Process for preparation of 5-{2-[benzyl-(1-(4-hydroxyphenyl)-1-methylethyl) amino]-1-hydroxyethyl} benzene-1, 3-diol hemifumarate

Abstract

The invention relates to an industrial large-scale preparation method of 5-{2-[benzyl-(1-(4-hydroxyphenyl)-1-methylethyl) amino]-1-hydroxyethyl} benzene-1, 3-diol hemifumarate, the salt is composed 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 the two molecules of fumaric acid are different from each other. The compound has the following structural formulas (2) and (1). The 5-{2-[benzyl-(1-(4-hydroxyphenyl)-1-methylethyl) amino]-1-hydroxyethyl} benzene-1, 3-diol hemifumarate is a useful intermediate for synthesizing 5-[(1RS)-2-[(1RS)-2-(4-hydroxyphenyl)-1-methylethyl) amino]-1-hydroxyethyl] benzene-1, 3-diol hydrobromide, and the common name of fenoterol hydrobromide in the pharmaceutical field is known by people.

Description

TECHNICAL FIELD

[0001] The present invention relates to the field of synthetic processes of pharmaceutically active ingredients, in particular to a process for the industrial scale preparation of 5-{2-[benzyl-(1-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol hemifumarate, which consists 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, having the following structural formula:

[0002] 5-{2-[benzyl-(1-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol hemifumarate is a useful intermediate for the synthesis of 5-[(1RS)-2-[(1RS)-2-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl]benzene-1,3-diol hydrobromide. BACKGROUND

[0003] The compound 5-[(1RS)-2-[(1RS)-2-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl]benzene-1,3-diol, also known as Fenoterol hydrobromide, has the following structure: .

[0004] As reported in the European Pharmacopoeia, 10.0 edition, page 2618, this compound, having the CAS number 1944-12-3, belongs to the class of beta-adrenergic receptor agonists and sympathomimetic agents.

[0005] Such derivatives are useful for the preparation of medicaments for the treatment of bronchospasm associated with asthma and bronchitis and for the treatment of reversible airway obstruction, such as bronchodilators.

[0006] Fenoterol was first described in US Patent No. 3,341,593, which describes a class of compounds having the following general formula: , wherein R can be hydrogen or methyl, hydrogen in the case of Fenoterol. The patent also discloses the possibility of using the compounds of the above general formula in the form of their salts, obtained by reacting the compound with a pharmacologically acceptable acid, such as hydrobromic acid (HBr).

[0007] However, in the summary of the invention of US 3,341,593, it is only very generally reported that due to the presence of one or two stereogenic centres ("asymmetric carbon atoms"), a mixture of isomers is formed; said stereogenic centres are indicated by the arrows in the following structural formula: , For fenoterol, where R is hydrogen, there are two stereogenic centres and four possible isomers, namely two diastereoisomers (RR, SS; RS, SR) as pairs of enantiomers. As reported in the cited European Pharmacopoeia, the mixture of isomers used as active ingredient is a mixture consisting of the RR, SS pair of enantiomers, which has a favourable pharmacological activity.

[0008] In the summary of the invention of US 3,341,593, the synthesis method is also described in general terms, but it does not specify how to obtain the desired mixture of stereoisomers.

[0009] The racemic compound similar to fenoterol, which is commercially available on the market, consists of the following pair of enantiomers This suggests to the chemist in the field a possible synthesis route, i.e. the reduction of the carbonyl function, which should allow obtaining a favourable imbalance of isomers by exploiting the stereogenic centres already present in the molecule (indicated by the arrows). Therefore, the skilled person has reason to believe that the RR product is mainly obtained from the R isomer and the SS isomer from the S isomer.

[0010] The applicant of the present application has experimentally tested this method through a laboratory-scale screening based on about 200 reduction experiments, in which heterogeneous or homogeneous catalysts, chiral and achiral additives, different solvents, temperatures, pressures and pH of the solutions were used. This experimental protocol, although it has achieved some excellent results in terms of yield of the carbonyl -> alcohol conversion (greater than 95%), in the most favourable cases, the RR, SS and RS, SR isomer ratio is 60 / 40. Due to the pre-existing stereogenic centres, the expected effect of asymmetric induction is much lower than expected and the RR, SS isomer ratio in the synthesis product with respect to the RS, SR isomers is not desirable.

[0011] After synthesis, repeated crystallisation is required to obtain the final mixture, in which the content of isomers with a favourable pharmacological activity complies with the values provided by the European Pharmacopoeia, 10.0 edition, but the overall yield is extremely low, making the solution industrially unacceptable.

[0012] In view of the above, there is therefore a need for an effective and industrially applicable method which allows maximising the formation of the RR, SS isomer mixture, rather than the RS, SR mixture. SUMMARY

[0013] The object is achieved by the present application, 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, which can be easily and in high yield converted into fenoterol hydrobromide.

[0014] The process of the present application comprises the following steps: a) preparing a solution comprising 1-[3,5-dihydroxyphenyl]-2-[[2-(4- hydroxyphenyl)-1-methylethyl](phenylmethyl)amino]ethanone and a protonic acid (HA) in a solvent selected from: - water; - an alcohol selected from methanol, ethanol and isopropanol, preferably methanol; - a mixture formed by water and an alcohol selected from methanol, ethanol and isopropanol, preferably methanol; obtaining a salt (intermediate A) having the following structural formula: , wherein A represents the deprotonated portion of the protonic acid HA; b) reducing the carbonyl function of intermediate A to obtain intermediate B:

[0015] c) treating intermediate B with a base and a water-immiscible organic solvent to obtain an organic solution of 5-{2-[benzyl-(1-(4-hydroxyphenyl)-1-methylethyl)amino]-1-hydroxyethyl}benzene-1,3-diol (intermediate C):

[0016] d) adding fumaric acid to the organic solution obtained in step c) or adding the organic solution obtained in step c) to fumaric acid, thus precipitating the hemifumarate salt (intermediate D) in crude form, formed by two molecules of intermediate C and one molecule of fumaric acid:

[0017] e) purifying 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 DRAWINGS

[0018] - Figure 1X-ray diffractogram (XRPD) of the product of the application is shown; Figure 2 DSC thermogram performed on the product of the application is shown. DETAILED DESCRIPTION

[0019] The present application 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 steps a) to e).

[0020] Step a) involves 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):

[0021] wherein A represents the deprotonated part of the protic acid HA, i.e. the conjugate base.

[0022] Step a) can be carried out according to one of the alternative methods a'), a") and a'"): a') mixing an aqueous solution of a protic acid with a solution of 1-[3,5-dihydroxyphenyl]-2-[[2-(4-hydroxyphenyl)-1-methylethyl](phenylmethyl)amino]ethanone in a water-immiscible organic solvent, to obtain a two-phase system; a") preparing a mixture of a protic acid with the compound 1-[3,5-dihydroxyphenyl]-2-[[2-(4-hydroxyphenyl)-1-methylethyl](phenylmethyl)amino]ethanone in an alcohol selected from methanol, ethanol and isopropanol, or in a mixture consisting of water and one of these alcohols; when the alcohol is used alone or in mixture with water, the alcohol is preferably methanol; a'") preparing 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 consisting of water and an alcohol selected from methanol, ethanol and isopropanol, in which the protic acid is present; followed by evaporation of the water-immiscible organic solvent.

[0023] The protic acid used in the salification operation of the starting compound can be an organic acid or an inorganic acid.

[0024] In the case of method a'), when an organic protic acid is used, the acidic aqueous solution is prepared using any 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).

[0025] Preferably, L(+) tartaric acid, D(-) tartaric acid and DL-tartaric acid are used.

[0026] The aqueous solution is prepared so that the concentration of the acid in water is 15-20 wt% and the pH of the aqueous solution is < 6.

[0027] The organic solvent used for initially dissolving the compound 1-[3,5-dihydroxyphenyl]-2-[[2-(4-hydroxyphenyl)-1-methylethyl](phenylmethyl)amino]ethanone can be selected from the group consisting of isopropyl acetate, methyl acetate, methyl isobutyl ketone and, preferably, ethyl acetate.

[0028] To the solution of 1-[3,5-dihydroxyphenyl]-2-[[2-(4-hydroxyphenyl)-1- methylethyl](phenylmethyl)amino]ethanone dissolved in the organic solvent, an amount of aqueous protonic acid is added so that the pH of the resulting aqueous solution is less than 6, preferably between 3 and 4.

[0029] In the case of method 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 alone or mixed with water and a protonic acid; the alcohol is selected from the group consisting of ethanol, isopropanol and, preferably, methanol, and the protonic acid is selected from the group consisting of: - fumaric acid (CAS 110-17-8); - succinic acid (CAS 110-15-6); - acetylsalicylic acid (CAS 50-78-2).

[0030] The protonic acid used to perform method a”) is preferably acetylsalicylic acid.

[0031] In the case of method a’) and in the case of method a”), the reaction temperature is between 10 and 30 °C, preferably between 20 and 25 °C.

[0032] Finally, the inventors noticed that, when operating according to the procedure of step a'), the use of certain protic acids does not cause the extraction of intermediate A in the aqueous phase; these acids are maleic acid (CAS 110-16-7), acetic acid (CAS 64-19-7), hydrobromic acid (CAS 10035-10-6) and sodium bisulfate (CAS 7681-38-1). In this case, it is operated according to procedure a'"), in which the organic solvent is evaporated from the two-phase system, methanol is added, obtaining an aqueous alcoholic solution containing intermediate A.

[0033] The protic acid used to perform procedure a'") is preferably maleic acid.

[0034] By operating according to any one of procedures a'), a") or a'"), a solution containing intermediate A suitable for use in the next step of the process is obtained.

[0035] Step b) involves the reduction of the carbonyl function of intermediate A to obtain intermediate B:

[0036] If step a) is performed according to procedure a'), the solution containing intermediate A does not contain an alcohol, the preliminary operation of step b) is the addition of an alcohol to said solution at a temperature of 0-30°C (preferably 0-15°C), said alcohol being selected from methanol, ethanol and isopropanol; the preferred alcohol is methanol.

[0037] The solution containing intermediate A obtained from step a) performed according to procedure a") or a'") or from the above preliminary operation is used for the reduction reaction of the carbonyl function.

[0038] The reaction is performed using a hydride selected from sodium borohydride (NaBH4), lithium borohydride (LiBH4), calcium borohydride (Ca(BH4)2), zinc borohydride (Zn(BH4)2) and lithium cyanoborohydride (LiBH3CN); the preferred one is sodium borohydride.

[0039] The molar ratio of the hydride used to intermediate A to be reduced is equal to or greater than 2. The reduction reaction can be completed by further adding the hydride and adding the protic acid used in step a); the acid is added while further adding the hydride in order to maintain the pH of the solution in the acidic range.

[0040] The reduction reaction is performed at a temperature of 0°C-35°C, preferably 0°C-25°C.

[0041] As a result of the reaction, an aqueous alcoholic solution containing intermediate B is obtained, which can be used directly in the next step.

[0042] Step c) involves treating the intermediate B in a hydroalcoholic solution with a base and a water-immiscible organic solvent, to obtain an organic solution of 5-{2-[benzyl-(1 -(4-hydroxyphenyl)-1 - methylethyl)amino]-1 -hydroxyethyl}benzene-1,3-diol (intermediate C): .

[0043] This step is carried out by a series of operations.

[0044] In the first operation, the base is added to the hydroalcoholic solution of step b) in an amount such that the pH of the solution is between 6 and 8, preferably between 6.5 and 7.5.

[0045] The base can be added in solid form, if the nature of the base allows it, or in aqueous solution. Suitable bases for carrying out step c) are aqueous ammonia, NaOH, KOH, LiOH, Na2CO3, K2CO3, NaHCO3, KHCO3. Preferably, NaOH is used. To carry out step c), the temperature is maintained between 0°C and 25°C, preferably between 0°C and 5°C.

[0046] Then, the hydroalcoholic solution is evaporated by operating under reduced pressure, obtaining a suspension formed by intermediate C in water.

[0047] Alternatively, the order of addition of the base and evaporation of the alcohol can be interchanged, i.e. the alcohol is first evaporated, obtaining an aqueous solution of intermediate B, to which the base is then added.

[0048] The mixture is then mixed with an organic solvent selected from ethyl acetate (AcOEt), isopropyl acetate (AcOiPr) and methyl isobutyl ketone (MIBK), pure or mixed with methanol, until dissolution is achieved; after this operation, a two-phase system is formed, consisting of an aqueous phase and an organic phase.

[0049] The pH of the aqueous phase is then adjusted to greater than or equal to 8, preferably between 8.5 and 10, using a base. For this operation, aqueous ammonia, NaOH, KOH, LiOH, Na2CO3, K2CO3, NaHCO3 and KHCO3 can be used; the preferred bases are NaOH and NaHCO3.

[0050] The phases are then separated under reduced pressure and the organic phase is concentrated, obtaining an organic solution containing intermediate C.

[0051] Step d) involves the precipitation of the hemifumarate salt (crude intermediate D) from the organic solution containing intermediate C, in the presence of fumaric acid: .

[0052] To perform step d), the alcohol (selected from the group consisting of methanol, ethanol and preferably isopropanol) is added to the concentrated organic solution containing intermediate C obtained at the end of the previous step at a temperature ranging from 20°C to 65°C (preferably from 20°C to 60°C) and the resulting solution is added to fumaric acid or vice versa.

[0053] The resulting reaction mixture is then stirred at a temperature ranging from 0°C to 35°C (preferably from 15°C to 30°C) for at least 8 hours, preferably from 16 to 24 hours; after this operation, the precipitation of a solid is observed, which is filtered to obtain crude intermediate D.

[0054] Finally, step e) of the process of the present application involves the purification of crude intermediate D to obtain the product defined hereinafter as pure hemifumarate, wherein the ratio of the isomers RR, SS: RS, SR reaches or is better than the desired ratio: .

[0055] To perform step e), intermediate D (crude hemifumarate) is suspended in an aliphatic, linear or branched C1-C5 alcohol; preferably methanol is used. The resulting suspension is stirred under reflux conditions and then stirring is continued at 20-25°C. The product is recovered by filtration.

[0056] The purification process is repeated several times to bring the content of the unwanted isomers RS, SR to less than 5%; usually, 2-3 purifications are required to achieve this result.

[0057] The content of the unwanted isomers of the compound 5-{(1 RS)-2-[benzyl-((1 RS)-(4-hydroxyphenyl)-1 -methylethyl)amino]-1 -hydroxyethyl}benzene-1,3-diol fumarate (2:1 ) thus obtained is lower than the initial value in intermediate D and it can be used as intermediate to undergo chemical reactions within the knowledge of the skilled chemist (some of which are illustrated in the experimental part), obtaining fenoterol hydrobromide complying with the provisions of the European Pharmacopoeia, 10.0 edition. In short, the process described above for the conversion of the pure hemifumarate into fenoterol hydrobromide involves the initial formation of 5-{(1 RS)-2-[benzyl-((1 RS)-(4-hydroxyphenyl)-1 -methylethyl)amino]-1 -hydroxyethyl}benzene-1,3-diol hydrobromide by means of a common acid-base reaction, followed by the removal of the benzyl group linked to the nitrogen atom by catalytic hydrogenation and finally the separation of the desired product by means of a hot-cold technique, using simple solvent crystallization.

[0058] Table 1 shows the results related to isomer imbalance obtained with the method of the present application (wherein run 1 is for comparative purposes); the isomer ratio was calculated for intermediate C prepared according to steps a), b) and c).

[0059] Table 1

[0060] Therefore, the advantage of the present application is to provide a useful method for the synthesis of an intermediate of fenoterol hydrobromide, wherein, during the synthesis, the stereoisomer predominantly formed is obtained, which, upon conversion to fenoterol, generates at the end of the synthesis process a racemic body complying with the provisions of the European Pharmacopoeia, 10.0 edition, without the need for long and laborious purification processes, such as column chromatography or repeated crystallization.

[0061] The present application will be further illustrated by the following examples.

[0062] Instruments, methods and experimental conditions HPLC: analytical method for intermediates A, B, C, D Instruments: Agilent Technologies 1100, 1200 series or 1260 Infinity; Chromatographic column: Inertsil ODS-3; 150 mm x 4.6 mm x 3.0 µm; Flow rate: 0.8 mL / min; Detector: 222 nm (DAD); Bandwidth and reference wavelength of the DAD detector: 4 nm, 360 nm, 40 nm; Temperature: 35°C; Injection volume: 10 µL; Pressure at t=0': 123 bar.

[0063] Mobile phase Mobile phase "A": CH3COONH 4(aq) 0.77 g / L; Mobile phase "B": CH3CN.

[0064] Gradient of the method

[0065] The sample was prepared at a concentration of 0.25 g / L with a mixture of mobile phase "A" / mobile phase "B" 80 / 20 (v / v) for the run.

[0066] The sample was dissolved in the mobile phase "B" until a milky heterogeneous solution was obtained, then the mobile phase "A" was added to volume, obtaining a homogeneous, colorless and clear solution.

[0067] The percentage of RR, SS isomers and RS, SR isomers related to intermediates C and D was determined according to the values of the percentage of 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).

[0068] NMR: Spectrometer: NMR JEOL 400 YH (400 MHz); Software: JEOL Delta v5.1.1; The spectra were recorded in deuterated solvents, for example: chloroform-d (D 99.8%), with 0.1% (v / v) tetramethylsilane (TMS) as internal standard; chloroform-d ("100%", D 99.96%), with 0.03% (v / v) TMS; and DMSO-d6.

[0069] MS: Instrument: Agilent 1260 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 voltage: 70 V; Positive, negative polarity; Gas temperature: 350°C; Gas flow rate: 12 L / min; Atomizer: 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: H2O + 0.10% HCOOH / CH3CN + 0.10% HCOOH 50% / 50% (v / v).

[0070] TLC MERCK: TLC Silica gel 60 F254 aluminum foil plates 20 x 20 cm, cod. 1.0554 / 0001.

[0071] TLC detector Cerium phosphomolybdate: 25 g of phosphomolybdic acid and 10 g of cerium (IV) sulfate were dissolved in 600 mL of H2O. 60 mL of 98% H2SO4 were added and the resulting mixture was brought to 1 L with water. The thin layer plates were immersed in this solution and then heated until the product was detected. Lamp detector: UV 254 nm and 366 nm.

[0072] XPRD XRPD analysis was performed using a Bruker ® D2 Phaser diffractometer (second edition). The X-ray source was an X-ray tube with a copper anode, operating at 30 kV and 10 mA. The analysis wavelength used was the copper K-alpha radiation (l = 1.54184 A). The K-beta radiation was filtered by a nickel filter. The X-ray detector was a solid-state linear detector, model LYNXEYE. The samples were coated in the form of a thin layer on a "zero background" silicon sample holder. The diffractograms were recorded in the angular range 4.0-40° 2Q, with a scan increment of 0.016° and a scan speed of 1.0 s / increment. During the analysis, the sample was rotated at a speed of 60 rpm. The data were analyzed using the DIFFRAC.EVA software (Bruker). It should be understood that all the angular values reported below are subject to an approximate error of about ± 0.2°.

[0073] DSC DSC analysis was performed using a Mettler Toledo DSC3 instrument, operating under a nitrogen atmosphere. The samples were prepared in 40 pL aluminum crucibles, equipped with a lid, which were crimped using a suitable crimper before the analysis, and then perforated on the lid to allow the free escape of gases possibly generated from the sample. The analysis was performed with a constant heating rate of 10 °C / min. The data were analyzed using the STARe software (Mettler Toledo).

[0074] Notes Unless otherwise indicated, the water used in the experimental descriptions should be understood as purified water.

[0075] Unless otherwise indicated, the organic solvents used in the experimental descriptions should be understood as "industrial" grade.

[0076] Unless otherwise indicated, the reagents and catalysts used in the experimental descriptions should be understood as of commercial quality.

[0077] In the following examples, the term "small volume" is used to describe the volume of the solution after the distillation step, meaning 10% or less of the starting volume.

[0078] The following conventions and abbreviations are used in the following examples: - a solution concentration expressed in percentage is to be understood as a mass percentage concentration, unless otherwise specified; - MIBK: methyl isobutyl ketone; - DCM: dichloromethane; - MeOH: methanol; - IPA: isopropyl alcohol; - AcOEt: ethyl acetate; - Pd / C 5%: palladium supported on carbon, mass percentage of Pd being 5%.

[0079] Example 1 This example relates to the preparation of compound 2, which is a precursor compound used in the process of the application.

[0080]

[0081] Dissolve 200 g of 4-methoxypropiophenone in 1200 mL of toluene and charge the flask. Bring the system to reflux and add benzylamine (168 g) over 1 hour while maintaining the reflux temperature and removing the water formed. Flush the line with 15 mL of toluene. Once the reaction is complete, remove 500 mL of toluene by distillation under non-vacuum conditions, followed by vacuum distillation of the system at 95°C to obtain an oily residue. Dissolve the residue in MeOH (1386 mL) under a nitrogen atmosphere and cool the solution to 0°C. Add sodium borohydride (16 g) in portions and stir the mixture at 0°C-5°C for 1 h. Once the reaction is complete, distill the mixture under vacuum until the residual volume is 500-600 mL. Add water (400 mL) and continue the distillation until the MeOH is completely removed. Dissolve the residue in 1120 mL of water and 640 mL of DCM. Separate the phases and re-extract the aqueous phase with DCM (100 mL). Combine the organic phases and wash with water (100 mL). Evaporate the organic phase solvent under vacuum. Dissolve the residue in MeOH (400 mL) and water (266 mL). Cool the system to <10°C and add dropwise a previously prepared solution of 37% HCl (133 g) and water (133 g). Stir the system at 0°C-5°C for 30 min, filter to obtain a solid and wash with water (270 mL). Dissolve the solid in toluene (1067 mL) and stir the suspension at 25°C for 30 min. Then filter the suspension and wash with toluene (107 mL). To the recovered solid, add toluene (667 mL) and water (400 mL). Add dropwise 30% sodium hydroxide (177 g) while maintaining the temperature <30°C. Separate the phases and re-extract the aqueous phase with toluene (213 mL). Combine the organic phases and wash with water (270 g). Evaporate the solvent and recover 226 g of compound 1.

[0082] Dissolve compound 1 (100 g; 0.392 mol) in 48% aqueous HBr (670 mL, 5.913 mol) at 50°C. Add dropwise an additional 60 mL of 48% H2O / HBr solution (5:1 v / v). Heat the reaction mixture to 110°C-120°C and continue stirring for 4 hours. The reaction is complete as detected by TLC. Cool the mixture to 0°C-5°C and continue stirring for 1 hour. Filter the precipitate (hydrobromide salt of compound 2) and wash with 48% H2O / HBr solution (5:1 v / v). Dissolve the precipitate in 210 mL of H2O and 85 mL of MIBK, then add NH4OH until the pH >10. Continue stirring the system at 0°C-5°C for 1 hour. Filter the precipitate and wash with cold MIBK and H2O, and finally dry at 50°C; recover the product 2 (79.34 g), which can be used directly in the subsequent reaction.

[0083] Example 2 This example relates to the preparation of compound 4, which is a precursor compound used in the process of the present application.

[0084]

[0085] Compound 3 (diacetoxyacetophenone) is a commercial product.

[0086] Compound 3 (100 g; 0.424 mol) was dissolved in DCM (500 mL) under a stream of nitrogen. The system was cooled to 10-15°C and then a solution of HCI in IPA (1.53 mL) was added dropwise to the system. The system was continuously stirred for 5 minutes, cooled to 0-5°C and a solution of Br2(23.87 mL; 0.466 mol) was added dropwise to the system maintaining the temperature T < 10°C. The system was continuously stirred for 30 minutes at 0-5°C. A solution of NaHC03(9 g) in H20 (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 re-extracted with DCM (90 mL). The organic phases were combined and washed with H20 and then concentrated to a small volume under vacuum at 35°C. MeOH (180 mL) and H20 (45 mL) were added thereto. The system was continuously stirred for 30 minutes at 0-5°C. The precipitate was filtered and washed with a mixture of MeOH / H20 (35:10 v / v) at 5°C. (After drying under reduced pressure) 112.88 g of product 4 was recovered.

[0087] Example 3 This example relates to the preparation of compound 5, which is a precursor compound used in the process of the present application.

[0088]

[0089] Compound 4 (50 g; 0.159 mol) prepared according to the method described in Example 2 was dissolved in 300 mL of MIBK degassed under nitrogen. 100 mL of solvent were evaporated under vacuum. 40 mL of MIBK degassed under nitrogen were added to the solution of compound 4 under a nitrogen atmosphere. The solution was heated to 50°C and 76.58 g (0.317 mol) of compound 2 prepared according to the method described in Example 1 were added. The system was continuously stirred at 105°C for 1.5 hours. TLC control: reaction complete. The system was cooled to -10°C and stirring was continued for 1 h. The precipitate was filtered and washed with MIBK degassed under nitrogen. The solvent was evaporated under vacuum at 50°C and the product 5 was recovered, which can be used directly in the reactions of the following examples.

[0090] Example 4 This example relates to the preparation of compound 6, which is a precursor compound used in the process of the application.

[0091]

[0092] A 20% aqueous solution of L(+)-tartaric acid (95.4 g; 0.636 mol dissolved in 380 mL of H2O) was prepared. 260 mL of the aqueous tartaric acid solution were added to the organic phase (solution containing intermediate 6, prepared according to the method described in the previous example). The system was kept under stirring at 20°C < T < 25°C for 10 minutes, then the phases were separated. The organic phase was re-extracted with the remaining acid solution. The acidic aqueous phases were combined and washed with AcOEt (105 mL). At 55°C under vacuum, 70 mL of the aqueous acid solution were evaporated; the remaining part containing the product (intermediate A) was used directly in the reaction of the following example.

[0097] Example 5 This example relates to step a') of the application. J J J = J J A 20% aqueous solution of L(+)-tartaric acid (95.4 g; 0.636 mol dissolved in 380 mL of H2O) was prepared. 260 mL of the aqueous tartaric acid solution were added to the organic phase (solution containing intermediate 6, prepared according to the method described in the previous example). The system was kept under stirring at 20°C < T < 25°C for 10 minutes, then the phases were separated. The organic phase was re-extracted with the remaining acid solution. The acidic aqueous phases were combined and washed with AcOEt (105 mL). At 55°C under vacuum, 70 mL of the aqueous acid solution were evaporated; the remaining part containing the product (intermediate A) was used directly in the reaction of the following example. J For analytical purposes, an aliquot of the solution containing intermediate A was basified with saturated aqueous NaHCO3solution and then extracted with AcOEt, chromatographed on silica gel eluting with toluene / AcOEt in a gradient from 8 / 2 to 1 / 1.

[0098] The residue obtained (HPLC purity > 90%) was analyzed, providing 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 = 8.6Hz 2H), 6.80 (d, J = 1.6Hz, 2H), 6.61 (d, J = 8.6Hz 2H), 6.44,(d, J = 1.6Hz, 1H), 3.89 (s, 2H), 3.69 (ABq, J =14.2Hz, 2H), 2.88-2.80 (m, 2H),2.38-2.33 (m, 1H), 0.90(d, J = 6.4Hz, 3H)。

[0098] 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.

[0099] Example 6 This example relates to the process of the application carried out in the order of steps b), c), d) and e).

[0100]

[0101] MeOH (485 mL) was added to the aqueous solution of intermediate A (prepared according to the procedure described in example 5) at 0-5°C.

[0102] NaBH4(21.15 g, 0.557 mol) was added portionwise to the new solution while maintaining T < 10°C. The system was continuously stirred at 0-5°C for 30 minutes. The control by TLC test confirmed that the reaction was not complete. L(+)-tartaric acid (47.7 g, 0.318 mol) and NaBH4(14.5 g, 0.38 mol) were added portionwise, then the system was continuously stirred at 0-5°C for 1 hour, the control by TLC test confirmed that the reaction was complete. A solution containing intermediate B was finally obtained.

[0103] To this solution 50 mL of 30% NaOH solution was added, keeping the temperature at 0-5°C until reaching pH 7. The methanol was evaporated under vacuum at 50°C. 430 mL of AcOEt / MeOH mixture (95:5 v / v) was added and the system was kept under constant stirring at 50°C until the product was completely dissolved. The solution was cooled to 20°C, 75 mL of 30% NaOH solution was added to reach pH 8 and 200 mL of saturated NaHC03 aqueous solution was added to reach pH 8.5 / 9. The phases were separated and the aqueous phase was re-extracted with 330 mL of AcOEt / MeOH mixture (95:5 v / v). The organic phases were combined and the resulting phase was washed with H20 and concentrated under vacuum at 50°C to a residual volume of 485 mL. This operation gave an organic solution containing intermediate C. To the resulting solution 86 mL of IPA was added and the resulting solution was added to fumaric acid (23.99 g; 0.208 mol) at 50°C. The system was kept under constant stirring at 25°C for 16 hours. The formation of a precipitate was observed, which was filtered off and washed with AcOEt / IPA mixture (95:5 v / v, 140 mL). The solid was dried at 48°C and 42.75 g of crude intermediate D was recovered.

[0104] The solid sample obtained was analyzed by HPLC, which showed a ratio of RR, SS to RS, SR of 82:18.

[0105] Crude intermediate D (20 g; 0.044 mol) was suspended in 200 mL of MeOH and the system was kept under constant stirring at reflux for 1 h, then cooled to 25°C and kept under constant stirring for 1 h. The precipitate was filtered off, washed with 30 mL of AcOEt / MeOH mixture (95:5 v / v) and finally dried at 50°C to give 14.77 g of crude intermediate D.

[0106] The solid sample obtained was analyzed by HPLC, which showed a ratio of RR, SS to RS, SR of 93:7.

[0107] The crude intermediate D obtained was suspended in 75 mL of MeOH and the system was kept under constant stirring at reflux for 1 h, then cooled to 25°C and kept under constant stirring for 1 h. The precipitate was filtered off, washed with 20 mL of AcOEt / MeOH mixture (95:5 v / v) and finally dried at 50°C to give 13.4 g of pure hemi-fumarate salt.

[0108] The solid sample obtained was analyzed by HPLC, which showed a ratio of RR, SS to RS, SR of 96:4.

[0109] The hemifumarate obtained at the end of the purification process was analyzed, and the following results are provided: 1 H-NMR (400 MHz, DMSO-d6): 1 H-NMR (400 MHz, DMSO-d6): δ 9.06 (bs, 3H),7.31-7.21 (m, 5H), 6.86 (d, J = 8.4Hz 2H), 6.65 (d, J = 8.4Hz, 2H), 6.62 (s, 1H), 6.15 (d, J = 2Hz, 2H), 6.05(t, J = 2Hz, 1H), 4.29 (t, J = 6.4Hz, 1H), 3.70 (ABq, J = 13.8Hz, 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).

[0110] (*Due to the presence of residual solvent peaks, the integral of the signal at 2.53–2.50 is equal to 5 instead of 2).

[0111] 13 C-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.

[0112] Mass (CI): m / z = 394 [M++1] XRPD testing provides Figure 1 The diffraction pattern is shown below; a list of XPRD diffraction peaks is also provided.

[0113] The strongest peaks are those that appear at 2θ of 6.83°, 9.88°, 11.41°, 16.43°, 16.70° and 22.10° ± 0.2°.

[0114] A DSC calorific value was determined for a 7.1 mg fennotefuranoside hemifumarate sample; the chromatogram is shown below. Figure 2The most characteristic values detected in DSC calorimetry are: an endothermic peak at 156°C with an onset temperature of 149°C; an endothermic peak at 175°C with an onset temperature of 167°C.

[0115] Example 7 This example relates to the preparation of crude fenoterol hydrobromide starting from the hemifumarate prepared according to the method described in Example 6.

[0116]

[0117] To the hemifumarate (4.08 g; 0.009 mol) was added 30 mL H2O and 40 mL AcOEt / MeOH (95:5 v / v) mixture, followed by 1 mL of 30% NaOH to pH 7.5 and 20 mL of NaHCO3 saturated aqueous solution to pH 9. The system was kept under constant stirring at 50°C for 15 minutes, then cooled to 25°C and the phases were separated. The aqueous phase was re-extracted with 15 mL of AcOEt / MeOH mixture (95:55 v / v). The combined organic phases were washed with H2O. The organic phase solvent was evaporated under vacuum at 50°C and the product shown in the following structural formula was recovered as a free base:

[0118] To the free base (3.55 g; 0.009 mol) was added MeOH (22 mL), 48% HBr (adjusted to pH 4-5) and 5% Pd / C (0.407 g). The solution was hydrogenated with a balloon at 40°C for 3 hours. The reaction was complete as controlled by TLC. The solution was filtered through celite and concentrated under vacuum at 50°C to a small volume. AcOEt (18 mL) was added and the solution was concentrated under vacuum at 50°C to a small volume. Then 35 mL of AcOEt / MeOH mixture (95:5 v / v) was added. The system was kept under constant stirring at 50°C for 10 minutes and then at 25°C for 16 hours. The precipitate was filtered, washed with 5 mL of AcOEt / MeOH (95:5 v / v) mixture and dried at 50°C, recovering 2.84 g of crude fenoterol hydrobromide.

[0119] Example 8 This example relates to the purification of fenoterol hydrobromide obtained in the previous examples.

[0120]

[0121] 10.50 g of fenoterol hydrobromide prepared according to the method described in Example 7 was suspended in 95 mL of degassed water for injection (PPI water). The system was heated to 50°C until the solid was 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, then filtered through diatomaceous earth and washed 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 was added. The system was concentrated to a small volume under vacuum at 50°C. Another 40 mL of degassed AcOH was added. The system was cooled to 25°C and stirred continuously for 1 h. The precipitate was obtained, filtered, and washed with 10 mL of degassed AcOH and two 15 mL aliquots of degassed AcOEt, recovering 9.29 g (wet) pure fenoterol hydrobromide.

[0122] 6.34 g of pure fenoterol hydrobromide was 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 48% HBr aqueous solution (diluted 1:10 with PPI water) was added to adjust the pH to 4. The aqueous solution containing the product was filtered through a Millipore filter to remove any impurities, and then 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. Another 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 thick suspension was obtained. 60 mL of AcOEt (degassed and filtered through a Millipore filter) was added, and the system was refluxed at a jacket temperature of 100 °C for 3 h, with water condensed during reflux periodically removed.

[0123] The system was cooled to 25°C and maintained at that temperature for 1 h, then filtered and washed with 5 mL of AcOEt. The product was dried under vacuum at 50°C for 2 h, and 5.98 g of fenoterol hydrobromide conforming to the European Pharmacopoeia, version 10.0, was recovered.

[0124] Example 9 This embodiment relates to the method of the present invention performed in the order of steps a), b), c), and d).

[0125]

[0126] The solution of 2.54 g containing intermediate 6, prepared according to the procedure described in example 4, was evaporated under vacuum. The residue was dissolved in 35 mL of MeOH; to the solution was added succinic acid (3.05 g, 0.0258 mol) and water (15 mL) and the system was continuously stirred until the solid was completely dissolved.

[0127] NaBH4(0.865 g; 0.023 mol) was added portionwise to the solution while maintaining T < 10°C. The system was continuously stirred at 25°C for 1 h. During this time, it was verified by TLC that the reaction was not complete. Succinic acid (3.05 g) was added and NaBH4(0.865 g) was added portionwise. The system was continuously stirred at 25°C for 30 min. Control by TLC verified that the reaction was complete. At 0-5°C, 30% NaOH was added to pH 7. Methanol was evaporated under vacuum at 50°C. A mixture of AcOEt / MeOH (95:5 v / v) was added (20 mL) and the system was continuously stirred at 50°C until the product was completely dissolved. The solution was cooled to 20°C and 30% NaOH was added to pH 8; subsequently, an aqueous solution of NaHCO3was added to reach a pH of 8.5-9. The phases were separated. The aqueous phase was re-extracted with a mixture of AcOEt / MeOH (95:5 v / v, 10 mL). The combined organic phases were washed with H2O. The organic phase was concentrated under vacuum at 50°C, evaporating about 12 mL of solvent, to obtain a solution containing intermediate C. To this solution was added 5 mL of IPA and the resulting solution was added to fumaric acid (0.981 g) while maintaining the system at 50°C. The system was continuously stirred at 50°C for 20 min and then at 25°C for 16 h. The precipitate was filtered and washed with a mixture of AcOEt / IPA (95:5 v / v, 5 mL) and dried at 50°C to obtain 1.55 g of crude intermediate D.

[0128] The HPLC analysis of the resulting solid sample showed a ratio of RR, SS and RS, SR of 81.5:18.5.

[0129] Example 10 This example relates to the process of the application carried out according to the order of steps a"), b), c) and d).

[0130]

[0131] A solution of maleic acid in water (11.14 g of maleic acid in 44.5 mL of water) was prepared. The solution of intermediate 6 in AcOEt (65 mL of solution containing 0.012 mol of intermediate) prepared according to the procedure described in example 4 was washed with the solution of maleic acid in water (the product was in the organic phase).

[0132] The organic solvent was evaporated from the two-phase system by rotary evaporation. MeOH (35 mL) was added under stirring until the presence of a solid was completely dissolved.

[0133] The system was cooled to 0-5°C and NaBH4(1.6 g; 0.042 mol) was added in portions while maintaining T < 10°C. The system was stirred at 5°C for 30 min. TLC control: the reaction was not complete. NaBH4(1.4 g; 0.037 mol) was added in portions while maintaining T < 10°C. The system was stirred at 5°C for 30 min. TLC control: the reaction was not complete. Maleic acid (5.78 g) dissolved in water (25 mL) and MeOH (25 mL) were added. NaBH4(1.91 g, 0.05 mol) was added in portions and the system was stirred at 5°C for 30 min. Water (10 mL) and MeOH (10 mL) were added to dissolve the precipitate formed. TLC control: the reaction was not complete. MeOH (25 mL) was added. Maleic acid (6.29 g) dissolved in water (30 mL) was subsequently added. NaBH4(1.29 g, 0.034 mol) was added in portions and the system was stirred at 5°C for 15 min. TLC control: the reaction was complete. 30% NaOH was added at 0-5°C until reaching a pH of about 8. Methanol was evaporated under vacuum at 50°C. A mixture of AcOEt / MeOH = 95 / 5 v / v (40 mL) was added and the system was stirred at 50°C until the product was completely dissolved. 50 mL of an aqueous solution of NaHCO3was added to reach a pH of about 8.5. The phases were separated and the aqueous phase was re-extracted twice with 20 mL of a mixture of AcOEt / MeOH = 95 / 5 v / v. The combined organic phases were washed twice with H2O (20 mL). The organic phase was concentrated under vacuum at 50°C and about 20 mL of solvent was evaporated to obtain a solution containing intermediate C. To this solution, IPA (7 mL) was added and the resulting solution was added to fumaric acid (1.8 g) while maintaining the temperature at 50°C. The system was stirred at 50°C for 1 h and then at 20°C for 16 h. The precipitate was filtered, washed with AcOEt (5 mL) and dried at 50°C to obtain 0.87 g of crude intermediate D.

[0134] The solid sample obtained was analyzed by HPLC, which showed a ratio of RR, SS to RS, SR of 86:14.

[0135] Example 11 This example relates to the process of the application carried out in the order of steps a"), b) and c).

[0136] An acidic aqueous solution (2.7 g 48% HBr and 4 mL water) was added to a solution of intermediate 6 (0.004 mol) prepared according to the method described in example 4 in AcOEt.

[0137] The biphasic 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 was raised to 0-5°C. NaBH4(0.456 g; 0.012 mol) was added in portions and the system was stirred at 5°C for 20 min. TLC control of the reaction: it was not complete. 48% HBr (1.81 mL) was added, then NaBH4(0.456 g; 0.04 mol) was added in portions. The system was stirred at 5°C for 20 min. The system was cooled to 0-5°C and 30% NaOH was added to about pH 7. The methanol was evaporated under vacuum at 50°C. 20 mL of a mixture AcOEt / MeOH = 95 / 5 and 10 mL water were added. The organic phase was washed with NaHCO 3(ss) The aqueous solution was adjusted to pH 8.8. The phases were separated and the aqueous phase was re-extracted with a mixture AcOEt / MeOH = 95 / 5 (30 mL). The combined organic phases were washed with H2O. The organic phase was concentrated under vacuum at 50°C to give intermediate C as an oil (2.19 g).

[0138] HPLC control showed a ratio of RR, SS to RS, SR of 78:22.

[0139] Example 12 This example relates to the process of the application carried out in the order of steps a"), b) and c).

[0140] A solution of NaHSO4was prepared dissolving NaHSO4(1.92 g) in 11 mL of water 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 complete dissolution. NaBH4(0.456 g; 0.012 mol) was added in portions, the temperature was lowered to 5°C and the system was stirred at this temperature for 20 min. TLC control: the reaction was not complete. At 5°C NaHSO4(3.84 g) was added and then NaBH4(0.912 g; 0.08 mol) was added in portions. The system was stirred at 25°C for 10 min and then cooled to 0-5°C, 30% aqueous NaOH was added to about pH 7. The methanol was evaporated under vacuum at 50°C. 11 mL of a mixture AcOEt / MeOH = 95 / 5 were added. The pH of the system was adjusted to about 8.5 with aqueous NaOH. The phases were separated and the aqueous phase was re-extracted with 20 mL of a mixture AcOEt / MeOH = 95 / 5. The combined organic phases were washed with H2O. The organic phases were concentrated under vacuum at 50°C to give intermediate C as an oil (1.92 g).

[0141] The ratio RR, SS and RS, SR was 80:20 in the HPLC control.

Claims

1. Process for the synthesis of 5-{2-[benzyl-(l-(4-hydroxyphenyl)-l- methylethyl)amino]-l-hydroxyethyl}benzene-l,3-diol hemifumarate, comprising the following steps: a) preparing a solution comprising l-[3,5-dihydroxyphenyl]-2-[[2-(4- hydroxyphenyl)-l-methylethyl](phenylmethyl)amino]ethanone and a protonic acid (HA) in a solvent selected from: - water; - an alcohol selected from methanol, ethanol and isopropanol; - a mixture formed by water and an alcohol selected from methanol, ethanol and isopropanol; obtaining a salt, intermediate A, having the following structural formula: ， wherein A" represents the deprotonated portion of the protonic acid HA; b) reducing the carbonyl function of intermediate A, obtaining intermediate B: c) treating intermediate B with a base and a water-immiscible organic solvent, obtaining an organic solution of 5-{2-[benzyl-(l-(4-hydroxyphenyl)-l- methylethyl)amino]-l-hydroxyethyl}benzene-l,3-diol (intermediate C): d) adding fumaric acid to the organic solution obtained in step c) or adding the organic solution obtained in step c) to fumaric acid, thus precipitating the hemifumarate salt in crude form (intermediate D), formed by two molecules of intermediate C and one molecule of fumaric acid: e) purifying crude intermediate D, obtaining the desired product, pure 5-{2-[benzyl-(l-(4-hydroxyphenyl)-l-methylethyl)amino]-l-hydroxyethyl}benzene-l,3-diol hemifumarate: 。 2. The method of claim 1, wherein, Step a) is carried out according to a first method a'), mixing an aqueous solution of a protonic acid with a solution of l-[3,5-dihydroxyphenyl]-2-[[2-(4- hydroxyphenyl)-l-methylethyl](phenylmethyl)amino]ethanone in a water- immiscible organic solvent, obtaining a two-phase system.

3. The method of claim 2, wherein, The aqueous solution of the protonic acid is prepared with a concentration of the protonic acid in water comprised between 15 and 20 wt% and the pH of the solution is < 6; the protonic acid is selected from L(+) tartaric acid, D(-) tartaric acid, DL-tartaric acid, citric acid, lactic acid and oxalic acid.

4. The method of any 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"), preparing a mixture of a protonic acid and the compound l-[3,5-dihydroxyphenyl]-2-[[2-(4- hydroxyphenyl)-l-methylethyl](phenylmethyl)amino]ethanone in a separate alcohol or in an alcohol mixed with water; the alcohol is selected from methanol, ethanol and isopropanol; the protonic acid is selected from fumaric acid, succinic acid and acetylsalicylic acid.

6. The method of any one of claims 2-5, wherein, The reaction temperature of step a') or step a") is comprised between 10 and 30 °C.

7. The method of claim 1, wherein, Step a) is carried out according to the third method a'") to prepare a two-phase system comprising: an organic solvent immiscible with water, said organic solvent having dissolved therein the compound 1-[3,5-dihydroxyphenyl]-2-[[2-(4-hydroxyphenyl)-1- methylethyl](phenylmethyl)amino]ethanone; and a phase consisting of water and an alcohol selected from methanol, ethanol and isopropanol, said phase having present a protic acid selected from maleic acid, acetic acid, hydrobromic acid and sodium bisulfate; followed by evaporation of the organic solvent immiscible with water.

8. The method of any one of claims 2-4, wherein, Before carrying out step b), an alcohol is added to the two-phase system, said alcohol being selected from methanol, ethanol and isopropanol, operating at a temperature comprised between 0 and 30°C.

9. The method according to any one of the preceding claims, wherein, The reduction reaction of step b) is carried out using a hydride selected from sodium borohydride, lithium borohydride, calcium borohydride, zinc borohydride and lithium cyanoborohydride, at a temperature comprised between 0 and 35°C; the molar ratio between the hydride used and the intermediate A to be reduced is equal to or greater than 2.

10. The method of any of the preceding claims, wherein, The reaction of step c) is carried out by means of the following sequence of operations: - addition of a base to the hydroalcoholic solution of step b) in an amount such as to bring the pH of the solution to a value comprised between 6 and 8, while maintaining the temperature between 0 and 25°C; - before or after the above-mentioned addition of base, evaporation of the alcohol present in the hydroalcoholic solution by operating under reduced pressure, to obtain a suspension formed by intermediate C in water; - addition of a pure organic solvent or an organic solvent mixed with methanol to the suspension, stirring until dissolution, to obtain a two-phase system consisting of an aqueous phase and an organic phase; the organic solvent is selected from ethyl acetate, isopropyl acetate and methyl isobutyl ketone; - adjustment of the pH of the aqueous phase to a value greater than or equal to 8, preferably comprised between 8.5 and 10, using a base selected from aqueous ammonia, NaOH, KOH, LiOH, Na2CO3, K2CO3, NaHCO3 and KHCO3; - separation of the phases under reduced pressure, concentration of the organic phase to obtain an organic solution containing intermediate C.

11. The method of any of the preceding claims, wherein, Before step d), an alcohol is added to the organic solution obtained at the end of step c), said alcohol being selected from methanol, ethanol and isopropanol, operating at a temperature comprised between 20 and 65°C, and the resulting solution is added to fumaric acid or vice versa, the resulting mixture is stirred at a temperature comprised between 0 and 35°C for at least 8 hours, so as to precipitate a solid which is recovered by filtration to obtain crude intermediate D.

12. The method of any of the preceding claims, wherein, In step e), intermediate D is suspended in a linear or branched C1-C5 aliphatic alcohol, the resulting suspension is first stirred under reflux conditions and then at a temperature comprised between 20 and 25°C, and finally the product is recovered by filtration, and said step e) is repeated twice or three times.

13. The process according to any one of the preceding claims, further comprising the further step of converting 5-{(1 RS)-2-[benzyl-((1 RS)-(4-hydroxyphenyl)-1 - methylethyl)amino]-1 -hydroxyethyl}benzene-1,3-diol hemifumarate into fenoterol hydrobromide, said conversion comprising the steps of: - by reacting the hemifumarate salt with a base to form 5-{(1 RS)-2-[benzyl-((1 RS)-(4-hydroxyphenyl)-1 -methylethyl)amino]-1 -hydroxyethyl}benzene-1,3-diol hydrobromide; - by catalytic hydrogenation to remove the benzyl group attached to the nitrogen atom in 5-{(1 RS)-2-[benzyl-((1 RS)-(4-hydroxyphenyl)-1 -methylethyl)amino]-1 -hydroxyethyl}benzene-1,3-diol; - by employing hot-cold techniques to crystallize the desired product from the solvent.

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