JPS5930691B2 - Method for producing hydroquinone derivatives - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula (wherein R1 represents a lower alkyl group, R2 and R3 are hydrogen atoms or lower alkyl groups, or R1 and R2 or R3 are bonded to -(CH2)4- group, n is 0
The present invention relates to a method for producing a mono-hydroquinone derivative represented by an integer of 1 to 11, and A and B represent a bond, or both A and B represent a hydrogen atom.

The compound represented by the general formula (1) obtained by the present invention is expected to have useful pharmacological effects, and is especially important as an intermediate for the production of coenzyme Q.

Coenzyme Q is a physiologically important quinone derivative involved in the electron transport system in living organisms. The object of the present invention is to provide a manufacturing method for obtaining such a manufacturing intermediate for coenzyme Q or its analogues in high yield. Conventionally, coenzyme Q
The main methods for producing coenzyme Q are (1) reacting the hydroquinone form of coenzyme Q or its derivative with prenyl alcohol or its derivative to obtain a condensation reaction product, which is then hydrolyzed and oxidized to produce coenzyme Q; How to obtain (Tokuko Sho 3)
(Refer to Publication No. 9-17513), (2) React the hydroquinone form of coenzyme Q with a prenyl alcohol derivative using an N-sulfinyl compound as a condensing agent, and hydrolyze and oxidize the reaction product to obtain coenzyme Q. Method (Tokuko 1977)
26496), (3) A method of reacting hydroquinone diacetate of coenzyme Q with a π-allyl type nickel complex of a prenyl halogen compound, hydrolyzing the resulting reaction product, and then oxidizing it (see Japanese Patent Publication No. 26496). (see Publication No. 5058021), etc. are known.

However, the acidic catalyst used in method (1) causes decomposition of prenyl alcohol or its derivatives, or the progress of other side reactions is significant, resulting in a reduction in the production yield of coenzyme Q to 30-40%. Furthermore, since it is not easy to remove impurities generated during the reaction, it is impossible to obtain highly pure products in good yields.

The method (2) has the same drawback as the method (1) that the reaction yield is low.

Furthermore, in the force method (3), it is difficult to avoid isomerization of isoprenoids, and the cis/trans ratio increases from K to %, which not only reduces the trans isomer but also makes it extremely difficult to purify it. The inventors of the present invention have conducted various studies to solve the drawbacks of these conventional methods, and as a result have completed a method for obtaining highly purified coenzyme Q and the like with a high yield of 80% or more.

That is, the present invention is based on the general formula (where A and B represent a hydrogen atom or a bond, n represents an integer of O to 11, and X and Y represent a bond, and X2 is・・・
When it represents a rogene atom and Y and X2 represent a bond, X
1 represents a halogen atom) and a compound represented by the general formula (in the formula, R1, R2, R3 have the same meanings as above, and X represents a halogen atom) were combined into hexamethyl triphosphate. The reaction is carried out in the presence of an amide to obtain a hydroquinone derivative represented by the general formula (wherein R1, R2, R3, AB and n have the same meanings as above).

Examples of the compound represented by the general formula () used in the present invention include geranyl bromide, falnesyl chloride, solanesyl bromide, decaprenyl bromide,
Examples include compounds composed of isoprene units such as isodecaprenyl chloride, phytyl bromide, isophyl chloride, and saturated compounds thereof.

In addition, the compound represented by the general formula (), which is another raw material, is a new compound that has not been described in any literature.
, R2, R3 and X have the same meanings as above) with magnesium.

Compounds represented by the general formula () include 2,3-dimethoxy-5-methyl-6-bromo-1,4-hydroquinone-bis-methoxymethyl ether, 2,3-dimethoxy-5-methyl-6-bromo 1 -4-Hydroquinone-bis-tetrahydropyranyl ether and the like. Further, the compound represented by the general formula () is, for example, 2,3-
It can be obtained by halogenating the 6-position of dimethoxy-5-methyl-1,4-quinone, reducing it to 1,4-hydroquinone, and then protecting the 1,4-1 position by a conventional method. . To describe the method of the present invention in more detail,
First, the compound represented by the general formula () is dissolved in a solvent and reacted with magnesium under mild conditions to obtain the compound represented by the general formula ().

Examples of the solvent used in this reaction include hexamethyltriamide phosphate (hereinafter abbreviated as HMPT) alone or a mixed solvent in which an ether solvent such as tetrahydrofuran, ether, dioxane, dimethoxyethane, etc. is added thereto. Note that this reaction is preferably carried out under anhydrous and inert gas flow. The reaction conditions may be selected such that the Grignard reagent is mildly formed, and heating may be applied if necessary. After the compound represented by the general formula () is added dropwise to magnesium, the reaction is further carried out at 0 to 60°C for 1 to 10 hours as necessary to complete the reaction. Next, in order to synthesize the compound represented by the general formula (1), the compound represented by the general formula () is gradually added dropwise to the solution of the compound represented by the general formula () obtained as described above. do.

The reaction conditions are not particularly limited, but generally the reaction may be carried out at 0°C to 50°C for about 2 to 20 hours, particularly preferably at 20 to 30°C for about 4 to 5 hours. Extraction of the target substance after the completion of the reaction can be carried out by, for example, pouring the reaction solution into water, performing solution extraction with a solvent such as ether, washing the ether layer with water, dehydrating the solvent, and distilling it off to obtain the general formula (1).
A compound represented by is obtained. The compound represented by the general formula (1) is oily at room temperature, shows 1 spot on thin layer chromatography without any particular purification, no side reaction products are observed, and almost no quantitative determination is possible. It can be obtained in a reasonable yield. In the method of the present invention, the compound represented by general formula (1) can be obtained in almost quantitative yield, and in extremely high purity without contamination with isomers.

Furthermore, according to the method of the present invention, a highly pure target product can be obtained in a quantitative yield even when the number n of the compound represented by the above general formula () is 6 or more. Furthermore, when coenzyme Q or its analogues are derived from the compound represented by general formula (1), the protecting group of the compound represented by general formula (1) has an acetal or ketal type bond. Since the elimination by acid is extremely smooth, high purity and high yield can be easily achieved 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 1(a) 2,3-dimethoxy-5-methyl-
Synthesis of 6-geranyl-1,4-hydroquinone-bis-methoxymethyl ether Under an argon atmosphere, 50 watts of magnesium was immersed in a mixed solvent of 3 ml of dry tetrahydrofuran (5 mD), and a small amount of iodine was added thereto.
Then 2,3-dimethoxy-5-methyl-6-bromo-
A tetrahydrofuran solution containing 700 watts of 1,4-hydroquinone-bis-methoxymethyl ether is added dropwise with stirring at room temperature.

Then, stir for another 3 hours at room temperature to dissolve the magnesium. The reaction solution was cooled with ice water, and 440 η of geranyl bromide was added dropwise thereto. Stir overnight at room temperature to complete the reaction. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ether using a conventional method. The ether layer was dried with Glauber's salt and the solvent was distilled off to give a pale yellow oily 2,3-
Dimethoxy-5-methyl-6-geranyl-1,4-hydroquinone-bis-methoxymethyl ether is obtained. Yield: 751η (yield: 92%). The physical properties of this product are as follows.

IR (Neat) 1660, 1165, 1065, 98
5? -1 NMR (CDCl3, δ) 1.57 (Sl3H
), 1.65 (Sl3H), 1.74 (Sl3H), 2
．． 0 (m, 4H), 2.17 (s, 3H), 3.37 (
d, 2H), 3,57 (s, 6H), 3.83 (Sl6
H), 5.02 (Sl4H), 5,05 (m, 2H) Mass spectrometry m/E4O8 (M+) (b) 2,3-dimethoxy-5-methyl-6-geranyl-1,4-hydroquinone-bis - To prepare coenzyme Q2 from methoxymethyl ether 682η, dissolve this in 20 ml of methanol, add 1 drop of hydrochloric acid, react at room temperature for 1 hour, then distill off the methanol, and remove the residue using a conventional method. Oxidation yields 525η of crude coenzyme Q2.

This is purified by passing it through a silica gel chromatography column to obtain purified coenzyme Q2. Yield: 478~ (90% yield). Next, the elemental analysis values (as ClOH26O4) of this product are as follows.

Calculated value C: 71.67% H: 8.23% Actual value C
:71.80% H:8.30%Example 2(a) 2
・3-dimethoxy-5-methyl-6-bromo-1.4-
Synthesis of hydroquinone-bis-2-tetrahydropyranyl ether One drop of concentrated hydrochloric acid was added to 3.47 g of 2,3-dihydropyran, and while cooling, the 2,3-dimethoxy-5-methyl-6-bromo- Add 1.74y of 1,4-no)hydroquinone.

After stirring overnight, dissolve in chloroform, wash with alkaline water, dry the solvent, and then concentrate 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: 2.277 (80% yield). The physical properties of this product are as follows.

IR292Oll46l, 120011075, 102
1,948cTn-1 mass spectrometry m/E43O(M+) (b) Synthesis of 2,3-dimethoxy-5-methyl-6-falnesyl-1,4-hydroquinone-bis-2'tetrahydropyranyl ether Under an argon stream, Magnesium 50Tn9 was immersed in a mixed solvent of 5 ml of dry ether and 3 m2 of 11 MPT, a trace amount of iodine was added thereto, and then 2,3-dimethoxy-5-methyl-6-bromo-1,4-hydroquinone-bis-gutetrahydropyranyl ether was added. An ether solution containing 860 m9 is added dropwise with stirring at room temperature.

Then, stir for another 3 hours at room temperature to dissolve the magnesium. The reaction solution was cooled with ice water, and 490 watts of falnesyl chloride was added dropwise thereto. The reaction was stirred overnight at room temperature to complete the reaction. The reaction solution is then poured into a saturated aqueous ammonium chloride solution and extracted with ether according to a conventional method. If the ether layer is dried with Glauber's salt and the solvent is distilled off,
2,3-dimethoxy-5-methyl-6farnesyl-1,4-hydroquinone-bis-2'-tetrahydropyranyl ether is obtained as a pale yellow oil. Yield 894 ~ (
yield 73%). 2.3- obtained in Example 2(b) above
Coenzyme Q3 is obtained by treating dimethoxy 5-methyl-6-phalnesyl-1,4-hydroquinone-bis-cutetrahydropyranyl ether 516 in the same manner as in Example 1(b).

Yield: 381~ (yield: 80%). Example 3 (a) Synthesis of 2,3-dimethoxy-5-methyl-6-solanesyl-1,4-hydroquinone-pismethoxymethyl ether Magnesium was added to a mixed solvent of 5 ml of dry tetrahydrofuran and 3 ml of HMPT under an argon stream. 50η, add a trace amount of iodine, and then add 2,3-dimethoxy-5-methyl-6-bromo-1,4
-Hydroquinone-bis-methoxymethyl ether 70
A tetrahydrofuran solution containing 0η is added dropwise with stirring at room temperature.

Then, stir for another 3 hours at room temperature to dissolve the magnesium. The reaction solution was cooled with ice water, and 1.4 y of solanesyl bromide was added dropwise thereto. The reaction solution was stirred at room temperature for 5 hours to complete the reaction. The reaction solution is then poured into a saturated aqueous ammonium chloride solution and extracted with ether according to a conventional method. The ether layer was dried with Glauber's salt and the solvent was distilled off.
2,3-dimethoxy-5-methyl 6-solanesyl-1,4-hydroquinone bis-methoxymethyl ether is obtained as a pale yellow oil.

Yield: 1.477 (yield: 83%). The physical properties of this product are as follows.

IR (Neat) 1665, 1165, 1065, 98
5cTn-1 2,3-dimethoxy-5-methyl-6-solanesyl-1,4-hydroquinone-bis-methoxymethyl ether 985η obtained in Example 3(a) was treated in the same manner as in Example 1(b). Then, coenzyme Q9 is obtained.

Yield: 769 m9 (yield: 88%). The melting point of this thing is 42
~43°C, and the elemental analysis values (as C54H92O4) are as follows.

Calculated value C: 81.56% H: 10.39% Actual value C: 81.42% H: 10.23% Example 4 (a) 2.3-dimethoxy-5-methyl-6-decaprenyl-1 ・4-Hydroquinone-bis-methoxymethyl ether Under a stream of argon, 50ml of magnesium was immersed in a mixed solvent of 5ml of dry tetrahydrofuran (TT3ml), a trace amount of iodine was added thereto, and then 2,3-dimethoxy-5-methyl-6 1 promotion 1・
A tetrahydrofuran solution containing 4-hydroquinone-bis-methoxymethyl ether 700Tr1f7 is added dropwise while stirring at room temperature.

Then, stir for another 3 hours at room temperature to dissolve the magnesium.

The reaction solution was cooled with ice water, and 1.6 V of decaprenyl bromide was added dropwise thereto. Stir overnight at room temperature to complete the reaction. Pour the reaction solution into saturated ammonium chloride aqueous solution,
Ether is extracted according to the usual method. The ether layer was dried with Glauber's salt and the solvent was distilled off to give a pale yellow oil of 2,3-dimethoxy-5-methyl-6-decaprenyl-1.4
-Hydroquinone-bis-methoxymethyl ether is obtained. Yield: 1.69y (yield: 89%). The physical properties of this product are as follows.

NMl. 5llIR (Neat) 1665, 1165, 1065, 985c
Tn-1 NMR (CDCl3δ) 1.6 (m, 33H), 2
．． 0(m) 39H), 3.38(d) 2H), 3.
60 (s) 6H), 3.85 (s) 6H), 5.
05 (s) 4H), 5.10 (M, IOH) Also, by using isodecaprenyl chloride in place of decaprenyl chloride and treating in the same manner, the corresponding target product is obtained.

2.3-dimethoxy obtained in Example 4(a) above
Coenzyme QlO can be obtained by treating 1.65V of 5-methyl-6-decaprenyl-1,4-hydroquinone-bis-methoxymethyl ether in the same manner as in Example 1(b).

Yield: 1.28V (yield: 86%). The melting point of this thing is 46
．． The temperature was 5 to 48°C, and its structure was identified by infrared absorption spectrum and nuclear magnetic resonance spectrum.

Claims (1)

[Claims] 1. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, A and B represent a hydrogen atom, or A and B represent a bond. , n represents an integer from 0 to 11, and when X_1 and Y represent a bond, X_2
represents a halogen atom, and when Y and X_2 represent a bond, X_1 represents a halogen atom. 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-
(X represents a halogen atom) in the presence of hexamethyltriamide phosphate ▲ There are mathematical formulas, chemical formulas, tables, etc. , R_2, R_3, A, B and n have the same meanings as above).