KR20210073972A - A new process for the preparation of (R)-2-((4-Aminophenethyl)amino)-1-phenylethanol - Google Patents

Abstract

The present invention relates to a method for producing (R)-2-((4-aminophenethyl)amino)-1-phenylethanol, which is an intermediate of mirabegron, using a zinc powder reduction catalyst with high purity and no side reaction products. It is possible to prepare an amide derivative in high yield, and by using it, it is possible to prepare high purity and high yield of mirabegron without a special purification process.

Description

(R)-2-((4-Aminophenethyl)amino)-1-phenylethanol A new process for the preparation of (R)-2-((4-Aminophenethyl)amino)-1 -phenylethanol}

The present invention relates to a novel method for preparing (R)-2-((4-aminophenethyl)amino)-1-phenylethanol, which is an intermediate of mirabegron.

According to International Patent Publication WO13/119910, overactive bladder disease is defined as a complex symptom of urgency accompanied by frequent urination and nocturia, and this symptom is usually associated with involuntary contraction of the bladder. In the bladder, there are beta 3 receptors, which act as purine receptors and sympathetic nerves, and beta 3 receptors bind norepinephrine and increase the concentration of cyclic adenosine monophosphate (cAMP) to relax the bladder smooth muscle and expand the bladder volume. It has the effect of extending the interval between urination. Mirabegron is a potent and selective beta 3 receptor agonist, which showed an increase in cAMP concentration and relaxation of bladder smooth muscle in rat and human bladder tissues, indicating that mirabegron stimulates bladder beta 3 receptors. It is shown to enhance urine storage function. Mirabegron, developed by Astellas Pharmaceuticals of Japan, was approved by the FDA on June 28, 2012 as a treatment for overactive bladder acting as a beta 3 receptor agonist. It is sold as Betmiga.

Currently, anticholinergic agents such as propiberine hydrochloride and oxybutynin hydrochloride are mainly used for the treatment of symptoms of frequent urination, nocturia, and urge incontinence, which can occur in patients with overactive bladder (OAB). , itching, constipation, erythema, and other side effects existing in anticholinergics are caused, and in order to overcome these side effects, Mirabegron, a drug with a mechanism of beta 3 receptor stimulation, is used. Unlike anticholinergic drugs, Mirabegron does not affect the parasympathetic nervous system, so it can reduce the risk of acute urinary retention in the urination phase, and the patient's compliance is high, so the prescription for elderly patients is increasing.

Various methods of synthesizing Mirabegron have been proposed. For example, in US Patent No. 6,346,532, an amine group is protected using Compound V as shown in Scheme 1 below, and nitrophenyl is reduced to aminophenol using Pd/C. , mirabegron was synthesized through a coupling reaction with an aminothiazole derivative and a deprotection group reaction. However, US Patent No. 6,346,532 has disadvantages in that the entire manufacturing process is lengthened due to the process of protecting and deprotecting the amine, and there are disadvantages in that an expensive Pd/C catalyst and dangerous hydrogen gas must be used during the reduction reaction.

<Scheme 1>

U.S. Patent No. 7,342,117 suggests an improved method for synthesizing mirabegron by directly reducing the amine of Compound V without a protecting group to obtain Compound VI, and then introducing an aminothiazole group as shown in Scheme 2 below, but this also There are disadvantages in that expensive noble metal catalysts such as Pd/C catalysts and dangerous hydrogen gas must be used.

<Scheme 2>

Most of the synthesizing methods suggested above must go through a process of reducing the nitro group of compound V (nitrophenyl) to an amine. However, in this process, the following compound VII is produced. This compound reacts with aminothiazole in the mirabegron synthesis process to form the following compound VIII (YM-541570) to generate a new related substance, YM-541570 It is difficult to remove in the crystallization process and remains in the final compound. In addition, some of the metal catalysts used in the reduction reaction cause an increase in the chiral isomer of compound IX.

For the nitro reduction reaction of compound V known so far, it is a common method to use a metal catalyst such as Pd/C, Ranny Ni, Fe, or Sn. As a technology developed to overcome the disadvantages of the above technology, there are Chinese Patent Laid-Open Patent CN103193730 and CN103232352, which are produced by preparing mirabegron using 2-(4-aminophenyl)ethanol as a starting material as shown in Reaction Scheme 3 below. The reaction can be avoided and the production of chiral isomers can be suppressed. However, in the case of the oxidation reaction from alcohol to aldehyde, it is difficult to apply to field production, and since expensive (R)-2-amino-1-phenylethanol is used, there is an economic disadvantage.

<Scheme 3>

Korean Patent No. 10-1868438 discloses a step of preparing a compound by reacting an aromatic amine derivative in which an alkylamine is substituted with a carboxyl protecting group and a thiazole derivative in which an alkylamine is substituted with a phthalimide as shown in Scheme 4 below to overcome the above disadvantages And after the decarboxyl protecting group reaction, the final compound was prepared through the dephthalimide protecting group reaction. Although this is more stable than the existing manufacturing method including hydrogen reaction, it is not economical because the reaction step is long compared to the reduction reaction using the existing metal catalyst due to the introduction process of the protecting group and the deprotection process.

<Scheme 4>

The present invention is a commercial mass production by further improving the problems of later technologies that have improved the problems of the use of expensive catalysts raised in the conventional synthesis of Mirabegron, the process problems unsuitable for mass production, and the problems of the hydrogen reaction or the reduction reaction using a metal catalyst. An object of the present invention is to provide a method for preparing an intermediate mirabegron capable of producing a suitable and economical mirabegron.

The present invention comprises the steps of: 1) reducing a nitro group to an amine group by reacting a compound represented by the following Chemical Formula 2 or a salt thereof with a hydrogen donor material and zinc powder in a solvent;

<Formula 2>

2) extracting by adjusting the pH of the product of step 1); and

3) crystallizing the extract obtained in step 2) to prepare (R)-2-((4-aminophenethyl)amino)-1-phenylethanol represented by the following formula (1); (R) A method for preparing -2-((4-aminophenethyl)amino)-1-phenylethanol is provided.

<Formula 1>

The zinc (zinc) powder is characterized in that the reaction is 0.5 to 8 times the weight of the compound represented by the formula (2).

The hydrogen donor material is ammonium or phosphate, and the ammonium is at least one selected from the group consisting of ammonium chloride, ammonium carbonate, ammonium hydrogen carbonate, ammonium phosphate, ammonium formate and ammonium sulfate, and the phosphate is monopotassium phosphate ( Monopotassium phosphate), dipotassium phosphate (Dipotassium phosphate), phosphoric acid (Phosphoric acid), monosodium phosphate (Monosodium phosphate) and disodium phosphate (Disodium phosphate) any one selected from the group consisting of or a mixture of two or more use.

As the solvent, any one or a mixture of two or more selected from the group consisting of tetrahydrofuran, acetonitrile, acetone, ethyl acetate, methylene chloride, chloroform and water is used.

In step 1), the pH of the mixed solution of the solvent and the hydrogen donor material is 5 to 7, and it is characterized in that it is carried out at 0° C. to 40° C. for 30 minutes to 3 hours.

Step 3) is characterized in that the pH is adjusted to 9 to 14.

In addition, the present invention comprises the steps of preparing (R)-2-((4-aminophenethyl)amino)-1-phenylethanol by the above preparation method; and reacting (R)-2-((4-aminophenethyl)amino)-1-phenylethanol with 2-aminothiazol-4-ylacetic acid to prepare Mirabegron; Provided is a method for manufacturing a gronn.

The manufacturing method according to the present invention can exclude hydrogen reaction, which is constrained by high manufacturing cost and low production efficiency, in on-site production, and uses an easily available zinc powder reduction catalyst to achieve high purity and yield without generating side reactants. It is possible to prepare high-quality amide derivatives having a high-purity, high-yield Mirabegron without a special purification process using this.

1 shows the HPLC analysis results of Mirabegron according to an embodiment of the present invention.
2 shows the results of HPLC analysis of (R)-2-((4-aminophenethyl)amino)-1-phenylethanol according to an embodiment of the present invention.
3 shows the isomer confirmation HPLC analysis result of (R)-2-((4-aminophenethyl)amino)-1-phenylethanol according to an embodiment of the present invention.
4 shows the results of HPLC analysis of (R)-2-((4-aminophenethyl)amino)-1-phenylethanol according to Comparative Example 1. FIG.
5 shows the results of HPLC analysis of (R)-2-((4-aminophenethyl)amino)-1-phenylethanol according to Comparative Example 2. FIG.
6 shows the results of HPLC analysis for isomer confirmation of (R)-2-((4-aminophenethyl)amino)-1-phenylethanol according to Comparative Example 3. FIG.

Hereinafter, the present invention will be described in more detail. In describing the present invention, if it is determined that a detailed description of a related known configuration or function may obscure the gist of the present invention, the detailed description thereof will be omitted.

The present invention comprises the steps of: 1) reducing a nitro group to an amine group by reacting a compound represented by the following Chemical Formula 2 or a salt thereof with a hydrogen donor material and zinc powder in a solvent;

<Formula 2>

2) filtering and washing the product of step 1) to remove zinc powder;

3) extracting by adjusting the pH; and

4) crystallizing the extract obtained in step 3) to prepare (R)-2-((4-aminophenethyl)amino)-1-phenylethanol represented by the following formula (1); (R) A method for preparing -2-((4-aminophenethyl)amino)-1-phenylethanol is provided.

<Formula 1>

Step 1) is a step of substituting an amine group by putting zinc powder in a mixed solution of a solvent in which Formula 2 is dissolved and a hydrogen donor material in order to replace the nitro group of Formula 2 with an amine group.

The zinc powder is preferably reacted at 0.5 to 12 times the weight of the compound represented by Formula 2, and more preferably 0.5 to 8 times by weight. In addition, in order to prevent decomposition or danger of the target compound due to rapid heat generation, the zinc powder is gradually added in portions to maintain an appropriate temperature.

The hydrogen donor material is ammonium or phosphate, and the ammonium is at least one selected from the group consisting of ammonium chloride, ammonium carbonate, ammonium hydrogen carbonate, ammonium phosphate, ammonium formate and ammonium sulfate, and the phosphate is monopotassium phosphate ( Monopotassium phosphate), dipotassium phosphate (Dipotassium phosphate), phosphoric acid (Phosphoric acid), monosodium phosphate (Monosodium phosphate) and disodium phosphate (Disodium phosphate) is any one or more selected from the group consisting of.

This reaction using zinc powder does not require a separate hydrogen gas, and does not require high temperature and high pressure reaction conditions. In addition, it is possible to minimize the generation of expected impurities (Compound VII, Compound VIII, Compound IX, etc.) generated in large amounts when using the above-mentioned Pd/C, Rani Ni, Fe, SnCl _{2 and the like.}

The solvent is preferably at least one selected from the group consisting of tetrahydrofuran, acetonitrile, acetone, ethyl acetate, methylene chloride, chloroform and water.

In addition, the pH of the solution in which the solvent and the hydrogen donor material are mixed is preferably 5 to 7, and if the reaction proceeds outside the above pH range, zinc powder may be dissolved or zinc hydroxide may be difficult to remove. Or, the salt of Formula 1 substituted with an amine group is generated, so that the target compound cannot be maximally obtained, and thus a problem of yield reduction may occur.

Step 1) is preferably performed at 0° C. to 40° C. for 30 minutes to 3 hours. If the temperature is less than 0 ° C, the reaction proceeds to the primary reduced intermediate and a complete reaction may not be achieved. If the temperature exceeds 40 ° C, the reaction rate and completion rate are accelerated, while the target compound is decomposed in a large amount, resulting in yield and A problem of lowering purity may occur.

In addition, the washing in step 2) is preferably performed using a mixed solution or water of the organic solvent and water used for the reaction, and the organic solvent is ethyl acetate, butyl acetate, isobutyl acetate, diethyl ether, dimethyl ether. , isopropyl ether, methyl ethyl ketone or dichloromethane.

Step 3) is characterized in that the pH is adjusted to 9 to 14, and ammonium or phosphate is removed.

The crystallization step of step 4) is a step of forming a salt with an amine group from the extract without a concentration process, and hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, formic acid, citric acid, oxalic acid, fumaric acid, or benzoic acid may be used, but limited thereto it's not going to be

In addition, the present invention comprises the steps of preparing (R)-2-((4-aminophenethyl)amino)-1-phenylethanol by the above preparation method; and preparing mirabegron by coupling the (R)-2-((4-aminophenethyl)amino)-1-phenylethanol with an aminothiazole derivative to prepare mirabegron. to provide.

Hereinafter, examples of the present invention will be described in detail, but the present invention is not limited to the following examples.

Example 1. (R)-2-((4- aminophenethyl )amino)-1- Phenylethanol (Formula 1) Synthesis example

10 g of (R)-2-{[2-(4-nitrophenyl)ethyl]amino}-1-phenylethanol-hydrochloride (Formula 2) was added to 25 ml of tetrahydrofuran (THF), and 80 ml of purified water was added After the addition, 10 g of ammonium chloride (NH ₄ Cl) was added. After adding 20 g of zinc powder in portions, it was reacted at room temperature for 1 hour. After completion of the reaction, the zinc powder was removed by filtration. To the filtrate, 50 ml of ethyl acetate was added, and an aqueous NaOH solution was added to adjust the pH. After adding concentrated hydrochloric acid to the obtained organic layer, it was cooled to 0-5° C. and crystallized with stirring for 1 hour. The resulting crystals were filtered, washed with ethyl acetate, and dried under reduced pressure at room temperature to obtain 8.4 g of Formula 1 (yield 93%, purity 99.91%, compound VII not detected).

Example 2. (R)-2-((4- aminophenethyl )amino)-1- Phenylethanol (Formula 1) Synthesis example

10 g of (R)-2-{[2-(4-nitrophenyl)ethyl]amino}-1-phenylethanol-hydrochloride (Formula 2) was added to 25 ml of tetrahydrofuran (THF), and 80 ml of purified water was added After addition, 20 g of potassium phosphate monobasic (KH ₂ PO _{4 ) was added.} After adding 20 g of zinc powder in portions, it was reacted at room temperature for 2 hours. After completion of the reaction, the zinc powder was removed by filtration. To the filtrate, 50 ml of ethyl acetate was added, and an aqueous NaOH solution was added to adjust the pH. After separating the layers to recover the organic layer, concentrated hydrochloric acid was added to the obtained organic layer, cooled to 0-5° C., and crystallized with stirring for 1 hour. The resulting crystals were filtered and dried under reduced pressure at room temperature to obtain 8.2 g of Formula 1 (yield 90%, purity 99.85%, compound VII not detected).

Example 3. Mirabegron Synthesis example

It was prepared according to the method of Example 1 of Korean Patent No. 10-0908796.

(R)-2-((4-aminophenethyl)amino)-1-phenylethanol-hydrochloride 8.00 g, 2-aminothiazol-4-ylacetic acid 4.32 g, concentrated hydrochloric acid 2.64 g, and water 120 ml were mixed. After that, 5.76 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-hydrochloride (EDC) was added at room temperature and stirred for 1 hour. A mixture of 2.40 g of sodium hydroxide and 40 ml of water was added dropwise to the reaction solution for crystallization. The resulting crystals were collected by filtration, washed with water, and dried under vacuum to obtain 10.1 g of mirabegron (yield 93%, purity 99.95%, compound VIII 0.02%).

comparative example One

It was prepared according to the method of Example 1 of International Patent Publication WO2015/155604.

After adding 10 g of Fe and 5.8 g of hydrochloric acid to 85 ml of purified water, 17.0 g of (R)-2-{[2-(4-nitrophenyl)ethyl]amino}-1-phenylethanol-hydrochloride and 50 ml of methanol were added. did. The reaction solution was heated to 80° C. and reacted for 3 hours. After completion of the reaction, it was cooled to 30° C. and Fe was removed by celite filtration. After the filtrate was concentrated under reduced pressure, ethyl acetate and methanol were added to the concentrated solution for crystallization. The resulting crystals were collected by filtration and dried under vacuum to obtain 13.3 g of Formula 1 (yield 86%, purity 98.82%, compound VII 0.19%).

comparative example 2

It was prepared according to the mirabegron preparation method of Journal of Chemical and Pharmaceutical Research, 2015, 7(4):1473-1478.

12.0 g of (R)-2-{[2-(4-nitrophenyl)ethyl]amino}-1-phenylethanol-hydrochloride and 130 ml of ethanol were added to the reactor, and then 42.2 g of stannous chloride dehydrate was slowly added thereto. The reaction solution was heated to 70° C. and reacted for 2 hours. After completion of the reaction, ethanol was removed by concentration under reduced pressure at 55°C. After adding 200 ml of a saturated sodium hydrogen carbonate solution to the concentrated mother liquor, it was extracted 4 times with 200 ml of ethyl acetate and twice with 200 ml of a 10% methanol/methylene chloride mixed solution. The extraction solution was concentrated under reduced pressure at 50° C. and then crystallized using methylene chloride and n-nucleic acid. The resulting crystals were collected by filtration and vacuum dried to obtain 9.1 g of Formula 1 (yield 84%, purity 92.91%, compound VII 0.17%).

comparative example 3

It was prepared according to the method of Reference Example 3 of Korean Patent Registration No. 10-0908796.

(R)-2-{[2-(4-nitrophenyl)ethyl]amino}-1-phenylethanol-hydrochloride 11.0 g, methanol 110 ml and 1.20 g wet 10% palladium-carbon (54.2% wet) are mixed. After that, the mixture was stirred under a hydrogen atmosphere until the suction of hydrogen was stopped. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. 40 ml of methanol was added to the residue to dissolve it at 40°C, and 220 ml of diisopropyl ether was added thereto for crystallization, followed by stirring at 20°C overnight. The resulting crystals were collected by filtration, washed with 30 ml of diisopropyl ether, and dried under vacuum to obtain 8.9 g of Formula 1 (yield 89%, purity 99.76%, compound VII 0.04%).

Table 1 below shows the synthesis results of Examples 1 to 2 and Comparative Examples 1 to 3.

reducing agent yield water compound VII compound IX Example 1 Zn(NH ₄ Cl) 93% 99.91% non-detection non-detection Example 2 Zn(KH ₂ PO ₄ ) 91% 99.85% non-detection non-detection Comparative Example 1 Fe 86% 98.82% 0.19% non-detection Comparative Example 2 SnCl ₂ 84% 92.91% 0.17% non-detection Comparative Example 3 Pd/C 89% 99.76% 0.04% 0.32%

As shown in Table 1, it can be seen that the selection of the reducing agent in the reduction step greatly affects the yield and purity of the intermediate aminophenyl (Formula 1). Among them, compound VII, a major impurity, reacts with aminothiazole during the manufacturing process of mirabegron to generate a related substance YM-541570 (compound VIII), and this impurity remains in the final compound because it is difficult to remove in the crystallization process. In the case of the manufacturing method using zinc presented in the present invention, unlike the comparative example, compound VII is not produced, so that a high-purity product can be manufactured without a separate purification process in the mirabegron manufacturing process. In addition, it can be seen that Pd/C (Comparative Example 3) among the metal catalysts used for the reduction reaction increases the chiral isomer of compound IX. Therefore, the invention of the present method is superior to the method of the comparative example, and the problem of the use of expensive catalysts raised in synthesizing Mirabegron and the process problems that are not suitable for mass production and the problems of the reduction reaction using a hydrogen reaction or a metal catalyst are improved after improving By further improving the problems of the techniques, an economical manufacturing method suitable for commercial mass production is provided.

Above, the present invention has been described by way of example, and various modifications will be possible without departing from the essential characteristics of the present invention by those of ordinary skill in the art to which the present invention pertains. Accordingly, the embodiments disclosed in this specification are intended to illustrate, not to limit the present invention, and the spirit and scope of the present invention are not limited by these embodiments. The protection scope of the present invention should be construed by the following claims, and all technologies within the scope equivalent thereto should be construed as being included in the scope of the present invention.

Claims (10)

1) reducing a nitro group to an amine group by reacting a compound represented by the following Chemical Formula 2 or a salt thereof with a hydrogen donor material and zinc powder in a solvent;
<Formula 2>

2) filtering and washing the product of step 1) to remove zinc powder;
3) extracting by adjusting the pH; and
4) A method for producing (R)-2-((4-aminophenethyl)amino)-1-phenylethanol represented by the following formula (1) comprising a; crystallizing the extract obtained in step 3)
<Formula 1>

The method according to claim 1, wherein the zinc powder is reacted with 0.5 to 8 times the weight of the compound represented by Formula 2
The method according to claim 1, wherein the hydrogen donor material is any one selected from the group consisting of ammonium chloride, ammonium carbonate, ammonium hydrogen carbonate, ammonium phosphate, ammonium formate and ammonium sulfate, or a mixture of two or more types.
According to claim 1, wherein the hydrogen donor material is monopotassium phosphate (Monopotassium phosphate), dipotassium phosphate (Dipotassium phosphate), phosphoric acid (Phosphoric acid), monosodium phosphate (Monosodium phosphate) and disodium phosphate (Disodium phosphate) consisting of Any one selected from the group or a manufacturing method characterized in that two or more types are mixed
The method according to claim 1, wherein the solvent is any one or two or more selected from the group consisting of tetrahydrofuran, acetonitrile, acetone, ethyl acetate, methylene chloride, chloroform and water.
The method according to claim 1, wherein the pH of the solution in which the solvent and the hydrogen donor material are mixed in step 1) is 5 to 7
The method according to claim 1, wherein in step 1), the reaction is performed at 0°C to 40°C.
The method according to claim 1, wherein the reaction time of step 1) is 30 minutes to 3 hours.
The method according to claim 1, wherein in step 3), the pH is adjusted to 9 to 14.
(R)-2-((4-aminophenethyl)amino)-1-phenylethanol by the preparation method according to any one of claims 1 to 9; and reacting (R)-2-((4-aminophenethyl)amino)-1-phenylethanol with 2-aminothiazol-4-ylacetic acid;

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