Process for preparation of substituted morpholine derivatives

Abstract

The name of the invention is a method for preparing derivatives of substituted morpholines. Provided herein are methods of preparing derivatives and prodrugs of substituted morpholines, or pharmaceutically acceptable salts thereof. Methods of preparing substituted morpholine derivatives and prodrugs having the following chemical structure are also provided.

Description

[0001] This application is a divisional application of the Chinese national phase patent application No. 202380015734.4, which was filed on June 27, 2024, after the international application No. PCT / US2023 / 015461, international application date March 17, 2023, entitled "Method for preparing substituted morpholine derivatives".

[0002] Cross-reference to related applications

[0003] This application claims priority to U.S. Provisional Application No. 63 / 321,423, filed March 18, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0004] This article describes methods for preparing derivatives and prodrugs of substituted morpholines or pharmaceutically acceptable salts thereof. Background Technology

[0005] The compound 2-((2-ethoxyphenoxy)methyl)morpholine is known to have 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 has been associated with numerous side effects, including nausea, vomiting, loss of appetite, increased erythrocyte sedimentation rate, abnormal EKG and EEG, epigastric pain, diarrhea, constipation, dizziness, orthostatic hypotension, lower extremity edema, dysarthria, tremor, psychomotor agitation, confusion, inappropriate secretion of antidiuretic hormone, increased transaminases, and seizures.

[0006] 2-((2-ethoxyphenoxy)methyl)morpholine is a chiral molecule whose desired biological properties are related to its (S)-enantiomer, which is known to exhibit five times greater pharmacological activity than the (R)-(+)-enantiomer. For example, see “Optical Isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4oxazine (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. Optical isomers of viloxazine analogs with known configurations were synthesized by resolving the intermediate 4-benzyl-2-(p-toluenesulfonyloxymethyl)tetrahydro-1,4-oxazine isomer.

[0007] 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 illustrated in U.S. Application Serial No. 63 / 162,671, the entire contents of which are incorporated herein by reference. Prodrugs are a class of derivatives that, in many cases, have little or no pharmacological activity and are converted in vivo into therapeutically active compounds. In some cases, prodrugs themselves may possess biological activity. Prodrug activation can occur via enzymatic or non-enzymatic cleavage of the temporary bond between the carrier and the drug molecule, or both sequentially or in combination. Additional methods for synthesizing 2-((2-ethoxyphenoxy)methyl)morpholine prodrugs would be beneficial.

[0008] Prodrugs can provide compounds with superior physicochemical properties compared to the parent molecule, thereby overcoming barriers to absorption, distribution, metabolism, excretion, and toxicity (ADMET). These prodrugs may exhibit improved absorption, solubility, permeability, stability, and pharmacokinetic properties. Prodrugs may also 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 can be converted to the parent drug via enzymatic or non-enzymatic processes. 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 with alkyl, aralkyl, acyl, carbamoyl, acyloxy, and combinatorial groups (e.g., diacyl acetal or acyl hydroxyalkyl). Other examples are described in the literature (see Yang, Liu et al., Acta Pharmaceutica Sinica B 2011:1(3), 143-159 and the references described therein).

[0009] Newly synthesized 2-((2-ethoxyphenoxy)methyl)morpholine analogs, prodrugs, enantiomers, and derivatives (derivative of the morpholinoamine group in the structure of 2-((2-ethoxyphenoxy)methyl)morpholine) produce chemically stable compounds that can 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 the treatment of central nervous system (CNS) disorders, or as intermediates in preparation.

[0010] The previously disclosed synthesis of these 2-((2-ethoxyphenoxy)methyl)morpholine analogs, prodrugs, and derivatives has many drawbacks, such as low reaction yields, reaction byproducts, difficulties in enantiomer separation, and the presence of impurities in the resulting products. Effective elimination or removal of impurities, especially those with genotoxic or other toxic effects, is crucial for ensuring drug safety. This article discloses solutions to these and other related problems.

[0011] It is also desirable to prepare (S)-enantiomers of 2-((2-ethoxyphenoxy)-methyl)morpholine analogs, prodrugs, and derivatives via a route that does not require the separation of precursors, and the method described herein provides a solution to this problem. Summary of the Invention

[0012] This paper presents new and improved methods for the preparation of morpholine derivatives and their various salts, as well as methods for the preparation of novel intermediate products. Synthetic methods for novel morpholine derivative intermediates, along with their identification and characterization, are also provided.

[0013] In one aspect, the present invention provides a method for manufacturing a morpholine derivative of formula (IIb) or a pharmaceutically acceptable salt thereof: The method includes:

[0014] (a) Make the following compound:

[0015]

[0016] It reacts with (S)-(+)-epiochlorohydrin to form chlorohydrin compounds of the following formula:

[0017]

[0018] (b) Contacting the chlorohydrin compound with a base and a phase transfer catalyst to form an epoxy compound of the following formula:

[0019]

[0020] (c) Contact the epoxy compound with a base and a compound of the following formula: To form diol compounds of the following formula:

[0021]

[0022] (d) Contact the diol compound with a base, and then add a sulfonyl halide to form an intermediate sulfonate ester of the following formula:

[0023] Where Z is a sulfonyl leaving group.

[0024] The intermediate sulfonate ester is cyclized in situ to yield an N-benzyl-protected morpholine compound of the following formula:

[0025] as well as

[0026] (e) Forming an HCl salt of the compound of formula IIb and recrystallizing it to obtain a high-purity (S)-enantiomer in the form of an HCl salt;

[0027] Where R 1 It is a C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; and each R 2 It is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl or heterocyclic alkyl; and n is 0, 1, 2, 3 or 4.

[0028] In one embodiment, the present invention provides a method for manufacturing a morpholine derivative of formula (IIb) or a pharmaceutically acceptable salt thereof: The method includes:

[0029] (a) Make the following compound:

[0030]

[0031] Reaction with (S)-(+)-epiochlorohydrin to form chlorohydrin compounds of the following formula

[0032]

[0033] (b) Contacting the chlorohydrin compound with a base and a phase transfer catalyst to form an epoxy compound of the following formula:

[0034]

[0035] (c) Contact the epoxy compound with a base and a compound of the following formula: To form diol compounds of the following formula:

[0036]

[0037] (d) Contact the diol compound with a base, and then add a sulfonyl halide to form an intermediate sulfonate ester of the following formula:

[0038] Where Z is a sulfonyl leaving group.

[0039] The intermediate sulfonate ester is cyclized in situ to yield an N-benzyl-protected morpholine compound of the following formula:

[0040] as well as

[0041] (e) Forming an HCl salt of the compound of formula IIb and recrystallizing it to obtain a high-purity (S)-enantiomer in the form of an HCl salt;

[0042] Where R 1 It is a C1-C6 alkyl, aryl, or heteroaryl group; and each R 2 It is independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl or heteroaryl; and n is 0, 1, 2, 3 or 4.

[0043] In another aspect, the present invention provides a method for manufacturing a morpholine derivative or prodrug of formula (IIf) or a pharmaceutically acceptable salt thereof: The method includes:

[0044] (a) Make the following compound:

[0045]

[0046] It reacts with (S)-(+)-epiochlorohydrin to form chlorohydrin compounds of the following formula:

[0047]

[0048] (b) Contacting the chlorohydrin compound with a base and a phase transfer catalyst to form an epoxy compound of the following formula:

[0049]

[0050] (c) Contact the epoxy compound with a base and a compound of the following formula: To form diol compounds of the following formula:

[0051]

[0052] (d) Contact the diol compound with a base, and then add a sulfonyl halide compound to form an intermediate sulfonate ester of the following formula:

[0053] Where Z is a sulfonyl leaving group.

[0054] The intermediate sulfonate is cyclized in situ to form an N-benzyl-protected morpholine compound of the following formula:

[0055]

[0056] (e) Forming an HCl salt of the compound of formula (IIb) and recrystallizing it to obtain a high-purity (S)-enantiomer in the form of an HCl salt;

[0057] (f) Convert the HCl salt of compound (IIb) into a free base;

[0058] (g) Contact the N-benzyl-protected morpholine compound with a chloroformate of the following formula: To form the intermediate N-benzylchlorocarbamate of the following formula:

[0059]

[0060] Upon heating, benzyl chloride is lost, yielding the following compound:

[0061]

[0062] (h) Add the chlorocarbamate compound to the metal salt of the amino acid derivative of the following formula: The amino acid derivatives mentioned above have been pretreated with a metal compound carbonate to form a protected amine of the following formula:

[0063] as well as

[0064] (i) Contacting the protected amine with an acid to provide the morpholine derivative having the following formula:

[0065]

[0066] Where R 1 It is a C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; each R 2 Independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; R 3 It is a C1-C6 alkyl group, R 4 It is a C1-C6 alkyl group, R 5 It is an amino protecting group; and n is 0, 1, 2, 3 or 4.

[0067] In one embodiment, the present invention provides a method for manufacturing a morpholine derivative or prodrug of formula (IIf) or a pharmaceutically acceptable salt thereof: The method includes:

[0068] (a) Make the following compound:

[0069]

[0070] It reacts with (S)-(+)-epiochlorohydrin to form chlorohydrin compounds of the following formula:

[0071]

[0072] (b) Contacting the chlorohydrin compound with a base and a phase transfer catalyst to form an epoxy compound of the following formula:

[0073]

[0074] (c) Contact the epoxy compound with a base and a compound of the following formula: To form diol compounds of the following formula:

[0075]

[0076] (d) Contact the diol compound with a base, and then add a sulfonyl halide to form an intermediate sulfonate ester of the following formula:

[0077] Where Z is a sulfonyl leaving group;

[0078] The intermediate sulfonate is cyclized in situ to form an N-benzyl-protected morpholine compound of the following formula:

[0079]

[0080] (e) Forming an HCl salt of the compound of formula (IIb) and recrystallizing it to obtain a high-purity (S)-enantiomer in the form of an HCl salt;

[0081] (f) Convert the HCl salt of compound (IIb) into a free base;

[0082] (g) Contact the N-benzyl-protected morpholine compound with a chloroformate of the following formula: To form the intermediate N-benzylchlorocarbamate of the following formula

[0083]

[0084] Upon heating, benzyl chloride is lost, yielding the following compound:

[0085]

[0086] (h) Add the chlorocarbamate compound to the metal salt of the amino acid derivative of the following formula: The amino acid derivatives mentioned above have been pretreated with a metal compound to form a protected amine of the following formula:

[0087] as well as

[0088] (i) Contacting the protected amine with an acid to provide the morpholine derivative having the following formula:

[0089]

[0090] Where R 1 It is a C1-C6 alkyl, aryl, or heteroaryl group; each R 2 Independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl; R 3 It is a C1-C6 alkyl group, R 4 It is a C1-C6 alkyl group, R 5 It is an amino protecting group; and n is 0, 1, 2, 3 or 4.

[0091] Further features can be understood by referring to the accompanying drawings, which should be read in conjunction with the following detailed description and embodiments. Attached Figure Description

[0092] Figure 1 The X-ray structure of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HBr was shown.

[0093] Figure 2 Compound 4 from Example 8 is shown. 1 H NMR spectrum.

[0094] Figure 3 Compound 6 from Example 8 is shown. 1 H NMR spectrum.

[0095] Figure 4 Compound 7 from Example 8 is shown. 1 H NMR spectrum.

[0096] Figure 5 Compound 12 from Example 8 is shown. 1 H NMR spectrum.

[0097] Figure 6 The synthetic method for preparing compound 12 (compound A) in Example 8 is shown.

[0098] Figure 7 The synthetic methods for preparing compounds B and C are demonstrated. Detailed Implementation

[0099] definition

[0100] The following terms are used throughout the text as defined below.

[0101] As used herein and in the appended claims, unless otherwise indicated herein or the context clearly contradicts, the singular articles such as “a / an” and “the”, and similar pronouns, shall be construed to cover both the singular and plural forms in the context of describing elements (particularly in the context of the following claims). Unless otherwise indicated herein, the description of value ranges herein is intended only 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 may be performed in any suitable order. Unless otherwise stated, any and all instances of language used, or exemplary language provided herein (e.g., “as”), are intended only to better illustrate the embodiments and do not limit the scope of the claims. The language in this specification should not be construed as indicating that any unclaimed element is necessary.

[0102] As used herein, “about” will be understood by those skilled 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 those skilled in the art, then given the context in which it is used, “about” will mean plus or minus 10% of a particular term.

[0103] Generally, mentioning an element such as hydrogen or H means including all isotopes of that element. For example, if the R group is defined as including hydrogen or H, it also includes deuterium and tritium. Therefore, it includes radioactive isotopes such as tritium, C, etc. 14 P 32 and S 35The compounds described herein are within the scope of this technology. Based on the disclosure herein, the procedure for inserting such markings into compounds of this technology will be apparent to those skilled in the art.

[0104] Generally, "substitution" refers to an organic group (e.g., an alkyl group) as defined below, in which one or more bonds with hydrogen atoms are replaced by bonds with non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds with carbon or hydrogen atoms are replaced by one or more bonds with heteroatoms (including double or triple bonds). Therefore, unless otherwise stated, a substituted group is substituted with one or more substituents. In some embodiments, the substituted group is substituted with one, two, three, four, five, or six substituents. Examples of substituents include: halogens (i.e., F, Cl, Br, and I); hydroxyl groups; alkoxy, alkenoxy, aryloxy, arylalkoxy, heterocyclic alkyl, heterocyclic alkyl-alkyl, heterocyclic alkyl-oxy, and heterocyclic alkylalkoxy; carbonyl (oxo); carboxylic esters; esters; polyurethanes; oximes; hydroxylamines; alkoxyamines; arylalkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyl groups; pentafluorothioalkyl (i.e., SF5); sulfonamides; amines; N-oxides; hydrazines; acyl hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imides; nitro groups; nitriles (i.e., CN); and so on.

[0105] As used herein, "alkyl" includes straight-chain and branched alkyl groups having 1 to 20 carbon atoms, and typically 1 to 12 carbon atoms, 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 alkyl groups include, but are not limited to, isopropyl, sec-butyl, tert-butyl, neopentyl, and isopentyl. Representative substituted alkyl groups may be substituted once or more by, for example, amino, thio, hydroxyl, cyano, alkoxy, and / or halogen groups (such as F, Cl, Br, and I). As used herein, the term "haloalkyl" is an alkyl group having one or more halogen groups. In some embodiments, haloalkyl refers to perhaloalkyl.

[0106] Cycloalkyl groups are cyclic alkyl groups, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 6, or 7. Cycloalkyl groups can be substituted or unsubstituted. Cycloalkyl groups also include polycyclic cycloalkyl groups, such as, but not limited to, norbornel, adamantyl, bornel, camphenyl, isocamphenyl, and caretenyl, as well as fused rings, such as, but not limited to, decahydronaphthyl. Cycloalkyl groups also include rings substituted with straight-chain or branched alkyl groups 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 by, for example, alkyl, alkoxy, amino, thio, hydroxy, cyano and / or halogen groups.

[0107] An alkenyl group is a straight-chain, branched, or cyclic alkyl group having 2 to 20 carbon atoms and including at least one double bond. In some embodiments, the alkenyl group has 1 to 12 carbon atoms, or typically 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 having two bonding sites, include, but are not limited to, CH-CH=CH2, C=CH2, or C=CHCH3.

[0108] As used herein, the term "aryl" or "aromatic" refers to a cyclic aromatic hydrocarbon that does not contain heteroatoms. Aryl groups include monocyclic, bicyclic, and polycyclic systems. Therefore, aryl groups include, but are not limited to, phenyl, azulel, phenanthrene, cyclopentadiene, diphenylene, fluorene, phenanthrene, triphenylene, pyrene, tetraphenylene, trunyl, biphenyl, anthracene, indene, indanyl, cyclopentadiene, and naphthyl. In some embodiments, the aryl group contains 6-14 carbon atoms; 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., indene, tetrahydronaphthyl, etc.). Aryl groups can be substituted or unsubstituted.

[0109] 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. A "heteroaryl" can consist of two or more fused rings (rings sharing two adjacent atoms). When a heteroaryl is a fused-ring system, the ring attached to the rest of the molecule has a fully delocalized π-electron system. Other rings in a fused-ring system may or may not have a fully delocalized π-electron system. Examples of heteroaryl rings include, but are not limited to, furans, thiophenes, diazonides, pyrroles, oxazoles, thiazoles, imidazoles, pyrazoles, isoxazoles, isothiazoles, triazoles, thiadiazoles, pyridines, pyridazines, pyrimidines, pyrazines, and triazines.

[0110] Whenever “heterogeneous” is used, it is intended to indicate a specified group, such as an alkyl or aryl group, in which at least one carbon atom has been replaced by a heteroatom selected from nitrogen, oxygen, and sulfur.

[0111] As used herein, "heterocyclic alkyl" refers to a ring system having one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. The ring may also contain one or more double bonds, provided they do not form a fully delocalized π-electron system within the ring. The ring as defined herein can be a stable 3- to 18-membered ring consisting of a carbon atom and one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The heterocyclic alkyl groups of the compounds disclosed herein 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, alkylsulfonamide, and trifluoromethanesulfonamide. "Heterocyclic alkyl" can consist of two or more fused rings (rings sharing two adjacent atoms). When the heterocyclic alkyl is a fused ring system, the ring attached to the remainder of the molecule is a heterocyclic alkyl as defined above. The other rings in a fused ring system can be cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclic alkyl.

[0112] As used in this article, the term "carboxylic acid ester" refers to the conjugate base of a carboxylic acid having the chemical formula -COO.

[0113] As used in this article, the term "ester" refers to -COOR b - and -C(O)OG groups. R bIt is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclic alkyl-alkyl, or heterocyclic alkyl group as defined herein. G is a carboxylate protecting group. Carboxylate protecting groups are well known to those skilled 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). Protecting groups can be added or removed using the procedures set forth therein, and the aforementioned literature is hereby incorporated in its entirety and for any and all purposes, as fully set forth herein.

[0114] The term "amide" (or "amide group") includes C- and N-amide groups, namely C(O)NR, respectively. c R d And -NRC(O)-R group. R c and R d Independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl-alkyl, or heterocycloalkyl as defined herein. Amide groups therefore include, but are not limited to, carbamoyl (-C(O)NH2) and formamido (NHC(O)H). In some embodiments, the amide is –NRC(O)-(C 1-5 The amide is an alkyl group and the group is referred to as "carbonylamino". In other embodiments, the amide is an -NHC(O)-alkyl group and the group is referred to as "alkanoylamino".

[0115] As used in this article, the term "amine" (or "amino group") refers to -NR e R f Group, wherein R e and R f The amine 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. In other embodiments, the amine is NH2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.

[0116] As used herein, the term "halogen" or "halogen group" refers to bromine (Br), chlorine (Cl), fluorine (F), or iodine (I). In some embodiments, the halogen is chlorine (Cl).

[0117] 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" may be combined with a prefix indicating the number of amino acids in the peptide; for example, "pentapeptide" is a peptide having five amino acids.

[0118] The term "amino acid" is recognized in the art and generally refers to natural or non-natural α or β amino acids. The term "amino acid" includes, but is not limited to, any of the standard L-amino acids commonly found in naturally occurring peptides or non-natural amino acids, D-isomers of amino acids, or racemic amino acids.

[0119] As used herein, the term "amino acid residue having a hydrophobic side chain" refers to the following amino acids: alanine (Ala), valine (Val), isoleucine (Ile), leucine (Leu), methionine (Met), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), or non-natural amino acids, including but not limited to ortholeucine, orthovaline, cyclohexylalanine, cyclohexylglycine, cyclopentylglycine, etc. In some embodiments, the amino acid residue having a hydrophobic side chain is valine (Val). In other embodiments, the amino acid residue may be racemic or chiral (L-amino acid (S-configuration) or D-amino acid (R-configuration)), such as L-valine ((S)-valine) or D-valine ((R)-valine)).

[0120] As used in this article, the term "acetyl" refers to a methyl group (CH3CO-) bonded to a carbonyl group.

[0121] Pharmaceutically acceptable salts of the compounds described herein are within the scope of this technology and include acid or base addition salts that retain the desired pharmacological activity and are not biologically undesirable (e.g., the salt is not excessively toxic, allergenic, or irritating, and is bioavailable). When the compounds of this technology have a basic group (e.g., an amino group), they can form pharmaceutically acceptable salts with inorganic acids (e.g., hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., 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 (e.g., aspartic acid and glutamic acid). When the compounds of this technology have an acidic group (e.g., a carboxylic acid group), they can form pharmaceutically acceptable salts with metals such as alkali metals and alkaline earth metals (e.g., Na). + Li + K + Ca 2+ Mg 2+ or Zn 2+Salts can be formed from ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, triethylamine, pyridine, methylpyridine, ethanolamine, diethanolamine, or triethanolamine) or basic amino acids (e.g., arginine, lysine, or ornithine). These salts can be prepared in situ during the isolation and purification of the compound, or by reacting the purified compound, in its free base or free acid form, separately with a suitable acid or base and then isolating the resulting salt.

[0122] Unless otherwise specified in the stereochemistry, stereoisomers (also known as optical isomers) of a compound include all chiral, diastereomeric, and racemic forms of the structure. Therefore, as is apparent from the description, compounds used in this technique include optical isomers enriched or resolved at any or all asymmetric atoms. Mixtures of racemic and diastereomeric isomers, as well as individual optical isomers, can be isolated or synthesized, thus substantially free of their enantiomers or diastereomeric counterparts, and these stereoisomers are all within the scope of this technique.

[0123] The term “pharmaceuticalally acceptable excipient” refers to substances that are widely accepted by industry and regulatory bodies, such as those listed in documents such as the USP-NF, the Food Chemicals Codex, the Federal Regulations (CFR), the FDA Guidelines for Inactive Ingredients, and monographs published in the summary of Parts 182 and 184 of 21 CFR that list substances generally considered safe (GRAS) food ingredients.

[0124] method

[0125] This article presents a novel method for manufacturing morpholine derivatives, prodrugs, and their pharmaceutically acceptable salts, in which the synthetic approach is improved, the stereochemistry is controlled, and impurities are reduced, thereby providing materials suitable for pharmaceutical applications.

[0126] On the one hand, this article provides a method for manufacturing morpholine derivatives of formula (IIb) or pharmaceutically acceptable salts thereof: The method includes:

[0127] (a) Make the following compound:

[0128]

[0129] It reacts with (S)-(+)-epiochlorohydrin to form chlorohydrin compounds of the following formula:

[0130]

[0131] (b) Contacting the chlorohydrin compound with a base and a phase transfer catalyst to form an epoxy compound of the following formula:

[0132]

[0133] (c) Contact the epoxy compound with a base and a compound of the following formula: To form diol compounds of the following formula:

[0134] as well as

[0135] (d) Contact the diol compound with a base, and then add a sulfonyl halide compound to form an intermediate sulfonate ester of the following formula:

[0136] Where Z is a sulfonyl leaving group.

[0137] The intermediate sulfonate ester is cyclized in situ to give an N-benzyl-protected morpholine compound (IIb) of the following formula:

[0138] as well as

[0139] (e) Forming an HCl salt of the compound of formula IIb and recrystallizing it to obtain a high-purity (S)-enantiomer HCl salt;

[0140] Where R 1 It is a C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; and each R 2 It is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl or heterocyclic alkyl; and n is 0, 1, 2, 3 or 4.

[0141] On the other hand, this article provides a method for manufacturing morpholine derivatives or prodrugs or pharmaceutically acceptable salts thereof, the method comprising:

[0142] (a) Make the following compound:

[0143]

[0144] It reacts with (S)-(+)-epiochlorohydrin to form chlorohydrin compounds of the following formula:

[0145]

[0146] (b) Contacting the chlorohydrin compound with a base and a phase transfer catalyst to form an epoxy compound of the following formula:

[0147]

[0148] (c) Contact the epoxy compound with a base and a compound of the following formula: To form diol compounds of the following formula:

[0149]

[0150] (d) The diol compound is contacted with a base and a sulfonyl halide to form an intermediate sulfonate ester, which is then cyclized to form an N-benzyl-protected morpholine compound of the following formula:

[0151]

[0152] (e) Forming an HCl salt of the compound of formula (IIb) and recrystallizing it to obtain a high-purity (S)-enantiomer in the form of an HCl salt; and

[0153] (f) Convert the HCl salt of compound (IIb) into a free base;

[0154] (g) Contact the N-benzyl-protected morpholine compound with a chloroformate of the following formula: To form the intermediate N-benzylchlorocarbamate of the following formula:

[0155]

[0156] Upon heating, benzyl chloride is lost, yielding the following compound:

[0157]

[0158] (h) Add the chlorocarbamate compound to the metal salt of the amino acid derivative of the following formula: The amino acid derivatives mentioned above have been pretreated with a metal compound to form a protected amine of the following formula:

[0159] as well as

[0160] (i) Contacting the protected amine with an acid to provide the morpholine derivative having the following formula:

[0161]

[0162] Where R 1 It is a C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; each R 2 Independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; R 3 It is a C1-C6 alkyl group, R 4 It is a C1-C6 alkyl group, R 5 It is an amino protecting group; and n is 0, 1, 2, 3 or 4.

[0163] For convenience and without imposing any limitations, the method for manufacturing morpholine derivatives is divided into several steps, each of which is disclosed herein with multiple non-limiting embodiments. These steps include steps a), b), c), d), e), f), g), h), and i) described above.

[0164] The above steps will be considered in more detail below.

[0165] The process in step a) can advantageously be carried out in the presence of a solvent. In some embodiments, the solvent is methanol. Alternatively, the process can also be heated. In an embodiment, the reaction is heated to a temperature of about 35°C.

[0166] The process in step b) can advantageously be carried out in the presence of a phase transfer catalyst. The process can also advantageously be carried out in the presence of a base. In some embodiments, the base is NaOH. The process may include one or more solvents as part of a 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 contains water. In some embodiments, the liquid-liquid two-phase system contains methyl tert-butyl ether (MTBE). The phase transfer catalyst may 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 tetrabutylammonium bisulfate. In some embodiments, the process can be operated at room temperature.

[0167] Step c) can be advantageously carried out in the presence of a base. In some embodiments, the base is Cs₂CO₃. In some embodiments, the base can be added in batches. The process may include one or more solvents as part of a solvent system. In some embodiments, the solvent system is a single-phase liquid system. In some embodiments, the solvent is toluene. Alternatively, the process may be heated after the base addition is complete. In some embodiments, the process may be heated to a temperature of about 110°C.

[0168] The process in step d) can advantageously be 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 may include one or more solvents as part of a solvent system. In some embodiments, the solvent system is a single-phase liquid system. In some embodiments, the solvent is toluene. Alternatively, the process may be heated after the addition of the base. In some embodiments, the process may be heated to a temperature of about 30°C. In some embodiments, the sulfonyl halide compound is selected from the group consisting of p-toluenesulfonyl chloride (toluenesulfonyl chloride), p-bromobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, and methanesulfonyl chloride. In some embodiments, the sulfonyl halide compound is p-toluenesulfonyl chloride (toluenesulfonyl chloride). Furthermore, after heating for a period of time, the process can be cooled to a lower temperature before the addition of 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 may 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 bases. In a preferred embodiment, the base is NaOH. The solvent used in the 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 variant, step d) is carried out in the presence of a phase transfer catalyst using a toluene solution of a diol in the presence of a solid or liquid base, wherein the reaction is cooled to 20°C before the batch addition of p-toluenesulfonyl chloride. After the reaction is complete, 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% (S) enantiomers. In some embodiments, the HCl salt contains more than 75% (S) enantiomers. In some embodiments, the HCl salt contains more than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the (S) enantiomers. In some embodiments, the HCl salt contains more than 95% of the (S) enantiomers. In some embodiments, the HCl salt contains more than 99% of the (S) enantiomers. In some embodiments, the HCl salt has an enantiomer excess of more than 75%. In some embodiments, the HCl salt has an enantiomer excess of more than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, the HCl salt has an enantiomer excess of more than 95%.In some embodiments, the HCl salt has an enantiomer excess of more than 99%. Variations of this embodiment of the invention are further disclosed in the Examples section (e.g., Example 8).

[0169] Step g) can advantageously be carried out in the presence of a solvent. In some embodiments, the solvent is dichloromethane. Alternatively, the process can be cooled before the addition of the chloroformate. In an embodiment, the reaction is cooled to a temperature of about 0°C.

[0170] 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, potassium salt, silver salt, or mercury salt. In some embodiments, the metal salt is a cesium salt. In some embodiments, the metal compound is a cesium compound, potassium compound, silver compound, or 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.

[0171] The process in step i) can advantageously be carried out in the presence of a solvent. In some embodiments, the solvent is ethyl acetate.

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

[0173] In some implementations, the compound of formula (IIa) is Where R 1 It is a C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; each R 2 Independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; and n is 0, 1, 2, 3, or 4. In some embodiments, R 2 Independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, R 2 Independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, each R 2 Independently selected from F, Cl, Br, I, C1-C6 alkyl or aryl. In some embodiments, each R 2 Independently selected from F, Cl, Br, I, or C1-C6 alkyl groups. 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 It is a C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl. In some embodiments, R 1 It is a C1-C6 alkyl group. In some embodiments, R 1 It is CH2CH3. In some implementations, R 1 It is CH3. In some embodiments, the compound of formula (IIa) is

[0174] In some implementations, the compound of formula (IIa') is Where R 1 It is a C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; each R 2 Independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; Z is a sulfonyl leaving group; and n is 0, 1, 2, 3, or 4. In some embodiments, R 2Independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, R 2 Independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, each R 2 Independently selected from F, Cl, Br, I, C1-C6 alkyl or aryl. In some embodiments, each R 2 Independently selected from F, Cl, Br, I, or C1-C6 alkyl groups. In some embodiments, Z is... In some implementation schemes, 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 It is a C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl group, and Z is a sulfonyl leaving group. In some embodiments, R 1 It is a C1-C6 alkyl group. In some embodiments, R 1 It is CH2CH3. In some implementations, R 1 It is CH3. In some embodiments, the compound of formula (IIa') is Z is a sulfonyl leaving group.

[0175] In some implementations, the compound of formula (IIb) is (IIb); where R 1 It is a C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; each R 2 Independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; and n is 0, 1, 2, 3, or 4. In some embodiments, R 2 Independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, R 2 Independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, each R 2 Independently selected from F, Cl, Br, I, C1-C6 alkyl or aryl. In some embodiments, each R 2 Independently selected from F, Cl, Br, I, or C1-C6 alkyl groups. 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 It is a C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl. In some embodiments, R1 It is a C1-C6 alkyl group. In some embodiments, R 1 It is CH2CH3. In some implementations, R 1 It is CH3. In some embodiments, the compound of formula (IIb) is

[0176] In some implementations, the compound of formula (Ic) is Where R 3 It is a C1-C6 alkyl group. In some embodiments, R 3 It is -CH3. In some implementations, R 3 It is -CH2CH3. In some implementations, R 3 It is -CH(CH3)2. In some embodiments, the compound of formula (Ic) is In some implementations, the compound of formula (Ic) is

[0177] In some implementations, the compound of formula (IIc) is Where R 1 It is a C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; each R 2 Independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; R 3 It is a C1-C6 alkyl group, and n is 0, 1, 2, 3, or 4. In some embodiments, R 2 Independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, R 2 Independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, each R 2 Independently selected from F, Cl, Br, I, C1-C6 alkyl or aryl. In some embodiments, each R 2 Independently selected from F, Cl, Br, I, or C1-C6 alkyl groups. 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 It is a C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl. In some embodiments, R 1 It is a C1-C6 alkyl group. In some embodiments, R 1 It is CH2CH3. In some implementations, R 1 It is CH3. In some embodiments, the compound of formula (IIc) is

[0178] In some implementations, the compound of formula (IId) is Where R 1 It is a C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; each R 2 Independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; R 3 It is a C1-C6 alkyl group, and n is 0, 1, 2, 3, or 4. In some embodiments, R 2 Independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, R 2 Independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, each R 2 Independently selected from F, Cl, Br, I, C1-C6 alkyl or aryl. In some embodiments, each R 2 Independently selected from F, Cl, Br, I, or C1-C6 alkyl groups. 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 implementation schemes, R 1 It is a C1-C6 alkyl group and R 3 It is a C1-C6 alkyl group. In some embodiments, R 1 It is -CH2CH3. In some implementations, R 1 It is -CH3. In some implementations, R 3 It is -CH3. In some implementations, R 3 It is -CH2CH3. In some implementations, R 3 It is -CH(CH3)2. In some embodiments, the compound of formula (IId) is In some implementations, the compound of formula (IId) is In some implementations, the compound of formula (IId) is

[0179] In some implementations, the compound of formula (Id) is Where R 4 It is a C1-C6 alkyl group, R 5 It is an amino protecting group. In some embodiments, it is linked with R. 4 The carbon atom of the substituent has an (R) configuration. In some embodiments, R is attached. 4 The carbon atom of the substituent has an (S) configuration. In some embodiments, the compound of formula (Id) is In some implementations, the compound of formula (Id) is In some implementation schemes, R 4 It is -CH3. In some implementations, R 4 It is -CH2CH3. In some implementations, R 4 It is -CH(CH3)2. In some embodiments, the compound of formula (Id) is In some implementations, the compound of formula (Id) is In some implementation schemes, R 5 It is a tert-butoxycarbonyl (Boc). In some embodiments, R 5 It is carboxybenzyl (Cbz).

[0180] In some implementations, the compound of formula (IIe) is Where R 1 It is a C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; each R 2 Independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; R 3 It is a C1-C6 alkyl group, R 4 It is a C1-C6 alkyl group, R 5 It is an amino protecting group; and n is 0, 1, 2, 3, or 4. In some embodiments, it is linked with R. 4 The carbon atom of the substituent has an (R) configuration. In some embodiments, R is attached. 4 The carbon atom of the substituent has an (S) configuration. In some embodiments, the compound of formula (IIe) is... In some implementations, the compound of formula (IIe) is In some implementation schemes, R 2 Independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, R 2 Independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, each R 2 Independently selected from F, Cl, Br, I, C1-C6 alkyl or aryl. In some embodiments, each R 2 Independently selected from F, Cl, Br, I, or C1-C6 alkyl groups. 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 implementation schemes, R 1 It is a C1-C6 alkyl group and R 3 It is a C1-C6 alkyl group. In some embodiments, R 1It is -CH2CH3. In some implementations, R 1 It is -CH3. In some implementations, R 3 It is -CH3. In some implementations, R 3 It is -CH2CH3. In some implementations, R 1 It is -CH(CH3)2. In some implementations, R 4 It is -CH3. In some implementations, R 4 It is -CH2CH3. In some implementations, R 4 It is -CH(CH3)2. In some implementations, R 5 It is a tert-butoxycarbonyl (Boc). In some embodiments, R 5 It is a carboxybenzyl (Cbz). In some embodiments, the compound of formula (IIe) is... In some implementations, the compound of formula (IIe) is In some implementations, the compound of formula (IIe) is In some implementations, the compound of formula (IIe) is

[0181] In some implementations, the compound of formula (IIf) is Where R 1 It is a C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; each R 2 Independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; R 3 It is a C1-C6 alkyl group, R 4 It is a C1-C6 alkyl group, and n is 0, 1, 2, 3, or 4. In some embodiments, R is attached. 4 The carbon atom of the substituent has an (R) configuration. In some embodiments, R is attached. 4 The carbon atom of the substituent has an (S) configuration. In some embodiments, the compound of formula (IIf) is... In some implementations, the compound of formula (IIf) is In some implementation schemes, R 2 Independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, R 2 Independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, each R 2 Independently selected from F, Cl, Br, I, C1-C6 alkyl or aryl. In some embodiments, each R 2Independently selected from F, Cl, Br, I, or C1-C6 alkyl groups. 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 implementation schemes, R 1 It is a C1-C6 alkyl group and R 3 It is a C1-C6 alkyl group. In some embodiments, R 1 It is -CH2CH3. In some implementations, R 1 It is -CH3. In some implementations, R 3 It is -CH3. In some implementations, R 3 It is -CH2CH3. In some implementations, R 1 It is -CH(CH3)2. In some implementations, R 4 It is -CH3. In some implementations, R 4 It is -CH2CH3. In some implementations, R 4 It is -CH(CH3)2. In some embodiments, the compound of formula (IIf) is In some implementations, the compound of formula (IIf) is In some implementations, the compound of formula (IIf) is In some implementations, the compound of formula (IIf) is

[0182] In some implementation schemes, R 1 It is a C1-C6 alkyl group. In some embodiments, R 1 It is -CH3. In some implementations, R 1 It is -CH2CH3. In some implementations, R 1 It is -CH(CH3)2.

[0183] In some implementations, each R 2 Independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl. In some embodiments, R 2 Independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, R 2 Independently selected from F, Cl, Br, I, CN, C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, each R 2 Independently selected from F, Cl, Br, I, C1-C6 alkyl or aryl. In some embodiments, each R 2Independently selected from F, Cl, Br, I, CN, NO2, or C1-C6 alkyl groups. In some embodiments, each R 2 Independently selected from F, Cl, Br, I, or C1-C6 alkyl groups. In some embodiments, each R 2 The components are independently selected from F, Cl, Br, I, CN, -CH3, or -CH2CH3. In some embodiments, each R... 2 Independently selected from F, Cl, Br, I, -CH3. In some implementations, each R 2 It is independently aryl, heteroaryl, or heterocycloalkyl. In some embodiments, R 2 It is F. In some implementations, R 2 It is Cl. In some implementations, R 2 It is Br. In some implementations, R 2 It is I. In some implementations, R 2 It is CN. In some implementations, R 2 It is NO2. In some implementations, R 2 It is a C1-C6 alkyl group. In some embodiments, R 2 It is CH3. In some implementations, R 2 It is CH2CH3. In some implementations, R 2 It is aryl. In some implementations, R 2 It is a heteroaryl group. In some implementations, R 2 It is a heterocyclic alkyl group.

[0184] In some implementation schemes, R 3 It is a C1-C6 alkyl group. In some embodiments, R 3 It is -CH3. In some implementations, R 3 It is -CH2CH3. In some implementations, R 3 It is -CH(CH3)2.

[0185] In some implementation schemes, R 4 It is a C1-C6 alkyl group. In some embodiments, R 4 It is -CH3. In some implementations, R 4 It is -CH2CH3. In some implementations, R 4 It is -CH(CH3)2.

[0186] In some implementation schemes, R 5 It is an amino protecting group. In some embodiments, R 5 It is a tert-butoxycarbonyl (Boc). In some embodiments, R 5 It is a carboxybenzyl (Cbz). In some embodiments, R5 It is 9-fluorenylmethoxycarbonyl (Fmoc). In some embodiments, R 5 It is benzyl (Bn).

[0187] In some implementation schemes, Z is In some implementation schemes, Z is

[0188] In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4.

[0189] The following non-limiting examples illustrate other implementation schemes.

[0190] Example

[0191] Example 1. Synthesis of (S)-2-((2-ethoxyphenoxy)methyl)morpholine

[0192] Option I.

[0193]

[0194] This synthetic route has previously been reported in US Patent US9403783B2.

[0195] Potassium carbonate (82.93 g, 600 mmol; 3 equivalents) and tetrabutylammonium sulfate (3.4 g, 10 mmol, 0.05 equivalents) were placed in a flask, and 74 g (800 mmol; 4 equivalents) of R-(-)-epimerinol was added, followed by 27.63 g of 2-ethoxyphenol (2,200 mmol, 1 equivalent) dissolved in 30 mL of THF. The mixture was heated to 55 °C overnight under N2. After cooling to room temperature, 300 mL of water was added and the solution was extracted with ethyl acetate (3×). The combined extracts were washed with brine (twice), dried over MgSO4, filtered, and concentrated. The remaining oil was then dissolved in 100 mL of toluene and evaporated (to remove excess epichlorohydrin). This process was repeated four times to give 50 g of a yellow oily epoxy ether.

[0196] 141 g; 1 mol; 5 equivalents of 2-aminoethyl hydrogen sulfate was placed in a 1 L flask, and 7.5 equivalents of 60% KOH prepared from 100 g KOH and 67 mL of water were added. Then, 50 g of crude epoxy ether dissolved in 200 mL of methanol was added. After heating at 55 °C for 2 hours, another 7.5 equivalents of 60% KOH were added, and the mixture was heated at 55 °C overnight. After cooling, the mixture was evaporated to remove methanol, and the residue was diluted with water and extracted with ethyl acetate (5×). The combined extracts were washed with brine (3 times), dried over MgSO4, and evaporated to give 49 g of crude (S)-2-((2-ethoxyphenoxy)methyl)morpholine free base as a yellow oil. The crude oily substance was dissolved in 100 mL of ethanol, and then 50 mL of a dioxane solution of 4N HCl diluted with 50 mL of ethyl acetate was added. Initially, a clear solution was obtained, and the solid HCl salt precipitated within approximately 2 minutes. The suspension was maintained at room temperature for 5 hours, and then the solid salt was filtered off and washed with ethyl acetate. The salt was dried in air under high vacuum to give 17.15 g of (S)-2-((2-ethoxyphenoxy)methyl)morpholine HCl salt. The product showed a single peak on HPLC, and the S content was determined to be 94.58% by SFC analysis.

[0197] The above process was repeated at a scale of 200 or 300 mmol. After mixing the batches and drying the samples under high vacuum, a total of 74.46 g of (S)-2-((2-ethoxyphenoxy)methyl)morpholine HCl was obtained. Chiral SFC analysis showed that the S content was 92.724%. 13 H 20 Analytical values ​​of NO3Cl: C, 57.04; H, 7.36; N, 5.12; Cl, ​​12.95. Experimental values: C, 56.82; H, 6.86; N, 5.00; Cl, ​​12.94.

[0198] Example 2. Synthesis of morpholine analogs from racemic 2-((2-ethoxyphenoxy)methyl)morpholine HCl

[0199] Option II.

[0200]

[0201] The numbering conventions of the compounds described in Example 2 below correspond to the compound numbering shown in Scheme II.

[0202] In exploratory studies, the process was improved with several novel modifications. These modifications included the use of a free base of 2-((2-ethoxyphenoxy)methyl)morpholine and diisopropylethylamine as a base catalyst in the first step, and the use of only 1.0 equivalent of chloroformate 2. Intermediate 3 was separated by extraction without the need for chromatography (avoiding the decomposition observed during chromatography of 3 on silica gel). The condensation reaction of 3 with Boc-L-valine (4) was carried out by initially forming a Cs salt in DMF and proceeding with condensation until intermediate 3 was consumed. Crude product 5 was dissolved in ethyl acetate and washed with water and sodium bicarbonate to give compound BOC 5, which appeared as a single spot on TLC and a single peak on HPLC. Treatment of the ethyl acetate solution of 5 with 2NHCl in dioxane gave product HCl salt 6. In the exploratory study, a portion of the product, in the form of a white solid, was separated by filtering the crude suspension in ethyl acetate / dioxane, with an overall yield of 34% (compared to a yield of 22% reported in U.S. Provisional Application Serial No. 63 / 162,671) and a syrupy liquid mother liquor with a purity of approximately 80%.

[0203] The initial scale-up was carried out using the aforementioned process, in four batches, yielding a total of 57g of solid HCl salt 6.

[0204] The samples were examined to assess whether scaling up the synthesis affected the ratio of diastereomers. Therefore, a portion of substance 6 was hydrolyzed with 1N NaOH to convert it into the free base of 2-((2-ethoxyphenoxy)methyl)morpholine, and then into its 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 (value in reference 1: +4.3°). Since this value is not zero, it is clear that one isomer of solid 6 is dominant, namely the R isomer.

[0205] Experimental details

[0206] Step 1.2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-chloroethyl ester (3).

[0207] 2-((2-ethoxyphenoxy)methyl)morpholine HCl (1·HCl, 32.8 g, 120 mmol) was suspended in 50 mL of water and stirred at 0 °C. A solution of 9.6 g NaOH dissolved in 100 mL of water was added in portions, while maintaining the solution at 0 °C for more than 30 minutes; stirring was then continued for 1.5 hours. The mixture was extracted with 4 × 100 mL of dichloromethane. The combined extracts were washed with brine, dried over magnesium sulfate, evaporated on a rotary evaporator, and then kept under vacuum overnight. A colorless oil (28.51 g) of the free base of 2-((2-ethoxyphenoxy)methyl)morpholine (1) (theoretical value 28.47 g) was obtained.

[0208] Dissolve 120 mmol of 2-((2-ethoxyphenoxy)methyl)morpholine base 1 in 200 mL of dichloromethane and stir at 0 °C (some may not completely dissolve). Add 41.8 mL (240 mmol) of diisopropylethylamine to the solution to obtain a clear yellow solution. Add 18.16 g (122 mmol) of 1-chloroethyl chloroformate 2 in 20 mL of dichloromethane to this solution over 15 minutes. Stir the solution and heat to room temperature over 1.5 hours, then stir at room temperature for 30 minutes. Add 100 mL of water and extract the mixture twice with dichloromethane. Wash the extract twice with brine and twice with 2N HCl (confirming the pH of the aqueous phase is pH 2), then wash with brine, bicarbonate, and brine. Dry the extract with magnesium sulfate and evaporate the solvent on a rotary evaporator, then evaporate under high vacuum for 2 hours. A yellow oily substance, ethyl carbamate 3 (theoretical value = 41.26 g), was obtained.

[0209] Step 2. (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutoxy]ethyl ester (5).

[0210] 29.32 g (90 mmol) of cesium carbonate was added to a solution of 39.63 g (183 mmol) of L-BOC-valine-OH(4) in 100 mL of DMF. The solution was stirred at room temperature for 30 minutes, and then 42.81 g of the above crude carbamate ethyl chloride 3 was added to 50 mL of DMF. 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 100 mL of water and 50 mL of brine, and extracted with ethyl acetate (4×). The extract was washed successively with sodium bicarbonate (2×), brine, 1N HCl, brine, sodium bicarbonate, and brine (2×), 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 as a yellow oil (theoretical value = 62.95 g).

[0211] Step 3. (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester, hydrochloride (6).

[0212] The above BOC product 5 (63.95 g) was dissolved in 110 mL of ethyl acetate, and 110 mL of a dioxane solution of 4N HCl was added. A brown solution was formed, and the mixture was stirred at room temperature for 3 hours, followed by the formation of a large amount of solid. The mixture was filtered and the solid was washed with ethyl acetate and cold 1:1 ethyl acetate:hexane. The white solid product was dried under vacuum to give 18.45 g (first batch). A brown oily mother liquor (40.7 g) was obtained. This was dissolved in 50 mL of ethyl acetate and kept at room temperature overnight, then in a refrigerator for 2 days. Filtered as before, a second batch of 2.3 g was obtained. The solid substance showed a single peak on HPLC (rapid method (10-70% CH3CN / 0.075% TFA / H2O) 15 min). The mother liquor showed the same main peak with about 10% 2-((2-ethoxyphenoxy)methyl)morpholine. HPLC was repeated for 40 minutes using a slow method (10-40% CH3CN / 0.075% TFA / H2O). Under these conditions, the solids consisted of 98% single component (peak 1) and 2% later elution component (peak 2). The mother liquor showed a peak 2 to peak 1 ratio of approximately 4:1, indicating that the two peaks are different diastereomers. This is due to the "decomposition" of the 2-((2-ethoxyphenoxy)methyl)morpholine center by L-valine.

[0213] Repeat the process. Combine the mother liquor materials. Perform water-acid-base extraction on the mother liquor by dissolving 15 g of the mother liquor material (syrupy liquid) in 50 mL of ethyl acetate, 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 trace amounts of the target compound. The HCl solution was mainly the desired amine 6 HCl salt plus some 2-((2-ethoxyphenoxy)methyl)morpholine and a small amount of impurities. The solution was adjusted to alkalinity with sodium bicarbonate, extracted with dichloromethane (3×), washed with brine, and dried over magnesium sulfate. The substance was found to be the free base of the desired compound 6 plus about 5% 2-((2-ethoxyphenoxy)methyl)morpholine. The material was kept at room temperature overnight and then decomposed.

[0214] The second 15g sample was treated similarly, but without converting it into a free base. The ethyl acetate phase contained most of the impurities and a small amount of product. Extraction of the HCl solution with dichloromethane yielded mainly the desired HCl salt 6 product (peak 2) plus 4% 2-((2-ethoxyphenoxy)methyl)morpholine. The aqueous phase mainly contained 2-((2-ethoxyphenoxy)methyl)morpholine.

[0215] The remaining 30 g of mother liquor was dissolved in 100 mL of ethyl acetate and extracted with 3 × 1N HCl. The aqueous HCl extract was then washed again with 2 × ethyl acetate (100 mL), and the aqueous HCl phase was extracted into dichloromethane (3 × 100 mL). The dichloromethane extract was washed with 50 mL of 1N HCl and the solution was rediscovered with dichloromethane. The combined dichloromethane extracts were dried over magnesium (sodium) sulfate, treated with Norit, filtered, and evaporated to give 24.29 g (34 g) of peak 2 product 6·HCl as a brown oil. This substance was treated again in the same manner to give a total of 22.5 g of product 6·HCl (98.6% product (isomer peak ratio 91.1:8.9), containing 1.4% 2-((2-ethoxyphenoxy)methyl)morpholine).

[0216] A similar process was used for 42 g of mother liquor from a different operation. This process uses only one HCl treatment, but with a larger amount of solvent. In this variant, 42 g of mother liquor was dissolved in 300 mL of ethyl acetate and extracted with 2 × 200 mL of 1N HCl. The aqueous HCl extract was then extracted with 2 × 250 mL and 1 × 100 mL of dichloromethane. The combined dichloromethane extract was washed with 100 mL of 1N HCl, dried over sodium sulfate, and evaporated to give 34 g of peak 2 product as a brown oil. The isomer peak ratio was 85.7:13.3, with the addition of 3.3% 2-((2-ethoxyphenoxy)methyl)morpholine. LC-MS: C 21 H 32N₂O₇[M+H] + :425.

[0217] Step 4. Preparation of (S)-2-((2-ethoxyphenoxy)methyl)morpholine from the racemic mixture

[0218] The racemic 2-2-((2-ethoxyphenoxy)methyl)morpholine HCl was separated by supercritical fluid chromatography (SFC) to obtain the (S)-isomer, which was the slower elution peak. The preparative separation method was performed using a Thar 350 preparative SFC (SFC-23) with a ChiralCel column (OD, 300 × 50 mm ID, 10 μm). The mobile phase was CO2 (A) and ethanol (0.1% NH3H2O), with a gradient of B 30%, a flow rate of 200 mL / min, and a back pressure of 100 bar. Analytical HPLC was performed using the following methods: Waters UPC2 analytical SFC (SFC-H) / ChiralPak IC, 150 × 4.6 mm ID, 3 μm / Mobile phase: A = CO2, B = ethanol (0.05% DEA) / Gradient: B 5-40% / Flow rate: 2.5 mL / min / Back pressure: 100 bar / Column temperature: 35 °C / Wavelength: 220 nm. The enantiomer of the (S)-isomer was obtained with an excess of 99.46%. In subsequent steps, the HCl salt was first converted to a free base using ammonium hydroxide to form a free base, which was then extracted into ethyl acetate, evaporated to an oil, and then preparative SFC was performed as described above. This produced a sharper peak than that produced by SFC of the HCl salt.

[0219] Example 3. Synthesis of morpholine analogs from (S)-2-((2-ethoxyphenoxy)methyl)morpholine HCl

[0220] Scheme IIIa. Synthesis of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester.

[0221]

[0222] The numbering convention for the compounds described in steps 1 to 3 corresponds to the compound numbering shown in scheme IIIa.

[0223] Step 1. (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-chloroethyl ester (3)

[0224] (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 fractionally while maintaining the solution at 0 °C for 30 minutes; stirring was then continued for 1.5 hours. The mixture was extracted with 4 × 100 mL of dichloromethane. The combined extracts were washed with brine, dried over magnesium sulfate, evaporated on a rotary evaporator, and then kept under vacuum overnight. A colorless oil (11.85 g) of (S)-2-((2-ethoxyphenoxy)methyl)morpholine free base was obtained. The process was repeated at a scale of 100 mmol 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.

[0225] (S)-2-((2-ethoxyphenoxy)methyl)morpholine (50 mmol) was mixed with 100 mL of dichloromethane and stirred at 0 °C (some remained undissolved). 17.5 mL (100 mmol) of diisopropylethylamine was added to the solution, yielding a clear yellow solution. 7.15 g (50 mmol) of 1-chloroethyl chloroformate 2 in 10 mL of dichloromethane was added to this solution over 15 minutes. The solution was stirred and heated 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 (to confirm the pH 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, followed by evaporation under high vacuum for 2 hours. A yellow oil (17.15 g) of chloroethyl chloroformate 3 was obtained. The process was repeated at a scale of 100 mmol to yield an additional 34.3 g of chlorinated compound 3. LC-MS: C 16 H 22 ClNNaO5[M+Na] + :366.

[0226] Step 2. (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutoxy]ethyl ester (5).

[0227] 12.2 g (37.5 mmol) of cesium carbonate was added to a solution of 16.27 g (75 mmol) of L-BOC-valine-OH(4) in 75 mL of DMF. The solution was stirred at room temperature for 30 minutes, and then 17.15 g (50 mmol) of the above crude ethyl carbamate 3 was added to 25 mL of DMF. 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 100 mL of water and 50 mL of brine, and extracted with ethyl acetate (4×). The extract was washed successively with sodium bicarbonate (2×), brine, 1N HCl, brine, sodium bicarbonate and brine (2×), 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 at a scale of 100 mmol to give another 52.4 g of crude BOC compound 5. LC-MS:C 26 H 40 N₂NaO₉[M+Na] + :547.

[0228] Step 3.2-[(o-ethoxyphenoxy)-methyl]-4-morpholinocarboxylic acid [(S)-1-amino-2-methylbutoxy]methyl methyl ester, hydrochloride (A).

[0229] The above BOC product 5 (26.2 g, 50 mmol) was dissolved in 60 mL of ethyl acetate, and 50 mL of a dioxane solution of 4N HCl (200 mmol) was added. A brown solution was formed and stirred at room temperature for 3 hours to give 23 g of crude HCl salt. The procedure was repeated at a scale of 100 mmol to give another 46 g of crude salt. The two batches were combined and suspended in 1000 mL of ethyl acetate. The solid formed was filtered off and dried (32 g). This solid (MS M+H 425) was identified as a diastereomer of the product. The ethyl acetate filtrate was concentrated to a volume of 400 mL and extracted with 2 × 250 mL of 1N HCl. The HCl layer (500 mL) was extracted with 2 × 300 mL of dichloromethane, and the combined extracts were dried over Na2SO4 and evaporated to give 32 g of a viscous oil (MS M+H 425). The oily and solid mixtures were combined and dissolved in a mixture of 150 mL acetonitrile and 250 mL water. The mixture was treated with Norit, filtered through diatomaceous earth, and lyophilized to give 61.5 g of compound A as a grayish-white viscous solid (HPLC purity, 100%). LC-MS: C 21 H 32 N₂O₇[M+H] + :425.

[0230] Scheme IIIb. Synthesize (S)-2-[(o-ethoxyphenoxy)methyl)morpholine HCl to 1-[(S)-2-amino-3-methylbutoxy]-2-methylpropyl ester (compound B) and (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholine HCl to 1-[(R)-2-amino-3-methylbutoxy]-2-methylpropyl ester (compound C).

[0231]

[0232] The numbering conventions for the compounds described below correspond to the compound numbering conventions shown in Scheme IIIb.

[0233] (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]-2-methylpropyl ester (Compound B)

[0234] The method for preparing (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]-2-methylpropyl ester (compound B) is similar to the method for preparing 2-[(o-ethoxyphenoxy)-methyl]-4-morpholinocarboxylic acid [(S)-1-amino-2-methylbutoxy]methyl methyl ester hydrochloride (compound A), except that 1-chloro-2-methylpropyl chloroformate is used instead of 1-chloroethyl chloroformate.

[0235] The method described above for preparing (S)-2-((2-ethoxyphenoxy)methyl)morpholine free base was carried out in two batches, using 50 mmol and 100 mmol of (S)-2-((2-ethoxyphenoxy)methyl)morpholine HCl (SFC separation, 99.3% S) as starting materials.

[0236] Step 1. (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 2-methyl-1-chloroethyl ester (3; Scheme II)

[0237] 2-((2-ethoxyphenoxy)methyl)morpholine was condensed with 1-chloro-2-methylpropyl chloroformate (2) at scales of 53 and 100 mmol to give 21 g and 42 g of product 3, respectively.

[0238] Synthesize (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(R)-2-(tert-butoxycarbonylamino)-3-methylbutoxy]-2-methylpropyl ester (4)

[0239] 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. 50 mmol of chlorocarbamate 3 in 20 mL of DMF was added to the suspension, 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 successively with brine, 2× NaHCO3, brine, 1N HCl, brine, NaHCO3, and brine, then dried over MgSO4 and evaporated to give 31.8 g of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(R)-2-(tert-butoxycarbonylamino)-3-methylbutoxy]-2-methylpropyl ester (4) as a light yellow oil.

[0240] Synthesis of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinic acid 1-[(S)-2-amino-3-methylbutoxy]-2-methylpropyl ester (Compound B)

[0241] To a solution of 31.8 g of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[S)-2-(tert-butoxycarbonylamino)-3-methylbutoxy]-2-methylpropyl ester (4) in 60 mL of ethyl acetate, 60 mL of dioxane solution in 4N HCl was added. The solution was stirred at room temperature for 4 hours, and then the solvent was evaporated to obtain 29 g of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]-2-methylpropyl ester hydrochloride (compound B) as a yellow oil.

[0242] The two reactions were repeated at a scale of 100 mmol to give 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 MgSO4, treated with Norit, and evaporated. The oil was dissolved in 140 mL of acetonitrile, and 350 mL of water was added. The solution was then lyophilized to give 60.2 g of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]-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 procedure separates the diastereomer into two equal peaks.

[0243] Synthesis of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(R)-2-amino-3-methylbutoxy]-2-methylpropyl ester hydrochloride (compound C)

[0244] The synthesis of compound B was repeated, except that N-BOC-D-Val was used to couple with chlorinated compound 3 to obtain intermediate 6. Compound 6 was deprotected at a scale of 100 mmol using a dioxane solution of 110 mL ethyl acetate and 110 mL 4N HCl to give 48.9 g of crude HCl salt. This was combined with crude HCl salt from a 50 mmol process, yielding a total of 74 g of crude salt. This was dissolved in 900 mL of 60:40 ethyl acetate:hexane and extracted with 1 L of 1N HCl. The HCl layer was washed with 400 mL of 50:50 ethyl acetate:hexane and then extracted with a total of 2 L of dichloromethane. The dichloromethane extract was dried over Na2SO4 and evaporated to give 76.88 g of crude (2S)-2-((2-ethoxyphenoxy)methyl)morpholine-4-carboxylic acid 1-((D-valine)oxy)-2-methylpropyl ester (compound C) in hydrochloride form. Crude salt (76 g) was dissolved in 200 mL of acetonitrile and 200 mL of water, treated with Norit, filtered through diatomaceous earth, and lyophilized to obtain 65.1 g of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinic acid 1-[(R)-2-amino-3-methylbutoxy]-2-methylpropyl ester hydrochloride (compound C) as a white solid. (HPLC 99.81%; LC-MS: C) 23 H 36 N₂O₇[M+H] + :453).

[0245] Example 4. Synthesis of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine

[0246] Scheme IV. Alternative route for the synthesis of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (5)

[0247]

[0248] The numbering conventions for the compounds described below correspond to the compound numbering shown in Scheme IV.

[0249] 2-Ethoxyphenol 1 reacts with (R)-epimyl chloride to give 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.

[0250] (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine was prepared by alkylation with benzyl bromide using (S)-2-((2-ethoxyphenoxy)methyl)morpholine as a raw material.

[0251] Example 5. Alternative Synthesis of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine

[0252] Scheme V. Synthesis of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine

[0253]

[0254] The numbering conventions for the compounds described below correspond to the compound numbering shown in Scheme V.

[0255] Efforts were made to design a route for the synthesis of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine that does not involve the benzylation of (S)-2-((2-ethoxyphenoxy)methyl)morpholine. Several possible routes have been proposed based on the synthesis of S- or racemic 2-((2-ethoxyphenoxy)methyl)morpholine. In our route, these syntheses use chiral epichlorohydrins as the source of the S-enantiomer. One possible route to (S)-2-((2-ethoxyphenoxy)methyl)morpholine is based on the previously disclosed synthesis of racemic 2-((2-ethoxyphenoxy)methyl)morpholine (Liang, Bhatt et al., US 9,403,783). This method is modified to use R-epiochlorohydrins as starting materials to yield epoxide intermediate 3. This epoxide was used to prepare (S)-2-((2-ethoxyphenoxy)methyl)morpholine (US3,712,890) by ring-opening and cyclization with aminoethyl hydrogen sulfate. Based on this, it is expected that ring-opening with hydroxyethyl benzylamine (12) will yield the same (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine via diol 13.

[0256] Example 6. Synthesis of salts of morpholine derivatives from (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine.

[0257] Option VI.

[0258]

[0259] The numbering conventions of the compounds described in Example 6 below correspond to the compound numbering shown in Scheme VI.

[0260] Dissolve (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (5) (3.87 g of the above substance, 10 mmol) in 25 mL of dichloromethane and stir in an ice bath. Add a solution of 1-chloroethyl chloroformate 6 (1.88 g, 13.2 mmol) in 5 mL of dichloromethane over approximately 2 minutes and maintain at approximately 3 °C for 90 minutes, then heat to room temperature and stir for 1 hour. Dilute the reaction mixture with dichloromethane (100 mL) and wash with water (50 mL), 1N HCl (50 mL), bicarbonate (50 mL), and brine (50 mL), dry over sodium sulfate, evaporate on a rotary evaporator, and then incubate overnight under vacuum. Dissolve the residue in acetonitrile (50 mL) and wash with hexane (3 × 100 mL) to remove the remaining benzyl chloride byproduct generated by debenzylation of 7. Concentrate the acetonitrile layer to give 3.47 g of chlorocarbamate 8.

[0261] N-Boc-L-valine 9 (3.47 g; 16 mmol) and cesium carbonate (2.6 mg; 8 mmol) were stirred in 20 mL DMF for 30 minutes. A solution of chlorocarbamate 8 (3.43 g, 10 mmol) from step 2 in 20 mL DMF was added to the mixture, and the mixture was stirred and heated at 85 °C for 1 hour. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL). The ethyl acetate solution was washed with water (2 × 100 mL), bicarbonate (75 mL), 1N HCl (2 × 100 mL), and brine (50 mL), and dried over sodium sulfate. The solvent was evaporated to give crude Boc-protected compound 10 (5.8 g) in a syrupy form.

[0262] All of the Boc-protected compound 10 (5.8 g; 10 mmol) obtained in step 3 was dissolved in ethyl acetate (25 mL), and a dioxane solution of 4N HCl (11 mL, 44 mmol) was added. The mixture was stirred at room temperature for 4 hours, and then concentrated under vacuum. The crude compound was dissolved in ethyl acetate (50 mL) and extracted with 1N HCl (2 × 70 mL). The HCl layer was extracted with dichloromethane (1 × 100 mL; 1 × 50 mL). HPLC analysis of the extract showed a purity of 96.6%. The dichloromethane layer was washed with 1N HCl (80 mL), dried over sodium sulfate, and evaporated. After vacuum drying overnight at room temperature, a pale yellow, foamy product of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester HCl (11, 3.65 g) was obtained. The final process yielded (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester HCl (11), which was free of unreacted (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine and lacked the byproduct of the reaction of benzyl chloride with N-Boc-L-lysine (9). This resulted in improved product purity (99.15% vs. 96.6%). Based on the 10 mmol of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine used, 3.65 g of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester HCl salt (11) was obtained, with an overall yield of 79.2%. LC-MS:C 21 H 32 N₂O₇[M+H] + :425. The product (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester (11) is a 1:1 mixture of diastereomers of the acetal center. One of the isomers (eluted more rapidly on reversed-phase HPLC) is readily available in solid form and can be recrystallized from ethanol / MTBE or ethyl acetate to provide a high-purity material with a recovery of approximately 85% of the theoretical amount. Further work showed that the solid HCl salt can be recrystallized from isopropanol to give fine needle-like crystals. After multiple experiments using different solvent systems, the slower-eluting isomer in the liquid still could not crystallize into the HCl salt. It appears that the two diastereomers may have different conformations, favoring the crystallization of the faster-eluting isomer. The recrystallized HCl salt forms needle-like crystals that are too small for structural determination by X-ray diffraction. Further crystallization attempts may be needed to see if suitable crystals can be obtained to determine whether the isomer has an S,S,S or S,R,S configuration.

[0263] Salts of morpholine derivatives

[0264] Experiments were also conducted to replace HCl salts with other acids. Previous experience treating HCl salts with 1N NaOH to separate free bases failed because the strong base hydrolyzed to give 2-((2-ethoxyphenoxy)methyl)morpholine. However, it was found that HCl salts soluble in ethyl acetate or dichloromethane could be washed with saturated sodium bicarbonate and brine, and dried with sodium sulfate or magnesium sulfate, to obtain a stable free base solution. This free base solution could then be treated with 1 equivalent of different acids to form other salts. Salts of maleic acid, citric acid, and p-toluenesulfonic acid and methanesulfonic acid were formed from mixed diastereomers of HCl salts, but recrystallization was not possible. A potential alternative involves first separating the solid diastereomers of the HCl salts by crystallization from ethyl acetate and the liquid diastereomers from the mother liquor to evaluate the various salts of each diastereomer separately. These isomers were then converted to free bases, and then to p-toluenesulfonates, to obtain crystalline solids. Attempts to crystallize mixtures of toluenesulfonate isomers were unsuccessful. Overall, it appears that the individual diastereomers of toluenesulfonate can be prepared and crystallized, and then mixed in a 1:1 ratio to obtain a suitable product.

[0265] Salt synthesis

[0266] 1.152 g (2.5 mmol) of a mixed diastereomer HCl salt was rapidly dissolved in 5 mL of ethyl acetate and inoculated with crystals retained from previous studies. After 1 hour, the solution was concentrated to a volume of 3 mL and allowed to stand overnight at room temperature, forming a thick, crystalline solid paste. Ethyl acetate (3 mL) was added, and the solid was collected by filtration and washed with 1 mL of ethyl acetate. After drying under vacuum, the first batch yielded 487 mg of HCl salt (84.5% of the theoretical value). The mother liquor was evaporated, and the gelatinous residue (593.9 mg) was dissolved in 3 mL of ethyl acetate and diluted with 3 mL of MTBE. The solution was allowed to stand overnight at room temperature, but no solid was obtained.

[0267] A mixture of diastereomers of an HCl salt (1.15 g, 2 mmol) was dissolved in 3.5 mL of ethyl acetate and seed crystals were added. Crystals formed within 1 hour. The solvent was removed by pipetting, and the solid was washed with 5 mL of 1:1 ethyl acetate:hexane and dried to give 562.2 mg of solid isomer. This solid was recrystallized overnight from 3.5 mL of isopropanol to give fine needle-like particles. The mother liquor was evaporated into a concentrated syrup, dissolved in 1 mL of ethyl acetate, and diluted with 1.5–2 mL of hexane. After standing at room temperature for 30 minutes, an oily substance separated out. Therefore, another 0.5 mL of ethyl acetate was added, and the mixture was warmed to dissolve 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 liquid isomer.

[0268] Free base was separated from the liquid HCl salt isomer. The solvent in the mother liquor (2.5 mmol scale) obtained from the crystallization of the HCl salt was evaporated, and the residue was dissolved in 6 mL of dichloromethane and washed with 2× bicarbonate.

[0269] Formation of methanesulfonates.

[0270] The dichloromethane solution of the free base derived from 593.9 mg (1.29 mmol) of liquid HCl isomer mother liquor was then treated with a methanol solution of 1.5 mL of 1N methanesulfonic acid. The solution was diluted with 2 mL of dichloromethane and washed with 1 × 3 mL of water. The solvent was evaporated, and some salt precipitated, so the mixture was redissolved in dichloromethane, dried over magnesium sulfate, and then dried. The residue was dissolved in ethyl acetate (2 mL) and MTBE (2 mL), but no solid formed. The solvent was removed (and the substance was further dried using 5 mL of toluene). It was then dissolved in isopropanol (0.5 mL) and allowed to stand overnight (no solid). The substance was dissolved in ethyl acetate and converted back to free base with bicarbonate, then washed with brine and dried over magnesium sulfate.

[0271] The formation of maleate.

[0272] The ethyl acetate solution of the free base was treated with a solution of 150 mg maleic acid in 2 mL isopropanol. Evaporation of the solvent (concentrated oil) (using TLC with 9:1 dichloromethane:methanol) showed separation of maleic acid from the free base. HPLC showed peaks for maleic acid and a slower-eluting isomer, but no 2-((2-ethoxyphenoxy)methyl)morpholine, indicating that the maleate salt was stable but not crystalline. The substance was dissolved in dichloromethane, washed with water, and evaporated to give 374 mg of oily maleate salt.

[0273] Formation of toluenesulfonate.

[0274] In another experiment, a liquid HCl salt isomer (174.7 mg, 412 mmol) was dissolved in 7 mL of ethyl acetate. The solution was washed with bicarbonate (2 × 5 mL), brine, dried over magnesium sulfate and evaporated (rotary evaporator, bath temperature <30 °C), and then vacuum dried for 30 min to obtain a free base. Ethyl acetate (2 mL) was added, followed by 0.5 mL of ethanol and 78.3 mg of p-toluenesulfonic acid monohydrate from 3 mL of ethyl acetate. The solution was concentrated to a volume of 0.5 mL and redistilled with 5 mL of ethyl acetate to remove trace amounts of ethanol, producing a viscous foam. The substance was dissolved in 2 mL of ethyl acetate, and hexane (approximately 2 mL) was added until turbidity was achieved. After standing, crystals formed. The mixture was allowed to stand over the weekend, yielding a large amount of white crystals. The solvent was removed by pipetting, and the residue was washed with a 1:1 ethyl acetate:hexane mixture and dried, yielding 188 mg of toluenesulfonate as a white solid in the first batch.

[0275] Repeat the above process, starting with the solid isomer HCl salt (486 mg, 1.054 mmol), dissolving it in ethyl acetate as described above, washing with sodium bicarbonate and brine, and drying with magnesium sulfate. Then treat the free alkaline solution with p-toluenesulfonic acid monohydrate (200.56 mg, 1.054 mmol), first dissolving in 1 mL of ethanol, then diluting with 2 mL of ethyl acetate. Dilute the solution with 1 mL of ethyl acetate and 1 mL of hexane. Remove the solvent to obtain 487.1 mg of toluenesulfonate as a foamy solid. Dissolve it in 2 mL of ethyl acetate and 2 mL of hexane, and crystallize overnight at room temperature to form crystalline toluenesulfonate. Remove the solvent with a pipette, wash the solid with 1:1 ethyl acetate:hexane, and dry the solid to obtain 345.8 mg of solid toluenesulfonate. Evaporate the mother liquor to obtain 187.4 mg of the substance.

[0276] A mixture of HCl salt isomers (780 mg, 1.692 mmol) was dissolved in 5 mL of ethyl acetate and converted to a free base as described above. The free base was dissolved in 5 mL of ethyl acetate, and 321.8 mg of p-toluenesulfonic acid monohydrate dissolved in 1 mL of methanol was added. The solution was diluted with 3–4 mL of hexane until partially turbid, and then seed crystals of the two pure enantiomers of the toluenesulfonate were added. TLC of the toluenesulfonate mixture (9:1 dichloromethane:methanol) showed slight separation of the isomers, with the liquid isomer-derived toluenesulfonate running slightly faster than the solid isomer. After standing overnight and trying other solvents (isopropanol, MTBE), no diastereomeric crystals formed.

[0277] Example 7. Final determination of the chirality of (S)-2-((2-ethoxyphenoxy)methyl)morpholine

[0278] Scientific literature on the enantiomers of 2-((2-ethoxyphenoxy)methyl)morpholine indicates that the S-isomer has significantly higher biological potency than the R-isomer. The allocation of enantiomers R and S traces back to older literature that correlates the absolute configuration with that of propranolol, established through correlation with S-lactic acid and some circular dichroism spectroscopy. (Howe et al., J. Med. Chem., 1976, 19, 1074.) Since (S)-2-((2-ethoxyphenoxy)methyl)morpholine prodrugs, including (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester, are potential candidates, we attempted to verify the chiral configuration as (S) by X-ray crystallography.

[0279] Although the X-ray structure of (S)-2-((2-ethoxyphenoxy)methyl)morpholine salts has not yet been reported, the racemic form has been crystallized, and its X-ray structure has been 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 toluenesulfonate, methanesulfonate, and hydrobromide salts (each containing a heavy atom to facilitate the 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 detection, but the needles were too fine for X-ray study.

[0280] Since suitable crystals of 2-((2-ethoxyphenoxy)methyl)morpholine were not obtained, we prepared a sample of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine derived from pure (S)-2-((2-ethoxyphenoxy)methyl)morpholine, obtained from the racemic mixture via chiral SFC (99.3% S). Treatment with an ethanol solution of 48% HBr and evaporation yielded a white solid HBr salt. Recrystallization of the HBr salt from ethanol yielded large, plate-like crystals. These were sent for X-ray analysis and determined to be suitable for study. The 4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HBr crystals showed an (S)-configuration and contained a single water molecule. The structure is as follows. Figure 1 As shown.

[0281] This study confirms all previous hypotheses regarding the S-isomer of 2-((2-ethoxyphenoxy)methyl)morpholine as a biologically effective isomer. It also confirms that this (S)-isomer is the configuration isolated from the resolution procedure of Howe et al., and is the same isomer as the slower-moving peak on the chiral SFC, and that this isomer isolates racemic 2-((2-ethoxyphenoxy)methyl)morpholine, yielding a large amount of (S)-2-((2-ethoxyphenoxy)methyl)morpholine for prodrug studies. Based on these results and the aforementioned correlations, the configurations of (S)-2-((2-ethoxyphenoxy)methyl)morpholine and (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine are confirmed to be (S).

[0282] Example 8. Novel chiral synthesis of morpholine derivative intermediates.

[0283] Scheme VIII. Synthesis of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester

[0284]

[0285] The numbering convention for the compounds described in Example 8 corresponds to the numbering convention for the compounds shown in Scheme VIII.

[0286] The route for (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine

[0287] The synthesis of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinoic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester HCl (12) (Scheme VIII) via a novel route proceeded as follows: first, N-benzylethanolamine (1) was used to open (S)-(+)-epiochlorool (2, chiral source), followed by the formation of chlorohydrin 3, epoxide 4, and diol 6, which were then cyclized to (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (7). This route was expanded using 1.2 mol of ethanolamine 1 as the starting material. Crude (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (7·HCl) was crystallized under optimized conditions via the novel route to give >99% (S)-isomers.

[0288] Experimental details.

[0289] Step 1: Dissolve 2-benzylaminoethanol (1, 90.73 g, 600 mmol) and (S)-(+)-epimerchlorohydrin (2, 61.06 g, 660 mmol, 1.1 equivalents) in 220 mL of methanol, stir under nitrogen, and heat to 35 °C for 22 hours. Evaporate the methanol and add 100 mL of toluene, then evaporate the toluene. Repeat the addition of toluene and evaporation three times to remove trace amounts of epichlorohydrin and / or methanol, and dry the oily substance under vacuum for 4 hours. A pale yellow oily product, chlorohydrin 3 (155 g), is obtained. HPLC (5-50-90% CH3CN; H2O / 0.075% TFA) showed a main peak at 6.23 min (64% purity).

[0290] Step 2: Crude chlorohydrin 3 (155 g) was dissolved in 300 mL MTBE. A solution of 2.4 g tetrabutylammonium hydrogen sulfate and 25.2 g (630 mmol) sodium hydroxide in 48 mL of water was added to this solution. The mixture was stirred under nitrogen at room temperature for 1.5 hours. The layers were separated, and the aqueous layer was extracted with 100 mL MTBE. The combined extracts were dried over magnesium sulfate, evaporated on a rotary evaporator, and then dried under high vacuum at room temperature for 3 hours. Epoxide 4 (113 g) was obtained as a pale yellow oil. HPLC analysis under the same conditions as for compound 3 showed that the product peak of epoxide 4 appeared at 6.74 min (64.3%). LC-MS: C 12 H 17 NO2[M+H] + :208.17.4 1 H NMR spectrum as follows Figure 2 As shown.

[0291] Step 3: Dissolve epoxide 4 (113 g) and 2-ethoxyphenol (5 g, 90.4 g, 655 mmol) in 450 mL of toluene. Stir the mixture (mechanical stirrer) and add cesium carbonate (106.3 g, 327 mmol) in portions over approximately 30 minutes, causing the temperature to rise from room temperature to 34°C. Stir the mixture and allow it to cool to 32°C over 30 minutes. Then gradually heat the mixture (heating mantle), raising the internal temperature to 110°C over 1 hour and maintaining it at 110°C for 1 hour until all epoxide 4 is depleted. Then allow the brown mixture to cool to room temperature, filter through diatomaceous earth, and evaporate the toluene to obtain a brown oil. Dissolve this oil in 200 mL of dichloromethane and add 200 mL of 2N NaOH. The mixture was stirred for 10 minutes, 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 saturated NaCl) (to remove cyclic amine byproducts), followed by washing with 2× brine. The organic phase was then treated with 2N NaOH until 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 the main peak of diol 6 at 14.48 min; using a 10–70–90 gradient, the diol peak eluted at 10.12 min. LC-MS:C 20 H 27 NO4[M+H] + 346.24.6 1 H NMR spectrum as follows Figure 3 As shown.

[0292] Step 4: Dissolve 149 g of diol 6 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. Heat to 30 °C and stir at room temperature for 30 minutes. Then cool the mixture to 20 °C in an ice bath and add p-toluenesulfonyl chloride (82.3 g, 430 mmol) fractionally over 1 hour while maintaining the internal temperature at 25 ± 2 °C, then stir at room temperature for 1.5 hours. Pour the mixture into 500 mL of cold water and stir for 20 minutes, then separate the layers. Extract the aqueous phase with toluene (3 × 150 mL), wash the extract with 2N NaOH (6 × 150 mL) and brine (2 ×), and dry over magnesium sulfate. Remove toluene using a rotary evaporator to obtain 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 as follows Figure 4 As shown.

[0293] (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. 130 mL of a dioxane solution of 4N HCl was added to the solution, and the mixture was stirred for 20 minutes. The solvent was then evaporated using a rotary evaporator to obtain 207 g of an orange oily salt, 7·HCl. 40 mL of ethanol was added to the crude salt, 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 inoculated with 99+% (S)-configured crystalline HCl salt and stored at -15°C for the weekend. The white crystalline product was filtered off, washed with a 1:3 ethanol:ethyl acetate solution, and air-dried to obtain 47.23 g of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HCl (7·HCl), which, according to chiral SFC analysis, had an S configuration of 99.5%. The mother liquor was essentially racemic (49:51) and was discarded.

[0294] A subsequent round of the above reaction (starting with 600 mmol of 1) yielded 48.87 g of 7·HCl, which recrystallized to give 47.09 g of 7·HCl. A subsequent round of the above reaction (with 170 mmol of 1) yielded 14.6 g of 7·HCl.

[0295] Starting from a total of 1.37 mol of 1, 108.92 g of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HCl (7) was obtained, with an overall yield of 21.8%. No chromatographic purification was required and the product was >99% (S)-enantiomer.

[0296] (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HCl is converted to (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester HCl

[0297] The key intermediate in the synthesis of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester 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 an 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).

[0298] Extrapolating to the synthesis of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester HCl (12) and other (S)-2-((2-ethoxyphenoxy)methyl)morpholine prodrugs, intermediate chlorocarbamate 9 is generated from (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (7) and 1-chloroethyl chlorocarboxylic acid 8, losing benzyl chloride to form 9, thus eliminating the need to generate and use (S)-2-((2-ethoxyphenoxy)methyl)morpholine throughout the process.

[0299] As shown in scheme VIII, (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine (7) was treated with chloroformate 8 to give N-benzyl-N-carbamoyl salt (not separated), eliminating benzyl chloride to form 1-chloroethylcarbamoline 9. Even at room temperature, the reaction of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine was very rapid, and carbamoline 9 did not convert to 2-((2-ethoxyphenoxy)methyl)morpholine under the stated conditions. In the initial study, the crude product was extracted with hexane / acetonitrile solvent extraction to remove the benzyl chloride formed during the elimination of benzyl chloride from 9. An improved method was discovered (see 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 could be washed away from the crude product with water.

[0300] The synthesis was carried out by reacting chlorocarbamate 9 with N-BOC-l-valine (10) to give N-BOC-l-valine ester (11). Treatment of 11 with HCl yielded (2S)-2-((2-ethoxyphenoxy)methyl)morpholino-4-carboxylic acid 1-((L-valineyl)oxy)ethyl ester HCl (12). A key observation was that the product (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester HCl (12) could be extracted from aqueous HCl solution into dichloromethane without any byproducts.

[0301] (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HCl (36.3 g, 100 mmol) was stirred with 200 mL of 2NNaOH and 160 mL of water at approximately 16 °C for 1 hour, followed by extraction 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.

[0302] Experimental details.

[0303] Step 5: Cool the solution of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine free base (32.7 g, 100 mmol) in 150 ml of dichloromethane in an ice-water bath. While cooling in the ice bath, add a solution of 1-chloroethyl chloroformate (8, 18.57 g, 130 mmol) in 50 ml of dichloromethane to the solution over 30 minutes, and stir the solution under N2 for 2 hours, then heat to room temperature and stir for another hour. To remove the byproduct benzyl chloride, slowly add 25 ml of dichloromethane containing triethylamine (30.3 g, 300 mol) over 30 minutes at room temperature, stirring for a total of 72 hours. Then wash with 150 ml of water, 150 ml of 1N HCl, 150 ml of bicarbonate, and 100 ml of brine, dry with Na2SO4, decolorize with Norit A, filter through diatomaceous earth and evaporate to obtain 35 g of chlorocarbamate (9). LC-MS:C 16 H 22 ClNO5Na[M+Na] + 366.12.

[0304] Step 6: Dissolve N-Boc-L-valine (34.32 g, 160 mmol) in 125 ml DMF and add cesium carbonate (26 g, 80 mmol) in portions. Stir the mixture at room temperature for 30 minutes, then add 75 ml DMF containing crude chlorocarbamate 9 (35 g) at room temperature. Stir the mixture at 85 °C for 1 hour, then cool to room temperature. Add 250 ml ethyl acetate (250 ml), wash the solution with 2 × 150 ml water, 1 × 125 ml bicarbonate, 2 × 250 ml 1N HCl, and 1 × 125 ml brine, dry over Na₂SO₄ and evaporate to obtain 55 g of crude (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutoxy]ethyl ester (11). LC-MS: C 26 H 40 N₂O₉Na[M+Na] + :547.14.

[0305] The above process was repeated on a 1.74-fold scale, starting with 63.16 g of (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholine HCl (174 mmol), to obtain an additional 91 g of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinecarboxylic acid 1-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutoxy]ethyl ester (11).

[0306] Step 7: Dissolve 55 g of crude (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutoxy]ethyl ester (11) (100 mmol) in 100 ml of ethyl acetate and add 100 ml of 4N HCl in dioxane. Stir the resulting solution at room temperature for 4 hours, then concentrate under vacuum. Dissolve 56 g of crude HCl salt (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester HCl in 300 ml of ethyl acetate and extract with 2 × 300 ml of 1N HCl. Wash the combined HCl layers with 200 ml of 50% ethyl acetate in hexane, then extract with 600 ml of dichloromethane. The dichloromethane layer was dried and evaporated with Na2SO4 to give 40 g of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester·HCl (12). LC-MS: C 21 H 32 N₂O₇[M+H] + 425.29.12 1 H NMR spectrum as follows Figure 5 As shown.

[0307] In subsequent operations, as described above, 91 g of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinoic acid 1-[(S)-2-(tert-butoxycarbonylamino)-3-methylbutoxy]ethyl ester (11) was treated with a dioxane solution of 4N HCl to obtain 62 g of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinoic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester·HCl (12). An additional 3.5 g was obtained from dichloromethane (the emulsion was allowed to stand overnight for separation). This was then lyophilized separately.

[0308] Multiple batches of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester·HCl (12, 18 g, 40 g, and 62 g) were combined (total 120 g) and dissolved in 200 ml acetonitrile and 400 ml water. The solution was decolorized with Norit and filtered through diatomaceous earth, then lyophilized to give a total of 112.92 g of the product (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinocarboxylic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester (12) in hydrochloride form as a grayish-white solid. HPLC showed a purity of 98.5%. The rinsing solution from the lyophilized flask was re-lyophilized to give an additional 6 g.

[0309] The total yield of (S)-2-[(o-ethoxyphenoxy)methyl]-4-morpholinoic acid 1-[(S)-2-amino-3-methylbutoxy]ethyl ester·HCl (12, 112.92 + 3.5 + 6 = 122.42 g) indicates an overall yield of 81.97% starting from (S)-4-benzyl-2-((2-ethoxyphenoxy)methyl)morpholino HCl.

[0310] Although this description has been made with reference to exemplary embodiments, those skilled in the art will understand that various changes can be made without departing from the scope, and equivalents can be substituted for elements thereof. Furthermore, many modifications can be made to adapt specific situations or materials to the teachings of this invention without departing from the essential scope. Moreover, exemplary embodiments have been disclosed in the drawings and description, and although specific terminology may have been used, they are used in a general and descriptive sense only, and not for limiting purposes, unless otherwise stated, and therefore the scope of the claims is not limited thereto. Furthermore, those skilled in the art will understand 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 compound of formula (IIa) Where R 1 It is a C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; each R 2 It is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl or heterocyclic alkyl; and n is 0, 1, 2, 3 or 4.

2. The compound according to claim 1, wherein n is 0.

3. The compound according to claim 1, wherein R 1 It is -CH3 or -CH2CH3.

4. The compound according to claim 1, wherein each R 2 It is independently selected from -F, -Cl, -Br, -I or C1-C6 alkyl groups.

5. The compound according to claim 1, wherein the compound is:

6. The compound according to any one of claims 1 to 5, having more than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of (S) enantiomers.

7. A compound of formula (IIa') Where R 1 It is a C1-C6 alkyl, aryl, heteroaryl, or heterocyclic alkyl; each R 2 It is independently selected from F, Cl, Br, I, CN, NO2, C1-C6 alkyl, aryl, heteroaryl or heterocyclic alkyl; n is 0, 1, 2, 3 or 4; and Z is a sulfonyl leaving group.

8. The compound according to claim 7, wherein n is 0.

9. The compound according to claim 7, wherein R 1 It is -CH3 or -CH2CH3.

10. The compound according to claim 7, wherein each R 2 It is independently selected from -F, -Cl, -Br, -I or C1-C6 alkyl groups.

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