JPS58162547A - Polyprenylaldehyde - Google Patents

Abstract

NEW MATERIAL:A polyprenylaldehyde shown by the formulaI(a group shown by the formula II is isoprene unit of the trans type; a group shown by the formula III is isoprene unit of the cis type; n is 11-19). USE:Useful as a raw material for drugs, cosmetics, etc. and also as an intermediate for synthesizing especially dolichol of mammals. PROCESS:A polyprenyl halide shown by the formula IV (X is halogen) is reacted with an acetoacetic ester shown by the formula V (R is lower alkyl) in the presence of a basic compound to give a polyprenylketocarboxylic ester, which is saponified and decarboxylated to give a polyprenylacetone. This compound is then subjected to Witting reaction with a compound shown by the formula VI, the -CHO protecting group of the reaction product is deprotected, to give a compound shown by the formulaI. The polyprenyl halide shown by the formula IV is directly obtained from an extract of ginkgo or Himalayan ceder or through its hydrolysis.

Description

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

More specifically, the invention relates to the general formula 0 formula% ) Represents a ren unit, and n represents an integer from 11 to 19. ) This invention relates to a novel polyprenyl aldehyde represented by:

The polyprenyl aldehyde 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. Permock.
It was first isolated from pig liver by Natu et al.
r@(London).

Ldan J 470 (1960)], which later represented the general formula (A) akbcouthaH8cHCHIb■sCH prene 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 isoprene units generally ranges from 12 to 18, and j-14,t
It was revealed that three homologs of s and 16 were the main constituents (R, W.

Keenan@ta1. , BiochemicalJ
ourml, 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, Harford et al. conducted an in vitro test using the white medulla of calves and pigs, and found that exogenous dolichol promoted the incorporation of sugar components such as mannose into lipids, and
As a result, it has been revealed that it has the effect of increasing the formation of glycoproteins, which are important for maintaining the life of living organisms [
Biochemical and Biophysics
alRe5earchCo+nmunication
, L! See L., 1036 (1977)]. 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.

T, KL, W, Keenan et al. found that it is important for rapidly growing organisms, such as those in infancy, to ingest dolichol from outside and supplement the dolichol obtained through biosynthesis within the body. (Archiveso
f Biochemistr)r and Biopi
See Vaics, 179.634 (1977)]0
Furthermore, Akamatsu et al. quantified dolichol phosphate ester in the apricot liver of rats, and found that the amount was significantly reduced compared to normal liver, and the glycoprotein synthesis function in liver tissue was significantly reduced. found that the function was improved by applying an external force of radrichol nystere [No. 54]
Presented at the Japanese Biochemical Society Convention (1981)].

As mentioned above, dolichols are substances that control extremely important functions for living organisms, and are useful as pharmaceuticals or intermediates thereof. -6! You can only get a 0.6f dori call [F, W
, Burgos et al., Biochemi
CalJournal, 88.470 (1963)]. It is extremely difficult to completely synthesize dolichol a using the current M-organic synthesis technology, as is clear from their complex and unique molecular structure. 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
No such convenient substance has hitherto been found. Conventionally, voriglenols (these are called pesoraprenols) represented by the following general formula (B) C+#Ls k = 4 to 6]
rrucola), but the number of cis isoprene units is 14.15.
#1 It is almost impossible to synthesize dolichols mainly consisting of 1 and 16 with the current organic synthesis technology. K again.

Hannus et al.
reported that a polyprenyl component was isolated from the leaves of S. vestris in a yield of 11 on a dry IT basis, and that this component was a polyprenyl acetate mixture containing 10 to 19 Indare X units primarily in the cis configuration. Pt
ytoclemistry, 13. 2563 (1
(974)], their report does not elucidate the details of the trans and cis configurations in the polyprenyl acetate. Additionally, D. F. Zincke
reported the presence of C9o polyprenols with an average value of 18 isogrene units or 18 isopre7 units in the medicinal extract of pine strobu (average μm 85 trobua).
see Mistry, 11.3387 (1972)],
This report does not provide a detailed analysis of the trans and cis configurations of the polyphrenol.

Some of the inventors and their collaborators previously described.

Extracts extracted with organic solvents from Ginkgo, Cypress and Himalayan cedar are hydrolyzed and treated by chromatography, fractional dissolution or other suitable separation methods to obtain 14-22 isoprene units. A polyprenyl fraction consisting of a polyprenol and/or a mixture of its acetate homologs is obtained in the same trans and cis configuration as the dolichols, and the skeleton polyprenyl fraction has a lower alpha-terminal content than the mammalian dolichols. exhibiting a distribution of polyprenyl congeners very similar to the distribution of polyprenyl congeners in mammalian dolichols, only in the absence of saturated isoprene units;
The polyprenyl fraction can optionally be separated relatively easily into its constituent individual polyprenyl congeners (uniform in the number of isoprene units), and thus the polyprenyl fraction and each polyprenyl congener separated therefrom It has been found that Haisai 1 is also very suitable as an intermediate for the synthesis of mammalian dolichols.

In order to efficiently produce mammalian dolichols using the above-mentioned polyprenyl compound, the present inventors have intensively studied a method of introducing a saturated isoprene unit into the α-terminus of the polyprenyl chain of the polyprenyl compound, and as a result, The present invention was completed by creating a polyprenyl aldehyde represented by the general formula (1) which is useful as an intermediate in such a method. Polyprenyl aldehyde represented by the general formula (1) [U
It is written as F polyprenyl aldehyde (1). ) is a polyprenyl halide [hereinafter referred to as polyprenyl halide (n)] represented by the general formula (1) (wherein Xri represents a halogen atom and n is as defined above). ] to the presence of a basic compound (F) to an acetoacetate represented by the general formula (in the formula, R represents a lower alkyl group) [hereinafter referred to as acetoacetate (II)]. ] The general formula (IV
) C) i3C) (3 υ (wherein R and nFi are as defined above) polyprenylketocarboxylic acid Nisdel [hereinafter F,
It is written as polyprenylketocarboxylic acid ester (fV).

] is saponified and decarboxylated to obtain polyprenylacetone represented by the general formula (V) (in which n is as defined above), and this is combined with the compound represented by the formula and Witsch (Wi
ttig) It can be produced by reacting and then removing the capsular group of the -CHD group in the product.

As mentioned above, polyprenyl halide (II) can be obtained directly from the extract of Himalayan cedar or by hydrolysis using the general formula % (where n is as defined above). Polyprenols or mixtures thereof represented by .) A total halogenating agent such as P
αs, PBr3 throat phosphorus trihalide, 8 axis 2.5
It can be easily obtained by halogenation with thionyl halide such as ours. This halogenation reaction is usually carried out by dissolving the polyprenol in an appropriate solvent such as hexane or diethyl ether, and then dissolving the polyprenol in the presence or absence of a base such as triethylamine or pyridine. At temperatures between 20°C and +50°C.
・Performed by adding a rogensing agent.

Polyprenornolide (n) and acetoacetate (
The reaction with III) is desirably carried out in a solvent, and examples of solvents that can be preferably used include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane. 1 dose of solvent is not critical, but 2 for polyprenyl halide (II)
~100 times (by weight), preferably < 5 to 80 times (by weight), more preferably 10 to 50 times (by weight) Use of a solvent that has been dried to an O light level facilitates the desired reaction. In order to carry out this reaction, it is essential to have a basic compound present. The basic compounds used include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium t-butoxide, potassium 1-butoxide, sodium methoxide, sodium ethoxide, etc. , hydroxide or alkoxide, monobutyllithium, meglulithium, etc. are suitable.

The basic compound is generally about 0.1 to 5.0 mol, preferably 0.5 to 3.0 mol per mol of acetoacetate (I).
It is used in a proportion of 7 to 1.5 moles, more preferably Fio. In a preferred embodiment, the solution or dispersion of the in-based compound is treated with nisder acetoacetate (I).
II) or conversely by adding acetoacetate (It
) by gradually adding the basic compound all at once or little by little to form anion/acetoacetate, and then adding polyprenyl halide (n) to the strainer for reaction.

The ratio of acetoacetic acid ester (IN) to polyprenyl halide (n) is critical, but the molar ratio of acetoacetic acid ester (1)/polyprenyl halide (II) is 1/2 to 20. /1, preferably 415-10
/1, more preferably 1/1 to 5/1. When forming acetoacetic acid ester (7-ion), use an atmosphere surrounded by an inert gas such as nitrous gas or argon at F-30°C.
It is desirable to carry out the reaction at am of +100°C, preferably -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 5 hours is sufficient. In this way, R-cleavage is performed and nine acetoacetic acid ester (
Polyprenyl polyhydride (II) is added to the anion solution of [) and reacted. Depending on the reaction conditions used, the reaction may be carried out smoothly by adding the polyprenyl halide ([I) in small portions or in a dropwise manner rather than adding the entire amount at once. The temperature within the reaction system during the addition of polyprenyl halide (H) and the subsequent completion of the reaction is not critical, but is preferably within the range of -1θ°C to the boiling point of the solvent used. . 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 temperature is too high, undesirable side reactions may proceed. From this point of view, it is preferable to employ a reaction temperature within the range of 0°C to 80°C. Polyprenylhala f-do(I)
In order to complete the reaction after adding l), 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 about 30 minutes to 24 minutes. It takes about an hour. In order to confirm the progress of the reaction, it is convenient and convenient to monitor the entire decrease in the raw material polyprenyl halide (II) by thin layer autographing.

After the reaction, isolation of the polyprenylketocarboxylic acid ester (%') from the reaction mixture can be easily accomplished by applying isolation methods used in conventionally known synthetic reactions. In particular, chromatography is conveniently used. Examples of adsorbents used in the RIAM method include silica gel, alumina, activated carbon, and cellulose. 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 skip this isolation step and directly perform the next step of synthesis reaction of polydalenylacetone (V), followed by a purification step.

Polyprenylketocarboxylic acid ester (■) can be saponified by applying the method conventionally used for the saponification reaction of higher fatty acid esters. 7 words,
Polyprenylketocarboxylic acid ester(s), aqueous methanol with sodium hydroxide or potassium hydroxide,
This objective can be achieved by stirring in aqueous ethanol or aqueous isocropanol. Sodium hydroxide The amount of potassium hydroxide used is approximately 1.0 to 2 per polyprenyl ketocarboxylic acid ester (■).
It is desirable that the amount is 0.0 molar equivalent, preferably 1.5 to 10.0 molar equivalent. The above-mentioned hydrous alcohols are suitable as reaction solvents, but hydrocarbon solvents such as hexasan, pentane, benzene, and toluene are used to increase the solubility of polyfrenyl ketocarbo/acid ester (IV). It is also preferable to add a small amount of. In order for the saponification reaction to proceed smoothly, the reaction temperature is preferably from 0°C to the boiling point of the solvent used, preferably within the range of 25 to 65°C. The time required for completion of 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 room temperature conditions or water-cooled conditions, and the reaction solution is further reduced to about 1 to 3 degrees. Under acidic conditions, a decarboxylation reaction occurs automatically,
Fo1nobrenylacetone (V) is formed. Nine days after the decarboxylation reaction was completed, the reaction solution was diluted with hexane,
Extract with benzene or diethyl ether, wash thoroughly with water, dry the organic layer, and evaporate the solvent to obtain the auto-1
-A crude product of polyprenylacetone (■) is obtained. Chromatography is preferably employed to purify this product. Adsorbents used in chromatography include silica gel, alumina, activated carbon, and cellulose, with silica gel being particularly suitable. As a developing solvent, hexane, pentane, petroleum ether, benzene,
It is preferable to use a mixture of a hydrocarbon solvent such as toluene and a small amount of a polar solvent such as diethyl ether, diinoglohylether, chloroform, ethyl acetate, or methyl acetate.

The Witzig reaction between polyprenylacetone (■) and 1,3-dioxan-2-ylmethyltriphenylphosphonium pro2, represented by the formula t'L, requires that this reaction be carried out in an inert solvent. be.

Examples of suitable solvents include dimethylformamide, tetrahydrofuran, diethyl ether,
Examples include benzene. In order for the desired reaction to proceed smoothly, it is preferable that the solvent used be sufficiently dried to an anhydrous state. Furthermore, from the same viewpoint, it is preferable to replace the reaction system with an inert gas such as nitrogen or argon. The solvent is 5 to 50 times the weight of polyprenylacetone (v) used in the reaction, especially lO
It is preferable to use up to 30 times the amount by weight.

In the reaction using the Witchig reagent, which has an oxygen atom at the β-position of the phosphorus atom, Witchig reagent and polyprenylacetone (V
) is preferably added dropwise to the mixture with polyprenylacetone (V) so that the phosphorylide formed from Witzig's reagent and the base is reacted with polyprenylacetone (V) as soon as it is formed. Here, as the basic compound used, for example, n-
Butyllithium, methyllithium, phenyllithium,
Preferred examples include sodium hydride, potassium hydride, lithium methoxide, sodium methoxide, sodium ethoxide, and sodium amide. A basic compound selected from these is added dropwise in an amount of about 0.5 to 15 molar equivalents to the Witzig reagent. At this time, the bath temperature is maintained at -30°C to +120°C, preferably 20°C to 100°C, and after the dropwise addition is completed, stirring is continued for about 5 to 5 hours in the above temperature range. The amount used is 0 for polyprenylacetate (CV).
．． It is desirable that the amount is 5 to 10.0 molar equivalents, preferably O, S to 80 molar equivalents, and more preferably 1.0 to 5.0 molar equivalents. After the Wittzig reaction is completed, the polyprenyl aldehyde (1) of the present invention can be obtained by treating it with a mineral acid such as hydrochloric acid or sulfuric acid to remove the protecting group of the 10 HO group. , Alternatively, in general formula (N), n is 12 to 1
Obtaining polyprenyl aldehyde represented by general formula (1') (where n is as defined above) included in polyprenyl aldehyde (1) by directly oxidizing polyphrenol, which is 9. I can do it. As the oxidizing agent for this purpose, oxidizing agents that are normally used for oxidizing allyl alcohol to α,β-unsaturated aldehyde can be used, such as manganese dioxide, chromic anhydride-pyridine, and pyridinium chlorochromate (PCU).
% pyridinium dichromate (PDC), etc., and manganese dioxide is particularly suitable. The amount of the oxidizing agent used is 1 to 200 times, preferably 2 to 100 times, the molar ratio of the polyprenol (■).

This oxidation reaction is preferably carried out in a solvent, and an example of a suitably used solvent is L-methylene chloride. When mancan dioxide is used as an oxidizing agent, halogenated hydrocarbons such as chloroform and carbon dioxide, petroleum ether, hydrocarbons such as xane, pentane and benzene, ketones such as acetone and methyl ethyl ketone, diethyl ether , ethers such as Shiitsubu a pill ether, etc. are also suitably used. The amount of the above solvent used is not critical, but it is 1 to 2
00 times by weight, preferably 2 to 100 times by weight, more preferably 5 to 50 times by weight. When carrying out this oxidation degree LU, it is desirable to use a reaction temperature of -30°C to +100°C, preferably -10°C to +60°C. In order to complete the reaction, it is necessary to stir the reaction mixture at the above reaction temperature.
．． It is preferable to react for about 5 to 48 hours. In order to confirm the progress of the reaction, it is convenient and preferable to monitor the decrease in the raw material polyprenol (Vl) by thin layer chromatography. After the reaction is completed, the reaction mixture is passed through
The uninvented polyprenyl aldehyde (1) can be obtained by distilling off the solvent from solution F.

Purification of polyprenyl aldehyde can be carried out by applying a conventionally known separation and purification method.

In particular, clottogelaphy is convenient and preferable. Examples of adsorbents used in chromatography include silica gel, alumina, activated carbon, florisil, and cellulose x, with silica gel being particularly preferred. The developing solvent is a mixture of a small amount of a hydrocarbon solvent such as hexane, pentane, petroleum ether, benzene, etc. and a polar layering agent such as chloroform, methylene chloride, diethyl ether, citrate ether, methyl acetate, ethyl acetate, acetone, etc. It is preferable to use

The polyprenyl aldehyde represented by the general formula (1) synthesized in this way is a compound useful as a synthetic raw material for mammalian dolichols, which is an undocumented IL-T standardized gold compound. From this compound, mammalian dolichol@ can be synthesized by the synthetic route shown in the following example.

C)(3 (■) C)(3 In the above formula, R represents a group represented by the formula (in the formula, n is as defined above).

Reaction (1) is a selective hydrogenation reaction of the isoprene unit having -CR2 groups of polyprenyl aldehyde (1), and is carried out using a hydrogenation catalyst such as palladium, nickel thread, or rhodium thread.

The resulting terminally saturated polyprenyl aldehyde (■) is treated with a reducing agent such as lithium aluminum hydride to reduce -C)10 groups to 10) hOH groups to obtain mammalian dolichols (■). It's a monkey.

Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples.In the Examples and Reference Examples, I) (Analysis was performed using a liquid film, and NMR analysis was performed using TMS as an internal standard. .FD-MASS analysis value is IH, 12c,
This is a value corrected as 160.79 Hr.

Reference example 1 Separation of polyprenol 11) Ginkgo leaves collected in Kurashiki City at the end of the month.

kf (undried type t) was dried with hot air at about 40'C for 24 hours, and then extracted by immersing it in chloroform Bot at room temperature (about 15C). Chloroporum was glazed from this extract, 5 tons of petroleum ether was added to the resulting concentrate to separate the insoluble components from P, and the P solution was separated using a silica gel column using concentrated #114Ik chloroform as a developing solvent.
of oil was obtained. This oily substance contains acetate/about 40011/
The resulting mixture was diluted with liquid, the liquid was concentrated, and the resulting oil was boiled with methanol 40 (1/1 40 d of water and 20 f of sodium hydroxide for 2 hours at 65 ml) to dissolve the acetone-soluble components. After heating to ℃, methanol was distilled off,
The residue was extracted with diethyl ether (50°/cm), and the ether layer was washed 5 times with approximately 100 m/ml of water, dried over anhydrous sodium sulfate, and the solvent was distilled off to give 24.
．． A 2F oil was obtained.

Next, this oily substance was separated using a mixture of n-hex//isopropyl ether=90/10 (volume ratio) using about 1 hour silica gel to obtain 218 tons of oily substance. This oily substance is a polyprenol with a purity of 95% or higher, and it is treated with a semi-preparative high performance liquid chromatography column (LiChrosorbRPI 8-1 +) manufactured by Merck & Co., Ltd.
Cts type) using acetone/methanol = 9U/1
Using a mixed solvent of 0 (volume ratio) as a synergist and a differential refraction needle as a detector, all nine high-performance liquid chromatography analyzes were performed, and the area ratio of each peak in the obtained chromatogram was determined.The results are as follows- That's right.

Peak number Number of cis isoprene units (n) Area ratio (%) 1 11
0.32 12
1.13 13
5.94 14 25
．． 65 15 39.
46 16 19.2
7 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 subjected to mass spectrometry, infrared absorption spectrum,
It was confirmed by 'H-NMR spectrum and L3C-NMR spectrum that these components were polyprenol having a structure represented by the general formula (2).

Field ionization mass spectrometry (FD-MASS) for each component
) results and IH-NMH δ value Table 1 shows 'C-
The NMR δ values are summarized in Table 2.

Reference Example 2 Synthesis of polyprenyl furomide Polyphrenol 12.4F of the general formula (Vt), which is n-15, and viridi 71d were added to 200d of n-hexane, and the resulting solution was heated at room temperature (approximately 20 ℃) under a nitrogen gas atmosphere 2.
Of phosphorus tribromide was added dropwise, and after completion of MP, the mixture was stirred overnight at room temperature under a nitrogen gas atmosphere. Next, this n-hexane solution was put into a separatory funnel, washed with 31 g of about 50 d of water, dried over anhydrous magnesium sulfate, and the n-hexane was distilled off to obtain a pale yellow liquid 12. Got Of0
When NMR analysis was performed on this product, a signal (
d, δ = 4.08) disappears and a new −Ckb
A signal attributed to Br (dt δ = 3.91) appears. Further, this liquid material was analyzed by Fl)-MA8S and found to have m/e=1304. These analysis results confirm that the above product is a polyprenyl bromide with n=15 and .=Br in the general formula (11).

Synthesis of polyprenyl bromide with n other than 15 was carried out using the same procedure.Example 1 30 at of anhydrous tetrahydrofuran and 64 tl'b of 50% sodium hydride were placed in a three-necked flask, and while stirring at room temperature, ethyl acetoacetate was added. 1.572 was added dropwise. After the intense hydrogen gas generation 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. Next, the reaction system was cooled to room temperature, and then the general formula (I) synthesized according to Reference Example 2 was added.
In I), polyprenyl furomide 4.3Of tetrahydrofuran (1υ11/
) solution was added dropwise and stirred at room temperature overnight. After removing the solvent from the reaction mixture by rotary evaporation, the residue was poured into about 20ml of water and extracted with diethyl ether. Next washing] 2. Dry over anhydrous magnesium sulfate, and remove diethyl ether using a rotary evaporator to obtain a yellow liquid. This yellow liquid was heated at 150°C for 30 minutes under a reduced pressure of 1 + mHf to remove low-boiling components, and the residue was subjected to silica gel column chromatography [hexane/ethyl acetate = 9872 (
(volume ratio) was purified by Bf, used as opening] to obtain 248v of a pale yellow liquid. The analysis results of this product are shown in 1 below.

IR analysis: 17'40.1?15,1660.830 (
1) -14,11(2H,q, -CO2CHzCHs
) FIJ-MASS analysis: From the analysis results of m/e = 1354, this pale yellow liquid is found to be ethyl prenylketocarboxylate in the general formula (IV), where n = 15 and K = CzHite@ruho'). confirmed.

This ethyl polyprenylketocarboxylate was then added to a solution of 0.5 f sodium hydroxide, 201 ml of ethanol, and 5 ml of water, and stirred for 3 hours under reflux conditions.
) and tJII! using a rotary evaporator. was added little by little to make the mixture acidic to 2, and then extracted with hexane. 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. This product was purified by silica gel column chromatography [using hexane/ethyl 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.
H), 1. fi2(s, 48H).

Cα4 1.7-2.4 (m, 75H), 5.05 (br,
18H)-FD-MASS analysis: m/e-1282
From the above analysis results, it was confirmed that the yellow liquid of Jin was polyphrenylacetone in which n=15 in the general formula (V).

This polyprenylacetone (1.92 F) and the Witschig excipient 1,3-dioxan-2-ylmethyl)
IJ phenylphosphonium bromide 1. Of(use a
(dried in MiJ at 60°C/lmHg for 2 hours) was dissolved in methylformamide (7.5-ml) and heated to 80-90°C under nitrogen X atmosphere, prepared from 16-ml of lithium and 7.5 ml of methanol. The lithium methoxide solution was added dropwise over a period of approximately 1 hour, and after the addition was completed, the lithium methoxide solution was added dropwise for an additional 2 hours.
The reaction was completed while being kept at ~90°C and monitored by thin layer chromatography.

The reaction mixture was poured into water, thoroughly extracted with hexane, washed with 7 layers of hexane brine, and dried over magnesium sulfate.
The liquid obtained by distilling off the solvent with a rotary evaporator was dissolved in 15 mL of tetrahydrofuran, 5 TIll of 10% hydrochloric acid was added, and 50 s of water stirred at room temperature for 5 hours was added to dilute the solution, followed by extraction with hexane.

The organic layer was washed successively with water, chlorine water, and brine, and then dried over magnesium sulfate. The solvent was distilled off using a rotary evaporator, and the resulting yellow liquid was subjected to silica gel chromatography [hexane/ethyl acetate = 97. /3 (volume ratio) was used as a developing solution] to obtain 1.28 ft. of colorless liquid.

According to the analysis results described in Section 1, this product has n in the general formula (1).
It was confirmed that it was a polyprenyl aldehyde with =15.

IR analysis: 2720, 1675, 1630, 1440° 1370. A polyprenyl aldehyde represented by the general formula (1) having a corresponding n value between 11 and 19 was synthesized from a polyprenyl bromide having a value other than 15. The yields were almost the same as those obtained when polyprenyl aldehyde with n=15 was synthesized. In addition, their If (spectral characteristic absorption and NMR
・Agreed. Furthermore, the results of Fu-MASS analysis were as follows.

Raw material polyprenyl bromide Produced polyprenyl aldehyde 11 103812
110413
117214 124016
137617
144418 15
1219 1580 Example 2 In the general formula <V+>, polyprenol 4, where R = 15, Of is hexa720 at and -1--tek 20
Dissolved in a mixed solvent with W4t, activated manganese dioxide 14
．． 5% of the mixture was added, and vigorous stirring was continued at room temperature for 7 hours. After a long time, it was filtered using a glass filter, and the solid content was thoroughly washed with hexane.The P liquid and the washing liquid were combined and the solvent was distilled off using a rotary evaporator, resulting in a liquid product 4. ．． Of silica gel chromatography [hexane/ethyl acetate = 1
00/2 (volume ratio) as a developing solvent],
3.1 tons of colorless liquid was obtained. The following analysis results showed that 411wt of this product was polyprenyl aldehyde in which n=14 in general formula (1) (n=15 in general formula (I')).

IR analysis: 2720, 1675, 1630, 1440° 1370.1080, 83t1cm ”9.85 (d,
IH) Fl)-MASS analysis: m/e-1240 By the same operation, in the general formula (V), when n is between 12 and 190,
A polyprenyl aldehyde represented by the general formula (1) having a corresponding value of n-1 was synthesized from a polyprenol having a value other than 5.

The yields are almost the same as those obtained by synthesizing polyprenyl aldehyde with n=14 in general formula (1). Also, the characteristics of their IR spectra absorption and NMR spectra Procedural Amendment (voluntary) Haruki Shimada, Commissioner of the Japan Patent Office 1, Indication of the case Patent Application No. 44859 1982 2.4 and Ming's name polyprenyl aldehyde f1081 RiRaRayt Co., Ltd. Tsuguo Hayashi 4, Agent Tel: Toto 03 (277) 3182 6 Contents of amendment (1) "(approximately 15°C)" on page 24, line 18 of the specification
Insert [1 week 1] between "in" and "chloroform."

(2) In the bottom line of page 57 of the specification, the following Example 3 is added after “Concordant. J”.

[Example 3 In the general formula (M) obtained in the same manner as Reference Example 1, n
is distributed from 11 to 19 and whose composition is substantially the same as that described in Reference Example 1, is reacted with phosphorus tribromide according to the method of Reference Example 2 to obtain a polyprenyl bromide mixture, 5j! except that .50g was used in place of polyprenyl bromide 4.309 which is n-15 in the general formula (picture) of Example 1.
The same operation as in Example 1 was carried out to obtain a colorless viscous liquid as the final product.1. - Obtained 59ft. IR1 of this
The 'H,-NMR analysis results were substantially the same as those obtained for the polyprenyl aldehyde of Example 1 in terms of characteristic absorption and position of characteristic signals. J

Claims (1)

[Scope of Claims] A polyprenyl aldehyde represented by the general formula (wherein -cHl-c, , c-ckh- represents a trans-type inogre prene unit, and n represents an integer from 11 to 19) .