JPH09124525A - Production of 3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaen-1-ol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as a preventing and treating agent for immunological function insufficiency on an industrial scale in high yield at a low cost by a specific method including a 5C-extension reaction of an allyl alcohol compound. SOLUTION: A compound of the formula I (A is a hydroxyl-protecting group) is reacted with 2-methyl-3,3-dimethoxy-1-butene and the carbonyl group of the resultant compound is reduced to extend 5 carbon atoms. The 5C-extension reaction is repeated m-times. The product is halogenated to a compound of the formula II (X is a halogen; (m) is 1-4), the obtained compound is reacted with a compound of the formula III (R<1> is an alkyl or an aryl) and finally the reaction product is desulfonated and deprotected to obtain the objective compound of the formula IV. The reduction of the carbonyl group in the 5C extension reaction is carried out e.g. by Meerwein-Ponndorf reduction using a secondary alcohol and an aluminum alkoxide. The compound of the formula II is preferably produced from citronellol.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to 3,7,11,1
5,19,23,27-heptamethyl-6,10,1
The present invention relates to a method for producing 4,18,22,26-octacosahexaen-1-ol (hereinafter abbreviated as DHP).

[0002]

2. Description of the Related Art DHP has been reported to be useful as a preventive or therapeutic drug for diseases caused by human or animal immune dysfunction (Japanese Patent Laid-Open No. 169724/1987).

This DHP, which is a kind of polyprenol, is structurally characterized in that the β and γ-positions of the hydroxyl groups are saturated and that all double bonds in the molecule have a trans configuration. Has become.

As a method for producing DHP having such a structural feature, only the method of the route shown in the following scheme 1 has been proposed (JP-A-59-7353).
No. 3).

[0005]

Embedded image The method shown in this scheme 1 is a method of obtaining a DHP of the formula (1) by extending the starting compound of the formula (10) by 2 carbons. Here, the compound of formula (10) as a starting material can be synthesized by the method shown in Scheme 2 below (Isler et al., He.
lv. Chim. Acta., 42 , 2616 (1959)).

[0006]

Embedded image By the way, in Scheme 2, in order to obtain the compound of the formula (10), all the double bonds of the hexaprenol of the formula (20) as a raw material must be in the trans-type configuration. Nols do not exist in nature and are not readily available raw materials.

Therefore, it is considered that the compound of formula (10) is preferably produced by using a compound having a short prenyl unit which is easily available as a natural product or a synthetic product, for example, geraniol as a starting material. In this case, two synthetic routes are possible. One is a method of partially extending the carbon chain by partially utilizing the method shown in Scheme 2 to synthesize the compound of formula (10) as shown in Scheme 3, and the other is a method of reacting the compound of formula (40) as a key reaction. ) Is utilized to oxidize geranyl acetate with selenium dioxide and a coupling reaction with butyllithium to synthesize hexaprenol of the formula (20) as shown in Scheme 4, which is used as a starting material in Scheme 2. Method (J.Chem.Soc.Perkin
Trans I, 761 (1981)).

[0008]

Embedded image

[0009]

Embedded image

[0010]

However, in the case of the method shown in Scheme 3, in order to carry out an extension of 5 carbons corresponding to one prenyl unit [compound of formula (33) → compound of formula (38)], Since 6 steps are required, it takes 2 steps to obtain the compound of formula (10) from geraniol.
There is a problem that the number of steps is 0 or more, the synthesis operation is complicated, and the total yield is low. Furthermore, equation (3
In the step of converting the compound of 5) into the compound of formula (36), there is a problem that double bonds at the β and γ-positions of the brom group also form cis isomers. As a result, when the compound of formula (10) is produced by the method of scheme 3, the yield of the compound having all trans-type double bonds is extremely low. Furthermore, it is very difficult from the present state of the art to efficiently industrially separate and obtain the compound of formula (10) from a mixture with an isomer in which the double bond has a cis configuration.

On the other hand, in the case of the method described in Scheme 4, toxic selenium dioxide is used in the step of obtaining the compound of formula (41) and the yield is as low as 44%. The desulfonation reaction of the compound of 1) is carried out under a reaction condition of an extremely low temperature of -78 ° C, and there is a problem that it is difficult to carry out industrially. Therefore, as the desulfonation reaction, it is possible to carry out a reductive desulfonation reaction using general metal lithium for the compound of the formula (47), but in this case, a protecting group is introduced. Nevertheless, as shown in Scheme 5 below, there is a problem in that the alcohol moiety competitively causes an elimination reaction and a compound of formula (51) is by-produced.

[0012]

Embedded image As described above, the compound of the formula (10), which is a raw material for producing DHP, is used in Scheme 3 or Scheme 4
It is difficult to manufacture at low cost and in good yield using the method described above.

As a method for producing DHP, β, an alcohol, can be directly produced from the corresponding polyprenyl alcohol.
A method of selectively partially hydrogenating the double bond at the γ-position is also conceivable, but such hydrogenation generally has poor regioselectivity, so even other double bonds that do not want to be reduced are excessively hydrogenated. As a result, it is difficult to selectively obtain only DHP.

The present invention is intended to solve the above-mentioned problems of the prior art, and to obtain DHP at low cost and in good yield,
It is an object to provide a method that can be industrially manufactured.

[0015]

According to the present invention, the above-mentioned problems are solved by the formula (1)

[0016]

Embedded image In the method for producing 3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaen-1-ol represented by: Step (A) Formula (2)

[0017]

Embedded image (Wherein A represents a hydroxyl-protecting group) is reacted with 2-methyl-3,3-dimethoxy-1-butene, and the carbonyl group of the compound is reduced. The formula (3)

[0018]

Embedded image (In the formula, m represents an integer of 1 to 4); Step (B): halogenating the compound of formula (3) to formula (4);

[0019]

Embedded image (In the formula, X represents a halogen atom.) Step of converting into a compound; Step (C) Compound of formula (4) and formula (5)

[0020]

Embedded image (Wherein R ¹ represents an alkyl group or an aryl group) and reacted with a compound of the formula (6)

[0021]

Embedded image And a step (D) of obtaining a compound of formula (1) by desulfonation and deprotection of the compound of formula (6). Will be solved by.

[0022]

BEST MODE FOR CARRYING OUT THE INVENTION The manufacturing method of the present invention will be described in detail for each step.

Step (A) In the present invention, the compound of the formula (2) is first treated with 2-
Methyl-3,3-dimethoxy-1-butene is reacted,
The compound of formula (3) is obtained by performing a 5-carbon extension reaction involving reducing the carbonyl group of the obtained compound m times (where m is an integer of 1 to 4).

Examples of the hydroxyl-protecting group represented by A in the formula (2) include known protecting groups used for the purpose of protecting alcohols, such as acetyl group, tetrahydropyranyl group and benzyl. Group, a t-butyldimethylsilyl group, and the like. Among them,
A benzyl group that can be simultaneously deprotected during the desulfonation reaction in step (D) described below is particularly preferable.

The 5-carbon extension reaction of this step will be described in more detail according to scheme 6.

[0026]

Embedded image As shown in Scheme 6, in the 5-carbon extension reaction of this step, first, the compound of the formula (2) is treated with 2-methyl-
3,3-dimethoxy-1-butene was reacted to obtain the compound of formula (6
The compound of 1) is obtained. Then, the compound of formula (61) is converted to the compound of formula (62) by reducing the carbonyl group. The compound of the formula (62) has the formula (3) in which m = 1.
Corresponding to the compound of

Next, the obtained compound of formula (62) is subjected to the same 5-carbon extension reaction as in the case of the compound of formula (2) to give a compound of formula (3) with m = 2. To obtain a compound of formula (64)

Further, the same 5-carbon extension reaction is repeated on the obtained compound of formula (64) to give a compound of formula (66) [corresponding to a compound of formula (3) with m = 3], A compound of formula (68) [corresponding to a compound of formula (3) with m = 4] is obtained.

The 2-methyl-3,3-dimethoxy-1-butene used in this 5-carbon extension reaction is a known compound, for example, J. Am. Chem. Soc., 92 , 4663 (1970).
It can be easily synthesized by the method described in.

Further, equations (2), (62), and (64)
Alternatively, the amount of 2-methyl-3,3-dimethoxy-1-butene used with respect to the compound of formula (66) (hereinafter abbreviated as substrate) is preferably 1 to 10 molar equivalents, more preferably 1. It is 1 to 1.5 molar equivalents.

Substrate and 2-methyl-3,3-dimethoxy-
An acid catalyst can be preferably used in the reaction with 1-butene. As such an acid catalyst, various commonly used mineral acids and organic acids can be used, and examples thereof include concentrated sulfuric acid, phosphoric acid and p-toluenesulfonic acid. Particularly, a pyridine salt of p-toluenesulfonic acid can be preferably used. The amount of the acid catalyst used is usually 0.01 to 10% by weight, preferably 0.05 to 1% by weight, based on the substrate.

Substrate and 2-methyl-3,3-dimethoxy-
A solvent is preferably used in the reaction with 1-butene. As the solvent, aromatic solvents such as benzene, toluene and xylene can be preferably used.
Of these, toluene can be preferably used. The amount of the solvent used is preferably 0.5 to 20 times by weight, more preferably 2 to 8 times by weight, the amount of the substrate.

Substrate and 2-methyl-3,3-dimethoxy-
The reaction temperature during the reaction with 1-butene is usually 50 to 15
The temperature is 0 ° C, preferably 80 to 110 ° C. The reaction time is usually 1 to 5 hours.

During the reaction of the substrate with 2-methyl-3,3-dimethoxy-1-butene, methanol is produced as the reaction progresses. Therefore, in order to proceed the reaction efficiently, it is preferable to carry out the reaction while distilling the produced methanol out of the reaction system.

The reduction of the compounds of formula (61), formula (63), formula (65) and formula (67) can be carried out by a known method. For example, these compounds can be prepared in high yield by the Meerbain-Pondruph reduction method using a secondary alcohol and an aluminum alkoxide, respectively.
2), formula (64), formula (66) and formula (68).

Here, the meabain-Pondruph reduction reaction is carried out by using the substrate and 2-methyl-3,3-dimethoxy-1-
The reaction mixture with butene can be obtained by separating and obtaining the compound to be reduced according to a conventional method, but the reaction mixture can be directly subjected to the reduction reaction from the viewpoint of the yield of the target compound and the simplification of the operation. preferable.

The secondary alcohol used in this reduction reaction is, for example, isopropanol or 2-
Butanol and the like can be mentioned, of which isopropanol is preferred.

The amount of secondary alcohol used is calculated by the formula (6
1), the compound of formula (63), formula (65) or formula (67), preferably 1 to 10 times by weight, more preferably 2 times.
6 times by weight.

As the aluminum alkoxide, for example, aluminum ethoxide, aluminum isopropoxide, aluminum 2-butoxide and the like can be mentioned, and aluminum isopropoxide which is inexpensive and easy to obtain is preferable.

The amount of the aluminum alkoxide used is preferably 5 to 100 mol%, more preferably 10 to 40 mol% based on the compound of formula (61), formula (63), formula (65) or formula (67). Is.

The reduction reaction temperature is usually 50 to 150.
C., preferably in the range of 80 to 110.degree.

Acetone is produced along with the progress of the reduction reaction. Therefore, in order to proceed the reaction efficiently, it is preferable to carry out the reaction while distilling acetone out of the reaction system.

After completion of the reaction, the reaction mixture was added with an excess amount of dilute hydrochloric acid with respect to the aluminum alkoxide used in the reaction.
An aqueous acid solution such as dilute sulfuric acid is added to decompose the aluminum alkoxide, and the obtained organic layer is separated. The compound of formula (3) is obtained by treating this organic layer according to a conventional method.

95% or more of the double bonds newly formed by the above-mentioned 5-carbon extension reaction are trans-type. Therefore, even if the 5-carbon extension reaction is repeated, the proportion of cis isomer produced as a by-product can be suppressed to a very low level.

The compound of formula (2) can be produced from easily available citronellol according to steps (a), (b) and (c) as shown in scheme 7.

[0046]

Embedded image (Step (a)) First, the citronellol of the formula (70) is
By introducing a protecting group A into the hydroxyl group, the formula (71)
To the compound.

The method of introducing the protective group A is a known method depending on each protective group, for example, the literature [Gree.
n `` Protective Groups in Organic Synthesis (2nd E
dition, John Wiley & Sons (1991)) ”] and the like. For example, when introducing a benzyl group as a protecting group, sodium hydroxide,
It is economically advantageous to react benzyl halides such as benzyl chloride and benzyl bromide with citronellol in an aqueous solution of an alkali compound such as an alkali metal hydroxide such as potassium hydroxide in the presence of a phase transfer catalyst. is there.

In this case, the concentration of the alkaline compound in the alkaline aqueous solution is preferably 40 to 50% by weight. Also,
The amount of the alkali compound used is preferably 1 to 10 molar equivalents, more preferably 3 to 5 molar equivalents, relative to citronellol. Further, it is sufficient to use a benzyl halide in an amount that is slightly excessive in molar equivalent with respect to citronellol.

As the phase transfer catalyst, for example, quaternary ammonium salts such as tetrabutylammonium chloride, tetrabutylammonium bromide and tetrabutylammonium sulfate can be preferably used. The amount of the phase transfer catalyst used is not particularly limited, but it may be usually set to an amount that provides a concentration within the range of 0.01 to 1 mol% with respect to the reaction mixture.

The reaction temperature is usually set in the range of 0 to 100 ° C, preferably 40 to 60 ° C. The reaction time is usually 1 to 10 hours.

After completion of the reaction, the reaction mixture is extracted with an organic solvent such as hexane, toluene, isopropyl ether,
The compound of formula (71) is obtained by separation treatment by a conventional method.

(Step (b)) Next, the compound of formula (71) is converted to the compound of formula (72) by reacting it with an epoxidizing agent.

Here, as the epoxidizing agent, for example,
Organic peroxides such as metachloroperbenzoic acid, monoperphthalic acid, t-butyl hydroperoxide, peroxides such as hydrogen peroxide, and air can be used, but they are industrially easy to handle. Thus, t-butyl hydroperoxide can be preferably used. As the t-butyl hydroperoxide, those commercially available as a 70% aqueous solution or a toluene solution can be preferably used.

It is sufficient to use the epoxidizing agent in such an amount that a slight molar equivalent excess is used with respect to the compound of the formula (71).

Upon epoxidation, it is preferable to use a metal catalyst such as dioxobis (acetylacetonato) molybdenum or vanadium oxide as a catalyst for promoting the reaction. The amount of such a metal catalyst used is appropriately adjusted in consideration of the reaction time and the reaction selectivity, but is preferably 0.01 to 10% by weight, more preferably 0.1% by weight relative to the compound of the formula (71). It is from 05 to 1% by weight.

A solvent is preferably used for the epoxidation. As such a solvent, aromatic solvents such as benzene and toluene can be preferably used, and among them, toluene is preferable. The amount of such a solvent to be used is preferably 0.5-
It is 10 times by weight, more preferably 2.0 to 5 times by weight.

The reaction temperature for epoxidation is usually 50 to 15
The temperature is 0 ° C, preferably 70 to 100 ° C. Further, the reaction time, the type and amount of the solvent used, the reaction temperature,
It depends on the type and amount of the catalyst used, but usually 1 to
20 hours.

After the reaction is completed, the reaction mixture is decomposed with a reducing agent such as hydrosulfite and sodium sulfite to decompose the excess epoxidizing agent, extracted with an organic solvent such as hexane, toluene and diisopropyl ether, and separated by a conventional method. Upon treatment, the compound of formula (72) is obtained.

(Step (c)) Next, the compound of formula (72) is converted to the compound of formula (2) by rearranging the epoxy group thereof into allyl alcohol.

Here, the rearrangement reaction can be carried out under known reaction conditions, for example, by heating and refluxing aluminum isopropoxide as a catalyst in toluene to achieve a high yield (Synthesis, 467). (1979)).

By the above steps (a) to (c), the formula (2) is obtained.
The compound can be obtained industrially efficiently.

Step (B) The compound of formula (3) obtained in step (A) is halogenated to be converted to the compound of formula (4). Further, examples of the halogen atom represented by X in the formula (3) include a chlorine atom and a bromine atom.

The halogenation can be carried out by a known method of converting an alcohol into a halide. For example, thionyl chloride or the like in a solvent such as isopropyl ether can be used according to the method described in JP-A-54-76507. It can be carried out by acting a halogenating agent on the compound of formula (2). Thereby, the compound of formula (3) can be obtained in high yield.

The amount of halogenating agent used is preferably 0.9 to 2 molar equivalents, more preferably 1.0 to 1.8 molar equivalents, relative to the compound of formula (3). The amount of the solvent used is not particularly limited, but is usually 0.5 to 5 times by weight the amount of the compound of the formula (3). The halogenation temperature is usually -20 to 50 ° C, and the reaction time is usually 0.5.
~ 24 hours.

Step (C) Next, the compound of formula (4) obtained in step (B) is reacted with the compound of formula (5) to obtain the compound of formula (6).

In the compound of the formula (5), the alkyl group represented by R ¹ is preferably a lower alkyl group such as methyl group, ethyl group and butyl group, and the aryl group is phenyl group, tolyl group and naphthyl group. Aromatic hydrocarbon groups such as groups are preferred. These alkyl groups or aryl groups may be substituted with various substituents as long as they do not adversely affect the reaction.

The reaction of the compound of formula (4) with the compound of formula (5) can be carried out according to known reaction conditions, for example, dimethylformamide, dimethylsulfoxide, dimethylimidazolidinone, N-methylpyrrolidone and the like. A base such as sodium methylate, sodium t-butoxide, potassium t-butoxide, etc. may be allowed to act in an aprotic polar solvent, whereby a compound of formula (6) can be obtained in high yield.

The amount of the base used is preferably 0.8 to 4 molar equivalents, more preferably 1.
It is 0 to 2 molar equivalents.

The amount of the compound of formula (5) used is preferably 0.5 to 2 molar equivalents, more preferably 0.8 to 1.2 molar equivalents, relative to the compound of formula (4). .

Although the amount of the aprotic polar solvent used is not particularly limited, it is usually preferably 0.5 to 10 times the weight of the compound of the formula (4).

The reaction temperature is usually -20 to 50 ° C, and the reaction time is usually 1 to 24 hours.

The compound of formula (5) is a known compound, for example, J. Chem. Soc. PerkinTrans I, 761 (1981).
It can be obtained by brominating the corresponding polyprenyl alcohol with phosphorus tribromide and then reacting it with a sulfinic acid salt such as sodium benzenesulfinate or sodium toluenesulfinate according to the method described in 1. Specifically, from readily available prenol, geraniol, farnesol and geranylgeraniol, compounds of formula (5) corresponding to cases where m is 4, 3, 2 and 1, respectively, can be obtained.

Step (D) The compound of formula (6) obtained in step (C) is converted to DHP by desulfonation and further deprotection. Here, the desulfonation and the deprotection can be carried out in two steps and sequentially, but it is preferable from the industrial viewpoint that the deprotection is carried out simultaneously with the desulfonation after appropriately selecting a protecting group.

Desulfonation (and deprotection) of the compound of the formula (6) can be carried out, for example, by a method of reacting an alkali metal in alcohol, a method of reacting an alkali metal in a lower amine (so-called Birch reduction), metal hydrogen. A method of acting a compound, a method of acting an amalgam of an alkali metal,
It can be carried out by a known desulfonation method such as a method of reacting an alkali metal with a polycyclic aromatic compound, but among them, it is preferable to use an alkali metal and a polycyclic aromatic compound.

As the alkali metal, for example, lithium, sodium, potassium or the like can be used. Further, as the polycyclic aromatic compound, naphthalene, anthracene, biphenyl and the like can be used.
From the viewpoint of economy and ease of handling, it is desirable to use sodium as the alkali metal and naphthalene as the polycyclic aromatic compound.

When the alkali metal and the polycyclic aromatic compound are used in the desulfonation reaction, both may be added to the reaction system alone or, for example, sodium metal is dispersed in molten naphthalene. It may be added in the form of a complex such as a sodium-naphthalene complex that is solidified by the above.

The amount of alkali metal used is preferably 4 to 20 molar equivalents, more preferably 5 to 10 molar equivalents, relative to the compound of formula (6). The amount of polycyclic aromatic compound used is preferably 4 to 2 relative to the compound of formula (6).
It is 0 molar equivalent, and more preferably 5 to 10 molar equivalent.

Desulfonation (and deprotection) is preferably carried out in the presence of a solvent. As such a solvent, for example, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane, diglyme and the like can be preferably used, and among them, tetrahydrofuran is preferable. The amount of the solvent used is preferably 2 to 50 times by weight, more preferably 4 to 10 times by weight based on the compound of the formula (6).

At the time of desulfonation (and deprotection), it is preferable to add a lower amine to the reaction system.
As a result, the content of all-trans DHP in the product can be improved.

Examples of such lower amines include:
Butylamine, diethylamine, diisopropylamine and the like can be preferably used, and diethylamine can be particularly preferably used. The lower amine is preferably used in an amount of 1 to 1 with respect to the compound of formula (6).
It is 0 molar equivalent, more preferably 2 to 4 molar equivalents.

The temperature for desulfonation (and deprotection) is usually -50 to 50 ° C, more preferably -30 to 0 ° C.

Desulfonation (and deprotection) described above
The conditions are milder than the conventional method in which an alkali metal is allowed to act at an extremely low temperature of -70 to -50 ° C in an amine solvent such as ammonia, methylamine or ethylamine,
It is also industrially superior.

When the deprotection of the protecting group is carried out subsequent to the desulfonation, depending on the kind of the protecting group, the aforementioned literature [Green, "Protective Groups in Organic Synthesis"
(2nd Edition, John Wiley & Sons (1991)) ”and the like, can be used to carry out the deprotection.

After completion of the desulfonation (and deprotection), DHP is separated and purified from the reaction mixture by pouring the reaction mixture into water and using a hydrocarbon solvent such as n-hexane or an aromatic solvent such as benzene. It can be carried out by extracting and distilling the solvent from the extract by a conventional method.

The purity of the isolated DHP can be further increased by means such as distillation and silica gel column chromatography.

[0086]

The present invention will be described below in detail with reference to examples.

Reference Example 1 (i): Synthesis of Farnesyl Bromide 66.6 g (0.3 mol) of farnesol (all-trans type) was charged into a 1 liter reaction vessel purged with argon, and 300 ml of isopropyl ether was further added to dissolve it. Let After cooling the solution to −20 ° C., 32.5 g (0.12 mol) of phosphorus tribromide was added, and −20 to −10 ° C.
For 2 hours. The obtained reaction mixture was poured into 400 ml of 5% aqueous sodium carbonate and the layers were separated. The organic layer was washed with saturated saline, and then the solvent was distilled off to obtain 77.0 g of farnesyl bromide (yield 90%). The physical properties of this compound are shown below.

FD-mass: M ⁺ = 285

(Ii): Synthesis of farnesyl phenyl sulfone (m = 2) of formula (5) In a 2 liter reaction vessel purged with argon, 77.0 g (0.27 mol) of farnesyl bromide obtained above was added. Sodium benzenesulfinate dihydrate 5
9.4 g (0.297 mol) was charged, 250 ml of dimethylformamide was added and dissolved, and the mixture was reacted at 20 to 30 ° C. for 3 hours.

Next, 500 ml of water was added to the obtained reaction mixture.
Was added and extracted with toluene. The extract was washed with saturated saline, and then the solvent was distilled off to obtain 88.7 g of farnesylphenyl sulfone (yield 95%). The physical properties of this compound are shown below.

FD-mass: M ⁺ = 346

¹ H-NMR [300 MHz, CDCl ₃ ,
δ (ppm)]: 1.30 (s, 3H, CH3), 1.
58 (s, 3H, CH ₃ ), 1.59 (s, 3H, C
_{H 3), 1.67 (s,} 3H, CH 3), 1.92~2.
12 (m, 8H), 3.81 (d, J = 8.0Hz, 2
H), 5.02 to 5.13 (m, 2H), 5.14 to
5.24 (m, 1H), 7.48 to 7.90 (m, 5
H).

Reference Example 2 (i): Synthesis of prenyl bromide A prenyl bromide was obtained in the same manner as in (i) of Reference Example 1 except that prenol (0.3 mol) was used instead of farnesol. The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 149

(Ii): Synthesis of prenylphenyl sulfone (m = 4) of the formula (5) In place of farnesyl bromide, the whole amount of prenyl bromide obtained in the above reaction was used, and
Prenylphenyl sulfone was obtained in the same manner as i) (yield 87%). The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 210

Reference Example 3 (i): Synthesis of Geranyl Bromide A geranyl bromide was obtained in the same manner as in Reference Example 1 (i), except that geraniol (0.3 mol) was used instead of farnesol. The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 217

(Ii): Synthesis of geranylphenyl sulfone (m = 3) of the formula (5), except that geranyl bromide obtained by the above reaction is used in place of farnesyl bromide, and (i) of Reference Example 1 is used.
Geranylphenyl sulfone was obtained in the same manner as i) (yield 85%). The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 278

Reference Example 4 (i): Synthesis of Geranylgeranyl Bromide Reference Example 1 except that geranylgeranylol (all-trans type) (0.3 mol) was used in place of farnesol.
Geranylgeranyl bromide was obtained in the same manner as in (i). The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 353

(Ii): Synthesis of geranylgeranylphenyl sulfone (m = 1) of formula (5) (ii) of Reference Example 1 except that geranylgeranyl bromide obtained in the above reaction is used in place of farnesyl bromide. Geranylgeranylphenyl sulfone was obtained in the same manner as in (yield 82%). The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 414

Example 1 Reaction (1a) (step (a)) : Synthesis of citronellyl benzyl ether of formula (71) (A = benzyl group) In a reaction vessel purged with argon, 156 g of citronellol of formula (70) (1 Mol), 139 g of benzyl chloride (1.
1 mol), 50 wt% sodium hydroxide aqueous solution 240
g (3 mol as sodium hydroxide) and 3.37 g (0.01 mol) of tetra-n-butylammonium sulfate were sequentially added at room temperature, the temperature was raised to 50 ° C., and the mixture was stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled and 300 ml of toluene was added for extraction. The toluene layer was washed with water until the washing liquid became neutral, and then the toluene was distilled off. From the obtained residue, 216.2 g of citronellyl benzyl ether was obtained by vacuum distillation (yield 87.9).
%). The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 246

Reaction (1b) (Step (b)) : Formula (7 )
2) Synthesis of epoxy compound (A = benzyl group) In a 2 liter reaction vessel, 196.8 g (0.8 mol) of citronellyl benzyl ether obtained in the reaction (1a), 7
0% t-butyl hydroperoxide aqueous solution 123.
4 g (0.96 mol) and 0.21 g of dioxobis (acetylacetonato) molybdenum (0.1% by weight based on citronellyl benzyl ether) were added, and 650 ml of toluene was added and dissolved. The temperature was raised to 75 to 80 ° C. and the reaction was carried out at the same temperature for 8 hours.

After the reaction was completed, the reaction mixture was cooled to room temperature, and 500 ml of a 5% sodium sulfite aqueous solution was added to decompose excess t-butyl hydroperoxide.
Separated. The organic layer was washed with water, the solvent was evaporated, and the obtained residue was distilled under reduced pressure to obtain 171.9 g of the epoxy compound of the formula (72) (yield 82.0%). The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 262

Reaction (1c) (step (c)) : Formula (2)
Synthesis of allyl alcohol compound (A = benzyl group) in a reaction vessel (1
157.2 g (0.6 mol) of the epoxy compound obtained in b)
And aluminum isopropoxide 42.9 g (0.2
1 mol) and 850 ml of toluene were added and dissolved. The temperature of the solution was raised to 100 to 110 ° C., and the reaction was carried out at the same temperature for 8 hours.

After completion of the reaction, the reaction mixture was cooled to room temperature, 300 ml of 10% hydrochloric acid aqueous solution was added, and the layers were separated. The organic layer was washed with 5% aqueous sodium carbonate and saturated brine in that order, and the solvent was evaporated. 140.7 of the allyl alcohol compound of formula (2) was obtained from the obtained residue by vacuum distillation.
g was obtained (yield 85.0%). The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 262

¹ H-NMR [300 MHz, CDCl ₃ ,
δ (ppm)]: 0.88 (dd, J = 1.0, 6.5
_{Hz, 3H, CH 3),} 0.98~1.72 (m, 7
H), 1.68 (s, 3H , CH 3), 2.22 (br
s, 1H, OH), 3.40 to 3.54 (m, 2H),
3.95 (t, J = 6.4 Hz, 1H), 4.46
(S, 2H), 4.77 to 4.80 (m, 1H), 4.
87-4.90 (brs, 1H), 7.20-7.40
(M, 5H).

Example 2 Reaction (2a) : Synthesis of allyl alcohol compound (m = 1, A = benzyl group) of formula (3) Obtained in reaction (1c) of Example 1 in a 2 liter reaction vessel. 131.0 g of allyl alcohol compound of formula (2)
(0.5 mol), 2-methyl-3,3-dimethoxy-1
-Butene 78.0 g (0.6 mol) and pyridinium p-toluenesulfonate 0.14 g were charged, and further toluene 450 ml was added and dissolved. The obtained solution was heated to 90 to 110 ° C. and reacted for 3 hours while distilling the produced methanol out of the reaction system.

The reaction mixture was cooled to room temperature, 20.4 g (0.1 mol) of aluminum isopropoxide and 450 ml of isopropanol were added, and the mixture was again heated at 75 to 90 ° C.
The mixture was heated to 0 ° C., and the reaction was carried out for 5 hours while distilling the produced acetone out of the reaction system.

After completion of the reaction, the reaction mixture was cooled to room temperature, 300 ml of 5% hydrochloric acid aqueous solution was added, and the layers were separated. The organic layer was washed with a 5% aqueous sodium carbonate solution and saturated brine in this order, and then the solvent was evaporated. From the obtained residue, 145.2 g of an allyl alcohol compound was obtained by molecular distillation (boiling point: 130 to 132 ° C./0.045 torr, yield: 88.
0%). The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 330

¹ H-NMR [300 MHz, CDCl ₃ ,
δ (ppm)]: 0.88 (d, J = 6.5 Hz, 3
_{H, CH 3), 1.02~1.74 (} m, 7H), 1.
59 (s, 3H, CH ₃ ), 1.69 (s, 3H, C
_{H 3), 1.80~2.10 (m,} 4H), 2.36
(Brs, 1H, OH), 3.40 to 3.50 (m, 2
H), 3.97 (t, J = 6.5 Hz, 1H), 4.4
6 (s, 2H), 4.77 to 4.80 (m, 1H),
4.90 (brs, 1H), 5.14 (t, J = 6.9)
Hz, 1H), 7.20 to 7.35 (m, 5H).

Reaction (2b) : Synthesis of the allyl alcohol compound (m = 2, A = benzyl group) of the formula (3) Instead of the allyl alcohol compound of the formula (2), the formula (2a) obtained above is used. An allyl alcohol compound (m = 2) of the formula (3) extended by 5 carbons was obtained in the same manner as in the above reaction (2a) except that the allyl alcohol compound (m = 1) of 3) was used (boiling point 145 ~ 147 ° C / 0.0
15 torr, yield 87%). The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 398

¹ H-NMR [300 MHz, CDCl ₃ ,
δ (ppm)]: 0.88 (d, J = 6.5 Hz, 3
_{H, CH 3), 1.02~1.74 (} m, 7H), 1.
59 (s, 6H, 2 × CH 3), 1.69 (s, 3H,
_{CH 3), 1.80~2.10 (m,} 8H), 2.36
(Brs, 1H, OH), 3.40 to 3.50 (m, 2
H), 3.97 (t, J = 6.5 Hz, 1H), 4.4
7 (s, 2H), 4.78 to 4.82 (m, 1H),
4.90 (brs, 1H), 5.06 to 5.17 (m,
2H), 7.20 to 7.35 (m, 5H).

Reaction (2c) : Synthesis of allyl alcohol compound of formula (3) (m = 3, A = benzyl group) Instead of the allyl alcohol compound of formula (2), the formula (2b) obtained in the above reaction (2b) is used. Except for using the allyl alcohol compound (m = 2) of 3), the allyl alcohol compound of formula (3) (m = 2) extended by 5 carbons was obtained in the same manner as in the above reaction (2a) (yield. 83%). The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 466

Reaction (2d) : Synthesis of allyl alcohol compound of formula (3) (m = 4, A = benzyl group) Instead of the allyl alcohol compound of formula (2), the formula (2c) obtained in the above reaction (2c) is used. Except for using the allyl alcohol compound (m = 3) of 3), the allyl alcohol compound of formula (3) (m = 4) extended by 5 carbons was obtained in the same manner as in the above reaction (2a) (yield. 79%). The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 534

Example 3 Reaction (3a) : Allyl halide compound of formula (4) (m
= 2, X = Cl, A = benzyl group) In an argon-substituted 2 liter reaction vessel, the allyl alcohol compound (m = 2) 119 of the formula (3) obtained in the reaction (2b) of Example 2 was obtained. 0.4 g (0.3 mol) and dimethylformamide 0.22 g (3 mmol) were added, and 500 ml of isopropyl ether was added and dissolved, and the mixture was cooled to 0 ° C, and thionyl chloride 57.1 was added at the same temperature.
g (0.48 mol) was added. After reacting at 0 to 10 ° C for 7 hours, the obtained reaction mixture was poured into 1000 ml of a 10% sodium carbonate aqueous solution, and the layers were separated. The organic layer was washed with saturated saline and then the solvent was distilled off to obtain 100 g of the allyl halide compound (m = 2, X = Cl) of the formula (4) (yield 80%). The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 416.5

¹ H-NMR [300 MHz, CDCl ₃ ,
δ (ppm)]: 0.89 (d, J = 6.5 Hz, 3
_{H, CH 3), 1.06~1.80 (} m, 5H), 1.
59 (s, 6H, 2 × CH 3), 1.71 (s, 3H,
_{CH 3), 1.88~2.18 (m,} 10H), 3.4
2-3.58 (m, 2H), 3.97 (s, 2H),
4.48 (s, 2H), 5.11 (t, J = 6.6H
z, 2H), 5.48 (t, J = 6.7Hz, 1H),
7.20-7.35 (m, 5H).

Reaction (3b) : Synthesis of allyl alcohol compound of formula (4) (m = 1, X = Cl, A = benzyl group) Example substituted for allyl alcohol compound of formula (3) (m = 2) In the same manner as in the above reaction (3a) except that the allyl alcohol compound (m = 1) of the formula (3) obtained in the reaction (2a) of 2 is used, the allyl alcohol compound (m = 1) of the formula (4) is used. , X = Cl) was obtained (yield 82%). The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 348.5

Reaction (3c) : Synthesis of allyl alcohol compound of formula (4) (m = 3, X = Cl, A = benzyl group) Example substituted for allyl alcohol compound of formula (3) (m = 2) In the same manner as in the above reaction (3a) except that the allyl alcohol compound (m = 3) of the formula (3) obtained in the reaction (2c) of 2 is used, the allyl alcohol compound (m = 3) of the formula (4) is used. , X = Cl) was obtained (yield 78%). The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 484.5

Reaction (3d) : Synthesis of allyl alcohol compound of formula (4) (m = 4, X = Cl, A = benzyl group) Example substituted for allyl alcohol compound of formula (3) (m = 2) In the same manner as in the above reaction (3a) except that the allyl alcohol compound (m = 4) of the formula (3) obtained in the reaction (2d) of 2 is used, the allyl alcohol compound (m = 4) of the formula (4) is used. , X = Cl) was obtained (yield 75%). The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 552.5

Example 4 Reaction (4a) : Synthesis of Condensate of Formula (6) (m = 2, A = benzyl group) Obtained in Reaction (3a) of Example 3 in a 1 liter reaction vessel purged with argon. 83.3 g (0.2 mol) of the obtained allyl halide compound of the formula (4) (m = 2, X = Cl) and the farnesylphenyl sulfone (m = 2) 69 of the formula (5) obtained in Reference Example 1. Charge with 0.2 g (0.2 mol),
Add 300 ml of N-methylpyrrolidone to dissolve,
C., then sodium t-butyrate 38.4
g (0.4 mol) was added. The internal temperature was raised to room temperature, and the reaction was continued at the same temperature for 2 hours. The reaction mixture was poured into 1000 ml of ice-cold water and extracted with toluene. The obtained extract was washed with saturated saline and then the solvent was distilled off to obtain 130.9 g of the condensate (m = 2) of the formula (6) (yield 90%). The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 726

¹ H-NMR [300 MHz, CDCl ₃ ,
δ (ppm)]: 0.88 (d, J = 6.5 Hz, CH
₃ ), 1.10 to 1.80 (m, 5H), 1.15
_{(S, 3H, CH 3)} , 1.52 (s, 3H, CH 3),
1.55 (s, 3H, CH ₃ ), 1.58 (s, 3H,
_{CH 3), 1.59 (s,} 6H, 2 × CH 3), 1.67
(S, 3H, CH ₃ ), 1.86 to 2.12 (m, 18
H), 2.29 (dd, J = 11.6, 12.8 Hz,
1H), 2.88 (d, J = 13.1Hz, 1H),
3.43 to 3.55 (m, 2H), 3.88 (ddd,
J = 10.8, 10.8, 3.0 Hz, 1H), 4.4
8 (s, 2H), 4.91 (d, J = 10.8Hz, 1
H), 5.00 to 5.18 (m, 5H), 7.20 to
7.35 (m, 5H), 7.42 to 7.62 (m, 3
H), 7.80-7.86 (m, 2H).

Reaction (4b) : Condensate of the formula (6) (m =
1, A = benzyl group) Allyl halide compound of formula (4) (m = 2, X = Cl)
In place of the allyl halide compound of formula (4) obtained in the reaction (3b) of Example 3 (m = 1, X = Cl),
And farnesyl phenyl sulfone of the formula (5) (m =
Except that geranylgeranylphenyl sulfone (m = 1) of formula (5) obtained in Reference Example 4 is used instead of 2).
Similar to the above reaction (4a), the condensate of the formula (6) (m =
1) was obtained (yield 91%). The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 726

Reaction (4c) : Condensate of the formula (6) (m =
3, A = benzyl group) Allyl halide compound of formula (4) (m = 2, X = Cl)
Instead of the allyl halide compound of formula (4) (m = 3, X = Cl) obtained in Reference Example 3 and in place of the farnesylphenyl sulfone (m = 2) of formula (5) A condensate (m = 3) of the formula (6) was obtained in the same manner as in the above reaction (4a) except that the geranylphenyl sulfone (m = 3) of the formula (5) obtained in 3 was used. Rate 88
%).

Reaction (4d) : Condensate of the formula (6) (m =
4, A = benzyl group) Allyl halide compound of formula (4) (m = 2, X = Cl)
In place of the allyl halide compound of formula (4) (m = 4, X = Cl) obtained in the reaction (3d) of Example 3,
And farnesyl phenyl sulfone of the formula (5) (m =
The condensate (m) of the formula (6) was obtained in the same manner as the above reaction (4a) except that the prenylphenyl sulfone (m = 4) of the formula (5) obtained in Reference Example 2 was used instead of the 2). = 4) was obtained (88% yield). The physical properties of this compound are shown below.

FD-Mass: M ⁺ = 726

Example 5 Reaction (5a) : Synthesis of DHP A condensate of the formula (6) (m = 2, A) obtained in the reaction (4a) of Example 4 was placed in a 2-liter reaction vessel purged with argon.
= Benzyl group) 72.7 g (0.1 mol) and diethylamine 14.6 g (0.2 mol) were charged, and 600 ml of tetrahydrofuran was added and dissolved to give -30 to -20.
Cooled to ° C. Sodium was added to the obtained solution at the same temperature.
Naphthalene complex (sodium content about 18% by weight) 77.
0 g (0.6 mol as sodium) was added, and -1
The reaction was carried out at 0 to 0 ° C for 2 hours.

Then, the reaction mixture was poured into 1000 ml of a saturated aqueous solution of ammonium chloride and extracted with n-hexane. The extract was washed with saturated saline and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate [n-hexane / ethyl acetate = 4: 1 (volume ratio)], and DHP31.
8 g was obtained (yield 64%). The physical properties of the obtained DHP are shown below.

FD-Mass: M ⁺ = 496

¹ H-NMR [300 MHz, CDCl ₃ ,
δ (ppm)]: 0.90 (d, J = 6.6 Hz, 3
_{H, CH 3), 1.10~1.70 (} m, 5H), 1.
59 (s, 18H, 6 × CH 3), 1.67 (s, 3
_{H, CH 3), 1.90~2.14 (} m, 22H),
3.57 to 3.72 (m, 2H), 5.05 to 5.16
(M, 6H).

Reaction (5b) : Synthesis of DHP Instead of the condensate of formula (6) (m = 2, A = benzyl group), the condensate of formula (6) obtained in reaction (4b) of Example 4 DHP was obtained in the same manner as in the above reaction (5a) except that (m = 1, A = benzyl group) was used (yield 70%).
The physical properties of this DHP are the same as those of the DHP obtained in reaction (5a).
Was the same as

Reaction (5c) : Synthesis of DHP Condensate of formula (6) obtained in reaction (4c) of Example 4 in place of the condensate of formula (6) (m = 2, A = benzyl group) DHP was obtained in the same manner as in the above reaction (5a) except that (m = 3, A = benzyl group) was used (yield 65%).
The physical properties of this DHP are the same as those of the DHP obtained in reaction (5a).
Was the same as

Reaction (5d) : Synthesis of DHP Condensate of formula (6) obtained in reaction (4d) of Example 4 in place of the condensate of formula (6) (m = 2, A = benzyl group) DHP was obtained in the same manner as in the above reaction (5a) except that (m = 4, A = benzyl group) was used (yield 67%).
The physical properties of this DHP are the same as those of the DHP obtained in reaction (5a).
Was the same as

Example 6 In the reaction (5a) of Example 5, a compound of the formula (6) in which A is an acetyl group is used in place of the compound of the formula (6) in which A is a benzyl group. Reaction of Example 5 (5
By reacting and treating in the same manner as a), DHP3
0.8 g (yield 62%) was obtained.

Example 7 In the reaction (5a) of Example 5, a compound of the formula (6) in which A is a tetrahydropyranyl group is used in place of the compound of the formula (6) in which A is a benzyl group. Was reacted in the same manner as the reaction (5a) of Example 5.

The obtained reaction mixture was poured into 1000 ml of saturated aqueous ammonium chloride solution and extracted with n-hexane. The extract was washed with saturated saline and the solvent was distilled off. To the obtained residue, 500 ml of methanol and 1 g of p-toluenesulfonic acid were added and reacted at room temperature for 5 hours.

Next, the reaction mixture was poured into 100 ml of an aqueous sodium hydrogencarbonate solution, extracted with n-hexane, the extract was washed with saturated saline and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography. [Eluent: n
-Hexane-ethyl acetate [n-hexane / ethyl acetate =
4: 1 (volume ratio)]] to obtain 33.7 g of DHP (yield 68%).

Example 8 In the reaction (5a) of Example 5, a compound of the formula (6) in which A is a t-butyldimethylsilyl group is used in place of the compound of the formula (6) in which A is a benzyl group. The reaction was performed in the same manner as the reaction (5a) of Example 5 except that

The obtained reaction mixture was poured into 1000 ml of a saturated aqueous solution of ammonium chloride and extracted with n-hexane. The extract was washed with saturated saline and the solvent was distilled off. To the obtained residue, 500 ml of tetrahydrofuran and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1
M) (100 ml) was added, and the mixture was reacted at room temperature for 1 hour.

Next, the reaction mixture was poured into 1000 ml of water, extracted with n-hexane, the extract was washed with saturated saline and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography [eluate]. : N-hexane-ethyl acetate [n-hexane / ethyl acetate = 4: 1 (volume ratio)]]
Purification was carried out to obtain 32.7 g of DHP (yield 66%).

[0157]

Industrial Applicability According to the present invention, a method for industrially producing DHP is provided.

Claims (2)

[Claims] (1) Formula (1) In the method for producing 3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaen-1-ol represented by: Step (A) Formula (2) [Chemical formula 2] (Wherein A represents a hydroxyl-protecting group) is reacted with 2-methyl-3,3-dimethoxy-1-butene, and the carbonyl group of the compound is reduced. By performing a 5-carbon extension reaction of m times, the formula (3): (In the formula, m represents an integer of 1 to 4); Step (B) The compound of the formula (3) is halogenated to obtain the compound of the formula (4): (In the formula, X represents a halogen atom); a step of converting to a compound; step (C) the compound of formula (4) and the compound of formula (5) (In the formula, R ¹ represents an alkyl group or an aryl group.)
By reacting with a compound of formula (6) And a step (D) of obtaining a compound of the formula (1) by desulfonation and deprotection of the compound of the formula (6). 2. A compound of formula (2), which is the starting material of step (A), is converted into the following step (a), step (b) and step (c) step (a) formula (70): By introducing a protecting group A into the hydroxyl group of citronellol of formula (71) (Wherein A represents a hydroxyl-protecting group); Step (b) The compound of formula (71) is reacted with an epoxidizing agent to obtain a compound of formula (72): The step of obtaining the compound of the formula (I); the step (c) of the compound of the formula (72) is obtained by the step of rearranging the epoxy group thereof into allyl alcohol to convert it into the compound of the formula (2). Production method.