JPH0597779A - Method for producing 2-aminoindane and its carbonate - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as a raw material for preventing and treating agents for cardiac diseases such as arrhythmia, hypertension, asthma, etc., by subjecting indanoneoxime to catalytic reduction under high pressure in a polar solvent in the presence of a nickel-supported catalyst, hydrogen and carbon dioxide. CONSTITUTION:An 2-indanoneoxime of formula I [R is H, lower alkyl, lower alkoxy or halogen; (n) is 0-4] is subjected to catalytic reduction under high pressure in the presence of a nickel-supported catalyst (e.g. a catalyst supporting reduced nickel on diatomaceous earth, silica, etc.), hydrogen and carbon dioxide in a polar solvent (e.g. 1-4C alcohol, diethyl ether or THF) to provide the objective compound of formula II.

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. 2-Aminoindane has been conventionally generally synthesized by reducing 2-indanone oxime, which is a derivative of indene, with hydrogen. However, this method has a problem that diindanylamine, which is a secondary amine, is simultaneously produced as a by-product. As a method of suppressing the by-production of diindanylamine, J. Org. Chem, Vol. 9, P. 380-391 (1944),
The catalytic reduction of 2-indanone oxime is performed in the presence of hydrochloric acid and palladium chloride. However, since the reaction product in this case is the hydrochloride of 2-aminoindane,
Furthermore, it is necessary to carry out operations such as solvent extraction and concentration after liberation with sodium hydroxide, etc., which complicates the process and the yield is low at about 60%. Further, the yield becomes about 50% in the process of synthesizing carbonate. Also, J. Org. Chem, Vol. 2
8, P. 2797-2804 (1963), suppresses diindanylamine by-product 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, and the separation yield is low. Also in the same report, reduction of 2-indanone oxime is 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 and the yield of carbonate are low as in the previous method.

Therefore, by suppressing side reactions in the hydrogenation process,
Moreover, it has been desired to develop a method capable of suppressing the loss in the separation and purification and the carbonate synthesis step.

[0005]

As described above, 2-aminoindane hydrochloride or sulfate is produced by using the additive for suppressing the secondary and tertiary amines produced as by-products in the hydrogenation reaction. There is a problem that 2-aminoindane or 2-aminoindane carbonate cannot be obtained in high yield.

It is an object of the present invention to provide a method for easily producing 2-aminoindane or 2-aminoindane carbonate in a high yield. It should be noted that salts of 2-aminoindan are more stable than 2-aminoindan and have the advantage of being suitable for long-term storage.

[0007]

[Means for Solving the Problems] The inventors have made earnest studies to solve the above problems. As a result, it was found that by using a mixed gas of hydrogen and carbon dioxide in the hydrogenation reaction, secondary products of secondary and tertiary amines can be suppressed, and the product is directly obtained as 2-aminoindane carbonate. Was completed. That is, conventionally, mineral acids or alkalis were added to suppress the side reaction, whereas addition of carbon dioxide in a gaseous state had the same effect of suppressing the side reaction as in the conventional case. Further, in the present invention, since the reaction product is directly obtained as a carbonate, the purification method can be achieved by simply separating the catalyst by filtration, washing with a solvent and then drying, and the yield is greatly improved.

That is, the present invention is characterized by subjecting 2-indanone oxime represented by the following formula (1) to high-pressure catalytic reduction in the presence of a nickel-supported catalyst and hydrogen and carbon dioxide in a polar solvent. 2 shown in (2)
-A method for producing aminoindan carbonate,

[0009]

[Chemical 3]

Further, 2-indanone oxime represented by the following formula (1) is subjected to high pressure catalytic reduction in a polar solvent in the presence of a nickel-supported catalyst and hydrogen and carbon dioxide,
A method for producing 2-aminoindane represented by the following formula (3), characterized in that the obtained reaction product is reacted with a base.

[0011]

[Chemical 4]

[0012]

[Operation] The present invention will be described in detail below. The 2-indanone oxime as the starting material of the present invention is, for example, WE R
osen et al.'s The Journal of Organic Chemistry (1963, Vo
l.28) or the method described in JP-A-60-218368. In this reaction, lower alcohols having 1 to 4 carbon atoms, lower ethers such as diethyl ether and methyl ethyl ether, tetrahydrofuran or dioxane, or a mixed solvent thereof is generally used as a solvent. This is because these are highly soluble in oximes and do not inhibit the reaction. The amount of solvent is selected within a range in which 2-indanone oxime is dissolved, but usually a solvent amount of 2 to 10 times that of oxime is suitable.

There are various kinds of nickel used as a catalyst. Generally, a reduced nickel catalyst having diatomaceous earth, silica, alumina, silica / alumina, etc. as a carrier, or a catalyst obtained by stabilizing the catalyst after reduction is used. Used. Alternatively, Raney nickel can also be used. The catalyst may be in the form of powder, pellets or flakes. Further, a small amount of an oxide of copper, chromium, manganese or the like as a cocatalyst may be added. The catalyst amount is 1 to 50% by weight based on nickel based on 2-indanone oxime,
It is more preferable to use 2 to 25% by weight. That is, it can be said that 2 to 100% by weight, and more preferably 5 to 50% by weight is suitable for the nickel diatomaceous earth catalyst supporting 50% by weight.

Of the mixed gas used in the reaction, the partial pressure of hydrogen is selected in the range of 30 to ²⁰⁰ kg / cm ² G. 30 kg / cm ² G
In the following, the reaction system is in a hydrogen-deficient state, so side reactions other than hydrogen are promoted. At 200 kg / cm ² G or more, side reactions such as hydrogenation of the benzene nucleus and cleavage of the 5-membered ring are promoted. More preferably, the condition of 50 to 150 kg / cm ² G is suitable.

The action of carbon dioxide is 2-
By associating with aminoindan, it is possible to sequentially generate a few
This is to suppress the side reaction of becoming a primary amine. The association of both occurs at a ratio of 2-aminoindan: carbon dioxide = 2: 1. From this, the amount of carbon dioxide used in the reaction must be 1/2 or more in terms of molar ratio with respect to the starting 2-indanone oxime, and it is suitable to use 1 to 20 times, more preferably 5 to 10 times.

The reaction temperature is selected within the temperature range in which the catalyst is active. The supported nickel catalyst may be 80 ° C. or higher, and Raney nickel may be 30 ° C. or higher, but at 160 ° C. or higher, 2-indanone oxime may be decomposed. It is not preferable. In this reaction, when using a supported nickel catalyst, 120-140 ℃,
When using a Raney nickel catalyst, 50 to 100 ° C is an appropriate temperature range.

When the reduction reaction is carried out under the above conditions for 10 minutes to 3 hours, more preferably 30 minutes to 2 hours, the hydrogen consumption is stopped and the reaction step can be terminated at that time. The reactor is generally made of stainless steel, pressure-resistant glass, or an autoclave in which stainless steel is lined with glass or Teflon, etc., but there is no particular restriction on the structure and style. After the completion of the reaction, a small amount of water is added to dissolve the 2-aminoindane carbonate, and then the catalyst is separated by a method such as filtration or precipitation. 2-Aminoindane is immediately recrystallized as a carbonate by adding a suitable solvent such as methanol or acetone to the filtrate or the supernatant. The 2-aminoindane carbonate recovered as crystals can be purified by washing with a solvent and drying. Alternatively, the free 2-aminoindane can be purified by releasing the carbonate with a base such as sodium hydroxide in a solvent such as methanol or ethanol and then distilling off the solvent. In either case, high-purity (99 wt% or more) 2-aminoindane carbonate or 2-aminoindane can be obtained in high yield. The present invention will be specifically described below with reference to examples, but the present invention is not limited to these conditions.

[0018]

【Example】

Example 1 2-indanone oxime 147 g (1.00 mol), nickel diatomaceous earth (Ni loading: 50 wt%) 12.0 g, ethanol 5
00g of stainless steel with an internal volume of 1.5 liters (SUS 316)
Prepared in an autoclave made of hydrogen and 80 kg / cm ^{2 of} hydrogen
Fill with G and carbon dioxide 10 kg / cm ² G (0.74 mol). After stirring, the temperature was raised to 130 ° C and the reaction was carried out for 1 hour.

Distilled water (50 g) was added to the reaction solution to dissolve crystals, which was then filtered to remove nickel diatomaceous earth. Next, 100 g of methanol is added to carry out recrystallization. The obtained crystals were further washed with methanol and then dried to measure the weight of the crystals. 140 g of 2-aminoindan carbonate
(0.86 mol) was obtained. The melting point of the crystal was 118.2 ° C, which was almost the same as the literature value (118-120 ° C).

Example 2 The procedure of Example 1 was repeated except that 500 g of methanol was used instead of ethanol as the solvent. 137 g (0.84 mol) of 2-aminoindan carbonate having a purity of 98% was obtained. Example 3 Instead of ethanol as a solvent, tetrahydrofuran was used.
The same procedure as in Example 1 was carried out except that 500 g was used. 130 g (0.80mo) of 2-aminoindane carbonate with a purity of 98%
l) Got it.

Example 4 The same procedure as in Example 1 was carried out except that nickel silica / alumina was used as the catalyst instead of nickel diatomaceous earth. 134 g (0.82 m) of 2-aminoindan with a purity of 98%
ol) obtained. Comparative Example 1 2-Aminoindane carbonate was synthesized in the same manner as in Example 1 except that carbon dioxide was introduced into the solution after hydrogenation. As a result of weighing, it was 65.0 g (0.40 mol).

Comparative Example 2 The procedure of Example 1 was repeated except that 12.0 g of 5% palladium carbon was used as the catalyst instead of nickel diatomaceous earth. Results of 2-aminoindan carbonate weighing 2
It was 0.0 g (0.12 mol).

[0023]

EFFECTS OF THE INVENTION According to the method of the present invention, the catalyst, solvent and additives used in the reduction can be easily separated from the 2-aminoindane carbonate, so that the yield is higher than conventional and economical. -Aminoindane can be produced.

Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C07C 217/74 6742-4H // C07B 61/00 300

Claims (2)

[Claims] 1. A 2-indanone oxime represented by the following formula (1) is subjected to high pressure catalytic reduction in a polar solvent in the presence of a nickel-supported catalyst and hydrogen and carbon dioxide. The manufacturing method of 2-amino indan carbonate shown. [Chemical 1] 2. A 2-indanone oxime represented by the following formula (1) is subjected to high pressure catalytic reduction in a polar solvent in the presence of a nickel-supported catalyst and hydrogen and carbon dioxide, and the obtained reaction product is reacted with a base. A method for producing 2-aminoindane represented by the following formula (3), which comprises: [Chemical 2]