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 making derivatives and prodrugs of substituted morpholines, or pharma- ceutically 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 and EEG 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 whose desirable biological properties are associated with the (S)-enantiomer, which is known to exhibit 5-fold increased pharmacological activity compared to the (R)-(+)-isomer. See, for example, “Optical Isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4 oxazine (viloxazine) and Related Compounds” (Journal of Medicinal Chemistry, Jan. 9, 1976, 19(8); 1074), in which it is disclosed 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 configuration. 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 Serial 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 may occur by enzymatic or non-enzymatic cleavage of a temporary bond between the carrier and the 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 and may overcome the barriers of absorption, distribution, metabolism, excretion, and toxicity (ADMET) compared to the parent molecule. These prodrugs may have improved absorption, solubility, permeability, stability, and pharmacokinetic performance. Prodrugs may exhibit extended half-lives compared to the parent molecule. Prodrugs may be prepared by modifying the parent drug and attaching the parent drug at a reactive site with a prodrug moiety that can be converted from the prodrug to the parent drug by enzymatic or non-enzymatic processes. Reactive sites on the drug include, but are not limited to, hydroxyl groups, carboxyl groups, amino groups, heteroamino groups, thiol groups, amide groups, and related reactive groups. These may be attached to sites bearing linking groups such as alkyl groups, aralkyl groups, acyl groups, carbamoyl groups, acyloxy groups, and diacylacetal groups 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 cited 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 analogues, prodrugs and derivatives suffer from many deficiencies, such as low reaction yields, reaction by-products, difficulty in separating the enantiomers, and impurities in the resulting products. Effective elimination or removal of impurities, especially impurities that are genotoxic or otherwise toxic, is of great importance to provide safe pharmaceutical products. Disclosed herein are solutions to these and other related problems.

[0009] The preparation of the (S)-enantiomer of 2-((2-ethoxyphenoxy)-methyl)morpholine analogues, prodrugs and derivatives by a route that does not require decomposition of a 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 processes for the preparation of morpholine derivatives and various salts thereof, 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 of morpholine derivatives.

[0011] In one aspect, the present invention provides a morpholine derivative of formula (IIb) [ka] or a pharma- ceutically 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 compound according to the formula: [ka] and forming an epoxide compound of the formula: (c) reacting an epoxide compound with a base and a formula [ka] contacting the compound of formula [ka] and forming a diol compound of (d) contacting a diol compound with a base, followed by the addition of a sulfonyl halide to obtain a compound of the 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 C 1 -C 6 alkyl, aryl, heteroaryl, or heterocycloalkyl; 2 are independently F, Cl, Br, I, CN, NO 2 , C 1 -C 6 and n is selected from 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 pharma- ceutically 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 compound according to the formula: [ka] and forming an epoxide compound of the formula: (c) reacting an epoxide compound with a base and a formula [ka] contacting the compound of formula [ka] and forming a diol compound of (d) contacting a diol compound with a base, followed by the addition of a sulfonyl halide to obtain a compound of the 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 C 1 -C 6 alkyl, aryl, or heteroaryl, and each R 2 are independently F, Cl, Br, I, CN, and C1 -C 6 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 pharma- ceutical 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 compound according to the formula: [ka] and forming an epoxide compound of the formula: (c) reacting an epoxide compound with a base and a formula [ka] contacting the compound of formula [ka] and forming a diol compound of (d) contacting a diol compound with a base, followed by the addition of a sulfonyl halide compound to produce a compound of the 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) into a free base; (g) reacting an N-benzyl-protected morpholine compound with the formula [ka] contacting the compound with a chloroformate of formula [ka] which upon heating loses benzyl chloride to form an intermediate N-benzyl chlorocarbamate salt of the formula [ka] The forming of the compound of formula (1) is obtained. (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 having the formula: [ka] providing a morpholine derivative having the formula: R 1 is C 1 -C 6 alkyl, aryl, heteroaryl, or heterocycloalkyl; 2 are independently F, Cl, Br, I, CN, NO 2 , C1 -C 6 selected from alkyl, aryl, heteroaryl, or heterocycloalkyl; R 3 is C 1 -C 6 is alkyl, R 4 is C 1 -C 6 is alkyl, R 5 is 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 pharma- ceutical 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 compound according to the formula: [ka] and forming an epoxide compound of the formula: (c) reacting an epoxide compound with a base and a formula [ka] contacting the compound of formula [ka] and forming a diol compound of (d) contacting a diol compound with a base, followed by the addition of a sulfonyl halide to obtain a compound of the 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) into a free base; (g) reacting an N-benzyl-protected morpholine compound with the formula [ka] contacting the compound with a chloroformate of formula [ka] which upon heating loses benzyl chloride to form an intermediate N-benzyl chlorocarbamate salt of the formula [ka] The forming of the compound of formula (1) is obtained. (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 having the formula: [ka] providing a morpholine derivative having the formula: R1 is C 1 -C 6 alkyl, aryl, or heteroaryl, and each R 2 are independently F, Cl, Br, I, CN, and C 1 -C 6 alkyl, aryl or heteroaryl; R 3 is C 1 -C 6 is alkyl, R 4 is C 1 -C 6 is alkyl, 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 description of the drawings]

[0016] [Figure 1] The X-ray structure of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HBr is shown. [Diagram 2] 1H NMR spectrum of compound 4 in Example 8 is shown. [Diagram 3] 1H NMR spectrum of compound 6 of Example 8 is shown. [Figure 4] 1H NMR spectrum of compound 7 of Example 8 is shown. [Diagram 5] 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 PREFERRED EMBODIMENTS

[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" and "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 indicated herein or clearly contradicted by context. The recitation of ranges of values ​​herein is intended merely to serve as a shorthand method of individually referring to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein may 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 is intended merely to facilitate a better understanding of the embodiments and does not limit the scope of the claims, unless otherwise indicated. No language in this specification should be construed as indicating any non-claimed element as essential.

[0019] As used herein, "about" is as understood by one of ordinary skill in the art and will vary to some extent depending on the context in which the word is used. If there are uses of the term that are not clear to a person 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 that contain radioisotopes such as are included within the scope of the present technology. Procedures for inserting 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] In general, "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 by 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 by 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. Exemplary substituents include halogen (i.e., F, Cl, Br, I); hydroxyl; alkoxy, alkeneoxy, aryloxy, aralkyloxy, heterocyclylalkyl, heterocyclylalkyl-alkyl, heterocyclylalkyl-oxy, and heterocyclylalkyl-alkoxy groups; carbonyl (oxo); carboxylate; ester; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; thiol; sulfide; sulfoxide; sulfone; sulfonyl; pentafluorosulfanyl (i.e., SF 5 ), sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; nitriles (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 groups. As used herein, the term haloalkyl is 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 3-8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3-5, 3-6, or 3-7. 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), as well as 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 doubly or more 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, for example, with alkyl, alkoxy, amino, thio, hydroxy, cyano, and / or halo groups.

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

[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 6-14 carbons in the ring portion of the group, and in other embodiments, 6-12, or 6-10 carbon atoms. The phrase "aryl group" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). Aryl groups may 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 in 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 pi-electron system. The other ring(s) of the fused ring system may or may not have a fully delocalized pi-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 in the ring system, independently selected from nitrogen, oxygen, and sulfur. The ring may also contain one or more double bonds, so long as they do not form a completely delocalized pi-electron system within the ring. A ring as defined herein can be a stable 3- to 18-membered ring consisting of carbon atoms and 1-5 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 sharing two adjacent carbon atoms). When the heterocycloalkyl is a fused ring system, the ring that connects to 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. bis a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycloalkyl-alkyl, 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 carboxylate functional groups 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 a C-amide group and an N-amide group, i.e., —C(O)NR, respectively. c R d R 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. Thus, an amide group can include a carbamoyl group (-C(O)NH 2 ) and formamide groups (NHC(O)H). In some embodiments, the amide is -NRC(O)-(C 1-5 In another embodiment, the amide is -NHC(O)-alkyl, and the group is referred to as "carbonylamino"; 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 -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 an alkylamino, dialkylamino, arylamino, or alkylarylamino. In other embodiments, the amine is an NH 2 , 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 linked 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 α- or β-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, and the like. 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 carbonyl group (CH 3 CO-)

[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, for example, pharma- ceutically 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 group, for example, pharma-ceutically 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 group, for example, 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 the 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 specified. That is, the compounds used in the present technology include those enriched or resolved optical isomers at any or all asymmetric atoms when clear from the depiction. Both racemic and diastereomeric mixtures, as well as individual optical isomers, can be isolated or synthesized 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 "pharmaceutical acceptable excipient" refers to substances that are widely recognized by industry and regulatory agencies, such as those listed in monographs published in the USP-NF, Food Chemicals Codex, Code of Federal Regulations (CFR), FDA Inactive Ingredients Guide, etc., as well as 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 the preparation of morpholine derivatives, prodrugs, and pharma- ceutically acceptable salts thereof, with improved synthetic methods, stereochemical control, and reduced impurities, thereby providing materials suitable for pharmaceutical use.

[0042] In one aspect, the present invention provides a morpholine derivative of formula (IIb) [ka] or a pharma- ceutically 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 compound according to the formula: [ka] and forming an epoxide compound of the formula: (c) reacting an epoxide compound with a base and a formula [ka] contacting the compound of formula [ka] and forming a diol compound of (d) contacting a diol compound with a base, followed by the addition of a sulfonyl halide compound to produce a compound of the formula [ka] where 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 HCl salt of the (S)-enantiomer in high purity; R 1 is C 1 -C 6 alkyl, aryl, heteroaryl, or heterocycloalkyl; 2 are independently F, Cl, Br, I, CN, NO 2 , C 1 -C 6 and n is selected from 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 producing a morpholine derivative or prodrug, or a pharma- ceutically 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 compound according to the formula: [ka] and forming an epoxide compound of the formula: (c) reacting an epoxide compound with a base and a formula [ka] contacting the compound of formula [ka] and forming a diol compound of (d) contacting the diol compound with a base and a sulfonyl halide to form an intermediate sulfonate, which cyclizes to form a sulfonyl halide 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) into a free base; (g) reacting an N-benzyl-protected morpholine compound with the formula [ka] contacting the compound with a chloroformate of formula [ka] which upon heating loses benzyl chloride to form an intermediate N-benzyl chlorocarbamate salt of the formula [ka] The forming of the compound of formula (1) is obtained. (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 having the formula: [ka] providing a morpholine derivative having the formula: R 1 is C 1 -C 6 alkyl, aryl, heteroaryl, or heterocycloalkyl; 2are 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 is alkyl, R 4 is C 1 -C 6 is alkyl, R 5 is an amino protecting group and n is 0, 1, 2, 3 or 4.

[0044] For convenience and without any limitation thereto, 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) may advantageously be carried out in the presence of a solvent. In some embodiments, the solvent is methanol. Alternatively, the process may be heated. In embodiments, the reactants are heated to a temperature of about 35° C.

[0047] The process of step b) may be advantageously carried out in the presence of a phase transfer catalyst. The process may be advantageously carried out in the presence of a base. In some embodiments, the base is NaOH. The process may 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 includes water. In some embodiments, the liquid-liquid two-phase system includes methyl tertiary-butyl ether (MTBE). The phase transfer catalyst may 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 may 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 Cs 2 CO 3 In some embodiments, the base may be added in small increments. The process may 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 may be heated upon completion of the addition of the base. In some embodiments, the process may be heated to a temperature of about 110° C.

[0049] The process of step d) may be advantageously carried out in the presence of a phase transfer catalyst. The process may be carried out in the presence of a base. The base may be solid or liquid. In some embodiments, the base is NaOH. The process may 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 may be heated upon completion of the addition of the base. In some embodiments, the process may 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). Additionally, after the heating period, the process may be cooled to a low temperature before adding p-toluenesulfonyl chloride. In some embodiments, the process may be cooled to a temperature of about 20° C. In some embodiments, the 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 with a solution of the diol in toluene in the presence of a solid or liquid base in the presence of a phase transfer catalyst, the reaction is cooled to 20° C., and then p-toluenesulfonyl chloride is added in portions.After the reaction is complete, the reaction mixture can be washed with water, followed by work-up procedures known in the art. Upon isolation of the N-benzyl-protected morpholine product, the product can be treated with HCl to form an HCl salt. In some embodiments, the HCl salt contains more than 60% of the (S) enantiomer. In some embodiments, the HCl salt contains more than 75% of the (S) enantiomer. In some embodiments, the HCl salt contains more than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the (S) enantiomer. In some embodiments, the HCl salt contains more than 95% of the (S) enantiomer. In some embodiments, the HCl salt contains more than 99% of the (S) enantiomer. In some embodiments, the HCl salt has an enantiomeric excess of more 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 the chloroformate. In 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 Cs 2 CO 3 , K 2 CO 3 , or Ag 2 CO 3 In some embodiments, the metal compound is Cs 2 CO 3 The process can be carried out in the presence of a base. In some embodiments, the base is Cs 2 CO 3 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) may 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 C 1 -C 6 alkyl, aryl, heteroaryl, or heterocycloalkyl; 2 are independently F, Cl, Br, I, CN, NO 2 , C 1 -C 6 In some embodiments, R is selected from alkyl, aryl, heteroaryl, or heterocycloalkyl, and n is 0, 1, 2, 3, or 4. 2 are independently F, Cl, Br, I, CN, NO2 , C 1 -C 6 In some embodiments, R is selected from alkyl, aryl, or heteroaryl. 2 are independently F, Cl, Br, I, CN, and C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I, and C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I or C 1 -C 6 In some embodiments, n is selected from 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 1 -C 6 In some embodiments, R is an alkyl, aryl, heteroaryl, or heterocycloalkyl. 1 is C 1 -C 6 In some embodiments, R 1 CH 2 CH 3 In some embodiments, R 1 CH 3 In some embodiments, the compound of formula (Ia) is [ka] It is.

[0054] In some embodiments, the compound of formula (IIa) [ka] and R 1 is C1 -C 6 alkyl, aryl, heteroaryl, or heterocycloalkyl; 2 are independently F, Cl, Br, I, CN, NO 2 , C 1 -C 6 In some embodiments, R is selected from alkyl, aryl, heteroaryl, or heterocycloalkyl, and n is 0, 1, 2, 3, or 4. 2 are independently F, Cl, Br, I, CN, NO 2 , C 1 -C 6 In some embodiments, R is selected from alkyl, aryl, or heteroaryl. 2 are independently F, Cl, Br, I, CN, and C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I, and C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I or C 1 -C 6 In some embodiments, n is selected from 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 1 -C 6 In some embodiments, R is an alkyl, aryl, heteroaryl, or heterocycloalkyl. 1 is C 1 -C 6 In some embodiments, R 1 CH 2 CH 3 In some embodiments, R 1 CH 3In some embodiments, the compound of formula (IIa) is [ka] It is.

[0055] In some embodiments, the compound of formula (IIa') [ka] and R 1 is C 1 -C 6 alkyl, aryl, heteroaryl, or heterocycloalkyl; 2 are independently F, Cl, Br, I, CN, NO 2 , C 1 -C 6 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 are independently F, Cl, Br, I, CN, NO 2 , C 1 -C 6 In some embodiments, R is selected from alkyl, aryl, or heteroaryl. 2 are independently F, Cl, Br, I, CN, and C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I, and C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I or C 1 -C 6 In some embodiments, Z is selected from: [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 C 1 -C 6 alkyl, aryl, heteroaryl, or heterocycloalkyl, and Z is a sulfonyl leaving group. 1 is C 1 -C 6 In some embodiments, R 1 CH 2 CH 3 In some embodiments, R 1 CH 3 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 C 1 -C 6 alkyl, aryl, heteroaryl, or heterocycloalkyl; 2 are independently F, Cl, Br, I, CN, NO 2 , C 1 -C 6 In some embodiments, R is selected from alkyl, aryl, heteroaryl, or heterocycloalkyl, and n is 0, 1, 2, 3, or 4. 2 are independently F, Cl, Br, I, CN, NO 2 , C 1 -C 6In some embodiments, R is selected from alkyl, aryl, or heteroaryl. 2 are independently F, Cl, Br, I, CN, and C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I, and C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I or C 1 -C 6 In some embodiments, n is selected from 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 1 -C 6 In some embodiments, R is an alkyl, aryl, heteroaryl, or heterocycloalkyl. 1 is C 1 -C 6 In some embodiments, R 1 CH 2 CH 3 In some embodiments, R 1 CH 3 In some embodiments, the compound of formula (IIb) is [ka] It is.

[0057] In some embodiments, the compound of formula (Ic) [ka] and R 3 is C 1 -C 6In some embodiments, R 3 Ha-CH 3 In some embodiments, R 3 Ha-CH 2 CH 3 In some embodiments, R 3 -CH(CH 3 ) 2 In some embodiments, the compound of formula (Ic) is [ka] In some embodiments, the compound of formula (Ic) is [ka] It is.

[0058] In some embodiments, the compound of formula (IIc) [ka] and R 1 is C 1 -C 6 alkyl, aryl, heteroaryl, or heterocycloalkyl; 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. In some embodiments, R 2 are independently F, Cl, Br, I, CN, NO 2 , C 1 -C 6 In some embodiments, R is selected from alkyl, aryl, or heteroaryl. 2 are independently F, Cl, Br, I, CN, and C 1 -C 6In some embodiments, each R 2 are independently F, Cl, Br, I, and C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I or C 1 -C 6 In some embodiments, n is selected from 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 1 -C 6 In some embodiments, R is an alkyl, aryl, heteroaryl, or heterocycloalkyl. 1 is C 1 -C 6 In some embodiments, R 1 CH 2 CH 3 In some embodiments, R 1 CH 3 In some embodiments, the compound of formula (IIc) is [ka] It is.

[0059] In some embodiments, the compound of formula (IId) [ka] and R 1 is C 1 -C 6 alkyl, aryl, heteroaryl, or heterocycloalkyl; 2 are independently F, Cl, Br, I, CN, NO 2 , C 1 -C 6selected from alkyl, aryl, heteroaryl, or heterocycloalkyl; R 3 is C 1 -C 6 alkyl, and n is 0, 1, 2, 3, or 4. In some embodiments, R 2 are independently F, Cl, Br, I, CN, NO 2 , C 1 -C 6 In some embodiments, R is selected from alkyl, aryl, or heteroaryl. 2 are independently F, Cl, Br, I, CN, and C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I, and C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I or C 1 -C 6 In some embodiments, n is selected from 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 C 1 -C 6 is alkyl, R 3 is C 1 -C 6 In some embodiments, R 1 Ha-CH 2 CH 3 In some embodiments, R 1 Ha-CH 3 In some embodiments, R 3 Ha-CH 3 In some embodiments, R 3 Ha-CH 2 CH 3In some embodiments, R 3 -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] It is.

[0060] In some embodiments, the compound of formula (Id) [ka] and R 4 is C 1 -C 6 is alkyl, 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. 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 Ha-CH 3 In some embodiments, R 4 Ha-CH 2 CH 3 In some embodiments, R 4 -CH(CH3 ) 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 C 1 -C 6 alkyl, aryl, heteroaryl, or heterocycloalkyl; 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 is alkyl, R 4 is C 1 -C 6 is alkyl, 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. 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 are independently F, Cl, Br, I, CN, NO 2 , C 1 -C 6 In some embodiments, R is selected from alkyl, aryl, or heteroaryl. 2 are independently F, Cl, Br, I, CN, and C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I, and C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I or C 1 -C 6 In some embodiments, n is selected from 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 C 1 -C 6 is alkyl, R 3 is C 1 -C 6 In some embodiments, R 1 Ha-CH 2 CH 3 In some embodiments, R 1 Ha-CH 3 In some embodiments, R 3 Ha-CH 3 In some embodiments, R 3 Ha-CH 2 CH 3 In some embodiments, R 1 -CH(CH 3) 2 In some embodiments, R 4 Ha-CH 3 In some embodiments, R 4 Ha-CH 2 CH 3 In some embodiments, R 4 -CH(CH 3 ) 2 In some embodiments, R 5 is t-butyloxycarbonyl (Boc). In some embodiments, R 5 is 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] It is.

[0062] In some embodiments, the compound of formula (IIf) [ka] and R 1 is C 1 -C 6 alkyl, aryl, heteroaryl, or heterocycloalkyl; 2 are independently F, Cl, Br, I, CN, NO 2 , C 1 -C 6 selected from alkyl, aryl, heteroaryl, or heterocycloalkyl; R3 is C 1 -C 6 is alkyl, R 4 is C 1 -C 6 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. 4 The carbon atom to which the substituent is attached is in the (S) configuration. In some embodiments, the compound of formula (IIf) [ka] In some embodiments, the compound of formula (IIf) is [ka] In some embodiments, R 2 are independently F, Cl, Br, I, CN, NO 2 , C 1 -C 6 In some embodiments, R is selected from alkyl, aryl, or heteroaryl. 2 are independently F, Cl, Br, I, CN, and C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I, and C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I or C 1 -C 6 In some embodiments, n is selected from 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 C 1 -C6 is alkyl, R 3 is C 1 -C 6 In some embodiments, R 1 Ha-CH 2 CH 3 In some embodiments, R 1 Ha-CH 3 In some embodiments, R 3 Ha-CH 3 In some embodiments, R 3 Ha-CH 2 CH 3 In some embodiments, R 1 -CH(CH 3 ) 2 In some embodiments, R 4 Ha-CH 3 In some embodiments, R 4 Ha-CH 2 CH 3 In some embodiments, R 4 -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] It is.

[0063] In some embodiments, R 1 is C 1 -C 6In some embodiments, R 1 Ha-CH 3 In some embodiments, R 1 Ha-CH 2 CH 3 In some embodiments, R 1 -CH(CH 3 ) 2 It is.

[0064] In some embodiments, each R 2 are independently F, Cl, Br, I, CN, NO 2 , C 1 -C 6 In some embodiments, R is selected from alkyl, aryl, heteroaryl, or heterocycloalkyl. 2 are independently F, Cl, Br, I, CN, NO 2 , C 1 -C 6 In some embodiments, R is selected from alkyl, aryl, or heteroaryl. 2 are independently F, Cl, Br, I, CN, and C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I, and C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I, CN, NO 2 , C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I or C 1 -C 6 In some embodiments, each R 2 are independently F, Cl, Br, I, CN, -CH 3 or -CH 2 CH 3 In some embodiments, each R 2are independently F, Cl, Br, I, -CH 3 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 NO 2 In some embodiments, R 2 is C 1 -C 6 In some embodiments, R 2 CH 3 In some embodiments, R 2 CH 2 CH 3 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 C 1 -C 6 In some embodiments, R 3 Ha-CH 3 In some embodiments, R 3 Ha-CH 2 CH 3 In some embodiments, R 3 -CH(CH 3 ) 2 It is.

[0066] In some embodiments, R 4 is C 1 -C 6 In some embodiments, R 4Ha-CH 3 In some embodiments, R 4 Ha-CH 2 CH 3 In some embodiments, R 4 -CH(CH 3 ) 2 It is.

[0067] In some embodiments, R 5 is an amino protecting group. In some embodiments, R 5 is 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] It 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] Further embodiments are illustrated by the following non-limiting examples. EXAMPLES

[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 done a total of 4 times to give 50 g of yellow oil of epoxy ether.

[0073] 2-Aminoethyl hydrogen sulfate (141 g; 1 mol; 5 equiv.) was placed in a 1 L flask to which 7.5 equiv. of 60% KOH, prepared from 100 g KOH and 67 mL water, was added, followed by 50 g of the 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 methanol and the residue was diluted with water and extracted with ethyl acetate (5 times). The combined extracts were washed with brine (3 times) and MgSO 4 The crude oil was dissolved in 100 mL of ethanol and 50 mL of 4N hydrochloric acid in dioxane diluted with 50 mL of ethyl acetate was added, initially giving a clear solution. The solid hydrochloride salt precipitated within about 2 minutes and 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 assayed at 94.58% S by SFC.

[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 NO 3 Analytical calculated for Cl: C, 57.04; H, 7.36; N, 5.12; Cl, ​​12.95. Found: C, 56.82; H, 6.86; N, 5.00; Cl, ​​12.94.

[0075] Example 2. Synthesis of morpholine analogues 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 new modifications. These included the use of 2-((2-ethoxyphenoxy)methyl)morpholine free base and diisopropylethylamine as base catalysts in the first step, and the use of only 1.0 equivalent of chloroformic acid 2. Intermediate 3 was isolated by extraction and no chromatography was used (to avoid the decomposition observed when 3 was chromatographed on silica gel). Condensation of 3 with Boc-L-valine (4) was carried out by first forming the Cs salt in DMF and carrying out the condensation until intermediate 3 was consumed. The crude 5 was dissolved in ethyl acetate and washed with water and sodium bicarbonate to give 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 gave 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 in an overall yield of 34% (compared to the 22% reported in U.S. Provisional Patent Application No. 63 / 162,671) along with a syrupy liquid mother liquor of approximately 80% purity.

[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 had affected the ratio of diastereoisomers. Thus, a portion of material 6 was hydrolyzed with 1N NaOH and converted 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 of +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] Experimental 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. 2-((2-ethoxyphenoxy)methyl)morpholine free base (1) was obtained as a colorless oil (28.51 g) (theory 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 did not completely dissolve). To the solution was added 41.8 mL (240 mmol) of diisopropylethylamine, resulting in a clear yellow solution. To the solution was added 18.16 g (122 mmol) of 1-chloroethyl chloroformate 2 in 20 mL of dichloromethane 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 extracts were washed twice with brine, twice with 2N HCl (ensuring that the pH of the aqueous phase was pH 2), and again with brine, bicarbonate, and brine. The extracts were 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 above crude chloroethyl carbamate 3 (42.81 g) 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 extracts were washed successively with sodium bicarbonate (2 times), brine, 1N 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 63.95 g of a yellow oil (theory = 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 4N HCl in dioxane was added. A brown solution formed and was stirred at room temperature for 3 hours, at which time 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 and then in the freezer for 2 days. A second crop of 2.3 g was obtained by filtration as before. The solid material was purified by HPLC (Fast (10-70% CH 3 CN / 0.075% TFA / H 2 0) 15 min) gave a single peak. The mother liquor showed the same major peak plus about 10% 2-((2-ethoxyphenoxy)methyl)morpholine. HPLC was run using the slow method (10-40% CH 3 CN / 0.075% TFA / H 20) 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 ratio of peak 2 to peak 1 of approximately 4:1, indicating that the two peaks were different diastereomers. This was established 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 a water-acid-base extraction by dissolving the mother liquor in 50 mL of ethyl acetate, washing with water, then 1N HCl (2 times). The ethyl acetate layer contained 2-((2-ethoxyphenoxy)methyl)morpholine, unreacted BOC compound 5, and traces of the desired compound. The HCl solution was primarily the desired amine 6 HCl salt, some 2-((2-ethoxyphenoxy)methyl)morpholine, and traces of impurities. This solution was made alkaline with sodium bicarbonate, extracted with dichloromethane (3 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 very 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 ethyl acetate and extracted three times with 1N HCl. The aqueous HCl extract was then rewashed twice with ethyl acetate (100 mL) and the aqueous HCl phase was extracted into dichloromethane (100 mL three times). The dichloromethane extract was washed with 50 mL of 1N HCl and the solution was reextracted 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 way 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 treatment was carried out on 42 g of mother liquor from another run. This process involved only one HCl treatment but more solvent was used. In that variation, 42 g of mother liquor was dissolved in 300 mL of ethyl acetate and extracted twice with 200 mL of 1N HCl. The HCl water 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 N 2 O 7 [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 late eluting peak. The preparative separation method was a Thar 350 preparative SFC (SFC-23) with a ChiralCel column, OD 300 × 50 mm, I.D 10 μm, and mobile phase A was CO. 2 A was ethanol (0.1% NH3H2O), B was ethanol (0.1% NH3H2O), gradient: B 30%, flow rate: 200 mL / min, back pressure: 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 was CO 2 , B was performed in ethanol (0.05% DEA) / gradient: B5-40% / flow rate: 2.5mL / min / back pressure: 100 bar / column temperature: 35°C / wavelength: 220 nm. The (S)-isomer was obtained with an enantiomeric excess of 99.46%. In the subsequent process, the HCl salt was first converted to the free base using ammonium hydroxide, extracted into ethyl acetate, evaporated to an oil, and then subjected to preparative SFC as described above. This gave a sharper peak than the SFC of the HCl salt.

[0088] Example 3. Synthesis of morpholine analogues 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 convention for compounds described in Steps 1 to 3 below corresponds 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 keeping the solution at 0° C. for 30 min and the solution was stirred for an additional 1.5 h. The mixture was extracted 4 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. 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 NO 3 [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 did not completely dissolve). To the solution was added 17.5 mL (100 mmol) of diisopropylethylamine, resulting in a clear yellow solution. To the solution was added 7.15 g (50 mmol) of 1-chloroethyl chloroformate 2 dissolved in 10 mL of dichloromethane 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 extracts were washed twice with brine, twice with 2N HCl (ensuring that the pH of the aqueous phase was pH 2), and again with brine, bicarbonate, and brine. The extracts were 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 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 ClNNaO 5 [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. The solution was stirred at room temperature for 30 min, and then 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 extracts were washed successively with sodium bicarbonate (2 times), brine, 1N 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 N 2 NaO 9 [M+Na] + :547.

[0092] Step 3. [(S)-1-Amino-2-methylbutoxy]methyl 2-[(o-ethoxyphenoxy)-methyl]-4-morpholinecarboxylate, hydrochloride (A). The above BOC product 5 (26.2 g, 50 mmol) was dissolved in 60 mL of ethyl acetate and 50 mL of 4N HCl in dioxane (200 mmol) was added. A brown solution formed and was stirred at room temperature for 3 h 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+H425) 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 1N HCl. The HCl layer (500 mL) was extracted twice with 300 mL of dichloromethane and the combined extracts were washed with Na 2 SO 4 The mixture was dried over ice and evaporated to give 32 g of a viscous oil (MS M+H425). 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 61.5 g of compound A as an off-white sticky solid (HPLC purity, 100%). LC-MS: 21 H 32 N 2 O 7 [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 set forth 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-methylbutoxy]-2-methylpropyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate, hydrochloride (Compound B) is similar to that 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 (Cs 2 CO 3) was 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 oil bath at 80 °C for 1.5 h under N 2 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 with brine, NaHCO 3 (2 times), Brine, 1N HCl, Brine, NaHCO 3 and brine, followed by washing with MgSO 4 Drying on ice and evaporation gave 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 4N HCl in dioxane. The solution was stirred at room temperature for 4 hours, 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 give 59 g of compound B as a yellow oil. The batches were combined and dissolved in 400 mL of ethyl acetate. Hexanes (300 mL) was then added and the solution was extracted with 400 mL (2 times) and 300 mL (2 times) 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 and diluted with MgSO 4 The oil was dried over ice, treated with Norit and evaporated. The oil was dissolved in 140 mL of acetonitrile, 350 mL of water was added and the solution was then lyophilized to give 60.2 g of 1-[(S)-2-amino-3-methylbutyloxy]-2-methylpropyl(S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinylcarboxylate hydrochloride (compound B) as a white solid. (HPLC 98.9%; LC-MS: C 23 H 36 N 2 O 7 [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 process for the synthesis of compound B was repeated, except that N-BOC-D-Val was used for coupling to the chloro compound 3 to give intermediate 6. Deprotection of 6 on a 100 mmol scale was accomplished using 110 mL of 4N 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 1N HCl. The HCl layer was washed with 400 mL of 50:50 ethyl acetate:hexane before being extracted with a total of 2 L of dichloromethane. The dichloromethane extracts were washed with Na 2 SO 4After drying on a kettle and evaporation, 76.88 g of crude 1-((D-valyl)oxy)-2-methylpropyl(2S)-2-((2-ethoxyphenoxy)methyl)morpholin-4-carboxylate (compound C) was obtained as the HCl salt. The crude salt (76 g) was dissolved in 200 mL acetonitrile and 200 mL water, treated with Norit, filtered through Celite, and lyophilized to obtain 65.1 g of 1-[(R)-2-amino-3-methylbutyloxy]-2-methylpropyl(S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinylcarboxylate hydrochloride (compound C) as a white solid. (HPLC 99.81%; LC-MS: C 23 H 36 N 2 O 7 [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 set forth 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) of the 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 set forth 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 does 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 are precedented. In our route, these syntheses use chiral epichlorohydrin as the source of the S-enantiomer. One route that seemed most 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). On this basis, 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 a salt of a morpholine derivative 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 about 2 min and held at about 3° C. for 90 min, then warmed to room temperature and stirred for 1 h. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (50 mL), 1N HCl (50 mL), bicarbonate (50 mL) and brine (50 mL), dried over sodium sulfate, evaporated on a rotary evaporator and evaporated on a vacuum pump overnight. The residue was dissolved in acetonitrile (50 mL) and washed with hexanes (3×100 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 (2×100 mL), bicarbonate (75 mL), 1N HCl (2×100 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 4N 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 1N HCl (2×70 mL). The HCl layer was extracted with dichloromethane (1×100 mL, 1×50 mL). HPLC of a sample of the extract showed a purity of 96.6%. The dichloromethane layer was washed with 1N 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-methylbutyroxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl (11) without unreacted (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine and without by-products from the reaction of benzyl chloride with N-Boc-L-lysine (9). This resulted in a product of improved 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-methylbutyroxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl (11) represents an overall yield of 79.2%. LC-MS:C 21 H 32 N2O 7 [M+H] +:425. The product 1-[(S)-2-amino-3-methylbutyroxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (11) is a 1:1 mixture of diastereomers at the acetal center. One of the isomers (which elutes faster on reversed-phase HPLC) can be easily obtained as a solid and recrystallized from ethanol / MTBE or ethyl acetate to provide highly pure material, with a recovery of about 85% of the theoretical amount. Further work showed that the solid HCl salt could be recrystallized from isopropanol to give thin, needle-like crystals. The liquid, slower-eluting isomer could not be crystallized as the HCl salt despite multiple attempts in different solvent systems. The two diastereoisomers may have different conformations that favor the crystallization of the faster-eluting one. The recrystallized HCl salt forms needle-like crystals that appear too thin to determine an X-ray structure. 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 experience with isolating the free base by treatment of the HCl salt with 1N NaOH had 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 gave a solution of the free base that remained stable. 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 so that the various salts of each diastereomer could be evaluated separately. These isomers were converted separately to the free base and then to the p-toluenesulfonate salt, both of which gave crystalline solids. Attempts to crystallize the isomeric mixture of tosyl salts were unsuccessful. Overall, it appears that the tosylate salts of the individual diastereoisomers can be prepared and crystallized, followed by a 1:1 blend to give the appropriate product.

[0111] Salt synthesis 1.152 g (2.5 mmol) of the mixed diastereomeric HCl salt was dissolved (immediately) 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 left 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 HCl salt was obtained in the first crop (84.5% of theory). 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 left at room temperature overnight, but no solid was obtained.

[0112] The mixture of diastereoisomers of the HCl salts (1.15 g, 2 mmol) was dissolved in 3.5 mL of ethyl acetate and seeded. Crystals formed within 1 h, so the solvent was removed by pipette and 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 from 3.5 mL of isopropanol overnight 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, so a further 0.5 mL of ethyl acetate was added and the mixture was warmed to dissolve and allowed to stand overnight. More solid was obtained, but HPLC showed it was a second crop of the faster eluting isomer and the mother liquor was only liquid for 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. A dichloromethane solution of the free base obtained from 593.9 mg (1.29 mmol) of the liquid HCl isomer mother liquor was then treated with 1.5 mL of 1N methanesulfonic acid in methanol. The solution was diluted with 2 mL of dichloromethane and washed once with 3 mL of water. The salt precipitated upon evaporation of the solvent, 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). It was then dissolved in isopropanol (0.5 mL) and left 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 no 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), with brine, dried over magnesium sulfate, evaporated (rotary evaporator with bath below 30° C.) and dried under vacuum for 30 min to give the free base. Ethyl acetate (2 mL) was added followed by 0.5 mL of ethanol and 78.3 mg of p-toluenesulfonic acid monohydrate in 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 give a sticky foam. The material was dissolved in ethyl acetate (2 mL) and hexanes (approximately 2 mL) were added until just cloudy. Crystals formed on standing and the mixture was allowed to stand over the weekend to give a lot 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 at room temperature overnight to form the crystalline tosylate salt. The solvent was removed by pipette, the solid was washed with 1:1 ethyl acetate:hexane, and the solid was dried to give 345.8 mg of the 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 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 turbid and seed crystals of the pure enantiomers of the crystalline tosylate salt were added. TLC (9:1 dichloromethane:methanol) of the mixture of tosyl salts 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 other solvents (isopropanol, MTBE) were also tried, no crystals of either diastereomer formed.

[0119] Example 7. Final assignment of chirality for (S)-2-((2-ethoxyphenoxy)methyl)morpholine The 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 older literature relating the absolute configuration of propranolol and was established by correlation with S-lactate and by circular dichroism spectroscopy (Howe, et al., J. Med. Chem., 1976, 19, 1074.). As (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] No X-ray structure has been reported for the (S)-2-((2-ethoxyphenoxy)methyl)morpholine salt, but the racemic material has been crystallized and the 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 determination of the absolute chiral structure). Crystals obtained from these salts were very thin needle-like or flocculent solids. The best sample (HBr salt, needle) was subjected to X-ray, but the needle was too thin for X-ray experiments.

[0121] As no suitable crystals could 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) generated 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 gave large plate-like crystal forms. 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 confirms all prior assumptions that the S-isomer of 2-((2-ethoxyphenoxy)methyl)morpholine is the biologically potent isomer. It also confirms that this (S)-isomer is the configuration isolated from the separation procedure of Howe et al., is the same isomer as the slow-moving peak in chiral SFC, and is the isomer from which racemic 2-((2-ethoxyphenoxy)methyl)morpholine was separated to produce large amounts of (S)-2-((2-ethoxyphenoxy)methyl)morpholine for prodrug experiments. These results and 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-methylbutyroxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl (12) via a new route (Scheme III) proceeds via ring opening of (S)-(+)-epichlorohydrin (2, source of chirality) from N-benzylethanolamine (1) to form 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 via the new route affords greater than 99% of the (S)-isomer.

[0125] Experimental 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 addition and evaporation of toluene 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% CH 3 CN;H 2 O / 0.075% TFA), the main peak was observed at 6.23 minutes (purity 64%).

[0126] Step 2: Crude chlorohydrin 3 (155 g) was dissolved in 300 ml MTBE. To the solution was added 2.4 g tetrabutylammonium hydrogen sulfate and a solution of 25.2 g (630 mmol) sodium hydroxide in 48 ml water. The mixture was stirred at room temperature under nitrogen for 1.5 h. The layers were separated and the aqueous layer was extracted with 100 ml MTBE. The combined extracts were dried over magnesium sulfate, rotary evaporated, and then dried at room temperature under high vacuum for 3 h. 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 min (64.3%). LC-MS: C 12 H 17 NO 2 [M+H] + :208.17.4 1 The 1 H NMR spectrum is shown in Figure 2, A to 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 min, resulting in a temperature increase from room temperature to 34° C. The mixture was stirred and cooled to 32° C. over 30 min. The mixture was then gradually heated (heating mantle) to increase the internal temperature to 110° C. over 1 h and held at 110° C. for 1 h 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 min, then extracted twice with 100 ml of dichloromethane, and 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 was pH 3). The mixture was stirred for 10 min, the organic layer was separated, and then washed twice with 1N HCl (100 ml saturated with NaCl) (to remove cyclic amine by-products) and then twice with brine. The organic phase was then treated with 2N NaOH until the pH was >10, stirred for 10 min, 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 NO 4 [M+H] + :346.24.6 1 The 1 H NMR spectrum is shown in Figure 5, A to B.

[0128] Step 4: Diol 6 (149 g) was dissolved in 400 ml toluene and 4.92 g (22 mmol) benzyltriethylammonium chloride was added. Under mechanical stirring, 103.65 g sodium hydroxide beads (2.6 mol) were added. The temperature was allowed to rise 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 in portions over 1 h while cooling in an ice bath to maintain the internal temperature at 25±2° C., followed by stirring at room temperature for 1.5 h. The mixture was poured into 500 ml cold water, stirred for 20 min, and the layers were separated. The aqueous phase was extracted 3 times with 150 ml toluene and the extracts were washed 6 times with 150 ml 2N NaOH, with brine (2 times) 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: 20 H 25 NO 3 [M+H] + :328.28.6 1 The 1 H NMR spectrum is shown in Figure 6, A to B.

[0129] (S)-4-Benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (160 g) was dissolved in 130 ml ethyl acetate and the solution cooled in an ice bath. To the solution was added 130 ml 4N HCl in dioxane and the solution was stirred for 20 minutes before the solvent was rotary evaporated to give 207 g of the salt 7·HCl as an orange oil. 40 ml ethanol was added to the crude salt and the mixture was warmed to dissolve before adding 100 ml ethyl acetate followed by 7.8 ml water. The solution was seeded with crystalline HCl salt of 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), with 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 a yield of 21.8%. 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-methylbutyroxy]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 in the course of 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 synthesized 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) and the benzyl chloride was removed to form the 1-chloroethyl carbamate 9. The reaction with (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine was very fast even at room temperature, and the carbamate 9 did not convert to 2-((2-ethoxyphenoxy)methyl)morpholine under the conditions. In early experiments, the crude product was extracted with a hexane / acetonitrile solvent extraction to remove the benzyl chloride formed during the removal of the benzyl chloride from 9. An improved method (described in detail below) was discovered in which triethylamine was added to the mixture to react with the benzyl chloride by-product to form a water-soluble quaternary salt called benzyltriethylammonium chloride, which was 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×) and 200 ml (1×) of dichloromethane. The solvent was evaporated to give 32.7 g of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine free base.

[0137] Experimental 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 min, and the solution was immersed in N 2 After stirring for 2 hours under reduced pressure, the mixture was allowed to warm to room temperature and stirred for an additional hour. To remove the by-product benzyl chloride, triethylamine (30.3 g, 300 mol) in 25 mL of dichloromethane was slowly added at room temperature over 30 minutes. 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, and then diluted with Na 2 SO 4 The mixture was dried over ice, decolorized with Norit A, filtered through Celite, and evaporated to give 35 g of chlorocarbamate (9). LC-MS:16 H 22 ClNO 5 Na[M+Na] + :366.12.

[0138] Step 6: N-Boc-L-valine (34.32 g, 160 mmol) was dissolved in 125 ml DMF and cesium carbonate (26 g, 80 mmol) was added in portions. The mixture was stirred at room temperature for 30 min, then crude chlorocarbamate 9 (35 g) in 75 ml DMF was added at room temperature and the mixture was stirred at 85° C. for 1 h and then cooled to room temperature. Ethyl acetate (250 ml) was added and the solution was washed with 150 ml water (2 times), 125 ml bicarbonate (1 time), 250 ml 1N HCl (2 times) and 125 ml brine (1 time) and NaCl was added. 2 SO 4 The mixture was dried over 100 ml 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: 26 H 40 N 2 O 9 Na[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 give 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-methylbutyroxy]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-methylbutyroxy]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 washed with Na 2 SO 4 The mixture was dried over 100 ml of water and evaporated to give 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate·HCl (12) 40 g. LC-MS: 21 H 32 N 2 O 7 [M+H] + :425.29. 12 1 The 1 H NMR spectrum is shown in Figure 7A to B.

[0141] 1-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (11) (91 g) was then treated with 4N HCl in dioxane as 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 (emulsion allowed to stand overnight) which was lyophilized separately.

[0142] Multiple lots of 1-[(S)-2-amino-3-methylbutyroxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate·HCl (12, 18 g, 40 g, 62 g) were combined (total 120 g) and dissolved in 200 mL acetonitrile and 400 mL water. The solution was decolorized with Norit, filtered through Celite, and then lyophilized to give a total of 112.92 g of the product 1-[(S)-2-amino-3-methylbutyroxy]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 give 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] Although 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 terms may be used, unless otherwise indicated, they are used in a general and descriptive sense only and not for purposes of limitation, and therefore the claims are not so limited. Moreover, those skilled in the art will recognize that certain steps of the methods described herein may be ordered in different orders or steps may be combined. It is therefore intended that the appended claims not be limited to the specific embodiments disclosed herein.

Claims

1. Morpholine derivatives of formula (IIb) 【Chemistry 1】 or a pharma- ceutically 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 produce a compound of the 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 the compound of formula 【Chemistry 6】 and forming a diol compound of (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 (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; ２ are independently F, Cl, Br, I, CN, NO ２ , C １ -C ６ The method of any of the preceding claims, wherein n is selected from alkyl, aryl, heteroaryl or heterocycloalkyl; and n is 0, 1, 2, 3 or 4.

2. Morpholine derivatives of formula (IIe) 【Chemistry 9】 or a pharma- ceutically acceptable salt thereof, the method comprising: (e) reacting the N-benzyl-protected morpholine compound of claim 1 with a compound of the formula 【Chemistry 10】 contacting the compound with a chloroformate of formula 【Chemistry 11】 which upon heating loses benzyl chloride to form an intermediate N-benzyl chlorocarbamate salt of the formula 【Chemistry 12】 The method includes forming a compound of formula (1), R １ is C １ -C ６ alkyl, aryl, heteroaryl, or heterocycloalkyl; 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.

3. Furthermore, (h) Formula 【Chemistry 13】 Addition of a chlorocarbamate compound (IId) to a metal salt of an amino acid derivative of the formula: 【Chemistry 14】 forming a protected amine of R １ is C １ -C ６ alkyl, aryl, heteroaryl, or heterocycloalkyl; 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, R ４ is C １ -C ６ alkyl, R ５ The method of claim 1 or 2, wherein is an amino protecting group and n is 0, 1, 2, 3 or 4.

4. Furthermore, (i) contacting the protected amine (IIe) with an acid to obtain a morpholine derivative (IIf) as an acid salt. 【Chemistry 15】 providing R １ is C １ -C ６ alkyl, aryl, heteroaryl, or heterocycloalkyl; 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, R ４ is C １ -C ６ alkyl, R ５ The method of any one of claims 1 to 3, wherein: is an amino protecting group; and n is 0, 1, 2, 3 or 4.

5. 5. The method of claim 4, comprising forming the free base of the morpholine derivative (IIf) with a mild base and exchanging one salt for another by treatment with another acid.

6. A method for preparing a morpholine derivative or a pharma- ceutically acceptable salt thereof, the method comprising the steps of: (a) Formula 【Chemistry 16】 is reacted with (S)-(+)-epichlorohydrin to give a compound of the formula 【Chemistry 17】 and forming a chlorohydrin compound of the formula: (b) contacting the chlorohydrin compound with a base and a phase transfer catalyst to produce a compound of the formula 【Chemistry 18】 and forming an epoxide compound of (c) reacting the epoxide compound with a base and a reaction product of the formula 【Chemistry 19】 contacting the compound of formula 【Chemistry 20】 and forming a diol compound of (d) contacting the diol compound with a base, followed by the addition of a sulfonyl halide compound to produce a compound of formula 【Chemistry 21】 wherein Z is a sulfonyl leaving group, which cyclizes in situ to form an intermediate sulfonate of the formula 【Chemical 22】 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 23】 contacting the compound with a chloroformate of formula 【Chemistry 24】 which upon heating loses benzyl chloride to form an intermediate N-benzyl chlorocarbamate salt of the formula 【Chemistry 25】 The forming of (h) Formula 【Chemistry 26】 Addition of a chlorocarbamate compound to a metal salt of an amino acid derivative of the formula: 【Chemical 27】 forming a protected amine of (i) contacting the protected amine (IIe) with an acid to obtain a morpholine derivative (IIf) as an acid salt. 【Chemistry 28】 providing a R １ is C １ -C ６ alkyl, aryl, or heteroaryl; 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, R ４ is C １ -C ６ alkyl, R ５ is an amino protecting group; and n is 0, 1, 2, 3 or 4.

7. 13. The method according to any of the preceding claims, wherein a phase transfer catalyst is used in step (b).

8. 8. The method of claim 7, wherein the phase transfer catalyst is tetrabutylammonium hydrogen sulfate.

9. 13. The method according to any of the preceding claims, wherein the phase transfer catalyst is used in step (d).

10. 10. The method of claim 9, wherein the phase transfer catalyst is benzyltriethylammonium chloride.

11. 11. The method of claim 10, wherein the product contains greater than 60% of the (S) enantiomer and the (S)-HCl salt can be crystallized to obtain an HCl salt containing greater than 90% of one enantiomer.

12. 2. 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.

13. The method of claim 12, wherein the sulfonyl halide compound is p-toluenesulfonyl chloride.

14. 13. The method according to any of the preceding claims, wherein the cyclization is carried out using NaOH.

15. 2. 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-products before carrying out the next step.

16. 2. The method according to any of the preceding claims, wherein the metal salt in step (h) is a cesium salt.

17. 2. A method according to any of the preceding claims, wherein the metal compound of step (h) is cesium carbonate.

18. 2. The method of any preceding claim, wherein step (a) further comprises an organic solvent.

19. 20. The method of claim 18, wherein step (a) further comprises heating to a temperature of at least 30°C.

20. 13. The method of any preceding claim, wherein step (b) is carried out at room temperature.

21. R １ is -CH ３ or -CH ２ CH ３ 2. A method according to any preceding claim, wherein:

22. Each R ２ are independently -F, -Cl, -Br, -I, or C １ -C ６ 2. The method of any preceding claim, wherein the alkyl group is selected from the group consisting of alkyl, aryl, aryl and alkyl.

23. R ３ is -CH ３ or isopropyl.

24. R ４ The method of any of the preceding claims, wherein is isopropyl.

25. R ５ The method according to any of the preceding claims, wherein is tert-butoxycarbonyl (Boc).

26. 10. The method of any preceding claim, wherein n is 0.

27. The morpholine derivative from step (i) has the following formula: ​ or a pharma- ceutically acceptable salt thereof.

28. The morpholine derivative from step (i) has the following formula: 【Chemistry 30】 or a pharma- ceutically acceptable salt thereof.

29. The morpholine derivative from step (i) has the following formula: 【Chemistry 31】 or a pharma- ceutically acceptable salt thereof.

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