KR20080056977A - Method for preparing octahydroindole-2-carboxylic acid - Google Patents

Abstract

A method for preparing an octahydroindole-2-carboxylic acid is provided to obtain a (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid or the octahydroindole-2-carboxylic acid with significantly increased reaction yield and reaction activity. To prepare an octahydroindole-2-carboxylic acid represented by a formula(1), a basic material is added to an indoline-2-carboxylic acid represented by a formula(3) and then hydrogenated in the presence of a group VIII metal catalyst. To prepare an octahydroindole-2-carboxylic acid represented by a formula(2), a basic material is added to an indoline-2-carboxylic acid represented by a formula(4) and then hydrogenated in the presence of a group VIII metal catalyst. Further, the adding weight of the basic material is 0.1 to 3.0 equivalent.

Description

Method for preparing octahydroindole-2-carboxylic acid {Method for preparing Octahydroindole-2-carboxylic acid}

The present invention relates to a method for producing (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid represented by the following general formula (1) or octahydroindole-2-carboxylic acid represented by the following general formula (2), and more specifically, (S)-(2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid or octahydroindole- by adding a basic substance to indolin-2-carboxylic acid or indolin-2-carboxylic acid and hydrogenating on a Group VIII metal catalyst A method for producing 2-carboxylic acid in high yield.

(2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid represented by the formula (1) and octahydroindole-2-carboxylic acid represented by the formula (2) are known as useful materials as a raw material of a medicament for treating or preventing hypertension have.

Looking at the conventional manufacturing method for producing (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid or octahydroindole-2-carboxylic acid as follows.

U.S. Patent No. 4,584,285 discloses hydrogenation by adding platinum oxide to ethyl indole-2-carboxylic acid dissolved in trifluoroacetic acid, followed by the addition of camphorsulfonic acid to cis, new-octa hydro-1H-indole-2 (S) -carboxylic acid. A method of obtaining is disclosed.

US Pat. No. 4,490,386 also discloses the preparation of octahydro-1H-indole-2-carboxylic acid by selective resolution of α-phenylethylamine from racemic (2α, 3aβ, 7aβ) -octahydro-1H-indole-2-carboxylic acid. US Pat. No. 5,258,525 discloses about 58% of hydrogen by reacting 2S-indolin-2-carboxylic acid with a deoxygenation solvent in the presence of a rhodium on carbon catalyst or a rhodium-palladium catalyst on carbon. A method for producing 2 (S)-(2α, 3aβ, 7aβ) -octahydro-1H-indole-2-carboxylic acid in yield is disclosed.

U.S. Pat.Nos. 4,935,525 and 4,914,214 disclose that (R, S) -2-ethoxycarbonylindolin is obtained by mixing tin with 2-ethoxycarbonylindole, which is then quenched with sodium hydroxide (R, S ) -2-carboxyindoline was prepared and (S) -2-carboxyindolin was separated by kinetic resolution of (+)-α-methylbenzylamine, and then hydrogenated in the presence of a rhodium catalyst to yield 86.1%. Mention is made of techniques for preparing (2S, 3aS, 7aS) -2-carboxyoctahydroindole.

However, in the prior art, octahydroindole-2-carboxylic acid is prepared by using a catalyst such as rhodium, palladium, platinum oxide, etc., starting from indolin-2-carboxylic acid as a starting material, and performing a hydrogenation reaction in a neutral or acidic atmosphere. And a yield of octahydroindole-2-carboxylic acid is only 86% or less.

After many studies to dramatically improve the low yield of octahydroindole-2-carboxylic acid according to the conventional manufacturing method as described above, the present inventors added a basic substance to indolin-2-carboxylic acid to the Group VIII metal catalyst. When the hydrogenation in the phase was found to be able to obtain a high reaction yield and reaction activity of 94% or more, based on this, a new method for preparing octahydroindole-2-carboxylic acid according to the present invention was completed.

Accordingly, it is an object of the present invention to add a basic material to (S) -indolin-2-carboxylic acid or indolin-2-carboxylic acid to proceed with hydrogenation on Group VIII metal catalysts in high yield (2S, 3aS, 7aS)- It is to provide a method for producing octahydroindole-2-carboxylic acid or octahydroindole-2-carboxylic acid.

The method for preparing (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid represented by the following general formula (1) of the present invention for achieving the above object is (S) -indolin-2- represented by the following general formula (3): Adding a basic substance to the carboxylic acid and hydrogenating the Group VIII metal catalyst.

Formula 1

In addition, the method for preparing octahydroindole-2-carboxylic acid represented by the following Chemical Formula 2 of the present invention for achieving the above object is added to the indolin-2-carboxylic acid represented by the following Chemical Formula 4 on the Group VIII metal catalyst Hydrogenating.

Formula 2

Hereinafter, the present invention will be described in more detail.

As described above, in the present invention, a basic substance is added to (S) -indolin-2-carboxylic acid represented by Chemical Formula 3 or indolin-2-carboxylic acid represented by Chemical Formula 4, and the presence of Group VIII metal catalyst is present. By proceeding hydrogenation under (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid represented by the formula (1) or octahydroindole-2-carboxylic acid represented by the formula (2) can be produced in a high yield of 94% or more It became.

In other words, when a basic material is added using (S) -indolin-2-carboxylic acid of Chemical Formula 3 as a starting material and the hydrogenation reaction is carried out in the presence of a Group VIII metal catalyst, as shown in Scheme 1 below ( 2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid can be prepared in high yield, and a basic material is added with indoline-2-carboxylic acid of the formula (4) which is a racemic compound as a starting material, and a Group VIII metal catalyst When the hydrogenation reaction is carried out in the presence of the octahydroindole-2-carboxylic acid can be prepared in a high yield as shown in the following scheme 2.

At this time, the basic substance which can be used for the manufacturing method according to the present invention is alkali metal hydroxide which is sodium hydroxide, potassium hydroxide, lithium hydroxide, rubidium hydroxide or cesium hydroxide; Alkali metal carbonates which are sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydrogen carbonate, lithium carbonate, rubidium carbonate or cesium carbonate; Ammonium hydroxide; Or NR ₁ R ₂ R ₃ (wherein R _{1 ,} R _{2 ,} R ₃ is a hydrogen atom or alkyl having up to 5 carbon atoms), pyridine or piperidine or a substituent thereof, pyrrole It may be selected from pyroolidine or a substituent thereof, quinoline or tetrahydroquinoline or an amine compound thereof.

The preferred amount of the basic substance is 0.1 to 3.0 equivalents, preferably 0.8 to 2.0 equivalents. If the amount of basic substance is less than 0.1 equivalent, the reaction rate is slow. If it exceeds 3.0 equivalent, there is a problem in the stability of the reactant.

The Group VIII metal catalyst used in the present invention is preferably composed of Group VIII metals of rhodium, palladium, platinum or ruthenium, and in order to obtain higher catalytic activity and reaction yield, it is preferable to use a catalyst carrying rhodium or ruthenium. desirable.

In the Group VIII metal catalyst, the content of the Group VIII metal is preferably 0.02 to 20 wt%. If the content of the Group VIII metal is less than 0.02 wt%, there is a problem that the reaction rate is slow, and if it is more than 20 wt%, the economy is inferior due to the catalyst price.

As the carrier of the Group VIII metal catalyst, a well-known known carrier can be used without limitation. Preferably, silica, silica alumina, alumina, zirconia, titania, aluminum phosphate or carbon is used as the carrier.

The hydrogenation reaction proceeds according to the hydrogenation reaction conditions of (S) -indolin-2-carboxylic acid or indolin-2-carboxylic acid known in the art. The hydrogenation reaction proceeds under the conditions of a reaction pressure of / cm ² and a molar ratio of hydrogen to hydrocarbon of 3.0 or more.

There is no particular restriction on the hydrogenation reactor, but a batch reactor or a continuous reactor is used, and in the case of the continuous reactor, the hydrogenation reaction proceeds under the conditions of the space velocity (WHSV) of the liquid phase reactant of 0.5 to 20.0 hr ⁻¹ .

Hereinafter, the present invention will be described in more detail with reference to the following Examples, but the scope of the present invention is not limited to the following Examples.

Comparative Example 1

3.0 g of (S) -indolin-2-carboxylic acid, 10 g of distilled water, 40 g of methanol, and 0.5 g of a rhodium-carbon (rhodium content 5 wt%) catalyst were charged into a 100 cc autocracker, and the reaction temperature was 60 deg. psig, reacted at 1000 rpm for 12 hours.

Samples were taken at regular time intervals and analyzed by high performance liquid chromatography. After the conversion reached 100% the reaction was terminated and the reactor temperature was lowered. A total of 16 hours was required and the yield for (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid was 70%.

Comparative Example 2

5.0 g of (S) -indoline-2-carboxylic acid, 85 g of methanol, and 1.0 g of ruthenium-carbon (ruthenium content 5 wt%) catalyst were charged to a 100 cc autoclave, reaction temperature of 80 ° C., hydrogen pressure of 50 bar, 1000 The reaction was carried out for 16 hours at rpm conditions. The yield for (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid was 20%.

Example 1

1.5 g of (S) -indoline-2-carboxylic acid, 0.35 g of sodium hydroxide, 30 g of distilled water, and 0.24 g of rhodium-carbon (rhodium content 5 wt%) catalyst were charged into a 100 cc autoclave, and the reaction temperature was 60 ° C., hydrogen. The reaction was carried out at a pressure of 30 bar at 1000 rpm.

Samples were taken at regular time intervals, neutralized with dilute hydrochloric acid, and analyzed by High Performance Liquid Chromatography. The conversion reached 100% in 3 hours, and (2S, 3aS, 7aS) -octahydro The yield for indole-2-carboxylic acid was 97%.

Example 2

1.5 g of (S) -indoline-2-carboxylic acid, 0.51 g of potassium hydroxide, 30 g of distilled water, and 0.24 g of rhodium-alumina (5 wt% of rhodium) catalyst were charged into a 100 cc autoclave, and the reaction temperature was 60 deg. The reaction was carried out at a pressure of 30 bar at 1000 rpm.

Samples were taken at regular time intervals, neutralized with dilute hydrochloric acid, and analyzed by High Performance Liquid Chromatography. The conversion reached 100% in 3 hours, and (2S, 3aS, 7aS) -octahydro The yield for indole-2-carboxylic acid was 96%.

Example 3

1.5 g of (S) -indoline-2-carboxylic acid, 0.48 g of sodium carbonate, 30 g of distilled water, and 0.24 g of rhodium-silica (rhodium content 5 wt%) catalyst were charged into a 100 cc autoclave, and the reaction temperature was 60 ° C. and hydrogen pressure. The reaction was carried out at 30 bar, 1000 rpm.

Samples were taken at regular time intervals, neutralized with dilute hydrochloric acid, and analyzed by High Performance Liquid Chromatography. The conversion reached 100% in 3 hours, and (2S, 3aS, 7aS) -octahydro The yield for indole-2-carboxylic acid was 97%.

Example 4

1.5 g of (S) -indolin-2-carboxylic acid, 0.72 g of pyridine, 30 g of distilled water, and 0.24 g of rhodium-silica alumina (rhodium content 5 wt%) catalyst were charged into a 100 cc autoclave, and the reaction temperature was 60 deg. The reaction was carried out at a pressure of 30 bar at 1000 rpm.

Samples were taken at regular time intervals, neutralized with dilute hydrochloric acid, and analyzed by High Performance Liquid Chromatography. The conversion reached 100% in 3 hours, and (2S, 3aS, 7aS) -octahydro The yield for indole-2-carboxylic acid was 96%.

Example 5

1.5 g of (S) -indolin-2-carboxylic acid, 0.77 g of piperidine, 30 g of distilled water and 0.24 g of rhodium-silica (rhodium content 5 wt%) catalyst were added to a 100 cc autoclave, and the reaction temperature was 60 ° C and hydrogen. The reaction was carried out at a pressure of 30 bar at 1000 rpm.

Samples were taken at regular time intervals, neutralized with dilute hydrochloric acid, and analyzed by High Performance Liquid Chromatography. The conversion reached 100% in 3 hours, and (2S, 3aS, 7aS) -octahydro The yield for indole-2-carboxylic acid was 97%.

Example 6

1.5 g of (S) -indoline-2-carboxylic acid, 1.17 g of quinoline, 30 g of distilled water, and 0.24 g of rhodium-silica (rhodium content 5 wt%) catalyst were charged into a 100 cc autoclave, and the reaction temperature was 60 ° C. and hydrogen pressure. The reaction was carried out at 30 bar, 1000 rpm.

Samples were taken at regular time intervals, neutralized with dilute hydrochloric acid, and analyzed by High Performance Liquid Chromatography. The conversion reached 100% in 3 hours, and (2S, 3aS, 7aS) -octahydro The yield for indole-2-carboxylic acid was 97%.

Example 7

1.5 g of (S) -indolin-2-carboxylic acid, 0.35 g of sodium hydroxide, 30 g of distilled water, and 0.24 g of ruthenium-zirconia (ruthenium content 5 wt%) catalyst were charged into a 100 cc autoclave, and the reaction temperature was 60 ° C., hydrogen. The reaction was carried out at a pressure of 50 bar at 1000 rpm.

Samples were taken at regular time intervals, neutralized with dilute hydrochloric acid, and analyzed by High Performance Liquid Chromatography. The conversion reached 100% in 3 hours, and (2S, 3aS, 7aS) -octahydro The yield for indole-2-carboxylic acid was 96%.

Example 8

3 g of indolin-2-carboxylic acid, 2.38 g of diisopropylethylamine, 45 g of distilled water, and 1.0 g of a rhodium-silica (5 wt% ruthenium content) catalyst were added to a 100 cc autoclave, and the reaction temperature was 60-. The reaction was carried out at 120 ° C., hydrogen pressure 50 bar, and 1000 rpm for 8 hours. The yield for octahydroindole-2-carboxylic acid was 96%.

Example 9

5 g of indolin-2-carboxylic acid, 3 g of triethylamine, 50 g of distilled water, and 1.0 g of ruthenium-titania (ruthenium content 5 wt%) catalyst were added to a 100 cc autoclave, and the reaction temperature was 80 to 110 ° C. The reaction was carried out for 6 hours at a hydrogen pressure of 50 bar and 1000 rpm. At this time, the yield of octahydroindole-2-carboxylic acid was 97%.

Example 10

(S) -Indolin-2-carboxylic acid: sodium hydroxide: distilled water = 1: 0.24: 5 The reaction mixture was introduced into a small reactor (a stainless steel reactor having an inner diameter of 1 inch and a length of 20 centimeters) by weight. Rhodium-alumina (Rhodium content 5 wt%) catalyst 3.0 to 5.0 g was used, the reaction temperature 40 ~ 200 ℃, the reaction pressure is normal pressure ~ 300 kg / ㎠, hydrogen / hydrogen mole ratio of 2.0 ~ 10.0, liquid reaction space velocity Reaction was performed under the reaction conditions of WHSV = 0.5 to 20.0 hr ^{- 1} . The yield for (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid was 95-99%.

Example 11

Indoline-2-carboxylic acid: sodium hydroxide: distilled water = 1: 0.24: 5 The reaction mixture was introduced into a small reactor (a stainless steel reactor having an inner diameter of 1 inch and a length of 20 centimeters) by weight. Ruthenium-zirconia (ruthenium content 5 wt%) catalyst 3.0 to 5.0 g was used, the reaction temperature 40 ~ 200 ℃, the reaction pressure is the atmospheric pressure ~ 300 kg / ㎠, hydrogen / hydrocarbon mole ratio of 2.0 ~ 10.0, liquid reaction space velocity The reaction was carried out under the reaction conditions of WHSV = 0.5 ~ 20.0hr ^{- 1} . The reaction yield was 94-99%.

As described above, the method for preparing octahydroindole-2-carboxylic acid according to the present invention is obtained by adding a basic substance to (S) -indolin-2-carboxylic acid or indolin-2-carboxylic acid and hydrogenating on a Group VIII metal catalyst. By preparing (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid or octahydroindole-2-carboxylic acid, there is an effect that a significant increase in reaction yield as well as reaction activity can be achieved.

Claims (8)

A method for producing octahydroindole-2-carboxylic acid represented by the following Chemical Formula 1, comprising adding a basic substance to indolin-2-carboxylic acid represented by the following Chemical Formula 3 and hydrogenating the Group VIII metal catalyst. Formula 1

Formula 3

A method for preparing octahydroindole-2-carboxylic acid represented by the following Chemical Formula 2, comprising adding a basic substance to indolin-2-carboxylic acid represented by the following Chemical Formula 4 and hydrogenating the Group VIII metal catalyst. Formula 2

Formula 4

The method of claim 1, wherein the basic material is an alkali metal hydroxide which is sodium hydroxide, potassium hydroxide, lithium hydroxide, rubidium hydroxide or cesium hydroxide; Alkali metal carbonates which are sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydrogen carbonate, lithium carbonate, rubidium carbonate or cesium carbonate; Ammonium hydroxide; Or NR ₁ R ₂ R ₃ (wherein R _{1 ,} R _{2 ,} R ₃ is a hydrogen atom or alkyl having up to 5 carbon atoms), pyridine or piperidine or a substituent thereof, pyrrole A method for producing octahydroindole-2-carboxylic acid, characterized in that it is selected from pyroolidine or a substituent thereof, or an amine compound which is quinoline, tetrahydroquinoline or a substituent thereof. The method for producing octahydroindole-2-carboxylic acid according to claim 1 or 2, wherein the amount of the basic substance added is 0.1 to 3.0 equivalents. The method for preparing octahydroindole-2-carboxylic acid according to claim 4, wherein the basic amount is 0.8 to 2.0 equivalents. The method for preparing octahydroindole-2-carboxylic acid according to claim 1 or 2, wherein the Group VIII metal is rhodium or ruthenium. The method for preparing octahydroindole-2-carboxylic acid according to claim 1 or 2, wherein the carrier used for the Group VIII metal catalyst is silica, silica alumina, alumina, zirconia, titania, aluminum phosphate or carbon. . The method for producing octahydroindole-2-carboxylic acid according to claim 1 or 2, wherein the Group VIII metal content of the Group VIII metal catalyst is 0.02 to 20 wt%.