JPS58167539A - Dihydropolyprenylcarboxylic acid and its esters - 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 dihydropolyprenylcarboxylic acids and esters thereof. More specifically, the present product Ij1 represents a lance-type imprene unit with the general formula (-C-C-C-CHx-1d), where n represents an integer of 11 to 19, and %R represents lower alkyl or a hydrogen atom. represents. ).

The dihydropolyprenylcarboxylic acid represented by the general formula (2) and its ester provided by the present invention are useful substances as raw materials for pharmaceuticals, cosmetics, etc., and are particularly useful as synthetic intermediates for mammalian dolichols. be.

Dolichols were described by J. F. Pennock in 1960.
It was first isolated from pig liver by Natu et al.
r. (London).

186, 470 (1960)], later this one represents a unit of the general formula (A) -Cm-CH-C1h-CHI-OR(A)1, and -CH3-C-C-CH2- is a cis-containing inprene. Represents a unit. The same shall apply hereinafter in this specification.

] A mixture of polyprenol homologs having the structure shown in formula (A), where j representing the number of cis-cap inprene units generally ranges from 12 to 181, and j-14,
It was revealed that three homologs of 15 and 16 were the main components of fp (R, W, Keenan et al.
al.

Biochemical Journal, 165
, 505 (1977)] Dolichols are widely distributed not only in the liver of pigs but also in the bodies of mammals, and are known to play extremely important functions in maintaining the life of living organisms. For example, J. B. and Harford et al. conducted a 1N in vitro test using the white medulla of calves and pigs, and found that exogenous dolichol promoted the uptake of sugar components such as mannose into lipids, and as a result, the It has been revealed that biochemical a
nd BiophysealR@5earch Co
mmunication, 76, 1036 (19
77)]. The effect of dolichols on promoting the incorporation of sugar components into lipids is more pronounced in already mature animals than in growing organisms, so the role of dolichols in preventing aging is attracting attention. In addition, RoW and Keenan et al. stated that it is important for living organisms that continue to grow rapidly, such as during childhood, to ingest dolichol from outside and supplement the dolichol that is biosynthesized within the body. -Iru (Archives
of Biochemlstry and Biop
hysics.

179.634 (1977)]. Furthermore, Akamatsu et al. quantified dolichol phosphate ester in the regenerated liver of rats, and found that the amount was significantly reduced compared to that in the normal liver, indicating that the glycoprotein synthesis function in the liver tissue was significantly reduced. They found that the function was improved by adding dolichol phosphate from the outside (presented at the 54th Annual Meeting of the Japanese Biochemical Society (19814)).

As mentioned above, dolichols are substances that control extremely important functions for living organisms and are useful as pharmaceuticals or their intermediates. Finally 0.6
It is too much to obtain the dolichol of g.
Burgos et al., Biochemistry
al Journal.

88.470 (1963)]. Total synthesis of dolichols is extremely difficult using current organic synthesis techniques, as is clear from their complex and highly variable molecular structures. It would be advantageous if dolichols could be obtained by relying on natural products as synthetic intermediates and simply subjecting them to simple synthetic chemical treatments, but such convenient substances have not been found so far.

Conventionally, polyprenols (these are called bellagrenols) represented by the following general formula (B) sCH 1 40Hx-C=C-1+1OH (B) [however, -4 to 6] have been used. Although it is known that dolichols can be collected from B. This is almost impossible with current organic synthesis technology.Also, K.

Hannul et al. M -o Pinus
1ylvestris) on a dry weight basis from mulberry
reported that this component was a polyprenylacetate mixture containing 10 to 19 II imprene units primarily in the cis configuration (Phytochamistry, 13, 2).
563 (1974)], their report does not reveal the details of the trans and cis configurations in nuclear polyprenylacetate. Furthermore, D, F,
Z 1nckIl et al. strobe pine (Pinus 5
The number of isoprene units in the leaf extract of
Co with an average value of 8 or 18 inprene units
It has been reported that o polyprenols exist (
Phytoch*m1stry, 11, 3387
(1972)], this report does not provide a detailed analysis of the trans and cis configurations of scissors polyprenol.

Some of the present inventors and their co-researchers firstly hydrolyzed the extracts extracted from Japanese cedar and Himalayan cedar using an organic solvent, as necessary, and then used chromatography, fractional dissolution, and other suitable methods. A polyprenyl fraction consisting of a polyprenol and/or a mixture of seven acetate congeners having p114 to p22 imprene units in the trans and cis configurations exactly as mammalian dolichols can be obtained by treatment using a separation method according to the present invention. , the polyprenyl fraction shows a distribution of polyprenyl congeners very similar to that in mammalian dolichols due to the absence of α-terminal saturated imprene units compared to mammalian dolichols; The polygrenyl fraction can be separated relatively easily into its constituent individual polyprenyl analogues (with a uniform number of isoprene units) if desired, and therefore the polyprenyl fraction and the canned polyprenyl analogues separated therefrom are We found that all of them are very suitable as intermediates for the synthesis of mammalian dolichols.

The present inventors have developed a method for efficiently producing mammalian dolichols using boria 2-nyl compounds as described above.
As a result of intensive studies on a method for introducing a K11l isoprene unit at the α-terminus of the polyprenyl chain of a 'lJ near'renyl compound, we found that the dihydropolyprenylcarboxylic acid represented by the general formula (1), which is useful as an intermediate in such a method, and The inventors created the ester and completed the present invention.

The dihydropolyprenylcarboxylic acid of the present invention in which R in the general formula (1) is a hydrogen atom [hereinafter referred to as T b dihydropolyprenylcarboxylic acid (1). ] is a polyprenylcarboxylic acid represented by the general formula % (in the formula, n is as defined above) [hereinafter referred to as polyprenylcarboxylic acid (It)]. ] in the presence of a hydrogenation catalyst
selective hydrogenation of the carbon-carbon double bond on the terminal side of the carboxylic acid, or reduction using lithium in liquid ammonia [Birch R
It can be manufactured by Further, the dihydropolyprenylcarboxylic acid ester of the present invention in which R in the general formula (1'') is a lower alkyl group can be produced by nisfuling the dihydropolyprenylcarboxylic acid of the present invention described above.

When carrying out the hydrogenation reaction described above, if extreme conditions are used, double bonds other than the desired carbon-carbon double bond on the carboxylic/acid terminal side can also be hydrogenated. Of course, if extremely mild conditions are used, the desired reaction will not proceed at all, or it will take too much time to complete, which is undesirable.From the above viewpoint, it is preferable to carry out the hydrogenation reaction. It is necessary to set the reaction conditions for the reaction.Here, metals such as rhodium, palladium, nickel, or compounds thereof can be used as the hydrogenation catalyst, but it is particularly preferable to use a rhodium complex compound. It is.

Examples of rhodium complex compounds that can be specifically used include Rhα(P(CsHls)s)s,)iRMZ2(
Examples include complex compounds prepared from P (CeH6) B ]3, Rb2 (1,5=cyclooctadiene)2α2 and menthyl diphenylphosphine or neomenthyldiphenylphosphine.

When an optically active ligand is used, optically active dihydropolyprenylcarboxylic acid (1) can be produced.

The amount of hydrogenation catalyst used is polyprenylcarboxylic acid (II
) is preferably in the range of 0.0001 to 0.5 molar equivalent, preferably 0.001 to 0.1 molar equivalent. It is preferable that ti be an alcoholic solvent such as methanol or ethanol, which has been treated with hydrogen in the coexistence of 2N and 2K, and then distilled, or a hydrocarbon solvent, such as benzene or toluene, which has been distilled in the coexistence of sodium and benzophenone. The amount of solvent used is not critical, but is between 5 and 100% relative to polyprenylcarboxylic acid (If).
A range of times the weight, preferably 10 to 50111 times, is suitable.

When carrying out a hydrogenation reaction, the hydrogen pressure, reaction temperature and reaction time vary depending on the equipment used, but usually
1~30 atm, 10℃~60℃ and 6)-7 respectively.
Two hours is preferred.・Also, during this hydrogenation reaction, basic compounds such as sodium mexide and triethylamine are added to polyprenylcarboxylic acid (■) at zero
．． The coexistence of 01 to 0.5 equivalent moles is preferable because the hydrogenation reaction is significantly accelerated.

After the hydrogenation reaction, the reaction solution is made acidic by adding dilute hydrochloric acid or dilute sulfuric acid, extracted using a solvent such as hexane, pentane, benzene, diethyl ether, etc., and dihydropolyprenylcarboxylic acid is obtained by distilling off the solvent from the extract. 1
1(1) is obtained.

Alternatively, when reducing polyprenylcarboxylic acid (II) by the Birch reduction method, the objective can be achieved by adding polyprenylcarboxylic acid (1) to liquid ammonia in which lithium is dissolved. can. The amount of lithium used is 1 to 100 equivalents, preferably 2 to 10 equivalents based on polyprenylcarboxylic acid (II).
It is equivalent. The amount of liquid ammonia used is not critical, but is between 5 and 1 K for polyprenylcarboxylic acid (II).
Range H of 00 times by weight, preferably 10 to 50 times by weight is suitable. When adding polyprenylcarboxylic acid (n), it is preferable to dissolve it in anhydrous diethyl ether or anhydrous tetrahydrofuran and add it as a solution for convenience and to improve the uniformity of the reaction solution.

This Birch reduction reaction takes place at the boiling point of liquid ammonia (approximately = 33
It is preferable to do this at ℃), but it is not necessary! Depending on the situation, it is also possible to carry out the reaction under low temperature cooling or under pressure at a temperature above the boiling point using a pressure-resistant device.

After stirring for about 0.5 to 10 hours at the above reaction temperature, for example, ammonium chloride is added to the reaction solution to decompose excess lithium, and ammonia is removed with a filter to form sidihydropolypre. A crude product of carboxylic acid (1) can be obtained.

Purification of polyprenylcarboxylic acid (1) can be carried out by applying conventionally known separation and purification techniques. Chromatography is particularly preferred because it is simple. Adsorbents that can be used in this chromatography include silica gel, alumina, activated carbon, florisil, cellulose, etc., but silica gel is particularly preferred. As a developing solvent, a small amount of a polar solvent such as chloroform, methylene chloride, diethyl ether, diinoglobyl ether, methyl acetate, ethyl acetate, or acetone is mixed with a hydrocarbon Mfl# medium such as hexane, pentane, petroleum ether, or benzene. It is preferable to use something you have in mind.

In the general formula (1), R is a lower alkyl group, dihydropolyprenylcarboxylic acid ester t-obtained dihydropolydalenylcarboxylic acid (1) O esterification reaction has conventionally been used for esterification of higher fatty acids. It can be carried out by applying any known method. For example, the purpose is achieved by dissolving the dihydropolyprenylcarboxylic acid <1) in a solution in which dry hydrogen chloride gas is bubbled in a lower alcohol, and continuing stirring at room temperature or at a temperature below the boiling point of the #'i solvent. can do. In addition, in order to synthesize the methyl ester of dihydropolyprenylcarboxylic acid (1), the dihydropolyprenylcarboxylic acid (1) is dissolved in a solvent such as Ka, anhydrous diethyl ether or anhydrous tetrahydro7rane, and diethyl ester of diazomethane is dissolved therein. The purpose can also be achieved by adding an ether solution and causing the reaction. Purification of these lower alkyl esters of dihydropolyprenylcarboxylic acid (1) was carried out using na! This can be done using much the same method as for In addition, when R in general formula (1) is a lower alkyl group, examples of the lower alkyl group include methyl group, ethyl group, n-propyl group, isobutyl group, n-
Examples include butyl group, isobutyl group, t-butyl group, n-pentyl group, neopen fh group, l1l-hexyl group, and the like.

Polyprenylcarboxylic acid (n) subjected to hydrogen saturation reaction
is polyprenylacetone represented by the general formula (in which n is as defined above). Compounds shown in and Witschich (Wit
tlg) General formula obtained by the reaction (in the formula n and R
1 corresponds to the above definition. A polyprenylcarboxylic acid ester represented by [hereinafter referred to as polyprenylcarboxylic acid ester (V)]. ] can be produced by hydrolyzing.

The above Witzig reaction is usually carried out in a % solvent. Examples of suitably used solvents include dimethylformand, tetrahydrofuran, and diethyl ether. A friend who makes the desired reaction proceed smoothly,
It is preferred that the solvent used be sufficiently dried to an anhydrous state.

Further, from the same viewpoint, it is desirable to replace the reaction system with an inert gas such as nitrogen or argon.

The amount of the solvent used is preferably 5 to 50 times the weight of borylnylacetone (lit).

As a reagent for carrying out the Witzig reaction, the general formula (I
Among the compounds represented by V), the following compounds are particularly preferably used.

When carrying out the Witchig reaction, it is necessary to form a phosphoryde by treating the Witchig reagent as described above with a basic compound, and the basic compounds used for this purpose include n-phthyllithium, methyllithium, Suitable examples include sodium hydride, potassium hydride, sodium methoxide, and sodium ethoxide. After adding these basic compounds to the above-mentioned solvent, the temperature is -30°C to +80°C, preferably -1θ°C.
While stirring under a temperature condition of ~+50°C, add the Wittzig reagent to this, and further add approximately 0.5 to +50°C in the above temperature range.
Phosphoride can be formed by continuing stirring for 24 hours. The amount of the basic compound used in this case is preferably about 0.5 to 1.5 molar equivalents based on the Witzig reagent. In this way ll141#! p-polyprenylcarboxylic acid ester by adding polyprenylacetone (1) to the phosphorylide solution and reacting at about 0°C to 100°C, 15°C to 80°C, more preferably 20°C to 50°C. (V) can be obtained.

The reaction time required to complete this reaction is generally within the range of about 0.5 to 24 hours. The amount of Witzig reagent used is 0.5 to 1 for polyprenylacetone (1).
0.0 molar equivalent, preferably 0.8 to 8.0 molar equivalent, more preferably 0 to 5.0 molar equivalent.

Polyprel carboxylate (■) can be obtained by hydrolyzing the polyprenyl carboxylic acid ester (V) synthesized as described above in accordance with the method applied to the hydrolysis reaction of ordinary fatty acid esters. . For example, polyprenylcarboxylic acid ester (V) is stirred in aqueous ethanol with sodium hydroxide in an amount of about 2 to 5 times the molar equivalent of the ester under reflux conditions for about 1 to 5 hours to produce polypropylene in good yield. Prenylcarvone 11 (It)
14 can be done. Polyprenylcarbon It!
(I) $P and its esters can be purified by various methods similar to known separation and purification methods, but purification by chromatography is especially convenient. Examples of the adsorbent used in this chromatography include silica gel, alumina, activated carbon, 7-throlysyl, cellulose, etc., and silica gel is particularly preferred. ! JK Solvent opener is a hydrocarbon bath agent such as hexane, be/thane, petroleum ether, benzene, toluene, etc., and a polar compound such as chloroform, methylene chloride, diethyl ether, diimpropyl ether, methyl acetate, ethyl acetate, acetone, etc. It is preferable to use a mixture containing a small amount of solvent.

The polyprenylacetone (ml) used in the above reaction is a polyprenyl halide represented by the general formula (in the formula, n is as defined above, and X represents an atom) [hereinafter, It is written as polyprenyl halide (Vl). ] in the presence of a basic compound to form an acetoacetate ester (hereinafter) represented by the general formula % (in which R8 represents a lower alkyl group), acetoacetate (
■). ] (In the formula, n and R8ri are as defined above.)
Polyprenylketocarboxylic acid ester represented by [hereinafter referred to as polyprenylketocarboxylic acid ester (■)].

) can be obtained by hydrolyzing and decarboxylating.

As mentioned above, polyprenyl halide (Vl) is a polybrenol represented by the general formula (in the formula, n is as defined above) that can be obtained directly from an extract of ginkgo or Himalayan cedar or by hydrolysis. It can be easily obtained by halogenating the mixture with a halogenating agent such as phosphorus trichloride such as Pαs or PBrs, or thionyl halide such as SOC# or SOBrg. This halogenation reaction is usually carried out by dissolving the above-mentioned polybrenol in a suitable solvent such as hexane or diethyl ether, and adding a base such as triethylamine, hyridine, etc. At a temperature of .degree. C. to +50.degree. C., it is carried out by adding a rogensing agent.

Borylnyl halide (Vl) and acetoacetate (■
The reaction with is preferably carried out in a solvent.

Suitable solvents include ether solvents such as diethyl ether, dihydrofuran, dioxane, and dimethoxyethane. The amount of the solvent to be used is not critical, or is 2 to 100 times (fi)%, preferably 5 to 80 times (weight)%, more preferably 10 to 50 times (1 amount) relative to polyprenyl halide (Vl). ).

It is preferable to use a sufficiently dried solvent so that the desired reaction proceeds smoothly. In order to carry out this reaction, the presence of a basic compound is essential. The basic compounds used include alkali metal hydrides such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium t-butoxide, potassium t-butoxide, sodium ethoxide, and sodium ethoxide; Oxides or alkoxides, n-butyllithium, methyllithium, etc. are suitable. The basic compound is acetoacetate (%/fD per mole generally about 0.1 to 5.0 moles, preferably 0.5
It is used in a proportion of 3.0 mol to 3.0 mol, more preferably 0.7 to 1.5 mol. In a preferred embodiment, acetoacetate (■
) or conversely, by adding a basic compound all at once or gradually in small amounts to a solution of acetoacetate (■), the anion of acetoacetate is first formed, and then polyprenyl is added to this. Halide (
Vl) and react. Acetoacetate (■)
The ratio of use of polyprenyl halide (Vl) and polyprenyl halide (Vl) is not critical, but the molar ratio of acetoacetate (V[)/polyprenyl halide (Vl) is 1/2 to 20/1.
, preferably U415-10/1.

More preferably, it is 1/1 to 5/1. Acetoacetate (when forming the anion of ■, nitrogen gas,
-30℃~+100 under inert gas atmosphere such as argon
It is desirable to carry out the reaction at a temperature of -10°C to +80°C, whereby the desired anion can be smoothly formed while suppressing side reactions. The time required for this anion formation varies depending on the reaction temperature used, but usually about 10 minutes to about 5 hours is sufficient. Polyprenyl halide (Vl) is added to the anionic solution of acetoacetate (■) thus prepared and reacted. Depending on the reaction conditions used, the reaction may proceed smoothly by adding small amounts of polyprenyl halide (Vl) several times or in a dropwise manner, rather than adding the entire amount at once. The temperature in the reaction system during the addition of polyprenyl halide (M) and thereafter until the reaction is completed is not critical, but -1
The temperature is preferably within the range from 0°C to the boiling point of the solvent used.

If the reaction temperature is too low, the reaction progresses slowly and it takes too much time to complete the reaction. On the other hand, if the reaction temperature is too high, undesirable side reactions will proceed. From this point of view, 0℃~8
Preferably, a reaction temperature within the range of 0°C is employed. In order to complete the reaction after adding polyprenyl halide (Vl), it is necessary to continue stirring the reaction mixture at the above reaction temperature, and the time required for this varies depending on the reaction temperature used, but is usually 30 minutes. ~24 hours of freshness. To confirm the progress of the reaction, the raw material polyprenyl hydride (vl
) It is convenient to monitor the decrease in 69, preferably 0. After the reaction, the polyprenyl ketocarbo/acid ester (material) is isolated from the reaction mixture by applying isolation methods conventionally used in known synthetic reactions. This can be easily achieved by Chromatography is particularly conveniently used. Adsorbents that can be used for chromatography include silica gel, alumina, activated carbon, and cellulose. Among these, silica gel is particularly preferably used. As the developing solvent, a mixture of a small amount of a polar solvent such as diethyl ether, chloroform, ethyl acetate, or ethyl alcohol with a hydrocarbon solvent such as hexane, pentane, petroleum ether, or benzene is suitable.

It is also possible to omit this isolation step and directly perform the next step of synthesis reaction of polyprenylacetone (1), followed by a purification step.

Polyprenylketocarbo/acid ester can be hydrolyzed by applying the method conventionally used for the hydrolysis reaction of higher fatty acid esters. example is,
Polyprenylketocarboxylic acid ester (sol) with sodium hydroxide or potassium hydroxide in aqueous methanol,
This can be achieved by stirring in aqueous ethanol or aqueous inpropanol. The amount of sodium hydroxide or potassium hydroxide used is approximately
.

-20.0 molar equivalents, preferably 1.5-10.0 molar equivalents. The above-mentioned hydrous alcohols are suitable as the reaction solvent, but to increase the solubility of the polyprenylketocarboxylic acid ester, a small amount of a hydrocarbon solvent such as hexane, pentane, benzene, or toluene may be added. It is also preferable. In order to allow the above-mentioned hydrolysis reaction to proceed smoothly, it is desirable to adopt a reaction temperature ranging from 0°C to the boiling point of the solvent used, preferably within the range of 25 to 65°C. The time it takes for the reaction to complete varies depending on the temperature conditions used.

Usually within the range of 0.5 to 24 hours.

After the hydrolysis reaction is carried out as described above, the reaction solution is neutralized using a mineral acid such as hydrochloric acid or sulfuric acid, preferably under room temperature conditions or water-cooled conditions, and the reaction solution is further adjusted to a pH of 1 to 3. Under moderately acidic conditions, a decarboxylation reaction automatically occurs, and polyprenylacetone (III), which is the compound of the present invention, is formed. After the decarboxylation reaction is completed, the reaction solution is extracted with hexane, benzene, diethyl ether, etc., washed thoroughly with water, the organic layer is dried, and the solvent is distilled off to obtain a crude product of the target compound polyprenylacetone (Ill). can get. In order to purify this product, Chroma Dog 2 Fi is preferably employed. Adsorbents used in chromatography include silica gel, alumina, activated carbon, cellulose, etc., and silica gel is particularly suitable. The developing solvent used is a mixture of a small amount of a hydrocarbon solvent such as hexane, pentane, petroleum ether, benzene, or toluene with a small amount of a polar solvent such as diethyl ether, diinflobil ether, chloroform, ethyl acetate, or methyl acetate. As mentioned above, the dihydropolyprenylcarboxylic acid represented by the general formula (1) and its ester are synthesized using polyprenylacetone (II) synthesized in Useful. General formula (
The mammalian dolichol fist represented by the general formula (A) can be obtained by reducing the compound represented by 1) with, for example, lithium aluminum hydride.

Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples. In addition, IR analysis in Examples and Reference Examples was performed using a liquid film, and NMk analysis was measured using TMS as an internal standard. FD-MASS analysis values are “H,” C,” O, 5
IsCI, 'Br To L, Te Correction L Rifi Terror 4゜Reference Example 1 Separation of Polyprenol 101q ginkgo leaves collected in Kurashiki City at the end of October (
The undried weight) was dried with hot air at about 40°C for 24 hours, and then extracted by immersing it in chloroform 80 at room temperature (about 15°C). 5 tons of petroleum ether was added to the concentrate obtained by distilling off chloroform from this extract to separate the insoluble components,
After 11iIJII of solution F, it was separated on a silica gel column using chloroform as a developing solvent to obtain an oily substance of about 379. Filter the mixture and concentrate the P solution.

The obtained oil was oxidized with 400 m of methanol, 40 m of water and hydroxylated.) I) After heating at 65°C for 2 hours with 20 g of cum, the methanol was distilled off, and the s'14ttl product was extracted by adding diethyl ether (500 d). ether J-
The product was washed 5 times with about 100 ml of water, rolled into balls, dried over anhydrous sodium sulfate, and the solvent was distilled off to give 24.29 as an oil.

This oil was then diluted with n-hexane/isoglobil ether-90/10 ('# fish ratio) using silica gel.
The mixture was separated to give 21.8p of oil. This oily substance is a polyprenol with a purity of 95% or more, and this oil has a semi-dispersive high performance liquid chromatography column manufactured by Merck & Co., Ltd. LiChrosorb RP18-10 (C1
8 types) and acetone/methane-ru 90/10 (
Capacity ratio) A high performance liquid chroma dog 2F analysis was carried out using a water difference refractometer as a detector using an Sm liquid as the O8 mixed solvent.
The results of determining the area ratio of each peak in the obtained chromatogram were determined as follows.

4 Cis-type inplane (b) Area ratio■
1 11
0.32 12
1.13 13
5.94 14
25.65
I5 39.46
16 19.27
17 5.
98 18
1.89 19
0.8 Using this high performance liquid chromatography, each component was separated from the above oily substance, and the components were determined to be represented by the general formula (K) by mass spectrometry, infrared absorption spectrum, 'H-NMR spectrum and 13 cm NMR spectrum. It was confirmed that it is a polyprenol with a structure similar to the following.

Field ionization mass spectrometry (FD-MASS) for each component
) results and “H-NMROJ values are shown in Table 1.
NMRC) Reference example 2 where J values are summarized in Shishi 2
! Synthesis of liprenyl bromide 11”15 is the general formula (
K) polybrenol 12.41i and pyridine 1-
was added to 200 wl On-hexane, and the resulting solution was heated with K2 at room temperature (approximately 20"C) under a nitrogen gas atmosphere.
After 5 drops of phosphorus tribromide No. 09 was added dropwise, the mixture was stirred overnight at room temperature under a nitrogen gas atmosphere. Next, this n-hexane solution was put into a separating funnel, washed three times with about 50 g of water, dried over anhydrous magnesium sulfate, and the n-hexane was distilled off to give 12.0 g of a moldy yellow liquid. I got it. When NMR analysis was performed on this product, a signal h (d, 1
I-4,08) disappeared and a new signal (d, δ-3,91) assigned to -CH2Br appeared. Furthermore, when this liquid material was analyzed using FD-MA8g, m/・
-1304 was rare. According to these analysis results, it was confirmed that the above product was polyprenyl pro-2, which is n-15, X-Br in the general formula (M).

Polyprenyl bromides with n other than 15 were also synthesized by similar operations.

Example 1 A three-necked flask was charged with 301 g of anhydrous tetrahydrofuran and 640 g of 50% sodium hydride, and 1.57 Il of ethyl acetoacetate was added dropwise to the flask while stirring at room temperature.

After the intense generation of hydrogen gas became calm, the temperature in the flask was gradually raised while purging the inside of the flask with nitrogen gas, and stirring was continued for 1 hour under the condition of refluxing the solvent. Then, the reaction system is placed in a chamber. After cooling to warm temperature, this - Example 2. In general formula (Vl) synthesized according to n=15. Polyprenyl bromide, which is X-Br 4.30 g of tetrahydrofuran (10
1 LJ) solution was added dropwise and stirred at room temperature overnight. After distilling off the solvent from the reaction mixture using a rotary evaporator, the residue was poured into about 2011 L of water and extracted with diethyl ether. Wash sequentially and dry with anhydrous 4A# magnesium,
Diethyl ether was distilled off using a rotary evaporator to obtain a yellow liquid.This yellow liquid was heated at 150°C for 30 minutes under a vacuum of 101°C to distill off low-boiling components, and the remaining general formula ( 1
) polyprenylacetone 1.9, which is n-15 in
A solution of 2 g dissolved in anhydrous tetrahydrofuran lO'MLl was added dropwise at room temperature, and after the dropwise addition was completed, the solution was dissolved at room temperature for 30 minutes.
Stirred for an additional 3 hours at ~60°C.

Then, after cooling to room temperature and adding about 11,111 parts of water, (b) the solvent was distilled off using a rotary evaporator, and '! ! Approximately 5 to 4 residues
0ml of water was added and extracted with hexane. The hexane layer was washed with saturated saline, dried over anhydrous magnesium sulfate,
The hexane was removed to obtain a yellow colored liquid.

This liquid was purified by silica gel column chromatography [using hexane/ethyl acetate = 98/2 (Tanimohi) as a developing solution] to obtain a colorless liquid with a concentration of 1.629. According to the analysis results below, this product conforms to the general formula (V) and n-
15, R' 1llIC2H8, it was confirmed to be ethyl alpolyprenylcarboxylate.

IR analysis: 1715.1640,1440,1385,1210°1135, 830. 79051-"lH-NMR analysis (35 intervals): x, zo (t, aH), 1.5a (s, 9H), t, 6
z(s, 4sH).

1.7-2.4 (m, 75H), 4.06 (Q
, 2H), &06(br, 1SH).

5.56 (br, IH) FD-MA88 analysis; m/e = 1352 Then, 1.62 g of this ethyl polyprenylcarboxylate was added to a solution of 0.3 g of sodium hydroxide, 3 d of water, and 20 d of ethanol, and the mixture was stirred for 5 hours. After stirring under reflux conditions, most of the ethanol was distilled off using a single rotary evaporator, 10 d of water was added, the pH was adjusted to about 5 with diluted hydrochloric acid, and the mixture was extracted with hexane. The hexane layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a yellow liquid. This product was subjected to silica gel column chromatography [hexane/ethyl acetate-90710 (volume ratio) was used as the developing solution]
A 1.4:l colorless liquid was obtained. According to the following analytical results, this product has n-
It was confirmed that it was polyprenylcarboxylic acid No. 15.

IR analysis + 3600-2900 (weak).

2800-2400 (weak).

1690.1660, 1630, 1440, 1375,
830e IRIH-NMR analysis (J and =): 1.53 (1,9H), 1.62 (1,48H).

1.7-2.4 (m, 75H), a06 (b
r, 18)1).

5.56 (br, 1) IL ~ 11.5 (br, IH)
.

Next, 1.42 g of this polyprenylcarboxylic acid was selectively hydrogenated by the method shown below. μ, μ′-dichlorobis(1,5-cyclooctadiene)logi′)A(1
) 0.7 and neomenthyldiphenylphos 7,
Add 5WLl of distilled absolute ethanol.

The resulting yellow solution was stirred for 30 minutes under 3 atmospheres of hydrogen pressure. Polyprenylcarboxylic acid 1.42
N and sodium methoxide 17 d of absolute ethanol 4 d
The solution was stirred under an argon atmosphere. In this way wj411! ! The catalyst solution and polyprenylcarboxylic acid f# liquid were transferred through the exhaust pipe to an autoclave that had been previously degassed and replaced with argon, and a hydrogenation reaction of 2.5 atm was applied at room temperature for 24 hours. I did it. The bath liquid after the reaction was concentrated using a rotary evaporator, diluted hydrochloric acid was added to the residue, extracted with hexane, dried with magnesium sulfate, the bath medium was distilled off, and a yellow and liquid-free substance was obtained.1.40.9
I got it. Add this to silica gel column chroma dog 2 fee (hexane/ethyl acetate = 90:10 (volume ratio)).
[Used as opening liquid] Colorless viscous liquid manufactured by Yoshinn 1
．． I got 25.9.9. This product was confirmed to be a dihydropolyprenylcarboxylic acid having n-15,R-H in the general formula (1) based on the following analysis results.

Analyze 1): 3600-2900 (weak),
2800-2400 (weak).

1705.1660,1440,1375,830m-
"') i-NMR analysis ((Z): 1.53 (1, 9H), 1.62 (1, 48H)
, 1.7-2.5 (ffl, 76H).

5.06 (br, 18H), ~10.0 (br, IH
) (δ present in raw material unsaturated polyprenylcarboxylic acid
5.56 (br, uH) disappears] FL)-MA8
8 analysis; m/e = 1328 By similar operation, polyprenyl bromide having a corresponding value of n and n=)l in the general formula (Vl) where n is a value other than 15 between 11 and 19 A dihydropolyprenylcarboxylic acid represented by the general formula (1) was synthesized. Their yield is n-
The results were almost the same as those obtained when dihydropolyprenylcarboxylic acid No. 15 was synthesized. In addition, the characteristic absorption of their IR spectra and the characteristic signal of their 'H-NMR spectra substantially coincided with those of the above dihydropolyprenylcarboxylic acid with n''=15 at that position.Furthermore, F
The results of the L)-MA88 analysis were determined as follows.

Raw material polyprenyl bromide (■) Produced dihydropolyphrenyl carbo Δ Shun value of On m
/ e value 11 105
612 112413
1192 14 126016
139617
146418
153219
1600 Example 2 In the general formula (■) synthesized by the method of Example 1, n is 1
Polyprenyl carbon which is 5 @1. xsg was soaked in tetrahydrone run for 5 hours, and the solution was immersed in lithium for 1 hour under a nitrogen stream.
Added over 2 minutes to a blue solution prepared from 00Tr11i and liquid ammonia 30H. -33°C for another 30 minutes
After continuing stirring with 3. Excess lithium was decomposed by adding Og ammonium chloride in portions. After distilling the ammonia off by distilling off the ammonia in the apparatus for 7 days, 3% aqueous hydrochloric acid was added to the residue, extracted with hexane, the hexane layer was dried over magnesium sulfate, and the solvent was distilled off using a rotary evaporator. A liquid was obtained. It was purified by silica gel column chromatography [using hexane/ethyl acetate-9o:io (volume ratio) as a developing solution], and the odor of the general formula (1) was 1 n=
15, dihydropolyprenylcarphone 1 with n=)l
1! IR analysis of this product, NM
The results of R analysis and Fi)-MASS analysis were consistent with those of the dihydropolyprenylcarboxylic alcohol obtained in Example 1.

By similar operation, in the general formula (river), n is 11 to 19.
A dihydropolyprenylcarboxylic acid represented by the general formula (1) having a corresponding n value of R-H was synthesized from a polyprenylcarboxylic acid having a value between 0 and other than 15.

Dihydropolyprenylcarboxylic acid was synthesized with a yield of an=15, which was almost the same as that in the nine cases.

Example 3 In the general formula (1) synthesized by the method of Example 1, n is 1
5. Dihydropolyprenylcarboxylic acid R-H91.
0317 was poured into 20 m of diethyl ether, followed by thin layer chromatography, and a solution of diazomethane in diethyl ether was added until the spot of the starting carboxylic acid disappeared. After adding a small amount of acetic acid to decompose excess diazomethane, the mixture was concentrated using a rotary evaporator to obtain a yellow liquid. This product was purified by silica gel chromatography [hexane/ethyl acetate-98:2 (volume ratio) was used as a developing solution] to obtain a colorless liquid having a concentration of 1.01.9. This product shows the following analysis results: In the general formula (1), n is 15. It was confirmed that it was methyl dihydropolyprenylcarboxylate produced by R-CHs.

IR analysis: 1735.1660.1i 0.1375
．． 830aw-””H-NMR analysis (a ppm):
1.53 (s, eH) tCα4 1.62 (m, 48H), 1.7-2.5 (
nl, 76H).

3.68 (1,3H), 5.06 (br, 18H)F
D-MAS8 analysis; m / @s = 1342 By the same operation, 1 where n is between 11 and 19 in general formula (1)
The corresponding n from a dihydropolyprenylcarboxylic acid that is sb and R-H with a value other than 5.

It is possible to synthesize ethyl dihydropolyprenylcarboxylate of general formula (1) having a value of Rm CHs.

Example 4 In the general formula (1) synthesized in Example 3, n is 15°R
-CHs, dihydropolyprenylcarboxylic acid ethyl o, 5o11, was dissolved in 20d of absolute ethanol and 50%
10 tons of sodium hydride was added and the mixture was heated under reflux for 14 hours. After cooling, ethanol was distilled off using a rotary evaporator, and water was added to the residue, which was then extracted with hexane and dried over magnesium sulfate. The hexane was distilled off using a rotary evaporator to obtain 0.43% of a pale yellow liquid. FD MAS of this
S analysis showed that the thickness was m/・-1356, so in the general formula O), n is 15 and R=C
It was confirmed that the product was ethyl dihydropolyprenylcarboxylate.

By similar operation, in general formula (1), n is 11 to 19.
It is also possible to synthesize ethyl dihydropolyprenylcarboxylate with R-C2H8 at a value other than 15.

Patent applicant: RiRa Co., Ltd. Patent attorney: Important Procedural amendment (voluntary): Mr. Saiju Toshimada, President of the Japan Patent Office 1, Indication of the case: Patent Application No. 5190S, filed in 1982, 2: Name of the invention: dihydropolyprenylcarbon Acids and their esters (108) Rira Shikuyoshi Director Tsuguo Okabayashi 4, Agent Tel: Tokyo 03 (277) 3182 6 Contents of amendment (1) Specification @ 2nd line from the bottom of page 28 [(approx. 15'C)
So J! Insert "1 week" between ":rchloroform".

(2) On page 46, line 11 of the specification, "Example 5 below is added after 1.

[Example 5] A polyprenol mixture whose general formula (rl) obtained in the same manner as Reference Example 1 has n distributed from 11 to 19t and whose composition is substantially the same as that described in Reference Example 1 was used as Reference Example. A polyprenyl bromide mixture was obtained by reacting it with phosphorus tribromide according to the method of 2, and 4.30 g of it was used instead of polyprenyl bromide 4,309 where n=15 in the general formula (W) of Example 1. The same operation as in Example 1 was carried out except that a colorless viscous liquid 1,189 was obtained as the final product. Il'L of this
,'H-NMR analysis results were substantially the same as those obtained for the dihydropolyprenylcarboxylic acid of Example 1 in terms of characteristic absorption and position of characteristic signals. ” Procedural amendment (voluntary) June 17, 1981 1, Incident indication 1988 patent! Ii No. 51903 2, Title of the invention: Dihydropolyprenyl carbon- and its esters 3
, Patent 1i1'1L: 1, Sakuzu, Kurashiki City
Address 621 (108) RiRa Co., Ltd. Representative Tjr Watanabe Ueno et al. - 4, Agent Sakuzuo, Kurashiki City [11+2045711 Telephone Tokyo 03 f27713182 Column for detailed explanation of the invention in the specification W 5゜ Subject of amendment 6, Amendment Contents (1) Specification I! Change ``from the liver'' in line 1 of page 3 I#J to ``from the liver, etc.''.

-2) Replace l-F", W, and J on line 12 of No. 5 JI of the specification with "
J,”K amended.

(8) l-Zinckel on page 7, line 1 of the manual
Change J to Zinkel J.

(Details of the invention of Jun Ming, Rui 1, at the end of i5! Ming [after Example 5, which was added to page 46 of the specification by procedural amendment 4I (voluntary) submitted on May 11, 1980]) Add Reference Example 41? and Reference Example 5 below.

Reference Example 4 A solution of 30w of anhydrous tetrahydrofuran and 380q of lithium aluminum hydride and 4.42f of nic acid dissolved in 1511 of anhydrous tetrahydrofuran was added dropwise to a three-necked flask with stirring.After the addition, it was poured little by little into diluted hydrochloric acid and stirred thoroughly. 9. Add hexane and separate the aqueous layer.
Extracted twice with hexane. The organic solvents were combined, washed with water, xg of water, and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain colorless liquid 4.12F. This material was subjected to silica gel column chromatography [hexane/
Using ethyl acetate = 90:10 (volume ratio) as a developing solution], a colorless liquid 3.82F was obtained. This product has j=1 in general formula (A) according to the following analysis results.
It was confirmed that it was Dolichor, which is 5.

IR analysis: 3320, 2920, 2850, 1440
, 1376°1060.830cm-'ppl'fl.

IH-NMRM7C3), 0.91 (d, 3H).

Cα4 1.60 (s, 9H), 1.68 (s, 48
H).

1.10-1.80 (m, 5H), 2.03 (b, 70
)1).

3.66 (m, 2M), 5.10 (b, 1g) 1)"C
-NMR (ppm/intensity): 16.006/640°17.679/353, 19.5571548, 23.
430/6330°25.3081567, 25.6
771542, 26.43615166.

26, ζ1997'548.2g, 825/492,2
9.31615!8゜32.021/456,32.2
4315500, 37.5481582゜39.757
/683,40.0291541. ．． 61.24115
51°124.214/445,124.282. /4
63,124.4481505゜124.993/49
9,125.07115242,131.210/21
3°134.937/290.135. Ou 5/34
9 t 135-229/3567 t135.3G5
/430°FL) - IASs analysis: m/e = 1312 Reference row 5 Add 20 sd of anhydrous diethyl ether and lithium aluminum hydride 20019 in a three-ring flask, %! ! After cooling the atmosphere to 10°C, 3.39f of ethyl dihydropolyprenylcarboxylate synthesized by the method of Example 4 and having the general formula (1) with 15 and R002H was dissolved in 10 dK of anhydrous diethyl ether. The liquid was added dropwise while stirring. After completion of the dropwise addition, stirring was continued overnight at room temperature. dk% water 0.2
0.2 ml of an aqueous solution of m,15-sodium hydroxide and 0.61 ml of water were poured into the pot in this order, and the mixture was stirred vigorously. The obtained white granular precipitate was separated, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to form a colorless liquid at 3.25F.
I got it. This product was subjected to silica gel column chromatography [hexane/ethyl acetate = 90:10 (volume ratio)]
3.03 ft'' of Dolichol with j=15 in the general formula (A) was obtained.The results of IR analysis, NMRM7C3 and FD-MASS analysis of this product were similar to those obtained in Reference Example 4. matched those of

Claims (1)

[Claims] General formula (where -Cut-C-C-CHx- represents a trans-cap isoprene unit, n represents an integer from 11 to 19, and Rd represents a lower alkyl group or a hydrogen atom. ).