JP2023016443A - Method for production of 1,4-diacetoxy-2-methylnaphthalene - Google Patents

Abstract

To provide an industrial production method for 1,4-diacetoxy-2-methylnaphthalene, which is useful as pharmaceuticals or the raw materials therefor.SOLUTION: A method for production of 1,4-diacetoxy-2-methylnaphthalene reacts bisulfite of 2-methylnaphthoquinone with dithionite, followed by a reaction with an acetylation agent.SELECTED DRAWING: None

Description

The present invention relates to a method for producing 1,4-diacetoxy-2-methylnaphthalene.

1,4-diacetoxy-2-methylnaphthalene is vitamin K4 useful as a hemostatic vitamin, phytonadione (vitamin K1) useful for hypoprothrombinemia, and for improving bone mass and pain in hypoprothrombinemia and osteoporosis. It is known as a production intermediate of useful menatetrenone (vitamin K2).

1,4-diacetoxy-2-methylnaphthalene is produced by reducing 2-methyl-1,4-naphthoquinone with sodium dithionite or the like to give naphthalene diol, which is then acetylated with acetic anhydride or the like. (Non-Patent Document 1).
Also, a method of reducing 2-methyl-1,4-naphthoquinone with zinc to form 2-methyl-1,4-naphthalenediol and then reacting it with acetic anhydride (Patent Document 1); A method of subjecting -naphthoquinone to a reductive acetylation reaction using Pd/C in the presence of acetic anhydride and 4-dimethylaminopyridine (DMAP) has also been reported (Patent Document 2).

CN102503818A US2017/0260117A1 JP-A-10-120614

J. Biol. Chem. , 133, 391, 1940

However, in any of the above methods, since 2-methyl-1,4-naphthoquinone, which has low stability to light and heat and is irritating to the skin, is used as a raw material, high-purity 1,4-diacetoxy -2-Methylnaphthalene is problematic as a method for producing it.
Accordingly, an object of the present invention is to provide a new industrial production method for 1,4-diacetoxy-2-methylnaphthalene, which is useful as a drug or raw material for its production.

Therefore, the present inventors have conducted various studies on a method for producing 1,4-diacetoxy-2-methylnaphthalene. It was found that by allowing the reaction to proceed at the same time, 2-methyl-1,4-naphthalenediol can be efficiently obtained. Subsequently, the present inventors have found that 1,4-diacetoxy-2-methylnaphthalene can be industrially produced in high yield and quality by acetylation by a conventional method, and have completed the present invention.

That is, the present invention provides the following inventions [1] and [2].
[1] A method for producing 1,4-diacetoxy-2-methylnaphthalene, which comprises reacting a hydrogen sulfite of 2-methylnaphthoquinone with a dithionite and then with an acetylating agent.
[2] A method for producing 1,4-diacetoxy-2-methylnaphthalene, which comprises simultaneously reacting a hydrogen sulfite of 2-methylnaphthoquinone with a dithionite and an alkali, and then reacting with an acetylating agent.

According to the method of the present invention, high-quality 1,4-diacetoxy-2-methylnaphthalene can be produced in high yield from 2-methylnaphthoquinone hydrogen sulfite which is stable and highly safe.

The method for producing 1,4-diacetoxy-2-methylnaphthalene (V) of the present invention comprises reacting bisulfite (I) of 2-methylnaphthoquinone with dithionite (II), then acetylating agent (IV). ) is reacted. The reaction formulas of the present invention are as follows.

（反応式中、Ｍは金属原子又はアミン類を示す）

(In the reaction formula, M represents a metal atom or amines)

The raw material used in the process of the present invention is 2-methylnaphthoquinone hydrogen sulfite (I). The hydrogen sulfite salt has high stability against light and heat and is almost non-irritating to the skin, as compared with 2-methylnaphthoquinone used in conventional production methods.
Hydrogen sulfites include alkali metal hydrogen sulfites, alkaline earth metal hydrogen sulfites, and amine hydrogen sulfites. Specific examples include sodium hydrogen sulfite, potassium hydrogen sulfite, calcium hydrogen sulfite, ammonium hydrogen sulfite, and dimethylpyridinol hydrogen sulfite.
2-Methylnaphthoquinone hydrogen sulfite can also be used in the form of hydrates such as trihydrate.
2-Methylnaphthoquinone hydrogen sulfite (I) can be produced by reacting 2-methylnaphthoquinone with a hydrogen sulfite, and is known to have high stability against light and heat (Patent Document 3). It is completely unknown that the reaction of dithionite (II) with dithionite (II) causes simultaneous progress of liberation (desalting) and reduction reactions.

Dithionite (II) includes metal dithionite salts such as sodium dithionite, potassium dithionite and zinc dithionite. Among these, sodium dithionite is preferable from the viewpoint of availability.
From the viewpoint of yield, the amount of dithionite used is preferably 1.0 to 5.0 times the mol of 2-methylnaphthoquinone hydrogen sulfite, and 1.2 to 4.0 times the mol. It is more preferably 1.5 to 3.0 mol, more preferably 1.5 to 3.0 mol.

The reaction between 2-methylnaphthoquinone hydrogensulfite (I) and dithionite (II) is preferably carried out in an aqueous solution or in a mixed solvent of water and an organic solvent. More specifically, from the viewpoint of freeing (desalting) and reducing reactions at the same time, a solution containing dithionite (II) is dropped into a solution containing 2-methylnaphthoquinone hydrogen sulfite (I). It is more preferable to react by
Solvents for the 2-methylnaphthoquinone hydrogensulfite (I)-containing solution include ester solvents such as ethyl acetate and butyl acetate; ether solvents such as isopropyl ether and tetrahydrofuran; aliphatic hydrocarbon solvents such as pentane and hexane; Aromatic hydrocarbon solvents such as toluene and xylene; halogenated hydrocarbon solvents such as dichloromethane and chloroform are used. Water is preferred as the solvent for the dithionite (II)-containing solution.

The reaction temperature for the reaction between 2-methylnaphthoquinone hydrogensulfite (I) and dithionite (II) is 10° C. or higher from the viewpoints of freeing (desalting) and reducing reactions at the same time and from the viewpoint of production efficiency. 80° C. or lower is preferable, 10° C. or higher and 60° C. or lower is more preferable, and 20° C. or higher and 50° C. or lower is even more preferable.
Moreover, the reaction time varies depending on the reaction temperature and the solvent used, but can be carried out in the range of about 2 hours to 48 hours.

In the reaction between 2-methylnaphthoquinone hydrogensulfite (I) and dithionite (II), an alkali is added to the reaction system to convert 2-methylnaphthoquinone hydrogensulfite (I) to dithionite (II ) and an alkali at the same time is preferable from the viewpoint of increasing the reaction rate and the reaction yield.
The alkali is preferably added to the dithionite (II) from the viewpoint that the 2-methylnaphthoquinone hydrogensulfite (I) reacts with the dithionite (II) and the alkali at the same time, and the dithionite ( II) More preferably, it is added dropwise to the containing solution. Therefore, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonate salts such as sodium carbonate and potassium carbonate; and alkali metal hydrogencarbonates such as sodium hydrogencarbonate are preferred.

2-
It is preferably used in an amount of 0.1- to 5-fold mol, more preferably 0.5- to 4-fold mol, more preferably 1.2- to 1.2-fold mol, relative to methylnaphthoquinone hydrogensulfite (I). It is more preferable to use 3.6-fold molar or less.
In addition, the alkali is 2-methylnaphthoquinone hydrogen sulfite (I) and dithionite (I
The dithionite (II
) is added to the containing solution and reacted by dropping the solution.

Since the reaction rate increases when an alkali is used, the amount of dithionite used is preferably 0.7 to 3.0 times the mol of 2-methylnaphthoquinone hydrogen sulfite. 0.7-fold mol or more and 2.0-fold mol or less is more preferable, and 1.0-fold mol or more and 1.5-fold mol or less is more preferable.
Moreover, when an alkali is used, the reaction is sufficient at 10° C. or higher and 50° C. or lower for about 1 hour to 10 hours.

By the above reaction, the free (desalting) and reduction reactions of 2-methylnaphthoquinone hydrogensulfite (I) proceed simultaneously, so that 2-methyl-1,4-naphthalenediol (III) is produced efficiently. Then, 2-methyl-1,4-naphthalenediol (III) is reacted with an acetylating agent to obtain 1,4-diacetoxy-2-methylnaphthalene (V).

The acetylating agent is not particularly limited as long as it is an acetylating agent that can be used for acetylating a hydroxyl group, and examples thereof include acetic anhydride, acetyl halide, methyl acetate, and N-methylacetamide. Acetyl chloride is preferred.
The acetylation reaction may be carried out under normal acetylation reaction conditions. For example, an acetylating agent is reacted in an organic solvent in the presence of a base such as pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline or triethylamine. All you have to do is A reaction time of 1 hour to 20 hours at 20° C. to 100° C. is sufficient.

According to the method of the present invention, 1,4-diacetoxy-2-methylnaphthalene (V) can be obtained in a high yield, so purification of the desired product from the reaction solution can be carried out by conventional methods such as washing and recrystallization. It is possible.

EXAMPLES Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1
(1) A mixed solution of 160 g of city water and 29.7 g of sodium dithionite (90.1% purity, 0.154 mol) was prepared. 17.4 g of 2-methylnaphthoquinone hydrogen sulfite trihydrate (97.7% purity, 0.051 mol) and 82 mL of ethyl acetate were added to a 300-mL four-necked flask and heated to 50°C. was dripped. After aging at the same temperature for 3 hours, the mixture was separated, and the organic layer was washed with 20% brine to obtain a 2-methyl-1,4-naphthalenediol ethyl acetate solution.
(2) 0.45 g (0.006 mol) of pyridine was added to the ethyl 2-methyl-1,4-naphthalenediol acetate solution, and 17.1 g (0.167 mol) of acetic anhydride was added dropwise at 65 to 70°C. Aged at room temperature for 3 hours. The organic layer was washed with city water and 5% sodium bicarbonate water, the organic layer was concentrated, and a mixed solution of isopropanol (IPA) and city water was added to the residue. The resulting slurry was filtered and dried under reduced pressure to obtain 12.0 g (0.046 mol) of 1,4-diacetoxy-2-methylnaphthalene as colorless crystalline powder. The HPLC purity was 99.96 Area %, and the yield from bisulfite trihydrate of 2-methylnaphthoquinone was 90.2%.

Example 2
In Example 1 (1), the reaction was carried out in the same manner as in Example 1 except that the amount of sodium dithionite used was 14.85 g (90.1% purity, 0.0768 mol) and the aging time was 24 hours. 9.3 g (0.036 mol) of 1,4-diacetoxy-2-methylnaphthalene was obtained. The HPLC purity was 99.97 Area %, and the yield from bisulfite trihydrate of 2-methylnaphthoquinone was 70.2%.

Example 3
(1) A mixed solution of 400 g of city water, 74.3 g of sodium dithionite (90.1% purity, 0.384 mol), and 49.1 g (0.308 mol) of 25% caustic soda was prepared. 87.0 g of 2-methylnaphthoquinone hydrogen sulfite trihydrate (97.7% purity, 0.257 mol) and 400 mL of ethyl acetate were added to a 1 L four-necked flask and heated to 50° C. to obtain the above mixed solution. was dripped. After aging at the same temperature for 1 hour, the mixture was separated, and the organic layer was washed with 20% brine to obtain a 2-methyl-1,4-naphthalenediol ethyl acetate solution.
(2) 2.21 g (0.028 mol) of pyridine was added to the ethyl 2-methyl-1,4-naphthalenediol acetate solution, and 85.4 g (0.837 mol) of acetic anhydride was added dropwise at 65 to 70°C. Aged at room temperature for 3 hours. The organic layer was washed with city water and 5% sodium bicarbonate water, the organic layer was concentrated, and a mixed solution of IPA and city water was added to the residue. The resulting slurry was filtered and dried under reduced pressure to obtain 62.9 g (0.244 mol) of 1,4-diacetoxy-2-methylnaphthalene as colorless crystalline powder. The HPLC purity was 99.95 Area % and the yield from bisulfite trihydrate of 2-methylnaphthoquinone was 94.7%.

Example 4
The reaction was carried out in the same manner as in Example 3, except that in (1) of Example 3, the amount of 25% caustic soda used was changed to 147.3 g (0.921 mol). 1 g (0.233 mol) was obtained. The HPLC purity was 99.92 Area %, and the yield from the hydrogensulfite trihydrate of 2-methylphthoquinone was 90.5%.

Example 5
In Example 3 (1), the reaction was carried out in the same manner as in Example 3 except that the amount of sodium dithionite used was 49.75 g (90.1% purity, 0.257 mol) and the aging time was 3 hours. 52.3 g (0.202 mol) of 1,4-diacetoxy-2-thylnaphthalene was obtained. The HPLC purity was 99.98 Area %, and the yield from the hydrogen sulfite trihydrate of 2-methylphthoquinone was 78.7%.

Example 6
The reaction was carried out in the same manner as in Example 3, except that the amount of 25% caustic soda used was changed to 20.6 g (0.129 mol) and the aging time was changed to 2 hours in (1) of Example 3. 61.3 g (0.237 mol) of 2-thylnaphthalene were obtained. The HPLC purity was 99.97 Area %, and the yield from the hydrogensulfite trihydrate of 2-methylphthoquinone was 92.3%.

Claims (2)

A method for producing 1,4-diacetoxy-2-methylnaphthalene, which comprises reacting a hydrogen sulfite of 2-methylnaphthoquinone with a dithionite and then reacting it with an acetylating agent. A method for producing 1,4-diacetoxy-2-methylnaphthalene, which comprises reacting a hydrogen sulfite salt of 2-methylnaphthoquinone with a dithionite salt and an alkali simultaneously, and then with an acetylating agent.