JP5060299B2 - Method for producing quinone compound - Google Patents

Description

  The present invention relates to a method for producing menatetrenone, which is a quinone compound.

  Menatetrenone is the following formula (1)

In addition to being used for the prevention and treatment of vitamin K deficiency, the vitamin K ₂ preparation containing the compound as an active ingredient is also used as an osteoporosis preventive and therapeutic agent.

Menatetrenone is also contained in natto, which is a fermented food, but chemical synthesis is the mainstream as an industrial production method.
There are several known production methods by chemical synthesis of menatetrenone, one of which is a method of oxidizing the precursor hydroquinone to obtain the desired quinone, menatetrenone. (Non-Patent Document 1).

The method disclosed in Non-Patent Document 1 is a method using silver oxide. Similarly, a method using a metal oxide such as manganese dioxide and lead peroxide (Patent Document 2) is known.
However, the use of metal oxides has the disadvantages that the reaction is difficult to control and a side reaction may occur, and that a treatment for preventing adverse effects on the environment is required after the reaction.

Therefore, a method using hydrogen peroxide has been developed (Patent Document 1).
However, hydrogen peroxide is a strong oxidizing agent, and there is a problem that special handling in consideration of safety is required when handling a large amount.

As a method for producing ubiquinones having a structure similar to menatetrenone, methods using molecular oxygen, which is a milder oxidant, are known (Patent Documents 3 to 6).
However, when molecular oxygen is used in the method for producing ubiquinones, it is known that oxygen alone has a remarkably low reaction rate, and complete oxidation cannot be expected (Patent Documents 5 and 6). In order to overcome this, it is known that it is essential to add a base (Patent Document 4), silica gel (Patent Document 5), copper or copper ions, ammonia or ammonium ions (Patent Document 6), etc. to the reaction solution. It was done. Such a method using an additive other than an oxidizer may cause a side reaction in the presence of the additive, and the post-reaction treatment is complicated, so that the metal oxide can be added to the quinone compound production method. There is a common problem with using it.

  Further, as a method for producing menatetrenone, a specific method using molecular oxygen has not been known at all.

Kozlov, E.I., Meditsinskaya Promyshlennost SSSR (1965), 19 (4), 16-21 JP 48-49733 A JP-A 49-55650 Japanese Patent Publication No. 39-17514 JP-A-52-72884 JP 54-151932 A JP 62-81347 A

  Accordingly, an object of the present invention is to provide a method for producing menatetrenone that does not adversely affect the environment, is safe even when produced in large quantities, and is easy to operate.

As described above, there is a problem in the conventional method for producing menatetrenone, and the present inventors have intensively studied the oxidation method of hydroquinone (2) which is a precursor of menatetrenone. Thus, it has been found that a sufficient reaction rate can be obtained without using any additive or causing a significant side reaction, and the oxidation reaction can proceed completely. This point was totally unexpected when using molecular oxygen alone as an oxidant, because the reaction rate was extremely low and complete oxidation was not expected for a long time. .
It was also found that by allowing water to coexist in the reaction solution, the oxidation reaction itself is not affected, but safety can be improved. Based on these findings, the inventors have found that menatetrenone can be produced by a method that does not adversely affect the environment, is safe even when produced in large quantities, and is easy to operate, and has completed the present invention.

That is, the first aspect of the present invention is:
The following formula (1)

A method for producing a compound represented by formula (2):

The reaction method which consists only of the solution which melt | dissolved the compound represented by this in the solvent is processed with an oxygen source, The manufacturing method characterized by the above-mentioned is provided.

  Moreover, the second aspect of the present invention is the following formula (1).

A process for producing a compound represented by
i) Formula (2)

A solution of the compound represented by formula (I) in an organic solvent immiscible with water, and ii) water or an aqueous sodium chloride solution,
The present invention provides a production method characterized by treating a reaction solution consisting of only an oxygen source.

  The oxygen source in the first and second embodiments is preferably air, and the treatment with the oxygen source is preferably blowing the oxygen source into the reaction solution.

  According to the present invention, menatetrenone can be produced by a method that does not adversely affect the environment, is safe even when produced in large quantities, and is easy to operate.

  Hydroquinone (2), which is a precursor of menatetrenone used in the present invention, is a known substance, and several synthesis methods are known. For example, by the following route disclosed in Non-Patent Document 1 Can be synthesized.

  As described above, the hydroquinone body (2) can be synthesized by condensing menadiol monoacetate (4) and all-trans-geranyl linalool (5) and treating with Claisen's alkaline solution.

  As described in Non-Patent Document 1, the condensation reaction of menadiol monoacetate (4) and all-trans-geranyl linalool (5) is performed by adding menadiol monoacetate (4), zinc chloride, and boron trifluoride in dioxane. The reaction can be performed by heating to 50 ° C., dropping a dioxane solution of all-trans-geranyl linalool (5) into the reaction mixture over 30 minutes, and then holding at 50 ° C. for 30 minutes.

  The solvent used in this condensation reaction can be used other than dioxane as long as it does not inhibit the reaction. For example, carbon tetrachloride, dichloromethane, chloroform, n-pentane, n-hexane, N, N-dimethyl Foramide, N-methylpyrrolidone, acetonitrile, dimethyl sulfoxide, benzene, toluene, xylene, methanol, ethanol, n-propanol, isopropanol, tert-butyl alcohol, methyl acetate, or ethyl acetate can be used. These can be used alone, but two or more can be mixed and used in an arbitrary ratio.

Further, the acid catalyst used in the condensation reaction can be used in addition to the above zinc chloride and BF ₃ · OEt ₂ , such as oxalic acid, potassium sulfate, potassium persulfate, zinc (II) triflate, or Metal salts such as copper (I) sulfate, para-toluenesulfonic acid, methanesulfonic acid, sulfophthalic acid, hydroxybenzenesulfonic acid, nitrobenzenesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, naphthylsulfonic acid, dodecylbenzenesulfonic acid, 4 4,4'-biphenyldisulfonic acid or sulfonic acid derivatives such as flavianic acid can be used.

As described in Non-Patent Document 1, the monoacetyl compound (3) obtained by the condensation reaction was added with Claisen's alkali (prepared by dissolving 35 g of KOH in 25 mL of water and diluting to 100 mL with CH ₃ OH). A 3% aqueous solution of sulfite and ether are added and stirred, followed by liquid separation to obtain a hydroquinone (2) ether solution. The extraction solvent after the Claisen treatment can be used in addition to ether, for example, carbon tetrachloride, dichloromethane, chloroform, n-pentane, n-hexane, N-methylpyrrolidone, benzene, toluene, xylene, tert- Examples include butyl alcohol, methyl acetate, and ethyl acetate. These can be used alone, but two or more can be mixed and used in an arbitrary ratio.

  The next step is an oxidation reaction of the production method of the present invention. In the present invention, the hydroquinone (2) extract obtained in the previous step may be used as it is, or the solvent may be changed by removing the extraction solvent by distillation under reduced pressure or the like. In any case, it suffices to prepare a solution in which the hydroquinone body (2) is dissolved with a solvent, and it is not necessary to add other additives except when adding water and a sodium chloride aqueous solution described later. The solvent is not particularly limited as long as it dissolves the hydroquinone (2) and does not inhibit the oxidation reaction. Examples thereof include carbon tetrachloride, dichloromethane, chloroform, n-pentane, n-hexane, N, N-dimethyl. Foramide, N-methylpyrrolidone, acetonitrile, dimethyl sulfoxide, benzene, toluene, xylene, methanol, ethanol, n-propanol, isopropanol, tert-butyl alcohol, methyl acetate, ethyl acetate and the like can be mentioned. These can be used alone, but two or more can be mixed and used in an arbitrary ratio, and can also be used as a hydrous solvent.

  The present invention is characterized in that it can be carried out using only a solution in which the hydroquinone (2) is dissolved with a solvent. That is, it is not necessary to add other additives in order to advance and complete the oxidation reaction. However, in consideration of safety, it is preferable to carry out a two-layer system by adding water or an aqueous sodium chloride solution. When carried out in a two-layer system, an organic solvent immiscible with water, such as carbon tetrachloride, dichloromethane, chloroform, n-pentane, n-hexane, N-methylpyrrolidone, benzene, toluene, xylene, tert-butyl alcohol, acetic acid Methyl, ethyl acetate, or a mixed solvent of two or more thereof is preferably used as the solvent. Whether water or an aqueous sodium chloride solution is used may be appropriately selected depending on the solvent used. For example, the better separation of the organic layer and the aqueous layer can be selected during the liquid separation after the reaction.

  The oxygen source used in the present invention refers to one that can introduce molecular oxygen into the reaction system, and examples thereof include oxygen gas and air. When oxygen gas or air is used as an oxygen source, it may be used as a mixed gas with another gas that does not inhibit the present invention, for example, nitrogen, helium, argon or the like.

The reaction substrate in the reaction solution and the molecular oxygen introduced into the reaction system are preferably brought into efficient contact by blowing an oxygen source. For example, if the reaction solution blowing air, Dari blown from the nozzle, Dari blown foamy air comprises a porous member on the tip of the nozzle, into the reactor, and bored a number of holes in the ring-shaped pipe It may be provided that air is blown out of the large number of holes as moderately sized bubbles, and various other device means can be taken.

The temperature condition for the oxidation reaction of the present invention may be appropriately selected at a temperature at which the reaction efficiently proceeds based on the contact efficiency with the solvent to be used and the oxygen source. In order to advance the reaction, the reaction can be carried out from 0 ° C. to the boiling point of the solvent. However, considering the reaction time, energy efficiency, etc., room temperature to 60 ° C. is preferable, 20 to 50 ° C. is more preferable, and 30 to 40 is particularly preferable. ° C is preferred.
The reaction time can be appropriately selected by monitoring the completion of the reaction by TLC or HPLC, and preferably 3 to 20 hours. Even if the reaction is carried out overnight for about 15 hours, the yield decreases as a side reaction. There is nothing.

  After the oxidation reaction, menatetrenone is obtained by post-treatment and purification by a conventional method. Specifically, the reaction solution may be concentrated under reduced pressure or the like to obtain a crude product, and then purified by column chromatography and / or recrystallization. From the viewpoint of safety, it is preferable to concentrate the reaction solution after washing it. From this viewpoint, the solvent used for the oxidation reaction is preferably an organic solvent that is not miscible with water.

EXAMPLES Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to these examples.
[Example 1]
First step (condensation reaction)
28.8 g of menadiol monoacetate (4) was dissolved in a mixed solvent of 67 mL of ethyl acetate and 67 mL of n-hexane, and 2.4 g of BF ₃ -Et ₂ O was added. While stirring this solution, 28.3 g of all-trans-geranyl linalool (5) was added dropwise at 45 ° C. over 1 hour 30 minutes to 2 hours, and then reacted at the same temperature for 5 hours. The reaction solution was washed 4 times with 20 mL of 5% aqueous sodium chloride solution. The organic layer was washed four times with a solution obtained by adding 2 g of sodium hydrosulfite to 40 mL of 10% aqueous potassium hydroxide solution. Further, the organic layer was washed 4 times with 20 mL of 5% aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure.

Second step (Claisen alkali treatment)
The concentrated residue was dissolved in 150 mL of toluene, and 4 g of sodium hydrosulfite, 23 g of potassium hydroxide, 17 mL of water, and 40 mL of methanol were added and stirred. The toluene layer was removed by liquid separation, the aqueous layer was washed with 90 mL of toluene, and extracted by adding 100 mL of ethyl acetate, 100 mL of n-hexane, and 220 mL of water to the aqueous layer, and the organic layer was extracted twice with 20 mL of 5% aqueous sodium chloride solution. After washing, the solution was separated.

Third step (oxidation reaction)
Sodium chloride aqueous solution (prepared from 14 g of NaCL and 80 mL of water) and 200 mL of n-hexane were added to the organic layer, and the reaction mixture was stirred while bubbling air. After completion of the reaction, the mixture was separated, and the organic layer was washed 3 times with 30 mL of water and concentrated. The concentrated residue was subjected to column chromatography (n-hexane), and the fraction containing the target product was concentrated to obtain crude menatetrenone as an oil. Crude menatetrenone was crystallized from ethanol to obtain crude crystals. Furthermore, menatetrenone (1) was obtained by recrystallizing the crude crystals with ethanol (yield 22% from (5)).

[Example 2]
First step (condensation reaction)
26 g of menadiol monoacetate (4) was dissolved in 130 mL of toluene, and while stirring at 50 ° C., a solution of 29 g of all-trans-geranyl linalool (5) dissolved in 10 mL of toluene and 3.6 g of BF ₃ -Et ₂ O were added to 20 mL of toluene. The solution dissolved in was simultaneously added dropwise over 30 minutes. Thereafter, the reaction was carried out at the same temperature for 30 minutes. The reaction solution was washed twice with 40 mL of 5% aqueous sodium chloride solution. The organic layer was washed twice with a solution obtained by adding 2 g of sodium hydrosulfite to 60 mL of 10% aqueous potassium hydroxide solution.

Second step (Claisen alkali treatment)
To the organic layer, 3 g of sodium hydrosulfite, 23 g of potassium hydroxide, 17 mL of water, and 40 mL of methanol were added, and the reaction mixture was stirred. After removing the toluene layer by liquid separation, the aqueous layer was washed with 140 mL of toluene, extracted by adding 200 mL of toluene, 30 mL of acetic acid, and 220 mL of water, and the organic layer was washed twice with 40 mL of 5% sodium chloride aqueous solution. The liquid was separated.

Third step (oxidation reaction)
80 mL of water was added to the organic layer and stirred while blowing air. After completion of the reaction, the mixture was separated, and the organic layer was washed with 30 mL of water three times and concentrated to obtain crude menatetrenone.

[Example 3]
First step (condensation reaction)
30.5 g of menadiol monoacetate (4) and 28.3 g of all-trans-geranyl linalool (5) were dissolved in 130 mL of toluene, and 2.1 g of BF ₃ -Et ₂ O was dissolved in 20 mL of toluene with stirring at 45 ° C. The solution was added dropwise over 30 minutes. Thereafter, the reaction was carried out at the same temperature for 60 minutes. The reaction solution was washed with 40 mL of 5% aqueous sodium chloride solution. The organic layer was washed twice with a solution obtained by adding 2 g of hydrosulfite sodium to 60 mL of a 10% aqueous potassium hydroxide solution.

Second step (Claisen alkali treatment)
To the organic layer, 4 g of sodium hydrosulfite, 23 g of potassium hydroxide, 17 mL of water, and 40 mL of methanol were added, and the reaction mixture was stirred. The toluene layer was removed by liquid separation, the aqueous layer was washed with 100 mL of toluene, extracted by adding 100 mL of n-hexane, 100 mL of ethyl acetate, and 220 mL of water to the aqueous layer, and the organic layer was extracted twice with 40 mL of 5% aqueous sodium chloride solution. After washing, the solution was separated.

Third step (oxidation reaction)
To the organic layer, 100 mL of n-hexane and an aqueous sodium chloride solution (NaCL 14 g and water 80 mL) were added, and the reaction mixture was stirred while bubbling air at 30 to 35 ° C. After completion of the reaction, the mixture was separated, and the organic layer was washed twice with 40 mL of 5% aqueous sodium chloride solution and concentrated to obtain crude menatetrenone.

[Example 4]
First step (condensation reaction)
30.5 g of menadiol monoacetate (4) was dissolved in 150 mL of toluene, and 2 mL of methanesulfonic acid was added. While stirring this solution, 27.7 g of all-trans-geranyl linalool (5) was added dropwise at 49 to 51 ° C. over 45 minutes, followed by reaction at the same temperature for 2 hours and 55 minutes. The reaction solution was washed twice with 40 mL of 5% aqueous sodium chloride solution. The organic layer was washed three times with a solution obtained by adding 2 g of hydrosulfite sodium to 40 mL of a 10% aqueous potassium hydroxide solution.

Second step (Claisen alkali treatment)
To the organic layer, 4 g of hydrosulfite sodium, 23 g of potassium hydroxide, 17 mL of water, and 40 mL of methanol were added and stirred. The toluene layer was removed by liquid separation, the aqueous layer was washed with 75 mL of toluene, extracted by adding 100 mL of ethyl acetate, 100 mL of n-hexane, and 220 mL of water to the aqueous layer, and the organic layer was extracted twice with 40 mL of 5% aqueous sodium chloride solution. After washing, the solution was separated.

Third step (oxidation reaction)
A sodium chloride aqueous solution (prepared from 14 g of NaCL and 80 mL of water) and 200 mL of n-hexane were added to the organic layer, and the reaction mixture was stirred for 3 hours while bubbling air at 25 ° C to 40 ° C. After completion of the reaction, the mixture was separated, and the organic layer was washed twice with 40 mL of water and concentrated to obtain crude menatetrenone.

[Example 5]
First step (condensation reaction)
After adding 260.2 kg of menadiol monoacetate (4) and 1300 L of toluene to the reaction can, 290.5 kg of all-trans-geranyl linalool (5) dissolved in 100 L of toluene and 3.5 kg of dodecylbenzenesulfonic acid were added to the jacket. Hot water at 55 ° C. was passed through, and the reaction mixture was stirred at an internal temperature of 50 ° C. or higher for 8 hours. After cooling with cold water, heat again with warm water at 50 ° C., add 412 L of potassium hydroxide / hydrosulfite aqueous solution prepared with potassium hydroxide 70 kg, hydrosulfite 40 kg and water 800 L at an internal temperature of 31.9 ° C. After stirring for 20 minutes, the aqueous layer was separated and discarded. Further, 508 L of the remaining potassium hydroxide / hydrosulfite aqueous solution and 400 L of water were added to the organic layer, and the mixture was stirred for 20 minutes. Then, the aqueous layer was separated and discarded.

Second step (Claisen alkali treatment)
30 kg of hydrosulfite was added and heated with warm water at 60 ° C. in a nitrogen atmosphere. When the internal temperature rose to 30 ° C., the hot water was stopped, a solution prepared from 205 kg of potassium hydroxide, 185 L of water and 389 L of methanol was added, and the reaction mixture was stirred for 30 minutes, then the stirring was stopped and left for 2 hours. . After separating the organic layer, 1300 L of toluene was added to the aqueous layer, and the mixture was stirred for 5 minutes. Then, the organic layer was separated and discarded. An aqueous layer was added to a stirring tank containing 2000 L of toluene and 2200 L of water, and the mixture was stirred for 30 minutes. Then, 300 kg of glacial acetic acid was added, and the mixture was further stirred for 30 minutes. After separating the aqueous layer, the organic layer was washed with an aqueous sodium chloride solution prepared from 113 L of 10% aqueous sodium chloride solution and 100 L of water, and further washed with an aqueous sodium chloride solution prepared from 97 L of 10% aqueous sodium chloride solution and 100 L of water. .

Third step (oxidation reaction)
After adding 800 L of water to the organic layer, warm water of 60 ° C. was passed through the jacket, and the reaction mixture was blown into the reaction solution at an internal temperature of 30 ° C. under a nitrogen stream (20 Nm ³ / hour) at a temperature of 20 Nm ³ / hour. Was stirred for 15 hours. After separating the aqueous layer, 300 L of water was added to the organic layer and stirred for 10 minutes, and then the aqueous layer was separated. Washing with 300 L of water was performed twice more. Toluene was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and the eluent was distilled off to obtain 219 kg of crude menatetrenone.

To the crude menatetrenone, 2367 L of 20% acetone-ethanol was added and dissolved by heating, followed by cooling. After adding 25 g of seed crystals at 11 ° C., the mixture was cooled to −26.3 ° C. The precipitated crystals were collected by filtration, washed with 704 L of 20% acetone-ethanol and then blown with nitrogen 3.8 Nm ³ / hour for 20 hours while heating with 60 ° C. warm water to remove 121.71 kg of menatetrenone (1). Obtained.

Claims (3)

The following formula (1)
A method for producing a compound represented by formula (2):
A process comprising: treating a reaction solution consisting only of a solution obtained by dissolving a compound represented by formula (2) in a solvent with an oxygen source. The following formula (1)
A process for producing a compound represented by
i) Formula (2)
A solution of the compound represented by formula (I) in an organic solvent immiscible with water, and ii) water or an aqueous sodium chloride solution,
A process comprising treating a reaction solution comprising only an oxygen source.   The production method according to claim 1 or 2, wherein the oxygen source is air.