JPS58142902A - Polyprenylketocarboxylic ester - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a polyprenyl ketocarboxylic acid ester.More particularly, the present invention relates to polyprenyl ketocarboxylic acid esters.

Represents the unit! Integer t-representation of 1Fill-'-19.

R#i Lower lower aluminum pipe group. ) The present invention relates to a novel polyprenylketocarboxylic acid ester represented by:

The polyprenylketocarboxylic acid ester represented by the general formula (1) provided by the present invention is a substance useful as a raw material for medicines, cosmetics, etc., and is particularly useful as a synthetic intermediate for mammalian dolichols.

Dolichols 1960 11c JF, Penno
It was first isolated from pig liver by ck C;)j/C [Natur・(London), LLi, 4
70 (1960)], which later became a structure represented by the general formula (M) -CH2-δf (-CH2-QH(A) unit; hereinafter the same applies hereinafter). A mixture of polyprenol congeners having formula 1 (
A) represents the number of cis-filled isoprene units in Hat general K distributed from 12 to 18, j=14. ls and 16
It was revealed that the 3″fM homolog of [RoW.

Ke@nan et al,, Bioch@m1aa
l Journal, 1@L505 (1977)]. Dolichol II is widely distributed not only in the liver of pigs but also in the bodies of mammals.

It is known that it plays an extremely important function in sustaining the life of living organisms. For example, J. B. Harfor
d et al. used the intracerebral white medulla of calves and pigs.
r.

Studies have shown that exogenous dolichol promotes the incorporation of sugar components such as mannose into lipids.

Bioah
*mtcal and biophysical
Research Consmunicat Lone 7
6. 1 G 36 (1977)]. The effect of dolichols on promoting the incorporation of sugar components into lipids is remarkable in growing organisms as well as in already mature animals, so the role of dolichols in preventing aging fat is attracting attention. ing. 1 big, R, W, ni...n&n
have stated that it is important for organisms that continue to grow rapidly, such as during the infant stage, to ingest dolichol from outside and supplement the dolichol that is biosynthesized within the body. *s of Blooh@m
1stry and Blophystca.

17G, 634 (1977)]. Furthermore, Akamatsu et al. quantified dolichol phosphate ester in the regenerated liver of rats, and found that the amount decreased significantly compared to that in the normal liver. We found that adding dolichol phosphate ester from the outside improves the wrinkle function in wrinkles, where the glycoprotein synthesis function in the liver tissue is greatly reduced. (published in 1981)〇 As mentioned above, trichomes are extremely important to living organisms.
It is a substance that controls various functions, and it has not been easy to obtain it for the skin as a drug or its intermediate.1 For example, it has been difficult to obtain 0.6
You only get a doli call of 2 [F, W, Bu
rgoa at al,, Bioch@m1calJ
See 8fL 470 (196-3)]
Total synthesis of O-dolichol at is extremely difficult with current organic synthesis techniques, as is clear due to their complex and unique molecular structures. It would be advantageous if dolichol*t- could be obtained by relying on natural products as synthetic intermediates and adding simple synthetic chemical treatments to them, but such a convenient substance has not been found so far. do not have. Conventionally,
Polyprenol II represented by the following general formula (B) (B) [wherein = 4 to 6] (
These are called vera 2 prenols).
Although it is known that they can be collected from B@tula verruelm, it is currently not possible to synthesize dolichols, which mainly contain 14.15 and 16 cis-isoprene 7 units, from these. This is almost impossible with organic synthesis technology. MafcK.

Hannum et al. isolated a polyprenyl component from the leaves of Lotsuba red pine (Tansakiri Udankanjikugumi) in a yield of 1-1 on a dry weight basis, and this component contained isoprene units lO~19
reported that it is a polygrenyl heptatate mixture having mainly phytoeh in the cis configuration.
mlstrL 13.2563 (1974)].

In their report, the trans and cis configurations in scissor polyprenylacetate are not elucidated in detail. Furthermore, D., F., and Zinckel et al. reported the presence of Qllo polyprenols with an average number of 18 isoprene units or 18 isopre7 units in leaf extracts of pine strobus (Plnus 5trobus). Teiruga(Phytoch@mtstr)r
, Ile3$87 (see 197), this report does not provide a detailed analysis of the trans and cis configurations of the polyprenol.

Some of the inventors and their collaborators, Fi and K.

Extracts extracted from ite soda and Himalayan cedar with organic solvents are hydrolyzed if necessary, and then processed by chroma dog 2 fee, fractional dissolution method, or other suitable separation method to obtain 14 to 22 isoprene unit tubes. A polyprenyl fraction consisting of a polyprenol and/or a mixture of its acetate analogues having exactly the same trans and cis configuration as dolichols can be obtained.

The polyprenyl fraction exhibits a distribution of polyprenyl congeners that is very similar to the distribution of polyprenyl congeners in mammalian dolichols, with the only absence of α-terminal saturated isoprene units compared to mammalian dolichol IIIK; The fraction can be relatively easily separated from mK into its constituent polyprenyl congeners (uniform in the number of 4 soprene units); therefore, the scissors polyprenyl fraction and each polyprenyl congener separated therefrom are It has been found that it is very suitable as an intermediate for the synthesis of four mastoid dolichols.

The present inventors have intensively studied a method of introducing a saturated isoprene unit into the α-terminus of the polyprenyl chain of a scissors polyprenyl compound in order to efficiently produce mammalian dolichol Jllt using the above-described polyprenyl compound. The general formula (summer) useful as an intermediate in such methods
We created a polyprenylketocarboxylic acid ester shown by the following formula and completed one bottle @ Ming.

According to the present invention, a polyprenyl halide represented by the general formula (in the formula, Xll1 represents a halogen atom, nit is as defined above) [hereinafter referred to as polyprenyl halide (1)]. ] of a basic compound (wherein R is 0 as defined above) [hereinafter referred to as acetoacetate (1!I)]. ]
A polyprenylketocarboxylic acid ester represented by the general formula (1) is produced by reacting with the polyprenylketocarboxylic acid ester (hereinafter referred to as polyprenylketocarboxylic acid ester (1)). )1 to obtain ζ - In the general formula 1) and (厘), R is preferably a menal group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group. It is an alkyl group having 1 to 4 carbon atoms such as a group, but may be an alkyl group having 5 to 8 carbon atoms.

Polyprenorno Fe□do (1) Fi As mentioned above, it is made directly from the extract of Iteyo merui or Castor cedar! Alternatively, a polyprenol represented by the general formula % (%) (in which n is 0 as defined above), which can be obtained through hydrolysis, or its base, can be treated with a chlorogenating agent, for example, P(js , mino-logogenated phosphorus such as PBrs,
Sα1m, 80Br* etc. can be easily obtained from K by halogenation with thionyl lide. This halogenation reaction Fi is usually carried out by adding the polyprenyl compound to a suitable solvent such as hexane or diethyl ether, and heating it at about -20°C to +50°C in the presence or absence of a base such as triethylaine or pyridine. Polyprenyl halide (1) and acetoacetate (1) were prepared by adding a halogenating agent at room temperature at
The reaction with 1) is preferably carried out in an fII medium.

Suitable solvents include ether solvents such as diethyl ether, tetrahydro7ran, dioxane, and dimethoxyethane. The amount #i of the solvent used is not critical, but it is 2 to 100 times (by weight), preferably 5 to 80 times (by weight) relative to polyprenyl halide (1).
, more preferably 10 to 50 times (by weight). It is preferable to use a sufficiently dried solvent in order for the desired reaction to proceed smoothly. In order to carry out the reaction, it is essential that a basic compound @ exists. Fi, sodium hydride as the basic compound used.

Potassium hydride, sodium hydroxide, potassium hydroxide,
Sodium t-butoxide, potassium 1-nodoxide,
Preferred are alkali metal hydrides, hydroxides, or alkoxides such as sodium methoxide and sodium methoxide, or n-butyllithium and methyllithium. The basic compound is acetoacetate (1) 1
Generally about 0.5 to 5.0 moles, preferably 0.5 to 3.0 moles, more preferably Fio, 7 to 5.0 moles per mole.
It is used in a proportion of 1.5 moles. In a preferred solid line embodiment, Fi, acetoacetate (lit) is added to a bath solution or dispersion of a basic compound, or conversely, the basic compound is added all at once or gradually in small amounts to a solution of acetoacetate (table). By adding, an acetoacetate anion is first formed, and then borylnyl halide (U) is added thereto for reaction.

Acetoacetate (1) and polyprenyl halide (M
) is not critical, but the molar ratio of acetoacetate (II)/polyprenyl halide (it) is 1/2 to 20/l, preferably #1415 to 10
/l *More preferably ti/1 to 5/l. When forming the anion of acetoacetate (II), the temperature is preferably -30°C to +100°C under an inert gas atmosphere such as bulk gas or argon.
Preferably, the reaction is carried out at a temperature of 80°C.

Thereby, the desired anion can be smoothly formed while suppressing side reactions. This anion formation Kll
The time for this reaction varies depending on the reaction temperature used, but usually about 30 minutes to 2 hours is sufficient. In this way l
The anion of nine acetoacetate (I) #II
K polyprenyl halide (Otori) is added and reacted.

Depending on the reaction conditions used, polyprenyl halide (1
) t-Rather than adding the entire amount at once, the reaction may be allowed to proceed smoothly by adding small amounts in several portions or in a dropwise manner. Polyprenyl halide 11
) The temperature in the reaction system during the time of addition and thereafter until the reaction is completed is preferably not critical or within a range from -10°C to the boiling point of the heating medium used.

If the reaction temperature is too low, the reaction progresses slowly and may not be completed.
It takes too much time to do it.

On the other hand, if the BL humidification temperature is too high, it becomes undesirable and side reactions proceed. Reaction source f within the range of 0°C to 80°C from this one point
It is preferable to adopt t-. In order to complete the reaction after adding polyprenyl...ride, it is necessary to stir the reaction mixture at the above reaction temperature, and the time for this will vary depending on the reaction temperature used. It is usually 1 iK for about 30 minutes to 24 hours. In order to confirm the progress of the reaction, it is convenient and preferable to monitor the decrease in the raw material polyprenyl halide (1) by thin layer chromatography.

In reaction*, polyprenylketocarboxylic acid ester (凰) from the reaction mixture can be easily synthesized by applying a single method conventionally used in known synthetic reactions. In particular, chromatography is conveniently used. Adsorbents that can be used in the RP method include silica gel, aluna, activated carbon, and cellulose. Among them, silica gel is particularly preferably used. As a developing solvent, use a hydrocarbon solution such as hexane, pentane, petroleum ester, or benzene.
It is preferable to mix 1 with a small amount of other alcohol such as diethyl ether, chloroform, ethyl acetate, or ethyl alcohol.

Polyprenylketocarboxylic acid ester (1), which can be synthesized as described above, is a novel compound that has never been found in the literature, and mammalian dolichols can be synthesized from this compound, for example, by the following reaction route.

(1) (V) (Vl)
(■) (■) . −.

1 → 17-CHs -CM-CHsCHsOH (K) However, in the above formula, raccoon - is the group f represented by the formula (in which n is as defined above).
: Representation, R and B: #i lower alkyl group representation 1
M represents an alkali metal.

Reaction (2) is a saponification reaction of polyprenylketocarboxylic acid ester (1), and this reaction is carried out by adding 1 to 5 times the molar amount of sodium hydroxide t to borinorenylketocarboxylic acid ester (1) in ethanol. - It is carried out by treating polyprenylketocarboxylic acid ester (1) in a commonly understood liquid. Reaction ① is a derotation reaction, and this reaction is carried out without isolating the n'fC polyprenylketocarboxylate (V) obtained in reaction ②, which is previously treated as a single substance and then treated with a salt m or a strong acid such as sulfuric acid. When processed with and done by 0
The polyprenylacetone (M) obtained in reaction (1) is subjected to the Wittig reaction (reaction 0) using a sample such as the following to obtain polyprenylcarboxylic acid ester (2). This polyprenyl carboxylic acid ester (■
) is hydrolyzed, and then the isofrene unit portion at the α-terminus is selectively hydrogenated (reaction ①) in the presence of palladium, nickel, and rhodium catalysts.

The resulting polyprenylcarboxylic acid (■) having 7 saturated isopre units at the α-terminus can be reduced with, for example, lithium aluminum hydride to synthesize an alcohol (alcohol), that is, mammalian dolichol.

Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples. In addition, in the examples and reference examples, No.Ii? - Analysis Fil[j[Tell Determination 1. ．． NMRfi analysis dT
1,1υ-MA8S prepared as MS tube internal standard
The analytical values are corrected values for IH, uC, and 1IO1 town as Br.

Reference Example 1 Ginkgo biloba Gky1 Gky collected in Kurashiki City at the end of October
(undried weight) was dried with hot air at about 40'IC for 24 hours, and then heated to chloroform (about 15°C) at 8°C. It was extracted by immersion in it. To the concentrate obtained by distilling off the chloroform from this extract, 51 g of petroleum ether was added to remove the insoluble components tP.
After separating and concentrating the P solution, chloropform tag! It was separated using a silica gel column as a solvent to obtain a corrugated material of about 37 f. Approximately 40 QILl of acetone was added to this oil to dissolve the acetone-decomposable components, the resulting mixture was passed through, the P solution was mixed with * at L, the resulting wavy material was mixed with 400,117° of methanol, 40 ml of water, and Sodium hydroxide 2
After heating at 65°C for 2 hours with 0F, methanol was distilled off.

Diethyl ether (500ml) was added to the residue for extraction, and the ether layer was washed with about 10ml of water 5 times, dried over anhydrous sodium sulfate, and the solvent was distilled off to give 24.2ml of water.
A wavy material was obtained.

This corrugated material was then washed with 1'l of approximately II# silica gel.
-1\xane/isopropylether=90/1G (
21. Jl wavy material 4J
4'ico This oily substance is a polyprenol with a purity of 95s or higher.
18-10 (C embroidery type) was used as a mixed target of acetone/methanol = 90710 (volume ratio), and a differential refractometer was used as a detector to perform fciIi 6-speed body chromatography analysis. The area ratio of each peak in the obtained chromatogram is tX.The result may be as shown above.

Beak Homare Sisho Imprement Rate Rank (n) Area Ratio (%) 1 11
0.32 12
1.13 l
a 5.94 eyes
2 & 6 5 15 39.4
6 16 19.2
7 17 5.9
8 18 1.8
9 19 0.8
Using this high-performance liquid chroma togelafy, each component was separated from the above oily substance, and the components were determined to be represented by the general formula (II/) by mass spectrometry, infrared absorption spectrum, 11-NMR spectrum, and Lsc-NMR spectrum. It was confirmed that it was a polyprenol having the structure shown.

Field ionization mass spectrometry (FD-MASS) for each component
) results and Kl) i-NMR 1 value! IIKs
"C-NMR δ values are summarized in Table 2. Reference Example 2 Synthesis of polyprenyl bromide Polyprenol 12.4f of general formula (IV) where n=15 and pyridine l
ll1j was added to 200d of n + hexane and the resulting solution was added i! 2. At a temperature of about 20℃ under nitrogen gas '1IA8. Phosphorus tribromide (OP) was added dropwise, and after completing one drop, the mixture was stirred overnight at room temperature under a nitrogen gas atmosphere. Next, this n-hexane solution was placed in a separatory funnel, washed three times with about 50% water, dried over anhydrous magnesium sulfate, and the n-hexane solution was distilled off to form a slightly yellow liquid wJ12. I got Of.

NMR analysis was conducted on this product.

10) Signal attributed to IsOH group of raw material polyprenol (d, J = 4.08) tIX disappears and new -
Signal assigned to CH5Br (d, δ = 3.91)
was taken care of. Moreover, this liquid substance was analyzed by FD-M 88, and the average m/·=1304 was 6 out of 6. From these analysis results V, the above product has the general formula (1) where n=15. It was confirmed that it was a polyprenyl chloride in which A=Br.

Polyprenyl bromides with n other than 15 and polyprenyl blonde mixtures with n arbitrarily distributed between 11 and 19 were also synthesized by similar operations.

Reference example 3 fkoshi/" Lima 2 books 1 〱〱〱〇〇　　　　　　　　　　　　　　
12.4f of polyprenol of the general formula (*), which is 5, and 1.0 liters of pyridine were added to 200 rag of 11-Henchusan, and the resulting dissolved IEK was mixed with 1.52% of thionyl chloride at room temperature under a nitrogen gas atmosphere. was added dropwise, and after the completion of one drop, the mixture was further stirred at room temperature for 2 hours. This reaction mixture was then post-treated in the same manner as in Reference Example 2 to obtain a pale yellow liquid 11.
Obtained 2F. When this product was subjected to IR analysis, it was found that the absorption caused by the OH groups of the raw material polyprenol had disappeared.

When performing NMR analysis, the signal attributed to -Cli*OHK of the raw material polyprenol disappeared.

Signal (d, δ=
3.95) appeared. Moreover, m/·=1260 was given by FD-MASS analysis. From the above, the above product has n=15. It was confirmed that it was a polyprenyl chloride of the general formula (1) where A=α.

Polyprenyl chloride in which n is other than 15 and borylnyl chloride mixture in which n is arbitrarily distributed between 11 and 19 were also synthesized by similar operations.

Example 1 A three-necked flask was charged with 30 cm of anhydrous tetrahydrofuran and 640 cm of 50% sodium hydride, and 1.57 V of acetoacetic ether was added dropwise while stirring at *m.
After the intense fCo water gas generation became calm,
Gradually raise the temperature while replacing the inside of the flask with nitrogen gas, and
The reaction system was continuously stirred for 1 hour under the refluxing condition of one solvent, and then the reaction system was cooled to room temperature.

In general formula (1) synthesized according to Reference Example 2, n=15. X:=-・Br polyprenyl blond 4.3Of nato2hydrofuran (l OwLl) 11
Solution 1j was added dropwise to the mixture, and the mixture was stirred overnight at 31°C. After being distilled off from the reaction mixture in a rotary evaporator, the residue was ca.
Pour into Qal water and extract with diethyl ether.

The obtained f'L'fc diethyl ether layer was mixed with water, diluted hydrochloric acid,
water.

Wash sequentially with heavy water and dry with anhydrous magnesium sulfate.
Diethyl ether was distilled off using a rotary evaporator to obtain a yellow liquid. This yellow liquid was heated at 150°C under reduced pressure for 30 minutes to distill off low-boiling components, and the am product was subjected to silica gel column chromatography [hexane/ethyl acetate-
98/2 (volume ratio) used as tm**] to obtain 2.48 t of a pale yellow liquid. The analysis results of this product are shown below.

IR analysis! 1740,171&,1660,830
cps-””H-NMR analysis; lε (branch) 1.21 (3
kl, t, -CO2CkLx C small).

4.11 (2H,q, -COsCkfj*CkIs
) FD-M 8S analysis: According to the analysis result of m/@=1354 or more, this pale yellow liquid is a prenylketocarboxylic ether with n=15% n=CsH* in the general formula (1). It was confirmed that there is.

By similar operation, in general formula (H), U is 11-%
From each polyprenyl blonde having a value other than 15 between -19 and corresponding general formula (1) &ζ, n=CsHs,
Synthesize polyprenylketocarboxylic ethyl esters where n is llb IL 13, 14, 16, 17.18 and 19, fto synthesize polyprenylketocarboxylic acid ether with yield edn = 15, and abbreviate it to the large case. Same and nine. The characteristic signals of their infrared absorption spectra and 1) f-NMR spectra were consistent with those of n=15 -F-period depolyprenylketocarboxylate ethyl at that position.

Example 2 Methyl acetoacetate 1.40f instead of ethyl acetoacetate
The same operation as in Example 1 was carried out except that 2.26 ft of a pale yellow liquid was obtained. When this product was subjected to NMR analysis, IR analysis, and FD-MA88 analysis, the following results were obtained. 111I was determined to be methyl borylnylketocarboxylate with ft=cHs.

IR analysis: 1740.1?20,1660.830
ms''/ccHs') i-NMR analysis: δ''rn3.25 (IH, t, mi1\C05C)h''Cα.

3.78 (3H,s, -COiC)is)FD
-M18B analysis: m/5=ta+.

By the same operation, methyl polyprenylketocarboxylate having a value other than 15 between Ln#ll and 190 and 11
A mixture of methyl polyprenylketocarboxylate arbitrarily distributed between 1 and 19% can also be synthesized.

Example 3 Ether acetoacetate K replaced with t-bunaru acetoacetate, 9
The same operation as in Example 1 was carried out except that 1 ft- was used.
A pale yellow liquid substance 2.28f was obtained. NMR analysis, IR analysis and FD-MASS analysis of this substance were conducted, and the following results were obtained.
=l 5. It was confirmed that R=CH(C)fs)2 was t-butyl polyprenylketocarboxylate.

! R analysis: 1740, 1715, 1660, 830
car-'IH-NMR analysis = bar 1.50 (9H,
s, CO2C(C)lJ)3 CHi 3.22(IH,t, -q<co=tB, )FL
)-MA8S analysis: m/e=1382 By the same operation, polyprenylketocarboxylic acid t-butyl in which n is a value other than 15 between 11 and 190, and polyprenylketocarboxylic acid t-butyl in which n is arbitrarily distributed between 11 and 19. Prenylketocarbon #kt-butyl mixture could also be synthesized.

Example 4 In general formula (1) instead of polyprenyl bromide, n=15. Polyprenyl chloride 400 where X=α
The same operation as Fi Example 1 was performed except that f was used, and the general formula (1) K=15, R=C2kh
Ethyl polyprenylketocarboxylate 2.20f was obtained.

Patent Applicant's Stock Company-wide Clearance Attorney, Attorney General Honda, Proceedings Amendment (Voluntary) May 1980 (Ship)...1\I Japan Patent Office Commissioner Hiroki Torita 1, Indication of the Case Showa s7 Year patent familiar j12429? ! 2. Name of the invention Polyprenylketocarboxylic acid ester (10g) Rira Co., Ltd. Representative Director Tsuguo Okabayashi 4 Agent Telephone: Tokyo 03 (277) 3182 6. Amendment (1) The bottom line of No. 16X of the specification Between "(approximately 15" 0) de" and "chloroform"K "1 henmen"meeting)'t6・
1(2) “Mu=Br Jt-[X
Changed to =Br J.

(5) “Mu=OJJ” in the fifth line from the bottom of page 25 of the specification
2° is changed to “X=CI J.

4゜5゜ Procedural Manual (Spontaneous) May 18, 1980 Mr. Kazuo Wakasugi, Commissioner of the Japan Patent Office, Indication of the case: Patent Application No. 26299, year 1057, Name of the invention: polyprenyl ketocarboxylic acid ester, amended. Patent applicant: 1621 Sakazu, Kurashiki City (10&) Rira Co., Ltd. Representative: Torishima Ueno et al. - 2 Agents Telephone Higashi Jl < 03 (277) 3182 Subject of amendment #4a lif! -6 in the detailed explanation of A, page 28, fg, line 13 of the detailed explanation of A, after “Toku9.”
Reference example 4t-join.

[Reference benefit 4 In the general formula synthesized in Example 1 (n -35, n
=CaHs ethyl polyprenylketocarboxylate 2
．． 48t, sodium hydroxide 0.5F, ethanol 20
111 and 5 d of water, stirred for 3 hours under laminar flow conditions, and after 9 hours, most of the ethanol was distilled off using a rotary evaporator tube, and the residue was poured into about 20 WJ of water and % concentrated hydrochloric acid was added little by little. In addition, the mixture was acidified to about 2 degrees and extracted with hexane. The hemp naan layer was thoroughly washed with saturated brine, dried over 9 ml of anhydrous sulfuric acid magnesium, and the solvent was distilled off to obtain a yellow viscous dragon-like substance. This product was purified using a silica gel column Chromadog 2F (using hexidene/enal acetate 98/2 (volume ratio) as a developing solution) to obtain a pale yellow viscous liquid 1.98F. The analysis results of this product are shown below.

IR analysis: l7] 5.1660.830a11-
""H-NMR analysis 8J and:? ? 11.53 (1,9k
i).

1.112 (1,48H), 1.7-2.4 (m,
75H).

&05 (br, 18H) From the analysis results of FD-MA819 analysis sm/e-1282, this pale yellow liquid has n-
Polyprenylacetone, which is No. 15, was confirmed.

Anhydrous tetrahydride 0furan 4゜d and 5 ml in a three-necked flask
Charge 220'lll of 0-9ium sodium hydride, stir with a rich solution, and then add ethyl diethylphosphonoacetate ((C snowf(so)mPcHscOscsHs+31.
Ot t I Od f) m Water? A solution dissolved in trahydrofuran was added dropwise. After completion of dripping s 1w1i
After stirring for 1 hour, the polyprenylacetone 1.92F was dissolved in anhydrous tetrahydrochloride 10
The solution containing 1 dK@ was added dropwise at room temperature, one drop addition completed*, and the mixture was stirred at room temperature for 30 minutes and at 50-60'C for an additional 3 hours. next i
After cooling with 1 iist and adding about 1 d of water, the solvent was distilled off using a rotary evaporator, about so- of water was added to the residue, extracted with hexane, and the 90-hexane 7 layer was diluted with saturated brine. wash,
It was dried over 9 mL of anhydrous sulfuric acid magnesium, and the hexane was distilled off to obtain a yellow-brown liquid.
2 volume ratio was used as a developing solution) to obtain 162f as a colorless liquid. This product was confirmed to be ethyl polyprenylcarboxylate in the formula (■) where n=15°R'=CgHn based on the analysis results described below.

IR fractional analysis l 7] 5-1640- i 440
s 1385-1210 m3] 35, 830
, 790am-'IH-NMR analysis: J""1.
20(t,3H), 1.53(1,OH).

Cα4 1.62 (8, 48H) * 1.7~2.4 (m
, ? 51)? 4.06 (Q = 2)f) -5
,06(br-J8H) * &5 a(br, I
H) FD-MAS8 analysis tm/e-1352 The above polyprenylcarboxylic acid ethyl 1.62V was then mixed with sodium hydroxide O, SR, water 3 g and ethanol 20. I
After stirring the solution under reflux conditions for 5 hours, most of the ethanol was distilled off using a rotary evaporator, water of 1011j was added, the temperature was adjusted to about 6 with diluted hydrochloric acid, and the inside was poured. The extracted hexane layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a yellow liquid. -90/1G (V amount ratio) was used as a developing solution] to obtain a colorless liquid of 1.42F. According to the following analytical results, this product is nm in the formula % (in the formula, the value is the same as defined above).
It was confirmed that polyprenylcarboxylic acid was produced in No. 15.

IR analysis! 3600-2900 (Weak).

2800-340G (Weak).

1690.1660.1630.1440,1375.
830 azpm IH-NMR analysis (J) Ic4a 1.53 (1,9H), 1J2 (11,48H).

1.7-2.4 (m, 75H), Nu (br,]
8H) 翫56(brslH)e ~11. ! $(br)
, ]) i) 0 Then this polyprecarboxylic acid 1.
42f was selectively hydrogenated by the method shown below. μ,
After putting 0.71 f of μ'-dichlorobis(1,S-cyclooctadiene) rhodicum (1) and 7.3 q of neomenthyl diphenylphosphine into a pressure-resistant vinyl and stirring with a magnetic star 2-, beriberi was applied. The atmosphere was purged with argon, distilled anhydrous ethanol 511j was added, and the resulting yellow fIIIWL was stirred for 30 minutes under a water bulk pressure of 3 atm. Apart from this, polyprenyl carbon 1111.42
F and sodium methoxide 171q in absolute ethanol 4
The dKflj solution was stirred under an argon atmosphere.

The catalyst solution and polyprenylcarboxylic solution prepared in this way were transferred through the exhaust pipe to an autoclave that had been previously subjected to beriberi and replaced with argon. , a water bulk addition reaction was carried out at room temperature for 24 hours under a hydrogen pressure of 6 atm◇
After the reaction, the solution was compressed using a rotary evaporator, diluted hydrochloric acid was added to the SII solution, extracted with hechunan, dried over magnesium sulfate, and the solvent was distilled off to obtain 1.40 f of a yellow colored liquid. Ta. This product was subjected to silica gel column chromatography [using hexane/ethyl acetate = 90110 (volume ratio) as a developing solution] to obtain a colorless viscous liquid 1.25F. According to the following analytical results, this formula (Ml)
O IR fractional analysis 3600-2900 (WES+K) confirmed to be n-15 dihydropolyprenylcarboxylic acid.

2800-240G (weak) e 1705.1610*1440.1375.830 Merchant H-NMR analysis (with δg fortune)! 1.53 (ss, 9H), 1.62 (1,48) 1
).

1.7~2.5 (m, 76H), &06(br
, 18H).

~] 0.0 (br a I H) [Is present in the raw material unsaturated polyprenylcarboxylic acid
, 5s (br, xH) disappeared] FD-MA88 analysis;
Put 0d of anhydrous tetrahydrofuran and 100q of aluminum hydride into a m/e-1328 three-necked flask, cool to 0°C under a nitrogen atmosphere, and then add 1.2Of of the above dihydropolyprenylcarboxylic acid to anhydrous tetrahydrofuran)'07 Tsun 5sJK @ Kashie solution was added dropwise while stirring.

When the dropwise addition was completed, the mixture was stirred at 0° C. for 1 hour and at room temperature for an additional 5 hours.The mixture was poured little by little into a diluted hydrochloric acid solution and thoroughly stirred. Hexane was added to separate the layers, and the aqueous layer was further extracted twice with hexane. The organic layers were combined and washed with water, sodium bicarbonate, and saturated saline, and then the drying value was distilled off over anhydrous magnesium sulfate to form a colorless liquid.
I got an F. This product was purified by silica gel column chromatography [hexane/ethyl acetate - 90 gl0 (volume ratio) was used as a developing solution] to obtain a colorless liquid with a concentration of 1.04 g.
t was obtained◇This 4 is based on the following analysis results, and the above formula (K
), it was confirmed that there was a dolichol with n=15.

IR analysis: 3320.2G20, 2850, 1440
, 1376°1060.830cII IH-NMR analysis (at Jgl)! 0.91 (d, 3H
).

1.60 (1,9H), 1.68 (1,48H) 1t,
10-1.80 (m, 51), 2.03 (b, 701)
) #3.66 (m, 2)1) , 5.10 (
b, I8H) 119C-NMR (ppm/strong I
K) Tomi 16.00@/640.

] 7.679/353, 19.5571548,
23.430/633025.3081567.2&6
771542, 26.43615] 66°26.699
1548.26.825/492, 29.316152
8゜32.021/456, 32.24515500,
37.54M'582゜39.757/683.40.
02M541.61.2411551.

124.214/446e124.282/463,1
24.4481505゜124.993/499,12
5.07115242. J31.2IO/213°1!
14.937/290.31005/349,135.
229/3567°F [

Claims (1)

[Claims] General formula (in the formula -CR2-di-c- represents a trans isoprene unit, represents an integer from nFiil to 19, and R
Fi represents a lower alkyl group. ) Polyprenylketocarboxylic acid ester 0