JPS58174351A - Dihydropolyprenylnitrile - Google Patents

Abstract

NEW MATERIAL:A dihydropolyprenylnitrile shown by the formula I (group shown by the formula II is trans type isoprenyl unit; group shown by the formula III is cis type isoprenyl unit; n is 11-19). USE:A raw material for drugs, cosmetic, etc., useful as an intermediate for synthesizing especially a dolichol of mammal. PROCESS:A polyprenylacetone shown by the formula IV is reacted with a cyanoacetic acid lower alkyl ester shown by the formula V (R<2> is lower alkyl) in the presence of a base and/or acid to give a polyprenylcyanocarboxylic ester shown by the formula VI, which is selectively reduced to give a dihydropolyprenylcyanocarboxylic ester shown by the formula VII which is further hydrolyzed and decarboxylated, to give a compound shown by the formula I .

Description

[Detailed description of the invention] Inventor's dihydropolyprenyl nitrile Kgll.

More specifically, the present invention is based on the general formula % (in the formula, -CHx- is trans-type isoprene 1jCH single unit 6.wa1, (output-key -CHx-ij v Yuyoi, Oi). %nU represents the 11th to 19th integer.)
This invention relates to a novel dihydropolyprenyl nitrile represented by

The dihydropolyprenylnitrile 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 were described in 1960 by J+F, Penn
[N
ature (London), 186, 470
(19s o)], which was later changed to the general formula (
A) Hz product bile (Y2→H(e) 7Hj [In the formula, -CH*-C=C-CH is trans isoprene sCH,,,wa1,shi□3-different□z- A mixture of polyprenol homologs having the structure shown in [uyxM i, on units, the same applies hereinafter], which represents the number of cis-type inprene units in formula (A). j
Generally distributed from 12 to 18, homologs of j-14, s s and 160311 were found to be biological (RoW).

Keenan et al., Biochemical
Journal, 165, 505 (1977)]. Dolichol is widely distributed not only in the liver of pigs but also in the bodies of mammals, and is known to have extremely important functions in maintaining the life of living organisms. for example,
J. B. Harford et al. used the white medulla of calves and pigs in vitro.

Tests have shown that exogenous dolichol promotes the incorporation of O-sugar components such as mannose into lipids, and as a result, has the effect of increasing the formation of glycoproteins, which are essential for maintaining the life of living organisms. (Biochemical
and Biophysical Research
Communication, 76, 1036
(1977)] I41. Since the effect of accelerating incorporation is remarkable in living organisms that are still in the adult stage, and in animals that have already matured, attention is being focused on the role of dolichols in preventing aging. In addition, R, W, and Keenan et al. argue that for living organisms that continue to grow rapidly during infancy, it is important to ingest dolichol from outside and supplement the dolichol produced by biosynthesis within the body. Arch
ives of biochemistry and
Biophysics.

179.634 (1977)]. Furthermore, we quantified dolichol phosphate ester in the regenerated liver of Akamatsu et al. rats, and found that the amount decreased significantly compared to normal liver.
We found that the glycoprotein synthesis function in the liver tissue was greatly reduced, and that this function was improved by externally adding dolichol phosphate [54th Japan Biochemical Ikihi 4&( Published in 1981) ] 0 As mentioned above, dolichols are substances that control extremely important functions for living organisms, and are useful as intermediates for pharmaceuticals, but they have not been easy to obtain in the past, and for example, After a complicated separation procedure from pig liver 101#, only 0.
Only 6t of dolicall is obtained [F, W,
Burgos et al., Biochemistry
alJournal, 88, 470 (1963
)reference〕. Total synthesis of dolichols is extremely difficult 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 a (these are called pecprenols) represented by the following general formula (B) [where k = 4 to 6] can be collected from Betula verrucola. Although this is known, it is almost impossible to synthesize dolichols having cis-type imprene units of 14.15 and 16, using current organic synthesis techniques. K again.

K (Annus et al. European red pine (Pinus s)
1% on a dry weight basis from the leaves of 1vestri)
reported that this component was a polyprenyl acetate mixture containing 10 to 19 isoprene units mainly in the cis configuration (Phytochemistry, 13, 2563
(1974)], their report does not elucidate the details of the trans and cis configurations in the polyprenyl acetate. In addition, D.F. Zincke
Pinus 5trobus
Number of isoprene units in the leaf extract of 18116117'
c reported the existence of Coo's polyprenols with an average value of 18 isopres/units (Phys.
tochemistry, 11 t3387 (19
72)], in this report, the polyprenol
A detailed analysis of the cis and cis configurations has not been performed.

Some of the Ministry of Invention et al. and their co-researchers first conducted necessary hydrolysis of the extracts extracted from ginkgo biloba and Himalayan cedar using organic solvents, and then used chromatography, fractional dissolution, and other methods. By treatment with a suitable separation method, polyprenols and/or their acetate analogues having 14 to 22 isoprene units in exactly the same trans, cis configuration as mammalian dolichols, 1:・□・1. A polyprenyl fraction consisting of a mixture is obtained, and the polyprenyl fraction has a distribution very similar to that of the polyprenyl congeners in mammalian dolichols, except that there is no α-terminal saturated Inglene unit compared to mammalian dolichols. It is shown that the polyprenyl fraction desirably separates relatively easily into its constituent individual polyprenyl congeners (uniform in the number of imprene units), and therefore that the polyprenyl fraction The fraction and the round polyprenyl homologues separated from it are all 41
1! It has been found that it is very suitable as an intermediate for the synthesis of M-mammalian dolichols.

The Ministry of the Invention and others have proposed Lua tJl!, which efficiently produces mammalian Dolichol fist using the polyprenyl compound as described above. l
v As a result of intensive study on a method for introducing a saturated inprene unit into the α-terminus of the polybrenyl chain of a 7'renyl compound, the above general formula (
9. We created the dihydropolyprenyl nitrile shown in 1) and completed the present invention. 1-111111 Dihydropolyprenyl nitrile of the present invention represented by general formula (1) [hereinafter referred to as dihydropolyprenyl nitrile (1)]
and arranged. ] is a polydalenyl halide [hereinafter referred to as polyprenyl halide (It)] represented by the general formula % (wherein, X represents a halogen atom and n is as defined above). ] in the presence of a basic compound to form an acetoacetate represented by the general formula % (in the formula, R1 represents a lower alkyl group) [hereinafter referred to as acetoacetate (1)]
and arranged. ] The general formula obtained by reacting with (■
) (wherein R1 and n are as defined above),
Arrange polyprenylketocarboxylic acid ester CF. ]
is hydrolyzed and decarboxylated to produce polyprenylacetone [hereinafter referred to as polyprenylacetone (V)] represented by the general formula (where nFi is defined as above). 〕year,
In the presence of a base and/or an acid, a cyanoacetic acid lower alkyl ester represented by the general formula (V (in the formula, R2 represents a lower alkyl group)) [hereinafter referred to as cyanoacetic acid ester (■)] is produced. A polyprenylcyanocarboxylic acid ester represented by the general formula (■) (in which B2 and n are as defined above) [hereinafter referred to as polyprenylcyanocarboxylic acid ester (■)] is obtained by reacting with the polyprenylcyanocarboxylic acid ester. ], and the polyprenylcyanocarboxylic acid ester (■) is selectively reduced to give the general formula () (in the formula 12 and ntj are as defined above).
The dihydropolyprenylcyanocarboxylic acid ester represented by [hereinafter referred to as dihydropolyprenylcyanocarboxylic acid ester (referred to as 1)] can be produced by hydrolyzing and deoxygenating the dihydropolyprenylcyanocarboxylic acid ester.

Polyprenyl halide (It)Fi, as mentioned above, is directly from the extract of Itae or Himalayan cedar! i! Alternatively, a polyprenol represented by the general formula (wherein n is as defined above) which can be obtained through hydrolysis, or a mixture thereof, is treated with a halogenating agent such as PCl5, PB.
Xm throat phosphorus trihalide, SOαx, 5OB
It can be easily obtained by halogenation with deonyl halide such as rz. This halogenation reaction is usually carried out by dissolving the above-mentioned polyprenol in a suitable solvent such as hequinane or diethyl ether, and heating the solution at about -20°C in the presence or absence of a base such as triethylamine or pyridine. This is done by adding the halogenating agent at a temperature of ~+50'C.

Polyprenyl halide (■) and acetoacetate (I
It is preferable to carry out the reaction with ll) in a seedling medium.

Suitable solvents include ether solvents such as diethyl ether, detrahydrofuran, dioxane, and dimethoxyethane. The convenience of solvent is not critical, but 2 for polyprenyl halide (1).
~100 times (by weight), preferably 5 to 80 times (by weight),
More preferably, it is 10 to 50 times (by weight). It is preferable to use a sufficiently dried solvent in order to allow the intended reaction to proceed smoothly. In order to carry out this reaction, the presence of a basic compound is essential. Basic compounds used include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium t
-butoxide, potassium t-butoxide, sodium methoxide, sodium ethoxide, alkali metal hydrides, hydroxides, or alkoxides, n-butyllithium, methyllithium, and the like are suitable. The basic compound %7 is generally about 0.1-5.0 mol, preferably 0.5-3.0 mol per mol of acetoacetate (Tomoe).
It is used in a molar ratio, more preferably 0.7 to 1.5 molar. In the preferred embodiment IIam, acetoacetate is added to the bath solution or dispersion of the basic compound, or conversely, the basic compound is added to the acetoacetate solution all at once or gradually in small amounts. The anion of acetoacetate is formed by adding polyprenyl halide (II) to it.
Add and react.

Acetoacetate (I) and polyprenyl...ride (
Although not critical, the molar ratio of acetoacetate (1)/polyprenornolide (If) is 1/2 to 20/I, preferably #: t415 to
10/1. When forming an anion of 0 acetoacetate (III), which is preferably 1/1 to 5/1, under an inert gas atmosphere such as nitrogen gas or argon.
It is desirable to conduct the reaction at a temperature of 30° C. to +100° C., preferably -10° C. to +80° C. This allows the desired anion to be formed while suppressing side reactions. The time for this anion formation varies depending on the reaction temperature used, but is usually about 10 minutes to 5 hours tf.
M degree is sufficient. Polyprenyl I was added to the anionic solution of acetoacetate (Ill) prepared in this way.
・Add Ride (II) and react. Depending on the reaction conditions used, the polyprenyl-ride (n) may be added in its entirety at once, or may be added in small portions or dropwise to allow the reaction to proceed smoothly. The temperature in the reaction system during the addition of polyprenyl-ride (Otori) and thereafter until the reaction is completed is not critical, but it should be within the range of -10°C to the boiling point of the solvent used. desirable. If the reaction temperature is too low, the reaction progresses slowly and takes too much time to complete the reaction.

On the other hand, if the reaction 5Iit is too high, undesirable side reactions will proceed. From this point of view, reaction 1 within the range of 0°C to 80°C
It is preferable to adopt 4K. In order to complete the reaction after adding polypre-retonyl halide (It), it is necessary to continue stirring the reaction mixture at the above reaction temperature.The time required for this varies depending on the reaction temperature used, but is usually about 30 minutes. In order to confirm the progress of the reaction, the raw material polyprenylnolide (n) was used to confirm the progress of the reaction.
It is convenient to monitor the decrease in F0, preferably 0. After the reaction, the polyprenylketocarboxylic acid ester (F/) is isolated from the reaction mixture by an isolation method conventionally used in known synthetic reactions. This can be easily achieved through application. Chromatography is particularly conveniently used. Adsorbents that can be used for chromatography include silica gel, alumina, activated carbon, and cellulose. Among them, silica gel is particularly conveniently used as a zero developing solvent, and hydrocarbon solvents such as hexane, pentane, petroleum ether, and benzene, diethyl ether, chloroform,
It is preferable to use a mixture of a small amount of ethyl acetate and ethyl alcohol, a polar solvent.
1 It is also possible to omit the isolation step with 0 polyprenylacetone (V) and directly perform the synthesis reaction of polyprenylacetone (V) in the next step, followed by the purification step.
The acid ester (fV) can be saponified by applying the method conventionally used for the saponification reaction of grade fatty acid esters. For example, the purpose can be achieved by stirring polyprenylketocarbo/acid ester (■) with sodium hydroxide or potassium hydroxide in aqueous methanol, aqueous ethanol or aqueous isopropanol. The amount of potassium hydroxide used is polyprenyl ketocarbo/acid ester (
It is desirable that the amount is about 1.0 to 20.0 molar equivalents, preferably 1.5 to 10.0 molar equivalents, based on (2). As the reaction solvent, the above-mentioned hydrous alcohols are suitable, but polyprenylketocarboxylic acid ester (, W)
0 Hexane, pentane, penze to increase solubility/
It is also preferable to add a small amount of a hydrocarbon solvent such as toluene. For the saponification reaction to proceed smoothly, it is desirable to adopt a reaction temperature from Fi, 0°C to the boiling point of the solvent used, preferably within the range of 25 to 65°C. The time required to complete the reaction varies depending on the temperature conditions employed at this time, but is usually within the range of 0.5 to 24 hours.

After carrying out the saponification reaction as described above, the reaction solution is neutralized using a mineral acid such as hydrochloric acid or sulfuric acid, preferably under 1111m conditions, and then under ice-cooling conditions. ...l~3
When conditions are set to a certain degree of harshness, a decarboxylation reaction automatically occurs, and polyprenylacetone (V) is formed. After the decarboxylation reaction is completed, the reaction solution is extracted with hexane, benzene, diethyl ether, etc., thoroughly washed with water, the organic layer is dried, and the solvent is removed to obtain polyprenylacetone (V
) is obtained. Chromatography is preferably employed to purify this product. Adsorbents used in this chromatography include silica gel, alumina, activated carbon, and cellulose, with silica gel being particularly preferred. The developing solvent is a hydrocarbon solvent such as hexane, pentane, petroleum ether, benzene, or toluene, diethyl ether, diisopropyl ether,
It is preferable to use a mixture of a small amount of a polar solvent such as chloroform, ethyl acetate, or methyl acetate.

Polyprenylacetone (V
) and cyanacetate (■) in the presence of a base and/or acid, bo-177'renylcyanocarboxylic acid ester (■) can be obtained.

As the cyanacetic acid ester (■) that is preferably used, Examples include.

The amount of cyanacetate (■) to be used is 0.5 to 100 molar equivalents, preferably 0.7 to 1.5 molar equivalents, more preferably 0.5 to 1.5 molar equivalents, based on polyprenylacetone (V).
It is 8 to 1.0 equivalent.

Polyprenylacetone (V) and cyanoacetate (V
The reaction with l) is preferably carried out in a solvent inert to this reaction. Examples of sm that can be suitably used include:
hexane, heptane, benzene, toluene, xylene,
An example is chloroform. The amount of solvent used is not critical, but is 5 to 20% relative to polyprenylacetone (V).
0 times by weight, more preferably 10 to 100 times by weight.

Polyprenylacetone (■) and cyanoacetate (■
) It is necessary to have a base and/or an acid present in order to proceed with the reaction. Examples of bases and acids that can be suitably used include ammonium acetate-acetic acid, acetamido-acetic acid, pyridine-acetic acid, piperidine, and ε-amino-n-caproic acid. The amount of the base and/or acid used is 0.01 to 10.0 molar equivalent, more preferably 0.1 to 1.0 molar equivalent #''St, relative to polyprenylacetone (V).

The reaction can be carried out by dissolving polyprenylacetone (■), cyanoacetate (■), and the above base and/or acid in the above solvent and stirring under heating conditions, but the reaction may not be completed. For this purpose, it is preferable to remove water produced in the brain. A simple method for removing water is to azeotrope it with the solvent used and transport it to the outside. Therefore, the reaction rJA degree is the boiling point of the solvent lll1
The reaction time is preferably 1 time, and the reaction can be completed by reacting for 1 to 24 hours, preferably 1 to 10 hours under these reaction conditions. The obtained polyprenylcyanocarboxylic acid ester (■) can be purified by applying conventionally known separation and purification techniques.

Chromatography is particularly preferred because it is simple. As the adsorbent and developing solvent for this chromatography, the adsorbent and developing solvent described above for the purification of polyprenylacetone (V) can be similarly used.

As a reducing agent for reducing polyprenylcyanocarboxylic acid ester (■) to dihydroboriprenylcyanocarboxylic acid ester (■), for example, a mild reducing agent such as sodium borohydride, cyanosodium borohydride, and sodium cyanoborohydride can be used. Any reducing agent can be used, with sodium borohydride being most preferably used. The amount of the reducing agent to be used depends on the reducing agent used, but is generally 0.5 to 10 equivalents, preferably Vi 1 to 5 equivalents, based on the polyprenyl cyanocarboxylic acid ester (■)K.

This reduction reaction is carried out in a suitable solvent. Examples of suitably used solvents include ethanol and ingropanol.

The temperature of the reduction reaction is usually room temperature, but if necessary
It is also possible to employ IIU at temperatures other than room temperature within the range of °C to +80 °C. The reaction can be completed by stirring for about 5 minutes to 10 hours under this temperature condition.

After the reaction is completed, dihydropolyprenylcyanocarboxylic acid ester (■) can be easily purified by chromatography in the same way as polyprenylcya 7-carboxylic acid ester (■).

Dihydropolyprenylcyanocarboxylic acid ester (■)
The hydrolysis reaction can be carried out by applying the method conventionally used for the hydrolysis reaction of higher fatty acid esters. For example, dihydropolyprenylcyanocarboxylic acid ester (■) t7 [achieved by stirring in an alcoholic solvent such as methanol, ethanol, ingropanol, ethylene glycol, propylene glycol with sodium or potassium hydroxide. can do. Sodium hydroxide or 7'b [The amount of potassium hydroxide used is approximately 1.0 to 20.0 molar equivalents, preferably 1.5 to 10.0 molar equivalents, relative to dihydropolyprenylcyanocarboxylic acid ester (■) It's 8il to be there! Delicious. As a reaction solvent, the above-mentioned alcohol is suitable, but in order to increase the solubility of dihydropolyprenylcyanocarboxylic acid ester (■), a small amount of a hydrocarbon solvent such as hexane, pentane, pentane, or toluene is added. It is also preferable to add In order to allow the above-mentioned hydrolysis reaction to proceed smoothly and to prevent the cyano group from being hydrolyzed, it is desirable to maintain the reaction temperature within the range of 0°C to 30°C. The time required for the reaction to form the lees varies depending on the temperature conditions employed at this time, but is generally within the range of about 0.5 to 24 hours.

After carrying out the hydrolysis reaction as described above, preferably 1
Under warm or water-cooled conditions, the reaction solution is extracted with a mineral acid such as hydrochloric acid or sulfuric acid at a temperature of 1 to 411 degrees, hexane, benzene, diethyl ether, ethyl acetate, etc., and the solvent is distilled off. Then, a dihydropolyprenylcyanocarboxylic acid corresponding to the compound KM in the general formula (■) in which R is a hydrogen atom is obtained. To decarboxylate this, 5 to
It is preferable to dissolve it in 100 times the weight of pyridine and heat under reflux for 1 to 5 hours together with 0.01 to 1.0 times the weight of copper powder. The copper powder is separated by F, and the P solution is concentrated, dissolved in a solvent such as hexane or diethyl ether, washed with water, dried in an Il bath, and the solvent is distilled off to obtain a crude product of dihydropolyprenyl nitrile (1). Chromatography is preferably employed to purify this product. Adsorbents used in this chromatography include silica gel, alumina,
Particularly suitable are activated carbon, cellulose, etc., and silica gel. As a developing solvent, hexane, pentane,
Hydrocarbon solvents such as petroleum ether and benzene, diethyl ether, diimpropyl ether, chloroform,
A small amount of a polar compound such as ethyl acetate is preferred.

Mammalian dolichols can be synthesized from dihydropolyprenylnitrile (1) synthesized by the above method, for example, by the synthetic route shown below.

Hs PP-CH2-C℃HzCN (X) However, in the above formula, the principle represents a group represented by the formula 1 (in the formula, n is I!iJ).

In reaction (2), dihydropolyprenyl nitrile (1) is hydrolyzed to obtain dihydropolyprenylcarboxylic acid represented by the general formula (X), and then a reduction reaction with water volumized aluminum lithium or the like (reaction (2)) K is carried out by the general formula ( XI)
A polyprenyl alcohol, a mammalian dolichol, can be synthesized.

Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples. In addition, I-circle analysis in Examples and Reference Examples was defined by g membrane, and NMR analysis was measured using TMS as an internal standard. Fl)-MASS analysis value is IH, 1IC, 14
Value corrected as N, 1g0, 711Br -T'
S0 Reference Example 1 Separation of Polypremer Ten ginkgo leaves (undried weight) collected in Kurashiki City at the end of October were dried with hot air at about 40°C for 24 hours.
Extraction was carried out by immersing the sample in chloroform 80°C at a temperature of about 15°C. The insoluble components were separated by adding 5 tons of petroleum ether to the animal product obtained by distilling off chloroform from this extract, and after concentrating the liquid, it was separated using a silica gel column using chloroform as a developing solvent. (Oil D was obtained. Approximately 400 g of acetone was added to this oil to dissolve the acetone soluble component, the resulting mixture was filtered, and F was purified. Methanol 400d.

2 hours 6 with water 401 and sodium hydroxide 20F
After heating to 5°C, methanol was removed, diethyl ether (500su) was added to the residue for extraction, the ether layer was washed 5 times with approximately 100sj of water, dried over anhydrous sodium sulfate, and the solvent was removed. An oily substance of 24.2F was obtained.

Next, this oily substance was separated using a mixture of n-hexane/isonolopyl ether ÷ 90/10 (volume ratio) using about one ring of silica gel to obtain a 21.8F oily substance. This oil is a polyprenol with a purity of more than 95%,
About this product: Merck & Co., Ltd.'s semi-dispersion liquid chromatocolumn LiChrosorbRP] 8-10 (Cxs
type) using acetone/methanol = 90/'10 (
The mixed bath agent of each gravity ratio is fljlIit, and the differential refraction 1
A high performance liquid chromatography analysis was performed using the chromatogram as a detector, and the area ratio of each peak in the obtained chromatogram was determined, and the results were as follows.

Peak number Number of cis isoprene units (n) Thickness m
1 11
0.32 12
1.13 13
5.94
14 25.65
15 39.4
6 16
19.27 17
5.98 18
1.89
19 0.8 Using this high performance liquid chromatography, each component was fractionated from the above oily substance, and subjected to mass spectrometry, infrared absorption spectrum, "H-NM
It was confirmed by R spectrum and lie-NMR spectrum that these components were polyprenol having m structure represented by general formula (■). 'Field ionization mass spectrometry (FD-MASS) for each component
) results and “)I-NMR δ values are shown in Table 1.
.

18C-NMR δ values are summarized in Table 2.

Reference Example 2 Synthesis of polyprenyl bromide Polyprenol 12.4f of the general formula (■) with n; ! I elementary gas '# under an atmosphere 2. Drop the phosphorus tribromide, and complete the dropping.
Stirred overnight under nitrogen gas atmosphere. Next, this n-hexane solution was placed in a separatory funnel, washed three times with approximately 50% of water, and dried over anhydrous magnesium sulfate to remove the n-hexane, resulting in a moldy yellow liquid 12. Of nine.

When we conducted NMR analysis on this product, we found that the signal "(
d+δ=4.08) lost 78 tratani-CHzBrK
An assigned signal (d, δ=3.91) appeared.

Further, when this liquid material was analyzed by FD-MASS, it was found that m/e=1304. Based on these analysis results,
In the above product general formula (II), n=15, X-
It was confirmed that it is polyprenyl bromide, which is Br.

By similar operation, polyprenyl bromides other than 9n or 15 and polyprenyl bromides with n arbitrarily distributed between 11 and 19 were synthesized wt Example 1 30 d of anhydrous tetrahydrofuran was placed in a three-necked flask Then, 640 μm of 50% sodium hydride were charged, and while stirring at room temperature, 1.57 tons of ethyl acetoacetate was added. After the intense generation of hydrogen gas slowed down, the temperature was gradually raised while replacing the inside of the flask with nitrogen gas, and stirring was continued for 1 hour under the condition of refluxing the solvent. The reaction system was then cooled in a chamber, and then added to the general formula (!) synthesized according to Reference Example 2.
polyprenyl bromide with n=15, X=Br in 4.3 Of tetrahydrofuran (10 il
/) solution was added dropwise and stirred at room temperature overnight. After removing the solvent from the reaction mixture using a rotary evaporator, approximately 201
The resulting diethyl ether layer was washed successively with water, diluted hydrochloric acid, water, and sodium bicarbonate, dried over anhydrous magnesium sulfate, and the diethyl ether was removed using a rotary evaporator. A yellow liquid was obtained. This yellow liquid was heated for 30 minutes at 150"C under reduced pressure to distill off low-boiling components, and the residue was subjected to silica gel column chromatography [hexane/ethyl acetate-98/2 (
(volume ratio) was used as a developing solution] to obtain 2.48 tons of a pale yellow liquid. The results of this analysis are shown below.

IR analysis' 1740 + 1715.1660 +
830cxa-"99m"H-NMR analysis: δ 1.21 (3H,t, -
COzCH*C: Pass.

Cα4? 4.11 (2H, q, -CO2C output) FD-
According to the MASS analysis results of m/e = 1354 or more, this slightly yellow liquid has n = 15 in general formula (IV).
, R1=C2H4''?';h It was confirmed that it was ethyl rupho IJ prenylketocarboxylate.
.

Next, this ethyl polyprenylketocarboxylate was added to a solution of sodium hydroxide 0.5 fs ethanol 201 and water 5 resistant, and under reflux conditions, hydrochloric acid was added little by little for 3 hours to make the mixture about 2 resistant. Extracted with xane.

The hexane layer was thoroughly washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a yellow viscous liquid wt. This product was purified by silica gel column chromatography [hexane/ethyl acetate-98/2 (volume ratio) was used as the developing solution] to produce a slightly yellow viscous IIi.
A liquid material of 1.98F was obtained. The analysis results of this item are shown below.
MR analysis: J ppm cα41.53 (S, 9H), 1.62 (8,48)1
).

1.7-2.4 (m, 75H), 5. os (
br, 18H) FD-MASS analysis: m/e=12
From the analysis results of s2 and above, this slightly yellow liquid has the general formula (V
), it was confirmed that it was polyprenylacetone with n=15.

Next, in a three-necked flask, 5 o- of benzene, 173 q of ethyl cyanoacetate, 35 q of vinegared ammonium, and 3511 ml of acetic acid were added.
%I and previously synthesized polyprenylacetone (V)
1.96 F was charged, and the reaction was allowed to continue for 10 hours at the boiling temperature of the solvent, azeotropically distilling the benzene with benzene and distilling it out of the system. The reaction solution was then cooled to Nil, washed with water in a separatory funnel, and dried over anhydrous magnesium sulfate.
The solvent was distilled off to obtain a yellow liquid. This product was subjected to silica gel column chromatography [hexane/ethyl acetate].
98/2 (volume ratio) was used as a developing solution] to obtain a colorless liquid of 1.42F. According to the following analysis results, this liquid has a general formula (■) of n-+a15. R”
It was confirmed that it was a polyprenylcyanocarboxylic acid ester where e=cskls.

IR analysis: 2220, 1725, 1660, 1600
,1440°1370.1275,1220,1060
．． 830 pieces-1pm 1H-NMR analysis: δ 1.30(t, 3f(
), 1.53 (8,91().

C14 1,62 (8,48H), 1.7-2.5 (m, 75
H).

4.20(q, 2H), 5.06(br, 18H)F
D-MASS analysis: m/e = 1377 Next, 1.40f of this polyprenyl cyanocarboxylic acid ester and Ingropanol 201 were placed in a three-flask, and about 501 Iv of sodium borohydride was added while stirring at rich temperature. Approximately 5011 after stirring for 1 hour at the same temperature
The mixture was poured into a saturated aqueous ammonium chloride solution (No. 7) and extracted with hexane.

The hexane layer was dried over anhydrous @#magnesium, and the solvent was distilled off to obtain a colorless liquid 1.35F.

Next, this liquid was dissolved in pyridy2Q+++jK, and t
@ powder 0. After adding IF and heating under reflux for 2 hours, the copper powder was separated and washed with hexane. The P solution and the washing solution were combined, most of the solvent was removed using a rotary evaporator, the residue was dissolved in hexane, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to form a yellow liquid. I got it. This liquid was purified by silica gel column chromatography [hexane/ethyl acetate -98/2 (volume ratio) was used as eluent] to obtain a colorless liquid of 1.01f. From the following analysis M, it was confirmed that this -0 is dihydropolyprenyl nitrile in which n=15 in the general formula (1).

IR analysis: 2245, 1660, 1440, 1375
．． 830+? FII "22m 1) 1-NMl (Analysis: δ 1.00 (d, 3l-
1).

Cα4 1.1-1.5 (m, 2H), 1.53 (8
', 9H), 1.62 (11,48H) 1.7~
2.5 (m, 73H), 5.05 (br, 18) 1
)FL)-MASS analysis: m/e-1307 Example 2~
9 In the general formula (II) by the same operation as in Example 1,
=, Br and n is 11.12, 13, 14, 16, 17.
In the corresponding general formula (1) from each polyprenyl bromide which is 18 and 19, n is 11.12, 13, 14
Each of the dihydropolyprenyls 16, 17, 18 and 19 was synthesized. The yield of each of these synthetic reactions was about 1 as that of Example 1. In addition, the characteristic absorption of the infrared absorption spectrum and the characteristic signal of the H-NMR spectrum of each dihydropolyprenyl nitrile are expressed by the general formula (1) synthesized in Example 1 at that position.
) were substantially identical to those of dihydropolyprenyl nitrile with n=15. Moreover, the value of FD-MASS analysis was outside the box.

2 11 10353
12 11034 13
11715 14
12396 16
13757 17 144
38 18 15119
19 1579 patent applicant
Rira Co., Ltd. Agent No need for a patent attorney Ai procedural amendment (voluntary) Showa! %7 May 14th, Haruki Shimada, Commissioner of the Patent Office 1, Display of the case Showa S7 patent application lI! 7845 No. 2, Name of the invention: Dihydropolyprenylnitrile (1081 Rira Ray Joten θ Tsuguo Okabayashi 4, Agent Tel: Tokyo 03 (277) 3182 5, Subject of amendment G Contents of amendment (1) Description No. Insert ``1 week'' between ``(at about 15°C)'' and ``chloroform'' in the fourth line from the bottom of page 26.

(2) Specification page 958 1m 11th line g) “11!7tJ
Example 10 below is added to CDh.

[Example 10 A polyprenol mixture obtained by heating in the same manner as in Reference Example 1, in which n is distributed from 11 to 19 in the general formula (.) and whose composition is substantially the same as that described in Reference Example 1, was used as a reference example. ! A polyprenyl bromide mixture was obtained by reacting it with phosphorus tribromide according to the method of Example 1, and 4.3°f thereof was substituted for the polyprenylpromide 4.50fQ) which is nx15 in the general formula (It) of Example 1. The final product was a colorless viscous liquid wipe with 0.0% colorless viscous liquid. ? I got 7 f. I of this
The IL%-NMB analysis results were substantially the same as those obtained for dihydropolyprenyl nitrile in Run #11 in terms of characteristic absorption and position of characteristic signals. ” Procedural amendment (voluntary) November 1980 II 22 F+ Kazuo Wakasugi, Commissioner of the Japan Patent Office1, Indication of the case, Special Fraud Application No. 57863 of 19802 Name of the invention, Dihydropolyprenyl nitrile (10B + Rira Co., Ltd.) 4. Agent phone: Tokyo 03 (277) 3182 5. Subject of amendment Contents of amendment 91!11 AlIIse page 8 line ``Colorless liquid 1.3
Obtained 5t. According to the analysis results below, this product was found to be a dihydropolyprenylcyanocarboxylic acid ester having the general formula (■) with n; 15 and R''=CzHs.

IR analysis: 2245, 1740, 1660, 1440
,1370°1295,1240.1185.1175
．． 1020.830 images, pprn''H-NMR analysis, δ 1.04 (dd, 3H).

Fog 4 1.30 (t, 3H), 3.36 (dd, IH)
, 4.22(q, 2H).

5.05 (br, 1sn) FD-MASS analysis: rrVe=1379 Next, a mixture of 30 saJ of ethanol, 3 m of water, and 0.32 sodium hydroxide was added to this liquid, and after stirring at room temperature for 1 hour, water was added. After adding 100 m#i of the mixture, 6N hydrochloric acid was added little by little to obtain State 2, and the mixture was extracted three times with ether. The organic layers were combined, washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a liquid product of 1.22 f. ” to join.

Claims (1)

[Claims] General formula (in the formula, -CHx-C formula -CHz- is a transformer-made imprene *f; L tab L, -CM! -tone -CH
x-11vxml 477'ren unit, n is 1
Spend an integer between 1 and 190. ) Dihydropolyprenylnitrile 0