JP2003206253A - Method for producing alkoxy-substituted 2-tetralone - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing an alkoxy-substituted 2-tetralone useful as an intermediate of medicines, etc., simply and in a good efficiency without requiring special facilities. <P>SOLUTION: This method for producing the alkoxy-substituted 2-tetralone is characterized by performing a reaction of an alkoxy-substituted naphthalene with hydrogen in a solvent in the presence of a precious metal catalyst and an acid catalyst. Also, the method for isolating and purifying the alkoxy- substituted 2-tetralone as a hydrogen sulfite adduct by treating the reaction mixture obtained by the reaction with a hydrogen sulfite salt is provided. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to alkoxy substitution 2
-Regarding a method for producing tetralone. Alkoxy substitution 2-
Tetralone is a 7-methoxy-2-aminotetralin (Europe) useful as an intermediate for manufacturing pesticides and pharmaceuticals, for example, an intermediate for morphine-like anti-inflammatory analgesics and antidepressants.
an Journal of Medicinal C
It is extremely useful as an intermediate of chemistry, Vol. 29, 259 (1994)).

[0002]

2. Description of the Related Art The following method is known as a method for producing an alkoxy-substituted 2-tetralone. As a method for producing dialkoxynaphthalene, 1) a method of reducing with sodium metal in alcohol to give dihydrodimethoxynaphthalene and then hydrolyzing (J. Am. Chem. Soc., 71, 3857)
(1949), J. Am. Chem. Soc. , 82
Vol. 1492 (1961)), 2) reduction with sodium metal in liquid ammonia,
Dihydrodimethoxynaphthalene, followed by hydrolysis (J. Am. Chem. Soc., Vol. 29,
1393 (1976), Japanese Patent Laid-Open No. 2-51418), and other methods using metallic sodium are known.

As a method utilizing the reduction of a naphthalene derivative, 3) a method of reacting a protected or unprotected hydroxy-substituted 2-naphthalene with hydrogen in the presence of a noble metal catalyst (JP-A-1).
No. 2-309554) is known.

Further, as a method for producing from a raw material other than dialkoxynaphthalene, 4) a method of reacting 2-methoxyphenylacetic acid halide with ethylene in the presence of aluminum chloride (JP-A-54-1)
No. 60357), 5) A method for producing methoxy-substituted 2-tetralone by acid catalyst after reducing, dehydrating and dihydroxylating 6-methoxy-1-tetralone or 7-methoxy-1-tetralone (Synthesis, 8 volumes). , 621 (198
0)), etc. are known.

[0005]

However, since the methods 1) and 2) both use metallic sodium, there is a problem in safety. Since the method 2) uses liquid ammonia, it requires special equipment. Further, in the method of catalytic reduction of the naphthalene derivative of 3),
Depending on the reaction conditions, hydroxy-substituted 2-tetralone is obtained as a by-product, but the main product is hydroxy-substituted 2-tetralol. In the method of 4), the reaction of methoxyphenylacetic acid halide with ethylene has a low yield,
This is not an industrially advantageous manufacturing method. The method 5) has a long number of steps and is not an industrially advantageous manufacturing method. As described above, any conventionally known method is a highly economical industrial production method of alkoxy-substituted 2-tetralone,
There was a problem to be solved.

[0006]

Means for Solving the Problems As a result of intensive studies on the industrially advantageous production method for solving the above-mentioned problems, the present inventors have found that readily available alkoxy-substituted naphthalene was used as a noble metal catalyst and an acid. It was found that an alkoxy-substituted 2-tetralone can be extremely effectively and selectively produced by reacting it with hydrogen in a solvent in the presence of a catalyst, and completed the present invention.

That is, the present invention provides a compound of the general formula (1) in a solvent in the presence of a noble metal catalyst and an acid catalyst.

[0008]

[Chemical 3]

(In the formula, R ¹ and R ² are different from each other, one is a hydrogen atom, the other is an alkoxy group having 1 to 6 carbon atoms, and R ³ is an alkyl group having 1 to 6 carbon atoms. The alkoxy-substituted naphthalene represented by formula (2) is reacted with hydrogen.

[0010]

[Chemical 4]

(Wherein R ¹ and R ² have the same meanings as described above), and a method for producing an alkoxy-substituted 2-tetralone.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.
In the present invention, the alkoxy-substituted naphthalene represented by the general formula (1) is reacted with hydrogen in a solvent in the presence of a noble metal catalyst and an acid catalyst to give the alkoxy-substituted 2-tetralone represented by the general formula (2). To manufacture.

In the alkoxy-substituted naphthalene represented by the general formula (1), R ¹ and R ² are different from each other, one of which is a hydrogen atom and the other is an alkoxy group having 1 to 6 carbon atoms. Examples of the alkoxy group having 1 to 6 carbon atoms include methoxy group, ethoxy group, n-propyloxy group, isopropoxy group, n-butoxy group, isobutyloxy group, n.
—A hexyloxy group and a cyclohexyloxy group.

R ³ represents an alkyl group having 1 to 6 carbon atoms,
As the alkyl group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group,
Examples thereof include n-pentyl group, n-hexyl group, and cyclohexyl group.

Alkoxy substitution 2 represented by the general formula (2)
-In tetralone, R ¹ and R ² are each represented by the general formula (1)
It is the same as the one defined in.

Alkoxy substitution 2 represented by the general formula (2)
-Of the tetralones, R ¹ is a methoxy group, R ² is a hydrogen atom, 7-methoxy-2-tetralone, and R ¹
Is a hydrogen atom and R ² is a methoxy group, 6-methoxy-2.
-Tetralone is a particularly useful compound as a pharmaceutical intermediate. Therefore, in the alkoxynaphthalene represented by the general formula (1), R ¹ is a methoxy group, R ² is a hydrogen atom, and R is
Preferred is 2,7-dimethoxynaphthalene in which ³ is a methyl group, and 2,6-dimethoxynaphthalene in which R ¹ is a hydrogen atom, R ² is a methoxy group, and R ³ is a methyl group.

The alkoxy-substituted naphthalene represented by the general formula (1) can be obtained by reacting 2,6-dihydroxynaphthalene or 2,7-dihydroxynaphthalene with an alkylating agent by a known method. For example, 2,7-dimethoxynaphthalene can be prepared by reacting 2,7-dihydroxynaphthalene with dimethyl sulfuric acid as an alkylating agent (J. Org. Chem., Vol. 51, 5252 (1).
986)).

In the hydrogenation of the alkoxy-substituted naphthalene represented by the general formula (1), in addition to the desired alkoxy-substituted 2-tetralone, 2,6- or 2,7-dialkoxytetralin or 6- or 7-alkoxy is used. Substitution 2
-Tetralol tends to be produced as a by-product, but the desired alkoxy-substituted 2-tetralone can be selectively obtained by selecting the metal species of the catalyst, the carrier and the like.

The metal catalyst used in the present invention is preferably a noble metal catalyst such as palladium, ruthenium,
A catalyst composed of a metal selected from the group consisting of rhodium and platinum can be mentioned. Preferred is a catalyst in which at least one selected from palladium, ruthenium, rhodium and platinum is supported on a carrier. It is also possible to use a binary catalyst such as palladium / silver.

Considering the reaction activity and the selectivity of the reaction, a catalyst in which palladium is supported on a carrier is more preferable. Examples of the carrier include activated carbon, alumina, silica, zeolite and the like. From the viewpoint of reaction activity and selectivity, activated carbon is preferable.

In the case of a catalyst in which a metal is supported on a carrier, the loading ratio of the metal on the carrier is usually 0.1 to 20% by weight,
Considering the reaction activity, preferably 0.2 to 10% by weight
Is.

The amount of the above-mentioned noble metal catalyst used is not particularly limited, but in view of economy, for example, it is 0.02 to 4% by weight in terms of metal based on the alkoxy-substituted naphthalene represented by the general formula (1). .

As the noble metal catalyst, a commercially available one may be used, or in the case of a catalyst in which a metal is supported on a carrier, one prepared by a known method such as an impregnation supporting method may be used.

This reaction is carried out in the presence of an acid catalyst,
As the acid catalyst, an inorganic acid containing a halogen atom can be used, and examples thereof include hydrobromic acid, hydrochloric acid, hydrofluoric acid, and perchloric acid. The use of hydrochloric acid is preferred in order to increase the production ratio of alkoxy-substituted 2-tetralone in the reaction product.

The amount of the above acid to be used depends on the kind of the acid used, but is usually 0.1 to 10 molar equivalents, preferably 0.5 to 5 molar equivalents.

In this reaction, the presence of water in the reaction system is desirable for the production of tetralone, and the required amount of water is usually 0.05 to 20 times the weight of the starting dialkoxynaphthalene. Is. Considering the selectivity and yield of the reaction, the weight is preferably 0.1 to 2 times. The coexisting water may be provided in the form of an aqueous solution of the above inorganic acid,
It may be provided in the form of being added as water.

The reaction solvent is not particularly limited,
For example, heptane, an aliphatic hydrocarbon solvent such as hexane,
Aromatic hydrocarbon solvents such as benzene, toluene, xylene, ethers, ether solvents such as methyl t-butyl ether, ester solvents such as ethyl acetate, methanol,
Alcohol solvents such as ethanol, isopropanol, t-butanol, nitrile solvents such as acetonitrile,
A mixed solvent of water and the above-mentioned solvent and the like, reaction rate,
Considering the selectivity, aromatic hydrocarbon solvents such as benzene, toluene and xylene are preferable.

The amount of the above solvent used is not particularly limited, but is usually 1 to 100 times the weight of the substrate dialkoxynaphthalene. Considering the operability and reaction rate of the reaction, the weight is preferably 2 to 20 times.

The hydrogen pressure in the above reaction is not particularly limited, and the reaction can be carried out under normal pressure or increased pressure.
The reaction under a pressure condition tends to accelerate the reaction, and is usually 100 to 5000 kPa, preferably 100 to 500 kPa.

The reaction temperature varies depending on the kind of the solvent, but can be selected, for example, from the condition of 0 to 150 ° C. in the above solvent, and is preferably 30 to 30 in view of reaction rate and selectivity.
It is 100 ° C.

The reaction time depends on the reaction temperature, hydrogen pressure, catalyst amount,
Although it depends on the charged concentration, it is not preferable to continue the reaction for an unnecessarily long time because the amount of undesired by-products such as the alkoxy-substituted 2-tetralone formed is further reduced. When the reaction solution can be sampled, the reaction can be stopped at a time when the yield of the alkoxy-substituted 2-tetralone is high and the amount of the by-product is smaller by checking the progress of the reaction. Usually, the reaction can be performed in 1 to 72 hours.

After the above reaction, the noble metal catalyst is separated from the reaction mixture by filtration at, for example, 0 to 40 ° C., and the solvent is distilled off as it is or after washing with water or the like. The alkoxy-substituted 2-tetralone represented by 2) can be obtained. The obtained alkoxy-substituted 2-tetralone can be further purified by ordinary operations such as recrystallization, column chromatography and distillation.

The alkoxy-substituted 2-tetralone represented by the general formula (2) can be efficiently isolated and purified as a hydrogen sulfite adduct by treating the reaction mixture with a hydrogen sulfite salt. Further, the isolated alkoxy-substituted 2-tetralone bisulfite adduct can be treated with an acid or a base to obtain the alkoxy-substituted 2-tetralone represented by the general formula (2).

The operation of treating the reaction mixture obtained by the above hydrogenation reaction with bisulfite will be described below.

Examples of the bisulfite salt used in the above treatment include potassium bisulfite, sodium bisulfite, calcium bisulfite and the like, and preferably sodium bisulfite.

The above treatment is carried out in water or a mixed solvent of water and an organic solvent which is compatible with water and does not react with bisulfite. A solution of bisulfite may be added to the solution of the reaction mixture, or a solution of the reaction mixture may be added to the solution of bisulfite.

Specific examples of the water-miscible organic solvent include 1,2-dimethoxyethane,
1,4-dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, polyethylene glycol dimethyl ether, acetonitrile, methanol, ethanol, n
-Propanol, isopropanol, t-butanol and the like can be mentioned, but the invention is not limited thereto.

The bisulfite varies depending on the type of metal salt and solvent used and the treatment conditions, but is usually used in an amount of, for example, 1 to 100 equivalents based on the alkoxy-substituted 2-tetralone represented by the general formula (2). It can be processed. Considering economy, the amount is preferably 1 to 20 equivalents, more preferably 1 to 10 equivalents.

The treatment temperature varies depending on the kind of the solvent, but is, for example, the freezing point of the solvent to 100 ° C. and the treatment time is, for example, 0.5 to 72 hours.

The hydrogen sulfite adduct obtained by the above treatment can be converted into an alkoxy-substituted 2-tetralone by acid treatment or base treatment. As an acid,
Examples thereof include inorganic acids such as sulfuric acid and hydrochloric acid. Examples of the base include lithium hydroxide, sodium hydroxide,
Examples thereof include alkali metal hydroxides such as potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate.

Alkoxy-substituted 2-from hydrogen sulfite adduct
As a treatment method for preparing tetralone, the adduct may be suspended in water and an acid or a base may be added, or the adduct may be added to a solution of the acid or the base.

The temperature at the time of the treatment varies depending on the kind of the solvent, but is, for example, the freezing point of the solvent to 100 ° C. The above treatment is usually preferably carried out under stirring, and the treatment time is, for example, 1 to 72 hours.

After treatment, the alkoxy-substituted 2-tetralone can be extracted with an organic solvent. The extraction solvent is not particularly limited as long as it is an organic solvent usually used in extraction operations, and examples thereof include toluene and ethyl acetate. The extraction solvent may be coexistent at the time of acid or base treatment.

[0044]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples. In addition, the composition in an Example shows the area percentage value obtained by the high performance liquid chromatography.

(Example 1) In a glass autoclave equipped with a stirrer, 2,7-dimethoxynaphthalene (50
6.7 mg, 2.69 mmol), p-xylene (1
0.2756 g), concentrated hydrochloric acid (510.9 mg), 10%
Palladium / activated carbon supported catalyst (262.4 mg, 55.
(3% water content) was charged, and the inside of the autoclave was replaced with nitrogen 5 times at room temperature, and then replaced with hydrogen (3 atm, 304 kPa equivalent) 5 times. Then, under heating at 100 ℃ 24
Stir for hours. After the reaction, cool to room temperature, release hydrogen,
When the reaction solution was analyzed by high performance liquid chromatography, it was confirmed that 55.1% of 7-methoxy-2-tetralone was produced. The other products had the following production ratios. 2,7-dimethoxytetralin: 10.2%, 7-methoxy-2-tetralol 5.2%, 7-methoxytetralin 3.2%, 2,7-dimethoxynaphthalene: 20.
5% column: Develosil HG-3 4.6x15
0 mm Mobile phase: 10 mM [NaH2PO4-Na2HPO4]
(PH = 6.8) / acetonitrile = 2/1 (vol /
vol) Flow rate: 1 ml / min Detection: UV 210 nm Injection volume: 5 μl

Example 2 In a glass autoclave equipped with a stirrer, 2,7-dimethoxynaphthalene (50
4.6 mg, 2.68 mmol), toluene (5.00
62 g), concentrated hydrochloric acid (506.6 mg), 10% palladium / activated carbon supported catalyst (262.4 mg, 55.3% hydrous product) were charged, and the autoclave was purged with nitrogen 5 times at room temperature, and then hydrogen (3 atm, (Equivalent to 304 kPa) was replaced 5 times. Then, it stirred under heating at 100 degreeC for 14 hours. After the reaction, the reaction solution was cooled to room temperature, hydrogen was released, and the reaction solution was analyzed by high performance liquid chromatography.
It was confirmed that 49.3% of methoxy-2-tetralone was produced. The other products had the following production ratios. 2,7-dimethoxytetralin: 7.2%, 7-methoxy-2-tetralol 5.2%, 7-methoxytetralin 2.4%, 2,7-dimethoxynaphthalene: 30.0
%

(Example 3) 2,7-dimethoxynaphthalene (503.2, 503.2,
2.67 mmol), toluene (5.201 g), concentrated hydrochloric acid (512.5 mg), 10% palladium / activated carbon supported catalyst (262.4 mg, 55.3% hydrous product),
At room temperature, the inside of the eggplant-shaped flask was replaced with nitrogen 5 times, and then replaced with hydrogen (1 atm, equivalent to 101 kPa) 5 times. Then, it stirred under heating at 50 degreeC for 14 hours. After the reaction, the reaction solution was cooled to room temperature, hydrogen was released, and the reaction solution was analyzed by high performance liquid chromatography to find that it was 7-methoxy-2-
It was confirmed that 13.7% of tetralone was produced.
The other products had the following production ratios. 2,7-dimethoxytetralin: 2.1%, 7-methoxy-2-tetralol 0.10%, 2,7-dimethoxynaphthalene: 82.6%

Example 4 In a glass autoclave equipped with a stirrer, 2,7-dimethoxynaphthalene (51
8.6 mg, 2.76 mmol), toluene (5.00
70 g), concentrated hydrochloric acid (127.0 mg), 10% palladium / activated carbon supported catalyst (264.8 mg, 55.3% hydrous product) were charged, and the autoclave was purged with nitrogen 5 times at room temperature, and then hydrogen (3 atm, (Equivalent to 304 kPa) was replaced 5 times. Then, it stirred under heating at 100 degreeC for 24 hours. After the reaction, the reaction solution was cooled to room temperature, hydrogen was released, and the reaction solution was analyzed by high performance liquid chromatography.
It was confirmed that 26.1% of methoxy-2-tetralone was produced. The other products had the following production ratios. 2,7-dimethoxytetralin: 9.6%, 2,7-methoxy-2-tetralol 7.8%, 7-methoxytetralin 13.3%, 2,7-dimethoxynaphthalene: 1
2.1%

Example 5 In a glass autoclave equipped with a stirrer, 2,7-dimethoxynaphthalene (1.5
1 g, 8.02 mmol), toluene (15.1 g),
Concentrated hydrochloric acid (1.53 g), 10% palladium / activated carbon-supported catalyst (848.4 mg, 55.3% water-containing product) were added, and the autoclave was replaced with nitrogen 5 times at room temperature, and then hydrogen (3 atm, equivalent to 304 kPa). Was replaced 5 times. Then, it stirred under heating at 100 degreeC for 8 hours. After the reaction, it was cooled to room temperature, hydrogen was released, and the reaction solution was analyzed.
It was confirmed that 49.7% of -methoxy-2-tetralone was produced. The other products had the following production ratios. 2,7-dimethoxytetralin: 5.3%, 7-methoxy-2-tetralol: 3.4%, 7-methoxytetralin 3.9%, 2,7-dimethoxynaphthalene: 22.
3%

Example 6 The catalyst was filtered off from the reaction solution obtained in Example 5 and washed with 10 g of toluene.
The obtained filtrate was washed 4 times with 25 ml of water, and then the toluene layer was concentrated. The obtained concentrate was dissolved in 1 ml of methanol, and the mixture was stirred under ice cooling for 30 minutes, and then the precipitated white crystals were filtered off and dried in a vacuum, and 210 mg of 2,7-dimethoxynaphthalene was recovered (recovery rate). 12.3%,
Purity 88%). The filtrate was reconcentrated, dissolved again in 8 ml of methanol, and an aqueous sodium hydrogen sulfite solution (2.04 g of sodium hydrogen sulfite / 6 ml of water) was added under ice cooling.
Stir for 30 minutes. Precipitated white crystals were separated by filtration and vacuum dried to obtain 3.49 g of hydrogen sulfite adduct. The white crystals were suspended in 5 ml of water, 2 g of sodium carbonate was added, and the mixture was stirred at room temperature for 1 hour, then, 10 ml of toluene ×
Extraction with 3 and concentration of toluene gave 743 mg of 7-methoxy-2-tetralone (yield 39%, purity 84%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.13
(D, J = 8.4 Hz, 1H), 6.75 (d, J =
8.4Hz, 1H), 6.66 (s, 1H), 3.78
(S, 3H), 3.54 (s, 2H), 2.99 (t,
J = 6.8Hz, 2H), 2.53 (t, J = 6.4H
z, 2H)

[0051]

INDUSTRIAL APPLICABILITY Since the present invention has the above-mentioned constitution, an alkoxy-substituted 2-tetralone useful as an intermediate for agricultural chemicals and pharmaceuticals can be industrially produced from an inexpensive alkoxy-substituted naphthalene.

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Claims (12)

[Claims] 1. A compound represented by the general formula (1): embedded image in a solvent in the presence of a noble metal catalyst and an acid catalyst. (In the formula, R ¹ and R ² are different from each other, one is a hydrogen atom, the other is an alkoxy group having 1 to 6 carbon atoms,
R ³ represents an alkyl group having 1 to 6 carbon atoms. ) Alkoxy-substituted naphthalene represented by the formula (2) is characterized by reacting with hydrogen. (In the formula, R ¹ and R ² have the same meanings as described above.) A method for producing an alkoxy-substituted 2-tetralone. 2. A noble metal catalyst is palladium, ruthenium,
The method according to claim 1, which is a catalyst composed of at least one metal selected from the group consisting of rhodium and platinum. 3. The method according to claim 1, wherein the noble metal catalyst is a palladium catalyst. 4. The production method according to claim 1, wherein a noble metal catalyst supported on a carrier is used. 5. The method according to claim 4, wherein the carrier is activated carbon. 6. The production method according to claim 1, wherein the acid catalyst is an inorganic acid containing a halogen atom. 7. The method according to claim 6, wherein the inorganic acid containing a halogen atom is hydrogen chloride or hydrochloric acid. 8. The method according to claim 1, wherein water is allowed to coexist in the reaction system.
The production method according to any one of 1. 9. The method according to claim 1, wherein an aromatic hydrocarbon solvent is used as the solvent. 10. The method according to claim 1, wherein ^one of R ¹ and R ² is a methoxy group, the other is a hydrogen atom, and R ³ is a methyl group. 11. A reaction mixture containing an alkoxy-substituted 2-tetralone obtained by the production method according to any one of claims 1 to 10 is treated with a bisulfite to convert the alkoxy-substituted 2-tetralone to a bisulfite adduct. The method for separating and purifying an alkoxy-substituted 2-tetralone, which comprises subjecting the hydrogen sulfite adduct to an acid- or base-treatment to give an alkoxy-substituted 2-tetralone. 12. The separation and purification method according to claim 11, wherein the bisulfite is sodium bisulfite.