane, heptane, benzene, toluene
xylene, etc. (b) Halogenated hydrocarbons: e.g. chloroform
methylene chloride, carbon tetrachloride, ethyl tetrachloride
perchloroethylene, trichlorethylene
Such. (c) Esters: For example, methyl acetate, ethyl acetate
ole, ethyl propionate, etc. (d) Ethers: For example, diethyl ether, di
Isopropyl ether, tetrahydrofuran,
such as dioxane. (e) Ketones: e.g. acetone, methylethyl
Ketone, diethyl ketone, diisopropyl ketone
etc. (f) Alcohols: e.g. methyl alcohol,
Ethyl alcohol, propyl alcohol, alcohol
alcohol, etc. When selecting the solvent to use,
Selectively enhance the polyprenyl compound of formula () above.
Extract efficiently and extract other substances as much as possible
From this point of view, it is desirable to have something that does not.
In the above solvent, hydrocarbons, halogenated hydrocarbons
esters, diethyl ether, diisopropylene
Less polar ethers and ketones such as pyruthers
Tons are particularly suitable. The amount of extraction solvent used is not critical;
depending on the type of solvent used, the type and condition of the leaves to be extracted, etc.
This can vary widely depending on the
1 part by weight of Japanese cedar or Himalayan cedar leaves (on a dry weight basis)
about 1 to about 100 parts by weight, preferably 5 to 50 parts by weight
parts by weight, more preferably within the range of 10 to 30 parts by weight
It is advantageous to use Extraction is done by soaking the leaves in the above solvent and if necessary
Stir continuously or intermittently.
be able to. The temperature during extraction is also not critical.
It varies widely depending on conditions such as the type and amount of solvent used.
range, but generally from about 0°C
Temperatures up to the reflux temperature of the solvent can be used;
Room temperature is usually sufficient. Under such conditions the extraction
It is usually advantageous to carry out the treatment for 1 to 10 days. Leaves and other solids are removed from the soaking liquid after the extraction process.
After that, remove the solvent as necessary to make a concentrated solution.
Ru. The extract thus obtained is then chromatographed.
graphie method, fractional dissolution method, fractional cryoprecipitation method,
Child distillation method or any two of these methods or
is subjected to a separation process consisting of more combinations.
to generate the desired polyprenyl fraction.
can be collected. Contains polyprenyl compounds in the above separation process.
Confirmation of the fraction contained in the
Silica gel plate for tographies, e.g. manufactured by Merck & Co.
TLC plate Silicagel 60F₂₅₄ precoated, layer thickness
using 0.25 mm and using n-hexane and ethyl acetate.
Thin layer using a 9:1 volume ratio mixed solvent as the developing solvent
Standard material in chromatography (10cm development)
R of solanesyl acetate as a quality_fValue is from 0.40
0.45, 0.18 to 0.25 (in the above formula ())
A₁represents a hydroxyl group) and
and/or 0.50 to 0.55 (A in the above formula ())₁but
When representing an acetyloxy group)_f
Depends on whether there is a spot at the value.
can become. However, in the following explanation
R of thin layer chromatography_fWhen mentioning values
Unless otherwise specified, measurements shall be made under the above conditions.
It should be understood that it means the specified value. Clones that can be used in the separation process of the above extract
Matography method, fractional dissolution method, fractional cryoprecipitation method
The operations of each method of molecular distillation and molecular distillation are known per se.
In the present invention, the method is similar to the known method.
For details on each method,
If the
Only the points to be noted are listed here. (A) Chromatography method [H.Heftman
“Chromatography”Reinhold Publishing Co.,
See New York (1961)] Thin layer chromatography for small amounts of extract
E method and liquid chromatography method are suitable.
However, when processing large quantities of extracts, columns
Chromatographic methods are preferred. As a carrier for chromatography that can be used
are silica gel, alumina, florisil, cera
carbon, activated carbon, cellulose, etc.
Among them, silica gel is preferred. Perform the separation using a silica gel column.
As a developing solvent, for example, hexane
/ethyl acetate (volume ratio 95:5 to 80:20),
Xane/isopropyl ether (volume ratio 95:5
~80:20), petroleum ether/methyl acetate (vol.
ratio 95:5 to 80:20), petroleum ether/isopro
Pill alcohol (99:1 to 90:10 by volume), base
Zhenzene/ethyl ether (volume ratio 95:5-80:
20), benzene/ethyl acetate (volume ratio 98:2~
Mixed solvent systems such as 80:20) or chloroform
Examples include. (B) Fractional dissolution method [L.C.Craig “Technique of
Organic Chemistry”Vol.3, Interscience,
(1951)] The polyprenyl compound of formula () above is penta
It is easily soluble in non-polar solvents such as hexane and hexane.
On the other hand, polar solvents such as methanol and water
Since it is poorly soluble, it can be separated using this difference in solubility.
Can be purified by separate dissolution methods, such as extract concentration
Dissolve a crude product such as a substance in the above non-polar solvent
and then a polar solvent that is immiscible with the non-polar solvent.
By washing with
Purities can be removed to a large extent. With this method
Examples of suitable non-polar solvents include:
Petroleum ether, pentane, hexane, hepta
petroleum benzyl, benzene, toluene, etc.
Hydrocarbon solvents, methylene chloride, chloro
Halogenated hydrocarbon solvents such as form are suitable
It is. Also, polar solvents that are immiscible with such non-polar solvents
Examples of solvents include water or methanol.
suitable. (C) Fractional cryoprecipitation method [E.W.Berg “Physical and
Chemical Methods of Separation”
Chapters 14, 15, McGrawHill, N.Y. (1963)
reference] The polyprenyl compound of the formula () is about -10
Solidifies below ℃. Therefore, the extract should be kept at −10° or less.
Cooling at temperatures below, preferably about -15 to about -30°C.
After solidifying the target material, solid-liquid separation is performed.
Depending on the temperature, impurities that do not solidify are purified.
can be manufactured. However, the polyp
Renyl compounds do not have very good crystallinity,
Since it becomes a wax-like solid, it can be completely removed by this method.
Since it is difficult to purify the
It is preferable to carry out in combination. (D) Molecular distillation method [G.Durrows, “Molecular
“Distillation” Clarendon Press, Oxford
(1960)] The compound of formula () above has a large molecular weight, so
Therefore, low molecular weight can be obtained by using molecular distillation method.
impurities can be removed. for example,
Ten^-3~Ten^-Five100~250℃ at mmHg vacuum
Molecular distillation is carried out under heating conditions to separate low-molecular fractions and high-molecular fractions.
It is divided into a molecular fraction. At this time, the polymer fraction
The target substance is retained and low molecular weight impurities are significantly removed.
can be removed. Sufficiently pure polyp by each of the above separation methods
If the Renyl fraction cannot be obtained, this
A combination of two or more of these separation methods
You can also use For example, chromatography method and fractional lysis
Method: Chromatography method and fractional cryoprecipitation method
Fractional dissolution method; Chromatography method and fractional cryoprecipitation method and fractionation
Separate dissolution method and molecular distillation method; Chromatography method, molecular distillation method and fractional dissolution
solution; Chromatography and molecular distillation methods; Molecular distillation method and fractional dissolution method; Molecular distillation method, fractional dissolution method, fractional cryoprecipitation method, etc.
Any combination can be used. Thus, in thin layer chromatography
R_fFlags with values 0.18 to 0.25 and/or 0.50 to 0.55
The cushion is isolated and recovered. R_fValue is 0.18-0.25
The fraction of A in the above formula () is₁
Mixing of homologs when represents a hydroxyl group
consisting essentially of, on the other hand, R_fValue is 0.50-0.55
The fraction of A in the above formula () is₁but
Mixing of homologues when representing acetyloxy group
consisting essentially of something. The fraction thus obtained can be further illustrated by
Subject to partition type high performance liquid chromatography.
In particular, it is possible to isolate individual homologue components.
You can also do it. In addition, in the above separation step, the extract is
The extract is hydrolyzed before being subjected to the separation operation.
In the above formula () that can be included therein,
A₁Homologues when represents an acetyloxy group
corresponding to A₁represents a hydroxyl group
It is possible to convert it into a homolog beforehand. mosquito
This makes the subsequent separation operation easier.
It may become. However, such hydrolysis
Of course, R after the separation operation is completed._fValues between 0.50 and 0.55
It can also be performed on fractions containing components.
can. This hydrolysis is a known fatty acid ester
The usual methods known for hydrolyzing
It can be done using any method, and
For example, hydroxyl in aqueous methanol or ethanol.
Dissolve sodium or potassium hydroxide
solution (the alkali metal hydroxide concentration is preferably
can be about 0.1-30% by weight) 100wt
Add the above extract or fraction to the amount
Add about 5 to 50 parts by weight and heat at about 25 to 90°C.
The reaction may be allowed to proceed for 0.5 to 5 hours. Polyp isolated and recovered by the method described above
R in Renyl fraction_fValue is 0.18-0.25
The fraction of A in the above formula () is₁Gahi
Multiple polypyrenes when representing a droxyl group
consists essentially of a mixture of R congeners, and R_f
Fractions with values between 0.50 and 0.55 are expressed in the above formula ().
Place A₁represents an acetyloxy group
From a mixture of several polyprenylacetate congeners
It becomes substantial. The former in the extract
The abundance ratio of the latter is approximately 1:20 to 1:5.
and also the polyprenos in each fraction
distribution of polyprenylacetate or polyprenylacetate congeners
The state (pattern) is roughly the same, and its distribution state
(pattern) is the type of plant used as raw material (i.e.
(Japanese cedar or Himalayan cedar), the youngness of the leaves and the harvesting period.
It remains almost constant regardless of factors such as region and region. Therefore, the fraction is generally
A compound of formula () (hereinafter referred to as polyprene-14)
), a compound of formula () where n is 15 (hereinafter referred to as poly
of the formula () where n is 16) and where n is 16.
At least one of the compounds (hereinafter referred to as polyprene-16)
Contains substantial amounts of each of the three essential components.
and the total content of these three types of compounds is
At least 70% weight based on cushion weight
%, preferably at least 75% by weight. Generally, the fraction contains polyprene-15
It contains a high content, and the content is
Usually 30-50% by weight, based on the weight of the
Typically in the range 32-47% by weight. Moreover, the fraction is generally made of polyprene.
14, Polyprene-15 and Polyprene-16 are unique
They are contained in a quantitative relationship, and the respective contents are a,
When b and c are weight%, the quantitative relationship is b>
It is normal that a>c. Additionally, the fraction contains polyprene-14.
Generally 20-35% by weight, more typically 23-32% by weight
%, and polyprene-16 generally 10-25% by weight
%, more typically 11-20% by weight (the
(based on the weight of the cushion). As mentioned above, the policy provided by the present invention
The prenyl composition (or fraction) is
Distribution of dolichols and polyprenol congeners
pattern, i.e. n and in the above formula ()
The distribution pattern of j in the above formula (A) is very similar.
It is distinctive in that it is
Distribution status of Ta dolichol (Human dolichol also
(showing almost the same distribution as Buta dolichol) and
The following is a comparison. In addition, inside the cutlet
The numbers indicate a more typical range. 【table】 The polyprenyl composition provided by the present invention is
Polyprenyl homologs of formula () shown in Table 1 above
The composition does not substantially contain any other ingredients.
The average value of n is usually within the range of 14.25 to 15.25.
be. Distribution state of polyprenyl congeners shown in Table 1 above
Also, it is clear from the comparison between formula () and formula (A) above.
As such, the polyprenyl group provided by the present invention
The composition has α of each polyprenyl compound in the composition.
- Attaching one saturated isoprene unit to the terminal
can induce mammalian dolichol by
can. In particular, the saturated isoprene to be combined
The unit is free from cis and trans configuration problems.
When bonding the saturated isoprene units, reaction is required.
There is no difficulty in operation. However, the present invention
Polyprenyl compositions provided by
An extremely important substance as a synthetic intermediate for Recall.
It can be said that there is. Polyprenyl compositions according to the invention can be administered to mammalian animals.
When inducing a recall, the composition
The composition may also be used, or if necessary, the composition
After isolating each polyprenyl compound constituting the
You can also make it correspond. However, the following description
In the case of the polyprenyl compound of the formula (),
This will be explained as a reaction to the polypropylene polymer.
Nyl compounds are polypropylene compounds with the distribution pattern described above.
It can be directly replaced with RENIL composition.
You should understand that there are certain things. The polyprenyl compound of formula () is combined with Dolico of formula (A).
In deriving the compound of formula () to its
or A in formula ()₁Other reactions
After substituting with a leaving atom or group with high properties, the saturated ionic acid
Can be reacted with Soprene unit introduction reagent
Ru. According to yet another aspect of the present invention,
If so, the general formula The polyprenyl compound represented by the general formula The following formula is obtained by reacting with a compound represented by In the above formulas () to (), X is a separable agent
Y represents MgHal or a lithium element;
represents a child, where Hal is a halogen atom;
Z is the formula −CH₂Represents the OH group or its functional precursor group.
eagle, I; [Formula] is trans isoprene Represents the unit; [formula] is cis type Represents an isoprene unit; n represents an integer from 11 to 19
Wasu, A compound represented by is produced, and Z is the functional precursor.
When representing a radical, the group is then replaced as necessary.
−CH₂The above formula is characterized by changing to OH
() Production of mammalian dolichols or their precursors
A manufacturing method is provided. In the above formula (), the leaving atom or group X and
As for hydroxyl group and acetyloxy group,
In addition, represented by Y in the above formula ()
Can be released by reacting with MgHal or lithium atoms.
Due to this, Y is bonded on the carbon where X was bonded.
A substance that has the property of causing a substitution reaction with the carbon
The following atoms or atomic groups are preferably mentioned.
group, i.e. halogen atoms, as well as the formula -
OCOR₁, −QR₂, −OPO(OR₃)₂,−SOR₃,−
S.O.₂R₃, −OCOOR₃, [Formula] [Formula] and selected from the group of [formula], where R₁teeth with hydrogen atoms, 1 to 3 fluorine or chlorine atoms
Substituted methyl group, alkyl group having 2 to 18 carbon atoms
Kyl or alkenyl group, 6 to 10 carbon atoms
aryl group or aralkyl group having 7 to 11 carbon atoms
represents a R group, R₂is a lower alkyl group, a lower alkyl group,
Kenyl group, aryl group having 6 to 10 carbon atoms, pi
Lysyl group, thiazolyl group, thiazolinyl group or
Represents a xazolyl group, R₃is a lower alkyl group,
Aryl group having 6 to 10 carbon atoms or number of carbon atoms
represents 7 to 11 aralkyl groups, Q is oxygen or
Represents a sulfur atom, and Hal is a halogen atom.
Ru. In addition, in this specification, the word "lower"
The group or compound with this term has the highest number of carbon atoms.
Contain up to 8 high, preferably up to 4
means. In the above definition, "1 to 3 fluorine or
is a methyl group substituted with a chlorine atom” is −
CH₂F, −CHF₂, −CF₃, −CH₂Cl, −CHCl₂and-
CCl₃are included, especially −CH₂F, −CF₃and −
CH₂Cl is preferred. In addition, alkyl groups and alkenyl are linear and branched.
be of either branched or cyclic type;
Examples of alkyl groups include methyl and ether.
chill, n-propyl, isopropyl, n-buty
, sec-butyl, isobutyl, tert-butyl,
n-pentyl, isoamyl, n-hexyl, n-
octyl, n-decyl, n-dodecyl, n-un
Decyl, stearyl, cyclopentyl, cyclohe
xyl, cycloheptyl, etc., and alkaline
Examples of the kenyl group include 3-butenyl and 3-pene.
tenyl, 4-pentenyl, geranyl, falnesi
oleyl, oleyl, etc. However, R₁to
"Alkyl having 2 to 18 carbon atoms"
Particularly preferred among the carbon and alkenyl groups are
Alkyl group having 2 to 6 atoms and 4 carbon atoms
~6 alkenyl groups, and R₂and R₃
"Lower alkyl group" and "lower alkyl group" represented by
methyl and ethyl groups, respectively.
n-propyl, i-propyl, butyl and vinyl
Nyl, 3-butenyl is particularly preferred. On the other hand, "aryl group having 6 to 10 carbon atoms"
The phenyl group and benzene nucleus are 1 to 3 low
phenyl groups substituted with alkyl groups, e.g.
Ruyl, xylyl, etc., as well as naphthyl groups are included.
"Aralkyl group having 7 to 11 carbon atoms"
In particular, substituted or unsubstituted phenyl groups
Substituted lower alkyl groups, such as benzyl,
enethyl, methylbenzyl, dimethylbenzyl,
Examples include α- or β-naphthylmethyl. Therefore, in the above formula (), represented by
Preferred examples of leaving atoms or groups include hydrogen.
In addition to the roxyl group and acetyloxy group, the following
I can list the following. (a) a halogen atom, such as chlorine, bromine or iodine;
atoms etc. (b) Formula −OCOR₁groups, such as formyl group, mono
Fluoroacetyloxy group, trifluoroacetate
thyloxy group, monochloroacetyloxy group,
Propionyloxy group, butyryloxy group,
tearoyloxy group, benzoyloxy group,
3,5-dimethylbenzoyloxy group, 4-ethyloxy
tilbenzoyloxy group, etc. (c) Formula −QR₂groups, such as methoxy, ethoxy
group, phenoxy group, 2-pyridyloxy group, 2
-Benzothiazolyloxy group, 2-benzoyloxy group
Sazolyloxy group, trimethylsilyloxy
group, dimethyl-t-butylsilyloxy group,
thylthio group, ethylthio group, phenylthio group,
Tolylthio group, 2-thiazolylthio group, 2-benzene
ndzothiazolylthio group, 2-benzoxazoli
ruthio group, 2-pyridylthio group, etc. (d) Formula −OPO(OR₃)₂groups, e.g. dimethyl phosphorus
Phonooxy group, diethylphosphonooxy group, di
phenylphosphonooxy group, etc. (e) Formula −SOR₃groups, e.g. methylsulfinyl
group, ethylsulfinyl group, propylsulfinyl group
Nyl group, phenylsulfinyl group, 4-tolyl
such as sulfinyl groups. (f) Formula −SO₂R₃groups, such as methylsulfonyl groups,
Ethylsulfonyl group, propylsulfonyl group,
Phenylsulfonyl group, 4-tolylsulfonyl
base etc. (g) Formula −OCO₂R³groups, e.g. methoxycarbonyl
Oxy group, ethoxycarbonyloxy group, pro-
Poxycarbonyloxy group, phenoxycarbo
Nyloxy group, 4-triloxycarbonyloxy group
Shi group etc. (h) a group of the formula [formula], such as N,N-dimethyl; Tylcarbamoyloxy group, N,N-diethyl
Carbamoyloxy group, N,N-dipropylcarbohydrate
Rubamoyloxy group, N,N-diphenylcar
Bamoyloxy group, N-phenyl-N-ethyl
carbamoyloxy group, etc. (i) a group of the formula [formula], for example trimethyl; Ammonium bromide group, triethyl ammonium
umiodide group, diphenylethyl ammo
such as nium bromide group. (j) a group of formula [formula], for example dimethyl Sulfonium bromide group, diethylsulfonium
Muiodide group, dipropylsulfonium group
Lomido group, phenylethylsulfonium bromide group
do group etc. Using the compound of formula () above in isolated form
In this case, one in which n is 15 is particularly suitable. On the other hand, before being reacted with the compound of formula ()
In the compound of the formula (), Z is the formula -CH₂OH
or its functional precursor group, where the function
The precursor group may be subjected to treatments such as hydrolysis or hydrogenolysis.
Protected with a protecting group that can be easily removed by
Droxymethyl and aldehyde groups are included, followed by
After deprotection, the aldehyde group of
complex metal hydride reducing agents, e.g. hydrogenation
Sodium boron, lithium borohydride, hydrogen
Lithium aluminum oxide, aluminum hydride
Hydroxymethyl is produced by reduction with thorium etc.
It can be changed to the base. However, as a specific example of such a functional precursor group,
The following can be mentioned. (1) Formula −CH₂OR_Fourthe basis of In the formula, R_Fouris a lower alkyl group, carbon number 7
~11 aralkyl groups, containing 1 to 8 carbon atoms
Aliphatic or cycloaliphatic ether residue or formula
Represents a silyl group of [Formula], where R₅₁, R₅₂and R₅₃are lower alkyl groups or fluorine groups, respectively.
Represents an enyl, tolyl or xylyl group. As an example, −CH₂OCH₃, −CH₂O.C.₂H_Five,−
CH₂O.C.₃H₇, −CH₂O.C._FourH₉, −CH₂O.C._FiveH₁₁,−
CH₂OCH₂OCH₃, −CH₂OCH₂O.C.₂H_Five,−
CH₂O.C.₂H_FourOCH₃, −CH₂O.C.₂H_FourO.C.₂H_Five,−
CH₂O.C.₃H₆OCH₃, −CH₂O.C.₃H₆O.C.₂H_Five,−
CH₂O.C.₂H_FourO.C.₂H_FourOCH₃,−
CH₂OCH₂O.C.₂H_FourOCH₃,
[Formula] [Formula] 【formula】 【formula】 【formula】 【formula】 【formula】 【formula】 −CH₂OSi(CH₃)₃, −CH₂OSiCH₃(C₂H_Five)
(C₃H₇), −CH₂OSi(CH₃)₂C_FourH₉-t,-
CH₂OSi(t-C_FourH₉)(C₆H_Five)₂, −CH₂OSi
(C₆H_Five)₃ etc. (2) Group of formula [formula] In the formula, Q₁and Q₂are oxygen or sulfur respectively
Represents an atom; R₆₁and R₆₂are lower class a
represents a rukyl group or together represents a lower
Represents an alkylene group. As an example, [Formula] [Formula] 【formula】 [Formula] [Formula] 【formula】 [Formula] [Formula] 【formula】 [Formula] [Formula] 【formula】 [Formula] [Formula] 【formula】 [Formula] [Formula] 【formula】 etc. Most of the compounds of formula () are known.
new compounds can be easily produced based on known compounds.
can be built. The compound of formula () and the opposite of the compound of formula ()
The response can be carried out by methods known per se.
For example, the reaction is generally carried out in an inert organic solvent.
It is desirable to do this at a later date. As a solvent to use
For example, diethyl ether, diisopropylether
ether, dioxane, tetrahydrofuran, dimethane
Toxyethane, diethylene glycol dimethyl ethane
The main solvents are ether solvents such as
used. This includes hexane, benzene, etc.
hydrocarbons, hexamethylphosphoramide, etc.
It is also possible to combine some of them and use them as a mixed solvent.
It is Noh. Among these, a particularly suitable solvent is tetra
It is hydrofuran. Also, the conversion of formula () to the compound of formula ()
The proportion of compounds used is not critical, and the formula used
() and/or depending on the type of compound of formula (), etc.
can vary widely, but in general the formula
0.5 of the compound of formula () per mole of the compound of ()
~10 moles, preferably 1 to 6 moles, more preferably
It is desirable to use within the range of 1.5 to 4 moles.
stomach. The reaction may be carried out in the absence or presence of a catalyst.
I can do it. In the absence of a catalyst, the reaction generally takes about 0
℃ to the reflux temperature of the reaction mixture, preferably about 0
Advantageously, it is carried out at temperatures between 80°C and about 80°C;
In addition, as the raw material compound of formula (), especially
Halogen atom, -OPO(OR₃)₂, oxazolyl
represents a cy group or a pyridyloxy group, where R₃
uses a compound of formula () as defined above.
It is advantageous to have one. On the other hand, when carrying out the reaction in the presence of a catalyst,
Catalysts that can be used include copper, nickel and palladium.
Examples of copper catalysts include copper catalysts.
Copper () compounds such as CuCl, CuBr, CuI, CuOAc
Things; Li₂CuCl_Four,CuCl₂,CuBr₂,CuI₂, Cu
(OAc)₂,Cu(CH₃COCHCOCH₃)₂Copper ()
Examples of nickel catalysts include compounds such as
Nickel complex; NiCl₂, NiBr₂,NiI₂, Ni
(NO₃)₂, Ni(CH₃COCHCOCH₃)₂Nitsuke such as
Pal() compounds etc. can be used;
Examples of radium catalysts include palladium complexes;
PdCl₂, Pd(OAc)₂, Pd(NO₃)₂, Pd
(CH₃COCHCOCH₃)₂Palladium () such as
Compounds, etc. are included. Among these catalysts, Y is used as the starting material.
When using a compound of formula () representing MgHal
Copper () or () catalysts are suitable for
On the other hand, using a compound of formula () where Y represents lithium,
In such cases, copper() catalysts are preferred. Kaka
In the former case, the amount of copper catalyst used is calculated using the formula ().
Generally 0.001 to 1.0 equivalents per mole of compound, preferably
is a proportion of 0.001 to 0.1 equivalent, and in the latter case
1 to 5 equivalents per mole of the compound of formula (), preferably
Preferably, the ratio can be 1.2 to 3 equivalents. In the presence of the above catalyst, the compound of formula () and the formula
The reaction temperature when reacting the compounds in () is
Generally in the range of -30°C to +30°C, preferably -20°C to
+20℃ range is appropriate, and the formula used
As a preferable group of X in the raw material compound of ()
is an acetyloxy group, -OCOR₁, −OCOOR₃,
[Formula] [Formula] Oxa Examples include zolyloxy and pyridyloxy groups.
, here R₁,R₃and Hal as defined above
It is. In addition, do not use too much catalyst and/or
When reacting at too high a temperature, the following formula In the formula, Z and n are as defined above, and
The isomer of the compound of formula () shown below is produced as a by-product.
This can lead to the formation of such isomers.
It is important to choose conditions that are as few as possible. Thus, the following formula In the formula, Z and n are as defined above, and
The indicated compound is obtained in good yield. of this compound
Separation and purification from the reaction mixture is performed by methods known per se.
method, e.g. using silica gel or alumina.
Romatography method, fractional dissolution method, molecular distillation method, etc.
This can be done using the following method. Removal of the protecting group from the compound of formula () is itself
The compound can be hydrolyzed or dissolved in water according to known methods.
This can be done by subjecting it to elementary addition decomposition.
Ru. For example, Z is of the formula -CH₂-O-R_Fourrepresents the group of
I and R_FourWhen represents a lower alkyl group,
The compound of formula () is converted into tetrahydrofuran, chloro
at room temperature in a solvent such as form or methylene chloride.
By treating with trimethyl iodide
can be deprotected and also in the group of the above formula
R_FourWhen represents an aralkyl group, ethyl
In a solution of lithium in amine, the formula () is
Add a tetrahydrofuran solution of the compound dropwise and react
After completion, remove excess lithium with e.g. saturated ammonium chloride.
deprotection by decomposition with an aqueous solution of
, and R in the group of the above formula_Fouris an ether residue
When representing the compound of formula (), for example,
Mixing of xane/ethanol [approximately 1/1 (volume ratio)]
After dissolving in the solvent, paratoluene sulfate is added to the solution.
Pyridine phonate (preferably about 0.1-0.2 equivalents)
In addition, react at a temperature of approximately 50 to 60°C for several hours to complete the reaction.
After completion, neutralize the reaction mixture with sodium carbonate, etc.
Furthermore, the above can be deprotected by
R in the group of formula_FourWhen represents a silyl group,
A solution of the compound of formula () in tetrahydrofuran is
tra-n-butylammonium fluoride (preferably
or about 2 equivalents) and stir overnight at room temperature.
Deprotection can be achieved by On the other hand, Z represents a group of the above formula [formula] And Q₁and Q₂does not represent a sulfur atom at the same time.
If the compound of formula () is
For example, dilute
Treat with hydrochloric acid (preferably at a concentration of about 10%).
By changing Z to an aldehyde group (-CHO)
and Q in the group of the above formula₁
and Q₂If at the same time represents a sulfur atom, then the formula
equivalent or more to the acetone solution of the compound (V)
HgCl₂and CdCO₃Add a small amount of water and leave at room temperature for several hours.
The group is converted into an aldehyde group by reaction.
can be done. The aldehyde group converted in this way is mild
For example, by reducing water under suitable reducing conditions,
Sodium borohydride, lithium borohydride,
Lithium aluminum hydride, aluminum hydride
reduction using complex metal hydrides such as sodium
Hydroxymethyl group -(CH₂OH)
can be changed to The reduction is known per se.
For example, hydrogenation
When using sodium boron, alcohol,
In solvents such as tetrahydrofuran and ether, approx.
It is desirable to carry out the reduction reaction at 0°C to room temperature.
Also, lithium borohydride, aluminum hydride
sodium lithium or sodium aluminum hydride
When using anhydrous ether, anhydrous tetra
In an anhydrous solvent such as hydrofuran at about -30℃ to room temperature
It is advantageous to carry out the reduction reaction at room temperature. After the reduction reaction is complete, the reaction mixture is diluted with water and alcohol.
Remove excess reducing agent by treating with water, ethyl acetate, etc.
After understanding the results, we decided to perform separation and purification using conventional methods.
The target alcohol [in the above formula ()]
Compounds in which Z represents a hydroxymethyl group]
It can be obtained in high yield. Mammalian dolichol synthesized as above
As mentioned above, it is used in fields such as pharmaceuticals and cosmetics.
It is useful as a valuable physiologically active compound. In addition, in the compound of the above formula (), X is
Breakability of groups other than droxyl and acetyloxy groups
Compounds when representing atoms or groups, i.e.:
formula In the formula, A₂is a halogen atom or the formula -
OCOR₁, −QR₂, −OPO(OR₃)₂,−SOR₃,−
S.O.₂R₃, −OCOOR₃,【formula】 [Formula] or group of [Formula] , where R₁is a hydrogen atom, 1 to 3 atoms
Methyl group substituted with nitrogen or chlorine atom, carbon
Alkyl or alkenyl having 2 to 18 atoms
group, aryl group having 6 to 10 carbon atoms, or carbon atom
Represents an aralkyl group having 7 to 11 children, R₂is low
class alkyl group, lower alkenyl group, number of carbon atoms 6
~10 aryl, pyridyl, thiazolyl groups
group, thiazolinyl group or oxazolyl group.
,R₃is a lower alkyl group, 6 to 10 carbon atoms
aryl group or aralkyl group having 7 to 11 carbon atoms
represents a sulfur group, and Q represents an oxygen or sulfur atom.
and Hal is a halogen atom; [Formula] is trans isoprene Represents the unit; [formula] is cis type Represents an isoprene unit; n is an integer from 11 to 19.
Ru, The polyprenyl compound represented by
This is a novel compound. Compound of the above formula ()
to the compound of the above formula (), i.e. the formula
A in ()₁A₂The method to change it to
Yes, and can be done for example as follows:
Ru. (1)A₂Formula () when represents a halogen atom
Compounds of: A₁Formula () when represents a hydroxyl group
compound with a halogenating agent such as trihalide
Halogenation with ion, thionyl halide, etc.
It can be obtained by The halogenation is an example
For example, in a solvent such as hexane, diethyl ether, etc.
With bases such as pyridine and triethylamine,
-20℃ to +50℃ in the presence or absence of
Adding the above halogenating agent dropwise at
This can be done by (2)A₂GA-OCOR₁Expression () to represent
Compound: A₁Formula () when represents a hydroxyl group
For esterification or transesterification of compounds of
Therefore, it can be manufactured. For example, beauty salon
The compound of formula () is converted into about 1 to 10 equivalents of
desired acid anhydride or acid halide in the presence of lysine.
(preferably about 1 to 5 equivalents) and about -30°C to +
This is done by reacting at a temperature of 50°C.
I can do it. (3)A₂is −QR₂Combination of formula () when representing
thing: A manufactured as described in the preceding paragraph (1)₂Gaha
Compounds of formula () when representing a rogen atom
In the presence of a base, the formula R₂Al denoted by QH
obtained by the action of choles or thiols.
can be done. Also, Q represents an oxygen atom
The compound in case is A₁represents a hydroxyl group
If the compound of formula () has formula R₂Hal's Halide
(Here, Hal represents a halogen atom)
It can also be synthesized by In the above reaction, the raw material compound is generally dimethyl fluoride.
In solvents such as lumamide, tetrahydrofuran, etc.
Sodium hydride, n-butyllithium etc.
At room temperature or under cooling in the presence of a base, the above
Treated with alcohol or thiol or halide
This can be done by understanding. (4)A₂is −OPO(OR₃)₂Expression () to represent
Compounds of: This compound is A₁represents a hydroxyl group
The compound of formula () is mixed with chloroform and methane.
In a solvent such as lene chloride, approximately equivalent or
in the presence of pyridine, usually at about 0°C to
At very room temperature, the formula ClOPO(OR₃)₂indicated by
By reacting with phosphorochloridate
Obtainable. (5)A₂-SOR₃Combination of formula () when representing
thing: This compound is produced as described in the previous section (3).
A₂ga-SR₂Compounds of formula () when representing
a small excess of an oxidizing agent, e.g. sodium periodate.
Produced by oxidizing with hydrogen peroxide
can do. The oxidation is aqueous methanol,
Usually carried out at room temperature in aqueous acetone etc.
I can. (6)A₂ga-SO₂R₃Expression () to represent
Compound: This compound is produced as described in the previous section (1).
A₂Formula () when represents a halogen atom
compound in dimethylformamide, tetrahydrogen
Temperatures from room temperature to approximately 70°C in a solvent such as Dorofuran.
In degrees, the formula R₃S.O.₂To react with Na
You can get more. (7)A₂ga-OCO₂R₃The expression when expressed as ()
Compounds of: This compound is A₁has a hydroxyloxy group
When the compound of formula () is expressed as a base, e.g.
HalCO in the presence of lysine₂R₃Halo charcoal indicated by
can be obtained by reacting with an acid ester
can. (8)A₂Expression when represents [expression] Compound (): This compound is A₁represents a hydroxyl group
Butyl compound of formula () in a suitable solvent
in the presence of a base such as lithium at about 0°C to room temperature.
Carbamoyl of formula [formula] at temperature produced by reacting with a halide
I can do it. (9)A₂Expression when represents [expression] Compound (): This compound is produced as described in the previous section (1).
A₂Formula when represents a halogen atom (Hal)
Compound () is generally added in large excess at room temperature.
By reacting with amine [formula] Obtainable. (10)A₂Expression when represents [expression] Compound (): This compound is produced as described in the previous section (3).
A₂ga-SR₃Compounds of formula () when representing
The formula R₃Let Hal's alkyl halide act
or manufactured as described in the preceding paragraph (1).
A₂When represents a halogen atom, the formula () is
The compound has the formula R₃-S-R₃The sulfide of
It can be manufactured by Next, the present invention will be explained more specifically with reference to Examples.
do. IR analysis in the examples uses liquid film for oily substances,
Solids were measured using KBr tablets, and NMR analysis was
Measurements were made using TMS as an internal standard. FD−MASS minute
Analysis is¹H,¹²C,¹⁴N,¹⁶O,¹⁹F,²⁸Si,
³¹P,³²S,³⁵Cl,⁷⁹This is the value corrected as Br.
Ru. Example 1 Yellow leaves collected in Tokyo from late autumn to early winter
Add 5 kg (undried weight) of yam leaves to a mixer.
After grinding into small pieces with
Mixture of oil ether/acetone = 4/1 (volume ratio)
Extracted using solvent (100). Wash the extract with water
After drying with anhydrous sodium sulfate, remove the solvent.
The residue was removed to give about 100 g of residue. n- to this one
Add 1 part of hexane to dissolve n-hexane soluble components.
After dissolving, filtering and concentrating the filtrate, apply it to a silica gel column.
using n-hexane/diethyl ether = 95/
n-hexane/acetic acid with a mixed solvent of 5 (volume ratio).
Silica using mixed solvent with chill = 9/1 (volume ratio)
Kagel thin layer chromatography (manufactured by Merck & Co., Ltd.)
TLC plate silicagel 60F₂₅₄precoated, layer thickness 0.25
R at 10cm expansion using mm_f=0.52
The fractions were separated to give about 17 g of an oil.
In this thin layer chromatography, solanecil
Acetate has an R of 0.41_fThe value was shown. This oily substance
200ml methanol, 20ml water and sodium hydroxide
After heating at 65℃ for 2 hours with 10g of methanol,
The residue was dissolved in diethyl ether (300ml).
Add and extract the ether layer with about 50ml of water 5 times.
After washing with water, dry with anhydrous sodium sulfate and remove the solvent.
was distilled off to obtain 10.3 g of oil. This oily substance
It is a polyprenol with a purity of 95% or more,
About this μ−Bondapak−C₁₈(C₁₈charcoal
silica gel surface treated with hydrogenated compound)
As a filler, acetone/methanol = 90/10 (by volume)
Using a mixed solvent of
For high performance liquid chromatography used as a
of each peak in the chromatogram obtained from
The area ratios were calculated and summarized in Table 5 below. In addition, Merck's semi-preparative high performance liquid chromatography
Column (C₁₈Type) using RD18-10, aceto
Mixed solvent of methanol/methanol = 90/10 (volume ratio)
By using it as a developing agent, the above oily substance
Separate each component from (polyprenol content 95% or more)
sample, mass spectrometry, infrared absorption spectrum,¹H-
NMR spectrum and¹³C-NMR spectrum
The structure of those components is represented by the general formula (1).
It was confirmed that the polyprenol contained in Field ionization mass spectrometry (FD-
MASS) results and¹Table of H−NMR δ values
2,¹³The C-NMR δ values are summarized in the third section.
Ta.¹In the H-NMR data, (b) is a broad signal;
(d) is a double line signal, (t) is a triple line signal.
means. 【table】 【table】 【table】 Example 2 A non-yellowed irises collected in Kurashiki City at the end of October.
10 kg (undried weight) of Chiyo leaves at approximately 40℃ for 24 hours
After drying with hot air, chloroform for 7 days at room temperature (approximately 15℃)
It was extracted by immersion in Form 80. Is this the extract?
Petroleum ether was added to the concentrate obtained by distilling off the chloroform.
Add ether 5, filter out insoluble components, and collect the filtrate.
After concentration, silica using chloroform as a developing solvent.
Same as used in Example 1 by Kagel column.
R by the same thin layer chromatography method._f=0.50
0.19 fraction was separated and approximately 37g of oil was obtained.
Ta. Add about 400 ml of acetone to this oil and acetate.
Dissolve the soluble components and filter the resulting mixture
The filtrate was concentrated, and the resulting oil was dissolved in methanol.
400 ml, together with 40 ml of water and 20 g of sodium hydroxide.
After heating to 65℃ for 2 hours, methanol was distilled off.
and add diethyl ether (500ml) to the residue.
Wash the ether layer 5 times with approximately 100ml of water.
After that, dry with anhydrous sodium sulfate and distill off the solvent.
Removal gave 24.2 g of oil. Next, this oil was mixed with about 1 kg of silica gel.
n-hexane/isopropyl ether = 90/10
Perform the above thin layer chromatography using a mixture of (volume ratio)
R by_f= 21.8 by separating the fraction of 0.19
g of oil was obtained. This oil has a purity of over 95%
It is a polyprenol with
The molecular weight distribution was measured using the same method as in Example 1.
It is shown in Table 5. Example 3 Igyou leaves collected in Kurashiki City in mid-June 5
Kg (wet weight) was measured according to the method of Example 1.
Do not perform saponification reaction with sodium hydroxide.
8.7 g of oil was obtained. this thing
is polyprenylacetate with a purity of over 90%
This is the same high speed as in Example 1.
Liquid chromatography [However, acetone/meth
Use a mixture of 70/30 (volume ratio) as a developing agent.
[use] to find the area ratio of each peak, and then
It is shown in Table 5. Also, as in Example 1, semi-preparative high-performance liquid chromatography
using a matocolumn [however, acetone/methanol
= 7% (by volume) mixed solvent is used as a developing agent.
] Separate each component, FD-MASS, IR,¹H-
NMR and¹³These results were determined by C-NMR analysis.
Polyprenylacetic acid whose components are represented by the general formula ()
I confirmed that it was Tate. high performance liquid chromatography
Table 5 below shows the area ratio of each peak based on graphi.
The FD-MASS analysis values of these components are shown in
Shown in the table below. 【table】 Example 4 Approximately 100 yen leaves collected in Kurashiki City at the end of October
After drying with hot air at 60℃ for 65 hours, 100g of each
Separately, soak in solvent 1 shown in the table for 7 days.
Extraction was performed at room temperature (approximately 25°C). The concentrated solution obtained by distilling off the extraction solvent from these extracts is
Measure the weight of the condensate and summarize it in the table as the total amount of extract.
I met. Dissolve these concentrates in 200 ml of hexane and
The solution was mixed with methanol/water = 9/1 (volume ratio).
After washing three times with approximately 100 ml of the combined solution, wash with anhydrous sulfuric acid macerate.
Dry with magnesium and remove the solvent to obtain an oil.
Ta. Mix this oil with 50ml of methanol and potassium hydroxide.
After heating with 1g at 65℃ for 2 hours, methanol
evaporate and add diethyl ether (100ml) to the residue.
Add 50 ml of saturated salt to the ether layer.
After washing three times with water, drying with anhydrous magnesium sulfate.
After drying and evaporating the solvent, an oil was obtained. this oily substance
using 100g of silica gel in n-hexane/acetic acid.
Separate with a mixture of ethyl = 9/1 (volume ratio) and poly
The prenol mixture was dispersed. Polyp at this time
Table 4 shows lenol weight as polyprenol content.
Shown all together. The composition of the obtained polyprenol mixture is
Substantially in Example 2 regardless of the type of solvent used.
Consistent with that of the obtained polyprenol mixture
there was. 【table】 In the table, the numerical ratio for miscible solvents is the capacity.
means ratio.
Example 5 Himalayan cedar leaves collected in Kurashiki City in late May
22.1 by performing the same operation as shown in Example 2 for 10Kg.
g of oil was obtained. Example 1 about this oily substance
Table 5 shows the molecular weight distribution measured using the same method as
Ta. 【table】 content
total
Example 6 Synthesis of polyprenylacetate Polyp of general formula () where n=15, X=OH
Dry 1.24 g of lenol and 1.0 g of pyridine.
acetic anhydride at room temperature in a solution dissolved in thyl ether.
Add 1.2g dropwise, and after the addition is complete, stir overnight at room temperature.
Ta. The resulting reaction mixture was washed with saturated brine,
Then dried over anhydrous sodium sulfate and diluted with diethyl
The ether was distilled off to obtain a pale yellow viscous liquid. child
Silica gel column chromatography
(using hexane/ethyl acetate as developing solution)
Further purification yielded 1.08 g of a slightly yellow liquid. this thing
According to IR analysis, it is approximately 3300cm^-1raw material port
The absorption caused by the OH group of liprenol disappears,
−OCOCH₃Due to 1745cm^-1and 1255cm^-1Suction
A profit appeared. In addition, where NMR analysis was performed
-C of filtration raw material polyprenolH ₂attributed to OH
The signal (doublet, δ = 4.08) disappears, and −C
A new signal (doublet, δ4.55) assigned to H ₂ OCOCH ₃ was observed. _-CH2OCOCH3 _ _{_}
The signal that should be attributed to [Formula] was observed to overlap with the signal (δ = 2.04) that should be attributed to [Formula]. Also, according to FD-MASS analysis, m/e=1284
I got it. From the above, this liquid has n=15 and X=
It was confirmed that it is a polyprenylacetate of the general formula (), which is OCOCH ₃ . Polyprenyl acetates with n other than 15 and polyprenyl acetate mixtures with n arbitrarily distributed between 11 and 19 were also synthesized by similar operations. Example 7 Synthesis of polyprenyl bromide 12.4 g of polyprenol of general formula () where n=15, X=OH and ml of pyridine were mixed into 200 ml of n-
in hexane and the resulting solution at room temperature (approx.
2.0 g of phosphorus tribromide was added dropwise under a nitrogen gas atmosphere at a temperature (°C) under a nitrogen gas atmosphere, and after the dropwise 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 about 50 ml of water, dried over anhydrous magnesium sulfate, and the n-hexane was distilled off to obtain 12.0 g of a slightly yellow liquid.
When this product was analyzed by NMR, the signal (doublet, δ = 4.08) assigned to the -CH ₂ OH group of the raw material polyprenol disappeared, and the signal was newly assigned to -CH ₂ Br. A signal (doublet, δ=3.91) appeared. Furthermore, when this liquid was analyzed by FD-MASS, m/e=
It was 1304. According to these analysis results, the above product has the general formula [] where n=15 and A ₂ =Br
It was confirmed that it was polyprenyl bromide. By similar operations, polyprenyl bromides with n other than 15 and polyprenyl bromide mixtures with n arbitrarily distributed between 11 and 19 were also synthesized. 0.66 g of the above polyprenyl bromide (n=15) was dissolved in 10 ml of dimethylformamide, 1.0 g of anhydrous sodium acetate was added thereto, the mixture was stirred overnight at about 50°C, and then about 50 ml of diethyl ether was added and filtered.
The filtrate was washed 10 times with about 20 ml of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 0.58 g of a pale yellow liquid. This material matches the polyprenylacetate (n=15) obtained in Example 6 in the NMR spectrum and m/e value determined by FD-MASS analysis, n=15, X=
It was confirmed that it was a polyprenylacetate of the general formula [], which is OCOCH ₃ . Example 8 Synthesis of polyprenyl chloride 12.4 g of polyprenol of the general formula () where n = 15, X = OH and 1.0 ml of pyridine were mixed into 200 ml of n-
1.5 g of thionyl chloride was added dropwise to the resulting solution at room temperature under a nitrogen gas atmosphere.
After the dropwise addition was completed, the mixture was further stirred at room temperature for 2 hours. This reaction mixture was then worked up 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, when NMR analysis was performed, the signal attributed to -CH ₂ OH of the raw material polyprenol disappeared, and a new signal (doublet, δ = 3.95) attributed to -CH ₂ Cl appeared. . Also FD−
MASS analysis gave m/e=1260. From the above, it was confirmed that the above product was a polyprenyl chloride of the general formula [] where n=15 and A ₂ =Cl. By similar operations, polyprenyl chlorides with n other than 15 and polyprenyl chloride mixtures with n arbitrarily distributed between 11 and 19 were also synthesized. Example 9 Synthesis of polyprenyl formate 0.8 ml of anhydrous sulfuric acid and 2 ml of 99% formic acid were mixed under ice cooling and stirred at room temperature for 2 hours. ] 1.24 g of polyprenol was added, and the mixture was stirred for 1 hour under ice-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. Although this product was very unstable, IR analysis revealed that the absorption caused by the OH groups of the raw material polyprenol disappeared, and absorptions caused by the -OCOH groups appeared at 1725 cm ^-1 and 1160 cm ^-1 . Furthermore, upon NMR analysis, a signal (singlet, δ=7.90) attributed to the -OCOH group was observed. From the above, this liquid has n=15 in the general formula [],
It was confirmed that the compound was A ₂ =-OCOH. Polyprenyl formate other than n=15 and n
A polyprenyl formate mixture with randomly distributed between 11 and 19 was also synthesized by a similar operation. Example 10 Synthesis of polyprenyl trifluoroacetate 1.24 g of polyprenol of general formula [ ] where n = 15, X = OH and 1.0 g of pyridine were dissolved in 10 ml of methylene chloride, and trifluoroacetic anhydride was added to the solution at 0 to 5°C. After dropping 0.5 g of the product, 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. When this product was subjected to IR analysis, absorption due to OH dilution of the raw material polyprenol disappeared, and absorption due to trifluoroacetate appeared at 1790 cm ^-1 , 1210 cm ^-1 and about 1140 cm ^-1 . As a result of NMR analysis, the signal attributed to -CH ₂ OH of the raw material polyprenol disappeared, and a new signal (doublet, δ = 4.72) attributed to -CH ₂ OCOCF ₃ was observed.
Moreover, m/e=1338 was obtained by FD-MASS analysis.
From the above, this liquid has n=15 and A ₂ =
It was confirmed that it was a compound of the general formula [], which is OCOCF ₃ . Polyprenyl trifluoroacetates with n other than 15 and polyprenyl trifluoroacetate mixtures with n arbitrarily distributed between 11 and 19 were also synthesized by similar operations. Example 11 Synthesis of polyprenyl monochloroacetate 1.24 g of polyprenol of the general formula [ ] where n = 15 and X = OH and 1.0 g of pyridine were dissolved in 10 ml of methylene chloride, and 0.4 g of monochloroacetic anhydride was added at 0 to 5°C. g was added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was then worked up in the same manner as in Example 10 to obtain 1.30 g of a pale yellow liquid, which was further purified by silica gel column chromatography (using hexane/ethyl acetate as a developing solution) to obtain 1.25 g of a pale yellow liquid.
g of liquid was obtained. When this product was subjected to IR analysis, the absorption caused by the OH groups of the raw material polyprenol disappeared, and the absorption caused by C=O appeared at about 1750 cm ^-1 . As a result of NMR analysis, the signal assigned to -CH ₂ OH of the raw material polyprenol disappeared, and a new signal assigned to -CH ₂ OCOCH ₂ Cl (doublet, δ = 4.57) and -OCOC H ₂ A signal (singlet, δ=3.93) attributed to Cl appeared. Also, according to FD-MASS analysis, m/e=1318
I got it. From the above, this liquid has n=15 and A ₂
It was confirmed that it was a compound of the general formula [ ] where = OCOCH ₂ Cl. Polyprenyl monochloroacetates with n other than 15 and polyprenyl monochloroacetate mixtures with n arbitrarily distributed between 11 and 19 were also synthesized by similar operations. Example 12 Synthesis of polyprenyl propionate 1.53 g of propionic anhydride instead of acetic anhydride
The same operation as in Example 6 was carried out except that 1.02 g of a pale yellow liquid was obtained. When this was analyzed by IR, the absorption caused by the OH group of the raw material polyprenol disappeared, and the absorption caused by -OCOC ₂ H ₅ was 1740 cm ^-1 and 1250 cm
^-1 absorption appeared. When NMR analysis was performed, the signal assigned to -CH 2 OH of the raw material polyprenol disappeared, and a signal assigned to -CH ₂ OCOC ₂ H ₅ (doublet, _δ = 4.56) was observed. . Also, according to FD-MASS analysis, m/e=1298
I got it. From the above, this liquid has n=15 and A ₂
It was confirmed that it was a compound of the general formula [], which is =-OCOC ₂ H ₅ . Polyprenyl propionates with n other than 15 and polyprenyl propionate mixtures with n arbitrarily distributed between 11 and 19 were also synthesized by similar operations. Example 13 Synthesis of polyprenyl oleate () 1.24 g of polyprenol of the general formula [ ] where n = 15, X = OH, 0.5 g of methyl oleate
and 0.01g of sodium hydride in 50ml of toluene
The mixture was heated at 110°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. This product was purified by silica gel column chromatography (using hexane/ethyl acetate as a developing solution) to obtain 0.48 g of a colorless viscous liquid. IR analysis of this liquid revealed that the absorption caused by the OH groups in the raw material polyprenol had disappeared. Furthermore, m/e=
Gave 1506. From the above, this product has the general formula [ ] where n = 15 and A ₂ = -OCO- (CH ₂
−) ₇ CH=CH−(CH ₂ −) ₇ CH ₃ was confirmed. () 1.17 g of polyprenol of the general formula [] where n=14, X=OH, 0.3 g of methyl oleate
and 0.05g of sodium hydroxide in 50ml of toluene
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, in the general formula [], n=
14, A ₂ = −OCO− (CH ₂ −) ₇ CH=CH− (CH ₂ −)
The compound was confirmed to be ₇ CH ₃ . Example 14 Synthesis of polyprenyl stearate In the general formula [ ], n = 15, X =
The transesterification reaction of OH polyprenol and methyl stearate produced a pale yellow liquid 1.2
I got g. FD-MASS analysis of this product revealed that in the general formula (), A ₂ is CH ₃
It gave m/e=1508 indicating that it is a polyprenyl compound with (CH ₂ ) ₁₆ COO group and n=15. Example 15 Synthesis of polyprenyl benzoate 0.28 g of benzoyl chloride was added at room temperature to a mixture of 1.24 g of polyprenol of the general formula [] where n=15 and X=OH and 10 ml of pyridine, and the mixture was stirred overnight at room temperature. The reaction mixture was then poured into about 150 ml of water, extracted with diethyl ether, and the resulting ether layer was washed with saturated brine, diluted hydrochloric acid, water, saturated sodium bicarbonate, and again with saturated brine, and then washed with anhydrous sulfuric acid. Drying over magnesium and distilling off the ether gave a yellow liquid. This was purified by silica gel column chromatography (using hexane/ethyl acetate as the developing solvent) to obtain a 0.92
g of a pale yellow liquid was obtained. When this product was subjected to IR analysis, absorption due to the OH groups of the raw material polyprenol disappeared, and absorption due to ester bonds appeared at 1715 cm ^-1 and 1270 cm ^-1 . Also FD−
MASS analysis gave m/e=1346. From the above, this liquid substance has the general formula []
It was confirmed that this is a compound in which n=15 and A ₂ =OCOC ₆ H ₅ . By similar operation, n becomes 15
Polyprenyl benzoate other than and n is 11 to 19
Polyprenyl benzoate mixtures arbitrarily distributed in the molecule were also synthesized. Example 16A Synthesis of polyprenyl methyl ether 1.24 g of polyprenol of the general formula [ ] where n = 15 and X = OH is dissolved in 10 ml of anhydrous diethyl ether hexane [1:1 (volume ratio)], and n-butyl 0.69 ml (1.1 mmol) of lithium (1.6M hexane solution) 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) to obtain 1.14 g of a pale yellow liquid.
When this material was analyzed by IR, the absorption caused by the OH group of the raw material polyprenol disappeared, and the absorption was 1120 cm ^-1 ,
Absorption due to ether bonds appeared at 1100 cm ^-1 and 1080 cm ^-1 . In the NMR analysis, a signal assigned to -OCH ₃ appeared at δ=3.27. FD−
MASS analysis gave m/e=1256. From the above, it can be seen that this liquid substance has n in the general formula []
= 15, _A2 = _-OCH3 . In addition, polyprenyl methyl ethers with n=15 and polyprenyl methyl ether mixtures with n arbitrarily distributed between 11 and 19 were also synthesized by similar operations. Example 16B Synthesis of polyprenyl phenyl ether Dimethoxyethane 30 was prepared by heating 168 mg of finely ground potassium hydroxide and 310 mg of phenol to about 60°C.
ml, add 1.30 g of polyprenyl bromide of the general formula [] where n = 15 and A ₂ = Br,
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 washed twice with a 5% aqueous sodium hydroxide solution, then washed with saturated brine, 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 yield 0.42 g.
A pale yellow liquid was obtained. IR analysis of this substance revealed that 1600 cm was caused by phenyl ether.
^-1 , 1580 cm ^-1 and 1220 cm ^-1 absorptions were observed. In NMR analysis, a signal (doublet, δ) attributed to -CH ₂ Br of raw material polyprenyl bromide
=3.91) disappears, and a new -C H ₂ -O-C ₆ H ₅
A signal (double, δ = 4.39) attributed to appears. Further, FD-MASS analysis gave m/e=1318. From the above, this liquid has the general formula [] where n = 15 and A ₂ = -OC ₆ H ₅ .
It was confirmed that the compound was In addition, by similar operations, polyprenylphenyl ethers in which n was other than 15 and polyprenylphenyl ether mixtures in which n was arbitrarily mixed between 11 and 19 were synthesized. Example 17 Synthesis of polyprenyl (2-pyridyl) ether 50% sodium hydride (0.5 g) was added to anhydrous dimethylformamide (25 ml), stirred at room temperature for 1 hour, and in the mixture n = 15 in the general formula () was added. ,
A solution of polyprenol (12.4 g) in which X=OH was dissolved in anhydrous dimethylformamide (10 ml) was added dropwise, and after the addition was completed, the mixture was stirred for an additional hour. Next, 2-chloropyridine (1.1 ml) was added, and stirring was continued at room temperature overnight. The reaction solution was poured into about 100 ml of water, extracted with diethyl ether, washed with water, dried, and concentrated to obtain a yellow liquid. Ta. This liquid was subjected to silica gel column chromatography (using hexane/ethyl acetate as a developing solution) to yield 9.9g.
A pale yellow liquid was obtained. NMR analysis of this product revealed that -C H ₂ OH of the raw material polyprenol
The signal assigned to (doublet, δ = 4.08) disappears, and the signal newly assigned to -CH ₂ O- (doublet, δ = 4.71), and
Signal attributed to [formula] (multiplet, δ=6.50−6.72, multiplet, δ=
A multiplet of 7.30-7.52, δ = 8.00-8.08) appeared. Moreover, when this liquid was analyzed by FD-MASS, m/e=1319 was given. From the above, it was confirmed that this product was polyprenyl (2-pyridyl) ether in the general formula () where n = 15 and A ₂ = 2-pyridyloxy group. Polyprenyl (2-pyridyl) ethers with n other than 15 and n
polyprenyl (2
-pyridyl) ether mixture was synthesized. Example 18 Synthesis of polyprenyl (2-benzothiazolyl) ether After washing 50% sodium hydride (528 mg) with dry hexane several times under a nitrogen gas atmosphere, anhydrous tetrahydrofuran (50 ml) and anhydrous dimethylformamide (50 ml) were added and stirred. , polyprenol (12.4
g) and stirred at 10°C for 1 hour. Next, 2-chlorobenzothiazole (1.3 ml) was added dropwise, and after completion of the dropwise addition, the mixture was kept at 10°C for 2 hours, stirred overnight at room temperature, poured into about 200 ml of water, extracted with diethyl ether, washed with water, dried, and concentrated. 12.5g of yellow liquid was obtained. This compound showed 1 spot on thin layer chromatography, 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. NMR analysis of this liquid revealed that the raw material polyprenol was -
Signal assigned to C H ₂ OH (doublet, δ=
4.08) disappears, and a signal newly assigned to -C H ₂ O- (doublet, δ = 5.96) and a signal assigned to the aromatic proton of [formula] (multiplet, δ = 6.97-7.62) appeared. Furthermore, when this liquid was analyzed by FD-MASS, m/e=1375 was given. From the above, it was confirmed that this liquid material was polyprenyl (2-benzothiazolyl) ether, which is n-15 in the general formula () and [Formula]. By similar operation, polyprenyl (2-benzothiazolyl) ether with n other than 15 and n with 11
A polyprenyl 2-benzothiazolyl) ether mixture arbitrarily distributed in ~19 was synthesized. Example 19 Synthesis of polyprenyl dimethyl t-butylsilyl ether Polyprenol (1.24 g), where n=15 and X=OH in the general formula (), was mixed with methylene chloride (10
ml), add triethylamine (202 mg), dimethyl t-butylsilyl chloride (151 mg), and 4-dimethylaminopyridine (5 mg), and stir overnight at room temperature. 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 purified with Mallinckrodt's silica gel.
Purified by column chromatography using CC-7 (using hexane as a developing solution), 1.30g
of liquid was obtained. When this product was analyzed by IR, the absorption caused by the OH group of the raw material polyprenol at approximately 3300 cm ^-1 disappeared, and by NMR analysis, it was found that -OSiMe ₂ t B
The signal assigned to u is (singlet, δ=0.85)
observed. Furthermore, m/e was determined by FD-MASS analysis.
=1356 was given. From the above, it was confirmed that this liquid was polyprenyldimethyl t-butylsilyl ether having the general formula () with n-15 and A ₂ =OSiMe ₂ tBu. By similar operations, polyprenyldimethyl t-butylsilyl ethers in which n is other than 15 and polyprenyldimethyl t-butylsilyl ether mixtures in which n is arbitrarily distributed between 11 and 19 were synthesized. Example 20 Synthesis of polyprenyl methyl sulfide Polyprenyl bromide (1.30 g), where n-15 of the general formula () and A ₂ =Br, was dissolved in 1.5 ml of benzene, and a 15% methyl mercaptan sodium solution (3 ml) was prepared. and benzyltriethylammonium chloride (50 mg), and stir 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 a signal attributed to S-C H ₃ (singlet, δ=
1.95) and a signal (doublet, δ=2.96) assigned to -CH ₂ SCH ₃ was observed. Also FD−
MASS analysis gave m/e=1272. From the above, this liquid is n-15 of the general formula (), A ₂
= SCH ₃ was confirmed. Polyprenyl methyl sulfide where n is other than 15 and n is 11 to 19
A polyprenyl methyl sulfide mixture arbitrarily distributed in was also synthesized by a similar operation. Example 21 Synthesis of polyprenylphenyl sulfide Thiophenol (2.2 g) and potassium carbonate (2.8 g) were added to dimethylformamide (50 ml), and while stirring at room temperature (approximately 20°C), the general formula () was synthesized.
Polyprenyl bromide (13.0 g) with n-15 and A ₂ =Br 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%
ml) and extracted with hexane. Next, the hexane layer was washed with a 10% aqueous sodium hydroxide solution, washed with water, dried over anhydrous magnesium sulfate, and the 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).
8.6g of slightly yellow liquid was obtained. about this thing
NMR analysis revealed _a signal ( doublet ,
δ = 3.91) disappears, and a signal newly assigned to -CH ₂ S- (doublet, δ = 3.47) and -
Signal assigned to SC ₆ H ₅ (multiplet, δ=
7.05−7.32) appeared. Also, use this liquid as FD.
-MASS analysis gave m/e=1334. From the above, it was confirmed that this product is _a polyprenylphenyl sulfide having the general formula () with n-15 and _A2 = _-SC6H5 . By similar operations, polyprenylphenyl sulfides in which n is other than 15 and polyprenylphenyl sulfide mixtures in which n is 11 to 19 and arbitrarily mixed were synthesized. Example 22 Synthesis of polyprenyl (2-thiazolinyl) sulfide 2-mercaptothiazoline (1.35 g) and 50% sodium hydride (0.48 g) were added to dimethylformamide (15 ml), stirred at room temperature for 1 hour, and the general formula () A solution of polyprenyl bromide (6.5 g) with n = 15 and A ₂ = Br dissolved in dimethylformamide (5 ml) was added dropwise, and after the addition was completed, the reaction solution was stirred overnight at room temperature.
Pour into water, extract with diethyl ether, wash with water,
After drying, it was concentrated to obtain a yellow liquid. This liquid was subjected to silica gel column chromatography (hexane/
2.8 using ethyl acetate as a developing solution)
g of a pale yellow liquid was obtained. About this thing NMR
Analysis revealed that -C of the raw material polyprenyl bromide
Signal attributed to H ₂ Br (doublet, δ=
3.91) disappears, and a signal newly assigned to -CH ₂ S (doublet, δ = 3.74),
Signals assigned to [Formula] (triplet, δ=3.32 and triplet, δ=4.16) appeared. Moreover, when this liquid was analyzed by FD-MASS, m/e=1343 was given. From the above, it was confirmed that this product was polyprenyl (2-thiazolinyl) sulfide, where n=15 in the general formula () and [Formula]. By similar operations, polyprenyl (2-thiazolinyl) sulfide with n=15 other than n=15 and polyprenyl (2-thiazolinyl) sulfide mixtures with n=11 to 19 arbitrarily mixed were synthesized. Example 23 Synthesis of polyprenyl (2-pyridyl) sulfide 2-mercaptopyridine (1.11 g) and 50% sodium hydride (0.48 g) were dissolved in dimethylformamide (25 ml) and stirred at room temperature for 1 hour.
Polyprenyl bromide (6.5 g) having the general formula () where n = 15 and A ₂ = Br was added, and after stirring at room temperature overnight, the reaction solution was poured into about 50 ml 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.
When this product was subjected to NMR analysis, the signal (doublet, δ = 3.91) assigned to -CH ₂ Br of the raw material polyprenyl bromide disappeared, and a new signal assigned to -CH ₂ S (doublet, δ=
3.78) and a signal assigned to -S -C5H4N ₍ multiplet, _δ =6.75-8.35) appeared. In addition, FD-MASS analysis of this liquid revealed that m/
Given e=1335. From the above, it was confirmed that this product is a polyprenyl (2- _pyridyl ) sulfide in which n=15 and _A2 = _-SC5H4N in the general formula (). Polyprenyl (2-pyridyl) sulfide other than n = 15 and n = 11 to
An optionally mixed polyprenyl (2-pyridyl) sulfide was synthesized in 19. Example 24 Synthesis of polyprenyl diethyl phosphate Polyprenol (1.24 g) and pyridine (0.16 ml) where n = 15 and X = OH in the general formula ()
was dissolved in 5 ml of methylene chloride and heated to 0°C under nitrogen atmosphere.
A solution of diethyl phosphorochloridate (181 mg) in methylene chloride (2 ml) was added dropwise. 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 diluted with diluted hydrochloric acid, water, saturated sodium bicarbonate,
After sequentially washing with saturated brine and drying over anhydrous magnesium sulfate, the ether was distilled off to obtain a pale yellow liquid (1.35 g). This compound showed 1 spot on thin layer chromatography, no side reactions were observed, the yield was almost quantitative, and no further purification was required. In IR analysis, it is caused by P=O
Due to absorption of 1260 cm ^-1 and P-O-C alkyl
A wide absorption range of 1050−940 cm ⁻¹ appeared. NMR
In the analysis, the signal attributed to [formula] (double doublet δ 4.38) and the signal attributed to [formula] (multiplet, δ 3.8 to 4.15 and triplet, δ1.28)
appeared. Further, FD-MASS analysis gave m/e=1378. From the above, this liquid has the general formula () where n = 15 and A ₂ = OP (O) (OEt) ₂ .
It was confirmed that the compound was In addition, by similar operations, polyprenyl diethyl phosphate mixtures in which n was other than 15 and polyprenyl diethyl phosphate mixtures in which n was arbitrarily distributed between 11 and 19 were synthesized. Example 25 Synthesis of polyprenylphenyl sulfoxide Polyprenylphenyl sulfide (1.33 g) with the general formula () where n = 15 and A ₂ = SC ₆ H ₅
Dissolve in MeOH (10 ml), add a solution of sodium metaperiodate (257 mg) in water (5 ml), 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) to obtain 1.06 g of liquid.
An IR analysis of this material revealed that the raw material polyprenylphenyl sulfide had no absorption at 1035 cm.
^-1 showed strong absorption due to sulfoxide.
As a result of NMR analysis, the signal (doublet, δ _{= 3.47) attributed to -CH 2} SC ₆ H ₅ of the raw material polyprenylphenyl sulfide disappeared, and -CH
₂ Signal assigned to SOC ₆ H ₅ (double, δ=
3.35) appeared. In FD-MASS analysis, m/e=
Gave 1350. From the above, it was confirmed that this product is _a polyprenylphenyl sulfoxide having the general formula () where n=15 and _A2 = _-SOC6H5 . By similar operation, polyprenylphenyl sulfoxide with n other than 15 and n with 11 to 19
A mixture of optionally mixed polyprenylphenyl sulfoxides was synthesized. Example 26 Synthesis of polyprenylphenyl sulfone Polyprenyl bromide (1.30 g), where n = 15 and A ₂ = Br in the general formula (), was added to a mixed solution of N,N-dimethylformamide (10 ml) and tetrahydrofuran (10 ml). Add sodium phenylsulfinate (0.33g) dissolved in
The mixture was further stirred at 50°C for 1 hour. The solvent was removed using a rotary evaporator, water was added, and the mixture was extracted with benzene. The benzene layer was washed with water and dried over anhydrous magnesium sulfate.
Removal of the solvent gave a yellow liquid. This material was subjected to silica gel column chromatography (hexane/
(using ethyl acetate as a developing solution),
0.94g of pale yellow liquid was obtained. ¹ H−
NMR analysis revealed _a signal ( doublet ,
δ = 3.91) disappears, and a new signal assigned to -CH ₂ SO ₂ C ₆ H ₅ (doublet, δ = 3.77) and a signal assigned to -SO ₂ C ₆ H ₅ (multiplet,
δ=7.31−7.93) appeared. Also, FD−
MASS analysis gave m/e=1366. From the above, this liquid has n=15 and A ₂ =
It was confirmed to be a compound represented by the general formula () of SO ₂ C ₆ H ₅ . Also, by the same operation, n
Polyprenylphenyl sulfone mixtures in which polyprenylphenyl sulfones other than =15 and n=11 to 19 were optionally mixed were synthesized. Example 27 Synthesis of polyprenylethyl carbonate Polyprenol (12.4 g), where n = 15 and X = OH in the general formula (), was mixed with anhydrous pyridine (50
ml), and ethyl chlorocarbonate (4.8 ml) was added dropwise with stirring at room temperature, and then stirring was continued at room temperature overnight. The mixture was then poured into about 300 ml 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 (hexane/ethyl acetate was used as a developing solution) to obtain 7.21 g of a slightly yellow liquid. NMR analysis of this liquid revealed a signal ( _doublet ,
δ = 4.08) disappears, and a new signal assigned to -C H ₂ OH (doublet, δ = 4.45) and a signal assigned to [formula] (triplet, δ = 1.20 and qualtet, δ = 4.05) appear. appeared. Moreover, when this liquid was analyzed by FD-MASS, m/e=1314 was given. From the above, it was confirmed that this liquid was polyprenylethyl carbonate with general formula () where n=15 and [formula].
By similar operations, polyprenylethyl carbonates with n other than 15 and polyprenylethyl carbonate mixtures with n arbitrarily distributed between 11 and 19 were synthesized. Example 28 Polyprenyl dimethyl carbamate Polyprenol (2.48 g) having the general formula () where n = 15 and -Butyllithium (1.4ml) was added. Then, under the same temperature conditions, dimethylcarbamoyl chloride (0.2 ml) was added to
After stirring at ℃ for 30 minutes and then at room temperature for 2 hours, the mixture was poured into about 20 ml of water and extracted with diethyl ether.
After washing with water and drying, the mixture was 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 slightly yellow liquid. When this liquid was subjected to NMR analysis, the signal (double, δ = 4.08) attributed to -CH ₂ OH of the raw material polyprenol disappeared, and a new -CH ₂ O
Signal attributed to − (doublet, δ=4.42)
and a signal (singlet, δ=2.80) assigned to [Formula] appeared. Further, when this liquid was analyzed by FD-MASS, m/e=1313 was given. From the above, it was confirmed that this liquid was polyprenyl dimethyl carbamate with general formula () where n=15 and [formula]. By similar operations, polyprenyl dimethyl carbamates with n other than 15 and polyprenyl dimethyl carbamate mixtures with n arbitrarily distributed between 11 and 19 were synthesized. Example 29 Synthesis of polyprenyltriethylammonium bromide Polyprenyl bromide (2.6 g), where n = 15 and A ₂ = Br in the general formula (), was added to anhydrous triethylamine (10 ml) and left overnight at room temperature, resulting in a pale yellow wax-like substance. Something precipitated. This precipitate was separated, thoroughly washed with anhydrous ether, and the solvent was removed under reduced pressure to obtain 2.35 g of a pale yellow waxy substance. When this product was analyzed (DMSO-d ₆ ), the signal (doublet, δ = 3.91) attributed to -CH ₂ Br of the raw material polyprenyl bromide disappeared, and -
Signal attributed to C H ₂ N (doublet, δ=
3.77) and signals assigned to -N(C ₂ H ₅ ) ₃ (triplet, δ=1.14 and qualtet, δ=3.22) appeared. This wax-like material was extremely hygroscopic and elemental analysis and IR analysis were impossible. Also
FD-MASS analysis was also impossible because it was an ammonium salt. However, according to NMR analysis, n=
15, it was confirmed to be polyprenyltriethylammonium bromide, where A ₂ =N (C ₂ H ₅ ) ₃ Br. By similar operation, polyprenyltriethylammonium bromide with n other than 15 and n with 11 to 19
An arbitrarily distributed polyprenyltriethylammonium bromide mixture was synthesized. Example 30 Synthesis of polyprenyl dimethylsulfonium bromide Polyprenyl bromide (2.6 g) having the general formula () where n=15 and A ₂ =Br was added to dimethyl sulfide (10 ml) and left overnight at room temperature. A yellow waxy substance was precipitated, which was separated, thoroughly washed with anhydrous ether, and the solvent was removed under reduced pressure to obtain 1.27 g of a yellow waxy substance. When this product was analyzed by NMR, the signal (doublet, δ=3.91) assigned to -CH ₂ Br of the raw material polyprenyl bromide disappeared, and the signal assigned to -CH ₂ S < (doublet, δ-5) and −
Signal assigned to S( CH ₃ ) ₂ (singlet, δ=
2.88). This material has high hygroscopicity and cannot be analyzed for elemental analysis, and FD-MASS analysis is also impossible because it is a sulfonium salt. However, from the NMR analysis results, the desired general formula ( ,
It was confirmed to be polyprenyldimethylsulfonium bromide where _A2 =-S( _CH3 ) _2Br . 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 31 Magnesium strips (0.316 g, 13 mmol), anhydrous tetrahydrofuran (0.5 ml) and 1,2-dibromoethane (0.08 ml) were placed in a three-neck flask purged with argon, and the mixture was bubbled vigorously using a hair dryer. heated to. Next, a solution of 2-[4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran (2.51 g, 10 mmol) in anhydrous tetrahydrofuran (3.0 ml) was added to the activated magnesium at a temperature such that the solvent just boiled. Dropped at speed. After the dropwise addition was completed, the mixture was stirred at 70°C for 15 minutes. Anhydrous tetrahydrofuran (60 ml) was added to this to prepare a Grignard solution. Separately, anhydrous tetrahydrofuran (6.42 g, ₅ mmol) of polyprenylacetate (6.42 g, 5 mmol) having the general formula () where n = 15 and 15 ml) solution and a solution of Li ₂ CuCl ₄ in anhydrous tetrahydrofuran (0.1 molar solution, 2.0 ml). 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. Wash the ether layer with saturated saline,
After drying over anhydrous magnesium sulfate, the solvent was distilled off using a rotary evaporator to obtain 7.95 g of a pale yellow liquid. This product is used for silica gel thin layer chromatography (hexane/ethyl acetate = 97/3 (volume ratio)
was used as a developing solution), the spots were mainly found at R _f =0.35. Also, this pale yellow liquid substance
As a result of FD-MASS analysis, m/e = 1284, which indicates the presence of raw material polyprenylacetate, was not detected at all. m/e=1396 shown below was detected as the main peak. Next, add this pale yellow liquid to hexane (40ml).
To this were added p-toluenesulfonic acid pyridine (0.13 g, 0.5 mmol) and ethanol (20 ml). This solution was heated and stirred at 55°C for 3 hours.
After cooling, sodium carbonate (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 using a rotary evaporator, and the remaining oil was heated at 0.5 Torr. and 150° C. for 30 minutes to remove low boiling components. The remaining liquid was subjected to silica gel column chromatography (hexane/ethyl acetate = 9/1 was used as a developing solution) to obtain a colorless and transparent liquid (5.64 g). This product gave a single spot at R _f =0.19 by silica gel thin layer chromatography (hexane/ethyl acetate = 9/1 (volume ratio) was used as the developing solution). Also, according to the analysis results shown below, this liquid has a general formula () where n=15 and Z=-CH ₂ OH
It was confirmed that this was the target compound. FD-MASS analysis m/e = 1312 (calculated value 1312) IR analysis (cm ^-1 ), 830, 1060, 1376, 1440, 2850,
2920, 3320 ¹³ C-NMR analysis (ppm/intensity) 135.365/430,
135.229/3567, 135.005/349, 134.937/290,
131.210/213, 125.071/5242, 124.993/499,
124.448/505, 124.282/463, 124.214/445,
61.241/554, 40.029/541, 39.757/683,
37.548/582, 32.245/5500, 32.021/456,
29.316/528, 26.825/492, 26.699/548,
26.436/5166, 25.677/542, 25.308/567,
23.430/6330, 19.557/548, 17.679/353,
16.006/640 ¹ H-NMR analysis (ppm, signal shape, proton ratio) 5.10 (b, 18H), 3.66 (m, 2H), 2.03 (b,
70H), 1.68 (s, 48H), 1.60 (s, 9H), 1.80−
1.10 (m, 5H), 0.91 (d, 3H) Also, IR indicating the presence of the isomerization product mentioned earlier
907 cm ^-1 in analysis, and δ= in ¹ H-NMR analysis
Absorption at 5.78 ppm (double doublet) was not detected at all. The 2-[4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran used above was synthesized as follows. 16.7g of 4-bromo-3-methylbutanol
It was dissolved in 200 ml of anhydrous methylene chloride, and 10.0 g of dihydropyran was added dropwise under ice cooling. After the addition was completed, the solution was stirred at room temperature for 2 hours, the solvent was distilled off, and the product was purified by silica gel column chromatography (using hexane/ethyl acetate as a developing solvent).
g of 2-[4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran was obtained. of this
The NMR spectrum was as follows. δ1.00
(doublet, 3H), 1.20−2.20 (multiplet, 9H),
3.20-3.90 (multiplet, 6H), 4.53 (broad, 1H). Examples 32 to 34 The same operation was carried out using the polyprenyl compounds shown in Table 6 (n=15) in place of the polyprenyl acetate used in Example 31. The results are shown in Table 6. Example 35 2-[4-bromo-3 used in Example 31
-methylbutoxy]-tetrahydro-2H-pyran with 4-bromo-3-methylbutylbenzyl ether and with CuBr instead of Li ₂ CuCl ₄ before carrying out the reaction with p-toluenesulfonic acid pyridine. I performed the steps up to. The liquid obtained so far was heated at 0.5 Torr. and 130° C. for 30 minutes to distill off low-boiling components to obtain 6.75 g of a pale yellow liquid. Next, this liquid was purified by silica gel column chromatography (hexane/isopropyl ether = 97/3 (volume ratio) was used as the developing ratio) to give 5.33g.
A slightly yellow liquid substance was obtained. This is silica gel thin layer chromatography (hexane/isopropyl ether = 95/5 (volume ratio) is used as the developing solution)
gave a single spot at R _f =0.59. According to the analysis results below, this product has n in the general formula ().
=15 _{, Z = CH2OCH2C6H5} . FD-MASS analysis; m/e=1402 IR analysis (cm ^-1 ); 698, 735, 840, 1100, 1387,
1450, 1662, 2840, 2930, 2970 ¹ H-NMR analysis (δppm, signal shape, proton number ratio); 7.28 (s, 5H), 5.07 (b, 18H), 4.42
(s, 2H), 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 ml) was added thereto. Lithium (0.10 g, 15 mg-atm) was added thereto, and the mixture was stirred 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 0°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. Thereafter, the solvent was distilled off and the remaining liquid was purified by silica gel column chromatography (hexane/ethyl acetate = 9/1 (volume ratio) was used as a developing solution) to obtain 4.80 g of a colorless and transparent liquid. R _f value of silica gel thin layer chromatography of this liquid,
and FD−MASS, IR, ¹³ C−NMR, ¹ H−
The NMR analysis results were the same as those for the liquid obtained in Example 31. Also indicates the presence of isomerization products
IR analysis: 907 cm ^-1 , ¹ H-NMR analysis: Absorption at δ = 5.78 ppm was not detected at all. Examples 36-44 In place of the polyprenyl acetate used in Example 35, other polyprenyl compounds (n = 15)
I did the same thing using . The results are shown in Table 6. In Examples 42 and 43, 907 cm ^-1 in IR analysis, δ = in ¹ H-NMR analysis
A weak absorption of 5.78 ppm was detected, confirming the presence of a small amount of isomerized products. 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, 19.5 mmol), anhydrous tetrahydrofuran (0.5 ml) and 1,2-dibromoethane (0.08 ml) were placed in a three-necked flask purged with argon, and heated with a hair dryer until it foamed violently. did. Then 4-bromo-3-methylbutylbenzyl ether (3.86g), 15mmol)
was added dropwise to the activated magnesium at such a rate that the solvent just came to a boil. After finishing dropping, add this mixture.
The mixture was stirred at 70°C for 30 minutes. Anhydrous tetrahydrofuran (25 ml) was added to this to prepare a Grignard solution. Separately, anhydrous cuprous iodide (1.43 g, 7.5 mmol) and anhydrous tetrahydrofuran (40 ml) were placed in a three-neck flask purged with argon, and the mixture 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. The obtained white suspension was synthesized by the same method as in Example 6. In the general formula (), n=15,
= OCOCH ₃ polyprenyl acetate (6.42
g, 5 mmol) of anhydrous tetrahydrofuran (10
ml) 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. Thereafter, saturated ammonium chloride water was added for hydrolysis, followed by extraction with ether. The ether layer was washed with saturated ammonium chloride water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting pale yellow liquid was heated at 0.5 Torr. and 130°C for 30 minutes to remove low-boiling components, and the residue was subjected to silica gel column chromatography (hexane/isopropyl ether =
97/3 (volume ratio was used as a developing solution) to obtain 4.63 g of a slightly yellow liquid. This liquid was subjected to silica gel thin layer chromatography (hexane/isopropyl ether = 95/5 (volume ratio) was used as a developing solution) to give a single spot at R _f =0.59. In addition, m/
e = 1402, and these analysis results indicate that in the general formula () obtained in Example 35, n = 15, Z
It was the same as that of the compound =CH ₂ OCH ₂ C ₆ H ₅ . Next, this liquid was subjected to a debenzylation reaction in the same manner as in Example 35, and the result was purified using silica gel column chromatography (hexane/ethyl acetate = 9/1 (volume ratio) was used as the developing solution). 4.15 g of a colorless transparent liquid was obtained. These R _f values in silica gel thin layer chromatography (using hexane/ethyl acetate = 9/1 (volume ratio) as the developing solution) and m/e values in FD-MASS analysis were the same as those obtained in Example 31. It was the same as that of the compound in formula () where n=15 and Z=CH ₂ OH. However, in IR analysis it is 907 cm ^-1 and ¹ H
- In NMR analysis, weak absorption was observed at δ = 5.78 ppm. Examples 50-51 The same operation was carried out using other polyprenyl compounds (n=15) in place of the polyprenyl acetate used in Example 49. The results are shown in Table 6. Example
The presence of small amounts of isomerized products was confirmed in both 50 and 51 by IR analysis and NMR analysis. Example 52 Polyprenyl bromide (n = 15) was used in place of the polyprenyl acetate used in Example 35, and without using copper bromide, and instead of being heated at 0°C for 2 hours after the completion of dropping the Grignard reagent. hand,
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 carried out using other polyprenyl compounds (n=15) in place of polyprenyl bromide. The results are shown in Table 6. [Table] [Table] [Table] Example 56 Lithium (1.7 g, 0.25 gram atom) and anhydrous ether (40
ml) and 2-[4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran (25.1
g, 100 mmol) in anhydrous ether (20 ml), confirm that heat is generated, and then
The mixture was cooled to ℃ and the remainder was added dropwise. After completion of dripping, 10℃
Stirring was continued for 2 hours. Separately, place anhydrous cuprous iodide (990.6 mg, 5.2 mmol) and anhydrous ether (20 ml) in a three-necked flask purged with argon, and add the lithium reagent solution (equivalent to 10 mmol) previously prepared at -10°C. was added dropwise over 10 minutes, and the mixture was further stirred at this temperature for 15 minutes. In addition, in the general formula [], n=15, X=
OCOCH ₃ is polyprenylacetate (3.21
g, 2.5 mmol) of anhydrous ether (15 ml) at -10
The mixture was added dropwise over 20 minutes at ℃, and stirring was continued for 1 hour at this temperature. 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 removed using a rotary evaporator to obtain 5.09 g of a pale yellow liquid. This product had a main spot at R _f =0.35 by silica gel thin layer chromatography (using hexane/ethyl acetate = 97/3 (volume ratio) as a developing solution). Moreover, m/e=1396 was given by FD-MASS analysis. This liquid was treated with p-
The mixture was reacted with pyridine toluenesulfonate, and the same procedure was repeated to obtain 2.12 g of a colorless and transparent liquid. This product gave the same results as Example 31 in silica gel thin layer chromatography, FD-MASS, IR, and ¹ H-NMR analyses. Example 57 A reaction was carried out using polyprenylphenyl sulfoxide in which n=15 and X=S(O)C ₆ H ₅ in place of the polyprenylacetate used in Example 56, and 1.15 g of a colorless transparent liquid was obtained. I got something. This liquid can be used for silica gel thin layer chromatography and
The results were the same as those obtained in Example 56 in FD-MASS analysis. Example 58 A reaction was carried out using polyprenylphenyl sulfone in which n = 15 and X = S(O) ₂ C ₆ H ₅ in place of the polyprenylacetate used in Example 56.
1.38 g of a colorless transparent liquid was obtained. This liquid can be analyzed by silica gel thin layer chromatography and FD-
The results were the same as those obtained in Example 56 in MASS analysis. Example 59 Lithium (1.7 g, 0.25 gram atom) and anhydrous ether (40
ml) and 2-[4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran (25.2
First, a small amount of anhydrous ether (20 ml) solution of 100 mmol) was added, and after confirming that heat was generated, the mixture was cooled to 0° C., and the remainder was added dropwise. After completion of dripping
The mixture was stirred at 10°C for 2 hours. Separately, in a three-neck flask purged with argon, polyprenyl bromide (3.80 g, 2.5 mmol) having the general formula () where n = 15 and X = Br and anhydrous ether (10 ml) were placed at 0 °C. A lithium reagent solution (equivalent to 10 mmol) 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 the solvent was removed using a rotary evaporator.
5.46g of pale yellow liquid was obtained. This liquid was treated with p-
The mixture was reacted with pyridine toluenesulfonate, and the same procedure was repeated to obtain 0.44 g of a colorless transparent liquid. This product had the same results as Example 31 in silica gel thin layer chromatography and FD-MASS analysis. Example 60 (A) Lithium (1.7 g, 0.25 gram atom) and anhydrous ether (40
ml) and added 2-[4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran (25.1 g, 100 mmol) in anhydrous ether (20 ml).
A small amount of the solution was first added, and after confirming that heat generation occurred, the solution 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, put a solution of polyprenol (3.11 g, 2.5 mmol) in anhydrous ether (5 ml) in which n = 15 and Ether solution of methyllithium (1.3mol/, 1.9ml,
2.5 mmol) was added dropwise, and after the addition was completed, the mixture was stirred at 0°C for 20 minutes. Next, anhydrous cuprous iodide (0.48 g, 2.5 mmol) and anhydrous tetrahydrofuran (6 ml) were placed in a three-necked flask that had been purged with argon, and the ether solution prepared in (B) was added dropwise to this at room temperature. After completion, the mixture was stirred at room temperature for 30 minutes, and then cooled to -65°C in a dry ice-acetone bath. Add to this the lithium reagent solution prepared in (A) (10 m
mol equivalent) was added dropwise at this temperature, followed by a solution of N,N-methylphenylaminotriphenylphosphonium iodide (1.24 g, 2.5 mmol) in anhydrous N,N-dimethylformamide (13 ml). 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. The ether layer was washed with 0.2N hydrochloric acid and dried over anhydrous magnesium sulfate. The solvent was removed on a rotary evaporator, the residue was mixed with 50 ml of hexane, then the precipitated triphenylphosphine oxide was filtered off and the filtrate was concentrated.
3.49 g of pale yellow liquid was obtained. This liquid was reacted with pyridine p-toluenesulfonate in the same manner as in Example 31, and the same procedure was repeated to obtain 2.10 g of a colorless transparent liquid. Silica gel thin layer chromatography, FD-MASS, IR, ^1H of this material
-NMR and ¹³ C-NMR analysis were the same as in Example 31. Example 61 Magnesium strips (0.316 g, 13 mmol), anhydrous tetrahydrofura (0.5 ml) and 1,2-dibromoethane (0.08 ml) were placed in a three-neck flask purged with argon and heated with a dryer until it bubbled vigorously. A solution of 4-(diphenyl-t-butylsilyloxy)-2-methylbutyl bromide (4.05 g, 10 mmol) in anhydrous tetrahydrofuran (5.0 ml) was then added to the activated magnesium at a rate that just brought the solvent to a boil. dripped. After the dropwise addition was completed, the mixture was stirred at 70°C for 30 minutes. Anhydrous tetrahydrofuran (60 ml) was added to this to prepare a Grignard solution. Separately, in a three-necked flask purged with argon, a solution of polyprenylacetate (6.42 g, 5 mmol) with the general formula () where n = 15 and X = COCOCH ₃ in anhydrous tetrahydrofuran (15 ml) was added to a solution of Li ₂ CuCl ₄ in anhydrous tetrahydrofuran ( 0.1 molar solution, 2.0
ml) 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. After that, saturated ammonium chloride water was added to this reaction mixture for hydrolysis.
Extracted 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.
After heating at 0.5 Torr. and 130°C for 30 minutes to remove low-boiling components, silica gel column chromatography (using hexane/ethyl acetate as a developing solution)
Purification was performed 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 ml) and tetra-n was dissolved at room temperature with stirring.
-Butylammonium fluoride (5 g) was added little by little, followed by stirring at room temperature for 2 hours. Tetrahydrofuran was distilled off, about 50 ml of ether 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) used as developing solution)
Purification was performed to obtain 3.82 g of a colorless transparent liquid. This product gave the same R _f value as the compound obtained in Example 31 by silica gel thin layer chromatography (using hexane/ethyl acetate = 9/1 (volume ratio) as a developing solution). Also FD−MASS, IR, ¹ H−
The analysis results of NMR and ¹³ C-NMR are also the same,
Therefore, in the general formula (), this liquid substance has n=
15, it was confirmed to be a compound where Z=CH ₂ OH. In addition, 4-(diphenyl-t-butylsilyloxy)-2-methylbutyl bromide used above was synthesized as follows. 4-Bromo-3-methylbutanol (16.7g)
was dissolved in 500 ml of anhydrous methylene chloride, triethylamine (13.2 g) and 4-dimethylaminopyridine (500 mg) were added, and t-butyldiphenylsilyl chloride (33.0 g) was added dropwise at room temperature. After the addition was complete, the mixture was dissolved. After stirring at room temperature overnight, the mixture was 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 product was subjected to column chromatography using Mallinckrodt's silica gel CC-7 (hexane/ethyl ether was used as the developing solution).
Purification yielded 38.1 g of a colorless transparent liquid. When IR analysis was performed on this, it was found that the absorption derived from the raw material OH group around 300 cm ^-1 had disappeared. Also
In NMR analysis, δ0.90 (3H, doublet), 1.02 (9H,
singlet), 1.1~1.7 (2H, multiplet), 1.7~2.2
(1H, multiplet), 3.22 (doublet, 2H), 3.63
(2H, triplet), 7.1−7.4 (5H, multiplet), 7.4−
A signal of 7.8 (5H, multiplet) was observed, and it was confirmed that it was the desired 4-(diphenyl-t-butylsilyloxy)-2-methylbutyl bromide. Example 62 Magnesium strips (0.316 g, 13 mmol), anhydrous tetrahydrofuran (0.5 ml) and 1,2-dibromoethane (0.08 ml) were placed in a three-necked flask purged with argon and heated with a hair dryer until it foamed violently. did. Then 4-methoxy-2-
A solution of methylbutyl bromide (1.81 g, 10 mmol) in anhydrous tetrahydrofuran (3.0 ml) was added dropwise to the activated magnesium at a rate such that the solvent just boiled. After finishing dropping, add this mixture to 70 ml.
The mixture was stirred at ℃ for 15 minutes. Anhydrous tetrahydrofuran (60 ml) was added to this to prepare a Grignard solution. Separately, in a three-neck flask purged with argon, add a solution of polyprenylacetate (6.42 g, 5 mmol) with the general formula () where n = 15 and X = -OCOCH ₃ in anhydrous tetrahydrofuran (15 ml) and a solution of Li ₂ CuCl ₄ in anhydrous tetrahydrofuran. (0.1 molar solution, 2.0
ml) 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 another 2 hours. After that, saturated ammonium chloride water was added to this reaction mixture for hydrolysis.
Extracted 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. The resulting oil was heated at 0.5 Torr. and 130°C for 30 minutes to reduce the boiling point. After distilling off the components, the residue 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, m/e = 1326
A peak was detected, and it was confirmed that this liquid was the target compound of the general formula () where n=15 and Z=CH ₂ OCH ₃ . This liquid was then dissolved in anhydrous methylene chloride (10 ml), trimethylsilane iodide (1.30 g, 6.5 mmol) was added at room temperature under argon, and an additional 10
Stir for hours. Thereafter, methanol (1 ml) 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 = 9/1 (volume ratio)
was used as a developing solution) to obtain 3.28 g of a colorless transparent liquid. Silica gel thin layer chromatography of this liquid (hexane/ethyl acetate = 9/
1 (volume ratio) used as developing solution), _FD-
MASS m/e value, IR, ¹ H-NMR, ¹³ C
-NMR analysis results were consistent with those of the compound obtained in Example 31 with general formula () where n=15 and Z=CH ₂ OH. Note that 4-methoxy-2-methylbutyl bromide used above was synthesized as follows. 50% sodium hydride (30.7g) in THF (400g)
A solution of 3-methyl-3-buten-1-ol (50.0 g) in THF (50 ml) was added, and after heating under reflux for 2 hours, methyl iodide (90.8 g) was suspended under ice-cooling.
Add THF (50 ml) solution dropwise and stir at room temperature overnight. Pour into water and extract with ether. The ether layer is washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was carefully distilled off, fractional distillation was carried out under normal pressure to obtain 66.5 g of liquid as a fraction at 99-102°C. According to IR analysis of this liquid, it is approximately 3300 cm.
The absorption caused by the -OH group of the raw alcohol of ^-1 disappeared. According to NMR analysis, δ1.69 (s, 3H),
2.23 (t, 2H), 3.26 (s, 3H), 3.57 (t, 2H),
4.71 (broad singlet, 2H) was observed. GC−
MASS analysis gave m/e=100. The above analysis confirmed that this liquid was 3-methyl-3-butenyl methyl ether. Sodium borohydride (2.5g) was dissolved in THF (320
ml), the above methyl ether (20.0 g) was added dropwise thereto, boron trifluoride ether complex (10.1 ml) was added dropwise at 25°C, stirring was continued for 1 hour, and then cooled to 0°C. Bromine (42.56g) and sodium methoxide in methanol solution (28wt%,
64.0g) from different dropping funnels at a temperature below 5°C. After stirring the reaction mixture for another 20 minutes at room temperature, saturated aqueous sodium bicarbonate solution (100 ml) is added, and water is further added until the white precipitate disappears. Separate the organic layer, extract the aqueous layer with ether,
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 the solvent was distilled off, the residue was distilled under reduced pressure to obtain 22.5 g of a colorless transparent liquid as a fraction at 60° C./5 mmHg. NMR analysis of this liquid revealed that δ0.96 (double,
3H), 1.38−2.10 (multiplet, 3H), 3.31 (singlet,
3H), 3.35 to 3.60 (multiplet, 4H) were observed.
This confirmed that this liquid was the target compound. Example 64 Magnesium strips (0.316 g, 13 mmol), anhydrous tetrahydrofuran (0.5 ml) and 1,2-dibromoethane (0.08 ml) were placed in a three-necked flask purged with argon, and heated with a hair dryer until it bubbled vigorously. . Next, 4,4-dimethoxy-
2-Methylbutyl bromide (2.11g, 10mmol)
was added dropwise to the activated magnesium at such a rate that the solvent just came to a boil. After the addition is complete, add this mixture to
The mixture was stirred at 70°C for 30 minutes. Anhydrous tetrahydrofuran (60 ml) was added to this to prepare a Grignard solution. Separately, in a three-neck flask purged with argon, add polyprenylacetate (6.42 g, 5 mmol) having the general formula () where n = 15 and X = OCOCH ₃ .
A solution of Li ₂ CuCl ₄ in anhydrous tetrahydrofuran (0.1 molar solution, 2.0 ml) was charged. The previously prepared Grignard solution was added dropwise to this at 0°C over 1 hour.
Stirring was continued for an additional 2 hours at 0°C. 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. FD-MASS this liquid
Upon analysis, only a very weak peak was detected at m/e = 1284, which indicates the presence of raw material polyprenylacetate, and in the general formula [], n = 15, Z = CH
m/e = 1356 indicating the target compound which is (OCH ₃ ) ₂
was detected as the main peak. Then, the above pale yellow liquid was added to a mixed solution of tetrahydrofuran (30 ml) and 10% aqueous hydrochloric acid (10 ml) 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. Saturate the ether layer with saline,
After washing with saturated aqueous sodium bicarbonate and saturated brine, it was dried over anhydrous magnesium sulfate and ether was 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 the main peak and the general formula ()
It was confirmed that n=15 and Z=CHO. Next, this liquid was dissolved in a mixed solvent of hexane (20 ml) and ethanol (10 ml), and sodium borohydride (1.0 g) was added at room temperature, followed by stirring for 1 hour.
Thereafter, the solvent was distilled off using a rotary evaporator, about 50 ml of ether was added, and the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed using a rotary evaporator, and the remaining oil was heated at 0.5 Torr. and 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 = 9/1 (volume ratio) as the developing solvent) to obtain 4.25 g of a colorless and transparent liquid.
I got it. IR, ¹ H−NMR, ¹³ C− of this
The NMR and FD-MASS analysis results were the same as the compound obtained in Example 31, where n=15 and Z=CH ₂ OH in the general formula (). In addition, the 4,4-dimethoxy-2- used above
Methyl butyl bromide was synthesized as follows. 4-bromo-3-methylbutyric acid ethyl ester (20.9 g) was dissolved in anhydrous toluene (400 ml), and -
Cool and stir at 78°C and add diisobutylaluminum hydride (1 molar solution, 120 ml) under nitrogen atmosphere.
was gradually added dropwise, 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 ml), water (100 ml) 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 14.8 g of a crude oil. IR analysis of this product revealed that 2820, which is due to the CHO group,
Weak absorption at 2720 cm ^-1 and strong absorption at 1720 cm ^-1 were observed. In addition, in NMR analysis, a signal attributed to -CHO was observed at δ=9.60. Dissolve the above oil in 300ml of methanol and add p-toluenesulfonic acid.
500 mg was added and 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 obtain 17.2 g of a colorless and transparent liquid. When this liquid was analyzed by IR, it was 2820 cm ^-1 ,
The characteristic absorptions originating from aldehydes at 2720 cm ^-1 and 1720 cm ^-1 disappeared, and several absorptions originating from acetals appeared at 1200 to 1000 cm ^-1 . In addition, in NMR analysis, δ1.00 (3H, doublet), 1.1 to 1.7 (2H, multiplet),
1.7~2.0 (1H, multiplet), 3.22 (6H, singlet),
Signals of 3.31 (2H, multiplet) and 4.32 (1H, triplet) were observed. Further, GC-MASS analysis gave m/e=210. This confirmed that this liquid was 4,4-dimethoxy-2-methylbutyl bromide. Example 64 Magnesium strips (0.316 g, 13 mmol), anhydrous tetrahydrofuran (0.5 ml) and 1,2-dibromoethane (0.08 ml) were placed in a three-necked flask purged with argon, and heated with a hair dryer until it foamed violently. did. Next, 4,4-dimethylthio-2-methylbutyl bromide (2.43g, 10m
mol) in anhydrous tetrahydrofuran (3.0 ml) was added dropwise to the activated magnesium at such a rate that the solvent just boiled. After the dropwise addition was completed, the mixture was stirred at 70°C for 15 minutes. Anhydrous tetrahydrofuran (60 ml) was added to this to prepare a Grignard solution. Separately, in a three-necked flask purged with argon, a solution of polyprenylacetate (6.42 g, 5 mmol) with the general formula () where n = 15 and X = -OCOCH ₃ in anhydrous tetrahydrofuran (15 ml) and a solution of LiCuCl ₄ in anhydrous tetrahydrofuran (0.1 molar solution, 2.0
ml) 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. After that, saturated ammonium chloride water was added to this reaction mixture for hydrolysis.
Extracted 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.
The mixture was heated at 0.3 Torr. and 150°C for 30 minutes to distill off low-boiling components. FD-MASS analysis of the remaining yellow liquid revealed that in the general formula (), n=15, Z=CH
A peak was detected at m/e=1388 indicating (SCH ₃ ) ₂ . Next, dissolve this oil in acetone (20ml) and
To this were added water (1 ml), mercuric chloride (0.25 g) and cadmium carbonate (0.25 g). After the mixture was stirred at room temperature for 25 hours, it was further added with 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 ml) and ethanol (10 ml), 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. Distill the solvent and remove the remaining oil.
The mixture was heated at 0.5 Torr. and 130°C for 30 minutes to remove low-boiling components. The residue was purified by silica gel chromatography (using hexane/ethyl acetate = 9/1 (volume ratio) as a developing solution) to obtain a colorless and transparent liquid (3.07 g). Silica gel thin layer chromatography of this liquid (hexane/ethyl acetate = 9/
1 (volume ratio) used as developing solution), _FD-
MASS m/e = value, also IR, ¹ H-NMR,
^{The 13} C-NMR analysis result was consistent with that of the compound obtained in Example 31 with the general formula () where n=15 and Z=CH ₂ OH. In addition, the 4,4-dimethylthio-2 used above
-Methylbutyl bromide 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 treated with anhydrous ether (200 g).
ml), 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).
17.4 g of a colorless and transparent liquid was obtained. An IR analysis of this product revealed no absorption attributable to the raw material aldehyde at 2820, 2720, and 1720 cm ^-1 , and an NMR analysis showed a signal (triplet, δ3.83) assigned to [formula].
A signal (singlet, δ2.08) assigned to [Formula] was observed. Also GC-
MASS analysis gave m/e=242. Example 65 The same operation as in Example 35 was carried out using anhydrous diethyl ether instead of anhydrous tetrahydrofuran to obtain 4.52 g of a colorless transparent liquid. Silica gel thin layer chromatography (hexane/
The R _f value of ethyl acetate = 9/1 (volume ratio) was used as the developing solution and the m/e value of FD-MASS were as in Example 35.
In the general formula () obtained in , n=15, Z=
It was identical to that of the CH ₂ OH compound. Also IR
The analysis showed weak absorption at 907 cm ^-1 . Example 66 In place of 4-bromo-3-methylbutylbenzyl ether used in Example 35, (S)-4-
Using bromo-3-methylbutylbenzyl ether ([α] ²⁰ _D = +6.05°, c = 1.10, C ₂ H ₅ OH),
In addition, in place of the polyprenyl acetate with n=15, a polyprenol mixture obtained in Example 2 in which n was distributed between 11 and 19 was made into a polyprenyl acetate mixture by the method of Example 6, and the same result was obtained. The operation yielded 4.72 g of a colorless and transparent liquid.
This liquid was collected using Merck's semi-preparative high performance liquid chromatography column LiChrosorb RP18-10 (C ₁₈ type), using a mixed solvent of acetone/methanol = 90/10 (volume ratio) as the eluent, and using a differential refractometer as the detector. Nine main peaks were confirmed using high performance liquid chromatography. The abundance ratio was determined from the area ratio of this chromatogram and is shown below. [Table] Using the same liquid chromatography, each fraction was separated and subjected to FD-MASS analysis, and each peak was confirmed to be from n=11 to 19. Also, regarding the separation of each peak
Perform IR, ¹ H-NMR, ¹³ C-NMR to target general formula () where n = 11 to 19 and Z = CH ₂ OH.
It was confirmed that the compound was The compound of peak No. 5 with n=15 gave exactly the same analytical value as the compound obtained in Example 31. Regarding other peaks, IR, ¹ H-NMR, and ¹³ C-NMR all had absorption signals at the same position, and the intensity ratios were only slightly different. In addition, when measuring the light intensity of the obtained liquid, [α]
²⁰ _D = +0.51° (neat). Example 67 2-[4-bromo-3 used in Example 31
(R)-2-[4-methylbutoxy]-tetrahydro-2H-pyran was synthesized using (R)-4-bromo-3-methylbutanol following the method described at the end of Example 31. -bromo-3-methylbutoxy]-tetrahydro-2H-pyran ([α] ²⁰ _D
= −3.61°, c=4.0, CHCl ₃ ), and n=
Using the polyprenylacetate mixture used in Example 66 in place of the polyprenylacetate in Example 66,
The same operation was performed to obtain 5.52 g of a colorless and transparent liquid. When this was subjected to high performance liquid chromatography analysis under the same conditions as in Example 66, the same results as in Example 66 were obtained. Also, FD−MASS, IR, ¹ H−
NMR and ¹³ C-NMR analysis also gave the same results as Example 66. Furthermore, when the light intensity of this liquid was measured, it was [α] ²⁰ _D = -0.51 (neat).

Claims (1)

[Claims] 1. General formula In the formula, A ₁ represents a hydroxyl group or an acetyloxy group; [Formula] represents a lance type isoprene unit; [Formula] represents a cis type isoprene unit; n is an integer from 11 to 19; Formula () consisting essentially of a mixture of polyprenyl compounds, and where n is 14
compounds of formula () where n is 15 and n
contains at least three compounds of the formula () where is 16 as essential components in substantial amounts, and the total content of these three compounds is at least 70% by weight based on the weight of the mixture. A polyprenyl composition characterized by: 2. A composition as claimed in claim 1 containing a maximum content of a compound of formula () in which n is 15. 3. A composition according to claim 1, containing a compound of formula () in which n is 15 in an amount ranging from 30 to 50% by weight, based on the weight of the mixture. 4 When the contents of the compound of formula () where n is 14, the compound where n is 15 and the compound where n is 16 are respectively a, b and c weight%, the following quantitative relationship: b>a The composition according to claim 1, which satisfies >c. 5 Based on the weight of the mixture, a compound of formula () where n is 14 in an amount within the range of 20 to 35% by weight and a compound of formula () where n is 16 in an amount of from 10 to 25% by weight.
A composition according to claim 1 containing in an amount within the range of % by weight. 6. The total content of the compound of formula () where n is 14, the compound of formula () where n is 15 and the compound of formula () where n is 16 is at least 75% by weight, based on the weight of the mixture. A composition according to claim 1. 7 The mixture contains a plurality of compounds of formula () as follows: n content (wt%) 11 0-3 12 0.1-6 13 4-17 14 20-35 15 30-50 16 10-25 17 2 The composition according to claim 1, comprising 10 18 0.1 to 5 19 0 to 3 . 8. The composition according to claim 1, wherein the average value of n is 14.25 to 15.25. 9. Extract the leaves of Ginkgo biloba with an oil-soluble organic solvent, hydrolyze the resulting extract if necessary, and then use chromatography, fractional dissolution, fractional cryoprecipitation, molecular distillation, or For a separation method consisting of a combination of two or more of these methods, a silica gel plate for thin layer chromatography is used and a mixed solvent of n-hexane and ethyl acetate in a volume ratio of 9:1 is used. Solanesyl acetate as a standard substance in thin layer chromatography (10 cm development) using a developing solvent.
A general formula characterized by isolating and collecting a fraction exhibiting an R _f value within the range of 0.18 to 0.25 and/or 0.50 to 0.55 under conditions where the R _f value is 0.40 to 0.45. In the formula, _A1 represents a hydroxyl group or an acetyloxy group; [Formula] represents a trans isoprene unit; [Formula] represents a cis isoprene unit; n is an integer from 11 to 19; Formula () consisting essentially of a mixture of polyprenyl compounds, and where n is 14
compounds of formula () where n is 15 and n
polyprenyl containing as essential components substantial amounts of at least three compounds of the formula () in which is 16, and the total content of these three compounds is at least 70% by weight, based on the weight of the mixture. Method for producing the composition. 10. The method of claim 9, wherein the organic solvent is selected from hydrocarbons, halogenated hydrocarbons, esters, ethers, alcohols, and ketones.