JPS5913486B2 - Hydroquinone - Google Patents

Description

[Detailed description of the invention] The present invention is based on the following general formula (See Publication No. 47-26496).

(3) Coenzyme Q.

A method of reacting hydroquinone-diacetate with a π-allylic nickel complex of an isoprenyl halogen compound, hydrolyzing the resulting reaction product, and then oxidizing it (JP-A-5
0-58021) etc. are known. However, in the method of Maetoshi 1), isoprenyl alcohol or its derivatives are decomposed by the acidic catalyst used, or other side reactions proceed significantly, resulting in a reduction in the production yield of coenzyme Q, and furthermore, during the reaction. Since it is not easy to remove the resulting impurities, it is impossible to obtain high purity* in a good yield. Furthermore, the method of Maetoshi 2), like the method (1), has the drawback of low reaction yield. In the method of 3), it is difficult to avoid isomerization of isoprenoids, and the ratio of cis/trans is as high as 1/4 to 1/3, which not only reduces the amount of trans isomers but also makes it extremely difficult to purify them. The inventors of the present invention have conducted various studies to solve these drawbacks of conventional methods, and as a result have completed a method for obtaining coenzyme Q and the like in high yield and purity. That is, the present invention is based on the general formula (where n is O
represents an integer of ~11, X represents a halogen atom, A and B represent a hydrogen atom, or A and B represent a bond, and these represent a combination of the same or different types) or a compound represented by the general formula ( A compound represented by the formula (A.B, n and X have the same meanings as above) and a compound represented by the general formula (wherein R
1 represents a lower alkyl group, R2 and R3 are a hydrogen atom or a lower alkyl group, or R and R2 or R3 are combined to form a compound represented by (CH2)4 group). A hydroquinone derivative represented by a characteristic general formula (wherein R1, R2, R3, A, .B and n have the same meanings as above) is obtained.

Examples of the compound represented by the general formula () or the compound represented by the general formula () used in the present invention include geranyl bromide, farnesyl chloride, solanesyl bromide, decaprenyl bromide, isodecaprenyl chloride, and phytyl bromide. , isophyl chloride, etc.

Furthermore, the compound represented by the general formula () is unknown in the literature, and its production method is, for example, brominating the 6-position of 2,3-dimethoxy-5-methyl-1,4-quinone with bromine, followed by reduction. to give 1,4-hydroquinone, and then protect the 1,4-1 position by a conventional method to obtain the general formula (in the formula R1, R2
, R3 has the same meaning as above, and X represents a halogen atom), and then reacted with alkyllithium or lithium to form a compound represented by the general formula (R1, R2 and R3 have the same meaning as above). A compound of the general formula (
) is obtained.

The present invention involves reacting the thus obtained compound represented by the general formula () or () with a compound represented by the general formula (). More specifically, the compound represented by the general formula () is prepared by dissolving the compound represented by the general formula (V) in an anhydrous solvent such as dehydrated tetrahydrofuran under a flow of an inert gas such as nitrogen or argon, and After cooling to a low temperature, for example -50° C., metallic lithium or alkyl lithium is added. In this case, the alkyllithium is methyllithium, ethyllithium,
n-butyllithium, phenyllithium, etc. may be used. The compound represented by the general formula () obtained as a reaction product does not need to be isolated, and immediately...
By adding copper, for example cuprous iodide, and reacting, a compound represented by the general formula () is obtained. This general formula (
) There is no particular need to isolate the compound represented by the general formula (1) by reacting it with the compound represented by the general formula (H) or () under the above reaction conditions. The reaction conditions at this time vary depending on the number of carbon atoms in the compound represented by the general formula (), but the reaction temperature must be below room temperature, preferably below 0°C, for example -5
The reaction is started at about 0°C, gradually raised in temperature, and then completed at 0°C or higher, for example, 15°C. Although the reaction time varies depending on the temperature, the reaction is almost completed in about 1 hour at room temperature, but it is preferable to carry out the reaction for 5 to 20 hours in order to react even a trace amount of unreacted substances. After completion of the reaction, the reactant is extracted with, for example, ether, washed with water, dehydrated, and then distilled off to obtain an oily compound represented by the general formula (1). This product showed 1 spot on TLC and the yield was almost quantitative. As described above, according to the method of the present invention, the compound represented by the general formula (1) can be obtained in almost quantitative yield, and it can also be obtained with extremely high purity and without contamination of isomers.

Furthermore, according to the method of the present invention, even if the compound represented by the general formula () or () has a substance in which n is 6 or more, a highly pure target product can be obtained in a quantitative yield. Furthermore, general formula (1)
In order to lead to coenzyme Q or its analogues from the compound represented by formula (1), the protective group of the compound represented by formula (1) has an acetal or ketal type bond, so removal by acid is extremely smooth. Therefore, it can be easily derived with high purity and good yield by conventional methods.

Next, the present invention will be explained with reference to examples, but the present invention is not limited to the following examples. Example 12.3-
Synthesis of dimethoxy-5-methyl-6-geranyl-1,4-hydroquinone-bis-methoxymethyl ether 2.
3-dimethoxy-5-methyl-6-bromo-1,4-hydroquinone-bis-methoxymethyl ether 700η
20 m of tetrahydrofuran dried under an argon stream.
1 and cooled to -50°C, 1.4 ml of n-butyllithium solution (15% n-hexane solution) was added and stirred for 15 minutes.

Next, 200 η of cuprous iodide was added, and stirring was continued for 1 hour.

Next, 440 η of geranyl bromide was added under cooling, and after stirring for 1 hour, the reaction was continued with stirring overnight at room temperature.
The reaction solution was poured into saturated ammonium chloride water, and this liquid was extracted with ether.

The ether layer was washed with water and dried over magnesium sulfate. When the solvent was distilled off, pale yellow 2,3-dimethoxy-5-methyl-6-geranyl-1,4-hydroquinone-bis-methoxymethyl ether was obtained as an oil. can get.

Yield: 800η (yield: 98%). Next, the physical properties of this product are as follows. IR(Neat)16601
1165, 1065, 985CTIL-1NMR (CD
Cl3, δ) 1.57 (Sl3H), 1.65 (Sl3
H), 1.74 (Sl3H), 2.0 (Ml4H), 2
．． 17 (Sl3H), 3.37 (Dl2H), 3.57
(Sl6H), 3.83 (Sl6H), 5.02 (Sl
4H), 5.05 (Ml2H) mass spectrometry m/E4O8
(M+) To prepare coenzyme Q2 from the obtained 2,3-dimethoxy-5-methyl-6geranyl-1,4-hydroquinone-bis-methoxymethyl ether 794W, dissolve this in 20 ml of methanol and add hydrochloric acid. After adding 1 drop and reacting at room temperature for 1 hour, methanol is distilled off and the residue is oxidized in a conventional manner to obtain 550η of crude coenzyme Q2.

This is purified by passing it through a silica gel chromatography column to obtain purified coenzyme Q2.

Yield 480W9 (76% overall yield from compound ()). The elemental analysis (as Cl9H26O4) of this product is as follows.

Calculated value C: 71.67% H: 8.23% Actual value C
: 71.56% H: 8.30% Example 22,3-dimethoxy-5-methyl-6-phalnesyl-1,4-hydroquinone-bis-2 tetrahydropyranyl ether synthesis (a) 2,3-dimethoxy- 5-methyl-6-
Preparation of bromo-1,4-hydroquinone-bis-2-tetrahydropyranyl ether 2,3-dihydropyran 3
．． Add 1 drop of concentrated hydrochloric acid to 4y, and slowly add 2 drops while cooling.
・4-dimethoxy-5-methyl-6-bromo-1.4-
Add 1.74f of hydroquinone.

After stirring overnight, it was dissolved in chloroform, washed with alkaline water, the solvent was dried, and then concentrated under reduced pressure to remove excess 2.3
-Dihydropyran is distilled off to obtain crude 2,3-dimethoxy-5-methyl-6-bromo-1,4-hydroquinone-bis-2-tetrahydropyranyl ether. Yield: 2.27y (yield: 80%). The physical properties of this product are as follows.

IR292Oll46l, 1200, 1075, 102
1,948 cm-1 Mass spectrometry m/E43O(M+) (b) Synthesis of 2,3-dimethoxy-5-methyl-6-phalnesyl-1,4-hydroquinone-bis-2-tetrahydropyranyl ether 2,3-dimethoxy- 5-methyl-6-furomo1,4-hydroquinone-bis-2
- 860 η of tetrahydropyranyl ether was dissolved in 20 ml of dry ether under a helium stream, and after cooling to -50°C, n-butyllithium solution (containing 15%, n-
Add 1.4 ml of hexane solution and stir for 20 minutes.

Next, 200η of cuprous iodide was added and the mixture was allowed to react for 1 hour.

Add 490η of falnesyl chloride to this solution and stir for 1 hour. Then stir overnight at room temperature. Pour the reaction solution into ice water and extract with ether. After washing the solvent layer with water and drying, the ether is distilled off to obtain 2,3-dimethoxy-5-methyl-6-phalnesyl-1,4-hydroquinone-bis-2-tetrahydropyranyl ether as a pale yellow oil. Yield 1.06y (yield 95%). This 2,3-dimethoxy-5-methyl-6falnesyl-1,4-hydroquinone-bis-2-tetrahydropyranyl ether 1
．． If 06y is treated in the same manner as in Example 1, coenzyme Q3 will be obtained.

Crude coenzyme Q3 yield: 660▼ Yield: 85% purified coenzyme Q
3 Yield 580W9 Yield 75%Example 3 2,3-dimethoxy-5-methyl-6-solanesyl-1
・Synthesis of 4-hydroquinone-bis-ethoxyethyl ether (a) 2,3-dimethoxy-5-methyl-6-
Preparation of bromo-1,4-hydroquinone-bis-ethoxyethyl ether A trace amount of p-toluenesulfonic acid was added to 4.9f of ethyl vinyl ether, and while cooling, 2.
Add 1.74y of 4-dimethoxy-5-methyl-6-bromo-1,4-hydroquinone.

After stirring at room temperature for 3 hours, chloroform was added, the solution was washed with alkali, and the solvent was dried.

Next, excess ethyl vinyl ether was distilled off by concentration under reduced pressure, resulting in crude 2,3-dimethoxy-5-methyl-6
-Bromo-1,4-hydroquinone-bis-ethoxyethyl ether is obtained. Yield 2.37f (yield 88%).
b) Synthesis of 2,3-dimethoxy-5-methyl-6-solanesyl-1,4-hydroquinone-bis-ethoxyethyl ether 2,3-dimethoxy-5-methyl-6-furomo-1,4-hydroquinone-bis- 815 liters of ethoxyethyl ether was dissolved in 20 ml of dry tetrahydrofuran under a nitrogen stream, cooled to -50°C, and then n-
Butyllithium solution (15% content, n-hexane solution)
Add 1.4ml and stir for 20 minutes.

Next, after adding 200ヮ of cuprous iodide, stirring was continued for 1 hour. Next, add 1.47 solanesyl bromide,
After stirring for 1 hour, continue stirring overnight. The following treatment is carried out in the same manner as in Example 1 to obtain pale yellow oily 2,3-dimethoxy-5-methyl-6-solanesyl-1,4-hydroquinone-bis-ethoxyethyl ether.

Yield 1.75y (yield 93%). If this product is treated in the same manner as in Example 1 without isolation, coenzyme Q9 can be obtained.

Crude coenzyme Q9 yield: 1.38t (overall yield 87%) Purified coenzyme Q: yield 1.29y (overall yield 81%) Example 4 2,3-dimethoxy-5-methyl-6-decaprenyl 1◆Synthesis of 4-hydroquinone-bis-methoxymethyl ether 2,3-dimethoxy-5-methyl-6-bromo 700~ of 1,4-hydroquinone-bis-methoxymethyl ether was added to 20 ml of ntrahydrofuran dried under an argon stream. Comb and cool to -50°C.

To this was added 1.4 ml of n-butyllithium solution (15% n-hexane solution) and stirred for 15 minutes. Next, add 200% cuprous iodide and stir for 1 hour. 1.6y of decaprenyl bromide was added to this solution, stirred for 1.5 hours, and then stirred overnight at room temperature. Following treatment in the same manner as in Example 1, a pale yellow oily 2,3-dimethoxy-5-
Methyl-6-decaprenyl-1,4-hydroquinone-
Bis-methoxymethyl ether is obtained.

Yield 1.85y (yield 97%). The physical properties of this product are as follows.

N23l. 5ll4D゜IR (Neat) 1665, 1165, 1065, 985
CT1L-1NMR (CDCl3, δ) 1.6 (m, 3
3H), 2.0 (Ml39H), 3.38 (d, 2H)
, 3.60 (Sl6H), 3.85 (Sl6H), 5.
05 (Sl4H), 5.1 (m, 10H) this 2・3-
Dimethoxy-5-methyl-6-decaprenyl-1,4-
Hydroquinone-bis-methoxymethyl ether 1.8
Coenzyme QlO can be obtained by treating 5y using a conventional method.

Crude coenzyme QlO yield 1.64y (overall yield 95%) Purified coenzyme QlO yield 1.557 (overall yield 90%) Example 52.3-dimethoxy-5-methyl-6-phytyl-1.4- Synthesis of hydroquinone-bis-methoxymethyl ether 700 watts of 2,3-dimethoxy-5-methyl-6-furomo 1,4-hydroquinone-bis-methoxymethyl ether was dissolved in tetrahydrofuran 20111 dried under an argon stream and heated to -50'C. Cool to

To this was added 1.4 ml of n-butyllithium solution (15% n-hexane solution) and stirred for 15 minutes.

Next, 200~ of cuprous iodide is added and stirred for 1 hour. Add 640η of phytyl chloride to this liquid.

After stirring and reacting for 2 hours, the reaction is continued overnight at room temperature.

Following treatment in the same manner as in Example 1, pale yellow oily 2.3-
Dimethoxy-5-methyl-6-phytyl-1,4-hydroquinone-bis-methoxymethyl ether is obtained.

Yield: 1.077 (97% yield). The physical properties of this product are as follows.

IRl66Olll65, 1065, 985cm Example 6 Synthesis of 2,3-dimethoxy-5-methyl-6-heptaprenyl-1,4-hydroquinone-bis-methoxymethyl ether 2,3-dimethoxy-5-methyl-6-bromo 1. 700~ of 4-hydroquinone-bis-methoxymethyl ether was dissolved in 20 ml of dry tetrahydrofuran under an argon stream, and after cooling to -50°C, n-
Butyllithium solution (15% n-hexane solution) 1
．． Add 4ml and stir for 15 minutes.

Next, cuprous iodide 200W! After adding 9, continue stirring for 1 hour.

Next, 1.12 y of heptaprenyl bumide was added under cooling, and after stirring for 1 hour, the reaction was continued with stirring overnight at room temperature. The reaction solution was poured into saturated ammonium chloride water and extracted with ether.

The ether layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off to obtain pale yellow oily 2,3-dimethoxy-5-methyl-6-heptaprenyl-1,4-hydroquinone bis-methoxymethyl ether. . Yield: 1.457 (97% yield). Next, the physical properties of this product are as follows.

IR (Neat) 1665, 1165, 1065, 98
5cTn-1 Obtained 2,3-dimethoxymethyl-5-
Example 1: Methyl-6-heptaprenyl-1,4-hydroquinone-bis-methoxymethyl ether 1.45y
Coenzyme Q7 can be obtained by processing in the same manner as in (b).

Yield: 0.99y (total yield from compound (): 75%). Next, the elemental analysis (as C44H66O4) of this product is as follows.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, n represents an integer from 0 to 11, X represents a halogen atom, and in each combination of A and B, (B represents a hydrogen atom or A and B represent a bond) or a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, A, B, n and X have the same meanings as above. )
There are compounds represented by the general formula ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 represents a lower alkyl group, R_2 and R
_3 is a hydrogen atom or a lower alkyl group, or R_1 and R_2 or R_3 are bonded to -(CH_2)_4-
There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, R_1, R_2, R_3, A, B and n have the same meanings as above) A method for producing a hydroquinone derivative represented by