JPH0133454B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula (wherein R represents a lower alkyl group and n represents an integer of 0 to 11).

The compound represented by the general formula () obtained by the present invention is a new compound and is expected to have useful pharmacological effects, especially coenzyme Q.
It is important as a manufacturing intermediate. 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.

The main conventional 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; How to obtain coenzyme Q (Tokukosho)
(Refer to Publication No. 39-17513), (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 produce coenzyme Q. How to get it (Tokuko Showa 47
-26496), (3) A method in which hydroquinone diacetate of coenzyme Q is reacted with a π-allylic nickel complex of a prenyl halogen compound, and the resulting reaction product is hydrolyzed and then oxidized. (Refer to Publication No. 58021/1983) etc. are known.

However, in method (1), prenyl alcohol or its derivatives are decomposed by the oxidation catalyst used, or other side reactions proceed significantly, so the production yield of coenzyme Q is reduced to 30-40%. Moreover, since it is not easy to remove impurities generated during the reaction, it is impossible to obtain highly pure products in good yield.

Like method (1), method (2) has the disadvantage of low reaction yield, and method (3) has the disadvantage that isomerization of isoprenoids is difficult to avoid, resulting in a cis/trans ratio of 1/4 to 1/4. 3, not only does the amount of trans isomer decrease, but it is also extremely difficult to purify it.

As a result of various studies aimed at solving the drawbacks of these conventional methods, the present inventors have completed a method for efficiently obtaining coenzyme Q and the like.

That is, the present invention is based on the general formula (In the formula, n represents an integer of 0 to 11) and a compound represented by the general formula [In the formula, R represents a lower alkyl group, M represents Li or MgX (X is a halogen atom)] by reacting with a compound represented by the general formula A hydroquinone derivative represented by the formula (wherein R and n have the same meanings as above) is obtained.

Examples of the compounds represented by the general formula () used in the present invention include geranial (n=1 in the general formula ()), fualnesal (n=2 in the general formula ()), and solanesar (n=2 in the general formula ()). 8), and compounds composed of isoprene units such as decaprenal (n=9 in general formula ()). In addition, compounds represented by the general formula (), which are other raw materials, may be expressed by the general formula (in the formula, R represents a lower alkyl group) or the general formula (wherein R represents a lower alkyl group and X represents a halogen atom), alkyllithium or phenyllithium is allowed to act on the compound, or magnesium is made to act on the compound represented by the general formula (). It can be prepared by Among the compounds represented by the above general formulas () and (), compounds in which R is a methyl group are particularly commercially advantageous.

To describe the method of the present invention in more detail, first, the compound represented by the general formula () or () is dissolved in a solvent, and a lithiation agent is added to prepare the compound represented by the general formula (). The lithiation agent used in this reaction is n-
Examples include butyllithium, ethyllithium, methyllithium, phenyllithium, etc., but especially n
-Butyllithium is preferred. Also general formula ()
Examples of the solvent used when preparing the compound represented by the general formula (2) by dissolving the compound represented by the above in a solvent and adding magnesium include tetrahydrofuran, ether, dimethoxyethane, hexamethylphosphoramide, and the like. Note that these reactions are preferably carried out in an anhydrous state and under an inert gas flow. The obtained compound represented by the general formula () does not need to be particularly isolated, and it is advisable to immediately subject it to the next reaction. That is, it is preferable to react with a compound represented by the general formula () to lead to a synthetic intermediate such as coenzyme Q represented by the general formula (). The reaction conditions at this time vary depending on the type of compound represented by the general formula (), but it is generally preferable to carry out the reaction at room temperature or below.The reaction is started at 0°C or below, the temperature is gradually raised, and then the reaction is carried out at room temperature. Terminate it.

After the reaction is completed, 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 (). 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 () can be obtained efficiently and with extremely high purity and isomer-free. Further, according to the present invention, even substances in which the number n of the compound represented by the general formula () is 6 or more can be obtained in high yield.

Furthermore, in order to derive coenzyme Q or its related substances from the compound represented by the general formula (), the compound represented by the general formula () is dissolved in liquid ammonia.
By treating with an alkali metal or the like to remove the hydroxyl group at the benzyl position, followed by acid treatment to remove the protective group and subsequent oxidation, coenzyme Q or its analogues can be easily derived in good yield. Note that the hydroxyl group at the benzyl position can also be removed without isolating the compound represented by the general formula ().

In the present invention, since the OH group of the above-mentioned 1,4-hydroquinone compound is protected with a specific protecting group, this protecting group can be easily removed by acid treatment. When the OH group of a 4-hydroquinone compound is protected with a methyl group, demethylation does not occur by similar acid treatment, so the selection of the above-mentioned specific protecting group in the present invention has great significance. .

Next, the present invention will be explained with reference to examples, but the present invention is not limited to the following examples.

Example 1 Drying 140 mg of magnesium under argon atmosphere
After soaking in 5 ml of THF and adding a small amount of iodine, a solution of 1.76 g of 6-bromo-2,3-dimethoxy-5-methyl-1,4-hydroquinone-bis-methoxymethyl ether dissolved in 10 ml of THF is added dropwise while stirring. . After reacting at room temperature for 1 hour, it was cooled to 0°C, and decaprenal (the above general formula ()) was added to this.
In the case of n=9), a solution of 3.45 g dissolved in 10 ml of THF was added dropwise, and the temperature was raised to room temperature over about 30 minutes. The reaction solution is poured into water and extracted with IPE, and the IPE layer is sequentially washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, and saturated brine, dried over anhydrous magnesium sulfate, and the solution medium is distilled off under reduced pressure to obtain 4.77 g of a hydroquinone derivative.

Next, the physical properties of the purified product are as follows.

IR (neat) 3580, 1600, 1180, 1080, 990 cm ^-1 NMR (CCl ₄ , δ) 1.65 (m, 33H), 2.0 (m, 36H) 2.25 (s, 3H), 3.20 (s, 3H) 3.25 ( s, 3H), 2.95 (bs, 1H) 3.80 (s, 6H) 4.90 (s, 2H), 5.00 (s, 2H) 5.0 (m, 9H) 5.57 (m, 2H) The obtained hydroquinone derivative was placed in an argon stream. Dissolve in 30 ml of dry THF, cool to below -50℃, and pour about 50 ml of ammonia into the bottom. Add 1.0 g of metallic calcium to this and stir for 30 minutes, then add 4.0 g of ammonium chloride and remove the ammonia after the blue color disappears. Add water to the residue and extract with IRE, then IPE
The layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to give 6-decaprenyl-2,3-dimethoxy-5-methyl-
4.56 g of 1,4-hydroquinone-bis-methoxymethyl ether are obtained.

To obtain coenzyme Q ₁₀ from this product, remove the protective group with acid according to the conventional method, then oxidize and purify with a silica gel column to obtain 2.30 g of coenzyme Q ₁₀ (total yield from decaprenal 54%). ).

Comparative Example (a) 140 mg of magnesium was immersed in 5 ml of dry THF under an argon atmosphere, and after adding a catalytic amount of iodine, 2,3,4,5-tetramethoxy-
1.46g of 6-methylbromobenzene in 10ml of THF
A solution dissolved in was added dropwise. After reacting at room temperature for 1 hour, the mixture was cooled to 0°C, and a solution of 3.45 g of decaprenal (n=9) dissolved in 10 ml of THF was added dropwise thereto, and the temperature was raised to room temperature over about 30 minutes. Pour the reaction solution into water and extract with IPE.
The layer was sequentially washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 4.50 g of a hydroquinone derivative.

The obtained hydroquinone derivative was dissolved in 30 ml of dry THF under an argon stream, cooled to below -50°C, and about 50 ml of ammonia was poured into the solution. After adding 1.0 g of metallic calcium to this and stirring for 30 minutes, 4.0 g of ammonium chloride was added and after the blue color disappeared, the ammonia was removed. IPE by adding water to the residue
After extracting with 4.20
g (yield 93%).

(b) 1.00 g of 2,3,4,5-tetramethoxy-6-methyldecaprenylbenzene in methanol 30
ml, 1 drop of hydrochloric acid was added, and the mixture was allowed to stand at room temperature for 24 hours, but the reaction did not proceed at all, and the starting material was recovered quantitatively.

Even if the acid concentration and/or reaction temperature were increased, the desired hydroquinone compound could not be obtained, and only decomposition products were produced. Therefore, coenzyme Q ₁₀ could not be obtained using the same method as in Example 1.

Example 2 2,3-dimethoxy-5- under argon atmosphere
Add 1.36 g of methyl-1,4-hydroquinone-bis-methoxymethyl ether to 20 ml of dry tetrahydrofuran, cool to 0°C, and dropwise add 3.2 ml of n-butyllithium hexane solution (15% by weight) while stirring at 0 to 10°C. Let it react for 1 hour. The reaction solution was reduced to -10
The mixture was cooled to .degree. C., and 0.76 g of geranial (when n=1 in the general formula ()) was added dropwise, and the temperature was raised to room temperature over about 30 minutes to obtain a hydroquinone derivative. The desired product is cooled to below -50℃ under an argon stream without separation, and added with about 30 ml of ammonia.
and then add 100 mg of metallic lithium in small pieces. After the solution turns deep blue, carefully add 2.0 g of ammonium chloride, and after the blue color disappears, remove the ammonia.

Add water to the residue and extract with IPE, and extract the IPE layer with water and
After washing with saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 6-geranyl-2,3-dimethoxy-5-methyl-1,4-
Hydroquinone-bis-methoxymethyl ether
Obtain 1.95g.

To obtain coenzyme Q ₂ from this product, remove the protective group with acid and oxidize it according to the conventional method, and then purify with a silica gel column to obtain 875 mg of coenzyme Q ₂ (total yield from geranial: 55%).

The physical properties of the hydroquinone derivative obtained by the above method are as follows.

IR (neat) 3580, 1600, 1180, 1080, 990 cm ^-1 NMR (CCl ₄ , δ) 1.66 (m, 9H), 2.1 (m, 4H) 2.26 (s, 3H), 2.95 (bs, 1H) 3.53 ( s, 3H), 3.57 (s, 3H) 3.87 (s, 6H), (s, 2H) 5.06 (s, 2H), 5.06 (m, 1H) 5.57 (m, 2H)

Claims (1)

[Claims] 1. General formula (In the formula, n represents an integer of 0 to 11) and a compound represented by the general formula [In the formula, R represents a lower alkyl group, and M is Li or
A general formula characterized by reacting with a compound represented by MgX (X represents a halogen atom) A method for producing a hydroquinone derivative represented by the formula (wherein R and n have the same meanings as above).