METHOD FOR THE PREPARATION of 5-{2-[BENZYL-(1-(4-HYDROXYPHENYL)-1-METHYLETHYL)AMINO]-1-HYDROXYETHYL}BENZENE-1,3-DIOL HEMIFUMARATE

Abstract

The present invention relates to a process for the industrial-scale production of 5-{2-[benzyl-(1-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol hemifumarate, a salt consisting of two molecules of 5-{2-[benzyl-(1-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol and one molecule of fumaric acid, and having the following formula: 5-{2-[benzyl-(1-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol hemifumarate is a useful intermediate in the synthesis of 5-[(1RS)-2-[(1RS)-2-(4-hydroxyphenyl)-1-methylethyl]-amino-1-hydroxyethyl]benzene-1,3-diol hydrobromide, which is used in the pharmaceutical field under the is known by the common name fenoterol hydrobromide.

Description

FIELD OF INVENTION

[0001] The present invention relates to the field of processes for the synthesis of active pharmaceutical ingredients, in particular to a process for the preparation of 5-{2-[benzyl-(1-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl benzene-1,3-diol hemifumarate, a salt consisting of two molecules of 5-{2-[benzyl-(1-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol and one molecule of fumaric acid, with the following formula: 5-{2-[benzyl-(1-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol hemifumarate is a useful intermediate in the synthesis of 5-[(1RS)-2-[(1RS)-2-(4-Hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl]benzene-1,3-diol hydrobromide. STATE OF THE ART

[0002] The compound 5-[(1RS)-2-[(1RS)-2-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl]benzene-1,3-diol hydrobromide, also known by the common name fenoterol hydrobromide, has the structure shown below:

[0003] The compound is identified with CAS registration number 1944-12-3, as stated in the European Pharmacopoeia 10.0 on page 2618, and belongs to the class of beta-adrenergic receptor agonists and sympathomimetics.

[0004] Such derivatives can be used to manufacture drugs such as bronchodilators for the treatment of bronchospasms associated with asthma and bronchitis, as well as for the treatment of reversible airway obstructions.

[0005] Fenoterol was first described in US patent no. 3,341,593, which described the class of compounds with the following general formula. where R can be hydrogen or methyl, and in the specific case of fenoterol, it is hydrogen. The patent also discloses the possibility of using compounds with the formula shown above in the form of their salts, which are obtained by reaction with a pharmacologically acceptable acid, such as hydrobromic acid (HBr).

[0006] However, the general description in US 3,341,593 reports in a very general form on the existence of isomeric mixtures due to the presence of one or two stereocenters (“asymmetric carbon atoms”), which are indicated by arrows in the following figure:

[0007] In the case of fenoterol, where R is hydrogen, there are two stereocenters and four possible isomers, i.e., two diastereomers as enantiomeric pairs (RR,SS; RS,SR). As reported in the cited passage of the European Pharmacopoeia, the isomeric mixture used as an active ingredient is the one consisting of the RR,SS enantiomeric pair, as it exhibits favorable pharmacological activity.

[0008] Although the general part of US 3,341,593 describes synthesis methods in general terms, it does not go into detail about obtaining the desired mixture of stereoisomers.

[0009] The commercial availability of the racemic compound, structurally similar to fenoterol, formed from the following enantiomeric pair, would suggest to a person skilled in the art the reduction of the carbonyl function as a possible synthetic route, which, by exploiting the stereocenter already present in the molecule (indicated by the arrow), should lead to a favorable isomeric disequilibrium. The person skilled in the art would therefore reasonably have assumed that the RR product could be obtained mainly from the R-isomer and the SS isomer mainly from the S-isomer.

[0010] This approach was experimentally tested by the applicant through a laboratory-scale screening based on approximately 200 reduction experiments using heterogeneous or homogeneous catalysts with chiral and non-chiral additives, different solvents, temperatures, pressures, and pH values ​​of the solutions. This series of experiments yielded some excellent results regarding the conversion yield of carbonyl to alcohol (over 95%), but with a ratio of RR,SS to RS,SR isomers of 60 / 40 in the most favorable cases. The anticipated effect of asymmetric induction due to the pre-existing stereocenter was much less than expected, and the product of the synthesis exhibits an unacceptable ratio between the RR,SS and RS,SR isomers.

[0011] After synthesis, repeated crystallizations are required to obtain a final mixture in which the content of isomers with favorable pharmacological activity corresponds to the values ​​of the European Pharmacopoeia 10.0, resulting in such a low overall yield that this solution is not industrially acceptable.

[0012] In light of the above, an efficient and industrially applicable process is therefore required that maximizes the formation of the RR,SS isomer mixture compared to the RS,SR mixture. SUMMARY OF THE INVENTION

[0013] This objective is achieved with the present invention, which relates to a process for the synthesis of 5-{2-[benzyl-(1-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol hemifumarate, a compound which can be easily converted to fenoterol hydrobromide in high yield.

[0014] The method of the invention comprises the following steps: a) Preparation of a solution containing 1-[3,5-Dihydroxyphenyl]-2-[[2-(4-hydroxyphenyl)-1-methylethyl](phenylmethyl)amino]ethanone and a protic acid (HA) in a solvent selected from: - Water, - an alcohol selected from methanol, ethanol and isopropanol, preferably methanol, - a mixture of water and an alcohol selected from methanol, ethanol and isopropanol, preferably methanol, Obtaining a salt, intermediate product A, with the following formula: where A - represents the deprotonated fraction of the protic acid HA; b) Reduction of the carbonyl function of intermediate A to obtain intermediate B: c) Treatment of intermediate B with a base and an organic solvent immiscible with water, yielding an organic solution of 5-{2-[benzyl-(1-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol (intermediate C): d) Addition of fumaric acid to the organic solution obtained in step c) or vice versa, resulting in the precipitation of the hemifumarate salt, which is formed from two molecules of intermediate C and one molecule of fumaric acid, in crude form (intermediate D): e) Purification of the crude intermediate D to obtain the desired product, pure 5-{2-[Benzyl-(1-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol hemifumarate: BRIEF DESCRIPTION OF THE IMAGES - Fig. shows the X-ray diffractogram (XRPD) of the invention product; - Fig. shows the DSC thermogram that was created for the product of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0015] The invention relates to a process for the synthesis of 5-{2-[benzyl-(1-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol hemifumarate by the above-mentioned steps a) to e).

[0016] Step a) consists of the preparation of a salt of 1-[3,5-Dihydroxyphenyl]-2-[[2-(4-hydroxyphenyl)-1-methylethyl](phenylmethyl)amino]ethanone with a protic acid (intermediate A): where A - the deprotonated fraction, i.e. the conjugate base, of the protic acid HA.

[0017] Step a) can be carried out according to one of the alternative procedures a'), a'') and a''': a') An aqueous solution of a protic acid and a solution of 1-[3,5-Dihydroxyphenyl]-2-[[2-(4-hydroxyphenyl)-1-methylethyl](phenylmethyl)amino]ethanone in an organic solvent immiscible with water are combined to form a two-phase system. a'') A mixture of a protic acid and the compound 1-[3,5-Dihydroxyphenyl]-2-[[2-(4-hydroxyphenyl)-1-methylethyl](phenylmethyl)amino]ethanone is prepared in an alcohol selected from methanol, ethanol and isopropanol, or in a mixture of water and one of these alcohols; the alcohol, either alone or in mixture with water, is preferably methanol. a'') a two-phase system is prepared comprising an organic solvent immiscible with water in which the compound 1-[3,5-Dihydroxyphenyl]-2-[[2-(4-hydroxyphenyl)-1-methylethyl](phenylmethyl)amino]ethanone is dissolved, and a phase of water and an alcohol selected from methanol, ethanol and isopropanol in which a protic acid is present, and the organic solvent immiscible with water is evaporated.

[0018] The protic acid used in the salt formation of the starting compound can be organic or inorganic.

[0019] In the case of method a') and when using an organic protic acid, the aqueous acid solution is obtained using one of the following acids: - L(+)-tartaric acid (CAS 87-69-4); - D(-)tartaric acid (CAS 147-71-7); - DL-tartaric acid (CAS 133-37-9); - Citric acid (CAS 77-92-9); - Lactic acid (CAS 50-21-5); and - Oxalic acid (CAS 144-62-7).

[0020] Preferably, L(+)-tartaric acid, D(-)-tartaric acid and DL-tartaric acid are used.

[0021] The aqueous solution is prepared with a concentration of 15 to 20 wt% acid in water and has a pH value of < 6.

[0022] The organic solvent in which the compound 1-[3,5-Dihydroxyphenyl]-2-[[2-(4-hydroxyphenyl)-1-methylethyl](phenylmethyl)amino]ethanone is first dissolved can be selected from isopropyl acetate, methyl acetate, methyl isobutyl ketone and preferably ethyl acetate.

[0023] To the solution of 1-[3,5-Dihydroxyphenyl]-2-[[2-(4-hydroxyphenyl)-1-methylethyl](phenylmethyl)amino]ethanone in organic solvent, an amount of aqueous protic acid solution is added such that the pH of the resulting aqueous solution is below 6 and preferably in the range of 3 to 4.

[0024] In case a''), a solution of 1-[3,5-Dihydroxyphenyl]-2-[[2-(4-hydroxyphenyl)-1-methylethyl](phenylmethyl)amino]ethanone is prepared in a solvent consisting of an alcohol selected from ethanol, isopropanol and preferably methanol, alone or mixed with water, and a protic acid selected from: - Fumaric acid (CAS 110-17-8); - Succinic acid (CAS 110-15-6); - Acetylsalicylic acid (CAS 50-78-2).

[0025] The preferred protic acid for carrying out procedure a'') is acetylsalicylic acid.

[0026] In both the case of process a') and in the case of process a''), the reaction temperature is in the range of 10 to 30 °C, preferably 20 to 25 °C.

[0027] Finally, the inventors found that when carrying out the process according to a'), the extraction of intermediate A in the aqueous phase with certain protic acids does not occur; these acids are maleic acid (CAS 110-16-7), acetic acid (CAS 64-19-7), hydrobromic acid (CAS 10035-10-6), and sodium hydrogen sulfate (CAS 7681-38-1). In this case, the process is carried out according to a''), in which the organic solvent of the two-phase system is evaporated and methanol is added, thereby obtaining a hydroalcoholic solution containing intermediate A.

[0028] The preferred protic acid for carrying out procedure a''') is maleic acid.

[0029] By working according to one of the procedures a'), a'') or a''') one obtains a solution which contains the intermediate product A suitable for the next step of the procedure.

[0030] Step b) consists of reducing the carbonyl function of intermediate A to intermediate B:

[0031] If step a) has been carried out according to procedure a'), the solution containing intermediate A contains no alcohol, and the preparatory step of step b) consists of adding an alcohol selected from methanol, ethanol and isopropanol to this solution at a temperature in the range of 0 to 30 °C, preferably 0 to 15 °C; the preferred alcohol is methanol.

[0032] The hydroalcoholic solution containing intermediate A, resulting from step a) according to procedure a'') or a''') or from the preliminary procedure described above, is used in the reduction reaction of the carbonyl function.

[0033] The reaction is carried out with a hydride selected from sodium borohydride (NaBH4), lithium borohydride (LiBH4), calcium borohydride (Ca(BH4)2), zinc borohydride (Zn(BH4)2) and lithium cyanoborohydride (LiBH3CN), with sodium borohydride being preferred.

[0034] The hydride is used in a molar ratio of at least 2 to the moles of intermediate A to be reduced. The reduction reaction can be completed by further additions of hydride and the protic acid used in step a); the addition of the acid together with the further additions of hydride is necessary to keep the pH of the solution in the acidic range.

[0035] The reduction reaction is carried out at a temperature in the range of 0 to 35 °C, preferably from 0 to 25 °C.

[0036] The result of the reaction is a hydroalcoholic solution containing intermediate B, which is used as such in the next step.

[0037] Step c) consists of treating intermediate B in a hydroalcoholic solution with a base and an organic solvent immiscible with water to obtain an organic solution of 5-{2-[Benzyl-(1-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol (intermediate C):

[0038] This step is carried out in a series of processes.

[0039] In the first step, a base is added to the hydroalcoholic solution from step b) in such an amount that the pH of the solution is between 6 and 8, preferably between 6.5 and 7.5.

[0040] The base can be added in solid form (provided its properties allow) or as an aqueous solution. Aqueous ammonia solutions, NaOH, KOH, LiOH, Na₂CO₃, K₂CO₃, NaHCO₃, and KHCO₃ are suitable for carrying out step c). NaOH is preferably used. For step c), the temperature is maintained in the range of 0 to 25 °C, preferably from 0 to 5 °C.

[0041] The alcohol present in the hydroalcoholic solution is then evaporated under reduced pressure, resulting in a suspension of intermediate product C in water.

[0042] Alternatively, it is possible to reverse the order of base addition and alcohol evaporation, i.e., to evaporate the alcohol first, obtaining an aqueous solution of intermediate B, to which the base is added.

[0043] The mixture is then mixed with an organic solvent selected from ethyl acetate (AcOEt), isopropyl acetate (AcOiPr) and methyl isobutyl ketone (MIBK), either pure or mixed with methanol, while stirring until dissolved; after this process a two-phase system is formed, consisting of an aqueous phase and an organic phase.

[0044] The pH of the aqueous phase is then adjusted with a base to a pH of greater than or equal to 8, preferably in the range of 8.5 to 10. Aqueous ammonia solution, NaOH, KOH, LiOH, Na( 2) CO( 3) , K( 2) CO( 3) , NaHCO( 3) and KHCO( 3) can be used; the preferred bases are NaOH and NaHCO( 3) .

[0045] The phases are then separated, and the organic phase is concentrated under reduced pressure, resulting in an organic solution containing the intermediate C.

[0046] Step d) consists of the precipitation of the hemifumarate salt (crude intermediate D) from the organic solution containing intermediate C in the presence of fumaric acid:

[0047] To carry out step d), an alcohol selected from methanol, ethanol and preferably isopropanol is added to the concentrated organic solution containing the intermediate C obtained at the end of the previous step, and the resulting solution is added to fumaric acid, or conversely, fumaric acid is added to this solution, at a temperature in the range of 20 to 65 °C, preferably 20 to 60 °C.

[0048] The reaction mixture thus obtained is then stirred at a temperature in the range of 0 to 35 °C, preferably from 15 to 30 °C, for at least 8 hours, preferably 16 to 24 hours; after this process, the precipitation of a solid is observed, which is filtered off to obtain the crude intermediate product D.

[0049] Finally, step e) of the method of the invention consists in purifying the crude intermediate product D to obtain a product which is defined below as pure hemifumarate, wherein the ratio between the isomer pairs RR,SS:RS,SR is the desired ratio or a higher one:

[0050] To carry out step e), the intermediate product D (crude hemifumarate) is suspended in an aliphatic, linear or branched C1-C5 alcohol; preferably methanol is used. The suspension is stirred under reflux and then at 20-25 °C. The product is recovered by filtration.

[0051] The cleaning process is repeated until the content of unwanted isomers RS, SR is less than 5%; usually 2 to 3 cleanings are required to achieve this result.

[0052] The compound thus obtained, 5-{(1RS)-2-[benzyl-((1RS)-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol fumarate (2:1), has a content of undesired isomers that is below the starting value in intermediate D and can be used as an intermediate to obtain fenoterol hydrobromide, which meets the specifications of the European Pharmacopoeia 10.0 corresponds to by subjecting it to chemical reactions known to the skilled person, some of which are described in the experimental part; In short, the conversion of the above-described pure hemifumaric acid hydrobromide to fenoterol hydrobromide involves first the formation of 5-{(1RS)-2-[benzyl-((1RS)-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol hydrobromide via usual acid-base reactions, the subsequent elimination of the benzyl group bonded to the nitrogen atom by catalytic hydrogenation, and finally the isolation of the desired product by simple solvent crystallization using a hot-cold technique.

[0053] Table 1 shows the results regarding the isomer disequilibrium that can be obtained using the method of the present invention (run 1 serves for comparison purposes); the isomer ratio is calculated based on the intermediate product C obtained according to steps a), b) and c). Table 1 throughput Procedure a' / a'' / a''' Protic acid Ratio of desired / undesired isomers 1 / no 59 / 41 2 a' L-tartaric acid 78 / 22 3 a' D-tartaric acid 83 / 17 4 a' DL-tartaric acid 84 / 16 5 a'' Fumaric acid 77 / 23 6 a''' Maleic acid 79 / 21 7 a' citric acid 75 / 25 8 a'' succinic acid 78 / 22 9 a' Oxalic acid 80 / 20 10 a' Lactic acid 85 / 15 11 a''' acetic acid 77 / 23 12 a'' Acetylsalicylic acid 79 / 21 13 a''' Hydrobromic acid 78 / 22 14 a''' Sodium hydrogen sulfate 80 / 20

[0054] The invention therefore offers the advantage of providing a process for the synthesis of an intermediate of fenoterol hydrobromide in which, during the synthesis process, predominantly the stereoisomers are formed which, when converted to fenoterol, yield the racemate according to the specifications of the European Pharmacopoeia 10.0 at the end of the process, without the need for lengthy and costly purification processes such as column chromatography or repeated crystallizations.

[0055] The invention is explained in more detail using the following examples. INSTRUMENTS, PROCEDURES AND EXPERIMENTAL CONDITIONS HPLC: Description of the procedure for the analysis of intermediates A, B, C, D Device: Agilent Technologies 1100, 1200 series or 1260 Infinity; Column: Inertsil ODS-3; 150mm × 4.6mm × 3.0µm; Flow rate: 0.8 ml / min; Detector: 222 nm (DAD); Bandwidth and reference for DAD detector: 4 nm, 360 nm, 40 nm; Temperature: 35 °C; Injection volume: 10 µl; Pressure at t = 0': 123 bar. MOBILE PHASE Mobile Phase “A”: CH3 COONH 4(aq) 0.77 g / L Mobile Phase “B”: CH3 CN GRADIENT OF THE METHOD Time (min) Mobile Phase “A” (%) Mobile Phase “B” (%) 0 80 20 30 20 80 40 20 80 41 80 20 50 20 20

[0056] The samples were prepared for the runs at a concentration of 0.25 g / l with a mixture of mobile phase “A” / mobile phase “B” 80 / 20 (v / v).

[0057] The samples were dissolved in mobile phase “B” until an opalescent heterogeneous solution was obtained, then they were brought to volume by adding mobile phase “A”, resulting in a homogeneous, colorless and clear solution.

[0058] The percentage of RR,SS and RS,SR isomers with respect to intermediates C and D was determined based on the percentage peak area as follows: - RR,SS isomers = % RR,SS area / (% RR,SS area + % RS,SR area); - RS,SR isomers = % RS,SR area / (% RR,SS area + % RS,SR area). NMR: Spectrometer: NMR JEOL 400 YH (400 MHz); Software: JEOL Delta v5.1.1;

[0059] Spectra recorded in deuterated solvents such as: Chloroform-d, D 99.8%, with 0.1% (v / v) tetramethylsilane (TMS) as internal standard; and Chloroform-d, “100%”, D 99.96%, with 0.03% (v / v) TMS and DMSO-d( 6) . MS: Device: Agilent1260 Infinity / 6120 Quadrupole LC / MS Software: OpenLAB 2 Ionization method: ESI - Electrospray Ionization MS parameters: Initial mass (m / z) 300 Da; Final mass (m / z) 500 Da; Scan time: 500 ms; Fragmentation: 70 V; Positive and negative polarity; Gas temperature: 350 °C; Gas flow rate: 12 l / min; Nebulizer: 30 psi (2.07 bar); Capillary positive voltage 3000 V; Capillary negative voltage 3000 V; flow rate: 0.3 ml / min; Injection: 1,0 µl; Mobile Phase: H2 O + 0.10% HCOOH / CH3 CN + 0.10% HCOOH 50% / 50% (v / v). TLC

[0060] MERCK: TLC silica gel 60 F 254 Aluminum plates 20 x 20 cm, code 1.0554.0001. TLC detectors

[0061] Cerium phosphomolybdate: 25 g of phosphomolybdic acid and 10 g of cerium(IV) sulfate are dissolved in 600 ml of water. 60 ml of 98% hydrogen peroxide (H₂SO₄) is added, and the resulting mixture is made up to 1 liter with water. The plate is saturated with the solution and then heated until the products are detected. Lamp detector: UV 254 nm and 366 nm XPRD

[0062] The XRPD analysis was performed using a Bruker ®The analysis was performed using a D2 phaser diffractometer (2nd edition). The X-ray source was a copper anode X-ray tube operated at 30 kV and 10 mA. The analytical wavelength used was copper Kα (λ = 1.54184 Å). Kβ was filtered out using a nickel filter. The X-ray detector was a LYNXEYE solid-state linear detector. Samples were applied as thin films to zero-background silicon sample holders. The diffractogram was recorded in the angular range of 4.0 to 40° 2θ with increments of 0.016° and a scan rate of 1.0 s / increment. The sample was rotated at 60 rpm during analysis. The data were analyzed using DIFFRAC.EVA software (Bruker). All angular values ​​given below are to be understood with the usual accuracy of ± 0.2°. DSC

[0063] DSC analysis was performed using a Mettler Toledo DSC3 instrument under a nitrogen atmosphere. Samples were prepared in 40 µL aluminum crucibles with lids and sealed with a suitable press prior to analysis. The lid was then pierced to allow any gas to escape from the sample. The analysis was performed at a constant heating rate of 10 °C / min. The data were analyzed using STARe software (Mettler Toledo). NOTES

[0064] Unless otherwise stated, the water used in the experiment descriptions refers to pure water.

[0065] Unless otherwise stated, the organic solvents used in the experiment descriptions are to be understood as "technically pure".

[0066] Unless otherwise stated, the reagents and catalysts used in the experiment descriptions are to be understood as being of commercially available quality.

[0067] The term “small volume”, used in the following examples in reference to the volume of a solution after a distillation step, means 10% or less of the initial volume.

[0068] The following examples use the following conventions and abbreviations: Unless otherwise stated, concentrations of solutions given as percentages are to be understood as weight percentages. - MIBK: Methyl isobutyl ketone; - DCM: Dichloromethane; - MeOH: Methyl alcohol; - IPA: Isopropyl alcohol; - AcOEt: Ethyl acetate; - Pd / C 5%: Palladium on carbon, 5 wt% Pd. EXAMPLE 1

[0069] This example relates to the preparation of compound 2, a precursor compound used in the process of the invention.

[0070] 200 g of 4-methoxyphenylacetone in 1200 ml of toluene were placed in a flask. The system was refluxed, and benzylamine (168 g) was added over a period of one hour while maintaining the reflux temperature and removing the water formed. The line was purged with 15 ml of toluene. After completion of the reaction, 500 ml of toluene were distilled off without vacuum, and the system was distilled under vacuum at 95 °C to an oily residue. The residue was dissolved under nitrogen with MeOH (1386 ml), and the solution was cooled to 0 °C. Sodium borohydride (16 g) was added portionwise, and the mixture was stirred for one hour at 0–5 °C. After completion of the reaction, the mixture was distilled under vacuum to a residual volume of 500–600 ml. 400 ml of water were added, and the distillation was continued until the MeOH was completely removed.The residue was dissolved in 1120 mL of water and 640 mL of DCM. The phases were separated, and the aqueous phase was re-extracted with DCM (100 mL). The organic phases were combined and washed with water (100 mL). The solvent from the organic phase was evaporated under vacuum. The residue was dissolved in MeOH (400 mL) and water (266 mL). The system was cooled below 10 °C, and a previously prepared solution of 37% HCl (133 g) and water (133 g) was added dropwise. The system was stirred for 30 minutes at 0–5 °C, the solid was filtered off, and washed with water (270 mL). The solid was suspended in toluene (1067 mL), and the suspension was stirred for 30 minutes at 25 °C. The suspension was then filtered and washed with toluene (107 mL). Toluene (667 ml) and water (400 ml) were added to the recovered solid.Maintaining a temperature of < 30 °C, 30% sodium hydroxide solution (177 g) was added dropwise. The phases were separated, and the aqueous phase was re-extracted with toluene (213 ml). The organic phases were combined and washed with water (270 g). The solvent was evaporated, yielding 226 g of compound 1.

[0071] Compound 1 (100 g; 0.392 mol) was added portionwise to a solution of 48% HBr in H₂O (670 mL, 5.913 mol) at 50 °C. Subsequently, a further 60 mL of a 48% H₂O / HBr solution (5:1 v / v) was added. The reaction mixture was heated to 110–120 °C and kept at temperature with stirring for 4 hours. TLC testing confirmed that the reaction had proceeded to completion. The mixture was cooled to 0–5 °C and kept at temperature with stirring for 1 hour. The precipitate (hydrobromide salt of compound 2) was filtered off and washed with a 48% H₂O / HBr solution (5:1 v / v). The precipitate was dissolved in 210 mL of H(2) O and 85 ml MIBK was suspended, and then NH4OH was added until a pH of > 10 was reached. The system was kept at 0-5 °C for 1 hour with stirring. The precipitate was filtered off and dissolved with cold MIBK and H( 2) O washed and finally dried at 50 °C; product 2 (79.34 g) was obtained and used as such in a subsequent reaction. EXAMPLE 2

[0072] This example relates to the preparation of compound 4, a precursor compound used in the process of the invention. Compound 3, diacetoxyacetophenone, is a commercially available product.

[0073] Compound 3 (100 g; 0.424 mol) was dissolved in DCM (500 ml) under a nitrogen stream. The system was cooled to 10–15 °C, and a solution of HCl in IPA (1.53 ml) was added dropwise. The system was stirred for 5 minutes, cooled to 0–5 °C, and Br₂ (23.87 ml; 0.466 mol) was added while maintaining a temperature below 10 °C. The system was stirred at 0–5 °C for 30 minutes. A solution of NaHCO₃ (9 g) in H₂O (450 ml) was added dropwise to the system at 0–5 °C. The system was then heated to 20 °C, and the phases were separated. The aqueous phase was extracted again with DCM (90 ml). The combined organic phases were washed with H₂O and concentrated to a small volume under vacuum at 35 °C. MeOH (180 ml) and H₂O (45 ml) were added. The system was kept at 0–5 °C for 30 minutes with stirring. The precipitate was filtered and washed with a mixture of MeOH / H₂O (35:10 v / v) at 5 °C.112.88 g of product 4 were obtained (after drying under reduced pressure). EXAMPLE 3

[0074] This example relates to the preparation of compound 5, a precursor compound used in the process of the invention.

[0075] 50 g (0.159 mol) of compound 4 prepared according to Example 2 were dissolved in 300 mL of nitrogen-degassed MIBK under a nitrogen atmosphere. 100 mL of solvent were evaporated under vacuum. 40 mL of nitrogen-degassed MIBK were added to the solution of compound 4 under nitrogen. The solution was heated to 50 °C and 76.58 g (0.317 mol) of compound 2 prepared according to Example 1 were added. The system was maintained at 105 °C with stirring for 1.5 hours. TLC check: reaction complete. The system was brought to -10 °C and stirred for a further 1 hour. The precipitate was filtered off and washed with nitrogen-degassed MIBK. The solvent was evaporated under vacuum at 50 °C and product 5 was recovered, which was used as such in the reaction of the following example. EXAMPLE 4

[0076] This example relates to the preparation of compound 6, a precursor compound used in the process of the invention. 115 ml of nitrogen-degassed MeOH, 2 ml of H₂O, and a 48% HBr solution in H₂O (27.01 ml; 0.238 mol) were added to compound 5 (0.159 mol) obtained as described in Example 3. The system was kept at 70 °C for 30 minutes with stirring. TLC check: reaction complete. The system was cooled to 0–5 °C and 22 ml of a nitrogen-degassed 30% NaOH-aqueous solution were added, bringing the pH of the system to 7. MeOH was evaporated under vacuum at 50 °C. Previously degassed H₂O (105 ml) and AcOEt (250 ml) were added, and the mixture was stirred at 50 °C until the product dissolved.30% NaOH (6 ml), previously degassed with nitrogen, was added to a pH of 8, and finally a nitrogen-degassed aqueous solution of NaHCO3 (120 ml) was added to a pH of 8.5 / 9. The phases were separated. The aqueous phase was re-extracted with nitrogen-degassed AcOEt (280 ml). The combined organic phases, containing intermediate 6, were washed with H2O and used as such in the reaction of the following example. EXAMPLE 5

[0077] This example refers to step a') of the invention.

[0078] A 20% aqueous solution of L(+)-tartaric acid (95.4 g; 0.636 mol in 380 mL H₂O) was prepared. 260 mL of the aqueous tartaric acid solution was added to the organic phase (solution containing intermediate 6, obtained as described in the previous example). The system was kept at 20 < T < 25 °C for 10 minutes with stirring, and the phases were separated. The organic phase was re-extracted with the remaining acid solution. The acidic aqueous phases were combined and washed with AcOEt₂ (105 mL). Under vacuum at 55 °C, 70 mL of the aqueous acid solution were evaporated; the remaining portion, containing the product (intermediate A), was used as such for the reaction of the following example.

[0079] For analytical purposes, an aliquot of the solution containing intermediate A was acidified with a saturated NaHCO3 aqueous solution, extracted with AcOEt and chromatographed on silica gel with toluene / AcOEt in a gradient from 8 / 2 to 1 / 1.

[0080] The resulting residue (HPLC purity > 90%) was analyzed and yielded the following data: 1 H-NMR (400 MHz, DMSO-d6): δ 9.54 (s, 2H), 9.09 (s, 1H), 7.33-7.14 (m, 5H), 6.86 (d, J = 8.6 Hz 2H), 6.80 (d, J = 1.6 Hz, 2H), 6.61 (d, J = 8.6 Hz 2H), 6.44, (d, J = 1.6 Hz, 1H), 3.89 (s, 2H), 3.69 (ABq, J = 14.2 Hz, 2H), 2.88-2.80 (m, 2H), 2.38-2.33 (m, 1H), 0.90 (d, J = 6.4 Hz, 3H). 13 C-NMR (400 MHz, DMSO-d6): δ 198.3, 158.3, 155.2, 140.0, 138.0, 130.2, 129.7, 128.3, 127.9, 126.6, 114.8, 106.9, 105.8, 56.8, 55.9, 54.2, 37.7, 14.8. EXAMPLE 6

[0081] This example relates to the method of the invention according to the sequence of steps: b); c); d) and e). 5-{2-[Benzyl-(1-(4-hydroxyphenyl)}-1-methylethyl)amino]-1-hydroxyethyl)benzene-1,3-diol hemifumarate MeOH (485 ml) was added to the aqueous solution of intermediate A described in Example 5 at 0-5 °C.

[0082] 21.15 g of NaBH4 (0.557 mol) were added portionwise to this new solution while maintaining T < 10 °C. The system was kept at 0–5 °C with stirring for 30 minutes. A TLC control was used to verify that the reaction was incomplete. L(+)-tartaric acid (47.7 g, 0.318 mol) and NaBH4 (14.5 g, 0.38 mol) were added portionwise, and the system was kept at 0–5 °C with stirring for 1 hour, with TLC verification of reaction completion. The result is a solution containing intermediate B.

[0083] To this solution, 50 ml of a 30% NaOH solution was added and the mixture was kept at 0–5 °C until a pH of 7 was reached. The methanol was evaporated under vacuum at 50 °C. 430 ml of an AcOEt / MeOH mixture (95:5 v / v) was added, and the system was kept at 50 °C with stirring until the product was completely dissolved. The solution was cooled to 20 °C, and 75 ml of a 30% NaOH solution were added until a pH of 8 was reached, followed by 200 ml of a saturated aqueous NaHCO3 solution until a pH of 8.5–9 was reached. The phases were separated, and the aqueous phase was re-extracted with 330 ml of an AcOEt / MeOH mixture (95:5 v / v). The organic phases were combined, and the resulting phase was treated with H( 2) OThe solution was washed and concentrated under vacuum at 50 °C to a residual volume of 485 ml. This process yielded an organic solution containing intermediate C. 86 ml of IPA were added to this solution, and the resulting solution was added to fumaric acid (23.99 g; 0.208 mol) at 50 °C. The system was kept at 25 °C for 16 hours with stirring. The formation of a precipitate was observed, which was filtered and washed with an AcOEt / IPA mixture (95:5 v / v, 140 ml). The solid was dried at 48 °C, yielding 42.75 g of the crude intermediate D.

[0084] An HPLC analysis was performed on a sample of the solid thus obtained, which yielded an RR,SS-to-RS,SR ratio of 82:18.

[0085] The crude intermediate D (20 g; 0.044 mol) was suspended in 200 ml of MeOH, and the system was stirred under reflux for 1 hour, then cooled to 25 °C and stirred for 1 hour. The precipitate was filtered, washed with 30 ml of a mixture of AcOEt / MeOH (95:5 v / v), and finally dried at 50 °C, yielding 14.77 g of the crude intermediate D.

[0086] An HPLC analysis was performed on a sample of the solid thus obtained, which yielded a ratio of RR,SS to RS,SR of 93:7.

[0087] The crude intermediate D thus obtained was suspended in 75 ml of MeOH, and the system was stirred under reflux for 1 hour, then cooled to 25 °C and stirred continuously for 1 hour. The precipitate was filtered, washed with 20 ml of an AcOEt / MeOH mixture (95:5 v / v), and finally dried at 50 °C, yielding 13.4 g of pure hemifumarate.

[0088] An HPLC analysis was performed on a sample of the solid thus obtained, which yielded a ratio of RR,SS to RS,SR of 96:4.

[0089] The hemifumarate obtained at the end of the purification process was analyzed and yielded the following results: 1 H-NMR (400 MHz, DMSO-d6): ( 1) H-NMR (400 MHz, DMSO-d( 6)) : δ 9.06 (bs, 3H), 7.31-7.21 (m, 5H), 6.86 (d, J = 8.4 Hz 2H), 6.65 (d, J = 8.4 Hz, 2H), 6.62 (s, 1H), 6.15 (d, J = 2 Hz, 2H), 6.05 ( t, J = 2 Hz, 1H), 4.29 (t, J = 6.4 Hz, 1H), 3.70 (ABq, J = 13.8 Hz, 2H), 2.88-2.74 (m, 2H), 2.53-2.50 (m, *), 2.39-2.33 (m, 1H), 0.84 (d, J = 6.4Hz, 3H).

[0090] (*The integration of the signal at 2.53-2.50 is 5 instead of 2 due to the presence of residual solvent peaks).

[0091] 13C-NMR (400 MHz, DMSO-d6): δ 166.0, 157.9, 155.2, 146.3, 140.0, 134.0, 130.1, 129.7, 128.5, 127.9, 126.6, 114.8, 103.9, 100.9, 70.6, 57.7, 56.3, 54.2, 38.3, 13.6. Mass (CI): m / z = 394 [M + +1]

[0092] An XRPD test revealed this in Fig. The diffractogram shown is displayed; the following table shows the list of XPRD diffractogram peaks: Angle 2θ (°) Intensity % Angle 2θ (°) Intensity % 6,83 100 19,13 8 8,21 4 19,41 2 9,46 4 20,29 3 9,88 68 20,50 9 11,41 19 20,95 7 11,76 2 21,66 11 12,57 5 21,82 12 13,32 3 22,10 22 13,64 13 23,75 6 13,99 2 24,15 3 16,01 11 25,54 2 16,43 14 26,14 3 16,70 33 26,84 5 18,97 12 27,71 3

[0093] The most intense peaks are those at angles of 6.83°, 9.88°, 11.41°, 16.43°, 16.70° and 22.10° ± 0.2° 2θ.

[0094] 7.1 mg of the fenoterol hemifumarate sample were subjected to DSC calorimetry; the test curve is in Fig. shown; the most characteristic values ​​found by DSC calorimetry are endothermy with a peak at 156 °C and a start at 149 °C, and endothermy with a peak at 175 °C and a start at 167 °C. EXAMPLE 7

[0095] This example relates to the preparation of crude fenoterol hydrobromide starting from the hemifumarate described in Example 6. 30 mL of H₂O and 40 mL of an AcOEt / MeOH (95:5 v / v) mixture were added to the hemifumarate (4.08 g; 0.009 mol), followed by 1 mL of 30% NaOH to a pH of 7.5 and 20 mL of a saturated aqueous NaHCO₃ solution to a pH of 9. The system was kept at 50 °C for 15 minutes with stirring, cooled to 25 °C, and the phases were separated. The aqueous phase was re-extracted with 15 mL of an AcOEt / MeOH mixture (95:55 v / v). The combined organic phases were treated with H( 2) o washed. The solvent of the organic phase was evaporated under vacuum at 50 °C and the product with the formula given below was obtained as the free base:

[0096] To this free base (3.55 g; 0.009 mol) 22 mL of MeOH, 48% HBr adjusted to pH 4–5, and 5% Pd / C (0.407 g) were added. The solution was hydrogenated with a gas bag for 3 hours at 40 °C. TLC control showed that the reaction was complete. The solution was filtered through Dicalit and concentrated to a small volume under vacuum at 50 °C. AcOEt (18 mL) was added, and the solution was concentrated to a small volume under vacuum at 50 °C. 35 mL of an AcOEt / MeOH mixture (95:5 v / v) was added. The system was kept at 50 °C for 10 minutes and at 25 °C for 16 hours with stirring. A precipitate was obtained, filtered, washed with 5 ml of a mixture of AcOEt / MeOH (95:5 v / v) and dried at 50 °C, yielding 2.84 g of crude fenoterol hydrobromide. EXAMPLE 8

[0097] This example relates to the purification of fenoterol hydrobromide obtained as in the previous example. 10.50 g of fenoterol hydrobromide, obtained by the procedure of Example 7, were suspended in 95 ml of degassed water for injection (PPI water). The system was heated to 50 °C until the solid had completely dissolved. The resulting aqueous solution was cooled to 25 °C and 1.05 g of carbon was added. The suspension was stirred for 30 minutes and then filtered through Dicalit, washing with 10 ml of degassed PPI water. The solution was concentrated to a small volume under vacuum at 52 °C. 35 ml of degassed AcOH were added. The system was concentrated to a small volume under vacuum at 50 °C. A further 40 ml of degassed AcOH was added. The system was cooled to 25 °C and kept stirred for 1 hour.A precipitate was formed, which was filtered and washed with 10 ml of degassed AcOH and two portions of 15 ml of degassed AcOEt, yielding 9.29 g (wet) of pure fenoterol hydrobromide.

[0098] 6.34 g of pure fenoterol hydrobromide were suspended in 70 ml of degassed water for injection (PPI water). The system was heated to 55 °C until the solid was completely dissolved. The resulting solution was cooled to 35 °C, and the pH was adjusted to 4 by adding a 48% HBr aqueous solution diluted 1:10 with PPI water. The aqueous solution containing the product was filtered through a millipore filter to remove impurities and washed with degassed PPI water. The solution was concentrated to a small volume under vacuum at 55 °C. 5 ml of degassed AcOEt was added and filtered through a millipore filter. The system was concentrated to a small volume under vacuum at 55 °C. A further 9 ml of AcOEt, degassed and filtered through a millipore filter, was added and the system was concentrated under vacuum at 55 °C until a dense suspension was obtained.60 ml of AcOEt, degassed and filtered through a millipore filter, were added and the system was heated under reflux at a jacket temperature of 100 °C for 3 h, with the water condensed during reflux being regularly removed.

[0099] The system was cooled to 25 °C, held at this temperature for 1 hour, and filtered while washing with 5 ml of AcOEt. The product was dried under vacuum at 50 °C for 2 hours, yielding 5.98 g of fenoterol hydrobromide, which meets the specifications of the European Pharmacopoeia 10.0. EXAMPLE 9

[0100] This example refers to the sequence of steps a), b), c) and d) of the method of the invention.

[0101] 2.54 g of a solution containing intermediate 6 (0.0065 mol) described in Example 4 were evaporated under vacuum. The residue was dissolved in 35 ml of MeOH; succinic acid (3.05 g, 0.0258 mol) and water (15 ml) were added to the solution, and the system was stirred until the solid was completely dissolved.

[0102] NaBH4 (0.865 g; 0.023 mol) was added portionwise to the solution while maintaining T < 10 °C. The system was kept at 25 °C with stirring for 1 hour. On a TLC control, the reaction was found to be incomplete. Succinic acid (3.05 g) and portionwise NaBH4 (0.865 g) were added, and the system was kept at 25 °C with stirring for 30 minutes. On the TLC control, the reaction was complete. At 0–5 °C, 30% NaOH was added until pH 7 was reached. The methanol was evaporated under vacuum at 50 °C. 20 mL of an AcOEt / MeOH mixture (95:5 v / v) was added, and the system was kept at 50 °C with stirring until the product was completely dissolved. The solution was cooled to 20 °C and 30% NaOH was added until a pH of 8 was reached; the pH was then adjusted to 8.5–9 using an aqueous NaHCO3 solution. The phases were separated.The aqueous phase was re-extracted with an AcOEt / MeOH mixture (95:5 v / v, 10 ml). The combined organic phases were treated with H(. 2) O The organic phase was concentrated under vacuum at 50 °C, evaporating approximately 12 mL of solvent to obtain a solution containing intermediate C. 5 mL of IPA were added to this solution, and the resulting solution was added to fumaric acid (0.981 g) while maintaining the system temperature at 50 °C. The system was kept at 50 °C for 20 minutes and then at 25 °C for 16 hours with stirring. The precipitate was filtered, washed with a mixture of AcOEt / IPA (95:5 v / v, 5 mL), and dried at 50 °C to yield 1.55 g of crude intermediate D.

[0103] An HPLC analysis was performed on a sample of the solid thus obtained, which yielded an RR,SS-to-RS,SR ratio of 81.5:18.5. EXAMPLE 10

[0104] This example refers to the sequence of steps a'''), b), c) and d) of the method of the invention.

[0105] An aqueous solution of maleic acid (11.14 g maleic acid in 44.5 ml water) was prepared. A solution of intermediate 6 in AcOEt (65 ml solution, corresponding to 0.012 mol intermediate), obtained as described in Example 4, was washed with the aqueous solution of maleic acid (the product was in the organic phase).

[0106] The organic solvent was evaporated from the two-phase system using a rotary evaporator. 35 ml of MeOH were added while stirring until the existing solid was completely dissolved.

[0107] The system was brought to a temperature of 0–5 °C, and NaBH4 (1.6 g; 0.042 mol) was added in portions while maintaining T < 10 °C. The system was held at 5 °C for 30 min with stirring. TLC control: reaction not complete. NaBH4 (1.4 g; 0.037 mol) was added in portions while maintaining T < 10 °C. The system was held at 5 °C for 30 min with stirring. TLC control: reaction not complete. Maleic acid (5.78 g), dissolved in water (25 mL) and MeOH (25 mL), was added. NaBH4 (1.91 g; 0.05 mol) was added in portions, and the system was held at 5 °C for 30 min with stirring. Water (10 ml) and MeOH (10 ml) were added to dissolve the precipitate. TLC control: reaction not complete. MeOH (25 ml) was added. Subsequently, maleic acid (6.29 g) dissolved in water (30 ml) was added.NaBH4 (1.29 g, 0.034 mol) was added portionwise, and the system was maintained at 5 °C with stirring for 15 minutes. TLC check: reaction complete. 30% NaOH was added at 0–5 °C until a pH of approximately 8 was reached. The methanol was evaporated at 50 °C under vacuum. 40 mL of a 95 / 5 v / v AcOEt / MeOH mixture was added, and the system was maintained at 50 °C with stirring until the product was completely dissolved. 50 mL of an aqueous NaHCO3 solution was added, bringing the pH to approximately 8.5. The phases were separated, and the aqueous phase was re-extracted twice with 20 mL of a 95 / 5 v / v AcOEt / MeOH mixture. The combined organic phases were treated twice with H(. 2) O(20 ml) washed. The organic phase was concentrated under vacuum at 50 °C by evaporating approximately 20 ml of solvent, yielding a solution containing intermediate C. 7 ml of IPA were added to the solution, and the resulting solution was added to fumaric acid (1.8 g) while maintaining a temperature of 50 °C. The system was kept at 50 °C for 1 hour and then at 20 °C for 16 hours with stirring. The precipitate was filtered, washed with AcOEt (5 ml), and dried at 50 °C, giving 0.87 g of crude intermediate D.

[0108] An HPLC analysis was performed on a sample of the solid thus obtained, which yielded a ratio of RR,SS to RS,SR of 86:14. EXAMPLE 11

[0109] This example refers to the sequence of steps a), b) and c) of the invention's method.

[0110] An acidic aqueous solution (2.7 g of 48% HBr and 4 ml of water) was added to a solution of intermediate 6 (0.004 mol) in AcOEt, prepared as described in Example 4.

[0111] The two-phase mixture was concentrated under reduced pressure in a rotary evaporator at 50 °C until the organic solvent was removed. MeOH (15 ml) was added and the temperature raised to 0–5 °C. NaBH4 (0.456 g; 0.012 mol) was added portionwise and the system was stirred for 20 minutes at 5 °C. TLC check: reaction not complete. HBr 48% (1.81 ml) was added, then NaBH4 (0.456 g; 0.04 mol) was added portionwise. The system was stirred for 20 minutes at 5 °C. The system was cooled to 0–5 °C and 30% NaOH was added until a pH of approximately 7 was reached. The methanol was evaporated under vacuum at 50 °C. 20 ml of an AcOEt / MeOH = 95 / 5 mixture and 10 ml of water were added. The pH was adjusted using an aqueous solution of NaHCO₃. 3(ss)The concentration was brought to 8.8. The phases were separated, and the aqueous phase was re-extracted with a 95 / 5 AcOEt / MeOH mixture (30 ml). The combined organic phases were washed with water. The organic phase was concentrated under vacuum at 50 °C, yielding intermediate C as an oil (2.19 g). An HPLC control yielded an RR,SS-to-RS,SR ratio of 78:22. EXAMPLE 12

[0112] This example refers to the sequence of steps a'''), b) and c) of the method of the invention.

[0113] A solution of NaHSO4 (1.92 g) in 11 ml of water was prepared and added to a solution of intermediate 6 (0.004 mol) in AcOEt, prepared as described in Example 4. The two-phase mixture was concentrated under reduced pressure at T = 50 °C until the organic solvent was removed. 13 ml of MeOH were added and the system was stirred until completely dissolved. NaBH4 (0.456 g; 0.012 mol) was added portionwise, the temperature was lowered to 5 °C, and the system was stirred at this temperature for 20 minutes. TLC check: reaction not completed. NaHSO4 (3.84 g) and then portionwise NaBH4 (0.912 g; 0.08 mol) were added at 5 °C. The system was stirred for 10 minutes at 25 °C, cooled to 0–5 °C, and adjusted to a pH of approximately 7 with 30% aqueous NaOH. The methanol was evaporated under vacuum at 50 °C. 11 ml of a 95 / 5 AcOEt / MeOH mixture were added.The system was brought to a pH of approximately 8.5 using an aqueous NaOH solution. The phases were separated, and the aqueous phase was re-extracted with 20 mL of a 95 / 5 AcOEt / MeOH mixture. The combined organic phases were washed with H₂O. The organic phase was concentrated under vacuum at 50 °C, yielding intermediate C as an oil (1.92 g).

[0114] The HPLC control revealed an RR,SS-to-RS,SR ratio of 80:20. QUOTES INCLUDED IN THE DESCRIPTION

[0000] This list of documents cited by the applicant was automatically generated and is included solely for the reader's convenience. The list is not part of the German patent or utility model application. The DPMA accepts no liability for any errors or omissions. Cited patent literature

[0000] US 3,341,593 [0005, 0006, 0008]

Claims

[1] Method for the synthesis of 5-{2-[benzyl-(1-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol hemifumarate, comprising the following steps: a) Preparation of a solution containing 1-[3,5-Dihydroxyphenyl]-2-[[2-(4-hydroxyphenyl)-1-methylethyl](phenylmethyl)amino]ethanone and a protic acid (HA) in a solvent selected from: - Water - an alcohol selected from methanol, ethanol and isopropanol - a mixture of water and an alcohol selected from methanol, ethanol and isopropanol Obtaining a salt, intermediate product A, with the following formula: where A - represents the deprotonated fraction of the protic acid HA; b) Reduction of the carbonyl function of intermediate A to obtain intermediate B: c) Treatment of intermediate B with a base and an organic solvent immiscible with water, yielding an organic solution of 5-{2-[benzyl-(1-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol (intermediate C): d) Addition of fumaric acid to the organic solution obtained in step c) or vice versa, leading to the precipitation of the hemifumarate salt, which is formed from two molecules of intermediate C and one molecule of fumaric acid, in crude form (intermediate D): e) Purification of the crude intermediate D to obtain the desired product, pure 5-{2-[Benzyl-(1-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol hemifumarate: [2] Method according to claim 1, wherein step a) is carried out according to a first method a') by combining an aqueous solution of a protic acid and a solution of 1-[3,5-Dihydroxyphenyl]-2-[[2-(4-hydroxyphenyl)-1-methylethyl](phenylmethyl)amino]ethanone in a solution formed in a water-immiscible organic solvent, thereby obtaining a two-phase system. [3] Method according to claim 2, wherein the aqueous solution of a protic acid in a concentration of 15 to 20 wt.% in water is prepared of a protic acid selected from L(+)-tartaric acid, D(-)tartaric acid, DL-tartaric acid, citric acid, lactic acid and oxalic acid, and has a pH of < 6. [4] Method according to one of claims 2 or 3, wherein the water-immiscible organic solvent is selected from ethyl acetate, isopropyl acetate, methyl acetate and methyl isobutyl ketone. [5] The method of claim 1, wherein step a) is carried out according to a second method a'') in which a mixture of a protic acid and the compound 1-[3,5-Dihydroxyphenyl]-2-[[2-(4-Hydroxyphenyl)-1-methylethyl](phenylmethyl)amino]ethanone is prepared, wherein the protic acid is selected from fumaric acid, succinic acid and acetylsalicylic acid, in an alcohol selected from methanol, ethanol and isopropanol, alone or mixed with water. [6] Method according to any one of claims 2 to 5, wherein the reaction temperature of step a') or step a'') is in the range of 10 to 30 °C. [7] Method according to claim 1, wherein step a) is carried out according to a third method a'''), comprising producing a two-phase system comprising a water-immiscible organic solvent in which the compound 1-[3,5-Dihydroxyphenyl]-2-[[2-(4-hydroxyphenyl)-1-methylethyl](phenylmethyl)amino]ethanone is dissolved, and a phase of water and an alcohol selected from methanol, ethanol and isopropanol, and in which a protic acid selected from maleic acid, acetic acid, hydrobromic acid and sodium hydrogen sulfate is present, and evaporating the water-immiscible organic solvent. [8] Method according to any one of claims 2 to 4, wherein, prior to carrying out step b), an alcohol selected from methanol, ethanol and isopropanol is added to the two-phase system, which is operated at a temperature in the range of 0 to 30 °C. [9] A method according to any of the preceding claims, wherein the reduction reaction of step b) is carried out with a hydride consisting of sodium borohydride, lithium borohydride, calcium borohydride, zinc borohydride and lithium cyanoborohydride, which is used in a molar ratio of at least 2, based on the moles of intermediate A to be reduced, at a temperature in the range of 0 to 35 °C. [10] Method according to any of the preceding claims, wherein the reaction of step c) is carried out by the following series of operations: - Addition of a base to the hydroalcoholic solution from step b) in such an amount that the pH of the solution is in the range of 6 to 8, while maintaining the temperature in the range between 0 and 25 °C; - before or after the addition of a base, evaporation of the alcohol present in the hydroalcoholic solution under reduced pressure, thereby obtaining a suspension of intermediate C in water; - Addition of an organic solvent selected from ethyl acetate, isopropyl acetate and methyl isobutyl ketone, pure or mixed with methanol, to the suspension while stirring until dissolution, thereby obtaining a two-phase system consisting of an aqueous phase and an organic phase; - Adjusting the pH of the aqueous phase to a value greater than or equal to 8, preferably in the range of 8.5 to 10, using a base selected from aqueous ammonia solution, NaOH, KOH, LiOH, Na2 CO3, K2 CO3, NaHCO3 and KHCO3; - Separation of the phases and concentration of the organic phase under reduced pressure, resulting in an organic solution containing the intermediate product C. [11] A method according to any of the preceding claims, wherein, prior to step d), an alcohol selected from methanol, ethanol and isopropanol is added to the organic solution obtained at the end of step c), and the resulting solution is added to fumaric acid or, conversely, fumaric acid is added to this solution at a temperature in the range of 20 to 65 °C, and the mixture thus obtained is stirred at a temperature in the range of 0 to 35 °C for at least 8 hours, resulting in the precipitation of a solid which is filtered off to obtain the crude intermediate D. [12] Method according to any of the preceding claims, wherein in step e) the intermediate product D is suspended in a linear or branched aliphatic C1-C5 alcohol, the resulting suspension is first stirred under reflux and then at 20-25 °C and finally the product is recovered by filtration, and wherein step e) is repeated two or three times. [13] A method according to any of the preceding claims, further comprising a further step of the conversion of the 5-{(1RS)-2-[benzyl-((1RS)-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol hemifumarate to fenoterol hydrobromide by the following steps: - Formation of 5-{(1RS)-2-[Benzyl-((1RS)-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol-hydrobromide by reaction of the hemifumar with a base; - Elimination of the benzyl group bonded to the nitrogen atom of 5-{(1RS)-2-[benzyl-((1RS)-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol by catalytic hydrogenation; - Isolation of the desired product by crystallization from the solvent using the hot-cold technique.

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