KR102163068B1 - The manufacturing method of intermediate for synthesis of silodosin and the manufacturing method of silodosin - Google Patents

Abstract

It relates to a method of manufacturing an intermediate for synthesizing silodosin and a method of manufacturing silodosin using the same.It increases price competitiveness, reduces risk factors in the manufacturing process, is easy for efficient mass production, and provides optically pure high purity silodosin. It provides a method for preparing an intermediate for synthesizing silodosin and a method for producing silodosin that can be used in a method for producing silodosin.

Description

TECHNICAL FIELD The manufacturing method of an intermediate for synthesizing silodosin, and a method of manufacturing silodosin using the same TECHNICAL FIELD The MANUFACTURING METHOD OF INTERMEDIATE FOR SYNTHESIS OF SILODOSIN AND THE MANUFACTURING METHOD OF SILODOSIN}

The present invention relates to a method for preparing an intermediate for synthesizing silodosin and a method for producing silodosin using the same, and more particularly, to a method for preparing an intermediate for synthesizing silodosin, and optically through a simple manufacturing process using the prepared new intermediate. It relates to a method for producing silodosin capable of obtaining pure high purity silodosin.

Silodosin is an indoline compound represented by the following formula (1), and the compound name is 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2, 2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-7-indoleincarboxamide.

[Formula 1]

Silodosin (Silodosin) has a selective suppression of urethral smooth muscle contraction, does not significantly affect blood pressure, lowers intraurethral pressure, and selectively exhibits inhibitory activity on α-adrenergic receptors. Accordingly, it is used as a treatment for urinary disorders accompanying an enlarged prostate.

Various methods of manufacturing silodosin are known. For example, Japanese Patent Registration No. 2944402 discloses a process for producing silodosin by the following mechanism 1.

[Mechanism 1]

In Mechanism 1 above, Boc represents a tert-butoxycarbonyl group.

The manufacturing method according to Mechanism 1 includes two steps that affect yield reduction and cost increase. First, as a step of performing optical resolution, compound (2) and another important intermediate, 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylmethanesulfonate, are N-alkylated, and then (S) -(+)- Since optical resolution is performed using mandelic acid, more than 50% of the expensive 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylmethanesulfonate is optically used. It is simply discarded in the dividing step. Another step is to introduce a 3-hydroxypropyl group at the N1 position of indoline, using 3-hydroxypropyl p-nitrobenzenesulfonate protected with tert-butyldimethylsilyl (TBDMS), TBDMS The cost is high and the reactivity is low, which causes a decrease in yield. In addition, since purification is performed through column chromatography, there is a limit to industrial use.

Japanese Laid-Open Publication No. 2001-199956 discloses a process for synthesizing compound 7(a), an important intermediate of silodosin, by the following mechanism 2.

[Mechanism 2]

In the above mechanism 2, R represents H, a protecting group.

The manufacturing method according to Mechanism 2 uses hydrogen peroxide in the step of introducing a ketone group into the nitro group, and when it is used in a large amount, the temperature rises rapidly and an explosion may occur. Accordingly, it is necessary to thoroughly manage the temperature and take special care because serious accidents may occur. In addition, since purification is possible only through column chromatography, there is a difficulty in mass production. In the next step, compound (7a) is synthesized by continuously performing an asymmetric reduction reaction using (R)-2-phenylglycinol in the presence of a platinum oxide catalyst and hydrogen, and hydrogenating in the presence of a palladium/carbon catalyst. . In this step, although expensive platinum oxide catalyst and palladium/carbon catalyst are used, according to the literature, the yield is very low, about 32.5%, and there is a risk of explosion because of the use of high pressure hydrogen gas, and a general reactor cannot be used. There is this.

Japanese Patent No. 5049013 discloses a process of synthesizing silodosin through the manufacturing process shown in Mechanism 3 below by using the compound (7a) synthesized in Mechanism 2.

[Mechanism 3]

The preparation method according to Mechanism 3 is a dialkyl represented by the following formula (A) produced by reacting compound (7a) with 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylmethanesulfonate. In order to remove by-products, it is a method of producing silodosin by chlorinating and purifying with oxalic acid, deprotecting and hydrolyzing it.

[Formula A]

However, in this method, oxalic acid is used for purification to remove the dialkyl by-product represented by the following formula (A), but since oxalic acid has no optical activity and does not have the effect of optical resolution, compound (7a), which is an intermediate with high optical purity. Must be used. In addition, hydrogen peroxide is used in the step of hydrolysis. When hydrogen peroxide is used in large quantities, the temperature rises rapidly and explosion may occur. Therefore, the temperature must be managed very thoroughly, and serious accidents may occur. There is this.

Accordingly, there is a need for development of an improved method for manufacturing silodosin, which can increase price competitiveness and manufacture optically pure silodosin, and reduce risk factors by using mild reaction conditions in the manufacturing process to enable mass production.

Patent Document 1: Japanese Patent Registration No. 2944402 Patent document 2: Japanese Laid-Open Publication No. 2001-199956 Patent Document 3: Japanese Patent No. 5049013

It is an object of the present invention for synthesizing silodosin that can be used in a method for producing silodosin that can increase price competitiveness, reduce risk factors in the manufacturing process, facilitate efficient mass production, and obtain optically pure high-purity silodosin It is to provide a method for producing an intermediate.

It is an object of the present invention to provide a method for producing silodosin that can increase price competitiveness, reduce risk factors in the manufacturing process, facilitate efficient mass production, and obtain optically pure high-purity silodosin.

The method for preparing an intermediate for synthesizing silodosin according to an embodiment of the present invention is to prepare a compound represented by the following formula 3 by introducing a tert-butoxycarbonyl protecting group at the N2 position of the compound represented by the following formula (2). Step, hydrolyzing the compound represented by the following formula 3 in the presence of a strong base to prepare a compound represented by the following formula 4, the compound represented by the following formula 4 and the compound represented by the following formula 5 in the presence of a base and a catalyst Under N-alkylation reaction to prepare a compound represented by the following formula (6), a step of preparing a compound represented by the following formula (7) by deprotecting the compound represented by the following formula (6), and And mixing the compound with an organic acid having optical activity to prepare an optically pure compound represented by the following formula (7a).

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 7a]

In each of Formulas 5 to 7a, R ₁ is H or a protecting group, and in Formula 5, LG represents a leaving group.

In the step of preparing the compound represented by Formula 3, the compound represented by Formula 2 may be reacted with di-tert-butyl dicarbonate.

In the step of preparing the compound represented by Formula 4, the strong base may be an alkali metal hydroxide.

The step of preparing the compound represented by Formula 3 and the step of preparing the compound represented by Formula 4 may be performed in one container continuous process (In-Situ) to prepare the compound represented by Formula 4 .

In the step of preparing the compound represented by Formula 5, the base may be an alkali metal carbonate or an organic base.

In the step of preparing the compound represented by Formula 5, the catalyst may be a phase transfer catalyst.

The step of preparing the compound represented by Formula 7 may be performed by deprotection reaction under acid conditions.

In the step of preparing the compound represented by Formula 7a, the organic acid may be one or more organic acids selected from the group consisting of tartaric acid, mandelic acid, 10-Camphorsulfonic acid, and malic acid, and the optical purity (enantiomeric excess: ee) is 95 % Or more and 99.7% or less.

The step of preparing the compound represented by Formula 6, the step of preparing the compound represented by Formula 7, and the step of preparing the compound represented by Formula 7a are carried out in one container continuous process (In-Situ) It may be to prepare the compound represented by Formula 7a.

The method for preparing silodosin according to an embodiment of the present invention is an N-alkylation reaction in the presence of a compound represented by the following Formula 7a, a compound represented by Formula 8, and an inorganic base having an optical purity (ee) of 95 to 99.7%. And mixing with an optically active organic acid to prepare a compound represented by the following formula (9), and hydrolyzing the compound represented by the following formula (9) in the presence of a strong base and an oxidizing agent to obtain a compound represented by the following formula (1). It includes the step of manufacturing.

[Formula 7a]

[Formula 8]

[Formula 9]

[Formula 1]

In each of Formulas 7a and 9, R ₁ is H or a protecting group, and in Formula 8, LG represents a leaving group.

In the step of preparing the compound represented by Formula 9, the inorganic base is an alkali metal carbonate.

In the step of preparing the compound represented by Formula 9, the organic acid may be at least one organic acid selected from the group consisting of tartaric acid, mandelic acid, 10-Camphorsulfonic acid, and malic acid, and the optical of the compound represented by Formula 9 The purity (ee) is 99.7% or more.

In the step of preparing the compound represented by Formula 1, the strong base is an alkali metal hydroxide, and the oxidizing agent is sodium percarbonate.

According to the method for preparing an intermediate for silodosin synthesis according to an embodiment of the present invention, it is easy to separate and purify the intermediate for silodosin synthesis, and do not use high-pressure hydrogen gas, expensive platinum oxide, palladium/carbon, It can increase safety, efficiency and price competitiveness.

According to the manufacturing method of silodosin according to an embodiment of the present invention, it is possible to increase price competitiveness, reduce risk factors in the manufacturing process, facilitate efficient mass production, and obtain optically pure high-purity silodosin.

1 is a schematic flowchart of a method of manufacturing an intermediate for synthesizing silodosin according to an embodiment of the present invention.
2 is a schematic flowchart of a method of manufacturing silodosin according to an embodiment of the present invention.

The above objects, other objects, features, and advantages of the present invention will be easily understood through the following preferred embodiments related to the accompanying drawings. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the embodiments introduced herein are provided so that the disclosed contents may be thorough and complete, and the spirit of the present invention may be sufficiently conveyed to those skilled in the art.

Hereinafter, a method of preparing an intermediate for synthesizing silodosin according to an embodiment of the present invention will be described.

1 is a schematic flowchart of a method of manufacturing an intermediate for synthesizing silodosin according to an embodiment of the present invention.

Referring to FIG. 1, a method of preparing an intermediate for synthesizing silodosin according to an embodiment of the present invention is by introducing a tert-butoxycarbonyl protecting group at the N2 position of the compound represented by the following Formula 2, Preparing a compound represented by the following formula (S100), hydrolyzing a compound represented by the following formula (3) in the presence of a strong base to prepare a compound represented by the following formula (4) (S200), a compound represented by the following formula (4), and Step of preparing a compound represented by the following formula 6 by N-alkylation reaction of the compound represented by Formula 5 in the presence of a base and a catalyst (S300), a deprotection reaction of the compound represented by the following Formula 6 to the following Formula 7 And preparing a compound represented by the following formula (7a) by mixing the compound represented by the following formula (7) with an organic acid having optical activity (S500).

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 7a]

In each of Formulas 5 to 7a, R ₁ is H or a protecting group, and in Formula 5, LG represents a leaving group. The protecting group is an acetyl group, a benzoyl group, a benzyl group, a trimethylsilyl group, a triethylsilyl group, or tert-butoxycarbonyl. The leaving group is an iodine group, a bromine group, a chlorine group, a methanesulfonate group, or a benzenesulfonate group.

By introducing a tert-butoxycarbonyl protecting group at the N2 position of the compound represented by Formula 2, a compound represented by Formula 3 was prepared (S100). The step of preparing the compound represented by Formula 3 (S100) may be to prepare a compound represented by Formula 3 by introducing a tert-butoxycarbonyl protecting group at the N2 position of the compound represented by Formula 2. In the step of preparing the compound represented by Formula 3, the compound represented by Formula 2 may be reacted with di-tert-butyl dicarbonate. For example, the step of preparing the compound represented by Formula 3 may be a step of reacting the compound represented by Formula 2 with di-tert-butyl dicarbonylate to introduce a tert-butoxycarbonyl protecting group at the N2 position. .

The step (S100) of preparing the compound represented by Formula 3 may be performed in the presence of a common organic solvent. As the organic solvent, for example, a selected single solvent selected from chloroform, dichloromethane, and ethyl acetate isopropyl acetate, or a mixed solvent thereof may be used. More specifically, dichloromethane may be used as the organic solvent.

The compound represented by Formula 3 is hydrolyzed in the presence of a strong base to prepare the compound represented by Formula 4 (S200). The step of preparing the compound represented by Formula 4 (S200) may be to prepare the compound represented by Formula 4 by hydrolyzing the compound represented by Formula 3 in the presence of a strong base. In the step of preparing the compound represented by Formula 4, the strong base may be an alkali metal hydroxide. For example, the step of preparing the compound represented by Formula 4 may be preparing the compound represented by Formula 4 by hydrolyzing the compound represented by Formula 3 in the presence of an alkali metal hydroxide to remove an acetyl group.

The alkali metal hydroxide can be, for example, sodium hydroxide, calcium hydroxide, or mixtures thereof. At this time, the reaction solvent may be water, a water-soluble organic solvent, or a mixed solvent thereof. The water-soluble organic solvent may be, for example, one or more selected from the group consisting of alcohols having 1 to 3 carbon atoms such as methanol, ethanol, propanol, and isopropanol, acetone, dimethyl sulfoxide, and acetonitrile. For example, as the water-soluble organic solvent, a mixed solvent of methanol and water, or a mixed solvent of ethanol and water may be used.

The step of preparing the compound represented by Formula 3 (S100) and the step of preparing the compound represented by Formula 4 (S200) are performed in one container continuous process (In-Situ) to prepare the compound represented by Formula 4 Can be.

The compound represented by Formula 4 and the compound represented by Formula 5 are subjected to N-alkylation reaction in the presence of a base and a catalyst to prepare a compound represented by Formula 6 (S300).

In the step of preparing the compound represented by Formula 6 (S300), the base may be, for example, an alkali metal carbonate or an organic base. The alkali metal carbonate may include, for example, at least one of sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate. The organic base may include, for example, at least one of triethylamine, pyridine, methylamine, and ethylamine.

In the step of preparing the compound represented by Formula 6 (S300), the catalyst may be, for example, a phase transfer catalyst. The phase transfer catalyst may include, for example, at least one of tetrabutylammonium bromide, 18-crown-6, tetrabutylammonium iodide, benzyl triethyl ammonium chloride, and tetra methyl ammonium chloride.

In the step (S300) of preparing the compound represented by Formula 6, a reaction solvent may be used. The reaction solvent is, for example, alcohols having 1 to 4 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol, dimethylformaldehyde (DMF), methylpyrrolidone (NMP) dimethylacetamide (DMAC), dimethyl sulfoxide ( DMSO), acetonitrile, and a single solvent selected from water or a mixed solvent thereof may be used.

The compound represented by Formula 7 is prepared by deprotecting the compound represented by Formula 6 (S400). The step of preparing the compound represented by Formula 7 (S400) may be performed by a deprotection reaction under acid conditions.

The step of preparing the compound represented by Formula 7 (S400) may be to prepare a compound represented by Formula 7 by deprotecting the compound represented by Formula 6 to remove the tert-butoxycarbonyl protecting group. The acid may be, for example, at least one of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, trifluoroacetic acid and trimethyl silyl chloride.

A reaction solvent may be used in the step (S400) of preparing the compound represented by Chemical Formula 7. The reaction solvent may be, for example, a single solvent selected from water, methanol, ethanol, isopropanol, ethyl acetate, chloroform, dichloromethane, acetone, and 1,4-dioxane, or a mixed solvent thereof.

In the step (S400) of preparing the compound represented by Chemical Formula 7, for example, the acid may be hydrochloric acid and the reaction solvent may be chloroform or dichloromethane.

The compound represented by Formula 7 is mixed with an organic acid having optical activity to prepare an optically pure compound represented by Formula 7a (S500). In the step of preparing the compound represented by Formula 7a (S500), the organic acid may include, for example, at least one of tartaric acid, mandelic acid, 10-Camphorsulfonic acid, and malic acid. More specifically, the organic acid may be (L)-(+)-tartaric acid.

A reaction solvent may be used in the step (S500) of preparing the compound represented by Formula 7a. The reaction solvent may be, for example, a single solvent selected from water, methanol, ethanol, isopropanol, acetone, and tetrahydrofuran, or a mixed solvent thereof. For example, a mixed solvent of acetone and water may be used as the reaction solvent.

In the step of preparing the compound represented by Formula 7a (S500), the optical purity (ee) of the compound represented by Formula 7a may be 95% or more and 99.7% or less. If the optical purity is less than 95%, it may be difficult to prepare the compound represented by Formula 9 having an optical purity of 99.7% or more.

The step of preparing the compound represented by Formula 6 (S300), the step of preparing the compound represented by Formula 7 (S400), and the step of preparing the compound represented by Formula 7a (S500) include one container continuous process (In -Situ) may be to prepare a compound represented by Formula 7a.

According to the method for preparing an intermediate for silodosin synthesis according to an embodiment of the present invention, it is easy to separate and purify the intermediate for silodosin synthesis, and do not use high-pressure hydrogen gas, expensive platinum oxide, palladium/carbon, It can increase safety, efficiency and price competitiveness. In addition, the optical purity of the intermediate for synthesizing silodosin can be increased.

Hereinafter, a method of manufacturing silodosin according to an embodiment of the present invention will be described.

2 is a schematic flowchart of a method of manufacturing silodosin according to an embodiment of the present invention.

Referring to FIG. 2, in a method for preparing silodosin according to an embodiment of the present invention, a compound represented by the following Formula 7a having an optical purity (ee) of 95 to 99.7% or an organic base thereof represented by Formula 8, And performing an N-alkylation reaction in the presence of an inorganic base and mixing with an optically active organic acid to prepare a compound represented by the following formula (9) (S600), and a compound represented by the following formula (9) as a strong base and an oxidizing agent. In the presence of hydrolysis to prepare a compound represented by the following formula (1) (S700).

[Formula 7a]

[Formula 8]

[Formula 9]

[Formula 1]

In each of Formulas 7a and 9, R ₁ is H or a protecting group, and in Formula 8, LG represents a leaving group. The protecting group is an acetyl group, a benzoyl group, a benzyl group, a trimethylsilyl group, a triethylsilyl group, or tert-butoxycarbonyl. The leaving group is an iodine group, a bromine group, a chlorine group, a methanesulfonate group, or a benzenesulfonate group.

In the presence of a compound represented by Formula 7a, a compound represented by Formula 8, and an inorganic base with an optical purity (ee) of 95 to 99.7%, an N-alkylation reaction was carried out, and the mixture was mixed with an optically active organic acid and represented by Formula 9. To prepare a compound (S600). When the optical purity of the compound represented by Formula 7a is less than 95%, it may be difficult to prepare the compound represented by Formula 9 having an optical purity of 99.7% or more.

In the step of preparing the compound represented by Formula 9 (S600), the compound represented by Formula 7a and the compound represented by Formula 8 are subjected to an N-alkylation reaction in the presence of an alkali metal carbonate. Purification and optical resolution are performed using an optically active organic acid to prepare a compound represented by Formula 9 having a dialkylated impurity content of 1% or less and an optical purity of 99.7% or more. If the optical purity of the compound represented by Formula 9 is less than 99.7%, the optical purity of the compound represented by Formula 1 finally obtained is less than 99.7%, so it may be difficult to obtain high-purity silodosin.

In the step (S600) of preparing the compound represented by Formula 9, the inorganic base is an alkali metal carbonate. The alkali metal carbonate may include, for example, at least one of sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate.

In the step of preparing the compound represented by Formula 9 (S600), the organic acid may be one or more selected from the group consisting of tartaric acid, mandelic acid, 10- Camphorsulfonic acid, and malic acid, and the optical purity of the compound represented by Formula 9 (ee) is over 99.7%.

Reaction solvents are alcohols having 1 to 4 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol, dimethylformaldehyde (DMF), methylpyrrolidone (NMP) dimethylacetamide (DMAC), dimethyl sulfoxide (DMSO), tetra A single solvent selected from hydrofuran, acetonitrile, and water, or a mixed solvent thereof may be used. The optically active organic acid may include at least one of tartaric acid, mandelic acid, 10-Camphorsulfonic acid, and malic acid. More specifically, the organic acid may be (L)-(+)-tartaric acid. When (L)-(+)-tartaric acid is used as the organic acid, ethanol may be used as the reaction solvent.

The compound represented by Formula 9 is hydrolyzed in the presence of a strong base and an oxidizing agent to prepare a compound represented by Formula 1 (S700). The step of preparing the compound represented by Formula 1 (S700) is a step in which a desalination reaction, a deprotection reaction, and hydrolysis proceed simultaneously. In the step of preparing the compound represented by Formula 1 (S700), a desalination reaction, a deprotection reaction, and hydrolysis are performed in the presence of the compound represented by Formula 9, an alkali metal hydroxide, and an oxide.

In the step of preparing the compound represented by Formula 1 (S700), the alkali metal hydroxide may include, for example, at least one of sodium hydroxide and potassium hydroxide.

In the step of preparing the compound represented by Formula 1 (S700), the oxidizing agent may be, for example, sodium percarbonate.

In the method for producing silodosin according to an embodiment of the present invention, an eco-friendly fruit used as a bleaching agent at home instead of hydrogen peroxide, which may explode as the temperature used in the existing silodosin production rapidly rises by using excessive carbon soda. It is suitable for industrial mass production by reducing the risk factor in the reaction process compared to the conventional synthesis method by using sodium carbonate.

In the step of preparing the compound represented by Formula 1 (S700), a reaction solvent may be used. The reaction solvent may be, for example, water, a water-soluble organic solvent, or a mixed solvent thereof. The water-soluble solvent may be one or more selected from the group consisting of alcohols having 1 to 3 carbon atoms, such as methanol, ethanol, propanol, and isopropanol, acetone, dimethyl sulfoxide, DMF, DMAC, and NMP. For example, in the step of preparing the compound represented by Formula 1, a mixed solvent of methanol and dimethyl sulfoxide (DMSO) may be used as a reaction solvent.

According to the manufacturing method of silodosin according to an embodiment of the present invention, it is possible to increase price competitiveness, reduce risk factors in the manufacturing process, facilitate efficient mass production, and obtain optically pure high-purity silodosin.

Hereinafter, the present invention will be described in more detail through specific examples. The following examples are only examples to aid understanding of the present invention, and the scope of the present invention is not limited thereto.

Example

Preparation of Formula 3: tert-butyl (1-(1-acetyl-7-cyanoindolin-5-yl)propan-2-yl)carbamate

100 g of acetyl-5-(2-aminopropyl)-2,3-dihydro-1H-indole-7-carbonitrile, 800 ml of dichloromethane, and 94.2 g of di-tert-butyl dicarbonate were added to the reactor, and 25 to It was stirred at 30° C. for 8 hours. After the reaction was completed, 500 ml of purified water was added, and after stirring, anhydrous sodium sulfate was added to the obtained organic layer, stirred for 30 minutes, filtered, and concentrated under reduced pressure to obtain Tert-butyl (1-(1-acetyl-7-cyanoindoline-5). -Yl)propan-2-yl)carbamate 140.9 g (99.8%) was obtained.

1H NMR (DMSO) δ: 0.987 (d, J = 6.8 Hz, 3H), 1.203 (s, 9H), 2.185 (s, 3H), 2.586 (d, J = 7.2 Hz, 2H), 3.046 (t, J = 7.6Hz, 2H), 3.563~3.599(m, 1H), 4.089(t, J = 8.4Hz, 2H), 6.765(d, J = 8.4Hz, 1H), 7.257(s, 1H), 7.331(s , 1H)

Preparation of Formula 4: tert-butyl (1-(7-cyanoindolin-5-yl_propan-2-yl)carbamate

140 g of prepared tert-butyl (1-(1-acetyl-7-cyanoindolin-5-yl)propan-2-yl) carbamate and 700 ml of methanol were added to the reactor, and cooled to 5 to 10°C, and then 5 407.7 ml of N sodium hydroxide was added dropwise and stirred at 25 to 30°C for 5 hours. 1120 ml of purified water was added to the reaction solution, stirred at 0 to 5° C. for 3 hours, filtered, dried, and tert-butyl (1-(7-cyanoindolin-5-yl_propan-2-yl)carbamate 118.3 g ( 96.3%) was obtained.

1H NMR (DMSO) δ: 0.945(d, J = 6.0Hz, 3H), 1.296(s, 9H), 2.456~2.369(m, 2H), 2.914(t, J = 8.4Hz, 2H), 3.445~3.505 (m, 3H), 6.482(s, 1H), 6.684(d, J = 8.8Hz, 1H), 6.876(s, 1H), 7.019(s, 1H)

Preparation of Formula 6: 3-(5-(2-((tert-butoxycarbonyl)amino)propyl)-7-cyanoindolin-1-yl)propylbenzoate

Tert-butyl (1-(7-cyanoindolin-5-yl_propan-2-yl) carbamate 115 g, 3-iodopropyl benzoate 132.8 g, sodium carbonate 48.5 g, 18-crown prepared in the reactor 6 10 g and 575 ml of DMF were added and stirred for 24 hours at 95 to 100° C. The reaction mixture was filtered and concentrated under reduced pressure, 920 ml of ethyl acetate and 575 ml of purified water were added, and the layers were separated after stirring, and the obtained organic layer was reduced pressure. It was concentrated to give 3-(5-(2-((tert-butoxycarbonyl)amino)propyl)-7-cyanoindolin-1-yl)propylbenzoate 163.3 g (92.3%).

1H NMR (DMSO) δ: 0.949(d, J = 6.0Hz, 3H), 1.281(s, 9H), 1.951~2.044(m, 2H), 2.393~2.425(m, 2H), 2.878(t, J = 8.8 Hz, 2H), 3.479~3.542(m, 3H), 3.634(t, J = 7.6 Hz, 2H), 4.331(t, J = 6.0 Hz, 2H), 6.686(d, J = 8.0Hz, 1H) , 6.911 (s, 1H), 7.008 (s, 1H), 7.445-7.487 m, 2H), 7.590-7.634 (m, 1H), 7.946-7.976 (m, 2H);

Example 1: Preparation of formula 7a (3-5-[(2R)-2-aminopropyl]-7-cyano-2,3-dihydro-1H-indol-1-yl propylbenzoate (2R,3R )-Tartrate)

160 g of 3-(5-(2-((tert-butoxycarbonyl)amino)propyl)-7-cyanoindolin-1-yl)propylbenzoate prepared in the reactor and 800 ml of chloroform were added and 35% 125.8 g of hydrochloric acid was slowly added dropwise and stirred at 25 to 30°C for 5 hours. After completion of the reaction, 480 ml of purified water was added to the reaction solution, neutralized with sodium carbonate, and the layers were separated. The obtained organic layer was treated with anhydrous sodium sulfate and carbon, filtered, and concentrated under reduced pressure.

After dissolving 480 ml of acetone and 480 ml of H ₂ O to the concentrate, L-(+)-tartaric acid (31.1 g) was added, stirred at 20 to 25° C. for 12 hours, and filtered. 480 ml of acetone and 480 ml of H ₂ O were added to the obtained crystals, heated to dissolve, and stirred at 20 to 25° C. for 12 hours, followed by filtration. To the obtained crystal, 800 ml of acetone and 800 ml of H ₂ O were added, dissolved by heating, stirred at 20 to 25°C for 12 hours, filtered and dried, and 3-[(2R)-2-aminopropyl]-7 -Cyano-2,3-dihydro-1H-indol-1-yl propylbenzoate (2R,3R)-tartaric acid salt 41.6 g (23.5%, ee value = 95% or more) is obtained.

1H NMR (DMSO) δ: 1.048(d, J = 6.4Hz, 3H), 2.008~2.059(m, 2H), 2.456~2.508(m, 1H), 2.749~2.794(m, 1H), 2.901(t, J = 8.8Hz, 2H), 3.262~3.280(m, 1H), 3.552(t, J = 8.8Hz, 2H), 3.656(t, J = 8.0Hz, 2H), 4.337(t, J = 6.0Hz, 2H), 7.000(s, 1H), 7.057(s, 1H), 7.444~7.487(m, 2H), 7.586~7.630(m, 1H), 7.941~7.969(m, 2H);

Preparation of Formula 9 (3-7-cyano-5-[(2R)-2-(2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl amino)propyl]-2 ,3-dihydro-1H-indol-1-yl propylbenzoate (2R,3R)-tartrate)

3-5-[(2R)-2-aminopropyl]-7-cyano-2,3-dihydro-1H-indol-1-yl propylbenzoate (2R,3R)-tataric acid 40 g, acetonitrile 320 ml, 20.6 g of anhydrous sodium carbonate, and 26.9 g of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylmethanesulfonate were added and stirred under reflux for 24 hours. The reaction solution was cooled, filtered, concentrated under reduced pressure, 400 ml of ethyl acetate and 320 ml of purified water were added to the concentrate, stirred, and the layers were separated, and the organic layer was concentrated under reduced pressure. 240 ml of ethanol and 10.5 g of L-(+)-tartaric acid were added to the concentrate, stirred at room temperature for 5 hours, filtered, dried under reduced pressure, and 3-7-cyano-5-[(2R)-2-(2-[ 2-(2,2,2-trifluoroethoxy)phenoxy]ethyl amino)propyl]-2,3-dihydro-1H-indol-1-yl propylbenzoate (2R,3R)-tartaric acid salt 45.1 To obtain g (yield 79.3%, ee value = 99.97% or more) was obtained.

1H NMR (DMSO) δ: 1.10(d, J = 6.4Hz, 3H), 1.992~2.059(m, 2H), 2.456~2.529(m, 3H), 2.886(t, J = 8.8Hz, 2H), 2.994 ~3.036(m, 1H), 3.352~3.458(m, 3H), 3.55(t, J = 8.4Hz, 2H), 3.658(t, J = 7.6Hz, 2H), 4.276(t, J = 5.6Hz, 2H), 4.338(t, J = 5.6Hz, 2H), 4.641~4.708(m, 2H), 6.916~7.102(m, 6H), 7.459(t, J = 7.8, 2H), 7.604(t, J = 8.8 Hz, 1H), 7.958 (t, J = 11.6, 2H);

Example 2: Preparation of silodosin (1-(3-hydroxypropyl)-5-[(2R)-2-(2-[2-(2,2,2-trifluoroethoxy)phenoxy] Ethyl amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide)

In the reactor 3-7-cyano-5-[(2R)-2-(2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl amino)propyl]-2,3- Dihydro-1H-indol-1-yl propylbenzoate (2R,3R)-tartrate 45 g, methanol 225 ml, and DMSO 135 ml were added to dissolve, and then 61.5 ml of 5N NaOH was added dropwise and 3 at 25 to 30°C. After stirring for an hour, 57.9 g of sodium percarbonate was added, followed by stirring at 25 to 30°C for 12 hours. 225 ml of purified water was added to the reaction solution, extracted twice with 450 ml of ethyl acetate, and the obtained organic layer was washed with 225 ml of purified water and 225 ml of a saturated aqueous sodium chloride solution, and then concentrated under reduced pressure. 315 ml of ethyl acetate was added to the concentrate, heated to 60°C, dissolved, cooled, stirred at 20-25°C for 5 hours, filtered to obtain 25.4 g of silodosin (yield 83.5%, ee value = 99.7% or more).

1H NMR (CDCl3) δ: 1.04 (d, J = 6.0Hz, 3H), 1.748~1.779 (m, 2H), 2.483 (dd, J = 13.2, 6.8Hz, 1H), 2.647 (dd, J = 13.6, 6.8Hz, 1H), 2.891~3.017(m, 5H), 3.150(t, J = 6.8Hz, 2H), 3.370(t, J = 8.4Hz, 2H), 3.700(t, J = 5.6Hz, 2H) 4.037~4.080(m, 2H), 4.244~4.307(m, 2H), 6.427(bs, 1H), 6.766(bs, 1H), 6.877(t, J = 8.0Hz, 2H), 6.941~7.020(m, 3H), 7.142 (s, 1H);

Preparation of Formula 4: tert-butyl (1-(7-cyanoindolin-5-yl_propan-2-yl)carbamate (In-situ reaction)

100 g of acetyl-5-(2-aminopropyl)-2,3-dihydro-1H-indole-7-carbonitrile, 800 ml of dichloromethane, and 94.2 g of di-tert-butyl dicarbonate were added to the reactor, and 25 to After stirring for 8 hours at 30 ℃ concentrated under reduced pressure.

700 ml of methanol was added to the concentrate, cooled to 5 to 10° C., 407.7 ml of 5 N sodium hydroxide was added dropwise, followed by stirring at 25 to 30° C. for 5 hours. 1120 ml of purified water was added to the reaction solution, stirred at 0 to 5° C. for 3 hours, filtered, dried, and tert-butyl (1-(7-cyanoindolin-5-yl_propan-2-yl)carbamate 118.7 g ( 95.8%) was obtained.

1H NMR (DMSO) δ: 0.945(d, J = 6.0Hz, 3H), 1.296(s, 9H), 2.456~2.369(m, 2H), 2.914(t, J = 8.4Hz, 2H), 3.445~3.505 (m, 3H), 6.482 (s, 1H), 6.684 (d, J = 8.8 Hz, 1H), 6.876 (s, 1H), 7.019 (s, 1H);

Example 3: Preparation of formula 7a (3-5-[(2R)-2-aminopropyl]-7-cyano-2,3-dihydro-1H-indol-1-yl propylbenzoate (2R,3R )-Tartrate) (In-situ reaction)

In the reactor, tert-butyl (1-(7-cyanoindolin-5-yl_propan-2-yl) carbamate 115 g, 3-iodopropyl benzoate 132.8 g, sodium carbonate 48.5 g, 18-crown-6 10 g and 575 ml of DMF were added, followed by stirring for 24 hours at 95 to 100° C. The reaction solution was filtered and concentrated under reduced pressure, 920 ml of ethyl acetate and 575 ml of purified water were added, and the layers were separated after stirring, and the resulting organic layer was reduced pressure.

800 ml of chloroform was added to the concentrate, 125.8 g of 35% hydrochloric acid was slowly added dropwise, followed by stirring at 25 to 30°C for 5 hours. After completion of the reaction, 480 ml of purified water was added to the reaction solution, neutralized with sodium carbonate, and the layers were separated and concentrated under reduced pressure.

After dissolving 480 ml of acetone and 480 ml of H ₂ O to the concentrate, L-(+)-tartaric acid (31.1 g) was added, stirred at 20 to 25° C. for 12 hours, and filtered. 480 ml of acetone and 480 ml of H ₂ O were added to the obtained crystals, heated to dissolve, and stirred at 20 to 25° C. for 12 hours, followed by filtration. To the obtained crystal, 800 ml of acetone and 800 ml of H ₂ O were added, dissolved by heating, stirred at 20 to 25°C for 12 hours, filtered and dried, and 3-[(2R)-2-aminopropyl]-7 -Cyano-2,3-dihydro-1H-indol-1-yl propylbenzoate (2R,3R)-tataric acid salt 44.7 g (22.8%, ee value = 95% or more) is obtained.

1H NMR (DMSO) δ: 1.048(d, J = 6.4Hz, 3H), 2.008~2.059(m, 2H), 2.456~2.508(m, 1H), 2.749~2.794(m, 1H), 2.901(t, J = 8.8Hz, 2H), 3.262~3.280(m, 1H), 3.552(t, J = 8.8Hz, 2H), 3.656(t, J = 8.0Hz, 2H), 4.337(t, J = 6.0Hz, 2H), 7.000(s, 1H), 7.057(s, 1H), 7.444~7.487(m, 2H), 7.586~7.630(m, 1H), 7.941~7.969(m, 2H);

As described above, the present invention has high price competitiveness because it does not use expensive platinum oxide and palladium/carbon. In addition, high-pressure hydrogen gas and hydrogen peroxide, which have the risk of accidents such as explosion, are not used in mass production. In addition, since it is easy to separate and purify intermediates produced during the synthesis, silodosin having a high optical purity of 99.7% or higher can be obtained more easily.

In the above, embodiments of the present invention have been described with reference to the accompanying drawings, but those of ordinary skill in the art to which the present invention pertains can be implemented in other specific forms without changing the technical spirit or essential features. You can understand that there is. Therefore, it should be understood that the embodiments described above are illustrative and non-limiting in all respects.

Claims (14)

Preparing a compound represented by the following Formula 3 by introducing a tert-butoxycarbonyl protecting group at the N2 position of the compound represented by the following Formula 2;
Hydrolyzing the compound represented by the following formula (3) in the presence of a strong base to prepare a compound represented by the following formula (4);
Preparing a compound represented by the following formula (6) by reacting a compound represented by the following formula (4) and a compound represented by the following formula (5) in the presence of a base and a catalyst;
Preparing a compound represented by the following formula (7) by deprotecting the compound represented by the following formula (6); And
A method of preparing an intermediate for synthesizing silodosin comprising the step of preparing a compound represented by the following formula 7a by mixing a compound represented by the following formula 7 with an optically active tartaric acid.
[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 7a]

In each of Formulas 5 to 7a,
R ₁ is H or a protecting group,
In Chemical Formula 5,
LG stands for Leaving Group. The method of claim 1,
In the step of preparing the compound represented by Formula 3,
A method for preparing an intermediate for synthesizing silodosin by reacting the compound represented by Formula 2 with di-tert-butyl dicarbonate. The method of claim 1,
In the step of preparing the compound represented by Formula 4,
The method for producing an intermediate for synthesizing silodosin wherein the strong base is an alkali metal hydroxide. The method of claim 1,
The step of preparing the compound represented by Formula 3 and the step of preparing the compound represented by Formula 4 are performed in one container continuous process (In-Situ) to prepare the compound represented by Formula 4 Method for producing an intermediate for synthesizing dosin. The method of claim 1,
In the step of preparing the compound represented by Formula 6,
The base is
An alkali metal carbonate or an organic base is a method for producing an intermediate for silodosin synthesis. The method of claim 1,
In the step of preparing the compound represented by Formula 6,
The catalyst is
A method for preparing an intermediate for synthesizing silodosin that is a phase transfer catalyst. The method of claim 1,
The step of preparing the compound represented by Formula 7
A method for producing an intermediate for synthesizing silodosin that is carried out by a deprotection reaction under acid conditions. The method of claim 1,
In the step of preparing the compound represented by Formula 7a,
The optical purity (enantiomeric excess: ee) is 95% or more and 99.7% or less of the method for producing an intermediate for silodosin synthesis. The method of claim 1,
The step of preparing the compound represented by Formula 6, the step of preparing the compound represented by Formula 7, and the step of preparing the compound represented by Formula 7a are carried out in one container continuous process (In-Situ) A method of preparing an intermediate for synthesizing silodosin to prepare a compound represented by Formula 7a. An intermediate for synthesizing silodosin represented by the following Chemical Formula 4.
[Formula 4]

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