KR20150066782A - Method of preparing 1-(indolin-5-yl)propan-2-ol derivatives - Google Patents

Abstract

The present invention relates to a novel method of preparing an indoline derivative usable as a synthetic intermediate of silodosin used in a medicine for dysuresia accompanied with prostatomegaly. The present invention can prepare an optically pure compound represented by a chemical formula (III) from a compound represented by a chemical formula (IV); then prepare a compound represented by a chemical formula (II) by making an alcohol group of the compound represented by chemical formula (III) act as a leaving group; and then prepare a high purity compound represented by a chemical formula (I) under a warm reaction condition. A, P, R_1, R_2 and Y in the chemical formulae are the same as defined in the specification.

Description

METHOD OF PREPARING 1- (INDOLIN-5-YL) PROPAN-2-OL DERIVATIVES <br> <br> <br> Patents - stay tuned to the technology PROPAN-2-OL DERIVATIVES

The present invention relates to a process for producing an indoline derivative useful as a raw material for producing a medicament, and more particularly to a process for producing an optically active 1- (indolin-5-yl) propane- All derivatives thereof.

Shilodocyanine 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 compound of the following formula (I) is useful as an intermediate used in the synthesis thereof.

(I)

In this formula,

A represents a hydrogen atom, a halogen atom, an aldehyde group, a cyano group or a carbamoyl group as a substituent,

P is a protecting group which is exemplified by t-butyldimethylsilyl, trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, dihydropyranyl, benzoyl, 4- methylbenzoyl, 3- Naphthoyl, 2-naphthoyl, acetyl, benzyl, 4-methylbenzyl, 3-nitrobenzoyl, 3-methylbenzyl, 4-cyanobenzyl, 3-cyanobenzyl, 4-propylbenzyl, 2- ethoxybenzyl, 4-

R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, N-butyl, t-butyloxycarbonyl, benzyloxycarbonyl, methylcarbonyl, ethylcarbonyl, benzylcarbonyl or phenylcarbonyl.

The method for preparing the compound of formula (I) is described in various prior arts, and the method of Scheme 1 below is the method disclosed in Japanese Patent No. 4634560.

[Reaction Scheme 1]

The process of Scheme 1 shows a process for the preparation of the compound (R) -5- (2-aminopropyl) -1- (3-benzoyloxypropyl) -7-cyanoindoline of the formula (I). That is, the compound of the structural formula 10 is synthesized through the reaction of indoline (2) in eight steps, and reacted with (R) -phenylethylamine (11) under a hydrogen atmosphere of a platinum catalyst. (R) -5- (2-aminopropyl) -1- (3-benzoyloxypropyl) -7-cyanoindoline of the structural formula 1 is prepared by proceeding the reaction. 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) &Lt; / RTI &gt; 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 novel method for producing an optically active indoline derivative capable of solving such problems.

It is an object of the present invention to provide a novel preparation method capable of producing an optically active 1- (indolin-5-yl) propan-2-ol derivative compound useful as an intermediate for synthesis of cinnamon in high purity and high yield will be.

In order to achieve the above object, the present invention provides a process for preparing a compound of the formula (I), which comprises reacting a compound of the formula (II) with a compound of the formula (VII)

(I)

[Formula II]

[Formula VII]

NHR ₁ R ₂ (VII)

In the above formula, A represents a hydrogen atom, a halogen atom, an aldehyde group, a cyano group or a carbamoyl group as a substituent,

P is a protecting group which is exemplified by t-butyldimethylsilyl, trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, dihydropyranyl, benzoyl, 4- methylbenzoyl, 3- Naphthoyl, 2-naphthoyl, acetyl, benzyl, 4-methylbenzyl, 3-nitrobenzoyl, 3-methylbenzyl, 4-cyanobenzyl, 3-cyanobenzyl, 4-propylbenzyl, 2- ethoxybenzyl, 4-

Y represents a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a methanesulfonate, a trifluoromethanesulfonate, a benzenesulfonate or a substituted benzenesulfonate,

R ₁ and R ₂ are each independently a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, t-butyloxycarbonyl, benzyloxycarbonyl, methylcarbonyl, ethylcarbonyl, benzylcarbonyl or phenylcarbonyl.

The present invention also provides a process for preparing a compound of formula (III) and a pharmaceutically acceptable salt thereof, wherein the compound of formula (IV) is reacted with (S) -propylene oxide.

[Formula (III)

[Formula IV]

Wherein A and P are as defined above.

Here, the compound of formula (IV) is preferably reacted with (S) -propylene oxide in the presence of a compound of formula (V) or a compound of formula (VI)

[Formula V]

i- PrMgX (V)

In the above formula, X represents a halogen atom, a chlorine atom, a bromine atom or an iodine atom

(VI)

R-Li (VI)

Here, R represents an alkyl group such as n-butyl, sec-butyl or t-butyl.

In the present invention, from the compound of formula (IV), an optically active compound of formula (I) can be obtained by using (S) -propylene oxide to produce a compound of formula (I), which is a synthetic intermediate of xylosinogen widely used as a therapeutic agent for dysuria associated with prostatic hyperplasia. (III) in an inert solvent to produce a compound of the formula (II) by making an alcohol group of the compound of the formula (III) as a leaving group, thereby preparing a compound of the formula (I) .

[Formula IV]

[Formula (III)

[Formula II]

(I)

Wherein A, P, R ₁ , R ₂ and Y 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) deprotecting the 1-acetyl-5-bromo-7-chloroindoline compound of formula 27 in the presence of lithium hydroxide to give the compound of formula 28, which is reacted with t-butyldimethylsilyloxypropyl chloride of formula 29 Lt; / RTI &gt; to give the compound of formula 30.

(2) Using isopropylmagnesium chloride or butyllithium in the obtained 5-bromo-1- (3- (t-butyldimethylsilyloxy) propyl) -7- (S) -1- (1- (3- (t-butyldimethylsilyloxy) propyl) -7-chloroindolin-5-yl) propan-2-ol) compound is prepared by reacting .

(3) reacting the obtained compound of formula (31) with methanesulfonyl chloride to prepare a compound of formula (32), followed by amination using ammonia water and methanol, and protecting the amine group with benzyl chloroformate (R) -benzyl 1- (1- (3- (t-butyldimethylsilyloxy) propyl) -7-chloroindolin-5-yl) propan-2-ylcarbamate.

(4) The obtained compound of the formula (33) is reacted with copper cyanide to obtain the (R) -benzyl 1- (1- (3- (t- butyldimethylsilyloxy) propyl) -7-cyanoindolin- ) Propan-2-ylcarbamate &lt; / RTI &gt;

(5) The resulting compound of Formula 34 was deprotected under hydrogen with Pd / C catalyst to obtain (R) -5- (2-aminopropyl) -1- (3- (tert- butyldimethylsilyloxy) Propyl) indolin-7-carbonitrile.

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

In the present invention, 5-bromo-1- (3- (t-butyldimethylsilyloxy) propyl) -7-chloroindoline compound of Formula 30 corresponding to the compound of Formula (IV) is reacted with isopropylmagnesium chloride or butyllithium (S) -1- (1- (3- (t-butyldimethylsilyloxy) propyl) -7-chloroindolin-5-yl) propane- 2-ol) compound. In this reaction, tetrahydrofuran is preferably used if it is possible to use an ether solvent such as tetrahydrofuran or diethyl ether as a solvent. This reaction can be carried out at -20 캜 to 25 캜, preferably 25 캜, when isopropylmagnesium chloride is used, and at -78 캜 to -50 캜, preferably -78 캜, when butyllithium is used It is possible.

(S) -1- (1- (3- (t-butyldimethylsilyloxy) propyl) -7-chloroindolin-5-yl) propan-2-ol of formula 31 is reacted with methanesulfonyl chloride Lt; / RTI &gt;

The compound of formula (32) is dissolved in an alcohol solvent such as methanol, ethanol, isopropanol, and the mixture is subjected to an amination reaction using ammonia water at 50 to 80 ° C, and thereafter dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran (R) -benzyl 1 - ((R) -benzyl) piperazine by reacting with an organic solvent of benzyl chloroformate in the presence of a tertiary amine such as triethylamine, ethylisopropylamine, tributylamine, diisobutylamine, 1- (3- (t-butyldimethylsilyloxy) propyl) -7-chloroindolin-5-yl) propan-2-ylcarbamate. The solvent used in this reaction is preferably methanol, and triethylamine is preferable as the tertiary amine.

The compound of formula 33 is dissolved in a polar solvent having a high boiling point such as dimethylacetamide, N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, etc. and reacted at 100 to 154 ° C using copper cyanide To prepare the compound of formula 34. [ The solvent used in this reaction is preferably dimethylacetamide, and the reaction temperature is preferably 152 to 154 占 폚.

Ammonium formate and Pd / C are added to the compound of formula (34) in an alcohol solvent such as methanol, ethanol, 2-propanol, and the mixture is refluxed to obtain the compound of formula (35). The alcohol solvent used in this reaction is preferably methanol.

The present invention provides a novel method for producing an indoline derivative which is an intermediate used for synthesizing silododin, which is widely used as a therapeutic agent for dysuria accompanied by enlargement of the prostate gland. According to the present invention, it is possible to efficiently produce an optically pure indoline derivative using (S) -propylene oxide and to synthesize it under mild reaction conditions, thereby avoiding expensive equipment such as a hydrogenation reactor, It is more economical than previously known methods because it does not use reagents such as catalysts or ligands.

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

5- Bromo -7- Chloroindoline  Produce

Methanol (500 mL) in which LiOH (0.96 g) was dissolved was added to 1-acetyl-5-bromo-7-chloroindoline (27.45 g) in a reactor and refluxed for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure. Ethyl acetate (500 mL) and water (500 mL) were added and the layers were separated to obtain an organic layer. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the title compound (22.09 g, 95%).

Example  2

5- Bromo -1- (3- (t- Butyldimethylsilyloxy ) Propyl) -7- Chloroindoline  Produce

(23.25 g), t-butyldimethylsilyloxypropyl chloride (24.01 g), potassium carbonate (27.64 g) and acetonitrile (300 mL) Lt; / RTI &gt; and cooled to room temperature. Ethyl acetate (400 mL) and water (400 mL) were added and the layers were separated to obtain an organic layer. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the title compound (30.72 g, 75.9%).

Example  3-1

(S) -1- (1- (3- (t- Butyldimethylsilyloxy ) Propyl) -7- Chloroindoline Yl) propan-2-ol &lt; / RTI &gt;

To the reactor was added 5-bromo-1- (3- (t-butyldimethylsilyloxy) propyl) -7-chloroindoline (38.40 g) and dried tetrahydrofuran (500 mL) Respectively. 1 M isopropylmagnesium chloride / tetrahydrofuran solution (50 mL) was added slowly at -20 to -15 ° C, stirred for 30 minutes, slowly added with 8.4 mL of propylene oxide, and gradually warmed to room temperature And stirred overnight. Methanol was slowly added dropwise to terminate the reaction. Ethyl acetate and water were added and the layers were separated to obtain an organic layer. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (24.96 g, 65%).

Example  3-2

(S) -1- (1- (3- (t- Butyldimethylsilyloxy ) Propyl) -7- Chloroindoline Yl) propan-2-ol &lt; / RTI &gt;

To the reactor was added 5-bromo-1- (3- (t-butyldimethylsilyloxy) propyl) -7-chloroindoline (38.40 g) and dried tetrahydrofuran (500 mL) Respectively. Slowly add 2.5 M n-butyllithium / n-hexane (60 mL) at -78 ° C, stir for 30 minutes, slowly add 10.40 mL of propylene oxide and 12.3 mL of boron trifluoride dimethyl ether complex at -78 ° C And then stirred for 2 hours. After slowly raising the temperature to room temperature, water was slowly added dropwise to terminate the reaction. Ethyl acetate and water were added and the layers were separated to obtain an organic layer. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (18.86 g, 49.1%).

Example  3-3

(S) -1- (1- (3- ( Benzyloxy ) Propyl) -7- Chloroindoline Yl) propan-2-ol &lt; / RTI &gt;

The reactor was charged with 1- (3- (benzyloxy) propyl) -5-bromo-7-chloroindoline (38.71 g) and dried tetrahydrofuran (500 mL) and then charged with argon. 1 M isopropylmagnesium chloride / tetrahydrofuran solution (120 mL) was added slowly at -20 to -15 ° C, stirred for 30 minutes, slowly added with 8.4 mL of propylene oxide, and gradually warmed to room temperature And stirred overnight. Methanol was slowly added dropwise to terminate the reaction. Ethyl acetate and water were added and the layers were separated to obtain an organic layer. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (21.59 g, 60%).

Example  4

(S) -1- (1- (3- (t- Butyldimethylsilyloxy ) Propyl) -7- Chloroindoline Yl) propan-2-yl Methanesulfonate  Produce

38.40 g of (S) -1- (1- (3- (t-butyldimethylsilyloxy) propyl) -7-chloroindolin-5-yl) propan-2-ol, 20.9 mL of triethylamine and 500 mL of dichloromethane was added, and 12.6 g of methanesulfonyl chloride was added slowly at 0 ° C. After stirring at 0 ° C for 2 hours, 250 mL of water was added and the layers were separated. The water layer was removed to obtain an organic layer, which was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (42.05 g, 91.0%).

Example  5-1

(R) -benzyl 1- (1- (3- (t- Butyldimethylsilyloxy ) Propyl) -7- Chloroindoline -5-yl) propan-2- Yl carbamate  Produce

To the reactor was added (S) -1- (1- (3- (t-butyldimethylsilyloxy) propyl) -7-chloroindolin-5-yl) propan-2-yl methanesulfonate (46.21 g) 40 mL) and 40% aqueous ammonia (250 mL) were charged, stirred at 70 to 80 ° C for 6 hours, and then cooled to room temperature. The solvent was removed under reduced pressure, and dichloromethane (500 mL) and water (500 mL) were added to separate layers to obtain an organic layer. The organic layer was washed with water, dried over magnesium sulfate and filtered. After adding triethylamine (27.87 mL), benzyl chloroformate (28.55 mL) was added slowly at 5-10 ° C. After stirring at room temperature for 6 hours, water was added and the layers were separated. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (38.27 g, 74.0%).

Example  5-2

(R) -benzyl 1- (1- (3- (t- Butyldimethylsilyloxy ) Propyl) -7- Chloroindoline -5-yl) -N-methylpropan-2- Amine  Produce

To the reactor was added 46.21 g of (S) -1- (1- (3- (t-butyldimethylsilyloxy) propyl) -7-chloroindolin- An amine / methanol solution (150 mL) and methanol (150 mL) were added thereto, stirred at 70 to 80 ° C for 6 hours, and then cooled to room temperature. The solvent was removed under reduced pressure, and dichloromethane (500 mL) and water (500 mL) were added to separate layers to obtain an organic layer. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (31.37 g, 79%).

Example  6

(R) -benzyl 1- (1- (3- (t- Butyldimethylsilyloxy ) Propyl) -7- Cyanoindoline -5-yl) propan-2- Yl carbamate  Produce

Propyl-2-ylcarbamate (51.72 g) was dissolved in dimethyl formamide (1 ml) in a reactor, Amide (160 mL), and copper cyanide (17.91 g) was added thereto. The reaction mixture was refluxed for 15 hours and then cooled to room temperature. The reaction mixture was poured into ice water (300 mL), and a 1N hydrochloric acid aqueous solution (500 mL) and ethyl acetate (1000 mL) were added to extract an organic layer, which was washed with water and saturated aqueous sodium chloride solution. Dried over sodium sulfate, filtered and concentrated to give the title compound (31.07 g, 61.2%).

Example  7

(R) -5- (2-aminopropyl) -1- (3- (t- Butyldimethylsilyloxy )profile) Indolin -7- Cabo Manufacture of nitrile

In the reactor, 49.76 g of (R) -benzyl 1- (3- (t-butyldimethylsilyloxy) propyl) -7-cyanoindolin-5-yl) propan- (50.44 g) and 10% Pd / C (2.49 g) were added to methanol (500 mL) and refluxed for 15 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth. The filtrate was concentrated, 0.1 mol hydrochloric acid aqueous solution (100 mL) and ethyl acetate (300 mL) were added, and the mixture was stirred for 10 minutes. An aqueous layer was obtained, and ethyl acetate (300 mL) was added, followed by neutralization with 5% aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain (R) -5- (2-aminopropyl) -1- (3- (tert- butyldimethylsilyloxy) propyl) indoline- Nitrile (32.1 g, 88.1%).

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 (3)

A process for preparing a compound of formula (I), which comprises reacting a compound of formula (II):
(I)

[Formula II]

[Formula VII]
NHR ₁ R ₂ (VII)
In the above formula, A represents a hydrogen atom, a halogen atom, an aldehyde group, a cyano group or a carbamoyl group as a substituent,
P is a protecting group which is exemplified by t-butyldimethylsilyl, trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, dihydropyranyl, benzoyl, 4- methylbenzoyl, 3- Naphthoyl, 2-naphthoyl, acetyl, benzyl, 4-methylbenzyl, 3-nitrobenzoyl, 3-methylbenzyl, 4-cyanobenzyl, 3-cyanobenzyl, 4-propylbenzyl, 2- ethoxybenzyl, 4-
Y represents a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a methanesulfonate, a trifluoromethanesulfonate, a benzenesulfonate or a substituted benzenesulfonate,
R ₁ and R ₂ are each independently a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, t-butyloxycarbonyl, benzyloxycarbonyl, methylcarbonyl, ethylcarbonyl, benzylcarbonyl or phenylcarbonyl. A process for preparing a compound of formula (III) and a pharmaceutically acceptable salt thereof, wherein a compound of formula (IV) is reacted with (S) -propylene oxide.
[Formula (III)

[Formula IV]

In the above formula, A represents a hydrogen atom, a halogen atom, an aldehyde group, a cyano group or a carbamoyl group as a substituent,
P is a protecting group which is exemplified by t-butyldimethylsilyl, trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, dihydropyranyl, benzoyl, 4- methylbenzoyl, 3- Naphthoyl, 2-naphthoyl, acetyl, benzyl, 4-methylbenzyl, 3-nitrobenzoyl, 3-methylbenzyl, 4-cyanobenzyl, 3-cyanobenzyl, 4-propylbenzyl, 2-ethoxybenzyl, 4-t-butylbenzyl, 4-nitrobenzyl, 3-nitrobenzyl or hydrogen. 3. Process according to claim 2, characterized in that it is reacted with (S) -propylene oxide in the presence of a compound of the formula (V) or a compound of the formula (VI)
[Formula V]
i- PrMgX (V)
In the above formula, X represents a halogen atom, a chlorine atom, a bromine atom or an iodine atom
(VI)
R-Li (VI)
Here, R represents an alkyl group such as n-butyl, sec-butyl or t-butyl.