WO2019081972A1

WO2019081972A1 - A method for preparing mandelic acid 4-nitrophenyl ethylamide from 4-nitrobenzyl cyanide

Info

Publication number: WO2019081972A1
Application number: PCT/IB2018/000932
Authority: WO
Inventors: Radim HORAK; Martin Grepl; Petr Funk; Kamil KORISTRK; Lubomir Kvapil; Miroslav Urbasek; Pavel Hradil
Original assignee: Saneca Pharmaceuticals A.S.
Priority date: 2017-08-09
Filing date: 2018-08-09
Publication date: 2019-05-02
Also published as: CZ2017461A3

Abstract

Preparation of a salt of 4-nitrophenyl ethylamine with (R)-mandelic acid and its use for the synthesis of mirabegron is disclosed. 4-Nitrophenyl ethylamine (1) is prepared by reduction of 4-nitrobenzyl cyanide (7) in a solvent with the use of a borane generated in-situ in the reaction mixture from NaBH4 and BF3.Et2O, 4-nitrophenyl ethylamine (1) being isolated from the solution as the mandelate 3.

Description

A method for preparing mandelic acid 4-nitrophenyl ethylamide from 4-nitrobenzyl cyanide

Field of the Invention The invention relates to preparation and purification of 4-nitrophenyl ethylamine of formula 1 with the use of the compound of formula 3 and the use of the compound 3 for the preparation of the amide 2.

Background Art

4-Nitrophenyl ethylamine (1) is the key compound for the preparation of mirabegron. With regard to the importance of the compound, a number of its syntheses are known. One of the methods is reduction of the azido derivative 4 with the use of cerium (III) chloride and sodium iodide with the yield of 75%. (Bartoli G. et al.: J. Org. Chem. 2008, 73, 1919. DOI:10.1021/jo7024288) Diagram 1. PPh₃ was also used as a reduction agent (Ba-Maung N. Y. et al. US 9051315; 2015).

Scheme 1 The yield of the reaction is acceptable but handling of azides is dangerous and industrially unfeasible, thus representing a purely laboratory method. Also, the starting substances are difficult to obtain. Another method which is known is substitution of bromine in the compound 5 with ammonia (Ba-Maung N. Y. et al., US 9051315; 2015) (Scheme 2). The same reaction and isolation of the product in the hydrobromide form in 75% yield is known from the reference literature. (Saulnier M. G. et al.: Tetrahedron Lett. 2004, 45, 397; DOI:10.1016/j.tetlet.2003.10.146).

5

Scheme 2

A disadvantage of this method is, besides not very good availability of the input compound, also formation of a number of side products and problematic purification of the prepared compound. Also, the reaction is conducted under pressure at a temperature of 130°C, which requires costly equipment.

In a great number of documents, nitration of the compound 6 is used to prepare the compound 1 (Scheme 3).

Scheme 3

This reaction is described in magazines, the yield of the reaction achieves approx. 40% (Liu D. Y. et al.: Inorg. Chem. Commun. 2014, 43, 173; DOI:10.1016/j.inoche.2014.02.035; Roberts J. D., Regan C. M.: J. Am. Chem Soc. 1953, 75, 2069.). The reaction is subject-matter of Chinese patent applications (Xu K., Tian Y.: CN 104557566 (2015); Cui L.: CN 104151170 (2014) (Scheme 3). A disadvantage of this reaction is a low yield, a great deal of waste products - especially waste acids from the nitration reaction.

A cheap and well available compound is the nitrile 7. Its reduction with the use of a solution of BH₃ in THF provides the desired product 1. (Kurouchi H. et al.: Chem. Eur. J. 2014, 20, 8682; DOI:10.1002/chem.201402447. (Scheme 4). The reduction is difficult to implement in the industrial scale due to the price of the borane, its toxicity and self-ignition property.

7 1

Scheme 4

Using NaBK_t in CF3COOH is more viable. However, the yield of the reduction is only 50%; the substance is isolated in the hydrobromide form. Also, corrosiveness of trifluoroacetic acid is detrimental for industrial application. (Hothi P. et al.: ChemBioChem 2008, 9, 2839; DOI: 10.1002/cbic.200800408).

Reduction of the nitrile 7 with the use of NaBH₄ and BF3.Et₂0 is more advantageous for industrial conditions. The described yield is high and achieves 94%. However, a disadvantage of the reaction is a higher number of impurities, which achieve a few percent and when isolated as hydrochloride or hydrobromide, the compound could only be purified after multiple crystallization. (Sucholeiki I. et al. J. Org. Chem. 1988, 53, 98) DOI:10.1021/jo00236a020). This method of reduction and purification in the hydrochloride form with the yield of 71% has been described (Umino N. et al.: Tetrahedron Lett. 1976, 2875.).

As mentioned, the compound 1 is used as a pharmaceutical intermediate. Drugs are subject to high requirements for purity while none of the side substances may exceed 0.1%. This means that intermediates of pharmaceutical production are subject to similar requirements. In the particular case, a purification procedure by means of salts as chloride or bromide is known. As mentioned above, this purification is not very efficient. Another drawback is that the base must also be subsequently released from the salt as it is used for further synthesis. The next synthetic stage is a reaction of the compound 1 with (R)-mandelic acid providing the compound 2 (Scheme 5).

Scheme 5 All the described procedures are virtually the same and use a reaction of the base of the compound 1 with (R)-mandelic acid. Individual procedures differ in whether (R)-mandelic acid is used to prepare a mixed anhydride that reacts with the base 1 in an environment of dichloromethane with a yield of approx. 90%. (Zhang Q. L. et al.: Org. Procc. Res. Dev. 2016, 20, 1993.). Or a reaction of (R)-mandelic acid with the base of the amine 1 in DMF in the presence of l-ethyl-3-(3-(dimethylarnino)-propyl)carbodiimide HC1 (EDC), triethylamine and a 1-hydroxybenzotriazole (HBT) is also frequently used (Pradhan N. S. et al., WO 2016024284 A3 (2016)). The yields are also high in this case.

Disclosure of the Invention

During verification of the possibilities of preparation of the compound 1, the procedure of reduction of the nitrile 7 by means of NaBHU and BF₃.Et₂0 was found to be economically the most convenient one. The achieved yields were lower than those presented in the literature (Sucholeiki I. et al. J. Org. Chem. 1988, 53, 98) and amounted to about 80%. However, the main problem was the content of several% of impurities, which had to be removed by multiple crystallization of the hydrochloride of 1.

It has been found out during the work that if mandelate was prepared, a pure product was surprisingly isolated that comprised a lower quantity of individual impurities than 0.1%. It has also been found out that this salt could be used in the next step of formation of the amide 2 without previous conversion of the salt to the base, which considerably facilitates the procedure.

2 (91 %) The invention consists in a method for preparing 4-nitrophenyl ethylamine (1) by reduction of 4-nitrobenzyl cyanide (7) with the use of a borane generated in the reaction mixture from NaBH₄ and BF₃.Et20, characterized in that 4-nitrophenyl ethylamine (1) is isolated from the solution as a mandelate. As a solvent for the reaction, e.g. tetrahydrofuran (THF) can be used. Other usable solvents are e.g. 2-methyl tetrahydrofuran or diethylene glycol dibutylether. It is advantageous to use an excess of BF₃-Et₂0 with respect to NaBFL_t, e.g. a 10% excess, or even more advantageously a 4:3 excess of BF₃ Et₂0 to NaBU . At this proportion of reagents, it will not be necessary to further heat up the mixture to boiling after addition of BF₃-Et₂0 dropwise. To ensure complete reacting of the input nitrile, it is sufficient to continue stirring the reaction mixture, which is heated up by the reaction heat to reflux, without heating, e.g. for 1 h.

The reaction product, the amine 1, can be extracted from the reaction mixture. For the extraction, e.g. dichloromethane, ethyl acetate, isopropyl acetate, butyl acetate, 2-MeTHF, toluene, butanol or anisole can be used. A suitable extraction agent is anisole. Salts with inorganic acids are unsuitable for isolation of the pure amine 1 because the next step of the synthesis is formation of the amide 2. The base would have to be released from the salts of the amine 1 and it would have to be completely free of the organic acid. Otherwise, there would be a risk of contamination of the amide 2 by the amide of this acid. As it has been surprisingly found out, the salt with (i-)-mandelic acid represents an exception. If the amine 1 is isolated in the form of the mandelate 3, the next reaction step can be conducted without isolation of the free base and without addition of more mandelic acid. The salt 3 can be obtained by precipitation with mandelic acid from an ethyl acetate, isopropyl acetate or anisole extract.

The method wherein the product is precipitated by addition of an EtOAc solution of mandelic acid dropwise into an anisole extract at the boiling point of EtOAc and hot filtration has proved to be the most successful. In this case, a product with the best filtration capability is obtained. Just an insignificant fraction of the contaminated salt 3 is obtained from the hot mother liquors after cooling. Compared to the hydrochloride of the amine 1, this salt 3 is easier to be filtered, it is not so sensitive to moisture and better removes impurities from the crude base. In the next stage of the synthesis, the amide 2 can be prepared from the salt 3. To produce the amide bond, e.g. the water-soluble carbodiimide EDC in combination with HBT can be used. The reaction can be conducted e.g. in DMF or preferably in acetonitrile, acetone, EtOAc, toluene or THF. Amide 2 can be advantageously used in the synthesis of pure mirabegron. Examples

Example 1 Preparation of a salt of 4-nitrophenyl ethylamine with mandelic acid (3) To a suspension of NaB¾ (4.7 g, 0.12 mol) in THF (40 mL), a solution of 4-nitrophenyl acetonitrile (20 g, 0.12 mol) in THF (140 mL) was added dropwise at the laboratory temperature and in an inert atmosphere. The dripping device was rinsed with THF (20 mL). After 5 minutes' stirring, ΒΡ₃Έί₂0 (16.3 mL, 18.7 g, 0.132 mol) was added to the suspension dropwise at the laboratory temperature. During the dripping (25 minutes), the reaction mixture was heated up to reflux (60-65°C). The reaction mixture was heated up to boiling for lh and subsequently it was cooled down to 15°C.

Methanol (60 mL) was added to the reaction mixture dropwise in an inert atmosphere at such a rate that the temperature should not exceed 20°C. After 5 minutes' stirring, concentrated HC1 (15.4 mL) was added dropwise at such a rate that the temperature should not exceed 20°C. After 1 hour's stirring at the laboratory temperature, the reaction mixture was concentrated almost until dry and diluted with demineralized water (200 mL). An adapter for extraction of reflux was put on the flask and the reaction mixture was brought to intensive boiling. The reflux was extracted until its temperature achieved 100°C. 50 mL of distillate was collected altogether and the total time of boiling of the reaction mixture was 1 h.

EtOAc (75 mL) was added to the reaction mixture cooled to 15°C and a 50% aqueous solution of NaOH (20 mL) was added dropwise under cooling and at such a rate that the temperature should not exceed 20°C. At the end of the dripping, pH was 10-11. The aqueous (bottom) layer was separated and reextracted with 25 mL of EtOAc. The united organic phases were dried with sodium sulphate and filtered with active carbon CX (1 g). A solution of (R)- mandelic acid (18.8 g, 0.12 mol) in EtOAc (150 mL) was added to the filtrate dropwise at the laboratory temperature during 10 minutes. After 5 minutes' stirring, the suspension was filtered with the use of nitrogen overpressure in the hot state and the filtration cake was washed with EtOAc (2x100 mL).

After drying of the filtration cake in vacuum, the amount of 19.1 g (50%) of light brown powder of the compound 3 with the HPLC purity of 97.5% was obtained. Melting point: 148- 152°C.

Example 2 Preparation of a salt of 4-nitrophenyl ethylamine with mandelic acid (3)

To a suspension of NaB¾ (4.7 g, 0.12 mol) in THF (40 mL), a solution of 4-nitrophenyl acetonitrile (20 g, 0.12 mol) in THF (140 mL) was added dropwise at the laboratory temperature and in an inert atmosphere. The dripping device was rinsed with THF (20 mL). After 5 minutes' stirring, BF₃ Et₂0 (20.5 mL, 23.6 g, 0.17 mol) was added to the suspension dropwise at the laboratory temperature. During the dripping (25 minutes), the reaction mixture was heated up to reflux (60-65°C). The reaction mixture was heated up to boiling for lh and subsequently it was cooled down to 15°C. Methanol (60 mL) was added to the reaction mixture dropwise in an inert atmosphere at such a rate that the temperature should not exceed 20°C. After 5 minutes' stirring, concentrated HC1 (15.4 mL) was added dropwise at such a rate that the temperature should not exceed 20°C. After 1 hour's stirring at the laboratory temperature, the reaction mixture was concentrated almost until dry and diluted with demineralized water (200 mL). An adapter for extraction of reflux was put on the flask and the reaction mixture was brought to intensive boiling. The reflux was extracted until its temperature achieved 100°C. 50 mL of distillate was collected altogether and the total time of boiling of the reaction mixture was 1 h.

After drying of the filtration cake in vacuum, the amount of 19.1 g (50%) of light brown powder of the compound 3 with the HPLC purity of 98.7% was obtained. Melting point: 149- 152°C.

Example 3 Preparation of a salt of 4-nitrophenyl ethylamine with mandelic acid (3)

To a suspension of NaB¾ (4.7 g, 0.12 mol) in THF (40 mL), a solution of 4-nitrophenyl acetonitrile (20 g, 0.12 mol) in THF (140 mL) was added dropwise at the laboratory temperature and in an inert atmosphere. The dripping device was rinsed with THF (20 mL). After 5 minutes' stirring, BF₃ Et₂0 (20.5 mL, 23.6 g, 0.17 mol) was added to the suspension dropwise at the laboratory temperature. During the dripping (25 minutes), the reaction mixture was heated up to reflux (60-65°C). The reaction mixture was stirred until the decrease to the laboratory temperature (lh), then it was additionally cooled down to 15°C.

Methanol (60 mL) was added to the reaction mixture dropwise in an inert atmosphere at such a rate that the temperature should not exceed 20°C. After 5 minutes' stirring, concentrated HC1 (15.4 mL) was carefully added dropwise at such a rate that the temperature should not exceed 20°C. After 1 hour's stirring at the laboratory temperature, the reaction mixture was concentrated almost until dry and diluted with demineralized water (200 mL). An adapter for extraction of reflux was put on the flask and the reaction mixture was brought to intensive boiling. The reflux was extracted until its temperature achieved 100°C. 50 mL of distillate was collected altogether and the total time of boiling of the reaction mixture was 1 h. Isopropyl acetate (75 mL) was added to the reaction mixture cooled to 15°C and a 50% aqueous solution of NaOH (20 mL) was added dropwise under cooling and at such a rate that the temperature should not exceed 20°C. At the end of the dripping, pH was 10-11. The aqueous (bottom) layer was separated and reextracted with 25 mL of isopropyl acetate. The united organic phases were dried with sodium sulphate and filtered with active carbon CX (1 g). A solution of (i-)-mandelic acid (18.8 g, 0.12 mol) in EtOAc (150 mL) was added to the filtrate dropwise at the laboratory temperature during 10 minutes. After 5 minutes' stirring under boiling, the suspension was filtered with the use of nitrogen overpressure in the hot state and the filtration cake was washed with EtOAc (2x100 mL). After drying of the filtration cake in vacuum, the amount of 19.1 g (50%) of yellowish powder of the compound 3 with the HPLC purity of 95.4% was obtained. Melting point: 145-151°C.

Example 4 Preparation of a salt of 4-nitrophenyl ethylamine with mandelic acid (3)

To a suspension of NaB¾ (4.7 g, 0.12 mol) in THF (40 mL), a solution of 4-nitrophenyl acetonitrile (20 g, 0.12 mol) in THF (140 mL) was added dropwise at the laboratory temperature and in an inert atmosphere. The dripping device was rinsed with THF (20 mL). After 5 minutes' stirring, BF₃-Et₂0 (20.5 mL, 23.6 g, 0.17 mol) was added to the suspension dropwise at the laboratory temperature. During the dripping (25 minutes), the reaction mixture was heated up to reflux (60-65°C). The reaction mixture was stirred until the decrease to the laboratory temperature (lh), then it was additionally cooled down to 15°C.

Butan-l-ol (75 mL) was added to the reaction mixture cooled to 15°C and a 50% aqueous solution of NaOH (20 mL) was added dropwise under cooling and at such a rate that the temperature should not exceed 20°C. At the end of the dripping, pH was 10-11. The aqueous (bottom) layer was separated and reextracted with 25 mL of butan-l-ol. The united organic phases were azeotropically dried and filtered with active carbon CX (1 g). A solution of (R)- mandelic acid (18.8 g, 0.12 mol) in EtOAc (150 mL) was added to the filtrate dropwise at the laboratory temperature during 10 minutes. After 5 minutes' stirring under boiling, the suspension was filtered with the use of nitrogen overpressure in the hot state and the filtration cake was washed with EtOAc (2x100 mL).

After drying of the filtration cake in vacuum, the amount of 14.5 g (38%) of yellowish powder of the compound 3 with the HPLC purity of 99.1% was obtained. Melting point: 150-153°C. Example 5 Preparation of a salt of 4-nitrophenyI ethylamine with mandelic acid (3)

To a suspension of NaBFL; (4.7 g, 0.12 mol) in THF (40 mL), a solution of 4-nitrophenyl acetonitrile (20 g, 0.12 mol) in THF (140 mL) was added dropwise at the laboratory temperature and in an inert atmosphere. The dripping device was rinsed with THF (20 mL). After 5 minutes' stirring, BF₃ Et₂0 (20.5 mL, 23.6 g, 0.17 mol) was added to the suspension dropwise at the laboratory temperature. During the dripping (25 minutes), the reaction mixture was heated up to reflux (60-65°C). The reaction mixture was stirred until the decrease to the laboratory temperature (lh), then it was additionally cooled down to 15°C.

Anisole (75 mL) was added to the reaction mixture cooled to 15°C and a 50% aqueous solution of NaOH (20 mL) was added dropwise under cooling and at such a rate that the temperature should not exceed 20°C. At the end of the dripping, pH was 10-11. The aqueous (bottom) layer was separated and reextracted with 25 mL of anisole. The united organic phases were azeotropically dried (70°C/50 mbar) and in the hot state (70°C) they were filtered with active carbon CX (1 g). A solution of (i?)-mandelic acid (18.8 g, 0.12 mol) in EtOAc (150 mL) was added to the filtrate, the temperature being maintained at 80°C, during 10 minutes. After 5 minutes' stirring under boiling, the suspension was filtered with the use of nitrogen overpressure in the hot state and the filtration cake was washed with EtOAc (2x100 mL).

After drying of the filtration cake in vacuum, the amount of 25.6 g (67%) of yellowish powder of the compound 3 with the HPLC purity of 99.3% was obtained, the contents of individual impurities being lower than 0.1 % (HPLC). Melting point: 152-154°C.

1H-NMR (399.9 MHz, DMSO- ₆) 6: 8.15 (d, 2H, J = 8.6 Hz), 7.47 (d, 2H, J = 8.6 Hz), 7.38 (d, 2H, J= 7.6 Hz), 7.26-7.20 (m, 2H), 7.17-7.12 (m, 1H), 4.57 (s, 1H), 3.05-2.90 (m, 4H), 2.50 (DMSO-i/₆), NH₃ ⁺, OH and protons of water were not visible. ¹³C-NMR (100.56 MHz, DMSO-i¾) 6: 175.1, 146.3, 146.0, 143.5, 130.0, 127.3, 126.2, 126.1, 123.5, 73.4, 39.4 (DMSO-</₆), 39.3, 33.1.

Example 6 Preparation of mandelic acid 4-nitrophenyl ethylamide 2

To a suspension of the salt 3 (3.18 g) in DMF (7.6 mL), triethylemine (1,4 mL), HBT (1.36 g) and EDC (2.05 g) were gradually added. The reaction mixture was stirred until the reaction of the input substance was completed (24 h). After this time period, demineralized water (35 mL) was poured into the reaction mixture. After cooling with ice, a solid substance was separated, which was filtered off, washed with demineralized water (10 mL), diluted HC1 1:10 (5 mL) and demineralized water (2x10 mL). After drying in vacuum, the amount of 2.31 g (77%) of 4- nitrophenyl ethylamide mandelic acid 2 was obtained. HPLC purity of the product was 99%. Melting point: 101-113°C (lit. (WO2014/132270 A2) mentions 105-115°C).

Example 7 Preparation of mandelic acid 4-nitrophenyl ethylamide 2

To a suspension of the salt 3 (3.18 g) in acetonitrile (32 mL), triethylemine (1.4 mL), HBT (1.36 g) and EDC (2.05 g) were gradually added. The reaction mixture was stirred until the reaction of the input substance was completed (24 h). After this time period, the reaction mixture was concentrated until dry and the evaporation product was stirred up in cold demineralized water (35 mL). After inoculation with a crystalline amide 2, a solid substance was separated, which was filtered off, washed with demineralized water (5 mL), diluted HC1 1 : 10 (5 mL) and demineralized water (2x5 mL).

After drying in vacuum, the amount of 2.43 g (81%) of 4-nitrophenyl ethylamide mandelic acid 2 was obtained. HPLC purity of the product was 99%. Melting point: 104-115°C (lit. (WO2014/132270 A2) mentions 105-115°C).

Example 8 Preparation of 4-nitrophenyl ethylamide mandelic acid 2

To a suspension of the salt 3 (3.18 g) in acetonitrile (32 mL), triethylemine (1.4 mL), HBT (1.36 g) and EDC (2.05 g) were gradually added. The reaction mixture was stirred until the reaction of the input substance was completed (24 h). After this time period, the reaction mixture was concentrated until dry and the evaporation product was divided between EtOAc (30 mL) and demineralized water (30 mL). The aqueous layer was separately extracted with EtOAc (10 mL). The united organic layers were washed with 1M HC1 (5 mL), a 5% solution of K2CO3 (5 mL), demineralized water (10 mL) and concentrated in vacuum at a temperature of20°C.

The evaporation product was dissolved in toluene (15 mL) in a hot state (90°C) and azeotropically dried. Free cooling under stirring resulted in separation of crystals of the product. After spontaneous cooling down to the laboratory temperature, the suspension was cooled with icy water to 5°C, aspirated, the filtration cake was washed with 3 mL of toluene and dried in vacuum (50°C).

After drying in vacuum, the amount of 2.5 g (83%) of 4-nitrophenyl ethylamide mandelic acid 2 was obtained. HPLC purity of the product was 99.3%. Melting point: 108-116°C (lit. ( O2014/132270 A2) mentions 105-115°C).

Example 9 Preparation of 4-nitrophenyl ethylamide mandelic acid 2

To a suspension of the salt 3 (25 g, 78.5 mmol) in EtOAc (187 ml), triethylamine (11 mL, 8 g, 78.5 mmol), HBT (10.6 g, 78.5 mmol) and EDC (16.6 g, 86.6 mmol) were gradually added. The reaction mixture was stirred until the reaction of the input substance was completed (approx. 10 h). After this time period, demineralized water (100 mL) was poured into the reaction mixture and concentrated HC1 (7.5 mL) was added dropwise. The aqueous (bottom) layer was separated and reextracted with EtOAc (30 mL). The united organic layers were washed with 1M HC1 (50 mL), a 5% solution of K2CO3 (50 mL), demineralized water (50 mL) and concentrated in vacuum at a temperature of 20°C.

The evaporation product was dissolved in toluene (90 mL) in a hot state (90°C) and azeotropically dried. Free cooling under stirring resulted in separation of crystals of the product. After spontaneous cooling down to the laboratory temperature, the suspension was cooled with icy water to 5°C, aspirated, washed with 25 mL of toluene and dried in vacuum (50°C).

The amount of 21.5 g (91%) of yellowish crystals of the amide 2 with HPLC purity of 99.8% was obtained, an individual impurity not exceeding 0.1%. Melting point: 108-116°C (lit. (WO2014/132270 A2) mentions 105-115°C).

1H-NMR (399.9 MHz, DMSO-i/₆) δ: 8.10-8.05 (m, 3H), 7.39 (d, 2H, J= 8.7 Hz), 7.36-7.23 (m, 5H), 6.16 (d, 1H, J= 4.7 Hz), 4.85 (d, 1H, J= 4.7 Hz), 3.46-3.30 (m, 2H), 3.33 (H₂0), 2.87 (t, 2H, J= 7.2 Hz), 2.50 (DMSO-< ₆). ^I3C-NMR (100.56 MHz, DMSO-<¼) 5: 172.0, 147.8, 145.9, 141.2, 130.0, 127.7, 127.2, 126.4, 123.1, 39.4(DMSO-<¾, 38.9, 34.6

Claims

1) A method of preparing 4-nitrophenyl ethylamine (1) by reduction of 4-nitrobenzyl cyanide (7) in a solvent with the use of a borane generated in-situ in the reaction mixture from NaBHU and BF3.Et₂0, characterized in that 4-nitrophenyl ethylamine (1) is isolated from the solution as the mandelate 3.

2) The method according to claim 1, characterized in that the resulting 4-nitrophenyl ethylamine (1) is extracted from the reaction mixture.

3) The method according to claim 1, characterized in that the resulting 4-nitrophenyl ethylamine (1) is extracted from the reaction mixture by means of anisole.

4) The method according to claim 1 , characterized in that the mandelate (3) is precipitated from the reaction mixture.

5) The method according to claim 4, characterized in that ethyl acetate is used as the solvent for the precipitation of the mandelate.

6) The method according to claim 4, characterized in that the filtration of the precipitated mandelate is carried out in a hot state. 7) A method for preparing mandelic acid 4-nitrophenyl ethylamide 2, characterized in that a reaction of 4-nitrophenyl emylamine mandelate 3 with l-ethyl-3-(3- dimethylamino)propyl)carbodiimide hydrochloride, triethylamine and 1- hydroxybenzotriazole is conducted in ethyl acetate.

8) A pure intermediate, 4-nitrophenyl ethylamide mandelic acid (2) with a purity of at least 97%.

9) The pure intermediate according to claim 8, prepared by the method of claim 7 with the use of the mandelate (3) obtained by the method of claim 1, which can be advantageously used in the synthesis of pure mirabegron.