Iap antagonist compounds and intermediates and methods of synthesis thereof

Abstract

Provided is a compound of formula (XXIII) and a method of making the same.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefits of U.S. Provisional Application No. 63 / 019,865, filed May 4, 2020, and U.S. Provisional Application No. 63 / 019,874, filed May 4, 2020, under 35 U.S.SC §119(e), which are hereby incorporated herein by reference in their entirety. Technical Field

[0003] This application relates to improved IAP antagonist compounds and intermediates, and methods for their synthesis. Background Technology

[0004] Apoptosis, or programmed cell death, is a key part of human physiology and normal immune responses. Insufficient or excessive apoptosis can lead to human diseases, including neurodegenerative diseases, autoimmune disorders, and many types of cancer. Inhibitors of apoptosis (IAP) are expressed in some cancers, such as lymphoma. Eight different human IAPs are characterized as: XIAP, hILP-2, c-IAP1, c-IAP2, ML-IAP, NAIP, survivin, and Apollon. Mary X.D. Riordan, Laura D. Bauler, Fiona L. Scott, and Colin S. Duckett, “Inhibitor of apoptosis proteins ineukaryotic evolution and development: a model of thematic conservation”, Developmental Cell 15(4):497-508 (2008). The most common structural features, mechanisms, and expression of IAPs in cancer are described in U.S. Patent No. 9,783,538, which is incorporated herein by reference in its entirety.

[0005] This article discloses improved IAP antagonist compounds, improved intermediates, and methods for synthesizing IAP antagonist compounds. Summary of the Invention

[0006] This document provides methods for preparing intermediates and compounds of formulas (XXII) and (XXIII), which are described below and in U.S. Patent No. 9,783,538.

[0007]

[0008] The present application provides compounds of Formula (la), (Va), (VII), (IX), (XXIII), and (XXIIIa) and methods of synthesizing compounds of Formula (la), (Va), (VII), (IX), (XXIII), and (XXIIIa). Compounds of Formula (IX) are intermediates in the synthesis of compounds of Formula (XXIII) and (XXIIIa). The present application provides compounds of Formula (I), (XVI), (XVIa), and (XX) and (XXIIIa) and methods of synthesizing compounds of Formula (I), (XVI), (XVIa), and (XX). Compounds of Formula (XXIII) and (XXIIIa) are antagonists of the IAP family of proteins and, in particular, XIAP and / or cIAPs (such as cIAP1 and / or cIAP2) and are useful in the treatment of IAP-mediated disorders.

[0009] In one aspect, as described in the Specific Description section below, provided herein is a method of making compound (XXIII), the method comprising contacting compound (XX) with compound (XIII) to obtain compound (XXI), and converting compound (XXI) to compound (XXIII).

[0010] In another aspect, as described in the Specific Description section below, provided herein is a method of making compound (XXIII), the method comprising converting compound (IX) to compound (X), then converting compound (X) to compound (XIII), and contacting compound (XX) with compound (XIII) to obtain compound (XXI), then converting compound (XXI) to compound (XXIII).

[0011] In a further aspect, as described in the Specific Description section below, provided herein is a method of making compound (IX).

[0012] In additional aspects, provided are compounds of Formula (la), (I), (XVIa), (IX), (X), (XI), (XX), (IIIa), and (Vb) as described herein.

[0013] Compounds of Formula (la), (Va), (VII), and (IX) are useful in the synthesis of compounds of Formula (XXIIIa) or a tautomeric form, a stereochemically isomeric form, a pharmaceutically acceptable salt, or a solvate thereof:

[0014]

[0015] wherein X, U, R 5 , R 6 , L 1 , L 2 , and P 1are defined as disclosed in U.S. Patent No. 9,783,538.

[0016] In exemplary embodiments, methods of synthesizing a compound of Formula (XXIIIa), a tautomeric form, a stereochemically isomeric form, a pharmaceutically acceptable salt, or a solvate thereof, and methods of synthesizing a compound of Formula (XXIIIa), a tautomeric form, a stereochemically isomeric form, a pharmaceutically acceptable salt, or a solvate thereof, with compounds of Formula (I), (XVI), (XVIa), and (XX) are provided:

[0017]

[0018] wherein X, U, R 5 , R 6 , L 1 , L 2 and P 1 are defined as disclosed in U.S. Patent No. 9,783,538, incorporated by reference herein in its entirety.

[0019] Compounds of Formula (XXIIIa) produced by the embodiments and synthetic methods disclosed herein are used for the prevention or treatment of a disease or condition and in formulations and pharmaceutical compositions comprising a compound of Formula (XXIIIa), as described in U.S. Patent No. 9,783,538, incorporated by reference in its entirety.

[0020] The above and other objects, features and advantages of the present disclosure will become more readily apparent from the following detailed description of exemplary embodiments, as disclosed herein. BRIEF DESCRIPTION OF DRAWINGS

[0021] Embodiments of the present application are described herein, by way of example only, with reference to the accompanying drawings, in which:

[0022] Figure 1 An exemplary synthesis of a compound of Formula (VIII) is depicted;

[0023] Figure 2 An exemplary synthesis of a compound of Formula (XXIII) is depicted;

[0024] Figure 3 An exemplary synthesis of a compound of Formula (VII) is depicted;

[0025] Figure 4 An exemplary synthesis of a compound of Formula (IX) is depicted;

[0026] Figure 5 An X-ray powder diffraction of Form C of a compound of Formula (XXIII) is depicted;

[0027] Figure 6is a plot depicting the effect of palladium content on the area % of compounds of formula (XXIII) at RRT 1.3 (25°C / 60% RH); and

[0028] Figure 7 is a plot depicting the effect of temperature on the impurity level at RRI 1.3 in the API made from compounds of formula (XXIII). DETAILED DESCRIPTION

[0029] The following examples and embodiments disclosed and described in the present application are illustrative. Those of ordinary skill in the art will appreciate that various modifications can be made to the embodiments without departing from the scope or intent of the present application or the disclosed exemplary embodiments, including variations with respect to the synthetic methods, processes, reactants, reagents, parameters, and conditions described herein. The present application relates to improved methods, reactants, and reagents for synthesizing compounds of formula (la), (Va), (VII), (IX), (XXIII), and (XXIIIa).

[0030] The present application provides compounds of formula (I), (XVI), (XVIa), and (XX) and methods of synthesizing compounds of formula (I), (XVI), (XVIa), and (XX). Compounds of formula (I), (XVI), (XVIa), and (XX) are useful for synthesizing compounds of formula (XXIIIa). Compounds of formula (XXIIIa) are antagonists of the IAP family of proteins and, in particular, XIAP and / or cIAPs (such as cIAP1 and / or cIAP2) and are useful for treating IAP-mediated conditions.

[0031] DEFINITIONS

[0032] As used in this specification, the following words and phrases are generally intended to have the meanings set forth below, but the context of each use will be understood to inform the meaning of the words and phrases used unless otherwise indicated.

[0033] The terms "comprise" and variations thereof, such as "comprises" and "comprising," shall take its open, inclusive meaning, that is, "including but not limited to," unless the context of the use indicates otherwise. The singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise.

[0034] References herein to "about" a value or parameter means "about" the value or parameter as well as embodiments relating to the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ± 10%. In other embodiments, the term "about" includes the indicated amount ± 5%. In certain other embodiments, the term "about" includes the indicated amount ± 2.5%. In certain other embodiments, the term "about" includes the indicated amount ± 1%. Additionally, terms such as "about X" include a description of "X".

[0035] Numerical ranges recited within the specification are intended to include individually every numerical value falling within the range, inclusive of the recited values. In this context, a range includes the range itself or individual values derived from the range.

[0036] Unless otherwise indicated, "alkyl" by itself or as part of another substituent means a straight or branched hydrocarbon group having the number of carbon atoms indicated (i.e., Ci-C6means one to six carbons). Representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Additional representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0037] Unless otherwise indicated, "aryl" by itself or as part of another substituent means a monocyclic, bicyclic, or polycyclic polyunsaturated hydrocarbon group containing from 6 to 14 ring carbon atoms, which can be a single ring or multiple rings which are fused together or linked to one another by covalent bonds (up to three rings). Non-limiting examples of unsubstituted aryl groups include phenyl, 1-naphthyl, and 2-naphthyl. The term "arylene" refers to a divalent aryl group, wherein the aryl group is as defined herein.

[0038] "Boc" means tert-butyloxycarbonyl.

[0039] "Ph" means phenyl.

[0040] "Protecting group" means a moiety that masks a reactive group. In some embodiments, by way of example only, protecting groups include, and are not limited to, tert-butyloxycarbonyl (Boc), carbonylbenzyloxy (Cbz), benzyl, p-methoxybenzyl, p-nitrobenzyl, or any other protecting group described by P.G.M. Wuts and T.W. Greene in Protective Groups in Organic Synthesis, 4th Ed.

[0041] In many cases, the compounds of the present disclosure are capable of forming acidic and / or basic salts due to the presence of amino and / or hydroxyl groups or groups similar thereto. Salts include, for example, salts with inorganic acids and salts with organic acids. Additionally, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is the free base, an addition salt can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from free base compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare salts. In general, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of water and an organic solvent; often, non-aqueous media, such as ethers (e.g., MTBE), ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN) are preferred. See, Remington's Pharmaceutical Sciences, 17th ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19, and Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002) for a list of suitable salts.

[0042] Also provided are pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, isomers (such as stereoisomers), tautomers, mixtures of isomers (such as mixtures of stereoisomers), and prodrugs of the compounds described herein. A "prodrug" refers to any precursor form of a biologically active compound. The prodrug undergoes biotransformation (e.g., enzymatic cleavage) or chemical transformation (e.g., hydrolysis) before exhibiting a pharmacological effect.

[0043] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful in preparing pharmaceutical compositions that are suitable for veterinary or human pharmaceutical use.

[0044] In certain instances, salts of the compounds are pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and that is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. In addition, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is the free base, an addition salt (particularly a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those of skill in this art will recognize a variety of synthetic methods that can be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from non-toxic inorganic and organic acids. The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent such as, for example, ethanol, ethyl acetate, an alcohol such as methanol, ethanol, isopropanol, or butanol, or acetonitrile (MeCN); or a mixture of water with an organic solvent. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed. (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19, and Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002).

[0045] The term "solvate" refers to a complex formed by combining solvent molecules with molecules or ions of a solute. The solvent can be an organic compound, an inorganic compound, or a mixture of both. As used herein, the term "solvate" includes "hydrate" (i.e., a complex formed by combining water molecules with molecules or ions of a solute), hemihydrate, clathrate, and the like. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. Generally, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure.

[0046] The term "stereochemically isomeric forms" of a compound refers to the stereoisomers of the compound.

[0047] The term "tautomer" means a compound that results from the migration of a proton in a molecule from one atom to another. Tautomer also refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. Non-limiting examples include enol-keto, imine-enamine, amide-imidic acid tautomers, tautomeric forms of heteroaryl containing the -N=C(H)-NH- ring atom arrangement (such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole), and tautomeric forms of hydroxyl substituted 6-membered heteroaryl (such as hydroxyl substituted pyridine, pyrimidine, pyrazine, or pyridazine) (such as 4-hydroxypyridine and pyridine-4(lH)-one), and the like. The compounds described herein can have one or more tautomers and thus include multiple isomers. One of ordinary skill in the art will recognize that other tautomeric ring atom arrangements are possible. All such isomeric forms of these compounds are expressly included in the present disclosure.

[0048] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, a compound containing an amide can exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown, and regardless of the equilibrium nature between tautomers, one of ordinary skill in the art will understand the compounds to include both the amide and imidic acid tautomer. Thus, a compound containing an amide is understood to include its imidic acid tautomer. Likewise, a compound containing an imidic acid is understood to include its amide tautomer.

[0049] The compounds of the present application, or pharmaceutically acceptable salts thereof, include asymmetric carbon centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)- or as (D)- or (L-) for amino acids. The present application is intended to include all such possible isomers, as well as, their racemic and optically pure forms. Optical activity of (+) and (-), (R)- and (S)-, or (D)- and (L)- can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor (i.e. a chiral auxiliary from a racemic precursor) or resolution of the racemic form (or a salt or derivative thereof) using, for example, chiral high pressure liquid chromatography. Where the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0050] “Stereoisomers” refer to compounds composed of the same atoms bonded by the same sequence of bonds but having different three-dimensional configurations, i.e., they are not superimposable on one another. The present invention contemplates various stereo isomers and mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0051] “Diastereomers” are stereoisomers that have at least two asymmetric centers but are not mirror images of one another.

[0052] Relative centers of compounds as depicted herein are indicated graphically using “thick bond” style (heavy or parallel lines) and absolute stereochemistry is depicted using wedge bonds (heavy or parallel lines).

[0053] Compounds of Formula (XXIIIa) are described in U.S. Patent No. 9,783,538, which is incorporated by reference herein in its entirety. In exemplary embodiments, the compound of Formula (XXIIIa) is 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one, which is referred to herein as the compound of Formula (XXII).

[0054] Formula (XXII) Compound (XXII)

[0055] as an IAP and cIAP / XIAP antagonist and can be used in various pharmaceutical formulations to treat various cancers described herein and in U.S. Patent No. 9,783,538.

[0056] In embodiments, the compound of Formula (XXII) is the L(+)-lactate salt form of the compound of Formula (XXII), which is used as an IAP and cIAP / XIAP antagonist and for the treatment of solid tumors and other conditions and diseases. The L(+)-lactate salt of the compound of Formula (XXII) is referred to herein as the compound of Formula (XXIII).

[0057] Methods of synthesizing compounds of Formula (XXIII) and (XXIIIa) are described in U.S. Patent Nos. 9,783,538; 9,617,248; 9,617,283; 9,663,512; 9,980,973; 9,018,214; and 9,676,768, which are incorporated by reference herein in their entirety. With respect to the synthetic routes and embodiments of the present application disclosed herein, the synthetic schemes 1-3 disclosed in U.S. Patent No. 9,783,538, columns 45-50, result in lower yields and purity of the end product of compounds of Formula (XXIII) and (XXIIIa). For example, synthetic scheme 1 disclosed in U.S. Patent No. 9,783,538, columns 45-46, depicts a general method for preparing a compound of Formula (VIIIa). However, with respect to the synthetic routes and embodiments of the present application, synthetic scheme 1 disclosed in U.S. Patent No. 9,783,538, columns 45-46, results in lower yields and purity of compounds of Formula (XXIII) and (XXIIIa). In addition, scheme 2 of U.S. Patent No. 9,783,538 results in low yields, produces a bis-hydroxymethyl impurity in the final product and other difficult to purge impurities in the intermediates and end product, such as the bis-hydroxymethyl impurity of Formula (XXIV):

[0058]

[0059] The synthetic method of U.S. Patent No. 9,783,538 also uses tert-butyllithium as a reagent, which limits the scope of large scale manufacturing, is a supply limited reagent, is less selective and has high flammability, volatility, pyrophoricity and reactivity.

[0060] The compounds, intermediates and synthetic methods of the present application and the embodiments disclosed herein are used in improved methods for preparing key intermediate compounds for preparing tert-butyl 5-bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-l-carboxylate of Formula (IX) such that the compounds of Formula (XXIII) and pharmaceutical formulations made from the compounds of Formula (IX) have higher purity, stability and yield.

[0061]

[0062] Compounds of Formula (XXIII) prepared according to the synthetic methods and embodiments disclosed herein have enhanced properties such as lower stickiness, higher purity, higher stability, and higher overall yield. Purity can be improved by minimizing aldehyde impurities in the end product and controlling palladium levels. In exemplary embodiments, the synthetic methods and embodiments disclosed herein for producing compounds of Formula (XXIII) produce an end product with a purity of 95% or greater, and in another embodiment an end product with a purity of 98% or greater.

[0063] Figure 1 An exemplary embodiment of the synthesis of compounds of Formula (VIII) from compounds of Formula (II) is depicted. Compounds of Formula (VIII) can be used in the synthesis depicted in Figure 2 to produce key intermediate compounds of Formula (IX).

[0064] Figure 2 An exemplary embodiment of an improved scalable process for synthesizing compounds of Formula (XXIII) is depicted. Figure 2 Compounds of Formula (IX) in are key intermediates in the production of compounds of Formula (XXIII).

[0065] The conversion of compounds of Formula (II) to compounds of Formula (VII) and (VIII) presents some challenges and deficiencies. For example, compounds of Formula (VI) are extremely difficult to obtain and are provided as a dilute solution. It takes months of time to manufacture the amount of compounds of Formula (VI) necessary for industrial processes, including industrial processes for producing compounds of Formula (IX) and (XXIII). Compounds of Formula (VI) are also highly sensitive to air and moisture, thus their use in the synthesis of compounds of Formula (IX) and (XXIII) becomes difficult, inefficient, and unpredictable. Typically, compounds of Formula (VI) are used in a 1 : 1 ratio with the compound of Formula (VII) in the synthesis of compounds of Formula (IX) and (XXIII). Figure 1 PEPPSI catalyst used in the synthesis of compounds of Formula (IX) to convert compounds of Formula (V) to compounds of Formula (VII) TM The PEPPSI catalyst ([1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(II) dichloride) is also expensive. Thus, it is advantageous to avoid the use of compounds of Formula (VI) and PEPPSI TM catalysts in the synthesis of compounds of Formula (IX).

[0066] Disclosed herein are alternative synthetic routes to produce the intermediate compounds of Formula (IX). The present application and the embodiments and examples disclosed herein address the problems with known methods for preparing the key intermediate compounds of Formula (IX) and the end product compound of Formula (XXIII). The exemplary synthetic routes do not require the use of the compound of Formula (VI) or PEPPSI TM catalyst in the synthesis of the key intermediates including the compound of Formula (IX) and the end product compound of Formula (XXIII). The exemplary synthetic routes also utilize new chemical entities, such as the use of the compound of Formula (I) to produce the compound of Formula (IX) and the end product compound of Formula (XXIII) and / or the use of the compounds of Formula (la), (I), (IX), (X), (XI), (XVIa), and (XX) to produce the compound of Formula (XXIII).

[0067] In embodiments, there is provided a method of preparing a compound of Formula (XXIII)

[0068]

[0069] comprising

[0070] (i) contacting a compound of Formula (XX)

[0071]

[0072] with a compound of Formula (XIII)

[0073]

[0074] under conditions sufficient to provide a compound of Formula (XXI) or a salt, solvate, or hydrate thereof,

[0075]

[0076] (ii) deprotecting the compound of Formula (XXI) or a salt, solvate, or hydrate thereof to provide a compound of Formula (XXII) or a salt, solvate, or hydrate thereof,

[0077] and

[0078] (iii) contacting the compound of Formula (XXII) with lactic acid to provide the compound of Formula (XXIII)

[0079] In one embodiment, the lactic acid used in step (iii) above is anhydrous lactic acid as described in co-pending application U.S. Provisional Application No. 63 / 019,87 entitled “Methods For Synthesizing Anhydrous Lactic Acid” filed May 4, 2020, which application is filed on the same day as the present application and is incorporated herein by reference.

[0080] In one embodiment, the compound of formula (XIII) is prepared by a process comprising:

[0081] (i) reacting a compound of formula (V)

[0082]

[0083] with a compound of formula (VI)

[0084]

[0085] in the presence of one or more palladium catalysts and ligands to provide a compound of formula (VII)

[0086]

[0087] (ii) brominating the compound of formula (VII) to obtain a compound of formula (VIII)

[0088]

[0089] (iii) protecting the compound of formula (VIII) to provide a compound of formula (IX)

[0090]

[0091] (iv) contacting the compound of formula (IX) with carbon monoxide under conditions sufficient to provide the compound of formula (X), a salt, solvate, or hydrate thereof

[0092]

[0093] (v) removing the tert-butyloxycarbonyl protecting group from the compound of formula (X) or a salt, solvate, or hydrate thereof to provide a compound of formula (XI)

[0094]

[0095] (vi) reducing the compound of formula (XI) to provide a compound of formula (XII)

[0096] and

[0097] (vii) contacting the compound of Formula (XII) with chloroacetyl chloride to provide the compound of Formula (XIII).

[0098] In one embodiment, there is provided a process for preparing a compound of Formula (XXIII)

[0099]

[0100] comprising

[0101] (i) contacting a compound of Formula (IX) or a salt, solvate or hydrate thereof

[0102]

[0103] with carbon monoxide under conditions sufficient to provide the compound of Formula (X), a salt, solvate or hydrate thereof

[0104]

[0105] (ii) removing the tert-butoxycarbonyl protecting group from the compound of Formula (X) or a salt, solvate or hydrate thereof to provide a compound of Formula (XI) or a salt, solvate or hydrate thereof,

[0106]

[0107] (iii) reducing the compound of Formula (XI) or a salt, solvate or hydrate thereof to provide a compound of Formula (XII) or a salt, solvate or hydrate thereof,

[0108]

[0109] (iv) contacting the compound of Formula (XII) or a salt, solvate or hydrate thereof with chloroacetyl chloride to provide the compound of Formula (XIII) or a salt, solvate or hydrate thereof,

[0110]

[0111] (v) contacting the compound of Formula (XIII) or a salt, solvate or hydrate thereof with a compound of Formula (XX)

[0112]

[0113] under conditions sufficient to provide a compound of Formula (XXI) or a salt, solvate or hydrate thereof,

[0114] and

[0115] (vi) deprotecting the compound of Formula (XXI) or salt, solvate, or hydrate thereof, to provide a compound of Formula (XXII) or salt, solvate, or hydrate thereof,

[0116] and

[0117] (vii) contacting the compound of Formula (XXII) with lactic acid to provide the compound of Formula (XXIII).

[0118] In embodiments, there is provided a method of preparing a compound of Formula (XXI) or salt, solvate, or hydrate thereof,

[0119]

[0120] comprising

[0121] contacting a compound of Formula (XX)

[0122]

[0123] with a compound of Formula (XIII)

[0124]

[0125] under conditions sufficient to provide a compound of Formula (XXI) or salt, solvate, or hydrate thereof.

[0126] In embodiments, there is provided a method of preparing a compound of Formula (XX)

[0127]

[0128] comprising

[0129] (i) debenzylating a compound of Formula (XIX)

[0130] and

[0131] (ii) contacting the debenzylated product with oxalic acid in a solvent to provide the compound of Formula (XX).

[0132] In embodiments of the method of preparing a compound of Formula (XX), the debenzylating in step (i) is performed in the presence of palladium on carbon and hydrogen gas. In embodiments of the method of preparing a compound of Formula (XX), the solvent in step (ii) is ethanol.

[0133] In embodiments, there is provided a method of preparing a compound of Formula (X) or salt, solvate, or hydrate thereof,

[0134]

[0135] comprising contacting a compound of formula (IX)

[0136]

[0137] with carbon monoxide under conditions sufficient to provide said compound of formula (X), salt, solvate, or hydrate thereof.

[0138] In one embodiment of the method of preparing a compound of formula (X), the conditions comprise a palladium catalyst, a ligand, and (i) phenyl formate or phenol and (ii) carbon monoxide.

[0139] In one embodiment of the method of preparing a compound of formula (X), the palladium catalyst is palladium (II) acetate and the ligand is rac-1,1’- binaphthalene-2,2’-diphenylphospholene.

[0140] In one embodiment of the method of preparing a compound of formula (X), the conditions further comprise a base. In embodiments, the base is triethylamine. Any other suitable base is contemplated within the scope of the embodiments presented herein.

[0141] In one embodiment of the method of preparing a compound of formula (X), the reaction temperature is in the range of about 45 °C to about 75 °C. In one embodiment of the method of preparing a compound of formula (X), the reaction temperature is in the range of about 55 °C to about 65 °C. In one embodiment of the method of preparing a compound of formula (X), the reaction solvent is acetonitrile.

[0142] In embodiments, there is provided a method of preparing a compound of formula (XI) or a salt, solvate, or hydrate thereof,

[0143]

[0144] comprising removing the tert-butyloxycarbonyl protecting group from a compound of formula (XI) or a salt, solvate, or hydrate thereof, under conditions sufficient to provide a compound of formula (XI) or a salt, solvate, or hydrate thereof,

[0145]

[0146] In embodiments, the method further comprises:

[0147] (i) reducing the compound of formula (XI) under conditions sufficient to provide a compound of formula (XII)

[0148] and

[0149] (ii) contacting the compound of formula (XII) with 2-chloroacetyl chloride to provide a compound of formula (XIII)

[0150]

[0151] In embodiments, the reduction is performed in the presence of lithium borohydride. Any other suitable reducing agent (e.g. NaBH4, LiAlH4) is contemplated within the scope of the embodiments presented herein.

[0152] In embodiments, the solvent used to reduce the compound of Formula (XI) is 2-methyltetrahydrofuran.

[0153] In embodiments, the contacting of Formula (XII) with 2-chloroacetyl chloride is performed at a temperature of about -10 °C to about 0 °C.

[0154] In embodiments, there is provided a method of preparing a compound of Formula (IX), or a salt, solvate, or hydrate thereof,

[0155]

[0156] which comprises

[0157] (i) boronating a compound of Formula (III), or a salt, solvate, or hydrate thereof, under conditions sufficient to provide a compound of Formula (Ilia),

[0158]

[0159] (ii) contacting the compound of Formula (Ilia) with 4-fluorobenzyl chloride or 4-fluorobenzyl bromide under conditions sufficient to provide a compound of Formula (IIIb), or a salt, solvate, or hydrate thereof,

[0160]

[0161] (iii) contacting the compound of Formula (IIIb) with a reducing agent to provide a compound of Formula (IIIc), or a salt, solvate, or hydrate thereof,

[0162]

[0163] (iv) cyclizing the compound of Formula (IIIc) to provide a compound of Formula (VII), or a salt, solvate, or hydrate thereof,

[0164]

[0165] (v) brominating the compound of Formula (VII) to provide a compound of Formula (VIII), or a salt, solvate, or hydrate thereof,

[0166] and

[0167] (vi) protecting a compound of Formula (VIII) with tert-butyloxycarbonyl to provide a compound of Formula (IX) or a salt, solvate, or hydrate thereof.

[0168] It will be appreciated that in Formula (III), the chloro group can be changed to any other suitable group, such as bromo, triflate, and the like.

[0169] In embodiments, there is provided a method of preparing a compound of Formula (IX) or a salt, solvate, or hydrate thereof,

[0170]

[0171] which comprises

[0172] (i) protecting a compound of Formula (V) or a salt, solvate, or hydrate thereof

[0173]

[0174] with tert-butyloxycarbonyl to provide a compound of Formula (Va) or a salt, solvate, or hydrate thereof,

[0175]

[0176] (ii) boronating said compound of Formula (Va) or a salt, solvate, or hydrate thereof to obtain a compound of Formula (Vb) or a salt, solvate, or hydrate thereof,

[0177]

[0178] wherein each R’ is independently H, alkyl, or aryl, or two alkyl groups or two aryl groups together with the atoms to which they are attached form a dioxaborolane ring;

[0179] (iii) contacting a compound of Formula (Vb) or a salt, solvate, or hydrate thereof

[0180] with 4-fluorobenzyl chloride or 4-fluorobenzyl bromide under conditions sufficient to provide a compound of Formula (Vc) or a salt, solvate, or hydrate thereof,

[0181] and

[0182] (iv) brominating said compound of Formula (Vc) to provide said compound of Formula (IX) or a salt, solvate, or hydrate thereof.

[0183] It will be appreciated that in Formula (V), the chloro group can be changed to any other suitable group, such as bromo, triflate, and the like.

[0184] In embodiments, a method of preparing a compound of Formula (XVIa) is provided, comprising contacting a compound of Formula (XVI)

[0185]

[0186] with oxalic acid in a solvent to provide a compound of Formula (XVIa)

[0187]

[0188] In embodiments of the method of preparing a compound of Formula (VIa), the solvent is methyl tert-butyl ether (MTBE).

[0189] Provided herein is a compound of Formula (XXIII)

[0190]

[0191] The compound has a purity of at least 95%.

[0192] Provided herein is a compound of Formula (XXIII)

[0193]

[0194] The compound has a purity of at least 98%.

[0195] Provided herein is a compound of Formula (XXIII), wherein, when the compound of Formula (XXIII) is stored at 25 °C and 60% relative humidity for 6 months, the compound of Formula (XXIII) comprises not more than about 0.5% a / a of a compound of Formula (XXV)

[0196]

[0197] As used herein, a / a refers to area over area as measured by HPLC. Thus, “not more than about 0.5% a / a of a compound of Formula (XXV)” means, by HPLC analysis, not more than 0.5% of the peak area belongs to a compound of Formula (XXV), or not more than 1.5% w / w of Formula (XXV) is present in the final compound (XXIII).

[0198] Provided herein is a compound of Formula (XXIII), wherein, when the compound of Formula (XXIII) is stored at 25 °C and 60% relative humidity for 6 months, the compound of Formula (XXIII) comprises not more than about 0.2% a / a of a compound of Formula (XXV).

[0199] Provided herein is a compound of Formula (XXIII), wherein the compound of Formula (XXIII) comprises no more than about 0.3% a / a of a compound of Formula (XXV) when the compound of Formula (XXIII) is stored at 25 °C and 60% relative humidity for 12 months.

[0200] Provided herein is a compound of Formula (XXIII), wherein the compound of Formula (XXIII) comprises no more than about 50 ppm of palladium, or no more than about 40 ppm, about 300, or about 20 ppm of palladium.

[0201] Provided herein is a composition comprising a compound of Formula (XXIII)

[0202]

[0203] wherein at least 95% of the compound of Formula (XXIII) is Form C.

[0204] In embodiments, Form C of Formula (XXIII) has an XRPD substantially as shown Figure 5

[0205] Provided herein is a compound of Formula (Ia) or a salt, solvate, or hydrate thereof,

[0206]

[0207] wherein R is CN or CH2NH2.

[0208] In some embodiments, the compound of Formula (Ia) has the structure of Formula (IIIb) or (IIIc), or a salt, solvate, or hydrate thereof,

[0209]

[0210] Provided herein is a compound of Formula (IIIa) or a salt, solvate, or hydrate thereof,

[0211]

[0212] wherein each R’ is independently H, alkyl, or aryl, or two alkyl groups or two aryl groups together with the atoms to which they are attached form a dioxaborolanyl ring.

[0213] In embodiments, the compound of Formula (IIIa) has the structure of Formula (IIIaa)

[0214]

[0215] Provided herein is a compound of Formula (Vb) or a salt, solvate, or hydrate thereof,

[0216] ​

[0217] wherein each R' is independently H, alkyl, or aryl, or two alkyl groups or two aryl groups together with the atom to which they are attached form a dioxaborolane ring.

[0218] In embodiments, the compound of Formula (Vb) has the structure of Formula (Vbb)

[0219]

[0220] Provided herein is a compound of Formula (I), or a salt, solvate, or hydrate thereof,

[0221]

[0222] wherein X is H or a protecting group;

[0223] Y is COR; and

[0224] R is OH, O-alkyl, or O-aryl.

[0225] Provided herein is a compound of Formula (XVIa):

[0226]

[0227] Provided herein is a compound of Formula (IX), or a salt, solvate, or hydrate thereof,

[0228]

[0229] Provided herein is a compound of Formula (XX):

[0230]

[0231] Provided herein is a compound of Formula (XI), or a salt, solvate, or hydrate thereof,

[0232]

[0233] Provided herein is a compound of Formula (XXV), or a salt, solvate, or hydrate thereof,

[0234]

[0235] Provided herein is a compound of Formula (IIIa):

[0236]

[0237] Provided herein is a compound of Formula (Vb):

[0238]

[0239] Provided herein are compounds (XXIII) prepared by any of the methods described herein.

[0240] Compounds of formula (VII) can be used in the synthesis of compounds of formula (IX) as shown in the synthesis schemes of Figure 1 and Figure 2

[0241]

[0242] In exemplary embodiments, provided are compounds of formula (la), salts, solvates, or hydrates thereof, and methods of synthesizing compounds of formula (la), salts, solvates, or hydrates thereof:

[0243]

[0244] wherein R is CN or CH2NH2.

[0245] In exemplary embodiments, provided are compounds of formula (IX), salts, solvates, or hydrates thereof, and methods of synthesizing compounds of formula (IX), salts, solvates, or hydrates thereof:

[0246]

[0247] In exemplary embodiments, provided are methods of synthesizing compounds of formula (IX) from compounds of formula (Va):

[0248]

[0249] In exemplary embodiments, provided are methods of synthesizing compounds of formula (VII), salts, solvates, or hydrates thereof:

[0250]

[0251] In exemplary embodiments, provided are methods of synthesizing compounds of formula (VII) from compounds of formula (IIIaa):

[0252] Also depicted as

[0253] In exemplary embodiments, provided are compounds of formula (I) and methods of synthesizing compounds of formula (I):

[0254]

[0255] wherein X is H or a protecting group;

[0256] Y is Br, CI, I, or COR; and

[0257] ​R is H, OH, O-alkyl, or O-aryl.

[0258] In exemplary embodiments, provided are compounds of Formula (XVI), salts, solvates, or hydrates thereof, and methods of synthesizing compounds of Formula (XVI), salts, solvates, or hydrates thereof:

[0259]

[0260] In exemplary embodiments, provided are compounds of Formula (XXa), salts, solvates, or hydrates thereof, and methods of synthesizing compounds of Formula (XXa), salts, solvates, or hydrates thereof:

[0261]

[0262] In exemplary synthesis shown in Figure 3 , a compound of Formula (VII) is produced.

[0263] In exemplary synthesis of a compound of Formula (VII) in Figure 3 , Y is OR' or B(OR')2, and each R' is independently H, alkyl, or aryl or two alkyl or aryl groups that form a ring with B.

[0264] Referring to Figure 3 , boronation of a compound of Formula (III) produces a boronate compound of Formula (Ilia). This step is described in Example 1.

[0265]

[0266] Boronation can be performed by reacting a compound of Formula (III) with a boronating agent and a catalyst. In exemplary embodiments, the boronating agent can be a compound of Formula Y-B(OR')2. For a compound of Formula (Ilia) and a boronating agent of Formula Y-B(OR')2, Y is OR' or B(OR')2, and each R' is independently H, alkyl, or aryl or two alkyl or aryl groups that form a ring with B. In exemplary embodiments, the boronating agent is bis(pinacolato)diboron and the catalyst is a palladium catalyst. In one embodiment, the compound of Formula (Ilia) is a compound of Formula (IIIaa):

[0267]

[0268] In exemplary embodiments, the catalyst is one or more palladium catalysts, including but not limited to Xphos-Pd-G2 catalyst, Pd(Oac)2, or Pd2(dba)3 along with a ligand such as PPh3, Xantphos, DPPE, DPPP, DPPB, DPPF, rac-BINAP, RuPhos, or tBuXphos. In exemplary embodiments, palladium catalyzed reactions can occur in the presence of a ligand. Suitable ligands include 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) used as a precursor to Suzuki coupling.

[0269] In another exemplary embodiment, the borylating agent is a compound of the formula Y-B(OR')2, Y is OR' and the compound of formula (III) is reacted with the borylating agent in the presence of a Grignard reagent or an alkyl lithium reagent.

[0270] Borylation of the compound of formula (III) to produce a compound of formula (Ilia) can occur in the presence of one or more bases such as potassium acetate, sodium acetate, triethylamine, diisopropylethylamine, pyridine in one or more organic solvents such as 2-methyltetrahydrofuran (2-MeTHF), THF, dioxane, toluene, xylene, or MTBE.

[0271] In exemplary steps of the synthesis of Figure 3 In exemplary steps of the synthesis of

[0272]

[0273] In exemplary embodiments, the compound of formula (Ilia) can be benzylated with a benzylating agent. For the compound of formula (Ilia), each R' is independently H, alkyl, or aryl or two alkyl or aryl groups that form a ring with B. In exemplary embodiments, the benzylating agent is a benzyl chloride derivative. Suitable benzyl chloride derivatives include, but are not limited to, 4-fluorobenzyl chloride and 4-fluorobenzyl bromide. The benzylating agent can be used in a Suzuki cross-coupling reaction to produce a compound of formula (IIIb).

[0274] The benzylating agents used in this synthesis step are stable in air and in the presence of moisture. They are also readily available in industrial quantities and are less expensive than the compound of formula (VI). The use of exemplary benzylating agents in this step increases the stability, predictability, and efficiency of the synthesis of the compounds of formula (IX) and (XXIII).

[0275] In exemplary embodiments, the compound of formula (IIIa) can be benzylated in the presence of a base. Suitable bases include, but are not limited to, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and potassium phosphate.

[0276] In exemplary embodiments, the compound of formula (IIIb) can be reduced to form a compound of formula (IIIc). This step is described in Example 2. Figure 3

[0277] The compound of formula (IIIb) can be reduced with a reducing agent. Suitable reducing agents include, but are not limited to, sodium borohydride and lithium aluminum hydride.

[0278] In exemplary embodiments, the compound of formula (IIIb) is reduced with a reducing agent in the presence of a nickel catalyst. Suitable nickel catalysts include, but are not limited to, nickel chloride, nickel (II) chloride hexahydrate. In exemplary embodiments, the compound of formula (IIIb) is reduced by hydrogenation over a Raney nickel catalyst.

[0279] In exemplary embodiments, the compound of formula (IIIc) is converted to a compound of formula (VII) in a cyclization reaction. This step is described in Example 3.

[0280] Figure 3

[0281] The cyclization reaction is performed by deprotonating the amino group in the presence of a base and displacing the fluorine atom on the pyridine ring. In exemplary embodiments, sodium bicarbonate is used as the deprotonating agent, triggering the dehalogenation and intramolecular nucleophilic displacement, leading to cyclization or ring closure. To facilitate deprotonation and dehalogenation, the compound of formula (IIIc) can be reacted with a base in the presence of a solvent. Suitable solvents include, but are not limited to, polar aprotic solvents or dimethyl sulfoxide (DMSO), THF, DMF, and DMAc. Suitable bases include, but are not limited to, NaHCO3, NaH, Na2CO3, and K2CO3.

[0282] Without utilizing a compound of formula (VI) or a PEPPSI TM catalyst that leads to inefficient and unpredictable synthesis, the compound of formula (VII) can be used in the synthesis of a compound of formula (IX) as shown in and

[0283] Example 1. Figure 1 Figure 2 In alternative embodiments, the compound of formula (VII) is prepared as shown in and Example 3A.

[0284] In exemplary embodiments, the compound of formula (VIII) is prepared as shown in Figure 1 and Example 3B. Figure 1 and Example 3B describe exemplary embodiments of the synthesis of a compound of formula (VIII).

[0285] From a compound of formula (V) in Figure 1 (VII) by reacting a compound of formula (V) with a compound of formula (VI). This step is described in Example 3A.

[0286]

[0287] In exemplary embodiments, a compound of formula (V) can be reacted with a compound of formula (VI) in the presence of one or more palladium catalysts, including but not limited to Xphos-Pd-G2 catalyst, Pd(Oac)2, or Pd2(dba)3 along with a ligand such as PPh3, Xantphos, DPPE, DPPP, DPPB, DPPF, rac-BINAP, RuPhos, or tBuXphos. In exemplary embodiments, palladium catalyzed reactions can occur in the presence of ligand 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) used as a Suzuki coupling precursor. The reaction can also occur in a suitable solvent such as N-methylpyrrolidine (NMP) and / or tetrahydrofuran (THF). Applicants have found that this synthesis step can be performed without the use of PEPPSI catalysts which lead to inefficient and unpredictable syntheses.

[0288] Figure 1 A compound of formula (VIII) in

[0289] This step is described in Example 3B.

[0290]

[0291] In exemplary embodiments, a compound of formula (VII) is brominated in the presence of a solvent to provide a compound of formula (VIII). Suitable brominating agents include N-bromosuccinimide and dibromomethylidene hydantoin, and suitable solvents include dimethylformamide. A compound of formula (VIII) can then be used to produce a compound of formula (XIII) for coupling reaction with a compound of formula (XX) to produce a compound of formula (XXI), as shown in the synthesis of Figure 2 .

[0292] A compound of formula (IX) in Figure 2 is prepared from a compound of formula (VIII) by a Boc protection step. This step is described in Example 6B.

[0293]

[0294] Boc protection can be achieved by reacting a compound of formula (VIII) with a Boc protecting group (such as di-tert-butyl dicarbonate). In an exemplary embodiment, the Boc protection reaction can occur in the presence of one or more reagents, including a base and a solvent. Suitable bases include, but are not limited to, sodium carbonate, N,N-dimethylaminopyridine, sodium hydroxide, triethylamine, sodium bicarbonate, potassium carbonate, and diisopropylethylamine. Suitable solvents include, but are not limited to, toluene, dichloromethane, ethyl acetate, and water as an optional co-solvent.

[0295] Other suitable protecting groups include the carboxybenzyl (Cbz) group.

[0296] Alternatively, Figure 4 The exemplary synthesis shown also produces a compound of formula (IX).

[0297] exist Figure 4 In the synthesis of compounds of formula (IX), Y is OR' or B(OR')2, and each R' is independently H, alkyl or aryl, or two alkyl or aryl groups that form a ring with B.

[0298] exist Figure 4 In the exemplary steps of the synthesis, the compound of formula (V) can be converted into the compound of formula (Va) by attaching a protecting group. This step is described in Example 4.

[0299]

[0300] In an exemplary embodiment, the protecting group is a Boc protecting group, and the compound of formula (Va) is prepared by reacting it with di-tert-butyl dicarbonate, which can be removed with a deprotecting agent. Protection can occur in the presence of a solvent. Suitable solvents for protection include, but are not limited to, toluene, dichloromethane, THF, and acetonitrile. Other protecting groups, including but not limited to benzyl, acetyl, and / or carboxybenzyl (CBz) protecting groups, are contemplated within the scope of the embodiments presented herein.

[0301] exist Figure 4 In an exemplary step of the synthesis, the compound of formula (Va) can be converted to the compound of formula (Vb) by borylation. This step is described in Example 5.

[0302]

[0303] Borylation can be performed by reacting a compound of Formula (Va) with a borylating agent and a catalyst. The borylating agent can be a compound of Formula Y-B(OR’)2. For a compound of Formula (Vb) and a borylating agent of Formula Y-B(OR’)2, Y is OR’ or B(OR’)2, and each R’ is independently H, alkyl, or aryl or two alkyl or aryl groups that form a ring with B. In exemplary embodiments, the borylating agent is bis(pinacolato)diboron and the catalyst is a palladium catalyst.

[0304] In exemplary embodiments, the catalyst is one or more palladium catalysts, including but not limited to Xphos-Pd-G2 catalyst, Pd(Oac)2, or Pd2(dba)3 along with a ligand such as PPh3, Xantphos, DPPE, DPPP, DPPB, DPPF, rac-BINAP, RuPhos, or tBuXphos. Palladium catalyzed reactions can occur in the presence of a ligand. In exemplary embodiments, the ligand is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) used as a Suzuki coupling precursor.

[0305] In another exemplary embodiment, the borylating agent is of Formula Y-B(OR’)2, Y is OR’ and the compound of Formula (Va) is reacted with the borylating agent in the presence of a Grignard reagent or an alkyl lithium reagent.

[0306] Borylation of a compound of Formula (Va) to produce a compound of Formula (Vb) can also occur in the presence of one or more bases such as potassium acetate, sodium acetate, triethylamine, diisopropylethylamine, pyridine in one or more organic solvents such as 2-methyltetrahydrofuran (2-MeTHF), THF, dioxane, toluene, xylene, or MTBE.

[0307] In exemplary steps in the synthesis of Figure 4 (Vc) can be benzylated to produce a compound of Formula (Vc). This step is described in Example 5.

[0308]

[0309] A compound of Formula (Vb) can be benzylated with a benzylating agent. As used herein, “benzylated with a benzylating agent” refers to the coupling of a boronate ester (Vb) with a compound of Formula (Vb), each R’ is independently H, alkyl, or aryl or two alkyl or aryl groups that form a ring with B. In exemplary embodiments, the benzylating agent is a benzyl chloride derivative. Suitable benzylating agents include, but are not limited to, 4-fluorobenzyl chloride and 4-fluorobenzyl bromide. The benzylating agent can be used in a Suzuki cross-coupling reaction to produce a compound of Formula (Vc).

[0310] The benzylating agents used in this synthesis step are stable in air and in the presence of moisture. They are also readily available in industrial quantities and are less expensive than the compound of formula (VI). The use of exemplary benzylating agents in this step increases the stability, predictability, and efficiency of the synthesis of the compound of formula (IX) and (XXIII).

[0311] The compound of formula (Vb) can be benzylated in the presence of a base. Suitable bases include, but are not limited to, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and potassium phosphate.

[0312] In an exemplary step of the synthesis of Figure 4 The compound of formula (Vc) can be brominated to produce the compound of formula (IX) in an exemplary step of the synthesis of

[0313]

[0314] Bromination can be carried out by reacting the compound of formula (Vc) with a brominating agent. Suitable brominating agents include, but are not limited to, 1-bromopyrrolidine-2,5-dione (BMS) and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH). Bromination can be carried out in the presence of an organic solvent. Suitable organic solvents include, but are not limited to, dimethylformamide (DMF), dichloromethane, acetonitrile, and ethyl acetate.

[0315] Figure 4 The synthesis of TM the compound of formula (IX) without utilizing the compound of formula (VI) or PEPPSI

[0316] The compound of formula (IX) is a key intermediate in the synthesis of the compound of formula (XXIII) and the active pharmaceutical ingredient manufactured from the compound of formula (XXIII). The synthesis of the compound of formula (XXIII) using the compound of formula (IX) is described below.

[0317] Figure 2 The compound of formula (IX) in

[0318]

[0319] Palladium-catalyzed carbonylation of a compound of Formula (IX) can be achieved by reacting a compound of Formula (IX) with phenol and carbon monoxide in the presence of a palladium catalyst. Suitable palladium catalysts can include Xphos-Pd-G2 catalyst, Pd(Oac)2, or Pd2(dba)3 along with a ligand such as PPh3, Xantphos, DPPE, DPPP, DPPB, DPPF, rac-BINAP, RuPhos, or tBuXphos. In exemplary embodiments, the palladium catalyst is palladium(II) acetate and the ligand is rac-BINAP. Alternatively, carbonylation of a compound of Formula (IX) can be achieved by reacting a compound of Formula (IX) with phenyl formate in the presence of a palladium catalyst.

[0320] Figure 2 A compound of Formula (X) in the above scheme can be converted to a compound of Formula (XI) by deprotection or removal of the Boc group. This step is described in Example 8.

[0321]

[0322] In exemplary embodiments, the Boc protecting group can be removed with a deprotecting agent. Suitable deprotecting agents include, but are not limited to, HC1, TFA, HBr, MsOH, TsOH, CSA, or other acids. In exemplary embodiments, deprotection can occur in the presence of a solvent. Suitable solvents include, but are not limited to, isopropanol, methanol, ethanol, t-butanol, THF, or MeCN.

[0323] Figure 2 A compound of Formula (XI) in the above scheme can be converted to a compound of Formula (XII) by reduction of the phenyl ester to form an alcohol compound of Formula (XII). This step is described in Example 9.

[0324]

[0325] Suitable reducing agents for reduction of the phenyl ester to an alcohol include, but are not limited to, lithium borohydride, sodium borohydride, lithium aluminum hydride, borane, sodium triacetoxyborohydride, lithium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, red aluminum, and DIBAL-H. Reduction can occur in the presence of a solvent such as THF compound (e.g., methyltetrahydrofuran).

[0326] Figure 2 A compound of Formula (XII) in the above scheme can be converted to a compound of Formula (XIII) by chloroacetylation of the amino group. This step is described in Example 10.

[0327]

[0328] Chloroacetylation can be achieved with 2-chloroacetyl chloride, acetonitrile, and a solvent such as dichloromethane, tetrahydrofuran, and / or toluene.

[0329] Reference is made to Figure 2 the preparation or synthesis of a compound of Formula (XX) from a compound of Formula (XIV).

[0330] Boc protection of a compound of Formula (XIV) results in an isolated diBoc intermediate. Treatment of the diBoc intermediate with a suitable base results in a compound of Formula (XV). This step is described in Example 11.

[0331]

[0332] In exemplary embodiments, Boc protection can be carried out by reacting a compound of Formula (XIV) with a tert-butyloxycarbonyl (Boc) protecting group. The reaction can occur in the presence of one or more reagents including one or more bases and / or solvents. Suitable bases include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium carbonate, N,N-dimethylaminopyridine, and triethylamine. Suitable solvents include, but are not limited to, toluene, methanol, dichloromethane, ethyl acetate, and ethanol.

[0333] Figure 2 A compound of Formula (XV) can be converted to a compound of Formula (XVI) by benzyl protection. This step is described in Example 12.

[0334]

[0335] In exemplary embodiments, benzyl protection is carried out with a benzylating agent. A suitable benzylating agent is benzaldehyde. Benzylization can occur in the presence of one or more solvents and reducing agents. Suitable solvents include, but are not limited to, dichloromethane, ethyl acetate, and ethanol. Suitable reducing agents include, but are not limited to, sodium triacetoxyborohydride, sodium borohydride (NaBH4), borane, and diisobutylaluminum hydride (DIBAL-H).

[0336] Alternatively, a compound of Formula (XV) can be converted by reaction with oxalic acid in a suitable solvent, such as methyl tert-butyl ether, and isolated as an oxalate salt compound of Formula (XVIa). This step is described in Example 13. The isolated oxalate salt compound of Formula (XVIa) can be used in the next step of the synthesis of Figure 2 to provide a final product of greater purity.

[0337] Chlorination of a compound of Formula (XVI) results in a chloro compound of Formula (XVII). This step is described in Example 14.

[0338]

[0339] Chlorination can be achieved by reacting a compound of Formula (XVI) with a chlorinating agent. Suitable chlorinating agents include, but are not limited to, methanesulfonyl chloride, thionyl chloride, sulfuryl chloride, phosphorus oxychloride (POCI3), and phosphorus trichloride (PCI3). In exemplary embodiments, chlorination can be achieved in the presence of one or more bases and / or solvents. Suitable bases include triethylamine and suitable solvents include, but are not limited to, dichloromethane, ethyl acetate, and ethanol.

[0340] Nucleophilic displacement of a compound of Formula (XVII) yields a compound of Formula (XIX). This step is described in Example 15.

[0341]

[0342] Nucleophilic displacement can be achieved by reacting a compound of Formula (XVII) with a nucleophile. In exemplary embodiments, the nucleophile is a compound of Formula (XVIII) (3-methylmorpholine hydrochloride). Nucleophilic displacement can be carried out in the presence of a solvent and a base. Suitable solvents include acetonitrile and suitable bases include, but are not limited to, potassium carbonate, sodium carbonate, and potassium phosphate. Additional additives can be used to facilitate the reaction, such as potassium iodide.

[0343] Deprotection of a compound of Formula (XIX) yields a compound of Formula (XX). This step is described in Example 16.

[0344]

[0345] Deprotection can be achieved by reacting a compound of Formula (XIX) with hydrogen and one or more palladium catalysts. Deprotection can occur in the presence of a solvent, such as ethanol, methanol, toluene, and heptane. In exemplary embodiments, the solvent is anhydrous ethanol. Suitable palladium catalysts include palladium on carbon and palladium hydroxide. Treatment with oxalic acid yields an oxalate salt compound of Formula (XX). Use of the oxalate salt compound of Formula (XX) reduces impurities in the final end-product compound of Formula (XXIII).

[0346] A high purity end-product of Formula (XXIII) can then be produced by a coupling reaction employing two additional key steps. Coupling between a compound of Formula (XIII) and a compound of Formula (XX) yields a compound of Formula (XXI), as described in Example 17.

[0347]

[0348] In exemplary embodiments, the coupling reaction can occur in a suitable solvent, such as acetonitrile, with potassium iodide and potassium carbonate.

[0349] Deprotection of a compound of Formula (XXI) yields a compound of Formula (XXII) by deprotection with a deprotecting agent. This step is described in Example 18.

[0350]

[0351] Suitable deprotecting agents include, but are not limited to, iodine, hydrochloric acid, TFA, HBr, MsOH, TsOH, CSA, or other acids. Deprotection can occur in a solvent such as isopropanol, methanol, ethanol, t-butanol, THF, or MeCN.

[0352] In the final and key step in the synthesis, the compound of formula (XXII) is reacted with anhydrous L-lactic acid to produce the final product compound of formula (XXIII) which is more suitable and more stable in pharmaceutical formulations.

[0353]

[0354] This final key step is described in Example 19 and produces the L-(+) lactic acid salt of the compound of formula (XXIII) which improves the purity of the produced compound and active pharmaceutical ingredient.

[0355] In alternative embodiments, there are provided key intermediate compounds of formula (I) and methods of synthesizing compounds of formula (I):

[0356]

[0357] wherein X is H or a protecting group;

[0358] Y is Br, Cl, I, or COR; and

[0359] R is H, OH, O-alkyl, or O-aryl. The protecting group can be a Boc protecting group.

[0360] In one embodiment, provided herein is a compound of formula (I) or a salt, solvate, or hydrate thereof,

[0361]

[0362] wherein X is H or a protecting group;

[0363] Y is COR; and

[0364] R is OH, O-alkyl, or O-aryl.

[0365] Figure 1 A general scheme depicting the synthesis of the compound of formula (XXIII) is provided.

[0366] Embodiment 1 is a method of manufacturing a compound of formula (VII):

[0367]

[0368] The method comprises the steps of:

[0369] converting the compound of formula (III)

[0370]

[0371] to a compound of formula (VII).

[0372] Embodiment 2 is the method of making a compound of formula (VII) as described in embodiment 1, the method comprising borylating a compound of formula (III) with a borylating agent to produce a compound of formula (Ilia):

[0373]

[0374] wherein each R' is independently H, alkyl, or aryl or two alkyl or aryl groups that form a ring with B.

[0375] Embodiment 3 is the method of making a compound of formula (VII) as described in embodiment 1, the method comprising borylating a compound of formula (III) in the presence of a palladium catalyst, a Grignard reagent, or an alkyl lithium reagent.

[0376] Embodiment 4 is the method of making a compound of formula (VII) as described in embodiment 1, the method comprising borylating a compound of formula (III) in the presence of a palladium catalyst and a ligand.

[0377] Embodiment 5 is the method of making a compound of formula (VII) as described in embodiment 4, wherein the borylating agent is Y-B(OR')2, Y is OR' or B(OR')2, and each R' is independently H, alkyl, or aryl or two alkyl or aryl groups that form a ring with B.

[0378] Embodiment 6 is the method of making a compound of formula (VII) as described in embodiment 3, wherein the palladium catalyst is XPhos-Pd-G2 catalyst.

[0379] Embodiment 7 is the method of making a compound of formula (VII) as described in embodiment 4, wherein the ligand is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0380] Embodiment 8 is the method of making a compound of formula (VII) as described in embodiment 1, the method further comprising benzylating a compound of formula (Ilia) with a benzylating agent to produce a compound of formula (Illb):

[0381]

[0382] Embodiment 9 is the method of making a compound of formula (VII) as described in embodiment 8, comprising benzylating a compound of formula (Ilia) in the presence of a base.

[0383] Embodiment 10 is the method of making a compound of formula (VII) as described in embodiment 8, wherein the benzylating agent is 4-fluorobenzyl chloride or 4-fluorobenzyl bromide.

[0384] Embodiment 11 is the method of making a compound of formula (VII) as described in embodiment 9, wherein the base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and potassium phosphate.

[0385] Embodiment 12 is the method of making a compound of formula (VII) as described in embodiment 8, further comprising reducing a compound of formula (Illb) with a reducing agent to produce a compound of formula (IIIc):

[0386]

[0387] Embodiment 13 is the method of making a compound of formula (VII) as described in embodiment 12, comprising reducing a compound of formula (Illb) in the presence of a nickel catalyst.

[0388] Embodiment 14 is the method of making a compound of formula (VII) as described in embodiment 12, wherein the reducing agent is hydrogen gas, sodium borohydride, or lithium aluminum hydride.

[0389] Embodiment 15 is the method of making a compound of formula (VII) as described in embodiment 13, wherein the nickel catalyst is selected from the group consisting of nickel chloride, nickel (II) chloride hexahydrate, and Raney nickel catalyst.

[0390] Embodiment 16 is the method of making a compound of formula (VII) as described in embodiment 12, further comprising deprotonating a compound of formula (IIIc) with a deprotonating agent.

[0391] Embodiment 17 is the method of making a compound of formula (VII) as described in embodiment 16, further comprising cyclizing a compound of formula (IIIc) in the presence of a polar aprotic solvent.

[0392] Embodiment 18 is the method of making a compound of formula (VII) as described in embodiment 16, wherein the deprotonating agent is sodium bicarbonate.

[0393] Embodiment 19 is the method of making a compound of formula (VII) as described in embodiment 16, wherein the polar aprotic solvent is dimethyl sulfoxide.

[0394] Embodiment 20 provides a compound of Formula (la):

[0395]

[0396] wherein R is CN or CH2NH2.

[0397] Embodiment 21 provides a method of manufacturing a compound of Formula (VII):

[0398]

[0399] comprising the steps of:

[0400] converting a compound of Formula (V):

[0401]

[0402] to a compound of Formula (VII).

[0403] Embodiment 22 is the method of manufacturing a compound of Formula (VII) as described in Embodiment 2, further comprising reacting a compound of Formula (V) with a compound of Formula (VI) in the presence of one or more palladium catalysts and a ligand.

[0404]

[0405] Embodiment 23 is the method of manufacturing a compound of Formula (VII) as described in Embodiment 3, wherein the one or more palladium catalysts are selected from the group consisting of XPhos-Pd-G2 catalyst, Pd(OAc)2, and Pd2(dba)3.

[0406] Embodiment 24 is the method of manufacturing a compound of Formula (VII) as described in Embodiment 4, wherein the ligand is selected from the group consisting of PPh3, Xantphos, DPPE, DPPP, DPPB, DPPF, rac-BINAP, RuPhos, XPhos, and tBuXphos.

[0407] Embodiment 25 provides a method of manufacturing a compound of Formula (IX):

[0408]

[0409] comprising the steps of:

[0410] converting a compound of Formula (V):

[0411]

[0412] to a compound of Formula (IX).

[0413] Embodiment 26 is the method of making a compound of formula (IX) as described in embodiment 25, further comprising reacting a compound of formula (V) with a protecting group to produce a compound of formula (Va).

[0414]

[0415] Embodiment 27 is the method of making a compound of formula (IX) as described in embodiment 26, wherein the protecting group is di-tert-butyl dicarbonate.

[0416] Embodiment 28 is the method of making a compound of formula (IX) as described in embodiment 26, further comprising borylating a compound of formula (Va) with a borylating agent to produce a compound of formula (Vb):

[0417]

[0418] Embodiment 29 is the method of making a compound of formula (IX) as described in embodiment 28, comprising borylating a compound of formula (Va) in the presence of a palladium catalyst, a Grignard reagent, or an alkyl lithium reagent.

[0419] Embodiment 30 is the method of making a compound of formula (IX) as described in embodiment 28, comprising borylating a compound of formula (Va) in the presence of a palladium catalyst and a ligand.

[0420] Embodiment 31 is the method of making a compound of formula (IX) as described in embodiment 29, wherein the borylating agent is Y-B(OR’)2, Y is OR’ or B(OR’)2, and each R’ is independently H, alkyl, or aryl or two alkyl or aryl groups that form a ring with B.

[0421] Embodiment 32 is the method of making a compound of formula (IX) as described in embodiment 29, wherein the palladium catalyst is selected from Pd-Ln (palladium-lanthanide complex), Pd-170 (XPhos Pd(t-Bu)Cl), XPhos-Pd-G2 catalyst, Pd(OAc)2, and Pd2(dba)3.

[0422] Embodiment 33 is the method of making a compound of formula (IX) as described in embodiment 30, wherein the ligand is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos).

[0423] Embodiment 34 is the method of making a compound of formula (IX) as described in embodiment 28, further comprising benzylating a compound of formula (Vb) with a benzylating agent to produce a compound of formula (Vc):

[0424]

[0425] Embodiment 35 is the method of making a compound of formula (IX) as described in embodiment 34, comprising benzylating a compound of formula (Vb) in the presence of an inorganic base.

[0426] Embodiment 35 is the method of making a compound of formula (IX) as described in embodiment 34, wherein the benzylating agent is l-(chloromethyl)-4-fluorobenzene or 4-fluorobenzyl bromide.

[0427] Embodiment 37 is the method of making a compound of formula (IX) as described in embodiment 35, wherein the inorganic base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and potassium phosphate.

[0428] Embodiment 38 is the method of making a compound of formula (IX) as described in embodiment 34, further comprising brominating a compound of formula (Vc) with a brominating agent.

[0429] Embodiment 39 is the method of making a compound of formula (IX) as described in embodiment 38, comprising brominating a compound of formula (Vc) in the presence of an organic solvent.

[0430] Embodiment 40 is the method of making a compound of formula (IX) as described in embodiment 38, wherein the brominating agent is selected from the group consisting of l-bromopyrrolidine-2,5-dione (BMS) and l,3-dibromo-5,5-dimethylhydantoin (DBDMH).

[0431] Embodiment 41 is the method of making a compound of formula (IX) as described in embodiment 39, wherein the organic solvent is selected from the group consisting of dimethylformamide (DMF), dichloromethane, acetonitrile, and ethyl acetate.

[0432] Embodiment 42 provides a compound of formula (I):

[0433]

[0434] wherein X is H or a protecting group;

[0435] Y is Br, Cl, I, or COR; and

[0436] R is H, OH, O-alkyl, or O-aryl.

[0437] Embodiment 43 provides a compound of formula (I), wherein X is tert-butyloxycarbonyl (Boc) and Y is Br.

[0438] Embodiment 44 provides a compound of formula (I), wherein the X is carboxybenzyl (Cbz).

[0439] Embodiment 45 provides a compound of formula (I), wherein X is a Boc group and Y is CO2Ph.

[0440] Embodiment 46 provides a compound of formula (I), wherein X is hydrogen and Y is CO2Ph.

[0441] Embodiment 47 provides a method of manufacturing a compound of formula (I):

[0442]

[0443] wherein X is H or a protecting group;

[0444] Y is Br, CI, I, or COR; and

[0445] R = H, OH, O-alkyl, or O-aryl

[0446] The method comprises the steps of:

[0447] converting a compound of formula (VIII)

[0448]

[0449] to a compound of formula (I).

[0450] Embodiment 48 is the method of manufacturing a compound of formula (I) as described in embodiment 47, further comprising reacting a compound of formula (VIII) with di-tert-butyl dicarbonate to produce a compound of formula (IX):

[0451]

[0452] Embodiment 49 is the method of manufacturing a compound of formula (I) as described in embodiment 48, wherein the reacting of the compound of formula (VIII) with di-tert-butyl dicarbonate occurs in a solution having one or more bases and one or more solvents.

[0453] Embodiment 50 is the method of manufacturing a compound of formula (I) as described in embodiment 49, wherein the one or more bases are selected from the group consisting of sodium carbonate, N,N-dimethylaminopyridine, sodium hydroxide, triethylamine, sodium bicarbonate, potassium carbonate, and diisopropylethylamine.

[0454] Embodiment 51 is the method of manufacturing a compound of formula (I) as described in embodiment 49, wherein the one or more solvents are selected from the group consisting of toluene, dichloromethane, ethyl acetate, and water.

[0455] Embodiment 52 is the method of making a compound of Formula (I) as described in Embodiment 48, further comprising reacting a compound of Formula (IX) with (i) phenyl formate or (ii) phenol and carbon monoxide in the presence of a palladium catalyst to produce a compound of Formula (X):

[0456]

[0457] Embodiment 53 is the method of making a compound of Formula (I) as described in Embodiment 52, wherein the reaction of a compound of Formula (IX) occurs in a solution with rac-1,1’- binaphthalene-2,2’-diphenylphospholene. In some embodiments, the solution further comprises a base and a solvent. In some embodiments, the solution further comprises triethylamine and acetonitrile.

[0458] Embodiment 54 is the method of making a compound of Formula (I) as described in Embodiment 52, wherein the carbon monoxide is gaseous.

[0459] Embodiment 55 is the method of making a compound of Formula (I) as described in Embodiment 52, wherein the palladium catalyst is selected from the group consisting of XPhos-Pd-G2 catalyst, Pd(OAc)2, and Pd2(dba)3.

[0460] Embodiment 56 is the method of making a compound of Formula (I) as described in Embodiment 55, wherein the reaction of a compound of Formula (IX) occurs in the presence of a ligand selected from the group consisting of PPh3, Xantphos, DPPE, DPPP, DPPB, DPPF, rac-BINAP, RuPhos, tBuXphos, and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos).

[0461] Embodiment 57 is the method of making a compound of Formula (I) as described in Embodiment 52, further comprising reacting a compound of Formula (X) with hydrochloric acid to produce a compound of Formula (XI):

[0462]

[0463] Embodiment 58 is the method of making a compound of Formula (I) as described in Embodiment 52, wherein the reaction of a compound of Formula (X) with hydrochloric acid occurs in a solution with isopropanol.

[0464] Embodiment 59 is the method of making a compound of Formula (I) as described in Embodiment 57, further comprising reducing a compound of Formula (XI) with a reducing agent to produce a compound of Formula (XII):

[0465]

[0466] Embodiment 60 is the method of making a compound of Formula (I) described in Embodiment 59, wherein the reducing agent is selected from lithium borohydride, sodium borohydride, lithium aluminum hydride, borane, sodium triacetoxyborohydride, lithium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, red aluminum, and DIBAL.

[0467] Embodiment 61 provides a method of making a compound of Formula (XIII):

[0468]

[0469] comprising the steps of:

[0470] converting a compound of Formula (XII)

[0471]

[0472] to a compound of Formula (XIII).

[0473] Embodiment 62 is the method of making a compound of Formula (XIII) described in Embodiment 61, further comprising reacting a compound of Formula (XII) with 2-chloroacetyl chloride.

[0474] Embodiment 63 is the method of making a compound of Formula (XIII) described in Embodiment 62, wherein the reacting of the compound of Formula (XII) with 2-chloroacetyl chloride occurs in the presence of acetonitrile.

[0475] Embodiment 64 provides a compound of Formula (XVIa):

[0476]

[0477] Embodiment 65 provides a method of making a compound of Formula (XVIa):

[0478]

[0479] comprising the steps of:

[0480] converting a compound of Formula (XIV)

[0481]

[0482] to a compound of Formula (XVIa).

[0483] Embodiment 66 is the method of making a compound of Formula (XVIa) described in Embodiment 65, further comprising reacting a compound of Formula (XIV) with di-tert-butyl dicarbonate to produce a compound of Formula (XV):

[0484]

[0485] Embodiment 67 is the method of making a compound of Formula (XVIa) as described in embodiment 66, wherein the reaction of the compound of Formula (XIV) with di-tert-butyl dicarbonate occurs in the presence of a base and a solvent.

[0486] Embodiment 68 is the method of making a compound of Formula (XVIa) as described in embodiment 67, wherein the base is selected from the group consisting of potassium hydroxide and sodium hydroxide.

[0487] Embodiment 69 is the method of making a compound of Formula (XVIa) as described in embodiment 67, wherein the solvent is selected from the group consisting of dichloromethane, ethyl acetate, and ethanol.

[0488] Embodiment 70 is the method of making a compound of Formula (XVIa) as described in embodiment 66, further comprising benzylating the compound of Formula (XV) with a benzylating agent to produce a compound of Formula (XVI):

[0489]

[0490] Embodiment 71 is the method of making a compound of Formula (XVIa) as described in embodiment 70, wherein the benzylating agent is benzaldehyde.

[0491] Embodiment 72 is the method of making a compound of Formula (XVIa) as described in embodiment 70, wherein the benzylating of the compound of Formula (XV) occurs in the presence of a reducing agent and a solvent.

[0492] Embodiment 73 is the method of making a compound of Formula (XVIa) as described in embodiment 72, wherein the reducing agent is selected from the group consisting of sodium triacetoxyborohydride, sodium borohydride (NaBH4), borane, and diisobutylaluminum hydride (DIBAL-H).

[0493] Embodiment 74 is the method of making a compound of Formula (XVIa) as described in embodiment 72, wherein the solvent is selected from the group consisting of dichloromethane, ethyl acetate, and ethanol.

[0494] Embodiment 75 is the method of making a compound of Formula (XVIa) as described in embodiment 70, further comprising reacting the compound of Formula (XVI) with oxalic acid in the presence of a solvent.

[0495] Embodiment 76 is the method of making a compound of Formula (XVIa) as described in embodiment 75, wherein the solvent is methyl tert-butyl ether.

[0496] Embodiment 77 provides a compound of Formula (XX):

[0497]

[0498] Embodiment 78 is a method of making a compound of Formula (XX):

[0499]

[0500] comprising the steps of:

[0501] converting a compound of Formula (XVI):

[0502]

[0503] or a salt thereof, to a compound of Formula (XX).

[0504] Embodiment 79 is the method of making a compound of Formula (XX) as described in Embodiment 78, further comprising chlorinating a compound of Formula (XVI):

[0505]

[0506] Embodiment 80 is the method of making a compound of Formula (XX) as described in Embodiment 79, wherein the chlorinating agent is selected from the group consisting of thionyl chloride, sulfuryl chloride, and phosphorus oxychloride (POCl3).

[0507] Embodiment 81 is the method of making a compound of Formula (XX) as described in Embodiment 79, wherein the chlorinating agent is methanesulfonyl chloride.

[0508] Embodiment 82 is the method of making a compound of Formula (XX) as described in Embodiment 79, wherein the chlorination of a compound of Formula (XVI) or a salt thereof occurs in the presence of a base and a solvent.

[0509] Embodiment 83 is the method of making a compound of Formula (XX) as described in Embodiment 82, wherein the base is triethylamine.

[0510] Embodiment 84 is the method of making a compound of Formula (XX) as described in Embodiment 82, wherein the solvent is selected from the group consisting of dichloromethane, ethyl acetate, and ethanol.

[0511] Embodiment 85 is the method of making a compound of Formula (XX) as described in Embodiment 79, further comprising reacting a compound of Formula (XVII):

[0512]

[0513] Embodiment 86 is the method of making a compound of formula (XX) as described in embodiment 85, wherein the nucleophile is (R)-3-methylmorpholine hydrochloride.

[0514] Embodiment 87 is the method of making a compound of formula (XX) as described in embodiment 85, wherein the reaction of the compound of formula (XVII) with the nucleophile occurs in the presence of a base, a solvent, and an additive.

[0515] Embodiment 88 is the method of making a compound of formula (XX) as described in embodiment 87, wherein the base is selected from the group consisting of potassium carbonate, sodium carbonate, and potassium phosphate.

[0516] Embodiment 89 is the method of making a compound of formula (XX) as described in embodiment 87, wherein the solvent is acetonitrile and the additive is potassium iodide.

[0517] Embodiment 90 is the method of making a compound of formula (XX) as described in embodiment 85, further comprising debenzylating a compound of formula (XIX) to produce a compound of formula (XXa).

[0518]

[0519] Embodiment 91 is the method of making a compound of formula (XX) as described in embodiment 90, wherein the debenzylating of the compound of formula (XIX) comprises reacting the compound of formula (XIX) with hydrogen and one or more palladium catalysts.

[0520] Embodiment 92 is the method of making a compound of formula (XX) as described in embodiment 91, wherein the palladium catalyst is selected from the group consisting of palladium on carbon and palladium hydroxide.

[0521] Embodiment 93 is the method of making a compound of formula (XX) as described in embodiment 91, wherein the debenzylating of the compound of formula (XIX) occurs in the presence of a solvent.

[0522] Embodiment 94 is the method of making a compound of formula (XX) as described in embodiment 93, wherein the solvent is selected from the group consisting of benzene, methanol, toluene, and heptane.

[0523] Embodiment 95 is the method of making a compound of formula (XX) as described in embodiment 93, wherein the solvent is anhydrous ethanol.

[0524] Embodiment 96 is the method of making a compound of formula (XX) as described in embodiment 91, wherein the hydrogen is gaseous.

[0525] Embodiment 97 is the method of making a compound of formula (XX) as described in embodiment 90, further comprising reacting the compound of formula (XXa) with oxalic acid.

[0526] Embodiment 98 is a method of manufacturing a compound of Formula (XXIII):

[0527]

[0528] comprising the steps of:

[0529] converting a compound of Formula (XX)

[0530]

[0531] to a compound of Formula (XXIII).

[0532] Embodiment 99 is the method of manufacturing a compound of Formula (XXIII) as described in embodiment 98, further comprising reacting a compound of Formula (XX) with a compound of Formula (XIII):

[0533]

[0534] to produce a compound of Formula (XXI):

[0535]

[0536] Embodiment 100 is the method of manufacturing a compound of Formula (XXIII) as described in embodiment 99, wherein the reacting a compound of Formula (XX) with a compound of Formula (XIII) occurs in the presence of potassium iodide, potassium carbonate, and acetonitrile.

[0537] Embodiment 101 is the method of manufacturing a compound of Formula (XXIII) as described in embodiment 99, further comprising reacting a compound of Formula (XXI) with a deprotecting agent to produce a compound of Formula (XXII)

[0538]

[0539] Embodiment 102 is the method of manufacturing a compound of Formula (XXIII) as described in embodiment 101, wherein the deprotecting agent is selected from the group consisting of iodine, TFA, HBr, MsOH, TsOH, and CSA.

[0540] Embodiment 103 is the method of manufacturing a compound of Formula (XXIII) as described in embodiment 101, wherein the deprotecting agent is HC1.

[0541] Embodiment 104 is the method of manufacturing a compound of Formula (XXIII) as described in embodiment 101, wherein the reacting a compound of Formula (XXI) with a deprotecting agent occurs in the presence of a solvent.

[0542] Embodiment 105 is the method of making the compound of formula (XXIII) as described in embodiment 104, wherein the solvent is selected from the group consisting of isopropanol, methanol, ethanol, tert-butanol, THF, and MeCN.

[0543] Embodiment 106 is the method of making the compound of formula (XXIII) as described in embodiment 101, further comprising reacting the compound of formula (XXII) with anhydrous L-(+)-lactic acid.

[0544] Embodiment 107 is the method of making the compound of formula (XXIII) as described in embodiment 106, wherein the purity of the compound of formula (XXIII) is equal to or greater than 95% by weight.

[0545] Embodiment 108 is the method of making the compound of formula (XXIII) as described in embodiment 106, wherein the palladium content of the compound of formula (XXIII) is less than 10 ppm.

[0546] Embodiment 109 is the method of making the compound of formula (XXIII) as described in embodiment 106, wherein the aldehyde impurity in the compound of formula (XXIII) represented by the area percentage of RRT 1.3 is less than or equal to 0.15 area percentage after storage at 5 °C and 60% relative humidity for 12 months.

[0547] Embodiment 110 is the method of making the compound of formula (XXIII) as described in embodiment 106, further comprising reacting the compound of formula (XXII) with anhydrous L-(+)-lactic acid in the presence of one or more crystallization solvents.

[0548] Embodiment 111 is the method of making the compound of formula (XXIII) as described in embodiment 110, wherein the one or more crystallization solvents are methyl isobutyl ketone (MIBK) and n-heptane.

[0549] Embodiment 112 is the method of making the compound of formula (XXIII) as described in embodiment 110, wherein the one or more crystallization solvents are isopropanol and n-heptane.

[0550] Embodiment 113 is the method of making the compound of formula (XXIII) as described in embodiment 110, wherein the one or more crystallization solvents are methyl ethyl ketone (MEK) and n-heptane.

[0551] Embodiment 114 is the method of making the compound of formula (XXIII) as described in embodiment 110, wherein the one or more crystallization solvents are tetrahydrofuran (THF) and n-heptane.

[0552] Embodiment 115 is the method of making the compound of formula (XXIII) described in Embodiment 110, wherein the one or more crystallization solvents are acetonitrile and methyl tert-butyl ether (MTBE).

[0553] Embodiment 116 is the method of making the compound of formula (XXIII) described in Embodiment 110, wherein the one or more crystallization solvents are methyl acetate and n-heptane.

[0554] Embodiment 117 is the method of making the compound of formula (XXIII) described in Embodiment 110, wherein the one or more crystallization solvents are ethyl acetate and n-heptane.

[0555] Embodiment 118 is the method of making the compound of formula (XXIII) described in Embodiment 110, further comprising seeding the reaction with a crystalline compound of the lactic acid salt of formula (XXIII).

[0556] Embodiment 119 is the method of making the compound of formula (XXIII) described in Embodiment 118, wherein seeding the reaction occurs at a temperature less than or equal to 60 °C.

[0557] Embodiment 120 is the method of making the compound of formula (XXIII) described in Embodiment 118, further comprising cooling the reaction at a rate of about 0.01 °C / min to about 1 °C / min.

[0558] Embodiment 121 is the method of making the compound of formula (XXIII) described in Embodiment 118, further comprising cooling the reaction at a rate of about 0.03 °C / min to about 0.3 °C / min.

[0559] The present application and the embodiments and examples disclosed herein address the problems with known methods for preparing compounds of formula (XXIII) and (XXIIIa). With reference to Figure 2 , the inventors have unexpectedly discovered that the hydroxymethyl group of compounds of formula (XII) can be synthesized using palladium catalyzed carbonylation to make the key ester intermediate compound of formula (X) in a highly crystalline form, followed by reduction. Further embodiments and examples herein describe new intermediates, chemical entities, and methods of synthesizing new chemical entities and intermediates. For example, compounds of formula (la), (I), (IX), (X), (XI), oxalate compounds of formula (XVIa) and (XX) are new chemical entities that can be used in the preparation and synthesis of compounds of formula (XXIII) and (XXIIIa).

[0560] Figure 2The synthesis of and other exemplary embodiments also provide new chemical entities of crystalline salt forms of Formula (XVI) and (XX) and new methods of synthesizing these crystalline salt compounds of Formula. The crystalline salts of the compounds of Formula (XVI) and (XX) have higher purity than the non-crystalline salt forms or free base forms and improve the purity of the synthesis of the end product compounds of Formula (XXIII) and (XXIIIa). In embodiments, the compound of Formula (XX) is in the oxalate salt form and is used in the oxalate salt form in the synthesis of the compound of Formula (XXIII).

[0561] Certain advantages are provided by using the new intermediate compounds of Formula (la), (Va), (VII), (IX), (X), and (XI) in the synthesis of the end product compound of Formula (XXIII) and other compounds of Formula (XXIIIa). The intermediates of Formula (la), (Va), (VII), (IX), (X), and (XI) bring about higher efficiency, predictability, isolation, purity, and stability of the synthesis of the end product compound of Formula (XXIII). Further advantages are provided by using the new intermediate compounds of Formula (IX), (X), (XI), (XVI), (XVIa), and (XX) in the synthesis of the end product compound of Formula (XXIII) and other compounds of Formula (XXIIIa). The intermediates of Formula (IX), (X), (XI), (XVI), (XVIa), and (XX) bring about higher efficiency, predictability, isolation, and purity of the synthesis of the end product compound of Formula (XXIII).

[0562] Embodiments and examples of the present application address problems with known methods for making the compound of Formula (XXIII) and other compounds of Formula (XXIIIa). The present application discloses unexpected improvements in the synthesis of the compounds of Formula (IX), (X), (XI), (XVI), (XVIa), and (XX) and the synthesis of the end product compound of Formula (XXIII). The use of palladium catalyzed carbonylation of the compound of Formula (IX) adds the hydroxymethyl group in the compound of Formula (XII) to make the key ester intermediate compound of Formula (X) in a highly crystalline form, which is then reduced to produce the highly pure stable end product compound of Formula (XXIII) that is less viscous and more suitable in pharmaceutical formulations.

[0563] The following examples describe exemplary reaction conditions, parameters, and reagents for exemplary steps in the synthesis of compounds of Formula (IX), (X), (XI), (XVI), (XVIa), (XX), the final product compound of Formula (XXIII), and other compounds of Formula (XXIIIa). The following examples illustrate some embodiments described herein. Those of ordinary skill in the art will appreciate that various changes in the examples can be made without departing from the scope or intent of the present application or the disclosed exemplary embodiments, including changes with respect to the synthetic methods, procedures, reactants, reagents, parameters, and conditions described herein. In the following examples, the abbreviation “NMT” stands for “not more than.”

[0564] Abbreviations

[0565] BOC or Boc tert-butoxycarbonyl

[0566] tBuXphos 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl

[0567] DCM dichloromethane

[0568] DMF dimethylformamide

[0569] DMSO dimethyl sulfoxide

[0570] DPPB 1,4-bis(diphenylphosphino)butane

[0571] DPPE 1,2-bis(diphenylphosphino)ethane

[0572] DPPF 1,1'-ferrocenediyl-bis(diphenylphosphane)

[0573] DPPP 1,3-bis(diphenylphosphino)propane

[0574] EtOAc ethyl acetate

[0575] EtOH ethanol

[0576] HCl hydrochloric acid

[0577] HBr hydrobromic acid

[0578] IPA isopropyl alcohol

[0579] KF Karl Fischer water test

[0580] Me methyl

[0581] MeCN or ACN acetonitrile

[0582] MEK methyl ethyl ketone

[0583] MeOH methanol

[0584] MsOH methanesulfonic acid

[0585] MIBK methyl isobutyl ketone

[0586] MTBE or TBME methyl tert-butyl ether

[0587] NBS N-bromosuccinimide

[0588] NMP N-methylpyrrolidine

[0589] NMT not more than

[0590] Ph phenyl

[0591] Pd(OAc)2 palladium acetate

[0592] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)

[0593] PPh3 triphenylphosphine

[0594] ppm parts per million

[0595] rac-BINAP (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0596] RRT relative retention time

[0597] RH relative humidity

[0598] RuPhos 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl

[0599] TFA trifluoroacetic acid

[0600] THF tetrahydrofuran

[0601] 2-Me-THF 2-methyltetrahydrofuran

[0602] TLC thin layer chromatography

[0603] TsOH toluenesulfonic acid

[0604] Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0605] XPhos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0606] XPhos-Pd-G2 chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0607] Example

[0608] Example 1 : Preparation and synthesis of compound of formula (IIIb):

[0609]

[0610] Potassium acetate (11.38 g, 115.97 mmol, 2.88 eq.), bis(pinacolato)diboron (11.35 g, 44.70 mmol, 1.11 eq.), XPhos-Pd-G2 (0.633 g, 0.80 mmol, 0.02 eq.), XPhos (0.69 g, 1.45 mmol, 0.036 eq.) and compound of formula (III) (8.0 g, 40.27 mmol, 1.0 eq.) were added to a dry three necked flask under nitrogen. 2-Me-THF (120 mL) was added, the reaction mixture was heated to a temperature of 75 °C for 5 hours (until compound of formula (III) disappeared) and the reaction mixture was cooled to a temperature of 60 °C.

[0611]

[0612] Potassium acetate (11.38 g, 115.97 mmol, 2.88 eq.), bis(pinacolato)diboron (11.35 g, 44.70 mmol, 1.11 eq.), XPhos-Pd-G2 (0.633 g, 0.80 mmol, 0.02 eq.), XPhos (0.69 g, 1.45 mmol, 0.036 eq.) and compound of formula (III) (8.0 g, 40.27 mmol, 1.0 eq.) were added to a dry three necked flask under nitrogen. 2-Me-THF (120 mL) was added, the reaction mixture was heated to a temperature of 75 °C for 5 hours (until compound of formula (III) disappeared) and the reaction mixture was cooled to a temperature of 60 °C. 1 H-NMR (CDCI3) analysis gave the following results: δ 8.26 (1H, s), 7.20 (1H, dd), 7.15 (2H, m), 7.03 (2H, t), 3.99 (2H, s), 1.80 (6H, s).

[0613] Example 2: Preparation and synthesis of compound of formula (IIIc):

[0614]

[0615] NiCl₂·6H₂O (10.90 g, 45.9 mmol, 2.5 eq.) was added to a solution of compound (IIIb) (5.0 g, 18.36 mmol, 1.0 eq.) in MeOH (60 mL). The reaction flask was transferred to an ice bath and NaBH₄ (1.64 g, 43.5 mmol, 2.37 eq.) was added fractionally over 15 minutes. The reaction mixture was stirred at 0 °C for 15 minutes and then at room temperature for another 3 hours (until the starting material disappeared as determined by TLC). The reaction was then cooled in an ice bath and quenched dropwise by adding 30% ammonia solution (50 mL). The reaction mixture was filtered, the filter cake was washed with MeOH (10 mL x 3), and the filtrate was concentrated. Then, 15 mL of 30% ammonia solution was added to the reaction mixture, and extraction was performed with dichloromethane (50 mL) and (4 x 20 mL). The combined organic extracts were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was then purified by column chromatography (DCM:MeOH = 10:1, 1% Et3N) to obtain 3.68 g (73% by weight) of the desired product as a pale yellow, viscous oil. The product... 1 1H-NMR (CDCl3) analysis yielded the following results: δ 8.22 (1H, s), 7.15 (2H, m), 7.07 (1H, dd), 7.02 (2H, t), 3.94 (2H, s), 3.01 (2H, s), 1.37 (6H, s).

[0616] Example 3: Preparation and synthesis of compounds of formula (VII):

[0617]

[0618] Solid NaHCO3 (11.2 g, 113.0 mmol, 10.0 eq.) was added to a solution of compound (IIIc) (3.68 g, 13.3 mmol, 1.0 eq.) in DMSO (55 mL). The slurry was then heated to 120 °C and held for 48 hours. TLC showed a small amount of unreacted starting compound (IIIc). NaHCO3 (2.24 g, 22.5 mmol, 2.0 eq.) was added, and the reaction mixture was stirred at 120 °C for another 4 hours. Trace amounts of unreacted starting material were detected by TLC. The crude reaction mixture was then slowly poured into 50 mL of ice / water, and the resulting yellow precipitate was filtered through a Buchner funnel. The filter cake was washed with ice water (20 mL), and the solid was dried at 45 °C for 16 hours to obtain 2.61 g (77%) of crude product as a pale yellow solid. 1H-NMR (CDC13) analysis gave the following results: δ 7.78 (1H, s), 7.14 (2H, m), 6.97 (2H, t), 6.56 (1H, s), 3.82 (2H, s), 3.66 (2H, s), 3.37 (2H, s), 1.34 (6H, s).

[0619] Example 3A: Preparation and synthesis of compound of formula (VII):

[0620]

[0621] Lithium bromide (71.32 g, 3.0 eq), palladium acetate (0.614 g, 0.01 eq) and XPhos (3.39 g, 0.026 eq) were added to a solution of compound of formula (V) (50 g, 1 eq) in N-methylpyrrolidine (100 mL) and tetrahydrofuran (150 mL). The reaction mixture was heated to a temperature of 30 °C to 36 °C and 4-fluorobenzylzinc chloride (821 mL, 1.5 eq, 0.5 M in THF) was added. The reaction mixture was heated to a temperature of 30 °C to 36 °C for 12 h. The reaction mixture was cooled to a temperature of 15 °C to 25 °C as soon as the reaction was complete and quenched with 13% aqueous ammonium chloride solution (220 mL). The reaction mixture was filtered and the aqueous phase was extracted with toluene (250 mL). The combined organic layers were concentrated to a volume of about 1.05 L and washed with 13% aqueous ammonium chloride solution (220 mL) at a temperature of 45 °C to 55 °C twice. The organic layer was concentrated to a volume of about 200 mL and cooled to a temperature of 15 °C to 25 °C. Heptane (500 mL) was added and stirred at a temperature of 15 °C to 25 °C for 30 min, filtered and washed with heptane (100 mL). The solid was dried under vacuum to a temperature of 40 °C for 8 h to 10 h to obtain compound of formula (VII) (68.5 g, 81.2% yield, 98.5% area HPLC purity).

[0622] Example 3B: Preparation and synthesis of compound of formula (VIII):

[0623]

[0624] A solution of N-bromosuccinimide (21.4 Kg, 1.01 eq) in dimethylformamide (178 Kg) was added to a solution of the compound of formula (VII) (32.4 Kg, 1 eq) in dimethylformamide (207 L) at a temperature of -18 °C to -12 °C. The reaction mixture was stirred at this temperature for 1 hour and after completion of the reaction water (455 Kg) was added. The resulting solid was filtered and washed with a mixture of dimethylformamide (95 Kg) and water (95 Kg) and again with water (196 Kg). The solid was dried under vacuum at a temperature of 50 °C for about 12 hours to obtain the compound of formula (VIII) (39.2 Kg, 84% yield, 98.6% area HPLC purity).

[0625] Example 4: Preparation and synthesis of the compound of formula (Va):

[0626]

[0627] BOC-anhydride (21.28 ml, 92 mmol) was added portionwise to a rapidly stirred mixture of the compound of formula (V) (6-chloro-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2- b]pyridine) (10 g, 54.7 mmol) and sodium carbonate 8% w / w in water (150 ml, 143 mmol) in THF (100 ml). The reaction mixture was stirred overnight. Triethylamine (TEA) (20 ml, 143 mmol) and BOC-anhydride (10.64 ml, 45.8 mmol) were added and stirred for a further 24 hours. Approximately 40% conversion occurred. The reaction mixture was partitioned with EtOAc (200 ml) and water (200 ml). The organics were separated, dried (MgS04), filtered and the solvent removed to provide a thick oil. Analysis of this oil after 16 h showed complete conversion to the desired compound. The compound was purified by flash chromatography on silica (220 g cartridge, 0-10% TBME / isohexane) to yield the compound of formula (Va) (6-chloro-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-1 -carboxylic acid tert-butyl ester) as a colourless oil (13 g, 44.6 mmol, 81% yield).1H-NMR in CDCI3gave the following results: δ 8.08 (d, J = 2.0 Hz, 1 H), 7.54 (d, J = 48.7 Hz, 1 H), 3.78 (s, 2H), 1.83-1.45 (m, 9H), 1.39 (s, 6H). 1 The1H-NMR was consistent with the product structure (97% purity and approximately 3% w / w isohexane). 1 1H-NMR (500 MHz, Chloroform-d) gave the following results: δ 8.08 (d, J = 2.0 Hz, 1 H), 7.54 (d, J = 48.7 Hz, 1 H), 3.78 (s, 2H), 1.83-1.45 (m, 9H), 1.39 (s, 6H).

[0628] Example 5: Preparation and synthesis of compounds of formula (Vc):

[0629]

[0630] Bis(pinacolato)diboron (BPin)2(5 g, 19.69 mmol), Pd-170 (XPhos Pd(t-Bu)CI (250 mg, 0.371 mmol), XPhos (300 mg, 0.629 mmol) and potassium acetate (5 g, 50.9 mmol) were placed in a three necked flask which had been evacuated by three backfills of nitrogen. A solution of the compound of formula (Va) (6-chloro-3,3-dimethyl-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine- 1 -carboxylic acid tert-butyl ester) (5 g, 17.68 mmol) in 2-MeTHF (50 ml) was added and the mixture was evacuated by three backfills of nitrogen before stirring was continued at a temperature (internal temperature) of 75 °C under nitrogen for 30 min (or until conversion of starting material was achieved by UPLC).

[0631]

[0632] Formula (Vbb) is also depicted herein as

[0633] Potassium carbonate 1.8M (25 ml, 45.0 mmol) was added followed by 1- (chloromethyl)-4-fluorobenzene (2.5 ml, 20.75 mmol) and stirring was continued at 75 °C under nitrogen for 4 hours. The reaction was cooled to ambient temperature and the organics were separated. The aqueous phase was extracted with EtOAc (50 ml). The organics were swelled and dried with MgS04and filtered and pre-absorbed onto silica (10 g) for purification by silica gel chromatography (80 g cartridge, 0-20% EtOAc / isohexane) to yield the compound of formula (Vc) (6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine- 1 -carboxylic acid tert-butyl ester) (5.8 g, 15.46 mmol, 87% yield) as a tan gum. The product was analysed by LCMS (Waters Acquity UPLC, X-Select, Waters X-Select UPLC C18, 1.7 pm, 2.1 x 30 mm, Acidic (0.1% formic acid) 3 min method, 5% - 95% MeCN / water) and the following results were obtained: 2370-69-2A, m / z 357.2 (M+H)+(ES+); 95% purity at 1.77 min (diode array).1H NMR of (Vc) (6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine- 1 -carboxylic acid tert-butyl ester) in CDCI3: 7.36 (d, 2H), 7.20 (s, 1H), 7.06 (d, 2H), 6.82 (s, 1H), 4.62 (s, 2H), 3.62 (s, 2H), 3.00 (s, 2H), 1.68 (s, 3H), 1.63 (s, 3H), 1.45 (s, 9H). 1H-NMR 2370-69-2A was consistent with the structure of the product (95% purity, 4% w / w EtOAc and 1% w / w isohexane). 1 H-NMR (500 MHz, Chloroform-d) yielded the following results: δ 8.01 (s, 1H), 7.91 & 7.21 (2 x s, 1H, rotomers), 7.21-7.13 (m, 2H), 7.00 (s, 2H), 3.92 (s, 2H), 3.75 (s, 2H), 1.53 (d, J = 14.2 Hz, 9H), 1.39 (s, 6H).

[0634] Example 6: Preparation and synthesis of compound of formula (IX) (tert-butyl 5-bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate):

[0635]

[0636] Compound of formula (Vc) (tert-butyl 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H- pyrrolo[3,2-b]pyridine-1-carboxylate) (0.25 g, 0.70 mmol) was dissolved in DMF (12 mL) and cooled to a temperature of 0 °C in a NaCI / ice bath. 1-Bromopyrrolidine-2,5-dione (0.125 g, 0.70 mmol) was added dropwise as a solution in DMF (2 mL) over 5 minutes. The reaction was allowed to warm to room temperature and stirred for 60 hours. The reaction mixture was poured into brine (40 mL) and extracted with TBME (2 x 20 mL). The combined organic layers were directly concentrated onto silica. The crude product was purified by silica gel chromatography (12 g cartridge, 0-20% EtOAc / isohexane) to yield compound of formula (IX) (190 mg, 0.43 mmol, 61.6% yield) as a white solid. 1 H-NMR (500 MHz, DMSO-d6) analysis yielded the following results: δ 7.85 (s, 1H), 7.27 (s, 2H), 7.16 (t, J = 8.7 Hz, 2H), 4.02 (s, 2H), 3.72 (s, 2H), 1.57-1.30 (m, 9H), 1.27 (s, 6H). m / z 435.1 & 437.1 (M+H)+(ES+), 99% purity (254 nm).

[0637] Example 6A: Preparation and synthesis of compound of formula (IX) (tert-butyl 5-bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate):

[0638]

[0639] Di-tert-butyl dicarbonate (68.0 Kg, 2.57 eq) was added to a solution of compound of formula (VIII) (41.6 Kg, 97.6% assay, 99.1% purity, 1 eq) in toluene (143.7 Kg) at a temperature of 15-25 °C. The mixture was cooled to 0-10 °C and stirred at this temperature for 10-20 min. A solution of sodium carbonate (19.2 Kg) in purified water (164.2 Kg) was added to the mixture and the mixture was stirred at a temperature of 15-25 °C for 22 hours until the reaction was complete. N,N-dimethylaminopyridine (0.4 Kg, 0.03 eq) was added to the mixture and the resulting mixture was stirred at a temperature of 15-25 °C for 12 hours. The organic phase was separated and the aqueous phase was extracted with toluene (145 Kg). The combined organic phase was concentrated under vacuum (NMT 50 °C) to about 5 volumes. The toluene was replaced with methanol (4 x 320 Kg) until the residual toluene was NMT 1% in about 5 volumes of methanol solution. The mixture was cooled to a temperature of 15-25 °C and methanol (258 Kg) and water (132 Kg) were added. The mixture was stirred at this temperature for 7 hours, filtered, washed with methanol (64 Kg) and dried under vacuum at a temperature of 30-40 °C to obtain compound of formula (IX) (47.98 Kg, 100% assay, 100% purity) as off-white solid.

[0640] Example 7: Preparation and synthesis of compound of formula (X) (1-tert-butyl-5-phenyl-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1,5-dicarboxylate):

[0641]

[0642] Phenol (33.20 Kg, 3.5 eq), palladium (II) acetate (0.7 Kg, 0.03 eq), rac-1,1’- binaphthalene-2,2’-diphenylphospholane (1.9 Kg, 0.03 eq) and triethylamine (30.0 Kg, 3.0 eq) were added to a solution of the compound of formula (IX) (43.0 Kg, 99.8% assay, 99.9% purity, 1 eq) in acetonitrile (356 Kg) in a pressure reactor. The pressure reactor was sealed and purged with nitrogen, then exchanged with carbon monoxide gas to 0.03 MPa to 0.05 MPa pressure. The reaction mixture was heated to a temperature of 55 °C to 65 °C and stirred at this temperature and pressure (0.03 MPa to 0.05 MPa) for 33 hours until the compound of formula (IX) was NMT 1.0%. The reactor was purged with nitrogen and cooled to a temperature of 15 °C to 30 °C, filtered and washed with acetonitrile (124 Kg). The filtrate was concentrated under vacuum to about 5 volumes at a temperature of not more than 50 °C and replaced with ethanol (3 x 170 Kg) until the residual acetonitrile was NMT 2.0%. The mixture was heated to a temperature of 45 °C to 50 °C and at this temperature water (26 Kg) was added. The mixture was stirred at this temperature for 4 hours and cooled to a temperature of 0 °C to 5 °C, stirred at this temperature for 4 hours and filtered. The filter cake was washed with a mixture of ethanol (62 Kg) and water (7 Kg) and dried under vacuum at a temperature of 40 °C to 45 °C to obtain the crude material (638.5 Kg). The crude solid was dissolved in methyl tert-butyl ether (639 Kg) at a temperature of 15 °C to 25 °C, filtered and rinsed with methyl tert-butyl ether (97 Kg). The filtrate was replaced with ethanol (2 x 170 Kg), distilled to about 5 volumes until the residual methyl tert-butyl ether was NMT 2%. The mixture was heated to a temperature of 70 °C to 80 °C and slowly cooled to 40 °C to 50 °C. At this temperature water (25 Kg) was added and cooled to 0 °C to 5 °C, stirred at this temperature for 4 hours to 6 hours and filtered. The filter cake was washed with a mixture of ethanol (62 Kg) and water (7 Kg) and dried under vacuum at a temperature of 40 °C to 50 °C until the residual ethanol was NMT 0.50% and KF was NMT 1%. The compound of formula (X) (38.8 Kg, 100% assay, 100% purity) was obtained as an off-white solid.

[0643] Example 8: Preparation and synthesis of the compound of formula (XI) (6-(4- fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid phenyl ester):

[0644]

[0645] A solution of hydrochloric acid in isopropanol (75.6 Kg, 5.5 M) was added to a solution of the compound of formula (X) (31.8 Kg, 100% assay, 100% purity, 1 eq) in isopropanol (226 Kg) at a temperature of 50 °C to 55 °C. The reaction mixture was stirred at this temperature for 9 hours until the reaction was complete (NMT 0.5% of compound of formula (X)). The reaction mixture was concentrated to approximately 4 volumes under vacuum at approximately 45 °C and then cooled to a temperature of 15 °C to 25 °C. After the addition of 2-methyltetrahydrofuran (191 Kg) and water (256 Kg), the pH was adjusted to 8 using aqueous sodium hydroxide solution. The aqueous layer was separated and the organic layer was washed with brine (170 Kg). The combined aqueous layers were extracted with 2-methyltetrahydrofuran (233 Kg) and the combined organic layers were concentrated to approximately 4 volumes under vacuum at approximately 45 °C. Fresh 2-methyltetrahydrofuran (3 x 240 Kg) was added and distilled to approximately 4 volumes until the water content was NMT 0.10%, thereby obtaining a 2-methyltetrahydrofuran solution of the compound of formula (XI) which was passed to the next step.

[0646] Example 9: Preparation and synthesis of the compound of formula (XII) (6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2,3-dihydro-lH-pyrrolo[3.2-b]pyridin-5-yl}methanol):

[0647]

[0648] A solution of lithium borohydride (32.2 Kg, 1.05 eq) in THF at a temperature of -10 to 0 °C was added to a solution of the compound of formula (XI) (obtained from Example 5) in 2-methyltetrahydrofuran at a temperature of -10 to 0 °C. The reaction mixture was stirred at this temperature for 9 hours until the reaction was complete (NMT 1.0% of unreacted compound of formula (XI)). The reaction mixture was then added to a solution of potassium phosphate monobasic (38 Kg) in water (340 Kg). The organic phase was washed 3 times with aqueous sodium hydroxide until a pH of 12.5 to 13.0 was obtained. The organic phase was washed with aqueous potassium phosphate monobasic at a pH of 6.4 to 7.0. The organic phase was separated and replaced with toluene (2 x 220 Kg), distilled to about 3 volumes until the residual 2-methyltetrahydrofuran was NMT 2%. The mixture was then heated to a temperature of 70 to 75 °C and gradually cooled to a temperature of 0 to 5 °C over 4 to 5 hours. n-Heptane (55 Kg) was added to the cold mixture and stirred at this temperature for 5 hours and filtered. The filter cake was washed with a mixture of toluene (22 Kg) and n-heptane (17 Kg), dried under vacuum at a temperature of 30 to 40 °C for about 15 hours to obtain the compound of formula (XII) as an off-white solid (15.5 Kg, 81.2% yield, 100% assay, 100% purity).

[0649] Example 10: Preparation and synthesis of the compound of formula (XIII) (2-chloro-1- (6-(4-fluorobenzyl)-5-(hydroxymethyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1- yl)ethenone):

[0650]

[0651] Add 2-chloroacetyl chloride (3.04 Kg, 1.10 eq) to a mixture of compound of formula (XII) (7.0 Kg, 100% assay, 100% purity, 1 eq) in acetonitrile (55 Kg) at a temperature of 5 to 10 °C. Warm the reaction mixture to a temperature of 7 to 13 °C and stir at this temperature for 2 hours until residual compound of formula (XII) is NMT 0.2%. Distill the reaction mixture under vacuum at a temperature of NMT 40 °C to 5 volumes, then add toluene (30.45 Kg) and distill to 5 volumes. Add methanol (66.5 Kg) and cool to a temperature of 0 to 5 °C. At this temperature, add a solution of potassium carbonate (7.56 Kg, 2.24 eq) in water (42.8 Kg) and stir for about 30 minutes. Adjust the pH of the reaction mixture to 3.5 to 4.5 using 3M hydrochloric acid (27 Lit). Add toluene (2 x 30 Kg) and distill to 10 volumes under vacuum at a temperature of NMT 20 °C. Add fresh toluene (60.9 Kg) and separate the organic layer. Wash the aqueous layer with toluene (30 Kg). Distill the combined organic layers to about 10 vol and cool to a temperature of 0 to 5 °C. Add n-heptane (47.6 kg) and continue stirring at this temperature for about 1 hour and filter. Wash the filter cake with a mixture of toluene (6 Kg) and n-heptane (4.76 Kg) to obtain compound of formula (XIII) (8.0 Kg, 90.8% yield, 99.3% assay, 99.76% purity).

[0652] Example 11: Preparation and synthesis of compound of formula (XV) ((2R,5R)-5- (hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester):

[0653]

[0654] Triethylamine (135.2 Kg, 3 eq) and di-tert-butyl dicarbonate (242.6 Kg, 2.5 eq) were added to a solution of compound of formula (XIV) (98.8 Kg, 90.9% assay, 95% purity, 1 eq) in ethanol (287.5 Kg). The mixture was allowed to react at a temperature of 15 to 30 °C for 12 hours until completion of the reaction (residual compound of formula (XIV) NMT 1%). A solution of sodium hydroxide (124.4 Kg, 30 eq) in water (362 Kg) was added and the mixture was heated to a temperature of 40 to 45 °C for 30 min, to a temperature of 50 to 60 °C for 30 min and to a temperature of 70 to 75 °C for 30 min until completion of the reaction. The reaction mixture was cooled to a temperature of 15 to 30 °C and the pH was adjusted to 9.0 to 9.5 using aqueous hydrochloric acid (308 Kg of 181.4 Kg in water). The mixture was filtered and washed with dichloromethane (718 Kg). The organic phase from the filtrate was separated and the aqueous layer was extracted with dichloromethane (3 x 719 Kg). The combined organic layers were washed with brine (901 Kg of 157 Kg sodium chloride in water) and concentrated under vacuum at a temperature of NMT 45 °C to about 4 volumes. The solvent was replaced with methyl-tert-butyl ether (2 x 336 Kg), distilled to about 4 volumes until residual dichloromethane was NMT 15%. The solvent was replaced with n-heptane (3 x 310 Kg) under vacuum at a temperature of NMT 45 °C, distilled to about 6 volumes until residual dichloromethane was NMT 0.5%, residual methyl-tert-butyl ether was NMT 3% and residual ethanol was NMT 0.5%. The mixture was cooled to a temperature of 10 to 20 °C, stirred at this temperature for 2.5 hours and filtered. The filter cake was washed with n-heptane (126 Kg) and dried under a stream of nitrogen until residual n-heptane was NMT 0.5% to obtain compound of formula (XV) (88.4 Kg, 84.8% yield, 97.6% assay, 100% chemical purity and 100% chiral purity) as a white solid.

[0655] Example 12: Preparation of compound of formula (XVI) ((2R,5R)-4-benzyl-5- (hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester):

[0656]

[0657] Benzaldehyde (46.8 Kg, 1.1 eq) was added to a solution of compound of formula (XV) (92.6 Kg, 97.6% assay, 100% purity, 1 eq) in dichloromethane (735.5 Kg) at a temperature of 15 °C to 30 °C. The mixture was cooled to a temperature of 0 °C to 10 °C and sodium triacetoxyborohydride (111.2 Kg, 1.3 Kg) was added. The reaction mixture was stirred at this temperature for 9.5 hours and then warmed to a temperature of 15 °C to 30 °C until the reaction was complete or until the compound of formula (XV) reached NMT 0.1%. The reaction mixture was quenched with sodium bicarbonate solution (960 Kg of 75 Kg in water). The reaction mixture was degassed by nitrogen sparging and extracted with dichloromethane (617 Kg). The organic layer was separated and treated with sodium bisulfite solution (730 Kg of 185 Kg in water) until the benzaldehyde content was NMT 1%. The organic layer was washed with brine (993 Kg of 300 Kg sodium chloride in water) and concentrated to about 6 volumes at NMT 35 °C under reduced pressure until the KF was NMT 0.2%. The resulting compound of formula (XVI) in dichloromethane (259 Kg, 90% yield, 43.7% assay, 96% purity) was used in Example 14 to make the compound of formula (XVII).

[0658] Example 13: Preparation and synthesis of the oxalate salt of the compound of formula (XVIa):

[0659]

[0660] Alternatively, the compound of formula (XV) can be converted to the oxalate salt compound of formula (XVIa) for use in the next step in Example 14. To produce the compound of formula (XVIa), methyl tert-butyl ether (5 vol) was slowly added to a solution of the compound of formula (XV) in dichloromethane (20 Kg, approximately 27.6% assay) and concentrated to 3 vol at a temperature of 30 °C. This process was repeated 3 more times to obtain a thin slurry with a white solid suspended. The slurry was filtered and washed with methyl tert-butyl ether (3 x 5 mL). The combined organic filtrate was washed with saturated sodium bicarbonate (2 x 10 mL), brine (10 mL), and dried over anhydrous sodium sulfate. The suspension was filtered and rinsed with methyl tert-butyl ether (3 x 3 mL). The resulting solution was stirred at a temperature of 15 °C to 30 °C and a solution of oxalic acid (1.43 g, 15.9 mmol) in methyl tert-butyl ether (27.7 mL, 6 vol) was slowly added over 15 minutes. The resulting white slurry was stirred for an additional 15 minutes at room temperature, filtered through a Buchner funnel, and washed with methyl tert-butyl ether (2 x 2 vol). The filter cake was dried under vacuum for 30 minutes to obtain the oxalate salt compound of formula (XVIa) as a white solid (4.64 g, 11.3 mmol, 79% yield). The solid was slurried with methyl tert-butyl ether (10 vol) and stirred for 15 minutes to produce a white slurry. The resulting white slurry was filtered through a Buchner funnel and washed with methyl tert-butyl ether (2 x 2 vol). The white filter cake was dried under vacuum for 30 minutes to produce the oxalate salt compound of formula (XVIa) as a white solid (4.43 g, 96% recovery, 100% purity). The oxalate salt compound of formula (XVIa) can also be used in the next step described in Example 14 to produce the compound of formula (XVII).

[0661] Example 14: Preparation and synthesis of the compound of formula (XVII) ((2R,5R)-4-benzyl-5-(chloromethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester):

[0662]

[0663] A solution of the compound of formula (XVI) (or its compound of formula (XVIa) as the oxalate salt) is charged with additional dichloromethane (761 Kg) and triethylamine (110 Kg, 3 eq) and cooled to a temperature of 0 °C to 10 °C. Methanesulfonyl chloride (62.8 Kg, 1.5 eq) is added and the reaction mixture is stirred at this temperature for 9.5 hours until conversion of the compound of formula (XVI) reaches NMT 10%. The mixture is warmed to a temperature of 15 °C to 30 °C and stirred at this temperature for an additional 5.5 hours until the reaction is complete or until the compound of formula (XVI) reaches NMT 1%. The reaction is quenched with a solution of ammonium chloride (200 Kg) in water (588 Kg). The organic layer is separated and the aqueous layer is extracted with dichloromethane (1013 Kg). The combined organic layers are washed with brine (931 Kg of sodium chloride in 312 Kg of water) and filtered using dichloromethane (1850 Kg) through a pad of silica gel (93 Kg). The filtrate is replaced with n-heptane (2 x 450 Kg) until the residual dichloromethane reaches NMT 0.2%. The mixture is cooled to a temperature of 0 °C to 5 °C and stirred at this temperature for 15 hours. The crystalline solid is filtered and washed with cold n-heptane (157 Kg) and dried under reduced pressure at a temperature of NMT 30 °C until the residual n-heptane is NMT 0.5% and the residual dichloromethane is NMT 0.5% to obtain the compound of formula (XVII) (99.0 Kg, 80.2% yield, 96.72% assay, 97.4% purity) as a light yellow solid.

[0664] Example 15: Preparation and synthesis of the compound of formula (XIX) ((2R,5S)-4-benzyl-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1 - carboxylic acid tert-butyl ester):

[0665]

[0666] Potassium iodide (64.4 Kg, 1.9 eq), potassium carbonate (86 Kg, 3.1 eq) and (R)-3- methylmorpholine hydrochloride (31 Kg, 1.07 eq of compound of formula (XVIII)) were added to a mixture of compound of formula (XVII) (70.8 Kg, 96.7% assay, 97.4% purity, 1 eq) in acetonitrile (536 Kg) at a temperature of 15 °C to 30 °C. The reaction mixture was initially heated to a temperature of 40 °C to 45 °C for about 30 minutes and then heated to a temperature of 57 °C to 62 °C. The reaction mixture was heated at this temperature for about 7.5 hours until the reaction was complete or until the compound of formula (XVII) reached NMT 0.5% and filtered to remove inorganic residues. The filtrate was replaced with n-heptane (2 x 274 Kg) by distillation under reduced pressure at a temperature of NMT 45 °C to about 6 volumes until the residual acetonitrile reached NMT 0.2%. The mixture was cooled to a temperature of -5 °C to 5 °C and stirred at this temperature for about 15 hours and filtered. The crude solid was dissolved in n-heptane (608 Kg) at a temperature of 15 °C to 30 °C and filtered through a pad of silica gel (40 Kg) using n-heptane (360 Kg) as a flushing liquid. The filtrate was concentrated to about 5 volumes, cooled to a temperature of -5 °C to 5 °C and maintained at this temperature for about 7 hours. The crystallized solid was filtered, washed with cold n-heptane (94 Kg) and dried under reduced pressure at a temperature of NMT 40 °C to obtain the compound of formula (XIX) (49.2 Kg, 60.6% yield, 100% assay, 99.9% purity) as a white solid.

[0667] Example 16: Preparation and synthesis of compound of formula (XX) ((2R,5S)-tert-butyl-2-methyl-5-{[(R)-3-methylmorpholino]methyl}piperazine-1-carboxylate oxalate salt):

[0668]

[0669] Palladium on carbon (0.65 Kg, 10% loading, 50% moisture) was added to a mixture of compound of formula (XIX) (13 Kg, 1 eq) in absolute ethanol (205 Kg). The reaction mixture was purged with nitrogen followed by purging with hydrogen. The reaction mixture was pressurized to 2 bar and heated to a temperature of 65-75 °C for 3 hours. The reaction mixture was cooled to a temperature of 15-25 °C, degassed with nitrogen, filtered and washed with ethanol (21 Kg). The filtrate was concentrated to about 7.8 volumes at a temperature of NMT 50 °C under reduced pressure and cooled to a temperature of 10-15 °C. Oxalic acid (2.9 Kg, 1 eq) was added and the reaction mixture was warmed to a temperature of 15-25 °C and stirred for 1 hour. Acetonitrile (159 Kg) was charged and stirred at this temperature for 40 minutes after which the temperature was cooled to 0-5 °C. The mixture was stirred at a temperature of 0-5 °C for 1 hour, filtered and washed with cold acetonitrile (2 x 40 Kg) and dried at a temperature of NMT 50 °C under reduced pressure to obtain compound of formula (XX) as oxalate salt (10.6 Kg, 81.5% yield, 99.88% purity) as a white solid.

[0670] Example 17: Preparation and synthesis of compound of formula (XXI) ((2R,5S)-tert- butyl-4-(2-(6-(4-fluorobenzyl)-5-(hydroxymethyl)-3,3-dimethyl-2,3-dihydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1- carboxylate):

[0671]

[0672] A mixture of compound of formula (XIII) (7.9 Kg, 1 eq), compound of formula (XX) (9.6 Kg, 1.1 eq), potassium iodide (7.1 Kg, 1.97 eq) and potassium carbonate (18.0 Kg, 5.94 eq) in acetonitrile (75 Kg) was stirred at a temperature of 15-25 °C for 3 hours until completion of the reaction or until compound of formula (XIII) reached NMT 0.5%. The reaction mixture was distilled to 4 volumes at a temperature of NMT 40 °C under reduced pressure and cooled to a temperature of 15-25 °C. Ethyl acetate (43 Kg) and water (63 Kg) were charged and stirred for 15 minutes. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (21 Kg). The combined organic layer was washed with a solution of potassium carbonate (3.2 Kg, 1.05 eq) in water (63 Kg) followed by a solution of potassium dihydrogen phosphate (3.6 Kg) and sodium chloride (3.6 Kg) in water (30 Kg) three times. The organic layer was washed with Quadrasil The solution of compound of formula (XXI) (114.6 Kg, 10.5% assay, 98.7% purity, 1 eq) obtained from previous step in Example 17 in methanol was cooled to a temperature of 0 °C to 10 °C and 6N hydrochloric acid in methanol (22 Kg, 7.7 eq) was added. The reaction mixture was warmed to a temperature of 15 °C to 25 °C and stirred at this temperature for 12 hours and then at a temperature of 30 °C to 40 °C for 2 hours until the reaction was complete or until compound of formula (XXI) reached NMT 0.5%. The reaction mixture was distilled under reduced pressure at a temperature of NMT 40 °C to about 5 volumes. The solvent was replaced with water (2 x 48 Kg) and then ethyl acetate (43 Kg) was added. The organic phase was separated and the aqueous phase containing the product was washed with ethyl acetate (43 Kg). The pH of the aqueous phase was adjusted to 11.5 to 12.0 with aqueous sodium hydroxide (37.6 Kg) and then extracted with ethyl acetate (3 x 54 Kg). The combined organic layers were washed twice with brine (7 Kg in 65 Kg of water). The organic layer was separated and azeotropically distilled under reduced pressure at a temperature of NMT 40 °C to 9 volumes using ethyl acetate (3 x 108 Kg) until the water content was NMT 0.7% to obtain compound of formula (XXII) (100.7 Kg, 88.6% yield, 8.9% assay, 98.2% purity) as a solution in ethyl acetate which was used as such in the next step in Example 19 to prepare compound of formula (XXIII).

[0673] Example 18: Preparation and synthesis of compound of formula (XXII) (1-(6-(4- fluorobenzyl)-5-(hydroxymethyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2- ((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethenone):

[0674]

[0675] The solution of compound of formula (XXI) (114.6 Kg, 10.5% assay, 98.7% purity, 1 eq) obtained from previous step in Example 17 in methanol was cooled to a temperature of 0 °C to 10 °C and 6N hydrochloric acid in methanol (22 Kg, 7.7 eq) was added. The reaction mixture was warmed to a temperature of 15 °C to 25 °C and stirred at this temperature for 12 hours and then at a temperature of 30 °C to 40 °C for 2 hours until the reaction was complete or until compound of formula (XXI) reached NMT 0.5%. The reaction mixture was distilled under reduced pressure at a temperature of NMT 40 °C to about 5 volumes. The solvent was replaced with water (2 x 48 Kg) and then ethyl acetate (43 Kg) was added. The organic phase was separated and the aqueous phase containing the product was washed with ethyl acetate (43 Kg). The pH of the aqueous phase was adjusted to 11.5 to 12.0 with aqueous sodium hydroxide (37.6 Kg) and then extracted with ethyl acetate (3 x 54 Kg). The combined organic layers were washed twice with brine (7 Kg in 65 Kg of water). The organic layer was separated and azeotropically distilled under reduced pressure at a temperature of NMT 40 °C to 9 volumes using ethyl acetate (3 x 108 Kg) until the water content was NMT 0.7% to obtain compound of formula (XXII) (100.7 Kg, 88.6% yield, 8.9% assay, 98.2% purity) as a solution in ethyl acetate which was used as such in the next step in Example 19 to prepare compound of formula (XXIII).

[0676] Example 19: Preparation and synthesis of compound of formula (XXIII) (1-{6-[4- fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H-2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2- [(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl)ethen-1-one, L-(+)-lactate salt):

[0677]

[0678] A solution of compound of formula (XXII) (from previous step in example 18) in ethyl acetate (98.7 Kg, 8.9% assay, 98.2% purity) was distilled under reduced pressure at a temperature NMT 40°C to 7.5 volumes until the water content was NMT 0.7%. A solution of anhydrous L-(+)-lactic acid (1.62 Kg, 1.10 eq) in ethyl acetate (20 Kg) with a water content NMT 0.7% was clarified and rinsed with ethyl acetate (4.0 Kg). The solution of compound of formula (XXII) in ethyl acetate was heated to a temperature of 40°C to 50°C and at this temperature 1 / 3 of the solution of anhydrous lactic acid in ethyl acetate was added. The mixture was seeded with a seed compound of formula (XXIII) (44 g) at this temperature and the remaining 2 / 3 of the solution of lactic acid in ethyl acetate was slowly added at a temperature of 40°C to 50°C over 2 hours. At this temperature n-heptane (66 Kg) was added and stirred for approximately 5.5 hours and then cooled to a temperature of 5°C to 15°C at a cooling rate of 1 °C per 5 minutes. The resulting slurry was stirred at this temperature for at least 10 hours, filtered and washed with a mixture of n-heptane (12 Kg) and ethyl acetate (16 Kg). The filter cake was dried under reduced pressure at a temperature NMT 45°C until the residual ethyl acetate was NMT 4500 ppm and the residual n-heptane was NMT 4500 ppm to obtain the compound of formula (XXIII) as a lactic acid salt in the form of a crystalline white solid (10.6 Kg, 100% yield, 99.58% purity; palladium content <1 ppm, form C).

[0679] Example 20: Experimental data for the crystallization of compound of formula (XXIII)

[0680] A batch of crude lactate salt of the compound of formula (XXIII) was prepared by reacting a solution of the compound of formula (XXIII) (37 g) in ethyl acetate (255 mL) with anhydrous L-(+)-lactic acid (1.1 eq). The resulting solution was evaporated to dryness to obtain crude lactate salt of the compound of formula (XXIII) (41.7 g, 96.5% yield, 98.81% area HPLC purity). This crude lactate salt of the compound of formula (XXIII) was used in the following crystallization studies.

[0681] Crystallization Experiment 1 : from methyl isobutyl ketone (MIBK) and n-heptane:

[0682] A suspension of the crude lactate salt of the compound of formula (XXIII) (4.0 g) in methyl isobutyl ketone (MIBK) (60 mL) was heated to a temperature of 80 °C to dissolve it. The solution was cooled to a temperature of 60 °C, seeded with the compound of formula (XXIII) and cooled to a temperature of 20 °C over 12 hours. n-Heptane (320 mL) was added over 1 hour. The resulting suspension was filtered and dried under vacuum to obtain the crystalline lactate salt of the compound of formula (XXIII) (68% yield, 99.16% area HPLC purity, XRPD: Form C).

[0683] Crystallization Experiment 2: from isopropanol and n-heptane:

[0684] A suspension of the crude lactate salt of the compound of formula (XXIII) (4.0 g) in isopropanol (12 mL) was heated to a temperature of 30 °C to dissolve it. n-Heptane (12 mL) was added over 2 hours. The resulting suspension was cooled to a temperature of 20 °C over 6 hours, filtered and dried under vacuum to obtain the crystalline lactate salt of the compound of formula (XXIII) (67% yield, 99.18% area HPLC purity, XRPD: Form C).

[0685] Crystallization Experiment 3: from methyl ethyl ketone (MEK) and n-heptane:

[0686] A suspension of the crude lactate salt of the compound of formula (XXIII) (4.0 g) in methyl ethyl ketone (MEK) (18 mL) was heated to a temperature of 60 °C to dissolve it. The solution was cooled to a temperature of 45 °C, seeded with the lactate salt of the compound of formula (XXIII) and cooled to a temperature of 20 °C over 3 hours. n-Heptane (12 mL) was added over 6 hours. The resulting suspension was filtered and dried under vacuum to obtain the crystalline lactate salt of the compound of formula (XXIII) (86% yield, 99.13% area HPLC purity, XRPD: Form C).

[0687] Crystallization Experiment 4: from tetrahydrofuran (THF) and n-heptane:

[0688] A suspension of crude lactate compound of formula (XXIII) (4.0 g) in tetrahydrofuran (THF) (9 mL) was heated to a temperature of 50 °C to dissolve it. The solution was cooled to a temperature of 35 °C and n-heptane (2 mL) was added, seeded with lactate compound of formula (XXIII) and cooled to a temperature of 20 °C over 6 h. n-Heptane (8 mL) was added over 6 h. The resulting suspension was filtered under vacuum and dried to obtain crystalline lactate compound of formula (XXIII) (81% yield, 99.23% area HPLC purity, XRPD: Form C).

[0689] Crystallization experiment 5: crystallization from acetonitrile and methyl-tert-butyl ether (MTBE):

[0690] A suspension of crude lactate compound of formula (XXIII) (4.0 g) in acetonitrile (10 mL) was heated to a temperature of 57 °C to dissolve it. The solution was cooled to a temperature of 50 °C, seeded with lactate compound of formula (XXIII). Methyl-tert-butyl ether (20 mL) was added and the solution was cooled to a temperature of 20 °C over 6 h. The resulting suspension was filtered under vacuum and dried to obtain crystalline lactate compound of formula (XXIII) (69% yield, 99.62% area HPLC purity, XRPD: Form C).

[0691] Crystallization experiment 6: preparation of lactate compound of formula (XXIII) from methyl acetate and n-heptane:

[0692] A solution of free base compound of formula (XXIII) (17.47 g, 28.62% assay; 5 g of free base) in ethyl acetate was replaced (3 times) with methyl acetate (50 mL). A solution of L-(+)-lactic acid (0.92 g) in methyl acetate (72 mL) was added and the reaction mixture was heated to a temperature of 50 °C. The solvent was replaced (3 times) with methyl acetate (50 mL). The solution was adjusted to a temperature of 40 °C over 50 min and seeded with lactate compound of formula (XXIII) (25 mg). The suspension was concentrated to 8 vol, n-heptane (40 mL) was added over 6 h and the suspension was cooled to a temperature of 20 °C over 6 h. The solid was filtered and dried at a temperature of 55 °C for 7 h to obtain crystalline lactate compound of formula (XXIII) (5.11 g, 88% yield, 99.67% area HPLC purity; Form C).

[0693] Crystallization experiment 7: preparation of lactate compound of formula (XXIII) from ethyl acetate and n-heptane:

[0694] A solution of the free base compound of formula (XXIII) (17.47 g, 28.62% assay; 5 g of free base) in ethyl acetate (50 mL) was replaced (3 times) with ethyl acetate (50 mL) to obtain <0.5% KF. A solution of L-(+)-lactic acid (0.92 g) in ethyl acetate (53 mL) was added and the reaction mixture was heated to a temperature of 78 °C. The solution was adjusted to a temperature of 65 °C over 50 min and seeded with the lactic acid salt compound of formula (XXIII) (25 mg). The solution was adjusted to a temperature of 40 °C over 90 min, n-heptane (73 mL) was added over 6 hours and the solution was cooled to a temperature of 20 °C over 6 hours. The solids were filtered and dried at a temperature of 55 °C for 7 hours to obtain the crystalline lactic acid salt compound of formula (XXIII) (5.4 g, 93% yield, 99.50% area HPLC purity; Form C).

[0695] Figure 5 X-ray powder diffraction results for Form C of the crystalline end-product compound of formula (XXIII) described in crystallization experiment 7 are provided.

[0696] Crystallization experiment 8: crystallization of crude lactic acid from ethyl acetate and n-heptane:

[0697] A suspension of crude lactic acid (11 Kg; 99.76% area HPLC purity) in ethyl acetate (158 Kg) was heated to reflux (at about 78 °C). The resulting solution was cooled to 65 °C and filtered to remove any insoluble material and finally rinsed with ethyl acetate (5 Kg). The resulting solution was heated to reflux (at about 78 °C) and cooled to 46-50 °C at a rate of 0.5 °C / min. After seeding with the lactic acid salt compound of formula (XXIII) (55 g) at 48 °C, the mixture was kept at this temperature for about 30 min. The slurry was then cooled to 20 °C over about 140 min and n-heptane (62 Kg) was added over 100 min. The slurry was then cooled to 10 °C over about 50 min and the mixture was stirred at this temperature for about 5 hours. The solids were filtered, washed with a mixture of ethyl acetate (20 Kg) and n-heptane (15 Kg) and dried under vacuum at a temperature of 40-50 °C for about 4 hours to obtain the crystalline lactic acid salt compound of formula (XXIII) (9.9 Kg, 90% yield; 99.91% area HPLC purity, Form C).

[0698] Based on experimental data, there is a correlation between the palladium content in the final end-product of formula (XXIII) and the oxidative degradation of aldehyde impurities in the drug product. This correlation was observed under storage conditions of 25 °C and 60% relative humidity (RH). The degradation was manifested by the appearance of the aldehyde impurity peak of formula (XXV) at a relative retention time (RRT) of 1.3.

[0699]

[0700] It was found that this impurity peak was not more than 0.2% a / a when stored at 2-8°C, but higher levels were observed at elevated temperatures. The experimental results for the drug product lots and corresponding formulations outlined in Tables 1-3 and Figures 6-7 and Tables 1, 4 and 5.

[0701] The lots of the compound of formula (XXIII) shown in Table 1 were used to obtain the experimental results.

[0702] Table 1: Manufactured API drug product lots

[0703] Sublot RRT 1.3 peak area Pd concentration 1 0.13％ 6.5 ppm 2 0.03％ 0.73 ppm 3 <0.1％ 1.9 ppm 4 0.05％ 49 ppm 5 0.05％ 50 ppm 6 <0.1％ <1 ppm

[0704] Table 2: Manufactured PIB drug product lots

[0705] Lot Sublot used Strength 1 1 200 mg 2 2 400 mg

[0706] Table 3: Manufactured capsule drug product lots

[0707] Lot Sublot used Strength 1 4 30 mg 2 4 180 mg 3 2&3 30 mg 4 2&3 180 mg

[0708] Table 4 and Figure 6 Stability data represented by the area percentage of RRT 1.3 and the effect of palladium content on aldehyde impurities under storage conditions of 25°C and 60% RH are provided.

[0709] Table 4: Stability data of area % of RRT 1.3 at 25°C / 60% RH

[0710]

[0711] TBD = To be determined

[0712] Table 5 and Figure 7 The effect of temperature on stability and aldehyde impurity levels represented by the area percentage of RRT 1.3 is provided in

[0713] Table 5: Stability data of area % of RRT 1.3 at 5°C and 25°C / 60% RH

[0714]

[0715] In Figures 6-7And the experimental results depicted in Table 1, Table 4 and Table 5 confirm that there is a correlation between the palladium content in the drug product and the oxidative degradation observed at 25°C / 60%RH, as seen by the percent of peak area that appears at RRT 1.3. It was found that these impurity peak levels were no more than 0.2% a / a upon storage at 2°C-8°C, but higher levels were observed at elevated temperatures. These results indicate that reduction of palladium and maximization of purity in the final product compound of Formula (XXIII) results in a more stable active pharmaceutical ingredient and drug formulation.

[0716] Disclosed herein are novel intermediate compounds of Formula (la), (Va), (VII), (IX), (X) and (XI), and the novel intermediate compounds can be used in the synthesis of the final product compound of Formula (XXIII) and other compounds of Formula (XXIIIa). The intermediates of Formula (la), (Va), (VII), (IX), (X) and (XI) lead to higher efficiency, predictability, isolation, purity and stability of the final product of Formula (XXIII) and during the synthesis of the final product compound. Embodiments and examples of the present application address the problems of known methods for preparing the compound of Formula (XXIII) and other compounds of Formula (XXIIIa).

[0717] Disclosed herein are novel intermediate compounds of Formula (IX), (X), (XI), (XVI), (XVIa) and (XX), and the novel intermediate compounds can be used in the synthesis of the final product compound of Formula (XXIII) and other compounds of Formula (XXIIIa). The intermediate compounds of Formula (IX), (X), (XI), (XVI), (XVIa) and (XX) lead to higher efficiency, predictability, isolation, purity and stability of the final product of Formula (XXIII) and during the synthesis of the final product compound. Embodiments and examples of the present application address the problems of known methods for preparing the compound of Formula (XXIII) and other compounds of Formula (XXIIIa).

[0718] The compound of Formula (XXIII) synthesized by the steps and intermediates disclosed herein can form a complex, prodrug or salt form disclosed in U.S. Patent No. 9.783,538.

[0719] The compound of Formula (XXIII) synthesized by the steps and intermediates disclosed herein can be used to treat the diseases and conditions disclosed in U.S. Patent No. 9.783,538.

[0720] The compound of Formula (XXIII) synthesized by the steps and intermediates disclosed herein can be administered according to the drugs, drug formulations, pharmaceutical compositions, dosage forms, excipients, therapeutic agents and dosing regimens disclosed in U.S. Patent No. 9.783,538.

[0721] Compounds of Formula (XXIII) synthesized by the steps and intermediates disclosed herein can be used in medicaments for treating diseases or conditions including IAP-mediated cancers. Treatable cancers include, but are not limited to, acute myeloid leukemia (AML), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), MALT lymphoma, head and neck cancer, and cervical cancer.

[0722] The exemplary compounds, intermediates, and synthetic methods disclosed produce key intermediate compounds of Formula (IX) and lead to higher purity and stability of the compounds of Formula (XXIII) as potent IAP antagonists. The exemplary synthetic pathways also use new chemical entities (e.g., compounds of Formula (la)) to produce compounds of Formula (IX) and (XXIII).

[0723] The exemplary compounds, intermediates, and synthetic methods disclosed produce key intermediate compounds of Formula (IX), (X), (XI), (XVI), (XVIa), and (XX) and lead to higher purity and stability of the compounds of Formula (XXIII) as potent IAP antagonists. The exemplary synthetic pathways also utilize new chemical entities (compounds of Formula (IX), (X), (XI), (XVIa), and (XX)) to produce compounds of Formula (XXIII).

Claims

1. A method of preparing a compound of Formula (XXIII) comprising (i-a) removing a tert-butyloxycarbonyl protecting group from a compound of Formula (X) or a salt thereof, (i) reducing a compound of Formula (XI) under conditions sufficient to provide a compound of Formula (XII), (ii) contacting the compound of Formula (XII) with 2-chloroacetyl chloride to provide a compound of Formula (XIII) (iii) contacting a compound of Formula (XIII) or a salt thereof with a compound of Formula (XX) under conditions sufficient to provide a compound of Formula (XXI) or a salt thereof, (iv) deprotecting the compound of formula (XXI) or salt thereof to provide a compound of formula (XXII) or salt thereof, and (v) contacting the compound of Formula (XXII) with lactic acid to provide the compound of Formula (XXIII).

2. The method of claim 1, wherein the compound of Formula (XI) is prepared by a method comprising: (i) reacting a compound of Formula (V) with a compound of Formula (VI) in the presence of one or more palladium catalysts and ligands to provide a compound of Formula (VII) (ii) brominating the compound of Formula (VII) to obtain a compound of Formula (VIII) (iii) protecting the compound of Formula (VIII) to provide a compound of Formula (IX) (iv) contacting the compound of Formula (IX) with carbon monoxide under conditions sufficient to provide the compound of Formula (X) or a salt thereof and (v) removing a tert-butyloxycarbonyl (Boc) protecting group from a compound of Formula (X) or a salt thereof to provide a compound of Formula (XI) 3. The method of claim 2, wherein the one or more palladium catalysts in step (i) are selected from the group consisting of XPhos-Pd-G2 catalyst, Pd(OAc)2, and Pd2(dba)3.

4. The method of claim 2, wherein the ligand in step (i) is selected from the group consisting of PPh3, Xantphos, DPPE, DPPP, DPPB, DPPF, rac-BINAP, RuPhos, XPhos, and tBuXphos.

5. The method of claim 2, wherein the conditions in step (iv) comprise reacting the compound of Formula (IX) with (i) phenyl formate or phenol and (ii) carbon monoxide in the presence of a palladium catalyst to produce the compound of Formula (X).

6. The method of claim 5, wherein the reaction of the compound of Formula (IX) occurs in solution in the presence of rac-1,1’-binaphthalene-2,2’-diphenylphospholene.

7. The method of claim 5, wherein the palladium catalyst in step (iv) is selected from the group consisting of XPhos-Pd-G2 catalyst, Pd(OAc)2, and Pd2(dba)3.

8. The method of claim 5, wherein the reaction of the compound of formula (IX) occurs in the presence of a ligand selected from PPh3, Xantphos, DPPE, DPPP, DPPB, DPPF, rac-BINAP, RuPhos, tBuXphos, and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos).

9. The method of claim 1, wherein the compound of formula (XX) is prepared by the method: The method comprises (i) debenzylating a compound of formula (XIX) and (ii) contacting the debenzylated product with oxalic acid in a solvent to provide the compound of formula (XX).

10. The method of claim 9, wherein the debenzylating in step (i) is performed in the presence of palladium on carbon and hydrogen gas.

11. A method of making a compound of formula (XXIII) comprising (i) contacting a compound of formula (IX) or a salt thereof with carbon monoxide under conditions sufficient to provide the compound of formula (X) or a salt thereof (ii) removing the tert-butyloxycarbonyl protecting group from the compound of formula (X) or a salt thereof to provide a compound of formula (XI) or a salt thereof, (iii) reducing the compound of formula (XI) or a salt thereof to provide a compound of formula (XII) or a salt thereof, (iv) contacting the compound of formula (XII) or a salt thereof with chloroacetyl chloride to provide the compound of formula (XIII) or a salt thereof, (v) contacting the compound of formula (XIII) or a salt thereof with a compound of formula (XX) under conditions sufficient to provide a compound of formula (XXI) or a salt thereof, and (vi) deprotecting the compound of formula (XXI) or a salt thereof to provide a compound of formula (XXII) or a salt thereof, and (vii) contacting the compound of formula (XXII) with lactic acid to provide the compound of formula (XXIII).

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