Method for the synthesis of (1R)-2-(dibenzylamino)-1-(3,4-dibenzyloxyphenyl)ethanol, novel intermediates of said method and use of the product in the synthesis of noradrenaline

Abstract

The invention relates to a method for the synthesis of (1R)-2-(dibenzylamino)-1-(3,4- dibenzyloxyphenyl)ethanol of formula (I): (I), to said compound of formula (I), and to the use thereof as an intermediate in the synthesis of noradrenaline.

Description

[0001] DESCRIPTION

[0002] Method for the synthesis of (1 R)-2-(dibenzylamino)-1-(3,4-dibenzyloxyphenyl)ethanol, novel intermediates of said method and use of the product in the synthesis of noradrenaline

[0003] Field of the Invention

[0004] The present invention relates to a novel method for the synthesis of (1 R)-2- (dibenzylamino)-1-(3,4-dibenzyloxyphenyl)ethanol, which is an intermediate useful in the synthesis of noradrenaline, to novel intermediates of said method and to the use of the products in the synthesis of noradrenaline.

[0005] Background of the Invention

[0006] Noradrenaline is a catecholamine that acts as a hormone and a neurotransmitter. The general function of norepinephrine in the human body is to mobilize the brain and body for action. The release of noradrenaline is lower when sleeping, increases when awake and reaches much higher levels in stressful or dangerous situations, the so-called fight- or-flight response. In the brain, noradrenaline increases excitation and alertness, promotes wakefulness, improves memory formation and recovery and focuses attention; it also increases restlessness and anxiety. In the rest of the body, noradrenaline increase heart rate and blood pressure, triggers the release of glucose from energy reserves, increases blood flow to the skeletal muscle, reduces blood flow to the gastrointestinal system and inhibits bladder voiding and gastrointestinal motility.

[0007] As a medicinal product, noradrenaline is often used as an injected vasopressor, the use thereof being accepted in the treatment of acute hypotension conditions, such as those that occur at times following pheochromocytoma, sympathectomy, poliomyelitis, spinal anesthesia, myocardial infarction, septic shock, transfusions and reactions to drugs. It is also indicated as a temporary coadjuvant in the treatment of cardiac arrest and acute hypotension. Noradrenaline, which is also often referred to as norepinephrine, is the compound 4- [(1 R)-2-amino-1-hydroxyethyl]benzene-1,2-diol and has the following chemical structure:

[0008] Noradrenaline

[0009] United States patent US 2,774,789 A describes a method of obtaining noradrenaline by means of the resolution of the racemic mixture of 4-[2-amino-1-hydroxyethyl]benzene- 1 ,2-diol using various chiral acids, particularly D-tartaric acid.

[0010] European patent EP 3 725 765 A1 describes a method for obtaining enantiomerically pure noradrenaline based on obtaining the compound of formula (A): and the subsequent enantioselective reduction thereof to obtain the corresponding alcohol derivative of formula which is finally debenzylated:

[0011] The compound of formula (A) is obtained from the halogenated derivative (C) and isolated in the form of a salt, since the corresponding compound in the form of a free base of formula (A’) is not stable and can hardly be isolated:

[0012] The yields of the process starting with the compound of formula (C) and ending in noradrenaline bitartrate monohydrate described in said patent application are below 52%.

[0013] There is a need to provide more optimized methods of obtaining noradrenaline, particularly with a higher yield, for the synthesis of said product on an industrial scale.

[0014] Summary of the Invention

[0015] After several tests, the inventors have developed an alternative method which, also starting from the compound of formula (C), allows obtaining noradrenaline or pharmaceutically acceptable salts thereof with better yields (the examples show a yield of 60.5%).

[0016] Surprisingly, the inventors have discovered that by using the intermediate (1 R)-2- (dibenzylamino)-1-(3,4-dibenzyloxyphenyl)ethanol of formula (I): high yields of noradrenaline, preferably of more than 60%, can be obtained.

[0017] Therefore, in a first aspect, the present invention relates to a compound of formula (I):

[0018] or a salt thereof. In a second aspect, the present invention relates to a method for obtaining the compound of formula (I): or a salt thereof which comprises reacting a compound of formula (III):

[0019] In a third aspect, the present invention relates to a method of preparing noradrenaline or pharmaceutically acceptable salts thereof comprising the steps of: a) debenzylating the compound of formula (I): to obtain noradrenaline of formula:

[0020] Noradrenaline b) optionally, forming a pharmaceutically acceptable salt of noradrenaline by means of adding a pharmaceutically acceptable acid to the noradrenaline obtained in step a).

[0021] In a fourth aspect, the present invention relates to the use of the compound of formula (I) for obtaining noradrenaline or a pharmaceutically acceptable salt thereof.

[0022] The method of obtaining noradrenaline starting from 2-halo-1-(3,4- dihydroxyphenyl)ethan-1-one (C) through the intermediate of formula (I) is shown in the following scheme:

[0023]

[0024] Description of the Figures

[0025] Figure 1 shows the X-ray powder diffraction spectrum measured with CuKaradiation of the compound of formula (I).

[0026] Detailed Description of the Invention

[0027] Method of preparing the compound of formula (I)

[0028] The second aspect of the present invention relates to a method for obtaining the compound of formula (I): or a salt thereof which comprises reacting a compound of formula (III):

[0029] The method involves the enantioselective reduction of the carbonyl group and is performed by means of using formic acid in the presence of a ruthenium catalyst, preferably the compound ((1S,2S)-N-(3-phenylpropyl)-N'-tosyl-1 ,2- diphenylethylenediamine)ruthenium chloride (II) commercially known as [(S,S)-Teth- TsDpen RuCI], the formula of which is as follows:

[0030] The reaction is preferably performed in an inert atmosphere, preferably in a nitrogen atmosphere, in a solvent such as, for example, a mixture of water and ethanol. Preferably, the reaction is performed at a temperature of between 70 and 80°C, preferably 75°C.

[0031] In a preferred embodiment, a mixture of the compound of formula (VII) and the ruthenium catalyst is prepared under inert atmosphere in the solvent and formic acid is slowly added to said mixture at a temperature of between 10 and 40°C, preferably between 20 and 30°C. After completing the addition, the mixture is maintained at a temperature of between 70 and 80°C, preferably 75°C, for a period of between 1 and 8 hours, preferably between 2 and 6 hours, more preferably between 3 and 5 hours, for example 4 or 5 hours. In a preferred embodiment, the molar ratio of the formic acid with respect to the compound of formula (III) is in the interval comprised between 2 and 10, preferably between 3 and 7, more preferably between 4 and 6, for example 5.

[0032] In a preferred embodiment, the molar ratio of the compound of formula (III) with respect to the ruthenium catalyst is in the interval comprised between 100 and 900, preferably between 200 and 800, more preferably between 300 and 700, even more preferably between 400 and 600, for example 475 or 500.

[0033] In one embodiment, the reaction medium is slowly cooled, allowing the precipitation of an off-white solid. Preferably, the reaction medium is cooled below 30°C, for example to room temperature or down to 20°C.

[0034] The first aspect of the present invention relates to (1 R)-2-(dibenzylamino)-1-(3,4- dibenzyloxyphenyl)ethanol of formula (I):

[0035] In a preferred embodiment, the compound of formula (I) is in the form of a crystalline solid. In a more preferred embodiment, said crystalline solid is characterized in that it has an X-ray powder diffraction spectrum measured with CuKa radiation comprising peaks at 8.4, 17.8, 18.7, 19.5, 21.1 and 21.4 °20 ± 0.2 °20. Preferably, the X-ray powder diffraction spectrum measured with CuKa radiation also comprises additional peaks at 7.2, 10.2, 10.8, 11.8, 20.2, 23.0 and 26.7 °20 ± 0.2 °20. In another embodiment, the crystalline form of the compound of formula (I) is characterized in that it has an X-ray powder diffraction spectrum measured with CuKaradiation essentially like the one shown in Figure 1.

[0036] In another embodiment, the crystalline form of the compound of formula (I) is characterized in that it has a differential scanning calorimetry (DSC) diagram comprising an endothermic peak having a threshold temperature of about 85.4°C ± 2°C.

[0037] In a third aspect, the present invention relates to a method of preparing noradrenaline or pharmaceutically acceptable salts thereof comprising the steps of: a) debenzylating the compound of formula (I): to obtain noradrenaline of formula:

[0038] Noradrenaline b) optionally, forming a pharmaceutically acceptable salt of noradrenaline by means of adding a pharmaceutically acceptable acid to the noradrenaline obtained in step a).

[0039] In one embodiment, the present step a) is performed by means of using formic acid in the presence of a palladium / carbon catalyst. The reaction is preferably performed in an inert atmosphere, preferably in a nitrogen atmosphere in a solvent such as, for example, a mixture of water and ethanol. Preferably, the reaction is performed at a temperature of between 60 and 90°C, preferably between 70 and 80°C, for example 75°C.

[0040] In a preferred embodiment, step a) of debenzylation is performed in the same reactor in which the compound of formula (I) has been prepared as described above, without isolating said compound. When this embodiment is used, the resulting reaction mixture of the method for the synthesis of compound (I) is brought to a temperature of between 20 and 40°C and the Pd / C catalyst is loaded into the reactor, the reaction medium is then brought to a temperature of between 50 and 70°C, preferably 60°C, and formic acid is added to the reaction medium after which the reaction mixture is brought to a temperature of between 60 and 90°C, preferably between 70 and 80°C, for example 75°C.

[0041] In a preferred embodiment, the debenzylation reaction time is between 1 and 3 hours, for example 2 hours.

[0042] In a preferred embodiment, the molar ratio of the formic acid used in this step with respect to the compound of formula (I) is in the interval comprised between 3 and 10, more preferably between 4 and 6, for example 5.

[0043] In a preferred embodiment, the weight ratio of the Pd / C catalyst with respect to the compound of formula (III) is in the interval comprised between 2% and 50%, preferably between 5% and 30%, more preferably between 15% and 25% and most preferably 25%.

[0044] In one embodiment, the reaction medium is slowly cooled and filtered to separate the catalyst, obtaining an acidic noradrenaline solution.

[0045] The noradrenaline solution can be brought to a temperature of between 30 and 45, preferably between 35 and 40°C by adding (L)-tartaric acid and maintaining stirring such that a precipitated solid which is the bitartrate monohydrate salt of noradrenaline appears.

[0046] Method of preparing the compound of formula (III) The compound of formula (III) can be obtained starting from 2-chloro-1-(3,4- dihydroxyphenyl)ethan-1-one of formula (C) by means of a method consisting of the steps: a) reacting the compound of formula (C) with dibenzylamine to provide the compound 2-(dibenzylamino)-1-(3,4-dihydroxyphenyl)ethanone of formula (IV): b) reacting the compound of formula (IV) with benzyl bromide to provide the compound of formula (III):

[0047] Step a) can be carried out in a solvent, such as acetone, preferably in an inert atmosphere, for example, a nitrogen atmosphere at temperatures between 15 and 30°C.

[0048] Step b) can be carried out in a solvent, such as acetone, in the presence of a base, such as potassium carbonate, preferably in an inert atmosphere, for example, a nitrogen atmosphere at temperatures between 55 and 65°C.

[0049] The term “salt” must be understood to mean any form of the defined compounds which take on an ionic form, or are charged and coupled with a counterion (a cation or anion) or are in dissolution. For example, salts of the compounds of formula (I) can be acid addition salts and can be synthesized from the original compound containing a basic moiety by means of conventional chemical methods. Generally, such salts are prepared, for example, by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid in water or in an organic solvent or in a mixture thereof. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Examples of acid addition salts include mineral acid addition salts such as, for example hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.

[0050] Use of the compound of formula (I)

[0051] The compound of formula (I), as well as the crystalline forms thereof, described herein is a novel intermediate of the method for the synthesis of noradrenaline and pharmaceutically acceptable salts thereof.

[0052] To that end, in another aspect, the invention relates to the use of the compound of formula (I) or of the crystalline forms of said compound in the preparation of noradrenaline and pharmaceutically acceptable salts thereof.

[0053] In the context of the present invention, X-ray diffractograms can be recorded using a powder diffraction system with a copper anode that emits CuKa radiation with a wavelength of 1 .54 A, particularly, following the method described in the examples.

[0054] In the context of the present invention, differential scanning calorimetry diagrams can be obtained as described in the examples.

[0055] In the context of the present invention, the threshold temperature or “T onset” refers to the temperature resulting from extrapolating the baseline before the start of transition and the baseline during every absorption (tangent of the curve). It can be calculated as defined in the DIN ISO 11357-1 :2016(E) standard.

[0056] In the context of the present invention, the terms “approximate” and “about” refer to the value which characterizes ±5% of said value. In the context of the present invention, the term “base” refers to a substance capable of accepting a proton (from an acid).

[0057] In order to facilitate the understanding of the preceding ideas, some examples of the experimental methods and embodiments of the present invention are described below. Said examples are merely illustrative.

[0058] Examples

[0059] Materials and methods

[0060] The chemical purity of the products obtained was analyzed by means of the high- performance liquid chromatography technique in an Acquity model Waters apparatus provided with a UV detector and thermostated oven for the column. A Kromasil 100-5- C18 column (125 x 4.6 mm, 5 pm) and mobile phase A (0.1% w / v sodium heptanesulfonate in water with the pH adjusted to 2.2 with phosphoric acid) and mobile phase B (acetonitrile) were used with the following conditions of analysis:

[0061] • Flow rate: 1.5 mL / min

[0062] • Column temperature: 25°C

[0063] • Wavelength: 280 and 254 nm

[0064] • Injection volume: 20 pL

[0065] • Diluent: 0.1% w / v sodium heptanesulfonate in water with the pH adjusted to 2.2 with phosphoric acid

[0066] • Gradient: The optical purity of the products obtained was analyzed by means of the high- performance liquid chromatography technique in an Acquity model Waters apparatus provided with a UV detector and a thermostated oven for the column. A Shodex CBS ORpak column (150 x 4.6 mm, 3 pm) and the mobile phase ammonium acetate 10 mM, pH 4.5 were used with the following conditions of analysis:

[0067] • Flow rate: 0.3 mL / min

[0068] • Column temperature: 10°C

[0069] • Wavelength: 280 nm

[0070] • Injection volume: 5 pL

[0071] • Diluent: HCI 4 mM

[0072] • Gradient: Isocratic (100% of mobile phase)

[0073] Differential scanning calorimetry (DSC)

[0074] DSC analysis was performed in a Mettler Toledo 822e apparatus with STARe SW15 software. Parameters: heating interval of 30 to 300°C with a ramp of 10°C / min and N2 flow of 50 ml / min. Measurement is performed with a closed perforated capsule.

[0075] Nuclear magnetic resonance

[0076] Proton nuclear magnetic resonance (1 H-NMR) and 13C-NMR analyses were performed in a 400 MHz Brucker Avance III spectrometer. Chemical shifts were referenced to the CDCI3signal (7.26 ppm for proton and 77.0 ppm for carbon).

[0077] X-ray crystallography (XRPD)

[0078] XRPD analysis was performed using a BRLIKER D2 PHASER model X-ray powder diffractometer equipped with a copper anode. The radiation used is CuKawith a wavelength of 1.54060 A. Scanning parameters: 3-50 °20, continuous scan, ratio: 5.6 degrees / minute.

[0079] Example 1. Obtaining 2-(dibenzylamino)-1-(3,4-dihydroxyphenyl)ethanone (IV) 100 g (0.54 mol) of 2-chloro-1-(3,4-dihydroxyphenyl)ethanone (C) were mixed with 400 ml of acetone under N2 atmosphere. 218 ml (1.08 mol, 2,02 eq) of dibenzylamine were added, maintaining the temperature between 20 and 25°C. The resulting mixture was heated to the reflux temperature and maintained at said temperature for 18 hours.

[0080] Once such maintaining of the temperature was completed, the reaction mixture was cooled to a temperature of about 40°C and filtered through a diatomaceous earth filter. The filter was washed with 3 fractions of 50 ml of acetone each and the solvent was removed by means of vacuum distillation to obtain a solid residue. 500 ml of acetonitrile were added to this solid and the mixture obtained was heated to the reflux temperature and maintained at said temperature for a time of about 30 minutes. The mixture obtained was then slowly cooled, the appearance of an abundant solid being observed at a temperature of about 48°C. The mixture was maintained at a temperature of between 48 and 50°C for about 15 minutes, then cooled to a temperature of about 20°C and kept under stirring at said temperature for 2 hours. The resulting solid was filtered and washed successively with 4 fractions of 50 mL of acetonitrile each. Finally, it was dried in an air oven at a temperature of 50°C to obtain 150.7 g (yield: 80.8%) of a light gray solid corresponding to 2-(dibenzylamino)-1-(3,4-dihydroxyphenyl)ethanone (IV).

[0081] Example 2. Obtaining 2-(dibenzylamino)-1-(3,4-dibenzyloxyphenyl)ethanone (III)

[0082] 885 g (2.55 mol) of 2-(dibenzylamino)-1-(3,4-dihydroxyphenyl)ethanone (IV) and 740.0 g (5.35 mol, 2.1 eq) of dipotassium carbonate were mixed with 5300 ml of acetone under N2 atmosphere. The mixture was stirred for 10 minutes and 635 ml (5.35 mol, 2.1 eq) of benzyl bromide were added, maintaining the temperature between 20 and 25°C. The resulting mixture was heated to a temperature of about 60°C and kept under stirring at said temperature for 18 hours.

[0083] Once such maintaining of the temperature was completed, the reaction mixture was cooled to a temperature of about 45°C and filtered through a diatomaceous earth filter. The filter was washed with 2 fractions of 885 ml of acetone each and the solvent was removed by means of vacuum distillation to obtain a pasty residue. 4425 ml of ethanol were added to this residue and the mixture obtained was heated to a temperature of about 80°C and maintained at said temperature for a time of about 15 minutes to obtain a solution. The mixture obtained was then slowly cooled, the appearance of an abundant solid being observed at a temperature of about 42°C. The mixture was maintained at a temperature of between 40 and 45°C for about 15 minutes, then cooled to a temperature of about 20°C and kept under stirring at said temperature for 3 hours. The resulting solid was filtered and washed successively with 4 fractions of 200 mL of ethanol each. Finally, it was dried in an air oven at a temperature of 50°C to obtain 1198.2 g (yield: 89.1%, HPLC purity: 99.60%) of a light brown solid corresponding to 2-(dibenzylamino)-1-(3,4- dibenzyloxyphenyl)ethanone (III).

[0084] Example 3. Obtaining 2-(dibenzylamino)-1-(3,4-dibenzyloxyphenyl)ethanone (III)

[0085] 10 g (53.8 mmol) of 2-chloro-1-(3,4-dihydroxyphenyl)ethanone (C) were mixed with 50 ml of acetonitrile under N2 atmosphere. 21.6 ml (107.4 mmol, 2.0 eq) of dibenzylamine were added, maintaining the temperature between 20 and 25°C. The resulting mixture was heated to a temperature of about 82°C and maintained at said temperature for 16 hours.

[0086] Once such maintaining of the temperature was completed, 50 ml of acetone were added and the reaction mixture was cooled to a temperature of about 40°C and filtered through a diatomaceous earth filter. The filter was washed with 3 fractions of 50 ml of acetone each and the mixture obtained was filtered through diatomaceous earth. The solvent was removed by means of vacuum distillation to obtain a solid residue. 100 ml of acetone were added and the mixture was left under stirring for 10 minutes. 14 ml (117.9 mmol, 2.2 eq) of benzyl bromide were added, maintaining the temperature between 20 and 25°C. The resulting mixture was heated to a temperature of about 60°C and kept under stirring at said temperature for 18 hours.

[0087] Once such maintaining of the temperature was completed, the reaction mixture was cooled to a temperature of about 45°C and filtered through a diatomaceous earth filter. The filter was washed with 2 fractions of 20 ml of acetone each and the solvent was removed by means of vacuum distillation to obtain a pasty residue. 93 ml of ethanol were added to this residue and the mixture obtained was heated to a temperature of about 80°C and maintained at said temperature for a time of about 5 minutes to obtain a solution. The mixture obtained was then slowly cooled, the appearance of an abundant solid being observed at a temperature of about 50°C. The mixture was maintained at a temperature of between 50 and 55°C for about 15 minutes, then cooled to a temperature of about 20°C and kept under stirring at said temperature for 2 hours. The resulting solid was filtered and washed successively with 4 fractions of 20 mL of ethanol each. Finally, it was dried in an air oven at a temperature of 50°C to obtain 22.2 g (yield: 78.7%, HPLC purity: 98.13%) of a light brown solid corresponding to 2-(dibenzylamino)-1-(3,4- dibenzyloxyphenyl)ethanone (III).

[0088] Example 4. Obtaining the bitartrate monohydrate salt 4-[(1 R)-2-amino-1- hydroxyethyl]benzene-1 ,2-diol (noradrenaline bitartrate monohydrate)

[0089] 50 g (94.8 mmol) of 2-(dibenzylamino)-1-(3,4-dibenzyloxyphenyl)ethanone (III) and 123.4 mg (0.199 mmol, 0.002 eq) of the catalyst (S,S)-Teth-TsDpen RuCI (II) were mixed under N2 atmosphere with 400 ml of ethanol and 25 ml of water at a temperature of about 20°C. 17.9 ml (475.7 mmol, 5.0 eq) of formic acid were slowly added, maintaining the temperature between 20 and 30°C. The resulting mixture was heated to a temperature of about 75°C and maintained at said temperature for 5 hours, obtaining a reaction mixture comprising the compound of formula (I).

[0090] Once such maintaining of the temperature was completed, the reaction mixture was cooled to a temperature of about 30°C and 12.5 g of 5% Pd / C were loaded. The reaction mass was heated to a temperature of about 60°C and 17.9 ml (475.7 mmol, 5.0 eq) of formic acid were added. The resulting mixture was heated to a temperature of about 75°C and maintained at said temperature for 2 hours, obtaining a reaction mixture comprising noradrenaline.

[0091] Once such maintaining of the temperature was completed, the reaction mass was cooled to a temperature of about 20°C and filtered through diatomaceous earth. The filter was washed with 2 fractions of 10 ml of ethanol each. The resulting solution comprising noradrenaline was heated to a temperature of between 35 and 40°C and a previously prepared solution of 14.94 g (99.6 mmol, 1.05 eq) of (L)-tartaric acid was slowly added to a mixture of 8 ml of water and 12 ml of ethanol. The resulting reaction mass is kept under stirring at a temperature of about 40°C for 30 minutes, the appearance of a precipitated solid being observed. The resulting reaction mass was slowly cooled to a temperature of between 0 and 2°C and maintained at said temperature for 3 hours. The resulting solid was filtered and washed successively with 4 fractions of 22 mL of ethanol each. Finally, it was dried in an air oven at a temperature of 50°C to obtain 26.9 g (yield: 84.1 %, HPLC purity: 99.40%, HPLC optical purity: 99.02%) of a slightly grayish solid corresponding to the bitartrate monohydrate salt 4-[(1 R)-2-amino-1- hydroxyethyl]benzene-1 ,2-diol (noradrenaline bitartrate monohydrate).

[0092] Example 5. Obtaining (1 R)-2-(dibenzylamino)-1-(3,4-dibenzyloxyphenyl)ethanol (I)

[0093] 200 g (379.5 mmol) of 2-(dibenzylamino)-1-(3,4-dibenzyloxyphenyl)ethanone (III) and 470.1 mg (0.76 mmol, 0.002 eq) of the catalyst [(S,S)-Teth-TsDpen RuCI] (II) were mixed under N2 atmosphere with 1000 ml of ethanol and 100 ml of water at a temperature of about 20°C. 71.5 ml (1896.3 mmol, 5.0 eq) of formic acid were slowly added, maintaining the temperature between 20 and 30°C. The resulting mixture was heated to a temperature of about 75°C and maintained at said temperature for 4 hours.

[0094] Once such maintaining of the temperature was completed, the reaction mass was slowly cooled. The formation of an off-white solid was observed at a temperature of about 60°C. The reaction mass was kept under stirring for 30 minutes at a temperature of between 60 and 65°C, with abundant precipitated solid being observed. The reaction mass was then slowly cooled to a temperature of about 20°C and kept under stirring at said temperature for 2 hours. The resulting solid was filtered and washed successively with 2 fractions of 100 mL of ethanol each. Finally, it was dried in an air oven at a temperature of 50°C to obtain 185.2 g (yield: 92.2%, HPLC purity: 99.48%, HPLC optical purity: 99.21 %) of a cream-colored solid corresponding to (1 R)-2-(dibenzylamino)-1-(3,4- dibenzyloxyphenyl)ethanol (I).

[0095] 1H-NMR (CDCh, 400 MHz) b(ppm): 7.41 (4H, m), 7.31 (16H, m), 6.84 (2H, m), 6.72 (1 H, dd), 5.11 (2H, s), 5.06 (2H, dd), 4.58 (1 H, dd), 3.87 (2H, d), 3.75 (1 H, s), 3.47 (2H, d), 2.58 (2H, m).

[0096] 13C-NMR (CDCh, 400 MHz) b(ppm): 149.0, 148.3, 138.3, 137.4, 137.3, 135.6, 129.1 ,

[0097] 128.4, 128.5, 127.8, 127.7, 127.4, 127.3, 127.2, 119.0, 115.0, 112.8, 71.4, 71.1 , 69, 61.7,

[0098] 58.4.

[0099] XRPD: The X-ray powder diffractogram of the compound obtained is shown in Figure 1 . The compound obtained is characterized in that it has a differential scanning calorimetry (DSC) diagram comprising an endothermic peak having a threshold temperature of about 85.4°C ± 2°C.

[0100] Example 6. Obtaining the bitartrate monohydrate salt 4-[(1 R)-2-amino-1- hydroxyethyl]benzene-1 ,2-diol (noradrenaline bitartrate monohydrate)

[0101] 10 g (18.9 mmol) of (1 R)-2-(dibenzylamino)-1-(3,4-dibenzyloxyphenyl)ethanol (I) and 1.6 g of 5% Pd / C were mixed with 80 ml of ethanol. The reaction mass was heated to a temperature of about 50°C and 4.0 ml (106.1 mmol, 5.6 eq) of formic acid were added. The resulting mixture was heated to a temperature of about 75°C and maintained at said temperature for 3 hours.

[0102] Once such maintaining of the temperature was completed, the reaction mass was cooled to a temperature of about 20°C and filtered through diatomaceous earth. The filter was washed with 2 fractions of 10 ml of ethanol each. The resulting solution was heated to a temperature of about 40°C and a previously prepared solution of 2.99 g (19.93 mmol, 1.05 eq) of (L)-tartaric acid slowly added to a mixture of 2.5 ml of water and 6 ml of ethanol. The resulting reaction mass is kept under stirring at a temperature of about 40°C for 15 minutes, the appearance of a precipitated solid being observed. The resulting reaction mass was slowly cooled to a temperature of between -2 and 0°C and maintained at said temperature for 1 hour. The resulting solid was filtered and washed successively with 2 fractions of 10 mL of ethanol each. Finally, it was dried in an air oven at a temperature of 50°C to obtain 5.6 g (yield: 89.0%, HPLC purity: 99.80%, HPLC optical purity: 99.41 %) of a slightly grayish solid corresponding to the bitartrate monohydrate salt 4-[(1 R)-2-amino-1-hydroxyethyl]benzene-1 ,2-diol (noradrenaline bitartrate monohydrate).

Claims

CLAIMS1 . A compound of formulaor a salt thereof.

2. The compound according to claim 1 , characterized in that it is in crystalline form.

3. The compound according to claim 2, characterized in that it has an X-ray powder diffraction spectrum measured with CuKaradiation comprising peaks at 8.4, 17.8, 18.7, 19.5, 21.1 and 21.4 °20 ± 0.2 °20.

4. The compound according to claim 3, characterized in that it has an X-ray powder diffraction spectrum measured with CuKaradiation essentially like the one shown in Figure 1.

5. The compound according to any of claims 3 to 4, characterized in that it has a differential scanning calorimetry (DSC) diagram comprising an endothermic peak having a threshold temperature of about 85.4°C ± 2°C.

6. A method of preparing a compound of formula (I):or a salt thereof comprising the enantioselective reduction of a compound of formula (III):

7. The method according to claim 6, characterized in that the compound of formula (III) is reacted with formic acid in the presence of a ruthenium catalyst.

8. The method according to claim 7, characterized in that the ruthenium catalyst is ((1S,2S)-N-(3-phenylpropyl)-N’-tosyl-1,2-diphenylethylenediamine)ruthenium chloride (II) commercially known as [(S.S)-Teth-TsDpen RuCI] of formula:

9. The method according to any of claims 6 to 8, characterized in that it is performed in an inert atmosphere, preferably in a nitrogen atmosphere.

10. The method according to any of claims 6 to 9, characterized in that it is performed in a solvent, preferably water, ethanol or a mixture thereof, more preferably in a mixture of water and ethanol.

11. The method according to any of claims 6 to 10, characterized in that it is performed at a temperature of between 70 and 80°C, preferably 75°C.

12. The method according to any of claims 6 to 11 , characterized in that a mixture of the compound of formula (III) and the ruthenium catalyst is prepared in the solvent and formic acid is slowly added to said mixture at a temperature of between 10 and 40°C.

13. The method according to any of claims 6 to 12, characterized in that the molar ratio of the formic acid with respect to the compound of formula (III) is in the interval comprised between 2 and 10, preferably between 3 and 7, more preferably between 4 and 6, for example 5.

14. The method according to any of claims 6 to 13, characterized in that the molar ratio of the compound of formula (III) with respect to the ruthenium catalyst is in the interval comprised between 100 and 900, preferably between 200 and 800, more preferably between 300 and 700, even more preferably between 400 and 600, for example 475 or 500.

15. A method of preparing noradrenaline or pharmaceutically acceptable salts thereof comprising the steps of: a) debenzylating the compound of formula (I):to obtain noradrenaline of formula:Noradrenalineb) optionally, forming a pharmaceutically acceptable salt of noradrenaline by means of adding a pharmaceutically acceptable acid to the noradrenaline obtained in step a).

16. The method according to claim 15, characterized in that step a) is performed by means of using formic acid in the presence of a palladium / carbon catalyst.

17. The method according to any of claims 15 to 16, characterized in that it is performed in an inert atmosphere, preferably in a nitrogen atmosphere.

18. The method according to any of claims 15 to 17, characterized in that it is performed in a solvent, preferably water, ethanol or a mixture thereof, more preferably in a mixture of water and ethanol.

19. The method according to any of claims 15 to 18, characterized in that step a) of debenzylation is performed in the same reactor in which the compound of formula (I) has been previously prepared according to the method of claims 6 to 14, without isolating said compound.

20. The method according to claim 19, characterized in that the resulting reaction mixture of the method for the synthesis of compound (I) is brought to a temperature of between 20 and 40°C and the Pd / C catalyst is loaded into the reactor, the reaction medium is then brought to a temperature of between 50 and 70°C, preferably 60°C, and formic acid is added to the reaction medium after which the reaction mixture is brought to a temperature of between 60 and 90°C, preferably between 70 and 80°C, for example 75°C.

21. The method according to any of claims 15 to 20, characterized in that the debenzylation reaction time is between 1 and 3 hours, for example 2 hours.

22. The method according to any of claims 15 to 21 , characterized in that the molar ratio of the formic acid used in this step with respect to the compound of formula (I) is in the interval comprised between 2 and 10, more preferably between 4 and 6, for example 5.

23. The method according to any of claims 15 to 22, characterized in that the weight ratio of the Pd / C catalyst with respect to the compound of formula (III) is in the interval comprised between 2% and 50%, preferably between 5% and 30%, more preferably between 15% and 25% and most preferably 25%.

24. The method according to any of claims 15 to 23, characterized in that the reaction medium is slowly cooled, obtaining a reaction mixture comprising noradrenaline.

25. The method according to claim 24, characterized in that the noradrenaline solution is brought to a temperature of between 30 and 45, preferably between 35 and 40°C by adding (L)-tartaric acid and maintaining stirring such that a precipitated solid which is the bitartrate monohydrate salt of noradrenaline appears.

26. Use of the compound of formula (I) for obtaining noradrenaline or pharmaceutically acceptable salts thereof.

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