HU231124B1 - Method for producing morphologically homogenous mirabegron and mirabegron monohydrochloride - Google Patents

Description

Process for the preparation of morphologically uniform mirabegron and mirabegron monohydrochloride

The present invention relates to

The present invention relates to a process for the preparation of (R) -2- (2-aminothiazol-4-yl) -4 '- [2 - [(2-hydroxy-2-phenyl) ethylamino] ethyl] acetanilide (mirabegron)

and mirabegron monohydrochloride of formula le

1c and the use of intermediates in the process for the preparation of mirabegron.

State of the art

Mirabegron 1 is a selective β3 agonist for the treatment of hyperactive bladder syndrome.

Known syntheses are generally multi-step, not technologically and economically advantageous.

SZTHKMÖ0248294

WO 99020607 discloses the preparation of the mirabegron dihydrochloride salt of formula 1b according to Scheme 1 below.

Scheme I.

One of the steps in the process is the reaction of 4mitrofenetham with optically active styrene oxides of formula 9. to clean, which is uneconomical on an industrial scale and difficult to implement for larger batch sizes. Due to the low yield and the high price of active aztirol oxide, it is not suitable for the industrial production of mirabegron. The use of protective groups also results in an additional operational step.

A key step in the process used in Chinese Patent Application CN 103896872 is the sulfur oxide reaction outlined in Scheme 1, which has the disadvantage that reacting the optically active styrene oxide of formula 9 with a primary amine yields three different, comparable amounts of product. it is recoverable and difficult to clean, so much of the expensive styrene oxide is waste.

In several patent applications - WO 2003037881, CN 104016943, CN 104016877 - mirabegron is prepared from mandelic acid or mandelic acid ester instead of silage oxide.

According to the process disclosed in Chinese Patent Application CN 103387500, an optically active styrene oxide 9 is used to prepare (R) -2- [benzyl (4-nitrophenethyl) amino] -b-phenylethanol 4. Said No. 9 styrene oxide is an extremely expensive reagent. Isomeric compounds formed during ring opening appear as potential contaminants in the reaction sequence, thus also contaminating the final product to varying degrees (Scheme 2).

Scheme 2

Indian Patent Application No. 3843 / CHE / 2012 discloses a powder X-ray form of mirabegron monohydrochloride, presumably containing water (referred to as Form R), and an isopropyl acetate solvate of mirabegron containing a base (referred to as Form S). No mention is made of the exact stoichiometry or the uniformity of these compositions.

International Patent Application Publication No. WO 2014132270 describes the preparation and preparation of mirabegron monohydrochloride.

Several syntheses of mirabegron are discussed in the Practical Synthesis of Mirabegron (J. Chem. Pharm. Res. 2015, 7, 1473-1478), however, none of the methods disclosed there provide productions and benefits that are realistically feasible in industry.

According to the process disclosed in Chinese Patent Application No. CN 104876890 (Scheme 3), the product obtained by reacting 4-nitrophenethylamine with racemic styroboxide 10 is resolved, and after hydrogenation, (7) -2- (4- aminophenethyl) amino-1-phenylethanol, a disadvantage of the process.

Scheme 3

Brief Summary of the Invention

The aim of the process according to the invention is to obtain a new industrial product which can be carried out under normal reaction conditions without toxic auxiliaries and which can be carried out in critical steps through crystalline and well-purified intermediates. It has also been possible to develop a synthetic process for the preparation of mirabegron of formula 1 which is also feasible.

Surprisingly, if the following sequence of synthesis is shown in Scheme 4 below, i.e., the racemic 2 - (benzyl ( 4-nitrophenethyl) amino) -1-phenylethanol, which is then resolved with (Z) -mandelic acid 6 to give (A) -2- [benzyl (4-trifluoromethyl) amino] -1-phenylethanol 4a mandelic acid salt and then liberating the base from the salt 4a to give the desired optically active compound 4, which is catalytically hydrogenated to give the amoethanol 2 and then the aminoethanol 2 to the 2-aminothiazole II acetic acid 3. If mimbregron 1 is prepared and then, if appropriate, mirabegron monohydrochloride le, the target is achieved.

Scheme 4

It is particularly surprising that resolution with mandelic acid in the presence of ethyl acetate at 40-50 ° C in a single crystallization step, without further purification, gives a diastereomeric salt in which the desired enantiomer is isolated as a salt with extremely high selectivity, 98.9%. that is, a very high degree of enantiomeric purification occurs. This is not expected in the light of those described in the literature (Id. F. Faigl, E. Fogassy, M. Nógrádi, E. Pálovics, J. Schindler, Tetrahedron: Asymmetry, 2008, 19, 519-536),

The present invention relates to a process for the preparation of mirabegron of formula 1. The process is characterized in that the racene of formula 5 is prepared by reacting 2-benzyl (4-nitrophenethyl) amino] -1-phenylethanol in a solvent with a mandelic acid or by reacting a salt of the compound of formula 5 with a salt of mandelic acid. [benzyl (4-trophenethyl) amino] -4 and then 4 is converted in one step to (N) -2- (4-aminophenethyl) amino-1-femW and 2 is converted to the 2-compound. Mirabegron base 1 is prepared by reaction with ammonothiazolyl acetic acid.

In a preferred embodiment of the process according to the invention, the conversion of compound 4 to compound 2 is preferably carried out by catalytic hydrogenation.

In another preferred embodiment of the process of the invention, the racemic 2- [benzyl (4-nitrophenethyl) amino] -1-phenylethanol of formula 5 is reacted with the compound of formula 6 (Xj-mandelic acid).

OH X ^OH oh

or a salt of the compound of the formula 5 is reacted with a salt of the?

releasing the optically active base 4 in a known manner.

In a further preferred embodiment of the process according to the invention, the racemic 2- [benzyl (4-nitrophenethyl) amino] -1-phenylethanol of the formula 5 is reacted with the (S) -mandelic acid of the formula 7.

OH

or a salt of the compound of formula 5 is reacted with a salt of Sj-mandelic acid of formula 7 and the crystallized salt of Sj-mandelic acid of formula 8a is crystallized.

After removal, the desired compound of formula 4 is recovered from the mother liquor and purified if necessary.

In a further preferred embodiment of the process according to the invention, the salt of the compound of formula 5 is the hydrochloride, hydrobromide, sulphate, dihydrogen phosphate salt or salt with organic acids, including acetic acid, propionic acid, benzoic acid, preferably the hydrochloride or acetate salt.

In a further preferred embodiment of the process according to the invention, the salt of the mandelic acid of the formula 6 or 7 is the sodium, potassium or ammonium salt, preferably the sodium salt.

In a further preferred embodiment of the process according to the invention, the solvent used in the resolution is a C1-C6 straight-chain or branched alcohol, preferably a C1-C4 aliphatic alcohol, esters of C1-C4 carboxylic acids with C1-C4 alcohols, acetonitrile, tetrahydrofuran, dioxane , toluene, t-butyl methyl ether, diisopropyl ether, water, or any mixture of two or more thereof.

In a further preferred embodiment of the process according to the invention, the solvent used in the resolution is acetonitrile, isopropyl acetate or ethyl acetate, preferably ethyl acetate.

In a further preferred embodiment of the process according to the invention, the temperature used during the resolution is 40-50 ° C, preferably 43-45 ° C.

In a further preferred embodiment of the process according to the invention, the ratio of mandelic acid 6 or 7 to 5 in the resolution is 0.1 to 1 molar equivalent, preferably 0.5 to 1.0 molar equivalent, most preferably 0.6 to 0.8 molar equivalent.

In a further preferred embodiment of the process according to the invention, the temperature range used for the crystallization of the salts 4a and 8a is -50 ° C to + 120 ° C, preferably -20 ° C to + 60 ° C.

The invention further provides the use of racemic 2- [benzyl (4-nitrophenethyl) amino] -1-phenylethanol in the preparation of mirabegron 1.

The invention further relates to the use of a salt of formula 4a (R> mandelic acid) for the preparation of mirabegron of formula I.

The invention further provides (S) -2- [benzyl (4-nitrophenethyl) amino] -1-phenylethanol of formula 8.

and the use of the (5) -mandelic acid salt of formula 8a for the preparation of mirabegron of formula 1.

DETAILED DESCRIPTION OF THE INVENTION

Our process is summarized in Scheme 4 above.

As a first step, the known and readily available 11 A-benzyl-4-mitrophenethylmin

and cheap and readily available racemic styrene oxide

our racemic 2- (benzyl- (4-nitrophenethyl) -femlethanol intermediate 5 was prepared.

which is new. a compound not yet described in the literature.

As a second step, (R) -2- [benzyl (4-nitrophenethyl) amino] -1-phenylethanol 4 was prepared by resolving the racemic compound 5.

The resolution can be performed with optically active acids by formation of diastereomeric salt pairs.

OH

wherein the desired isomer of formula 4 is a salt of (A) -mandelic acid of formula 4a

crystalline from the system, with good yield and high optical purity, i.e. very low enantiomeric impurity 8

triggers. The salt 4a is then liberated to give the desired optically active compound 4.

The third step in the process is the catalytic hydrogenation of the compound of formula 4 to give the (R) -2- (4-aminophenethyl) amine of formula 2.

.4 as a final step in the preparation of mirabegron, the compound of formula 2 is reacted with the 2-aminothiazolyl acetic acid blank of formula 3.

Η ₂ Ν ~ ζ J f

N

It is extremely important to react the above compound of formula 2 in the purest chemical and optical form possible, since the impurities of the latter determine the purity of the final product.

Alternatively, the above resolution step may be performed by reacting a compound of formula 5 with an almond of formula 7.

then after removal of the diastereomeric salt of formula 8a

8a The desired compound of formula 4 is recovered from the mother liquor and purified if necessary.

In Formula 8 above, an optical rotation of (a] ^ _s ~ ₀ + 22.7 ° (c 1, ethanol).

The characteristics of the diastereomeric salt of formula 8a as determined by structural analysis methods are as follows:

¹ HNMR (δOO, DMSO-d ₆ ): 8.07 (d,> 8.7Hz, 2H); 7.42 (-dd, 2 H); 734 (te, 2 H); 7.33 (-d, 2 H); 7.28 (m. 3H); 7.26 (2H); 7.23 (m, 1 H); 7.22 (m. 2H); 720 (m, 1 H); 7.16 (fd, 2H); 5.01 (s, 1 H); 4.68 (dd, J1-73Hz, J2-5.6Hz, 1H); 3.76 (d,> 13.9Hz, 1H); 3.69 (d, JM 3.9 Hz, 1H); 2.83 (te. 2H); 2.74 (te. 2H); 2.70 (dd, Jh43.2Hz, J2-7.3Hz, 1H); 2.65 (dd, JW3.2Hz, J2-5.6Hz, 1H)

CNMR (a600, in DMSO): 174.33; 149.48; 145.95; 144.88; 140.51; 13932; 130.23; 128.87; 12831; 128.18; 128.04; 127.81; 126.99; 126.93; 126.83: 126.40; 123.37; 72.59; 70.86; 61.88; 58.25; 55.09; 32.52

Alternatively, any salt of mandelic acid 6 or 7 may be reacted with a salt of compound 5 and crystallized from the diastereomeric salt 4a or 8a after any removal of the salt. The salt of the mandelic acid of formula 6 or 7 is in this case any alkali metal salt or ammonium salt, preferably the sodium, potassium or ammonium salt, preferably the sodium salt. The salt of the compound of formula 5 is a salt with any hydrogen halide, preferably hydrochloride or hydrobromide, or a salt with any monohydric organic acid, preferably acetate, or a salt with one or more polyvalent inorganic acids, preferably sulfate, dihydrogen phosphate.

Examples of monovalent organic acids are acetic acid, propionic acid and benzoic acid. The compound of formula 5. its salt is preferably the hydrochloride or acetate salt.

In the reaction of the compound of the formula 5 with both the (R) -mandelic acid of the formula 6 and the mandelic acid of the formula (5) 7, the solvent used may be a straight-chain or branched alcohol having a C1-C8 carbon number, preferably a C1-Q aliphatic alcohol, C1 Esters of C1-C4 carboxylic acids with C1-C4 alcohols, acetonitrile, tetrahydrofuran, diosane, toluene, t-butyl methyl ether, diisopropyl ether, water or any mixture of two or more of the above solvents. Preferred solvents are acetomethyl, isopropyl acetate and ethyl acetate, with ethyl acetate being most preferred.

The 6th resp. The useful ratio of mandelic acid 7 to 5 is 0.1 to 1 molar equivalent, preferably 0.5 to 1.0 molar equivalent, most preferably 0.6 to 0.8 molar equivalents. In an amount of 0 to 0.9 molar equivalents, preferably 0 to 0.5 molar equivalents, most preferably 0.2 to 0.4 molar equivalents. The latter achiral acids can be low-carbon organic acids, preferably formic acid, acetic acid, propionic acid, most preferably acetic acid. The temperature range used for crystallization of the salts of formula 8a is -50 ° C to + 120 ° C, preferably -20 ° C to + 100 ° C, most preferably -20 ° C to + 60 ° C, most preferably.

In the mirabegron obtained according to our method, the 12

and 13 compounds

as potential contaminants may occur, the determination of these in mirabegron is within the skill of the art. Compounds 12 and 13 can be used as analytical standards.

In our experiments, we found that the resolution of the enantiomeric salt during resolution with other chiral acids did not meet the expectations and that the treatment of the diastereomeric salt was difficult. Unexpectedly, it has been found that the diastereomeric salt of mandelic acid is crystallized with a suitable solvent in a suitable temperature range to give a material which is highly enantiomerically pure.

In our procedure, the monohydrochloride salt of formula le was prepared from the mirabegron base of formula 1 with hydrochloric acid in a manner described in Table 1 below. The most characteristic peaks of the compound of formula le are: 20 (± 0.2 ° 20): 2.15; 4.33; 8.68; 17.66; 19.59; 21.57: 24.77; 25.47; even more characteristic peaks are as follows: 20 (± 0.2 ° 20): 2.15; 19.59; 24.77; 25.47.

The characteristic X-ray powder diffractogram of mirabegron monohydrochloride 1c is shown in Figure 1, and signals with an intensity of 1% or greater are summarized in Table 1 below.

.spreadsheet

Position and relative intensities (> 1%) of X-ray powder diffraction peaks characteristic of mirabegron monohydrochloride 1c

Apex 2Ö (°) d (Á) Relative intensity (%) 1 2.15 41.09 17 2 4.33 20.40 5 3 6.51 13.58 4 4 8.68 10.19 11 5 13.04 6.79 1 6 17.11 5.18 7 7 17.66 5.02 28 8 18.06 4.91 4 9 18.37 4.83 1 10 18.72 4.74 4 11 19.59 4.53 89 12 20.32 4.37 13 13 21.57 4.12 16 14 23.02 3.86 3 15 24.04 3.70 3 16 24.77 3.59 100 .17 25.47 3.50 31 18 26.53 3.36 5 19 27.39 3.26 11 20 28.52 3.13 1 21 29.05 3.07 6 22 30.31 2.95 5 23 31.69 2.82 3 24 32.97 2.72 8 25 34.66 2.59 7

The X-ray powder diffraction data reported in the present application were obtained under the following measurement conditions:

Apparatus: PANalytical Empyrean X-ray powder diffractometer

Measurement layout: Transmission

X-ray tube Type: Empyrean is a long fine-focus, high-resolution tube Anode; Cu Wavelength: Focus: Ka (1.541874 Å) line focus Source-side optical element Divergence gap: Mirror: ek Fixed gap 1/2 ^a Focusing elliptical mirror Soller gap: Anti-scatter gap: 0.04 for you Fixed gap 1/2 *

Diffractal side optical elements

Anti-scatter gap: Soller gap: Programmable slot in fixed mode; 1/2 ° 0.04 wt

Sample table Type: With reflection-transmission, rotatable sample holders

Sample rotation speed; 1 rpm Direct beam clamp

("Beam knife"); Transmission Detector Type; Mode: PIXcel 3D 1 x 1 area detector Scanning line detector (1D) mode Active detector window size: Mmtae preparation: 3,3473 * inserting samples between two Mylar foils without powdering Measurement conditions Temperature: room temperature G yomi lake voltage: Anode arc voltage: 45 kV 40 mA Scan mode: Measuring range: Step: continuous (0/0) scan 2.0000 - 34.99640 20 0.013 Γ 20 One step time: 109,650 seconds Number of measuring cycles: Measurement time: -20 minutes

A typical DSC curve for mirabegron monohydrochloride is shown in Figure 2.

Conditions for differential scanning calorimetry (DSC) measurement

Appliance:

Atmosphere:

Sampling frequency:

Temperature program:

Jar:

TA Instruments Discovery DSC Differential Scanning Calorimeter Flowing Na (50 mL / min)

0.1 second / dot ° C-235 ⁹ C WX / min

Hermetically sealed. Fake

The advantage of the process according to the invention is that the desired product can be obtained by simple crystallization steps, without the use of toxic solvents, reagents or auxiliaries, in an environmentally friendly, efficient, easy-to-implement and economical way.

The advantage of the resolution process according to the invention is that, under the conditions used, a product of extremely high chemical and optical purity is obtained in a high yield in a crystallization step, so that the final product mirabegron and the mirabegron monohydrochloride salt obtained therefrom are pure.

Further details of the invention are given in the following examples without limiting the scope of the invention in any way.

Example 1 Preparation of 2- (benzo (4-niphenophenyl) amino) methylethanol of formula 5

Dissolve 11.25 g (40 mmol) of A-benzyl-4-methophenethylamine 11 in 120 ml of butanol, add 6.24 g (52 mmol) of racemic styrene oxide 10 and stir at reflux. until the starting compound 11 is depleted. The reaction mixture was cooled, stirred at 4-5 ° C, the precipitate was filtered off and washed twice with hutanol. 8.14 g (21.6 mmol; 54%) of crystals are obtained. M.p .: 60-62 ° C.

¹ H-NMR (DMSO-d 6; 600 MHz): 8.07 (d,> 8.6 Hz. 2H); 733 (d,> 8.6 Hz, 2 H); 7.28 (fet, 2H); 7.25 (2H); 7.23 (fet, 1H); 7.21 (fet, 2H): 7.19 (m, 1H); 7.16 (2H); 5.00 (br d,> 3.1 Hz, 1H): 4.68 (m, 1H): 3.75 (d,> 13.8 Hz, 1H); 3.68 (d,> 13.8 Hz, 1H); 2.82 (fet, 2H); 2.73 (fet, 2H); 2.69 (dd,> 43.2 Hz, J ₂ -7.3 Hz, 1H); 2.64 (dd, h-13.2 Hz,> = 5.6 Hz, 1H).

Example 2

A4a) _: 2 _: benzoylphenylphenyl) amino] phenyl

To a 45 ° C solution of 2- [benzyl (4-nitrophenethyl) amino] -1-phenylethan (75.2 g, 0.20 mol) in ethyl acetate (310 mL) was added 21.3 g (0.14 mol). (R) - (-) - mandelic acid 6 followed by 99% acetic acid (3.72 g, 0.062 mol). The resulting mixture was stirred for 1 hour, then the suspension was cooled to about 0 ° C and stirred for an additional 3 hours. The crystals were filtered off and washed on the filter with cold ethyl acetate-DIPE (ki). Drying gave 48.3 g (0.091 mol; 91% based on half of the starting racemate) of the title compound as white crystals. (Isomer A: 1.1%.

IR (KBr): 3426; 3062; 1598: 1518; 1494; 1453: 1392; 1348; 1317; 1185; 1085; 1061; 746; 735; 698 1 HNMR (α100, DMSO-d 4: 8.07 (d,> 8.6Hz, 2H); 7.42> dd, 2H); 7.34 (A, 2 H); 7.34 (d, 2 H); 7.29 (m. 3H); 7.26 H, 2 H); 7.23 (m, 1 H); 7.22 (m. 2H); 7.20 (m, 1 H); 7.17 (-dd, 2Hk 5.01 (s, 1H)): 4.68 (Λ 1H), 3.76 (d,> 13.8Hz, 1H), 3.69 (d,> 13.8Hz, 1H), 2.83 (A, 2H), 2.74 ( A, 2H); 2.70 (dd, J> 13 »2Hz, J2 ~ 7.4Hz, 1H); 2.65 (dd, J1M3.2Hz, J2-5.5Hz, 1H) CNMR (a600, DMSO-d6): 174.33; 149.48 ; 145.95; 144.87; 140.51; 139.31; 130.23; 128.88; 128.32: 128.19: 128.04; 127.81; 126.99; 126.93; 126.84; 126.40; 123.37; 72.60; 70.86; 61.88; 58.26: 55.09;

Example 3 Preparation of (R) -2-benzyl (4-Ritrophenethyl) methanol-1-phenylethanol (4)

The diastereomeric salt 4a (15.9 g, 30.0 mmol) obtained in Example 2 was suspended in ethyl acetate (150 ml), stirred with aqueous NaOH (50 ml) and the organic layer was washed, dried and evaporated. 11.4 g of pale beige are obtained.

Example 4 Preparation of Formula 2 (1b-2- (4-aminopheneth) 8-am

28.2 g (75 mmol) of (R) -2- [benzyl (4-methophenethyl) amino] -1-phenylethylol (4a) are suspended in 280 ml of methanol, 1.13 g of 10% palladium on carbon are added and the mixture is hydrogenated at room temperature. The catalyst was filtered off and the methanolic solution was evaporated. To the residue were added methanol and diisopropyl ether. The suspension was stirred at an internal temperature of 50 ° C for 1 hour and then cooled to room temperature. The material was filtered off and washed with diisopropyl acetate. After drying, 16.77 g of white crystals 2 are obtained. M.p .: 101-103 ° C. This was suspended in water and stirred for 3 hours after the addition of triethylamine. The material is filtered off and washed with water. Drying gave 16.14 g (63 mmol, 84%) of the title compound as white crystals. Op .: 102-103 ^<S C.

Example 5

(? /) Of the formula le - 2- (2-aminothiazol-4-yl) -4-K2 ^is -L2-hydroxy-2-phenyl) ethylamino | ethyl acetanilide monohydrochloride (mirabegron monohydrochloride) Preparation of

Mirabegron base (1) obtained by the known method (EP 1440969) from 15 from 15 (15.0 g, 37.8 mmol) in 2-propanol (210 ml) was heated to 75 ° C and 6.80 ml (37%) was added. 5 mmol) in a 5.52 M HCl / 2-propanol solution. After stirring for 15 minutes, the resulting crystalline mixture was cooled to room temperature and the precipitate was filtered off. After drying, 16.15 g (37.3 mmol; 99%) of the title compound are obtained. Mp 221-223 ° C. (Figures 1 and 2)

Elemental analysis

Calculated: C 58.26%, H 5.82%, N 12.94%, S 7.40%, Cl 8.19%.

Found: C 58.11%, H 5.78%, N 12.86%, S 7.41%, Cl 8.20%.

Example 6

Preparation of (2J-hydroxy-2-phenylacetyl-4M2-1 (2H) -hydroxy-2-phenyl) ethylaminomethylacetamd impurity 12

(0.77 g, 3 mmol) of (k) -2- (4-aminophenethyl) amino-1-phenylethanol (2) are suspended in 9 ml of water, 1.5 ml of 2.02 M hydrochloric acid and 0.46 g ( 3 mmol) (7?) - mandelic acid (6). After stirring briefly, 0.63 g of EDC hydrochloride was added and the mixture was stirred at room temperature. The hydrochloride of the title compound is filtered off, washed with water and, after drying, recrystallized from aqueous ethanol.

¹ H-NMR (DMSO-d 6; 600 MHz): 10.02 (s, 1H); 8.99 (br. 2H); 7.66 (d, J = 8.6 Hz, 2 H); 7.51 (~ d, 2 H); 7.39 (m. 4H); 7.35 (lake, 2 H); 7.31 (m, 1 H); 7.28 (lake, 1H): 7.17 (d, J = 8.6 Hz, 2H); 6.45 (d, J = 4.9 Hz, 1 H); 6.21 (br d, 1 = 4.1 Hz, 1 H); 5.11 (d, J = 4.9 Hz, 1 H); 4.97 (m, 1 H); 3.15 (m, 1 H); 3.14 (m. 2H); 3.01 (dd, J ₁ = 12.5 Hz, J 2 = 10.6 Hz, 1H); 2.94 (m. 2H).

Example 7

13 The formula (25) -hydroxy-2-phenylacetyl-4 -f2- ^l | (2.ff) -hydroxy-2-phenyl) etnamino] etinacetamIid impurity Preparation

(R) -2- (4-Amophenethyl) amino-1-phenylethanol (2) (0.77 g, 3 mmol) was suspended in water (9 mL) and 2.02 M hydrochloric acid (1.5 mL) was added with stirring. (3 mmol) of (S) -mandelic acid (7). After stirring briefly, 0.63 g of EDC hydrochloride was added and the mixture was stirred at room temperature. The hydrochloride of the title compound is filtered off, washed with water and, after drying, recrystallized from aqueous ethanol.

1 H-NMR (DMSO-d ₆ ; 600 MHz): 10.01 (s, 1H); 8.99 (br. 2H); 7.66 (d, J = 8.5 Hz, 2H): 7.51 (d d, 2H); 7.38 (m. 4H); 7.35 (lake, 2 H); 7.31 (m, 1 H); 7.28 (lake, 1 H); 7.17 (d, J = 8.5 Hz, 2 H); 6.45 (d, J = 4.7 Hz, 1 H); 6.19 (br. 1H); 5.11 (d, J = 4.7 Hz, 1 H); 4.96 (m, 1 H); 3.13 (m, 3 H); 3.00 (m, 1 H); 2.93 (m. 2H).

Claims (14)

Patent claims A process for the preparation of mirabegron of formula 1, characterized in that the racemic 2- [benzyl (4-nitrophenethyl) amino] -1-phenylethanol of formula 5 (S) -2- [benzyl (4-nitrophenethyl) amino] -1-phenylethanol in a solvent, by reaction with mandelic acid or by reacting a salt of the compound of formula 5 with a salt of mandelic acid, then converting the compound of formula 4 to the (R) -2- (4-aminophenethyl) amino-1-phenylethanol of formula 2 in one step, then the compound of formula 2 SZTNH-100267060 reacted with 2-aminoazolyl acetic acid 3 ΗχΝ <J ^N 'OH prepared mirabegron the formula I base. Process according to Claim 1, characterized in that the conversion of compound 4 to compound 2 is preferably carried out by catalytic hydrogenation. Process according to Claim 1 or 2, characterized in that the racemic 2- [benzyl (4-nitrophenethyl) amino] -1-phenylethanol of the formula 5 is reacted with the (Sj-mandelic acid of the formula 6) OH. 4a releases the optically active base 4 in a known manner. Process according to Claim 1 or 2, characterized in that the racemic 2- [benzyl (4'-nitrophenyl) amino] -1-phimethanol of the formula 5 is reacted with the compound of the formula 7 OH or a salt of the compound of formula 5 can be reacted with the salt of the formula (the mandelic acid salt of formula 8a and the crystallized 6a) mandelic acid salt. After removal of 8a, the desired compound of formula 4 is recovered from the mother liquor and purified if necessary. 5. Figures 1-4. Process according to any one of claims 1 to 4, characterized in that the salt of the compound of formula 5 is a hydrochloride, hydrobromide, sulphate, dihydrogen phosphate salt or a salt with organic acids, including acetic acid, propionic acid or benzoic acid, preferably the hydrochloride or acetate salt. 6. Figures 1-5. Process according to any one of claims 1 to 7, characterized in that the salt of the mandelic acid of formula 6 or 7 is a sodium, potassium or ammonium salt, preferably a sodium salt, 7, The l.-ó. A method according to any one of the preceding claims, characterized in that the solvent used during the resolution C _r C \ -C, straight or branched chain alcohols, preferably GC _C4 aliphatic alcohol, with -C ₄ alkyl-carboxylic acids, CG lower alcohol ester thereof, -acetonitrile, tetrahydrofuran, dioxane, toluene, , t-butyl methyl ether, diisopropyl ether, water, or any mixture of two or more thereof. Process according to any one of claims 7, characterized in that the solvent used in the resolution is acetonitrile, isopropyl acetate or ethyl acetate, preferably ethyl acetate. 9. Figures 1-8. Process according to any one of claims 1 to 4, characterized in that the temperature used during the resolution is 40 to 50 ° C, preferably 43 to 45 ° C. 10, Figures 1-9. Process according to any one of claims 1 to 4, characterized in that the ratio of mandelic acid of formula 6 or 7 to compound 5 during the resolution is 0.1 to 1 molar equivalent, preferably 0.51.0 molar equivalents, most preferably 0.6 to 0.8 molar equivalents. 11. Figures 1, -10. Process according to any one of claims 1 to 4, characterized in that the temperature range used for the crystallization of the salts of the formulas 4a and 8a is -50 ° C to + 120 ° C, preferably -20 ° C to 60 ° C. Use of a racemic 2- [benzyl (4-methylthiophenyl) amino] -1-phenylethanol compound 5 to prepare mirabegron 1. 13. Use of a salt of formula 4a (Rj-mandelic acid) for the preparation of mirabegron of formula 1. 14. The (O) -2- [benzyl (4-nitrophenyl) amino] -1-phenylethanol of formula 8 ..N She. N υ Ö Use of a salt of HO 'and 8a (Sj-mandelic acid for the preparation of mirabegron of formula 1 according to claim 4).