CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of U.S. Provisional Application No. 63/297,123, filed on January 6, 2022, which is incorporated by reference herein in their entirety for all purposes.

BACKGROUND

Ketanserin is a selective 5-HT2 serotonin receptor antagonist with weak adrenergic receptor blocking properties. Ketanserin also blocks 5-HT receptors on platelets, antagonizing platelet aggregation promoted by serotonin. Improved methods are needed for synthesizing ketanserin. The objects, features, and advantages of the invention will become more apparent from the following detailed description.

SUMMARY

In an aspect, the present disclosure provides a method of providing a compound of Formula B, the method comprising reacting a compound of Formula A with a compound of Formula E in a solvent, to provide a compound of Formula B wherein R and R ² are each, individually, hydrogen or Ci-6 alkyl.

In an aspect, the present disclosure provides a method of providing a compound of Formula C, the method comprising reacting a compound of Formula B with a compound of Formula F in a solvent, to provide a compound of Formula C wherein:

R and R ² are each, independently, hydrogen or Ci-6 alkyl;

R ¹ is a leaving group or -OR ^a , wherein R ^a is selected from hydrogen and Ci-6 alkyl.

In an aspect, the present disclosure provides a method of providing a compound of Formula C-LG, the method comprising reacting a compound of Formula C with a halogenating agent in a solvent to yield a compound of Formula C-LG wherein

R ¹ is selected from the group consisting of a leaving group and -OR ^a ;

LG is halo; and

R ^a is selected from hydrogen and Ci-6 alkyl.

In an aspect, the present disclosure provides a method of providing a compound of Formula L, the method comprising reacting a compound of Formula K with tosyl hydrazide in a solvent to yield a compound of Formula L wherein R ³ is a protecting group.

In an aspect, the present disclosure provides a method of providing a compound of Formula D, the method comprising reacting a compound of Formula L with Compound SMI and a base in a solvent to yield a compound of Formula D wherein R ³ is a protecting group. In an aspect, the present disclosure provides a method of providing a compound of

Formula D’, the method comprising reacting a compound of Formula D with an acid in a solvent to yield a compound of Formula D’ wherein

R ³ is a protecting group; and

X is a counterion.

In an aspect, the present disclosure provides a method of providing a Compound 1, the method comprising reacting a compound of Formula C with a compound of Formula D’ a base, and a solvent to yield Compound 1 wherein

R ¹ is a leaving group; and

X is a counter ion.

In an aspect, the method comprises a method of isolating a sample of compound 1 from a mixture comprising Compound 1.

DETAILED DESCRIPTION

I. Definitions

The following explanations of terms and methods are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. The singular forms “a,” “an,” and “the” refer to one or more than one, unless the context clearly dictates otherwise. The term “or” refers to a single element of stated alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise. As used herein, “comprises” means “includes.” Thus, “comprising A or B,” means “including A, B, or A and B,” without excluding additional elements. All references, including patents and patent applications cited herein, are incorporated by reference in their entirety, unless otherwise specified.

Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, percentages, temperatures, times, and so forth, as used in the specification or claims, are to be understood as being modified by the term “about.” Accordingly, unless otherwise indicated, implicitly or explicitly, the numerical parameters set forth are approximations that may depend on the desired properties sought and/or limits of detection under standard test conditions/methods. When directly and explicitly distinguishing embodiments from discussed prior art, the embodiment numbers are not approximates unless the word “about” is expressly recited. Without wishing to be limited by this statement, it is understood that, while various options for variables are described herein, the disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non- operable embodiments caused by certain combinations of the options. For example, while various options for variables X, L, and Y are described herein, the disclosure may be interpreted as excluding structures for non-operable compound caused by certain combinations of variables X, L, and Y (e.g., when each of X, L, and Y is -O-).

As used herein, “alkyl”, “Ci, C2, C3, C4, C5 or Ce alkyl” or “Ci-C 6 alkyl” is intended to include Ci, C2, C3, C4, C5 or Ce straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or Ce branched saturated aliphatic hydrocarbon groups. For example, C _r C ₆ alkyl is intends to include C _b C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkyl groups. Examples of alkyl include, moi eties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., Ci-Ce for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms.

As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “C3-C6” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6 alkenylene linker” or “C2-C6 alkynylene linker” is intended to include C2, C3, C4, C5 or Ce chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C ₂ -C ₆ alkenylene linker is intended to include C2, C3, C4, C5 and Ce alkenylene linker groups.

As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-l,2,3,6-tetrahydropyridinyl.

As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g, fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g, C3-C12, C3-C10, or C3-Cs). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non-aromatic.

As used herein, the term “heterocycloalkyl” refers to a saturated or partially unsaturated 3- 8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. _t 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6- diazaspiro[3.3]heptanyl, l,4-dioxa-8-azaspiro[4.5]decanyl, l,4-dioxaspiro[4.5]decanyl, 1- oxaspiro[4.5]decanyl, l-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-l,l'-isobenzofuran]-yl, 7'H- spiro[cyclohexane-l,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-l,l'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, l,4,5,6-tetrahydropyrrolo[3,4- c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-lH-pyrazolo[3,4- c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2- azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2- azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa- azaspiro[3.4]octan-6-yl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and the like. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be nonaromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

It is understood that when a variable has two attachments to the rest of the formula of the compound, the two attachments could be at the same atom or different atoms of the variable. For example, when a variable (e.g., variable X) is cycloalkyl or heterocycloalkyl, and has two attachments to the rest of the formula of the compound, the two attachments could be at the same atom or different atoms of the cycloalkyl or heterocycloalkyl.

As used herein, the term “aryl” includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. For example, an aryl is phenyl.

As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. , 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidised (i.e., N^O and S(O) _P , where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl). In some embodiments, the heteroaryl is thiophenyl or benzothiophenyl. In some embodiments, the heteroaryl is thiophenyl. In some embodiments, the heteroaryl benzothiophenyl.

Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodi oxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (c.g, tetralin, methylenedioxyphenyl such as benzo[d][l,3]dioxole-5-yl).

As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =0), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O'.

As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

As used herein, the term “optionally substituted haloalkyl” refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and/or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.

As used herein, the term “leaving group” (LG) refers to an atom or group of atoms that break away from the remainder of a molecule during a chemical reaction. The LG can be any suitable group such as, for example, a halogen, mesylate, tosylate, or any other groups that can be suitable for nucleophilic substitution catalyzed by a nucleophile and/or base or by metal catalyzed displacement (e.g., copper, palladium, and the like). These methods are well described in Handbook of Reagents for Organic Synthesis, Catalyst Components for Coupling Reactions; Gary Molander, 1st. edition, 2013; John Wiley & sons.

It is to be understood that the present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples.

It is to be understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

It is to be understood that compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J ., March ’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 ^th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3 ^rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser ’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognised reference textbooks of organic synthesis known to those in the art.

It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilized.

One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognise that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3 ^rd edition, John Wiley & Sons: New York, 1999.

It will be appreciated that during the synthesis of the compounds of the disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxy carbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

Once a compound has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound into another compound; (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or (iv) forming a prodrug thereof.

Unless explained otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting.

II. Method for the Synthesis of Ketanserin

Disclosed herein is a process for synthesizing the compound ketanserin (Compound 1)

Ketanserin (Compound 1) which was developed in the 1980s as an antihypertensive agent by Janssen.

The present methods avoid the use of toxic solvents and offer improved efficiency over prior methods, such as those described by Fakhraian and Heydary (J. Heterocyclic Chem., 51, 151, 2014) and Vandenberk et al. in U.S. Pat. No. 4,335,127.

In one embodiment, the process for synthesizing ketanserin described herein commences according to Scheme 1 :

Scheme 1

In some aspects, disclosed herein are methods for synthesizing a compound of Formula B by reacting an alkyl chloroformate of Formula E with a compound of Formula A.

With reference to Scheme 1, R is selected from the group consisting of hydrogen and Ci-6 alkyl. In certain embodiments R is hydrogen. In some embodiments, R is ethyl. In certain embodiments, R ² is Ci-6 alkyl. In some embodiments, R ² is ethyl. In some embodiments, R ² is isobutyl. In certain embodiments, R is Ci-6 alkyl, which is removed prior to or during contact with the chloroformate, such as isobutyl chloroformate reagent illustrated in Scheme 1. In certain embodiments, one equivalent of intermediate A is provided, and in such embodiments, intermediate A is contacted with about 0.5 equivalents of isobutyl chloroformate to about 3 equivalents of isobutyl chloroformate, such as from about 1 equivalent to about 2 equivalents, such as from about 1.1 equivalents to about 1.6 equivalents, for example, about 1.1, 1.2, 1.3, 1.4, 1.5 or 1.6 equivalents.

In some embodiments, the molar ratio of alkyl chloroformate E to a compound of Formula A is about 1.00: 1, about 1.05: 1, about 1.10: 1, about 1.15: 1, about 1.20: 1, about 1.25: 1, about 1.30: 1, about 1.35: 1, about 1.40: 1, about 1.45: 1, about 1.50: 1, about 1.55:1, about 1.60: 1, about 1.65: 1, about 1.70: 1, about 1.75: 1, about 1.80: 1, about 1.85: 1, about 1.90:1, about 1.95: 1, about 2.00: 1, about 2.05: 1, or about 2.10: 1.

In some embodiments, the reaction is carried out in flow. In some embodiments, the reaction is carried out in batch. In some embodiments, the solvent is a Class 1 solvent. In some embodiments, the solvent is a Class 2 solvent. In some embodiments, the solvent is a Class 3 solvent. In some embodiments, the solvent is chloroform, xylene, dioxane, DCM, IP Ac, THF, MTBE, 2-MeTHF, DMAc, toluene, n-heptane, methyl cyclohexane, NMP, MeCN, EtOAc, orDME. In some embodiments, the solvent is an alkyl amide solvent. In some embodiments, the solvent is NMP. In some embodiments, the solvent is DMAc.

In some embodiments, the temperature of the reaction of Scheme 1 is about 25 °C, about 30 °C, about 35 °C, about 40 °C, about 45 °C, about 50 °C, about 55 °C, about 60 °C, about 65 °C, about 70 °C, or about 75 °C.

In some embodiments, upon completion of the reaction, the completed reaction is cooled from a temperature of about 25 °C to about 75 °C, about 45°C to about 55°C, to a temperature of about 25°C, at a constant rate over a period of at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours.

In some embodiments, the crude reaction mixture is carried onto the next reaction without further purification. In some embodiments, the crude reaction mixture is further filtered and dried before being carried onto the next reaction without further purification.

In some embodiments, the reaction of Scheme 1 yields a compound of Formula B at about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% yield.

In some embodiments, the reaction of Scheme 1 yields a compound of Formula B at about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% purity.

The starting material A illustrated above and in Scheme 1 can be provided as is known to those of ordinary skill in the art of chemical synthesis. With continued reference to Scheme 1, the present inventors discovered that the illustrated transformation of reagent A to intermediate B offers significantly better yield, purity and efficiency of the procedures of Vandenberg et al. (US Patent 4,335,127; 1982) and Fakhraian and Heydary (Reinvestigation of the Synthesis of Ketanserin (5) and its Hydrochloride Salt (5.HC1) via 3-(2-Chloroethyl)-2,4-( IT/,37/)-quinazolinedione (2) or Dihydro-5J/-oxazole(2,3-Z>)quinazolin-5-one (1), JHeterocyclic Chem. 51, 151 (2014). In one embodiment R is ethyl and this compound is referred to herein as Al.

In addition the reaction can be conducted in the presence of a solvent that is substantially free of Class 1 and Class 2 solvents, whereas the procedure of Fakhraian required chloroform, a Class 2 solvent. According to the ICH guidelines for residual solvents, solvents in Class 2 should be limited in pharmaceutical products because of their inherent toxicity. Attempted duplication of the conditions of Fakhraian according to Scheme 2

Scheme 2 led to a yield of only 43.6% due to poor conversion of starting material. The present inventors discovered that replacement of the toxic solvent chloroform with alkyl amide solvents, such as NMP, DMF and DMAc, gave complete conversion and dramatically improved yield. Moreover, the toxic reagent ethyl chloroformate, used in excess in prior procedures, was replaced with isobutyl chloroformate as illustrated in Scheme 2A, without reduction in efficiency. With continued reference to Scheme 1, in one embodiment the reaction is conducted in a solvent substantially free of class 1 solvents. In one embodiment, the reaction of Scheme 1 is conducted in a solvent medium substantially free of class 2 solvents. In one embodiment the solvent is an 7V-alkyl amide solvent, such as including MA-di alkyl amide solvents. By way of example, in one embodiment, the reaction of Scheme 1 is conducted in a solvent comprising NMP, DMF, DMAc or a combination thereof.

With continued reference to Scheme 1, in one embodiment, R is Ci-6 alkyl. In one embodiment, R is hydrogen. In another embodiment, R is methyl or ethyl.

In one embodiment of a method for synthesizing ketanserin disclosed herein proceeds according to Scheme 3

Scheme 3 wherein a compound of Formula B is contacted with an alkylamine of Formula F, such as ethanolamine, to form a compound of Formula C wherein R and R ² are each, independently, hydrogen or Ci-6 alkyl; R ¹ is selected from the group consisting of a leaving group, and -OR ^a , wherein R ^a is selected from hydrogen and Ci-6 alkyl. In some embodiments, R ¹ is -OH. In some embodiments, R ² is isobutyl. In some embodiments, R is ethyl.

In some embodiments, the molar ratio of a compound of Formula F to a compound of Formula B is about 1.0: 1, about 1.5: 1, about 2.0: 1, about 2.5: 1, about 3.0: 1, about 3.5: 1, about 4.0:1, about 4.5: 1, about 5.0: 1, about 5.5:1, about 6.0: 1, about 6.5: 1, about 7.0: 1, about 7.5: 1, or about 8.0: 1. In some embodiments, the reaction is carried out in flow. In some embodiments, the reaction is carried out in batch.

In some embodiments, the solvent is NMP. In some embodiments, the solvent is DMAc.

In some embodiments, the temperature of the reaction is about 120 °C, about 125 °C, about 130 °C, about 135 °C, about 140 °C, about 145 °C, about 150 °C, about 155 °C, about 160 °C, about 165 °C, about 170 °C, about 175 °C, or about 180 °C.

In some embodiments, upon completion of the reaction, the completed reaction is cooled from a temperature of about 130 °C to about 170 °C, about 145°C to about 155°C, to a temperature of about 25°C, at a constant rate over a period of at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours.

In some embodiments, solvent is added to the cooled reaction mixture to precipitate out the desired product. In some embodiments, the solvent is water.

In some embodiments, the reaction mixture is then further cooled from a temperature of about 25°C to about 30 °C, to a temperature of about -5 °C to about 5 °C, at a constant rate over a period of at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours.

In some embodiments, the cooled reaction mixture is then filtered, washed with solvent, and dried. In some embodiments, the solvent is water. In some embodiments, the reaction mixture is dried at a temperature of about 35 °C, about 40 °C, about 45 °C, about 50 °C, or about 55 °C.

In some embodiments, the reaction yields a compound of Formula C at about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% yield. In some embodiments, the reaction yields a compound of Formula C at about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% purity.

In one embodiment, compound B is not isolated prior to contacting with ethanolamine. In one embodiment the reaction of Scheme 3 proceeds in a solvent free from Class 1 and Class 2 solvents. Prior procedure employed xylene as a solvent to produce a compound C. Xylene is an ICH Class 2 solvent. In one embodiment, the reaction of Scheme 3 is conducted in a solvent medium substantially free of Class 1 and Class 2 solvents. In one embodiment the solvent is an TV-alkyl amide solvent, such as including N, 7V-dialkyl amide solvents. By way of example, in one embodiment, the reaction of Scheme 3 is conducted in a solvent comprising NMP, DMF, DMAc or a combination thereof.

With continued reference to Scheme 3, in one embodiment, compound C has the formula

In one embodiment of a method for synthesizing ketanserin disclosed herein, a compound of formula C, such as Compound Cl, is converted to a compound of formula C-LG according to Scheme 4

Scheme 4

With reference to Scheme 4 and Formula C-LG, LG is a leaving group. In one embodiment, the LG is selected from the group consisting of halides and sulfonates. In one embodiment of Scheme 4 and compounds of formula C-LG, LG is selected from chloro, bromo, iodo, mesylate, tosylate and besylate. R ¹ is selected from the group consisting of a leaving group, and -OR ^a , wherein R ^a is selected from hydrogen and Ci-6 alkyl.

In some embodiments, R ¹ is -OH. In some embodiments, the LG is -Cl.

In some embodiments, a compound of formula C is reacted with a halogenating agent to yield a compound of formula C-LG. In some embodiments, the halogenating agent is thionyl chloride.

In some embodiments, the molar ratio of halogenating agent to a compound of Formula C is about 1.00: 1, about 1.05: 1, about 1.10:1, about 1.15: 1, about 1.20: 1, about 1.25: 1, about 1.30: 1, about 1.35: 1, about 1.40: 1, about 1.45: 1, about 1.50: 1, about 1.55: 1, about 1.60: 1, about 1.65: 1, about 1.70: 1, about 1.75: 1, about 1.80: 1, about 1.85: 1, about 1.90: 1, about 1.95: 1, about 2.00: 1, about 2.05: 1, or about 2.10: 1.

In some embodiments, the solvent is 1,4-di oxane. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is toluene. In some embodiments, the solvent is tetrahydrofuran.

In some embodiments, the temperature of the reaction is about 20 °C, about 25 °C, about 30 °C, about 35 °C, about 40 °C, about 45 °C, about 50 °C, about 55 °C, about 60 °C, about 65 °C, about 70 °C, or about 75 °C.

In some embodiments, upon completion of the reaction to prepare a compound of Formula C-LG, the completed reaction is cooled. In some embodiments, the temperature is cooled from about 55°C to about 65°C, to a temperature of about 20 °C to about 30 °C, e.g., about 25°C. In some embodiments, the cooling over a period of at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours. In some embodiments, the cooling occurs at a constant rate.

In some embodiments, an aqueous base is added to the cooled reaction mixture. In some embodiments, the base is sodium carbonate. In some embodiments, after addition of the aqueous base, the pH of the reaction mixture is about 6.0, about 7.0, or about 8.0.

In some embodiments, the organic phase is then extracted and diluted by another solvent. In some embodiments, the solvent is water. In some embodiments, the extraction and dilution is repeated, e.g., repeated one, two, three, or more times. In some embodiments, the diluted mixture is then filtered, washed with solvent, and dried.

In some embodiments, the solvent is water. In some embodiments, the reaction mixture is dried at a temperature of about 35 °C, about 40 °C, about 45 °C, about 50 °C, or about 55 °C.

In some embodiments, the reaction yields a compound of Formula C-LG at about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% yield.

In some embodiments, the reaction yields a compound of Formula C-LG at about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% purity. In a particular embodiment, a compound of formula C-LG has the structure

Further to the Schemes above, including Schemes 1 - 4, in one embodiment a compound of formula D’ is provided , wherein X is a counterion. In particular embodiments, a compound C-LG is contacted with a compound of formula D according to Scheme 5: Scheme 5 wherein the contacting results in the product, ketanserin.

With continued reference to Scheme 5, in one embodiment X is an inorganic counterion, by way of example a halide, such as chloro. Typically, contacting a compound of Formula C-LG with a compound of formula D occurs in the presence of a base, such as an organic or inorganic base. With reference to Scheme 5, in particular embodiments, the base comprises a carbonate base, such as a metal carbonate base, in particular potassium carbonate, cesium carbonate or sodium carbonate, or a bicarbonate base, such as sodium bicarbonate.

In one embodiment, the reaction illustrated in Scheme 5 proceeds in the presence of a solvent, in particular a solvent that is not a Class 1 solvent, by way of example in one embodiment the solvent comprises 2-butanone.

With reference to Scheme 5, in one embodiment, providing the compound of Formula D

D

Scheme 6 wherein PG is a protecting group as is known to those of skill in the art and Ar is an aryl group.

With reference to Scheme 6, the product is, in one embodiment, provided in a salt form, for example of formula D’

. In one embodiment PG is an acid-sensitive protecting group, for example a Boc group. Accordingly, in one embodiment, the process illustrated in Scheme 6 comprises contacting a compound DI is provided by contacting (Compound SMI).

In one embodiment of a process according to Schemes 1 - 6, a compound is provided by contacting a compound of the formula tosyl hydrazide (TsNHNHz), thereby producing a hydrazone compound of the formula In one embodiment of a process according to Schemes 1 - 6, in particular Scheme 5, ketanserin is isolated in the form of a salt. In another embodiment, ketanserin is isolated in the form of a free base. In one embodiment, ketanserin free base or a salt thereof is contacted with an acid to form a ketanserin salt. Where a salt is contacted with an acid, it may result in a different salt form of ketanserin. In particular embodiments ketanserin is contacted with an acid comprising L-tartaric acid, L-malic acid, succinic acid, or a combination thereof.

In some embodiments, the present disclosure provides optimized syntheses of ketanserin relative to previously known syntheses of ketanserin. A known synthesis of ketanserin is provided in Hossein Fakhraian and Mehdi Heydary, J Heterocyclic Chem 51, 151 (2014) and is described in Scheme 7.

Scheme 7

III. Methods of Treatment

Also disclosed herein are methods for using ketanserin produced as described herein, such as a method for using ketanserin disclosed herein as a 5-HT2 serotonin receptor modulator, including, without limitation the use of ketanserin as a monotherapy or in combination with another agent, such as psychedelic agent. The ketanserin of the present disclosure can be used as a 5-HT2 serotonin receptor modulator to modulate the activity of one or more other agent, such as a psychedelic agent. In one embodiment, such a combination of ketanserin with a psychedelic agent can be used for increasing neuronal plasticity. The ketanserin of the present disclosure can also be used to treat any brain disease. The ketanserin of the present disclosure can also be used for increasing at least one of translation, transcription or secretion of neurotrophic factors.

In some embodiments, ketanserin of the present disclosure is used to treat neurological diseases. In some embodiments, the ketanserin has, for example, anti- addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof. In some embodiments, the neurological disease is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood or anxiety disorder. In some embodiments, the neurological disease is a migraine, headaches (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer’s disease, Parkinson’s disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder). In some embodiments, the neurological disease is a migraine or cluster headache. In some embodiments, the neurological disease is a neurodegenerative disorder, Alzheimer’s disease, or Parkinson’s disease. In some embodiments, the neurological disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is addiction (e.g., substance use disorder). In some embodiments, the neuropsychiatric disease or neurological disease is depression. In some embodiments, the neuropsychiatric disease or neurological disease is anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post- traumatic stress disorder (PTSD). In some embodiments, the neurological disease is stroke or traumatic brain injury. In some embodiments, the neuropsychiatric disease or neurological disease is schizophrenia.

In some embodiments, ketanserin of the present disclosure is used in combination with a psychedelic agent for increasing neuronal plasticity. In some embodiments, ketanserin described herein is used for treating a brain disorder.

In some embodiments, the present disclosure provides a method of treating a disease, including administering to a subject in need thereof, a therapeutically effective amount of ketanserin of the present disclosure. In some embodiments, the disease is a musculoskeletal pain disorder including fibromyalgia, muscle pain, joint stiffness, osteoarthritis, rheumatoid arthritis, muscle cramps. In some embodiments, the present invention provides a method of treating a disease of women’s reproductive health including premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), post-partum depression, and menopause.

In certain embodiments, ketanserin disclosed herein is used alone or in combination to treat hypertension: hypertensive crisis during or after surgery, hypertension at pre-eclampsy or HELLP syndrome with a diastolic blood pressure of 110 mm Hg or higher. In certain other embodiments, ketanserin disclosed herein is used alone or in combination to treat microcircular failure during sepsis and purpura fulminans.

In some embodiments, the ketanserin of the present disclosure have activity as 5-HT2A modulators. In some embodiments, the compounds of the present disclosure elicit a biological response by activating the 5-HT2A receptor (e.g., allosteric modulation or modulation of a biological target that activates the 5-HT2A receptor). 5-HT2A agonism has been correlated with the promotion of neural plasticity (Ly et al., 2018). 5-HT2A antagonists abrogate the neuritogenesis and spinogenesis effects of hallucinogenic compounds with 5-HT2A agonist activity, for example, DMT, LSD, and DOI. In some embodiments, the ketanserin of the present disclosure is used as 5-HT2A modulators in combination with a psychedelic to promote neural plasticity (e.g., cortical structural plasticity). In some embodiments, promotion of neural plasticity includes, for example, increased dendritic spine growth, increased synthesis of synaptic proteins, strengthened synaptic responses, increased dendritic arbor complexity, increased dendritic branch content, increased spinogenesis, increased neuritogenesis, or any combination thereof. In some embodiments, increased neural plasticity includes, for example, increased cortical structural plasticity in the anterior parts of the brain. EXAMPLES

Example 1: Route scouting for synthesis of ketanserin (Compound 1)

Original synthetic approach of Compound 1

In order to develop optimized syntheses of ketanserin relative to, e.g, the route described in Hossein Fakhraian and Mehdi Heydary, J Heterocyclic Chem 51, 151 (2014) (the “original route”), a route scouting synthetic chemistry campaign was performed. Newly developed synthetic approach of Compound 1

MW: 307 37 Compound D'-2

Compound D1

The summary of the process is listed below:

Total yield comparison

Research and Development of Compounds of Formula B

Synthetic scheme Initial' ^{MW: 165 19} MW: 265.31

Molecular Weight: 165.19 MW: 265.31

New method: ^A1 B2

Summary:

Toxic raw material ethyl chloroformate was replaced by normal reagent isobutyl chloroformate. Meanwhile, unfriendly solvent CHCk (ICH Class 2) was replaced by N- methylpyrrolidone (NMP). After optimization of the work-up, this step was telescoped with the next step, eliminating the need to isolate and purify B2.

The original procedure evaluation The literature process was repeated. The reaction was heterogeneous, with much unreacted starting material remaining. The filtered solid was raw material Al, which was confirmed by 'H-N R. 4.7 g of target product was obtained in 99.3% purity after concentration of the filter liquor.

Table Al-1 Purpose: Repeat the literature process

Original procedure:

1. Ethyl 2-aminobenzoate (7.5g, 45.4mmoL) was added dropwise to a 25-mL double-necked flask equipped with magnetic stir bar and containing ethylchloroformate (7 g, 64.5 mmoL) and chloroform (25 mL). The reaction was stirred for 0.5h at 45-55 °C, during which a white precipitate was formed.

2. The precipitate was recovered by filtration and the filtrate was concentrated to dryness to afford 4.7 g of crude ethyl 2-(ethoxycarbonyl)phenyl carbamate in 43.6% yield.

Optimize reaction condition

• A set of 18 solvents was used in a series of experiments conducted on 0.1 g scale to screen for reaction conditions to improve reaction homogeneity and conversion. To each vial in parallel synthesis equipment is charged with Al, various solvents and ethyl chloroformate. After stirring for Ih, HPLC results indicated good conversion in NMP and DMAc solvents, in which the reaction mixtures were homogeneous.

Table Al-2 Purpose: Screen reaction solvents

One reaction scaled up to 20 g Al was carried out to prepare the reference standard of B2. After workup, 30.3 g B2 was obtained in 100% purity and 94.2% yield. The NMR is consistent with the structure of B2.Table Al-3 Purpose: confirm optimization condition

Current process:

MW: 165.19

1. Charge isobutyl carb onochlori date (0.98-1.01X, 1.2 eq.) into Rl.

2. Charge NMP (5-8X) into Rl .

3. Charge ethyl 2-aminobenzoate (20.0g, 1.0 X.) into Rl.

4. Adjust Rl to 45~55°C.

5. Stir Rl for 2-4 hr at 45~55°C.

6. Adjust Rl to 20~30°C.

7. Add process water (34-36X) into Rl .

8. Stir Rl for 4-6 hr at 20~30°C.

9. Filter and wash cake with H2O (4-6X).

10. Dry the wet cake at 40-50 °C for 48 hr.

Current process 2

1. Charge isobutyl carb onochlori date (0.98-1.01X, 1.2 eq.) into Rl.

2. Charge NMP (5-8X) into Rl .

3. Charge ethyl 2-aminobenzoate (20.0g, 1.0 X.) into Rl.

4. Adjust Rl to 45~55°C.

5. Stir Rl for 2-4 hr at 45~55x.

6. Adjust Rl to 20~30°C. Research and Development of Compound Cl

Synthetic scheme Summary:

Compared to the original process, unfriendly solvent XYLENE (ICH Class 2) was replaced by NMP in the improved process. Reaction in flow mode was investigated, and the best reaction condition involved heating at 150°C for 2 h. The work-up was optimized by effecting direct separation by the addition of water as anti-solvent. The original procedure evaluation

When the literature process was repeated, the reaction mixture was sampled after 4 h at 145 to 155°C. The process is reproducible.

Table B-l Purpose: Repeat the literature process

Optimize reaction condition • DMAc and NMP solvents were explored as replacement solvents for xylene in step 2 to develop a telescoped process. Two trials were performed reacting 0.5 g B 1 with ethanolamine. After stirring the two reactions for 5 h, HPLC results were promising when NMP or DMAc were used as solvent.

Table B-2 Purpose: Screen reaction solvents in step 2

• Screened temperature 170°C and 150°C gave similar purity of Cl -97%. However at 170°C, the formation of impurity with HPLC retention time of 4.17 min increased. Reaction at 150°C for 2 h minimizes this impurity. Table B-2 Purpose: Screen temperature in step 2 in flow mode

Because of the toxicity of ethyl chloroformate, isobutyl chloroformate was tried (in NMP). After the addition of water (40v), product Cl precipitated from the reaction mixture in 99.6% HPLC purity. Table B-3 Purpose: Optimization of reaction condition

The solubility data of Cl was collected. These data showed the suitability of NMP/H2O as the crystallization system. Table B-4 Purpose: The solubility test of Cl (25°C) One reaction was scaled up to 40 g input Al to verify the optimized process. After workup by adding 10 Vol. process water, 46.3 g Cl was obtained in 100% purity and 91.5% isolated yield.

Table B-4 Purpose: Verify the optimized process of Cl

Current process:

1. Charge isobutyl carb onochlori date (0.98-1.01X, 1.2 eq.) into Rl.

2. Charge NMP (5-8X) into Rl .

3. Charge ethyl 2-aminobenzoate (40.0g, 1.0 X.) into Rl.

4. Adjust Rl to 45-55 °C.

5. Stir Rl for 2-4 hr at 45-55 °C.

6. Adjust Rl to 20-30 °C.

7. Charge 2-aminoethanol (2.0-2.2X, 5.5 eq.) into Rl.

8. Stir Rl for 0.5-1 hr at 20-30 °C.

9. Adjust Rl to 145-155 °C.

10. Stir Rl for 4-6 hr at 145-155 °C.

11. Adjust Rl to 20-30 °C.

12. Charge H ₂ O (10-16X) into Rl.

13. Stir Rl for 3-5 hr at 20-30 °C. 14. Filter and wash cake with H2O (2~5X).

15. Dry the wet cake at 40-50 °C for 24 hr.

Research and Development of Compound C2

5 Synthetic scheme

Molecular Weight: 224.64

Molecular Weight: 206.20 C2

C1

Summary:

Unfriendly solvent CHCh (ICH Class 2) used in the original Janssen process was replaced by THF as a process improvement.

10 A crystallization process was developed to purify C2.

The original procedure evaluation

The literature process was repeated. After work up, 9.8 g C2 was obtained in 98.0% purity. The structure is confirmed by NMR.

Table C-l Purpose: Repeat the literature process Optimize reaction condition

• Reaction conditions were screened against a panel of solvents: DCM, Dioxane, DMF, MeCN, THF, toluene, IP Ac, MTBE, and CHCh, and chlorination reagents: SOCh, SOCh+DMF(cat), (COC1) ₂ , NCS+PPh ₃ ,PhCOCl, TsCl+Et ₃ N, HC1). The results showed that use of THF as solvent and 2.0 eq. SOCh gave good results.

Table C-2 Purpose: Optimize reaction condition through HTS

Conversion = (C2+C2-IMP1)/(C2+C1+C2-IMP1)

IMP1 Purity = IMP 1/100

• One reaction was conducted on 10 g input scale of Cl to verify the optimized reaction conditions. After 4 h of reaction, the C1/C2 =0.06/99.9.

Table C-3 Purpose: verify the optimized reaction condition

• The solubility data of C2 was collected. These data showed the suitability of THF/H2O as the crystallization system. Table C-4 Purpose: The solubility test of C2 (25°C)

One reaction was scaled up to 24 g Cl to verify the optimized process. After workup by addition of 30 Vol. process water, 25.1 g C2 was obtained in 99.9% purity and 96% yield. Table C-5 Purpose: Verify the optimized process of C2

Current process:

1. Charge Cl (24 g, 1.0 eq.) into R1.

2. Charge Tetrahydrofuran (8.5-9.5X) into R1. 3. Charge Thionyl chloride (1.10-1.22X, 2.0 eq.) into Rl.

4. Adjust Rl to 57-67 °C.

5. Stir Rl for 2-12 hr at 57-67 °C.

6. Adjust Rl to 40-50 °C.

7. Adjust Rl to 15-25 °C. 8. Charge 20% sodium carbonate aqueous solution (7-12X) to Rl over 2-10 hr to adjust to pH

6-8 at 15-30 °C.

9. Stir Rl for 0.1-0.5 hr at 15-30 °C.

10. Stand Rl for 0.1-0.5 hr.

11. Separate the upper layer and remove the bottom layer. 12. Adjust Rl to 15-30 °C.

13. Charge Process Water (5-8X) into Rl.

14. Stir Rl for 1-2 hr at 15-30 °C.

15. Charge Process Water 15-25X into Rl 16. Stir Rl for 0.5-1 hr at 15-30 °C.

17. Filter and wash cake with Process Water (1-3X).

18. Dry the wet cake at 40-50 °C for 24 hr 15-35 hr.

Research and Development of Compound LI Synthetic scheme

MW: 199 25 MW: 186 23 MW: 367.46

Compound K1 tosyl hydrazide Compound L1

Summary:

The work-up was optimized by effecting direct separation by addition of water as anti-solvent. The original procedure evaluation The literature process was repeated: One reaction on 20 g Compound KI input scale was carried out. After work up, 29.6 g LI was obtained in 100% purity. The structure of LI was confirmed by NMR.

Table E2-1 Purpose: The preparation of Compound LI.

Optimize reaction condition

• The solubility data of Compound LI was collected. These data showed the suitability of dioxane/EEO or dioxane as the crystallization system.

Table E2-2 Purpose: The solubility test of Compound LI (25°C)

• One reaction was scaled up to 20 g Compound KI to verify the optimized process. After workup (20 Vol. water was added) and drying, 33.5 g Compound LI was obtained in 98.8% yield. The isolated crude yield is 90.8%. Table E2-3 Purpose: Verify the optimized process of LI.

Current process: 1. Charge tert-butyl 4-oxopiperidine-l -carboxylate (20 g, 1.0 X.) into R1.

2. Charge 4-methylbenzenesulfonohydrazide (0.89-0.92X, 1.2 eq.) into Rl.

3. Charge 1,4-di oxane (8-1 OX) into Rl.

4. Stir Rl for 3-5 hr at 20-30 °C.

5. Charge H ₂ O (15-20X) into Rl. 6. Stir Rl for 2-3 hr at 20-30 °C.

7. Filter and wash cake with H2O (3-5X).

8. Dry the wet cake at 40-50 °C for 42 hr.

Research and Development of Compound DI Synthetic scheme

MW: 367.46 MW: 124.11 MW: 307.37

Compound L1 Compound SM1 Compound D1

Summary:

A crystallization process was developed for the purification of Compound DI. The original procedure evaluation

The literature process was repeated: One reaction was scaled up to 10 g Compound LI to prepare the reference standard of Compound DI. After work up, 4.6 g target product (DI) was obtained in 99.2% purity. The structure is supported by NMR. Table Fl-1 Purpose: The preparation of DI Optimize reaction condition

• The solubility data of Compound DI was collected. These data showed the suitability of dioxane/JLO as the crystallization system. Table Fl-2 Purpose: The solubility test of Compound DI (25°C)

• Reaction conditions were screened using solvents: Dioxane, DME, 2-MeTHF, ACN; base: KHMDS, CS2CO3, K3PO4, K2CO3, and DBU. Table Fl-2 Purpose: Optimize reaction condition through HTS of Compound DI

One reaction was scaled up to 20 g Compound LI to verify the optimized process. After recrystallization in heptane and drying, 10.5 g of Compound DI was obtained in 99.0% purity, 93.5% assay, and 62.6% isolated yield. Table Fl-5 Purpose: Verify the optimized process of Compound DI.

Current process:

1. Charge tert-butyl 4-(/?-tolylsulfonylhydrazono) piperidine- 1 -carboxylate (10 g, 1.0 X.) into Rl.

2. Charge 4-fluorobenzaldehyde (0.39-0.41X, 1.2 eq.) into Rl.

3. Charge CS2CO3 (1.3-1.4X, 1.5 eq.) into Rl.

4. Charge 1,4-dioxane (10-12X) into Rl.

5. Stir Rl for 1-2 hr at 20-30 °C.

6. Adjust Rl to 105-115 °C.

7. Stir Rl for 15-18 hr at 105-115 °C.

8. Quench the reaction with saturation NH4C1 aq. (8-1 OX) below 30 °C.

9. Extract Rl with IPAc (4-5X).

10. Separate the bottom aqueous layer and remove the upper layer.

11. Extract Rl with IPAc (4-5X).

12. Separate the bottom aqueous layer and remove the upper layer.

13. Combine organic phases into Rl .

14. Wash Rl with H2O (4-5X).

15. Separate the upper layer and remove the bottom layer. 16. Concentrate R1 to (2~3X) below 40 °C.

17. Charge N-HEPTANE (4~5X) into R1.

18. Concentrate R1 to (2~3X) below 40 °C.

19. Charge N-HEPTANE (4~5X) into R1.

20. Concentrate R1 to (2~3X) below 40 °C.

21. Charge N-HEPTANE (2~3X) into R1.

22. Adjust R1 to -5~5 °C.

23. Stir Rl for 2 hr at -5~5 °C.

24. Filter and wash cake with N-HEPTANE (1~2X).

25. Dry the wet cake at 20-30 °C for 18 hr.

Research and Development of Compound D’-2

Synthetic scheme

MW: 307 37 MW: 207 25

Compound D1 Compound D'-2

Summary:

The work-up was optimized as a direct separation.

The original procedure evaluation

• One reaction was scaled up to 1 g Compound DI for preparing Compound D2. After work up by addition of MTBE, the target product was obtained in 98.3% purity and confirmed by

H-NMR.

Table G-l Purpose: Purpose: The preparation of Compound D2

Optimize reaction condition

• Reaction conditions were screened using solvents: MeOH, MeCN, water, DCM, THF, and Dioxane; acids: 98 wt% H2SO4, TfOH, MeSChH, and TFA. The results showed that the combination of acids and solvents shown in Table G-2 would work well. Table G-2 Purpose: Optimize reaction condition through HTS of Compound D2

Conversion = D2/(D2 + DI)

The solubility data of Compound D2 was collected. These data showed the suitability of IP Ac as reaction solvent and the crystallization system.

Table G-3 Purpose: The solubility test of Compound D2 (25°C)

One reaction on 3 g scale was carried out to optimize reaction conditions, using HCl/IPAc solution. This condition was further confirmed on larger scale reaction.

Table G-4 Purpose: Reaction condition optimized

• One reaction was scaled up to 20 g Compound DI for preparing Compound D’-2. After workup, filtration and drying, the target product (Compound D’-2) was obtained in 99.9% purity and 84.4% yield. Table G-5 Purpose: Verify the optimized process of Compound D’-2.

Current process:

1. Charge Compound DI (100.0 g, 1.0 eq.) into Rl.

2. Charge ISOPROPYL ACETATE (6.0-7.0X) into Rl . 3. Adjust Rl to -5~5 °C.

4. Add 20% HC1 gas in ISOPROPYL ACETATE (4.5-5. OX, 8 eq.) solution into Rl at -5-5 °C.

5. Adjust Rl to 15-30 °C.

6. Stir Rl for 2-8 hr at 15-30 °C.

7. Filter and wash cake with ISOPROPYL ACETATE (1-3 V). 8. Dry the wet cake at 40-50 °C for 15-35 hr.

Research and Development of Compound 1

Synthetic scheme Summary:

The work-up was optimized using direct separation. The original procedure evaluation

• The literature process was repeated. After slurrying in water, the target product was obtained in 93.8% purity. The target product was confirmed by LCMS and H-NMR.

Table FP-1 Purpose: Repeat the literature process Optimize reaction condition

Reaction condition were screened using solvents: 2-Butanone, MeCN, and EtOH; bases: Na2CCh, and NaHCCh. The best results (93.1% purity) were obtained using MeCN as solvent and 5.0 eq. NaHCCh.

Table FP-2. Optimize reaction conditions

Key Analysis data

One reaction was conducted on 0.5 g scale of Compound C2 to confirm the optimized reaction conditions. Most of an intermediate, which is formed in situ from Compound C2, remained.

NMR supports the following structure for the intermediate: (Compound I-C) Table FP-3 Purpose: Confirm optimized reaction condition on larger scale reaction of

Compound 1

Mixed reaction solvent systems were screened. A good result was obtained from using 2- Butanone/FCO.

Table FP-4 Purpose: Screen the reaction solvent systems for preparation of Compound 1.

The ratio of 2-Butanone/H2O was screened. Good results were obtained from using 10V/4V 2-

Butanone / H2O. Table FP-5 Purpose: Screen the ratio of l-Butanone/HiO for preparing Compound 1

• The XRPDs for the crude free base API (ketanserin) and commercial sample were different. Recrystallization conditions were developed.

• After recrystallization from DMSO/H2O, the free base API exhibited a XRPD matching that for a commercial sample

• The impurity profile of the recrystallized free base API was similar to that of the commercial sample LCMS showed that the structure of the major impurity RRT=1.31 might be

Molecular Weight: 582.68

The solubility data of Compound 1 was collected. These data showed the suitability of DMSO/H2O (2/1) as reaction solvent and crystallization system.

Table FP-6 Purpose: The solubility test of Compound 1 (25°C)

One reaction was conducted on 5 g scale of Compound C2 to confirm the optimized reaction condition. After work up, 6.7 g target product was obtained in 98.0% purity. Table FP-7 Purpose: Confirm optimized reaction condition on larger scale reaction of Compound 1.

Current process:

1. Charge 3-(2-chloroethyl)-lH-quinazoline-2, 4-dione (5 g, 1.0 X.) into Rl. 2. Charge (4-fluorophenyl)-(4-piperidyl) methanone hydrochloride salt (1.15-1.25X, 1.1 eq.) into Rl .

3. Charge Na ₂ CO ₃ (1.35-1.45X, 3 eq.) into Rl.

4. Charge 2-BUTANONE (8-10X) into Rl .

5. Charge H ₂ O (4-5X) into Rl . 6. Adjust Rl to 75-85 °C.

7. Stir Rl for 45-68 hr at 75-85 °C.

8. Adjust Rl to 20-30 °C.

9. Stir Rl for 3-5 hr at 20-30 °C.

10. Filter and wash cake with water (3-5X). 11. Dry the wet cake at 40-50 °C for 18 hr. Research and Development of purification of Compound 1

Synthetic scheme

Molecular Weight: 395.43 Molecular Weight: 395.43

Compound 1 Compound 1 Summary:

The processes for purification and recrystallization were optimized.

Optimize work-up condition

• Investigation showed that the impurity RRT=1.31 can be purged by treating the API solution in DMSO with 2X CUNO. The purity was improved from 97.4% to 99.4%, and the level of impurity RRT-1.31 was reduced from 1.75% to 0.41%. The amount of CUNO will be further optimized in the future manufacture campaign.

Table FP-1 Purpose: Purification of Compound 1 by cycling CUNO

Current process:

1. Charge 3-[2-[4-(4-fluorobenzoyl)-l-piperidyl] ethyl]- lH-quinazoline-2, 4-dione (4 g, 1.0 X.) into R1.

2. Charge DMSO (25-30X) into R1.

3. Adjust R1 to 45-55 °C.

4. Stir R1 for 1-2 hr at 45-55 °C.

5. Cycle R1 with CUNO (2-3 X) for 5-8 h.

6. Wash CUNO with DMSO (3-5 X).

7. Add H ₂ O (5-10X) into R1 at 45-55 °C.

8. Add Compound 1 seed (0.001-0.01X) into R1 at 45-55 °C.

9. Stir R1 for 1-2 hr at 45-55 °C.

10. Add H2O (10-15X) into R1 at 45-55 °C.

11. Stir R1 for 2-3 hr at 45-55 °C.

12. Adjust R1 to 20-30 °C.

13. Stir R1 for 0.5 hr at 20-30 °C.

%.

14. Filter and wash cake with water (5-10X).

15. Dry the wet cake at 40-50 °C for 18 hr.

Learning and experience

The literature process of preparing ketanserin was not robust without adding water as a hydrotropic solvent. The Na2CO3 did not dissolve in the ketanserin reaction system, and the solid-liquid heterogeneity gave rise to poor conversion when the reaction was scaled up. The addition of water gave a liquid-liquid heterogeneous reaction mixture. The process of preparing ketanserin was made more robust by several unexpected improvements. Scale Up

Using methods and techniques known to one skilled in the art, the synthetic route described above was scaled up to provide compound 1 at kilogram scale. Parameters optimized in the development of scaled-up syntheses included isolation, purification and filtration techniques, selection of solvent, selection of reaction time, and selection of reaction temperature. Compound 1 was obtained at 1 -kilo scale at about 70% yield and at the 5-kilo scale at about 55% yield.

NUMBERED EMBODIMENTS

1. A method for the preparation of ketanserin 1

2. A process for preparing ketanserin 1 according to the following synthetic route: Compound D1

Synthesis of a compound of Formula B

3. A method of any one of the previous embodiments comprising a method for providing a compound of Formula B, the method comprising reacting a compound of Formula A with a compound of Formula E in a solvent, to provide a compound of Formula B wherein R and R ² are each, individually, hydrogen or Ci-6 alkyl.

4. A method of providing a compound of Formula B, the method comprising reacting a compound of Formula A with a compound of Formula E in a solvent, to provide a compound of Formula B wherein R and R ² are each, individually, hydrogen or Ci-6 alkyl.

5. The method of any one of the previous embodiments, wherein R is ethyl.

6. The method of any one of the previous embodiments, wherein R ² is ethyl.

7. The method of any one of the previous embodiments, wherein R ² is isobutyl.

8. The method of any one of the previous embodiments, wherein the molar ratio of the compound of Formula E to the compound of Formula A is about 1.00:1, about 1.05: 1, about 1.10:1, about 1.15:1, about 1.20: 1, about 1.25: 1, about 1.30: 1, about 1.35: 1, about 1.40: 1, about

1.45:1, about 1.50:1, about 1.55: 1, about 1.60: 1, about 1.65: 1, about 1.70: 1, about 1.75: 1, about

1.80:1, about 1.85:1, about 1.90: 1, about 1.95: 1, about 2.00: 1, about 2.05: 1, or about 2.10:1.

9. The method of any one of the previous embodiments, wherein the solvent is chloroform, xylene, dioxane, DCM, IP Ac, THF, MTBE, 2-MeTHF, DMAc, toluene, n-heptane, methyl cyclohexane, NMP, MeCN, EtOAc, or DME.

10. The method of any one of the previous embodiments, wherein the solvent is an alkyl amide solvent.

11. The method of any one of the previous embodiments, wherein the solvent is NMP.

12. The method of any one of the previous embodiments, wherein the solvent is DMAc.

13. The method of any one of the previous embodiments, wherein the reaction temperature is about 25 °C, about 30 °C, about 35 °C, about 40 °C, about 45 °C, about 50 °C, about 55 °C, about 60 °C, about 65 °C, about 70 °C, or about 75 °C.

14. The method of any one of the previous embodiments, wherein upon completion of the reaction, the reaction mixture is cooled from a temperature of about 25 °C to about 75 °C, about 45°C to about 55°C, to a temperature of about 25°C, at a constant rate over a period of at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours. The method of any one of the previous embodiments, wherein the reaction is run in batch.

The method of any one of the previous embodiments, wherein the reaction is run in flow.

The method of any one of the previous embodiments, wherein the crude reaction mixture is then used in the next reaction without further purification.

18. The method of any one of the previous embodiments, wherein the cooled reaction mixture is then filtered, washed with solvent, and dried.

19. The method of any one of the previous embodiments, wherein the solvent is water.

20. The method of any one of the previous embodiments, wherein the reaction mixture is dried at a temperature of from about 35 °C to about 55 °C.

21. The method of any one of the previous embodiments, wherein the reaction mixture is dried at a temperature of from about 35 °C, to about 40 °C, to about 45 °C, to about 50 °C, or to about 55 °C.

22. The method of any one of the previous embodiments, wherein the reaction mixture is dried at a temperature of about 35 °C, about 40 °C, about 45 °C, about 50 °C, or about 55 °C.

23. The method of any one of the previous embodiments, wherein the reaction yields a compound of Formula B at about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% yield.

24. The method of any one of the previous embodiments, wherein the reaction yields a compound of Formula B at about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% purity.

Synthesis of a compound of Formula C

25. The method of any one of the previous embodiments, further comprising reacting a compound of Formula B with a compound of Formula F in a solvent, to provide a compound of Formula C wherein:

R and R ² are each, independently, hydrogen or Ci-6 alkyl;

R ¹ is a leaving group or -OR ^a , wherein R ^a is selected from hydrogen and Ci-6 alkyl.

26. A method comprising reacting a compound of Formula B

B with a compound of Formula F in a solvent, to provide a compound of Formula C wherein:

R and R ² are each, independently, hydrogen or Ci-6 alkyl;

R ¹ is a leaving group or -OR ^a , wherein R ^a is selected from hydrogen and Ci-6 alkyl.

27. The method of any one of the previous embodiments, wherein R ¹ is -OH.

28. The method of any one of the previous embodiments, wherein R ² is isobutyl. 29. The method of any one of the previous embodiments, wherein R is ethyl.

30. The method of any one of the previous embodiments, wherein the molar ratio of a compound of Formula F to a compound of Formula B is about 1.0: 1, about 1.5: 1, about 2.0: 1, about 2.5: 1, about 3.0: 1, about 3.5: 1, about 4.0: 1, about 4.5: 1, about 5.0: 1, about 5.5: 1, about 6.0:1, about 6.5: 1, about 7.0: 1, about 7.5:1, or about 8.0:1.

31. The method of any one of the previous embodiments, wherein the reaction is carried out in flow.

32. The method of any one of the previous embodiments, wherein the reaction is carried out in batch.

33. The method of any one of the previous embodiments, wherein the solvent is NMP.

34. The method of any one of the previous embodiments, wherein the solvent is DMAc.

35. The method of any one of the previous embodiments, wherein the temperature of the reaction is from about 100 °C to about 200 °C.

36. The method of any one of the previous embodiments, wherein the temperature of the reaction is from about 120 °C to about 180 °C.

37. The method of any one of the previous embodiments, wherein the temperature of the reaction is about 120 °C, about 125 °C, about 130 °C, about 135 °C, about 140 °C, about 145 °C, about 150 °C, about 155 °C, about 160 °C, about 165 °C, about 170 °C, about 175 °C, or about 180 °C.

38. The method of any one of the previous embodiments, wherein, upon completion of the reaction, the completed reaction is cooled from a temperature of about 130 °C to about 170 °C, about 145°C to about 155°C, to a temperature of about 25°C, at a constant rate over a period of at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours.

39. The method of any one of the previous embodiments, wherein solvent is added to the cooled reaction mixture to precipitate out the desired product.

40. The method of any one of the previous embodiments, wherein the solvent is water.

41. The method of any one of the previous embodiments, wherein the reaction mixture is then further cooled from a temperature of about 25°C to about 30 °C, to a temperature of about - 5 °C to about 5 °C, at a constant rate over a period of at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours.

42. The method of any one of the previous embodiments, wherein the cooled reaction mixture is then filtered, washed with solvent, and dried.

43. The method of any one of the previous embodiments, wherein the solvent is water.

44. The method of any one of the previous embodiments, wherein the reaction mixture is dried at a temperature of about 35 °C, about 40 °C, about 45 °C, about 50 °C, or about 55 °C.

45. The method of any one of the previous embodiments, wherein the reaction yields a compound of Formula C at about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% yield.

46. The method of any one of the previous embodiments, wherein the reaction yields a compound of Formula C at about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% purity.

Synthesis of a compound of Formula C-LG

47. The method of any one of the previous embodiments, further comprising reacting a compound of Formula C with a halogenating agent in a solvent to yield a compound of Formula C-LG wherein R ¹ is selected from the group consisting of a leaving group and -OR ^a ;

LG is halo; and

R ^a is selected from hydrogen and Ci-6 alkyl.

48. A method comprising reacting a compound of Formula C with a halogenating agent in a solvent to yield a compound of Formula C-LG wherein

R ¹ is selected from the group consisting of a leaving group and -OR ^a ;

LG is halo; and

R ^a is selected from hydrogen and Ci-6 alkyl.

49. The method of any one of the previous embodiments, wherein R ¹ is -OH.

50. The method of any one of the previous embodiments, wherein LG is -Cl.

51. The method of any one of the previous embodiments, wherein the halogenating agent is thionyl chloride.

52. The method of any one of the previous embodiments, wherein the molar ratio of halogenating agent to a compound of Formula C is about 1.00: 1, about 1.05: 1, about 1.10: 1, about 1.15: 1, about 1.20: 1, about 1.25: 1, about 1.30: 1, about 1.35: 1, about 1.40: 1, about 1.45: 1, about 1.50: 1, about 1.55: 1, about 1.60: 1, about 1.65: 1, about 1.70: 1, about 1.75: 1, about 1.80: 1, about 1.85: 1, about 1.90: 1, about 1.95: 1, about 2.00: 1, about 2.05: 1, or about 2.10: 1.

53. The method of any one of the previous embodiments, wherein the solvent is tetrahydrofuran.

54. The method of any one of the previous embodiments, wherein the solvent is 1,4-di oxane.

55. The method of any one of the previous embodiments, wherein the solvent is acetonitrile.

56. The method of any one of the previous embodiments, wherein the solvent is toluene. 57. The method of any one of the previous embodiments, wherein the temperature of the reaction is about 20 °C, about 25 °C, about 30 °C, about 35 °C, about 40 °C, about 45 °C, about 50 °C, about 55 °C, about 60 °C, about 65 °C, about 70 °C, or about 75 °C.

58. The method of any one of the previous embodiments, wherein, upon completion of the reaction to prepare a compound of Formula C-LG, the completed reaction is cooled from a temperature of about 20 °C to about 75 °C, about 55°C to about 65°C, to a temperature of about 25°C, at a constant rate over a period of at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours.

59. The method of any one of the previous embodiments, wherein an aqueous base is then added to the cooled reaction mixture.

60. The method of any one of the previous embodiments, wherein the base is sodium carbonate.

61. The method of any one of the previous embodiments, wherein, after addition of the aqueous base, the pH of the reaction mixture is about 6.0, about 7.0, or about 8.0.

62. The method of any one of the previous embodiments, wherein the organic phase is then extracted and diluted by another solvent.

63. The method of any one of the previous embodiments, wherein the additional solvent is water.

64. The method of any one of the previous embodiments, wherein the diluted mixture is then filtered, washed with solvent, and dried.

65. The method of any one of the previous embodiments, wherein the solvent is water.

67. The method of any one of the previous embodiments, wherein the reaction mixture is dried at a temperature of about 35 °C, about 40 °C, about 45 °C, about 50 °C, or about 55 °C.

68. The method of any one of the previous embodiments, wherein the reaction yields a compound of Formula C-LG at about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% yield.

69. The method of any one of the previous embodiments, wherein the reaction yields a compound of Formula C-LG at about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% purity. Synthesis of a compound of Formula L

70. The method of any one of the previous embodiments, further comprising reacting a compound of Formula K

K with tosyl hydrazide in a solvent to yield a compound of Formula L

L wherein R ³ is a protecting group.

71. A method comprising reacting a compound of Formula K

K with tosyl hydrazide in a solvent to yield a compound of Formula L

L wherein R ³ is a protecting group.

72. The method of any one of the previous embodiments, wherein R ³ is Boc.

73. The method of any one of the previous embodiments, wherein the molar ratio of tosyl hydrazide to a compound of Formula L is about 0.5:1, about 0.90:1, about 0.95:1, about 1.00:1, about 1.05:1, about 1.10:1, or about 1.5:1.

74. The method of any one of the previous embodiments, wherein the molar ratio of tosyl hydrazide to a compound of Formula L is about 0.85:1, about 0.90:1, about 0.95:1, about 1.00:1, about 1.05:1, about 1.10:1, or about 1.15:1.

75. The method of any one of the previous embodiments, wherein the solvent is dioxane. 76. The method of any one of the previous embodiments, wherein the temperature of the reaction is from about 20 °C to about 40 °C.

77. The method of any one of the previous embodiments, wherein the temperature of the reaction is about 20 °C, about 25 °C, about 30 °C, about 35 °C, or about 40 °C.

78. The method of any one of the previous embodiments, wherein the reaction mixture is diluted with a solvent upon completion.

79. The method of any one of the previous embodiments, wherein the solvent is water.

80. The method of any one of the previous embodiments, wherein the reaction mixture is then filtered, washed with solvent, and dried.

81. The method of any one of the previous embodiments, wherein the solvent is water.

82. The method of any one of the previous embodiments, wherein the reaction mixture is dried at a temperature of about 35 °C, about 40 °C, about 45 °C, about 50 °C, or about 55 °C.

83. The method of any one of the previous embodiments, wherein the reaction yields a compound of Formula L at about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% yield.

84. The method of any one of the previous embodiments, wherein the reaction yields a compound of Formula L at about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% purity.

Synthesis of a compound of Formula D

85. The method of any one of the previous embodiments, further comprising reacting a compound of Formula L with Compound SMI and a base in a solvent to yield a compound of Formula D wherein R ³ is a protecting group.

86. A method comprising reacting a compound of Formula L with Compound SMI and a base in a solvent to yield a compound of Formula D wherein R ³ is a protecting group.

87. The method of any one of the previous embodiments, wherein R ³ = Boc.

88. The method of any one of the previous embodiments, wherein the molar ratio of Compound SMI to a compound of Formula L is about 1.00:1, about 1.05:1, about 1.10:1, about 1.15:1, about 1.20:1, about 1.25:1, about 1.30:1, about 1.35:1, about 1.40:1, about 1.45:1, about 1.50:1, about 1.55:1, about 1.60:1, about 1.65:1, about 1.70:1, about 1.75:1, about 1.80:1, about 1.85:1, about

1.90:1, about 1.95:1, about 2.00:1, about 2.05:1, or about 2.10:1.

89. The method of any one of the previous embodiments, wherein the molar ratio of base to a compound of Formula L is about 1.00:1, about 1.05:1, about 1.10:1, about 1.15:1, about 1.20:1, about 1.25:1, about 1.30:1, about 1.35:1, about 1.40:1, about 1.45:1, about 1.50:1, about 1.55:1, about 1.60: 1, about 1.65: 1, about 1.70: 1, about 1.75: 1, about 1.80: 1, about 1.85: 1, about 1.90: 1, about 1.95: 1, about 2.00: 1, about 2.05: 1, or about 2.10: 1.

90. The method of any one of the previous embodiments, wherein the base is a carbonate base.

91. The method of any one of the previous embodiments, wherein the base is cesium carbonate.

92. The method of any one of the previous embodiments, wherein the solvent is dioxane.

93. The method of any one of the previous embodiments, wherein the solvent is DME.

94. The method of any one of the previous embodiments, wherein the solvent is 2-Me THF.

95. The method of any one of the previous embodiments, wherein the compound of Formula

LI is added as a solution.

96. The method of any one of the previous embodiments, wherein the compound of Formula LI is added as a solution in dioxane.

97. The method of any one of the previous embodiments, wherein the temperature of the reaction is about 80 °C to about 130 °C.

98. The method of any one of the previous embodiments, wherein the temperature of the reaction is about 80 °C, to about 85 °C, to about 90 °C, to about 95 °C, to about 100 °C, to about 105 °C, to about 110 °C, to about 115 °C, to about 120 °C, to about 125 °C, or to about 130 °C.

99. The method of any one of the previous embodiments, wherein the temperature of the reaction is about 80 °C, about 85 °C, about 90 °C, about 95 °C, about 100 °C, about 105 °C, about 110 °C, about 115 °C, about 120 °C, about 125 °C, or about 130 °C.

100. The method of any one of the previous embodiments, wherein upon completion of the reaction to prepare a compound of Formula D, the completed reaction is cooled from a temperature of about 80 °C to about 130 °C, about 90°C to about 115°C, to a temperature of about 25°C, at a constant rate over a period of at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours.

101. The method of any one of the previous embodiments, wherein the reaction is quenched with aqueous ammonium chloride solution upon completion.

102. The method of any one of the previous embodiments, wherein the quenched reaction mixture is extracted with a solvent. 103. The method of any one of the previous embodiments, wherein the solvent is IP Ac.

104. The method of any one of the previous embodiments, wherein the cooled reaction mixture is then filtered, washed with solvent, and dried.

105. The method of any one of the previous embodiments, wherein the solvent is water.

106. The method of any one of the previous embodiments, wherein the reaction mixture is dried at a temperature of about 35 °C, about 40 °C, about 45 °C, about 50 °C, or about 55 °C.

107. The method of any one of the previous embodiments, wherein the reaction yields a compound of Formula D at about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% yield.

108. The method of any one of the previous embodiments, wherein the reaction yields a compound of Formula D at about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% purity.

Synthesis of a compound of Formula D ’

109. The method of any one of the previous embodiments, further comprising reacting a compound of Formula D with an acid in a solvent to yield a compound of Formula D’ wherein

R ³ is a protecting group; and

X is a counterion.

110. A method comprising reacting a compound of Formula D with an acid in a solvent to yield a compound of Formula D’ wherein

R ³ is a protecting group; and

X is a counterion.

111. The method of any one of the previous embodiments, wherein the acid is a hydrohalide.

112. The method of any one of the previous embodiments, wherein the acid is hydrochloride gas.

113. The method of any one of the previous embodiments, wherein X is a halide.

114. The method of any one of the previous embodiments, wherein X is chloride.

115. The method of any one of the previous embodiments, wherein the solvent is IP Ac.

116. The method of any one of the previous embodiments, wherein the solvent is MTBE.

117. The method of any one of the previous embodiments, wherein the acid is added at a temperature of about -20 °C to about 25 °C.

118. The method of any one of the previous embodiments, wherein the acid is added at a temperature of about -20 °C, to about -15 °C, to about -10 °C, to about -5 °C, to about 0 °C, to about 5 °C, to about 10 °C, to about 15 °C, to about 20 °C, or to about 25 °C.

119. The method of any one of the previous embodiments, wherein the acid is added at a temperature of about -20 °C, about -15 °C, about -10 °C, about -5 °C, about 0 °C, about 5 °C, about 10 °C, about 15 °C, about 20 °C, or about 25 °C.

120. The method of any one of the previous embodiments, wherein after addition of the acid, the reaction is heated from a temperature of about -20 °C to about 10 °C, about -5 °C to about 5°C, to a temperature of about 25°C, at a constant rate over a period of at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours.

121. The method of any one of the previous embodiments, wherein after completion of the reaction the reaction mixture is then filtered, washed with solvent, and dried.

122. The method of any one of the previous embodiments, wherein the solvent is IP Ac.

123. The method of any one of the previous embodiments, wherein the reaction mixture is dried at a temperature of about 35 °C, about 40 °C, about 45 °C, about 50 °C, or about 55 °C.

124. The method of any one of the previous embodiments, wherein the reaction yields a compound of Formula D’ at about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% yield.

125. The method of any one of the previous embodiments, wherein the reaction yields a compound of Formula D’ at about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% purity.

Synthesis of Compound 1

126. The method of any one of the previous embodiments, further comprising reacting a compound of Formula C with a compound of Formula D’ a base, and a solvent to yield Compound 1 wherein

R ¹ is a leaving group; and

X is a counter ion.

127. A method comprising reacting a compound of Formula C with a compound of Formula D’ a base in a solvent to yield Compound 1 wherein

R ¹ is a leaving group; and

X is a counter ion.

128. The method of any one of the previous embodiments, wherein R ¹ is halo.

129. The method of any one of the previous embodiments, wherein R ¹ is -Cl.

130. The method of any one of the previous embodiments, wherein X is a halide.

131. The method of any one of the previous embodiments, wherein X is chloride.

132. The method of any one of the previous embodiments, wherein the base is a carbonate base.

133. The method of any one of the previous embodiments, wherein the base is sodium carbonate.

134. The method of any one of the previous embodiments, wherein the base is sodium bicarbonate.

135. The method of any one of the previous embodiments, wherein the molar ratio of the base to a compound of Formula C is about 1.0:1, about 1.5:1, about 2.0:1, about 2.5:1, about 3.0:1, about 3.5:1, about 4.0:1, about 4.5:1, about 5.0:1, about 5.5:1, about 6.0:1, about 6.5:1, or about 7:1.

136. The method of any one of the previous embodiments, wherein the molar ratio of the base to a compound of Formula D’ is about 1.0:1, about 1.5:1, about 2.0:1, about 2.5:1, about 3.0:1, about 3.5:1, about 4.0:1, about 4.5:1, about 5.0:1, about 5.5:1, about 6.0:1, about 6.5:1, or about 7:1.

137. The method of any one of the previous embodiments, wherein the molar ratio of a compound of Formula C to a compound of Formula D’ is about 0.70: 1, about 0.75: 1, about 0.80: 1, about 0.85:1, about 0.90:1, about 0.95:1, about 1.00:1, about 1.05:1, about 1.10:1, about 1.15:1, about 1.20:1, about 1.25:1, about 1.30:1, about 1.35:1, about 1.40:1, about 1.45:1, about 1.50:1, about 1.55: 1, about 1.60: 1, about 1.65: 1, about 1.70: 1, about 1.75: 1, about 1.80: 1, about 1.85: 1, about 1.90: 1, about 1.95: 1, about 2.00: 1, about 2.05: 1, or about 2.10: 1.

138. The method of any one of the previous embodiments, wherein the solvent comprises 2- butanone.

139. The method of any one of the previous embodiments, wherein the solvent comprises water.

140. The method of any one of the previous embodiments, wherein the solvent comprises acetonitrile.

141. The method of any one of the previous embodiments, wherein the solvent comprises ethanol.

142. The method of any one of the previous embodiments, wherein the solvent comprises a mixture of 2-butanone and water.

143. The method of any one of the previous embodiments, wherein the solvent comprises a mixture of 2-butanone and water at a ratio of about 0.40:1, about 0.45:1, about 0.50:1, about 0.55:1, about 0.60:1, about 0.65: 1, about 0.70: 1, about 0.75: 1, about 0.80: 1, about 0.85: 1, about 0.90: 1, about 0.95: 1, or about 1.00: 1.

144. The method of any one of the previous embodiments, wherein the solvent comprises a mixture of 2-butanone and water at a ratio of about 1.0:1, about 1.5: 1, about 2.0:1, about 2.5: 1, about 3.0: 1, about 3.5: 1, about 4.0: 1, about 4.5: 1, about 5.0: 1, about 5.5: 1, or about 6.0: 1.

145. The method of any one of the previous embodiments, wherein the base is added to the mixture slowly, at a constant rate over a period of at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least about 23 hours, or at least about 24 hours.

146. The method of any one of the previous embodiments, wherein the base is added as a solid.

147. The method of any one of the previous embodiments, wherein the base is added as an aqueous solution. 148. The method of any one of the previous embodiments, wherein the temperature of the reaction is about 40 °C, to about 45 °C, to about 50 °C, to about 55 °C, to about 60 °C, to about 65 °C, to about 70 °C, to about 75 °C, to about 80 °C, to about 85 °C, to about 90 °C, or to about 95 °C.

149. The method of any one of the previous embodiments, wherein the temperature of the reaction is about 50 °C, to about 50 °C, to about 55 °C, to about 60 °C, to about 65 °C, to about 70 °C, to about 75 °C, to about 80 °C, to about 85 °C.

150. The method of any one of the previous embodiments, wherein the temperature of the reaction is about 40 °C, about 45 °C, about 50 °C, about 55 °C, about 60 °C, about 65 °C, about 70 °C, about 75 °C, about 80 °C, about 85 °C, about 90 °C, or about 95 °C.

151. The method of any one of the previous embodiments, wherein upon completion of the reaction to prepare Compound 1, the completed reaction is cooled from a temperature of about 40 °C to about 95 °C, about 65°C to about 75°C, to a temperature of about 25°C, at a constant rate over a period of at least about 15 minutes, at least about 30 minutes, at least about 60 minutes, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, or at least about 12 hours.

152. The method of any one of the previous embodiments, wherein the cooled reaction mixture is then filtered, washed with solvent, and dried.

153. The method of any one of the previous embodiments, wherein the solvent is water.

154. The method of any one of the previous embodiments, wherein the reaction mixture is dried at a temperature of about 35 °C, about 40 °C, about 45 °C, about 50 °C, or about 55 °C.

155. The method of any one of the previous embodiments, wherein the reaction yields Compound 1 at about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% yield.

156. The method of any one of the previous embodiments, wherein the reaction yields Compound 1 at about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99% purity.

157. The method of any one of the previous embodiments, wherein the reaction yields Compound 1 at greater than about 90%, greater than about 91%, greater than about 92%, greater than about 93%, greater than about 94%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, greater than about 99%, or greater than about 99% purity.

Purification of Compound 1

158. The method of any one of the previous embodiments, further comprising isolating a sample of compound 1 from a mixture comprising Compound 1.

159. The method of any one of the previous embodiments, wherein the mixture is dissolved in a solvent to create a solution.

160. The method of any one of the previous embodiments, wherein the solvent is DMSO.

161. The method of any one of the previous embodiments, wherein the solution is cycled through CUNO.

162. The method of any one of the previous embodiments, wherein the ratio of CUNO to Compound 1 is about 0.5: 1, about 1.0: 1, about 1.5: 1, about 2.0: 1, about 2.5: 1, about 3.0: 1, or about 3.5: 1.

163. The method of any one of the previous embodiments, wherein the temperature of the solution is about 40 °C, about 45 °C, about 50 °C, about 55 °C, about 60 °C, about 65 °C, about 70 °C, about 75 °C, about 80 °C, about 85 °C, about 90 °C, or about 95 °C.

164. The method of any one of the previous embodiments, wherein the solution is filtered to remove the CUNO.

165. The method of any one of the previous embodiments, wherein the removed CUNO is further washed with DMSO.

166. The method of any one of the previous embodiments, wherein the solution is further filtered and combined.

167. The method of any one of the previous embodiments, wherein water is added to the solution.

168. The method of any one of the previous embodiments, wherein the mixture is filtered, washed with solvent, and dried.

169. The method of any one of the previous embodiments, wherein the mixture is washed with water.

170. The method of any one of the previous embodiments, wherein the mixture is dried at a temperature of about 35 °C, about 40 °C, about 45 °C, about 50 °C, or about 55 °C. 171. The method of any one of the previous embodiments, wherein the purification yields Compound 1 of at least 97.5%, at least 98.0%, at least 98.5%, at least 99.0%, at least 99.5%, or at least 100% purity. In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be taken as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.