JP2020007291A - Method of producing silodosin synthesis intermediate and method of producing silodosin using the same - Google Patents

Abstract

To provide a method of producing a silodosin synthesis intermediate and a method of producing silodosin using the same, which increase the price competitive power, reduce hazardous materials in production processes, facilitate efficient mass production, and can provide optically pure silodosin with high purity.SOLUTION: The methods of producing the silodosin synthesis intermediate and silodosin include synthesizing 3-(5-(2-((tert-butoxycarbonyl)amino)propyl)-7-cyanoindolin-1-yl)propyl benzoate as an intermediate, mixing it with an organic acid having optical activity, and performing optical resolution.SELECTED DRAWING: None

Description

  TECHNICAL FIELD The present invention relates to a method for producing an intermediate for silodosin synthesis and a method for producing silodosin using the same, and more particularly, to a method for producing an intermediate for silodosin synthesis, and a simple production method using the produced novel intermediate. The present invention relates to a method for producing silodosin capable of obtaining optically pure high-purity silodosin in the process.

  Silodosin is an indoline compound represented by the following chemical formula 1, and the compound name is 1- (3-hydroxypropyl) -5-[(2R) -2-(− ２2- [2- (2 , 2,2-trifluoroethoxy) phenoxy] ethyl {amino) propyl] -7-indolinecarboxamide.

  Since silodosin has a selective urethral smooth muscle contraction inhibitory action, it lowers intraurethral pressure without significantly affecting blood pressure, and exhibits an inhibitory activity selectively on α-adrenergic receptors. Thus, it is used as a therapeutic agent for dysuria associated with benign prostatic hyperplasia.

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

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

  The manufacturing method according to the mechanism 1 includes two steps that affect the yield reduction and the cost increase. First, in the stage of optical resolution, compound (2) and another important intermediate, 2- (2- (2,2,2-trifluoroethoxy) phenoxy) ethyl methanesulfonate, were subjected to N-alkylation reaction. After that, since optical resolution proceeds using (S)-(+)-mandelic acid, 50% or more of expensive 2- (2- (2,2,2-trifluoroethoxy) phenoxy) ethyl methanesulfonate is used. Is discarded as it is in the optical division stage. Another step is to introduce a 3-hydroxypropyl group at the N1 position of the indoline, using tert-butyldimethylsilyl (TBDMS) protected 3-hydroxypropyl p-nitrobenzenesulfonate. TBDMS is expensive but has low reactivity, which causes a decrease in yield. In addition, since purification proceeds by column chromatography, there is a limit to industrial use.

  JP-A-2001-199956 discloses a process of synthesizing compound 7 (a), which is an important intermediate of silodosin, by the following mechanism 2.

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

  In the production method using the mechanism 2, hydrogen peroxide is used at the stage of introducing a ketone group to a nitro group. However, when a large amount of hydrogen peroxide is used, the temperature may rise rapidly and an explosion may occur. Therefore, the temperature must be controlled thoroughly, and serious accidents may occur, so special care must be taken. Further, since purification can be performed only by column chromatography, there is a difficulty in mass production. Further, in the next stage, the asymmetric reduction reaction proceeds continuously using (R) -2-phenylglycinol in the presence of a platinum oxide catalyst and hydrogen, and the hydrogenation reaction proceeds in the presence of a palladium / carbon catalyst. To synthesize the compound (7a). At this stage, an expensive platinum oxide catalyst and a palladium / carbon catalyst are used, but according to the literature, the yield is extremely low at 32.5%, and there is a danger of explosion due to the use of high-pressure hydrogen gas. Disadvantages include the inability to use a conventional reactor.

  Japanese Patent No. 5049013 discloses a process for synthesizing silodosin by using the compound (7a) synthesized by the above mechanism 2 and by the production process shown by the following mechanism 3.

  The production method according to the above-mentioned mechanism 3 is a method for producing a dialkyl secondary compound represented by the following chemical formula A, which is produced by reacting compound (7a) with 2- (2- (2,2,2-trifluoroethoxy) phenoxy) ethylmethanesulfonate. In this method, the product is purified by salification with oxalic acid to remove the product, and then deprotection and hydrolysis to produce silodosin.

  However, in this method, oxalic acid is used for purification to remove the dialkyl by-product represented by the above formula A. However, oxalic acid has no optical activity and has no effect of optical resolution, and therefore, is not a mirror image. The compound (7a), which is an intermediate having a high body excess, must be used. In addition, hydrogen peroxide is used in the hydrolysis stage, but when hydrogen peroxide is used in large quantities, the temperature may rise rapidly and an explosion may occur, so the temperature must be thoroughly controlled, In such a case, a serious accident may occur, so there is a problem that special care must be taken.

  Therefore, there is a need for the development of improved methods for producing silodosin that can be mass-produced by increasing price competitiveness, producing optically pure silodosin, and reducing hazards under mild reaction conditions during the production process. Have been.

Japanese Patent No. 2944402 JP 2001-199956 A Patent No. 5049013

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

  An object of the present invention is to provide a method for producing silodosin, which can enhance price competitiveness, reduce risk factors in the production process, facilitate efficient mass production, and obtain optically pure silodosin with high purity. That is.

  The method for preparing an intermediate for synthesizing silodosin according to an embodiment of the present invention comprises introducing a tert-butoxycarbonyl protecting group at the N2 position of a compound represented by the following Chemical Formula 2 to obtain a compound represented by the following Chemical Formula 3. And hydrolyzing the compound represented by the following formula 3 in the presence of a strong base to produce a compound represented by the following formula 4, and a compound represented by the following formula 4 Reacting the compound represented by the following formula 5 with N-alkylation in the presence of a base and a catalyst to prepare a compound represented by the following formula 6, and deprotecting the compound represented by the following formula 6 Reacting to prepare a compound represented by the following formula 7; and mixing the compound represented by the following formula 7 with an organic acid having optical activity to form an optically pure compound represented by the following formula 7a: And a step of producing a compound represented.

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

  In 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 proceed in a continuous process (In-Situ; in-situ process) in a single container. The compound represented by Formula 4 can be prepared.

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

  In 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 performing a deprotection reaction under an acid condition.

  In the step of preparing the compound represented by Formula 7a, the organic acid may be at least one selected from the group consisting of tartaric acid, mandelic acid, 10-camphorsulfonic acid, and malic acid. The enantiomeric excess (ee) can be greater than or equal to 95% and less than or equal to 99.7%.

  The step of preparing the compound represented by the formula (6), the step of preparing the compound represented by the formula (7), and the step of preparing the compound represented by the formula (7a) include a continuous process (In) in a single container. -Situ; an in-situ process) to produce the compound represented by Formula 7a.

  The method for preparing silodosin according to an embodiment of the present invention includes the steps of: converting the compound represented by Formula 7a having an enantiomeric excess (ee) of 95 to 99.7% from the compound represented by Formula 8 and the presence of an inorganic base; Preparing a compound represented by the following formula 9 by mixing with an optically active organic acid under an N-alkylation reaction under the following conditions; and reacting the compound represented by the following formula 9 with a strong base and an oxidizing agent. Hydrolyzing to produce a compound represented by Formula 1 below.

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 may be an alkali metal carbonate.

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

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

  According to the method for producing an intermediate for silodosin synthesis according to one embodiment of the present invention, separation and purification of the intermediate for silodosin synthesis are easy, without using high-pressure hydrogen gas, expensive platinum oxide, and palladium / carbon, It can increase safety, efficiency and price competitiveness.

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

1 is a schematic flowchart of a method for producing an intermediate for synodosin synthesis according to an embodiment of the present invention. 1 is a schematic flowchart of a method for producing silodosin according to an embodiment of the present invention.

  The above and other objects, features, and advantages of the present invention will be easily understood from the following preferred embodiments with reference to the accompanying drawings. However, the present invention is not limited to the embodiments described herein, but can be embodied in other forms. Rather, the embodiments described are provided so that this disclosure will be thorough and complete, and will allow the ordinary person of ordinary skill to be fully familiar with the teachings of the present invention.

  Hereinafter, a method for producing an intermediate for synodosin synthesis according to an embodiment of the present invention will be described.

  FIG. 1 is a schematic flowchart of a method for producing an intermediate for synodosin synthesis according to one embodiment of the present invention.

  Referring to FIG. 1, a method for preparing an intermediate for synthesizing silodosin according to one embodiment of the present invention comprises introducing a tert-butoxycarbonyl protecting group at the N2 position of a compound represented by the following chemical formula 2, and formulating the compound by the following chemical formula 3. 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 produce a compound represented by the following formula 4 (S200); Reacting the compound represented by Formula 4 and the compound represented by Formula 5 with N-alkylation in the presence of a base and a catalyst to produce a compound represented by Formula 6 (S300); Deprotecting the compound of Formula 6 to produce a compound of Formula 7 (S400); Mixed with an organic acid with, including the step of producing a compound represented by optically pure chemical formula 7a (S500).

In each of Chemical Formulas 5 to 7a, R ₁ is H or a protecting group, and in Chemical 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 a tert-butoxycarbonyl group. The leaving group is an iodine group, a bromine group, a chlorine group, a methanesulfonate group, or a benzenesulfonate group.

  A compound represented by Formula 3 is prepared by introducing a tert-butoxycarbonyl protecting group at the N2 position of the compound represented by Formula 2 (S100). The step (S100) of preparing the compound represented by Formula 3 is a step of preparing a compound represented by Formula 3 by introducing a tert-butoxycarbonyl protecting group at the N2 position of the compound represented by Formula 2. possible. The step of preparing the compound represented by Formula 3 may include reacting the compound represented by Formula 2 with di-tert-butyl dicarbonate. For example, the step of preparing the compound represented by Formula 3 is a step of reacting the compound represented by Formula 2 with di-tert-butyl dicarbonate to introduce a tert-butoxycarbonyl protecting group at the N2 position. possible.

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

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

  The alkali metal hydroxide can be, for example, sodium hydroxide, potassium hydroxide, or a mixture thereof. Here, as the reaction solvent, water, a water-soluble organic solvent, or a mixed solvent thereof can be used. The water-soluble organic solvent may be at least one selected from the group consisting of alcohols having 1 to 3 carbon atoms such as methanol, ethanol, propanol, and isobutanol, acetone, dimethyl sulfoxide, and asset nitrile. For example, a mixed solvent of methanol and water or a mixed solvent of ethanol and water can be used as the water-soluble organic solvent.

  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 a continuous process (In-Situ; in-situ process) in a single container. And preparing a compound represented by Formula 4.

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

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

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

  In the step (S300) of preparing the compound represented by Formula 6, a reaction solvent may be used. Examples of the reaction solvent include alcohols having 1 to 4 carbon atoms such as methanol, ethanol, propanol, isobutanol, butanol, dimethylformaldehyde (DMF), methylpyrrolidone (NMP), dimethylacetamide (DMAC), and dimethylsulfoxide (DMSO). , Acetonitrile, and water, or a mixed solvent thereof.

  The compound represented by Formula 6 is deprotected to produce a compound represented by Formula 7 (S400). The step of preparing the compound represented by Formula 7 (S400) may be performed by performing a deprotection reaction under an acid condition.

  The step of preparing the compound represented by Formula 7 (S400) comprises deprotecting the compound represented by Formula 6 to remove the tert-butoxycarbonyl protecting group, thereby converting the compound represented by Formula 7 It can be a manufacturing stage. The acid can be, for example, at least one of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, trifluoroacetic acid and trimethylsilyl chloride.

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

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

  The compound represented by Formula 7 is mixed with an optically active organic acid to prepare an optically pure compound represented by Formula 7a (S500). In the step (S500) of preparing the compound represented by Formula 7a, 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 can be (L)-(+)-tartaric acid.

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

  In the step (S500) of preparing the compound represented by Formula 7a, the enantiomeric excess (ee) of the compound represented by Formula 7a may be 95% or more and 99.7% or less. If the enantiomeric excess is less than 95%, it may be difficult to produce a compound represented by the chemical formula 9 having an enantiomeric excess 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) are a single step. The process may be performed in a continuous process (In-Situ; in-situ process) in a container to produce 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, the intermediate for silodosin synthesis can be easily separated and purified, without using high-pressure hydrogen gas, expensive platinum oxide, or palladium / carbon. It can increase safety, efficiency and price competitiveness. Furthermore, the enantiomeric excess of the intermediate for silodosin synthesis can be increased.

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

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

  Referring to FIG. 2, a method for preparing silodosin according to an embodiment of the present invention comprises converting a compound represented by Formula 7a having an enantiomeric excess (ee) of 95 to 99.7% or an organic base thereof into a compound represented by Formula 8: And N-alkylation reaction in the presence of a compound represented by the following formula and an inorganic base, and mixing with an optically active organic acid to produce a compound represented by the following formula 9 (S600); The method includes hydrolyzing the compound represented by Formula 9 in the presence of a strong base and an oxidizing agent to produce a compound represented by Formula 1 (S700).

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 a tert-butoxycarbonyl group. The leaving group is an iodine group, a bromine group, a chlorine group, a methanesulfonate group, or a benzenesulfonate group.

  An N-alkylation reaction is carried out in the presence of a compound represented by the formula 7a, a compound represented by the formula 8, and an inorganic base having an enantiomeric excess (ee) of 95 to 99.7%, and an optical activity The compound represented by Formula 9 is prepared by mixing the organic compound with an organic acid having the compound (S600). If the enantiomeric excess of the compound represented by Chemical Formula 7a is less than 95%, it may be difficult to produce the compound represented by Chemical Formula 9 in which the enantiomeric excess is 99.7% or more.

  In the step (S600) of preparing the compound represented by Formula 9, the compound represented by Formula 7a and the compound represented by Formula 8 are N-alkylated in the presence of an alkali metal carbonate. Purification and optical resolution are carried out using an organic acid having optical activity, and a compound represented by the formula 9 having a dialkylated impurity content of 1% or less and an enantiomeric excess of 99.7% or more is obtained. To manufacture. If the enantiomeric excess of the compound represented by the chemical formula 9 is less than 99.7%, the enantiomer excess of the compound represented by the chemical formula 1 which is finally obtained is less than 99.7%. It may be difficult to obtain silodosin of purity.

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

  In the step (S600) of preparing the compound represented by Formula 9, the organic acid is at least one selected from the group consisting of tartaric acid, mandelic acid, 10-camphorsulfonic acid, and malic acid. The enantiomeric excess (ee) of the compound represented by is 99.7% or more.

  Examples of the reaction solvent include alcohols having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isobutanol, and butanol; dimethylformaldehyde (DMF); , Acetonitrile, and water, or a mixed solvent thereof. Optically active organic acids can include at least one of tartaric acid, mandelic acid, 10-camphorsulfonic acid, and malic acid. More specifically, the organic acid can be (L)-(+)-tartaric acid. When (L)-(+)-tartaric acid is used as an organic acid, ethanol can be used as a 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 dechlorination reaction, a deprotection reaction, and a hydrolysis are simultaneously performed. In the step (S700) of preparing the compound represented by Formula 1, a dechlorination reaction, a deprotection reaction, and a hydrolysis reaction are performed in the presence of the compound represented by Formula 9, an alkali metal hydroxide, and an oxide. Will be performed.

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

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

  The method for producing silodosin according to one embodiment of the present invention is used as a bleach even at home instead of hydrogen peroxide, which has been used for producing existing silodosin and may explode when the temperature is rapidly increased. By using the used environmentally friendly sodium percarbonate, the risk factor in the reaction process is reduced compared to the existing synthesis method, and it is industrially suitable for mass production.

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

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

  Hereinafter, the present invention will be described more specifically based on specific examples. The following examples are merely examples to help the understanding of the present invention, and the scope of the present invention is not limited thereto.

  Preparation of Chemical 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 charged into the reactor, and 25 Stirred at 30 ° C. for 8 hours. After completion of the reaction, 500 ml of purified water was added, and anhydrous sodium sulfate was added to the organic layer obtained by stirring and separating the layers, and the mixture was stirred for 30 minutes, filtered, concentrated under reduced pressure, and concentrated under reduced pressure to tert-butyl (1- (1) -Acetyl-7-cyanoindolin-5-yl) propan-2-yl) carbamate 140.9 g (99.8%) was obtained.

  1H NMR (DMSO) δ: 0.987 (d, J = 6.8Hz, 3H), 1.203 (s, 9H), 2.185 (s, 3H), 2.586 (d, J = 7.2Hz, 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-cyanoindoline-5-yl) propan-2-yl) carbamate

  140 g of the prepared tert-butyl (1- (1-acetyl-7-cyanoindoline-5-yl) propan-2-yl) carbamate and 700 ml of methanol were added to the reactor, and the mixture was cooled to 5 to 10 ° C. 407.7 ml of 5N sodium hydroxide was added dropwise, and the mixture was 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-cyanoindoline-5-yl) propan-2-yl) carbamate 118 0.3 g (96.3%) were obtained.

  1H NMR (DMSO) δ: 0.945 (d, J = 6.0 Hz, 3H), 1.296 (s, 9H), 2.456-2.369 (m, 2H), 2.914 (t, J = 8.4 Hz, 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 Chemical Formula 6: 3- (5- (2-((tert-butoxycarbonyl) amino) propyl) -7-cyanoindolin-1-yl) propylbenzoate

  In a reactor, 115 g of the prepared tert-butyl (1- (7-cyanoindoline-5-yl) propan-2-yl) carbamate, 132.8 g of 3-iodopropylbenzoate, 48.5 g of sodium carbonate, 18-crown −610 g and 575 ml of DMF were charged, and the mixture was stirred at 95 to 100 ° C. for 24 hours. After 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 organic layer obtained by stirring and separating the layers was concentrated under reduced pressure to give 3- (5- (2-((tert-butoxy). 163.3 g (92.3%) of carbonyl) amino) propyl) -7-cyanoindoline-1-yl) propylbenzoate were obtained.

  1H NMR (DMSO) δ: 0.949 (d, J = 6.0 Hz, 3H), 1.281 (s, 9H), 1.951 to 2.044 (m, 2H), 2.393 to 2.425 (m, 2H), 2.878 (t, J = 8.8 Hz, 2H), 3.479 to 3.542 (m, 3H), 3.634 (t, J = 7.6 Hz, 2H), 4.331 (t, J = 6.0 Hz, 2H), 6.686 (d, J = 8.0 Hz, 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 Chemical Formula 7a (3-5-[(2R) -2-aminopropyl] -7-cyano-2,3-dihydro-1H-indol-1-ylpropylbenzoate (2R, 3R) -tartaric acid salt)

  160 g of the produced 3- (5- (2-((tert-butoxycarbonyl) amino) propyl) -7-cyanoindoline-1-yl) propyl benzoate and 800 ml of chloroform were put into a reactor, and 35% hydrochloric acid 125 0.8 g was slowly added dropwise, and the mixture was 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 480 ml of acetone and 480 ml of H ₂ O were added to and dissolved in the concentrated solution, L-(+)-tartaric acid (31.1 g) was added, and the mixture was stirred at 20 to 25 ° C. for 12 hours and then filtered. To the obtained crystals, 480 ml of acetone and 480 ml of H ₂ O were added, and dissolved by heating. After stirring at 20 to 25 ° C. for 12 hours, the mixture was filtered. 800 ml of acetone and 800 ml of H ₂ O are added to the obtained crystals, and the mixture is heated and dissolved. After stirring at 20 to 25 ° C. for 12 hours, the mixture is filtered, dried and dried to give 3-5-[(2R). -2-Aminopropyl] -7-cyano-2,3-dihydro-1H-indol-1-ylpropylbenzoate (2R, 3R) -tartrate 41.6 g (23.5%, ee value = 95). %that's all).

  1H NMR (DMSO) δ: 1.048 (d, J = 6.4 Hz, 3H), 2.008 to 2.059 (m, 2H), 2.456 to 2.508 (m, 1H), 2.749 to 2.794 (m, 1H), 2.901 (t, J = 8.8Hz, 2H), 3.262 to 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 to 7.487 (m, 2H), 7.586 to 7.630 (m, 1H), 7.941 to 7.969 (m, 2H);

  Preparation of Chemical Formula 9 (3-7-cyano-5-[(2R) -2- (2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino) propyl] -2,3-dihydro -1H-indol-1-ylpropylbenzoate (2R, 3R) -tartrate)

  3-5-[(2R) -2-aminopropyl] -7-cyano-2,3-dihydro-1H-indol-1-ylpropylbenzoate (2R, 3R) -tartrate 40 g, acetonitrile 320 ml, anhydrous sodium carbonate 20.6 g and 26.9 g of 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl methanesulfonate were added, and the mixture was stirred under reflux for 24 hours. The reaction solution was cooled, filtered, and concentrated under reduced pressure. 400 ml of ethyl acetate and 320 ml of purified water were added to the concentrated solution. After stirring, 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 concentrated solution, and the mixture was stirred at room temperature for 5 hours, filtered, dried under reduced pressure, and dried under reduced pressure to obtain 3-7-cyano-5-[(2R) -2- ( 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino) propyl] -2,3-dihydro-1H-indol-1-ylpropylbenzoate (2R, 3R) -tartrate 45.1 g Was obtained (yield: 79.3%, ee value = 99.97% or more).

  1H NMR (DMSO) δ: 1.10 (d, J = 6.4 Hz, 3H), 1.992 to 2.059 (m, 2H), 2.456 to 2.529 (m, 3H), 2.886 (t, J = 8.8 Hz, 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 = 8.8Hz, 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] ethylamino) propyl] -2,3-dihydro-1H-indole-7-carboxamide)

  In the reactor, 3-7-cyano-5-[(2R) -2- (2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino) propyl] -2,3-dihydro- 45 g of 1H-indol-1-ylpropylbenzoate (2R, 3R) -tartrate, 225 ml of methanol and 135 ml of DMSO were added and dissolved, and then 61.5 ml of 5N NaOH was added dropwise, and the mixture was added at 25 to 30 ° C. for 3 hours. After stirring, 57.9 g of sodium percarbonate was added, and the mixture was stirred at 25 to 30 ° C for 12 hours. 225 ml of purified water was added to the reaction solution, and the organic layer obtained by extracting twice with 450 ml of ethyl acetate 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 concentrated solution, which was dissolved by heating to 60 ° C., cooled, stirred at 20 to 25 ° C. for 5 hours, and then filtered to obtain 25.4 g of silodosin (83.5% yield). Ee value = 99.7% or more).

  1H NMR (CDCl3) δ: 1.04 (d, J = 6.0 Hz, 3H), 1.748-1.779 (m, 2H), 2.483 (dd, J = 13.2, 6.8 Hz, 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-cyanoindoline-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 charged into the reactor, and 25 After stirring at 30 ° C. for 8 hours, the mixture was concentrated under reduced pressure.

  700 ml of methanol was added to the concentrated solution, and after cooling to 5 to 10 ° C, 407.7 ml of 5N 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, and the mixture was stirred at 0 to 5 ° C. for 3 hours, filtered, dried and tert-butyl (1- (7-cyanoindoline-5-yl) propan-2-yl) carbamate 118 0.7 g (95.8%) were obtained.

  1H NMR (DMSO) δ: 0.945 (d, J = 6.0 Hz, 3H), 1.296 (s, 9H), 2.456-2.369 (m, 2H), 2.914 (t, J = 8.4 Hz, 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);

  Example 3: Preparation of Chemical Formula 7a (3-5-[(2R) -2-aminopropyl] -7-cyano-2,3-dihydro-1H-indol-1-ylpropylbenzoate (2R, 3R) -tartaric acid Salt) (In-situ reaction)

  In a reactor, 115 g of tert-butyl (1- (7-cyanoindoline-5-yl) propan-2-yl) carbamate, 132.8 g of 3-iodopropylbenzoate, 48.5 g of sodium carbonate, and 10 g of 18-crown-6 And DMF (575 ml) were added, and the mixture was stirred at 95 to 100 ° C. for 24 hours. After the reaction solution was filtered and concentrated under reduced pressure, 920 ml of ethyl acetate and 575 ml of purified water were added, and after stirring, the organic layer obtained by layer separation was depressurized.

  800 ml of chloroform was added to the concentrated solution, 125.8 g of 35% hydrochloric acid was gradually added dropwise, and the mixture was 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, separated into layers, and concentrated under reduced pressure.

After 480 ml of acetone and 480 ml of H ₂ O were added to and dissolved in the concentrated solution, L-(+)-tartaric acid (31.1 g) was added, and the mixture was stirred at 20 to 25 ° C. for 12 hours and then filtered. To the obtained crystals, 480 ml of acetone and 480 ml of H ₂ O were added, and dissolved by heating. After stirring at 20 to 25 ° C. for 12 hours, the mixture was filtered. 800 ml of acetone and 800 ml of H ₂ O are added to the obtained crystals, and the mixture is heated and dissolved. After stirring at 20 to 25 ° C. for 12 hours, the mixture is filtered, dried and dried to give 3-5-[(2R). -2-Aminopropyl] -7-cyano-2,3-dihydro-1H-indol-1-ylpropylbenzoate (2R, 3R) -tartrate 44.7 g (22.8%, ee value = 95). %that's all).

  1H NMR (DMSO) δ: 1.048 (d, J = 6.4 Hz, 3H), 2.008 to 2.059 (m, 2H), 2.456 to 2.508 (m, 1H), 2.749 to 2.794 (m, 1H), 2.901 (t, J = 8.8Hz, 2H), 3.262 to 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 to 7.487 (m, 2H), 7.586 to 7.630 (m, 1H), 7.941 to 7.969 (m, 2H);

  As described above, the present invention does not use expensive platinum oxide and palladium / carbon, and has high price competitiveness. In addition, high-pressure hydrogen gas and hydrogen peroxide, which may cause an accident such as an explosion, are not used for mass production. Further, since the intermediate produced in the synthesis process can be easily separated and purified, silodosin having a high enantiomeric excess of 99.7% or more can be more easily obtained.

As described above, the embodiments of the present invention have been described based on the accompanying drawings. However, those having ordinary knowledge in the technical field to which the present invention pertains without changing the technical idea or essential features of the present invention. It can be understood that the specific embodiment of the present invention can be implemented. Accordingly, it should be understood that the above-described embodiments are illustrative in all aspects and are not limiting.

Claims (14)

Introducing a tert-butoxycarbonyl protecting group at the N2 position of the compound represented by Formula 2 to produce a compound represented by Formula 3;
Hydrolyzing a compound represented by the following Formula 3 in the presence of a strong base to produce a compound represented by the following Formula 4;
Reacting the compound represented by Formula 4 and the compound represented by Formula 5 with N-alkylation in the presence of a base and a catalyst to produce a compound represented by Formula 6;
Deprotecting the compound represented by Formula 6 below to produce a compound represented by Formula 7;
Mixing the compound represented by the following formula 7 with an optically active organic acid to produce an optically pure compound represented by the following formula 7a. .

(In each of the above Chemical Formulas 5 to 7a, R ₁ is H or a protecting group,
In Formula 5, LG represents a leaving group. ) In preparing the compound represented by Formula 3,
The method of claim 1, wherein the compound represented by Formula 2 is reacted with di-tert-butyl dicarbonate. In preparing the compound represented by Formula 4,
The method for producing an intermediate for silodosin synthesis according to claim 1, wherein the strong base is 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 are performed in a single container in a continuous process (In-Situ; in-situ process). The method for producing an intermediate for synodosin synthesis according to claim 1, wherein the compound represented by Chemical Formula 4 is produced. In preparing the compound represented by Formula 5,
The method for producing an intermediate for silodosin synthesis according to claim 1, wherein the base is an alkali metal carbonate or an organic base. In preparing the compound represented by Formula 5,
The method for producing an intermediate for synodosin synthesis according to claim 1, wherein the catalyst is a phase transfer catalyst.   The method of claim 1, wherein the step of preparing the compound represented by Formula 7 is performed by performing a deprotection reaction under an acid condition. In preparing the compound represented by Formula 7a,
The organic acid is at least one selected from the group consisting of tartaric acid, mandelic acid, 10-camphorsulfonic acid, and malic acid;
2. The method for producing an intermediate for silodosin synthesis according to claim 1, wherein the enantiomeric excess (ee) is 95% or more and 99.7% or less.   The step of preparing the compound represented by the formula (6), the step of preparing the compound represented by the formula (7), and the step of preparing the compound represented by the formula (7a) include a continuous process (In) in a single container. The method for producing an intermediate for silodosin synthesis according to claim 1, wherein the compound represented by the chemical formula 7a is produced by proceeding in (Situ; in-situ step). An intermediate for silodosin synthesis represented by the following chemical formula 4.

A compound represented by the following chemical formula 7a having an enantiomeric excess (ee) of 95 to 99.7% is subjected to an N-alkylation reaction in the presence of a compound represented by the following chemical formula 8 and an inorganic base, to thereby obtain optical activity Preparing a compound represented by the following Chemical Formula 9 by mixing with an organic acid having:
Hydrolyzing a compound represented by the following chemical formula 9 in the presence of a strong base and an oxidizing agent to produce a compound represented by the following chemical formula 1.

(In each of the above formulas 7a and 9, R ₁ is H or a protecting group,
In Formula 8, LG represents a leaving group. ) In preparing the compound represented by Formula 9,
The method for producing silodosin according to claim 11, wherein the inorganic base is an alkali metal carbonate. In preparing the compound represented by Formula 9,
The organic acid is at least one selected from the group consisting of tartaric acid, mandelic acid, 10-camphorsulfonic acid, and malic acid;
The method for producing silodosin according to claim 11, wherein the enantiomer excess (ee) of the compound represented by Formula 9 is 99.7% or more. In preparing the compound represented by Formula 1,
The strong base is an alkali metal hydroxide,
The method for producing silodosin according to claim 11, wherein the oxidizing agent is sodium percarbonate.

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