Process for the preparation of derivatives of substituted morpholines

Abstract

Provided herein are methods for preparing derivatives and prodrugs of substituted morpholines, or pharma- ceutically acceptable salts thereof, further comprising the following chemical structure: [Formula 1] Methods for preparing substituted morpholine derivatives and prodrugs are provided, having the formula: TIFF2025509083000153.tif37159.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 321,423, filed March 18, 2022, the entire contents of which are incorporated herein by reference.

[0002] Described herein are methods for preparing derivatives and prodrugs of substituted morpholines, or pharmaceutically acceptable salts thereof. [Background technology]

[0003] The compound 2-((2-ethoxyphenoxy)methyl)morpholine is known to have several desirable pharmacological uses, including the treatment of depression, bedwetting, narcolepsy, sleep disorders, and alcoholism, among others. 2-((2-ethoxyphenoxy)methyl)morpholine was previously marketed in several European countries for the treatment of major depressive disorder (MDD). It is a norepinephrine reuptake inhibitor ("NRI"), but may also promote the release of serotonin from neuronal stores. However, treatment with 2-((2-ethoxyphenoxy)methyl)morpholine is associated with a number of side effects, including nausea, vomiting, anorexia, increased erythrocyte sedimentation rate, EKG (electrocardiogram) and EEG (electroencephalogram) abnormalities, epigastric pain, diarrhea, constipation, dizziness, orthostatic hypotension, lower extremity edema, dysarthria, tremor, psychomotor agitation, mental confusion, inappropriate secretion of antidiuretic hormone, increased transaminases, and convulsions.

[0004] 2-((2-ethoxyphenoxy)methyl)morpholine is a chiral molecule, and its desirable biological properties are associated with the (S)-enantiomer, which is known to exhibit five times greater pharmacological activity than the (R)-(+)-isomer. See, for example, "Optical Isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4 oxazine (viloxazine) and Related Compounds" (Journal of Medicinal Chemistry, January 9, 1976, 19(8);1074), which discloses that optical isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4-oxazine and 2-(3-methoxyphenoxymethyl)tetrahydro-1,4-oxazine have been prepared and assigned absolute configurations. The synthesis of optical isomers of viloxazine analogs of known configuration was achieved by resolution of the intermediate 4-benzyl-2-(p-toluenesulfonyloxymethyl)tetrahydro-1,4-oxazine isomers.

[0005] To minimize the side effects associated with 2-((2-ethoxyphenoxy)methyl)morpholine, chemists have synthesized derivatives, prodrugs, and analogs that retain the pharmacological properties of 2-((2-ethoxyphenoxy)methyl)morpholine, as shown in U.S. Patent Application No. 63 / 162,671, the entire contents of which are incorporated herein. A prodrug is a type of derivative that often has little or no pharmacological activity and is converted in vivo to a therapeutically active compound. In some cases, the prodrug itself may have biological activity. Activation of the prodrug can occur by enzymatic or non-enzymatic cleavage of a temporary bond between the carrier and drug molecule, or a combination of both, sequentially or simultaneously. Additional methods for synthesizing prodrugs of 2-((2-ethoxyphenoxy)methyl)morpholine would be beneficial.

[0006] Prodrugs may provide compounds with superior physicochemical properties compared to the parent molecule, potentially overcoming barriers to absorption, distribution, metabolism, excretion, and toxicity (ADMET). These prodrugs may have improved absorption, solubility, permeability, stability, and pharmacokinetic performance. Prodrugs may also exhibit extended half-lives compared to the parent molecule. Prodrugs can be prepared by modifying the parent drug and attaching a prodrug moiety at a reactive site, which can be converted from the prodrug to the parent drug by enzymatic or non-enzymatic processes. Reactive sites on drugs include, but are not limited to, hydroxyl groups, carboxyl groups, amino groups, heteroamino groups, thiol groups, amide groups, and related reactive groups. These can be coupled to sites bearing linking groups such as alkyl groups, aralkyl groups, acyl groups, carbamoyl groups, acyloxy groups, and diacylacetal or acylhydroxyalkyl groups to form prodrugs. Other examples are described in the literature (see Yang, Liu, et al., Acta Pharmaceutica Sinica B2011:1(3), 143-159 and references therein).

[0007] The newly synthesized 2-((2-ethoxyphenoxy)methyl)morpholine analogs, prodrugs, enantiomers, and derivatives are produced by derivatizing the amine group of morpholine in the structure of 2-((2-ethoxyphenoxy)methyl)morpholine to produce novel compounds and chemically stable compounds that serve as intermediates. These 2-((2-ethoxyphenoxy)methyl)morpholine analogs, enantiomers, prodrugs, and derivatives can be used in pharmaceutical compositions and for the treatment of central nervous system (CNS) disorders, or as intermediates in their preparation.

[0008] Previously disclosed synthetic methods for these 2-((2-ethoxyphenoxy)methyl)morpholine analogs, prodrugs, and derivatives suffer from many deficiencies, including low reaction yields, reaction by-products, difficulty in separating enantiomers, and impurities in the resulting products. Effective elimination or removal of impurities, especially those that are genotoxic or otherwise toxic, is critical to providing safe pharmaceuticals. Disclosed herein are solutions to these and other related problems.

[0009] The preparation of the (S)-enantiomer of 2-((2-ethoxyphenoxy)-methyl)morpholine analogs, prodrugs and derivatives by a route that does not require decomposition of the precursor is also desirable, and a solution to this problem is provided by the processes described herein. Summary of the Invention

[0010] Provided herein are new and improved methods for the preparation of morpholine derivatives and their various salts, as well as methods for the preparation of novel intermediate reaction products. Additionally, methods are provided for the synthesis, identification, and characterization of novel intermediates for morpholine derivatives.

[0011] In one aspect, the present invention provides a morpholine derivative of formula (IIb) [ka] or a pharmaceutically acceptable salt thereof, the method comprising: Formula (a) [ka] The compound of formula (I) is reacted with (S)-(+)-epichlorohydrin to give the compound of formula (I). [ka] and forming a chlorohydrin compound of the formula: (b) contacting a chlorohydrin compound with a base and a phase transfer catalyst to form a chlorohydrin compound of the formula [ka] and forming an epoxide compound of the formula: (c) reacting an epoxide compound with a base and a compound of formula [ka] contacting a compound of formula [ka] and forming a diol compound of the formula: (d) contacting a diol compound with a base, followed by the addition of a sulfonyl halide to form a compound of formula [ka] wherein Z is a sulfonyl leaving group, which cyclizes in situ to form an intermediate sulfonate of the formula [ka] and forming an N-benzyl-protected morpholine compound of formula (e) forming an HCl salt of the compound of formula IIb and recrystallizing it to obtain the highly pure (S)-enantiomer as the HCl salt; R 1 is C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl, and each R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, heteroaryl, or heterocycloalkyl; and n is 0, 1, 2, 3, or 4.

[0012] In one embodiment, the present invention provides a morpholine derivative of formula (IIb) [ka] or a pharmaceutically acceptable salt thereof, the method comprising: Formula (a) [ka] The compound of formula (I) is reacted with (S)-(+)-epichlorohydrin to give the compound of formula (I). [ka] and forming a chlorohydrin compound of the formula: (b) contacting a chlorohydrin compound with a base and a phase transfer catalyst to form a chlorohydrin compound of the formula [ka] and forming an epoxide compound of the formula: (c) reacting an epoxide compound with a base and a compound of formula [ka] contacting a compound of formula [ka] and forming a diol compound of the formula: (d) contacting a diol compound with a base, followed by the addition of a sulfonyl halide to form a compound of formula [ka] wherein Z is a sulfonyl leaving group, which cyclizes in situ to form an intermediate sulfonate of the formula [ka] and forming an N-benzyl-protected morpholine compound of formula (e) forming an HCl salt of the compound of formula IIb and recrystallizing it to obtain the highly pure (S)-enantiomer as the HCl salt; R 1 is C1-C6 alkyl, aryl, or heteroaryl, and each R 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl; and n is 0, 1, 2, 3, or 4.

[0013] In another aspect, the present invention provides a morpholine derivative of formula (IIe) [ka] or a prodrug or pharmaceutically acceptable salt thereof, the method comprising: Formula (a) [ka] The compound of formula (I) is reacted with (S)-(+)-epichlorohydrin to give the compound of formula (I). [ka] and forming a chlorohydrin compound of the formula: (b) contacting a chlorohydrin compound with a base and a phase transfer catalyst to form a chlorohydrin compound of the formula [ka] and forming an epoxide compound of the formula: (c) reacting an epoxide compound with a base and a compound of formula [ka] contacting a compound of formula [ka] and forming a diol compound of the formula: (d) contacting a diol compound with a base, followed by the addition of a sulfonyl halide compound to form a compound of formula [ka] wherein Z is a sulfonyl leaving group, which cyclizes in situ to form an intermediate sulfonate of the formula [ka] forming an N-benzyl-protected morpholine compound of formula (I) (e) forming an HCl salt of the compound of formula (IIb) and recrystallizing it to obtain the highly pure (S)-enantiomer as the HCl salt; (f) converting the HCl salt of compound (IIb) to a free base; (g) reacting the N-benzyl-protected morpholine compound with the formula [ka] contacting the compound with a chloroformate of formula [ka] which upon heating results in loss of benzyl chloride and the formation of an intermediate N-benzyl chlorocarbamate salt of the formula [ka] and (h) formula [ka] Addition of a chlorocarbamate compound to a metal salt of an amino acid derivative of the formula: [ka] forming a protected amine of (i) contacting a protected amine with an acid, [ka] and providing a morpholine derivative having the formula: R 1 is C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl, and each R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, heteroaryl, or heterocycloalkyl; R 3 is C1-C6 alkyl, and R 4 is C1-C6 alkyl, and R 5is an amino protecting group and n is 0, 1, 2, 3 or 4.

[0014] In one embodiment, the present invention provides a morpholine derivative of formula (IIe) [ka] or a prodrug or pharmaceutically acceptable salt thereof, the method comprising: Formula (a) [ka] The compound of formula (I) is reacted with (S)-(+)-epichlorohydrin to give the compound of formula (I). [ka] and forming a chlorohydrin compound of the formula: (b) contacting a chlorohydrin compound with a base and a phase transfer catalyst to form a chlorohydrin compound of the formula [ka] and forming an epoxide compound of the formula: (c) reacting an epoxide compound with a base and a compound of formula [ka] contacting a compound of formula [ka] and forming a diol compound of the formula: (d) contacting a diol compound with a base, followed by the addition of a sulfonyl halide to form a compound of formula [ka] wherein Z is a sulfonyl leaving group, which cyclizes in situ to form an intermediate sulfonate of the formula [ka] forming an N-benzyl-protected morpholine compound of formula (I) (e) forming an HCl salt of the compound of formula (IIb) and recrystallizing it to obtain the highly pure (S)-enantiomer as the HCl salt; (f) converting the HCl salt of compound (IIb) to a free base; (g) reacting the N-benzyl-protected morpholine compound with the formula [ka] contacting the compound with a chloroformate of formula [ka] which upon heating results in loss of benzyl chloride and the formation of an intermediate N-benzyl chlorocarbamate salt of the formula [ka] and (h) formula [ka] Addition of a chlorocarbamate compound to a metal salt of an amino acid derivative of the formula [ka] forming a protected amine of (i) contacting a protected amine with an acid, [ka] and providing a morpholine derivative having the formula: R 1 is C1-C6 alkyl, aryl, or heteroaryl, and each R 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl; R 3 is C1-C6 alkyl, and R 4is C1-C6 alkyl, and R 5 is an amino protecting group and n is 0, 1, 2, 3 or 4.

[0015] Further features can be understood by reference to the accompanying drawings, which should be read in conjunction with the following detailed description and examples. [Brief explanation of the drawings]

[0016] [Figure 1] The X-ray structure of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HBr is shown. [Figure 2] 1H NMR spectrum of compound 4 in Example 8. [Figure 3] 1H NMR spectrum of compound 6 of Example 8. [Figure 4] 1H NMR spectrum of compound 7 of Example 8. [Figure 5] 1 shows the 1H NMR spectrum of compound 12 of Example 8. [Figure 6] A synthetic method for preparing compound 12 (compound A) of Example 8 is shown. [Figure 7] Synthetic methods for preparing Compound B and Compound C are shown. DETAILED DESCRIPTION OF THE INVENTION

[0017] definition The following terms are used throughout in accordance with the definitions set out below.

[0018] As used herein and in the appended claims, singular terms, such as "a," "an," and "the," and similar references in the context of describing elements (particularly in the context of the claims below), should be considered to encompass both the singular and the plural, unless otherwise stated herein or clearly contradicted by context. The recitation of ranges of values ​​herein is intended merely to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples, or illustrative language (e.g., "such as") presented herein, unless otherwise indicated, is intended merely to facilitate understanding of the embodiments and does not pose a limitation on the scope of the claims. No language in the specification should be construed as indicating any non-claimed element as essential.

[0019] As used herein, "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which the term is used. If there are uses of the term that are not clear to persons of ordinary skill in the art, "about" will mean up to plus or minus 10% of the particular term, given the context in which the term is used.

[0020] In general, a reference to a particular element, such as hydrogen or H, is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Thus, tritium, C 14 , P 32 , and S 35 Compounds containing radioisotopes such as are included within the scope of the present technology. Procedures for incorporating such labels into the compounds of the present technology will be readily apparent to those of skill in the art based on the disclosure herein.

[0021] Generally, "substituted" refers to an organic group (e.g., an alkyl group) as defined below in which one or more bonds to a hydrogen atom contained therein are replaced with a bond to a non-hydrogen or non-carbon atom. Substituents also include groups in which one or more bonds to a carbon atom(s) or hydrogen atom(s) are replaced with one or more bonds (including double or triple bonds) to a heteroatom. Thus, unless otherwise specified, a substituent is substituted with one or more substituents. In some embodiments, a substituent is substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituents include halogens (i.e., F, Cl, Br, I); hydroxyl; alkoxy groups, alkenoxy groups, aryloxy groups, aralkyloxy groups, heterocyclylalkyl groups, heterocyclylalkyl-alkyl groups, heterocyclylalkyl-oxy groups, and heterocyclylalkyl-alkoxy groups; carbonyl (oxo); carboxylate; ester; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; thiol; sulfide; sulfoxide; sulfone; sulfonyl; pentafluorosulfanyl (i.e., SF5), sulfonamide; amine; N-oxide; hydrazine; hydrazide; hydrazone; azide; amide; urea; amidine; guanidine; enamine; imide; isocyanate; isothiocyanate; cyanate; thiocyanate; imine; nitro group; nitrile (i.e., CN), and the like.

[0022] As used herein, "alkyl" groups include straight-chain and branched alkyl groups having 1 to about 20 carbon atoms, typically 1 to 12 carbon atoms, or in some embodiments, 1 to 8 carbon atoms. As used herein, "alkyl group" includes cycloalkyl groups, as defined below. Alkyl groups can be substituted or unsubstituted. Examples of straight-chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include isopropyl, sec-butyl, t-butyl, neopentyl, and isopentyl groups. Representative substituted alkyl groups may be substituted one or more times with, for example, amino, thio, hydroxy, cyano, alkoxy, and / or halo groups such as F, Cl, Br, and I. As used herein, the term haloalkyl refers to an alkyl group having one or more halo groups. In some embodiments, haloalkyl refers to a perhaloalkyl group.

[0023] Cycloalkyl groups include, but are not limited to, cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, cycloalkyl groups have 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups can be substituted or unsubstituted. Cycloalkyl groups further include, but are not limited to, polycyclic cycloalkyl groups (e.g., norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl), and fused rings (e.g., decalinyl, etc.). Cycloalkyl groups also include rings substituted with straight- or branched-chain alkyl groups, as defined above. Representative substituted cycloalkyl groups can be mono- or di- or multi-substituted (such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups, or mono-, di-, or tri-substituted norbornyl or cycloheptyl groups), which can be substituted with, for example, alkyl, alkoxy, amino, thio, hydroxy, cyano, and / or halo groups.

[0024] Alkenyl groups are straight-chain, branched, or cyclic alkyl groups having 2 to about 20 carbon atoms and further containing at least one double bond. In some embodiments, alkenyl groups have 1 to 12 carbon atoms, or typically 1 to 8 carbon atoms. Alkenyl groups can be substituted or unsubstituted. Examples of alkenyl groups include, among others, vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl groups. Alkenyl groups can be substituted similarly to alkyl groups. Divalent alkenyl groups, i.e., alkenyl groups having two points of attachment, include, but are not limited to, CH-CH=CH2, C=CH2, or C=CHCH3.

[0025] As used herein, an "aryl" or "aromatic" group is a cyclic aromatic hydrocarbon that does not contain heteroatoms. Aryl groups include monocyclic, bicyclic, and polycyclic ring systems. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenylenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenyl, anthracenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments, aryl groups contain 6 to 14 carbon atoms in the ring portion of the group, and in other embodiments, 6 to 12 or 6 to 10 carbon atoms. The term "aryl group" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). Aryl groups can be substituted or unsubstituted.

[0026] As used herein, "heteroaryl" refers to a cyclic aromatic compound containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur within the ring. A "heteroaryl" group can be composed of two or more fused rings (rings that share two adjacent atoms). When a heteroaryl is a fused ring system, the ring that connects to the rest of the molecule has a fully delocalized π-electron system. The other ring(s) in the fused ring system may or may not have a fully delocalized π-electron system. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, phthalazinone, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazine.

[0027] When "hetero" is used, it is intended to mean the specified group, such as an alkyl or aryl group, in which at least one carbon atom has been replaced with a heteroatom selected from nitrogen, oxygen, and sulfur.

[0028] As used herein, "heterocycloalkyl" refers to a ring having one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur in its ring system. The ring may also contain one or more double bonds, so long as they do not form a completely delocalized π-electron system within the ring. Rings, as defined herein, can be stable 3- to 18-membered rings consisting of carbon atoms and from 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The heterocycloalkyl groups of the presently disclosed compounds can be unsubstituted or substituted. If substituted, the substituent(s) can be one or more groups independently selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, amino, protected amino, carboxamide, protected carboxamide, alkylsulfonamide, and trifluoromethanesulfonamide. A "heterocycloalkyl" group can be composed of two or more fused rings (rings that share two adjacent carbon atoms). When a heterocycloalkyl is a fused ring system, the ring that connects the remainder of the molecule is a heterocycloalkyl as defined above. The other ring(s) of the fused ring system can be a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl.

[0029] As used herein, the term "carboxylate" refers to a carboxylic acid whose conjugate base is represented by the chemical formula -COO.

[0030] As used herein, the term "ester" refers to an ester of -COOR b R refers to the -C(O)OG group and the -C(O)OG group. bis a substituted or unsubstituted alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, heterocycloalkyl-alkyl group, or heterocycloalkyl group, as defined herein. G is a carboxylate protecting group. Carboxylate protecting groups are well known to those skilled in the art. An extensive list of protecting groups for the carboxylate functional group can be found in Protective Groups in Organic Synthesis, Greene, TW; Wuts, PGM, John Wiley & Sons, New York, NY, (3rd Edition, 1999), which can be added or removed using the procedures described therein, which is incorporated herein by reference in its entirety for all purposes as if set forth herein in its entirety.

[0031] The term "amide" (or "amido") refers to C-amide and N-amide groups, i.e., -C(O)NR, respectively. c R d This includes the -NRC(O)-R group and the -NRC(O)-R group. c and R d are independently hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl-alkyl, or heterocyclyl group as defined herein. Amide groups therefore include, but are not limited to, carbamoyl groups (-C(O)NH) and formamide groups (NHC(O)H). In some embodiments, an amide is -NRC(O)-(C 1-5 In another embodiment, the amide is -NHC(O)-alkyl, and the group is referred to as "alkanoylamino."

[0032] As used herein, the term "amine" (or "amino") refers to a group selected from the group consisting of -NR e R f R refers to the group e and R fare independently hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl-alkyl, or heterocycloalkyl group as defined herein. In some embodiments, the amine is alkylamino, dialkylamino, arylamino, or alkylarylamino. In other embodiments, the amine is NH, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.

[0033] As used herein, the term "halogen" or "halo" refers to bromine (Br), chlorine (Cl), fluorine (F), or iodine (I). In some embodiments, the halogen is chlorine (Cl).

[0034] As used herein, the term "polypeptide" or "peptide" refers to two or more amino acids joined by a peptide (i.e., amide) bond between the carboxyl terminus of one amino acid and the amino terminus of another. The term "peptide" can be combined with a prefix indicating the number of amino acids in the peptide; for example, a "pentapeptide" is a peptide of five amino acids.

[0035] The term "amino acid" is art-recognized and generally refers to natural or unnatural alpha or beta amino acids. The term "amino acid" includes, but is not limited to, any of the standard L-amino acids commonly found in naturally occurring peptides, or unnatural amino acids, D-isomers of amino acids, and racemic amino acids.

[0036] As used herein, the term "amino acid residue having a hydrophobic side chain" refers to the following amino acids: alanine (Ala), valine (Val), isoleucine (Ile), leucine (Leu), methionine (Met), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp); or unnatural amino acids, including, but not limited to, norleucine, norvaline, cyclohexylalanine, cyclohexylglycine, cyclopentylglycine, etc. In some embodiments, the amino acid residue having a hydrophobic side chain is valine (Val). In other embodiments, the amino acid residue may be racemic or chiral (L-amino acid (S-configuration) or D-amino acid (R-configuration)), such as L-valine ((S)-valine) or D-valine ((R)-valine).

[0037] As used herein, the term "acetyl" refers to a methyl group attached to a carbonyl group (CH3CO-).

[0038] Pharmaceutically acceptable salts of the compounds described herein are within the scope of the present technology and include acid or base addition salts that retain the desired pharmacological activity and are not biologically undesirable (e.g., the salt is not overly toxic, allergenic, or irritating and is bioavailable). When the compounds of the present technology have a basic group, such as an amino group, pharmaceutically acceptable salts can be formed with inorganic acids (e.g., hydrochloric acid, boric acid, nitric acid, sulfuric acid, phosphoric acid, etc.), organic acids (e.g., alginic acid, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and p-toluenesulfonic acid), or acidic amino acids (e.g., aspartic acid, glutamic acid, etc.). When the compounds of the present technology have an acidic group, such as a carboxylic acid ... alkali metals and alkaline earth metals (e.g., Na + , Li + , K. + , Ca 2+ , Mg 2+ , or Zn 2+), ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, or triethanolamine) or basic amino acids (e.g., arginine, lysine, or ornithine). These salts are prepared in situ during the isolation and purification of the compounds, or by separately reacting the purified compounds in their free base or free acid form with the appropriate acid or base, respectively, and isolating the salt formed.

[0039] Stereoisomers (also known as optical isomers) of a compound include all chiral, diastereomeric, and racemic forms of a structure unless a specific stereochemistry is indicated. That is, compounds used in the present technology include enriched or resolved optical isomers at any or all asymmetric atoms where clear from the depiction. Both racemic and diastereomeric mixtures, as well as individual optical isomers, can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and all of these stereoisomers are within the scope of the present technology.

[0040] The term "pharmaceutically acceptable excipient" refers to substances that are widely recognized by industry and regulatory authorities, such as those listed in monographs such as the USP-NF, Food Chemicals Codex, Code of Federal Regulations (CFR), FDA Inactive Ingredients Guide, and those listed in the compendium of 21 CFR parts 182 and 184, which lists substances that are generally regarded as safe (GRAS) food ingredients.

[0041] method Provided herein are novel methods for preparing morpholine derivatives, prodrugs, and pharmaceutically acceptable salts thereof with improved synthetic methods, stereochemical control, and reduced impurities, thereby providing materials suitable for pharmaceutical use.

[0042] In one aspect, provided herein is a morpholine derivative of formula (IIb) [ka] or a pharmaceutically acceptable salt thereof, the method comprising: Formula (a) [ka] The compound of formula (I) is reacted with (S)-(+)-epichlorohydrin to give the compound of formula (I). [ka] and forming a chlorohydrin compound of the formula: (b) contacting a chlorohydrin compound with a base and a phase transfer catalyst to form a chlorohydrin compound of the formula [ka] and forming an epoxide compound of the formula: (c) reacting an epoxide compound with a base and a compound of formula [ka] contacting a compound of formula [ka] and forming a diol compound of the formula: (d) contacting a diol compound with a base, followed by the addition of a sulfonyl halide compound to form a compound of formula [ka] wherein Z is a sulfonyl leaving group, which cyclizes in situ to form an intermediate sulfonate of formula (IIb): [ka] and forming an N-benzyl-protected morpholine compound of formula (e) forming an HCl salt of the compound of formula IIb and recrystallizing it to obtain the highly pure (S)-enantiomer HCl salt; R 1 is C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl, and each R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, heteroaryl, or heterocycloalkyl; and n is 0, 1, 2, 3, or 4.

[0043] In another aspect provided herein, there is provided a method for preparing a morpholine derivative or prodrug, or a pharmaceutically acceptable salt thereof, the method comprising: Formula (a) [ka] The compound of formula (I) is reacted with (S)-(+)-epichlorohydrin to give the compound of formula (I). [ka] and forming a chlorohydrin compound of the formula: (b) contacting a chlorohydrin compound with a base and a phase transfer catalyst to form a chlorohydrin compound of the formula [ka] and forming an epoxide compound of the formula: (c) reacting an epoxide compound with a base and a compound of formula [ka] contacting a compound of formula [ka] and forming a diol compound of the formula: (d) contacting the diol compound with a base and a sulfonyl halide to form an intermediate sulfonate, which cyclizes to form a compound of the formula: [ka] forming an N-benzyl-protected morpholine compound of formula (I) (e) forming an HCl salt of the compound of formula (IIb) and recrystallizing it to obtain the highly pure (S)-enantiomer as the HCl salt; (f) converting the HCl salt of compound (IIb) to a free base; (g) reacting the N-benzyl-protected morpholine compound with the formula [ka] contacting the compound with a chloroformate of formula [ka] which upon heating results in loss of benzyl chloride and the formation of an intermediate N-benzyl chlorocarbamate salt of the formula [ka] and (h) formula [ka] Addition of a chlorocarbamate compound to a metal salt of an amino acid derivative of the formula [ka] forming a protected amine of (i) contacting a protected amine with an acid, [ka] and providing a morpholine derivative having the formula: R 1 is C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl, and each R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, heteroaryl, or heterocycloalkyl; R 3is C1-C6 alkyl, and R 4 is C1-C6 alkyl, and R 5 is an amino protecting group and n is 0, 1, 2, 3 or 4.

[0044] For convenience, and without any limitation thereof, the method for preparing morpholine derivatives is divided into several steps, each of which is disclosed herein in multiple non-limiting embodiments, including steps a), b), c), d), e), f), g), h), and i) shown above.

[0045] The above steps are discussed in more detail below.

[0046] The process of step a) can be advantageously carried out in the presence of a solvent. In some embodiments, the solvent is methanol. Alternatively, the process can be heated. In various embodiments, the reactants are heated to a temperature of about 35°C.

[0047] The process of step b) can be advantageously carried out in the presence of a phase transfer catalyst. The process can be advantageously carried out in the presence of a base. In some embodiments, the base is NaOH. The process can include one or more solvents as part of the solvent system. In some embodiments, the solvent system is a liquid-liquid two-phase system. In some embodiments, the solvent system is a single-phase liquid system. In some embodiments, the liquid-liquid two-phase system comprises water. In some embodiments, the liquid-liquid two-phase system comprises methyl tertiary-butyl ether (MTBE). The phase transfer catalyst can be selected from quaternary ammonium salts, such as benzyltrimethylammonium salts, tetrabutylammonium salts, or other phase transfer catalysts known in the art. In a preferred embodiment, the phase transfer catalyst is tetrabutylammonium hydrogen sulfate. In some embodiments, the process can be carried out at room temperature.

[0048] The process of step c) can be advantageously carried out in the presence of a base. In some embodiments, the base is Cs2CO3. In some embodiments, the base can be added in small increments. The process can include one or more solvents as part of the solvent system. In some embodiments, the solvent system is a single-phase liquid system. In some embodiments, the solvent is toluene. Alternatively, the process can be heated upon completion of the addition of the base. In some embodiments, the process can be heated to a temperature of about 110°C.

[0049] The process of step d) can be advantageously carried out in the presence of a phase transfer catalyst. The process can be carried out in the presence of a base. The base can be solid or liquid. In some embodiments, the base is NaOH. The process can include one or more solvents as part of the solvent system. In some embodiments, the solvent system is a single-phase liquid system. In some embodiments, the solvent is toluene. Alternatively, the process can be heated upon completion of the base addition. In some embodiments, the process can be heated to a temperature of about 30° C. In some embodiments, the sulfonyl halide compound is selected from the group consisting of p-toluenesulfonyl chloride (tosyl chloride), brosyl chloride, nosyl chloride, and mesyl chloride. In some embodiments, the sulfonyl halide compound is p-toluenesulfonyl chloride (tosyl chloride). Furthermore, after the heating period, the process can be cooled to a low temperature before adding p-toluenesulfonyl chloride. In some embodiments, the process can be cooled to a temperature of about 20° C. In some embodiments, p-toluenesulfonyl chloride is added in portions. The phase transfer catalyst can be selected from quaternary ammonium salts, such as benzyltrimethylammonium salts, tetrabutylammonium salts, or other phase transfer catalysts known in the art. In a preferred embodiment, the phase transfer catalyst is benzyltriethylammonium chloride. The solid or liquid base can be a carbonate, such as an alkali carbonate, NaOH, KOH, tetrabutylammonium hydroxide, LiOH, an amine, such as a trisubstituted amine (e.g., triethylamine or tributylamine), DMAP, or other suitable base. In a preferred embodiment, the base is NaOH. Solvents used in the process include, but are not limited to, ethers, such as methyl t-butyl ether, aromatic solvents (e.g., toluene), or other suitable solvents. In a preferred embodiment, the solvent is toluene. In one variation, step d) is carried out using a solution of the diol in toluene in the presence of a phase transfer catalyst and a solid or liquid base, the reaction is cooled to 20°C, and then p-toluenesulfonyl chloride is added in small portions.After the reaction is complete, the reaction mixture can be washed with water, followed by work-up procedures known in the art. Once the N-benzyl-protected morpholine product is isolated, the product can be treated with HCl to form an HCl salt. In some embodiments, the HCl salt contains greater than 60% of the (S) enantiomer. In some embodiments, the HCl salt contains greater than 75% of the (S) enantiomer. In some embodiments, the HCl salt contains greater than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the (S) enantiomer. In some embodiments, the HCl salt contains greater than 95% of the (S) enantiomer. In some embodiments, the HCl salt contains greater than 99% of the (S) enantiomer. In some embodiments, the HCl salt has an enantiomeric excess of greater than 75%. In some embodiments, the HCl salt has an enantiomeric excess of greater than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, the HCl salt has an enantiomeric excess of greater than 95%. In some embodiments, the HCl salt has an enantiomeric excess of greater than 99%. Variations of this embodiment of the invention are further disclosed in the Examples section (e.g., Example 8).

[0050] The process of step g) can be advantageously carried out in the presence of a solvent. In some embodiments, the solvent is dichloromethane. Alternatively, the process can be cooled before the addition of chloroformate. In various embodiments, the reaction can be cooled to a temperature of about 0°C.

[0051] The process of step h) can be advantageously carried out in the presence of a solvent. In some embodiments, the solvent is dimethylformamide (DMF). In some embodiments, the metal salt is a cesium salt, a potassium salt, a silver salt, or a mercury salt. In some embodiments, the metal salt is a cesium salt. In some embodiments, the metal compound is a cesium compound, a potassium compound, a silver compound, or a mercury compound. In some embodiments, the metal compound is a cesium compound. In some embodiments, the metal compound is Cs2CO3, K2CO3, or Ag2CO3. In some embodiments, the metal compound is Cs2CO3. The process can be carried out in the presence of a base. In some embodiments, the base is Cs2CO3. Alternatively, the process may be heated. In embodiments, the reactants are heated to a temperature of about 85°C.

[0052] The process of step i) can be advantageously carried out in the presence of a solvent. In some embodiments, the solvent is ethyl acetate.

[0053] In some embodiments, the compound of formula (Ia) [ka] and R 1 is C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl, and each R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, heteroaryl, or heterocycloalkyl, and n is 0, 1, 2, 3, or 4. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, or heteroaryl. 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, each R 2is independently selected from F, Cl, Br, I, C1-C6 alkyl, or aryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, or C1-C6 alkyl. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, the compound of Formula (Ia) is [ka] and R 1 is C-C alkyl, aryl, heteroaryl, or heterocycloalkyl. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is CH2CH3. In some embodiments, R 1 is CH3. In some embodiments, the compound of Formula (Ia) [ka] is.

[0054] In some embodiments, the compound of formula (IIa) [ka] and R 1 is C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl, and each R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, heteroaryl, or heterocycloalkyl, and n is 0, 1, 2, 3, or 4. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, or heteroaryl. 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, each R 2is independently selected from F, Cl, Br, I, C1-C6 alkyl, or aryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, or C1-C6 alkyl. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, the compound of Formula (IIa) is [ka] and R 1 is C-C alkyl, aryl, heteroaryl, or heterocycloalkyl. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is CH2CH3. In some embodiments, R 1 is CH3. In some embodiments, the compound of formula (IIa) is [ka] is.

[0055] In some embodiments, the compound of formula (IIa') [ka] and R 1 is C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl, and each R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, heteroaryl, or heterocycloalkyl; Z is a sulfonyl leaving group; and n is 0, 1, 2, 3, or 4. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, or heteroaryl. 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, each R2 is independently selected from F, Cl, Br, I, C1-C6 alkyl, or aryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, or C1-C6 alkyl. In some embodiments, Z is [ka] In some embodiments, Z is [ka] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, the compound of Formula (IIa) is [ka] and R 1 is C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl, and Z is a sulfonyl leaving group. 1 is C1-C6 alkyl. In some embodiments, R 1 is CH2CH3. In some embodiments, R 1 is CH3. In some embodiments, the compound of formula (IIa) is [ka] and Z is a sulfonyl leaving group.

[0056] In some embodiments, the compound of formula (IIb) [ka] and R 1 is C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl, and each R 2is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, heteroaryl, or heterocycloalkyl, and n is 0, 1, 2, 3, or 4. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, or heteroaryl. 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, C1-C6 alkyl, or aryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, or C1-C6 alkyl. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, the compound of Formula (IIb) is [ka] and R 1 is C-C alkyl, aryl, heteroaryl, or heterocycloalkyl. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is CH2CH3. In some embodiments, R 1 is CH3. In some embodiments, the compound of formula (IIb) is [ka] is.

[0057] In some embodiments, the compound of formula (Ic) [ka] and R 3 is C1-C6 alkyl. In some embodiments, R 3 is —CH3. In some embodiments, R3 is -CH2CH3. In some embodiments, R 3 is —CH(CH 3 ) 2. In some embodiments, the compound of formula (Ic) [ka] In some embodiments, the compound of formula (Ic) is [ka] is.

[0058] In some embodiments, the compound of formula (IIc) [ka] and R 1 is C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl, and each R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, heteroaryl, or heterocycloalkyl; R 3 is C1-C6 alkyl and n is 0, 1, 2, 3, or 4. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, or heteroaryl. 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, C1-C6 alkyl, or aryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, or C1-C6 alkyl. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, the compound of Formula (IIc) is [ka] and R 1 is C-C alkyl, aryl, heteroaryl, or heterocycloalkyl. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is CH2CH3. In some embodiments, R 1 is CH3. In some embodiments, the compound of formula (IIc) [ka] is.

[0059] In some embodiments, the compound of formula (IId) [ka] and R 1 is C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl, and each R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, heteroaryl, or heterocycloalkyl; R 3 is C1-C6 alkyl and n is 0, 1, 2, 3, or 4. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, or heteroaryl. 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, C1-C6 alkyl, or aryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, or C1-C6 alkyl. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, the compound of Formula (IId) is [ka] In some embodiments, R 1 is C1-C6 alkyl, and R 3 is C1-C6 alkyl. In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 is —CH3. In some embodiments, R 3 is —CH3. In some embodiments, R 3 is -CH2CH3. In some embodiments, R 3 is —CH(CH 3 ) 2. In some embodiments, the compound of formula (IId) is [ka] In some embodiments, the compound of formula (IId) is [ka] In some embodiments, the compound of formula (IId) is [ka] is.

[0060] In some embodiments, the compound of formula (Id) [ka] and R 4 is C1-C6 alkyl, and R 5 is an amino protecting group. In some embodiments, R 4 The carbon atom to which the substituent is attached is in the (R) configuration. In some embodiments, R 4 The carbon atom to which the substituent is attached is in the (S) configuration. In some embodiments, the compound of formula (Id) is [ka] In some embodiments, the compound of formula (Id) is [ka] In some embodiments, R 4 is —CH3. In some embodiments, R 4 is -CH2CH3. In some embodiments, R 4 is —CH(CH 3 ) 2. In some embodiments, the compound of formula (Id) is [ka] In some embodiments, the compound of formula (Id) is [ka] In some embodiments, R 5 is t-butoxycarbonyl (Boc). In some embodiments, R 5 is carboxybenzyl (Cbz).

[0061] In some embodiments, the compound of formula (IIe) [ka] and R 1 is C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl, and each R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, heteroaryl, or heterocycloalkyl; R 3 is C1-C6 alkyl, and R 4 is C1-C6 alkyl, and R 5 is an amino protecting group and n is 0, 1, 2, 3, or 4. In some embodiments, R 4 The carbon atom to which the substituent is attached is in the (R) configuration. In some embodiments, R 4 The carbon atom to which the substituent is attached is in the (S) configuration. In some embodiments, the compound of Formula (IIe) is [ka] In some embodiments, the compound of formula (IIe) is [ka] In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, or heteroaryl. 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, C1-C6 alkyl, or aryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, or C1-C6 alkyl. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, the compound of Formula (IIe) is [ka] In some embodiments, R 1 is C1-C6 alkyl, and R 3 is C1-C6 alkyl. In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 is —CH3. In some embodiments, R 3 is —CH3. In some embodiments, R 3 is -CH2CH3. In some embodiments, R 1 is —CH(CH). In some embodiments, R 4 is —CH3. In some embodiments, R 4 is -CH2CH3. In some embodiments, R 4 is —CH(CH). In some embodiments, R 5 is t-butyloxycarbonyl (Boc). In some embodiments, R 5is carboxybenzyl (Cbz). In some embodiments, the compound of formula (IIe) is [ka] In some embodiments, the compound of formula (IIe) is [ka] In some embodiments, the compound of formula (IIe) is [ka] In some embodiments, the compound of formula (IIe) is [ka] is.

[0062] In some embodiments, the compound of formula (IIf) [ka] and R 1 is C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl, and each R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, heteroaryl, or heterocycloalkyl; R 3 is C1-C6 alkyl, and R 4 is C1-C6 alkyl and n is 0, 1, 2, 3, or 4. In some embodiments, R 4 The carbon atom to which the substituent is attached is in the (R) configuration. In some embodiments, R 4 The carbon atom to which the substituent is attached is in the (S) configuration. In some embodiments, the compound of formula (IIf) is [ka] In some embodiments, the compound of formula (IIf) is [ka] In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, or heteroaryl. 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, C1-C6 alkyl, or aryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, or C1-C6 alkyl. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, the compound of Formula (IIf) is [ka] In some embodiments, R 1 is C1-C6 alkyl, and R 3 is C1-C6 alkyl. In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 is —CH3. In some embodiments, R 3 is —CH3. In some embodiments, R 3 is -CH2CH3. In some embodiments, R 1 is —CH(CH). In some embodiments, R 4 is —CH3. In some embodiments, R 4 is -CH2CH3. In some embodiments, R 4 is —CH(CH 3 ) 2. In some embodiments, the compound of formula (IIf) is [ka] In some embodiments, the compound of formula (IIf) is [ka] In some embodiments, the compound of formula (IIf) is [ka] In some embodiments, the compound of formula (IIf) is [ka] is.

[0063] In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is —CH3. In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 is -CH(CH3)2.

[0064] In some embodiments, each R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, heteroaryl, or heterocycloalkyl. 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl, aryl, or heteroaryl. 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, C1-C6 alkyl, or aryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, CN, NO, C-C alkyl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, or C1-C6 alkyl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, CN, —CH or —CHCH. In some embodiments, each R 2is independently selected from F, Cl, Br, I, and —CH. In some embodiments, each R 2 is independently aryl, heteroaryl, or heterocycloalkyl. In some embodiments, R 2 is F. In some embodiments, R 2 is Cl. In some embodiments, R 2 is Br. In some embodiments, R 2 is I. In some embodiments, R 2 is CN. In some embodiments, R 2 is NO. In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is CH3. In some embodiments, R 2 is CH2CH3. In some embodiments, R 2 is aryl. In some embodiments, R 2 is heteroaryl. In some embodiments, R 2 is heterocycloalkyl.

[0065] In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is —CH3. In some embodiments, R 3 is -CH2CH3. In some embodiments, R 3 is -CH(CH3)2.

[0066] In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4 is —CH3. In some embodiments, R 4 is -CH2CH3. In some embodiments, R 4 is -CH(CH3)2.

[0067] In some embodiments, R 5 is an amino protecting group. In some embodiments, R 5is t-butoxycarbonyl (Boc). In some embodiments, R 5 is carboxybenzyl (Cbz). In some embodiments, R 5 is 9-fluorenylmethoxycarbonyl (Fmoc). In some embodiments, R 5 is benzyl (Bn).

[0068] In some embodiments, Z is [ka] In some embodiments, Z is [ka] is.

[0069] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0070] The present invention includes aspects described in the following sections. [Section 1] Morpholine derivatives of formula (IIb) TIFF0007735585000113.tif29170 or a pharmaceutically acceptable salt thereof, the method comprising: Formula (a) TIFF0007735585000114.tif19170 The compound of formula (I) is reacted with (S)-(+)-epichlorohydrin to give the compound of formula (I). TIFF0007735585000115.tif21170 and forming a chlorohydrin compound of the formula: (b) contacting the chlorohydrin compound with a base and a phase transfer catalyst to form a chlorohydrin compound of the formula TIFF0007735585000116.tif22170 and forming an epoxide compound of the formula: (c) reacting the epoxide compound with a base and a formula TIFF0007735585000117.tif31170 contacting a compound of formula TIFF0007735585000118.tif34170 and forming a diol compound of the formula: (d) contacting the diol compound with a base, followed by the addition of a sulfonyl halide compound to form a compound of formula TIFF0007735585000119.tif35170 wherein Z is a sulfonyl leaving group, which cyclizes in situ to form an intermediate sulfonate of the formula TIFF0007735585000120.tif31170 and forming an N-benzyl-protected morpholine compound of formula (e) forming an HCl salt of the compound of formula IIb and recrystallizing it to obtain the highly pure (S)-enantiomer HCl salt; (f) converting the HCl salt of compound (IIb) to a free base, R 1 is C 1 -C 6 alkyl, aryl, or heteroaryl, and each R 2 are independently F, Cl, Br, I, CN, NO 2 、C 1 -C 6 wherein n is selected from alkyl, aryl, heteroaryl, or heterocycloalkyl; and n is 0, 1, 2, 3, or 4. [Section 2] Morpholine derivatives of formula (IIe) TIFF0007735585000121.tif27170 or a pharmaceutically acceptable salt thereof, the method comprising: (e) The N-benzyl-protected morpholine compound according to item 1 is reacted with a compound of the formula TIFF0007735585000122.tif14170 contacting the compound with a chloroformate of formula TIFF0007735585000123.tif38170 which upon heating results in loss of benzyl chloride and the formation of an intermediate N-benzyl chlorocarbamate salt of the formula TIFF0007735585000124.tif28170 wherein the compound of formula (I) is obtained. R 1 is C 1 -C 6 alkyl, aryl, heteroaryl, or heterocycloalkyl, and each R 2 are independently F, Cl, Br, I, CN, NO 2 、C 1 -C 6 selected from alkyl, aryl, heteroaryl, or heterocycloalkyl; R 3 is C 1 -C 6 alkyl, and n is 0, 1, 2, 3, or 4. [Section 3] Furthermore, (h) formula TIFF0007735585000125.tif27170 Addition of a chlorocarbamate compound (IId) to a metal salt of an amino acid derivative of the formula: TIFF0007735585000126.tif32170 forming a protected amine of R 1 is C 1 -C 6 alkyl, aryl, heteroaryl, or heterocycloalkyl, and each R 2 are independently F, Cl, Br, I, CN, NO 2 、C 1 -C 6 selected from alkyl, aryl, heteroaryl, or heterocycloalkyl; R 3 is C 1 -C 6 alkyl, and R 4 is C 1 -C 6 alkyl, and R 5 is an amino-protecting group; and n is 0, 1, 2, 3, or 4. [Section 4] Furthermore, (i) contacting the protected amine (IIe) with an acid to form a morpholine derivative (IIf) as an acid salt; TIFF0007735585000127.tif29170 providing R 1 is C 1 -C 6 alkyl, aryl, heteroaryl, or heterocycloalkyl, and each R 2 are independently F, Cl, Br, I, CN, NO 2 、C 1 -C 6 selected from alkyl, aryl, heteroaryl, or heterocycloalkyl; R 3 is C 1 -C 6 alkyl, and R 4 is C 1 -C 6 alkyl, and R 5

[0023] Items 4. The method according to any one of Items 1 to 3, wherein: is an amino-protecting group; and n is 0, 1, 2, 3, or 4. [Section 5] Item 5. The method according to item 4, comprising forming the free base of the morpholine derivative (IIf) with a mild base and exchanging one salt for another by treating with another acid. [Section 6] A method for preparing a morpholine derivative or a pharmaceutically acceptable salt thereof, the method comprising: Formula (a) TIFF0007735585000128.tif19170 The compound of formula (I) is reacted with (S)-(+)-epichlorohydrin to give the compound of formula (I). TIFF0007735585000129.tif21170 and forming a chlorohydrin compound of the formula: (b) contacting the chlorohydrin compound with a base and a phase transfer catalyst to form a chlorohydrin compound of the formula TIFF0007735585000130.tif21170 and forming an epoxide compound of the formula: (c) reacting the epoxide compound with a base and a formula TIFF0007735585000131.tif29170 contacting a compound of formula TIFF0007735585000132.tif34170 and forming a diol compound of the formula: (d) contacting the diol compound with a base, followed by the addition of a sulfonyl halide compound to form a compound of formula TIFF0007735585000133.tif35170 wherein Z is a sulfonyl leaving group, which cyclizes in situ to form an intermediate sulfonate of the formula TIFF0007735585000134.tif29170 forming an N-benzyl-protected morpholine compound of formula (I) (e) forming an HCl salt of the compound of formula (IIb) and recrystallizing it to obtain the highly pure (S)-enantiomer as the HCl salt; (f) converting the HCl salt of compound (IIb) into a free base; (g) reacting said N-benzyl-protected morpholine compound with the formula TIFF0007735585000135.tif14170 contacting the compound with a chloroformate of formula TIFF0007735585000136.tif38170 which upon heating results in loss of benzyl chloride and the formation of an intermediate N-benzyl chlorocarbamate salt of the formula TIFF0007735585000137.tif30170 and (h) formula TIFF0007735585000138.tif26170 Addition of a chlorocarbamate compound to a metal salt of an amino acid derivative of the formula TIFF0007735585000139.tif32170 forming a protected amine of (i) contacting the protected amine (IIe) with an acid to form a morpholine derivative (IIf) as an acid salt; TIFF0007735585000140.tif28170 providing a R 1 is C 1 -C 6 alkyl, aryl, or heteroaryl, and each R 2 are independently F, Cl, Br, I, CN, NO 2 、C 1 -C 6 selected from alkyl, aryl, heteroaryl, or heterocycloalkyl; R 3 is C 1 -C6 alkyl, and R 4 is C 1 -C 6 alkyl, and R 5 is an amino protecting group; and n is 0, 1, 2, 3, or 4. [Section 7] 10. The method of any of the preceding claims, wherein a phase transfer catalyst is used in step (b). [Section 8] Item 8. The method according to Item 7, wherein the phase transfer catalyst is tetrabutylammonium hydrogen sulfate. [Section 9] 10. The method of any of the preceding claims, wherein the phase transfer catalyst is used in step (d). [Section 10] Item 10. The method of item 9, wherein the phase transfer catalyst is benzyltriethylammonium chloride. [Section 11] Item 11. The method of item 10, wherein the product contains more than 60% of the (S) enantiomer, and the (S)-HCl salt can be crystallized to obtain an HCl salt containing more than 90% of one enantiomer. [Section 12] 10. The method of any preceding claim, wherein the sulfonyl halide is selected from the group consisting of p-toluenesulfonyl chloride (tosyl chloride), brosyl chloride, nosyl chloride, and mesyl chloride. [Section 13] Item 13. The method according to item 12, wherein the sulfonyl halide compound is p-toluenesulfonyl chloride. [Section 14] 10. The method of any of the preceding claims, wherein cyclization is carried out using NaOH. [Section 15] 10. The process of any of the preceding claims, wherein the crude chlorocarbamate compound formed in step (e) is washed with an alkane solvent, evaporated, or treated with triethylamine to remove benzyl chloride by-product before proceeding to the next step. [Section 16] 10. The method of any preceding claim, wherein the metal salt in step (h) is a cesium salt. [Section 17] 10. The method of any preceding claim, wherein the metal compound in step (h) is cesium carbonate. [Section 18] 10. The method of any preceding claim, wherein step (a) further comprises an organic solvent. [Section 19] Item 19. The method of item 18, wherein step (a) further comprises heating to a temperature of at least 30°C. [Section 20] 10. The method of any preceding claim, wherein step (b) is carried out at room temperature. [Section 21] R 1 is -CH 3 or -CH 2 CH 3 10. The method of any preceding claim, wherein: [Section 22] Each R2 are independently -F, -Cl, -Br, -I, or C 1 -C 6 4. The method of any preceding claim, wherein the alkyl is selected from the group consisting of alkyl, methyl ... [Section 23] R 3 is -CH 3 or isopropyl. [Section 24] R 4 4. The method of any preceding claim, wherein is isopropyl. [Section 25] R 5 The method of any of the preceding claims, wherein is tert-butoxycarbonyl (Boc). [Section 26] 10. The method of any preceding claim, wherein n is 0. [Section 27] The morpholine derivative from step (i) has the following formula: TIFF0007735585000141.tif24170 Item 27. The method according to any one of Items 2 to 26, comprising administering to a patient in need thereof a compound according to any one of Items 2 to 26, or a pharmaceutically acceptable salt thereof. [Section 28] The morpholine derivative from step (i) has the following formula: TIFF0007735585000142.tif26170 Item 27. The method according to any one of Items 2 to 26, comprising administering to a patient in need thereof a compound according to any one of Items 2 to 26, or a pharmaceutically acceptable salt thereof. [Section 29] The morpholine derivative from step (i) has the following formula: TIFF0007735585000143.tif25170 Item 27. The method according to any one of Items 2 to 26, comprising administering to a patient in need thereof a compound according to any one of Items 2 to 26, or a pharmaceutically acceptable salt thereof. Further embodiments are illustrated by the following non-limiting examples. [Example]

[0071] Example 1. Synthesis of (S)-2-((2-ethoxyphenoxy)methyl)morpholine [ka] This synthetic route has been previously reported in US Patent Registration US9403783B2.

[0072] Potassium carbonate (82.93 g, 600 mmol; 3 equiv.) and tetrabutylammonium sulfate (3.4 g, 10 mmol, 0.05 equiv.) were placed in a flask, and 74 g (800 mmol; 4 equiv.) of R-(-)-epichlorohydrin was added, followed by 27.63 g of 2-ethoxyphenol (2,200 mmol, 1 equiv.) dissolved in 30 mL of THF. The mixture was heated to 55 °C overnight under N2. After cooling to room temperature, 300 mL of water was added, and the solution was extracted with ethyl acetate (3 times). The combined extracts were washed with brine (2 times), dried over MgSO4, and evaporated. The residual oil was dissolved in 100 mL of toluene and evaporated (to remove excess epichlorohydrin). This was repeated four times to yield 50 g of a yellow oily epoxy ether.

[0073] 2-Aminoethyl hydrogen sulfate (141 g; 1 mol; 5 equiv.) was placed in a 1 L flask and 7.5 equiv. of 60% KOH (prepared from 100 g of KOH and 67 mL of water) was added, followed by 50 g of crude epoxy ether dissolved in 200 mL of methanol. After heating at 55 °C for 2 h, an additional 7.5 equiv. of 60% KOH was added, and the mixture was heated at 55 °C overnight. After cooling, the mixture was evaporated to remove the methanol, and the residue was diluted with water and extracted with ethyl acetate (5 times). The combined extracts were washed with brine (3 times), dried over MgSO4, and evaporated to give crude (S)-2-((2-ethoxyphenoxy)methyl)morpholine free base as a yellow oil (49 g). The crude oil was dissolved in 100 mL of ethanol and 50 mL of 4 N hydrochloric acid in dioxane diluted with 50 mL of ethyl acetate was added, initially yielding a clear solution. The solid hydrochloride salt precipitated within approximately 2 minutes. The suspension was kept at room temperature for 5 hours, after which the solid salt was filtered off and rinsed with ethyl acetate. The salt was dried in air and under high vacuum to give 17.15 g of (S)-2-((2-ethoxyphenoxy)methyl)morpholine HCl salt. The product showed a single peak by HPLC and analyzed by SFC at 94.58% S.

[0074] The above process was repeated on a 200 mmol or 300 mmol scale. After blending the batches and drying the sample under high vacuum, a total of 74.46 g of (S)-2-((2-ethoxyphenoxy)methyl)morpholine HCl was obtained. Chiral SFC analysis showed 92.724% S. 13 H 20 Analytical calculated values ​​for NO3Cl: C, 57.04; H, 7.36; N, 5.12; Cl, ​​12.95. Found values: C, 56.82; H, 6.86; N, 5.00; Cl, ​​12.94.

[0075] Example 2. Synthesis of morpholine analogs from racemic 2-((2-ethoxyphenoxy)methyl)morpholine HCl [ka] The numbering convention for the compounds described in Example 2 below corresponds to the compound numbers shown in Scheme II.

[0076] In exploratory studies, the process was improved with several novel modifications. These included using the free base of 2-((2-ethoxyphenoxy)methyl)morpholine and diisopropylethylamine as the base catalyst in the first step and using only 1.0 equivalent of chloroformic acid 2. Intermediate 3 was isolated by extraction, without chromatography (to avoid the decomposition observed when 3 was chromatographed on silica gel). Condensation of 3 with Boc-L-valine (4) was achieved by first forming the Cs salt in DMF and then proceeding until intermediate 3 was consumed. Crude 5 was dissolved in ethyl acetate and washed with water and sodium bicarbonate, affording the Boc compound 5 as a single spot on TLC and a single peak on HPLC. Treatment of an ethyl acetate solution of 5 with 2N HCl in dioxane afforded the product HCl salt 6. In exploratory testing, a portion of the product was isolated as a white solid 6 by filtration of a crude suspension in ethyl acetate / dioxane, along with a syrupy liquid mother liquor of approximately 80% purity, in an overall yield of 34% (compared to the 22% yield reported in U.S. Provisional Patent Application No. 63 / 162,671).

[0077] An initial scale-up was performed using the described process in four batches, yielding a total of 57 g of solid HCl salt 6.

[0078] A sample was checked to assess whether the scale-up synthesis affected the ratio of diastereoisomers. Thus, a portion of material 6 was hydrolyzed with 1N NaOH to convert it to 2-((2-ethoxyphenoxy)methyl)morpholine free base, which was then converted to the HCl salt. This sample of 2-((2-ethoxyphenoxy)methyl)morpholine HCl obtained from the prodrug was [α] D 21 = +1.75°, indicating that the R-enantiomer of 2-((2-ethoxyphenoxy)methyl)morpholine HCl predominates (reference 1 value +4.3°). Since the value was not zero, it is clear that solid 6 is dominated by one isomer, which would be the R-isomer.

[0079] Experiment details Step 1. 1-Chloroethyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (3). 2-((2-Ethoxyphenoxy)methyl)morpholine HCl (1 HCl, 32.8 g, 120 mmol) was suspended in 50 mL of water and stirred at 0 °C. A solution of 9.6 g of NaOH in 100 mL of water was added portionwise over 30 min while maintaining the temperature at 0 °C, and the solution was stirred for an additional 1.5 h. The mixture was extracted four times with 100 mL of dichloromethane. The combined extracts were washed with brine, dried over magnesium sulfate, rotary evaporated, and placed on a vacuum pump overnight. 28.51 g of 2-((2-ethoxyphenoxy)methyl)morpholine free base (1) was obtained as a colorless oil (theoretical yield: 28.47 g).

[0080] 2-((2-Ethoxyphenoxy)methyl)morpholine base 1 (120 mmol) was dissolved in 200 mL of dichloromethane and stirred at 0 °C (some of the material was not completely dissolved). 41.8 mL (240 mmol) of diisopropylethylamine was added to the solution, resulting in a clear yellow solution. 18.16 g (122 mmol) of 1-chloroethyl chloroformate 2 dissolved in 20 mL of dichloromethane was added to the solution over 15 min. The solution was stirred and allowed to warm to room temperature over 1.5 h, then stirred at room temperature for 30 min. Water (100 mL) was added, and the mixture was extracted twice with dichloromethane. The extract was washed twice with brine, twice with 2 N HCl (ensure that the pH of the aqueous phase was pH 2), and then again with brine, bicarbonate, and brine. The extract was dried over magnesium sulfate, and the solvent was evaporated on a rotary evaporator and then evaporated under high vacuum for 2 h. A yellow oil (42.81 g) of chloroethyl carbamate 3 was obtained (theory=41.26 g).

[0081] Step 2. 1-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (5). To a solution of 39.63 g (183 mmol) of L-BOC-valine-OH (4) in 100 mL of DMF was added 29.32 g (90 mmol) of cesium carbonate. The solution was stirred at room temperature for 30 min, and then the crude chloroethyl carbamate 3 (42.81 g) from above in 50 mL of DMF was added. The mixture was stirred and heated at 80 °C for 1 h (until no 5 remained by TLC). The solution was cooled to room temperature, treated with 100 mL of water and 50 mL of brine, and extracted with ethyl acetate (4 times). The extract was washed sequentially with sodium bicarbonate (2 times), brine, 1 N HCl, brine, sodium bicarbonate, and brine (2 times) before being dried over magnesium sulfate. Norit was added, and the mixture was filtered through Celite and evaporated to give the crude BOC product 5 as a yellow oil (63.95 g, theoretical yield = 62.95 g).

[0082] Step 3. 1-[(S)-2-Amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate, hydrochloride (6). The above BOC product 5 (63.95 g) was dissolved in 110 mL of ethyl acetate and 110 mL of 4 N HCl in dioxane was added. A brown solution formed and was stirred at room temperature for 3 hours, during which a large amount of solid formed. The mixture was filtered, and the solid was washed with ethyl acetate and quenched with 1:1 ethyl acetate:hexane. The white solid product was dried under vacuum to give 18.45 g (first crop). The mother liquor (40.7 g) was obtained as a brown oil. This was dissolved in 50 mL of ethyl acetate and stored at room temperature overnight, then in the freezer for 2 days. A second crop of 2.3 g was obtained by filtration as before. The solid material gave a single peak by HPLC (fast method (10-70% CH3CN / 0.075% TFA / H2O) 15 min). The mother liquor showed the same major peak as well as approximately 10% 2-((2-ethoxyphenoxy)methyl)morpholine. HPLC was repeated using a slower method (10-40% CH3CN / 0.075% TFA / HO) for 40 min. Under these conditions, the solid was 98% one component (peak 1) and 2% a later-eluting component (peak 2). The mother liquor showed a peak 2 to peak 1 ratio of approximately 4:1, indicating that the two peaks were different diastereomers. This was evidenced as a result of "decomposition" of the 2-((2-ethoxyphenoxy)methyl)morpholine center by L-valine.

[0083] The process was repeated. The mother liquor material was combined. A 15 g portion of the mother liquor (a syrupy liquid) was subjected to aqueous-acid-base extraction by dissolving the mother liquor in 50 mL of ethyl acetate, washing with water, and then with 1 N HCl (twice). The ethyl acetate layer contained 2-((2-ethoxyphenoxy)methyl)morpholine, unreacted BOC compound 5, and a trace of the desired compound. The HCl solution consisted primarily of the desired amine 6 HCl salt, some 2-((2-ethoxyphenoxy)methyl)morpholine, and trace impurities. This solution was made alkaline with sodium bicarbonate, extracted with dichloromethane (three times), washed with brine, and dried over magnesium sulfate. The material was found to be the free base of the desired compound 6 and approximately 5% 2-((2-ethoxyphenoxy)methyl)morpholine. The material was allowed to stand at room temperature overnight, where it decomposed.

[0084] A second 15 g portion was treated similarly, but without conversion to the free base. The ethyl acetate phase contained most of the impurities and little product. The HCl solution was extracted with dichloromethane to give primarily the desired HCl salt 6 product (peak 2) and 4% 2-((2-ethoxyphenoxy)methyl)morpholine. The aqueous phase contained primarily 2-((2-ethoxyphenoxy)methyl)morpholine.

[0085] The remaining 30 g of mother liquor was dissolved in 100 mL of ethyl acetate and extracted three times with 1 N HCl. The aqueous HCl extract was then rewashed twice with ethyl acetate (100 mL), and the aqueous HCl phase was extracted into dichloromethane (3 x 100 mL). The dichloromethane extract was washed with 50 mL of 1 N HCl, and the solution was re-extracted with dichloromethane. The combined dichloromethane extracts were dried over magnesium (sodium) sulfate, treated with Norit, filtered, and evaporated to give 24.29 g (34 g) of peak 2 product 6·HCl as a brown oil. This material was treated again in the same manner to give a total of 22.5 g of product 6·HCl (98.6% product (isomer peak ratio 91.1:8.9)), containing 1.4% 2-((2-ethoxyphenoxy)methyl)morpholine.

[0086] A similar procedure was performed on 42 g of mother liquor from another run. This process involved only one HCl treatment, but more solvent was used. In this variation, 42 g of mother liquor was dissolved in 300 mL of ethyl acetate and extracted twice with 200 mL of 1N HCl. The aqueous HCl extract was then extracted twice with 250 mL of dichloromethane and once with 100 mL. The combined methylene chloride extract was washed with 100 mL of 1N HCl, dried over sodium sulfate, and evaporated to give 34 g of peak 2 product as a brown oil. The peak isomer ratio was 85.7:13.3, with 3.3% 2-((2-ethoxyphenoxy)methyl)morpholine. LC-MS: C 21 H 32 N2O7[M+H] + :425.

[0087] Step 4. Preparation of (S)-2-((2-ethoxyphenoxy)methyl)morpholine from the racemate Racemic 2-2-((2-ethoxyphenoxy)methyl)morpholine HCl was chromatographed by supercritical fluid chromatography, and the (S)-isomer was isolated as the later eluting peak. The preparative separation was performed using a Thar 350 preparative SFC (SFC-23) on a ChiralCel column, OD 300 × 50 mm, I.D 10 μm, with mobile phase A being CO2 and B being ethanol (0.1% NH3HO), with a gradient of 30% B, a flow rate of 200 mL / min, and a back pressure of 100 bar. Analytical HPLC was performed using a Waters UPC2 analytical SFC (SFC-H) / ChiralPak IC, 150 × 4.6 mm, ID 3 μm; mobile phase: A CO₂, B ethanol (0.05% DEA); gradient: B 5-40%; flow rate: 2.5 mL / min; back pressure: 100 bar; column temperature: 35 °C; wavelength: 220 nm. The (S)-isomer was obtained in 99.46% enantiomeric excess. Subsequent processing involved first converting the HCl salt to the free base using ammonium hydroxide, extracting into ethyl acetate, and evaporating to an oil, followed by preparative SFC as described above. This resulted in sharper peaks than the SFC of the HCl salt.

[0088] Example 3. Synthesis of morpholine analogs from (S)-2-((2-ethoxyphenoxy)methyl)morpholine HCl Scheme IIIa. Synthesis of 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate. [ka] The numbering rules for compounds described in Steps 1 to 3 below correspond to the compound numbers shown in Scheme IIIa.

[0089] Step 1. (S)-1-Chloroethyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (3) (S)-2-((2-ethoxyphenoxy)methyl)morpholine HCl (1, 13.7 g, 50 mmol) was suspended in 50 mL of water and stirred at 0° C. 50 mL of 2N NaOH was added portionwise while maintaining the solution at 0° C. for 30 minutes, and the solution was stirred for an additional 1.5 hours. The mixture was extracted four times with 100 mL of dichloromethane. The combined extracts were washed with brine, dried over magnesium sulfate, evaporated on a rotary evaporator, and placed on a vacuum pump overnight. A colorless oil (11.85 g) of (S)-2-((2-ethoxyphenoxy)methyl)morpholine free base was obtained. The process was repeated on a 100 mmol scale to give an additional 23.7 g of (S)-2-((2-ethoxyphenoxy)methyl)morpholine free base. LC-MS: C 20 H 25 NO3[M+Na] + :328.

[0090] (S)-2-((2-ethoxyphenoxy)methyl)morpholine (50 mmol) was mixed with 100 mL of dichloromethane and stirred at 0 °C (some of the solution was not completely dissolved). 17.5 mL (100 mmol) of diisopropylethylamine was added to the solution, resulting in a clear yellow solution. 7.15 g (50 mmol) of 1-chloroethyl chloroformate 2 dissolved in 10 mL of dichloromethane was added to the solution over 15 minutes. The solution was stirred and allowed to warm to room temperature over 1.5 hours, then stirred at room temperature for 30 minutes. Water (100 mL) was added, and the mixture was extracted twice with dichloromethane. The extract was washed twice with brine, twice with 2N HCl (ensuring that the pH of the aqueous phase was pH 2), and then again with brine, bicarbonate, and brine. The extract was dried over magnesium sulfate, and the solvent was evaporated on a rotary evaporator and then evaporated under high vacuum for 2 hours. A yellow oil of chloroethyl carbamate 3 was obtained. The process was repeated on a 100 mmol scale to give an additional 34.3 g of chloro compound 3. LC-MS: 16 H 22 ClNNaO5[M+Na] + :366.

[0091] Step 2. 1-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (5). To a solution of 16.27 g (75 mmol) of L-BOC-valine-OH (4) in 75 mL of DMF was added 12.2 g (37.5 mmol) of cesium carbonate. After stirring the solution at room temperature for 30 min, 17.15 g (50 mmol) of the crude chloroethyl carbamate 3 from above in 25 mL of DMF was added. The mixture was stirred and heated at 80 °C for 1 h (until no 5 remained by TLC). The solution was cooled to room temperature, treated with 100 mL of water and 50 mL of brine, and extracted with ethyl acetate (4 times). The extract was washed sequentially with sodium bicarbonate (2 times), brine, 1 N HCl, brine, sodium bicarbonate, and brine (2 times) before being dried over magnesium sulfate. Norit was added, and the mixture was filtered through Celite and evaporated to give the crude BOC product 5 as 26.2 g of a yellow oil. The process was repeated on a 100 mmol scale to give an additional 52.4 g of crude BOC compound 5. LC-MS: 26 H 40 N2NaO9[M+Na] + :547.

[0092] Step 3. [(S)-1-amino-2-methylbutoxy]methyl 2-[(o-ethoxyphenoxy)-methyl]-4-morpholinecarboxylate, hydrochloride salt (A). The above BOC product 5 (26.2 g, 50 mmol) was dissolved in 60 mL of ethyl acetate and 50 mL of 4 N HCl in dioxane (200 mmol) was added. A brown solution formed and was stirred at room temperature for 3 hours to give 23 g of crude HCl salt. The procedure was repeated on a 100 mmol scale to give an additional 46 g of crude salt. The two batches were combined and suspended in 1000 mL of ethyl acetate. The solid that formed was filtered and dried (32 g). This solid (MS M+H 425) was confirmed to be one diastereomer of the product. The ethyl acetate filtrate was concentrated to a volume of 400 mL and extracted twice with 250 mL of 1 N HCl. The HCl layer (500 mL) was extracted twice with 300 mL of dichloromethane, and the combined extracts were dried over Na2SO4 and evaporated to give 32 g of a viscous oil (MS M+H 425). The oil and solid were combined, dissolved in a mixture of 150 mL acetonitrile and 250 mL water, treated with Norit, filtered through Celite, and lyophilized to give 1.5 g of compound A6 as an off-white sticky solid (HPLC purity, 100%). LC-MS: C 21 H 32 N2O7[M+H] + :425.

[0093] Scheme IIIb. Synthesis of 1-[(S)-2-amino-3-methylbutyloxy]-2-methylpropyl(S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (compound B) and 1-[(R)-2-amino-3-methylbutyloxy]-2-methylpropyl(S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (compound C) from (S)-2-((2-ethoxyphenoxy)methyl)morpholine HCl. [ka] The numbering convention for the compounds listed below corresponds to the compound numbers shown in Scheme IIIb.

[0094] 1-[(S)-2-amino-3-methylbutyloxy]-2-methylpropyl(S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (Compound B) The process for preparing 1-[(S)-2-amino-3-methylbutyloxy]-2-methylpropyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (Compound B) is similar to the process for preparing [(S)-1-amino-2-methylbutoxy]methyl methyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate, hydrochloride (Compound A), except that 1-chloro-2-methylpropyl chloroformate is used instead of 1-chloroethyl chloroformate.

[0095] The method described above for the preparation of (S)-2-((2-ethoxyphenoxy)methyl)morpholine free base was employed in two batches, starting with 50 mmol and 100 mmol of (S)-2-((2-ethoxyphenoxy)methyl)morpholine HCl (SFC separation, 99.3% S).

[0096] Step 1. (S)-2-Methyl-1-chloroethyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (3; Scheme II) Condensation of 2-((2-ethoxyphenoxy)methyl)morpholine with 1-chloro-2-methylpropyl chloroformate (2) was carried out on a 53 mmol and 100 mmol scale to give 21 g and 42 g of product 3, respectively.

[0097] Synthesis of 1-[(R)-2-(tert-butoxycarbonylamino)-3-methylbutyloxy]2-methylpropyl(S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (4) 16.51 g of BOC-L-Val-OH (76 mmol) and 12.22 g (37.5 mmol) of cesium carbonate (CsCO) were stirred in 50 mL of DMF for 30 min at RT. To the suspension was added 50 mmol of chlorocarbamate 3 in 20 mL of DMF, and the mixture was heated in an 80 °C oil bath for 1.5 h under N. After cooling to room temperature, 100 mL of water was added, and the mixture was extracted four times with ethyl acetate. The combined extracts were washed successively with brine, NaHCO (twice), brine, 1N HCl, brine, NaHCO, and brine, dried over MgSO, and evaporated to give 31.8 g of 1-[(R)-2-(tert-butoxycarbonylamino)-3-methylbutyloxy]-2-methylpropyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (4) as a pale yellow oil.

[0098] Synthesis of 1-[(S)-2-amino-3-methylbutyloxy]-2-methylpropyl(S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (Compound B) To a solution of 31.8 g of 1-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutyloxy]-2-methylpropyl(S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (4) in 60 mL of ethyl acetate was added 60 mL of 4 N HCl in dioxane. The solution was stirred at room temperature for 4 hours, and then the solvent was evaporated to give 29 g of 1-[(S)-2-amino-3-methylbutyloxy]-2-methylpropyl(S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate hydrochloride (Compound B) as a yellow oil.

[0099] The previous two reactions were repeated on a 100 mmol scale to yield 59 g of compound B as a yellow oil. The batches were combined and dissolved in 400 mL of ethyl acetate. Hexane (300 mL) was then added, and the solution was extracted with 400 mL (twice) and 300 mL (twice) of 1N HCl. The organic phase was discarded, and the aqueous HCl phase was washed five times with 200 mL of 50% ethyl acetate / hexane. The organic phase was discarded, and the aqueous HCl phase was extracted four times with 200 mL of dichloromethane. The dichloromethane solution was washed with 100 mL of 1N HCl, dried over MgSO4, treated with Norit, and evaporated. The oil was dissolved in 140 mL of acetonitrile, 350 mL of water was added, and the solution was lyophilized to give 60.2 g of 1-[(S)-2-amino-3-methylbutyloxy]-2-methylpropyl(S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylate hydrochloride (Compound B) as a white solid (HPLC 98.9%; LC-MS: C 23 H 36 N2O7[M+H] + :453). A long elution program allowed the diastereoisomers to separate into two equal peaks.

[0100] Synthesis of 1-[(R)-2-amino-3-methylbutyloxy]-2-methylpropyl(S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate hydrochloride (Compound C) The synthesis process for compound B was repeated, except that N-BOC-D-Val was used for coupling to chloro compound 3, to give intermediate 6. Deprotection of 6 on a 100 mmol scale was carried out using 110 mL of 4 N HCl in dioxane in 110 mL of ethyl acetate to give 48.9 g of crude HCl salt. This was combined with the crude HCl salt from the 50 mmol process to give a total of 74 g of crude salt. This was dissolved in 900 mL of 60:40 ethyl acetate:hexane and extracted with 1 L of 1 N HCl. The HCl layer was washed with 400 mL of 50:50 ethyl acetate:hexane and then extracted with a total of 2 L of dichloromethane. The dichloromethane extract was dried over Na2SO4 and evaporated to give 76.88 g of crude 1-((D-valyl)oxy)-2-methylpropyl(2S)-2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate (compound C) as the HCl salt. The crude salt (76 g) was dissolved in 200 mL of acetonitrile and 200 mL of water, treated with Norit, filtered through Celite, and lyophilized to give 65.1 g of 1-[(R)-2-amino-3-methylbutyloxy]-2-methylpropyl(S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylate hydrochloride (Compound C) as a white solid (HPLC 99.81%; LC-MS: C 23 H 36 N2O7[M+H] + :453).

[0101] Example 4. Synthesis of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine Scheme IV. Alternative Route to the Synthesis of (S)-4-Benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (5) [ka] The numbering convention for the compounds listed below corresponds to the compound numbers shown in Scheme IV.

[0102] 2-Ethoxyphenol 1 was reacted with (R)-epichlorohydrin to give the intermediate epoxide 3, which was then treated with aminoethyl sulfate and sodium hydroxide to give (S)-2-((2-ethoxyphenoxy)methyl)morpholine. The process was enantioselective, yielding approximately 92.5% (S) product.

[0103] (S)-4-Benzyl-2-((2-ethoxyphenoxy)methyl)morpholine was prepared from (S)-2-((2-ethoxyphenoxy)methyl)morpholine by alkylation with benzyl bromide.

[0104] Example 5. Alternative synthesis of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine Scheme V. Synthesis of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine [ka] The numbering convention for the compounds listed below corresponds to the compound numbers shown in Scheme V.

[0105] Efforts were made to design a synthesis of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine via a route that did not involve benzylation of (S)-2-((2-ethoxyphenoxy)methyl)morpholine. Several possible routes based on the synthesis of S- or racemic 2-((2-ethoxyphenoxy)methyl)morpholine have precedents. In our route, these syntheses use chiral epichlorohydrin as the source of the S-enantiomer. One route that appeared likely to lead to (S)-2-((2-ethoxyphenoxy)methyl)morpholine was based on the previously disclosed synthesis of racemic 2-((2-ethoxyphenoxy)methyl)morpholine (Liang, Bhatt et al., U.S. Pat. No. 9,403,783). This process was adapted to obtain the epoxide intermediate 3 starting from R-epichlorohydrin. This epoxide was used to prepare (S)-2-((2-ethoxyphenoxy)methyl)morpholine via ring-opening and cyclization with aminoethyl hydrogen sulfate (U.S. Pat. No. 3,712,890). Based on this, ring-opening of 3 with hydroxyethylbenzylamine (12) is expected to provide the same (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine via diol 13.

[0106] Example 6. Synthesis of salts of morpholine derivatives from (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine. [ka] The numbering convention for the compounds described in Example 6 corresponds to the compound numbers shown in Scheme VI.

[0107] (S)-4-Benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (5) (3.87 g, 10 mmol of the above material) was dissolved in 25 mL of dichloromethane and stirred in an ice bath. A solution of 1-chloroethyl chloroformate 6 (1.88 g, 13.2 mmol) in 5 mL of dichloromethane was added over approximately 2 minutes and maintained at approximately 3°C for 90 minutes, then warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (50 mL), 1 N HCl (50 mL), bicarbonate (50 mL), and brine (50 mL), dried over sodium sulfate, evaporated on a rotary evaporator, and then evaporated overnight on a vacuum pump. The residue was dissolved in acetonitrile (50 mL) and washed with hexane (3 x 100 mL) to remove residual amounts of benzyl chloride by-product from the debenzylation via 7. The acetonitrile layer was concentrated to give 3.47 g of chlorocarbamate 8.

[0108] N-Boc-L-valine 9 (3.47 g; 16 mmol) and cesium carbonate (2.6 mg; 8 mmol) were stirred in 20 mL of DMF for 30 min. To this mixture was added a solution of chlorocarbamate 8 (3.43 g, 10 mmol) from step 2 in 20 mL of DMF, and the mixture was stirred and heated at 85 °C for 1 h. After cooling to room temperature, the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate solution was washed with water (2 x 100 mL), bicarbonate (75 mL), 1 N HCl (2 x 100 mL), and brine (50 mL) and dried over sodium sulfate. The solvent was evaporated to give crude Boc-protected compound 10 (5.8 g) as a syrup.

[0109] The entire Boc-protected compound 10 from step 3 (5.8 g; 10 mmol) was dissolved in ethyl acetate (25 mL) and 4 N HCl in dioxane (11 mL, 44 mmol) was added. The mixture was stirred at room temperature for 4 hours and then concentrated under vacuum. The crude compound was dissolved in ethyl acetate (50 mL) and extracted with 1 N HCl (2 x 70 mL). The HCl layer was extracted with dichloromethane (1 x 100 mL, 1 x 50 mL). HPLC of a sample of the extract showed a purity of 96.6%. The dichloromethane layer was washed with 1 N HCl (80 mL), dried over sodium sulfate, and evaporated. After drying under vacuum at room temperature overnight, the 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl product (11, 3.65 g) was obtained as a pale yellow foam. This final process afforded 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl (11), free of unreacted (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine, and free of by-products from the reaction of benzyl chloride with N-Boc-L-lysine (9). This resulted in improved product purity (99.15% vs. 96.6%). Based on 10 mmol of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine used, 3.65 g of 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl (11) represented an overall yield of 79.2%. LC-MS:C 21 H 32 N2O7[M+H] +:425. The product, 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (11), is a 1:1 mixture of diastereomers at the acetal center. One of the isomers (faster eluting by reverse-phase HPLC) is readily obtained as a solid and can be recrystallized from ethanol / MTBE or ethyl acetate to provide highly pure material, with a recovery of approximately 85% of the theoretical amount. Further investigation revealed that the solid HCl salt can be recrystallized from isopropanol to give thin needle-like crystals. The liquid, slower-eluting isomer failed to crystallize as the HCl salt despite repeated attempts with different solvent systems. The two diastereoisomers may have different conformations that favor the crystallization of the faster-eluting isomer. The recrystallized HCl salt forms needle-like crystals, which appear too thin for X-ray structure determination. Further crystallization attempts may be justified to determine whether this isomer has the S,S,S or S,R,S configuration to see if suitable crystals can be obtained.

[0110] Salts of morpholine derivatives Experiments were also completed to exchange the HCl salt for alternative acids. Previous attempts to isolate the free base by treating the HCl salt with 1N NaOH failed due to strong base hydrolysis to give 2-((2-ethoxyphenoxy)methyl)morpholine. However, it was found that washing the HCl salt in solution in ethyl acetate or dichloromethane with saturated sodium bicarbonate and brine and drying over sodium sulfate or magnesium sulfate afforded a stable solution of the free base. The solution of the free base could then be treated with one equivalent of a different acid to form other salts. Salts with maleic acid, citric acid, p-toluenesulfonic acid, and methanesulfonic acid were produced from the mixed diastereomeric HCl salt, but recrystallization was not possible. Possible alternative approaches include first separating the solid diastereomers of the HCl salt by crystallization from ethyl acetate and then separating the liquid diastereomers from the mother liquor, allowing the various salts of each diastereomer to be evaluated separately. When these isomers were converted separately to the free base and then to the p-toluenesulfonate salt, both gave crystalline solids. Attempts to crystallize the isomeric mixture of tosylates were unsuccessful. Overall, it appears that preparing and crystallizing the tosylate salts of the individual diastereoisomers, followed by a 1:1 blend, will give the appropriate product.

[0111] Salt synthesis 1.152 g (2.5 mmol) of the mixed diastereomeric HCl salt was (immediately) dissolved in 5 mL of ethyl acetate and seed crystals reserved from a previous experiment were added. After 1 h, the solution was concentrated to a volume of 3 mL and allowed to stand at room temperature overnight, forming a thick paste of crystalline solid. Ethyl acetate (3 mL) was added, and the solid was collected by filtration and rinsed with ethyl acetate (1 mL). After drying on a vacuum pump, 487 mg of the HCl salt was obtained in the first crop (84.5% of theoretical). The mother liquor was evaporated, and the gummy residue (593.9 mg) was dissolved in 3 mL of ethyl acetate and diluted with 3 mL of MTBE. The solution was allowed to stand at room temperature overnight, but no solid was obtained.

[0112] A mixture of diastereomeric HCl salts (1.15 g, 2 mmol) was dissolved in 3.5 mL of ethyl acetate and seeded. Crystals formed within 1 h; the solvent was removed by pipette. The solid was washed with 5 mL of 1:1 ethyl acetate:hexane and dried to give 562.2 mg of solid isomers. The solid was recrystallized overnight from 3.5 mL of isopropanol to give thin needles. The mother liquor was evaporated to a thick syrup, dissolved in 1 mL of ethyl acetate, and diluted with 1.5–2 mL of hexane. After standing at room temperature for 30 min, an oil separated; therefore, an additional 0.5 mL of ethyl acetate was added, and the mixture was warmed to dissolve and allowed to stand overnight. Additional solid was obtained; however, HPLC showed that this was a second crop of the faster-eluting isomer, while the mother liquor contained only the slower-eluting isomer.

[0113] Isolation of the free base from the liquid HCl salt isomers. The solvent of the mother liquor obtained from the crystallization of the HCl salt (2.5 mmol scale) was evaporated, the residue was dissolved in 6 mL of dichloromethane, and the solution was washed twice with bicarbonate.

[0114] Mesylate formation. Next, a dichloromethane solution of the free base, obtained from 593.9 mg (1.29 mmol) of the liquid HCl isomer mother liquor, was treated with 1.5 mL of 1 N methanesulfonic acid in methanol. The solution was diluted with 2 mL of dichloromethane and washed once with 3 mL of water. Evaporation of the solvent precipitated the salt, so the mixture was redissolved in dichloromethane, dried over magnesium sulfate, and dried. The residue was dissolved in ethyl acetate (2 mL) and MTBE (2 mL), but no solids formed. The solvent was removed (and further dried using 5 mL of toluene). This was then dissolved in isopropanol (0.5 mL) and allowed to stand overnight (no solids). The material was dissolved in ethyl acetate and converted to the free base with bicarbonate, then washed with brine and dried over magnesium sulfate.

[0115] Maleate formation. A solution of the free base in ethyl acetate was treated with a solution of 150 mg of maleic acid in 2 mL of isopropanol. The solvent was evaporated (thick oil). (TLC using 9:1 dichloromethane:methanol shows separation of the maleic acid and the free base). HPLC showed peaks for maleic acid and the slower-eluting isomer, but not 2-((2-ethoxyphenoxy)methyl)morpholine, indicating that the maleate salt is stable, but again, not crystalline. The material was dissolved in dichloromethane, washed with water, and evaporated to give 374 mg of the maleate salt as an oil.

[0116] Tosylate formation. In another experiment, the liquid HCl salt isomer (174.7 mg, 412 mmol) was dissolved in 7 mL of ethyl acetate. The solution was washed twice with bicarbonate (5 mL), brine, dried over magnesium sulfate, evaporated (rotary evaporator with bath temperature below 30 °C), and dried under vacuum for 30 minutes to give the free base. Ethyl acetate (2 mL) was added, followed by 78.3 mg of p-toluenesulfonic acid monohydrate in 0.5 mL of ethanol and 3 mL of ethyl acetate. The solution was concentrated to a volume of 0.5 mL and re-evaporated with 5 mL of ethyl acetate to remove traces of ethanol and yield a sticky foam. The material was dissolved in ethyl acetate (2 mL), and hexane (approximately 2 mL) was added until just cloudy. Crystals formed upon standing, and the mixture was allowed to stand over the weekend, yielding copious amounts of white crystals. The solvent was removed by pipette, and the residue was washed with 1:1 ethyl acetate:hexane and dried to give 188 mg of the tosylate salt as a white solid in the first crop.

[0117] The above process was repeated, starting with the solid isomeric HCl salt (486 mg, 1.054 mmol), which was dissolved in ethyl acetate, washed with sodium bicarbonate, brine, and dried over magnesium sulfate. The solution of the free base was then treated with p-toluenesulfonic acid monohydrate (200.56 mg, 1.054 mmol), first dissolved in 1 mL of ethanol and then diluted with 2 mL of ethyl acetate. This solution was diluted with 1 mL of ethyl acetate and 1 mL of hexane. The solvent was removed to give 487.1 mg of the tosylate as a foamy solid. This was dissolved in 2 mL of ethyl acetate and 2 mL of hexane and allowed to crystallize overnight at room temperature to form the crystalline tosylate salt. The solvent was removed by pipette, and the solid was washed with 1:1 ethyl acetate:hexane. The solid was dried to give 345.8 mg of solid tosylate salt. The mother liquor was evaporated to give 187.4 mg of material.

[0118] The mixture of isomers of the HCl salts (780 mg, 1.692 mmol) was dissolved in 5 mL of ethyl acetate and converted to the free base as described above. The free base was dissolved in 5 mL of ethyl acetate and 321.8 mg of p-toluenesulfonic acid monohydrate in 1 mL of methanol was added. The solution was diluted with 3–4 mL of hexane until partially cloudy, and seed crystals of the pure enantiomers of the crystalline tosylate salts were added. TLC of the mixture of tosylate salts (9:1 dichloromethane:methanol) showed slight separation of the isomers, with the tosylate salt from the liquid isomer flowing slightly faster than the tosylate salt from the solid isomer. After standing overnight and trying other solvents (isopropanol, MTBE), no crystals of either diastereomer formed.

[0119] Example 7. Final assignment of chirality for (S)-2-((2-ethoxyphenoxy)methyl)morpholine Scientific literature on 2-((2-ethoxyphenoxy)methyl)morpholine enantiomers indicates that the S-isomer is biologically much more potent than the R-isomer. The assignment of the R and S enantiomers dates back to earlier literature relating the absolute configuration of propranolol and was established by correlation with S-lactic acid and by circular dichroism spectroscopy (Howe, et al., J. Med. Chem., 1976, 19, 1074). Because (S)-2-((2-ethoxyphenoxy)methyl)morpholine prodrugs, including 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate, are potential drug candidates, we sought to verify their chiral configuration as (S) by X-ray crystallography.

[0120] Although the X-ray structure of the (S)-2-((2-ethoxyphenoxy)methyl)morpholine salt has not been reported, the racemic material has been crystallized and its X-ray structure determined as its hydrochloride salt (J. Ouhabi, M. Saux, A. Carpy, Acta Crystallographica, Section C: Crystal Structure Communications, 1990, 46, 2160). The tosylate, mesylate, and hydrobromide salts were prepared for potential X-ray experiments (each salt incorporates a heavy atom to facilitate the determination of the absolute chiral structure). The crystals obtained from these salts were very thin needle-like or fluffy solids. The best sample (HBr salt, needle) was subjected to X-ray, but the needle was too thin for X-ray experiments.

[0121] Because suitable crystals could not be obtained with the 2-((2-ethoxyphenoxy)methyl)morpholine salt, a sample of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine was prepared (99.3% S) from pure (S)-2-((2-ethoxyphenoxy)methyl)morpholine obtained from the racemate by chiral SFC. This was treated with 48% HBr in ethanol and evaporated to give a white solid of the HBr salt. Recrystallization of the HBr salt from ethanol yielded large plate-like crystals. These were subjected to X-ray analysis and deemed suitable for the experiment. The 4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HBr crystals were shown to have the (S)-configuration and one molecule of water in the crystal. The structure is shown in Figure 1.

[0122] This experiment confirmed all prior assumptions that the S-isomer of 2-((2-ethoxyphenoxy)methyl)morpholine is the biologically potent isomer. Furthermore, this (S)-isomer is the same configuration as the slow-moving peak in chiral SFC isolated from the separation procedure by Howe et al., confirming that it is the isomer isolated from racemic 2-((2-ethoxyphenoxy)methyl)morpholine to generate large amounts of (S)-2-((2-ethoxyphenoxy)methyl)morpholine for prodrug experiments. These results, along with the correlations described above, confirm that the conformations of (S)-2-((2-ethoxyphenoxy)methyl)morpholine and (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine are (S).

[0123] Example 8. Novel chiral synthesis of intermediate morpholine derivatives. Scheme VIII. Synthesis of 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate [ka] The numbering convention for the compounds described in Example 8 corresponds to the compound numbers shown in Scheme VIII.

[0124] Route to (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine The synthesis of 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl (12) via a new route (Scheme III) proceeds via ring-opening of N-benzylethanolamine (1) with (S)-(+)-epichlorohydrin (2, the source of chirality), followed by the formation of chlorohydrin 3, epoxide 4, diol 6, and cyclization to (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (7). This route was scaled up starting from a total of 1.2 mol of ethanolamine 1. Crystallization of crude (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (7 HCl) under optimal conditions affords greater than 99% of the (S)-isomer via the new route.

[0125] Experiment details. Step 1: 2-Benzylaminoethanol (1, 90.73 g, 600 mmol) and (S)-(+)-epichlorohydrin (2, 61.06 g, 660 mmol, 1.1 equiv.) were dissolved in 220 mL of methanol, stirred under nitrogen, and warmed to 35 °C for 22 h. The methanol was evaporated, 100 mL of toluene was added, and the toluene was evaporated. The toluene addition and evaporation was repeated three more times to remove traces of epichlorohydrin and / or methanol, and the oil was dried on a vacuum pump for 4 h. The product chlorohydrin 3 (155 g) was obtained as a pale yellow oil. HPLC (5-50-90% CH3CN; HO / 0.075% TFA) showed a major peak at 6.23 min (64% purity).

[0126] Step 2: Crude chlorohydrin 3 (155 g) was dissolved in 300 ml of MTBE. To the solution was added 2.4 g of tetrabutylammonium hydrogen sulfate and a solution of 25.2 g (630 mmol) of sodium hydroxide in 48 ml of water. The mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. The layers were separated, and the aqueous layer was extracted with 100 ml of MTBE. The combined extracts were dried over magnesium sulfate, evaporated on a rotary evaporator, and then dried under high vacuum at room temperature for 3 hours. Epoxide 4 was obtained as a pale yellow oil (113 g). HPLC using the same conditions as for 3 showed a product peak for epoxide 4 at 6.74 minutes (64.3%). LC-MS: C 12 H 17 NO2[M+H] + :208.17.4 1 The 1 H NMR spectrum is shown in Figure 2A-B.

[0127] Step 3: Epoxide 4 (113 g) and 2-ethoxyphenol (5, 90.4 g, 655 mmol) were dissolved in 450 mL of toluene. The mixture was stirred (mechanical stirrer) and cesium carbonate (106.3 g, 327 mmol) was added portionwise over approximately 30 minutes, resulting in a temperature increase from room temperature to 34°C. The mixture was stirred and allowed to cool to 32°C over 30 minutes. The mixture was then gradually heated (heating mantle) to an internal temperature of 110°C over 1 hour and held at 110°C for 1 hour until all of the epoxide 4 was consumed. The brown mixture was then cooled to room temperature, filtered through Celite, and the toluene was evaporated to give a brown oil. The oil was dissolved in 200 mL of dichloromethane and 200 mL of 2N NaOH was added. The mixture was stirred for 10 minutes and then extracted twice with 100 ml of dichloromethane. The extracts were washed twice with 100 ml of 2N NaOH (to remove unreacted phenol) and twice with brine. 200 ml of brine was added to the dichloromethane layer, followed by 55 ml of concentrated HCl (until the aqueous layer reached pH 3). The mixture was stirred for 10 minutes, the organic layer separated, and then washed twice with 1N HCl (100 ml saturated with NaCl) (to remove the cyclic amine byproduct) and then twice with brine. The organic phase was then treated with 2N NaOH until the pH was greater than 10, stirred for 10 minutes, washed twice with brine, and dried over magnesium sulfate. The solvent was evaporated and dried on a vacuum pump to give 149 g of diol 6 as a light brown oil. HPLC using a 50-90% gradient as before showed the main peak of diol 6 at 14.48 min, but using a 10-70-90% gradient, the diol peak eluted at 10.12 min. LC-MS:C 20 H 27 NO4[M+H] + :346.24.6 1 The 1 H NMR spectrum is shown in Figure 5A-B.

[0128] Step 4: Diol 6 (149 g) was dissolved in 400 mL of toluene, and 4.92 g (22 mmol) of benzyltriethylammonium chloride was added. Under mechanical stirring, 103.65 g of sodium hydroxide beads (2.6 mol) was added. The temperature was raised to 30°C and stirred at room temperature for 30 min. The mixture was then cooled to 20°C in an ice bath, and p-toluenesulfonyl chloride (82.3 g, 430 mmol) was added portionwise over 1 h while maintaining the internal temperature at 25±2°C with ice bath cooling, followed by stirring at room temperature for 1.5 h. The mixture was poured into 500 mL of cold water, stirred for 20 min, and the layers were separated. The aqueous phase was extracted three times with 150 mL of toluene, and the extract was washed six times with 150 mL of 2 N NaOH and twice with brine, and dried over magnesium sulfate. The toluene was removed on a rotary evaporator to give 160 g of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine 7 as a yellow oil. The crude product (free base) showed approximately 80% (S) by chiral SFC. LC-MS: C 20 H 25 NO3[M+H] + :328.28.6 1 The 1 H NMR spectrum is shown in Figure 6A-B.

[0129] (S)-4-Benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (160 g) was dissolved in 130 ml of ethyl acetate and the solution was cooled in an ice bath. To the solution was added 130 ml of 4 N HCl in dioxane, and the solution was stirred for 20 minutes. The solvent was then rotary evaporated to give 207 g of the salt 7·HCl as an orange oil. 40 ml of ethanol was added to the crude salt, and the mixture was warmed to dissolve it. 100 ml of ethyl acetate was then added, followed by 7.8 ml of water. The solution was seeded with crystalline HCl salt in the 99+% (S) configuration and placed in a -15°C freezer over the weekend. The white crystalline product was filtered off, washed with 1:3 ethanol:ethyl acetate, and air-dried to give 47.23 g of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HCl (7 HCl), which had 99.5% S configuration by chiral SFC analysis. The mother liquor was essentially racemic (49:51) and was discarded.

[0130] Continuing the previous reaction (from 600 mmol of 1) gave 48.87 g of 7·HCl, which was recrystallized to give 47.09 g of 7·HCl. Continuing the previous reaction (from 170 mmol of 1) gave 14.6 g of 7·HCl.

[0131] Starting with a total of 1.37 mol of 1, 108.92 g of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HCl (7) was obtained in 21.8% yield. No chromatographic purification was required, and the product is >99% (S)-enantiomer.

[0132] Conversion of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HCl to 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl The key intermediate in the synthesis of 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl (12) from (S)-2-((2-ethoxyphenoxy)methyl)morpholine is the chlorocarbamate (9), which is first obtained by the reaction of (S)-2-((2-ethoxyphenoxy)methyl)morpholine with 1-chloroethyl chloroformate (8). Using (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine as a precursor, the reaction with 1-chloroethyl chloroformate was designed to generate the NH compound during N-debenzylation (see Olofson, et al., J. Org. Chem. 1984, 49, 2081-2082; the published procedure used N-ethylpiperidine as an example).

[0133] Extrapolating to the synthesis of 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl (12) and other (S)-2-((2-ethoxyphenoxy)methyl)morpholine prodrugs, the intermediate chlorocarbamate 9 was prepared from (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (7) and 1-chloroethyl chloroformate 8 by loss of benzyl chloride to form 9, avoiding the need to prepare and use (S)-2-((2-ethoxyphenoxy)methyl)morpholine in the overall process.

[0134] As shown in Scheme VIII, (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (7) was treated with chloroformic acid 8 to give the N-benzyl-N-carbamoyl salt (not isolated), followed by removal of the benzyl chloride to form 1-chloroethyl carbamate 9. The reaction with (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine was very fast, even at room temperature, and carbamate 9 did not convert to 2-((2-ethoxyphenoxy)methyl)morpholine under the conditions described. In early experiments, the crude product was extracted with a hexane / acetonitrile solvent to remove the benzyl chloride formed during removal of the benzyl chloride from 9. An improved method (described below) was discovered in which triethylamine was added to the mixture to react with the benzyl chloride by-product, forming a water-soluble quaternary salt called benzyltriethylammonium chloride, which was then washed off the crude product with water.

[0135] The synthesis was completed by reacting chlorocarbamate 9 with N-BOC-l-valine (10) to give N-BOC-l-valine ester (11). Treatment of 11 with HCl afforded 1-((L-valyl)oxy)ethyl(2S)-2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate HCl (12). An important observation is that the product, 1-[(S)-2-amino-3-methylbutyloxy]ethyl(S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate·HCl (12), can be extracted into dichloromethane from aqueous HCl without leaving any by-products.

[0136] (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HCl (36.3 g, 100 mmol) was stirred with 200 ml of 2N NaOH and 160 ml of water at about 16° C. for 1 hour, then extracted with 400 ml (1 portion) and 200 ml (1 portion) of dichloromethane. Evaporation of the solvent gave 32.7 g of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine free base.

[0137] Experiment details. Step 5: A solution of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine free base (32.7 g, 100 mmol) in 150 mL of dichloromethane was cooled in an ice-water bath. To the solution, while cooling in an ice bath, was added a solution of 1-chloroethyl chloroformate (8, 18.57 g, 130 mmol) in 50 mL of dichloromethane over 30 minutes. The solution was stirred under N for 2 hours, then allowed to warm to room temperature and stirred for an additional hour. To remove the benzyl chloride by-product, triethylamine (30.3 g, 300 mol) in 25 mL of dichloromethane was slowly added over 30 minutes at room temperature. After stirring for a total of 72 hours, the mixture was washed with 150 mL of water, 150 mL of 1N HCl, 150 mL of bicarbonate, 100 mL of brine, dried over Na2SO4, decolorized with Norit A, filtered through Celite, and evaporated to give 35 g of chlorocarbamate (9). LC-MS: C 16 H 22ClNO5Na[M+Na] + :366.12.

[0138] Step 6: N-Boc-L-valine (34.32 g, 160 mmol) was dissolved in 125 mL of DMF, and cesium carbonate (26 g, 80 mmol) was added portionwise. The mixture was stirred at room temperature for 30 minutes, and then crude chlorocarbamate 9 (35 g) in 75 mL of DMF was added at room temperature. The mixture was stirred at 85° C. for 1 hour and then cooled to room temperature. Ethyl acetate (250 mL) was added, and the solution was washed with 150 mL of water (twice), 125 mL of bicarbonate (once), 250 mL of 1 N HCl (twice), and 125 mL of brine (once), dried over Na2SO4, and evaporated to give 55 g of crude 1-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (11). LC-MS:C 26 H 40 N2O9Na[M+Na] + :547.14.

[0139] The above process was repeated on a 1.74-fold scale starting with 63.16 g of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HCl (174 mmol) to afford an additional 91 g of 1-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (11).

[0140] Step 7: 55 g of crude 1-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (11) (100 mmol) was dissolved in 100 mL of ethyl acetate and 100 mL of 4N HCl in dioxane was added. The resulting solution was stirred at room temperature for 4 hours and concentrated under vacuum. The crude HCl salt 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl (56 g) was dissolved in 300 mL of ethyl acetate and extracted twice with 300 mL of 1N HCl. The combined HCl layers were washed with 200 mL of 50% ethyl acetate in hexane and then extracted with 600 mL of dichloromethane. The dichloromethane layer was dried over NaSO and evaporated to give 40 g of 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate·HCl (12). LC-MS: C 21 H 32 N2O7[M+H] + :425.29.12 1 The 1 H NMR spectrum is shown in Figure 7A-B.

[0141] Subsequently, 91 g of 1-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (11) was treated with 4 N HCl in dioxane as described above to give 62 g of 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate·HCl (12). An additional 3.5 g was obtained from dichloromethane (the emulsion was allowed to stand overnight), which was then separately lyophilized.

[0142] Multiple lots of 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate·HCl (12, 18 g, 40 g, and 62 g) were combined (120 g total) and dissolved in 200 mL of acetonitrile and 400 mL of water. The solution was decolorized with Norit, filtered through Celite, and lyophilized to yield a total of 112.92 g of the product, 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (12), as the HCl salt, as an off-white solid. HPLC indicated the product was 98.5% pure. The rinse from the lyophilization flask was again lyophilized to yield an additional 6 g.

[0143] The overall yield of 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate·HCl (12, 112.92 + 3.5 + 6 = 122.42 g) represents an overall yield of 81.97% from (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HCl.

[0144] While the present description has been given with reference to exemplary embodiments, those skilled in the art will recognize that various changes can be made and equivalents can be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Also, although the drawings and description disclose exemplary embodiments and specific terminology may be used, unless otherwise indicated, these terms are used in a generic and descriptive sense only and not for purposes of limitation, and therefore should not be construed as limiting the scope of the claims. Moreover, those skilled in the art will recognize that certain steps of the methods described herein may be ordered in an alternate order or steps may be combined. Therefore, it is intended that the scope of the appended claims not be limited to the specific embodiments disclosed herein.

Claims

1. Morpholine derivatives of formula (IIb) 【Chemical 1】 or a pharmaceutically acceptable salt thereof, the method comprising: (a) Formula 【Chemistry 2】 is reacted with (S)-(+)-epichlorohydrin to give a compound of the formula 【Chemistry 3】 and forming a chlorohydrin compound of the formula: (b) contacting the chlorohydrin compound with a base and a phase transfer catalyst to form a compound of formula 【Chemistry 4】 and forming an epoxide compound of the formula: (c) reacting the epoxide compound with a base and a reaction product of the formula 【Chemistry 5】 contacting a compound of formula 【Chemistry 6】 and forming a diol compound of the formula: (d) contacting the diol compound with a base, followed by the addition of a sulfonyl halide compound to produce a compound of formula 【Chemistry 7】 wherein Z is a sulfonyl leaving group, which cyclizes in situ to form an intermediate sulfonate of the formula 【Chemistry 8】 and forming an N-benzyl-protected morpholine compound of formula (e) forming an HCl salt of the compound of formula IIb and recrystallizing it to obtain the highly pure (S)-enantiomer HCl salt; (f) optionally converting the HCl salt of compound (IIb) to the free base; and optionally further forming a pharmaceutically acceptable salt of the morpholine derivative of formula (IIb) by treating the free base formed in step (f) with an acid. Including, R １ is C １ -C ６ alkyl, aryl, or heteroaryl, and each R ２ are independently F, Cl, Br, I, CN, NO ２ , C １ -C ６ wherein n is selected from alkyl, aryl, heteroaryl or heterocycloalkyl; and n is 0, 1, 2, 3 or 4.

2. A method for preparing a morpholine derivative or a pharmaceutically acceptable salt thereof, the method comprising: (a) Formula 【Chemistry 9】 is reacted with (S)-(+)-epichlorohydrin to give a compound of the formula 【Chemistry 10】 and forming a chlorohydrin compound of the formula: (b) contacting the chlorohydrin compound with a base and a phase transfer catalyst to form a compound of formula 【Chemistry 11】 and forming an epoxide compound of the formula: (c) reacting the epoxide compound with a base and a reaction product of the formula 【Chemistry 12】 contacting a compound of formula 【Chemistry 13】 and forming a diol compound of the formula: (d) contacting the diol compound with a base, followed by the addition of a sulfonyl halide compound to produce a compound of formula 【Chemistry 14】 wherein Z is a sulfonyl leaving group, which cyclizes in situ to form an intermediate sulfonate of the formula 【Chemistry 15】 forming an N-benzyl-protected morpholine compound of formula: (e) forming an HCl salt of the compound of formula (IIb) and recrystallizing it to obtain the highly pure (S)-enantiomer as the HCl salt; (f) converting the HCl salt of compound (IIb) to a free base; (g) reacting the N-benzyl-protected morpholine compound with a compound of the formula 【Chemistry 16】 contacting the compound with a chloroformate of formula 【Chemistry 17】 which upon heating loses benzyl chloride to form an intermediate N-benzyl chlorocarbamate salt of the formula 【Chemistry 18】 and (h) Formula 【Chemistry 19】 Addition of a chlorocarbamate compound to a metal salt of an amino acid derivative of the formula 【Chemistry 20】 forming a protected amine of (i) contacting the protected amine with an acid to form a compound of formula (IIf) 【Chemical Formula 21】 providing an acid salt of the compound of R １ is C １ -C ６ alkyl, aryl, or heteroaryl, and each R ２ are independently F, Cl, Br, I, CN, NO ２ , C １ -C ６ selected from alkyl, aryl, heteroaryl, or heterocycloalkyl; R ３ is C １ -C ６ alkyl, and R ４ is C １ -C ６ alkyl, and R ５ is an amino protecting group, n is 0, 1, 2, 3 or 4, Optionally, in step (i), the free base of the compound of formula (IIf) is formed by treating the formed acid salt with a base.

3. 3. The process according to claim 1 or 2, wherein the phase transfer catalyst used in step (b) is tetrabutylammonium hydrogen sulfate.

4. 3. The process of claim 1 or 2, wherein a phase transfer catalyst is used in step (d).

5. 5. The method of claim 4, wherein the phase transfer catalyst is benzyltriethylammonium chloride.

6. The method of claim 5, wherein the HCl salt before recrystallization in step (e) contains more than 60% of the (S) enantiomer, and the (S)-HCl salt can be crystallized to obtain an HCl salt containing more than 90% of one enantiomer.

7. 3. The method of claim 1, wherein the sulfonyl halide is selected from the group consisting of p-toluenesulfonyl chloride (tosyl chloride), brosyl chloride, nosyl chloride, and mesyl chloride.

8. The method of claim 7, wherein the sulfonyl halide compound is p-toluenesulfonyl chloride.

9. 3. The method of claim 1 or 2, wherein the cyclization is carried out using NaOH.

10. 3. The method of claim 2, wherein the crude chlorocarbamate compound formed in step (g) is washed with an alkane solvent, evaporated, or treated with triethylamine to remove benzyl chloride by-products before proceeding to the next step.

11. 3. The method of claim 2, wherein the metal salt in step (h) is a cesium salt.

12. 3. The method of claim 2, wherein the metal compound of step (h) is cesium carbonate.

13. 3. The method of claim 1 or 2, wherein step (a) further comprises an organic solvent.

14. 14. The method of claim 13, wherein step (a) further comprises heating to a temperature of at least 30°C.

15. 3. The method of claim 1 or 2, wherein step (b) is carried out at room temperature.

16. R １ is -CH ３ or -CH ２ CH ３ The method according to claim 1 or 2, wherein

17. Each R ２ are independently —F, —Cl, —Br, —I, or C １ -C ６ 3. The method of claim 1 or 2, wherein the alkyl is selected from the group consisting of alkyl, methyl ...

18. R ３ is -CH ３ or isopropyl.

19. R ４ The method of claim 2, wherein is isopropyl.

20. R ５ The method of claim 2, wherein is tert-butoxycarbonyl (Boc).

21. 3. The method of claim 1, wherein n is 0.

22. The free base or acid salt of the compound of formula (IIf) from step (i) can be prepared according to the following formula: 【Chemical 22】 or a pharmaceutically acceptable salt thereof.

23. The free base or acid salt of the compound of formula (IIf) from step (i) can be prepared according to the following formula: 【Chemical 23】 or a pharmaceutically acceptable salt thereof.

24. The free base or acid salt of the compound of formula (IIf) from step (i) can be prepared according to the following formula: 【Chemistry 24】 or a pharmaceutically acceptable salt thereof.

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