WO2007032378A1

WO2007032378A1 - Process for producing quinone compound

Info

Publication number: WO2007032378A1
Application number: PCT/JP2006/318138
Authority: WO
Inventors: Tadashi Tomiyama; Akisuke Saika
Original assignee: Eisai R & D Management Co., Ltd.
Priority date: 2005-09-15
Filing date: 2006-09-13
Publication date: 2007-03-22

Abstract

A process for producing the compound represented by the following formula (1), which is menatetrenone. It is characterized in that a reaction solution consisting only of a solution obtained by dissolving the compound represented by the following formula (2): in a solvent is treated with an oxygen source without adding any additive other than water or an aqueous sodium chloride solution thereto. The process does not adversely influence the environment, is safe even in mass production, and is easy to operate.

Description

Method for producing quinone compound

Technical field

[0001] The present invention relates to a method for producing menatetrenone, which is a quinone compound.

Background art

[0002] Menatetrenone has the following formula (1)

[0003] [Chemical 1]

Vitamin K preparations containing the compound as an active ingredient are vitamin K deficient

2

It is also used as a preventive and osteoporosis preventive and therapeutic agent used for the prevention and treatment of dementia

[0004] Menatetrenone is also contained in fermented foods such as natto and the like. The main industrial production method is chemical synthesis.

There are several known methods for the production of menatetrenone by chemical synthesis. One of the known strengths is to oxidize the precursor, iodoquinone, and the target quinone, menatetrenone. The method of obtaining is known (Non-Patent Document 1).

[0005] The method disclosed in Non-Patent Document 1 is a method using acid silver, and similarly, a method using metal oxide such as manganese dioxide and lead peroxide (Patent Document 2). While known! / Repelling power, the use of metal oxides makes it difficult to control the reaction and may cause side reactions and requires treatment to prevent adverse environmental effects after the reaction. And so on.

[0006] Therefore, a method using hydrogen peroxide was developed (Patent Document 1).

However, hydrogen peroxide is a strong oxidant, and there is a problem that special handling with consideration for safety is required when handling large quantities. [0007] In addition, a method of using molecular oxygen, which is a milder oxidant, is known as a method for producing ubiquinones having a structure similar to that of menatetrenone! 6) However, when molecular oxygen is used in the production process of ubiquinones, it is known that oxygen alone cannot be used to produce a complete acid solution with a remarkably low reaction rate (patents) In order to overcome such problems, References 5 and 6), base (Patent Document 4), silica gel (Patent Document 5), copper or copper ion and ammonia or ammonia ion (Patent Document 6), etc. are added to the reaction solution. It was known to be essential to add to. Such a method using an additive other than an acid oxidant may cause a side reaction in the presence of the additive, and the post-reaction process becomes complicated. There are common problems with using metal oxides.

[0008] In addition, as a method for producing menatetrenone, no specific method using molecular oxygen has been known.

[0009] Non-patent literature l: Kozlov, E 丄, Meditsinskaya Promyshlennost SSSR (1965), 19 (4), 16- 2 1

Patent Document 1: Japanese Patent Laid-Open No. 48-49733

Patent Document 2: JP-A 49-55650

Patent Document 3: Shoko 39-17514

Patent Document 4: JP-A 52-72884

Patent Document 5: Japanese Patent Laid-Open No. 54-151932

Patent Document 6: Japanese Patent Laid-Open No. 62-81347

Disclosure of the invention

Problems to be solved by the invention

[0010] Therefore, an object of the present invention is to provide a method for producing menatetrenone that does not adversely affect the environment, is safe even in mass production, and is easy to operate.

Means for solving the problem

[0011] As described above, there is a problem in the conventional method for producing menatetrenone, and the present inventors have conducted extensive studies on the acid method of hydroquinone (2), which is a precursor of menatetrenone. Surprisingly, it has been found that molecular oxygen allows the reaction to proceed completely without using any additives and without causing significant side reactions and the oxidation reaction proceeds completely. This is totally unexpected in the light of the long-standing technical knowledge that when using molecular oxygen alone as the oxidant, it is not possible to obtain a complete acid with a very low reaction rate. It was outside.

It was also found that the presence of water in the reaction solution does not affect the acid-acid reaction itself, but can improve safety. Based on these findings, the present inventors have found that menatetrenone can be produced by a method that does not adversely affect the environment, is safe even in mass production, and is easy to operate.

[0012] That is, the first aspect of the present invention is

(1)

[0013] [2]

A process for producing a compound represented by the formula (2)

[0014] [Chemical 3]

The present invention provides a production method characterized in that a reaction solution consisting only of a solution in which a compound represented by formula (1) is dissolved in a solvent is treated with an oxygen source.

[0015] Further, the second aspect of the present invention is the following formula (1)

[0016] [Chemical 4]

A process for producing a compound represented by

i) Formula (2)

[Chemical 5]

A solution in which the compound represented by is not miscible with water, dissolved in an organic solvent, and

ii) water or aqueous sodium chloride solution,

The present invention provides a production method characterized by treating a reaction solution consisting of only with an oxygen source.

[0018] Further, in the first and second embodiments, it is preferable that the oxygen source is air. The treatment with the oxygen source is preferably blowing of the oxygen source into the reaction solution.

The invention's effect

[0019] According to the present invention, menatetrenone can be produced by a method that does not adversely affect the environment, is safe even in mass production, and is easy to operate.

BEST MODE FOR CARRYING OUT THE INVENTION

[0020] 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, the following disclosed in Non-Patent Document 1 It can be synthesized by the route of

[0021] [Chemical 6]

ZnC! J / BF ₃ -OEt21 dioxane

[0022] As described above, the hydroquinone (2) can be synthesized by condensing menadiol monoacetate (4) and all-trans-gerlinalolol (5) and treating with Claisen's alkaline solution.

[0023] As described in Non-Patent Document 1, the condensation reaction of menadiol monoacetate (4) and all-trans-gera-lurinalol (5) is the same as menadiol monoacetate (4), And boron trifluoride in dioxane at 50 ° C, and all-trans-gerlin-rulinalol (5) in dioxane is added dropwise to the reaction mixture over 30 minutes, then kept at 50 ° C for 30 minutes. Can be done.

[0024] 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-dimethylformamide, N-methylpyrrolidone, acetonitrile, dimethylsulfoxide, benzene, toluene, xylene, methanol, ethanol, n-propanol, isopropanol, tert-butyl alcohol, methyl acetate, or acetic acid Ethyl etc. can be used. These can be used alone or in a mixture of two or more forces that can be used alone.

[0025] The acid catalyst used in the condensation reaction is not limited to the above zinc chloride and BF-OEt.

3 2 Can be used, for example, metal salts such as oxalic acid, potassium sulfate, potassium persulfate, zinc (π) triflate, or copper (I) sulfate, para-toluenesulfonic acid, methanesulfonic acid, sulfophthalic acid , Sulfonic acid derivatives such as hydroxybenzenesulfonic acid, nitrobenzenesulfonic acid, benzenesulfonic acid, black benzenesulfonic acid, naphthylsulfonic acid, dodecylbenzenesulfonic acid, 4,4-biphenyldisulfonic acid, or flavianic acid Can be used.

[0026] As described in Non-Patent Document 1, the monoacetyl group (3) obtained by the condensation reaction is an alkane of Claisen (prepared by dissolving 35 g of KOH in 25 mL of water and diluting to 10 mL with CHOH).

Three

In addition, a 3% aqueous solution of nodyl sulfite and ether can be mixed, stirred and then separated to obtain a hydroquinone (2) ether solution. The extraction solvent after the Claisen treatment can be used in addition to ethers, for example, carbon tetrachloride, dichloromethan, chloroform, _n -pentane, n-hexane, N-methylpyrrolidone, benzene, toluene. , Xylene, tert-butyl alcohol, methyl acetate, ethyl acetate and the like. These can be used alone, but two or more can be mixed and used in an arbitrary ratio.

[0027] The next step is an oxidation reaction of the production method of the present invention. In the present invention, the extract of the nanoquinone (2) 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. V. Regardless of the deviation, it is only necessary 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 an aqueous sodium chloride solution described later. The solvent is not particularly limited as long as it dissolves the nodo-idroquinone (2) and does not inhibit the oxidation reaction. For example, carbon tetrachloride, dichloromethane, black mouth form, _n -pentane, and n- Xane, N, N-dimethylformamide, N-methylpyrrolidone, acetonitrile, dimethyl sulfoxide, benzene, toluene, xylene, methanol, ethanol, _n -propanol, isopropanol, tert-butyl alcohol, methyl acetate, ethyl acetate, etc. Can be mentioned. These can be used alone. The above can be mixed at an arbitrary ratio and 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. In other words, it is not necessary to add other additives in order to complete the oxidation reaction. However, in consideration of safety, it is preferable to carry out in a two-layer system by adding water or sodium chloride aqueous 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 It is preferable to use alcohol, methyl acetate, ethyl acetate, or a mixed solvent of two or more thereof as a solvent. Whether to use water or an aqueous sodium chloride solution may be appropriately selected depending on the solvent used. For example, it is possible to select a method in which separation of the organic layer and the aqueous layer is favorable during separation after the reaction.

[0029] The oxygen source used in the present invention is 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 the 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.

[0030] 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, when air is blown into the reaction solution ^ Nozzle force is blown, or a bubble-like air is blown with a porous member at the tip of the nozzle, or many holes are drilled in the reaction can with ring-shaped pipes A variety of other instrumental measures can be taken, such as having a thing and letting the air blow out of its numerous holes into a moderately sized bubble.

[0031] The temperature condition of the oxidation reaction of the present invention may be appropriately selected as the temperature at which the reaction proceeds efficiently based on the contact efficiency with the solvent and oxygen source used, and the like. In order to proceed the reaction, it can be carried out from o ° c to the boiling point of the solvent, but considering the reaction time and energy efficiency, room temperature to 60 ° C is preferred, and 20 to 50 ° C is further preferred. In particular, 30-40 ° C is preferred.

The reaction time can be selected as appropriate by monitoring the completion of the reaction with TLC or HPLC. Preferably, the reaction time is 3 to 20 hours, and even if the reaction is continued for about 15 hours all night, the yield does not decrease due to side reaction! /.

[0032] After the oxidation reaction, menatetrenone is obtained by post-treatment and purification by a conventional method. Specifically, the reaction solution is concentrated under reduced pressure to obtain a crude product, which is then purified by column chromatography and Z or recrystallization. From the viewpoint of safety, it is preferable to wash the reaction solution with water and concentrate it. The solvent used in the acid-acid reaction is not miscible with water, and an organic solvent is preferred.

Example

Hereinafter, the present invention will be described by way of specific 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 0.24 g of BF—Et was added. While stirring this solution

3 2

Lutrans-Gera-Rurinalol (5) 28.3 g 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 4 times with a solution obtained by adding 2 g of sodium idrosulfite to 40 mL of 10% potassium hydroxide aqueous solution. Further, the organic layer was washed 4 times with 20 mL of 5% sodium chloride aqueous solution. The organic layer was concentrated under reduced pressure.

[0034] Second step (Claisen alkali treatment)

The concentrated residue was dissolved in 150 mL of toluene, and 4 g of sodium hydrosulfite, 23 g of lithium hydroxide, 17 mL of water, and 40 mL of methanol were added and stirred. The toluene layer is separated by separation, the aqueous layer is washed with 90 mL of toluene, extracted with 100 mL of ethyl acetate, 1-OOmL of n-hexane, and 220 mL of water, and the organic layer is 5% sodium chloride. After washing twice with 20 mL of aqueous solution, liquid separation was performed.

[0035] Third step (oxidation reaction)

To the organic layer were added sodium chloride aqueous solution (14 g of NaCL and 80 mL of water was prepared) and 200 mL of n-hexane, and the reaction mixture was stirred while publishing air. After the reaction is complete The layers were 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-xan), and the fraction containing the target product was concentrated to obtain ¾ ^ natetrenone as an oil. ¾ ^ Natetrenone was crystallized with ethanol to obtain crude crystals. Furthermore, menatetrenone (1) was obtained by recrystallizing crude crystals with ethanol (22% yield from (5)).

[Example 2]

First step (condensation reaction)

Dissolve 26 g of menadiol monoacetate (4) in 130 mL of toluene, stir at 50 ° C, a solution of 29 g of All-Trans-Gera-Lurinalol (5) in 10 mL of toluene, and BF — Et 03.6 g in 20 mL of toluene. The solution dissolved in was simultaneously added dropwise over 30 minutes. That

3 2

Thereafter, the reaction was carried out at the same temperature for 30 minutes. The reaction solution was washed twice with 40 mL of 5% sodium chloride aqueous solution. The organic layer was washed twice with a solution obtained by adding 2 g of hydrosulfite sodium to 60 mL of a 10% potassium hydroxide aqueous solution.

[0037] 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. The toluene layer is removed by liquid separation, the aqueous layer is washed with 140 mL of toluene, extracted by adding 200 mL of toluene, 30 mL of acetic acid, and 220 mL of water to the aqueous layer, and the organic layer is washed twice with 40 mL of 5% sodium chloride aqueous solution. And then separated.

[0038] 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 3 times with 30 mL of water and concentrated to obtain crude menatetrenone.

[0039] [Example 3]

First step (condensation reaction)

Menadiol monoacetate (4) 30.5g and All-Trans-Gera-Lurinalol (5) 2 8. 3g was dissolved in 130mL of toluene and stirred at 45 ° C.

3 2

The solution dissolved in mL was added dropwise over 30 minutes. Thereafter, the reaction was continued for 60 minutes at the same temperature. The reaction solution was washed with 40 mL of 5% sodium chloride aqueous solution. The organic layer was washed twice with a solution prepared by adding 2 g of idrosulfite sodium to 60 mL of a 10% potassium hydroxide aqueous solution. [0040] 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 is removed by liquid separation, the aqueous layer is washed with toluene lOOmL, extracted with 100 mL of n-hexane, 100 mL of ethyl acetate, and 220 mL of water, and the organic layer is 5% sodium chloride sodium salt. After washing twice with 40 mL of aqueous solution, liquid separation was performed.

[0041] Third step (oxidation reaction)

To the organic layer, l-hexane lOOmL and a sodium chloride aqueous solution (NaCL 14 g and water 80 mL) were added, and the reaction mixture was stirred while publishing 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% sodium chloride aqueous solution and concentrated to obtain natrenone.

[0042] [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 49-51 ° C. over 45 minutes, and then reacted at the same temperature for 2 hours and 55 minutes. The reaction solution was washed twice with 40 mL of 5% sodium chloride aqueous 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% potassium hydroxide aqueous solution.

[0043] 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 stirred. Remove the toluene layer by liquid separation, wash the aqueous layer with 75 mL of toluene, add 100 mL of ethyl acetate, 100 mL of n-hexane, and 220 mL of water to the aqueous layer, and extract the organic layer with 5% sodium chloride aqueous solution. After washing twice with 40 mL, liquid separation

[0044] Third step (oxidation reaction)

The organic layer was charged with sodium chloride aqueous solution (14 g of NaCL and 80 mL of water was prepared) and 200 mL of n-hexane, and the reaction mixture was stirred for 3 hours while publishing air at 25 ° C to 40 ° C. After completion of the reaction, the solution is separated, and the organic layer is washed twice with 40 mL of water and concentrated. Got non.

[0045] [Example 5]

First step (condensation reaction)

Add 260.2 kg of menadiol monoacetate (4) and 1300 L of toluene to the reaction vessel, and add 290.5 kg of all-trans gellar-lurinalol (5) and 3.5 kg of dodecylbenzenesulfonic acid dissolved in 100 L of toluene. Then, warm water of 55 ° C was passed through the jacket, 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 hot water at 50 ° C, and at an internal temperature of 31.9 ° C, an aqueous solution of potassium hydroxide and potassium Z hydrosulfite prepared with 70 kg of potassium hydroxide, 40 kg of hydrosulfite and 800 L of water The mixture was stirred for 20 minutes, and the aqueous layer was separated and discarded. Further, the remaining aqueous solution of potassium hydroxide Z hydrosulfite and 508 L of water 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.

[0046] Second step (Claisen alkali treatment)

30 kg of hydrosulfite was added and heated with hot water at 60 ° C under 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, and 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, and 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 prepared from 97 L of 10% aqueous sodium chloride solution and 100 L of water. Washed with aqueous sodium chloride solution.

[0047] Third step (oxidation reaction)

After adding 800 L of water to the organic layer, warm water at 60 ° C was passed through the jacket, and air was blown into the reaction solution at a temperature of 30 ° C under nitrogen flow (20 N m ³ / hour) for 20 Nm ³ Z hours. The reaction mixture 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 and the residue was purified by silica gel column chromatography. Obtained 219 kg of trenone.

^ ^ After adding 2367L of 20% acetone / ethanol to natetrenone, the mixture was heated and dissolved, and then cooled. The precipitated crystals were collected by filtration, washed with 704 L of 20% acetone ethanol, heated with 60 ° C hot water and blown with nitrogen 3.8 Nm ³ Z for 20 hours to remove the solvent, and menatetrenone (1) 121. 71 kg Got.

Claims

The scope of the claims

A process for producing a compound represented by the formula (2)

[Chemical 8]

A process comprising: treating a reaction solution consisting of only a solution obtained by dissolving the compound represented by formula (2) with a solvent with an oxygen source.

[2] Formula (1)

[Chemical 9]

A process for producing a compound represented by

i) Formula (2)

[Chemical 10]

ii) water or 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.