JPS58138701A - Polyprenyl compound and its preparation - Google Patents

Abstract

PURPOSE:To prepare a polyprenyl compound useful as a synthetic intermediate of mammal dolichols, by reacting a polyprenyl halide or polyprenyl sulfide with a specific compound in the presence of an anionizing agent. CONSTITUTION:A polyprenol of formulaI(n is 11-19) obtained from the extract of the leaves of ginkgo or Himalayan cedar is converted to the compound of formula II[group of formula III is trans-isoprene unit; group of formula IV is cis-isoprene unit; A is halogen or -S(O)mR<3> (m is 0-2; R<3> is lower alkyl, phenyl, etc.)]e.g. by halogenation, etc. The resultant compound of formula II (one of A and X is -S(O)mR<3> and the other is halogen) or formula V (X is same as A; Z is -CH2OH, etc.) is made to react with an anionizing agent (e.g. NaH) and then with the compound of formula V (X and A are halogen) or formula II to obtain the objective compound of formula VI[when A is halogen, R<1> is H; and when X is halogen, R<2> is H and the other is -(O)mR<3>].

Description

[Detailed description of the invention]

The present invention relates to a novel polyprenyl compound and a method for producing the same. More specifically, the present invention is based on the following general formula (1) (wherein -C)12-C-C-CH2-U trough)
, mW 7 represents a 7sCH unit, -Ckh-a 碌Hs- represents a cis-cut isogrene unit, n represents an integer from 11 to 19, 2 represents -CHxOH and 9 represents its functional precursor group, R1 and R8 represents a hydrogen atom with the condition that one of them is a hydrogen atom% and the other is -8(0)mR'', and m is an integer of zero, 1, or max. represents 1
8 is a lower alkyl group or a phenyl group, naphthyl group, or pyridyl group which may be substituted with a halogen atom; Represents a thiazolinyl group. ] The present invention relates to a polyprenyl compound represented by the following and a method for producing the same. The polyprenyl compound represented by the general formula (1) provided by the present invention is useful as a raw material for medicines, cosmetics, etc., and is particularly useful as a synthetic intermediate for leprosy dolichols. Trifuls were described in 1960 by J.F., Penn.
It was first isolated from pig liver by Ock et al. (N
ature (LOndOn), 186,470 (196
0)], which later represents the general formula (A) Hs unit, and -CH5-1=A-CjHs- represents a C-type imprene unit. The same shall apply hereinafter in this specification. ] A mixture of polyprenol analogues having the structure shown in formula (A), where j representing the number of cis-isopre7 units generally ranges from 12 to 18, and j−r+, 1
It was revealed that the main components are s and 16 homologs (R, W. K!epJln ej al, , B10C11e
rnlCal Journal t LLL1605(
(1977)]. Dolichol@ is widely distributed not only in the liver of pigs but also in the bodies of mammals, and is known to play an extremely important function in maintaining the life of living organisms. For example, J. B. Hardard et al. used the white medulla of calves and pigs in vitro. Tests have shown that r% exogenous dolichol promotes the incorporation of O-sugar components such as mannose into lipids, and as a result, has the effect of increasing the influence of superimposed glycoproteins in sustaining the life of living organisms. clarifying (fiiochemica)
l and Biopb) rsical research
chCommunication Lit 1036
(1977). ] The effect of dolichols on promoting the incorporation of sugar components into lipids is remarkable both in growing organisms and in already mature animals, so the role of dolichols in preventing aging has attracted attention. ing. Previously, R, W., Keenan et al. have shown that for rapidly growing organisms such as those in infancy, it is necessary to ingest dolichol from outside and supplement the dolichol obtained by biosynthesis within the body. It states that
ves of Biochemistry and B
iophysics. 171i), 634 (1977)] Akamatsu et al. quantified dolichol phosphate in the regenerated liver of rats, and found that the amount was significantly reduced compared to that in the normal liver. We found that the glycoprotein synthesis function in the liver tissue was greatly reduced, and that cough function was improved by adding dolichol phosphate from the outside (54th Annual Meeting of the Japanese Biochemical Society (1981)). ). As mentioned above, dolichols are extremely important for living organisms.
・It is a substance that controls multiple functions, and is useful as an intermediate for pharmaceuticals or health care, and has not been easy to obtain.
For example, from a pig's liver jill 101w, through complicated operations, one can obtain the dolicalls of ``o'' and ``et''.
%/%CF, W, Burgos at al.
,BiochanjcalJournaL IJLw
470 (196B)]. It is extremely difficult to completely synthesize dolichols using current organic synthesis techniques, as is clear from their complex and unique molecular structures. It would be advantageous if dolichols could be obtained by relying on natural products as synthetic intermediates and adding simple synthetic chemical treatments to them, but such convenient substances have not been found so far. Conventionally, polyprenol ll1i (these are called penlaprenols) represented by the following general formula (B) [however, k-4 to 6] can be collected from 7 la campa (αI and 1a verrucola). Although this is known, it is almost impossible to synthesize dolichols mainly containing cis-cap isoprene units of 14.15 and 16 using current organic synthesis techniques. K again. Nunnus et al. isolated a polyprenyl component from the leaves of European red pine (il U trigram cedar punishment) at a yield of l'jl on a dry weight basis, and this component was found to contain 10 to 10 inogren units.
Although it is stated in 1 that it is a polyprenylacetate mixture having 19 molecules mainly in the cis configuration (Phyto
chemistry, 1312563 (1974)
], their report does not elucidate the details of the trans and cis configurations in the polyprenylacetate. Furthermore, D., JP, Zinckel et al. reported the presence of Coo's polyprenols with an average value of 18 imprene units across 18111 imprene units in the leaf extract of Pinus 5trobus. There is (Phytochemt)
5try s 1153387 (1972)],
In this report, no detailed analysis was conducted regarding the trans and cis configurations of the polyprenol. Some of the present inventors and their co-researchers first hydrolyzed the extracts extracted from ginkgo biloba and Himalayan cedar using an aUS medium using a chromatography, fractional dissolution method, etc. Polyprenols having 14 to 22 isoprene units in the same trans, cis configuration (by treatment with a suitable fractionation method) with 14 to 22 isoprene units in the same trans, cis configuration are treated with their acetate congeners. A polyprenyl fraction consisting of a thermocompound is obtained, and the polyprenyl fraction has a
- exhibiting a polyprenyl congener O distribution very similar to the distribution of polyprenyl congeners in mammalian dolichol IiK, with only the absence of an increased number of saturated isoprene units; stomach-
Therefore, the polyprenyl fraction and the round polyprenyl homologs separated from it are extremely useful as synthetic intermediates for mammalian dolichols. found that it is suitable for The present inventors have conducted intensive research on a method for introducing the above-mentioned polyprenyl compound, which can be obtained from Japanese cedar and Himalayan cedar, into a milk-dolichol chain. We have discovered that a novel polyprenyl compound represented by the general formula (1) can be easily produced by the method described above, and that the polyprenyl compound represented by the general formula (1) can be easily converted into mammalian dolichols, The present invention has now been completed. That is, according to the present invention, by reacting a compound represented by the general formula (■) with a compound represented by the formula (■) with the aid of an anionizing agent, a polyprenyl compound represented by the general formula % formula % () can be prepared. Obtainable. In the above formula, one of Mu and X is a halogen atom, and the other is -
On the condition that it is 8 (0) Otori R1, the halogen atom 9 represents -fi (0) ml", and n, Z, R1 and R"
d is more or less as defined above, and m and Rs are also more or less as defined above. However, when M is a halogen atom, R1 is a hydrogen atom, and when X is a halogen atom, V is a hydrogen atom. -5(
O) Reductive elimination of the Otori R1 group and 2 is -CH
*When it is a functional precursor group of OH, it is replaced by -CH*O
It is possible to obtain mammalian dolichol si by converting to H. The compound represented by the general formula (1) can be obtained directly from the extracts of the Japanese sorcery and the Malayan cedar collection, and can be obtained by the general formula (W) [where nFi is as defined above]. It can be easily produced from the polyprenol shown by ◇]. The polyprenyl halide sFi of the general formula (II) in which the group is a halogen atom, the polyprenol represented by the general formula (W), or a mixture thereof can be halogenated with a halogenating agent such as phosphorus triphenide, thionyl halide, etc. You can get it by doing this. This halogenation reaction is carried out in the presence or absence of a base such as triethylamine or pyridine in a pervasive #I medium such as hexane or diethyl ether at a temperature of about -20'C to +50°C. Preferably pcts%SOQ, PBr
s, 80Br goose can be removed as required. The polyprenyl sulfide Ii of the general formula (II) in which m is -SR'' is a combination of the above-mentioned polyprenyl halides and 41
1 is synthesized by reacting with a mercaptan (R18H). This reaction is generally carried out in the presence of a base such as sodium hydroxide, n-butyl lithium, sodium hydroxide, potassium hydroxide, sodium t-butyl in a solvent such as dimethylformamide, tetofhydride, etc. Also, OA performed under Hiro cooling.
The polyprenyl sulfide of the general formula (1), which is "OR", is prepared by treating the above polyprenyl sulfide with a small excess of an oxidizing agent such as sodium percarbonate or hydrogen peroxide. This oxidation reaction is
Normally, it is carried out in the vicinity of water-containing methanol, water-containing acetone, etc. Muga-BOtR”
The polyprenyl halide of the general formula (1) is an alkali metal organic sulfinic acid in which the polyprenyl halide is phased out in a solvent such as dimethylformamide or tetraE-Drofuran at a temperature of *S to about 70°C. Salt (R”
80 snow M; here Md can be obtained by reacting with metal 0) which preferably represents FiNm. In addition, in the above theory 911, R1 represents a lower alkyl group, or a phenyl group, a naphthyl group, a pyridyl group, or a thiazolinyl group which may be substituted with a dichlorogen atom, and is preferably a phenyl group or an L lower alkyl group.
It is a phenyl group substituted by a halogen atom, particularly preferably a phenyl group, a tolyl group or a monochlorophenyl group. General formula (1) and U (1M) K > IteZ tj
: -CH*OH also represents a functional precursor group, and the functional precursor group includes -CH2 protected with a protecting group that can be easily removed by treatment such as hydrolysis or hydrogenolysis.
Included are OH and -CIO groups. The latter, that is, the preserved one CH0 group is released and then reduced under mild conditions.
For example, lithium borohydride, sodium borohydride, lithium aluminum hydride, sodium aluminum hydride, etc. can be converted to an 10HsOH group by reduction with K. Examples of such functional precursor groups include the following. (1) A group of the formula -OH Mayuzumi OR' [wherein R4 is a lower alkyl group, a 7-ralkyl group having 7 to 11 carbon atoms, an aliphatic or aliphatic ether residue having 1 to 8 carbon atoms, Number of carbon atoms 1 to 11 @ (D aliphatic or aromatic acyl group "t i H formula -8i Ri
tRasRis 6 based on siri tteb L, where R
@t, Rat and Rss each represent a lower alkyl group, phenyl group, tolyl group or xylyl group.]
-CH5OCHs, -CkisOCs as 4 bodies 1%
Hs, -CH5OCsHy, -CHmOC4m, -〇HzOCsHo, -CH5OCHjOCHs, -CH
5OCkhOCsHs, -CH5OCsHsOCHs,
-CHj08 i (CHs) s, -CH20
8i(CsH+s) (Cs out Cds, -C1hO
1ii i (Cfim)*CaHt, -CoutOa i (t-C4H*)(CsHi)s, -CH5
ρ8i(C@)is)s 1 E KakyoJtf Mot
Lb. [In the formula, Ql and Q-rich each represent a sulfur atom or a sulfur atom; Rsl and R@s each represent a lower alkyl group, or together represent a lower alkyl group. ] The functional 1tllK group of 1CH5OH represented by 2 may be other than the above, such as a dcarboxyl group or a lower alkoxycarboxyl group. Most of the compounds represented by the general formula (Ill) are known compounds, and can be easily manufactured using known metals. In the present invention, the reaction between the compound represented by the general formula (1) and the compound represented by the general formula (1) is preferably carried out in an inert camellia medium. As the solvent, ether-based solvents such as diethyl ether, dioxyl ether, dioquinane, tetrahydrofuryl fluoride, dimethoxyethane, and diethylene glycol dimethyl ether are mainly used. It is also possible to blend such ether type #1 with an inactive polar 11IIIA such as hequinamether phosphoric triamide and use it as a vortex mixture. Note that the solvent used in this reaction is anhydrous 1
It is preferable that it is sufficiently dried to 1K. This reaction is carried out with the aid of an anionizing agent derived from a strong group such as sodium hydride, ttrium hydride, methyllithium, n-butyllithium, t-butyllithium, etc. , in an inert S medium as described above, from about -80°C to +80°C, preferably from about -30°C to +5°C.
At a temperature of
~2.0 mol, preferably 1.0-1.24 mol
Z i) s -CHzO)1 TEToh II (1) When using a metal oxide, it is 1.6 to 4.0 mol, preferably 2.0 to 2.4 mol per mol of O. 90° C. to +80° C., preferably -30° C. to about +80° C.
The compound represented by the general formula (1) where X is a halogen atom and the compound represented by the general formula (II) where X is a halogen atom at +5° C.
Approximately 0.8 to 1 mole of raw material compound having ml" group
3.0 mol, preferably 1.0 to 1.5 mol, of the opening is added and reacted.The thus obtained polyprenyl compound represented by the general formula (1) has 1,5(O) and R3 bonded to it. The carbon atom that exists between this and 2 and to which the methyl group is bonded. However, the present invention does not limit the ratio, nor does it limit the presence or absence of optical activity. , zo is the same as 2 in the general formula (1), and Kaka9 is -CH5CIH0], and when 2'' is a group other than a hydroxymethyl group, the group is By converting it into a human tetraxymethyl group, a mammalian tri; The functional precursor group of the E-oxymethyl group was retained.
When it is a cHO group, it is also possible to convert it into a free -C)[) group or a hydroxymethyl group, and then replace -8(0)mR'' with a hydrogen atom. In particular, when the general formula (1
) When 2 in A is a group containing a sulfur atom, the skeleton group is an i-form group that does not contain a sulfur atom.
It is likely that the polyprenyl compound represented by the general formula (1) is converted into zOH, and then -8(0)aR'' is converted into a hydrogen atom. -8(0) mR'' radical elimination reaction, known organic fulphytes, sulfonate compounds and sulfones are the ninth most effective way to achieve the same purpose. Similarly, for example, Na-H
g series (B, M, Trout et al. Tetrahedron Latters * 347
) (1976)], Mu1-1g series (1,J, cor
ey et ml, J, Am, Chem, 8oc, e
4141, 1639 (1964), L8isido
et al. J, Am. chem, 80C, I 81, -5817 (1959
) - Teru], alkali metal-74 series (E, M, Kali
ser et ml, 5ynthesis. 391 (1972), J.F.liielmann
et aL'I'@trahedron Lette
rs, 37G? (1969), H,0°Huimsin
, f'ur@and Applied Chani
5trye 49 t13G? (1977)], Raney Ni system (K, H4rai@t aL T@trah
adron Leiier L 43s9 (1971)]. A method using an alkali 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 approximately 5 to 50% of the stoichiometric amount.
50 times is preferable. Examples of amines include methylamine, ethylamine, goupyramine, and dimethylamine.
hmm. Of these, methylamine, ethylamine and ammonia are particularly preferred, including lower alcohols such as diether, lower alcohols, and ammonia. This reaction is carried out at about -80°C to +10°C, preferably at about -50°C, under an inert gas atmosphere such as argon.
Preferably, the reaction is carried out at a temperature of ~0°C. Protection from compounds represented by general formula (1) or (V)
Elimination of the group can be carried out by subjecting the compound to hydrolysis or hydrogenolysis according to methods known per se. For example, when d%2 or 2'' represents a group of the above formula -C-0-14' and R4 represents a lower alkyl group,
General formula (1) can be solved by treating the compound of (V) with trimethyl iodide in a mixture of tetrahydrochloride, chloroform, and methylene chloride at room temperature, and When R4 in the group of the above formula represents an aralkyl group, a tetrahydrofol solution of the compound of general formula (1) and (V) is added dropwise to a solution of ethylamine and lithium, and the reaction is carried out. After the completion of the process, the lithium carbonate can be released by decomposing it with saturated ammonium chloride solution, and at the same time, the lithium carbonate can be decomposed with -8
)mR'' group can be removed0 When R4 in the group of the above formula represents an ether residue, general formula (1)
(V) t) After dissolving the compound in a mixed solvent of hexane/ethanol (approximately 1/l), add para-toluenesulfonic acid pyridine (preferably ゛(
Add about 0.1 to 0.2 equivalent amount) and react at a temperature of about 50 to 60°C for several hours, and after the reaction is complete, neutralize the reaction mixture with carbonic acid, cum, etc. − can,
Furthermore, when R4 in the group of the above formula represents a silyl group, tetra-n-butylamine difluoride (preferably about Disassociation can be achieved by adding 2 ms and stirring overnight. and when Ql and Ql simultaneously represent an oxygen atom, the compound of general formula (1) (V) is mixed with tetrahydrofuran and isopropanol in a medium such as dilute hydrochloric acid (preferably 11.< By treating the compound with a concentration of about 10,114, it is possible to change the zt or z) aldehyde group (-〇). In addition, when at least one of Ql and Qs in the group of the above formula represents a sulfur atom, the general formula (1
) It is preferable to change 2 into an aldehyde group by unbinding the compound of formula (1).
5 and a small amount of water and reacting at room temperature for several hours can be used. (by reducing the nine aldehyde groups under mild reducing conditions), for example, borohydride F
Hydroxymethyl group
(CHsOH)K 0# quantity which can be changed can be carried out according to methods known per se, for example, when using sodium borohydride, Kit alcohol,
It is preferable to carry out the reduction reaction in a solvent such as tetrahydrofuran or ether at a temperature of about 0°C to the mold temperature. Advantageously, the reduction reaction is carried out in an anhydrous solvent such as anhydrous tetrahydro-79, at a temperature of about -30 DEG C. to deuterated water. After the reduction reaction is completed, the reaction mixture is treated with water, alcohol, ethyl acetate, etc. to decompose the HarufIIO reducing agent.
By carrying out the separation according to a conventional method, the corresponding alcohol [a compound in which 2° in the above formula (1) in which 9 is CV) represents a hydroxymethyl group] can be obtained in high yield. As mentioned above, the compound in which 2 in K in general formula (1) is a hydroxymethyl group is -8(0)
The mR'' group is subjected to a reductive elimination reaction to convert it into a compound in which 2'' in general formula (V) is a hydroxymethyl group. As mentioned above, the mammalian dolichol synthesized as described above is useful as a valuable physiologically active compound in the fields of pharmaceuticals and cosmetics. Next, the present invention will be explained in more detail with reference to Examples and Reference Examples. In addition, the analysis of work 8 in the examples and reference examples is based on i.
The ua column was set, and the NMR analysis was performed using TM& as an internal standard. i'D-MAS8 analysis value is "H%" Cs 14N
s ”Os ”811”8 ,”C1sγ-Br It is a value corrected by Example 1 4-phenylsulfonyl-3-methyl-1-7'tanol 114f synthesized according to Reference Example 11 (described later) was dissolved in a mixture of anhydrous tetrahydrofuran 3 (1+J) and anhydrous hexamethylphosphoric triamide 31Ij,
Cool to approximately -10°C to O'C and heat to n- under nitrogen gas atmosphere.
Hexane solution of Ptyrrhytecum (1.6 molar solution) 6.
56aj was added and stirred for 15 minutes, and then synthesized according to Reference Example 2 (described later), polyprenylene Jl/7'C11Dro, 5 of the general formula (I) where 9n=15 and A=Br.
After adding 90 drops of anhydrous tetrahydro 7 (5yd) solution of 2 f, stirred at the same temperature for 1 hour, then m
Stirring was continued overnight at al (about 20'C). The reaction solution was then poured into 200ml of water, neutralized with diluted hydrochloric acid, extracted with methylene chloride, and the resulting methylene nonachloride layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A pale yellow casing was obtained. This casing was purified by silica gel column chromatography (using methylene chloride/tetrahydro7ran as the eluent) to produce a yellow, one-color liquid.5.
Obtained 4 Of. This t is the result of the analysis below □Yop
n-15, R”JI, R snow w -80*C5Hi,
Za-CHsQHtes! It can be seen that it is 4-phenylsulfonyl-4-polybrenyl-3-methyl-1-butanol [metal compound (1)] of general formula (1). 11D-111188s m/ *-1452IR(
at ”)t3!S25,3040.29?5,293
0,2850゜Z 670 e ] Is 80 e
1450 t 1380 t i 310 *1150
．． 1090. 840. 725. @9ODCI
mlH-NMII(J) 99m 1.02 and 1.06 (d, 3H,>C, respectively). 1.12 (1,9H, also-, 1,64 (1,484 consecutive). a, oo (t, IH,'>c) pao=), 3.
46~s, so (Kametan, (small 0). 4.80 (t, 11. person cH'), a07 (b8,
17H, entering q/). ? -42~'Ij 4 (m*5kl #80s
+-CsHi) 0 Since this substance is a chemical molecule, the H-NMR analysis was performed on the above characteristic signals. Examples 2 to 16 Compounds represented by general formula (1) and general formula Table 1-1 and $121 as compounds indicated by - (lid), respectively.
The same operation as in Example 1 was carried out using -IK-Kyugyu in the amount described in the same paper to synthesize the corresponding polyprenyl compound represented by the general formula (1). The yield of the polyprenyl compound is shown in Tables 1-1 and 1-2, and the physical property values are shown below. FD-MA8 S s m/e-14661R (at-
”)! 3525.1670, 1600.1140〉
cH-&)嘗→, 3.40~s, sBm, 2at-C珈0-)C4,85 (t, IH, entered/) t&12 (black 1117) 1. A cup of tea. FD-MA 88s m/e-1466IR(am
-”) s 3525, 1670, 1595.1140
2.40 (s, 3H, -8O to yCjis),
2.87~3゜l 1 (m. 1 H, 7C1jJiOs) t 3.40~3.8
7 (mt 2H* “1”O-) *tss(t
t' la, Lc+ > t5.12 (bs, 17H,
Enter C1l/). FD-MA88sm/et 1486 IR(am-”)s 3525, 1670.1580.
1150DCI m IH-NMR (J) Rho 10 (de a
H* > C qs ) epm L40~3.87 (m, 3H, -CHzO-, >c
Ho*-). 4.78 (t, IH, Tai Cdan-) = 5.08 (bs*1
7H-person C

[). FD-MAa8 sm/e-1486 IR(am-") g 3525, 1670.1'68
0.1475,114212.90~3.14 (me
xli, >C1j-sos-), 3.38-3.
86 (ms2Ht-cm"O-) t 4-80 (
t * l H * person CM/), 5.07 (bstly
Ht person CH/), 7.44 and 7.80 (F
D-MAS8'sm/e-1502 IR(a)13B25.1670,1620,15
90,1300°1140.1120 L80~3.08 (m t I He >CM-80
m-) e 3.40-3.91 (m t2H, -C
HHO2), 4.81 (t, 1a, Acn
z), &09(bss 17H,,tcH/
)t 7,31~8.55 (m, 7) 1°-go snow-
4 IOH? ) FD-MAS 8s m/e= 1494IR(m-
”)! 1740.1670, 1580.1140DC
Is'H-NMR (J): 1.0 g (d, 3H,,
CH-Cila). pm 1.98 (s, 3H, 01'Cjls), L8
8~3.10 (m, IH.〉CBJOTO'), 3.81/)~4J2 (m,
2H, -QbO-). 4.111(t, IH, person CH') * 5.08 (
bs -17H, person C ¥). 7.35-7.98 (m, 5H, -80*-Cs
) FD-MAa S s m/e= 1536
1 R(aw-') wealth 1670, 1590, 1145
,1075.10354H--c珈0-) -4-52
(bs -I He W 枞)e 478(t, I
H, input CH/), &05(bs, 17Hs person q/). 7.36-7.98 (m, 5H, -80*-Csjb)
FD-MAa 8 s m/e= 1552I R(a
m-") ■67G, 1590, 1450, 1300,
1150゜090 4.70 (m, IH,!-Q->, 4.85
<t, 1a,) Scm. &09(bl, 17H, ^CH/ ), 7.32
~7.98 (m, 5H. -8o fable-I Koro 1 breath 0 FD-MA88sm/e=1524 I R(a+-”)■670.1590.1311G
, 1250, 1150° 1090, 845 2, sO ~ 3.08 (m, I H\CH-Box
-) 't s, s 4~3.74 (m. 2H, -CHzO-), 4.81 (t, 1a
ll, /'&%ct/), hot (bs. 17H, person CH/), 7.21~7.98 (m
, 5H,-50s-CsHs)FD-MAaS
s m/e= 1642IR(jl) 寞166G, 1
580, 1500, 1300.1140°1100,
700 00 mouth 1” H-NMR (J) sl, 0B and 1.06
(respectively d. 92m all,")ct(le), 4.35 and 4.42 (respectively s, gII. -0-CIls-C@Ml)? 7.07-7
．． 93 (m, SR, -8O*Cs1is)FD
-MA88 s m/e-1420IR(at-')
t3325.1@70,1580,1380,1050
゜730, 690t, 5s-3,01(m, IH,)CMP-), 3
．． 5s(t, !Hp-qdanxue(he), 4.81(t,
FH, person q tan/), 5.07 (bs, 17H.)%CH-'), 6.9 door, 4υ(m +
5 f(,-8-CIMI)FD-Mmu885m/e
-1436 IR (il) wealth 31325e1670,11580,1
38011035°725, 690 3.03 (m, IH,'>c+5o-), 3.54
<t, 211. -C) (20-). 4.80 (t, IH, Futsui/), 翫07 (bl, 17H
, immersion). 7.01~7.68 (m, SR, -80-Csli
i) iFD-MAS S m/e-1496IR
(ffi-1)81670.1590-sofu-(ko・
kLs) FD-MAR8s m/@ = 1494IR(am-
')"1670e1590e1380*1i50Dct
s LH-NMR (J) 11.03 (d, 3H,
CH-cHs). 92m 4H, -OCiimCj(*O-) e4.73(t
, xH, -0df (0-), 4.81 (jslHs person q
)), 翫08(bl, 17H, entering q/). F, 36-8.00 (m, SR, JO*-C@lls
) Example 17 In general formula (1) synthesized according to Reference Example 8, n
m 15 , A-1 & 1OsCsHs polyprenylphenyl sulfone 6,83 F was treated with anhydrous tetokuhyde ci
Dissolved in a mixture of 7-Ran 30- and anhydrous hexamedelphosphoric triamide 3-, cooled to about -10 to 0°C,
Under a nitrogen gas atmosphere, 3.28- of n-butyl lytecum hequinane (1.6 mol clear liquid) was added, stirred for 15 minutes, and then 4-promo-3-methylbutyl tetrahydrobirael ether 1.51 fO anhydrous tetrahydro 7 ran was added. 2
- Drop the solution and mourn. After dropping, stir at the same temperature of 111 degrees for 1 hour, then continue stirring at IL temperature (#20 degrees Celsius) at 90 degrees Celsius.
The reaction solution was poured into 2.00 liters of water and extracted with methylene chloride. The methylene chloride layer was washed with water, further dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a pale yellow color. This liquid was purified by silica gel column chromatography (using methylene chloride/ethyl acetate as the eluent) to obtain slightly yellow liquid 11G11. This product was confirmed to be sulfonylpolyprenyl)-3-methylbutyltetrahydropyranyl ether (compound) based on the following analysis results. FD-MAg 8s m/e-1536IR(aw
-”)■660,1590.1450.1380.1
310°1150.1090,1040. 7904.
75-4jlB (ba, 18H, person CH/), 7
．． 31-7.95 (m. 5)1. -8on-Cs! ! i) Example 18 Ie obtained in Example 17, 4-(1'-phenylsulfonylpolyprenyl)-3-methylbutyl tetrahydropyranyl ether 6,89 f tethanol 200s
After dissolving uK, 30 d of 1N-salt solution was added, and the mixture was stirred for 4 hours at the temperature of the mold. After neutralizing with aqueous sodium bicarbonate, most of the ethanol was distilled off under reduced pressure, and the remaining residue was poured into 20 od of water and extracted with hexane. The hexane layer was washed with water, dried over anhydrous magnesium sulfate, and the hexane layer was distilled off.
The residue was subjected to silica gel column chromatography (using methylene chloride/ethyl acetate as a developing solution) to obtain colorless to slightly yellow liquid 6.111F. According to the analysis results below, this product has n'''15 in 1 general formula (1).
, Rlsw-fKhcsHs, R''-H,Z--CH
It was confirmed that the sOH compound is 4-(1'-phenylsulfonylpolyphrenyl)-3-methyl-1-butanol [Compound (2)]. FD-MA881m/@=141$2 Summer R(am-')s3525,1670,1590,1
450,1380°1810.1150,1090 Dc1s "H-)Q[IL(J)10.70~0.
95 (m, 3H,)CB-Cjis). 29m 144~4.02 (me 3H, -CH2O-,>C
#80). 4.7t Fh, x s (bs, 1811, ,
J'1111cg 勺. 7.31~7.11O(m, SH, -K)sc@1
m) Examples 19 to 24 The compounds represented by the general formula (1) and the compounds shown in Section 2 as the compound represented by the general formula (1) were listed in the same table and used in round amounts to produce Example 17. Do the same operation as
A polyprenyl compound represented by the corresponding general formula (1) was synthesized, and the yield of the cough polyprenylated compound is shown in Table 2.
The physical property values are shown below. FD-M 8B"m/a-1541! IR(am-')1166091580,1500,1
450,1300°114G, 1100.740.70
0 1H-NMR (6%” > 80.70~o, *a
(me 3H,)CM-Cjis). 124-15m (m, 2H, -CJisO-),
3. $7~4. QQ(m. (Ing 5 H@-80t0gm) *7-
27 (s e 5 H* -cH -csHs)F
D-MAg 8s m/e-1494IR(a-')
! 1740, 1660, 1590, 1450, 1300
゜1240.1150,1090'H-NMR(llCDCl") s O,73-(
), 98 (m,SR,)C)l-Cfls). pm IJ 8 (!I, 3H, (X'CHs), 164~
4.17 (m, su, -CilsO-.)c#ωg-), 4.74 ~ 翫HA (bs, lan, person O
H/). T,! 127.93 (m*5H, -80g-ca
li four IFD-MA811 sm/e-1520I R(i”
) Customer 1670.1590. ,1440,1300,1
1! to. 1080.103B, 740. 690”H-NM
R(J',, @8) I O,72~0.98 (m,
3H,%B-Cc). tys~4.10 (m, 5H, -Cjieg0-,
) c 4 sen), 4.41 (bs, iHe bar-→, t
75-5.26 (bl, 18H?Acm/), 7.00
~ Fu-69 (me SRe 8O-Csiil
) FD-MA88 tm7'e-i 504I R(i
”) Wealth 1670, 1590, 1450, 1150, 10
75°1040, 740. 690'H-NMR (1'p!")! 0.71~0.
96 (rn, 3H, /CC10°3.10~4.
00 (me 5H, -C5ip-,) ca, -), 4
．． 47 (bs. xHt-t)e 4.70~! L26 (bs, 18
H, person OH/). 6.95-7.40 (m, 5H,-8-CsHi)
Fl)-11Ass tm/exi 505I R(g
m-1) depth 1°670,158G, 1460.142
0,1300°1150.1130,1080,104
0. 7601H-NMR (J CDCI @ ppm) g O, 70 ~ 0.98 (m * 3H,
7Cf1-C11s). 3.1t4.02(m, 5H, -C!ll0-, -8-
CM Ku), 4.46 (bs. Ill, -product HO-), 4.71~&2B (bl,
18H, entering q/). 6.75-8.48 (m, 4H, -8-Cg+
ji4N) Town FD-MAS8zm/e-1513 IR(at"-') 11660.1570.130G,
1150, 1080. '11040.10
00. 960. 92.0. 790DCIs”H-NMR(a)t 0.70-0.9
8 (me3H,/CH-Clis). 99m 3.10-4.00 (m, 7H, -CIlsO-
, 〉Cjl-t, -8CkhCkhN-, either 0-
Qim-), 4.15 (t, 2H, -aCI
hCH wet N-e) either tD-c le), 4.48
(BS, I H* J!”) t4.76~&
5s (bl, 18H, large C1 (/ ) or more, general formula (I
) and (1) show synthesis examples of compounds with n-18, but homologues of these compounds where n is 11 to
General formulas (1) and (1) that are 1 s or less between 190
0 Compound 41-j was able to contain an acid in the same round shape ◇ And those n Therefore, the m/・ value determined by FD-Reijin 8S analysis is missing by an amount that is due to the difference in the number of Ingren units from the homolog of n-15. 3-Methylbutylbenzylney 1h # ((a) fi"m+6.05"',
C-a 1.10, C-HsOH,) Let was added dropwise to 20s# of dry dimethylformamide, and phenylsulfinic anhydride sodium ν 111 was added to 50-5
After stirring at 5℃ for 16 hours and further at 65-70℃ for 1.5 hours, the contents were mixed with water! Pour into 0〇-, extract with methylene chloride, wash thoroughly with water, and sulfuric anhydride! Dry with gnesicum and trade 90 methoxychloride under reduced pressure,! ! The H-NMR spectrum of the 0ζO product was prepared using a silica gel chromatograph (using ethyl acetate/methylene chloride as a developing solution) to obtain 114 tons of colorless liquid. It can be concluded that this substance is 4-phenylsulfonyl-3-methylbutylbenzyl ether.
c-cJll) 1pm 2,'12~8.30 (m*2H*-80tC
1lt-) t 3.38 (t e 2 H. -C珈G-> t 4.34 (1, 2H, -ocB*
−@ ) * t, z s < s. Reference Example 1 (described later) K Therefore, a polyprenol maple compound having general formula (W) in which n is distributed from 11 to 191 and whose composition is substantially similar to that described in Reference Example IK was prepared as Reference Example 2 ( A polyprenyl compound was synthesized by reacting it with phosphorus tribromide according to the method described in (described later), and the 6.52 f was converted to the above 4-phenyl sulphate by reacting it with -8 in the same manner as in Example 1. -1 methylbutyl benzyl ether 01.91f was used in the same machine as in Example 1 to obtain a colorless to yellow viscous body of 4.20 f, with an IR spectrum of 90ζ010. Characteristic collection and IH-NM
The characteristic signal of R Nubetacil is the compound synthesized in Example 12 @O and at that position.
This substance corresponds to the general formula (1) and has 1-n Bm--8
0 hella, Z --CHm0CH4"t"number; b 4-
It was confirmed to be phenylsulfonyl-4-yNI)phrenyl-8-methylbutyl benzyl ether. ζO sticky casing 4.00f is KJ&lled in the same way as Reference Example 14 (described later) (at this time, it is disengaged at the same time) II
A discolored liquid substance 112F was obtained. This housing is used as a high-speed housing chromatography column Li Chros for Ryuken preparative use manufactured by Melta.
Using orb RP18-10 (Cts/(7')), nine main peaks were detected by high-performance liquid chromatography using a mixed solvent of iacetone/methanol-90/10 as the first liquid and a differential refraction needle as a detector. Check the location and see below.
4ASg1 11 0.1
1040'11 12 1.0
110・1 13! L9
11764 14 247 1
! 44n 15 39J
1312 @ 16 19.3
131107 17 &?
1448s 1 Lu 17 1
51 @・ 19 0.8
1584 Same casing black! It was confirmed that each peak was separated from n''-11 to 19040 by FD-M 8s analysis using Togelafy. About Il,'
H-NMR>YU'IC-NMR+folding vs.
゛(Those 040 are n-11-19, Z--C&O
Hj has a certain general formula (V) t) ms+ that it is a compound
The compound with 90 beak 5son ■15 is Reference Example 1
4 (write Il) gives the Tokumarukashamono and the gold (same) analysis value A, @0 Beak KTo nine things, IR. Both IH-NMR and IIC-NMR have absorption signals at the same position, and the intensity ratio is slightly different.The optical rotation of the 90★9 obtained is (aw)V.
= + O-11 (neat) According to the results of the 0 or more O experiment, the above 4-phenylsulfonyl-4-po-9 pre-1-3-methylbutyl benzyl ether obtained in the present example was optical # It has been confirmed that it is a 1iIk body) and that n is distributed from 11 to 19, and that it occurs in a variety of foods. Nine (1) -4-promo 4-3-methylbutyl benzyl ether KTh,t(R) -4-promo 3-
Methyl butyl benzyl ether ((*)”
S'sC-1,10, CmHsOH) was used in the same manner as above.
-Polybrenyl-3-methylbutylbenzyl ether 1
By synthesizing a metal material and simultaneously desulfonating it and layering it with the disengaged group II, the p-optical rotation is (g)V-0,5
1" (neat) liquid was obtained and analyzed. This liquid had n distributed from 11 to 191 and 9Z' --C
It is certain that it is a mixture of compounds of general formula (V) which is HsOH! It was done. Reference example 1 Separation of polyprenol Ite Sotsutaki 10101 collected in Kurashiki City at the end of October
1 undried weight) was dried with hot air at about 40° C. for 24 hours, and then extracted by dipping in so-called roform 80 at about 15° C. Petroleum ether St was added to the condensate obtained by distilling off chloroform from the ζO extraction wave to remove insoluble components.
After separating and diluting the P solution, the proverbial roform is lkl? ! Using it as a solvent, it was separated using a silica gel column to obtain about 5 tons of oil, and about 400 tons of acetone was added to the 90ζO cake to dissolve the acetone, and the resulting oil was filtered. P
The liquid was drawn with a chain line, and the resulting oil was boiled for 2 hours at 6S with methanol 400-5 water 40-1 and sodium hydroxide 201
'CK was heated to remove methanol, and the residue was extracted with diethyl ether (SOIIlj).
The ether layer was washed five times with about 100IIIIO water, dried over sodium monosulfate, and the #I agent was distilled off! 42
An oil of F was obtained. Next, this oily substance was mixed with n-hexane/isopropyl ether-90/10 (IF amount ratio) using silica gel of approximately 1.
Separate the mixture to obtain a 21.8F oil. This oil is a polyprenol with a purity of 95% or higher, and is prepared using a semi-preparative high-speed housing Roto column Li (!hrosorbRP 18-10 manufactured by Merck & Co., Ltd.).
(01s type) using acetone/methanol-90
/100 mixed solvent as the eluent and a water difference refractometer as the detection probe.The results of determining the area ratio of each peak in the obtained Crow V) Durham are as follows. Noto) de Atsuku. 1 11 0.32
12 1.13 13
194 14, 2-piece 6i
I$ 39.46
141 1927 17
5.98 18 18
9 19
0.8 For this reason, each component was separated from the above oil using liquid shield chromatography, and the quality analysis, infrared absorption spectrum, IH-NMR spectrum, and II
The IC-NMR spectrum reveals that these components have the general formula <
It was confirmed that it was a polyprenol having the structure shown by W). Field ionization method quality analysis (FD-MASS) for each component
) results and 'H-NMR J value! 3, “C
-NMR δ values are summarized in Table 4. Reference Example 2 Synthesis of Polyprenyl Bromide Polyprenol 12.4F of the general formula (Pi'), which is n''-15, and pyridine 1- were added to 200114 hexane to obtain a solution K11ll (approximately 20°C). Add 2.0 tons of phosphorus tribromide dropwise under a nitrogen gas atmosphere, and after the dropwise addition is complete, stir overnight under a nitrogen gas atmosphere.Next, put this n-hexane solution into a separatory funnel and add approximately 31g1 with sO- water
After washing, drying with anhydrous magnesium oxide and distilling off n-hexane, a moldy yellow OS-like substance 12. O
When NMR analysis was performed on this product, -CH! of the raw material polyprenol was obtained. The signal assigned to the OH group (d, J=tos) disappears and a new -CH5
A signal (d, J-3, 91) associated with BrK appeared and this liquid was analyzed by FD-MASS and found to be m/e-1304. According to these analysis results, the above product has n-15,
It was confirmed that the polyprenyl bromide was AmBr. By similar operations, polyprenyl chlorides with in other than 15 and polyprenyl bromide mixtures with n arbitrarily distributed between 11 and 19 were also synthesized.Reference Example 3 Synthesis of polyprenyl chloride When n=15 Polyprenol 12.4f of a certain general formula (N) and pyridine 1.0-2001
1.5 ft of thiochloride was added dropwise to the resulting solution under a nitrogen gas atmosphere, and after the completion of the reaction, the mixture was stirred for an additional 2 hours at 11 temperature. This reaction mixture was then post-treated in the same manner as in Reference Example 2 to obtain pale yellow liquid 11.2F. When IR analysis was performed on this product, it was found that the OH of the raw material polyprenol
The livestock yield caused by this problem had disappeared. -C of the raw material polyprenol when conducting nine NMR analysis! ! The signal attributed to 20HK disappeared. New 10HI (signal assigned to j (atδ=
3.95) appeared. 9, m/e-1260 was determined to be 4 by FD-MA8S analysis. From the above, it was concluded that the above product was a polyprenyl chloride of the general formula [ll] where n-15, A, = α. By similar operations, polyprenyl chlorides with n other than 15 and polyprenyl chloride mixtures with n arbitrarily distributed between 11 and 190 were also synthesized. Reference Example 4 Synthesis of polyprenylphenyl sulfide 2.2f of thiophenol and 2.8V of potassium carbonate were added to dimethylformamide 501, and while stirring at the mold temperature (about 20°C), n-15 in general formula (II), A-B
Polyprenyl bromide 13, Of, was added dropwise. After the addition was completed, stirring was continued overnight at room temperature, and the reaction solution was poured into about 100 d of water and extracted with hexane. Next, the hexane mixture was washed with a 10 fA*ll sodium aqueous solution, dried over anhydrous magnesium sulfate, and the hexane was distilled off to obtain a yellow liquid. This yellow liquid was subjected to silica gel column chromatography (methylene chloride was
This was used as an opening solution) to obtain 8.6 tons of slightly yellow liquid. When this product was analyzed by NMR, the signal (d, δ-3,91) belonging to -C1iglr K11 of the raw material polyprenyl bumide disappeared, and the new -
C■ Signal belonging to 2s- (d, δ-3,47)
and the signal assigned to −80s (m, δson7
．． 05-7.82) appeared. In addition, this liquid substance is F
D-MASB analysis gave m/e=1334. From the above, this product is n x in general formula (I)
m 15, A m -8CsHs te@ruboria'
v 2A/7 x = confirmed to be a rusulphide, 90. Similar operation f'FK to polyprenylphenyl sulfide where n is other than 15 and polyprenylphenyl sulfide where n is 11 to 19 and optionally mixed. Mixtures can also be synthesized. 4.05 F of 2-mercaptothiazoline and 1.44 F of sodium hydride were added to 45-dimethylformamide and stirred at the mold temperature for 1 hour. Prenylbromide 19
．． 5F to dimethylformamide 15117 +11! L
&! tt'''''FL・167ゞ-51,1> Stir at room temperature9. Next, the reaction solution was poured into about 150,111 g of water, extracted with diethyl ether, washed with water, dried, and condensed to obtain a yellow liquid. This liquid was purified by silica gel column chromatography (using hexane/ethyl acetate as a developing solution) to obtain a pale yellow liquid of 8.4F. This product was analyzed by NMR, and at nine points, a signal assigned to -cHar of the raw material polyprenyl bromide (d, J = 3
．． 91) disappeared, and the signal assigned to -CHm8 K (d, J-J-3,32 and t, δ = 4.1
6) appears and becomes a friend. Also, when this casing was analyzed by FD-MASS, it was found that ζrom/・=1343. From the above O, this product has the general formula (It) smell (2
-thiazolinyl) sulfide. Polyprenyl (2-thiazolinyl) sulfides other than n-15 and polyprenyl (2-thiazolinyl) sulfide mixtures optionally mixed in n-11 to n-19 can also be synthesized by similar operations. Reference Example 6 Synthesis of polyprenyl (2-pyridyl) sulfide 2.22f of 2-mercaptopyridine and 0.96t of 50% sodium hydride were mixed in dimethylformamide 50s+jK
After dissolving and stirring at room temperature for 1 hour, polyprenyl bromide 13. Of was added thereto, and the mixture was stirred overnight at 1Ⅲ. After 9 hours, the reaction solution was poured into about 50 ml of water and extracted with diethyl ether. Then, the diethyl ether layer was washed with water, dried over anhydrous il@magnesium, and the ether was distilled off to obtain a yellow liquid. This liquid was purified by silica gel column chromatography (hexane/ethyl acetate was used as the opening liquid) to obtain a slightly yellow liquid of 7.8 f. NMR about this thing
Analysis revealed that the raw material polyprenylfluoride 0-CijB
The signal assigned to r (d. δ-3,47) disappears, and the signal assigned to -C small s (d e J = 3.78) * Yohys"6kL4NK Rj'i is signal (m, δ-
6,75-8,35) appeared. In addition, when this liquid was analyzed by FD-MASS, m/e
Give = 1335 and circle. From the above, it can be seen that this polyprenyl (2
・-pyridyl) sulfide was confirmed. In the same manner, a mixture of polyprenyl (2-pyridyl) sulfinic acid and polyprenyl (2-pyridyl) sulfide other than In-15 was also synthesized, in which fl''=11 to 19 was arbitrarily mixed. Reference Example 7 Poly Synthesis of prenylphenyl sulfoxide In the general formula (1), n=15, A, 8C@Hi?
T. Polyprenylphenyl sulfide 8.47F was dissolved in methanol 65%, and 1.47F of polyprenylphenyl sulfide was dissolved in 65% methanol.・
Add a solution of 4f dissolved in water and stir overnight by weight. Add brine, extract with ether, wash the ether layer with water and saturated brine, and add anhydrous sulfuric acid! After drying over magnesium and distilling off the ether, a yellow liquid was obtained. This was purified by silica gel column chromatography (using hexane/ether as mm*) to obtain a 6.75 F liquid. IR analysis of this product revealed strong absorption due to sulfoxide, compared to 1035, which had no absorption in raw material polyprenylphenyl sulfide. NMR analysis revealed that the starting material was polyprenylphenyl sulfide.
Signal assigned to Hz 8C・Ha (d, δ-3,
47) # rA loss L, -CH2SOCsHa
KM) A signal (d, J-3, 35) appeared. Fi)-MAS8 analysis gave m/e-1350. From the above, it was confirmed that this product is a polyprenylphenyl sulfoxide in which n=15 and -Ha in the general formula (1). By similar operations, polyprenylphenyl sulfoxides in which n is other than 15 and polyprenylphenyl sulfoxide mixtures in which n is 11 to 19 and optionally mixed were also synthesized. Reference Hs Synthesis of polyprenylphenyl sulfone In the general formula (Rin), polyp=15 and A=Bj
1p. 3. Of tN, N-shime fx*x
``Mua Kendo 100m and Tetrahydro 7 Run 1oo
A mixed solvent of WLl was poured into a bath, 3.3 t of anhydrous sodium phenylsulfinate was added, and further heated in IUI for 17 hours.
Stir at 50°C for 1 hour. (b) Remove the solvent with a rotary evaporator, add water and wash the benzene layer extracted with water,
Dry over anhydrous magnesium sulfate. After removing the S+ wrinkles, a yellow liquid was obtained.9. This product was purified by silica gel column chromatography (using hexane/ethyl acetate as a developing solution) to obtain 11.4 fO pale yellow liquid. This thing! As a result of H-Hatoide fractionation analysis, the signal (d, J = 3.91) assigned to -CIisir K of the raw material polyprenyl blonde disappeared, and the signal assigned to -CIisir K of the raw material polyprenyl blonde disappeared, and the signal attributed to -CIisir K -
CH28 (hcmHs K-assigned signal (d, J
A signal (m, δ-7,31-7,93>) assigned to -802011-6 appeared.
In addition, when FD-MA8B analysis was performed, m/e-13
Give me ss. From the above, it was confirmed that this liquid was a compound represented by the general formula (1) where n=15 and Mu-80sC@Hs. Also, by the same operation, 1n-x
Polyprenylphenyl sulfone other than s and n is 11
A polyprenylphenyl sulfone mixture, which is optionally mixed in ~19, is also a synthetic saleta. Reference Example 9 Synthesis of 4-phenylthio-8-methyl-1-butanol 3-methyl-3-buten-1-ol 17.2F. Add benzenethiol 11°Of and azobisisobutyronitrile 0.5f into benzene 50@J, iii
After stirring for 5 hours at the R flow temperature of benzene under a gas atmosphere, the solvent was distilled off, and the resulting concentrated solution was purified by silica gel column chromatography (methylene chloride/ethyl acetate was used as the developing solution). pale yellow liquid 14.7f
I got it. The characteristic signals of this IH-NMR spectrum are as follows. ”H-NMR(δTradeT)1 0.98 (d, 3H,)C-CJis)2-5
6~3-02 (m + 2 H* −BCJJ* −
→3.57 (t, 2H, -C small 0-) 6.94-7J8 (m, 5H, 8Csjis) This pale yellow liquid is produced from this kernel and 4-phenylthio-3-methyl-1-butanol (@to It was confirmed that Sν(to0)I). Reference 1 Example 1o 4-phenylsulfinyl-3-methyl 4-phenylthio-3-methyl-1-butanol 1.
96F was dissolved in 00wLl of methanol, 2.57f of prime sodium metapercarbonate was dissolved in 5Q+++j of water, a solution of 9 was added thereto, and the mixture was stirred overnight at 111m. Next, add brine, extract with diethyl ether, and dissolve the ether layer in water and
After washing with saturated brine and drying over anhydrous magnesium sulfate, the ether was distilled off to obtain a pale yellow liquid. This was purified by silica gel chromatography (using methylene chloride/ethyl acetate as a developing solution) to obtain a colorless to pale yellow liquid of 1.6°F. The characteristic signal of the IH-NMR spectrum of this product was p as shown below. IHNMR (JCDcls): 92m 1.00(d,sH,-)C-so) 246-115(m, 2H,-8OCH2-)3
．． 55(t, 21(, -C 2O-)7.02-7.6
6 (m e 5 H, -8oc@Hs) From this, it was determined that this liquid was 4-phenylsulfinyl. Methachloroperbenzoin *11.6f to methylene chloride 150
++JF- was added to 4-phenylf-3-methyl-1-7'tanol while stirring while cooling to 0°C.5. Of methylene chloride (50su) bath solution was slowly added dropwise. After the dropwise addition was completed, stirring was continued for 1 hour at 0°C. After that, the precipitated methachlorobenzoic acid was separated orally and 10% was added to the oral fluid.
Add 100 d of i% sodium hydroxide aqueous solution and stir at room temperature.
Stirred for 0 minutes. Next, the methylene chloride layer was separated, washed with water, dried over anhydrous magnesium sulfate, and then diluted with methylene chloride/
was distilled off, and the concentrated product was subjected to silica gel chromatography (using methylene chloride/ethyl acetate as a developing solution).
5.82 t of colorless liquid was obtained using an oval mill. 1.The characteristic signal of this H-NMR spectrum is
; It was as follows. IHNMR (BCDC18). 92m 1, o o < a, 3H, ->cc small) 2.7
7-3.30 (m, 2H, -80sCMs-→8.5
4 (t, 2ii, -C small 0-) 7.25-7.116 (m, 5H, 80sCsjii)
This means that this liquid is 4-phenylsulfonyl-3-
It was confirmed that it was methyl-1-butanol ((〘S02〕~OH)). 4F of talomic anhydride was gradually added to the methyl stoichiometric reactor 1211, and the mixture was stirred at room temperature for 1 hour. 0 then 4-phenylsulfonyl-3-meth
A solution of 4.56 t of 1-butanol in hexamedel phosphoric acid was gradually added, and after stirring for 6 hours, it was poured into 100ml of water and extracted with diethyl ether. The residue was washed with water, dried over anhydrous sulfuric acid (IJ), and then the ether was distilled off. The residue was dissolved in 100@l of benzene and added with ethylene glycol (0- and p-)luenesulfonic acid.
, xfl+. Then, dehydration treatment was performed under am. Add contents to water 100＠
The benzene layer was separated, washed with aqueous sodium bicarbonate and water, and then dried over anhydrous sodium sulfate.The benzene was distilled off under reduced pressure, and the residue was purified by silica gel Chromadog 2.
Purification (using methylene chloride/ethyl acetate as a developing solution) gave 3.20f of a colorless liquid. The characteristic signals of the 1H-NMR spectrum of this substance are as follows. .48 (m, 2H, -8σ1
-CHs-) 3.55-3.94 (m, 4H, -
0CHzC, 1i30-)4.76 (t, I
H, -040-)7.40~8.04 (m, 5H,
80++C*Hs) Reference fl13 4-:yenylsulfonyl-3-1f-Black liquid 2. Get 511. Since the characteristic signals of the I H-NMR spectrum of this substance are as shown below, this substance is 4-phenylsulfonyl-3-methyl-1-
It was confirmed to be butanal dimethyl acetal. "H-NMR(a'p@"): 1.05(d,3)I,ncs-cub>2.72~
3.50 (m, '2H, -802Cklx -→
3.22 (s, 6H, -OCdans)4.3□(
t, IH, -8-11. -)7.40~8.05 (m
, 5H, 80sCsHs) Reference Example 14 5.30f of compound (1) synthesized in Example 1 was dissolved in anhydrous ethylamine 100-, and cooled to -20°C. To this was added 0.50 f of Kinpo lithium and stirred under a nitrogen gas atmosphere, and the reaction solution changed to one color, and the mixture was stirred for 1 a minute. Then imprene 2- and methanol 2-
-1 Furthermore, 2 t of ammonium chloride was added to decompose the excess lytecum, and when the system became white, it was poured into 20 Qwj of water using a ζ filter, extracted with hexane, the hexane layer was thoroughly washed with water, and anhydrous magnesium sulfate was added. Dry with **Hexane was distilled off under reduced pressure to obtain! ! The product was purified using silica gel column chromatography (using methylene chloride/ethyl acetate as a developing solution) to obtain a colorless viscous liquid 3.51F. This is the general formula (V) IKk according to the analysis results below.
Iten-15, Z' = -C)ho)l Tet. It was confirmed that the compound was FD-M 883 m/ei-1312IR (am-
”) t3320, 2920.285G, 1440.13
76°1060.830 1 field C-NMR (1'pfQ/' intensity)! 135.36
5/430,135J29/3567.135.005
/34G. 134.937/290, 131.210/213.
125.07115242゜□24.993/499
, 1□4.4481505.1□4.28□/463.
'124.214/445. 61.24115
51, 40.0291541゜39.757/6
83. 37.5481582, 32.2451
550G. 32.02174B6.29.3161528,
26.825/492°26.6991548,26.
43615166.2 Mr. 6771542*2 & 3081
567.23.430/6310,19.557154
8゜17.679/353.16.006/640"H
NMR (1) pmf s/l g-like, 7a) y ratio) t
o, 91 (d, 3H), 1.10-1.80 (m, 5H
), 1.60 (8,9H). 1.68 (s, 48H) t2.03 (bt70H), 3
J6 (m, 2M). tlo (b, tsH) Reference Examples 15-22 Examples 2-6.
's@ and (2) were reduced and sulfurized in the same manner as in Reference Example 14, and in the general formula (V) having physical property values consistent with those of the product obtained in Reference Example 14, n=15, Z'W
A compound which is -CH*OH was obtained.9. The yields are summarized in Table 5 as dolichol yields. Reference Example 23 The compound (γ)5Bat synthesized in Example 8 was desulfonated in the same manner as in Reference Example 14, but the amount of metallic lithium used was 0.56F), and the obtained crude product (hexane was removed under reduced pressure with K11il). (residue obtained) in ethanol 1
Dissolved in 50-s10% sodium hydroxide aqueous solution 30-
9. Add and stir for 5 hours while keeping warm. Next, most of the ethanol is distilled off under reduced pressure. ! Product III was poured into 20 od of water and extracted with hexane. The hexane layer was thoroughly washed with water, dried over anhydrous magnesium sulfate, and the hexane was distilled off under reduced pressure. The copper residue was purified by silica gel column chromatography ( (using methylene chloride/ethyl acetate as a developing solution) to give a colorless viscous oil *3.41F. j O4C)C) FD-MA8S11R, 5”C-N
MR&! The and lH-NMR spectra are consistent with those obtained in Reference Example 14, and this substance has n in general formula (V).
It was confirmed that the compound was -15,z9-sylide OH. 11 When the compound -6,08F synthesized in Example 20 was desulfonated and hydrolyzed in the same manner as above, a compound @3.46t with the general formula (V) where nW15.2''=-CHjOk3 was obtained. Reference Examples 24 to 30 The compounds synthesized in Examples 9.10v17 and 21 to 24 (88 (9), A% 4b prefecture 1%) and the state were reductively desulfurized in the same manner as in Reference Example 14, respectively. , the obtained nine crude products (-\residue after quinane distillation) are z/ /
1150 WIKFm Kashis I N-H (j Water #Q30- was added and stirred at room temperature for 3 hours. Most of the ethanol was distilled off under reduced pressure by TK, and the residue was dissolved in water 200-
Then, the process was carried out in the same manner as in Reference 23 to obtain n-1s s Z'--Ckl*OH in the general formula (V) having the physical property values consistent with those of the product obtained in Reference Example 14.
Obtain a compound that is 9. The yields are summarized in Table 6 as dolichol yields. Reference example 31 Example 11? Obtained nine compounds L: 1IIJ1) I and &28f were dissolved in 159m of ethanol, and 1N-Hα aqueous solution 20-
Add and stir at rIi temperature for 5 hours. Next, most of the ethanol was distilled off under reduced pressure, and the residue was poured into 200 ml of water and extracted with methylene chloride. The methylene chloride layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. A slightly yellow liquid was obtained. The IR spectrum of the ζO product is indistinguishable from that of the good compound (1) synthesized in Example 1. The above slightly yellow liquid is the same as Reference Example 14! IK desulfonation gives the general formula (V) K on 'CD-15, Z'=-C
The compound that is HsOkl 2.98ftll9o Koo4
OOFD-MASS, IR%”C-NMR and 111
-NMR spectrum is general formula (V) obtained in Reference Example 14
K>Iten;15, Z'-cH20H"e
It was consistent with that of the I compound. Reference example 3-43 Solid line #1! When good compounds (2) and - synthesized in Reference Example 14 were desulfonated in the same manner as in Reference Example 14, the benzyl group was eliminated at the same time as the desulfonation, and the physical properties consistent with those of the obtained product in Reference Example 14 were obtained. In the general formula (V) showing the value n-15%Z'=-CH proverb OH
A compound was obtained. The yield is shown in Table 6. Reference Example 34 Compound (6) 4.5 Of obtained in Example 15 was desulfonated in the same manner as Reference Example 14 (with the exception that 0.43 F of lyticum metal was added at -30°C), and the resulting large group product was (9 residues obtained by removing hexane under reduced pressure) was dissolved in 200% of ethanol, and 3% of IN-hydrochloric acid aqueous solution was dissolved in 200% of ethanol.
After adding 0- and stirring for 5 hours at stormy temperature, the mixture was neutralized with an aqueous sodium bicarbonate solution, and most of the ethanol was distilled off under reduced pressure. l! 4'
Fi! Pour the material into water 200@1, extract with hexane,
The hexane layer was thoroughly washed with water and then dried over anhydrous sodium sulfate. Hed? After distilling off the san under reduced pressure and dissolving the obtained residue in 30-ml ethanol, adding 0.5 f of sodium fluoride hydride and stirring for 4 hours at room temperature,
The reaction solution was poured into 150 ml of water and extracted with hexane. The heminan layer was thoroughly washed with water and then dried over anhydrous magnesium sulfate. Hexane was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (using methylene chloride/ethyl acetate as the eluent) to obtain 2.68 ft of a colorless and transparent viscous liquid. This f2)4(M)FD-
The MASS%IR, C-NMR and l)1-NMR spectra are consistent with those obtained in Reference Example 14, and this substance has general formula (V) with n=15 and Z'5=-CHs.
It was confirmed that the compound was OH. Further, the compound μs)4.8Of obtained in Example 16 was treated in the same manner as above, and in the general formula (V), n=15, Z
'--CHsOH compound 3.16F obtained by patent applicant RiRa Co., Ltd. Agent Ken Honda! . Procedural amendment (voluntary) May 11, 1980 Haruki Shimada, Commissioner of the Japan Patent Office1, Indication of the case 1982 patent WAf18208562, Title of invention: Prenyl compound and its manufacturing method (108) Rira Co., Ltd. Representative Director: Tsugu Okabayashi (Male 4), Agent: Lu (1)”? Telephone: Tokyo 03 (277) 3182 a Contents of the amendment (1) Change "hereinafter" to "other than" in the third line of page 48 of the specification. (2) Page 55 of the specification, fm line 7 (DrC approximately 15°C)
Insert ``1 henma'' between ``chloroform'' and ``chloroform''.

Claims (1)

[Claims] 1. General formula [in the formula, -CN3-C-C-Ckix-u)')
y SW (represents 7 prenoprene units, nFiil
represents an integer of ~19, 2 represents -CH20H or its functional precursor group, and R1 and R2 represent a hydrogen atom or -8( 0:)mR”, where m is zep,
It represents an integer of 2, R1 is a lower alkyl group, 9 is a phenyl group optionally substituted with a halogen atom, a naphthyl group, a pyridyl group, and 0 represents a thiazolinyl group.] A polyprenyl compound represented by the following. 2. The polyprenyl compound according to claim 1, wherein R1 is a water bulk atom. 3. Range i8 of the % house argument where m is 2! Apology 1 item 0
Polyprenyl compound. 4. The polyprenyl compound according to claim 1, subsections 2 and 9, and w43, wherein R1 is a phenyl group optionally substituted with a lower alkyl group or an I.rogen atom. 5. The polyprenyl compound according to claim 1, 2, 3, or 4, wherein z is -CH5OH. 6. 10HsOH or -cHO protected by a protecting group in which z can be removed by hydrolysis or hydrogenolysis
Claims 11, 2, and 3 are
The polyprenyl compound described in . 7. A method for producing a polyprenyl compound represented by the general formula, which comprises reacting a compound represented by the general formula n with a compound represented by the formula n with the aid of an anionizing agent [the above formula CHs
゛Ya, 434÷TSukug-fd, ) tI8゜I, oh. x represents the y position, n represents an integer from 11 to 19, and m and
”ヲTablet)L,Z Fi-CH20H19 is OII*
R1 and R3 each represent a hydrogen atom,
9 is 11 for 7X elementary atoms on the condition that the other is -g (o) Otori R3! (0) mR'', when m is a halogen atom, R1 is a water atom, and when x is a halogen atom, R'' is a hydrogen atom), where m is zero, V represents a lower alkyl group, 9th represents a phenyl group, naphthyl group, or pyridyl group which may be substituted with a halogen atom, and 9th represents a thiazolinyl group. ]. 8, M is a halogen atom, and X is -8(0)mR"
The manufacturing method according to claim 7. The OS suppression method described in Clause 7 or 8 of Patent No. 111* where 903m is 3. ...' 110, 1
`` is a lower alkyl group and 9 is a phenyl group optionally substituted with a halogen atom, Patent Claim 0
1111 Section 7, Section 8 or Section 9 ICO Manufacturing Method.