Processes and intermediates for the preparation of viloxazine and other 2-substituted morpholine derivatives

Abstract

The present invention relates to an efficient and industrially applicable process for preparing 2-substituted morpholine derivatives such as viloxazine and to intermediates useful therefor.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention is in the field of drug synthesis, and more particularly relates to an efficient and industrially applicable process for the preparation of 2-substituted morpholine derivatives such as viloxazine and intermediates useful therefor. [Background technology]

[0002] Background of the Invention Viloxazine is the international non-proprietary (INN) or common name for 2-[(2-ethoxyphenoxy)methyl]morpholine, a well-known racemic morpholine derivative with CAS number 46817-91-8, originally discovered by Imperial Chemical Industries in the late 1960s when their scientists attempted to synthesize a compound with a propranolol-like structure with CNS modulating properties. Viloxazine acts as a selective norepinephrine reuptake inhibitor (SNRI) and has the following chemical structure: [ka]

[0003] Viloxazine hydrochloride was approved by the U.S. Food and Drug Administration (FDA) in April 2021 under the trade name Qelbree® for the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adolescents. However, before being repurposed for ADHD treatment in the United States, viloxazine hydrochloride was previously sold in Europe under different trade names (Viloxazin®, Emovit®, Viloxazina®, Viloxazinum®, Vivalan®, Vivarin®, Vivarint®, and Vicilan®) as an antidepressant from the 1970s until 2002, when it was discontinued for commercial reasons unrelated to safety or efficacy.

[0004] Despite its commercial availability, the methods described in the art for its synthesis are generally considered unsatisfactory, mainly due to the low yields of most of them and / or the genotoxic nature of some of the intermediates or reagents used. It is therefore of utmost importance to ensure that this active pharmaceutical ingredient is obtained in high purity.

[0005] Viloxazine was first described in BE708557A (also published as US3714161) by reacting o-ethoxyphenol with epichlorohydrin under basic conditions, and the resulting epoxide intermediate 1-(2-ethoxyphenoxy)-2,3-epoxypropane was heated with benzylamine and then treated with chloroacetyl chloride. The resulting cyclic amide was reduced with lithium aluminum hydride and then hydrogenated to remove the benzyl group to give viloxazine, which can optionally be isolated as the hydrochloride salt. (See also Mallion KB, Todd AH, Turner RW, Bainbridge JG, Greenwood DT, Madinaveitia J, et al. 2-(2-Ethoxyphenoxymethyl)tetrahydro-1,4-oxazine hydrochloride, a potential psychotropic agent. Nature 1972;238:157-8.) [ka]

[0006] However, this pioneering method for synthesizing viloxazine was unsatisfactory due to its low yield (20% overall based on the propanolamine intermediate) and lengthy synthesis, as later reported by the same authors (Greenwood DT, Mallion KB, Todd AH, Turner RW. 2-Aryloxymethyl-2,3,5,6-tetrahydro-1,4-oxazines, a new class of antidepressants. J Med Chem. 1975; 18(6): 573-7).

[0007] US 3,857,839 and US 3,712,890 relate to a process for preparing viloxazine in which the epoxide intermediate 1-(2-ethoxyphenoxy)-2,3-epoxypropane is reacted with a 2-aminoethyl derivative (e.g., 2-aminoethyl hydrogen sulfate) in ethanol in the presence of sodium hydroxide to form viloxazine free base, which can be isolated as viloxazine HCl. Example 10 of US 3,857,839 describes a process variation in which the intermediate addition product is isolated prior to cyclization. [ka] In the scheme, R 3 may in particular be H or benzyl, and Z represents a halogen atom or a displaceable radical such as a sulfonyloxy radical.

[0008] In this case, low yields are reported and also involve the use of genotoxic reactants such as epichlorohydrin, alkylating agents or large amounts of NH2-CH2-CH2-SO3H for the formation of amino alcohol intermediates.

[0009] WO2011130194 relates to methods for preparing viloxazine salts and polymorphs thereof. This patent application acknowledges that the aforementioned methods for synthesizing viloxazine have many drawbacks, including low reaction yields and unacceptably high levels of impurities in the resulting products. Effective elimination or removal of impurities, particularly those with genotoxic or other toxic properties, is crucial for safe pharmaceutical preparations. Certain reagents traditionally used in viloxazine preparation, such as epichlorohydrin and 2-aminoethyl sulfate, present particular problems due to their toxicity. However, WO2011130194 actually utilizes two methods already disclosed in previous publications (see Examples 1 and 17-18, respectively). In short, this patent application aims to improve the preparation of the initial epoxide and the subsequent workup and isolation of viloxazine salts. [ka]

[0010] Another approach for the preparation of viloxazine involves intramolecular CO bond formation of an alkanol-epoxide via boron trifluoride as the key transformation in a relatively long (7-step) total synthesis (Gosh P, Deka M, Saikia, A. Lewis Acid Mediated Intramolecular CO Bond Formation of Alkanol-Epoxide Leading to Substituted Morpholine Derivatives: Total Synthesis of (+)-Viloxazine. Tetrahedron 2016, 72, 690-698). [ka]

[0011] Imperial Chemical Industries conducted further research toward the preparation of suitable 2-functionalized morpholine intermediates in connection with the synthesis of antidepressant compounds (Loftus F, The Synthesis of Some 2-Substituted Morpholines, Synthetic Communications, 10(1), 59-73 (1980)). N-benzyl-2-chloromethylmorpholine (1) was prepared by dissolving N-benzylethanolamine in excess epichlorohydrin, and the solution was stirred at 40 °C. The excess epichlorohydrin was then removed by distillation under reduced pressure, leaving the intermediate amine (designated 8 in the literature and 2 herein) as a gum, which was dissolved in 98% sulfuric acid, and the solution was rapidly heated to 150 °C. Workup of the reaction mixture afforded N-benzyl-2-chloromethylmorpholine (3) as a colorless oil in 79% yield. [ka]

[0012] This last route, developed by Imperial Chemical Industries to prepare N-benzyl-2-chloromethylmorpholine or related benzyl-substituted derivatives, has been repeated in more recent work, although not for the purpose of synthesizing viloxazine (step (ii) of Preparation 12) or Audouze K, Nielsen EO, Peters D. New series of morpholine and 1,4-oxazepane derivatives as dopamine D receptor ligands: synthesis and 3D-QSAR model. J Med Chem. 2004; 47(12): 3089-3104 (preparation of compound 6c, procedure E)).

[0013] However, the procedures described in the art for obtaining the morpholine intermediate (3) in the sequence shown in Reaction Scheme 5 above have two important drawbacks: The initial ethanolamine derivative (1) is mixed neat (without solvent) with an excess of epichlorohydrin (1.1-10 equivalents), which is effectively genotoxic. This excess epichlorohydrin must be removed by distillation upon completion of step 1 or by column chromatography at the end of the process. Purification by distillation may not reproducibly yield the product in a sufficiently pure state, while purification by column chromatography is unsuitable, or at least undesirable, for industrial-scale production because it requires very large amounts of solvent, making the process expensive and environmentally disadvantageous. Concentrated sulfuric acid is added in excess to the mixture after step 1, resulting in a highly exothermic reaction. Exothermic reactions can lead to thermal runaway, which begins when the heat produced by the reaction exceeds the heat removed and the reaction goes out of control. Furthermore, because the heat produced increases with the volume of the reaction mixture, while the heat removed depends on the surface area available for heat transfer, the scale at which the reaction is carried out can have a significant impact on the likelihood of runaway. Therefore, on an industrial scale, highly exothermic processes should be avoided whenever possible. Summary of the Invention [Problem to be solved by the invention]

[0014] In summary, the processes disclosed in the prior art for the preparation of viloxazine or suitable intermediates therefor are not industrially applicable for various reasons (low yields, too time consuming, presence of impurities with undesirable pharmacological properties, risk of runaway reactions on large scale, etc.) Therefore, there is a need to develop new processes for obtaining key intermediates in the synthesis of viloxazine and related compounds that overcome all or some of the problems associated with known methods in the art. [Means for solving the problem]

[0015] Summary of the Invention The present invention addresses the aforementioned needs by providing a simple and industrially applicable method for preparing 2-substituted morpholine derivatives, such as viloxazine, and useful intermediates therefor. Specifically, the method provided herein enables obtaining 2-chloromethylmorpholine intermediates of general formula (III) in high yield and purity under milder and more suitable conditions compared to common procedures in the art for preparing these compounds. Subsequent conversion of the 2-chloromethylmorpholine intermediate to viloxazine or related compounds is straightforward, making this methodology practical for industrial implementation. The present invention also provides novel salts of N-benzyl-2-chloromethylmorpholine encompassed by general formula (III).

[0016] After comprehensive research, the inventors have realized that the method disclosed by Loftus and followed by other authors for preparing N-benzyl-2-chloromethylmorpholine (see Reaction Scheme 5) cannot be scaled up in an industrial manner, in particular for the following reasons: · Epichlorohydrin (genotoxic) from step 1 always remains in some amount in the reaction mixture before adding concentrated sulfuric acid; Epichlorohydrin can undergo explosive polymerization when in contact with strong acids (e.g., sulfuric acid) (Wiley Guide to Chemical Incompatibilities, p. 498); To avoid the presence of epichlorohydrin after the reaction is complete, the use of substoichiometric amounts of epichlorohydrin promotes the formation of the dimeric impurity (8): [ka] The intermediate 1-chloro-2-propanol-N derivative (compound (2) in Reaction Scheme 5) is unstable and cannot be stored in solution for long periods or isolated by solvent distillation without forming unwanted impurities, because it gives rise to by-products, mainly azetidine (6) and epoxide (7): [ka] The addition of concentrated sulfuric acid, even at low temperatures and slowly, is highly exothermic and difficult to control, especially on a large scale. Therefore, a runaway reaction can occur in the presence of highly corrosive concentrated H2SO4; The use of concentrated sulfuric acid means a small reaction volume, difficult stirring, and an exothermic work-up with the formation of tar.

[0017] In conclusion, the method as described, inter alia, by Loftus is unsuitable for industrial purposes.

[0018] Therefore, the present inventors have carried out comprehensive experiments aimed at improving the preparation of N-benzyl-2-chloromethylmorpholine and other N-substituted 2-chloromethylmorpholines, with the aim of implementing them in the industrial preparation of 2-substituted morpholine derivatives, more specifically viloxazine. As a result of this work, the present inventors have unexpectedly discovered a new methodology based on the following important findings: The use of an organic solvent together with a Lewis acid in the first step (preparation of intermediate (2)) allows for a more stable and manageable reaction medium without significant secondary reactions or impurity formation compared to the solvent-free (neat) reactions proposed in the art; Contrary to the state of the art (see, for example, US Pat. No. 2,777,846), the sulfuric acid cyclization reaction to give the morpholine ring works in the presence of water, rather than being a dehydration reaction requiring an anhydrous medium by using concentrated sulfuric acid or oleum (fuming sulfuric acid); Therefore, a mixture of H2SO4 / water can be used to extract intermediate (2) from the reaction mixture and carry out the cyclization in step 2; This H2SO4 / water mixture allows, on the one hand, the removal of non-basic impurities, including residual genotoxic epichlorohydrin (thus, if necessary, an excess of epichlorohydrin can be used in step 1); Furthermore, when intermediate (2) is extracted with a mixture of H2SO4 / water and concentrated sulfuric acid is added to carry out the second step, the exothermic behavior is well controlled, and morpholine compound (3) is obtained in very good yield and with a very clean profile.

[0019] Overall, this experimental procedure allows for controlled exothermic behavior when handling large amounts of reagents and reactants, while also providing the desired product with fewer impurities. Furthermore, the reaction mixture is less dense, making it easier to work with. Those skilled in the art will appreciate that this method is not limited to N-benzylethanolamine (1), and other amino-protected ethanolamine compounds can also be used.

[0020] Thus, in a first aspect, the present invention provides a compound of general formula (III) or a salt or solvate thereof [ka] (In the formula, R 1 is an amino protecting group) 1. A method for preparing a) In the presence of a Lewis acid and an organic solvent, epichlorohydrin is reacted with a compound of general formula (I) or a salt or solvate thereof [ka] (In the formula, R 1 is an amino protecting group) to obtain a compound of general formula (II) or a salt or solvate thereof [ka] (In the formula, R 1 is an amino protecting group) obtaining a reaction mixture comprising b) mixing the reaction mixture with an aqueous sulfuric acid solution to obtain an aqueous-sulfuric acid phase containing the sulfate salt of the compound of general formula (II); and c) Mixing the aqueous-sulfuric acid phase containing the sulfate of the compound of general formula (II) with concentrated sulfuric acid to obtain the compound of general formula (III) or a salt or solvate thereof. The present invention covers a method including:

[0021] The compounds of formula (III), and their salts or solvates, are intermediates in the synthesis of viloxazine and other 2-substituted morpholine compounds. Thus, the ultimate production of viloxazine and related derivatives by the methods provided herein for preparing compounds of general formula (III) or their salts or solvates is also encompassed by the present invention.

[0022] In a further aspect, the present invention is directed to a salt of 4-benzyl-2-(chloromethyl)morpholine, said salt being selected from the oxalate, fumarate or tosylate salts.

[0023] These aspects and preferred embodiments thereof are further defined in the detailed description and claims that follow.

[0024] For a better understanding of the present invention, its objects and advantages, the following figures are attached hereto as set forth below. [Brief explanation of the drawings]

[0025] [Figure 1] FIG. 1 shows a general scheme of a process for preparing viloxazine HCl in accordance with the present invention. [Figure 2] FIG. 2 shows a scheme of a process for preparing viloxazine HCl according to an embodiment of the present invention, starting from N-benzylethanolamine (1). (A3VLX free base, i.e., the free base of compound (3), is used for further conversion to 4VLX, i.e., compound (4)). [Figure 3] FIG. 3 shows a scheme of a process for preparing viloxazine HCl according to an embodiment of the present invention, starting from N-benzylethanolamine (1). (A3VLX oxalate, i.e., the oxalate salt of compound (3), is used for further conversion to 4VLX, i.e., compound (4)). [Figure 4] FIG. 4 shows the 1H NMR of 4-benzyl-2-(chloromethyl)morpholine oxalate (the oxalate of compound (3) or A3VLX oxalate), which is the compound of Example 5. [Figure 5] FIG. 5 shows a differential scanning calorimetry (DSC) of the compound of Example 5, 4-benzyl-2-(chloromethyl)morpholine oxalate (the oxalate of compound (3) or A3VLX oxalate). [Figure 6] FIG. 6 shows the 1H NMR of 4-benzyl-2-(chloromethyl)morpholine fumarate (the fumarate of compound (3) or A3VLX fumarate), which is the compound of Example 6. [Figure 7] FIG. 7 shows the DSC of 4-benzyl-2-(chloromethyl)morpholine fumarate, the compound of Example 6 (the fumarate of compound (3) or A3VLX fumarate). [Figure 8] FIG. 8 shows 1H NMR of 4-benzyl-2-(chloromethyl)morpholine tosylate (tosylate of compound (3) or A3VLX tosylate), which is the compound of Example 7. [Figure 9] FIG. 9 shows the DSC of 4-benzyl-2-(chloromethyl)morpholine tosylate (the tosylate of compound (3) or A3VLX tosylate), which is the compound of Example 7. [Figure 10] FIG. 10 shows an X-ray powder diffraction (XRPD) pattern of viloxazine obtained according to an embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0026] Detailed Description of the Invention The present inventors have developed a new method for the preparation of 2-substituted morpholine derivatives, such as viloxazine, and intermediates useful therefor. The method of the present invention is simple, reproducible, and well suited to industrial scale.

[0027] definition Those skilled in the art know that numerical values relating to measurements are subject to measurement errors that limit their accuracy. When terms such as "about" or "approximately" are applied to a particular value (e.g., "about 200°C" or "and 200°C") or range (e.g., "about x to approximately y"), the value or range is interpreted as being as accurate as the method used to measure it. Unless explicitly stated otherwise, common practice in scientific and technical literature applies, and thus the last digit of a numerical value preferably indicates the precision of the measurement. Therefore, unless another error range is given, the maximum range is preferably ascertained by applying the convention of rounding to the last decimal place. For example, a value of 3.5 preferably has an error range of 3.45 to 3.54, and a range of 2% to 10% preferably encompasses a range of 1.5% to 10.4%. Such variations in the specified values are understood by those skilled in the art and are within the context of the present invention. Furthermore, to provide a more concise explanation, some quantitative expressions given herein are not modified with the term "about." Whether or not the term "about" is explicitly used, any quantity given herein is meant to refer to the actual given value, and is understood to also refer to approximations to such given value that are reasonably inferred based on ordinary skill in the art, including equivalents and approximations based on experimental and / or measurement conditions for such given value.

[0028] Concentrations, amounts, and other numerical data may be expressed or presented in a range format herein. It should be understood that such range formats are used merely for convenience and brevity and, therefore, should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also all individual numerical values or subranges subsumed within that range, as if each numerical value and subrange were explicitly recited. As an example, a numerical range of "about 1% to about 5%" should be interpreted as including not only the explicitly recited values of about 1% to about 5%, but also each individual value and subrange within the specified range. Thus, this numerical range includes individual values such as 2, 3, and 4, and subranges such as 1 to 3, 2 to 4, and 3 to 5. This same principle applies to ranges reciting only one numerical value.

[0029] As used herein, "room temperature" or its abbreviation "rt" means that a reaction or process is carried out without heating or cooling. Generally, room temperature can be understood as a temperature of about 15°C to about 30°C, or more specifically, about 20°C to about 25°C.

[0030] As used herein, the term "Lewis acid" refers to a molecule that can accept a pair of electrons and form a coordinate covalent bond.

[0031] As used herein, the term "aqueous sulfuric acid" refers to dilute sulfuric acid, i.e., not concentrated sulfuric acid. Preferably, this refers to an aqueous solution containing sulfuric acid at a concentration of up to 90% (w / w) (i.e., 90 g of acid per 100 g of solution), more preferably in the range of 10-90% (w / w). Aqueous sulfuric acid can be obtained by slowly adding concentrated sulfuric acid to water under stirring in a cooling bath, monitoring the solution temperature to prevent excessive increase. The concentration of concentrated sulfuric acid is typically 95-98% (w / w).

[0032] The term "organic solvent" includes, for example, cyclic and acyclic ethers (e.g., EtO, iPrO, tBuO, MeOtBu, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran), hydrocarbon solvents (e.g., pentane, hexane, cyclohexane, heptane), halogenated solvents (e.g., dichloromethane, chloroform), alcohols (e.g., methanol, ethanol, propanol, isopropanol, sec-butanol, t-butanol), aromatic solvents (e.g., toluene, xylene), ketones (e.g., acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), esters (e.g., EtOAc, iPrOAc), nitriles (e.g., acetonitrile, benzonitrile, propionitrile), amides (e.g., DMF, DMA, HMPA), sulfoxides (DMSO), and mixtures thereof.

[0033] The term "vol" refers to volume equivalents, i.e., milliliters of solvent per gram of reference starting material. For example, 1 vol means 1 mL of solvent per gram of reference starting material.

[0034] The term "amino protecting group" (APG) refers to a group that blocks an NH functionality for subsequent reaction and can be removed under controlled conditions. Amino protecting groups are well known in the art. Exemplary amino protecting groups are described in Green TW et al. Protective Groups in Organic Synthesis", 3rd Edition (1999), edited by John Wiley & Sons. Virtually any amino protecting group can be used to practice the present invention. Illustrative, non-limiting examples of APGs include: Carbamate [-COOR]. R is C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C 10 Aryl, (C6-C 10)aryl(C1-C6)alkyl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl. Examples of carbamates include methyl carbamate (MOC), t-butyl carbamate (BOC), benzyl carbamate (CBz), 9-fluorenylmethyl carbamate (FMOC), trichloroethyl carbamate (TROC), and trimethylsilyl carbamate; Amide [-COR]. R is C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C 10 Aryl, (C6-C 10 ) aryl(C1-C6) alkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl. Examples of amides include formamide, acetamide, phenylacetamide, haloacetamide, benzamide, and picolinamide; Amine [-R]. R is C1-C6 alkyl, C6-C 10 Aryl and (C6-C 10 )aryl(C1-C6)alkyl. Examples of amines include methylamine, tert-butylamine, benzylamine, p-methoxybenzylamine, 3,4-dimethoxybenzylamine, allylamine, methoxymethylamine, triphenylmethylamine, benzoylamine, dinitrophenylamine, p-methoxyphenylamine; and Silylamine [-Si(R)(R')(R'')]. R, R', and R'' are independently C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 It can be selected from aryl, C1-C6 alkoxy and halogen. Examples of silylamines include trimethylsilylamine, triethylsilylamine, tert-butyldimethylsilylamine, tert-butyldiphenylsilylamine, triisopropylsilylamine, triphenylsilylamine.

[0035] As those skilled in the art know, amino protecting groups are generally named with reference to the nitrogen atom. Thus, terms such as "carbamate," "amide," "amine," and "silylamine," as used herein, actually refer to the chemical group formed with the nitrogen atom, i.e., NCOOR, NCOR, NR, or NSi(R)(R')(R"), respectively.

[0036] The term "alkyl" refers to a straight- or branched-chain alkane derivative containing one to six ("C1-C6 alkyl"), preferably one to three ("C1-C3 alkyl") carbon atoms, attached to the rest of the molecule through a single bond. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, and hexyl.

[0037] The term "alkenyl" refers to a straight or branched hydrocarbon chain radical containing 2 to 6 ("C2-C6 alkenyl"), preferably 2 to 3 ("C2-C3 alkenyl") carbon atoms, containing at least one double bond, and attached to the rest of the molecule by a single bond. Examples of alkenyl groups include ethenyl, propenyl, allyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

[0038] The term "cycloalkyl" refers to a radical derived from a cycloalkane containing 3 to 7 carbon atoms ("C3-C7 cycloalkyl"), preferably 3 to 6 carbon atoms ("C3-C6 cycloalkyl"). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0039] The term "aryl" refers to an aromatic group having 6 to 10, preferably 6 or 10, carbon atoms and containing one or two aromatic nuclei joined or fused by a carbon-carbon bond. Examples of aryl groups include phenyl, naphthyl, diphenyl, indenyl, etc. Phenyl is preferred.

[0040] The term "arylalkyl" refers to, for example, (C6-C 10 )aryl(C1-C6)alkyl and (C6-C 10 (C1-C3) aryl(C1-C3) alkyl refers to an alkyl group as defined above substituted with an aryl group as defined above. Examples of such groups include benzyl, phenylethyl, phenylpropyl, naphthylmethyl, etc. Benzyl is preferred.

[0041] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or bicyclic ring system containing 3 to 10, preferably 5 to 7, ring atoms and containing one or more, specifically 1, 2, 3, or 4, ring heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon. Examples of heterocyclyl groups include tetrahydropyran, morpholine, piperazine, piperidine, and [1,4]dioxane.

[0042] The term "heteroaryl" refers to an aromatic monocyclic or bicyclic ring system containing 3 to 10, preferably 5 to 7, ring atoms and containing one or more, specifically 1, 2, 3, or 4, ring heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon. Examples of heteroaryl groups include pyrrole, furan, thiophene, pyridine, and pyrimidine.

[0043] The term "alkoxy" refers to an alkyl, as defined above, having 1 to 6 carbon atoms ("C1-C6 alkoxy"), preferably 1 to 3 carbon atoms ("C1-C3 alkoxy"), attached to the remainder of the molecule through an oxygen. Examples of alkoxy include methoxy, ethoxy, isopropoxy, tertbutoxy, and the like.

[0044] The term "halogen" refers to bromine, chlorine, iodine or fluorine.

[0045] As is understood in the art, the aforementioned radicals may have some degree of substitution. Thus, any of the groups of the present invention may be substituted. The groups may be substituted at one or more available positions with one or more substituents. Such substituents include, for example, C 1-6 Alkyl, C 3-7 Cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl, halogen, -CN, NO2, CF3, -N(R a )(R b ), -OR c , -SR d , -C(O)R e , -C(O)OR f , -C(O)N(R g )(R h ), -OC(O)R i where R a , R b , R c , R d , R e , R f , R g , R h and R i are independently hydrogen, C1-C6 alkyl, C6-C 10 It is selected from aryl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl and trifluoromethyl.

[0046] The present invention also provides "salts" of the compounds described herein. For example, the salts may be acid addition salts, base addition salts, or metal salts, and can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods known in the art. Such salts are generally prepared, for example, by reacting the free acid or base form of the compound with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture thereof. Non-aqueous media such as ether, ethyl acetate, ethanol, acetone, isopropanol, or acetonitrile are generally preferred. Examples of acid addition salts include inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate, and organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, trifluoroacetate, and camphorsulfonate. Examples of base addition salts include inorganic base salts such as ammonium salts, and organic base salts such as ethylenediamine, ethanolamine, N,N-dialkyleneethanolamine, triethanolamine, glutamine, amino acid basic salts, etc. Examples of metal salts include sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, and lithium salts.

[0047] In certain embodiments, the salt is an acid addition salt such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, trifluoroacetate, or camphorsulfonate. Preferably, the salt is selected from HCl, H2SO4, pTsOH, oxalate, and fumarate.

[0048] The term "solvate" according to the present invention is understood to mean any form of a compound in which another molecule (often a polar solvent) is bound via a non-covalent bond. Examples of solvates include hydrates and alcoholates, such as methanolates. Solvation methods are generally known in the art. The compounds of the present invention may exhibit different polymorphic forms, and the present invention is intended to encompass all such forms.

[0049] Preparation of compounds of general formula (III) The compounds of general formula (III) and their salts or solvates can be obtained by a process comprising two steps, as shown in the following scheme. [ka]

[0050] Process 1 Part 1(a) of step 1 involves the reaction of a compound of general formula (I) or a salt or solvate thereof with epichlorohydrin in the presence of a Lewis acid and an organic solvent to obtain a compound of general formula (II) or a salt or solvate thereof.

[0051] R in the compounds of general formula (I), (II) and (III) 1 is an amino protecting group, preferably selected from carbamate, amide, amine or silylamine as previously defined. In a more particular embodiment, the amino protecting group is a benzylamine, i.e., R 1 is -CH2-Ph.

[0052] The amount of epichlorohydrin can generally range from 1 to 2 equivalents or 1 to 1.5 equivalents (e.g., about 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 equivalents) relative to the compound of general formula (I). Larger amounts may be used, but are generally unnecessary. In certain embodiments, about 1.1 or 1.2 equivalents of epichlorohydrin are used.

[0053] Suitable Lewis acids include, but are not limited to, LiClO 4、 LiCl, LiBr, LiI·2H2O, CsClO4, Mg(ClO4)2, MgCl 2、 Examples of Lewis acids include MgBr, Mg(OAc), CaCl, CaSO, TiCl, FeCl, FeCl, FeCl, CuCl, CuBr, CuCl, CuBr, ZnCl, ZnBr, Zn(OAc), BBr, BF, BF·OEt, B(OPh), B(OCH), SnCl, TiCl, AICI, SnCl, SnBr, SnCl, and SnBr, or mixtures thereof. 4、 It is selected from the group consisting of LiCl, LiBr, LiI·2H2O, CsClO4, and Mg(ClO4)2 or mixtures thereof, more particularly LiClO4.

[0054] The amount of Lewis acid (e.g., LiClO4) can generally range from 1 to 2 equivalents or 1 to 1.5 equivalents (e.g., about 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 equivalents) relative to the compound of general formula (I). Larger amounts may be used, but are generally unnecessary. In certain embodiments, about 1.1 or 1.2 equivalents of Lewis acid are used.

[0055] The reaction of epichlorohydrin with the compound of formula (I), or a salt or solvate, is carried out in the presence of an organic solvent, such as, for example, a cyclic or acyclic ether (e.g., EtO, iPrO, tBuO, MeOtBu, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran), a hydrocarbon solvent (e.g., pentane, hexane, cyclohexane, heptane), a halogenated solvent (e.g., dichloromethane, chloroform), an aromatic solvent (e.g., toluene, xylene), a ketone (e.g., acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), a sulfoxide (e.g., dimethyl sulfoxide), or a mixture thereof. In certain embodiments, the reaction is carried out in the presence of an aromatic solvent, such as toluene and / or xylene, preferably toluene.

[0056] The amount of organic solvent (e.g., toluene or xylene) can generally range from 5 vol to 20 vol (e.g., about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 vol), more particularly, from 10 vol to 16 vol. In certain embodiments, about 10, 11, 12, 13, 14, 15, or 16 vol of organic solvent is used.

[0057] The reaction can be carried out at a temperature between 0°C and 50°C, more particularly between rt and 40°C, even more particularly at about 35°C.

[0058] In a preferred embodiment, about 1 equivalent of the compound of general formula (I) or a salt or solvate, about 1.2 equivalents of epichlorohydrin, and about 1.1 equivalents of LiClO4 are placed in about 10 vol of toluene, and the reaction is carried out at about 35°C for 2 to 4 hours.

[0059] Part 2(b) of Step 1 involves working up the reaction mixture. Once the reaction is complete, the reaction mixture can be worked up by mixing it with aqueous sulfuric acid to obtain an aqueous-sulfuric acid phase containing the sulfate salt of the compound of general formula (II) and an organic phase. Non-basic impurities remain in the organic phase and can be easily removed.

[0060] Preferably, prior to mixing with the aqueous sulfuric acid solution, the reaction mixture is washed with water and / or aqueous NaCl solution to remove the Lewis acid.

[0061] The aqueous sulfuric acid solution typically has a concentration of 90% (w / w) or less, such as 10-90% (w / w), 20-80% (w / w), 30-70% (w / w), or 40-60% (w / w). In certain embodiments, 50% w / w HSO is used.

[0062] A particular work-up method for the reaction mixture comprises one or more water washes and / or one or more washes with aqueous NaCl and mixing the remaining organic phase with aqueous sulfuric acid so that the corresponding intermediate compound of general formula (II) is extracted from the organic phase as a sulfate salt into the aqueous-sulfuric acid phase and can be used directly, i.e., without isolation, in the second step.

[0063] In more specific embodiments, the workup method includes washing the reaction mixture with water (e.g., about 10 vol or more) to obtain an aqueous phase and an organic phase, separating the aqueous and organic phases, washing the organic phase with aqueous NaCl (e.g., about 10 vol or more of a 12% aqueous NaCl solution) to obtain a second aqueous phase and a second organic phase, separating the second aqueous and second organic phases, and mixing aqueous sulfuric acid (e.g., about 1-2 vol of a 50% w / w aqueous H2SO4 solution) with the second organic phase. The aqueous-sulfuric acid phase containing the intermediate compound of general formula (II) as the sulfate salt can then be separated and further transformed to obtain a compound of general formula (III), or a salt or solvate thereof.

[0064] Further particularly preferred conditions for the post-treatment process are: · Washing the reaction mixture with approximately 10 vol of H2O to obtain an aqueous phase and an organic phase; Separation of the aqueous and organic phases; washing the organic phase with about 10 vol of NaCl 12% w / w to obtain a second aqueous phase and a second organic phase; separating the second aqueous phase and the second organic phase; and Extracting the second organic phase with about 1.55 vol of a 50% w / w aqueous solution of H2SO4 (about 1.66 equivalents relative to the starting compound of general formula (I)) to obtain an aqueous-sulfuric acid phase containing the sulfate salt of the compound of general formula (II). is.

[0065] Process 2 The second step involves increasing the sulfuric acid concentration by mixing the aqueous-sulfuric acid phase containing the sulfate salt of the compound of general formula (II) obtained in step 1 with concentrated sulfuric acid, such as 95 to 98% (w / w) H2SO4, to obtain the compound of general formula (III) or a salt or solvate thereof.

[0066] Concentrated sulfuric acid is generally added until the reaction mixture reaches 5 to 15 equivalents (e.g., about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 equivalents) of sulfuric acid relative to the compound of general formula (I), preferably about 10 equivalents (about 86% w / w H2SO4 aqueous solution). Therefore, considering that the aqueous-sulfuric acid phase containing the sulfate salt of the compound of general formula (II) obtained in step 1 already contains sulfuric acid, the amount of concentrated sulfuric acid added or mixed in step 2 can generally be in the range of 1 to 5 vol (e.g., about 1, 2, 3, 4, or 5 vol), preferably about 3 vol (about 8.5 equivalents), relative to the compound of general formula (I).

[0067] In a preferred embodiment, 3 vol of HSO 98% w / w (approximately 8.5 equivalents relative to the starting compound of general formula (I)) is mixed with the aqueous-sulfuric acid phase containing the sulfate salt of the compound of general formula (II) obtained in step 1.

[0068] The reaction mixture is then typically heated to 100° C. to 140° C. (e.g., about 120° C. to 125° C.) Generally, the reaction is carried out for 5 hours to 24 hours, for example, about 16 hours, or for 5 hours to 16 hours, for example, about 8 or 9 hours.

[0069] Once the reaction is complete, the reaction mixture can be worked up by methods that include adding water, dichloromethane (DCM), and a base such as NaOH or NH3 to the reaction mixture, separating the aqueous and organic phases, and distilling or partially distilling the organic phase. Temperature control during the addition of water and base is highly desirable for safety reasons, especially when performing large-scale syntheses.

[0070] Further particularly preferred conditions for the post-treatment process are: Adding about 20 vol of H2O, about 10 vol of DCM, and about 11 vol of NH3 25% w / w aqueous solution to the reaction mixture to obtain an aqueous phase and an organic phase; Separating the aqueous and organic phases; and concentrating the organic phase containing the compound of general formula (III) is.

[0071] The compound of general formula (III) can be isolated, for example, in the form of a salt. These salts can be obtained by conventional methods by reacting the compound of general formula (III) with an acid in a solvent in which the salt is insoluble and precipitates as such, which can be separated, for example, by filtration. Precipitation can be promoted by cooling the reaction mixture and / or by partial distillation of the solvent.

[0072] Alternatively, the compound of general formula (III) can be used as it is, i.e., without isolation, in the next step (conversion to the compound of formula (IV)). In such a case, further particularly preferred conditions for the work-up process are: Adding about 20 vol of H2O, about 10 vol of DCM, and about 11 vol of NH3 25% w / w aqueous solution to the reaction mixture to obtain an aqueous phase and an organic phase; Separation of the aqueous and organic phases; Concentrating the organic phase to approximately 3 vol; Add about 3 vol of toluene and concentrate twice to 3 vol to obtain 3 vol of organic phase (e.g., toluene). is.

[0073] The organic phase obtained from the work-up process contains the compound of general formula (III) and can be used as is for the subsequent conversion to the compound of formula (IV) (one-pot approach).

[0074] Certain salts of the compound of formula (III) The present invention also provides 4-benzyl-2-(chloromethyl)morpholine, i.e., a compound of general formula (III) 1is benzyl). Specifically, the present invention encompasses the oxalate, fumarate, and tosylate salts of 4-benzyl-2-(chloromethyl)morpholine, whose structure is: [ka]

[0075] These salts can be obtained by conventional methods by reacting 4-benzyl-2-(chloromethyl)morpholine with the corresponding acid, i.e., oxalic acid, fumaric acid, or p-toluenesulfonic acid. In certain embodiments, the formation of these acid addition salts is carried out in a solvent in which the salt is insoluble and precipitates immediately, allowing it to be separated, for example, by filtration. Precipitation can be facilitated by cooling the reaction mixture and / or by partial distillation of the solvent.

[0076] For example, 4-benzyl-2-(chloromethyl)morpholine oxalate can be obtained by reacting 4-benzyl-2-(chloromethyl)morpholine with oxalic acid in a suitable organic solvent, such as a mixture of acetone / ethanol / heptane, causing the salt to precipitate and facilitating its isolation.

[0077] In certain embodiments, a solution of 4-benzyl-2-(chloromethyl)morpholine (3) in acetone (e.g., about 5 vol) is added to a solution of oxalic acid (e.g., about 1 equivalent) in ethanol (e.g., about 2 vol). Heptane (e.g., about 5 vol) is then added, and the resulting slurry is filtered, washed with heptane, and dried to provide the oxalate salt of 4-benzyl-2-(chloromethyl)morpholine.

[0078] 4-benzyl-2-(chloromethyl)morpholine fumarate can be obtained, for example, by reacting 4-benzyl-2-(chloromethyl)morpholine with fumaric acid in a suitable organic solvent, such as isopropanol or isopropanol / heptane, causing the salt to precipitate and facilitating its isolation.

[0079] In certain embodiments, a solution of 4-benzyl-2-(chloromethyl)morpholine (3) in isopropanol (e.g., about 3 vol) is added to a solution of fumaric acid (e.g., about 1.2 equivalents) in isopropanol (e.g., about 8 vol), and the mixture is heated, preferably at about 70°C. The mixture is cooled to room temperature, and then some of the solvent is vacuum distilled off (e.g., about 3-4 vol) until some crystals appear. Preferably, once a precipitate forms, heptane (e.g., about 5 vol) is added to facilitate stirring. The resulting suspension is filtered, rinsed with heptane, and dried to provide the fumaric acid salt of 4-benzyl-2-(chloromethyl)morpholine.

[0080] For example, 4-benzyl-2-(chloromethyl)morpholine tosylate can be obtained by reacting 4-benzyl-2-(chloromethyl)morpholine with p-toluenesulfonic acid in a suitable organic solvent, such as a mixture of acetone and ethanol, causing the salt to precipitate and facilitating its isolation.

[0081] In certain embodiments, a solution of p-toluenesulfonic acid (e.g., about 1 equivalent) in EtOH (e.g., about 1 volume) is slowly added to a solution of 4-benzyl-2-(chloromethyl)morpholine (3) in acetone (e.g., about 10 volume) at room temperature to form a precipitate. The resulting suspension is filtered, rinsed with acetone, and dried to provide the tosylate salt of 4-benzyl-2-(chloromethyl)morpholine.

[0082] The above-mentioned salts of 4-benzyl-2-(chloromethyl)morpholine are novel compounds and can be used in the synthesis of viloxazine or its salts or solvates, and therefore constitute further aspects of the present invention, as does their use in obtaining viloxazine or its salts or solvates. A process for obtaining said salts of 4-benzyl-2-(chloromethyl)morpholine constitutes a further aspect of the present invention.

[0083] Conversion of (III) to (IV) The compound of general formula (IV) and its salts or solvates can be obtained from the compound of general formula (III) and its salts or solvates by reacting with 2-ethoxyphenol in the presence of a base in an organic solvent, as shown in the following scheme. [ka]

[0084] In certain embodiments, the compound of general formula (III) is used as a free base. In another specific embodiment, the compound of general formula (III) is used as a salt such as oxalate, fumarate or tosylate of 4-benzyl-2-(chloromethyl)morpholine. If the compound of general formula (III) is in the form of a salt such as oxalate, the free form of the compound of general formula (III) can be obtained by first treating the salt with a base (for example, extraction with NaHCO).

[0085] In certain embodiments, a compound of general formula (III) or a salt or solvate thereof is used without isolation to obtain a compound of general formula (IV) or a salt or solvate thereof (one-pot method).

[0086] The amount of 2-ethoxyphenol can generally range from 1 to 6 equivalents relative to the compound of general formula (I) (e.g., about 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, or 6.0 equivalents). Larger amounts may be used, but are generally unnecessary. In certain embodiments, the amount of 2-ethoxyphenol is in the range of 1 to 1.5 equivalents relative to the compound of general formula (I) (e.g., about 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 equivalents). In even more specific embodiments, about 1 or 1.1 equivalents of 2-ethoxyphenol are used.

[0087] Suitable bases include hydroxides, alkali metal hydrides and alkali metal alcoholates, such as NaOH, KOH, NaH, NaOtBu, KOtBu, NaOMe, NaOEt, hi certain embodiments, the base is KOH.

[0088] The amount of base (e.g., KOH) can generally range from 1 to 6 equivalents relative to the compound of general formula (I) (e.g., about 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, or 6.0 equivalents). Larger amounts may be used, but are generally unnecessary. In certain embodiments, the amount of base ranges from 1 to 1.5 equivalents relative to the compound of general formula (I) (e.g., about 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 equivalents). In even more specific embodiments, about 1 or 1.1 equivalents of base are used.

[0089] The reaction of 2-ethoxyphenol with a compound of general formula (III) or a salt or solvate can conveniently be carried out in the presence of an organic solvent such as, for example, a cyclic or acyclic ether (e.g., EtO, iPrO, tBuO, MeOtBu, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran), a hydrocarbon solvent (e.g., pentane, hexane, cyclohexane, heptane), a halogenated solvent (e.g., dichloromethane, chloroform), an alcohol (e.g., methanol, ethanol, propanol, isopropanol, sec-butanol, t-butanol), an aromatic solvent (e.g., toluene, xylene), a ketone (e.g., acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), an ester (e.g., ethyl acetate, isopropyl acetate), a nitrile (e.g., acetonitrile, benzonitrile, propionitrile), an amide (e.g., dimethylformamide, dimethylacetamide, hexamethylphosphoramide), a sulfoxide (e.g., dimethyl sulfoxide) or a mixture thereof. In certain embodiments, the reaction is carried out in the presence of an amide solvent such as DMF, a sulfoxide solvent such as DMSO, or a mixture of a sulfoxide solvent and an aromatic solvent, for example a mixture of DMSO and toluene.

[0090] When the compound of formula (III) or its salt or solvate is used without isolation (one-pot method), it is already contained in an organic phase, for example, toluene. In such a case, the addition of DMSO results in an organic solvent consisting of a mixture of DMSO and toluene.

[0091] The amount of organic solvent (e.g., DMF, DMSO, or DMSO / Tol) for conversion to a compound of general formula (IV) or a salt or solvate thereof can generally range from 5 vol to 20 vol (e.g., about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 vol), more particularly, from 11 to 13 vol. In a particular embodiment, the organic solvent is 11 vol of DMF. In another particular embodiment, the organic solvent is a mixture of 3 vol of toluene (from the previous step) and 10 vol of DMSO.

[0092] The reaction can be carried out at a temperature of from 80°C to 150°C, more particularly from 90°C to 120°C, and even more particularly at about 95°C, 100°C or 110°C.

[0093] In a preferred embodiment, about 1 equivalent of a compound of general formula (III) or a salt or solvate thereof obtained from a compound of general formula (I) or a salt or solvate thereof is reacted with about 4 equivalents of 2-ethoxyphenol and about 4 equivalents of KOH in about 11 Vol of DMF, and the reaction is carried out at about 110° C. for about 2 hours.

[0094] In a preferred embodiment, about 1 equivalent of a compound of general formula (III) or a salt or solvate thereof obtained from the compound of general formula (I) or a salt or solvate thereof is reacted with about 1.1 equivalents of 2-ethoxyphenol and about 1.1 equivalents of KOH in about 13 vol of DMSO or 13 vol of DMSO / toluene (10 vol of DMSO + 3 vol of toluene), and the reaction is carried out at about 100°C for about 2 hours to 10 hours (e.g., 7 hours).

[0095] Once the reaction is complete, the reaction mixture can be worked up by methods that include adding water and extracting with an organic solvent such as ethyl acetate or toluene. Temperature control during the addition of water is highly desirable for safety reasons, especially when performing large-scale syntheses.

[0096] Further particularly preferred conditions for the post-treatment process are: Add about 20 vol H2O and about 10 vol ethyl acetate to the reaction mixture to obtain an organic phase and an aqueous phase; Separating the organic and aqueous phases; Extracting the aqueous phase with approximately 3 vol of ethyl acetate to obtain a second organic phase; Combining the two organic phases: washing the combined organic phases with water; and Concentrating the combined organic phases, e.g., to about 10 vol is.

[0097] Further particularly preferred conditions for the post-treatment process are: Adding about 6-10 vol H2O (e.g., 8 vol H2O) and about 1 vol toluene to the reaction mixture to obtain an organic phase and an aqueous phase; Separating the organic and aqueous phases; Optionally, extracting the aqueous phase with about 2 vol of toluene to obtain a second organic phase; combining the two organic phases, if applicable; and Distilling the organic phase or the combined organic phases, for example to about 3 or 4 vol (hydration) Includes:

[0098] The resulting product of formula (IV) generally does not require further purification, but can be further purified, if desired, by a conventional, industrially acceptable process, such as, for example, by a crystallization process of the product as a free base (if a solid) or, more preferably, via the formation of an addition salt (if an oil). Illustrative, non-limiting examples of solvents suitable for said crystallization include ketones (e.g., acetone, etc.), nitriles (e.g., acetonitrile, etc.), alcohols (e.g., i-PrOH, EtOH, etc.), esters (e.g., ethyl acetate (AcOEt), etc.), ethers, etc., preferably acetone or acetonitrile.

[0099] Illustrative, non-limiting examples of suitable acid addition salts include inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.; and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, trifluoroacetate, camphorsulfonate, etc. In certain embodiments, the obtained product of formula (IV) is converted to its oxalate salt for purification purposes.

[0100] For example, the oxalate salt of the compound of general formula (IV) can be obtained by a process comprising adding an oxalic acid solution to the worked-up reaction mixture to form a suspension, adding heptane to the suspension, stirring the suspension, filtering the suspension, washing with heptane and drying the solid formed.

[0101] Further particularly preferred conditions for the formation and purification by crystallization of the oxalate salt of the compound of general formula (IV) are: adding about 6 or 7 vol of toluene to a compound of formula (IV) in about 3 or 4 vol of toluene (a total of about 10 vol of toluene); Add about 2 vol of heptane; adding a solution of oxalic acid, said solution being obtained by dissolving about 1 equivalent of oxalic acid relative to the first compound of general formula (I) in about 3 vol of ethanol to form a suspension; filtering the suspension to obtain a solid; and washing the solid with about 2 vol of toluene and about 2 vol of heptane; is.

[0102] Conversion of (IV) to (V) The compound of formula (V) and its salts or solvates can be obtained from the compound of general formula (IV) and its salts or solvates by reacting with ethyl chloroformate, as shown in the following scheme. [ka]

[0103] Preferably, R 1 is a benzyl group (Bn). 1 When is not Bn, other conditions can be used for removal of the amino protecting group, as one skilled in the art will clearly recognize.

[0104] In certain embodiments, the compound of general formula (IV) is used as a free base.In another particular embodiment, the compound of general formula (IV) is used as a salt.When the compound of general formula (IV) is in the form of a salt such as oxalate, the free form of the compound of general formula (IV) can be obtained by first treating the salt with a base (for example, extracting with NaHCO3).

[0105] The amount of ethyl chloroformate can generally range from 1.1 to 3 equivalents, more preferably from 1.5 to 2.5 equivalents (e.g., about 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, or 2.5 equivalents) relative to the compound of general formula (I). Larger amounts may be used, but are generally unnecessary. In certain embodiments, about 1.5 or 2 equivalents of ethyl chloroformate are used.

[0106] Suitable bases include amines such as DIPEA. In certain embodiments, the base is DIPEA.

[0107] The amount of base (e.g., DIPEA) can generally range from 1 to 2 equivalents relative to the compound of general formula (I) (e.g., about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 equivalents). Larger amounts may be used, but are generally unnecessary. In certain embodiments, about 1 equivalent of base is used.

[0108] The reaction of ethyl chloroformate with the compound of general formula (IV) or a salt or solvate is carried out in the presence of an organic solvent such as, for example, a cyclic or acyclic ether (e.g., EtO, iPrO, tBuO, MeOtBu, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran), a hydrocarbon solvent (e.g., pentane, hexane, cyclohexane, heptane), a halogenated solvent (e.g., dichloromethane, chloroform), an alcohol (e.g., methanol, ethanol, propanol, isopropanol, sec-butanol, t-butanol), an aromatic solvent (e.g., toluene, xylene), a ketone (e.g., acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), an ester (e.g., ethyl acetate, isopropyl acetate), a nitrile (e.g., acetonitrile, benzonitrile, propionitrile), an amide (e.g., dimethylformamide, dimethylacetamide, hexamethylphosphoramide), a sulfoxide (e.g., dimethyl sulfoxide) or a mixture thereof. In certain embodiments, the reaction is carried out in the presence of an aromatic solvent such as toluene or a halogenated solvent such as DCM.

[0109] The amount of organic solvent (eg, toluene or DCM) can generally range from 3 vol to 10 vol (eg, about 3, 4, 5, 6, 7, 8, 9, or 10 vol), more particularly about 6 vol.

[0110] The reaction can be carried out at a temperature between 40° C. and 50° C., ie at reflux temperature when DCM is the solvent used.

[0111] In a preferred embodiment, a compound of general formula (IV) or a salt or solvate thereof obtained from about 1 equivalent of a compound of general formula (I) or a salt or solvate thereof is reacted with about 1.5 to 2 equivalents of ethyl chloroformate and about 1 equivalent of DIPEA in about 6 vol of toluene or DCM, and the reaction is carried out at about 40°C to 50°C for 2 to 4 hours.

[0112] Once the reaction is complete, the reaction mixture can be worked up by methods including: Adding water to the reaction mixture or, if necessary, hydrolyzing excess ethyl chloroformate with water and a base to obtain an organic phase and an aqueous phase; Separation of the aqueous and organic phases; Extracting the aqueous phase with an organic solvent such as toluene; combining the organic phases; and To concentrate.

[0113] Further particularly preferred conditions for the post-treatment process are: adding water to the reaction mixture, or adding about 0.5 equivalents of DIPEA and about 5 vol of H2O relative to the compound of general formula (I), and heating the resulting mixture under reflux for about 1 hour to hydrolyze unreacted ethyl chloroformate, thereby obtaining an organic phase and an aqueous phase; Separating the organic and aqueous phases; Extracting the aqueous phase with 2 vol of toluene or DCM to obtain a second organic phase; combining the two organic phases to obtain a combined organic phase; and Distill the combined organic phase down to 2 vol (hydrated) is.

[0114] The reaction product can then be purified by methods including, for example, crystallization in heptane.

[0115] Further particularly preferred conditions for the crystallization of compounds of general formula (V) and their salts or solvates are: about 12 vol of heptane, optionally followed by cooling (e.g., in an ice / water bath) to form a suspension; and filtering the suspension to obtain a solid, and washing the resulting solid with about 2 vol of heptane; is.

[0116] Further particularly preferred conditions for the crystallization of compounds of general formula (V) and their salts or solvates are: Add approximately 18 vol of heptane and concentrate to 18 vol. Adding about 3 vol of heptane and concentrating to 18 vol, optionally followed by cooling (e.g., in an ice / water bath) to form a suspension; and filtering the suspension to obtain a solid, and washing the resulting solid twice with approximately 2 or 4 vol of heptane; is.

[0117] Conversion of (V) to viloxazine Viloxazine and its salts or solvates can be obtained from the compound of formula (V) and its salts or solvates as shown in the following scheme: [ka]

[0118] Suitable bases include hydroxides, alkali metal hydrides and alkali metal alcoholates, such as NaOH, KOH, NaH, NaOtBu, KOtBu, NaOMe, NaOEt, hi certain embodiments, the base is NaOH.

[0119] The amount of base (e.g., NaOH) can generally range from 1.5 to 4 equivalents relative to the compound of general formula (I) (e.g., about 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 equivalents). Larger amounts may be used, but are generally unnecessary. In certain embodiments, about 3 equivalents of base are used.

[0120] The reaction of the base with the compound of formula (V) or salt or solvate is carried out in the presence of an organic solvent such as, for example, a cyclic or acyclic ether (e.g., EtO, iPrO, tBuO, MeOtBu, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran), a hydrocarbon solvent (e.g., pentane, hexane, cyclohexane, heptane), a halogenated solvent (e.g., dichloromethane, chloroform), an alcohol (e.g., methanol, ethanol, propanol, isopropanol, sec-butanol, t-butanol), an aromatic solvent (e.g., toluene, xylene), a ketone (e.g., acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), an ester (e.g., ethyl acetate, isopropyl acetate), a nitrile (e.g., acetonitrile, benzonitrile, propionitrile), an amide (e.g., dimethylformamide, dimethylacetamide, hexamethylphosphoramide), a sulfoxide (e.g., dimethyl sulfoxide) or a mixture thereof, optionally with water. In certain embodiments, the reaction is carried out in the presence of an alcohol, such as isopropanol (IPA).

[0121] The amount of organic solvent (e.g., IPA) can generally range from 5 vol to 15 vol (e.g., about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 vol), more specifically about 9 vol. When used with an organic solvent, the amount of water is generally 1 to 2 equivalents.

[0122] The reaction can be carried out at reflux temperature, in certain embodiments, for example, the temperature is 80° C. to 85° C. when IPA or IPA / water is the solvent used.

[0123] In a preferred embodiment, about 1 equivalent of a compound of formula (V) or a salt or solvate thereof obtained from the compound of general formula (I) or a salt or solvate thereof is reacted with about 3 equivalents of NaOH in about 9 Vol of IPA (optionally with about 1 equivalent of water), and the reaction is carried out under reflux for about 16 to 20 hours (e.g., 18 hours).

[0124] Preferred conditions for the post-treatment process are: Add about 15 vol of ethyl acetate and 10 vol of water, preferably under temperature control for safety reasons, to obtain an aqueous phase and an organic phase; Extracting the aqueous phase with ethyl acetate; · Concentrate to approximately 11 vol; combining the organic phases; and Concentrating the combined organic phase is.

[0125] Preferred conditions for the post-treatment process are: Adding about 10 vol of water, preferably under temperature control for safety reasons; · Concentrate to approximately 11 vol; Add approximately 10 vol of DCM to obtain organic and aqueous phases; Separating the organic and aqueous phases; optionally washing the organic phase with 10 vol of water; and Concentrate the organic phase to about 2 or 3 vol. is.

[0126] If desired, viloxazine free base may be further converted to its hydrochloride salt by reaction with HCl.

[0127] The preferred conditions for the formation and crystallization of viloxazine HCl are: Adding about 1.1 equivalents of HCl (5-6N) in IPA, optionally followed by cooling to form a suspension; filtering the suspension to form a solid; and Washing the solid with about 2 vol of AcOEt. is.

[0128] The preferred conditions for the formation and crystallization of viloxazine HCl are: Add approximately 14 vol of AcOEt and concentrate to approximately 10 vol; adding approximately 1.1 equivalents of HCl 37% w / w to form a suspension; filtering the suspension to form a solid; and Washing the solid with about 3 vol of AcOEt. is.

[0129] All features described in this specification (including the claims, description and drawings) may be made in any combination except for such mutually exclusive feature combinations.

[0130] The following examples are merely illustrative of certain embodiments of the present invention and are not to be construed as limiting in any way. [Example]

[0131] 1 H NMR Proton nuclear magnetic resonance analyses were recorded on a 400 or 500 MHz spectrometer in deuterated chloroform (CDCl3), dimethyl sulfoxide (DMSO-d6). DSC: Differential scanning calorimetry DSC analyses were recorded using a DSCQ100 (TA Instruments). XRPD: X-ray powder diffraction pattern XRPD analysis was performed using a D8 DISCOVER DAVINCI (Bruker) diffractometer.

[0132] Example 1. Formation of 4-benzyl-2-(chloromethyl)morpholine (3) from N-benzylethanolamine (1) [ka] Step 1: Formation of intermediate (2) [A2VLX sulfate] N-Benzylethanolamine (100 g, 0.66 mol) was dissolved in 1 L of toluene (10 vol), then 62 ml of epichlorohydrin (73.72 g, 1.2 equiv.) was added and stirring was initiated. Finally, 77.24 g of LiOCl4 (1.1 equiv.) was added and the suspension or biphasic system was warmed to 35 °C for 2.5 h until the reaction was complete.

[0133] The reaction mixture was cooled to room temperature and 1 L of water (10 vol) was added. The resulting two-phase system was then separated and the organic phase was re-washed with 1 L of brine (12% w / w NaCl, 10 vol).

[0134] To the remaining toluene phase, 155 ml of 50% w / w aqueous sulfuric acid (1.66 equivalents of H2SO4) was added, and the mixture was vigorously stirred. Intermediate (2) then transferred to the aqueous phase, which was separated and used in step 2 without delay (storing the aqueous-sulfuric acid phase containing the sulfate salt of intermediate (2) leads to the formation of impurities in just a few hours, even at low temperatures).

[0135] Step 2: Formation of morpholine (3) [A3VLX] While stirring, 300 ml of sulfuric acid 98% (8.5 equivalents) was added to the above aqueous phase (final concentration of sulfuric acid: 86% w / w), and the reaction mixture was heated to 120° C. for 9 hours until the reaction was complete.

[0136] The reaction mixture was cooled to room temperature and 2 L of water (20 vol) was carefully added so that the temperature did not exceed 30° C. To this solution was added 1 L of dichloromethane (10 vol) and the reaction mixture was neutralized with 1-1.2 L of aqueous ammonia solution (25%, 10-12 vol) until the pH reached 8-9, keeping the temperature below 30° C. at all times.

[0137] The two-phase system is separated and the final product, 4-benzyl-2-(chloromethyl)morpholine (3), is in the organic phase.

[0138] As described in Example 3, the formation of intermediate (2) is accompanied by three impurities:

[0139] [ka]

[0140] The dimeric impurity (8) can then give rise to two further impurities during the cyclization step with concentrated H2SO4.

[0141] [ka]

[0142] Advantageously, all these impurities are not formed in the process according to the invention, or are formed only in very small amounts.

[0143] Example 2. Formation of N-benzyl-2-(chloromethyl)morpholine (3) using prior art conditions (Comparative Example) [ka] Racemic epichlorohydrin (6.2 ml, 1.2 eq.) and benzylaminoethanol (1) (10 g, 8.58 ml, 66 mmol, 1 eq.) were blended to form a viscous solution. The reaction mixture was stirred at room temperature.

[0144] When the reaction was complete (2-5 hours), 25 ml of H2SO4 was added (a strong exotherm occurred, bringing the mixture to 70°C). * The mixture was heated to 130°C.

[0145] After 1 hour the reaction mixture turned black / brown and the reaction was complete, it was cooled to room temperature and 100 ml of water was added while maintaining the system at or below room temperature.

[0146] Afterwards, 100 ml of dichloromethane was added and the mixture was made basic with aqueous NaOH to obtain a basic medium.

[0147] The two layers were separated and the organic phase was vacuum distilled to a residue. Yield: 9g / 60% of colored oil

[0148] Example 3 - Synthesis of intermediate (2) and impurity profile depending on reaction conditions [ka] The impurity profile of the intermediate (2) obtained under the reaction conditions of Step 1 essentially as shown in Examples 1 and 2 was evaluated. [Table 1]

[0149] As can be seen, intermediate 2 decomposes in the reaction medium at room temperature, primarily to azetidine, epoxide, and dimer impurities. However, compared to prior art conditions (Tests 1 and 2), the toluene / LiClO4 conditions (Test 3) according to embodiments of the present invention resulted in a higher yield of the desired compound 2, fewer decomposition products, and reduced exothermic behavior in the subsequent steps.

[0150] Intermediate (2) cannot be stored for long periods due to its rapid decomposition, and furthermore, when excess epichlorohydrin is removed by distillation under reduced pressure, as proposed in the art, intermediate (2) also decomposes during the distillation process.

[0151] The only conditions that allow the product to remain stable in the reaction medium are the use of an organic solvent / Lewis acid system, and furthermore the use of H2SO4 / water extraction avoids subsequent distillation.

[0152] Example 4. Formation of N-benzyl-2-(chloromethyl)morpholine (3) under prior art conditions (Comparative Example) N-benzyl-2-(chloromethyl)morpholine (3) was prepared as disclosed in Loftus F, The Synthesis of Some 2-Substituted Morpholines, Synthetic Communications, 10(1), 59-73 (1980).

[0153] Specifically, N-benzylethanolamine (5 g, 33 mmol) was dissolved in epichlorohydrin (25.8 ml, 330 mmol), and the solution was stirred at 40°C for 30 minutes. Excess epichlorohydrin was removed by distillation under reduced pressure. The residue was dissolved in 98% sulfuric acid (9.94 ml). Due to the highly exothermic behavior, it was necessary to control the temperature during the addition of concentrated sulfuric acid. The solution was then heated to 150°C for 30 minutes. The resulting solution was cooled and added to ice (100 g) (highly exothermic process), basified with 40% NaOH (highly exothermic process), and the product was extracted with toluene. The toluene was evaporated and dried under vacuum to give 4 g (53% yield) of product.

[0154] HPLC analysis of the product revealed that the purity of intermediate (3) (A3VLX) was 89.79% with significant impurities including:

[0155] [ka]

[0156] Example 5. Formation of 4-benzyl-2-(chloromethyl)morpholine oxalate (the oxalate salt of compound (3) or A3VLX oxalate) The organic phase solvent described in Example 1 was subjected to partial distillation to a final volume of 500 ml, after which 500 ml of acetone was added. The system was subjected to another partial distillation to a final volume of 500 ml, after which 500 ml of acetone was added again and partial distillation was performed to a final volume of 500 ml.

[0157] To this solution system, 59.4 g of oxalic acid (1 equivalent) dissolved in 200 ml of EtOH (2 vol) was carefully added, and precipitation of oxalate was observed during the addition.

[0158] To the resulting suspension was also added 500 ml of heptane (5 vol), and the resulting slurry was filtered, washed with heptane, and dried to give 183 g of 4-benzyl-2-(chloromethyl)morpholine oxalate (88% yield from (1)). HPLC purity 99.42%, DSC

[0159] 4-benzyl-2-(chloromethyl)morpholine oxalate 1 The H NMR and DSC are shown in Figures 4 and 5, respectively. 1 H NMR (500 MHz, DMSO-d6): δ 12,57 (bs, 2H); 7,31 (m, 4H); 7,24-7,28 (m, 1H); 3,81-3,84 (m, 1H); 3,66-3,74 (m, 3H); 3,60-3,63 (m, 1H); 3,53-3,58 (m, 2H); 2,88-2,90 (m, 1H); 2,76-2,78 (m, 1H); 2,36 (td, J = 11,7; 3,5 Hz, 1H); 2,21 (t, J = 10,8 Hz, 1H).

[0160] Example 6. Formation of 4-benzyl-2-(chloromethyl)morpholine fumarate (the fumarate salt of compound (3) or A3VLX fumarate salt) A solution of 4-benzyl-2-(chloromethyl)morpholine (3) (3 g) in isopropanol (9 ml, 3 Vol) was added to a solution of fumaric acid (1.85 g, 1.2 eq) in isopropanol (24 ml, 8 Vol) and the mixture was heated at 70°C.

[0161] The solution mixture was cooled to room temperature, after which some of the solvent was distilled off under vacuum (usually 3-4 vol) until some crystals appeared, at which point heptane was added (5 vol) to facilitate stirring.

[0162] The resulting suspension was filtered, rinsed with heptane, and dried to give 3 g of a white solid of 4-benzyl-2-(chloromethyl)morpholine fumarate (49% yield from (1)). HPLC purity 99.69%, DSC

[0163] 4-benzyl-2-(chloromethyl)morpholine fumarate 1 The H NMR and DSC are shown in Figures 6 and 7, respectively. 1 H NMR (400 MHz, DMSO-d6): δ 7,37-7,20 (m, 5H); 6,60 (s, 2H); 3,84-3,74 (m, 1H); 3,66-3,44 (m, 6H); 2,76 (dt, J = 11,3; 1,9 Hz, 1H); 2,60 (dd, J = 11,5; 2,1 Hz, 1H); 2,10 (td, J = 11,4; 3,3 Hz, 1H); 1,93 (dd, J = 11,2; 9,1 Hz, 1H).

[0164] Example 7. Formation of 4-benzyl-2-(chloromethyl)morpholine tosylate (tosylate salt of compound (3) or A3VLX tosylate salt) To a solution of 4-benzyl-2-(chloromethyl)morpholine (3) (4 g) in acetone (40 ml, 10 Vol) at room temperature was added a solution of p-toluenesulfonic acid (3.37 g, 1 equiv.) in EtOH (4 ml, 1 Vol) dropwise, resulting in the formation of a precipitate during or shortly after the addition.

[0165] The resulting suspension was filtered, rinsed with acetone, and dried to give 4.9 g of 4-benzyl-2-(chloromethyl)morpholine tosylate as a white solid (52% yield from 1). HPLC purity 98.55%, DSC

[0166] 4-benzyl-2-(chloromethyl)morpholine tosylate 1 The H NMR and DSC are shown in Figures 8 and 9, respectively. 1H NMR (400 MHz, DMSO-d6): δ 9 ,98 (s, 1H); 7,51-7,42 (m, 5H); 7,17-7,06 (m, 2H); 4,38 (m, 1H); 4,13-3,98 (m, 1H); 3,89 (m, 1H); 3,86-3,55 (m, 3H); 3,31 (m, 1H); 3,16-2,89 (m, 1H); 2,26 (s, 3H).

[0167] Example 8. Formation of 4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (4) oxalate from 4-benzyl-2-(chloromethyl)morpholine (3) oxalate [ka] 10 vol of dichloromethane, 5 vol of water and 15 vol of NaHCO3 (7% w / w) were added to the oxalate salt of intermediate (3). The mixture was stirred for 30 minutes and the phases were separated by decantation. The organic phase was concentrated to give a residue.

[0168] 11 vol of DMF, 4 equivalents of KOH and 4 equivalents of 2-ethoxyphenol were added to the above residue and the reaction mixture was heated at 110° C. for 2 hours.

[0169] When the reaction became exothermic, the reaction mass was cooled to room temperature and 20 vol of water and 10 vol of ethyl acetate were added. The phases were separated by decantation. The aqueous phase was extracted with 3 vol of ethyl acetate. The organic phases were combined and washed three times with 6 vol of water (to remove DMF). The organic phase was concentrated to 10 vol, and 1 equivalent of oxalic acid dissolved in 1.5 vol of EtOH and 1 vol of ethyl acetate was added dropwise to the solution. The suspension was filtered and washed with 2 vol of ethyl acetate (62% yield from (1) and 83% yield from (3)).

[0170] Example 9. Formation of ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (5) from 4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (4) oxalate [ka] 10 vol of dichloromethane, 5 vol of water and 15 vol of NaHCO3 (7% w / w) were added to the oxalate salt of intermediate (4). The mixture was stirred for 30 minutes and the phases were separated by decantation. The organic phase was concentrated to give a residue.

[0171] 6 vol of toluene, 1 equivalent of DIPEA and 2 equivalents of ethyl chloroformate were added to the above residue and the reaction mixture was heated at 40° C. for 2 hours.

[0172] When the reaction became exothermic, the reaction mass was cooled to room temperature and 10 vol of water was added. The phases were separated by decantation. The aqueous phase was extracted with 2 vol of toluene.

[0173] The organic phases were combined and concentrated to 2 vol. 12 vol of heptane was added and the water / ice bath was set to 0 / 5°C. It began to crystallize. The suspension was filtered and washed with 2 vol of heptane (66% yield from (4)).

[0174] Example 10. Formation of 2-((2-ethoxyphenoxy)methyl)morpholine chloride from ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (5) [ka] Intermediate (5) was dissolved in 9 vol of isopropanol, 3 equivalents of NaOH were added and the mixture was heated under reflux for 16 hours.

[0175] Upon completion of the reaction, the reaction mass was cooled to room temperature and 15 vol of ethyl acetate and 10 vol of water were added. The phases were separated by decantation. The aqueous phase was extracted with 4 vol of ethyl acetate. The organic phases were combined and concentrated to 4 vol. 10 vol of ethyl acetate was added and this was reconcentrated to 4 vol. 1.1 equivalents of HCl in IPA (5-6N) was added dropwise to the product dissolved in ethyl acetate. The solution was cooled and the hydrochloride salt began to crystallize. The suspension was filtered and washed with 2 vol of ethyl acetate (92% yield from (5)).

[0176] Example 11. Formation of 4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (4) oxalate from 4-benzyl-2-(chloromethyl)morpholine (3) [ka] The organic phase in DCM remaining from the workup of intermediate (3) was exchanged for toluene, followed by two 6 vol toluene drags and finally concentrated to 3 vol.

[0177] To the organic phase in toluene was added 10 vol DMSO, 1.1 eq KOH and 1.1 eq 2-ethoxyphenol 2 and the reaction mixture was heated at 100° C. for 2 h.

[0178] The reaction became exothermic, the reaction mass was cooled to room temperature, and 10 vol of water and 1 vol of toluene were added. The phases were separated by decantation. The aqueous phase was extracted with 2 vol of toluene. The organic phases were combined and concentrated to 4 vol (hydrated). An additional 6 vol of toluene was added to make 10 vol. 2 vol of heptane was added, and 1 equivalent of oxalic acid dissolved in 3 vol of EtOH was added dropwise to this solution of intermediate (4). The suspension was filtered and washed with 2 vol of toluene and 2 vol of heptane (72% yield from (1)).

[0179] Example 12. Formation of ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (5) from 4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (4) [ka] 5 vol of dichloromethane and 8 vol of NaHCO3 (5% w / w) were added to the oxalate salt of intermediate (4). The mixture was stirred for 30 minutes and the phases were separated by decantation. The organic phase was concentrated to 6 vol (hydrated).

[0180] 1 equivalent of DIPEA and 1.5 equivalents of ethyl chloroformate were added to intermediate (4) in 6 vol of DCM and the reaction mixture was heated under reflux for 2 hours.

[0181] When the reaction became exothermic, 0.5 equivalents of DIPEA and 5 vol of water were added and the system was refluxed again for 1 hour (hydrolysis of excess ethyl chloroformate).

[0182] The reaction mass was then cooled to room temperature and the phases were separated by decantation. The aqueous phase was extracted with 2 vol of DCM. The organic phases were combined and concentrated to 2 vol. 18 vol of heptane was added and it was concentrated to 18 vol. Another 3 vol of heptane was added and it was concentrated again to 18 vol. It started to crystallize little by little. The temperature of the suspension was set to 0 / 5°C using an ice / water bath. The suspension was filtered and washed with 2 vol of cold heptane (69% yield from (4)).

[0183] Example 13. Formation of 2-((2-ethoxyphenoxy)methyl)morpholine chloride from ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (5) [ka] Intermediate (5) was dissolved in 9 vol of isopropanol, 3 equivalents of NaOH and 1 equivalent of water were added and the mixture was heated under reflux for 16 hours.

[0184] Upon completion of the reaction, the reaction mass was cooled to room temperature and 10 vol of water was added. It was concentrated to 11 vol (to remove IPA) and 10 vol of DCM was added. The phases were separated by decantation. The organic phase was concentrated to 3 vol, stripped with 14 vol of ethyl acetate and concentrated to 10 vol. To the product dissolved in ethyl acetate, 1.1 equivalents of HCl 37% w / w was added dropwise and the product began to crystallize. The suspension was filtered and washed with 2 vol of ethyl acetate (92% yield from (5)). HPLC purity (99.77%). See XRPD in Figure 10.

Claims

1. A compound of formula (III) or a salt or solvate thereof 【Chemical 1】 (In the formula, R １ is an amino protecting group) 1. A method for preparing a) In the presence of a Lewis acid and an organic solvent, epichlorohydrin is reacted with a compound of formula (I) or a salt or solvate thereof 【Chemistry 2】 (In the formula, R １ is an amino protecting group) to obtain a compound of general formula (II) or a salt or solvate thereof 【Chemistry 3】 (In the formula, R １ is an amino protecting group) obtaining a reaction mixture comprising b) mixing the reaction mixture with an aqueous sulfuric acid solution to obtain an aqueous-sulfuric acid phase containing the sulfate salt of the compound of general formula (II); and c) mixing the aqueous-sulfuric acid phase containing the sulfate of the compound of general formula (II) with concentrated sulfuric acid to obtain the compound of general formula (III) or a salt or solvate thereof; A method comprising:

2. 2. The method of claim 1, wherein the compound of general formula (III) is 4-benzyl-2-(chloromethyl)morpholine, optionally isolated in salt form, said salt being selected from the group consisting of oxalate, fumarate, and tosylate.

3. where the Lewis acid is LiClO ４、 LiCl, LiBr, LiI·2H ２ O, CsClO ４ , Mg(ClO ４ ) ２ , MgCl ２、 MgBr ２ , Mg(OAc) ２ , CaCl ２ , CaSO ４ , TiCl ４ , FeCl, FeCl ２ , FeCl ３ , CuCl, CuBr, CuCl ２ , CuBr ２ , ZnCl ２ , ZnBr ２ , Zn(OAc) ２ , BBr ３ , BF ３ , BF ３ ·OEt ２ , B(OPh) ３ , B(OCH ３ ) ３ , SnCl, TiCl, AICI ３ , SnCl ２ , SnBr ２ , SnCl ４ , and SnBr ４ The method according to claim 1 or 2, selected from the group consisting of

4. Lewis acid is LiClO ４、 LiCl, LiBr, LiI・2H ２ O, CsClO ４ , and Mg(ClO ４ ) ２ 4. The method of claim 3, wherein the compound is selected from the group consisting of:

5. Lewis acid is LiClO ４ The method of claim 4, wherein

6. The compound of general formula (III) or a salt or solvate thereof is further converted into a compound of general formula (IV) or a salt or solvate thereof by reaction with 2-ethoxyphenol in an organic solvent in the presence of a base. 【Chemistry 4】 (In the formula, R １ is an amino protecting group) The method according to any one of claims 1 to 5, wherein

7. 7. The process according to claim 6, wherein the compound of general formula (IV) is obtained in the form of an oxalate salt.

8. The compound of general formula (IV) or a salt or solvate thereof can be further converted into a compound of formula (V) or a salt or solvate thereof by reaction with ethyl chloroformate. 【Chemistry 5】 The method according to claim 6 or 7, wherein

9. 9. The method according to claim 8, wherein the compound of formula (V) or a salt or solvate thereof is further converted into viloxazine or a salt or solvate thereof by a method comprising the addition of a base.

10. 1. A process for preparing viloxazine, comprising: a) In the presence of a Lewis acid and an organic solvent, epichlorohydrin is reacted with a compound of formula (I) or a salt or solvate thereof 【Chemistry 6】 (In the formula, R １ is an amino protecting group) to obtain a compound of general formula (II) or a salt or solvate thereof 【Chemistry 7】 (In the formula, R １ is an amino protecting group) obtaining a reaction mixture comprising b) mixing the reaction mixture with an aqueous sulfuric acid solution to obtain an aqueous-sulfuric acid phase containing the sulfate salt of the compound of general formula (II); and c) reacting the aqueous-sulfuric acid phase containing the sulfate of the compound of general formula (II) with concentrated sulfuric acid to obtain the compound of general formula (III) or a salt or solvate thereof; d) Reacting a compound of formula (III) or a salt or solvate thereof with 2-ethoxyphenol in the presence of a base in an organic solvent to obtain a compound of formula (IV) or a salt or solvate thereof 【Chemistry 8】 (In the formula, R １ is an amino protecting group) to obtain e) reacting a compound of general formula (IV) or a salt or solvate thereof with ethyl chloroformate to obtain a compound of formula (V) or a salt or solvate thereof 【Chemistry 9】 to obtain e) reacting a compound of formula (V) or a salt or solvate thereof with a base to obtain viloxazine or a solvate thereof. A method comprising:

11. 11. The process for preparing viloxazine according to claim 10, wherein the compound of general formula (III) is 4-benzyl-2-(chloromethyl)morpholine, optionally isolated in salt form, said salt being selected from the group consisting of oxalate, fumarate, and tosylate.

12. A salt of 4-benzyl-2-(chloromethyl)morpholine selected from the oxalate, fumarate or tosylate salt.

Images