JPS6042343A - Production of dihydropolyprenyl alcohol - Google Patents

Abstract

PURPOSE:To produce the titled compound economically, by hydrolyzing a novel enamine or imine obtained by the isomerization of polyprenylamine, in the presence of an acid catalyst, and converting the formyl group of the resultant aldehyde to hydroxymethyl group. CONSTITUTION:The novel substance of formula I or formula II [R<1> and R<2> are lower alkyl, cycloalkyl, aryl, etc.; A is group of formula III (two isoprenyl units are trans and n isoprenyl units are cis); n is integer of 11-19] is hydrolyzed in the presence of an acid catalyst to obtain the compound of formula IV. The objective compound of formula V playing an important role in the maintenance of the life of mammals can be produced economically, without using an expensive C5 chain extender, from a polyprenyl compound extracted from ginkgo tree, etc., by reducing the CHO group of the compound of formula IV to CH2OH group. The novel substance of formula I or formula II can be produced by isomerizing the compound of formula VII which is obtained easily by the reduction of the compound of formula VI (R<3> is H or R<2>).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula % (1) [wherein A represents a group represented by the formula, where -CI-h-C-CH
2- represents 7 units of inprene, and n is 11 to 1
It is an integer of 9. ] It relates to the manufacturing method of dihydropolyprenyl alcohol shown by these.

The dihydropolyprenyl alcohol of the above formula (1) is called dolichol as described in JP-A No. 57-91932, and is a homologue mainly having cis-inprene units of 14.15 and 16. It is known that they are widely distributed in the bodies of mammals in the form of mixtures and play an essential role in maintaining life.

Some of the present inventors and their joint researchers previously proposed that the formula extracted from ginkgo and cedar leaves as a method for preparing the dihydropolyprenyl alcohol 'tfU is as defined above. ) We have proposed a method of C5 elongation using polyprenol or its acetate ester as a raw material and making full use of the Grignard reaction (see JP-A-58-83648). In this method, expensive 4-hydroxy-2-methylbutyl halide or its functional precursor is used for the 05 extension.

The present inventors conducted intensive studies on the method for producing the dihydropolyprenyl alcohol of formula (1) without using a C5 chain extender as described above. It represents an alkyl group, a cycloalkyl group, an aryl group or an aralkyl group, or R1 and R2 together represent an alkylene group having 2 to 5 carbon atoms, and A is as defined above. ) is hydrolyzed in the presence of an acid catalyst to produce an aldehyde of the general formula (3% formula% () (wherein A is as defined above), and the -ci of the aldehyde is -io group'1-C
The enamines of formula (III) and the imines of formula (IV) for which we have found a process consisting of converting them into H20H groups are both new compounds, but according to the invention they are of the general formula (in which R1 and A is as defined above, and R3
is a hydrogen atom or is the same as R2 above. ) The polyprenylamine can be produced by isomerizing the polyprenylamine represented by Easily manufactured by 1-
I can do that.

In each of the above formulas, lζ1 and R2 are independently an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, impropyl, and n-butyl, and 5 to 4 carbon atoms such as cyclopentyl, cyclohexyl, and methylcyclohexyl.
10 cycloalkyl groups, aryl groups having 6 to 10 carbon atoms such as phenyl, tolyl, and naphthyl, and aralkyl groups having 7 to 10 carbon atoms such as benzyl and phenethyl. I cut it. I(? and R” are -
Together -(CH2)2-1 ((-R2)a-1-
CH(CM()C ratio-1-(c locus)4-1-〇H2C1
((CH3)CH,!-1-(CR2 people-1-CI(2
C((JS20-) can be an alkylene group having 2 to 5 carbon atoms. R3 is a hydrogen atom or
It is the same as 2.

Polyprenylcarbo:/acid amide (■) f: Examples of reducing agents for reducing polyprenylamine (Vl) include lithium aluminum hydride, sodium aluminum hydride, sodium borohydride, lithium borohydride, etc. Metal hydrogen complex compounds are 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 1 to 5 equivalents, based on the polyprenylcarboxylic acid amide (■).

This reduction reaction is carried out in a suitable solvent. When lithium aluminum hydride is used as the reducing agent, ether solvents such as diethyl ether and tetrahydrofuran are used, and when sodium borohydride is used, alcohol solvents such as ethanol and isopropanol, and pyridine are exemplified.

The temperature for the reduction reaction is usually preferably around 1ζ, the boiling point of the solvent, and the reaction can be brought to a conclusion by stirring under this temperature condition for about 2 to 20 hours.

Isolation and purification of polyprenylamine (Vl) is usually carried out by known separation and purification methods, and chromatography is preferably employed. Materials used in chromatography include silica gel, alumina, activated carbon, and cellulose, with silica gel and alumina being preferred. As developing solvents, hydrocarbon solvents such as hexa/, pentane, petroleum ether, and benzene, diethyl ether, diisoglobil ether, chloroform, and N'#m:
Polar solvents such as r-f, ethanol, and +1-butylamine are suitable.

The isomerization reaction of polyprenylamine (Vl) to the compound of formula (Ill)-1: or formula (IV) by hydrogen transfer is
For example, it can be carried out using a rhodium(1) complex catalyst. The amount of catalyst used is polyprenylamine (0.0001 to 1 mol per VD, preferably 0.00
1 to 0.1 molar equivalent, more effective'□-preferably 0.005
~0.05 mol Shiraki Deru. It is preferable to carry out this reaction in a solvent atmosphere under an inert atmosphere such as argon or nitrogen. Examples of solvents include diethyl ether,
': Although ether solvents such as rl-lahydro7rane and 1,2-dimethquinethane can be used, it is preferable to use tetrahydrofuran. The amount of solvent used is not critical, but it is 2 for polyprenylamine (CVI).
~200 times (by weight), preferably 5 to 50 times (by weight). Reaction temperature (・':J: A range from 20°C to the temperature at which the solvent wanders is possible, but 40°C to 60°C is more preferable, and the reaction temperature is stirred at this temperature for about 2 to 20 hours. It is desirable that the enamine of formula (Iff) is obtained from polyprenylamine in which R3≠H in formula (Vl), and the enamine of formula (IV) is obtained from polyprenylamine in which R3-H in formula (vl). The imine is 4f.In this gap, the optically active diphosphine ligand example is @-〇→-2
,2'-bis(diphenylphosphino)-1゜1'-binaphthyl (hereinafter abbreviated as R-BINAP) as a rhodium(1) complex (Rh(R-BI NAP)(
1,5-cycloocL:aatene)]α0
When compound 4 or the like is used, an asymmetric hydrogen transfer reaction occurs, and it is also possible to obtain a compound of formula (Ill) or 20V) which exhibits improved optical activity.

The 1-7j hydrolysis of converting the enamine of the formula (Iff) or the imine of the formula (Iff) to the aldehyde of the formula (V) can be carried out according to the conventionally known hydrolysis method. Ruri, for example, Mecha Chemical Society import [New Experimental Chemistry Course, Vol.
”, pp. 662-663 (Maruzen Publishing). Stirring the enamine (Ill) or imine (IV) together with an aqueous hydrochloric acid solution or an aqueous sulfuric acid solution at room temperature, preferably in a solvent such as tetrahydrofuran, diethyl ether, ethyl alcohol, or furoyl alcohol;
Shiri￥ can be given. The obtained ζ polyethylene aldehyde compound can be purified by applying conventionally known separation and purification techniques. Chromatography is particularly preferred because it is simple. As the chromatography conditions, substantially the same conditions as those for polyprenylamine (t4) described above can be used.

Examples of the reducing agent for reducing the formyl group of the aldehyde of formula (V) obtained as described above to a human f-coxymethyl group include sodium borohydride, lithium borohydride, lithium aluminum hydride, It is convenient to use a fine metal hydride such as sodium aluminum hydride. The reduction can be carried out according to a method known per se. For example, when using sodium borohydride, it is preferable to carry out the reduction reaction in a solvent such as alcohol, tetrahydro7rane, ether, etc. at about 0°C to room temperature. In addition, when sodium aluminum hydride is used for lithium borohydride, lithium aluminum hydride, etc., after completion of the reduction reaction with an anhydrous solvent such as anhydrous ether or anhydrous tetrahydrofuran, the reaction mixture is diluted with water, alcohol, or ethyl acetate. After decomposing the excess reducing agent by treating with the like, the desired dihydropolyprenyl alcohol t' concentration can be obtained by separating the resin according to a conventional method. C, especially chromatography, is conveniently used to separate and prepare the dihydropolyprenyl alcohol. As the adsorbent and developing solvent for this chromatography, the same ones as in the case of separation of polyprenylamine (\4) manufactured by 1fJ mentioned above are used.

The amide of the formula (■) used in the method of the present invention is a compound that has not been described in known literature, but according to the research of the present inventors, the amide can be obtained by halogenating the polyprenol of the formula (n). The resulting polyprenyl halide (JP-A-58
83648), for example, by the following synthetic route.

(X) A↓C- In each of the above formulas, A, R', f and R'' are as defined above, X is a halogen atom, preferably Br or α, and R4 and R7 are carbon atoms having 6 or less carbon atoms. Alkyl groups are preferably methyl, ethyl, propyl or butyl groups; R5 and t are lower alkyl groups, preferably methyl or ethyl groups.

Polyprenyl halide (■) and acetoacetate (I
The reaction with X) is preferably carried out in a solvent.

Suitable solvents include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane. The amount of solvent used is not critical, but is 2% for polyprenyl halide (■).
~100 times by weight, preferably 5 to 80 times by weight, more preferably 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, it is essential that all the basic compounds be present. 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 methoxide, and sodium ethoxide; Oxides or alkoxides, n-butyllithium, methyllithium, etc. are suitable. The basic compound is generally about 0.1 to 1 mole of acetoacetate (■)
It is used in a proportion of 5.0 mol, preferably 0.5 to 3.0 mol, more preferably 0.7 to 1.5 mol. In a preferred embodiment, nisder acetoacetate (IX) is added to a solution or dispersion of the basic compound, or conversely, the basic compound is added all at once or in small portions to a solution of acetoacetate (IX). By adding, an anion of Nisder acetoacetate is formed without stirring, and then polyprenyl halide (■) is added thereto for reaction. The ratio of acetoacetate (IX) and polyprenyl halide (■) used is not critical, but the molar ratio of acetoacetate (■)/polyprenyl halide (■) is 1/2 to 20/1. , preferred, < is 415~
The ratio is 10/1, more preferably 1/1 to 5/1. When forming the anion of acetoacetate (■), under an inert gas atmosphere such as nitrogen, argon, etc.
It is preferable to carry out the reaction at a temperature of 10 DEG C. to +100 DEG C., preferably 10 DEG C. to +80 DEG C. This allows the desired anion to 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. Polyprenyl halide (■) was added to the anionic solution of acetoacetate (■) thus prepared.
Add and react. Depending on the reaction conditions used, the entire reaction may be able to proceed smoothly by adding polyprenyl halide (■) 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 (■) and the subsequent completion of the reaction is not critical, but is preferably within the range of -10°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 process 6. on the other hand,
If the reaction temperature is too high, undesirable side reactions will proceed.

From this point of view, it is preferable to employ a reaction temperature within the range of 0°C to 80°C. In order to complete the polyprenyl halide reaction, 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 hours. In order to check the progress of the reaction, it is convenient to follow the decrease of the raw material polyprenyl halide (■) by thin layer chromatography.
DeRuri is preferable.

After the reaction, the polyprenylketocarboxylic acid ester (X) can be easily isolated from the reaction mixture by using the separation method that has been conventionally used in the joint research of Kokyu. I am satisfied with my accomplishment. And Kuni chromatography is used on stool feathers. The solvent for this chromatography is the same as in the case of polyprenylamine (■) F'i'lj: )1''H. is used.

It is also possible to carry out this single PA' reaction directly to the next step of polyphrenylacetone (XI) synthesis reaction 1,6, and then to carry out the purification step.

Polyprenylketocarboxylic acid ester (X) can be saponified by applying a method conventionally used for the curing reaction of higher fatty acid esters. For example, the objective can be achieved by stirring the polyprenylketocarbonate ester (X) with sodium hydroxide or potassium hydroxide in aqueous methanol, aqueous ethanol or aqueous isoglopanol. What is Sodium Hydroxide 7? The fft of potassium hydroxide used is approximately 1.
0 to 20, 0 molar equivalents, preferably 1. 5 ~
1 0. Preferably, the amount is 0 mol, i. Hydrous alcohols such as those mentioned above are suitable as reaction solvents, but if the solubility of polyprenylketocarboxylic acid ester (X) is increased, hexano, pentane,
It is also preferable to add a small amount of a hydrocarbon solvent such as benzene or toluene. In order to make the saponification reaction proceed smoothly, the reaction temperature ranges from 0°C to the boiling point of the solvent used.
Preferably, it is desirable to employ a temperature within the range of 25 to 65°C. The time required for the reaction to be completed varies depending on the temperature considerations employed, but is generally within a range of approximately 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 at room temperature or under water-cooled conditions, and then the reaction solution is further removed. 11-3
Under moderately acidic conditions, a decarboxylation reaction automatically occurs to form polyprenylacetone (XI). 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 distilled off to obtain polyprenylacetone (
A crude product of XI) is obtained. Chromatography is preferably employed to purify this product. The chromatography conditions were as follows: polyprenylamine (
Almost the same conditions as in the case of Vl) are used. Examples of suitably used solvents include dimethylformamide, tetrahydrofuran, and diethyl ether. In order to allow 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 desirable to replace the reaction system with an inert gas such as nitrogen or argon. There is no particular restriction on the amount of solvent used, but it is generally about 5 to 5 parts by weight per 1 part by weight of polyprenylacetone 0a).
0 parts by weight of solvent are used, preferably 10 to 30 parts by weight. Particularly preferred examples of the Witzig reagent (Xl[) include the following compounds.

When carrying out the Witschig reaction, Witschig reagent (XI
It is necessary to form a phosphorylide by treating [) with a basic compound, and basic compounds preferably used for this purpose include, for example, n-butyllithium,
Methyllithium, sodium hydride, potassium hydride,
Examples include sodium methoxide and sodium ethoxide. After adding such a basic compound to the above-mentioned mortar, the temperature is about -30°C to +80°C, preferably -10°C.
While stirring at a temperature of ~+50°C, the Witschich reagent is added dropwise to this, and after the dropwise addition is completed, stirring is continued for an additional approximately 0.5 to 24 hours in the above temperature range to form a phosphorylide. can. The amount of the basic compound to be used in this case is preferably about 0.5 to 1.5 moles relative to the Witstech reagent (Xll). In this phosphorylide solution, polyprenylacetone (XI)'
in addition to about 0°C to 100°C, preferably 15°C to 80°C
By reacting with The reaction time required to complete this reaction is generally within the range of about 0.5 to 24 hours. The amount of Witschig reagent (XI[) used is 0.5 to 10% relative to polyprenylacetone (XI).
．． 0 molar equivalent, preferably 0.8 to 8.0 molar equivalent, more preferably 10 to 5.0 molar equivalent. The resulting polyprenylcarboxylic acid ester (X[) can be produced as 11f by various methods based on known separation and purification methods, but purification by chromatography is particularly convenient. As an adsorbent and developing solvent for chromatography, polyprenylamine 7 (Vl)
The adsorbents and developing solvents described above for the purification of .

The hydrolysis reaction of polyprenylcarboxylic acid ester (Xl[l) is carried out according to the method applied to the usual hydrolysis reaction of fatty acid esters. For example, polyprenylcarboxylic acid ester (X[n) k is prepared under reflux conditions for about 1 to 5 hours with about 2 to 5 times the molar amount of sodium dispersion relative to the polyprenylcarboxylic acid ester (■) in aqueous ethanol. By stirring, polyprenylcarboxylic acid (xIv) t- can be obtained in good yield, and it can be easily purified by chromatography using all the adsorbents and developing solvents described above in the case of purifying polyprenylamine (Vl). be able to.

Amide threat using polyprenylcarboxylic acid (vacuum) and amine (XV) can be carried out by a commonly known method. For example, it can be carried out using a dehydration condensation agent such as N,N'-dicyclohexylcarbodiimide, N,N'-diethylcarbodiimide, phosphorous acid trialkyl ester, phosphorus oxychloride, etc. Jishik cI-
,, Kishi 2. It is convenient to use carbodiimide; however, it is desirable to carry out this reaction in a solvent. Examples of solvents preferably used include halogenated hydrocarbon thread bath media such as methylene chloride and chloroform. The amount of solvent used is not critical, but is 2 to 100 times, preferably 5 to 50 times the weight of polyprenylcarboxylic acid (XM).

For the purpose of using a sufficiently dried solvent, approximately 1 mol of polyprenylcarboxylic acid (X[V) is sufficient. The reaction temperature is preferably in the range from -20°C to the Buddha point of the solvent, and more preferably in the range from 0°C to room temperature. Although the reaction time varies depending on the temperature conditions used, 1 to 2 hours is usually sufficient. In a preferred embodiment, dicyclohexylcarbodiimide is slowly added to a methylene chloride solution of polyprenylcarboxylic acid (XM) under water cooling, and after stirring for 15 to 30 minutes, amine (xv) is gradually added, and the mixture is slowly heated to room temperature. Warm up.

After pouring the solution obtained by separating the floating solids into cold water, the organic layer was separated and washed sequentially with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, and saturated saline solution. After complete drying, the solvent was distilled off. A crude product of prenylcarboxylic acid amide (■) is obtained. Purification of this product can be easily carried out by chromatography using the adsorbent and developing solvent described above for the purification of polyprenylamine (Vl).

Similar solvent, similar basic compound, similar reaction conditions (
temperatures, proportions of reactants used, etc.) and similar compounds are particularly preferably used.

The method of the present invention preserves the unique trans and cis configurations of the isoprene sites in polyprenyl compounds extracted from carp, cedar, etc./1 saturated isoprene unit without requiring a C5 chain extender. It is a product that enables the production of four individuals, and its industrial concept is large. In JP-A-58-83643, there is a polyprenyl fraction extracted from Himalayan cedar, which is listed in b0, and is a mixture of polyprenyl homologs, but it is not possible to produce dihydropolyprenyl alcohol from a mixture. If the method of the present invention is applied to the raw material mixture, it is possible to obtain a dihydroborigrenyl alcohol homolog mixture which exhibits essentially the same pattern of homologue distribution as that in the raw material mixture.

Hereinafter, the present invention will be specifically explained using examples of implementation and diagnosis. In addition, the IR analysis in Examples and Reference Examples was carried out using a liquid film, and the NMR analysis was carried out using TMS as an internal standard. Fluorescent ionization method fluorescent analysis (Ji”l)-MA
SS analysis) m/e value (d: ”H, +2C.

Corrected as 14N, 160.79Br fc Ih-c
be.

Reference Example 1 A three-necked flask was charged with 30 rtl of anhydrous tetrahydrofuran and 640 η of 50% sodium hydride, and while stirring at room temperature, 1.572 ml of ethyl acetoacetate was added dropwise.

After the intense generation of hydrogen gas became hidden, 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 was cooled to room temperature.

In addition to this, Example 7 described in JP-A No. 58-83643
4. A polyprenyl bromide synthesized according to iζ formula (■) in which X=Br and n in the group represented by A is 15.
3Of tetrahydrofuran (lQa#) solution was added dropwise and stirred overnight at room temperature. After distilling off the solvent from the reaction mixture using a rotary evaporator, the residue was poured into about 20 g of water and extracted with diethyl ether, and the resulting diethyl ether layer was washed successively with water, diluted hydrochloric acid, water, and sodium bicarbonate. The mixture was dried over anhydrous magnesium sulfate, and diethyl ether was distilled off using a rotary evaporator to obtain a yellow powder. 1. This yellow liquid substance. HP
The low-boiling components were distilled off by heating at 150°C for 30 minutes under reduced pressure, and the residue was subjected to silica gel column chromatography [hexane/ethyl acetate = 98/2 (volume ratio) was used as the developing solution]. Purified pale yellow liquid 2.48f
I got it. The analysis results of this product are shown below.

IR analysis: I 740.1715.1660.830
crn'4.11 (2H,q, -COs+CH2C
Ha) FD-MASS analysis: According to the analysis results of tn/e=1354 or higher, this pale yellow liquid is a polyprenyl ketocarboxylic acid in which R7=C2H5 and n in the group represented by A is 15 in formula (X). It was confirmed to be ethyl.

Next, this ethyl polyprenylketocarboxylate was mixed with 0.5 f of sodium hydroxide, 20 txl of ethanol, and 5 txl of water.
After adding it to the solution of d and stirring it under reflux conditions for 3 hours,
Most of the ethanol was distilled off using a rotary evaporator, the residue was poured into about 20 d of water, and concentrated hydrochloric acid was added little by little for about 2 d.
The mixture was made acidic 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. Silica gel column chromatography of kernels [
Purified by using S ether = 98/2 (volume ratio) as a developing solution with hexane/vinegar to form a slightly yellow viscous liquid 198
I got 2. The analysis result of this product is shown below.

IR analysis: 17] 5,1660,830an-11
H-NMR analysis: δl)"" 1.53 (s, 9H)
+ 1.62 (St 481 ().

C(l<1.7~2.4 (rn, 75H), 5.05
(1>r, 18H) FD-MASS analysis: m/e=
From the analysis results of 1282 or more, this slightly yellow liquid has the formula (X
It was confirmed that it was polyprenylacetone in which n in the group represented by 8 in I) was 15.

Next, add 40 tons of anhydrous tetrahydrofuran to a three-necked flask.
nl and 50% sodium hydride, and while stirring at room temperature, diethylphosphonoacetate ethyl ((C
2HsO)2PCH+C02C2Hs) i, of
A solution of anhydrous tetrahydrofuran (C = i-1t) was added dropwise. After the addition was completed, the mixture was further chilled at Kashibuchi for 1 hour, and then the previously synthesized formula (XI) was added. 3 and polyprenylacetone 1.92f in which n in the group represented by A is 15 is anhydrous tetrahydrofuran] Om
e K kJ )j ￥ Then add the solution dropwise to 7 at room temperature, and after the completion of dropping, continue at room temperature for 30 minutes, then at 50-60t; 3 hours 4
i;l stirred. After cooling to room temperature and adding about 1 g of water, the solvent was distilled off on a rotary evaporator and the residue had a
Me water was added and extracted with hexane. The hexane layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the hexane was distilled off to obtain a yellow liquid. This liquid was purified by silica gel column chromatography (hexane/ethyl acetate-98/2 volume ratio was used as a developing solution) to obtain a colorless liquid of 1.62F. The following analysis results confirmed that this product was polyprenylcarboxylic acid ethyl having the formula (■) where R7=C2H5 and n in the group represented by A was 15.

IR analysis: 1715, 1640, 1440, 1385,
12] 0゜1135, 830, 790cm-1pl
n IH-NMR analysis: δ i, 20(t, 3H), 1.5
3 (s, 9H).

Cα4 1.62 (S, 48H), 1.7-2.4' (ln9
75)I), 4.06((112H), 5.06(b
r, 18H), 5.56 (br, IH) FD-MASS
Analysis: m/e = 1352 1,502 of the above ethyl polyprenylcarboxylate was then added to a solution of 0,132 sodium hydroxide, 3 me of water and 27 ml of ethanol, stirred at reflux temperature for 5 hours, and then evaporated in a rotary evaporator to remove most of the ethyl carboxylate. Distill the ethanol, add 3Qml of water, and dilute with diluted hydrochloric acid water.
was brought to about 5 and then extracted with hexane. The hexane layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain a yellow liquid 1.3.5 S'.

The following analysis results confirmed that this product was a polyprenylcarboxylic acid in which n in the group represented by A in formula (XIV) was 15.

IR analysis: 3600-2900 (weak).

2800-2400 (weak), 1685, 166
0 (shoulder).

1635.1435, 1370, 1285, 1245.
830tan-1pn1 1H-NMR analysis: δ 1.53 (S, 9H), 1.6
2 (S, 48H) ICα4 1.7-2.4 (m, 75H), 5.06 (br, 18
)I).

5.63 (br, IH), ~11.5 (br, IH)
Next, the above polyprenylcarboxylic acid 1 was added to a three-necked flask.
．． 32F and 10 ml of methylene chloride were added, and N,N'-dicyclohexylcarbodiimide 206 was added under cooling with ice water.
After slowly adding (2) and stirring for 15 minutes, a solution of 73 mg of diethylamine in methylene chloride (2 ml) was added dropwise little by little using a syringe. After warming the reaction mixture to room temperature while stirring, the suspended solids were separated from P, and the r solution was poured into cold water IQm.
The organic layer was washed successively with 3% hydrochloric acid, water, saturated sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a yellow liquid. Obtained. This product was purified by silica gel column chromatography [using hexane/ethyl acetate-97/3 (volume ratio] as the developing solution) to obtain a colorless liquid 1.12F.The following analysis results showed that formula 9 R in (■)
'= R3= C2H5, n in the group represented by A is 15
It was confirmed that it was a polyprenylcarboxylic acid amide.

IR analysis: 1660 (sboulder), 1620
,1440,1370゜12.60,1120.830
cm-'pm NMR analysis: δ 1. ．． 05(t, 6H), 1.53(
S, 9H).

Cα4 1.62 (S, 48H), 1.7-2.5 (
m, 75H), 3.26 (q.

41() + 5-05 (br + ] 8H)
+ 5.72 (br,] IH) FD-MASS analysis: tn/e=1379 By the same operation, in formula (■), X=Br, 11 in the group represented by A is other than 15 between 11 and 19 Each polyprenylcarboxylic acid amide of the formula (■) where R' = R3 = C2H5 was synthesized by selecting the corresponding value of n from each polyprenyl bromide having the value of . Their yield is above n-15, R1=R3=C
The polyprenylcarboxylic acid amide of 2H5 was synthesized and was almost the same as that of ζmaai. The characteristic absorption of their IR spectra and the characteristic signal of their 'H-NMR spectra are the above n-15, R', at that position:
Consistent with that of R3=C2H5O polyprenylcarboxylic acid amide.

Example 1 Anhydrous diethyl ether in a three-necked flask 10. In the formula (■) synthesized in Reference Example 1 by adding Wl and 40 ~ lithium aluminum hydride and cooling with ice water, R'=R''=
C2Hs, anhydrous diethyl ether (5
m/) solution was added dropwise, and the mixture was heated under reflux for 5 hours. Cool with ice water and stir vigorously until 90 Tn! Add water from Step 7,
30 minutes! i: After continued stirring, the mixture was filtered through a glass filter, and the white residue was thoroughly washed with dienal ether. The tear fluid and washing solution were combined and the solvent was distilled off under reduced pressure to obtain a slightly yellow liquid.

This product was purified by silica gel column chromatography [using hexane/ethanol-9515 (volume ratio) as a developing solution] to obtain a colorless liquid of 0.91r.

According to the analysis results below, this product has R1=
It was confirmed that R2=C2H5, a polyprenylamine in which n in the group represented by A is 15.

IR analysis: 1660, 1440, 1375, 1190,
1160゜1060.1050,830crn-''H
-NMR analysis: δppin O,93(t,6H),
1.5-1.8 (60H).

tJ4 1.8-2.3 (m, 72H), 2.3s (q, 4H)
.

2.92 (d, 2H), 4.9-5.3 (br, 191
() FD-MASS analysis: m/e = 1365 Then, R11 ((BINAP) (
1,5-cyclooctadiene))Q! 047
．． After adding 5 mJ of anhydrous tetrahydro 7 run and dissolving it, a solution of the polyprenylamine 0.85 P in anhydrous tetrahydrofuran (5 m/) was added, and the mixture was heated and stirred at 60° C. for 20 hours under a nitrogen atmosphere. After cooling, the solvent was distilled off under reduced pressure to obtain a 0.85F liquid material. According to the following analysis results, this product has the formula (III).
It was confirmed that R2=CIH5 is an enamine in which n in the group represented by A is 15.

IR analysis: 1660 (Shoulder), 1645
,1440°137('1.,1240,1090,9
30.8306n''H-NMR analysis: δppm 0
．． 93 (d, 3H), 1.00 (t, 6H).

CDα3 x, 5a (s, 914), x, 62 (s, 48H).

1.7-2.3(73)1), 2.88(q, 4H).

3.97 (dd, IH), 5.06 (br, 18H).

5.76(d, II()) This enamine o, sor was dissolved in 30 mJ of tetrahydrofuran.
To the mixture was added 100 ml of dihydrochloric acid, stirred at room temperature for 3 hours, added 100 ml of drained water, and evaporated the solvent with hexane to obtain 0.729 g of a yellow liquid. This product was subjected to silica gel column chromatography [hexane/acetate ether = 907
1 (volume ratio) was used as a developing solution] to obtain colorless liquid O, 632. This product was confirmed to be a polyprenyl aldehyde in which n in the group represented by A in formula (V) is 15, based on the following analysis results.

IR analysis: 3600 (weak), 2950, 291
0,2850°2730 (Weak), 1725,16
60,1440,1375°830crn” IH-NMR analysis: 619m0.9] (d, 3H), 1
．． 60 (8,9H).

Cα4 1.68C8, 48H), 5.05 (b, 18H), 9
．． 70 (t, IH) FD-MASS analysis: m/e=13
10 Next, dissolve 0.60 f of the above polyprenyl aldehyde in 5 ml of hexane, add 2.5 ml of ethanol, and cool with ice water while stirring.
After adding P and reacting for 1 hour, a saturated aqueous ammonium chloride solution was added. After adding water, the hexane layer was separated, and the aqueous layer was extracted twice with hexane. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a colorless liquid of 0.58F. This product was subjected to silica gel column chromatography [hexane/ethyl acetate-90:
10 (volume ratio) as a developing solution] and purified by the formula (
Dihydropolyprenyl alcohol 0.52f4c in which n in the group represented by A in 1) is 15 was obtained. The results of IR analysis, NMR analysis and FD-MASS analysis of this product were as follows.

IR analysis: 3320, 2920, 2850, 1440
, 1376°1060.830crn' pn1 1H-NMR analysis: δ 0.91 (d, 3H), 1.
60 (s, 9H).

CC/4 1.68 (S, 48H), 1.10-1.80 (m, 5
H).

2.03 (b, 70H), 3.66 (m, 2H),
5.1 o(b, 18H) 13C-NMR (pprr
v strength): 16.006/640°17.679/35
3,19.5571548,23.43(+/6330
゜25.3081567.25.6771542.26
．． 43615166゜26.6991548,26.8
25/492, 29.3161528゜32.021/
456, 32.24515500, 37.548158
2゜39.757/683 + 40.029154]
, 61.2411551.

124.214/445, 124.282/463
, 124.4481505°124.993/499
, ] 25.07] 15242, 131.2] 0/2
13°134.937/290,135.005/34
9,135.229/3567°135.365/43
0° FD-MASS analysis: m/e = 1332 n in the group represented by A synthesized by the same procedure as in Reference Example 1
is a value greater than or equal to 15 between 11 and 19, and R'= R
A dihydropolyprenyl alcohol of formula (1) having a corresponding value of n was synthesized from a polyprenylamide of formula (■) where 2=02H5.

Their yields were approximately the same as those obtained when dihydropolyprenyl alcohol with n=15 was synthesized. In addition, the results of their IR analysis and NMR analysis are as follows: n=1
The position of absorption coincided with that of dihydropolyprenyl alcohol in No. 5.

Examples 2 to 7 (Synthesis of enamine of formula (Hl) or imine of formula (IV)) Polyprenylcarboxylic acid in which n in the group represented by A is 15 in formula CM synthesized according to Reference Example 1 1.3
2 t (] mxnol ) and the amine (I
mmol) in the same manner as in Reference Example 1 to synthesize the corresponding polyprenylcarboxylic acid amide, which was reduced in the same manner as in Example 1, and further isomerized by a hydrogen transfer reaction to obtain the corresponding formula ( Synthesize the enamine of In) or the imine of formula (IV). However, in Examples 6 and 7, the temperature of the hydrogen transfer reaction was set to 40°C. The substituents R1, R3 of the raw material amine and the formula (III
) or imine of formula (IV) are shown in Table 1.

Table 1 Example Amine of formula (XV) Produced enamine (III)
Also 2 CHa CHa O, 87 3n-C4H9n-c4H9o, 94 4 +cH2+o, s s 5 C6H6CH2C6H5CH20,926C6H5
HO,08 7cyclo-C6H11HO,84 The analysis results of the produced enamine (III) and imine (IV) are shown below.

Enamine (R'=R2=CH3) IR analysis of Example 2 1660 (shoulder), 1650, 1440° 1370.1065,930,830tYn-""H-
NMR analysis: δppHl c Dc 130.91 (d + 3I() 11.5
5 (S + 9H) +1.63 (S, 48H)
, 1.7-2.3 (73H), 2.50 (S
, 6H).

4, o3 (dd, IH), 5. o6 (br, 1sH)
, 5.5o(d,IH) Enamine of Example 3 (R”R
2=n-C4H9) IR analysis:] 660 (Shoul
der), 1645, 1440° 1370.1240.
1090,930,830crn ''H-NMR min 1
i: δppn13.96 (da, IH).

Dc13 5.06 (br, ]8f(), 5.75(d, IH) Actual ga example 4 o: r-nami7 [ltz + R2-(
-CH,1-)-4) IR analysis: ]660(Si1
0ulder), 1645, 1440°1370.12
40.1090,930,830c1n'”H-NIV
iR analysis: δppn+ CDQ! 30.93(d, 3H), i, 53(s).

1.5-2.3 (134H) including 1.62 (S)
.

2.6-3.1 (m, 4H), 3.96 (d
d, IH).

5.05 (br, 18H), 5.76 (d, IH) Enamine of Example 5 (R' = R'' = CH3C6H5) I
R analysis:] 660 (SIIOulder), 16
45.1600.1500゜1440.1370,93
0,830,750,690 on '1H-NMR analysis? δppm CD (Ja i, 5-1.8 (60H).

1.8-2.2 (73H), 3.60 (s, 4H), 3
．． 96 (dd, IH).

5.06 (br, 18H), 5.76 (d, IH
), 7.1-7.6(m, 101() Example 6 imine (R” = C6H5) IR analysis: 166(1(Sh
OL] bler), 1645, 1595, 1440°1
370.830,750,695(7)-1') f-N
MR analysis: δCEo s 1 ' 3 (s), l
0.85 to 2.6 (]35H) including -62 ('')
, 5.06 (br, 18H).

6.3-7.3 (m, 5H), 7.83 (i
Tl, IH) Implementation (3'U Immi of 7:' (R1=
CyC1o-c sHt t ) IR analysis' l 6
60 + 1440.1370, 830crn-''
J, (-NMR analysis = δppm cDα35.o6(br,]l).

7.23 (m, I H) Of) K C1) Carbon content of nocihydro f4 recrenyl alcohol The enamine or imine synthesized above was used in the form shown in Table 2, and processed in the same manner as in Example 1. By ice decomposition and further reduction, dihydropolyprenyl alcohol in which n in the group represented by A in formula (1) is 15 was obtained in the following yield.

Table 2 2 CHs CHs O,800,533n-C4Hs
n-C4H90,820,494-C-CH2-)4
0.80 0.505 C6H5CH2C6H5CH2
0,850,47 to 6 C5Hs O,800,47 Rice In order to obtain the required amount of imine, the above operation (1) was carried out on an expanded scale.

I R of these produced dihydropolyprenyl alcohols
The results of analysis, NMR analysis and FD-MASS analysis were consistent with those of dihydropolyprenyl alcohol with n=15 synthesized in Example.

In addition, the number of cis-isoprene units (n
) is a value between 11 and J9 other than 15, using the same polyprenylcarboxylic acid amide as above, the formula (1
) dihydropolyprenyl alcohol was synthesized. The results of the IR analysis and NMR analysis agreed with those of the n-15 dihydropolyprenyl alcohol synthesized in Example 1 in terms of the absorption position.

Patent applicant RiRashi Co., Ltd. Agent: Patent Attorney Ken Honda

Claims (1)

[Claims] 1. General formula % Formula % [In the formula, R1 and R2 each represent a lower alkyl group, a cycloalkyl group, an aryl group, or an aralkyl group, or R1 and R2 together represent a carbon atom number of 2 ~
5 represents an alkylene group, A represents a group represented by the formula, where -CI'N2-6C-C
jlz- represents a trans-isogrene unit, and 11 is an integer from 11 to 19. ] The compound represented by is hydrolyzed in the presence of an acid catalyst to obtain an aldehyde represented by the general formula (wherein A is as defined above), and the --cno group of the aldehyde is converted to 10H.
Method for producing dihydropolyprenyl alcohol represented by the general formula (3% formula % (in the formula, A is as defined above)) characterized by conversion to a 20H group 0 2, general formula [in the formula R1 represents a lower alkyl group, a cycloalkyl group, an aryl group, or an aralkyl group; R3 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, or an aralkyl group; or R1 and R3 together represent a group having 2 to 2 carbon atoms; 5 represents an alkylene group, A represents a group represented by the formula, where -Cm-C=C-CI-
h- represents a cis-isoprene unit, and n is 11-1
It is an integer of 9. ] Polyprenylamine represented by the general formula (wherein R1 and A are as defined above, and R2 is the same as R3 when the above R3 is other than a hydrogen atom) isomerically and then hydrolyzed in the presence of an acid catalyst to obtain an aldehyde represented by the general formula (wherein A is as defined above), and convert the -CHO group of the aldehyde into a monodentate OH
A process for producing dihydropolyprenyl alcohol represented by the general formula % (wherein A is as defined above), characterized by converting it into a dihydropolyprenyl alcohol. 3. General formula [wherein R1 is a lower alkyl group, a cycloalkyl group 1
Aryl group or aralkyl group R3 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group or an aralkyl group, or R' and t taken together represent an alkylene group having 2 to 5 carbon atoms, and A represents the formula trans-isoturene unit, -〇H2-A=b
yl-(represents a cis-isoprene unit, 11 is 11
It is an integer between ~19. ] The amide represented by is reduced to a polyprenylamine represented by the general formula), and the polyprenylamine is converted into a polyprenylamine represented by the general formula (where R1 and A are as defined above,
is the same as the above R3 when R3 is other than a hydrogen atom. ) isomerized into a compound represented by the formula and then hydrolyzed in the presence of an acid catalyst to form the general formula) A-C)h-crystal-C-CHO (wherein A is as defined above). The aldehyde shown above is replaced with -CH0 group by -CH20
A method for producing dihydropolyprenyl alcohol represented by the general formula % (wherein A is as defined above), characterized by converting it into an H group.