JP2016088847A - Method for producing (-)-1-(3-hydroxypropyl)-5-[[(2r)-2-({2-[2-(2,2,2-trifluoro ethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1h-indole-7-carboxamide]) - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for efficiently producing a high purity (-)-1-(3-hydroxypropyl)-5-[[(2R)-2-({2-[2-(2,2,2-trifluoro ethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide]) in which the amount of a certain impurity is reduced.SOLUTION: The method includes hydrolyzing 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoro ethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile in water-soluble organic solvent, water, or a mixture of water-soluble organic solvent and water, under the presence of alkali, using an oxidizer, at reaction temperature of 15°C or less.SELECTED DRAWING: None

Description

  The present invention relates to silodosin (chemical name: (-)-1- (3-hydroxypropyl) -5-[[(2R) -2-({2- [2- (2,2,2-trifluoroethoxy) Phenoxy] ethyl} amino) propyl] -2,3-dihydro-1H-indole-7-carboxamide]).

  Following formula (2)

Silodosin represented by the formula has selective urinary tract smooth muscle contraction inhibitory action, reduces urethral pressure without significantly affecting blood pressure, and selectively acts on the α _1A adrenergic receptor subtype, It is known as a therapeutic drug that improves dysuria associated with benign prostatic hyperplasia. Since silodosin used as such a therapeutic agent is desired to have a very high purity, it is extremely important to suppress the generation of impurities during the production process.

  As a manufacturing method of silodosin, following formula (1)

1- (3-hydroxypropyl) -5-[(2R) -2-({2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl} amino) propyl] -2 represented by Hydrolysis of the cyano group of 3-dihydro-1H-indole-7-carbonitrile (hereinafter also referred to as carbonitrile) using an oxidizing agent in the presence of an alkali in a mixed solvent of a water-soluble organic solvent and water. Patent Documents 1 and 2 describe a method of producing silodosin by using a carbamoyl group.

  In addition, as a manufacturing method of the said carbonitrile body, in patent document 1, following formula (3)

1- (Benzoyloxypropyl) -7-cyano-5-[(2R) -2-({2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl} amino) propyl] Indoline and the following formula (4)

(X in the formula represents a functional group eliminated by a nucleophilic substitution reaction.)
And a compound represented by the following formula (5):

1- (Benzoyloxypropyl) -7-cyano-5-[(2R) -2-({2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl} amino) propyl] After purification by precipitating crystals of indoline (hereinafter also referred to as N-alkylated indoline derivative) and using the resulting N-alkylated indoline derivative as an oxalate, the phenyl ester group is removed in an appropriate solvent. A method for producing a hydroxyl group by hydrolysis is described. Further, in Patent Document 2, purification is performed by precipitating a crystal in which the N-alkylated indoline derivative obtained in the same manner is a tartrate salt, and then the phenyl ester group is hydrolyzed in an appropriate solvent to form a hydroxyl group. A method for producing carbonitrile bodies is described.

  Silodosin thus obtained is purified by recrystallization from, for example, ethyl acetate in Patent Document 1 and Patent Document 2, and in Patent Document 3 by a method different from Patent Document 1 and Patent Document 2. Although it is a synthesized silodosin, a method is described in which the obtained silodosin is purified by column chromatography.

Japanese Patent No. 5049013 International Publication No. 2012/147019 Pamphlet Japanese Patent No. 2944402

  As described above, an active pharmaceutical ingredient is required to have a very high purity. For example, a purity of 99.9% or more is often required. In the hydrolysis reaction, as the reaction proceeds, the carbamoyl group of the obtained silodosin is further hydrolyzed, and the following formula (6)

(-)-1- (3-hydroxypropyl) -5-[[(2R) -2-({2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl} amino) represented by Propyl] -2,3-dihydro-1H-indole-7-carboxyl (hereinafter also referred to as carboxyl form) was found to be a by-product. Furthermore, the rate of formation of the carboxyl body increases as the reaction proceeds and the amount of silodosin produced increases. For example, when the reaction conversion rate of the above reaction reaches 99%, the amount of carboxyl body is 0.1% in terms of HPLC purity. It was also confirmed that this was the case. This carboxyl body is difficult to remove by a purification operation, and the purification method by column chromatography described in Patent Document 3 is complicated and not suitable for an industrial technique. Although the purity of silodosin could be improved by the purification method by the recrystallization operation described, the impurities could not be removed.

  In addition, when the reaction is terminated immediately after the hydrolysis tends to increase during the hydrolysis (reaction conversion rate 85%, carboxyl content 0.02%), carbonitrile is sufficiently converted to silodosin. Since the reaction was stopped in the meantime, the yield and purity were reduced, and it was difficult to obtain a sufficient amount of high-purity silodosin.

  Accordingly, an object of the present invention is to provide a method for producing high-purity silodosin in which the content of carboxyl bodies is reduced in a method for producing silodosin by hydrolyzing a carbonitrile body.

  In order to solve the above problems, the present inventor has intensively studied a silodosin synthesis method. As a result, by reducing the reaction temperature of the hydrolysis reaction of the carbonitrile body, surprisingly, the carboxyl body formation reaction is selectively reduced in speed, and the production of the carboxyl body can be achieved without affecting the production of silodosin. It turned out that it can suppress. The reason why such an effect can be obtained may be that there is a large difference in activation energy between the carboxyl body formation reaction and the silodosin formation reaction.

  That is, the present invention provides the following formula (1):

1- (3-hydroxypropyl) -5-[(2R) -2-({2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl} amino) propyl] -2 represented by Hydrolysis of 3-dihydro-1H-indole-7-carbonitrile in a water-soluble organic solvent, water or a mixed solvent of water-soluble organic solvent and water using an oxidizing agent in the presence of an alkali. (−)-1- (3-hydroxypropyl) -5-[[(2R) -2-({2- [2- (2,2,2 -Trifluoroethoxy) phenoxy] ethyl} amino) propyl] -2,3-dihydro-1H-indole-7-carboxamide]).

  According to the present invention, silodosin in which the content of impurities, particularly carboxyl bodies, is reduced can be produced with high yield by setting the reaction temperature when hydrolyzing a carbonitrile body to 15 ° C. or lower. In addition, since the silodosin obtained has a reduced content of carboxyl, it can be easily purified to a high purity.

  The present invention provides a method for producing silodosin by hydrolyzing a carbonitrile body by adding an oxidizing agent in a water-soluble organic solvent, water or a mixed solvent of a water-soluble organic solvent and water. The method is characterized by being 15 ° C. or lower.

  First, the carbonitrile body and reaction solvent used in the present invention will be described.

(Carbonitrile body)
The carbonitrile body used in the present invention is not particularly limited, and those produced by a known method can be used. Specifically, the method described in Patent Document 1, that is, the method of hydrolyzing the phenyl ester group of an oxalate salt of an N-alkylated indoline derivative, and the N-alkylated indoline derivative described in Patent Document 2 It can be produced by a method of hydrolyzing the phenyl ester group of tartrate.

  The carbonitrile body only needs to contain 80% or more of the carbonitrile body, and considering the purity and yield of the finally obtained silodosin crystals, the carbonitrile body preferably contains 85% or more of the carbonitrile body. Furthermore, it is preferable that it contains 90% or more of a carbonitrile body. The carbonitrile body is almost always obtained in the form of an oil, but the form is not particularly limited, and may be in the form of an oil, or may be obtained in the form of a solid by salt formation. It may be a solution of the solvent used, and may contain other solvents as long as the hydrolysis reaction is not affected.

(Reaction solvent)
As a solvent used in the present invention, a water-soluble organic solvent, water or a water-soluble organic solvent which is miscible with water in any proportion such as lower alcohols such as methanol, ethanol, propanol and isopropyl alcohol, acetone, tetrahydrofuran, dioxane and dimethyl sulfoxide. A mixed solvent of water and dimethyl sulfoxide is preferable among them.

(Alkali / oxidizer)
Hydrolysis can be performed using alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkalis such as alkali metal carbonates such as sodium carbonate and potassium carbonate, and in particular, alkali metal hydroxides are used. Preferably. The oxidizing agent used for the hydrolysis is not particularly limited, and it is sufficient that the cyano group is oxidized to obtain carbamoyl, but this is particularly preferably performed in the presence of hydrogen peroxide.

(Hydrolysis reaction step)
The reaction step is not particularly limited except that the reaction temperature is 15 ° C. or lower, and it is sufficient that silodosin is obtained by contacting the carbonitrile body with an alkali and an oxidizing agent in the solvent.

  The hydrolysis reaction may be performed by completely dissolving the carbonitrile body in a solvent, or may be performed in a slurry state, and the amount of the solvent used for preparing the solution is not particularly limited. The order of adding the alkali and the oxidizing agent is not particularly limited, but it is preferable to add the oxidizing agent while cooling after adding the alkali because it generates heat with the reaction. In this case, the operation of adding alkali may be performed at room temperature. The amount of alkali and oxidizing agent used for hydrolysis may be the amount used for general hydrolysis, and is preferably 0.5 to 2 equivalents relative to the carbonitrile body.

  In the hydrolysis step, the hydrolysis reaction is carried out at a reaction temperature of 15 ° C. or lower. However, considering the reaction rate, it is preferably 0 ° C. to 15 ° C. It is particularly preferable to do this. Since it is desirable to carry out the reaction time until the reaction conversion rate becomes 95% or more, the optimum condition varies depending on the reaction temperature, but it is preferably 3 hours or more and less than 48 hours.

  The silodosin-containing reaction solution produced in this way is obtained by a known method, for example, adding sodium sulfite aqueous solution to the reaction solution to terminate the reaction, extracting with ethyl acetate, and then crystallizing the silodosin crystals. Can be obtained.

  Since silodosin obtained by the production method of the present invention has a reduced carboxyl content, silodosin that has undergone the crystallization step is very high in purity and can be efficiently used for pharmaceuticals without excessive purification operations. The resulting high purity silodosin can be produced.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not restrict | limited by these Examples.

  In this example, the carbonitrile, the purity of silodosin and the amount of impurities of silodosin were measured by high performance liquid chromatography (HPLC) as follows. In the present invention, the volume of the solution is at 25 ° C.

<Purity and impurity measurement method>
Equipment: High-performance liquid chromatograph (Waters)
Detector: UV absorption detector (manufactured by Waters)
Measurement wavelength: 225 nm
Column: Inertsil ODS-3, inner diameter 4.6 mm, length 50 mm (manufactured by GL Sciences)
Column temperature: Constant temperature around 25 ° C. Mobile phase A: A mixture of 900 mL of a buffer solution adjusted to pH 2.4 by adding triethylamine to an aqueous solution in which 2.8 g of phosphoric acid was dissolved in 1000 mL of water, and 100 mL of acetonitrile were mixed. Solution mobile phase B: Acetonitrile mobile phase liquid feed: The concentration ratio is controlled by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 1.
Flow rate: 1.0 mL / min
Measurement time: 60 minutes

Under the above conditions, a peak is confirmed at about 23 minutes for carbonitrile and about 10 minutes for silodosin. In the following Examples and Comparative Examples, the purity or content of the above compound is the ratio of the area value of each compound peak to the sum of all peak area values (excluding solvent-derived peaks) measured under the above conditions. is there.

  In this example, the reaction conversion rate of hydrolysis of the carbonitrile body was calculated by the following formula.

  Reaction conversion rate (%) = (HPLC area value of silodosin) / (HPLC area value of silodosin + HPLC area value of carbonitrile) × 100

Example 1
A 100 mL three-necked flask equipped with a stirring blade and a thermometer was charged with 3.55 g of oily carbonitrile (HPLC purity 91.45%), and 35.5 mL of dimethyl sulfoxide was added to confirm that all the solid had dissolved. Thereafter, 2.5 mL of 20% aqueous sodium hydroxide solution was added, mixed with stirring, and cooled to 10 ° C. To this, 1.5 mL of 30% aqueous hydrogen peroxide was added dropwise so that the solution temperature did not exceed 10 ° C., and the mixture was stirred at 10 ° C. for 17 hours. When confirmed by HPLC, the reaction conversion rate was 99% and the area ratio of the carboxyl body was 0.01%. The reaction mixture was quenched by adding 60 mL of 2% aqueous sodium sulfite solution, and extracted with 50 mL of ethyl acetate. After concentrating ethyl acetate to 5 mL, heating to 65 ° C., confirming dissolution of the precipitated crystals, cooling to 4 ° C., and stirring at the same temperature for 2 hours. The precipitated crystals were collected by filtration under reduced pressure, washed with 5 mL of ethyl acetate, and dried under reduced pressure to obtain 2.78 g of silodosin crystals (purity 99.73%, carboxyl group content 0.01%). Rate 75.5%).

Reference example 1
2.78 g of the silodosin crystals obtained in Example 1 were placed in a 50 mL three-necked flask equipped with a stirring blade and a thermometer, and 28 mL of ethyl acetate was added. The solution was heated to 65 ° C., and after confirming that the crystals were dissolved, cooling was performed. After cooling to room temperature, it was cooled to 4 ° C. and stirred for 2 hours. The precipitated crystals were collected by filtration under reduced pressure, washed with 3 mL of ethyl acetate, and dried under reduced pressure to obtain silodosin crystals. The same purification operation was performed once more to obtain 2.39 g of silodosin crystals (purity 99.94%, carboxyl body content 0.01%) (yield 86.0%: total yield 64.9%). ).

Example 2
After adding 4.05 g of oily carbonitrile (HPLC purity 91.45%) to a 100 mL three-necked flask equipped with a stirring blade and a thermometer, and adding 40 mL of dimethyl sulfoxide, it was confirmed that all solids were dissolved. 2.8 mL of 20% aqueous sodium hydroxide solution was added, mixed with stirring, and cooled to 10 ° C. To this, 1.7 mL of 30% aqueous hydrogen peroxide was added dropwise so that the solution temperature did not exceed 15 ° C., and the mixture was stirred at 15 ° C. for 17 hours. When confirmed by HPLC, the reaction conversion rate was 99% and the area ratio of the carboxyl body was 0.02%. The reaction mixture was quenched by adding 70 mL of 2% aqueous sodium sulfite solution, and extracted with 60 mL of ethyl acetate. After concentrating ethyl acetate to 40 mL, heating to 65 ° C., confirming dissolution of the precipitated crystals, cooling to 4 ° C., and stirring at the same temperature for 2 hours. The precipitated crystals were collected by filtration under reduced pressure, washed with 3 mL of ethyl acetate, and dried under reduced pressure to obtain 2.96 g of silodosin crystals (purity 99.72%, carboxylate content 0.02%). (Rate 70.43%).

  Further, 2.50 g of the obtained crystals were subjected to the same purification operation as in Reference Example 1 to obtain 2.20 g of silodosin crystals (purity 99.92%, carboxyl group content 0.02%). Rate 88.0%, overall yield 62.0%).

Example 3
An oily carbonitrile body (22.52 g, HPLC purity 91.45%) was put into a 100 mL three-necked flask equipped with a stirring blade and a thermometer, and 230 mL of dimethyl sulfoxide was added to confirm that all solids were dissolved. 15.8 mL of 20% aqueous sodium hydroxide solution was added, mixed with stirring, and cooled to 10 ° C. To the solution, 9.5 mL of 30% hydrogen peroxide solution was added dropwise so that the solution temperature did not exceed 5 ° C., and stirred at 10 ° C. for 40 hours. When confirmed by HPLC, the reaction conversion rate was 99%, and no carboxyl form was confirmed. The reaction was stopped by adding 380 mL of a 2% aqueous sodium sulfite solution to the resulting reaction solution, and then extracted with 340 mL of ethyl acetate. After concentrating ethyl acetate to 225 mL, heating to 65 ° C. and confirming dissolution of the precipitated crystals, the mixture was cooled to 4 ° C. and stirred at the same temperature for 2 hours. The precipitated crystals were collected by filtration under reduced pressure, washed with 25 mL of ethyl acetate, and dried under reduced pressure to obtain 16.75 g of silodosin crystals (purity 99.67%, carboxyl body less than 0.01%) (yield) 71.68%).

  Further, the same purification procedure as in Reference Example 1 was performed to obtain 15.49 g of silodosin crystals (purity 99.96%, carboxyl body less than 0.01%) (yield 92.4%, overall yield 66. 2%).

Comparative Example 1
Into a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 13.34 g (HPLC purity 91.45%) of an oily carbonitrile was added, and after confirming that all solids were dissolved by adding 134 mL of dimethyl sulfoxide, 9.4 mL of 20% aqueous sodium hydroxide solution was added, mixed with stirring, and cooled to 20 ° C. To this, 5.6 mL of 30% aqueous hydrogen peroxide was added dropwise so as to maintain the solution temperature at 20 ° C., and the mixture was stirred at 20 ° C. for 17 hours. When confirmed by HPLC, the reaction conversion rate was 99% and the area ratio of the carboxyl body was 0.21%. The obtained reaction solution was quenched with 230 mL of a 2% aqueous sodium sulfite solution, and then extracted with 150 mL of ethyl acetate. After concentrating ethyl acetate to 130 mL, heating to 65 ° C. and confirming the dissolution of the precipitated crystals, the solution was cooled to 4 ° C. and stirred at the same temperature for 2 hours. The precipitated crystals were collected by filtration under reduced pressure, washed with 15 mL of ethyl acetate, and dried under reduced pressure to obtain 10.30 g of silodosin crystals (purity 99.09%, carboxylate content 0.21%). Rate 74.41%).

  Further, the same purification operation as in Reference Example 1 was performed to obtain 799 g of silodosin crystals (purity 99.49%, carboxyl body content 0.21%) (yield 77.6%, overall yield 57). .7%).

Comparative Example 2
After adding 4.05 g of oily carbonitrile (HPLC purity 91.45%) to a 100 mL three-necked flask equipped with a stirring blade and a thermometer, and adding 40 mL of dimethyl sulfoxide, it was confirmed that all solids were dissolved. 2.8 mL of 20% aqueous sodium hydroxide solution was added, mixed with stirring, and cooled to 20 ° C. To this, 1.7% of 30% hydrogen peroxide water was added dropwise so as to maintain the solution temperature at 20 ° C., and the mixture was stirred at 20 ° C., and the reaction was stopped when the area ratio of the carboxyl body was 0.02% by HPLC. . The reaction addition rate was about 85%. The reaction mixture was quenched by adding 70 mL of 2% aqueous sodium sulfite solution, and extracted with 60 mL of ethyl acetate. After concentrating ethyl acetate to 30 mL, heating to 65 ° C. and confirming the dissolution of the precipitated crystals, the mixture was cooled to 4 ° C. and stirred at the same temperature for 2 hours. The precipitated crystals were collected by filtration under reduced pressure, washed with 3 mL of ethyl acetate, and dried under reduced pressure to obtain 2.38 g of silodosin crystals (purity 98.90%, carboxylate content 0.02%). Rate 56.63%).

  Further, the same purification operation as in Reference Example 1 was performed to obtain 2.06 g of silodosin crystals (purity 99.88%, carboxyl group content 0.02%) (yield 86.6%, overall yield 49). 0.0%).

Claims (1)

Following formula (1)

1- (3-hydroxypropyl) -5-[(2R) -2-({2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl} amino) propyl] -2 represented by Hydrolysis of 3-dihydro-1H-indole-7-carbonitrile in a water-soluble organic solvent, water or a mixed solvent of water-soluble organic solvent and water using an oxidizing agent in the presence of an alkali. (−)-1- (3-hydroxypropyl) -5-[[(2R) -2-({2- [2- (2,2,2 -Trifluoroethoxy) phenoxy] ethyl} amino) propyl] -2,3-dihydro-1H-indole-7-carboxamide]).