JP2002275131A - Method for producing optically active 2-aminotetralin derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an optically active 2-aminotetralin derivative, involving converting the unnecessary isomer after optical resolution to the racemic form to put it to recycling use as the raw material for the optical resolution. SOLUTION: This method comprises the steps of making an optical resolution of a 2-aminotetralin derivative of the general formula 1(* denotes R-form or S-form; and R<1> to R<4> are each H, a 1-5C straight-chain or branched alkyl, 1-5C straight-chain or branched alkoxy or halogen atom) followed by separation into the necessary isomer and unnecessary isomer, chlorinating the amino group of the 2-aminotetralin derivative as the unnecessary isomer followed by making a dehydrochlorination and hydrolysis successively to form a 2-tetralone derivative, then reducing the 2-tetralone derivative to effect conversion to the racemic form of the 2-aminotetralin derivative, which is used as the raw material for the optical resolution.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing an optically active 2-aminotetralin derivative, and more particularly to a method of converting an unnecessary isomer after optical resolution into a racemate and recycling it to a raw material for optical resolution. The present invention relates to a method for producing an optically active 2-aminotetralin derivative, which has been improved so that

[0002]

BACKGROUND OF THE INVENTION The optically active 2-aminotetralin derivative represented by the general formula (I) according to claim 1 is a useful pharmaceutical intermediate, and its R-form or S-form is optically resolved from a racemic form. Is obtained by

By the way, in general, after obtaining the required optical isomer by optical resolution, the unnecessary optical isomer is recovered,
It is converted into a raw material and reused in the optical splitting process again. However, the optical activity 2 represented by the above general formula (I)
-A method for recovering the aminotetralin derivative after resolution has not yet been proposed. Therefore, the optically active 2-aminotetralin derivative has a problem that the production cost is high.

[0004]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above circumstances, and has as its object to convert unnecessary isomers after optical resolution into racemates and to recycle them as raw materials for optical resolution. It is an object of the present invention to provide a method for producing an optically active 2-aminotetralin derivative which has been improved so that it can be performed.

[0005]

SUMMARY OF THE INVENTION The object of the present invention is as follows.
After optically resolving a 2-aminotetralin derivative represented by the following general formula (I), it is separated into a necessary isomer and an unnecessary isomer. Are chlorinated and then sequentially subjected to a dehydrochlorination reaction and a hydrolysis reaction to obtain a 2-tetralone derivative, which is then converted to a racemic 2-aminotetralin derivative by a reduction reaction of the 2-tetralone derivative to obtain an optical resolution. Activity 2 characterized by being used as a raw material
-Achieved by the process for producing aminotetralin derivatives.

[0006]

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[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
Examples of the 2-aminotetralin derivative represented by the general formula (I) include 2-amino-7-methoxytetralin, 2-amino-7-ethoxytetralin, 2-amino-5-methoxytetralin and the like.

The optical resolution of the above-mentioned 2-aminotetralin derivative can be easily carried out, for example, according to a known method using optically active mandelic acid as a resolving agent. Separation of the necessary isomer and the unnecessary isomer (R-form and S-form) is carried out by solid-liquid separation (filtration) utilizing the solubility of both, and usually the necessary isomer is separated. The optical activity of the mandelic acid used is selected so as to be solid. It should be noted that which of the R-form and the S-form is the required isomer depends on the purpose of use.

In the production method of the present invention, the unnecessary isomer (one of the R-form or the S-form is excessively contained) through a chlorination reaction, a dehydrochlorination reaction, a hydrolysis reaction, and a reduction reaction of an amino group in order. The filtrate obtained is converted to the racemate. The following chemical formula shows one example of the production method of the present invention, and a preferred embodiment includes an oximation reaction between the hydrolysis reaction and the reduction reaction.

[0010]

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Chlorination reaction of amino group (the above compound (1)
To (2)) can be carried out using an alkyl hyperchlorite as a chlorinating agent. Specific examples of the alkyl hyperchlorite include t-butyl hyperchlorite, n-butyl hyperchlorite, n-amyl hyperchlorite, and the like. These alkyl hyperchlorites can also be produced and supplied in a reaction system from hypochlorous acid and alcohol. The amount of the hyperchlorite to be used is generally 0.5 to 5 parts by weight, preferably 0.5 to 2 parts by weight, per 1 part by weight of compound (1).

The chlorination reaction with alkyl hyperchlorite is carried out in the presence of a base such as sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, pyridine and the like. The amount of the base to be used is generally 0.5 parts, per 1 part by weight of compound (1).
To 5 parts by weight, preferably 0.5 to 1 part by weight.

Examples of the reaction solvent include esters such as ethyl acetate, ethers such as diethyl ether, alcohols such as t-butanol, and mixed solvents of alcohol and water. The amount of the reaction solvent to be used is generally 3 to 20 parts by weight, preferably 5 to 10 parts by weight, per 1 part by weight of compound (1). The temperature of the chlorination reaction is usually 0 to 30 ° C, preferably 0 to 10 ° C, and the reaction time is usually 0.5 to 6 hours, preferably 1 to 2 hours.

The dehydrochlorination reaction (conversion of the above compound (2) to (3)) is carried out by the action of a strong base such as sodium alkoxide, caustic soda and caustic potash. The amount of the strong base is usually 1 to 1 part by weight of the compound (2).
To 20 parts by weight, preferably 1 to 5 parts by weight. The reaction temperature of the dehydrochlorination reaction is usually 20 to 80 ° C., preferably 3 to 80 ° C.
0 to 50 ° C., and the reaction time is usually 0.5 to 5 hours,
Preferably, it is 1-2 hours.

The hydrolysis reaction (conversion of compound (3) to (4)) is carried out in the presence of an acid. Examples of the acid include sulfuric acid, hydrochloric acid, perchloric acid and the like. The amount of the acid to be used is generally 1 to 10 parts by weight, preferably 1 to 5 parts by weight, per 1 part by weight of compound (2). The hydrolysis temperature is
The reaction temperature is usually 20 to 80 ° C, preferably 30 to 50 ° C, and the reaction time is usually 0.5 to 5 hours, preferably 0.5 to 2 hours. By the hydrolysis reaction, a 2-tetralone derivative (the above compound (4)) is obtained.

The oximation reaction (conversion of the above compound (4) to (5)) can be carried out according to a known method using, for example, hydroxylamine hydrochloride (NH ₂ OH · HCl). The amount of the hydroxylamine hydrochloride to be used is generally 0.3 to 2 with respect to 1 part by weight of the compound (4).
Parts by weight, preferably 0.3 to 1 part by weight.

The oximation reaction is carried out in the presence of a strong base such as sodium alkoxide, caustic soda, caustic potash and the like. The amount of the base to be used is generally 2.5-5 parts by weight, preferably 2.5-3 parts by weight, per 1 part by weight of compound (4). Examples of the reaction solvent include esters such as ethyl acetate, ethers such as diethyl ether, alcohols such as ethanol, and mixed solvents of alcohol and water.
The amount of the reaction solvent to be used is generally 1 to 10 parts by weight, preferably 1 to 5 parts by weight, per 1 part by weight of compound (4).

The temperature of the oximation reaction is usually from 20 to 80.
° C, preferably 30 to 60 ° C, and the reaction time is usually 0.5 to 3 hours, preferably 0.5 to 1 hour. When the next reduction reaction is carried out via an oximation reaction, the 2-tetralone derivative (compound (4)) may be of any type (i.e., R ¹ , R ² , R ³ , and R ⁴ may be any of those described above). 2) easily and reliably perform the reduction reaction to
There is an advantage that an aminotetralin derivative can be obtained.

The reduction reaction (conversion of compound (5) to (6)) is preferably carried out after recrystallizing oxime (5) with an organic solvent. Examples of the organic solvent used for recrystallization include methanol, ethanol, and the like, and the amount of the solvent is usually 5 to 20 parts by weight, preferably 5 to 10 parts by weight, based on 1 part by weight of the oxime (5). According to such a recrystallization operation, there is an advantage that the next reduction reaction (catalytic hydrogenation reaction) is efficiently performed because impurities are removed.

The reduction reaction is carried out by a known method (J. Chem. Soc., 2
63, 6-41, 1965, etc.). For example, a catalytic hydrogenation reaction performed by supplying hydrogen in the presence of a Raney nickel catalyst can be employed. In particular, when the reaction does not pass through the oximation reaction (in the case of reduction of the 2-tetralone derivative), the reaction is performed in the presence of aqueous ammonia. By this reduction reaction, a 2-aminotetralin derivative (racemate) is obtained. The obtained racemate is used as a raw material for the above-mentioned optical resolution.

[0021]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples unless it exceeds the gist of the present invention.

Example 1 12.8 g (0.0%) of 2-amino-7-methoxytetrali
72 mol), 10.93 g of (-) mandelic acid (0.07
2 mol) and 70 ml of ethanol were stirred at 60 ° C., then cooled to room temperature, and the precipitated crystals were separated by filtration. By recrystallizing the obtained crystals twice with ethanol, S
5.12 g of -2-amino-7-methoxytetralin was obtained. On the other hand, the filtrate was concentrated, a 10% by weight aqueous solution of NaOH was added, and the mixture was extracted with toluene. Next, the toluene phase separated from the aqueous phase was concentrated, and 7.68 g of R-form excess 2-amino-7-methoxytetralin was recovered.

Then, a solution of 7.68 g (0.043 mol) of the above 2-amino-7-methoxytetralin, 76 ml of ethyl acetate and 3.64 g (0.043 mol) of sodium bicarbonate was added at 0 ° C. to t-butyl hyperchlorite. 4.70 g (0.
043 mol) was added. After reacting for 1 hour, sodium ethoxide and ethanol were added, and the mixture was heated at 45 ° C. for 1.5 hours. After cooling, 50 ml of 10% by weight sulfuric acid was added, and the mixture was further heated at 45 ° C. for 30 minutes. After cooling, the reaction solution was extracted with ethyl acetate and concentrated to obtain 6.53 g (85%) of 7-methoxy-2-tetralone.

Next, 6.53 g (0.037 mol) of the above-mentioned 7-methoxy-2-tetralone, 2.8 g (0.040 mol) of hydroxylamine hydrochloride, ethanol 20
The mixture was neutralized by adding a 2N aqueous solution of NaOH at 60 ° C. to the mixed solution of ml. After stirring at 60 ° C. for 1 hour, the mixture was acidified with acetic acid and cooled to room temperature. The precipitated crystals were filtered to obtain crude oxime crystals. Thereafter, the product was recrystallized from methanol to obtain 6.38 g (90%) of an oxime of 7-methoxy-2-tetralone.

Next, 1.3 g of Raney nickel was added as a catalyst to a mixture of 6.38 g (0.033 mol) of the oxime of 7-methoxy-2-tetralone, 7.65 g of 25% by weight aqueous ammonia and 50 ml of ethanol. ,
The catalytic hydrogenation reaction was performed at normal pressure. After reacting at 50 ° C for 6 hours, the catalyst was filtered, and the collected filtrate was concentrated to give 2-
5.25 g of racemic amino-7-methoxytetralin
(89%).

Example 2 32 g (0.18 mol) of 2-amino-7-methoxytetrali, 27.33 g (0.18 mol) of (+) mandelic acid and 175 ml of ethanol were stirred at 60 ° C., and then cooled to room temperature. The precipitated crystals were separated by filtration. By recrystallizing the obtained crystals twice with ethanol, R-
12.16 g of 2-amino-7-methoxytetralin were obtained. On the other hand, the filtrate was concentrated, a 10% by weight aqueous solution of NaOH was added, and the mixture was extracted with toluene. Next, the toluene phase separated from the aqueous phase was concentrated to recover 19.84 g of S-form excess 2-amino-7-methoxytetralin.

Next, a solution of 19.84 g (0.11 mol) of the above 2-amino-7-methoxytetralin, 190 ml of ethyl acetate and 9.41 g (0.11 mol) of sodium bicarbonate at 0 ° C. in t-butyl hyperchlorite. 12.14g
(0.11 mol) was added. After reacting for 1 hour, sodium ethoxide and ethanol were added, and the mixture was added at 45 ° C for 1 hour.
Heat for 5 hours. After cooling, 130 ml of 10% by weight sulfuric acid
Was added and further heated at 45 ° C. for 30 minutes. The reaction mixture was cooled, extracted with ethyl acetate, concentrated, and then concentrated.
15.19 g (77%) of tetralone were obtained.

Then, a mixed solution of 15.19 g (0.086 mol) of the above 7-methoxy-2-tetralone, 6.58 g (0.095 mol) of hydroxylamine hydrochloride and 50 ml of ethanol at 60 ° C. was added with a 2N NaOH aqueous solution. Was added to neutralize. After stirring at 60 ° C. for 1 hour, the mixture was acidified with acetic acid and cooled to room temperature. The precipitated crystals were filtered to obtain crude oxime crystals. afterwards,
By recrystallization from methanol, 7-methoxy-2
13.98 g (85%) of the oxime of tetralone were obtained.

Then, 13.98 g (0.073 mol) of the oxime of 7-methoxy-2-tetralone described above, 25
16.77 g by weight of ammonia water, 120 m of ethanol
2.85 g of Raney nickel as a catalyst was added to 1 of the mixed solution, and a catalytic hydrogenation reaction was carried out at normal pressure. 6 at 50 ° C
After reacting for an hour, the catalyst was filtered, and the collected filtrate was concentrated to give racemic 2-amino-7-methoxytetralin 1
1.67 g (90%) were obtained.

[0030]

According to the present invention described above, the optical activity 2 is improved so that unnecessary isomers after optical resolution can be converted into racemates and recycled for use as raw materials for optical resolution.
A method for producing an aminotetralin derivative is provided, and the industrial value of the present invention is remarkable.

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Claims (1)

[Claims] 1. After optically resolving a 2-aminotetralin derivative represented by the following general formula (I), it is separated into a necessary isomer and an unnecessary isomer. After chlorinating the amino group of the tetralin derivative, a dehydrochlorination reaction and a hydrolysis reaction are sequentially performed to obtain 2
A method for producing an optically active 2-aminotetralin derivative, comprising obtaining a tetralone derivative, converting the 2-tetralone derivative into a racemic 2-aminotetralin derivative by a reduction reaction, and using the racemic material as a raw material for optical resolution. . Embedded image