JPH0597778A - Method for producing 2-aminoindane and salts thereof - Google Patents

Abstract

(57) [Summary] [Objective] The conventional method for synthesizing 2-aminoindane requires a complicated process and the yield is low, so that it is not satisfactory. [Structure] 1,2-Aminoindane is immediately obtained by isomerizing 1,2,3,4-tetrahydroisoquinoline in the presence of a solid acid catalyst.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention is pharmacologically useful for preventing various heart diseases such as arrhythmia, hypertension and asthma.
The present invention relates to a method for producing 2-aminoindanes useful as a raw material for therapeutic agents.

[0002]

2. Description of the Prior Art Derivatives of 2-aminoindan generally show excellent physiological activity, and examples of applications as various pharmaceuticals include JP-B-54-6551, JP-B-62-12214, and JP-B-62-12800. Publication, J. Org. Chem, Vol. 9, P. 380-391.
(1944) and many others have been reported. In both cases,
It is disclosed that a drug having high side effects and less side effects than conventional products can be produced.

On the other hand, various methods for synthesizing 2-aminoindane, which is the core of the structure, have been studied, but no industrially effective method has been found at present. The previously reported method for synthesizing 2-aminoindane requires complicated steps and the yield is not satisfactory. In the most general method, first, 2-indanone obtained by oxidizing or brominating indene with formic acid and then decomposing with sulfuric acid is added with hydroxylamine to synthesize 2-indanone oxime. 2-by reducing indanone oxime
Aminoindane can be obtained, but in any reaction, the total yield is low at 30 to 40% because a large amount of organic solvent and catalyst are required. Therefore, studies have been conducted for each process for the purpose of improving the yield, but in the present situation, no outstanding results have been obtained yet.

For example, there is a problem that the reaction product is decomposed and polymerized due to a large amount of heat generation in the oxidation process with performic acid. Regarding this, in Japanese Patent Laid-Open No. 63-39833, heat generation is suppressed by dropping hydrogen peroxide solution into a mixture of indene and formic acid. However, the yield of 2-indanone is inadequate at 50 to 60% based on indene. Further, in the reduction step of 2-indanone oxime, there is a problem that diindanylamine which is a secondary amine is by-produced. About this, J. Org. Chem, Vol. 9, P. 380-391 (1944)
In the above, by-products of diindanylamine are suppressed by catalytically reducing 2-indanone oxime in the presence of hydrochloric acid and palladium chloride. However, since the reaction product in this case is the hydrochloride of 2-aminoindane, it is further liberated with sodium hydroxide, etc., and then extracted with solvent.
Since operations such as concentration are required, the process becomes complicated and the yield is low at about 60%. Also, J. Org. Chem, Vol. 28, P.
2797-2804 (1963) suppresses by-production of diindanylamine by catalytically reducing 2-indanone oxime in the presence of sodium hydroxide or sodium methylate. However, this method requires a large amount of solvent / catalyst for the raw material, and the separation step of the additive is complicated, resulting in a low separation yield. In the same report, reduction of 2-indanone oxime is also carried out using a palladium carbon catalyst in the presence of concentrated sulfuric acid-glacial acetic acid. However, also in this case, the sulfate of 2-aminoindan is produced, and the separation yield is low as in the previous method.

That is, in the conventional method, in addition to the large number of manufacturing steps, each unit operation is complicated and the yield is insufficient. Therefore, there are many technical problems in industrialization, and the method is industrially advantageous. Was desired to be developed.

[0006]

In the above-mentioned conventional method, many intermediate steps are required until the desired product is obtained,
In addition, it was necessary to treat many by-products and by-products. Moreover, since the yield is low, it was difficult to carry out industrially. An object of the present invention is to provide 2-aminoindane and various salts thereof by an industrially feasible method by way of a novel reaction step that can greatly simplify the production process. ..

The salts of 2-aminoindan are more stable than 2-aminoindan and have the advantage that they are suitable for long-term storage.

[0008]

[Means for Solving the Problems] In order to solve the above-mentioned problems, various studies on synthesis methods were conducted. As a result, 1,2, which is a structural isomer of 2-aminoindan,
It has been found that 3,4-tetrahydroisoquinoline is selectively isomerized to 2-aminoindane by an acid catalyst. In particular, the inventors have found that the use of a solid acid as a catalyst improves the selectivity and the separability from the catalyst, and completed the present invention. Since this method does not require auxiliary materials and a solvent, 2-aminoindane can be obtained from 1,2,3,4-tetrahydroisoquinoline, which is relatively easily available, in a single reaction.
It has become possible to simplify the manufacturing process.

That is, the present invention is characterized in that 1,2,3,4-tetrahydroisoquinoline represented by the following formula (1) is isomerized in the presence of a solid acid catalyst. -A method for producing aminoindan,

[0010]

[Chemical 3]

Further, 1, 2, 3, 4 represented by the following formula (1)
-A method for producing a 2-aminoindane salt represented by the following formula (3), characterized in that tetrahydroisoquinoline is isomerized in the presence of a solid acid catalyst, and the obtained reaction product is reacted with an acid.

[0012]

[Chemical 4]

[0013]

[Operation] The present invention will be described in detail below. The starting material 1,2,3,4-tetrahydroisoquinoline of the present invention can be easily obtained by catalytically reducing isoquinoline contained in coal tar or the like with a nickel catalyst or the like.
The raw materials may be purified by distillation or the like, but a mixture can also be used. Moreover, you may mix with a suitable organic solvent.

In the isomerization reaction, the acid acts as a catalyst, but in the case of inorganic / organic acids, a solid acid is effective because it easily forms a salt with isoquinoline. For example, various types of zeolite such as silica / alumina, A type, Y type, etc. are preferable. The function of the catalyst is to dissociate the C—N bond present in the heterocycle of tetrahydroisoquinoline to form a more stable C—C bond, which produces 2-aminoindane. It is generally used after removing the adsorbed components on the catalyst surface by pretreatment such as temperature rise, but it is also possible to use without pretreatment. The catalyst may be in the form of powder, pellets or flakes. The amount of the catalyst used is appropriately 1 to 50% by weight, more preferably 2 to 25% by weight, based on tetrahydroisoquinoline.

An inert gas or hydrogen is suitable for the atmosphere in the reactor, but hydrogen is particularly preferable because it has an activating effect on the catalyst. The pressure is selected in the range of atmospheric pressure to 10 kg / cm ² G, but the effect of pressure is not particularly recognized, so atmospheric pressure to 4 kg / cm ²
It is preferred to operate at low pressure conditions of cm ² G. The reaction temperature is selected within the temperature range in which the catalyst is active, and 250 to 600 ° C is suitable for any catalyst system. However, since the activity is low at low temperatures and the by-products tend to increase at high temperatures, 400 to 500 ° C., which exhibits particularly high activity and high selectivity, is preferable.

The reaction can be terminated under the above conditions for 10 minutes to 3 hours, more preferably 30 minutes to 2 hours, when the yield of 2-aminoindane is maximized. The reactor can be made of stainless steel, pressure resistant glass, or an autoclave in which stainless steel is lined with glass or Teflon, but a flow-through type device such as a catalyst packed bed or a fluidized bed can also be used. There are no particular restrictions on the style. The retention time when using the distribution method is
0.1 to 15 seconds, and more preferably 1 to 8 seconds are suitable.

After completion of the reaction, the catalyst is separated by a method such as filtration or sedimentation. By distilling and purifying the filtrate or the supernatant with a precision distiller, high-purity (99% by weight or more) 2-aminoindane can be obtained in high yield. Further, the obtained 2-aminoindane easily reacts with hydrochloric acid, sulfuric acid or carbon dioxide gas to form various salts. These can be recovered as high-purity salt crystals by filtering and washing with an organic solvent such as alcohol, ether, or ketone.

The present invention will be specifically described below with reference to examples, but the present invention is not limited to these conditions.

[0019]

【Example】

Example 1 133 g of 1,2,3,4-tetrahydroisoquinoline (
1.00 mol) and 15 g of silica / alumina were charged into a stainless steel (SUS 316) autoclave having an internal volume of 1.5 l, heated in a hydrogen atmosphere at normal pressure, and stirred from 450 ° C. to 1
Stopped after an hour. The obtained reaction liquid was quantitatively analyzed by gas chromatography. The yield of 2-aminoindane by the reaction was 19 mol%.

Next, the reaction solution was subjected to atmospheric distillation at a reflux ratio of 5 using a batch type precision distillation apparatus (theoretical plate number: 50). 21 g of 2-aminoindan having a purity of 99% (yield: 16 mol%)
Was obtained. Example 2 133 g of 1,2,3,4-tetrahydroisoquinoline (
1.00 mol), 15 g of Y-type zeolite molded product with an internal volume of 1.5
It was charged in a stainless steel (SUS 316) autoclave of 1 l, heated in a hydrogen atmosphere at normal pressure, stirred at 450 ° C, and stopped 1 hour later. The obtained reaction liquid was quantitatively analyzed by gas chromatography. The yield of 2-aminoindane by the reaction was 15 mol%.

Next, the reaction solution was subjected to atmospheric distillation at a reflux ratio of 5 using a batch type precision distillation apparatus (theoretical plate number: 50). 17 g of 2-aminoindan having a purity of 99% (yield: 13 mol%)
Was obtained. Example 3 1,2,3,4-tetrahydroisoquinoline was added to silica.
It was supplied to a tubular reactor (tube diameter 1.0 inch, bed height 4.0 cm) filled with 10 g of alumina at 450 g and normal pressure at 40 g / h (retention time: 10.7 sec). As a result of quantitative analysis of the obtained reaction liquid by gas chromatography, the yield of 2-aminoindane by the reaction was 12 mol%.

Next, the reaction solution was subjected to atmospheric distillation at a reflux ratio of 5 using a batch-type precision distillation apparatus (theoretical plate number: 50). 13 g of 2-aminoindan having a purity of 99% (yield: 10 mol%)
Was obtained. Comparative Example 1 A mixture of 116 g of indene and 500 g of formic acid was added dropwise to 120 g of hydrogen peroxide solution in a 2.0-liter glass flask at room temperature over 2 hours, and the mixture was further stirred for 15 hours. The reaction solution is 1.0
It was extracted with 1 of dichloroethane and the organic layer was separated. The resulting dichloroethane layer was added to 15 g of a 1.0 l glass flask.
The mixture was added dropwise to 600 g of a wt% sulfuric acid aqueous solution at 90 ° C. over 2 hours, and stopped when the azeotrope of dichloroethane and water was almost distilled. A part of the obtained solid was dissolved in acetone and quantitatively analyzed by gas chromatography. 2-
The yield of indanone was 58 mol%.

Then, the solid 2-indanone mixture was dissolved in 500 g of pyridine in a 2.0 l glass flask and 20 wt.
% Hydroxylamine hydrochloride aqueous solution (200 g) was mixed at room temperature. Immediately, the obtained solid was filtered and washed with water. Again, a part of the solid was dissolved in acetone and quantitatively analyzed by gas chromatography. The yield of 2-indanone oxime is 90 mol% (yield to indene: 52 mol
%)Met.

Next, a 2.0-liter stainless steel autoclave
2-indanone oxime, enothal 5 obtained in
Mix 00g and Raney nickel 10g, hydrogen pressure 5kg
/cm ² G, stirred at 60 ° C. for 1 hour. The reaction mixture obtained is
When quantitative analysis was performed by chromatography, 2
-The yield of aminoindane is 62 mol% (yield to indene:
 32 mol%).

Finally, the reaction solution was subjected to atmospheric distillation at a reflux ratio of 5 using a batch type precision distillation apparatus (theoretical plate number: 50). 40 g of 2-aminoindane having a purity of 99% (yield to indene: 30 mol%) was obtained.

[0026]

According to the method of the present invention, 1, 2, 3, 4
2-aminoindan can be synthesized by isomerizing tetrahydroisoquinoline with a solid acid catalyst,
Compared with the conventional synthesis method, the steps can be greatly simplified, and 2-aminoindane can be economically produced.

Claims (2)

[Claims] 1. A 2-aminoindane represented by the following formula (2), characterized by isomerizing 1,2,3,4-tetrahydroisoquinoline represented by the following formula (1) in the presence of a solid acid catalyst. Production method. [Chemical 1] 2. A method of isomerizing 1,2,3,4-tetrahydroisoquinoline represented by the following formula (1) in the presence of a solid acid catalyst, and reacting the obtained reaction product with an acid: A method for producing a 2-aminoindane salt represented by the formula (3). [Chemical 2]