Process for the preparation of epinephrine and norepinephrine

Abstract

A method of preparing epinephrine or norepinephrine is provided. The method includes reacting a starting material comprising 2-chloro-l-(3,4-dihydroxyphenyl)ethan-l- one with an amine nucleophile RNH2 (R=H for the synthesis of epinephrine or Me for the synthesis of norepinephrine) under conditions suitable for nucleophilic substitution of the starting material to form a substituted starting material and reacting the substituted starting material with a tethered ligand transition metal catalyst under conditions suitable for transfer¬ hydrogenation to produce epinephrine or norepinephrine.

Description

[0001]PROCESS FOR THE PREPARATION OF EPINEPHRINE AND NOREPINEPHRINE CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of United States provisional patent application 63 / 538,560, filed September 15, 2023, the complete contents of which are hereby incorporated by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Biomedical Advanced Research and Development Authority (BARDA) Contract No.75A50120C00092 awarded by the Department of Health and Human Services. The government has certain rights in the invention. FIELD OF THE INVENTION The present invention relates to synthetic methods for the preparation of epinephrine and norepinephrine utilizing a catalytic asymmetric transfer hydrogenation process which is carried out under mild conditions. BACKGROUND OF THE INVENTION Epinephrine (adrenaline) is a hormone and neurotransmitter which belongs to the catecholamines. In the human body, it is formed from tyrosine when the latter is reacted via dihydroxyphenylalanine, dopamine, and norepinephrine, finally producing epinephrine. Epinephrine, being a sympathetic agent, stimulates the adrenergic receptors of the sympathetic nervous system, increasing the pulse rate, cardiac output, and systolic blood pressure, reducing intestinal peristalsis, relaxing the bronchial muscles and dilating the bronchi, dilating the pupils, increasing the basal metabolic rate by promoting O2 consumption, hyperglycemia and glycosuria by mobilizing the glycogen reserves in the liver and increasing lipolysis, inter alia, thereby increasing the free fatty acids in the blood. Because of its wide range of activities epinephrine is of considerable commercial interest in the treatment of anaphylactic shock, inter alia, or as an addition to local anesthetics. Norepinephrine (noradrenaline) is a precursor to epinephrine that functions in the brain and body as a hormone and neurotransmitter. As a stress hormone, Norepinephrine affects parts of the brain where attention and responding actions are controlled. Along with epinephrine, norepinephrine also underlies the fight-or-flight response, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle. Norepinephrine also has a neurotransmitter role when released diffusely in the brain as an anti-inflammatory agent. Norepinephrine is mainly used as a treatment for shock and can treat hypotension caused by acute myocardial infarction, extracorporeal circulation, pheochromocytoma excision and the like. Epinephrine is usually manufactured by non-stereoselective hydrogenation of 3′,4′- dihydroxy-2-N-methylaminoacetophenone or a derivative thereof with protected OH functions or amino function and subsequent racemate separation. Enantioselective methods of synthesis are also known. One of these is described, for example, in Tetrahedron Letters 5 (1979), 425-428. According to this method, 3′,4′-dihydroxy-2-N-methylaminoacetophenone is reacted to produce adrenaline by hydrogenation under a hydrogen pressure of about 50 bar using a chiral hydroxyalkylferrocenylphosphine as catalyst. The amount of catalyst to substrate is about 1:100, based on the molar ratio. Under these conditions, L-1-(3′,4′- dihydroxyphenyl)-2-methylaminoethan-1-ol (epinephrine) is obtained in an enantiomeric excess over the S-enantiomer of 60% ee after about 2 to 4 days reaction. This process, however, is unsuitable for producing epinephrine on an industrial scale for a number of reasons: in spite of the use of large amounts of catalyst in the asymmetric reaction step, the product cannot be produced in sufficiently pure form for pharmaceutical purposes except by the use of expensive purification procedures, as this reaction produces epinephrine only as a mixture containing a relatively high proportion of the opposite enantiomer as a contaminant. The relatively long reaction time of the asymmetric hydrogenation step, i.e., 2 to 4 days, also constitutes a reaction step which is very equipment- intensive and expensive for industrial purposes, with not inconsiderable safety risks. There remains a need for novel processes for preparing epinephrine and norepinephrine with improved yield and chiral purity. SUMMARY Embodiments of the disclosure provide an efficient synthetic process which enables the manufacture of high purity epinephrine and norepinephrine active pharmaceutical ingredients (APIs). The process involves a novel and high-yielding catalytic asymmetric transfer hydrogenation process which is carried out under mild conditions. An aspect of the disclosure provides a method of preparing epinephrine or norepinephrine, comprising reacting a starting material comprising 2-chloro-1-(3,4- dihydroxyphenyl)ethan-1-one with an amine nucleophile under conditions suitable for nucleophilic substitution of the starting material to form a substituted starting material and reacting the substituted starting material with a tethered ligand transition metal catalyst under conditions suitable for transfer-hydrogenation to produce epinephrine or norepinephrine. In some embodiments, the tethered ligand transition metal catalyst is a tethered ruthenium catalyst. In some embodiments, the tethered ligand transition metal catalyst is selected from the group consisting of [(S,S)-Teth-TsDpen RuCl], RuCl[(R,R)-Ts DPEN](p- cymene), RuCl[(R,R)-Ms DPEN](p-cymene), RuCl[(R,R)-Fs DPEN](p-cymene), RuCl[(R,R)-Ts DACH](p-cymene), RuCl[(R,R)-Nitro DACH](p-cymene), and [(S,S)-Teth- TsDENEB RuCl]. In some embodiments, the amine nucleophile is NH3or CH3NH2. In some embodiments, the conditions suitable for nucleophilic substitution comprise performing the nucleophilic substitution at a temperature of 5-40°C. In some embodiments, the conditions suitable for nucleophilic substitution comprise performing the nucleophilic substitution in a solvent selected from the group consisting of an alcoholic solvent, ether, polar amide, chlorinated solvent, water, and acetonitrile. In some embodiments, the solvent is selected from the group consisting of methanol, water, isopropyl alcohol, and acetonitrile. In some embodiments, the conditions suitable for nucleophilic substitution comprise a reaction time of 1-24 hours. In some embodiments, the method further comprises reacting the substituted starting material with a protic acid. In some embodiments, the protic acid is aqueous HCl or methanolic HCl. In some embodiments, the conditions suitable for transfer-hydrogenation comprise performing the transfer-hydrogenation at a temperature of 40-70°C. In some embodiments, the conditions suitable for transfer-hydrogenation comprise performing the transfer-hydrogenation in a solvent selected from the group consisting of an alcoholic solvent, ether, polar amide, chlorinated solvent, water, and acetonitrile. In some embodiments, the solvent is selected from the group consisting of methanol and isopropyl alcohol. In some embodiments, the conditions suitable for transfer-hydrogenation comprise a reaction time of 4-15 hours. In some embodiments, the method is performed at ambient pressure. Another aspect of the disclosure provides a method of preparing a salt of epinephrine or norepinephrine produced by a method as described herein. In some embodiments, the salt is selected from the group consisting of tartrate salt, maleate salt, fumarate salt, and hydrochloride salt. In some embodiments, the method further comprises isolating the salt of epinephrine or norepinephrine. Another aspect of the disclosure provides a method of preparing a free base of epinephrine or norepinephrine. The method comprises reacting a salt of epinephrine or norepinephrine with aqueous ammonia under conditions suitable to form a free base. In some embodiments, the method further comprises isolating the free base. DETAILED DESCRIPTION As shown in scheme 1, embodiments of the disclosure provide the synthesis of the physiological active molecules epinephrine 3b and norepinephrine 3a from an achiral starting material 1. The synthesis starts with a nucleophilic substitution of a leaving group, e.g. chlorine, by an amine nucleophile RNH2 (R=H for the synthesis of epinephrine or Me for the synthesis of norepinephrine). The chiral center is subsequently established with a transfer- hydrogenation using tethered catalysts yielding the target molecules in excellent yield and stereoselectivity. The work-up and purification may entail the formation of a salt of the corresponding amine which can be isolated e.g., as the tartaric acid of epinephrine 4b or norepinephrine 4a. The free amine can be obtained with aqueous ammonia to yield norepinephrine 5a as a free base. Scheme 1 Accordingly, embodiments provide a method of preparing epinephrine or norepinephrine, comprising reacting a 2-chloro-1-(3,4-dihydroxyphenyl)ethan-1-one with an amine nucleophile under conditions suitable for nucleophilic substitution of the starting material to form a substituted starting material and reacting the substituted starting material with a tethered ligand transition metal catalyst under conditions suitable for transfer- hydrogenation to produce epinephrine or norepinephrine. In the first step of the process, a molar ratio of the starting material to the amine nucleophile is at least about 1:2, e.g. about 1:2 to about 1:50. A “nucleophile” refers to a chemical species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. Because nucleophiles donate electrons, they are by definition Lewis bases. All molecules or ions with a free pair of electrons can act as nucleophiles. Nucleophilic reactions include those in which the nucleophile is an alcohol (alcoholysis), or contains and amino group (aminolysis), etc. Exemplary nucleophiles that may be used in the practice of the invention include but are not limited to: H2O, alcohols, thioacids, thiols, phosphates, halides, isonitriles, and azides, etc. In some embodiments, the amine nucleophile is NH3or CH3NH2. The nucleophilic substitution occurs in the present of a solvent, e.g. a solvent selected from the group consisting of an alcoholic solvent, ether, polar amide, chlorinated solvent, water, and acetonitrile. In some embodiments, the solvent is selected from the group consisting of methanol, water, isopropyl alcohol, and acetonitrile. In some embodiments, the conditions suitable for nucleophilic substitution comprise performing the nucleophilic substitution at a temperature of about 0-100°C, e.g. 5-40°C. In some embodiments, the conditions suitable for nucleophilic substitution comprise a reaction time of 1-24 hours, e.g. about 5-12 hours. In the second step of the process, the substituted starting material is reacted with a catalyst in the presence of a hydride source under conditions suitable for transfer- hydrogenation. Suitable hydride sources include H2 gas or hydrogen donor compounds such as formic acid, dihydroanthracene, or alcohols (e.g. methanol, isopropanol, propanol, etc.). The conditions suitable for transfer-hydrogenation may comprise performing the transfer- hydrogenation at a temperature of about 0-100°C, e.g. about 40-70°C. In some embodiments, the conditions suitable for transfer-hydrogenation comprise performing the transfer- hydrogenation in a solvent selected from the group consisting of an alcoholic solvent, ether, polar amide, chlorinated solvent, water, and acetonitrile. In some embodiments, the solvent is selected from the group consisting of methanol and isopropyl alcohol. In some embodiments, the conditions suitable for transfer-hydrogenation comprise a reaction time of about 1-30 hours, e.g. about 4-15 hours. The resulting product may then be isolated / purified by known methods. The tethered ligand transition metal catalyst may be a tethered ruthenium, titanium, vanadium, iron, cobalt, nickel, zinc, zirconium, rhodium, or palladium catalyst. In some embodiments, the tethered ligand transition metal catalyst is selected from the group consisting of [(S,S)-Teth-TsDpen RuCl], RuCl[(R,R)-Ts DPEN](p-cymene), RuCl[(R,R)-Ms DPEN](p-cymene), RuCl[(R,R)-Fs DPEN](p-cymene), RuCl[(R,R)-Ts DACH](p-cymene), RuCl[(R,R)-Nitro DACH](p-cymene), and [(S,S)-Teth-TsDENEB RuCl]. A tethered catalyst may refer to a catalyst in a polymer-bound form, e.g. immobilized on a solid support. In some embodiments, non-tethered catalysts may be used alternatively or in addition to tethered catalysts. The method may further comprise an optional step in between the nucleophilic substitution and the transfer-hydrogenation. In this step, the substituted starting material may be reacted with a protic acid. In some embodiments, the protic acid is aqueous HCl or methanolic HCl. The reaction may occur at 0-100°C, e.g. 20-40°C, for about 1 minute to 12 hours, e.g.2-60 minutes. A molar ratio of the substituted starting material to the protic acid is at least about 1:1, e.g. about 1:2 to 1:20. Further embodiments provide a method of preparing a salt of epinephrine or norepinephrine produced by a method as described herein. In some embodiments, the salt is selected from the group consisting of tartrate salt, maleate salt, fumarate salt, and hydrochloride salt. In some embodiments, the method further comprises isolating / purifying the salt of epinephrine or norepinephrine. Suitable methods for forming and isolating / purifying salts are known in the art. Further embodiments provide a method of preparing a free base of epinephrine or norepinephrine. The method comprises reacting a salt of epinephrine or norepinephrine produced by a method as described herein with aqueous ammonia under conditions suitable to form a free base. In some embodiments, the method further comprises isolating / purifying the free base. Suitable methods for preparing and isolating / purifying a free base are known in the art. The described methods allow the synthesis and manufacturing of the described compounds described with improved yield and chiral purity. It does not require a chiral resolution. The hydrogenation can be run under normal pressure and does not require pressurized conditions. In some embodiments, any or all steps of the method is performed at ambient pressure, e.g. about 0.5-2 bars. Performing a method as described herein, the resulting compounds can be obtained in a total yield of 75% or more, e.g. 80%, 85%, 90%, or 95% or more, with an optical purity of 98% ee or more and a chemical purity of 98% or more. The described process is very efficient and easily scalable in large scale. The process avoids the use of hydrogen gas and pressure as was needed in previous methods of high pressure hydrogenation. Embodiments also avoid the use of protecting groups. Further embodiments provide compounds prepared by the methods as described herein. Some embodiments provide a composition comprising the compounds prepared as described herein. In some embodiments, the composition is a pharmaceutical composition which further comprises a pharmaceutically acceptable excipient. The preparation of pharmacologically suitable compositions for use as medicaments is well known to those of skill in the art. Typically, such compositions are prepared either as liquid solutions or suspensions, however solid dry forms such as tablets, pills, powders and the like are also contemplated. The liquid may be an aqueous liquid. Solid forms suitable for solution in, or suspension in, liquids prior to administration may also be prepared. The preparation may also be emulsified. The active ingredients may be mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredients. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol and the like, or combinations thereof. In addition, the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and the like. If it is desired to administer an oral form of the composition, various thickeners, flavorings, diluents, emulsifiers, dispersing aids or binders and the like may be added. The composition of the present invention may contain any such additional ingredients so as to provide the composition in a form suitable for administration. The final amount of compound in the formulations may vary. However, in general, the amount in the formulations will be from about 1% to about 99%. A weight percent of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included. For example if a particular element or component in a composition or article is said to have 8 wt. %, it is understood that this percentage is in relation to a total compositional percentage of 100%. Further, with respect to the compositions, the dry weight basis is used. That is, the wt. % is based on a total weight of dried material so that a weight of water does not significantly contribute to the total weight of material, unless stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated. Before exemplary embodiments of the present invention are described in greater detail, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods and materials are now described. All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed. It is noted that, as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation. As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible. The invention is further described by the following non-limiting examples which further illustrate the invention, and are not intended, nor should they be interpreted to, limit the scope of the invention. EXAMPLES Example 1. Synthesis of norepinephrine / noradrenaline Scheme 2 Synthesis of 2-amino-1-(3,4-dihydroxyphenyl)ethan-1-one hydrochloride, 2a: To a 3-neck RBF, 2-chloro-1-(3,4-dihydroxyphenyl)ethan-1-one (5.0 g, 26.7 mmol) and ACN (10.0 mL) were charged. To the reaction mixture, NH4OH (28%) (30.1 mL, 241.1 mmol) was added. The reaction mixture was stirred for 16 h at room temperature, filtered, and washed with MeOH (3x20 mL), and the product (2-amino-1-(3,4-dihydroxyphenyl)ethan-1- one) was obtained as an off-white solid with 2.69 g (60%) isolated yield. To a 2 neck RBF, 2-amino-1-(3,4-dihydroxyphenyl)ethan-1-one (10.0 g, 167.16 mmol) and MeOH (40 mL) were charged. To the reaction mixture 3M HCl in MeOH (79.7 mL, 239.29 mmol) was added slowly. The reaction mixture was stirred for 10 min. and filtered through a charcoal bed and washed with methanol (3X20 mL). The filtrate was concentrated (most of the MeOH was removed) and MTBE (150 mL) was added. The slurry was stirred for 30 min and filtered, and washed with MTBE (20 mL) to afford an off-white solid (9.6 g, 86%). 1H NMR (600 MHz, DMSO-d6) δ 9.43-8.67 (brs, 4H), 7.40 (t, J = 7.2 Hz, 2H), 6.92 (d, J = 8.4 Hz, 1H), 4.41 (s, 2H);13CNMR (150 MHz, DMSO-d6) δ 190.7, 152.0, 145.5, 125.5, 121.7, 115.4, 114.8, 44.1. Table 1. Synthesis of (R)-4-(2-amino-1-hydroxyethyl)benzene-1,2-diol, 3a: A 3-neck RBF was charged with compound 2a (10 g, 49.11 mmol), methanol (100 mL, 10V) and catalyst (45.6 mg, 0.15 mol%), followed by HCOOH+TEA (5:2) (7 mL). The reaction mixture was stirred at 60-65oC for 7 h, in which the reaction was not completed. More HCOOH+TEA (5:2) (6 mL) was added and the reaction was continued for another 6 h, in which the reaction was completed. The reaction was cooled to rt, treated with 12.5 mL of NH4OH, and the slurry was stirred for 15 min. Water (10 V) was added and stirred for 30 min. The slurry was filtered and washed with water (10 V) and MeOH (4V). The solid was dried under vacuum at 50 ºC for 16 h. Product 2a was obtained as an off-white solid (7.86 g, 91%) and er ratio >99.9:0.1. 1H NMR (400 MHz, DMSO-d6) δ 6.71 (s, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.54 (d, J = 6.8 Hz, 1H), 4.26 (q, J = 4.0 Hz, 1H), 2.56 (m, 2H);13CNMR (100 MHz, DMSO-d6) δ 145.4, 144.6, 135.7, 117.2, 115.5, 113.9, 74.6, 50.5. Enantiomeric ratio was determined by SFC: Chiralpak CBH, 4.0 mm x 100 mm, particle size: 5 µm, temperature: 25 ºC, A: 10 mM Sodium phosphate monobasic, pH 5.8, B: Isopropyl alcohol, isocratic: A / B: 98 / 2, v / v, flow rate 0.75 mL / min. Table 2. Synthesis of Nor-Epinephrine tartrate salt, 4a: A 3-neck RBF was charged with water (5 V) and L-tartaric acid (9.78 g, 1.12 equiv, 65.1 mmol), and stirred to get a clear solution. Compound 3a (10.1 g, 59.7 mmol) was charged, rinsing with water (1 V) – aged for 0.5 – 1 h, warmed up to 35-40 ºC to complete salt formation. A dark black colored solution was observed. To remove undissolved dark colored mass, the solution was passed through filter paper (black layer deposition observed) and washed with water (1V). The solution was passed through 20 wt% (1:1 Solka / floc and Norit CGP carbon column) – brown colored solution was observed (repeated three times to make effective use of the carbon) and washed with water (1 V). The aqueous salt solution was distilled to ~2 vol at 50-55 ºC at 80 mbar vacuum. The solution was filtered and washed with total 10 vol ethanol, 3 each for displacement, slurr and displacement. Product 3 was obtained as white solid with 17.0 g (85% yield, 95.5% wt% assay). 1H NMR (600 MHz, DMSO-d6) δ 6.79 (s, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 4.64 (d, J = 8.8 Hz, 1H), 4.04 (s, 2H)*, 2.94 (d, J = 11.8 Hz, 1H), 2.76 (t, J = 11.1 Hz, 1H).13CNMR (150 MHz, DMSO-d6): δ 175.3*, 145.7, 145.4, 133.4, 117.2, 115.9, 114.0, 72.6*, 69.4, 46.4. Table 3. Example 2. Synthesis of epinephrine / adrenaline Scheme 3 Synthesis of 1-(3,4-dihydroxyphenyl)-2-(methylamino)ethan-1-one hydrogen chloride, 2b: A 250 mL 3-neck RBF equipped with an internal thermometer, addition funnel, and N2line was charged with 2-chloro-1-(3,4-dihydroxyphenyl)ethan-1-one (10.0 g, 53.6 mmol) and ACN (6V). The reaction mixture was treated dropwise with 40% CH3NH2 / H2O (32.4 mL, 7.0 equiv) over a period of 25 min. During the addition, the slurry changed color from dark beige to greyish green, and the internal temperature rose from 18.3ºC to 23.7ºC before falling back to 18.6ºC. The slurry was heated to 35 ºC for 1 h. After cooling to room temperature, the reaction mixture was treated with 1V ACN, filtered, and washed with 1V ACN, 1V of water, and 1V of ACN. The cake was suction dried and dried under vacuum oven at 40ºC for 12 h. The product 1-(3,4-dihydroxyphenyl)-2-(methylamino)ethan-1-one (8.25 g, 85%) was collected as a greyish / light green colored solid. A 1L flask with overhead stirrer, internal thermometer, addition funnel, and N2line was charged with 1-(3,4-dihydroxyphenyl)-2-(methylamino)ethan-1-one (10.0 g, 55.0 mmol) and MeOH (6V). To this slurry, 3M HCl in MeOH (73.5 mL) was added at rt, followed by 2 V water. During the addition, the slurry changed from greyish / green to a dark brown solution. After 1 h, distillation was performed under reduced pressure to remove methanol (70 mL). To the reaction mixture IPA (20 mL) was charged. The mixture was filtered and washed with 3 V x IPA. Product 1b (8.5 g, 71% yield) was obtained as an off-white solid. 1H NMR (400 MHz, D2O) δ 7.45 (dd, J = 8.4, 2.0 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.62 (s, 2H), 2.79 (s, 3H);13CNMR (100 MHz, D2O) δ 191.4, 151.4, 144.2, 125.8, 123.2, 115.7, 115.2, 53.6, 32.7. Table 4. Synthesis of (R)-4-(1-hydroxy-2-(methylamino)ethyl)benzene-1,2-diol, 3b: A 3-neck RBF was charged with compound 2b (10 g, 217.6 mmol), catalyst (37 mg, 0.13 mol%), and MeOH (100 mL, 10V). This solution was treated with formic acid / TEA (5:2) (10.5 mL). The reaction mixture was stirred at reflux for 20 h. The reaction mixture was cooled to RT and treated with NH4OH (15 mL). The slurry was stirred for 15 min before adding water (150 mL) and stirring for another 30 min. The slurry was filtered and washed with water (20 V). The cake was suction dried under vacuum, and the product 3b (7.5 g, 89% yield, er ratio 99.3:0.7) was obtained as an off-white solid. Purification: To a 2 L reactor equipped with an overhead stirrer, internal thermometer, addition funnel, and Nitrogen line, water (300 mL, 7.5 V) and L-tartaric acid (18.06 g, 120 mol) was added. 40.04 g of 3b (218 mol, 1 eq, Assay – 96wt%) was then added to the tartaric acid solution and stirred at 20-25 °C for 1 h. The reaction mass was filtered through celite / charcoal bed (8 g of celite / 10 g of charcoal) and the bed was washed with water (100 ml, 2.5 V). The filtrate was collected, charged to the jacketed reactor, and ammonium hydroxide (150 mL, 3.7V) was added over 30 minutes. The reaction mixture was stirred at 20-25 °C for 1 h. Methanol (5V, 205 mL) was added to the reaction mixture and stirred for an additional 30 minutes. The slurry was filtered and washed with water / IPA mixture (100 ml / 100 ml) followed IPA (200 ml). The cake was suction dried for 1 h, and further dried in vacuum oven at 30-35 °C for 13 h and the product 3b (34.89 g, 89.4% yield (corrected for purity), HPLC wt% - 98.5 wt%, Ruthenium content – 4.55 ppm) was obtained as an off-white solid. 1H NMR (400 MHz, D2O) δ 6.90-6.88 (m, 2H), 6.81 (dd, J = 8.2, 2.1 Hz, 1H), 4.87 (dd, J = 7.1, 5.8 Hz, 1H), 3.22 (d, J = 6.4 Hz, 2H), 2.71 (s, 3H);13CNMR (100 MHz, D2O): δ 144.2, 144.1, 132.0, 118.5, 116.3, 113.8, 68.2, 54.4, 32.9. Enantiomeric ratio was determined by SFC: Chiralpak CBH, 4.0 mm x 100 mm, particle size: 5 µm, temperature: 25 ºC, A: 10 mM Sodium phosphate monobasic, pH 5.8, B: Isopropyl alcohol, isocratic: A / B: 98 / 2, v / v, flow rate 0.75 mL / min. Table 5. While the invention has been described in terms of its preferred embodiments, those skilled in the art will recognize that the invention can be practiced with modification within the spirit and scope of the appended claims. Accordingly, the present invention should not be limited to the embodiments as described above, but should further include all modifications and equivalents thereof within the spirit and scope of the description provided herein.

Claims

CLAIMS 1. A method of preparing epinephrine or norepinephrine, comprising reacting a starting material comprising 2-chloro-1-(3,4-dihydroxyphenyl)ethan-1-one with an amine nucleophile under conditions suitable for nucleophilic substitution of the starting material to form a substituted starting material; and reacting the substituted starting material with a tethered ligand transition metal catalyst under conditions suitable for transfer-hydrogenation to produce epinephrine or norepinephrine.

2. The method of claim 1, wherein the tethered ligand transition metal catalyst is a tethered ruthenium catalyst.

3. The method of claim 1, wherein the tethered ligand transition metal catalyst is selected from the group consisting of [(S,S)-Teth-TsDpen RuCl], RuCl[(R,R)-Ts DPEN](p-cymene), RuCl[(R,R)-Ms DPEN](p-cymene), RuCl[(R,R)-Fs DPEN](p-cymene), RuCl[(R,R)-Ts DACH](p-cymene), RuCl[(R,R)-Nitro DACH](p-cymene), and [(S,S)-Teth-TsDENEB RuCl].

4. The method of claim 1, wherein the amine nucleophile is NH3 or CH3NH2.

5. The method of claim 1, wherein the conditions suitable for nucleophilic substitution comprise performing the nucleophilic substitution at a temperature of 5-40°C.

6. The method of claim 1, wherein the conditions suitable for nucleophilic substitution comprise performing the nucleophilic substitution in a solvent selected from the group consisting of an alcoholic solvent, ether, polar amide, chlorinated solvent, water, and acetonitrile.

7. The method of claim 6, wherein the solvent is selected from the group consisting of methanol, water, isopropyl alcohol, and acetonitrile.

8. The method of claim 1, wherein the conditions suitable for nucleophilic substitution comprise a reaction time of 1-24 hours.

9. The method of claim 1, further comprising reacting the substituted starting material with a protic acid.

10. The method of claim 9, wherein the protic acid is aqueous HCl or methanolic HCl.

11. The method of claim 1, wherein the conditions suitable for transfer-hydrogenation comprise performing the transfer-hydrogenation at a temperature of 40-70°C.

12. The method of claim 1, wherein the conditions suitable for transfer-hydrogenation comprise performing the transfer-hydrogenation in a solvent selected from the group consisting of an alcoholic solvent, ether, polar amide, chlorinated solvent, water, and acetonitrile.

13. The method of claim 12, wherein the solvent is selected from the group consisting of methanol and isopropyl alcohol.

14. The method of claim 1, wherein the conditions suitable for transfer-hydrogenation comprise a reaction time of 4-15 hours.

15. The method of claim 1, wherein the method is performed at ambient pressure.

16. A method of preparing a salt of epinephrine or norepinephrine, comprising performing the method of claim 1 to produce epinephrine or norepinephrine; and forming a salt of epinephrine or norepinephrine.

17. The method of claim 16, wherein the salt is selected from the group consisting of tartrate salt, maleate salt, fumarate salt, and hydrochloride salt.

18. The method of claim 16, further comprising isolating the salt of epinephrine ornorepinephrine.

19. A method of preparing a free base of epinephrine or norepinephrine, comprising performing the method of claim 16 to produce a salt of epinephrine or norepinephrine; and reacting the salt with aqueous ammonia under conditions suitable to form a free base.

20. The method of claim 19, further comprising isolating the free base.

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