KR20150066777A - Indoline derivatives and method of preparing the same - Google Patents

Abstract

The present invention relates to a new indoline derivative usable as a synthetic intermediate of silodosin used in a medicine for dysuresia accompanied with prostatomegaly, and a preparing method thereof. The preparing method according to the present invention using chemical formula (I) and chemical formula (II) can optically synthesize a pure indoline derivative, which is the synthetic intermedia of the silodosin, under a warm reaction condition. R and P in the chemical formula (I) and chemical formula (II) are the same as defined in the detailed specification.

Description

TECHNICAL FIELD [0001] The present invention relates to optically active indolin derivatives and methods for producing the same. BACKGROUND ART [0002] INDOLINE DERIVATIVES AND METHOD OF PREPARING THE SAME [

TECHNICAL FIELD The present invention relates to an indoline derivative useful as a raw material for manufacturing pharmaceuticals and a method for producing the same. More specifically, the present invention relates to a novel indoline derivative useful as a synthetic intermediate of xylosin, which is used as a therapeutic agent for dysuria, and a method for producing the same.

Shilodensin has been widely used as a therapeutic agent for dysuria accompanied by enlargement of the prostate gland through the action of blocking the? -Adrenergic receptor, and a method for producing a compound represented by the following formula (A) as an intermediate used for its synthesis is described in various prior patents.

(A)

In this formula,

R represents hydrogen, an aldehyde group, a cyano group or a carbamoyl group as a substituent,

P is a protecting group which may be substituted with at least one protecting group selected from the group consisting of benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl, , 3-nitrobenzoyl, 1-naphthoyl, 2-naphthoyl, acetyl, benzyl, 4-methylbenzyl, 3-methylbenzyl, 4-cyanobenzyl, Butylbenzyl, 4-t-butylbenzyl, 4-nitrobenzyl, 3-nitrobenzyl, t-butyl-dimethylsilyl, trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, dihydropyranyl or hydrogen.

[Reaction Scheme 1]

The method of Reaction Scheme 1 is a method disclosed in Japanese Patent No. 4634560, wherein a compound of Formula 10 is synthesized from indolin (2) through an eight-step reaction, which is reacted with (R) -phenylethylamine (R) -5- (2-aminopropyl) -1- (3-benzoyloxypropyl) -7-cyanoindoline of the structural formula 1 was prepared by reacting the compound have. This method has a problem in that it requires a special reactor which can not use a general reactor and which can withstand high pressure and can control the pressure because platinum and palladium which are expensive metals are used sequentially and also hydrogen gas of high pressure is used.

[Reaction Scheme 2]

The method of Scheme 2 is a method as described in WO 2011/030356 wherein 1- (3-benzyloxypropyl) -7-cyanoindoline (12) is reacted with a D-alanine derivative (13) (R) -5- (2-aminopropyl) -1- (3-benzyloxypropyl) -7-carbamoylindoline of the structural formula 17 was prepared through a series of reactions. In this method, not only a derivative of the structural formula 14 is synthesized through the two-step reaction from the unnatural amino acid D-alanine, which is not present in the natural world, but also palladium and hydrogen gas are used to remove the benzyl and allyl groups used as an alcohol protecting group There is a problem that it must be used.

[Reaction Scheme 3]

The method of Scheme 3 is accomplished by reacting a compound of formula 18 with hydrogen gas in the presence of an iridium metal catalyst and a ligand (Sa, S) -SIPHOX in the manner disclosed in WO 2013/097456. This method has a problem that it is necessary to use an iridium catalyst which is a expensive metal and a ligand which is difficult to synthesize in order to synthesize an optically active indolin derivative.

[Reaction Scheme 4]

The method of Reaction Scheme 4 is a method disclosed in U.S. Patent No. 2010-0076010 by reacting the compound of Structural Formula 20 with D-alanine derivative (21) to obtain Compound (22) ≪ / RTI > However, this process is very reactive, such as isopropylmagnesium chloride, zinc and palladium metal, so that the step of completely shutting off the air and the oxygen and continuing the reaction is continued, and in order to prepare the compound (26) It is necessary to carry out a hydrogen reaction under the above-mentioned conditions.

Nitroalkanes and amine compounds having substituents at the alpha position have received much attention due to their pharmacological activity. In the above Reaction Scheme 1, a method of synthesizing an amine of the structural formula 1 having an optical activity through a hydrogen reaction in the presence of a metal catalyst from the nitroalkene compound of the structural formula 6 has been extensively tried, but a problem that the optical purity is generally as low as less than 60% have. Thus, attempts have also been made to synthesize amines such as Formula 12 with high optical purity through reaction with already-optically active D-alanine derivatives.

However, since the above method uses a high-pressure hydrogen gas in combination with expensive metals such as iridium, platinum, and palladium during the manufacturing process, it requires a special reactor capable of withstanding pressure and controlling the pressure. Accordingly, the present inventors have sought to develop a process for producing an optically active indoline derivative which can solve such a problem.

An object of the present invention is to provide a novel process for efficiently producing an optically active indoline derivative useful as an intermediate for the synthesis of neodymium under mild reaction conditions, and a novel compound to be used therefor and a process for producing the same.

In order to achieve the above object, the present invention provides a process for the preparation of a compound of formula (A), which comprises reacting a compound of formula (I): ## STR2 ## with sodium borohydride in the presence of acetic acid.

(A)

(I)

In this formula,

R represents hydrogen, an aldehyde group, a cyano group or a carbamoyl group as a substituent,

P is a protecting group which may be substituted with at least one protecting group selected from the group consisting of benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl, , 3-nitrobenzoyl, 1-naphthoyl, 2-naphthoyl, acetyl, benzyl, 4-methylbenzyl, 3-methylbenzyl, 4-cyanobenzyl, Butylbenzyl, 4-t-butylbenzyl, 4-nitrobenzyl, 3-nitrobenzyl, t-butyl-dimethylsilyl, trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, dihydropyranyl or hydrogen.

The compounds of formula (I) and salts thereof for achieving another object of the present invention can be prepared by a process wherein a compound of formula (II) is reacted with trifluoroacetic acid and triethylsilane .

(I)

[Formula II]

Wherein R and P are as defined above.

The compound of the formula (II) and its salt for achieving still another object of the present invention can be produced by a process wherein a compound of the following formula (III) is reacted with a metal salt of phthalimide.

[Formula II]

[Formula (III)

Wherein R and P are as defined above.

In the present invention, in order to produce an optically active indolin derivative which is a synthetic intermediate of xylosin, which is widely used as a therapeutic agent for dysuria associated with enlargement of the prostate gland, optically pure (III) is obtained by using (2R) -bromopropionyl chloride, ) Is efficiently produced and a phthalimide group acting as a kind of amine protecting group is used to produce a compound of the formula (A) under mild reaction conditions. Specifically,

(1) reacting a compound of formula (III) with a metal salt such as lithium, sodium or potassium salt of phthalimide to prepare optically pure new formula (II) compound;

(2) reacting a compound of formula (II) with triethylsilane to prepare a novel compound of formula (I);

(3) The optically pure compound of formula (A) can be prepared in high purity and high yield by reacting the compound of formula (I) with sodium borohydride in the presence of acetic acid.

[Formula (III)

[Formula II]

(I)

(A)

Wherein R and P are as defined above.

A series of reactions according to the present invention can be illustrated schematically as shown in the following reaction formula (5).

[Reaction Scheme 5]

The method of the present invention shown in the above Reaction Scheme 5 will be outlined as follows.

(1) First, 1- (3-benzoyloxypropyl) -indolinine of formula (4) and (2R) -bromopropionyl chloride are reacted in the conventional manner in the presence of Lewis acid AlCl ₃ to obtain ≪ / RTI >

(2) By reacting the resulting (S) -5- (2-bromopropionyl) -1- (3-benzoyloxypropyl) -indoline compound of the formula (28) with lithium, sodium or potassium salt of phthalimide (R) -1- (3-benzoyloxypropyl) -5- (2-phthalimido) -indoline compound of the formula (29) is prepared by reacting the compound with the same metal salt.

(3) The obtained indoline derivative of the formula (29) is reacted with triethylsilane and trifluoroacetic acid to prepare the compound of the formula (30).

(4) The obtained compound of formula (30) is reacted with dimethylformamide and phosphorus oxychloride to obtain (R) -5- (2-phthalimidopropyl) -1- (3-benzoyloxypropyl) - Formylindolin was prepared.

(5) The obtained compound of formula (31) is reacted with pyridine and hydroxylamine hydrochloride, and then treated with acetic anhydride to prepare a compound of formula (32).

(6) The obtained compound of formula (32) is treated with sodium borohydride to obtain (R) -5- (2-aminopropyl) -1- (3-benzoyloxypropyl) -7-cyano Indoline.

Each step of the above reaction is described in more detail.

First, 1- (3-benzoyloxypropyl) -indolinine of formula (4) and (2R) -bromopropionyl chloride are reacted in the conventional manner in the presence of Lewis acid AlCl ₃ to obtain the compound of formula (28) .

The (S) -5- (2-bromopropionyl) -1- (3-benzoyloxypropyl) -indoline compound of formula (28) reacts with the lithium, sodium or potassium salt of phthalimide to give the compound of formula 29) (R) -1- (3-benzoyloxypropyl) -5- (2-phthalimido) -indoline compound is prepared. In this reaction, non-hydrogenated solvents such as tetrahydrofuran, diethyl ether, dimethylformamide, dioxane and dichloromethane can be used, and dimethylformamide is preferably used. This reaction is also preferable because it can be reacted at room temperature.

The compound of formula (30) is prepared by dissolving the compound of formula (29) in an organic solvent such as toluene or dichloromethane, and reducing in the presence of trifluoroacetic acid at room temperature to 40 ° C. The reducing agent that can be used at this time is preferably triethylsilane.

The obtained compound of the formula (30) is dissolved in a non-hydrogenated solvent such as tetrahydrofuran, diethyl ether, dimethylformamide, dioxane or dichloromethane, and reacted with phosphorus oxychloride at -10 to 0 ° C to obtain the compound of the formula (31) Can be obtained. The solvent is preferably dimethylformamide.

The compound of the formula (31) is dissolved in a solvent such as tetrahydrofuran, diethyl ether, dimethylformamide, dioxane or dichloromethane, and then, in the presence of an amine base such as triethylamine, diisobutylethylamine or pyridine, Amine hydrochloride, followed by treatment with acetic anhydride to give the compound of formula (32). The amine base to be used at this time is preferably pyridine, and the solvent is preferably tetrahydrofuran.

The compound of the formula (32) is dissolved in a mixture of water and an alcohol such as methanol, ethanol, 2-propanol, and then reacted with sodium borohydride while maintaining the hydrogen ion concentration of the solution at 4 to 6 with acetic acid, An indoline derivative can be produced. The alcohol used is preferably 2-propanol.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to optically and synthetically synthesize an indoline derivative, which is an intermediate used for synthesizing siloxadin, which is widely used as a therapeutic agent for urinary disturbance accompanied by enlargement of the prostate gland, under mild reaction conditions.

Hereinafter, the present invention will be described more specifically by way of examples. It is to be understood, however, that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example  One

(S) -1- (3- Benzoyloxypropyl ) -5- (2- Bromopropionyl ) Indolin  Produce

To the reactor was added (S) -2-bromopropionyl chloride (28.14 g) and dichloromethane (200 mL), and the mixture was stirred at -10 to -15 占 폚 and aluminum chloride (26.67 g) was added. A solution of 1- (3-benzoyloxypropyl) -indoline (28.14 g) dissolved in dichloromethane (130 mL) was added thereto at -10 to -15 ° C, and the reaction solution was stirred for 4 hours. The cold purified water (150 mL) and 1 molar hydrochloric acid aqueous solution (50 mL) were added, stirred for 10 minutes, and layer separated. The separated organic layer was washed with saturated brine solution (150 mL) and dried over anhydrous sodium sulfate. The solution was filtered and the filtrate was concentrated to prepare (S) -1- (3-benzoyloxypropyl) -5- (2-bromopropionyl) indoline as an oil (31.22 g, 75.0%).

Example  2

(R) -1- (3- Benzoyloxypropyl ) -5- (2- Phthalimopropionyl ) Indolin  Produce

(S) -1- (3-benzoyloxypropyl) -5- (2-bromopropionyl) indoline (41.63 g) prepared in Example 1, phthalimide (15.44 g) and potassium carbonate ) Was dissolved in tetrahydrofuran (300 mL) and stirred overnight at room temperature. After concentration under reduced pressure, dichloromethane (200 mL) and saturated aqueous ammonium hydroxide solution (200 mL) were added, stirred for 20 minutes, and layered. The separated organic layer was washed twice with 5% aqueous sodium bicarbonate solution (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and the filtrate was concentrated to obtain (R) -1- (3-benzoyloxypropyl) -5- (2-phthalimidopropionyl) indoline (45.84 g, 95.0%).

Example  3

(R) -1- (3- Benzoyloxypropyl ) -5- (2- Phthalimido propyl ) Indolin  Produce

(48.25 g), toluene (350 mL) and triethylsilane (23.26 g) prepared in Example 2, And trifluoroacetic acid (5.70 g) were placed in a reactor, followed by stirring at room temperature for 6 hours. Purified water (250 mL) was added, stirred for 20 minutes, and layered. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain (R) -1- (3-benzoyloxypropyl) -5- (2-phthalimidopropyl) indoline (44.52 g, 95.0%).

Example  4

(R) -1- (3- Benzoyloxypropyl ) -7- Formyl -5- (2- Phthalimido propyl ) Indolin  Produce

Phosphorus oxychloride (30.66 g) was slowly added dropwise to the reactor containing dimethylformamide (60 mL) at 0 ° C for 15 to 20 minutes, followed by stirring for 30 minutes. Dimethylformamide solution (60 mL) in which (R) -1- (3-benzoyloxypropyl) -5- (2-phthalimidopropyl) indoline (46.85 g) prepared in Example 3 was dissolved was added to the reactor at 0 Lt; RTI ID = 0.0 > C < / RTI > After the dropwise addition was completed, the temperature was raised to 50 캜, stirred for 3 hours, and then cooled to room temperature. The reaction solution was slowly added dropwise to cooled water (800 mL) and stirred overnight to precipitate crystals. The solid was filtered off, washed with purified water and methanol, and then dried in a vacuum oven to obtain (R) -1- (3-benzoyloxypropyl) -7-formyl-5- (2- phthalimidopropyl) indoline (46.16 g, 92.0%).

Example  5

(R) -1- (3- Benzoyloxypropyl ) -7- Cyano -5- (2- Phthalimido propyl ) Indolin  Produce

(R) -1- (3-benzoyloxypropyl) -7-formyl-5- (2-phthalimidopropyl) indoline (49.66 g) obtained in Example 4 was dissolved in tetrahydrofuran , Hydroxylamine hydrochloride (10.47 g) and pyridine (38 mL) were added, and the mixture was stirred at 50 ° C for 2 hours. Acetic anhydride (24 mL) was slowly added dropwise, stirred for 30 minutes, and then heated to reflux for 3 hours. Purified water (250 mL) and ethyl acetate (300 mL) were added to the reaction mixture, stirred for 10 minutes, and layered. The organic layer was washed with 1 molar hydrochloric acid aqueous solution (100 mL) and then washed twice with 5% aqueous sodium bicarbonate solution (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and dried in a vacuum oven to obtain (R) -1- (3-benzoyloxypropyl) -7-cyano-5- (2- phthalimidopropyl) indoline (35 g, 70.9%).

Example  6

(R) -5- (2-aminopropyl) -1- (3- Benzoyloxypropyl ) -7- Cyano Indolin  Produce

(49.65 g) and sodium borohydride (18.92 g) prepared in Example 5, (R) -1- (3- benzoyloxypropyl) -7-cyano- Was dissolved in 2-propanol (300 mL) and purified water (50 mL), and the mixture was stirred for 24 hours. And the mixture was stirred at 80 째 C for 3 hours while adjusting the pH of the solution to 4.0-5.0 with acetic acid. The reaction solution was concentrated, and a 0.1 mol hydrochloric acid aqueous solution (100 mL) and ethyl acetate (200 mL) were added, followed by stirring for 10 minutes. The ethyl acetate layer was removed by layer separation, and ethyl acetate (300 mL) was added to the aqueous layer, followed by neutralization with 5% aqueous sodium bicarbonate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 34.90 g of 95.5 (R) -5- (2- aminopropyl) -1- (3- benzoyloxypropyl) %).

As described above, according to the method of the present invention, it is possible to produce an indoline derivative which is an intermediate used for synthesizing gadolin, at a yield equal to or higher than that of the conventional method. Further, in the conventional method, expensive special equipment for the hydrogenation reaction is required, but in the present invention, it is possible to synthesize optically pure gas under mild reaction conditions using a general reactor.

Claims (5)

A process for preparing a compound of formula (A), characterized in that a compound of formula (I) is reacted with sodium borohydride in the presence of acetic acid.
(I)

(A)

In this formula,
R represents hydrogen, an aldehyde group, a cyano group or a carbamoyl group as a substituent,
P is a protecting group which may be substituted with at least one protecting group selected from the group consisting of benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl, , 3-nitrobenzoyl, 1-naphthoyl, 2-naphthoyl, acetyl, benzyl, 4-methylbenzyl, 3-methylbenzyl, 4-cyanobenzyl, Butylbenzyl, 4-t-butylbenzyl, 4-nitrobenzyl, 3-nitrobenzyl, t-butyl-dimethylsilyl, trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, dihydropyranyl or hydrogen. Claims 1. A compound of formula (I) < / RTI >
(I)

In this formula,
R represents hydrogen, an aldehyde group, a cyano group or a carbamoyl group as a substituent,
P is a protecting group which may be substituted with at least one protecting group selected from the group consisting of benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl, , 3-nitrobenzoyl, 1-naphthoyl, 2-naphthoyl, acetyl, benzyl, 4-methylbenzyl, 3-methylbenzyl, 4-cyanobenzyl, Butylbenzyl, 4-t-butylbenzyl, 4-nitrobenzyl, 3-nitrobenzyl, t-butyl-dimethylsilyl, trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, dihydropyranyl or hydrogen. A process for the preparation of a compound of formula (I) or a salt thereof, which comprises reacting a compound of formula (II): EMI11.1 with trifluoroacetic acid and triethylsilane.
(I)

[Formula II]

In this formula,
R represents hydrogen, an aldehyde group, a cyano group or a carbamoyl group as a substituent,
P is a protecting group which may be substituted with at least one protecting group selected from the group consisting of benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl, , 3-nitrobenzoyl, 1-naphthoyl, 2-naphthoyl, acetyl, benzyl, 4-methylbenzyl, 3-methylbenzyl, 4-cyanobenzyl, Butylbenzyl, 4-t-butylbenzyl, 4-nitrobenzyl, 3-nitrobenzyl, t-butyldimethylsilyl, trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, dihydropyranyl or hydrogen. Claims 1. A compound of the formula (II) < / RTI >
[Formula II]

In this formula,
R represents hydrogen, an aldehyde group, a cyano group or a carbamoyl group as a substituent,
P is a protecting group which may be substituted with at least one protecting group selected from the group consisting of benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl, , 3-nitrobenzoyl, 1-naphthoyl, 2-naphthoyl, acetyl, benzyl, 4-methylbenzyl, 3-methylbenzyl, 4-cyanobenzyl, Butyldimethylsilyl, trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, dihydropyranyl, or hydrogen may be used in place of . A process for producing a compound of the formula (II) or a salt thereof, wherein a compound of the formula (III) is reacted with a metal salt of phthalimide.
[Formula II]

[Formula (III)

In this formula,
R represents hydrogen, an aldehyde group, a cyano group or a carbamoyl group as a substituent,
P is a protecting group which may be substituted with at least one protecting group selected from the group consisting of benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl, , 3-nitrobenzoyl, 1-naphthoyl, 2-naphthoyl, acetyl, benzyl, 4-methylbenzyl, 3-methylbenzyl, 4-cyanobenzyl, Butylbenzyl, 4-t-butylbenzyl, 4-nitrobenzyl, 3-nitrobenzyl, t-butyl-dimethylsilyl, trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, dihydropyranyl or hydrogen.