JPS58206554A - Novel polyprenyl compound - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [group of formula II is trans-isoprene unit; group of formula III is cis-isoprene unit; n is 10-18; Z is -CH2OH or its functional precursor; one of R<1> and R<2> is H, the other is -S(O)mR<3> (m is 0-2); R<3> is lower alkyl or phenyl or naphthyl which may be substituted with halogen]. USE:It is used as a raw material of medicines or cosmetics. Especially, it is used as a synthetic intermediate of mammarian dolichols. PREPARATION:The reaction of a compound of formula IV with another compound of formula V (one of A and X is halogen, the other is -S(O)mR<3>, when A is halogen, R<1> is H, when X is halogen, R<2> is H) is carried out in the presence of an anionizing agent such as lithium hydride or methyl lithium at -80-80 deg.C, preferably at -30-5 deg.C, to give the compound of formula I .

Description

[Detailed description of the invention] The present invention relates to regular polyprenyl compounds.

More specifically, the present invention relates to the following bifurcated formula (1) CH3 [wherein -(51s-C=C-CH2- represents a trans-imprene sCH unit, and -CH2-C=C-CIHs+- represents a cis-imprene unit] unit, n represents an integer from 10 to 18, and 2 represents -CH20H or its functional precursor group. One of R1 and R2 is a hydrogen atom, and the other is -5(O)
-3 hydrogen atom or -8(0)mR
3, where m represents an integer of zero, 1 or 2, and R3 represents a lower alkyl group or a phenyl group, a naphthyl group, a pyridyl group or a thiacylyl group which may be substituted with a halogen atom. ] Regarding the polyprenyl compound shown.

The novel polyprenyl compound represented by the general formula (1) provided by the present invention is useful as a raw material for medicines, chemicals, etc.9, and is particularly useful as a synthetic intermediate for mammalian dolichols. Dolichols were classified into J, F, and P in 1960.
It was first isolated from L. ennock et al. [Nature (London), 186,
470 (1960)], which was later transformed into the general formula (
A) and CI(a -CE-I2-CH-CI2-CH2-OH(A)Ha [In the formula, -Yuba and -C-GLI- represent a trans-type imprene unit. Unknown a Toyonaka The same applies hereinafter. ], wherein j representing the number of cis-type Inglene units in formula (A) is generally distributed from 12 to 18, and j-14,1s
It was revealed that the three-legged homologues of 16 and 16 were the main components [R, W, Keenan et al.
.

Biochemical Journal, 165
, 505 (1977)].

Dolichols are found not only in pig liver but also in pig milk:
It is known that it is widely distributed in the body and plays an extremely important function in maintaining the life of living organisms. For example, J. B. and Harfora et al. conducted an in vitro test using the white medulla of calves and pigs, and found that exogenous dolichol promoted the incorporation of sugar components such as mannose into lipids, and that it had a negative impact on rice milling and the vitality of living organisms. It has been revealed that it has the effect of increasing the formation of shield proteins, which are important for maintenance [Biochemical and Bioph
ysical Research Communicat
ion, 76, 1036 (1977)]. The effect of dolichols on promoting the incorporation of sugar components into lipids is more pronounced in mature animals than in growing organisms, so the role of dolichols in preventing aging has attracted attention. There is. Also, R, W,
@enan et al. state that it is important for living organisms that continue to grow rapidly, such as during childhood, to ingest dolichol from outside and supplement the dolichol obtained by biosynthesis within the body ( Archives of Bioc
hemiatry ancl biopmysics
.

179.634 (1977)]. In addition, Akamatsu et al. quantified dolichol phosphate ester in the regenerated liver shell of rats and found that the amount was significantly decreased compared to that in the normal liver17. They found that the irritability was reduced and that the addition of dolichol phosphate from the outside improved the irritability [presented at the 54th Annual Meeting of the Japanese Biochemical Society (1981)].

As mentioned above, dolichols are substances that control extremely important functions for living organisms, and are useful as pharmaceuticals or intermediates thereof. 0.6 after operation
Only the dolichol of g can be obtained.a [F, W, Bu
rgoa et al., Biochemical
Journal.

88.470 (1963)]. Total synthesis of dolichols is extremely difficult using current organic synthesis techniques, as is clear from their complex and unique molecular structures. Relying on natural products as synthetic intermediates, this is easy! It would be possible to obtain dolichol quickly by simply adding a synthetic chemical treatment, but no such convenient substance has been found so far.

Conventionally, the following general formula (B) Q(a CEis CHs -C-CH-CH2(CH2-C=C-Qlx
% ■ [However, it is known that the polyprenols shown in k-4 to 6 (these are called Beckprenols) can be collected from white birch (Betula verrucola), but they cannot be obtained from these. It is almost impossible to synthesize dolichols mainly having 14.15 and 16 cis-type imbulene units using current organic synthesis techniques.

Some of the non-inventors and those who died in their joint research first discovered Japanese red pine (
After the necessary hydrolysis of the extract extracted with an organic solvent from the leaves of 3 genus 1 plants of the Pinaceae family, such as Pinus pine (Pinus) and Japanese black pine, Polyprenols containing 13 to 21 isogrene units in the same trans, cis configuration as mammalian dolichols and/or seven A polyprenyl fraction consisting of a mixture of acetate homologs is obtained, the polyprenyl fraction has no α-terminal saturated isogrene units compared to mammalian dolichols, and the number of cis-unsaturated Inglea units is 1. The polyprenyl fraction exhibits a distribution of polyprenyl congeners very similar to the distribution of polyprenyl congeners in the mammalian tricholes, except that the number of its constituent individual (imprene units) uniform)
It has been found that the scales are relatively easily separated into polyprenyl homologs, and that both the polyprenyl fraction and each polyprenyl homolog separated therefrom are highly suitable as intermediates for the synthesis of mammalian dolichols.

The present inventors 1. efficiently produced mammalian dolichols using the polyprenyl compound described above. As an intermediate in such a method, we have carefully researched a method of introducing a cis-unsaturated Ingla unit and a saturated innovale/pole position introduced therein to the α-bed end of the polyprenyl chain of the polyprenyl compound in order to The present invention has been completed by developing a useful polyprenyl compound represented by the general formula (1).

That is, the compound of the present invention can be obtained by reacting a compound represented by the general formula (It) with a compound represented by the general formula (l[I) with the aid of an anionizing agent.

In the above formulas, AD and and R2 are as defined above. However, when A is a hydrogen atom, R1 is a hydrogen atom, and X is...
When a rogen atom is used, R2 is a hydrogen atom.

-5(
O) Reductively eliminating the R3 group and converting 2 into -CH
If the functional precursor group of 2o'u is -CHz
Mammalian dolichols can be obtained by conversion to OH.

The compound represented by the general formula (U) can be obtained directly or through hydrolysis from extracts of leaves of Japanese red pine, Japanese black pine, etc. General formula CM) [wherein n is as defined above. It can be easily produced from the polyprenol shown in ].

Polyprenyl halides of the general formula (II) in which A is a halogen atom are prepared by converting the polyprenol represented by the general formula (IV) or a mixture thereof with a halogenating agent such as phosphorus trihalide, thinyl halide, etc. can be obtained (by rogenation). For example, the halogenation reaction as described above is carried out at a temperature of about -20°C to +50°C in the presence or absence of a base such as triethylamine or pyridine in a suitable solvent such as hexypnochloride or diethyl ether. Agent preference t L < tri Pcg3.5O
(22, PBr3.5OBrzl, etc.).

Further, polyprenyl sulfides of the general formula (II) in which A is 18R3 are synthesized by reacting the above-mentioned polygrenylno-lides with the corresponding mercaptan (R35H). This reaction is generally carried out in the presence of a base such as sodium hydride, n-methyllyticum, sodium hydroxide, potassium hydroxide, sodium t-butoxide in a solvent such as dimethylformamide, tetrahydrochloride, at room temperature or at a cooled temperature. done below. A is 18OR3
Polyprenyl sulfides of general formula (II) can be prepared by treating the polyprenyl sulfide compound described above with a small excess of an oxidizing agent such as sodium periodate or hydrogen peroxide. This oxidation reaction is usually carried out using water-containing methanol, aqueous acetone, etc. at or near room temperature. Borylnyl sulfo 7 of the general formula (If) where A is -802R3 Group 1ri The above polyprenyl halides are treated in a solvent such as dimethylformamide or tetrahydrofuran at a temperature of room temperature to about 70°C, and the M machine sulfo, Fino Sword Alkali Gold A
It can be obtained by reacting with Hani (R35O21Vl; here, a mH alkali metal is coated, preferably Na). In the above explanation, R3 is a lower aryal group or a phenyl group which may be substituted with a halogen atom, It represents a naphthyl group, a pyridyl group or a thiazolinyl group, preferably a phenyl group or a phenyl group substituted with a lower alkyl group or a halogen atom, and particularly preferably a phenyl group, a tolyl group or a monochlorophenyl group.

In general formulas (1) and (III), Z is -CH20
H or a functional precursor group thereof, and the functional precursor group includes -CH20H and -C
The H0 group is included. The latter i.e. the protected one CH0
After deprotection, the group can be converted to a 10R20H group by reduction under mild conditions, such as reduction with lithium fluoride hydride, sodium fluorine hydride, sodium aluminum hydride, sodium aluminum hydride, etc. can be transformed. However, the following may be mentioned as examples of such functional precursor groups: group, an aliphatic or alicyclic ether residue having 1 to 8 carbon atoms, an aliphatic or aromatic aful group having 2 to 11 carbon atoms or a formula -8iRsIRszRs
represents the nlyl group of a, where circle 1, cell 2 and Ria
each represents a lower alkyl group, phenyl group, tolyl group or xylyl group. ] Specific examples include -C)L20CH3, -CH20C2H
5, -CH20C3H7, -CH20C2H5, -CH
xOCsHlt, -CHzOCHzOCHa, -CH
zCCHsOCzHs, -CH5OCsHi=OCHs
.

-CH208i (e2 output XC stop r) C output, -JJbO8
i(CHs)*C4out-t1-Ca+08i(t-c4
H9)(CsHs)2, -C&08i(CaHB)a
Fi Toka can be mentioned.

[In the formula, Q12 and Q2 each represent an oxygen or sulfur atom; Ral'& Ru each represent a lower alkyl group, or together represent a lower alkylev group. ] The functional precursor group of 10H20H represented by Z may be other than the above, such as a carboxyl group or a lower alkoxycarbonyl group.

The compound represented by the general formula (IiI) is synthesized according to a known method starting from 7tronellol or citronellal. For example, it can be used in the following reaction steps to synthesize a compound in which 2 is a protected OH group, W, or a protected CuO group in the general formula (ffl).

Ha Ha Hs (■) Reaction (■) is a reaction that protects the OH group of citronellol or the CuO group of citronellal.For the reaction, the double viscous part is rinsed with ozone, and then treated with dimethyl sulfide or triphenyl unsulfinonato. In reaction 2, alcohol is obtained by a reduction reaction with sodium borohydride, but if treated with sodium borohydride immediately after the osinolysis of reaction 2, the same alcohol can be obtained. It will be done.

Reaction (2) converts alcohol into iocide and is usually carried out via tosylate. Reaction (1) is the synthesis of a phosphonium salt, and is carried out by reaction with triphenylphosphine.

Reaction (1) is a Kuitzig reaction and is obtained by treating the above phosphonium salt with, for example, n-butyllithium. Reaction (2) often involves selectively deprotecting only the tetrahydropyranyl ether moiety by treating with pyridinyl p-toluene sulfonate in a mild alcohol such as methanol or ethanol. Reaction (2) is the conversion of allyl alcohol to...ride, usually in the presence of a catalytic amount of viridi7 or triethylamine,
The compound represented by the general formula (II), which is difficult to synthesize directly from citronellol or citronellal using the above method, can also be synthesized by treatment with a chlorogenating agent such as Brs, Pα3. The reaction between the compound represented by the general formula (If) and the compound represented by the general formula (lit) according to the present invention is generally undesirable and undesirable. As the zero bath medium carried out in an active solvent, ether solvents such as diethyl ether, diimpropyl ether, diochitin, tetrahydrofuran, dimethylene ethane, diethylene glycol dimethyl ether, etc. are mainly used. It is also possible to mix an inert polar hexasol such as hexylpmethylphosphoric triamide with such an ether solvent and use it as a mixing section. Incidentally, it is preferable that the solvent used in this reaction is sufficiently dried to an anhydrous state.

This reaction is carried out with the aid of an anionizing agent selected from 5gi bases such as sodium hydride, potassium hydride, methyllithium, n-butyllithium, t-butyllithium, etc. Usually from about -80°C to +80'f in an inert solvent as described above.

Preferably, at a temperature of about -30°C to +5°C, the human temperature is -8 (
0) 0.8 to 2.0 mol per mol of the compound represented by the general formula (II) where mR3 or the compound represented by the general formula (1) where X is -8(0)mR3, Preferably i, o to 1.2 mol [however, when a compound of general formula (III) in which Z is 10H20H is used, 1.6 to 4.0 mol per mol thereof, preferably Bo 2.0~2.
4 mol] of non-anionized Ut to form a carbanion, at a temperature of about -80°C to +80°C, preferably -30°C to +5°C, ) Compound *'z or A
The compound represented by the general formula (I[) in which is a halogen atom is added in an amount of 1'IO, 8 to 3.0 mol, preferably 1. 0～
It is added at a ratio of 1.5 mol and allowed to react. The polyprenyl compound represented by the general formula (1) thus obtained has -8(
0) Contains asymmetric centers at two locations: the carbon atom to which mR3 is bonded and the carbon atom between this and Z to which the methyl group is bonded, and the production ratio of diastereomers depends on the reaction conditions, etc. However, the present invention does not limit the ratio, nor does it limit the presence or absence of optical activity.

-8(0) polyprenyl compound represented by general formula (1)
) By performing the reductive elimination reaction (hereinafter sometimes referred to as reductive desulfurization) of the mR3 group, the general formula (V) and Ha -alI2-C11-CHs-Z' (V) [in the formula Z
l is the same as 2 in general formula (I) or -CH2
Get 0H. ] When Zl is a group other than a hydroxymethyl group, the compound shown in the following formula is converted to a hydroxymethyl group, thereby protecting the mammalian dolichols. Alternatively, the functional precursor group of the hydroquine methyl group of the polyprenyl compound of general formula (I) or the functional precursor group is protected.
In the case of a HO group, it is also possible to convert it into a free -CHO group or a hydroxymethyl group and then replace -8(0)mR3 with a hydrogen atom. In particular, when 2 in general formula (1) is a group containing an iodine atom, the group is replaced with a group not containing an iodine atom, such as -CHO or -CH2.
It is desirable to replace -8(0)mR3 with a hydrogen atom after converting it to 0H.

The reductive elimination reaction of the -S(0)mR3 group of the polyprenyl compound represented by the general formula (1) or the chemical partition deprotected from it can be carried out using known organic sulfides, sulfoquinodo 1
For example, Na-H
g-based CBoM, Trost et al.

Tetrahedron Letters, 347
(1976)], Al-)ig system (E, J, C
orey et al., J. Am. Chem.
Sac,.

86.1639 (1964), K. 5isido et.
al., J., Am.

Chem, Soc, 81, 5817 (1959)], alkali metal-amine systems [E, M, Kaiser
et al., 5 synthesis.

391 (1972), J.F. Biellmann
at al, TetraheckronLette
rs, 3707 (196-9), H, O, Hu
iaman, Pure and Applied C
hemiatry, 49, 1307 (1977
)], -) Ne-Ni system [K, Hirai et al.
al, Tetrahedron Letters,
4359 (1971)]. A method using an alkali metal or metal amine system is particularly preferably employed. In this method, lithium, sodium, potassium, etc. can be used as the alkali metal, with lithium being particularly preferred. The amount of alkali metal used is preferably about 5 to 50 times the stoichiometric amount. In addition, examples of amines include methylamine, ethylamine,
Mention may be made of di- and di-lower alkylamines such as globylamine, dimethylamine, diethylamine, and ammonia, with methylamine, ethylamine and ammonia being particularly preferred.

This reaction is carried out under an inert gas atmosphere such as nitrogen or argon, from about -80°C to +10°C, preferably at about -50"C.
It is desirable to carry out at a temperature of ~O<0>C.

- The elimination of the ⋯⋯⋯ group from the compound represented by the branch formula (1) and i4' (V) is carried out in accordance with the method of the public, and the ≧compound v
This can be done by subjecting it to a 1J gold hydrolysis plant or to hydrogenolysis.

For example, 2CuZ'i; the formula -CH2-0-R'
(7) When R4 represents an alkyl group, the compound of general formula (1) or (V) is dissolved in a solvent such as tetrahydrofuran, chloroform, methylene chloride, etc. at room temperature and treated with trimethyl iodide. In addition, when R4 in the group of the above formula represents an aralkyl group, the compound of general formula (1) or (V) is added to a solution of ethylamine and lithium. A layer of tetrahydrofuran is added dropwise, and after the reaction is completed, excess lithium can be deprotected by decomposing it, for example, in a diluted ammonium water bath, and at the same time -5(o) and R3 groups can be removed. When R4 in the group of the above formula represents an ether residue,
For example, the compound of general formula (1) or (V) is mixed with hexane/
Pyridine para-toluenesulfonate (preferably about 0.1 to 0.2 equivalent weight) was added to each solution dissolved in a mixed solvent of ethanol (approx. The protection can be achieved by reacting for a period of time and neutralizing the reaction mixture with sodium carbonate etc. after the completion of the reaction.Furthermore, when R4 in the group of the above formula represents a silyl group, the general formula (1) Deprotection can be achieved by adding tetra-n-butylammonium fluoride (preferably about 2 equivalents) to a solution of compound (V) in tetrahydrofuran and stirring overnight at room temperature.

and when Ql and Ql simultaneously represent an oxygen atom, the compound of general formula (1) or (V) can be prepared using cloth@
Treatment with an acid (preferably one with a concentration of about 10%) converts Z or 2' into an aldehyde group (-CUO). In addition, ql and Q in the group of the above formula
When at least one of l is a sulfur atom, the general formula (1
) is preferably deprotected to convert Z into an aldehyde group. For this purpose, for example, an equivalent or more amount of Hgα2 and CdCO is added to an acetone bath solution of the compound of general formula (I).
A method can be used in which a small amount of water is added to 3 and reacted at room temperature for several hours. Hydroxymethyl group can be obtained by reducing hydrogen chloride and aluminum hydride using lead metal hydrides such as lithium lithium and aluminum hydride.
(CHzOH). The reduction can be carried out according to a method known per se, for example, when using sodium borohydride, an alcohol,
It is preferable to carry out the reduction reaction in a solvent such as tetrahydrofuran or ether at about 0°C to room temperature, and when using lithium borohydride, lithium aluminum hydride or sodium aluminum hydride, It is preferable to carry out the reduction reaction in an anhydrous bath medium such as anhydrous ether or gamma-free tetrahydrofuran at about -30°C to room temperature.

Reaction mixing proboscis after completion of reduction reaction? After decomposing the excess reducing agent by treatment with water, alcohol, ethyl acetate, etc., complete separation is performed according to a conventional method to obtain the corresponding alcohol [2 or 2' in the general formula (I) or (V) is hydroxyl]. compound representing a methyl group] can be obtained in high yield. In the case of a compound in which 2 in general formula (I) is a hydroxymethyl group, 2' in general formula (V) is subjected to the reductive elimination reaction of -S(0)mR3 group as described above. It is converted into a compound that is a methyl group.

As mentioned above, the salivary NjJ compound dolichol synthesized as described above is useful as a physiologically active compound that corrects saliva in the fields of pharmaceuticals and cosmetics. The Yocine invention will be explained in more detail.

In addition, the IR analysis of Example 2 and Silkworm Example A was carried out by liquid film measurement.
NMR analysis was performed using TMS as an internal standard. The analysis time of electric field magnetic bed mass spectrometry (CF'D-MASS) is 1H,
12C114N, 160.28 Sl, 32S, 35
The corrected value is α79Br.

0Q TanoS) Chloroform 'rl' t at room temperature (approximately 15°C)
Soak it in monkey for a week and extract it. Petroleum ether Tt was added to the filtrate obtained by distilling off chloroform from this extract to remove non-bath components, and the p solution was applied to a silica gel column using concentrated chloroform as a developing solvent. After separation, an oily product with a weight of approximately 35.9% was obtained. Approximately 40% acetone on this Tsukuda $ snout
0- is added to dissolve the acetate/soluble components, the resulting mixture is selected as P, and P is selected as #! L, obtained Afc oily #IIJf
) After heating at 65°C for 2 hours with 400 m of water and 209 m of sodium hydroxide, methanol gold was distilled off, and diethyl ether (500 m) was added to the residue.
) was extracted, washed five times with 100 ml of ethereal water, dried over VC6 and anhydrous sodium sulfate, and the solvent was distilled off to obtain 21.7 g of an oily product.

Next, this oily substance was separated using a mixture of n-hexane/inglobil ether=90/10 (volume ratio) using about 1 inch of silica gel to obtain 19.5p of an oily substance. This oily substance is coated with polyprenol, which has a fineness of over 95%.
About this product: Merck's semi-preparative high performance liquid chromatography column LiChroaorbRP 18-10 (C
1g type) using acetone/methanol-90710
A high performance liquid chromatography analysis was carried out using a mixed solvent as a bath separation liquid and a differential refractometer as a detector, and the area ratio of each peak in the obtained chromatogram was determined as follows.

9 18 1, the bottom fraction was fractionated from the above-mentioned old product using high performance liquid chromatography and analyzed, infrared, absorption spectrum, 'H-N
A
It was confirmed that the polyprenol was applied to k'F#.

The results of FD-MASS and H-NMR for each component were determined by JLvc, 'C-N
The 1viR Noro values are summarized in Table 2.

Polyprenol 12.4 of general formula (■) where n=15
Pp and 11 L of pyridine were added to 2 ood of hexane, and 2.02 liters of phosphorus tribromide was added dropwise to the resulting solution at room temperature (approximately 20°C) under a nitrogen gas atmosphere.
Stirred overnight under nitrogen gas atmosphere. Next, this n-hexane solution was put into a separating funnel, washed three times with about 50 d of water, dried over anhydrous magnesium sulfate, and the n-hexane was distilled off to obtain a slightly yellow liquid L2. I got Or'z. When this product was subjected to NMR analysis, the signal (d, δ = 4.08) attributed to the -CH20H group of the raw material polyprenol disappeared.
A signal (d, δ=3.91) assigned to r appeared. Moreover, when this liquid material was analyzed by iFD-MASS, m/e=1304 was found. According to the analysis results of these authors, the above product has the general formula [formerly n=15, A
It was confirmed that it was polyprenyl bromide with =Br.

Polyprenyl bromide with n other than 15 and borig V with n arbitrarily distributed between 10 and 18 by similar operation
The mixture was also created.

Reference 3 Polyprenol 12.4r and pyridine l of the general formula (IV) where sweet acid 11 = 15 of borylnyl cucoride, Oml f 20 Q
ml of n-hexane, thionyl chloride tsr*a was added to the resulting solution at room temperature under a nitrogen gas atmosphere, and after the dropwise addition was completed, the reaction mixture was roughly stirred at room temperature for 2 hours. By treating wheat in the same manner as in Example 2, pale yellow liquid 11.2f was obtained. IR about this thing
When analyzed, it was found that the absorption caused by the 0 group of the raw material polyprenol had disappeared.

In addition, when NMR analysis was performed, the signal assigned to -Cg20H of the raw material polyprenol disappeared, and the signal assigned to -CB2α was newly assigned to digal (d, δ-3).
, 95) appeared and obtained m/e=12fjQt'4 by FD-MASS analysis. From the above, the product j above has the general formula [
It was confirmed that it was polyprenyl chloride.

Polyprenyl chlorides with n other than 15 and polyprenyl chloride mixtures with n arbitrarily distributed between 10 and 18 were also synthesized f''L by the work of colleagues.

Reference Example 4 Synthesis of polyprenylphenyl sulfide In addition to 2.27 thiophenol and 2.8 ff of potassium carbonate and 50 IIL of dimethylformamide,
In the general formula (n), n=15. A
=Br polyprenyl bromide 13, Of' was added dropwise. After completion of the dropwise addition, stirring was continued overnight at room temperature, and the reaction solution was poured into about 100 ml of water and extracted with hexane. The hexane layer was then washed with 10% sodium hydroxide aqueous solution, washed with water, dried over anhydrous magnesium sulfate, and the hexane layer was distilled off to give 1 as a yellow liquid. This yellow liquid was purified by 7 silica gel column chromatography (methinone chloride was used as a developing solution) to obtain a slightly yellow liquid of 8.61. When this product was subjected to NMR analysis, the signal (4, δ = 3.91) attributed to -CHzBr K of the raw material polyprenyl bromide disappeared, and a new -
Signal attributed to Cdan2S- (d, δ = 3.47)
Signals assigned to 2 and 3 CaHs (m, δ =
7.05-7.32) appeared. Also, when this liquid noise was analyzed by FD-MASS, m/e=1
334't'' was given.

From the above, this is the general formula (in the old case, n=15
*A = -8c6H5 terophorifrenyl phenyl sulfide was confirmed. By similar operations, mixed polyprenylphenyl sulfides with n other than 15 and polyprenylphenyl sulfides with n between 10 and 18 were synthesized.

2-mercaptothiazoline 4.05F and 50% sodium hydride 1.44fk dimethylformamide 45rn
After stirring for 1 hour at room temperature, general formula (n)
In n=15. A = Br polyprenyl bromide 19.5 Pi dissolved in 15M dimethylformamide was added dropwise, and after completion under Cw - stirring was carried out at room temperature overnight.

′? The reaction solution was poured into about 150 μ of water, extracted with diethyl ether, washed with water, dried, and dried to obtain a yellow solid. This liquid was purified by silica gel column chromatography (hexane/acetate ether used as a general eluent) to obtain 8.4 g of a pale yellow liquid. About this thing
MEt analysis revealed that -C of the raw material polyprenyl bromide
Returned to HzBr, 100%/gnal (d, δ = 3.91)
disappeared.

Signals newly assigned to -CH28'/c (d, δ
-δ23.32 and t,δ=4.16) appeared, and when this whole body was analyzed by FD-MASS, m
/e21343t-Given.

From the above, this formula is 2(2) in the general formula (ff).
-thiazolinyl) sulfide.

Polyprenyls other than n”=15 (2
-thiazolinyl) sulfide 2 and polyprenyl (2-thiazolinyl) optionally mixed with n=1'o~18
A sulfide mixture was also synthesized. Reference Example 6 Synthesis of polyprenyl (2-pyridyl) sulfide 2-mercaptopyridine and 50% 2-mercaptopyridine were dissolved in 0.96r'i of dimethylformamide and 50% of 2-mercaptopyridine at room temperature. After stirring for a period of time, n=15. A: Br deru borif.

Renilpromide 13. After stirring overnight at room temperature, the reaction solution was poured into about 50 g of water and extracted with diethyl ether. Then, the diethyl ether layer was washed with water,
A yellow liquid was obtained by drying with anhydrous magnesium sulfate and distilling off the ether, which was then purified with a rilk sori gel knife (using hexane 7/acetic acid trapping ether as a developing solution). A pale yellow liquid with a weight of .82 was obtained. NMR analysis of this product revealed a signal (d) attributed to -CH2Br of the raw material polyprenyl bromide.

δ = 3.91) disappears, and a new signal assigned to KCdan2SK (d,〇23.78) and -δ-C5dan4N
signal (rn, δ = 6.75-8.35
) appeared, and when this liquid was analyzed by 6FD-MASS, m/'e=1335 was given.

From the above, it can be seen that this polyprenyl (formula (II)) has n=15 and A 5C5H4N.
It was confirmed to be 2-pyridyl) sulfide. By similar operations, polyprenyl (2-pyridyl) sulfides other than n-15 and polyprenyl (2-pyridyl) sulfide mixtures in which n=10 to 18 were optionally mixed were also synthesized.

Reference Example 7 Synthesis of polyprenylphenyl sulfoxide In the general formula (n), n = 15 +, A = 5Cs
Hs Tero polyprenylphenyl sulfide 8.47
? Dissolve in 65 g of ethanol, add 1.64 g of sodium metaperiodate dissolved in 32 g of water, and stir overnight at room temperature. After extracting with brine and ether, the ether layer was washed with water and saturated brine, dried over anhydrous noble acid Magnencum, and all erthyl was distilled off to obtain a yellow liquid. This was carried out using silica gel column chromatography (
6. Purify with hexane/ether (used as gold developer).
751 liquids were obtained. When this product was subjected to IR analysis, strong absorption due to sulfoxide appeared in 10350-1, which had no absorption in raw material polyprenylphenyl sulfide. Nml R analysis showed that it was attributed to 10HzSCsHs of raw material polyprenylphenyl sulfide.
7 gnals (ct, δ = 3.47) disappear, -Cdan 2
Signal assigned to SOC6H5 (d, δ23.:3
5) appeared. Also, from the F D -M A S S analysis, m/e = 1350 k yield 'fCO' or more.
This is the general formula (n) where n=15. A knee 5O
It was confirmed that it was polyprenylphenyl sulfoxide made with CsHs. By similar operation, polyprenylphenyl sulfoxide with n other than 15 and n with 10 to 1
Polyprenylphenyl sulfoxide [1], which was optionally mixed in 8, was also synthesized.

Reference J Example 8 Synthesis of polyprenylphenyl sulfone Polyprenyl bromide 13. where n=15tA-Br in the general formula (n). Of was dissolved in a mixed solvent of 1001d of N,N-dimethylformamide and 100'Ll of tetrahydrofuran, and anhydrous sodium phenylsulfinate 33'? 17 hours at room temperature, then 50°C in a colander for 17 hours.
Stir for hours. The solvent was removed on a rotary evaporator and +7 Kf was added for benzene/extraction. The benzene layer was washed with water and dried over anhydrous magnesium sulfate.

Removal of the solvent gave a yellow liquid. This product was purified by column chromatography (hexane/ethyl acetate solution was used as a developing solution) to obtain a pale yellow liquid of 9.4%. When this material was subjected to 'H-NMR analysis, the signal n (d, δ = 3.91) assigned to -CH2Br vC of the raw material polyprenyl bromide disappeared, and a new signal (d , 4
= 3.77) and a signal assigned to ~5O2C6dan5 (m, δ near, 31-7.93), F'D-MAS S analysis was performed and m/e-1
366i was given. From the above, this liquid is n-45,
A=-8O2Csi(s) General formula (If) Make sure that the compound shown is true. Similarly, polypunyl phenyl sulfones other than 15 and 10 to 18 are optionally mixed. A polyprenylphenyl sulfone mixture was also synthesized.

Example 1 In the general formula (II) synthesized according to Reference Example 8, n:
15, A = -S02C6) f5 Volip L/2/l/7zNylsulfone 6.53yi Anhydrous tetrahydrofuran 30 stones and anhydrous Hekijo methyl phosphoric triamide 3mJ is bathed in a mixture of about -10~ 0'C
3.281 d of a hexane bath solution (1.6 mol solution) of n-bunallithium was poured into the solution under a nitrogen gas atmosphere.

58-Bromo-3,7-dimethyl-62-octenyl tetrahydropyranyl ether stirred for 15 minutes.
927 in anhydrous tetrahydrofuran was added dropwise.

After dropping, stir at the same temperature for 1 hour, then return to room temperature (approx.
Stirring was continued overnight at 0 °C), then the reaction solution was diluted with tap water at 200 °C.
The monochloride/methylene layer extracted with methylene chloride was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a pale yellow liquid. Sold this liquid.

It was cleaved by Kagel's lamb chromatography (using methylene chloride/ethyl acetate as the developing solution).

Slight yellow liquid 6.74 ? 'I got it. According to the following analysis results, this product has 2 in general formula (1) and n2i5. QFD-0vIAss, which was confirmed to be a chemical compound [compound (1)] with R'ni5O2esHs, R2=H, Z=-0M2-0: m/e=1+N)4LR
(cln'): 1660.1590.1450.13
80.1310°114・, 1120.1080.1
035.1020.835CDα3, IH-NMR (δ): 99m 7.31-7.95 (rn, 5H, -8O2C6H
5).

4.75-5.35 (bs, t9u, book value).

4.46 (br, LH, -CH">.

-ゝO- 3.10 to 4.00 (m, 5M) The 21 compounds are polymers and have complex IH-N,)IR spectra, so they were analyzed using the above signals.

(The following 1H-NMR analysis was conducted in the same manner.) Practical disintegration example 2 Compound (1) 6.727 obtained in the practical flit was dissolved in 200 m of ditanol, IN-hydrochloric acid water, @liquid 3 'Q
M was added and stirred at room temperature for 4 hours. After neutralizing with sodium bicarbonate solution, most of the ethanol was completely distilled off under reduced pressure, and the residue was diluted with water.
0QrnJ and extracted with hexane.

After washing the hexane layer with water, it was dried over anhydrous magnesium sulfate, the hexane was distilled off, and the residue was purified by silica gel column chromatography (using methylene chloride/ethyl acetate as a developing solution) to form a colorless to slightly yellow liquid.6. 08
I got r money. According to the analysis results below, this product has n = 15 and R' = -8Os+C in general formula (1).
5Hs, R2=H, Z=-CH20H [compound (2)] was confirmed.

FD-MASS: m/e21520 IR (cln-'): ~3500.1670.1590
．． 1440.1375°1290, 1140.1090
．． 1070.1050.830'f-I-NMR (δC
Dα3): 99m 7.31-7.90 (m, 5H, 5OzCsf(a)
.

4.75-5.35 (br, l 9H, ACH',
).

3.36-4.05 (m, 3M, , :CH-8O2C
sHs+-CkbOH) Examples 3 to 8 Compounds represented by general formula (It) and general formula (III
) The same operations as in Example 1 were carried out using the compounds shown in Table 3 as the compounds shown in Table 3, respectively, and the corresponding polyprenylated adducts shown by general formula (1) were synthesized. . The yield of the polyprenyl compound is shown in Table 3, and the physical properties of the compound synthesized in Example 3 are shown below.
Compound (8)] FD-MASS: m/e=1610 IR (CM-1): 1660.1580.1500
．． 1450.1370°1300, 1140.1100
．． 1085.830CDα3 1H-NMR (δ): 7.05-7.95 (
m, 5H.

99m -8O2-CsHs), 7.25(s, 5tf, -Q
C) i2c6see5).

4.75~5.35 (br, 19f(,/':(
Llf(”).

4.3 g (3,2)i, -0CH2C6H5)
, 3.38~4.00 (m+IH,nCHb02(
-6f45), 3.20~3.55('', 2H+-C
H2-0-CHzCsf(s)''': Compound synthesized in Example 4 [Compound (4)] Fry MASS: m
/e=1562 ■R(crn-ri:1740.1660.159
0. 1450. 1370°1300.1240,1
150,1090,8:30"H-NMR (δCDα3
): 7.32L7.93 (m, 5h.

99m-802-CsHs), 4.75-5.35(or
, IgH, Acn').

3.35-4.20 (m, 3H, -CFT, t
o−+〉CH−8O2C6Hs).

1,'lls (a, 3)1. -occdan3) Compound synthesized in Example 5 [Compound (6)] FD-MASS
:m/e =1588IR(cIR-1) : 16
70.1590.1440.1370.1150゜11
20, 1080.1035.1020.830'H-N
MR (δCDα3): 7.00 to 7.69 (m, 5
H.

99m-So-CeHs), 4.75-5.35(br,
19H.

)%-cH'l 4.43'(bs, In,-CH<
'. -).

〇- 2,7~4.1 (m, 5H, -CH20-+, l
'cH-8OC5Hs) FD-MASS: m/e
=1572IR(z-”) :1670.1590.1
440.1370.1150゜1075.1040.8
30 − 4.47 (b s ; l H, Cfj−<0) +
3.1~4.0 (m, 15K, -CH20
-+''; CH-8CsHs) Compound synthesized in Example 7 [Compound (7)] FD-MASS: m/e21573Ik1111): 1670.1580.1460
．． 1420.1370゜1150, 1130.1080
．． 1040.830-8-C5H4N), 4.70
~5.35 (br, 19H, ^cm-).

3.10~4.05 (m, 5H, -CH20-+
"; CH-8C5H4N) Compound synthesized in Example 8 [
Compound (8)] FD-MAss: m/e21581 1R(c!R'): 1670.1580.1440
．． 1370.1150°1080, 1040.1000
．． 960.920.8304.10(t, 2k()
, 3.10 to 4.05 (m, 7H) or more, synthesis examples of compounds in which n = 15 in the general formula CI) have been shown, but homologues of these compounds where n is between 10 and 18. Compounds of general formula (I) other than 15 could also be synthesized in exactly the same manner. And the percent absorption of the IR spectrum of compounds other than those n=15 and "H-N
The %note signal of the MR spectrum coincides with that of the homolog of n=15 at that position, and the m/e1 direct signal by FD-MASS analysis (from that of the homolog of '111=15 corresponds to the difference in the number of isoprene units). There was a difference.

In addition, a polyprenyl sulfone mixture was prepared in the same manner as in Reference Example 8 by using the polyprenol homolog mixture (polyprenol fraction before separation into each single polyprenol component) obtained in the same manner as in Reference Example 1 as it was. By treating this in the same manner as in Example 1-8, compounds (1) to (
Each cognate Example 9 corresponding to 8) 8-phenylsulfonyl-3,7-cymef-6 Z
- Octenol 1.4SP to anhydrous tetrahydrofuran 3
The hexane bath solution of n-butyllithium (
After adding 6.56- (1.6 molar solution) and stirring for 15 minutes, n=15. A solution of polyprenyl bromide 6.52F of general formula (II), which is A2Br, in anhydrous tetrahydrofuran (5d) was added dropwise.

After the dropwise addition was completed, the mixture was stirred at the same temperature for 1 hour, and then stirred overnight at room temperature (approximately 20°C). Next, the reaction mixture was poured into 200ml of water, neutralized with diluted hydrochloric acid, extracted with methylene chloride, the resulting methylene chloride/layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Then, a pale yellow liquid was obtained. ) 4.96 tons of a bright yellow liquid was obtained by total silica gel column talomadography (using methylene chloride/tetrahydrofuran as a gold developer). From the analysis results below, n = 15,
R' = H% R2 = -8O2C6H5, Z =
It was confirmed that it was 8-phenylsulfonyl-8-polyprenyl-3,7-dimethyl-62-octenol [compound (9)] of the general formula (■), which is -CH20H.

FD-MAS S: m/e=1520IR(,”)
:~3500.1670.1590.1440°137
5, 1290.1140.1 ()90.1070°10
50,830 SO2C6dan') + 4.75~5.35 (br
, 19H, person CH/'l.

3.57 (t, 2H, -CHzOH) Example 1
0 to 24 Examples using the compounds shown in Table 4-1 and Table 4-2 as the compound represented by the general formula (n) and the compound represented by the general formula (■) in the amounts described in the same table, respectively. The same operation as in 1 was performed to synthesize the corresponding polyprenyl compound represented by general formula (1). The state of the polyprenyl compound is shown in Tables 4-1 and 4-2, and the physical properties are shown below -f=.

FD-MASS: m/e=1534I'kt(cm
'): ~35[J, 1rj7U, 1600,144
υ.

1370.1290. 114, 1090.
lo'70゜1050.830 1H-NM RC50"3): 7.3'J-7,7
9 (m, 4H.

29m-802-C6H4), 4.75-5.35(Dr
+19H.

λC and -), , 3.57(t, 24-CH20H)F
D-MASS analysis: m/e=1534IR (L:M-1
): ~3500.1670.1595. 1440°1375, l 290. 1140. 1090.
1070°1050, 830 CDα3”H-N MR (δ) near, 74 and 7.3
0 (each 29m d, 2H, -5O2-C6H4-CH3), 4.75~
5.35 (br.

19H 9 people CH"), 3.56 (t, 2H, -C
ri+0Ef) Imperial Prefecture FD = viAS S: m/'e 21554I
RCcm'): ~3500.1670,1590,1
440,1370°1290.1140,1090,1
070. t050,8301H-NMR(δCDc'3
): 7.28-8.13 (rn, 4H.

29m-8O2CeH4-tel), 4.75-5.3
5 (or, 19H.

A! >CH/), 3.58(t, 2H, -Ci
(zOH) FD-MASS: m/e 21554 IR (crn-1): ~3500, 1670, 1585
．． '1445,1375°1290.1145,1
090,1075,1050,830, CDα3'H-NMR (o, l: 7.44 and 7.80 (semi-d.

29m 21(, -8O2-Csi(4-Qri, 4.75~
5.35 (br.

19) f, person CH', 3.56(t, 2H, -
CH20H) FD-MASS: rn/e21570 IRI'α-1): ~3500. 1670. 162
Q, 1591), 1440°1370, 1
300.1140,1120.830CDα3.

"H-NMR (δ), 7.30-8.55 (m
, 7H.

29m -8O2-CIOdan7), 4.75-5.35(O
r, 19H.

person CH-), 3.58 (t, 2H,-CH2
0H) FD-MASS: m/e=1562 IR (m-1): 1740, 1670, 1580, 1
440,1370°1140.830 CD (23''H-NMR (δ): 7.35-7.98
(m, 5H.

29m -8O2-C6H5), 4.75-5.30('l
)r, 191(λCH/), 4.02(t,
2H, -Cdan20CCH3)F'D-1VIAss:
m/'e21604IR(α-1):1670. 1
590,1440. 1i370°1145, 107
5. 1035. 830, CDα3'H-NMR (om), 7.35-7.98 (m
, 5M+p -802-C61-f5), 4.75-5.35 (
br, 19h.

, 3.24-4.00 (m, 4H, -CH20-
) FD-MASS: m/e 21620 IR (LM-): 1670, 1590, 1445, 1
375,1300°1150.1090.830 1H-NMR (δCDα3): 7.30-7.98
(m, 5)I.

29m-SOz-Csi(s: , 4.75-5.35
(br+t 9HI^CH/), 4.55
(br, Ii(,-Cdangu32).

3.1(1-:3.88(m, 4M, -CH20-) [
Compound (to)] FD-MASS: m/e = 1592 IR (w'>: 1670, 1590, 1440, 13
70,1310°1250. '1150,1090.8
301) I-NMJδCDα3): 7. i 5-7
．． 99 (m, 51 (.

99m-8O2-C6H5), 4.75-5.35(br, 1
9H.

person CH/), ;3.30~3.75(m, zt(,
-CH20-) Cedar FD-MASS: m/e=1610 IR ((3-'): 1660, 1580, 1500, 1
440,1370°1300.1140,1100.8
30"H-NMR (δCDα") -7,05~7.9
4 (m, IOH.

99m -8O2C6dan 5 + -0-CH2-C6 Hayashi 5).

4.75-5.35 (br, 19H,)bcuy).

4.37 (s, 2H, -0-CH2-Cc+Hs
), 3.37 (L2H, -CH20CHzCaHs
) Kage 223 tachi 2eni dan 2! Yuli Mioka New Uniji JfJ
'b-62-octenol [Compound ■] FD-ivlAss: m/'e=1488IR (c
IR”): ~330 t), 1670.1580.
l 440°1380.1050.830”f(-NMR(δCDα3): 6.95-7.4
0(m, 5H.

99m-8-C6H5), 4.75-5.35(br, 1
9H, Acu/).

3.55 (t, 2H, C20H) Fl)-MASS: m/e21504 ■R (cr!1″): ~3300, 1670, 1580
,1440,1380°1035.830,740. '
685 "H-NMR (δCDα"): 7.01-7.68
(m, 5H.

99m bOC5H5) + 4-75~5.35 (ml
19 H) +3.54 (t, 2H, -CH20H) Hardware/Water]
'FD-MASS:1564 IR(c!n''):1670,1590.1440,1
370,1180°1'120,1060,1040,
1010.830CDα3′d-NR[a(δ): 7.32~8
．． 00(m, 5f(.

99m-8O2-C6H5), 4.75-5.30(br
, 19) 1°: 3.20(s, 6H, -QCCH3 FD-MASS: m/e=1562IR((:II
! '): 1670, 1590, 1440, 1370,
1180°1120.1050.830 CDα3 NMR (δ)77.36-8, OO (ml
5'(+pI)m -8O2-C6dan5), 4.75-5.35(br
, 19H.

'CH/), 3.50-3.9a (m, 4H.

-0Cfl! 2C■20-) The synthesis examples of compounds where n-15 in the general formula (1) have been shown above.
Compounds of general formula (1) having a number between 0 and 180 but other than 15 could also be synthesized in exactly the same manner. And if (the characteristic absorption of the spectrum and the characteristics of the R spectrum/gnal of the compounds other than n=15 coincide with that of the homolog of n=15 at that position, F D -M A m/e value by S S analysis is 1l
It differed from that of the homolog of =15 by an amount corresponding to the difference in the number of isoprene units.

In addition, the polyprenol/homogen mixture obtained in the same manner as in Reference Example 1 (the polybrenol fraction before being separated into each mono-polyprenol component) was used as it was, and brominated in the same manner as in Reference Example 2. By treating in the same manner as in 9 to 24, homologue mixtures corresponding to compounds (9) to 2 were synthesized.

Continuation of page 1 0 shots clear person Masao Mizuno 335-18 Shimojo, Kurashiki City 0 shots clear person Takuji Nishida 3-9 Kurashiki Heights, Kurashiki City

Claims (1)

[Claims] 1. In the general formula % formula % 0, j-C=C-CkTs- represents a trans-type ingleprene unit, n represents an integer from 10 to 18,
Z represents -CH20H or its functional precursor group; R
1 and R2, one is a hydrogen atom and the other is -8(0)rQ
Hydrogen atom or -8(0)mR on the condition that R3
3, where m represents an integer of zero, 11 or 2, and R3 represents a phenyl group, a naphthyl group, a pyridyl group or a thiazolinyl group, which may be substituted with a lower alkyl group or a halogen atom. ] A polyprenyl compound represented by 2. The polyprenyl compound according to claim 1, wherein m is 2. 3. The polyprenyl compound according to claim 1 or 2, wherein R3 is a lower alkyl group or a phenyl group optionally substituted with a halogen atom. 4.2 is protected by a protecting group that can be removed by hydrolysis or hydrogenolysis -CH20H or -CHO
The polyprenyl compound according to claim 1, 2 or 3.