Tomoxetine hydrochloride and preparation method thereof

Abstract

The invention provides atomoxetine hydrochloride and a preparation method thereof, and relates to the technical field of medicinal chemistry and organic synthesis. The method provided by the invention comprises the following steps: adopting acetophenone, methylamine hydrochloride and a formaldehyde aqueous solution as raw materials, carrying out Mannich reaction to construct a beta-amino carbonyl skeleton, reducing carbonyl into hydroxyl by adopting sodium borohydride, then reacting with di-tert-butyl dicarbonate to form an amino protecting group, adopting o-methylphenol as a raw material, and preparing the beta-amino carbonyl skeleton. The method comprises the following steps: adding p-toluenesulfonic acid monohydrate and a (2-hydroxybenzyl) phosphine oxide catalyst to construct an ether bond through a Mitsunobu reaction, then removing a t-butyloxycarboryl protecting group, and carrying out chiral resolution and salinization reaction by using S-mandelic acid to obtain atomoxetine hydrochloride. The method of dropwise adding the formaldehyde aqueous solution in batches and controlling the reaction temperature is adopted, so that the generation of impurities can be reduced, and the yield is effectively improved; the p-toluenesulfonic acid monohydrate and the (2-hydroxybenzyl) phosphine oxide catalyst capable of participating in catalytic circulation are used for catalyzing the Mitsunobu reaction, the economic principle is met, and the purity and the yield of the product are greatly improved.

Description

Technical Field

[0001] This invention relates to the fields of medicinal chemistry and organic synthesis, and in particular to atomoxetine hydrochloride and its preparation method. Background Technology

[0002] Atomoxetine hydrochloride, chemically known as R-(-)-N-methyl-3-phenyl-3-(2-methylphenoxy)propylamine hydrochloride, is an important selective norepinephrine reuptake inhibitor widely used clinically to treat attention deficit hyperactivity disorder (ADHD). As the first non-centrally excitatory ADHD treatment, it significantly increases the concentrations of NE and dopamine in the prefrontal cortex by selectively inhibiting the presynaptic membrane norepinephrine transporter (NET), demonstrating advantages such as definite efficacy and high safety.

[0003] Existing technologies for preparing atomoxetine hydrochloride via the Mannich reaction and photoelectrophoresis using dimethyl azodicarbonate (DEAD) and triphenylphosphine (PPh3) as catalysts can be carried out at low temperatures, with mild and relatively rapid reactions. However, in actual production, the Mannich reaction has complex side reactions, produces many impurities, has a yield of less than 60%, and the purity of the crude product is less than 70%, which is also quite complicated to purify. The quality of the intermediate methylamine acetone is difficult to control. At the same time, the photoelectrophoresis reaction must rely on stoichiometric amounts of triphenylphosphine and hazardous azo reagents, and inevitably produces stoichiometric byproducts (such as triphenylphosphine oxide and hydrazine derivatives), which bring difficulties to subsequent separation and purification. This makes it unsuitable for industrial production, and such a low-economic reaction is obviously not in line with the current advocacy of green and sustainable chemistry.

[0004] Therefore, there is an urgent need to provide a solution to improve the above problems. Summary of the Invention

[0005] The purpose of this invention is to provide atomoxetine hydrochloride and its preparation method.

[0006] This invention improves the Mannich reaction and photoelectrophoresis process in the preparation of atomoxetine hydrochloride, reducing the generation of byproducts and significantly increasing the purity of the crude product. Furthermore, the photoelectrophoresis process eliminates the traditional stoichiometric triphenylphosphine and hazardous azo reagents, avoiding the generation of stoichiometric byproducts that could hinder subsequent separation and purification. It creatively utilizes a (2-hydroxybenzyl)phosphine oxide catalyst that can participate in the catalytic cycle and p-toluenesulfonic acid monohydrate to catalyze the photoelectrophoresis reaction, aligning with the current advocacy of green and sustainable chemistry. This achieves higher production efficiency, lower costs, and a simpler operating procedure, making it more suitable for large-scale industrial production.

[0007] In a first aspect, the present invention provides a method for preparing atomoxetine hydrochloride, characterized by comprising the following steps:

[0008] (1) Add acetophenone and methylamine hydrochloride to solvent A, add formaldehyde aqueous solution with a mass fraction of 37% dropwise in batches, and carry out Mannich reaction to obtain N-methyl-β-benzoyl ethylamine hydrochloride;

[0009] (2) The N-methyl-β-benzoyl ethylamine hydrochloride obtained in step (1) was dissolved in solvent B, and sodium borohydride was added to carry out a reduction reaction to obtain N-methyl-3-phenyl-3-hydroxypropylamine;

[0010] (3) The N-methyl-3-phenyl-3-hydroxypropylamine obtained in step (2) was dissolved in solvent C, and ditert-butyl dicarbonate was added and reacted under heating conditions to obtain N-tert-butyloxycarbonyl-N-methyl-3-phenyl-3-hydroxypropylamine.

[0011] (4) The N-tert-butoxycarbonyl-N-methyl-3-phenyl-3-hydroxypropylamine obtained in step (3) was dissolved in solvent D, and a photo-extending reaction was carried out in the presence of p-toluenesulfonic acid monohydrate and (2-hydroxybenzyl)phosphine oxide catalyst to generate a sulfonate intermediate. After cooling, o-methylphenol and inorganic base reagent were added, and a nucleophilic substitution reaction was carried out in a polar aprotic solvent to obtain N-methyl-N-tert-butoxycarbonyl-3-phenyl-3-o-toluoxypropylamine.

[0012] (5) Dissolve the N-methyl-N-tert-butoxycarbonyl-3-phenyl-3-o-tolyloxypropylamine obtained in step (4) in solvent E, add deprotecting agent dropwise to carry out deprotection reaction to remove the tert-butoxycarbonyl protecting group and obtain N-methyl-3-phenyl-3-o-tolyloxypropylamine;

[0013] (6) The N-methyl-3-phenyl-3-o-tolyloxypropylamine obtained in step (5) was dissolved in solvent F, and (S)-mandelic acid was added to obtain (R)-atomoxetine mandelic acid by chiral resolution through temperature gradient controlled crystallization.

[0014] (7) The (R)-atomoxetine mandelate obtained in step (6) is dissociated in alkaline solution, extracted with organic solvent, and then subjected to a salting reaction with hydrochloric acid-ethanol solution in organic phase. The atomoxetine hydrochloride is then purified by recrystallization.

[0015] Optionally, solvent A in step (1) includes one of methanol, ethanol, isopropanol, n-butanol, ethyl acetate, and tetrahydrofuran.

[0016] Optionally, the molar ratio of acetophenone, methylamine hydrochloride and the 37% formaldehyde aqueous solution in step (1) is 1:(2.0-6.0):(0.5-2.0).

[0017] Optionally, the batch dripping in step (1) includes slow dripping in 3-5 equal portions at intervals of 1.5h-2.5h.

[0018] Optionally, the reaction temperature of the Mannich reaction in step (1) is 30℃-90℃ and the reaction time is 4h-24h.

[0019] Optionally, solvent B in step (2) includes one of methanol, ethanol, isopropanol, and tetrahydrofuran.

[0020] Optionally, the molar ratio of N-methyl-β-benzoylethylamine hydrochloride to sodium borohydride in step (2) is 1:(3.0-3.5).

[0021] Optionally, the sodium borohydride in step (2) is added in 3-5 equal portions, with an interval of 10-20 minutes between each addition.

[0022] Optionally, the reduction reaction in step (2) is carried out at a temperature of 10℃-40℃ and for a reaction time of 1.5h-5.0h.

[0023] Optionally, the solvent C in step (3) includes one of dichloromethane, trichloromethane, and toluene.

[0024] Optionally, the molar ratio of N-methyl-3-phenyl-3-hydroxypropylamine to ditert-butyl dicarbonate in step (3) is 1:(0.9-1.5).

[0025] Optionally, the reaction temperature under heating conditions described in step (3) is 20℃-50℃, and the reaction time is 0.5h-1.5h.

[0026] Optionally, the solvent D in step (4) includes one of toluene, xylene, and ethers.

[0027] Optionally, the molar ratio of N-tert-butoxycarbonyl-N-methyl-3-phenyl-3-hydroxypropylamine, p-toluenesulfonic acid monohydrate and (2-hydroxybenzyl)phosphine oxide catalyst in step (4) is 1:(0.5-2.0):(0.02-0.2).

[0028] Optionally, the (2-hydroxybenzyl)phosphine oxide catalyst in step (4) includes (2-hydroxybenzyl)diphenylphosphine oxide.

[0029] Optionally, the reaction temperature of the photoelongation reaction in step (4) is 80℃-120℃, and the reaction time is 15h-30h.

[0030] Optionally, the inorganic base reagent in step (4) includes one of cesium carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, and sodium ethoxide.

[0031] Optionally, the polar aprotic solvent in step (4) includes one of N,N-dimethylformamide and dimethyl sulfoxide.

[0032] Optionally, the nucleophilic substitution reaction in step (4) is carried out at a temperature of 80℃-140℃ and for a reaction time of 2h-8h.

[0033] Optionally, the solvent E mentioned in step (5) includes one of dichloromethane, trichloromethane, tetrahydrofuran, and ethyl acetate.

[0034] Optionally, the molar ratio of N-methyl-N-tert-butoxycarbonyl-3-phenyl-3-o-tolyloxypropylamine to the deprotecting agent in step (5) is 1:(3-8).

[0035] Optionally, the deprotecting agent in step (5) includes one of trifluoroacetic acid, p-toluenesulfonic acid, and hydrochloric acid.

[0036] Optionally, in step (5), the deprotectant is slowly added dropwise under ice bath conditions.

[0037] Optionally, the deprotection reaction in step (5) is carried out at a temperature of 0°C-40°C and for a reaction time of 2h-8h.

[0038] Optionally, the solvent F in step (6) includes ethers.

[0039] Optionally, the molar ratio of N-methyl-3-phenyl-3-o-tolyloxypropylamine to (S)-mandelic acid in step (6) is 1:(0.2-0.8).

[0040] Optionally, the temperature gradient controlled crystallization method in step (6) includes stirring and crystallizing at 40℃-60℃ for 1h-3h, and then cooling to -10℃-20℃ to continue crystallization for 6h-8h.

[0041] Optionally, the alkaline solution in step (7) includes a 30% aqueous solution of sodium hydroxide.

[0042] Optionally, the organic solvent in step (7) includes ethers.

[0043] Optionally, the reaction temperature of the salting reaction in step (7) is -10℃ to 20℃, and the reaction time is 1.0h to 4.0h.

[0044] Optionally, the hydrochloric acid-ethanol solution in step (7) is an ethanol solution of 30% HCl.

[0045] Optionally, the recrystallization process in step (7) includes dissolving the crystals by heating and reflux in anhydrous ethanol, cooling to 40℃-60℃ and stirring to crystallize for 2 hours, and further cooling to -10℃-20℃ and stirring to crystallize for 4-6 hours.

[0046] Secondly, the present invention also provides atomoxetine hydrochloride prepared by any of the above-mentioned optional preparation methods, wherein the yield of the prepared atomoxetine hydrochloride is ≥10% and the purity is ≥99.9%. Attached Figure Description

[0047] Figure 1 This is a diagram of the catalytic cycle of (2-hydroxybenzyl)diphenylphosphine oxide during the photoelectrophoresis reaction in Example 4 of the present invention. Detailed Implementation

[0048] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise defined, the technical or scientific terms used herein should have the ordinary meaning understood by those skilled in the art to which this invention pertains.

[0049] This invention provides a method for preparing atomoxetine hydrochloride, comprising the following steps:

[0050] (1) Add acetophenone and methylamine hydrochloride to solvent A, add formaldehyde aqueous solution with a mass fraction of 37% dropwise in batches, and carry out Mannich reaction to obtain N-methyl-β-benzoyl ethylamine hydrochloride;

[0051] (2) The N-methyl-β-benzoyl ethylamine hydrochloride obtained in step (1) was dissolved in solvent B, and sodium borohydride was added to carry out a reduction reaction to obtain N-methyl-3-phenyl-3-hydroxypropylamine;

[0052] (3) The N-methyl-3-phenyl-3-hydroxypropylamine obtained in step (2) was dissolved in solvent C, and ditert-butyl dicarbonate was added and reacted under heating conditions to obtain N-tert-butyloxycarbonyl-N-methyl-3-phenyl-3-hydroxypropylamine.

[0053] (4) The N-tert-butoxycarbonyl-N-methyl-3-phenyl-3-hydroxypropylamine obtained in step (3) was dissolved in solvent D, and a photo-extending reaction was carried out in the presence of p-toluenesulfonic acid monohydrate and (2-hydroxybenzyl)phosphine oxide catalyst to generate a sulfonate intermediate. After cooling, o-methylphenol and inorganic base reagent were added, and a nucleophilic substitution reaction was carried out in a polar aprotic solvent to obtain N-methyl-N-tert-butoxycarbonyl-3-phenyl-3-o-toluoxypropylamine.

[0054] (5) Dissolve the N-methyl-N-tert-butoxycarbonyl-3-phenyl-3-o-tolyloxypropylamine obtained in step (4) in solvent E, add deprotecting agent dropwise to carry out deprotection reaction to remove the tert-butoxycarbonyl protecting group and obtain N-methyl-3-phenyl-3-o-tolyloxypropylamine;

[0055] (6) The N-methyl-3-phenyl-3-o-tolyloxypropylamine obtained in step (5) was dissolved in solvent F, and (S)-mandelic acid was added to obtain (R)-moxetine mandelic acid by chiral resolution through temperature gradient controlled crystallization.

[0056] (7) The (R)-moxetine mandelate obtained in step (6) is dissociated in alkaline solution, extracted with organic solvent, and then subjected to a salting reaction with hydrochloric acid-ethanol solution in organic phase. The atomoxetine hydrochloride is then purified by recrystallization.

[0057] In fact, the method of adding formaldehyde aqueous solution dropwise in batches and controlling the reaction temperature can reduce the generation of impurities and effectively improve the yield. The use of p-toluenesulfonic acid monohydrate and (2-hydroxybenzyl)phosphine oxide catalyst that can participate in the catalytic cycle to catalyze the photocatalytic reaction is in line with the principle of economy and can significantly improve the purity and yield of the product.

[0058] In some embodiments, solvent A used in step (1) includes one of methanol, ethanol, isopropanol, n-butanol, ethyl acetate, and tetrahydrofuran. In practice, solvent A is necessary to simultaneously and sufficiently dissolve both the nonpolar acetone and the polar salt methylamine hydrochloride.

[0059] In some embodiments, the molar ratio of acetophenone, methylamine hydrochloride, and the added 37% formaldehyde aqueous solution in step (1) is 1:(2.0-6.0):(0.5-2.0). In practice, acetophenone, as the carbonyl component in the Mannich reaction, provides an α-carbon site to bind to the imine ion (from the condensation of methylamine and formaldehyde). Furthermore, the electron-withdrawing effect of the benzene ring activates the carbonyl group, promoting nucleophilic addition. Methylamine hydrochloride provides the amino group, condensing with formaldehyde to generate the imine ion as a key intermediate. Additionally, the hydrochloride form helps to suppress the volatilization of free methylamine, acting as a pH buffer. The formaldehyde used is a 37% formaldehyde aqueous solution, which facilitates the slow release of formaldehyde and controls the reaction rate.

[0060] Using acetophenone as the primary standard and other reagents as references, excess methylamine hydrochloride may increase the free amine content and raise the pH of the reaction solution, leading to acetophenone undergoing aldol condensation under alkaline conditions. Formaldehyde may also undergo side reactions, generating impurities and consuming formaldehyde, resulting in incomplete main reactions and reduced intermediate product yield. Insufficient methylamine hydrochloride, on the other hand, leads to incomplete acetophenone conversion, excessive formaldehyde accumulation, and increased impurity formation due to side reactions. If formaldehyde is excessive, the product N-methyl-β-benzoylethylamine can further react with formaldehyde, causing hydroxymethylation of the nitrogen atom. This makes the byproduct difficult to separate by crystallization, reducing the final purity. Insufficient formaldehyde results in acetophenone residue, preventing effective consumption of methylamine hydrochloride and leading to the presence of CH3NH3 in the system. + Accumulation, low pH, inhibits the formation of imine ions.

[0061] In some embodiments, step (1) involves batch addition, including adding the formaldehyde solution slowly in 3-5 equal portions at intervals of 1.5-2.5 hours. In practice, batch-interval addition of the formaldehyde aqueous solution can control the effective concentration of formaldehyde, avoid local overdose leading to side reactions, and ensure that formaldehyde preferentially participates in the main reaction (forming an imine intermediate with methylamine) rather than reacting secondaryly with the product or intermediate. This reduces the formation of byproducts, increases the yield of the target product, and the intermittent addition also controls the rate of exothermic reaction to prevent temperature runaway.

[0062] In some embodiments, the reaction temperature for the Mannich reaction is 30°C-90°C, and the reaction time is 4h-24h. In practice, controlling the appropriate reaction temperature can accelerate the formation of imine ions while avoiding side reactions. If the temperature is too low, the reaction rate is too low, reducing the conversion rate; if the temperature is too high, the condensation of acetophenone aldehydes and alcohols leads to an increase in byproducts, and methylamine also volatilizes at excessively high temperatures, causing an imbalance in the stoichiometry. If the reaction time is too long, the amide bonds of the product may hydrolyze, leading to a decrease in yield, and the long reaction time also increases energy consumption; if the time is too short, the reaction may be incomplete, and residual starting materials may affect subsequent reactions. Therefore, the synergistic effect of appropriate reaction temperature and reaction time can avoid side reactions and the risk of hydrolysis, thereby improving the yield of the target product.

[0063] In some embodiments, solvent B used in step (2) includes one of methanol, ethanol, isopropanol, and tetrahydrofuran. In practice, solvent B is necessary to simultaneously and sufficiently dissolve both N-methyl-β-benzoylethylamine hydrochloride and sodium borohydride. Methanol effectively dissolves both to form a homogeneous reaction system; it also provides a proton-rich environment, stabilizing the active hydroxyl anions released from NaBH4 and assisting in proton transfer, promoting the reduction of carbonyl groups to hydroxyl groups; furthermore, the weak acidity of methanol inhibits excessive decomposition of sodium borohydride, suppressing side reactions.

[0064] In some embodiments, the molar ratio of N-methyl-β-benzoylethylamine hydrochloride to sodium borohydride used in step (2) is 1:(3.0-3.5). In practice, sodium borohydride acts as a reducing agent, providing hydride anions (H-) to attack the carbonyl carbon, while the N-methyl-β-benzoylethylamine hydrochloride substrate provides the carbonyl group (C=O) as a reduction target. The amide bond (-CO-NH-) in the substrate is selectively reduced to a hydroxyl group under the action of sodium borohydride. Theoretically, sodium borohydride can provide 4 H-, but in practice only 1-2 are effective for amide reduction. Therefore, sodium borohydride reducing agent needs to be in excess to ensure complete carbonyl reduction; however, it is also necessary to control the amount of sodium borohydride to avoid over-reduction of the substrate to generate byproducts, and excess sodium borohydride increases the difficulty of subsequent processing.

[0065] In some embodiments, sodium borohydride is added in step (2) in 3-5 equal portions, with each addition spaced 10-20 minutes apart. In fact, this batch-interval addition is to avoid the concentrated decomposition of sodium borohydride leading to violent exothermic reactions and hydrogen release. Simultaneously, it ensures the gradual reduction of the carbonyl group (C=O) to the hydroxyl group (C-OH), suppressing excessive reduction, reducing unnecessary waste and byproduct formation, and improving the yield and purity of the main product.

[0066] In some embodiments, in step (2), the reduction reaction temperature is 10℃-40℃, and the reaction time is 1.5h-5.0h. In fact, controlling the low temperature can suppress excessive reduction of sodium borohydride and also suppress side reactions to avoid amide hydrolysis or the formation of borate ester byproducts; controlling the reaction temperature to 10℃-40℃ avoids excessively low temperatures leading to excessively low reaction rates, and excessively high temperatures leading to increased byproducts. Synergistically regulating the reaction time avoids insufficient reaction and residual raw materials due to too short a time, and excessive time leading to depletion of sodium borohydride, which may trigger intermediate degradation and partial hydrolysis of the product. Therefore, synergistically regulating the reaction temperature and reaction time can prevent the increase of side reactions while ensuring the reaction rate; and improve the yield and purity of the target product.

[0067] In some embodiments, the solvent C used in step (3) includes one of dichloromethane, chloroform, and toluene. In practice, solvent C is necessary to simultaneously and sufficiently dissolve both N-methyl-3-phenyl-3-hydroxypropylamine and di-tert-butyl dicarbonate. Dichloromethane can sufficiently dissolve N-methyl-3-phenyl-3-hydroxypropylamine and di-tert-butyl dicarbonate to form a homogeneous reaction system; it also provides an inert environment, preventing side reactions with di-tert-butyl dicarbonate, hydroxyl groups, or amino groups; and its low boiling point facilitates low-temperature rotary evaporation after the reaction, avoiding thermal decomposition of the product.

[0068] In some embodiments, the molar ratio of N-methyl-3-phenyl-3-hydroxypropylamine to ditert-butyl dicarbonate used in step (3) is 1:(0.9-1.5). In practice, N-methyl-3-phenyl-3-hydroxypropylamine provides the primary amino group as a protecting site, generating a Boc-protected intermediate, while ditert-butyl dicarbonate ((Boc)₂O) acts as the amino protecting agent, introducing a tert-butyloxycarbonyl (Boc). Each molecule of (Boc)₂O can protect one molecule of amino group. Theoretically, protecting 1 mol of amino group requires 1 mol of (Boc)₂O. However, in practice, (Boc)₂O may undergo side reactions such as hydrolysis, so excess (Boc)₂O is needed to ensure complete reaction and complete amino group protection. Insufficient (Boc)₂O may lead to incomplete protection, causing side reactions of the amino group in subsequent reaction steps; excessive (Boc)₂O is wasteful, and excess (Boc)₂O may trigger hydroxyl side reactions. Therefore, adjusting the appropriate ratio can ensure complete amino group protection and reduce the formation of byproducts.

[0069] In some embodiments, in step (3), the reaction temperature under heating conditions is 20℃-50℃, and the reaction time is 0.5h-1.5h. In reality, too low a temperature may lead to a low reaction rate, reducing the conversion rate, while too high a temperature may lead to the high-temperature decomposition of (Boc)₂O; too short a time may lead to incomplete reaction and residual raw materials, while too long a time may lead to partial hydrolysis of the Boc group in the product, reducing the yield of the target product, and the solvent dichloromethane may participate in the chlorination side reaction, generating byproducts and reducing the purity of the target product. Therefore, synergistic control of the reaction temperature and reaction time can ensure the stability of the protecting group while activating (Boc)₂O; and ensure complete conversion of the reaction while avoiding reagent decomposition.

[0070] In some embodiments, the solvent D used in step (4) includes one of toluene, xylene, or ethers. In practice, the choice of solvent D is necessary to ensure the simultaneous and sufficient dissolution of N-tert-butoxycarbonyl-N-methyl-3-phenyl-3-hydroxypropylamine, p-toluenesulfonic acid monohydrate, and the (2-hydroxybenzyl)phosphine oxide catalyst. Toluene effectively dissolves all three and provides an inert environment, preventing side reactions with p-toluenesulfonic acid monohydrate and the (2-hydroxybenzyl)phosphine oxide catalyst. Furthermore, the use of toluene in conjunction with a Dean-Stark apparatus allows for azeotropic removal of the water generated in the reaction, shifting the reaction equilibrium to the right and accelerating the reaction efficiency.

[0071] In some embodiments, the molar ratio of N-tert-butoxycarbonyl-N-methyl-3-phenyl-3-hydroxypropylamine, p-toluenesulfonic acid monohydrate, and (2-hydroxybenzyl)phosphine oxide catalyst used in step (4) is 1:(0.5-2.0):(0.02-0.2). In practice, N-tert-butoxycarbonyl-N-methyl-3-phenyl-3-hydroxypropylamine provides a hydroxyl group as a reaction site to generate a sulfonate intermediate; p-toluenesulfonic acid monohydrate (TsOH·H2O) acts as a sulfonating agent to activate the hydroxyl group; and (2-hydroxybenzyl)phosphine oxide acts as a catalyst to catalyze the sulfonation reaction, which conforms to the mechanism of photocatalytic reactions. Insufficient TsOH·H2O may lead to incomplete hydroxyl conversion, while excessive TsOH·H2O may cause hydrolysis of the sulfonate or deactivation of the catalyst; an appropriate amount of (2-hydroxybenzyl)phosphine oxide can catalyze the reaction, while an excess may trigger side reactions (such as polymerization).

[0072] In some embodiments, the (2-hydroxybenzyl)phosphine oxide catalyst used in step (4) comprises (2-hydroxybenzyl)diphenylphosphine oxide. In fact, (2-hydroxybenzyl)diphenylphosphine oxide participates in the reaction in a catalytic cycle, and the catalyst can be repeatedly recycled; furthermore, TsOH·H2O forms a hydrogen bond network through the P=O bonds of the (2-hydroxybenzyl)phosphine oxide catalyst, which can promote the protonation of hydroxyl groups and increase the reaction rate.

[0073] In some embodiments, the reaction temperature of the photoelectrophoresis reaction in step (4) is 80℃-120℃, and the reaction time is 15h-30h. In reality, if the reaction temperature is too low, the toluene-water azeotropic dehydration will be incomplete, and the reaction rate will decrease. If the temperature is too high, the (2-hydroxybenzyl)phosphine oxide catalyst will decompose, and the sulfonate will undergo thermal cracking. If the reaction time is too short, the reaction will be incomplete, and the raw materials will remain. If the reaction time is too long, the product will be hydrolyzed, and the toluene solvent will participate in the chlorination reaction, resulting in a decrease in the yield and purity of the target product.

[0074] In some embodiments, the inorganic base reagent used in step (4) includes one of cesium carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, and sodium ethoxide. In fact, the inorganic base reagent has a base catalytic effect, capable of neutralizing the phenolic hydroxyl group in o-methylphenol to generate a phenoxy anion, thus enhancing nucleophilicity. Specifically, cesium carbonate, as a strongly soluble base, enhances the uniformity of the reaction and avoids side reactions caused by local pH inconsistencies.

[0075] In some embodiments, the polar aprotic solvent used in step (4) includes one of N,N-dimethylformamide and dimethyl sulfoxide. In fact, polar aprotic solvents can greatly accelerate the nucleophilic substitution reaction between the sulfonate intermediate generated by the photoelectrophoresis and the phenoxy anion of o-methylphenol. Furthermore, the use of N,N-dimethylformamide, a polar aprotic solvent with good solubility, can effectively dissolve inorganic bases, generated phenolates, organic intermediates, and other substances, providing a homogeneous reaction environment that allows the reactants to fully contact each other, thereby further increasing the reaction rate.

[0076] In some embodiments, the nucleophilic substitution reaction in step (4) is carried out at a temperature of 80°C-140°C and for a time of 2-8 hours. In fact, controlling the appropriate reaction temperature and reaction time can optimize the reaction rate, suppress side reactions, ensure high yield and high purity, and lay a solid foundation for subsequent chiral resolution and final salt formation.

[0077] In some embodiments, the solvent E used in step (5) includes one of dichloromethane, trichloromethane, tetrahydrofuran, and ethyl acetate. In practice, solvent E is necessary to sufficiently and effectively dissolve N-methyl-N-tert-butoxycarbonyl-3-phenyl-3-o-tolyloxypropylamine, allowing it to fully contact the deprotecting agent and form a homogeneous or micro-homogeneous reaction environment, ensuring efficient and smooth reaction. Furthermore, dichloromethane has good chemical stability, can withstand strongly acidic conditions without decomposition or side reactions, and can sufficiently dissolve N-methyl-N-tert-butoxycarbonyl-3-phenyl-3-o-tolyloxypropylamine, ensuring smooth reaction and compatibility with the deprotecting agent, forming a homogeneous system.

[0078] In some embodiments, the molar ratio of N-methyl-N-tert-butoxycarbonyl-3-phenyl-3-o-tolyloxypropylamine to the deprotecting agent used in step (5) is 1:(3-8). In practice, N-methyl-N-tert-butoxycarbonyl-3-phenyl-3-o-tolyloxypropylamine is the core target molecule of the reaction, and its Boc protecting group needs to be removed. The deprotecting agent provides an acidic environment, catalyzing and driving the cleavage reaction of the Boc protecting group. Using an excess of the deprotecting agent relative to N-methyl-N-tert-butoxycarbonyl-3-phenyl-3-o-tolyloxypropylamine can ensure the complete completion of the reaction, suppress side reactions, and improve the purity of the product.

[0079] In some embodiments, the deprotecting agent used in step (5) includes one of trifluoroacetic acid, p-toluenesulfonic acid, and hydrochloric acid. In practice, Boc deprotection typically requires acidic conditions. The protons provided by the acidic environment rapidly protonate the carbonyl oxygen on the Boc group, making it an excellent leaving group, thereby triggering the cleavage of the entire Boc group to generate highly reactive tert-butyl cations and carbon dioxide. Furthermore, trifluoroacetic acid can effectively dissolve most organic substrates, ensuring a rapid and homogeneous reaction; due to its extremely high acid concentration, trifluoroacetic acid exhibits very high deprotection efficiency.

[0080] In some embodiments, the deprotecting agent is slowly added dropwise in step (5) under ice bath conditions. In fact, when the deprotecting agent is mixed with the reaction system, it often generates significant heat of dilution. If it is added rapidly in large quantities, the huge heat generated instantaneously may cause the temperature of the reaction solution to rise sharply and the solvent to boil violently. Slowly adding the deprotecting agent dropwise under ice bath conditions can control the thermal effect of the reaction, ensuring the safety of the experiment and the high purity of the product.

[0081] In some embodiments, the solvent F used in step (6) includes ethers. In practice, solvent F is necessary to be able to dissolve N-methyl-3-phenyl-3-o-tolyloxypropylamine and (S)-mandelic acid well so that they can come into sufficient contact and react.

[0082] In some embodiments, the molar ratio of N-methyl-3-phenyl-3-o-tolyloxypropylamine to (S)-mandelic acid used in step (6) is 1:(0.2-0.8). In fact, N-methyl-3-phenyl-3-o-tolyloxypropylamine is the target to be resolved, and (S)-mandelic acid is the chiral resolving agent. Controlling the appropriate amount of both can ensure product purity while improving product yield.

[0083] In some embodiments, the temperature gradient controlled crystallization method in step (6) includes stirring and crystallizing at 40℃-60℃ for 1h-3h, and then cooling to -10℃-20℃ to continue crystallization for 6h-8h. In fact, stirring and crystallizing at 40℃-60℃ for 1h-3h generates a small number of high-quality, pure crystal nuclei by controlling low supersaturation and allowing them to grow initially, laying a quality foundation for subsequent crystallization. Cooling to -10℃-20℃ to continue crystallization for 6h-8h maximizes crystal growth and improves the final product yield by creating high supersaturation.

[0084] In some embodiments, the alkaline solution used in step (7) includes a 30% aqueous sodium hydroxide solution. In fact, after the alkaline solution is added, OH- reacts with mandelic acid molecules, taking away their protons to generate sodium mandelate and water. This breaks the ionic bonds that originally maintained the salt structure, thereby releasing the (R)-atormoxetine free amine.

[0085] In some embodiments, the organic solvent used in step (7) includes ethers. In fact, the organic solvent is added to extract (R)-atormoxetine free amine from the alkaline aqueous phase to the organic phase, achieving a crucial separation of the product from the impurities.

[0086] In some embodiments, the reaction temperature of the salting reaction in step (7) is -10℃ to 20℃, and the reaction time is 1.0h to 4.0h. In fact, low temperature is the key to ensuring the successful salting reaction, and its main purpose is to control the heat of reaction, suppress side reactions, and obtain ideal crystal properties.

[0087] In some embodiments, the hydrochloric acid-ethanol solution used in step (7) is an ethanol solution of 30% HCl.

[0088] In some embodiments, the recrystallization process in step (7) includes heating and refluxing to dissolve in anhydrous ethanol, cooling to 40°C-60°C and stirring to crystallize for 2 hours, and further cooling to -10°C-20°C and stirring to crystallize for 4-6 hours.

[0089] The present invention also provides atomoxetine hydrochloride prepared using any of the above embodiments, wherein the yield of the prepared atomoxetine hydrochloride is ≥10% and the purity is ≥99.9%.

[0090] Example 1

[0091] Example 1 provides a method for preparing N-methyl-β-benzoylethylamine hydrochloride, comprising the following steps:

[0092] 4.48 g (66.4 mmol) of methylamine hydrochloride was dissolved in 2 mL of concentrated hydrochloric acid, and 2.0 g (16.6 mmol) of acetophenone was dissolved in 12 mL of isopropanol. The solutions were transferred to a 50 mL three-necked flask and heated to an internal temperature of 55-60 °C. 1.347 g (16.6 mmol) of 37% formaldehyde aqueous solution was dissolved in 6 mL of isopropanol and added slowly in three batches at 2-hour intervals, with continuous stirring for 10 hours. The solvent was removed by rotary evaporation. 10 mL of distilled water was added, and the mixture was stirred and cooled to adjust the pH to 1. The precipitate was removed by suction filtration. Unreacted acetophenone was removed by petroleum ether extraction. The pH of the aqueous phase was adjusted to 7 with 30 wt% potassium carbonate. The mixture was stirred continuously at 40 °C for 5 min while maintaining the pH at 7. The mixture was then filtered. The filtrate was extracted twice with 30 mL of a mixed organic solvent (ethyl acetate: petroleum ether = 1:6). The pH was adjusted to 9-10, and the mixture was stirred continuously for 5 min. The mixture was then filtered again. Finally, the mixture was extracted twice with 15 mL of dichloromethane. The dichloromethane phases were combined and concentrated by rotary evaporation to obtain 2.52 g of a pale yellow solid, N-methyl-β-benzoylethylamine hydrochloride, with a yield of 68.74%.

[0093] Example 2

[0094] Example 2 provides a method for preparing N-methyl-3-phenyl-3-hydroxypropylamine, comprising the following steps:

[0095] 1.42 g of N-methyl-β-benzoylethylamine hydrochloride prepared in Example 1 was added to a 100 mL three-necked flask, followed by 10 mL of methanol. Then, 0.91 g (24 mmol) of sodium borohydride was added in four portions over one hour. The reaction was carried out at 0-5 °C for 2 hours. The reaction was quenched with 10 mL of distilled water and extracted three times with 15 mL of dichloromethane. The dichloromethane phases were combined, concentrated, and dried to obtain 1.34 g of N-methyl-3-phenyl-3-hydroxypropylamine, with a yield of 94.25% and a purity of 97.37%.

[0096] Example 3

[0097] Example 3 provides a method for preparing N-tert-butoxycarbonyl-N-methyl-3-phenyl-3-hydroxypropylamine, comprising the following steps:

[0098] 5 g (8 mmol) of N-methyl-3-phenyl-3-hydroxyaniline prepared in Example 2 was added to 25 mL of dichloromethane in a 250 mL three-necked flask. 7.2 g (8 mmol) of (Boc)2O was added, and the mixture was stirred at 35 °C for 1 hour. The dichloromethane was removed by rotary evaporation to obtain 1.22 g of N-tert-butoxycarbonyl-N-methyl-3-phenyl-3-hydroxypropylamine, with a yield of 92.30% and a purity of 99.69%.

[0099] Example 4

[0100] Example 4 provides a method for preparing N-methyl-N-tert-butoxycarbonyl-3-phenyl-3-o-tolyloxypropylamine, comprising the following steps:

[0101] In a 50 mL three-necked flask, 2.12 g (12.0 mmol) of N-tert-butoxycarbonyl-N-methyl-3-phenyl-3-hydroxypropylamine prepared in Example 3, 2.28 g (12.0 mmol) of p-toluenesulfonic acid monohydrate, and 185 mg (0.600 mmol) of (2-hydroxybenzyl)diphenylphosphine oxide were added sequentially and dissolved in 75 mL of toluene. The mixture was heated under reflux and stirred for 16 hours using a Dean-Stark apparatus. The reaction mixture was cooled, and 1.557 g (14.4 mmol) of o-methylphenol, 4.69 g (14.4 mmol) of cesium carbonate, and 30 mL of N,N-dimethylformamide (DMF) were added. The mixture was heated under reflux for 3 hours. The mixture was concentrated, and 300 mL of dichloromethane was added. The yellow precipitate was collected by filtration (p-toluenesulfonic acid could be recovered). The filtrate was concentrated and processed to obtain N-methyl-N-tert-butoxycarbonyl-3-phenyl-3-o-toluoxypropylamine. The yield was 65.41%, and the purity was 94.38%.

[0102] Example 5

[0103] Example 5 provides a method for preparing N-methyl-3-phenyl-3-o-tolyloxypropylamine, comprising the following steps:

[0104] 1.65 g (10 mmol) of N-methyl-N-tert-butoxycarbonyl-3-phenyl-3-o-tolyloxypropylamine prepared in Example 4 was added to a 50 mL single-necked flask, followed by 5 mL of dichloromethane. 5 mL of trifluoroacetic acid (65 mmol) was slowly added dropwise in an ice bath. After the addition was complete, the mixture was stirred at room temperature for 3 h. Dichloromethane and trifluoroacetic acid were removed by rotary evaporation. 5 mL of ice water was added, and the mixture was extracted twice with 10 mL of dichloromethane. The organic phases were combined, washed with saturated sodium bicarbonate solution until neutral, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 1.54 g of N-methyl-3-phenyl-3-o-tolyloxypropylamine, with a yield of 60.15%.

[0105] Example 6

[0106] Example 6 provides a method for preparing (R)-atormoxetine mandelate, comprising the following steps:

[0107] 1.54 g (6.04 mmol) of N-methyl-3-phenyl-3-o-tolyloxypropylamine prepared in Example 5 was added to a 25 mL single-necked flask, along with 10 mL of methyl tert-butyl ether. The mixture was stirred and heated to 40-45 °C, and then 0.46 g (3.02 mmol) of (S)-mandelic acid was added. The mixture was stirred and crystallized at 40-45 °C for 2 hours, then allowed to cool naturally to 0-5 °C and stirred for 6-8 hours. After centrifugation, the filter cake was washed with 2 mL of methyl tert-butyl ether and dried to obtain 0.69 g (1.69 mmol) of (R)-atormoxetine mandelic acid. The yield was 28%.

[0108] Example 7

[0109] This embodiment 7 provides a method for preparing atormoxine hydrochloride, including the following steps:

[0110] Add 0.69 g (1.69 mmol) of (R)-atormoxetine mandelate, 4 mL of methyl tert-butyl ether, and 1 mL of water to a 25 mL three-necked flask, then add 0.35 g of 30% sodium hydroxide aqueous solution dropwise. After the addition is complete, the reaction solution is stirred for 1 hour after it becomes clear. Separate the solutions; extract the aqueous phase with 2 mL of methyl tert-butyl ether, combine the organic phases, wash with 4 mL of water, separate the solutions, and retain the organic phase solution. Cool the methyl tert-butyl ether organic solution to 0℃-5℃, add 2 mL of 30% HCl ethanol solution to the solution, and a large amount of white solid precipitates. Stir at 0℃-5℃ for 2 hours, centrifuge, and dry to obtain 0.37 g (1.27 mmol) of crude atormoxetine hydrochloride. Yield: 75%.

[0111] 0.37 g (1.27 mmol) of crude atomoxetine hydrochloride and 1 mL of anhydrous ethanol were added to a 25 mL three-necked flask. The mixture was heated to reflux and stirred for 1 h. Heating was then stopped, and the mixture was cooled to 50-55 °C and stirred to crystallize for 2 h. The temperature was then lowered to 0-10 °C and stirred to crystallize for 4-6 h. The mixture was filtered, and the filter cake was collected and placed in a 40 °C forced-air drying oven to obtain 0.33 g (1.14 mmol) of white solid atomoxetine hydrochloride. The yield was 90%, and the purity was 99.91%.

[0112] While embodiments of the present invention have been described in detail above, it will be apparent to those skilled in the art that various modifications and variations can be made to these embodiments. However, it should be understood that such modifications and variations fall within the scope and spirit of the invention as set forth in the claims. Furthermore, the invention described herein may have other embodiments and can be implemented or carried out in various ways.

Claims

1. A method for preparing atomoxetine hydrochloride, characterized in that, Includes the following steps: (1) Add acetophenone and methylamine hydrochloride to solvent A, add formaldehyde aqueous solution with a mass fraction of 37% dropwise in batches, and carry out Mannich reaction to obtain N-methyl-β-benzoyl ethylamine hydrochloride; (2) The N-methyl-β-benzoyl ethylamine hydrochloride obtained in step (1) was dissolved in solvent B, and sodium borohydride was added to carry out a reduction reaction to obtain N-methyl-3-phenyl-3-hydroxypropylamine; (3) The N-methyl-3-phenyl-3-hydroxypropylamine obtained in step (2) was dissolved in solvent C, and ditert-butyl dicarbonate was added and reacted under heating conditions to obtain N-tert-butyloxycarbonyl-N-methyl-3-phenyl-3-hydroxypropylamine. (4) The N-tert-butoxycarbonyl-N-methyl-3-phenyl-3-hydroxypropylamine obtained in step (3) was dissolved in solvent D, and a photo-extending reaction was carried out in the presence of p-toluenesulfonic acid monohydrate and (2-hydroxybenzyl)phosphine oxide catalyst to generate a sulfonate intermediate. After cooling, o-methylphenol and inorganic base reagent were added, and a nucleophilic substitution reaction was carried out in a polar aprotic solvent to obtain N-methyl-N-tert-butoxycarbonyl-3-phenyl-3-o-toluoxypropylamine. (5) Dissolve the N-methyl-N-tert-butoxycarbonyl-3-phenyl-3-o-tolyloxypropylamine obtained in step (4) in solvent E, add deprotecting agent dropwise to carry out deprotection reaction to remove the tert-butoxycarbonyl protecting group and obtain N-methyl-3-phenyl-3-o-tolyloxypropylamine; (6) The N-methyl-3-phenyl-3-o-tolyloxypropylamine obtained in step (5) was dissolved in solvent F, and (S)-mandelic acid was added to obtain (R)-atomoxetine mandelic acid by chiral resolution through temperature gradient controlled crystallization. (7) The (R)-atomoxetine mandelate obtained in step (6) is dissociated in alkaline solution, extracted with organic solvent, and then subjected to a salting reaction with hydrochloric acid-ethanol solution in organic phase. The atomoxetine hydrochloride is then purified by recrystallization.

2. The method according to claim 1, characterized in that, The solvent A in step (1) includes one of methanol, ethanol, isopropanol, n-butanol, ethyl acetate, and tetrahydrofuran; and / or, the molar ratio of acetophenone, methylamine hydrochloride, and the 37% formaldehyde aqueous solution is 1:(2.0-6.0):(0.5-2.0); and / or, the batch addition includes slow addition in 3-5 equal portions at intervals of 1.5-2.5 hours; and / or, the reaction temperature of the Mannich reaction is 30℃-90℃, and the reaction time is 4-24 hours.

3. The method according to claim 1, characterized in that, The solvent B in step (2) includes one of methanol, ethanol, isopropanol, and tetrahydrofuran; and / or, the molar ratio of N-methyl-β-benzoylethylamine hydrochloride to sodium borohydride is 1:(3.0-3.5); and / or, the sodium borohydride is added in 3-5 equal portions, with an interval of 10-20 minutes between each addition; and / or, the reaction temperature of the reduction reaction is 10℃-40℃, and the reaction time is 1.5h-5.0h.

4. The method according to claim 1, characterized in that, The solvent C in step (3) includes one of dichloromethane, chloroform, and toluene; and / or, the molar ratio of N-methyl-3-phenyl-3-hydroxypropylamine to ditert-butyl dicarbonate is 1:(0.9-1.5); and / or, the reaction temperature under heating conditions is 20℃-50℃, and the reaction time is 0.5h-1.5h.

5. The method according to claim 1, characterized in that, In step (4), solvent D includes one of toluene, xylene, and ethers; and / or, the molar ratio of N-tert-butoxycarbonyl-N-methyl-3-phenyl-3-hydroxypropylamine, p-toluenesulfonic acid monohydrate, and (2-hydroxybenzyl)phosphine oxide catalyst is 1:(0.5-2.0):(0.02-0.2); and / or, the (2-hydroxybenzyl)phosphine oxide catalyst includes (2-hydroxybenzyl)diphenylphosphine oxide; and / or, the reaction temperature of the photoextension reaction is 80℃-120℃, and the reaction time is 15h-30h; and / or, the inorganic base reagent includes one of cesium carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, and sodium ethoxide; and / or, the polar aprotic solvent includes one of N,N-dimethylformamide and dimethyl sulfoxide; and / or, the reaction temperature of the nucleophilic substitution reaction is 80℃-140℃, and the reaction time is 2h-8h.

6. The method according to claim 1, characterized in that, In step (5), solvent E includes one of dichloromethane, trichloromethane, tetrahydrofuran, and ethyl acetate; and / or, the molar ratio of N-methyl-N-tert-butoxycarbonyl-3-phenyl-3-o-tolyloxypropylamine to the deprotecting agent is 1:(3-8); and / or, the deprotecting agent includes one of trifluoroacetic acid, p-toluenesulfonic acid, and hydrochloric acid; and / or, the deprotecting agent is slowly added dropwise under ice bath conditions; and / or, the reaction temperature of the deprotection reaction is 0℃-40℃, and the reaction time is 2h-8h.

7. The method according to claim 1, characterized in that, The solvent F in step (6) includes ethers; and / or, the molar ratio of N-methyl-3-phenyl-3-o-tolyloxypropylamine to (S)-mandelic acid is 1:(0.2-0.8); and / or, the temperature gradient controlled crystallization method includes stirring and crystallizing at 40℃-60℃ for 1h-3h, and then cooling to -10℃-20℃ to continue crystallization for 6h-8h.

8. The method according to claim 1, characterized in that, The alkaline solution in step (7) includes a 30% sodium hydroxide aqueous solution; and / or, the organic solvent includes ethers; and / or, the reaction temperature of the salting reaction is -10℃ to 20℃, and the reaction time is 1.0h to 4.0h; and / or, the hydrochloric acid-ethanol solution is an ethanol solution of 30% HCl; the recrystallization process includes dissolving under reflux in anhydrous ethanol, cooling to 40℃ to 60℃ and stirring to crystallize for 2h, and further cooling to -10℃ to 20℃ and stirring to crystallize for 4h to 6h.

9. Atomoxetine hydrochloride prepared by the method according to any one of claims 1 to 8, characterized in that, The overall yield of the prepared atomoxetine hydrochloride is ≥10%; the purity is ≥99.9%.

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