JPH09151144A - Production of all trans polyprenol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially and advantageously obtain the subject compound useful as a material for medicines by desulfonating the intermediate prepared from an allylsulfonyl compound and an allyl halide in the presence of two specific compounds. SOLUTION: A compound of formula I ((m) and (n) are each 0 or an integer of >=1; Y and Z are both H or together form a C-C bond; R<1> is an alkyl or an aryl; A is a protecting group for OH) is desulfonated by treating with an alkali metal and a polycyclic aromatic compound to obtain polyprenols of formula II (R<2> is H or A), in more details, polyprenol and β,γ-dihydro-polyprenol, in which all the double bonds are trans form. Preferably, sodium as the alkali metal and naphthalene as the polycyclic aromatic compound are used. In the case that Y and Z in the compound of formula I together form a C-C bond, a compound of formula III is reacted with a compound of formula IV (X is a halogen). When Y and Z in the formula I are both H, the compound of formula III is reacted with the compound of formula IV.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to polyprenols,
More specifically, it relates to a method for producing polyprenol and β, γ-dihydropolyprenol in which all double bonds in the molecule are trans. The polyprenol provided by the present invention is a compound useful as a raw material for a drug or a synthetic intermediate thereof, such as coenzyme Q ₁₀ . Further, β, γ-dihydropolyprenol provided by the present invention is a compound having physiological activity in general, for example,
β, γ-dihydroheptaprenol is useful as a prophylactic or therapeutic drug for diseases caused by immune dysfunction in humans or animals (see JP-A-62-169724).

[0002]

As a general synthetic method of polyprenol, a method of desulfonation of a compound of formula (13) obtained from an allyl sulfone compound of formula (11) and an allyl halide compound of formula (12) is known. (See Scheme 1 below).

[0003]

Embedded image

(In the formula, m and n represent 0 or an integer of 1 or more. R ¹ represents an alkyl group or an aryl group,
A represents a protective group for a hydroxyl group. X represents a halogen atom,
R ² represents a hydrogen atom or the same hydroxyl-protecting group as A. )

The synthetic method shown in the above scheme 1 is a synthetic method in which a compound having a short prenyl chain is combined to construct a long polyprenyl chain, which is advantageous in synthesizing a long chain polyprenol. You can say that. This synthetic method can also be applied to the synthesis of β, γ-dihydropolyprenol in which the double bond at the β, γ position of the hydroxyl group of polyprenol is saturated.

Here, as the desulfonation method in the above scheme 1, a method of reacting metallic sodium in ethanol or tetrahydrofuran [Yamazaki et al., Chemical Pharmaceutical Bulletin, Chem. Pharm. Bull. Three
2, p. 3959 (1984)], a method of acting sodium amalgam [Sato et al., Journal of the Chemical Society Perkin Transaction I (J. Chem. Soc. Perkin Tra
ns I), p. 761 (1981)], ammonia; a method of reacting an alkali metal such as metallic lithium or metallic sodium in a lower amine such as anhydrous methylamine or anhydrous ethylamine (so-called Birch reduction)
[Sato et al., Journal of the Chemical Society Perkin Transaction I (J. Chem. So
c. Perkin Trans I), pp. 761 (1981) and JP-A-53-84908], a method of reacting a metal hydride or an organometal hydride in the presence of a palladium catalyst [Inomata et al., Chemistry.・ Letters (Chem. Lett.), P. 1177 (1986)
Year))], etc. are known.

[0007]

When it is attempted to synthesize polyprenol in which all double bonds in the molecule are trans-type by the method shown in the above scheme 1, not only is the desulphonation carried out in good yield. , It is necessary to construct the double bond stereoselectively and regioselectively.

However, in the case of the desulfonation in Scheme 1, if the above-mentioned desulfonation method is adopted, a large excess of sodium metal and alcohol are required, and the obtained reaction product is a regioisomer of the double bond. Since it contains 30% of the body, there is a problem that the selectivity is low.

Also in the above desulphonation method, the reaction product obtained has a regioisomer of a double bond of 30.
%, And there is a problem that the selectivity is low. In addition, mercury-containing waste is generated, which may cause environmental pollution. On the other hand, in the desulphonation method utilizing the above-mentioned Birch reduction, the target compound can be obtained with a good selectivity of 90%, but it is necessary to use ammonia or a lower amine having a low boiling point, and the reaction selection It is necessary to carry out the reaction at an extremely low temperature in order to improve the properties. However, the cryogenic reaction is a reaction that is difficult to carry out industrially, and since low-boiling lower amines are generally difficult to recover in an anhydrous state, there are difficulties in recovering and reusing the solvent. .

Further, in the method using the above metal hydride or organometal hydride, the selectivity of the reaction is 95.
%, But the lithium triethylborohydride used as the reducing agent is expensive, and it is necessary to coexist with an expensive palladium catalyst. Therefore, it is difficult to say that this is an advantageous method for industrial implementation.

Therefore, in order to selectively and industrially produce a polyprenol in which all double bonds in the molecule are trans-type by using the method shown in the above scheme 1, appropriate desulfonation conditions are required. Is a technical issue.

[0012]

Means for Solving the Problems As a result of diligent study on the conditions for desulfonation in the method of the above scheme 1, the present inventors have found that desulphonation was carried out using an alkali metal and a polycyclic aromatic compound. It was found that the above problems can be solved by carrying out. Furthermore, the present inventors have applied similar desulfonation conditions to select β, γ-dihydropolyprenol, which has a chemical structure similar to that of polyprenol and in which all double bonds in the molecule are trans. The present inventors have completed the present invention by finding that they can be produced in an industrially and industrially advantageous manner.

That is, the present invention uses the formula (2)

[0014]

Embedded image

(In the above formula, m and n represent 0 or an integer of 1 or more, and Y and Z both represent a hydrogen atom,
Together they represent a carbon-carbon bond. R ¹ represents an alkyl group or an aryl group, and A represents a hydroxyl group-protecting group. ) Is treated with an alkali metal and a polycyclic aromatic compound to desulfonate the compound of formula (1)

[0016]

Embedded image

(Where m, n, Y and Z are as defined above, R ² represents a hydrogen atom or the same hydroxyl group-protecting group as A), is there.

In the above equations (1) and (2), R
Examples of the alkyl group represented by ¹ include a methyl group, an ethyl group and a butyl group. Moreover, examples of the aryl group represented by R ¹ include a phenyl group, a tolyl group, and a naphthyl group. These alkyl groups and aryl groups may be substituted with various substituents as long as they do not adversely affect the reaction. Further, as the hydroxyl-protecting group represented by A, a protecting group used for the purpose of protecting alcohol can be used, and examples thereof include an acetyl group, a benzoyl group, a tetrahydropyranyl group, a benzyl group, and t-.
Butyl dimethyl silyl group etc. are mentioned.

In the compound represented by the formula (2) used in the present invention, the compound corresponding to the case where Y and Z are united to represent a carbon-carbon bond is a known compound, for example, JP-A-53 / 1978. It can be manufactured according to the method described in JP-A-84908. That is, as shown in Scheme 1 above, the allyl sulfone compound of the formula (11) and the allyl halide compound of the formula (12) are n-
It can be obtained by reacting in the presence of a base such as butyllithium.

The allyl sulfone compound of the formula (11) is a known compound, for example, the above-mentioned document [Journal of the Chemical Society Parkin.
Transaction I (J. Chem. Soc. Perkin Trans
I), page 761 (1981)], the corresponding polyprenyl alcohol is brominated with phosphorus tribromide and then reacted with a sulfinate salt such as sodium benzenesulfinate or sodium toluenesulfinate. Can be obtained. Specifically, an allylsulfone compound of the formula (11) in which m is 0, 1, 2, 3 can be obtained from prenol, geraniol, farnesol and geranylgeraniol.

In the allyl halide compound of the formula (12), after protecting the hydroxyl group of the corresponding polyprenol with a protecting group, the terminal double bond is selectively epoxidized,
It can be obtained by converting the resulting epoxy compound into a secondary allyl alcohol by a rearrangement reaction and halogenating the produced alcohol with a halogenating agent such as thionyl chloride or phosphorus tribromide [JP-A-53-849].
No. 08 publication and literature [Terao et al., Synthesi
s), p. 467 (1979)]]. The synthetic route is shown in Scheme 2 below.

[0022]

[Chemical 6]

Further, in the compound represented by the general formula (2), a compound corresponding to the case where both Y and Z represent a hydrogen atom can be obtained in the same manner as above. That is, it can be obtained by reacting the allyl sulfone compound (11) with the corresponding allyl halide compound (12 ′) derived from β, γ-dihydropolyprenol (see scheme 3 below). In addition,
The allyl halide compound (12 ′) can also be obtained by selectively hydrogenating the double bonds at the β and γ positions of the allyl halide compound (12).

[0024]

Embedded image

The desulfonation according to the present invention is carried out by treating the compound represented by the above formula (2) (hereinafter, sometimes abbreviated as a substrate) with an alkali metal and a polycyclic aromatic compound. Be implemented.

The alkali metal used in the present invention includes
For example, lithium, sodium, potassium and the like can be mentioned. Moreover, examples of the polycyclic aromatic compound used in the present invention include polycyclic aromatic hydrocarbons such as naphthalene, anthracene, and biphenyl. Among these, it is preferable to use sodium as the alkali metal and naphthalene as the polycyclic aromatic compound from the viewpoints of economy and ease of handling.

The alkali metal and the polycyclic aromatic compound may be added individually to the reaction system,
For example, it may be added in the form of a sodium-naphthalene complex in which metallic sodium is dispersed and solidified in melted naphthalene.

The amount of alkali metal used is preferably 4 to 20 molar equivalents, more preferably 5 to 10 molar equivalents, relative to the substrate. The amount of polycyclic aromatic compound used is
It is preferably 4 to 20 molar equivalents, more preferably 5 to 10 molar equivalents, relative to the substrate.

The desulfonation according to the invention is preferably carried out in the presence of a solvent. As the solvent, for example,
Ether-based solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane and diglyme are 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, that of the substrate.

Further, in the present invention, by adding a lower amine to the reaction system, it is possible to improve the content of the compound in which all double bonds in the molecule are trans type in the reaction product. it can. As such a lower amine, for example, butylamine, diethylamine, diisopropylamine and the like can be used, and among them, diethylamine is preferable. The amount of lower amine used is preferably 1 to 10 molar equivalents, more preferably 2 to 4 molar equivalents, relative to the substrate.

Desulphonation according to the invention usually involves -50
It is carried out at a temperature in the range of -50 ° C, preferably -30-0 ° C.

After the completion of the reaction, the desired compound can be isolated from the reaction mixture by a conventional method. For example, the reaction mixture is poured into water and a hydrocarbon solvent such as n-hexane or an aroma such as toluene. It can be carried out by extracting with a solvent such as a group-based solvent or an ether-based solvent such as diisopropyl ether and distilling the solvent off from the obtained extract.

When a product in a form in which the hydroxyl group is protected by the protecting group A is obtained by the above-mentioned desulfonation, the protecting group A for the hydroxyl group can be prepared, for example, in the literature [Green, "Pro.
tective Groups in Organic Synthesis (2nd Edition),
John Wiley & Sons (1991) ”] and the like, and deprotection can be carried out to obtain polyprenols having a free hydroxyl group. In the desulfonation according to the present invention, if a benzyl group is used as the hydroxyl-protecting group A, the hydroxyl-protecting group A can be obtained simultaneously with the desulfonation.
Is deprotected, and polyprenols having a free hydroxyl group can be obtained in one step.

The polyprenols of the formula (1) obtained by the above method can be further purified by means such as distillation and silica gel column chromatography.

[0035]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Reference Example 1: Synthesis of compound of formula (2) (Y and Z: C—C bond, m = 2, n = 1, A: benzyl group) In a 1 liter reaction vessel purged with argon, the formula ( 12)
55.7 g (0.2 mol) of the allyl halide compound (n = 1, X = Cl, A: benzyl group) and 69.2 g of the allyl sulfone compound (farnesylphenyl sulfone) of the formula (11) in which m is 2. 0.2 mol), and N-
300 ml of methylpyrrolidone was added and dissolved. The resulting solution was cooled to 0 ° C. and sodium t-butyrate 3
8.4 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 1 liter of ice-cold water and extracted with toluene. The obtained extract was washed with saturated brine, the solvent was evaporated, and the compound of formula (2) (Y and Z: C—C bond, m = 2, n
= 1, A: benzyl group) (101.1 g, yield 86)
%). The physical properties of the obtained compound are shown below. FD-mass: M ⁺ = 588

Reference Example 2: Compound of formula (2) (Y = Z =
Synthesis of H, m = 2, n = 1, A: benzyl group In a 1 liter reaction vessel purged with argon, the compound of formula (1
2 ′) allyl halide compound (Y = Z = H, n = 1,
X = Cl, A: benzyl group) 56.1 g (0.2 mol)
And 69.2 g (0.2 mol) of the allyl sulfone compound (farnesylphenyl sulfone) of the formula (11) in which m is 2 were added, and 300 ml of N-methylpyrrolidone was added and dissolved. The resulting solution was cooled to 0 ° C. and 38.4 g (0.4 mol) sodium t-butyrate 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 1 liter 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 a compound of the formula (2) (Y = Z = H, m
= 2, n = 1, A: benzyl group) (107.4 g) was obtained (yield 91%). The physical properties of the obtained compound are shown below. FD-mass: M ⁺ = 590

Reference Examples 3 to 5 The compounds shown in Table 1 were used as the allyl halide compound of the formula (12) and the allyl sulfone compound of the formula (11), respectively, and the corresponding formula ( The compound of 2) was obtained. 0.2 mol of both the allyl halide compound of the formula (12) and the allyl sulfone compound of the formula (11) was used. Yield and physical properties (FD-m
(ass) is also shown in Table 1. In addition, Bn in Table 1 represents a benzyl group.

[0039]

[Table 1]

Reference Examples 6 to 8 Allyl Halide Compounds of Formula (12 ') and Formula (11)
The compounds shown in Table 2 were used as the allyl sulfone compounds of 1 and the same operation as in Reference Example 2 was carried out to obtain the corresponding compound of the formula (2). 0.2 mol of each of the allyl halide compound of the formula (12 ′) and the allyl sulfone compound of the formula (11) was used. Table 2 shows yields and physical properties.
Are shown together. Bn in Table 2 represents a benzyl group.

[0041]

[Table 2]

Example 1: Synthesis of compound of formula (1) (Y and Z: C--C bond, m = 2, n = 1, R ² = H) In a 2 liter reaction vessel purged with argon, the reference example was prepared. Compound of formula (2) obtained in 1 (Y and Z: CC bond,
m = 2, n = 1, A: benzyl group) 58.8 g (0.1
Mol) and diethylamine 14.6 g (0.2 mol)
Was charged, and 600 ml of tetrahydrofuran was added to dissolve it, and the mixture was cooled to -30 to -20 ° C. 77 g of sodium-naphthalene complex (sodium content of about 18% by weight) was added to the obtained reaction mixture at the same temperature (0.6% as sodium).
Mol) was added, and the mixture was further reacted at −10 to 0 ° C. for 2 hours. The reaction mixture was poured into 1 liter 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)] to give 3,7,11,15,19-. Pentamethyl-2,6,10,14,18-eicosapentaen-1-ol [Compounds of formula (1): Y and Z: C
-C bound to give m = 2, n = 1, R 2 = H ] 22.2 g (62% yield). The physical properties of the obtained compound are shown below. FD-mass: M ⁺ = 358

Example 2: Compound of formula (1) (Y = Z =
Synthesis of H, m = 2, n = 1, R ² = H) A compound of the formula (2) obtained in Reference Example 2 (Y = Z = H, m = 2) was placed in a 2 liter reaction vessel purged with argon. , N =
1, A: benzyl group) 59.0 g (0.1 mol) and diethylamine 14.6 g (0.2 mol) were charged, and 600 ml of tetrahydrofuran was added and dissolved therein.
Cool to ~ -20 ° C. The obtained reaction mixture was added to the sodium-naphthalene complex (sodium content of about 18 at the same temperature).
77% (0.6 mol as sodium) was added, and the mixture was further reacted at −10 to 0 ° C. for 2 hours. Pour the reaction mixture into 1 liter of saturated aqueous ammonium chloride solution,
It was extracted with n-hexane. The extract was washed with saturated saline and the solvent was distilled off. The obtained residue is subjected to silica gel column chromatography [eluent: n-hexane-ethyl acetate [n-hexane / ethyl acetate = 4: 1 (volume ratio)]].
And purified with 3,7,11,15,19-pentamethyl-
2,6,10,14-Eicosatetraen-1-ol [Compound of Formula (1): Y = Z = H, m = 2, n = 1, R
² = H] 24.8 g was obtained (yield 69%). The physical properties of the obtained compound are shown below. FD-mass: M ⁺ = 360

Examples 3 to 8 By using 0.1 mol of the compound obtained in Reference Examples 3 to 8 as the compound of formula (2), the same procedure as in Example 1 was carried out to obtain the corresponding compound of formula (1). The compound was obtained. The yield and physical property values are shown in Table 3. Bn in Table 3 represents a benzyl group.

[0045]

[Table 3]

Example 9: Compound of formula (1) (Y = Z =
Synthesis of H, m = 2, n = 1, R ² = H) The compound of formula (2) (Y = Z = H, m = 2, n = 1, A:
(Acetyl group) 55.4 g (0.1 mol) was used and the same operation as in Example 2 was carried out to give 3,7,11,15,19-.
Pentamethyl-2,6,10,14-eicosatetraen-1-ol [Compound of formula (1): Y = Z = H, m =
2, n = 1, R ² = H] 25.6 g was obtained (yield 71
%).

Example 10: Compound of formula (1) (Y = Z
= H, m = 2, n = 1, R ² = H) The compound of formula (2) (Y = Z = H, m = 2, n = 1, A : Tetrahydropyranyl group) 50.8 g (0.1 mol) and diethylamine 14.6 g (0.2 mol) were charged, and 600 ml of tetrahydrofuran was added and dissolved therein, -30 to -2.
Cooled to 0 ° C. To the obtained reaction mixture was added 77 g of sodium-naphthalene complex (sodium content: about 18% by weight) (0.6 mol as sodium) at the same temperature, and the mixture was further reacted at -10 to 0 ° C for 2 hours. The obtained reaction mixture was poured into 1 liter of a saturated aqueous solution of ammonium chloride and extracted with n-hexane. The obtained 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. The obtained reaction mixture was poured into 1 liter of an aqueous sodium hydrogen carbonate solution, and extracted with n-hexane. The obtained extract was washed with saturated saline and the solvent was distilled off. The obtained residue is subjected to silica gel column chromatography [eluent: n-hexane-ethyl acetate [n-hexane / ethyl acetate = 4: 1 (volume ratio)]].
And purified with 3,7,11,15,19-pentamethyl-
2,6,10,14-Eicosatetraen-1-ol [Compound of Formula (1): Y = Z = H, m = 2, n = 1, R
² = H] 25.2 g was obtained (yield 70%).

Example 11: Compound of formula (1) (Y = Z
= H, m = 2, n = 1, R ² = H) The compound of formula (2) (Y = Z = H, m = 2, n = 1, A : T-butyldimethylsilyl group) 62.6 g (0.1 mol) and diethylamine 14.6 g (0.2 mol) were charged, and 600 ml of tetrahydrofuran was added and dissolved therein, and the mixture was -30 to -30.
Cooled to -20 ° C. 77 g of sodium-naphthalene complex (sodium content of about 18% by weight) (0.6 mol as sodium) was added to the obtained reaction mixture at the same temperature,
Further, the reaction was carried out at -10 to 0 ° C for 2 hours. The obtained reaction mixture was poured into 1 liter of a saturated aqueous solution of ammonium chloride and extracted with n-hexane. The obtained extract was washed with saturated saline and the solvent was distilled off. To the obtained residue, 500 ml of tetrahydrofuran and 100 ml of a tetrahydrofuran solution (1M) of tetrabutylammonium fluoride.
Was added and reacted at room temperature for 1 hour. The obtained reaction mixture was poured into 1 liter of water and extracted with n-hexane. The obtained extract was washed with saturated saline and the solvent was distilled off.
The obtained residue is subjected to silica gel column chromatography [eluent: n-hexane-ethyl acetate [n-hexane /
Ethyl acetate = 4: 1 (volume ratio)]], 3,7,
11,15,19-pentamethyl-2,6,10,14
- eicosatetraenoic 1-ol [compound of formula (1): Y = Z = H, m = 2, n = 1, R 2 = H ] 24.9
g was obtained (68% yield).

[0049]

INDUSTRIAL APPLICABILITY According to the present invention, polyprenols having all trans double bonds in the molecule can be selectively and industrially produced advantageously.

Claims (1)

[Claims] (1) Formula (2) (In the formula, m and n represent 0 or an integer of 1 or more, and Y
And Z both represent a hydrogen atom or, when combined, represent a carbon-carbon bond. R ¹ represents an alkyl group or an aryl group, and A represents a hydroxyl group-protecting group. The compound represented by the formula (1) is treated with an alkali metal and a polycyclic aromatic compound for desulfonation, and the compound represented by the general formula (1): (In the formula, m, n, Y, and Z are as defined above, and R ² represents a hydrogen atom or the same hydroxyl group-protecting group as A).