Method for preparing substituted morpholine derivatives

Abstract

Provided herein are methods for preparing derivatives and prodrugs of substituted morpholines or pharmaceutically acceptable salts thereof. Also provided are methods for preparing derivatives and prodrugs of substituted morpholines having the following chemical structure:

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 321,423, filed on March 18, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] Described herein are methods for preparing derivatives and prodrugs of substituted morpholines or pharmaceutically acceptable salts thereof. Background Art

[0004] The known compound 2-((2-ethoxyphenoxy)methyl)morpholine has several promising pharmacological uses, including the treatment of depression, nocturnal enuresis, narcolepsy, sleep disorders, and alcoholism. 2-((2-ethoxyphenoxy)methyl)morpholine was previously marketed in several European countries for the treatment of major depressive disorder (MDD). It is an inhibitor of norepinephrine ("NRI") reuptake, but can also enhance the release of serotonin from neuronal stores. However, treatment with 2-((2-ethoxyphenoxy)methyl)morpholine is associated with numerous side effects, including nausea, vomiting, loss of appetite, increased erythrocyte sedimentation, EKG and EEG abnormalities, upper abdominal pain, diarrhea, constipation, dizziness, orthostatic hypotension, lower extremity edema, dysarthria, tremor, psychomotor agitation, confusion, inappropriate secretion of antidiuretic hormone, increased transaminases, and seizures.

[0005] 2-((2-ethoxyphenoxy)methyl)morpholine is a chiral molecule whose desirable biological properties are associated with the (S)-enantiomer, which is known to exhibit five times the pharmacological activity compared to the (R)-(+)-isomer. For example, see "Optical Isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4-oxazine (viloxazine) and Related Compounds" (Journal of Medicinal Chemistry, January 9, 1976, 19(8); 1074), which discloses the preparation of optical isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4-oxazine and 2-(3-methoxyphenoxymethyl)tetrahydro-1,4-oxazine and specifies the absolute configuration. The optical isomers of viloxazine analogs with known configurations were synthesized by resolving the intermediate 4-benzyl-2-(p-toluenesulfonyloxymethyl)tetrahydro-1,4-oxazine isomers.

[0006] To minimize the side effects associated with 2-((2-ethoxyphenoxy)methyl)morpholine, chemists have synthesized derivatives and analogs that retain the pharmacological properties of 2-((2-ethoxyphenoxy)methyl)morpholine, as shown in U.S. Application Serial No. 63 / 162,671, the entire contents of which are incorporated herein. Prodrugs are a class of derivatives that, in many cases, have little or no pharmacological activity and are converted into therapeutically active compounds in vivo. In some cases, prodrugs themselves can have biological activity. Prodrug activation can occur through enzymatic or nonenzymatic cleavage of a temporary bond between the carrier and the drug molecule, or a combination of both, either sequentially or simultaneously. Additional methods for synthesizing 2-((2-ethoxyphenoxy)methyl)morpholine prodrugs would be beneficial.

[0007] Prodrugs can provide compounds with superior physicochemical properties than the parent molecule, thereby overcoming obstacles to absorption, distribution, metabolism, excretion and toxicity (ADMET). These prodrugs may show improved absorption, solubility, permeability, stability and pharmacokinetic properties. Prodrugs may exhibit longer half-lives compared to the parent molecule. Prodrugs can be prepared by coupling the parent drug to a prodrug moiety that modifies the parent drug at a reactive site, and the prodrug can be converted to the parent drug by an enzymatic or non-enzymatic process. The reactive sites on the drug may include, but are not limited to, hydroxyl, carboxyl, amino, heteroamino, thiol, amide and related reactive groups. These couplings form prodrugs having alkyl, aralkyl, acyl, carbamoyl, acyloxy and moieties with combined groups (e.g., diacyl acetals or acyl hydroxyalkyls). Other examples are described in the literature (see Yang, Liu et al., Acta Pharmaceutica Sinica B 2011: 1(3), 143-159 and references described therein).

[0008] Newly synthesized 2-((2-ethoxyphenoxy)methyl)morpholine analogs, prodrugs, enantiomers, and derivatives (derivatives of the morpholineamine group in the structure of 2-((2-ethoxyphenoxy)methyl)morpholine) produce chemically stable compounds that serve as novel compounds and intermediates. These 2-((2-ethoxyphenoxy)methyl)morpholine analogs, enantiomers, prodrugs, and derivatives can be used in pharmaceutical compositions and for treating central nervous system (CNS) disorders, or as intermediates in their preparation.

[0009] Previously disclosed syntheses of these 2-((2-ethoxyphenoxy)methyl)morpholine analogs, prodrugs, and derivatives suffer from numerous drawbacks, such as low reaction yields, the presence of reaction byproducts, difficulty separating enantiomers, and the presence of impurities in the resulting products. Effectively eliminating or removing impurities, particularly those with genotoxic or other toxic properties, is crucial to ensuring drug safety. Disclosed herein are solutions to these and other related problems.

[0010] It would also be desirable to prepare the (S)-enantiomer of 2-((2-ethoxyphenoxy)-methyl)morpholine analogs, prodrugs, and derivatives by routes that do not require resolution of the precursor, and the methods described herein provide a solution to this problem. Summary of the Invention

[0011] This article provides new and improved methods for preparing morpholine derivatives and their various salts, as well as methods for preparing novel intermediate reaction products. Also provided are methods for synthesizing novel intermediates of morpholine derivatives and methods for identifying and characterizing the same.

[0012] In one aspect, the present invention provides a method for producing a morpholine derivative of formula (IIb) or a pharmaceutically acceptable salt thereof: The method comprises:

[0013] (a) making the following compound:

[0014]

[0015] Reacts with (S)-(+)-epichlorohydrin to form a chlorohydrin compound of the formula:

[0016]

[0017] (b) contacting the chlorohydrin compound with a base and a phase transfer catalyst to form an epoxide compound of the formula:

[0018]

[0019] (c) contacting the epoxy compound with a base and a compound of the formula: To form the diol compound of the following formula:

[0020]

[0021] (d) contacting the diol compound with a base and then adding a sulfonyl halide to form an intermediate sulfonate ester of the formula:

[0022] Wherein Z is a sulfonyl leaving group,

[0023] The intermediate sulfonate is cyclized in situ to obtain an N-benzyl-protected morpholine compound of the following formula:

[0024] as well as

[0025] (e) forming an HCl salt of the compound of formula IIb and recrystallizing it to obtain a highly pure (S)-enantiomer in the form of an HCl salt;

[0026] where R 1 is C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl; and each R 2 independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl; and n is 0, 1, 2, 3 or 4.

[0027] In one embodiment, the present invention provides a method for producing a morpholine derivative of formula (IIb) or a pharmaceutically acceptable salt thereof: The method comprises:

[0028] (a) making the following compound:

[0029]

[0030] Reacts with (S)-(+)-epichlorohydrin to form a chlorohydrin compound of the formula

[0031]

[0032] (b) contacting the chlorohydrin compound with a base and a phase transfer catalyst to form an epoxide compound of the formula:

[0033]

[0034] (c) contacting the epoxy compound with a base and a compound of the formula: To form the diol compound of the following formula:

[0035]

[0036] (d) contacting the diol compound with a base and then adding a sulfonyl halide to form an intermediate sulfonate ester of the formula:

[0037] Wherein Z is a sulfonyl leaving group,

[0038] The intermediate sulfonate is cyclized in situ to obtain an N-benzyl-protected morpholine compound of the following formula:

[0039] as well as

[0040] (e) forming an HCl salt of the compound of formula IIb and recrystallizing it to obtain a highly pure (S)-enantiomer in the form of an HCl salt;

[0041] where R 1 is C1-C6 alkyl, aryl or heteroaryl; and each R 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl or heteroaryl; and n is 0, 1, 2, 3 or 4.

[0042] In another aspect, the present invention provides a method for producing a morpholine derivative or prodrug of formula (IIf) or a pharmaceutically acceptable salt thereof: The method comprises:

[0043] (a) making the following compound:

[0044]

[0045] Reacts with (S)-(+)-epichlorohydrin to form a chlorohydrin compound of the formula:

[0046]

[0047] (b) contacting the chlorohydrin compound with a base and a phase transfer catalyst to form an epoxide compound of the formula:

[0048]

[0049] (c) contacting the epoxy compound with a base and a compound of the formula: To form the diol compound of the following formula:

[0050]

[0051] (d) contacting the diol compound with a base and then adding a sulfonyl halide compound to form an intermediate sulfonate ester of the formula:

[0052] Wherein Z is a sulfonyl leaving group,

[0053] The intermediate sulfonate ester is cyclized in situ to form an N-benzyl protected morpholine compound of the formula:

[0054]

[0055] (e) forming an HCl salt of the compound of formula (IIb) and recrystallizing it to obtain a highly pure (S)-enantiomer in the form of an HCl salt;

[0056] (f) converting the HCl salt of the compound (IIb) into a free base;

[0057] (g) contacting the N-benzyl protected morpholine compound with a chloroformate of the formula: To form the intermediate N-benzylchlorocarbamate of the following formula:

[0058]

[0059] Upon heating, the benzyl chloride is lost to give the following compound:

[0060]

[0061] (h) adding the chlorocarbamate compound to a metal salt of an amino acid derivative of the following formula: wherein the amino acid derivative has been pretreated with a metal compound carbonate to form a protected amine of the formula:

[0062] as well as

[0063] (i) contacting the protected amine with an acid to provide the morpholine derivative having the formula:

[0064]

[0065] where R 1 is a C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl group; each R 2 R is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl; 3 is a C1-C6 alkyl group, R 4 is a C1-C6 alkyl group, R 5 is an amino protecting group; and n is 0, 1, 2, 3 or 4.

[0066] In one embodiment, the present invention provides a method for making a morpholine derivative or prodrug of formula (IIf) or a pharmaceutically acceptable salt thereof: The method comprises:

[0067] (a) making the following compound:

[0068]

[0069] Reacts with (S)-(+)-epichlorohydrin to form a chlorohydrin compound of the formula:

[0070]

[0071] (b) contacting the chlorohydrin compound with a base and a phase transfer catalyst to form an epoxide compound of the formula:

[0072]

[0073] (c) contacting the epoxy compound with a base and a compound of the formula: To form the diol compound of the following formula:

[0074]

[0075] (d) contacting the diol compound with a base and then adding a sulfonyl halide to form an intermediate sulfonate ester of the formula:

[0076] wherein Z is a sulfonyl leaving group;

[0077] The intermediate sulfonate ester is cyclized in situ to form an N-benzyl protected morpholine compound of the formula:

[0078]

[0079] (e) forming an HCl salt of the compound of formula (IIb) and recrystallizing it to obtain a highly pure (S)-enantiomer in the form of an HCl salt;

[0080] (f) converting the HCl salt of the compound (IIb) into a free base;

[0081] (g) contacting the N-benzyl protected morpholine compound with a chloroformate of the formula: To form the intermediate N-benzyl chlorocarbamate of the formula

[0082]

[0083] Upon heating, the benzyl chloride is lost to give the following compound:

[0084]

[0085] (h) adding the chlorocarbamate compound to a metal salt of an amino acid derivative of the following formula: wherein the amino acid derivative has been pretreated with a metal compound to form a protected amine of the formula:

[0086] as well as

[0087] (i) contacting the protected amine with an acid to provide the morpholine derivative having the formula:

[0088]

[0089] where R 1 is a C1-C6 alkyl, aryl or heteroaryl group; each R 2R is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl or heteroaryl; 3 is a C1-C6 alkyl group, R 4 is a C1-C6 alkyl group, R 5 is an amino protecting group; and n is 0, 1, 2, 3 or 4.

[0090] Additional 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

[0091] Figure 1 Shown is the X-ray structure of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HBr.

[0092] Figure 2 Compound 4 from Example 8 is shown 1 H NMR spectrum.

[0093] Figure 3 Compound 6 from Example 8 is shown 1 H NMR spectrum.

[0094] Figure 4 Compound 7 from Example 8 is shown 1 H NMR spectrum.

[0095] Figure 5 Compound 12 from Example 8 is shown 1 H NMR spectrum.

[0096] Figure 6 The synthetic method for preparing Compound 12 (Compound A) in Example 8 is demonstrated.

[0097] Figure 7 Synthetic methods for preparing compounds B and C are demonstrated. DETAILED DESCRIPTION

[0098] definition

[0099] The following terms are used throughout as defined below.

[0100] As used herein and in the appended claims, unless otherwise indicated herein or the context clearly contradicts, in the context of describing an element (especially in the context of the following claims), singular articles such as "a / an" and "the" and similar references should be interpreted as covering both the singular and the plural. Unless otherwise indicated herein, the description of a range of values ​​herein is intended only to serve as a shorthand method for individually referring to each individual value belonging to the range, and each individual value is incorporated into this specification as if individually described herein. Unless otherwise indicated herein or the context clearly contradicts, all methods described herein can be performed in any suitable order. Unless otherwise stated, any and all examples used, or exemplary language provided herein (e.g., "such as") are only intended to better illustrate the embodiments and do not limit the scope of the claims. The language in this specification should not be interpreted as indicating that any unclaimed element is required.

[0101] As used herein, "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If the use of the term is unclear to one of ordinary skill in the art, "about" will mean up to plus or minus 10% of the particular term, given the context in which it is used.

[0102] Generally speaking, reference to an 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, radioactive isotopes such as tritium, C 14 、P 32 and S 35 The procedures for inserting such labels into the compounds of the present technology will be apparent to those skilled in the art based on the disclosure herein.

[0103] In general, "substituted" refers to an organic group (e.g., an alkyl group) as defined below, in which one or more bonds to hydrogen atoms contained therein are replaced by bonds to non-hydrogen atoms or non-carbon atoms. Substituted groups also include groups in which one or more bonds to carbon or hydrogen atoms are replaced by one or more bonds to heteroatoms (including double or triple bonds). Therefore, unless otherwise indicated, a substituted group is substituted with one or more substituents. In some embodiments, a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituents include: halogen (i.e., F, Cl, Br, and I); hydroxy; alkoxy, alkenyloxy, aryloxy, aralkyloxy, heterocycloalkyl, heterocycloalkyl-alkyl, heterocycloalkyl-oxy, and heterocycloalkylalkyl-oxy; carbonyl (oxo); carboxylate; ester; polyurethane; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; thiol; sulfide; sulfoxide; sulfone; sulfonyl; pentafluorosulfanyl (i.e., SF5), sulfonamide; amine; N-oxide; hydrazine; hydrazide; hydrazone; azide; amide; urea; amidine; guanidine; enamine; imide; isocyanate; isothiocyanate; cyanate; thiocyanate; imine; nitro; nitrile (i.e., CN); and the like.

[0104] As used herein, "alkyl" includes straight and branched chain alkyl groups having 1 to about 20 carbon atoms, and typically having 1 to 12 carbons, or in some embodiments, 1 to 8 carbon atoms. As used herein, "alkyl" 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. Examples of branched chain alkyl groups include, but are not limited to, isopropyl, sec-butyl, tert-butyl, neopentyl, and isopentyl. Representative substituted alkyl groups can be substituted once or multiple times, for example, by amino, sulfanyl, hydroxyl, cyano, alkoxy, and / or halo (such as F, Cl, Br, and I). As used herein, the term "haloalkyl" is an alkyl group with one or more halo groups. In some embodiments, haloalkyl refers to a perhaloalkyl group.

[0105] Cycloalkyl is a cyclic alkyl group, such as but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In some embodiments, cycloalkyl has 3 to 8 ring members, and in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 6 or 7. Cycloalkyl can be substituted or unsubstituted. Cycloalkyl also includes polycyclic cycloalkyl, such as but not limited to norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl and carenyl, and fused ring, such as but not limited to decahydronaphthyl etc. Cycloalkyl also includes rings substituted with straight or branched alkyl as defined above. Representative substituted cycloalkyl groups may be monosubstituted or substituted more than once, such as, but not limited to, 2,2-disubstituted, 2,3-disubstituted, 2,4-disubstituted, 2,5-disubstituted, or 2,6-disubstituted cyclohexyl groups, or monosubstituted, disubstituted, or trisubstituted norbornyl or cycloheptyl groups, which may be substituted, for example, with alkyl, alkoxy, amino, thiol, hydroxy, cyano, and / or halo groups.

[0106] Alkenyl is a straight chain, branched or cyclic alkyl group having 2 to about 20 carbon atoms and also including at least one double bond. In some embodiments, the alkenyl group has 1 to 12 carbons, or typically, has 1 to 8 carbon atoms. The alkenyl group can be substituted or unsubstituted. Alkenyl groups include, for example, vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl and hexadienyl. Alkenyl groups can be substituted similarly to alkyl groups. Divalent alkenyl groups, i.e., alkenyl groups with two points of attachment, include but are not limited to CH-CH=CH2, C=CH2 or C=CHCH3.

[0107] As used herein, "aryl" or "aromatic" groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Aryl groups include monocyclic, bicyclic, and polycyclic ring systems. Therefore, aryl includes, but is not limited to, phenyl, azulenyl, and heptatrienyl, biphenylene, diphenyl, fluorenyl, phenanthrenyl, triphenylene, pyrenyl, naphthacene, chrysene, biphenyl, anthracenyl, indenyl, indanyl, pentalene, and naphthyl. In some embodiments, aryl contains 6-14 carbon atoms, and in other embodiments, the ring portion of the group contains 6 to 12 or even 6-10 carbon atoms. The phrase "aryl" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). Aryl can be substituted or unsubstituted.

[0108] 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 group is a fused ring system, the ring connected to the rest of the molecule has a completely delocalized π electron system. The other rings in the fused ring system may or may not have a completely delocalized π electron system. Examples of heteroaromatic rings include, but are not limited to, furan, thiophene, diazinone, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazine.

[0109] Whenever "hetero" is used, it is intended to mean the designated group, such as alkyl or aryl, in which at least one carbon atom has been replaced by a heteroatom selected from nitrogen, oxygen and sulfur.

[0110] As used herein, "heterocycloalkyl" refers to a ring having one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur in the ring system. The ring may also contain one or more double bonds, as long as they do not form a completely delocalized π electron system in the ring. The ring defined herein can be a stable 3 to 18-membered ring consisting of carbon atoms and one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The heterocycloalkyl of the compounds disclosed in the present invention can be unsubstituted or substituted. When substituted, the substituent can be one or more groups independently selected from the group consisting of: halogen, hydroxyl, protected hydroxyl, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, carboxyl, protected carboxyl, amino, protected amino, carboxamide, protected carboxamide, alkylsulfonamido, and trifluoromethanesulfonamido. "Heterocycloalkyl" can be composed of two or more fused rings (rings sharing two adjacent atoms). When the heterocycloalkyl is a fused ring system, the ring connected to the rest of the molecule is a heterocycloalkyl as defined above. The other ring in the fused ring system can be cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl.

[0111] As used herein, the term "carboxylate" refers to the conjugate base of a carboxylic acid having the chemical formula -COO.

[0112] As used herein, the term "ester" refers to -COOR b - and -C(O)OG groups. bR is 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 of ordinary skill in the art. A detailed 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), and protecting groups can be added or removed using the procedures described therein, and the document is hereby incorporated by reference in its entirety and for any and all purposes, as if fully described herein.

[0113] The term "amide" (or "amido") includes both C- and N-amide groups, namely, C(O)NR c R d and -NRC(O)-R groups. c and R d is independently hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl-alkyl, or heterocycloalkyl group as defined herein. Amide groups thus include, but are not limited to, carbamoyl (-C(O)NH2) and carboxamido (NHC(O)H). In some embodiments, an amide is -NRC(O)-(C 1-5 In some embodiments, the amide is -NHC(O)-alkyl and the group is referred to as a "carbonylamino" group, and in other embodiments, the amide is -NHC(O)-alkyl and the group is referred to as an "alkanoylamino" group.

[0114] As used herein, the term "amine" (or "amino") refers to a -NR e R f Group, where R e and R f is 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 group. In other embodiments, the amine is NH2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.

[0115] 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).

[0116] 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 amino acid. 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 having five amino acids.

[0117] The term "amino acid" is art-recognized and generally refers to a natural or unnatural α or β amino acid. 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, or racemic amino acids.

[0118] As used herein, the term "amino acid residue with a hydrophobic side chain" refers to the following amino acids: alanine (Ala), valine (Val), isoleucine (Ile), leucine (Leu), methionine (Met), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), or unnatural amino acids, including but not limited to norleucine, norvaline, cyclohexylalanine, cyclohexylglycine, cyclopentylglycine, etc. In some embodiments, the amino acid residue with a hydrophobic side chain is valine (Val). In other embodiments, the amino acid residue can 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)).

[0119] The term "acetyl" as used herein refers to a methyl group bonded to a carbonyl group (CH3CO-).

[0120] Pharmaceutically acceptable salts of the compounds described herein are within the scope of the present technology and include acid addition salts or base addition salts that retain the desired pharmacological activity and are not biologically undesirable (e.g., the salt is not overly toxic, allergic, or irritating and is bioavailable). When the compound of the present technology has a basic group (such as, for example, an amino group), it can be formed with inorganic acids (such as hydrochloric acid, boric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (such as alginate, 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 (such as aspartic acid and glutamic acid). When the compound of the present technology has an acidic group (such as, for example, a carboxylic acid group), it can be formed with metals such as alkali metals and alkaline earth metals (such as Na + 、Li + , K + , Ca 2+ Mg 2+ or Zn 2+), ammonia or organic amines (such as dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine or triethanolamine) or basic amino acids (such as arginine, lysine or ornithine) to form salts. Such salts can be prepared in situ during the isolation and purification of the compound, or by reacting the purified compound in the form of a free base or free acid with a suitable acid or base separately and isolating the salt thus formed.

[0121] Unless specific stereochemistry is explicitly indicated, stereoisomers (also referred to as optical isomers) of a compound include all chiral, diastereomeric, and racemic forms of the structure. Thus, as will be apparent from the depictions, the compounds used in the present technology include enriched or resolved optical isomers at any or all asymmetric atoms. Racemic and diastereomeric mixtures, as well as individual optical isomers, can be separated or synthesized to be substantially free of their enantiomeric or diastereomeric partners, and such stereoisomers are within the scope of the present technology.

[0122] The term "pharmaceutically acceptable excipient" refers to those substances that are widely accepted by industry and regulatory agencies, such as those listed in monographs published in, for example, the USP-NF, the Food Chemicals Codex, the Code of Federal Regulations (CFR), the FDA Inactive Ingredient Guide, and in the compendium of 21 CFR parts 182 and 184 that lists substances that are generally regarded as safe (GRAS) food ingredients.

[0123] method

[0124] Provided herein are novel methods for making morpholine derivatives, prodrugs, and pharmaceutically acceptable salts thereof, which improve the synthetic methodology, control the stereochemistry, and reduce impurities, thereby providing materials suitable for pharmaceutical applications.

[0125] In one aspect, provided herein is a method for producing a morpholine derivative of formula (IIb) or a pharmaceutically acceptable salt thereof: The method comprises:

[0126] (a) making the following compound:

[0127]

[0128] Reacts with (S)-(+)-epichlorohydrin to form a chlorohydrin compound of the formula:

[0129]

[0130] (b) contacting the chlorohydrin compound with a base and a phase transfer catalyst to form an epoxide compound of the formula:

[0131]

[0132] (c) contacting the epoxy compound with a base and a compound of the formula: To form the diol compound of the following formula:

[0133] as well as

[0134] (d) contacting the diol compound with a base and then adding a sulfonyl halide compound to form an intermediate sulfonate ester of the formula:

[0135] Wherein Z is a sulfonyl leaving group,

[0136] The intermediate sulfonate is cyclized in situ to obtain an N-benzyl-protected morpholine compound (IIb) of the following formula:

[0137] as well as

[0138] (e) forming an HCl salt of the compound of formula IIb and recrystallizing it to obtain a high-purity (S)-enantiomer HCl salt;

[0139] where R 1 is C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl; and each R 2 independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl; and n is 0, 1, 2, 3 or 4.

[0140] In another aspect, provided herein is a method for producing a morpholine derivative or prodrug or a pharmaceutically acceptable salt thereof, the method comprising:

[0141] (a) making the following compound:

[0142]

[0143] Reacts with (S)-(+)-epichlorohydrin to form a chlorohydrin compound of the formula:

[0144]

[0145] (b) contacting the chlorohydrin compound with a base and a phase transfer catalyst to form an epoxide compound of the formula:

[0146]

[0147] (c) contacting the epoxy compound with a base and a compound of the formula: To form the diol compound of the following formula:

[0148]

[0149] (d) contacting the diol compound with a base and a sulfonyl halide to form an intermediate sulfonate, which cyclizes to form an N-benzyl protected morpholine compound of the formula:

[0150]

[0151] (e) forming an HCl salt of the compound of formula (IIb) and recrystallizing it to obtain a highly pure (S)-enantiomer in the form of an HCl salt; and

[0152] (f) converting the HCl salt of the compound (IIb) into a free base;

[0153] (g) contacting the N-benzyl protected morpholine compound with a chloroformate of the formula: To form the intermediate N-benzylchlorocarbamate of the following formula:

[0154]

[0155] Upon heating, the benzyl chloride is lost to give the following compound:

[0156]

[0157] (h) adding the chlorocarbamate compound to a metal salt of an amino acid derivative of the following formula: wherein the amino acid derivative has been pretreated with a metal compound to form a protected amine of the formula:

[0158] as well as

[0159] (i) contacting the protected amine with an acid to provide the morpholine derivative having the formula:

[0160]

[0161] where R 1 is a C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl group; each R 2 R is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl; 3 is a C1-C6 alkyl group, R 4 is a C1-C6 alkyl group, R 5 is an amino protecting group; and n is 0, 1, 2, 3 or 4.

[0162] For the sake of convenience and without limiting the present invention, the method for producing a morpholine derivative is divided into several steps, each of which is disclosed herein in a number of non-limiting embodiments. These steps include steps a), b), c), d), e), f), g), h), and i) described above.

[0163] The above steps will be considered in more detail below.

[0164] The process of step a) can be advantageously carried out in the presence of a solvent. In some embodiments, the solvent is methanol. Alternatively, the process can also be heated. In embodiments, the reaction is heated to a temperature of about 35°C.

[0165] The process of step b) can be advantageously carried out in the presence of a phase transfer catalyst. The process can be advantageously carried out in the presence of a base. In some embodiments, the base is NaOH. The process can include one or more solvents as part of the solvent system. In some embodiments, the solvent system is a liquid-liquid two-phase system. In some embodiments, the solvent system is a single-phase liquid system. In some embodiments, the liquid-liquid two-phase system comprises water. In some embodiments, the liquid-liquid two-phase system comprises methyl tert-butyl ether (MTBE). The phase transfer catalyst can be selected from quaternary ammonium salts, such as benzyltrimethylammonium salt, tetrabutylammonium salt or other phase transfer catalysts known in the art. In a preferred embodiment, the phase transfer catalyst is tetrabutylammonium hydrogen sulfate. In some embodiments, the process can be operated at room temperature.

[0166] The process of step c) can advantageously be carried out in the presence of a base. In some embodiments, the base is Cs2CO3. In some embodiments, the base can be added in batches. The process can include one or more solvents as part of the solvent system. In some embodiments, the solvent system is a single-phase liquid system. In some embodiments, the solvent is toluene. Alternatively, the process can be heated after the addition of the base is complete. In some embodiments, the process can be heated to a temperature of about 110°C.

[0167] The process of step d) can be advantageously carried out in the presence of a phase transfer catalyst. The process can be carried out in the presence of a base. The base can be solid or liquid. In some embodiments, the base is NaOH. The process can include one or more solvents as part of the solvent system. In some embodiments, the solvent system is a single-phase liquid system. In some embodiments, the solvent is toluene. Alternatively, the process can be heated after the addition of the base is completed. In some embodiments, the process can be heated to a temperature of about 30°C. In some embodiments, the sulfonyl halide compound is selected from the group consisting of p-toluenesulfonyl chloride (toluenesulfonyl chloride), p-bromobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, and methanesulfonyl chloride. In some embodiments, the sulfonyl halide compound is p-toluenesulfonyl chloride (toluenesulfonyl chloride). In addition, after heating for a period of time, the process can be cooled to a lower temperature before adding p-toluenesulfonyl chloride. In some embodiments, the process is cooled to a temperature of about 20°C. In some embodiments, p-toluenesulfonyl chloride is added in batches. The phase transfer catalyst can be a quaternary ammonium salt, such as benzyltrimethylammonium salt, tetrabutylammonium salt, 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 metal 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. The solvent used in this process includes, but is not limited to, ethers, such as methyl tert-butyl ether, aromatic solvents (e.g., toluene), or other suitable solvents. In a preferred embodiment, the solvent is toluene. In one variation, step d) is carried out using a toluene solution of a diol in the presence of a phase transfer catalyst in the presence of a solid or liquid base, wherein the reaction is cooled to 20° C. before adding p-toluenesulfonyl chloride in batches. After completion of the reaction, the reaction mixture can be washed with water and then subjected to post-treatment procedures known in the art. After isolating 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 more than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%. In some embodiments, the HCl salt has an enantiomeric excess of more 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 (eg, Example 8).

[0168] 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 chloroformate is added. In embodiments, the reaction is cooled to a temperature of about 0°C.

[0169] The process of step h) can be advantageously carried out in the presence of a solvent. In some embodiments, the solvent is dimethylformamide (DMF). In some embodiments, the metal salt is a cesium salt, a potassium salt, a silver salt, or a mercury salt. In some embodiments, the metal salt is a cesium salt. In some embodiments, the metal compound is a cesium compound, a potassium compound, a silver compound, or a mercury compound. In some embodiments, the metal compound is a cesium compound. In some embodiments, the metal compound is Cs2CO3, K2CO3, or Ag2CO3. In some embodiments, the metal compound is Cs2CO3. The process can be carried out in the presence of a base. In some embodiments, the base is Cs2CO3. Alternatively, the process can also be heated. In embodiments, the reaction is heated to a temperature of about 85°C.

[0170] The process of step i) can be advantageously carried out in the presence of a solvent. In some embodiments, the solvent is ethyl acetate.

[0171] In some embodiments, the compound of formula (Ia) is where R 1 is a C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl group; each R 2 is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl; and n is 0, 1, 2, 3, or 4. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl or heteroaryl. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl or heteroaryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, C1-C6 alkyl or aryl. 2 is independently selected from F, Cl, Br, I or C1-C6 alkyl. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, the compound of formula (Ia) is where R 1is C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl. 1 is C1-C6 alkyl. In some embodiments, R 1 is CH2CH3. In some embodiments, R 1 is CH3. In some embodiments, the compound of formula (Ia) is

[0172] In some embodiments, the compound of formula (IIa) is (IIa); where R 1 is a C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl group; each R 2 is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl; and n is 0, 1, 2, 3, or 4. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl or heteroaryl. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl or heteroaryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, C1-C6 alkyl or aryl. 2 is independently selected from F, Cl, Br, I or C1-C6 alkyl. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, the compound of formula (IIa) is where R 1 is C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl. 1 is C1-C6 alkyl. In some embodiments, R 1 is CH2CH3. In some embodiments, R 1 is CH3. In some embodiments, the compound of formula (IIa) is

[0173] In some embodiments, the compound of formula (IIa') is where R 1 is a C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl group; each R 2 is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl; Z is a sulfonyl leaving group; and n is 0, 1, 2, 3, or 4. In some embodiments, R 2is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl or heteroaryl. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl or heteroaryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, C1-C6 alkyl or aryl. 2 is independently selected from F, Cl, Br, I or C1-C6 alkyl. In some embodiments, Z is In some embodiments, Z is 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 where R 1 is C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl and Z is a sulfonyl leaving group. 1 is C1-C6 alkyl. In some embodiments, R 1 is CH2CH3. In some embodiments, R 1 is CH3. In some embodiments, the compound of formula (IIa') is wherein Z is a sulfonyl leaving group.

[0174] In some embodiments, the compound of formula (IIb) is (IIb); where R 1 is a C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl group; each R 2 is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl, or heterocycloalkyl; and n is 0, 1, 2, 3, or 4. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl or heteroaryl. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl or heteroaryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, C1-C6 alkyl or aryl. 2 is independently selected from F, Cl, Br, I or C1-C6 alkyl. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, the compound of formula (IIb) is where R 1 is C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl.1 is C1-C6 alkyl. In some embodiments, R 1 is CH2CH3. In some embodiments, R 1 is CH3. In some embodiments, the compound of formula (IIb) is

[0175] In some embodiments, the compound of formula (Ic) is where R 3 is C1-C6 alkyl. In some embodiments, R 3 is -CH3. In some embodiments, R 3 is -CH2CH3. In some embodiments, R 3 is -CH(CH3)2. In some embodiments, the compound of formula (Ic) is In some embodiments, the compound of formula (Ic) is

[0176] In some embodiments, the compound of formula (IIc) is where R 1 is a C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl group; each R 2 R is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl; 3 is C1-C6 alkyl, and n is 0, 1, 2, 3 or 4. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl or heteroaryl. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl or heteroaryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, C1-C6 alkyl or aryl. 2 is independently selected from F, Cl, Br, I or C1-C6 alkyl. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, the compound of formula (IIc) is where R 1 is C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl. 1 is C1-C6 alkyl. In some embodiments, R 1 is CH2CH3. In some embodiments, R 1 is CH3. In some embodiments, the compound of formula (IIc) is

[0177] In some embodiments, the compound of formula (IId) is where R 1 is a C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl group; each R 2 R is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl; 3 is C1-C6 alkyl, and n is 0, 1, 2, 3 or 4. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl or heteroaryl. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl or heteroaryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, C1-C6 alkyl or aryl. 2 is independently selected from F, Cl, Br, I or C1-C6 alkyl. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, the compound of formula (IId) is In some embodiments, R 1 is a C1-C6 alkyl group and R 3 is C1-C6 alkyl. In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 is -CH3. In some embodiments, R 3 is -CH3. In some embodiments, R 3 is -CH2CH3. In some embodiments, R 3 is -CH(CH3)2. In some embodiments, the compound of formula (IId) is In some embodiments, the compound of formula (IId) is In some embodiments, the compound of formula (IId) is

[0178] In some embodiments, the compound of formula (Id) is where R 4 is a C1-C6 alkyl group, R 5 In some embodiments, R 4 The carbon atom of the substituent has the (R) configuration. In some embodiments, R 4 The carbon atom of the substituent has the (S) configuration. In some embodiments, the compound of formula (Id) is In some embodiments, the compound of formula (Id) is In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CH2CH3. In some embodiments, R 4 Is -CH(CH3)2. In some embodiments, the compound of formula (Id) is In some embodiments, the compound of formula (Id) is In some embodiments, R 5 In some embodiments, R 5 It is carboxybenzyl (Cbz).

[0179] In some embodiments, the compound of formula (IIe) is where R 1 is a C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl group; each R 2 R is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl; 3 is a C1-C6 alkyl group, R 4 is a C1-C6 alkyl group, R 5 is an amino protecting group; and n is 0, 1, 2, 3 or 4. In some embodiments, R 4 The carbon atom of the substituent has the (R) configuration. In some embodiments, R 4 The carbon atom of the substituent has the (S) configuration. In some embodiments, the compound of formula (IIe) is In some embodiments, the compound of formula (IIe) is In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl or heteroaryl. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl or heteroaryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, C1-C6 alkyl or aryl. 2 is independently selected from F, Cl, Br, I or C1-C6 alkyl. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, the compound of formula (IIe) is In some embodiments, R 1 is a C1-C6 alkyl group and R 3 is C1-C6 alkyl. In some embodiments, R 1is -CH2CH3. In some embodiments, R 1 is -CH3. In some embodiments, R 3 is -CH3. In some embodiments, R 3 is -CH2CH3. In some embodiments, R 1 is -CH(CH3)2. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CH2CH3. In some embodiments, R 4 is -CH(CH3)2. In some embodiments, R 5 In some embodiments, R 5 is carboxybenzyl (Cbz). In some embodiments, the compound of formula (IIe) is In some embodiments, the compound of formula (IIe) is In some embodiments, the compound of formula (IIe) is In some embodiments, the compound of formula (IIe) is

[0180] In some embodiments, the compound of formula (IIf) is where R 1 is a C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl group; each R 2 R is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl; 3 is a C1-C6 alkyl group, R 4 is C1-C6 alkyl, and n is 0, 1, 2, 3 or 4. In some embodiments, R 4 The carbon atom of the substituent has the (R) configuration. In some embodiments, R 4 The carbon atom of the substituent has the (S) configuration. In some embodiments, the compound of formula (IIf) is In some embodiments, the compound of formula (IIf) is In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl or heteroaryl. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl or heteroaryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, C1-C6 alkyl or aryl. 2is independently selected from F, Cl, Br, I or C1-C6 alkyl. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, the compound of formula (IIf) is In some embodiments, R 1 is a C1-C6 alkyl group and R 3 is C1-C6 alkyl. In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 is -CH3. In some embodiments, R 3 is -CH3. In some embodiments, R 3 is -CH2CH3. In some embodiments, R 1 is -CH(CH3)2. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CH2CH3. In some embodiments, R 4 Is -CH(CH3)2. In some embodiments, the compound of formula (IIf) is In some embodiments, the compound of formula (IIf) is In some embodiments, the compound of formula (IIf) is In some embodiments, the compound of formula (IIf) is

[0181] In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is -CH3. In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 It is -CH(CH3)2.

[0182] In some embodiments, each R 2 is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl. 2 is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl or heteroaryl. In some embodiments, R 2 is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl or heteroaryl. In some embodiments, each R 2 is independently selected from F, Cl, Br, I, C1-C6 alkyl or aryl. 2is independently selected from F, Cl, Br, I, CN, NO2 or C1-C6 alkyl. 2 is independently selected from F, Cl, Br, I or C1-C6 alkyl. 2 is independently selected from F, Cl, Br, I, CN, -CH3 or -CH2CH3. In some embodiments, each R 2 In some embodiments, each R 2 are independently aryl, heteroaryl or heterocycloalkyl. 2 is F. In some embodiments, R 2 Is Cl. In some embodiments, R 2 is Br. In some embodiments, R 2 is 1. In some embodiments, R 2 In some embodiments, R 2 is NO2. In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is CH3. In some embodiments, R 2 is CH2CH3. In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 It is a heterocycloalkyl group.

[0183] In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is -CH3. In some embodiments, R 3 is -CH2CH3. In some embodiments, R 3 It is -CH(CH3)2.

[0184] In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CH2CH3. In some embodiments, R 4 It is -CH(CH3)2.

[0185] In some embodiments, R 5 is an amino protecting group. 5 In some embodiments, R 5 is carboxybenzyl (Cbz). In some embodiments, R5 is 9-fluorenylmethoxycarbonyl (Fmoc). In some embodiments, R 5 It is benzyl (Bn).

[0186] In some embodiments, Z is In some embodiments, Z is

[0187] 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.

[0188] Additional embodiments are illustrated by the following non-limiting examples.

[0189] Example

[0190] Example 1. Synthesis of (S)-2-((2-ethoxyphenoxy)methyl)morpholine

[0191] Plan I.

[0192]

[0193] This synthetic route has been previously reported in U.S. patent US9403783B2.

[0194] 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 (3x). The combined extracts were washed with brine (twice), dried over MgSO4, filtered, and concentrated. The residual oil was then dissolved in 100 mL of toluene and evaporated (to remove excess epichlorohydrin). This was repeated four times to yield 50 g of the epoxide as a yellow oil.

[0195] 2-Aminoethyl hydrogen sulfate (141g; 1mol; 5 equivalents) is put into a 1L flask, and 7.5 equivalents of 60%KOH prepared by 100gKOH and 67mL water are added thereto, followed by 50g of crude epoxy ether dissolved in 200mL of methanol. After heating at 55°C for 2 hours, another 7.5 equivalents of 60%KOH are added, and the mixture is heated at 55°C overnight. After cooling, the mixture is evaporated to remove methanol, and the residue is diluted with water and extracted with ethyl acetate (5×). The combined extracts are washed with salt water (3 times), dried over MgSO4 and evaporated to give the crude (S)-2-((2-ethoxyphenoxy)methyl)morpholine free base (49g) as a yellow oil. The crude oil was dissolved in 100 mL of ethanol and 50 mL of 4N HCl in dioxane diluted with 50 mL of ethyl acetate was added. This initially gave a clear solution, with solid HCl salt precipitating in about 2 minutes. The suspension was kept at room temperature for 5 hours, then the solid salt was filtered off and rinsed with ethyl acetate. The salt was dried under air and high vacuum to give 17.15 g of (S)-2-((2-ethoxyphenoxy)methyl)morpholine HCl salt. This product was a single peak on HPLC and had an S content of 94.58% as determined by SFC.

[0196] The above process was repeated on a 200 or 300 mmol scale. After mixing 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 an S content of 92.724%. 13 H 20 Anal. Calcd. for NO3Cl: 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.

[0197] Example 2. Synthesis of Morpholine Analogs from Racemic 2-((2-Ethoxyphenoxy)methyl)morpholine HCl

[0198] Plan II.

[0199]

[0200] The numbering convention for the compounds described in Example 2 below corresponds to the compound numbering shown in Scheme II.

[0201] In exploratory studies, the process was improved by several novel modifications. These modifications included the use of the free base of 2-((2-ethoxyphenoxy)methyl)morpholine and diisopropylethylamine as the base catalyst in the first step, and the use of only 1.0 equivalent of chloroformate 2. Intermediate 3 was isolated by extraction without the need for chromatography (avoiding the decomposition observed when 3 was chromatographed on silica gel). Condensation of 3 with Boc-L-valine (4) was performed by initially forming the Cs salt in DMF and allowing the condensation to proceed until intermediate 3 was consumed. The crude product 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 studies, a portion of the product was isolated by filtration of the crude suspension in ethyl acetate / dioxane as a white solid with an overall yield of 34% (compared to 22% yield reported in U.S. Provisional Application Serial No. 63 / 162,671) and a syrupy liquid mother liquor 6 with a purity of approximately 80%.

[0202] The initial scale-up was carried out using the described process in four batches, yielding a total of 57 g of solid HCl salt 6.

[0203] Samples were examined to assess whether the scaled-up synthesis affected the ratio of diastereoisomers. Therefore, a portion of material 6 was hydrolyzed with 1N NaOH to convert it to 2-((2-ethoxyphenoxy)methyl)morpholine free base, which was converted to the HCl salt. The optical rotation of the 2-((2-ethoxyphenoxy)methyl)morpholine HCl sample obtained from the prodrug was [α] D 21 = +1.75°, indicating that the R-enantiomer of 2-((2-ethoxyphenoxy)methyl)morpholine HCl is dominant (reference 1 value +4.3°). Since this value is not zero, it is clear that one isomer in solid 6 is dominant, that is, the R isomer.

[0204] Experimental details

[0205] Step 1. 1-Chloroethyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (3).

[0206] 2-((2-Ethoxyphenoxy)methyl)morpholine HCl (1·HCl, 32.8 g, 120 mmol) is suspended in 50 mL of water and stirred at 0° C. A solution of 9.6 g of NaOH dissolved in 100 mL of water is added portionwise while the solution is kept at 0° C. for more than 30 minutes; stirring of the solution is continued for a further 1.5 hours. The mixture is extracted with 4×100 mL of dichloromethane. The combined extracts are washed with brine, dried over magnesium sulfate, and evaporated on a rotary evaporator and then kept on the vacuum pump overnight. 2-((2-ethoxyphenoxy)methyl)morpholine free base (1) is obtained as a colorless oil (28.51 g) (theoretical value 28.47 g).

[0207] 2-((2-ethoxyphenoxy)methyl)morpholine base 1 (120 mmol) was dissolved in 200 mL of dichloromethane and stirred at 0 ° C (some were not completely dissolved). 41.8 mL (240 mmol) of diisopropylethylamine was added to the solution to give a clear yellow solution. A solution of 18.16 g (122 mmol) of 1-chloroethyl chloroformate 2 in 20 mL of dichloromethane was added to the solution over 15 minutes. The solution was stirred and warmed to room temperature over 1.5 hours, then stirred at room temperature for 30 minutes. Water (100 mL) was added, and the mixture was extracted twice with dichloromethane. The extract was washed twice with brine and twice with 2N HCl (confirming that the pH value of the aqueous phase was pH 2), then washed with brine, bicarbonate, and brine. The extract was dried over magnesium sulfate, and the solvent was evaporated on a rotary evaporator, then evaporated under high vacuum for 2 hours. Chloroethyl carbamate 3 is obtained as a yellow oil (42.81 g) (theoretical value=41.26 g).

[0208] Step 2. (S)-1-[(S)-2-(tert-Butoxycarbonylamino)-3-methylbutoxy]ethyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (5).

[0209] 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 minutes, 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 hour (until TLC showed no 5 remaining). The solution was cooled to room temperature and treated with 50 mL of brine added to 100 mL of water and extracted with ethyl acetate (4×). The extract was washed with sodium bicarbonate (2×), brine, 1 N HCl, brine, sodium bicarbonate and brine (2×) in sequence, and then dried over magnesium sulfate. Norit was added, and the mixture was filtered through diatomaceous earth and evaporated to give 63.95 g of crude BOC product 5 (theoretical value=62.95 g) as a yellow oil.

[0210] Step 3. (S)-1-[(S)-2-amino-3-methylbutoxy]ethyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate, hydrochloride (6).

[0211] Above-mentioned BOC product 5 (63.95g) is dissolved in 110mL ethyl acetate, and adds the dioxane solution of 110mL 4N HCl.Form brown solution, and at room temperature stir 3 hours, form a large amount of solid subsequently.Filter mixture and use ethyl acetate and cold 1:1 ethyl acetate: hexane washing solid.White solid product is vacuum dried, obtain 18.45g (first batch).Obtain the mother liquor (40.7g) of brown oily.It is dissolved in 50mL ethyl acetate, and remain at room temperature and spend the night, then in refrigerator 2 days.As before filter, obtain second batch 2.3g.Solid matter is unimodal on HPLC (fast method (10-70%CH CN / 0.075%TFA / H O) 15 minutes).Mother liquor demonstrates identical main peak plus about 10% 2-((2-ethoxyphenoxy) methyl) morpholine. HPLC was repeated using a slow method (10-40% CH3CN / 0.075% TFA / H2O) for 40 minutes. Under these conditions, the solids were 98% of a single component (peak 1) and 2% of 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 are different diastereomers. This is due to "decomposition" of the 2-((2-ethoxyphenoxy)methyl)morpholine center by L-valine.

[0212] The process was repeated. The mother liquor materials were combined. The mother liquor was subjected to a water-acid-base extraction by dissolving a 15 g portion of the mother liquor material (syrupy liquid) in 50 mL of ethyl acetate and washing first with water and then with 1N HCl (2×). The ethyl acetate layer contained 2-((2-ethoxyphenoxy)methyl)morpholine, unreacted BOC compound 5, and traces of the target compound. The HCl solution was primarily the desired amine 6 HCl salt plus some 2-((2-ethoxyphenoxy)methyl)morpholine and a small amount of impurities. The solution was made basic with sodium bicarbonate, extracted with dichloromethane (3×), washed with brine, and dried over magnesium sulfate. The material was found to be the free base of the desired compound 6 plus approximately 5% of 2-((2-ethoxyphenoxy)methyl)morpholine. The material was kept at room temperature overnight whereupon it decomposed.

[0213] A second portion (15 g) was similarly treated but was not converted to the free base. The ethyl acetate phase contained most of the impurities and a small amount of product. Extraction of the HCl solution with dichloromethane gave primarily the desired HCl salt 6 product (peak 2) plus 4% 2-((2-ethoxyphenoxy)methyl)morpholine. The aqueous phase contained primarily 2-((2-ethoxyphenoxy)methyl)morpholine.

[0214] The remaining 30 g of mother liquor was dissolved in 100 mL of ethyl acetate and extracted with 3 x 1 N HCl. The aqueous HCl extract was then rewashed with 2 x ethyl acetate (100 mL), and the aqueous HCl phase was then extracted into dichloromethane (3 x 100 mL). The dichloromethane extract was washed with 50 mL of 1 N HCl, and the solution was re-extracted with dichloromethane. The combined dichloromethane extracts were dried over sodium magnesium sulfate, treated with Norit, filtered, and evaporated to yield 24.29 g (34 g) of Peak 2 product 6·HCl as a brown oil. This material was processed again in the same manner to yield 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).

[0215] A similar process was used for 42g of mother liquor from different operations. This process was treated with HCl only once, but with more solvent. In this variant, 42g of mother liquor was dissolved in 300mL of ethyl acetate and extracted with 2×200mL of 1N HCl. The aqueous HCl extract was then extracted with 2×250mL and 1×100mL of dichloromethane. The combined dichloromethane extracts were washed with 100mL of 1N HCl, dried over sodium sulfate, and evaporated to give 34g of peak 2 product as a brown oil. The isomer peak ratio was 85.7:13.3, plus 3.3% 2-((2-ethoxyphenoxy)methyl)morpholine. LC-MS: C 21 H 32N2O7[M+H] + :425.

[0216] Step 4. Preparation of (S)-2-((2-ethoxyphenoxy)methyl)morpholine from the racemate

[0217] Racemic 2-2-((2-ethoxyphenoxy)methyl)morpholine HCl was chromatographed via supercritical fluid chromatography to isolate the (S)-isomer as the slower eluting peak. The preparative separation was performed using a Thar 350 preparative SFC (SFC-23) using a ChiralCel column OD, 300×50 mm ID, 10 μm, mobile phase A: CO 2 , mobile phase B: ethanol (0.1% NH 3 H 2 O), gradient: B 30%, flow rate: 200 mL / min, and 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 is CO 2 , B is ethanol (0.05% DEA) / gradient: B 5-40% / flow rate: 2.5 mL / min / back pressure: 100 bar / column temperature: 35° C. / wavelength: 220 nm. An enantiomeric excess of 99.46% was obtained for the (S)-isomer. In the subsequent procedure, the HCl salt was first converted to the free base using ammonium hydroxide to form the free base, which was extracted into ethyl acetate, evaporated to an oil, and then subjected to preparative SFC as described above. This produced a sharper peak than that produced by SFC of the HCl salt.

[0218] Example 3. Synthesis of Morpholine Analogs from (S)-2-((2-ethoxyphenoxy)methyl)morpholine HCl

[0219] Scheme IIIa. Synthesis of 1-[(S)-2-amino-3-methylbutoxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate.

[0220]

[0221] The numbering convention for the compounds described in Steps 1 to 3 below corresponds to the compound numbering shown in Scheme IIIa.

[0222] Step 1. (S)-1-Chloroethyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (3)

[0223] (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 minutes; stirring of the solution was continued for an additional 1.5 hours. The mixture was extracted with 4 x 100 mL of dichloromethane. The combined extracts were washed with brine, dried over magnesium sulfate, and evaporated on a rotary evaporator, then kept on the vacuum pump overnight. (S)-2-((2-ethoxyphenoxy)methyl)morpholine free base was obtained as a colorless oil (11.85 g). The process was repeated on a 100 mmol scale to give an additional 23.7 g of (S)-2-((2-ethoxyphenoxy)methyl)morpholine free base. LC-MS: C 20 H 25 NO3[M+Na] + :328.

[0224] (S)-2-((2-ethoxyphenoxy)methyl)morpholine (50mmol) was mixed with 100mL of dichloromethane and stirred at 0°C (some were not completely dissolved). 17.5mL (100mmol) of diisopropylethylamine was added to the solution to give a clear yellow solution. A solution of 7.15g (50mmol) of 1-chloroethyl chloroformate 2 in 10mL of dichloromethane was added to the solution over 15 minutes. The solution was stirred and warmed to room temperature over 1.5 hours, then stirred at room temperature for 30 minutes. Water (100mL) was added, and the mixture was extracted twice with dichloromethane. The extract was washed twice with brine and twice with 2N HCl (confirming that the pH value of the aqueous phase was pH 2), then washed with brine, bicarbonate, and brine. The extract was dried over magnesium sulfate, and the solvent was evaporated on a rotary evaporator, then evaporated under high vacuum for 2 hours. Chloroethyl carbamate 3 was obtained as a yellow oil (17.15g). The process was repeated on a 100 mmol scale to yield another 34.3 g of chloro compound 3. LC-MS: C 16 H 22 ClNNaO5[M+Na] + :366.

[0225] Step 2. (S)-1-[(S)-2-(tert-Butoxycarbonylamino)-3-methylbutoxy]ethyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (5).

[0226] 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 minutes, and then 17.15 g of the above crude chloroethyl carbamate 3 (50 mmol) in 25 mL of DMF was added. The mixture was stirred and heated at 80° C. for 1 hour (until TLC showed no 5 remaining). The solution was allowed to cool to room temperature and treated with 100 mL of water plus 50 mL of brine and extracted with ethyl acetate (4×). The extract was washed with sodium bicarbonate (2×), brine, 1N HCl, brine, sodium bicarbonate and brine (2×) in sequence, and then dried over magnesium sulfate. Norit was added, and the mixture was filtered through diatomaceous earth and evaporated to give 26.2 g of crude BOC product 5 as a yellow oil. The process was repeated on a 100 mmol scale to give another 52.4 g of crude BOC compound 5. LC-MS: C 26 H 40 N2NaO9[M+Na] + :547.

[0227] Step 3. [(S)-1-amino-2-methylbutoxy]methyl methyl 2-[(o-ethoxyphenoxy)-methyl]-4-morpholinecarboxylate, hydrochloride (A).

[0228] The above-mentioned BOC product 5 (26.2g, 50mmol) is dissolved in 60mL ethyl acetate and a solution of 50mL 4N HCl in dioxane (200mmol) is added. A brown solution is formed and stirred at room temperature for 3 hours to obtain 23g of crude HCl salt. This procedure is repeated on a 100mmol scale to obtain another 46g of crude salt. Two batches are merged and suspended in 1000mL ethyl acetate. The formed solid is filtered out and dried (32g). This solid (MS M+H 425) is determined to be a diastereomer of the product. The ethyl acetate filtrate is concentrated to a 400mL volume and extracted with 2×250mL 1N HCl. The HCl layer (500mL) is extracted with 2×300mL dichloromethane and the combined extracts are dried and evaporated through Na SO to obtain 32g of thick oil (MS M+H 425). The oil and solid were combined and dissolved in a mixture of 150 mL of acetonitrile and 250 mL of 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: C 21 H 32 N2O7[M+H] + :425.

[0229] Scheme IIIb. Synthesis of 1-[(S)-2-amino-3-methylbutoxy]-2-methylpropyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (Compound B) and 1-[(R)-2-amino-3-methylbutoxy]-2-methylpropyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (Compound C) from (S)-2-((2-ethoxyphenoxy)methyl)morpholine HCl

[0230]

[0231] The numbering convention for the compounds described below corresponds to the compound numbering shown in Scheme IIIb.

[0232] (S)-2-amino-3-methylbutoxy]-2-methylpropyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (Compound B)

[0233] The method for preparing 1-[(S)-2-amino-3-methylbutoxy]-2-methylpropyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (Compound B) was similar to the method for preparing [(S)-1-amino-2-methylbutoxy]methylmethyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate, hydrochloride (Compound A), except that 1-chloro-2-methylpropyl chloroformate was used instead of 1-chloroethyl chloroformate.

[0234] The method described above for preparing (S)-2-((2-ethoxyphenoxy)methyl)morpholine free base was used in two batches starting with 50 mmol and 100 mmol of (S)-2-((2-ethoxyphenoxy)methyl)morpholine HCl (SFC separation, 99.3% S).

[0235] Step 1. (S)-2-Methyl-1-chloroethyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (3; Scheme II)

[0236] Condensation of 2-((2-ethoxyphenoxy)methyl)morpholine with 1-chloro-2-methylpropyl chloroformate (2) was carried out on 53 and 100 mmol scales to give 21 g and 42 g of product 3, respectively.

[0237] Synthesis of 1-[(R)-2-(tert-Butoxycarbonylamino)-3-methylbutoxy]-2-methylpropyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (4)

[0238] 16.51 g of BOC-L-Val-OH (76 mmol) and 12.22 g (37.5 mmol) of cesium carbonate (Cs2CO3) were stirred in 50 mL of DMF at room temperature for 30 minutes. 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 under N2 for 1.5 hours. After cooling to room temperature, 100 mL of water was added and the mixture was extracted with 4× ethyl acetate. The combined extracts were washed sequentially with brine, 2× NaHCO3, brine, 1 N HCl, brine, NaHCO3 and brine, then dried over MgSO4 and evaporated to give 31.8 g of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylic acid 1-[(R)-2-(tert-butoxycarbonylamino)-3-methylbutoxy]-2-methylpropyl ester (4) as a light yellow oil.

[0239] Synthesis of 1-[(S)-2-amino-3-methylbutoxy]-2-methylpropyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (Compound B)

[0240] To a solution of 31.8 g of 1-[S)-2-(tert-butoxycarbonylamino)-3-methylbutoxy]-2-methylpropyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (4) in 60 mL of ethyl acetate was added 60 mL of a 4N solution of HCl in dioxane. The solution was stirred at room temperature for 4 hours, and then the solvent was evaporated to give 29 g of 1-[(S)-2-amino-3-methylbutoxy]-2-methylpropyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate hydrochloride (Compound B) as a yellow oil.

[0241] Repeating the two aforementioned reactions on a 100 mmol scale yielded another 59 g of compound B as a yellow oil. These batches were combined and dissolved in 400 mL of ethyl acetate. Hexane (300 mL) was then added, and the solution was extracted with 2 × 400 mL and 2 × 300 mL of 1N HCl. The organic phase was discarded and the aqueous HCl phase was washed with 5 × 200 mL of 50% ethyl acetate / hexane. The organic phase was discarded and the aqueous HCl phase was extracted with 4 × 200 mL of dichloromethane. The dichloromethane solution was washed with 100 mL of 1N HCl, dried over MgSO , 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 yield 60.2 g of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylic acid 1-[(S)-2-amino-3-methylbutyloxy]-2-methylpropyl ester hydrochloride (compound B) as a white solid. (HPLC 98.9%; LC-MS: C 23 H 36N2O7[M+H] + :453). The long elution program resolved the diastereomers into two equal peaks.

[0242] Synthesis of (S)-1-[(R)-2-amino-3-methylbutyloxy]-2-methylpropyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate hydrochloride (Compound C)

[0243] Repeat the building-up process of compound B, except using N-BOC-D-Val to couple with chloro compound 3 to obtain intermediate 6.Use the dioxane solution of 110mL 4N HCl in 110mL ethyl acetate to carry out deprotection to compound 6 with 100mmol scale, obtain 48.9g thick HCl salt.It is merged with the thick HCl salt from 50mmol technique, obtain 74g crude salt altogether.It is dissolved in 900mL 60:40 ethyl acetate: in hexane, and extract with 1L 1N HCl.Use 400mL 50:50 ethyl acetate: hexane washing HCl layer, then use 2L dichloromethane extractions that amount to.Dichloromethane extract is through Na SO Drying and evaporation obtain 76.88g of thick (2S)-2-((2-ethoxyphenoxy) methyl) morpholine-4-formic acid 1-((D-valyl) oxygen base)-2-methyl propyl ester (compound C) in hydrochloride form. The crude salt (76 g) was dissolved in 200 mL of acetonitrile and 200 mL of water, treated with Norit, filtered through celite, and lyophilized to give 65.1 g of (S)-1-[(R)-2-amino-3-methylbutyloxy]-2-methylpropyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate hydrochloride (Compound C) as a white solid. (HPLC 99.81%; LC-MS: C 23 H 36 N2O7[M+H] + :453).

[0244] Example 4. Synthesis of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine

[0245] Scheme IV. Alternative routes for the synthesis of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (5)

[0246]

[0247] The numbering convention for the compounds described below corresponds to the compound numbering shown in Scheme IV.

[0248] 2-Ethoxyphenol 1 is reacted with (R)-epichlorohydrin to give the intermediate epoxide 3, which is then treated with aminoethyl sulfate and sodium hydroxide to give (S)-2-((2-ethoxyphenoxy)methyl)morpholine. This process is enantioselective and provides approximately 92.5% (S) of the product.

[0249] (S)-4-Benzyl-2-((2-ethoxyphenoxy)methyl)morpholine was prepared from (S)-2-((2-ethoxyphenoxy)methyl)morpholine by alkylation with benzyl bromide.

[0250] Example 5. Alternative Synthesis of (S)-4-Benzyl-2-((2-ethoxyphenoxy)methyl)morpholine

[0251] Scheme V. Synthesis of (S)-4-Benzyl-2-((2-ethoxyphenoxy)methyl)morpholine

[0252]

[0253] The numbering convention for the compounds described below corresponds to the compound numbering shown in Scheme V.

[0254] Efforts were made to design a route to synthesize (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine that did not involve benzylation of (S)-2-((2-ethoxyphenoxy)methyl)morpholine. Several potential routes have been proposed based on the synthesis of S- or racemic 2-((2-ethoxyphenoxy)methyl)morpholine. In our approach, these syntheses utilize chiral epichlorohydrin as a source of the S-enantiomer. One potential route to (S)-2-((2-ethoxyphenoxy)methyl)morpholine is based on a previously published synthesis of racemic 2-((2-ethoxyphenoxy)methyl)morpholine (Liang, Bhatt et al., US Pat. No. 9,403,783). This approach was modified to provide the epoxy intermediate 3 starting from R-epichlorohydrin. This epoxide was used to prepare (S)-2-((2-ethoxyphenoxy)methyl)morpholine by ring opening and cyclization with aminoethyl hydrogen sulfate (US Pat. No. 3,712,890). On this basis, it was anticipated that ring opening of 3 with hydroxyethylbenzylamine (12) would provide the same (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine via diol 13.

[0255] Example 6. Synthesis of salts of morpholine derivatives from (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine.

[0256] Plan VI.

[0257]

[0258] The numbering convention for the compounds described in Example 6 below corresponds to the compound numbers shown in Scheme VI.

[0259] (S)-4-Benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (5) (3.87 g of the above, 10 mmol) 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 minutes and maintained at about 3°C ​​for 90 minutes, then warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (50 mL), 1N HCl (50 mL), bicarbonate (50 mL), and brine (50 mL), dried over sodium sulfate, and then evaporated on a rotary evaporator and then on a vacuum pump overnight. The residue was dissolved in acetonitrile (50 mL) and washed with hexanes (3×100 mL) to remove the remaining amount of benzyl chloride by-product produced by debenzylation of 7. The acetonitrile layer was concentrated to give 3.47 g of chlorocarbamate 8.

[0260] 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 minutes. To the 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 hour. After the mixture was cooled to room temperature, it was diluted with ethyl acetate (100 mL). The ethyl acetate solution was washed with water (2×100 mL), bicarbonate (75 mL), 1 N 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.

[0261] The entire Boc-protected compound 10 obtained in step 3 (5.8 g; 10 mmol) was dissolved in ethyl acetate (25 mL) and a 4N HCl solution in dioxane (11 mL, 44 mmol) was added. The mixture was stirred at room temperature for 4 hours and then concentrated in vacuo. 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 analysis of the extract sample showed a purity of 96.6%. The dichloromethane layer was washed with 1N HCl (80 mL), then dried over sodium sulfate and evaporated. After drying in vacuo overnight at room temperature, the product (S)-2-amino-3-methylbutoxy]ethyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl (11, 3.65 g) was obtained as a light yellow foam. The final process yielded 1-[(S)-2-amino-3-methylbutoxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl (11), which contained no unreacted (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine and was devoid of byproducts from the reaction of benzyl chloride with N-Boc-L-lysine (9). This resulted in an improved product purity (99.15% vs. 96.6%). Based on 10 mmol of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine used, 3.65 g of 1-[(S)-2-amino-3-methylbutoxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl salt (11) was obtained in an overall yield of 79.2%. LC-MS: C 21 H 32 N2O7[M+H] + :425. The product, (S)-1-[(S)-2-amino-3-methylbutoxy]ethyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (11), was a 1:1 mixture of diastereomers of the acetal center. One of the isomers (which eluted faster on reverse phase HPLC) could be readily obtained as a solid and could be recrystallized from ethanol / MTBE or ethyl acetate to provide high purity material with a recovery of approximately 85% of theoretical. Further work showed that the solid HCl salt could be recrystallized from isopropanol to give fine needle-shaped crystals. After multiple trials using different solvent systems, the slower eluting isomer from the liquid still could not be crystallized as the HCl salt. It appears that the two diastereomers may have different conformations that favor the crystallization of the faster eluting isomer. The recrystallized HCl salt formed needle-shaped crystals that were too small for structural determination by X-ray. Further crystallization attempts may be necessary to see if suitable crystals can be obtained to determine whether the isomer has the S,S,S or S,R,S configuration.

[0262] Salts of morpholine derivatives

[0263] Experiments were also conducted to replace the HCl salt with other acids. Previous attempts to isolate the free base by treating the HCl salt with 1N NaOH failed because the strong base would hydrolyze to produce 2-((2-ethoxyphenoxy)methyl)morpholine. However, it was discovered that the HCl salt dissolved in ethyl acetate or dichloromethane could be washed with saturated sodium bicarbonate and brine and dried over sodium sulfate or magnesium sulfate to obtain a free base solution that remained stable. The free base solution could then be treated with one equivalent of different acids to form other salts. Maleic, citric, and p-toluenesulfonic and methanesulfonic acid salts were generated from the mixed diastereomeric HCl salt, but recrystallization was not possible. A potential alternative approach involves first isolating the solid diastereomers of the HCl salt by crystallization from ethyl acetate and 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 to obtain a crystalline solid. Attempts to crystallize the tosylate isomer mixture were unsuccessful. Overall, it appears that the tosylate salts of the individual diastereomers can be prepared and crystallized, and then mixed 1:1 to give the appropriate products.

[0264] Salt synthesis

[0265] 1.152g (2.5mmol) of mixed diastereomer HCl salt is (quickly) dissolved in 5mL ethyl acetate and seeded with the crystals retained in early research. After 1 hour, the solution is concentrated to 3mL volume and left standstill overnight at room temperature to form a thick crystalline solid paste. Add ethyl acetate (3mL) and collect the solid by filtration and rinse with 1mL ethyl acetate. After vacuum pump drying, the first batch obtains 487mg HCl salt (84.5% of theoretical value). The mother liquor is evaporated and the glue residue (593.9mg) is dissolved in 3mL ethyl acetate and diluted with 3mL MTBE. The solution is left standstill overnight at room temperature, but no solid is obtained.

[0266] The diastereomeric mixture of HCl salt (1.15g, 2mmol) was dissolved in 3.5mL ethyl acetate and seeded. Crystals were formed within 1 hour and the solvent was removed with a pipette. The solid was rinsed and dried with 5mL 1:1 ethyl acetate: hexane to obtain 562.2mg of solid isomer. This solid was recrystallized overnight with 3.5mL isopropanol to obtain a fine needle-shaped object. The mother liquor was evaporated to a thick syrup, dissolved in 1mL ethyl acetate, and diluted with 1.5-2mL hexane. After standing at room temperature for 30 minutes, an oily substance was separated, so 0.5mL ethyl acetate was added and the mixture was warmed to dissolution and allowed to stand overnight. Another solid was obtained, but HPLC showed that it was only the second batch of faster-eluting isomers, while the mother liquor was only the slower-eluting isomers of the liquid.

[0267] Separation of the free base from the liquid HCl salt isomers: The solvent of the mother liquor (2.5 mmol scale) from the crystallization of the HCl salt was evaporated and the residue was dissolved in 6 mL of dichloromethane and the solution was washed 2x with bicarbonate.

[0268] Formation of the mesylate salt.

[0269] The methanol solution of 1.5mL 1N methylsulfonic acid is then used to process the dichloromethane solution of the free alkali that derives from 593.9mg (1.29mmol) liquid HCl isomer mother liquor.Solution is diluted with 2mL dichloromethane, and with 1 × 3mL water washing.Evaporating solvent, and some salt precipitations, therefore make mixture be dissolved in the dichloromethane again, through dried over magnesium sulfate and drying.Make resistates be dissolved in ethyl acetate (2mL) and MTBE (2mL), but do not have solid to form.Remove solvent (and use 5mL toluene further to dry this material).Then make it be dissolved in the isopropyl alcohol (0.5mL), stand and spend the night (no solid).This material is dissolved in ethyl acetate and is converted into free alkali again with bicarbonate, then use salt water washing, and through dried over magnesium sulfate.

[0270] Formation of maleate salt.

[0271] The ethyl acetate solution of free alkali is treated with a solution of 150mg maleic acid in 2mL isopropyl alcohol. Evaporating solvent (thick oil) (using 9:1 dichloromethane: methanol carries out TLC) shows that maleic acid is separated from free alkali. HPLC shows the peak of maleic acid and the slower eluting isomer, but does not have 2-((2-ethoxyphenoxy) methyl) morpholine, shows that maleate is stable, but is not crystallization. This material is dissolved in dichloromethane, washed with water and evaporated to obtain 374mg of maleate in oily form.

[0272] Formation of the tosylate salt.

[0273] In another experiment, liquid HCl salt isomer (174.7mg, 412mmol) was dissolved in 7mL ethyl acetate. The solution was washed with bicarbonate (2×5mL), brine, dried over magnesium sulfate and evaporated (rotary evaporator, bath temperature <30°C), and vacuum dried for 30 minutes to obtain the free base. Ethyl acetate (2mL) was added, followed by 78.3mg of p-toluenesulfonic acid monohydrate in 0.5mL ethanol and 3mL ethyl acetate. The solution was concentrated to a volume of 0.5mL and re-evaporated with 5mL ethyl acetate to remove trace ethanol, resulting in a viscous foam. The substance was dissolved in 2mL ethyl acetate and hexane (about 2mL) was added until turbidity. Crystals formed after standing, and the mixture was left to stand over the weekend to obtain a large amount of white crystals. The solvent was removed by pipetting and the residue was rinsed with 1:1 ethyl acetate: hexane and dried to obtain 188mg of toluenesulfonate in the first batch as a white solid.

[0274] Repeat the above process, starting from the solid isomer HCl salt (486mg, 1.054mmol), make it be dissolved in ethyl acetate as mentioned above, and use sodium bicarbonate, salt water washing, and dried over magnesium sulfate.Then use p-toluenesulfonic acid monohydrate (200.56mg, 1.054mmol) to process the free alkali solution, first dissolve in 1mL ethanol, then dilute with 2mL ethyl acetate. The solution is diluted with 1mL ethyl acetate and 1mL hexane. Remove solvent, obtain 487.1mg toluenesulfonate in the form of foam solid. Make it be dissolved in 2mL ethyl acetate and 2mL hexane, and crystallize at room temperature overnight to form crystalline toluenesulfonate. Remove solvent with pipette and rinse solid and dry solid with 1:1 ethyl acetate: hexane to obtain 345.8mg solid toluenesulfonate. The mother liquor is evaporated to obtain 187.4mg material.

[0275] The isomer mixture of HCl salt (780mg, 1.692mmol) is dissolved in 5mL ethyl acetate, and is converted into free alkali as mentioned above.Free alkali is dissolved in 5mL ethyl acetate, and adds the tosic acid monohydrate that 321.8mg is dissolved in 1mL methyl alcohol.Use 3-4mL hexane diluent, until part is muddy, then add the seed of two kinds of pure enantiomers of crystallization toluenesulfonate.The TLC display isomer of toluenesulfonate mixture (9:1 methylene chloride: methyl alcohol) is slightly separated, and the running speed of the toluenesulfonate in liquid isomer source is slightly faster than the running speed of the toluenesulfonate of solid isomer.Leave standstill and spend the night and try other solvent (isopropyl alcohol, MTBE) after, all do not form the crystal of any diastereomer.

[0276] Example 7. Final determination of the chirality of (S)-2-((2-ethoxyphenoxy)methyl)morpholine

[0277] The scientific literature on the enantiomers of 2-((2-ethoxyphenoxy)methyl)morpholine indicates that the S-isomer is much more biologically potent than the R-isomer. The assignment of the R and S enantiomers dates back to older literature that correlates the absolute configuration with that of propranolol and is established by correlation with S-lactic acid and some circular dichroism spectra. (Howe et al., J. Med. Chem., 1976, 19, 1074.) Since (S)-2-((2-ethoxyphenoxy)methyl)morpholine prodrugs, including 1-[(S)-2-amino-3-methylbutoxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate, are potential drug candidates, we attempted to verify the chiral configuration as (S) by X-ray crystallography.

[0278] Although the X-ray structure of the (S)-2-((2-ethoxyphenoxy)methyl)morpholine salt has not yet been reported, the racemic material has been crystallized and the X-ray structure determined to be its HCl salt (J. Ouhabi, M. Saux, A. Carpy, Acta Crystallographica, Section C: Crystal Structure Communications, 1990, 46, 2160). For potential X-ray studies, we prepared tosylate, mesylate, and hydrobromide salts (each containing heavy atoms to facilitate determination of absolute chirality). The crystals obtained from these salts were very fine needle-like or cotton-like solids. The best sample (HBr salt, needle-like) was submitted for X-ray examination, but the needles were too thin to be studied by X-ray.

[0279] Since suitable crystals of the 2-((2-ethoxyphenoxy)methyl)morpholine salt were not obtained, a sample of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine was prepared from pure (S)-2-((2-ethoxyphenoxy)methyl)morpholine obtained from the racemate by chiral SFC (99.3% S). This was treated with 48% HBr in ethanol and evaporated to give the HBr salt as a white solid. The HBr salt was recrystallized from ethanol to give large flaky crystals. These were sent for X-ray analysis and were determined to be suitable for study. The 4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HBr crystals were shown to have the (S)-configuration and to have one water molecule in the crystals. The structure is as shown in FIG. Figure 1 shown.

[0280] This study confirmed all previous assumptions regarding the S-isomer of 2-((2-ethoxyphenoxy)methyl)morpholine as the biologically active isomer. It also confirmed that the (S)-isomer was the configuration isolated from the resolution procedure of Howe et al. and was the same isomer as the slower-migrating peak on chiral SFC. Furthermore, this isomer resolved racemic 2-((2-ethoxyphenoxy)methyl)morpholine, generating a large amount of (S)-2-((2-ethoxyphenoxy)methyl)morpholine for prodrug studies. Based on these results and the correlations mentioned above, the (S)-configuration of (S)-2-((2-ethoxyphenoxy)methyl)morpholine and (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine was confirmed to be (S).

[0281] Example 8. Novel chiral synthesis of morpholine derivative intermediates.

[0282] Scheme VIII. Synthesis of 1-[(S)-2-amino-3-methylbutoxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate

[0283]

[0284] The numbering convention for the compounds described in Example 8 corresponds to the compound numbering shown in Scheme VIII.

[0285] Route to (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine

[0286] The synthesis of (S)-1-[(S)-2-amino-3-methylbutoxy]ethyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl (12) by a novel route (Scheme VIII) proceeds as follows: N-benzylethanolamine (1) first opens (S)-(+)-epichlorohydrin (2, chiral source), then forms chlorohydrin 3, epoxide 4 and diol 6, and finally cyclizes to (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (7). This route has been expanded to start with 1.2 mol of ethanolamine 1. Via the novel route, crude (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (7·HCl) crystallized under optimized conditions to give >99% of the (S)-isomer.

[0287] Experimental details.

[0288] Step 1: 2-Benzylaminoethanol (1,90.73 g, 600 mmol) and (S)-(+)-epichlorohydrin (2,61.06 g, 660 mmol, 1.1 equivalents) were dissolved in 220 ml of methanol, stirred under nitrogen and warmed to 35° C. for 22 hours. The methanol was evaporated and 100 mL of toluene was added and evaporated. The addition of toluene and evaporation were repeated three more times to remove traces of epichlorohydrin and / or methanol, and the oil was dried using a vacuum pump for 4 hours. The product chlorohydrin 3 (155 g) was obtained as a light yellow oil. HPLC (5-50-90% CH CN; H O / 0.075% TFA) showed a major peak at 6.23 minutes (purity 64%).

[0289] Step 2: Crude chlorohydrin 3 (155g) was dissolved in 300mL MTBE. A solution of 2.4g tetrabutylammonium hydrogen sulfate and 25.2g (630mmol) sodium hydroxide in 48ml water was added to the solution. The mixture was stirred at room temperature under nitrogen for 1.5 hours. The layers were separated and the aqueous layer was extracted with 100ml MTBE. The combined extracts were dried over magnesium sulfate and evaporated on a rotary evaporator, then dried under high vacuum for 3 hours at room temperature. Epoxide 4 (113g) was obtained as a light yellow oil. HPLC using the same conditions as compound 3 showed that the product peak of epoxide 4 appeared at 6.74min (64.3%). LC-MS: C 12 H 17 NO2[M+H] + :208.17.4 1 H NMR spectrum Figure 2 shown.

[0290] Step 3: Epoxide 4 (113g) and 2-ethoxyphenol (5,90.4g, 655mmol) are dissolved in 450ml toluene. The mixture is stirred (mechanical stirrer) and cesium carbonate (106.3g, 327mmol) is added portionwise in about 30 minutes, causing the temperature to rise to 34°C from room temperature. The mixture is stirred and cooled to 32°C in 30 minutes. The mixture is then gradually heated (heating mantle) and the internal temperature is raised to 110°C in 1 hour, and maintained at 110°C for 1 hour, until all epoxide 4 are exhausted. The brown mixture is then cooled to room temperature, filtered through diatomaceous earth, and toluene is evaporated to obtain a brown oil. The oil is dissolved in 200mL dichloromethane and 200mL 2N NaOH is added. The mixture was stirred for 10 minutes and then extracted with 2×100 mL of dichloromethane, and the extract was washed with 2×100 mL of 2N NaOH (to remove unreacted phenol) and 2× brine. 200 mL of brine and 55 mL of concentrated brine were added to the dichloromethane layer (until the pH of the aqueous layer was 3). The mixture was stirred for 10 minutes, the organic layer was separated, and then washed with 2×1N HCl (100 ml of saturated NaCl) (to remove the cyclic amine by-product), and then washed with 2× brine. The organic phase was then treated with 2N NaOH until the pH>10, stirred for 10 minutes, washed twice with brine, and dried over magnesium sulfate. The solvent was evaporated and then dried on a vacuum pump to give 149 g of diol 6 as a light brown oil. As before, HPLC using a 50-90% gradient showed that the main peak of diol 6 appeared at 14.48 minutes; when a 10-70-90 gradient was used, the diol peak eluted at 10.12 minutes. LC-MS: C 20 H 27 NO4[M+H] + :346.24.6 1 H NMR spectrum Figure 3 shown.

[0291] Step 4: Dissolve diol 6 (149 g) in 400 mL of toluene and add 4.92 g of benzyltriethylammonium chloride (22 mmol). Add 103.65 g of sodium hydroxide beads (2.6 mol) with mechanical stirring. Warm to 30°C and stir at room temperature for 30 minutes. The mixture is then cooled to 20°C in an ice bath, and p-toluenesulfonyl chloride (82.3 g, 430 mmol) is added portionwise over 1 hour while cooling in an ice bath, maintaining the internal temperature at 25 ± 2°C, followed by stirring at room temperature for 1.5 hours. The mixture is poured into 500 mL of cold water, stirred for 20 minutes, and the layers separated. The aqueous phase is extracted with toluene (3 x 150 mL), and the extract is washed with 2N NaOH (6 x 150 mL), brine (2 x), and dried over magnesium sulfate. The toluene is removed on a rotary evaporator to yield 160 g of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine 7 as a yellow oil. Chiral SFC showed that the crude product (free base) was approximately 80% (S). LC-MS: C 20 H 25 NO3[M+H] + :328.28.7 1 H NMR spectrum Figure 4 shown.

[0292] (S)-4-Benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (160 g) was dissolved in 130 ml of ethyl acetate and the solution was cooled in an ice bath. To this solution was added 130 ml of 4N HCl in dioxane and stirred for 20 minutes, after which the solvent was evaporated on a rotary evaporator to yield 207 g of the salt, 7·HCl, as an orange oil. To the crude salt was added 40 mL of ethanol and the mixture was warmed until dissolved. Then, 100 ml of ethyl acetate was added, followed by 7.8 ml of water. The solution was seeded with crystalline HCl salt with 99+% (S) configuration and placed in a -15°C freezer over the weekend. The white crystalline product was filtered, washed with 1:3 ethanol:ethyl acetate, and air-dried to yield 47.23 g of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HCl (7·HCl), which showed 99.5% S configuration according to chiral SFC analysis. The mother liquor was essentially racemic (49:51) and was discarded.

[0293] A subsequent cycle of the above reaction (starting from 600 mmol of 1) gave 48.87 g of 7·HCl, which was recrystallized to give 47.09 g of 7·HCl. A subsequent cycle of the above reaction (170 mmol of 1) gave 14.6 g of 7·HCl.

[0294] Starting from a total of 1.37 mol of 1, 108.92 g of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HCl (7) were obtained in an overall yield of 21.8%. No chromatographic purification was required and the product was >99% of the (S)-enantiomer.

[0295] Conversion of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HCl to (S)-1-[(S)-2-amino-3-methylbutyloxy]ethyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl

[0296] The key intermediate in the synthesis of 1-[(S)-2-amino-3-methylbutoxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl (12) from (S)-2-((2-ethoxyphenoxy)methyl)morpholine is the chlorocarbamate (9) initially obtained by the reaction of (S)-2-((2-ethoxyphenoxy)methyl)morpholine with 1-chloroethyl chloroformate (8). Using (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine as a precursor, the reaction with 1-chloroethyl chloroformate was designed to generate the NH compound during N-debenzylation (see Olofson et al., J. Org. Chem. 1984, 49, 2081-2082; the published procedure uses N-ethylpiperidine as an example).

[0297] Extrapolating to the synthesis of 1-[(S)-2-amino-3-methylbutoxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl (12) and other (S)-2-((2-ethoxyphenoxy)methyl)morpholine prodrugs, the intermediate chlorocarbamate 9 was generated from (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (7) and 1-chloroethyl chloroformate 8 with loss of benzyl chloride to form 9, thus eliminating the need to generate and use (S)-2-((2-ethoxyphenoxy)methyl)morpholine in the entire process.

[0298] As shown in Scheme VIII, (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (7) is treated with chloroformate 8 to give the N-benzyl-N-carbamoyl salt (not isolated), which eliminates the benzyl chloride to form 1-chloroethylcarbamate 9. Even at room temperature, the reaction of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine is very rapid, and carbamate 9 is not converted to 2-((2-ethoxyphenoxy)methyl)morpholine under the described conditions. In initial studies, the crude product was extracted with hexane / acetonitrile solvent extraction to remove the benzyl chloride formed during the elimination of the benzyl chloride from 9. An improved method was discovered (described below) in which triethylamine was added to the mixture to react with the benzyl chloride byproduct to form benzyltriethylammonium chloride, a water-soluble quaternary salt that can be washed out of the crude product with water.

[0299] The synthesis was completed by reacting chlorocarbamate 9 with N-BOC-l-valine (10) to give N-BOC-l-valine ester (11). 11 was treated with HCl to give (2S)-1-((L-valyl)oxy)ethyl 2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylate HCl (12). A key observation was that the product, (S)-1-[(S)-2-amino-3-methylbutyloxy]ethyl 2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl (12), could be extracted from aqueous HCl into dichloromethane without carrying over any byproducts.

[0300] (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 and then extracted with 1×400 ml and 1×200 ml of dichloromethane. The solvent was evaporated to give 32.7 g of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine free base.

[0301] Experimental details.

[0302] 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 this solution was added a solution of 1-chloroethyl chloroformate (8, 18.57 g, 130 mmol) in 50 ml of dichloromethane over 30 minutes while cooling in an ice-water bath. The solution was stirred under N2 for 2 hours, then warmed to room temperature and stirred for another hour. To remove the by-product benzyl chloride, triethylamine (30.3 g, 300 mol) in 25 ml of dichloromethane was slowly added over 30 minutes at room temperature. The mixture was stirred for a total of 72 hours and then washed with 150 ml of water, 150 ml of 1N HCl, 150 ml of bicarbonate, 100 ml of brine, dried over Na2SO4, decolorized with Norit A, filtered through celite and evaporated to give 35 g of chlorocarbamate (9). LC-MS:C 16 H 22 ClNO5Na[M+Na] + :366.12.

[0303] Step 6: N-Boc-L-valine (34.32 g, 160 mmol) was dissolved in 125 ml of DMF and cesium carbonate (26 g, 80 mmol) was added portionwise. The mixture was stirred at room temperature for 30 minutes, and then crude chlorocarbamate 9 (35 g) in 75 ml of DMF was added at room temperature. The mixture was then stirred at 85°C for 1 hour and then cooled to room temperature. 250 ml of ethyl acetate (250 ml) was added and the solution was washed with 2 x 150 ml of water, 1 x 125 ml of bicarbonate, 2 x 250 ml of 1N HCl and 1 x 125 ml of brine, dried over Na2SO4 and evaporated to give 55 g of crude (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylic acid 1-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutoxy]ethyl ester (11). LC-MS: C 26 H 40 N2O9Na[M+Na] + :547.14.

[0304] The above process was repeated on a 1.74x scale starting from 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-methylbutoxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (11).

[0305] Step 7: 55 g of crude 1-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutoxy]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 then concentrated in vacuo. The crude HCl salt of 1-[(S)-2-amino-3-methylbutoxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl (56 g) was dissolved in 300 ml of ethyl acetate and extracted with 2 x 300 ml of 1N HCl. The combined HCl layers were washed with 200 ml of 50% ethyl acetate in hexane and then extracted with 600 ml of dichloromethane. The dichloromethane layer was dried over Na2SO4 and evaporated to give 40 g of 1-[(S)-2-amino-3-methylbutyloxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate·HCl (12). LC-MS: C 21 H 32 N2O7[M+H] + :425.29.12 1 H NMR spectrum Figure 5 shown.

[0306] In a subsequent operation, 1-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutoxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (11) (91 g) was treated with 4N HCl in dioxane as described above to give 62 g of 1-[(S)-2-amino-3-methylbutoxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl (12). An additional 3.5 g was obtained from dichloromethane (the emulsion was allowed to stand overnight to separate). This was lyophilized separately.

[0307] Multiple batches of 1-[(S)-2-amino-3-methylbutoxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate HCl (12, 18 g, 40 g, and 62 g) were combined (total 120 g) and dissolved in 200 ml of acetonitrile and 400 ml of 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-methylbutoxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate (12), as an off-white solid in the form of its hydrochloride salt. HPLC indicated the product to be 98.5% pure. The rinse from the lyophilized flask was re-lyophilized to yield an additional 6 g.

[0308] The total yield of 1-[(S)-2-amino-3-methylbutoxy]ethyl (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylate·HCl (12, 112.92+3.5+6=122.42 g) represents a total yield of 81.97% starting from (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholineHCl.

[0309] Although this description has been made with reference to exemplary embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope. In addition, many modifications may be made to adapt specific circumstances or materials to the teachings of the present invention without departing from the basic scope. Furthermore, in the drawings and descriptions, exemplary embodiments have been disclosed, and although specific terms may have been employed, unless otherwise indicated, they are used in a general and descriptive sense only, and not for limiting purposes, and the scope of the claims is not thereby limited. Furthermore, it will be understood by those skilled in the art that certain steps of the methods discussed herein may be arranged in an alternative order, or the steps may be combined. Therefore, the appended claims should not be limited to the specific embodiments disclosed herein.

Claims

1. A method for producing a morpholine derivative of formula IIf or a pharmaceutically acceptable salt thereof, the method comprising: (a) making the following compound: Reacts with (S)-(+)-epichlorohydrin to form a chlorohydrin compound of the formula: (b) contacting the chlorohydrin compound with a base and a phase transfer catalyst to form an epoxide compound of the formula: (c) contacting the epoxy compound with a base and a compound of the formula: To form the diol compound of the following formula: (d) contacting the diol compound with a base and then adding a sulfonyl halide compound to form an intermediate sulfonate ester of the formula: Wherein Z is a sulfonyl leaving group, The intermediate sulfonate ester is cyclized in situ to form an N-benzyl protected morpholine compound of the formula: (e) forming an HCl salt of the compound of formula (IIb) and recrystallizing it to obtain a highly pure (S)-enantiomer in the form of an HCl salt; (f) converting the HCl salt of the compound (IIb) into a free base; (g) contacting the N-benzyl protected morpholine compound with a chloroformate of the formula: To form the intermediate N-benzylchlorocarbamate of the following formula: Upon heating, the benzyl chloride is lost to give a chlorocarbamate compound of the following formula: (h) adding the chlorocarbamate compound of formula (IId) to a metal salt of an amino acid derivative of the following formula: wherein the amino acid derivative has been pretreated with a metal compound to form a protected amine of the formula: as well as (i) contacting the protected amine with an acid to provide the morpholine derivative (IIf) in the form of an acid salt: where R 1 is a C1-C6 alkyl, aryl or heteroaryl group; each R 2 R is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl or heterocycloalkyl; 3 is a C1-C6 alkyl group, R 4 is a C1-C6 alkyl group, R 5 is an amino protecting group; and n is 0, 1, 2, 3 or 4.

2. The method according to claim 1, wherein the phase transfer catalyst is tetrabutylammonium hydrogen sulfate.

3. The method according to claim 1, wherein a phase transfer catalyst is used in step (d).

4. The method of claim 3, wherein the phase transfer catalyst is benzyltriethylammonium chloride.

5. The process of claim 4, wherein the product of step (e) forming the HCl salt of the compound of formula (IIb) contains more than 60% of the (S) enantiomer and the (S)-HCl salt can be crystallized to obtain the HCl salt having more than 90% of one enantiomer. The method according to claim 1 , wherein the sulfonyl halide is selected from the group consisting of p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride and methanesulfonyl chloride. The method according to claim 6 , wherein the sulfonyl halide compound is p-toluenesulfonyl chloride. The method according to claim 1 , wherein the cyclization is carried out using NaOH.

9. The process of claim 1, wherein the crude chlorocarbamate compound formed in step (g) is washed with an alkane solvent, evaporated or treated with triethylamine to remove benzyl chloride by-product before proceeding to the next step.

10. The method of claim 1, wherein the metal salt of step (h) is a cesium salt.

11. The method of claim 1, wherein the metal compound of step (h) is cesium carbonate.

12. The method according to claim 1, wherein step (a) further comprises an organic solvent.

13. The method of claim 12, wherein step (a) further comprises heating to a temperature of at least 30°C.

14. The method of claim 1, wherein step (b) is performed at room temperature.

15. The method according to claim 1, wherein R 1 It is -CH3 or -CH2CH3.

16. The method according to claim 1, wherein each R 2 Independently selected from -F, -Cl, -Br, -I or C1-C6 alkyl.

17. The method according to claim 1, wherein R 3 It is -CH3 or isopropyl.

18. The method according to claim 1, wherein R 4 It is isopropyl.

19. The method according to claim 1, wherein R 5 It is tert-butoxycarbonyl.

20. The method of claim 1, wherein n is 0.

21. The process of claim 1, wherein the morpholine derivative from step (i) has the formula: or a pharmaceutically acceptable salt thereof.

22. The process of claim 1, wherein the morpholine derivative from step (i) has the formula: or a pharmaceutically acceptable salt thereof.

23. The process of claim 1, wherein the morpholine derivative from step (i) has the formula: or a pharmaceutically acceptable salt thereof.

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