JPS5914014B2 - Production method of 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 represent a hydrogen atom or a lower alkyl group, or R1
and R2 or R3 combine to represent a -(CH2)4 group, n represents an integer of O to 11, and A and B represent a bond, or A and B both represent a hydrogen atom. show)
This invention relates to a method for producing a hydroquinone derivative represented by:

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 Kino2 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)
(Refer to Publication No. 26496), (3) Hydroquinone-diacetate of coenzyme Q and π- of prenyl halogen compound
A method of reacting with an acrylic type nickel complex, hydrolyzing the obtained reaction product, and then oxidizing it (Japanese Patent Application Laid-Open No. 5058021
(see Publication No.) etc. are known.

However, in the method (1) above, prenyl alcohol or its derivatives are decomposed by the acidic catalyst used, or other side reactions proceed significantly, so the production yield of coenzyme Q is reduced 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) above has the same drawback as the method (1) in that the reaction yield is low, and the method (3) above has the disadvantage that isomerization of isoprenoids is difficult to avoid and the cis/trans ratio increases from % to %. Not only is the trans-isomer reduced, but it is also extremely difficult to purify.

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 and B represent a bond, and n is O-11
and when X1 and Y represent a bond, X2 represents a halogen atom, and when Y and X2 represent a bond, X1 represents a halogen atom) and the compound represented by the general formula (where R1 represents a lower alkyl group, R2
and R3 is a hydrogen atom, a lower alkyl group, or R
1 and R2 or R3 combine to represent a 1(CH2)4- group) to react with a compound represented by the general formula (wherein R1, R2, R3, AB and n have the same meanings as above). This is to obtain a hydroquinone derivative represented by

Examples of the compound represented by the general formula () used in the present invention include geranyl furomide, 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.

Furthermore, the compound represented by the general formula () is a compound that has not been described in any literature, and is produced by, for example, halogenating the 6-position of 2,3-dimethoxy-5-methyl-1,4-quinone and then reducing it to 1. 4-hydroquinone and 1 by a conventional method.
・Protect the 4-1 position to obtain a compound represented by the general formula (in the formula, Rl.R2 and R3 have the same meanings as above, and X represents a rogen atom), and then add magnesium to this in a solvent. By reacting under mild conditions, the general formula (wherein R,, R2, R3 and X have the same meanings as above)
It can be obtained by preparing a compound represented by the following formula and then reacting this compound with cuprous halide.

Examples of solvents used when synthesizing the compound represented by the general formula () from the compound represented by the general formula () via the compound represented by the general formula (V) include ether, tetrahydrofuran, dioxane, dimethoxyethane, and phosphorus. Anhydrous solvents such as acid hexamethyltriamide (hereinafter referred to as HMPT) are preferred, particularly HMPT alone or a mixed solvent of tetrahydrofuran and HMPT. To explain in more detail the preparation of the compound represented by the general formula (), a solution of the compound represented by the general formula () in the above solvent is added dropwise to magnesium under a stream of an inert gas such as nitrogen or argon. and react. At this time, it is sufficient to select conditions that allow the Grignard reagent to be formed mildly, and heating may be carried out if necessary. As for the reaction conditions, after adding the compound represented by the general formula (), the reaction is carried out at 0 to 60°C for an additional 1 to 10 hours as required. Next, an equivalent amount of cuprous halide, such as cuprous iodide, is added to the thus obtained Grignard compound represented by the general formula (V) at room temperature, and the reaction is terminated by stirring for 15 to 60 minutes. . 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.

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. To extract the target substance after the completion of the reaction, for example, pour the reaction solution into water, perform liquid-liquid extraction with a solvent such as ether, wash the ether layer with water, dehydrate the solvent, and distill it off to obtain the general formula (1 )
A compound represented by is obtained. The compound represented by the general formula () is oily at room temperature, shows 1 spot on thin layer chromatography without any particular purification, no side reaction products are observed, and the yield is almost quantitative. You can get it at 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 the compound represented by general formula (1) is derived from coenzyme Q or its analogues, the protecting group of the compound represented by general formula (1) has an acetal type or ketal type bond. Since the elimination by acid is extremely smooth, 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 1(a) 2,3-dimethoxy-5-methyl-
Synthesis of 6-geranyl-1,4-hydroquinone-bis-methoxymethyl ether 50η of a magnesium ribbon was soaked in 5 ml of dry tetrahydrofuran, a trace amount of iodine was added, and 2,3-dimethoxy-5-methyl was added while stirring under an argon stream. A solution of 700 η of -6-promo 1,4-hydroquinone-bis-methoxy ether dissolved in 15a of tetrahydrofuran is added dropwise.

Then stir until the magnesium is dissolved. HMPT37nl and cuprous iodide 390W1j? in the reaction solution.
Add and stir for another 30 minutes at room temperature. Next, 440 η of geranyl bromide was added to this reaction solution, and the mixture was stirred and reacted at room temperature for 3 hours.

After the reaction is completed, the mixture is poured into a saturated aqueous ammonium chloride solution and extracted with ether. After washing the ether layer with water, it is dried over anhydrous magnesium sulfate. The solvent was distilled off to give pale yellow oil 2.
・3-dimethoxy-5-methyl-6-geranyl 1,4
-Hydroquinone-bis-methoxymethyl ether is obtained. Yield: 759 w (yield: 93%). Next, the scope of this object is shown below.

IR (Neat) 166011165, 1065, 9
85CT1L-1NMR (CDCl3, δ) 1.57
(s, 3H), 1,65 (Sl3H), 1.74 (Sl
3H), 2.0 (Ml4H), 2.17 (Sl3H),
3.

37 (Dl2H), 3.57 (Sl6H), 3.83 (
s, 6H), 5.02 (s, 4H), 5.05 (Ml2
H) Mass spectrometry m/E4O8(M+) (b) To prepare coenzyme Q2 from 2,3-dimethoxy-5-methyl-6-geranyl-1,4-hydroquinone-bis-methoxymethyl ether 793, this After dissolving the product in 20 ml of methanol, adding one drop of hydrochloric acid and reacting at room temperature for 1 hour, methanol is distilled off and the residue is oxidized in a conventional manner to obtain crude coenzyme Q2 (578 w).

This is purified by passing it through a silica gel chromatography column to obtain purified coenzyme Q2. Yield: 556 kg (Example 1(a)
total yield of 84%). Next, the elemental analysis value (
Cl, H26O4) are as follows. Calculated value C: 71.67H: 8.23 (%) Actual value
C: 71.51H: 8.20 (%) Reference Example 2 Preparation of 3-dimethoxy-5-methyl-6-bromo 1,4-hydroquinone-bis-2/-tetrahydropyranyl ether 2, 3-dihydropyran 3 Add 1 drop of concentrated hydrochloric acid to .4y, and slowly add 1.74y of 2,3-dimethoxy-5-methyl-6-bromo-1,4-hydroquinone while cooling.

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 produce crude 2,3-dimethoxy5-methyl-6-promo-1,4-hydroquinone-
Bis-2'-tetrahydropyranyl ether is obtained. Yield: 2,277 (80% yield). The physical properties of this product are as follows. IR292O, 1461, 1
200, 1075, 1021, 948? -1 mass spectrometry
n/E43O(M+) Example 2 Synthesis of 2,3-dimethoxy-5-methyl-6-phalnesyl-1,4-hydroquinone-bis-2'tetrahydropyranyl ether 55 g of magnesium was mixed with 7 ml of dried isopropyl ether and 3 ml of HMPT. Immerse in a mixed solvent, add a catalytic amount of iodine, and stir under an argon stream to add 860% of 2,3-dimethoxy-5-methyl-6-bromo-1,4-hydroquinone-bis-2'-tetrahydropyranyl ether. A solution dissolved in 15 ml of dry isopropyl ether was slowly added dropwise and allowed to react at room temperature for 3 hours, then 390 watts of cuprous iodide was added and allowed to react for 30 minutes.

Next, add 490% of falnesyl chloride and add 3% at room temperature.
Stir for an hour. Pour the reaction solution into ice water and extract with ether.

The ether layer is washed with water, dried, and then the ether is distilled off to obtain 2,3-dimethoxy-5-methyl-6-phalnesyl-1,4-hydroquinone-bis-2'-tetrahydropyranyl ether. Yield 0.867 (yield 70%)
. Coenzyme Q3 can be obtained by treating 0.867 of this 2,3-dimethoxy-5-methyl-6-falnesyl-1,4-hydroquinone-bis-2'tetrahydropyranyl ether in the same manner as in Example 1(b). .

Crude coenzyme Q3 yield: 670 η (yield 87%) Purified coenzyme Q3 yield: 422η (yield 55%) Example 32,3-dimethoxy-5-methyl-6-solanesyl-1,4-hydroquinone-bis-methoxy Synthesis of methyl ether 50η of magnesium was soaked in 5ml of dry tetrahydrofuran, iodine was added in a catalytic amount, and 2.
3-dimethoxy-5-methyl to 6-bromo-1,4-hydroquinone-bis-methoxymethyl ether 700η
A solution containing 30 ml of dry tetrahydrofuran was slowly added, and after reacting at room temperature for 3 hours,
Add 390η of copper and react for 30 minutes.

Next, 1.47 g of solanesyl bromide was added to this reaction solution, stirred for 2 hours, and then allowed to stand overnight at room temperature.

If the following treatment is carried out in the same manner as in Example 1, pale yellow oily 2.3
-dimethoxy-5-methyl-solanesyl 1,4-hydroquinone-bis-methoxymethyl ether is obtained.

Yield: 1.497 (84% yield). The physical properties of this product are as follows.

IR (Neat) 1665, 1165, 1065, 9
850 m-1 2,3-dimethoxy-5-methyl-6 solanesyl-1,4-hydroquinone-bismethoxymethyl ether 1.497 was treated in the same manner as in Example 1(b) to obtain coenzyme Q9. It will be done.

Yield: 1.19y (total yield: 75%). The elemental analysis values (as C54H, 2O4) of this product are as follows.

Calculated value C: 81.56% H: 10.39% actual value
C: 81.44% H: 10.51% Example 42.3
-dimethoxy-5-methyl-6-solanesyl-1 ・4
-Synthesis of hydroquinone-bis-ethoxyethyl ether (a) Synthesis of 2,3-dimethoxy-5-methyl-6-bromo-1,4-hydroquinone-bis-ethoxyethyl ether One drop of concentrated ethyl vinyl ether 2,9f Add hydrochloric acid and gradually add 2,3-dimethoxy5-methyl-6-bromo-1,4-hydroquinone while cooling.
Add.

After stirring at room temperature for 3 hours, chloroform is added to dissolve the mixture, and this solution is washed with alkali, and then the solvent is dried.

Next, by concentrating under reduced pressure and distilling off excess ethylpinyl ether, crude 2,3-dimethoxy-5-methyl-6
-Bromo-1,4-hydroquinone-bis-ethoxyethyl ether is obtained.

Yield 1.3f (yield 90%). The physical properties of this product are as follows.

IR (Neat) 2880, 1450, 1406, 1
338, 1142, 1080 cm-1 NMR (CDCl
3, δ) 1.13 and 1.17 (2 Tl6H)
1.43 and 1.52 (2 Dl6H) 2.36 (
Sl3H) 3.7 (Ml4H) 3.86 (Sl6H) 5
．． 35 (Ml2H) mass spectrometry m/E4O6 (M+) (
b) 2,3-dimethoxy-5-methyl-6-bromo-
Example 3 except that 820 W of 2,3-dimethoxy5-methyl-6-bromo-1,4-hydroquinone-bis-ethoxyethyl ether was used instead of 1,4-hydroquinone-bis-methoxymethyl ether. Process in the same way,
Coenzyme Q9 was obtained in a yield of 0.95V (total yield 60% from Example 4(a), melting point 41.5-42.5°C).

Example 5 Synthesis of 2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-hydroquinone-bis-methoxymethyl ether Magnesium 50W1f was immersed in a mixed solvent of 7 ml of dry tetrahydrofuran and 3 ml of HMPT, and a catalytic amount of iodine was added thereto. was added, and while stirring under an argon stream, a solution of 2,3-dimethoxy-5-methyl-6-bromo-1,4-hydroquinone-bismethoxymethyl ether 700Tn9 dissolved in 20 ml of dry tetrahydrofuran was added dropwise. After reacting at room temperature for 3 hours, cuprous iodide 390Tf19 was added and the reaction was further continued for 1 hour.

Next, 1.537 g of decaprenyl bromide was added to this reaction solution, and the mixture was stirred at room temperature for 5 hours.

The following treatment is carried out in the same manner as in Example 1(a) to obtain pale yellow oily 2,3-dimethoxy-5-methyl-6decaprenyl-1,4-hydroquinone-bismethoxymethyl ether. Yield: 1.647 (86% yield). The physical properties of this product are as follows.

nD1.5114IR (Neat) 1665, 116
5, 1065, 985? -1NMR(CDCl3, δ
) 1.6 (m, 33H), 2.0 (m, 39H), 3
．． 38 (d, 2H), 3.60 (s, 6H), 3.85
(s, 6H), 5.05 (Sl4H), 5.10 (Ml
lOH) Obtained 2,3-dimethoxy-5-methyl-6
Coenzyme QlO is obtained by treating 1.64f of decaprenyl-1,4-hydroquinone-bis-methoxymethyl ether in the same manner as in Example 1(b).

Crude coenzyme QlO yield: 1.387 (total yield from Example 5(a) 80%) Purified coenzyme QlO yield: 1.337 (
Total yield 77% from Example 5(a)) Purified coenzyme Q,
.

The melting point was 46.5-48°C. Example 6 (a) Synthesis of 2,3-dimethoxy-5-methyl-6-phytyl-1,4-hydroquinone-bis-methoxymethyl ether Soak 50η of magnesium in a mixed solvent of 7 ml of dry tetrahydrofuran and 3 ml of HMPT.
To this was added a catalytic amount of iodine, and while stirring under an argon atmosphere, 700 η of 2,3-dimethoxy5-methyl-6-furomo1,4-hydroquinone-bis-methoxymethyl ether was added to the mixture, and 200 η of tetrahydrofuran was dried.
After adding the solution dissolved in m1 dropwise and reacting at room temperature for 2 hours, 390° of cuprous iodide was added and the reaction was further allowed to proceed at room temperature for 1 hour.

Next, 640η of phytyl chloride was added to this reaction solution,
Stir 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: 0.997 (90% yield). The physical properties of this product are as follows. IRl66O, 1165, 1
065,985cm Also, when isophyl chloride is used in place of phytyl chloride, the corresponding desired product can be obtained in the same manner.

)) If 470η of 2,3-dimethoxy-5-methyl-6-phytyl-1,4-hydroquinone-bis-methoxymethyl ether is treated in the same manner as in Example 1(b), 2
・3-dimethoxy-5-methyl-6-phytyl-1,4
-benzoquinone is obtained.

Yield: 354η (total yield from Example 6(a): 81%)
. The physical properties of this product are as follows. IRl
67Ol46Ol264l2l O, 1160cTrL-1 Elemental analysis value (as C29H48O4)

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, 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 X_
When 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), and there are general formulas, mathematical formulas, chemical formulas, tables, etc. (In the formula, R_1 represents a lower alkyl group, R_2 and R
_3 represents a hydrogen atom or a lower alkyl group, or R_1 and R_2 or R_3 are bonded to -(CH_
2) There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by reacting with compounds represented by A method for producing hydroquinone derivatives represented by (having the same meaning).