IAP antagonist compounds and their intermediates, and methods for synthesizing them

Abstract

Compounds of formula (XXIII) and methods for their preparation are provided (XXIII). TIFF2023523854000238.tif41170

Description

Technical Field

[0001] [Cross - Reference to Related Applications] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 019,865, filed May 4, 2020, and U.S. Provisional Patent Application No. 63 / 019,874, filed May 4, 2020, under 35 U.S.C. § 119(e), the entire contents of which are hereby incorporated by reference.

[0002] This application relates to improved IAP antagonist compounds and their intermediates, and methods for synthesizing the same.

Background Art

[0003] Apoptosis, or programmed cell death, is an essential component of human physiological functions and normal immune responses. Insufficient or excessive apoptosis can cause human diseases, including neurodegenerative diseases, autoimmune diseases, and many types of cancer. Apoptosis inhibitors (IAPs) are expressed in several cancers such as lymphoma. Eight different human IAPs, namely XIAP, hILP - 2, c - IAP1, c - IAP2, ML - IAP, NAIP, Survivin, and Apollon, have been characterized (Non - Patent Document 1). The common structural features, mechanisms, and expression of IAPs in cancer are described in U.S. Patent No. 9,783,538, which is hereby incorporated by reference in its entirety.

[0004] Disclosed herein are improved IAP antagonist compounds and improved intermediates, and methods for synthesizing IAP antagonist compounds.

Prior Art Documents

Non - Patent Documents

[0005]

Non - Patent Document 1

Summary of the Invention

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

Chemical formula

[0007] This application provides compounds of formula (Ia), formula (Va), formula (VII), formula (IX), formula (XXIII) and formula (XXIIIa), and methods for synthesizing the compounds of formula (Ia), formula (Va), formula (VII), formula (IX), formula (XXIII) and formula (XXIIIa). The compound of formula (IX) is an intermediate in the synthesis of the compounds of formula (XXIII) and (XXIIIa). This application provides compounds of formula (I), formula (XVI), formula (XVIa) and formula (XX), and formula (XXIIIa), and methods for synthesizing the compounds of formula (I), formula (XVI), formula (XVIa) and formula (XX). The compounds of formula (XXIII) and formula (XXIIIa) are antagonists of proteins of the IAP family, particularly XIAP, and / or cIAP (such as cIAP1 and / or cIAP2, etc.), and are useful for the treatment of conditions mediated by IAP.

[0008] In one aspect, as described hereinafter in the section of the mode for carrying out the invention, there is provided a method for preparing compound (XXIII) which comprises contacting compound (XX) with compound (XIII) to obtain compound (XXI) and then converting compound (XXI) to compound (XXIII).

[0009] In another aspect, as described hereinafter in the section of the mode for carrying out the invention, there is provided a method for preparing compound (XXIII) which comprises converting compound (IX) to compound (X), then converting compound (X) to compound (XIII), contacting compound (XX) with compound (XIII) to obtain compound (XXI), and then converting compound (XXI) to (XXIII).

[0010] In a further aspect, there is provided a method for preparing compound (IX) as described hereinafter in the section of the mode for carrying out the invention.

[0011] In an additional aspect, there are provided compounds of formula (Ia), formula (I), formula (XVIa), formula (IX), formula (X), formula (XI), formula (XX), formula (IIIa) and formula (Vb) as described herein.

[0012] Compounds of formula (Ia), formula (Va), formula (VII) and formula (IX) are useful for synthesizing a compound of formula (XXIIIa), or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof:

Chemical formula

[0013] In an exemplary embodiment, there is provided a method for synthesizing a compound of formula (XXIIIa), a tautomer, stereochemical isomer, pharmaceutically acceptable salt or solvate thereof, and a method for synthesizing a compound of formula (XXIIIa), a tautomer, stereochemical isomer, pharmaceutically acceptable salt or solvate thereof using the compounds of formula (I), formula (XVI), formula (XVIa) and formula (XX). [Chemical formula] (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, which is incorporated herein by reference in its entirety).

[0014] The compounds of formula (XXIIIa) produced by the embodiments and synthetic methods disclosed herein are for use in the prevention or treatment of diseases or conditions and in formulations and pharmaceutical compositions containing the compounds of formula (XXIIIa) as described in U.S. Patent No. 9,783,538, which is incorporated herein by reference in its entirety).

[0015] The above and other objects, features and advantages of the present disclosure will become more readily apparent from the following detailed description of the exemplary embodiments disclosed herein.

[0016] Embodiments of the present application will be described by way of example only with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0017]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

[0018] The following examples and embodiments disclosed and described in the present application are exemplary. Those skilled in the art will understand that various modifications to the embodiments may exist, including variations regarding the synthetic methods, processes, reactants, reagents, parameters, and conditions described herein, without departing from the scope or spirit of the present application or the disclosed exemplary embodiments. The present application relates to improved methods, reactants, and reagents for synthesizing the compounds of formula (Ia), formula (Va), formula (VII), formula (IX), formula (XXIII), and formula (XXIIIa).

[0019] The present application provides compounds of formula (I), formula (XVI), formula (XVIa), and formula (XX), and methods for synthesizing the compounds of formula (I), formula (XVI), formula (XVIa), and formula (XX). The compounds of formula (I), formula (XVI), formula (XVIa), and formula (XX) are useful for synthesizing the compound of formula (XXIIIa). The compound of formula (XXIIIa) is an antagonist of IAP family proteins, particularly XIAP, and / or cIAP (such as cIAP1 and / or cIAP2, etc.), and is useful for the treatment of IAP-mediated conditions.

[0020] **Definitions** As used herein, the following terms are generally intended to have the meanings shown below, unless the context in which they are used indicates otherwise.

[0021] The terms "comprise," "comprises," "comprising," and the like, as well as variations thereof, are to be construed in an open and inclusive sense, i.e., "including but not limited to." Further, the singular forms "a," "an," and "the" that do not clearly indicate a plurality in context include plural referents unless the context clearly dictates otherwise.

[0022] As used herein, a reference to "about" a value or parameter includes (and describes) embodiments directed to that value or parameter itself. In certain embodiments, the term "about" includes the recited amount ±10%. In other embodiments, the term "about" includes the recited amount ±5%. In certain other embodiments, the term "about" includes the recited amount ±2.5%. In certain other embodiments, the term "about" includes the recited amount ±1%. Also, terms such as "about X" include the recitation of "X."

[0023] Throughout this disclosure, the recitation of numerical ranges is intended to serve as a shorthand reference for individually referring to each separate value falling within the range defined by the recited values, and each separate value is hereby incorporated by reference into this specification as if it were individually recited herein.

[0024] "Alkyl," by itself or as part of another substituent, unless otherwise specified, has the number of carbon atoms designated (i.e., C 1 ~C 6means a straight-chain or branched hydrocarbyl group having from 1 to 6 carbons). Representative alkyl groups include straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Further representative alkyl groups include straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0025] "Aryl", by itself or as part of another substituent, unless otherwise specified, refers to a monocyclic, bicyclic, or polycyclic polyunsaturated aromatic hydrocarbon radical containing from 6 to 14 ring carbon atoms, which can be a single ring or a plurality of rings (up to 3 rings) that are fused together or linked by covalent bonds. Non-limiting examples of unsubstituted aryl groups include phenyl, 1-naphthyl, and 2-naphthyl. The term "arylene" refers to divalent aryl, where aryl is as defined herein.

[0026] "Boc" refers to the tert-butyloxycarbonyl group.

[0027] "Ph" refers to the phenyl group.

[0028] "Protecting group" refers to a moiety that masks a reactive group. By way of example only, in some embodiments, protecting groups include, but are not limited to, tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), benzyl, p-methoxybenzyl, p-nitrobenzyl, or any other protecting group described in Protective Groups in Organic Synthesis 4th Edition by P. G. M. Wuts and T. W. Greene.

[0029] In many cases, the compounds of the present disclosure are capable of forming acid salts and / or base salts due to the presence of amino groups and / or hydroxy groups or groups similar thereto. Examples of salts include salts with inorganic acids and salts with organic acids. Further, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying the solution of the acid salt. Conversely, when the product is a free base, an addition salt can be produced by dissolving the free base compound in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from free base compounds. Those skilled in the art will recognize the various synthetic methods that can be used to prepare salts. Generally, such salts can be prepared by reacting the free acid or free base forms of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent, or a mixture of both, and generally, non-aqueous media such as ether (e.g., MTBE), ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol or butanol) or acetonitrile (MeCN) are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17 th 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).

[0030] Also provided are pharmaceutically acceptable salts, isotope-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" is a precursor form of any biologically active compound. A prodrug undergoes in vivo conversion (e.g., enzymatic cleavage) or chemical conversion (e.g., hydrolysis) before exhibiting a pharmacological effect.

[0031] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials useful in the preparation of pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0032] In certain instances, salts of the compounds are pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" of a given compound refers to salts that retain the biological effects and properties of the given compound and are not undesirable in a biological or other respect. Examples of "pharmaceutically acceptable salts" or "physiologically acceptable salts" include salts with inorganic acids and salts with organic acids. Further, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying the solution of the acid salt. Conversely, when the product is a free base, addition salts, particularly pharmaceutically acceptable addition salts, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize the various synthetic methods that can be used to prepare non-toxic 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 invention can be synthesized by conventional chemical methods from parent compounds containing basic or acidic moieties. Generally, such salts can be prepared by reacting the free acid or free base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both, and generally non-aqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol or butanol) or acetonitrile (MeCN) are preferred. A list of suitable salts is provided in Remington's Pharmaceutical Sciences, l7 thSee 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).

[0033] The term "solvate" refers to a complex formed by the combination of solvent molecules with the 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 the combination of water molecules with the molecules or ions of a solute), hemihydrate, channel hydrate, etc. 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 non-solvated forms and are encompassed within the scope of the present disclosure.

[0034] The term "stereochemical isomer" of a compound refers to the stereoisomers of that compound.

[0035] The term "tautomer" means a compound that results from the phenomenon of a proton of one atom of a molecule moving to another atom of the molecule. Also, a tautomer refers to one of two or more structural isomers that exist in an equilibrium state and are readily convertible from one isomer to another. Non-limiting examples include enol-keto, imine-enamine, amide-imido acid tautomers, tautomers of heteroaryl groups containing an -N=C(H)-NH- ring atom arrangement such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole, and tautomers of hydroxy-substituted 6-membered heteroaryl groups such as 4-hydroxypyridine and pyridin-4(1H)-one (e.g., hydroxy-substituted pyridine, pyrimidine, pyrazine, or pyridazine). The compounds described herein may have one or more tautomers and thus include various isomers. One of ordinary skill in the art will recognize that other tautomeric ring atom arrangements are possible. All such isomers of these compounds are expressly included in this disclosure.

[0036] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with its imido acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between tautomers, one of ordinary skill in the art will understand that this compound includes both the amide and imido acid tautomers. Thus, amide-containing compounds are understood to include their imido acid tautomers. Similarly, imido acid-containing compounds are understood to include their amide tautomers.

[0037] The compounds of the present invention or their pharmaceutically acceptable salts contain asymmetric centers and, accordingly, can give rise to enantiomers, diastereomers and other stereoisomers that can be defined as (R)- or (S)- from the perspective of absolute stereochemistry, or (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using a chiral synthon or chiral reagent, or can be separated 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, or separation of a racemate (or a racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other geometrically asymmetric center, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0038] "Stereoisomers" refer to compounds made up of the same atoms bonded by the same bonds but having different three-dimensional structures and are non-interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, including "enantiomers", which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0039] "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.

[0040] The relative centers of the compounds shown herein are illustrated schematically using the "thick bond" style (bold or parallel lines), and the absolute stereochemistry is depicted using wedge bonds (bold or parallel lines).

[0041] The compound of formula (XXIIIa) is described in U.S. Patent No. 9,783,538 (which is hereby incorporated by reference in its entirety). In an exemplary embodiment, 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). Formula (XXII): [Chemical formula] The compound of formula (XXII) acts as an IAP and cIAP / XIAP antagonist and can be used in various pharmaceutical formulations for treating various cancers described herein and in U.S. Patent No. 9,783,538.

[0042] In certain embodiments, the compound of formula (XXII) is in the form of the L(+)-lactate salt of the compound of formula (XXII), acts as an IAP and cIAP / XIAP antagonist, and is used 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).

[0043] The synthetic methods of the compounds of formula (XXIII) and formula (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 herein by reference in their entirety. The synthetic schemes 1 to 3 disclosed in columns 45 to 50 of U.S. Patent No. 9,783,538 have lower yields and purities of the final products of the compounds of formula (XXIII) and formula (XXIIIa) compared to the synthetic routes and embodiments of the present application disclosed herein. For example, synthetic scheme 1 disclosed in columns 45 to 46 of U.S. Patent No. 9,783,538 shows a general method for preparing the compound of formula (VIIIa). However, in synthetic scheme 1 disclosed in columns 45 to 46 of U.S. Patent No. 9,783,538, the yields and purities of the compounds of formula (XXIII) and formula (XXIIIa) are lower compared to the synthetic route and embodiments of the present application. Also, scheme 2 of U.S. Patent No. 9,783,538 has a low yield, bis-hydroxymethyl impurities occur in the final product, and other impurities that are difficult to purge occur in the intermediate and the final product, such as the bis-hydroxymethyl impurity of formula (XXIV): [Chemical formula] such as the bis-hydroxymethyl impurity of etc. occurs.

[0044] The synthetic method of U.S. Patent No. 9,783,538 also uses tert-butyllithium as a reagent, which has limitations in large-scale production, is a reagent with limited supply, has low selectivity, and has high flammability, volatility, pyrophoricity, and reactivity.

[0045] The compounds, intermediates, and synthetic methods of the present application and the embodiments disclosed herein are used in an improved preparation process of the important intermediate 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), and the compounds of formula (XXIII) and formula (IX):

Chem.

[0046] The compound of formula (XXIII) prepared according to the synthetic methods and embodiments disclosed herein has improved properties such as low tackiness, high purity, higher stability and higher overall yield. The purity can be improved by minimizing aldehyde impurities and controlling the palladium concentration in the final product. In an exemplary embodiment, the synthetic methods and embodiments for generating the compound of formula (XXIII) disclosed herein result in a final product with a purity of 95% or more, and in another embodiment, a final product with a purity of 98% or more.

[0047] Figure 1 shows an exemplary embodiment of synthesizing the compound of formula (VIII) from the compound of formula (II). The compound of formula (VIII) can be used in the synthesis shown in Figure 2 to generate an important intermediate compound of formula (IX).

[0048] Figure 2 shows an exemplary embodiment of an improved scalable process for the synthesis of the compound of formula (XXIII). The compound of formula (IX) in Figure 2 is an important intermediate in generating the compound of formula (XXIII).

[0049] The conversion from the compound of formula (II) to the compounds of formula (VII) and formula (VIII) presents several problems and drawbacks. For example, the compound of formula (VI) is rare and is supplied as a dilute solution. It can take several months to produce the amount of the compound of formula (VI) required for industrial processes, including its use in the production of the compounds of formula (IX) and formula (XXIII). Also, since the compound of formula (VI) is very sensitive to air and moisture, it is difficult, inefficient, and unpredictable to use in the synthesis of the compounds of formula (IX) and formula (XXIII). The PEPPSI™ catalyst ([1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride), typically used in the synthesis of Figure 1 for converting the compound of formula (V) to the compound of formula (VII), is also expensive. Therefore, it is advantageous to avoid the use of the compound of formula (VI) and the PEPPSI™ catalyst when synthesizing the compound of formula (IX).

[0050] An alternative synthetic route for producing the intermediate compound of formula (IX) is disclosed herein. The problems of the known preparation processes of the important intermediate compound of formula (IX) and the final product compound of formula (XXIII) are addressed by this application, as well as the embodiments and examples disclosed herein. The exemplary synthetic route does not require the use of the compound of formula (VI) or the PEPPSI™ catalyst in the synthesis of the important intermediate containing the compound of formula (IX) and the final product compound of formula (XXIII). The exemplary synthetic route also utilizes new chemical substances such as the compounds of formula (Ia), formula (I), formula (IX), formula (X), formula (XI), formula (XVIa), and formula (XX) for producing the compound of formula (I) and / or the compound of formula (XXIII) for producing the compound of formula (IX) and the final product compound of formula (XXIII).

[0051] In one embodiment, formula (XXIII):

Chemical formula

[0052] In one embodiment, the lactic acid used in step (iii) above is anhydrous lactic acid as described in U.S. Provisional Application No. 63 / 019,875, filed on May 4, 2020, entitled "Methods For Synthesizing Anhydrous Lactic Acid", which is a co-pending application filed on the same day as this application and incorporated herein by reference.

[0053] In one embodiment, the compound of formula (XIII) is (i) In the presence of one or more palladium catalysts and ligands, a compound of formula (V): [Chemical formula] is reacted with a compound of formula (VI): [Chemical formula] React with the compound of formula (VII): [Chemical formula] to provide a compound of formula (VII); (ii) Brominate the compound of formula (VII) to obtain a compound of formula (VIII): [Chemical formula] and obtain a compound of formula (VIII); (iii) Protect the compound of formula (VIII) to obtain a compound of formula (IX): [Chemical formula] and provide a compound of formula (IX); (iv) Contact the compound of formula (IX) with carbon monoxide and a compound of formula (X): [Chemical formula] under conditions sufficient to provide a compound, salt, solvate or hydrate of the compound of formula (X); (v) Remove the tert-butyloxycarbonyl protecting group from the compound of formula (X), or a salt, solvate or hydrate thereof, to obtain a compound of formula (XI): [Chemical formula] and provide a compound of formula (XI); (vi) Reduce the compound of formula (XI) to obtain a compound of formula (XII): [Chemical formula] and provide a compound of formula (XII); (vii) Contact the compound of formula (XII) with chloroacetyl chloride to provide a compound of formula (XIII); prepared by a method comprising

[0054] In one embodiment, formula (XXIII): [Chemical formula] A method for preparing a compound of the formula: (i) Formula (IX): [ka] or a salt, solvate or hydrate thereof with carbon monoxide and a compound of formula (X): [ka] or a salt, solvate, or hydrate thereof; (ii) removing the tert-butyloxycarbonyl protecting group from a compound of formula (X), or a salt, solvate or hydrate thereof, to obtain a compound of formula (XI): [ka] or a salt, solvate or hydrate thereof; (iii) reducing a compound of formula (XI) or a salt, solvate or hydrate thereof to obtain a compound of formula (XII): [ka] or a salt, solvate or hydrate thereof; (iv) contacting the compound of formula (XII), or a salt, solvate, or hydrate thereof, with chloroacetyl chloride to produce a compound of formula (XIII): [ka] or a salt, solvate or hydrate thereof; (v) reacting a compound of formula (XIII) or a salt, solvate or hydrate thereof with a compound of formula (XX): [ka] and a compound of formula (XXI): [ka] or a salt, solvate, or hydrate thereof; (vi) Deprotecting the compound of formula (XXI), or a salt, solvate or hydrate thereof, to give a compound of formula (XXII): [Chemical formula] or a salt, solvate or hydrate thereof, and (vii) Contacting the compound of formula (XXII) with lactic acid to give a compound of formula (XXIII), A method is provided which comprises the above steps.

[0055] In one embodiment, a method for preparing a compound of formula (XXI): [Chemical formula] or a salt, solvate or hydrate thereof, comprising contacting a compound of formula (XX): Formula (XX): [Chemical formula] with a compound of formula (XIII): [Chemical formula] under conditions sufficient to provide a compound of formula (XXI) or a salt, solvate or hydrate thereof.

[0056] In one embodiment, a method for preparing a compound of formula (XX): [Chemical formula] comprising: (i) Debenzylating a compound of formula (XIX): [Chemical formula] and (ii) Contacting the debenzylated product with oxalic acid in a solvent to give a compound of formula (XX). A method is provided which comprises the above steps.

[0057] In certain embodiments of the method for preparing the compound of formula (XX), the debenzylation in step (i) is carried out in the presence of palladium on carbon and hydrogen gas. In certain embodiments of the method for preparing the compound of formula (XX), the solvent in step (ii) is ethanol.

[0058] In certain embodiments, formula (X):

Chemical formula

Chemical formula

[0059] In one embodiment of the method for preparing the compound of formula (X), the conditions include a palladium catalyst, a ligand, and (i) phenyl formate or phenol, and (ii) carbon monoxide.

[0060] In one embodiment of the method for preparing the compound of formula (X), the palladium catalyst is palladium(II) acetate and the ligand is rac-1,1'-binaphthyl-2,2'-diphenylphosphine.

[0061] In one embodiment of the method for preparing the compound of formula (X), the conditions further include a base. In certain embodiments, the base is triethylamine. Any other suitable base is contemplated within the scope of the embodiments presented herein.

[0062] In one embodiment of the method for preparing the compound of formula (X), the reaction temperature ranges from about 45°C to about 75°C. In one embodiment of the method for preparing the compound of formula (X), the reaction temperature ranges from about 55°C to about 65°C. In one embodiment of the method for preparing the compound of formula (X), the reaction solvent is acetonitrile.

[0063] In certain embodiments, formula (XI):

Chemical formula

Chemical formula

[0064] In certain embodiments, the above method comprises (i) reducing a compound of formula (XI) under conditions sufficient to provide a compound of formula (XII):

Chemical formula

Chemical formula

[0065] In certain embodiments, the reduction is carried out in the presence of lithium borohydride. Any other suitable reducing agent (e.g., NaBH 4 , LiAlH 4 ) is contemplated within the scope of the embodiments presented herein.

[0066] In certain embodiments, the solvent for reducing the compound of formula (XI) is 2-methyltetrahydrofuran.

[0067] In certain embodiments, the contacting of the compound of formula (XII) with 2-chloroacetyl chloride is carried out at a temperature of about -10 °C to about 0 °C.

[0068] In certain embodiments, formula (IX):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0069] In formula (III), it will be understood that the chloro group may be changed to any other suitable group, such as bromo, triflate, etc.

[0070] In certain embodiments, formula (IX):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0071] It will be understood that in formula (V), the chloro group may be changed to any other suitable group, such as bromo, triflate, etc.

[0072] In one embodiment, a method for preparing a compound of formula (XVIa), comprising Formula (XVI):

Chemical formula

Chemical formula

[0073] In one embodiment of the method for preparing a compound of formula (VIa), the solvent is methyl tert-butyl ether (MTBE).

[0074] A compound of formula (XXIII) having a purity of at least 95%:

Chemical formula

[0075] A compound of formula (XXIII) having a purity of at least 98%:

Chemical formula

[0076] This specification provides a compound of formula (XXIII). When the compound of formula (XXIII) is stored at 25 °C and 60% relative humidity for 6 months, the compound of formula (XXIII) contains about 0.5% a / a or less of formula (XXV):

Chemical formula

[0077] This specification provides a compound of formula (XXIII). When the compound of formula (XXIII) is stored at 25 °C and 60% relative humidity for 6 months, the compound of formula (XXIII) contains about 0.2% a / a or less of the compound of formula (XXV).

[0078] This specification provides a compound of formula (XXIII). When the compound of formula (XXIII) is stored at 25 °C and 60% relative humidity for 12 months, the compound of formula (XXIII) contains about 0.3% a / a or less of the compound of formula (XXV).

[0079] This specification provides a compound of formula (XXIII), and the compound of formula (XXIII) contains about 50 ppm or less of palladium, or about 40 ppm, about 300 ppm, or about 20 ppm or less of palladium.

[0080] Formula (XXIII):

Chemical formula

[0081] In certain embodiments, the compound of formula (XXIII) of Form C has an XRPD substantially as shown in Figure 5.

[0082] Formula (Ia):

Chemical formula

[0083] In some embodiments, the compound of formula (Ia) has a structure of formula (IIIb) or (IIIc), or a salt, solvate or hydrate thereof.

Chemical formula

[0084] Formula (IIIa):

Chemical formula

[0085] In certain embodiments, the compound of formula (IIIa) has a structure of formula (IIIaa).

Chemical formula

[0086] Formula (Vb):

Chemical formula

[0087] In certain embodiments, the compound of formula (Vb) has the structure of formula (Vbb).

Chemical formula

[0088] Formula (I):

Chemical formula

[0089] Formula (XVIa):

Chemical formula

[0090] Formula (IX):

Chemical formula

[0091] Formula (XX):

Chemical formula

[0092] Formula (XI):

Chemical formula

[0093] Formula (XXV):

Chem.

[0094] Formula (IIIa):

Chem.

[0095] Formula (Vb):

Chem.

[0096] Compounds (XXIII) prepared by any of the methods described herein are provided herein.

[0097] Formula (VII):

Chem.

[0098] In an exemplary embodiment, compounds of formula (Ia), salts, solvates or hydrates thereof, and methods for synthesizing compounds of formula (Ia), salts, solvates or hydrates thereof are provided:

Chem.

[0099] In an exemplary embodiment, there is provided a compound of formula (IX), a salt, solvate or hydrate thereof, and a method for synthesizing the compound of formula (IX), a salt, solvate or hydrate thereof: [Chemical formula]

[0100] In an exemplary embodiment, formula (Va): [Chemical formula] There is provided a method for synthesizing a compound of formula (IX) from a compound of.

[0101] In an exemplary embodiment, there is provided a method for synthesizing a compound of formula (VII), a salt, solvate or hydrate thereof: [Chemical formula]

[0102] In an exemplary embodiment, [Chemical formula] There is provided a method for synthesizing a compound of formula (VII) from a compound of formula (IIIaa), also shown as: [Chemical formula] In an exemplary embodiment, there is provided a compound of formula (I) and a method for synthesizing the compound of formula (I):

[0103] (wherein X is H or a protecting group, [Chemical formula] Y is Br, Cl, I or COR, R is H, OH, O-alkyl or O-aryl).

[0104] In an exemplary embodiment, there is provided a compound of formula (XVI), a salt, solvate or hydrate thereof, and a method for synthesizing the compound of formula (XVI), a salt, solvate or hydrate thereof:

Chemical formula

[0105] In an exemplary embodiment, there is provided a compound of formula (XXa), a solvate or hydrate thereof, and a salt compound of formula (XX), and a method for synthesizing the compound of (XXa), a solvate or hydrate thereof and a salt compound of formula (XX):

Chemical formula

[0106] In the exemplary synthesis shown in Figure 3, a compound of formula (VII) is produced.

[0107] In the synthesis of the compound of formula (VII) in Figure 3, Y is OR' or B(OR') 2 wherein each R' is independently H, an alkyl group or an aryl group, or two alkyl groups or aryl groups that form a ring with B.

[0108] Referring to Figure 3, the boronization of the compound of formula (III) produces a boronic ester compound of formula (IIIa). This step is described in Example 1.

Chemical formula

[0109] Boronization can be carried out by reacting the compound of formula (III) with a boronizing agent and a catalyst. In an exemplary embodiment, the boronizing agent can be a compound of formula Y - B(OR') 2 For the compound of formula (IIIa) and the boronizing agent of formula Y - B(OR') 2 Y is OR' or B(OR') 2and each R’ is independently H, an alkyl group or an aryl group, or two alkyl groups or aryl groups that form a ring with B. In an exemplary embodiment, the boronating agent is bis(pinacolato)diboron and the catalyst is a palladium catalyst. In one embodiment, the compound of formula (IIIa) is of formula (IIIaa):

Chemical formula

[0110] In an exemplary embodiment, the catalyst is one or more palladium catalysts, including but not limited to Xphos-Pd-G2 catalysts having ligands such as PPh 3 , Xantphos, DPPE, DPPP, DPPB, DPPF, rac-BINAP, RuPhos or tBuXphos, Pd(Oac) 2 or Pd 2 (dba) 3 . In an exemplary embodiment, the palladium-catalyzed reaction can occur in the presence of a ligand. Suitable ligands include 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl (Xphos) used as a precursor for the Suzuki coupling.

[0111] In another exemplary embodiment, the boronating agent is a compound of formula Y-B(OR’) 2 , Y is OR’, and the compound of formula (III) is reacted with the boronating agent in the presence of a Grignard reagent or an alkyllithium reagent.

[0112] Borating the compound of formula (III) to produce the compound of formula (IIIa) can occur in one or more organic solvents such as 2-methyltetrahydrofuran (2-MeTHF), THF, dioxane, toluene, xylene or MTBE, in the presence of one or more bases such as potassium acetate, sodium acetate, triethylamine, diisopropylethylamine, pyridine.

[0113] In an exemplary process of the synthesis of FIG. 3, the compound of formula (IIIa) can be benzylated to produce the compound of formula (IIIb). This process is described in Example 1.

Chemical formula

[0114] In an exemplary embodiment, the compound of formula (IIIa) can be benzylated with a benzylating agent. For the compound of formula (IIIa), each R' is independently H, an alkyl group or an aryl group, or two alkyl groups or aryl groups that form a ring with B. In an exemplary embodiment, 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 the compound of formula (IIIb).

[0115] The benzylating agent used in this synthesis step is stable in air and in the presence of moisture. Also, this benzylating agent is readily available in industrial quantities and is less expensive than the compound of formula (VI). By using the exemplary benzylating agent in this step, the stability, predictability, and efficiency of the synthesis of the compounds of formula (IX) and formula (XXIII) are improved.

[0116] In an exemplary embodiment, 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.

[0117] In an exemplary process of the synthesis of FIG. 3, the compound of formula (IIIb) can be reduced to form the compound of formula (IIIc). This procedure is described in Example 2.

Chemical formula

[0118] 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.

[0119] In an exemplary embodiment, the reduction occurs 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, etc. In an exemplary embodiment, the compound of formula (IIIb) is reduced by hydrogenation on a Raney nickel catalyst.

[0120] In an exemplary step of the synthesis of FIG. 3, the compound of formula (IIIc) is converted to the compound of formula (VII) in a cyclization reaction. This step is described in Example 3.

Chemical formula

[0121] The cyclization reaction is carried out by deprotonation of the amino group and substitution of the fluorine atom on the pyridine ring in the presence of a base. In an exemplary embodiment, sodium bicarbonate acts as a deprotonating agent, inducing dehalogenation and intramolecular nucleophilic substitution, causing cyclization or ring closure. To promote 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, NaHCO 3 , NaH, Na 2 CO 3 and K 2 CO 3 and the like.

[0122] As shown in FIGS. 1 to 2, the compound of formula (VII) can be used in the synthesis of the compound of formula (IX) without using the compound of formula (VI) or the PEPPSI (trademark) catalyst that cause inefficiency and unpredictability in the synthesis.

[0123] In an alternative embodiment, the compound of formula (VII) is prepared as shown in FIG. 1 and Example 3A. FIGS. 1 and 3B describe exemplary embodiments of synthesizing the compound of formula (VIII).

[0124] Starting from the compound of formula (V) in FIG. 1, the compound of formula (VII) is prepared by reacting the compound of formula (V) with the compound of formula (VI). This step is described in Example 3A.

Chemical formula

[0125] In an exemplary embodiment, the compound of formula (V) is, but not limited to, Xphos-Pd-G2 catalyst having ligands such as PPh 3 , Xantphos, DPPE, DPPP, DPPB, DPPF, rac-BINAP, RuPhos or tBuXphos, Pd(Oac) 2 or Pd 2 (dba) 3 and can be reacted with the compound of formula (VI) in the presence of one or more palladium catalysts. In an exemplary embodiment, the palladium-catalyzed reaction can occur in the presence of the ligand 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) used as a precursor for the Suzuki coupling. The reaction can also occur in a suitable solvent such as N-methylpyrrolidinone (NMP) and / or tetrahydrofuran (THF). The applicant has found that this step of the above synthesis can be carried out without using the PEPPSI catalyst that causes inefficiency and unpredictability in the synthesis.

[0126] The compound of formula (VIII) in Figure 1 can be produced by brominating the compound of formula (VII) with a brominating agent. This step is described in Example 3B.

Chem.

[0127] In an exemplary embodiment, the compound of formula (VII) is brominated in the presence of a solvent to provide the compound of formula (VIII). Suitable brominating agents include N-bromosuccinimide and dibromodimethylhydantoin, and a suitable solvent is dimethylformamide. Then, the compound of formula (VIII) can be used to produce the compound of formula (XIII), and as shown in the synthesis of Figure 2, it can be coupled with the compound of formula (XX) to produce the compound of formula (XXI).

[0128] The compound of formula (IX) in Figure 2 is prepared from the compound of formula (VIII) by a Boc protection step. This step is described in Example 6B.

Chem.

[0129] Boc protection can be achieved by reacting the 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.

[0130] Other suitable protecting groups include the carboxybenzyl (Cbz) group.

[0131] Alternatively, the exemplary synthesis shown in FIG. 4 can also produce the compound of formula (IX).

[0132] In the synthesis of the compound of formula (IX) in FIG. 4, Y is OR' or B(OR') 2 where each R' is independently H, an alkyl group or an aryl group, or two alkyl groups or aryl groups that form a ring with B.

[0133] In an exemplary step of the synthesis in FIG. 4, the compound of formula (V) can be converted to the compound of formula (Va) by attaching a protecting group. This step is described in Example 4.

Chemical formula

[0134] In an exemplary embodiment, the protecting group is a Boc protecting group, and the compound of formula (Va) is prepared by reaction with di-tert-butyl dicarbonate that can be removed with a deprotecting agent. The protection can be carried out in the presence of a solvent. Suitable solvents for protection include, but are not limited to, toluene, dichloromethane, THF, and acetonitrile. Other protecting groups are contemplated within the scope of the embodiments presented herein and include, but are not limited to, protecting groups such as benzyl group, acetyl group, and / or carboxybenzyl group (CBz).

[0135] In an exemplary step of the synthesis in FIG. 4, the compound of formula (Va) can be converted to the compound of formula (Vb) by boronation. This step is described in Example 5.

Chemical formula

[0136] Boronation can be carried out by reacting the compound of formula (Va) with a boronating agent and a catalyst. The boronating agent can be a compound of the formula Y-B(OR') 2 The compound of formula (Vb) and the compound of formula Y-B(OR') 2For the boronating agent, Y is OR' or B(OR') 2 where each R' is independently H, an alkyl group or an aryl group, or two alkyl groups or aryl groups that form a ring with B. In an exemplary embodiment, the boronating agent is bis(pinacolato)diboron and the catalyst is a palladium catalyst.

[0137] In an exemplary embodiment, the catalyst is one or more palladium catalysts, including but not limited to, Xphos-Pd-G2 catalysts having ligands such as PPh 3 , Xantphos, DPPE, DPPP, DPPB, DPPF, rac-BINAP, RuPhos or tBuXphos, Pd(Oac) 2 or Pd 2 (dba) 3 . The palladium-catalyzed reaction can occur in the presence of a ligand. In an exemplary embodiment, the ligand is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) used as a precursor for the Suzuki coupling.

[0138] In another exemplary embodiment, the boronating agent is a compound of the formula Y-B(OR')[[]]END]] 2 where Y is OR', and the compound of formula (Va) is reacted with the boronating agent in the presence of a Grignard reagent or an alkyllithium reagent.

[0139] Also, the boronating of the compound of formula (Va) to produce the compound of formula (Vb) can occur in one or more organic solvents such as 2-methyltetrahydrofuran (2-MeTHF), THF, dioxane, toluene, xylene or MTBE in the presence of one or more bases such as potassium acetate, sodium acetate, triethylamine, diisopropylethylamine, pyridine.

[0140] In an exemplary step of the synthesis of Figure 4, the compound of formula (Vb) can be benzylated to produce the compound of formula (Vc). This step is described in Example 5.

Chemical formula

[0141] The compound of formula (Vb) can be benzylated with a benzylating agent. As used herein, "benzylating with a benzylating agent" refers to the coupling of boronate (Vb) with a compound of the formula: [Chemical formula] (wherein X is a suitable leaving group (e.g., halo, tosyl, triflate, etc.)). For the compound of formula (Vb), each R' is independently H, an alkyl group or an aryl group, or two alkyl groups or aryl groups that form a ring with B. In an exemplary embodiment, 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).

[0142] The benzylating agent used in this synthetic step is stable in air and in the presence of moisture. Also, this benzylating agent is readily available in industrial quantities and is less expensive than the compound of formula (VI). By using an exemplary benzylating agent in this step, the stability, predictability, and efficiency of the synthesis of the compounds of formula (IX) and formula (XXIII) are improved.

[0143] 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.

[0144] In an exemplary step of the synthesis of Figure 4, the compound of formula (Vc) can be brominated to produce a compound of formula (IX). This step is described in Example 6. [Chemical formula]

[0145] Bromination can be carried out by reacting a 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). The 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.

[0146] The synthesis of Figure 4 can be used to produce a compound of formula (IX) without using a compound of formula (VI) or a PEPPSI™ catalyst that causes inefficiencies and unpredictability in the synthesis.

[0147] The compound of formula (IX) is an important intermediate in the synthesis of a pharmaceutical active ingredient produced from a compound of formula (XXIII) and a compound of formula (XXIII). The synthesis of a compound of formula (XXIII) using the compound of formula (IX) is described below.

[0148] The compound of formula (IX) in Figure 2 can be converted to a compound of formula (X) by reacting with phenol by carbonylation with a palladium catalyst to form a phenyl ester compound of formula (X). This step is described in Example 7.

Chemical formula

[0149] Carbonylation of the compound of formula (IX) with a palladium catalyst can be achieved by reacting the compound of formula (IX) with phenol and carbon monoxide in the presence of a palladium catalyst. Suitable palladium catalysts include Xphos-Pd-G2 catalysts having ligands such as PPh 3 , Xantphos, DPPE, DPPP, DPPB, DPPF, rac-BINAP, RuPhos or tBuXphos, Pd(Oac) 2 or Pd 2(dba) 3 Examples include. In an exemplary embodiment, the palladium catalyst is palladium(II) acetate and the ligand is rac-BINAP. Alternatively, the carbonylation of the compound of formula (IX) can be achieved by reacting the compound of formula (IX) with phenyl formate in the presence of a palladium catalyst.

[0150] The compound of formula (X) in Figure 2 can be converted to the compound of formula (XI) by deprotecting or removing the Boc group. This step is described in Example 8.

Chemical formula

[0151] In an exemplary embodiment, the Boc protecting group can be removed with a deprotecting agent. Suitable deprotecting agents include, but are not limited to, HCl, TFA, HBr, MsOH, TsOH, CSA, or other acids. In an exemplary embodiment, deprotection can occur in the presence of a solvent. Suitable solvents include, but are not limited to, isopropyl alcohol, methanol, ethanol, t-butanol, THF, or MeCN.

[0152] The compound of formula (XI) in Figure 2 can be converted to the compound of formula (XII) by phenyl ester reduction to form the alcohol compound of formula (XII). This step is described in Example 9.

Chemical formula

[0153] Suitable reducing agents for reducing phenyl esters to alcohols include, but are not limited to, lithium borohydride, sodium borohydride, lithium aluminum hydride, borane, sodium triacetoxyborohydride, L-selectride, K-selectride, Red-Al, and DIBAL-H. The reduction can occur in the presence of a solvent such as a THF compound (e.g., methyltetrahydrofuran).

[0154] The compound of formula (XII) in Figure 2 can be converted to the compound of formula (XIII) by chloroacetylating the amino group. This step is described in Example 10.

Chemical formula

[0155] Chloroacetylation can be achieved using 2-chloroacetyl chloride, acetonitrile, and a solvent such as dichloromethane, tetrahydrofuran, and / or toluene.

[0156] Referring to Figure 2, the compound of formula (XX) is prepared or synthesized from the compound of formula (XIV).

[0157] Protecting the compound of formula (XIV) with Boc gives a diBoc intermediate, which is not isolated. Treating this diBoc intermediate with a suitable base gives the compound of formula (XV). This step is described in Example 11.

Chemical formula

[0158] In an exemplary embodiment, Boc protection can be carried out by reacting a compound of formula (XIV) with a tert-butyloxycarbonyl (Boc) protecting group. This 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.

[0159] The compound of formula (XV) in Figure 2 can be converted to the compound of formula (XVI) by benzyl group protection. This step is described in Example 12.

Chemical formula

[0160] In an exemplary embodiment, protection of the benzyl group is carried out using a benzylating agent. A suitable benzylating agent is benzaldehyde. Benzylation can be carried out in the presence of one or more solvents and a reducing agent. 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 (NaBH 4 )), borane, and diisobutylaluminum hydride (DIBAL-H).

[0161] Alternatively, the compound of formula (XV) can be converted to the oxalate compound of formula (XVIa) by reaction with oxalic acid in a suitable solvent such as methyl tert-butyl ether and isolated. This step is described in Example 13. The isolated oxalate compound of formula (XVIa) can be used in the next step of the synthesis in Figure 2 to provide a higher purity final product.

[0162] By chlorinating the compound of formula (XVI), a chloro compound of formula (XVII) is obtained. This step is described in Example 14.

Chemical formula

[0163] Chlorination can be achieved by reacting the compound of formula (XVI) with a chlorinating agent. Suitable chlorinating agents include, but are not limited to, methanesulfonyl chloride, thionyl chloride, sulfuryl chloride, phosphoryl chloride (POCl 3 ), and phosphorus trichloride (PCl 3 ). In an exemplary embodiment, chlorination can be achieved in the presence of one or more bases and / or solvents. A suitable base includes triethylamine, and suitable solvents include, but are not limited to, dichloromethane, ethyl acetate, and ethanol.

[0164] Nucleophilic substitution of the compound of formula (XVII) gives a compound of formula (XIX). This step is described in Example 15.

Chemical formula

[0165] Nucleophilic substitution can be achieved by reacting the compound of formula (XVII) with a nucleophile. In an exemplary embodiment, the nucleophile is a compound of formula (XVIII) (3-methylmorpholine, hydrochloride). Nucleophilic substitution can be carried out using a nucleophile in the presence of a solvent and a base. A suitable solvent includes acetonitrile, and suitable bases include, but are not limited to, potassium carbonate, sodium carbonate, and potassium phosphate. To facilitate the reaction, it is also possible to use additional additives such as potassium iodide.

[0166] By debenzylating the compound of formula (XIX), a compound of formula (XX) is obtained. This step is described in Example 16. [Chemistry]

[0167] Debenzylation can be achieved by reacting a compound of formula (XIX) with hydrogen and one or more palladium catalysts. Debenzylation can occur in the presence of solvents such as ethanol, methanol, toluene, and heptane. In an exemplary embodiment, the solvent is anhydrous ethanol. Suitable palladium catalysts include palladium on activated carbon and palladium hydroxide. Treatment with oxalic acid produces an oxalate compound of formula (XX). By using the oxalate compound of formula (XX), impurities in the final product, the compound of formula (XXIII), are reduced.

[0168] Next, the high-purity final product of formula (XXIII) can be produced by a coupling reaction involving two additional important steps. The coupling between the compound of formula (XIII) and the compound of formula (XX) produces a compound of formula (XXI) as described in Example 17. [Chemistry]

[0169] In an exemplary embodiment, the coupling reaction can occur with potassium iodide and potassium carbonate in a suitable solvent such as acetonitrile.

[0170] The compound of formula (XXII) is produced by deprotecting the compound of formula (XXI) with a deprotecting agent. This step is described in Example 18. [Chemistry]

[0171] Suitable deprotecting agents include, but are not limited to, iodine, hydrochloric acid, TFA, HBr, MsOH, TsOH, CSA or other acids. Deprotection can be carried out in a solvent such as isopropyl alcohol, methanol, ethanol, t-butanol, THF or MeCN.

[0172] In the final and important step of the synthesis, the compound of formula (XXII) is reacted with anhydrous L-lactic acid to produce the final resulting compound of formula (XXIII) which is more suitable and stable in pharmaceutical formulations.

Chemical formula

[0173] This last important step is described in Example 19 and produces the L-(+)-lactate salt of the compound of formula (XXIII), which raises the purity of the resulting compound and the pharmaceutical active ingredient.

[0174] In an alternative embodiment, an important intermediate compound of formula (I) and a method for synthesizing the compound of formula (I) are provided.

Chemical formula

[0175] In one embodiment, formula (I):

Chemical formula

[0176] Figure 1 shows a general scheme for the synthesis of the compound of formula (XXIII).

[0177] Embodiment 1 is a method for preparing a compound of formula (VII):

Chemical formula

Chemical formula

[0178] Embodiment 2 is a method for preparing a compound of formula (VII) according to Embodiment 1, which comprises boronating a compound of formula (III) with a boronating agent to produce a compound of formula (IIIa):

Chemical formula

[0179] Embodiment 3 is a method for preparing a compound of formula (VII) according to Embodiment 1, which comprises boronating a compound of formula (III) in the presence of a palladium catalyst, a Grignard reagent or an alkyllithium reagent.

[0180] Embodiment 4 is a method for preparing a compound of formula (VII) according to Embodiment 1, which comprises boronating a compound of formula (III) in the presence of a palladium catalyst and a ligand.

[0181] Embodiment 5 is a method for preparing a compound of formula (VII) according to Embodiment 4, wherein the boronating agent is Y - B(OR') 2 where Y is OR' or B(OR') 2 and each R' is independently H, an alkyl group or an aryl group, or two alkyl groups or aryl groups that form a ring with B.

[0182] Embodiment 6 is a method for preparing the compound of formula (VII) according to Embodiment 3, wherein the palladium catalyst is an XPhos-Pd-G2 catalyst.

[0183] Embodiment 7 is a method for preparing the compound of formula (VII) according to Embodiment 4, wherein the ligand is 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl.

[0184] Embodiment 8 is a method for preparing the compound of formula (VII) according to Embodiment 1, further comprising benzylating the compound of formula (IIIa) with a benzylating agent to produce a compound of formula (IIIb):

Chemical formula

[0185] Embodiment 9 is a method for preparing the compound of formula (VII) according to Embodiment 8, comprising benzylating the compound of formula (IIIa) in the presence of a base.

[0186] Embodiment 10 is a method for preparing the compound of formula (VII) according to Embodiment 8, wherein the benzylating agent is 4-fluorobenzyl chloride or 4-fluorobenzyl bromide.

[0187] Embodiment 11 is a method for preparing the compound of formula (VII) according to Embodiment 9, wherein the base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and potassium phosphate.

[0188] Embodiment 12 is a method for preparing the compound of formula (VII) according to Embodiment 8, further comprising reducing the compound of formula (IIIb) with a reducing agent to produce a compound of formula (IIIc):

Chemical formula

[0189] Embodiment 13 is a method for preparing the compound of formula (VII) according to Embodiment 12, which includes reducing the compound of formula (IIIb) in the presence of a nickel catalyst.

[0190] Embodiment 14 is a method for preparing the compound of formula (VII) according to Embodiment 12, wherein the reducing agent is hydrogen gas, sodium borohydride or lithium aluminum hydride.

[0191] Embodiment 15 is a method for preparing the compound of formula (VII) according to Embodiment 13, wherein the nickel catalyst is selected from the group consisting of nickel chloride, nickel(II) chloride hexahydrate, and Raney nickel catalyst.

[0192] Embodiment 16 is a method for preparing the compound of formula (VII) according to Embodiment 12, which further includes deprotonating the compound of formula (IIIc) with a deprotonating agent.

[0193] Embodiment 17 is a method for preparing the compound of formula (VII) according to Embodiment 16, which further includes cyclizing the compound of formula (IIIc) in the presence of a polar aprotic solvent.

[0194] Embodiment 18 is a method for preparing the compound of formula (VII) according to Embodiment 16, wherein the deprotonating agent is sodium bicarbonate.

[0195] Embodiment 19 is a method for preparing the compound of formula (VII) according to Embodiment 16, wherein the polar aprotic solvent is dimethyl sulfoxide.

[0196] Embodiment 20 provides a compound of formula (Ia):

Chemical formula

[0197] Embodiment 21 is a compound of formula (VII): [Chemical formula] A method for preparing a compound of Formula (V): [Chemical formula] including the step of converting a compound of

[0198] Embodiment 22 is a method for preparing a compound of formula (VII) according to Embodiment 2, further including reacting a compound of formula (V) with a compound of formula (VI): [Chemical formula] in the presence of one or more palladium catalysts and ligands.

[0199] Embodiment 23 is a method for preparing a compound of formula (VII) according to Embodiment 3, wherein one or more palladium catalysts are selected from the group consisting of XPhos-Pd-G2 catalyst, Pd(OAc) 2 and Pd 2 (dba) 3 .

[0200] Embodiment 24 is a method for preparing a compound of formula (VII) according to Embodiment 4, wherein the ligand is selected from the group consisting of PPh 3 , Xantphos, DPPE, DPPP, DPPB, DPPF, rac-BINAP, RuPhos, XPhos and tBuXphos.

[0201] Embodiment 25 provides a method for preparing a compound of formula (IX): [Chemical formula] including the step of converting a compound of formula (V): [Chemical formula] into a compound of formula (IX).

[0202] Embodiment 26 is a method for preparing a compound of formula (IX) according to Embodiment 25, further comprising reacting a compound of formula (V) with a protecting group to form a compound of formula (Va):

Chemical formula

[0203] Embodiment 27 is a method for preparing a compound of formula (IX) according to Embodiment 26, wherein the protecting group is di-tert-butyl dicarbonate.

[0204] Embodiment 28 is a method for preparing a compound of formula (IX) according to Embodiment 26, further comprising boronating a compound of formula (Va) with a boronating agent to form a compound of formula (Vb):

Chemical formula

[0205] Embodiment 29 is a method for preparing a compound of formula (IX) according to Embodiment 28, comprising boronating a compound of formula (Va) in the presence of a palladium catalyst, a Grignard reagent, or an alkyllithium reagent.

[0206] Embodiment 30 is a method for preparing a compound of formula (IX) according to Embodiment 28, comprising boronating a compound of formula (Va) in the presence of a palladium catalyst and a ligand.

[0207] Embodiment 31 is a method for preparing a compound of formula (IX) according to Embodiment 29, wherein the boronating agent is Y-B(OR’) 2 where Y is OR’ or B(OR’) 2 each R’ is independently H, an alkyl group, an aryl group, or two alkyl groups or aryl groups that form a ring with B.

[0208] Embodiment 32 is a method for preparing the compound of formula (IX) according to Embodiment 29, wherein the palladium catalyst is selected from the group consisting of Pd-Ln (palladium-lanthanoid compartment complex), Pd-170 (XPhos Pd (crotyl) Cl), XPhos-Pd-G2 catalyst, Pd(OAc) 2 and Pd 2 (dba) 3 and is selected from the group consisting of.

[0209] Embodiment 33 is a method for preparing the compound of formula (IX) according to Embodiment 30, wherein the ligand is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos).

[0210] Embodiment 34 is a method for preparing the compound of formula (IX) according to Embodiment 28, which further comprises benzylating the compound of formula (Vb) with a benzylating agent to produce a compound of formula (Vc):

Chemical formula

[0211] Embodiment 35 is a method for preparing the compound of formula (IX) according to Embodiment 34, which comprises benzylating the compound of formula (Vb) in the presence of an inorganic base.

[0212] Embodiment 35 is a method for preparing the compound of formula (IX) according to Embodiment 34, wherein the benzylating agent is 1-(chloromethyl)-4-fluorobenzene or 4-fluorobenzyl bromide.

[0213] Embodiment 37 is a method for preparing the compound of formula (IX) according to Embodiment 35, wherein the inorganic base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and potassium phosphate.

[0214] Embodiment 38 is a method for manufacturing the compound of formula (IX) according to Embodiment 34, which further comprises brominating the compound of formula (Vc) with a brominating agent. ​

[0215] Embodiment 39 is a method for preparing the compound of formula (IX) according to Embodiment 38, which comprises brominating the compound of formula (Vc) in the presence of an organic solvent.

[0216] Embodiment 40 is a method for preparing the compound of formula (IX) according to Embodiment 38, wherein the brominating agent is selected from the group consisting of 1-bromopyrrolidine-2,5-dione (BMS) and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH).

[0217] Embodiment 41 is a method for preparing the compound of formula (IX) according to Embodiment 39, wherein the organic solvent is selected from the group consisting of dimethylformamide (DMF), dichloromethane, acetonitrile, and ethyl acetate.

[0218] Embodiment 42 provides a compound of formula (I): [Chemical formula] (wherein X is H or a protecting group, Y is Br, Cl, I, or COR, and R is H, OH, O-alkyl, or O-aryl).

[0219] Embodiment 43 provides a compound of formula (I) wherein X is tert-butoxycarbonyl (Boc) and Y is Br.

[0220] Embodiment 44 provides a compound of formula (I) wherein X is carboxybenzyl (Cbz).

[0221] Embodiment 45 provides a compound of formula (I) wherein X is a Boc group and Y is CO 2 Ph.

[0222] Embodiment 46 provides a compound of formula (I) wherein X is hydrogen and Y is CO 2 Ph.

[0223] Embodiment 47 is a method for preparing a compound of formula (I): [Chemical formula] (wherein X is H or a protecting group, Y is Br, Cl, I or COR, and R is H, OH, O-alkyl or O-aryl), which comprises a step of converting a compound of formula (VIII): Formula (VIII): [Chemical formula] into a compound of formula (I).

[0224] Embodiment 48 is a method for preparing a compound of formula (I) according to Embodiment 47, which further comprises reacting a compound of formula (VIII) with di-tert-butyl dicarbonate to produce a compound of formula (IX): [Chemical formula]

[0225] Embodiment 49 is a method for preparing a compound of formula (I) according to Embodiment 48, wherein the reaction of a compound of formula (VIII) with di-tert-butyl dicarbonate occurs in a solution containing one or more bases and one or more solvents.

[0226] Embodiment 50 is a method for preparing a compound of formula (I) according to 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.

[0227] Embodiment 51 is a method for preparing a compound of formula (I) according to Embodiment 49, wherein the one or more solvents are selected from the group consisting of toluene, dichloromethane, ethyl acetate and water.

[0228] ​Embodiment 52 is a method for preparing a compound of formula (I) according to 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):

Chemical formula

[0229] Embodiment 53 is a method for preparing a compound of formula (I) according to Embodiment 52, wherein the reaction of the compound of formula (IX) occurs in a solution containing rac-1,1'-binaphthyl-2,2'-diphenylphosphine. In some embodiments, the solution further comprises a base and a solvent. In some embodiments, the solution further comprises triethylamine and acetonitrile.

[0230] Embodiment 54 is a method for preparing a compound of formula (I) according to Embodiment 52, wherein carbon monoxide is in the gas phase.

[0231] Embodiment 55 is a method for preparing a compound of formula (I) according to Embodiment 52, wherein the palladium catalyst is selected from the group consisting of XPhos-Pd-G2 catalyst, Pd(OAc) 2 and Pd 2 (dba) 3 Embodiment 55 is a method for preparing a compound of formula (I) according to Embodiment 52, wherein the palladium catalyst is selected from the group consisting of XPhos-Pd-G2 catalyst, Pd(OAc), and Pd(dba).

[0232] Embodiment 56 is a method for preparing a compound of formula (I) according to Embodiment 55, wherein the reaction of the compound of formula (IX) occurs in the presence of a ligand selected from the group consisting of PPh 3 , Xantphos, DPPE, DPPP, DPPB, DPPF, rac-BINAP, RuPhos, tBuXphos, and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos).

[0233] Embodiment 57 is to react the compound of formula (X) with hydrochloric acid to obtain a compound of formula (XI):

Chemical formula

[0234] Embodiment 58 is a method for preparing a compound of formula (I) according to embodiment 52, wherein the reaction of the compound of formula (X) with hydrochloric acid occurs in a solution containing isopropanol.

[0235] Embodiment 59 is to reduce the compound of formula (XI) with a reducing agent to formula (XII):

Chemical formula

[0236] Embodiment 60 is a method for preparing a compound of formula (I) according to embodiment 59, wherein the reducing agent is selected from the group consisting of lithium borohydride, sodium borohydride, lithium aluminum hydride, borane, sodium triacetoxyborohydride, L-selectride, K-selectride, Red-Al and DIBAL.

[0237] Embodiment 61 is a method for preparing a compound of formula (XIII):

Chemical formula

Chemical formula

[0238] Embodiment 62 is a method for preparing a compound of formula (XIII) according to embodiment 61, further comprising reacting the compound of formula (XII) with 2-chloroacetyl chloride.

[0239] Embodiment 63 is a method for preparing a compound of formula (XIII) according to Embodiment 62, wherein the reaction of the compound of formula (XII) with 2-chloroacetyl chloride occurs in the presence of acetonitrile.

[0240] Embodiment 64 provides a compound of formula (XVIa):

Chemical formula

[0241] Embodiment 65 is a method for preparing a compound of formula (XVIa):

Chemical formula

Chemical formula

[0242] Embodiment 66 further includes reacting the compound of formula (XIV) with di-tert-butyl dicarbonate to produce a compound of formula (XV):

Chemical formula

[0243] Embodiment 67 is a method for preparing a compound of formula (XVIa) according to 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.

[0244] Embodiment 68 is a method for preparing a compound of formula (XVIa) according to Embodiment 67, wherein the base is selected from the group consisting of potassium hydroxide and sodium hydroxide.

[0245] Embodiment 69 is a method for preparing the compound of formula (XVIa) according to Embodiment 67, wherein the solvent is selected from the group consisting of dichloromethane, ethyl acetate, and ethanol.

[0246] Embodiment 70 is a method for preparing the compound of formula (XVIa) according to Embodiment 66, further comprising benzylating the compound of formula (XV) with a benzylating agent to form a compound of formula (XVI):

Chemical formula

[0247] Embodiment 71 is a method for preparing the compound of formula (XVIa) according to Embodiment 70, wherein the benzylating agent is benzaldehyde.

[0248] Embodiment 72 is a method for preparing the compound of formula (XVIa) according to Embodiment 70, wherein the benzylation of the compound of formula (XV) occurs in the presence of a reducing agent and a solvent.

[0249] Embodiment 73 is a method for preparing the compound of formula (XVIa) according to Embodiment 72, wherein the reducing agent is selected from the group consisting of sodium triacetoxyborohydride, sodium borohydride (NaBH 4 ), borane, and diisobutylaluminum hydride (DIBAL-H).

[0250] Embodiment 74 is a method for preparing the compound of formula (XVIa) according to Embodiment 72, wherein the solvent is selected from the group consisting of dichloromethane, ethyl acetate, and ethanol.

[0251] Embodiment 75 is a method for preparing the compound of formula (XVIa) according to Embodiment 70, further comprising reacting the compound of formula (XVI) with oxalic acid in the presence of a solvent.

[0252] Embodiment 76 is a method for preparing the compound of formula (XVIa) according to Embodiment 75, wherein the solvent is methyl tert-butyl ether.

[0253] Embodiment 77 provides a compound of formula (XX):

Chemical formula

[0254] Embodiment 78 is a method for preparing a compound of formula (XX):

Chemical formula

Chemical formula

Chemical formula

[0255] Embodiment 79 is a method for preparing a compound of formula (XX) according to Embodiment 78, which further includes chlorinating a compound of formula (XVI) or a salt thereof with a chlorinating agent to produce a compound of formula (XVII):

Chemical formula

[0256] Embodiment 80 is a method for preparing a compound of formula (XX) according to Embodiment 79, wherein the chlorinating agent is selected from the group consisting of thionyl chloride, sulfuryl chloride, and phosphoryl chloride (POCl 3 ).

[0257] Embodiment 81 is a method for preparing a compound of formula (XX) according to Embodiment 79, wherein the chlorinating agent is methanesulfonyl chloride.

[0258] Embodiment 82 is a method for preparing a compound of formula (XX) according to Embodiment 79, wherein the chlorination of the compound of formula (XVI) or a salt thereof occurs in the presence of a base and a solvent.

[0259] Embodiment 83 is a method for preparing the compound of formula (XX) according to Embodiment 82, wherein the base is triethylamine.

[0260] Embodiment 84 is a method for preparing the compound of formula (XX) according to Embodiment 82, wherein the solvent is selected from the group consisting of dichloromethane, ethyl acetate and ethanol.

[0261] Embodiment 85 is a method for preparing the compound of formula (XX) according to Embodiment 79, further comprising reacting the compound of formula (XVII) with a nucleophile to form a compound of formula (XIX):

Chemical formula

[0262] Embodiment 86 is a method for preparing the compound of formula (XX) according to Embodiment 85, wherein the nucleophile is (R)-3-methylmorpholine hydrochloride.

[0263] Embodiment 87 is a method for preparing the compound of formula (XX) according to Embodiment 85, wherein the reaction between the compound of formula (XVII) and the nucleophile occurs in the presence of a base, a solvent and an additive.

[0264] Embodiment 88 is a method for preparing the compound of formula (XX) according to Embodiment 87, wherein the base is selected from the group consisting of potassium carbonate, sodium carbonate and potassium phosphate.

[0265] Embodiment 89 is a method for preparing the compound of formula (XX) according to Embodiment 87, wherein the solvent is acetonitrile and the additive is potassium iodide.

[0266] Embodiment 90 is a method for preparing the compound of formula (XX) according to Embodiment 85, further comprising debenzylating the compound of formula (XIX) to form a compound of formula (XXa):

Chemical formula

[0267] Embodiment 91 is a method for preparing a compound of formula (XX) according to Embodiment 90, wherein the debenzylation of the compound of formula (XIX) comprises reacting the compound of formula (XIX) with hydrogen and one or more palladium catalysts.

[0268] Embodiment 92 is a method for preparing a compound of formula (XX) according to Embodiment 91, wherein the palladium catalyst is selected from the group consisting of palladium on activated carbon and palladium hydroxide.

[0269] Embodiment 93 is a method for preparing a compound of formula (XX) according to Embodiment 91, wherein the debenzylation of the compound of formula (XIX) occurs in the presence of a solvent.

[0270] Embodiment 94 is a method for preparing a compound of formula (XX) according to Embodiment 93, wherein the solvent is selected from the group consisting of benzene, methanol, toluene, and heptane.

[0271] Embodiment 95 is a method for preparing a compound of formula (XX) according to Embodiment 93, wherein the solvent is absolute ethanol.

[0272] Embodiment 96 is a method for preparing a compound of formula (XX) according to Embodiment 91, wherein hydrogen is in the gas phase.

[0273] Embodiment 97 is a method for preparing a compound of formula (XX) according to Embodiment 90, which further comprises reacting the compound of formula (XXa) with oxalic acid.

[0274] Embodiment 98 is a method for preparing a compound of formula (XXIII):

Chemical formula

Chemical formula

[0275] Embodiment 99 is a compound of formula (XX) to a compound of formula (XIII):

Chemical formula

Chemical formula

[0276] Embodiment 100 is a method for preparing a compound of formula (XXIII) according to embodiment 99, wherein the reaction between the compound of formula (XX) and the compound of formula (XIII) occurs in the presence of potassium iodide, potassium carbonate and acetonitrile.

[0277] Embodiment 101 is a compound of formula (XXI) reacting with a deprotecting agent to form a compound of formula (XXII):

Chemical formula

[0278] Embodiment 102 is a method for preparing a compound of formula (XXIII) according to embodiment 101, wherein the deprotecting agent is selected from the group consisting of iodine, TFA, HBr, MsOH, TsOH and CSA.

[0279] Embodiment 103 is a method for preparing a compound of formula (XXIII) according to embodiment 101, wherein the deprotecting agent is HCl.

[0280] Embodiment 104 is a method for preparing a compound of formula (XXIII) according to embodiment 101, wherein the reaction between the compound of formula (XXI) and the deprotecting agent occurs in the presence of a solvent.

[0281] Embodiment 105 is a method for preparing the compound of formula (XXIII) according to Embodiment 104, wherein the solvent is selected from the group consisting of isopropyl alcohol, methanol, ethanol, t-butanol, THF and MeCN.

[0282] Embodiment 106 is a method for preparing the compound of formula (XXIII) according to Embodiment 101, which further comprises reacting the compound of formula (XXII) with anhydrous L-(+)-lactic acid.

[0283] Embodiment 107 is a method for preparing the compound of formula (XXIII) according to Embodiment 106, wherein the purity of the compound of formula (XXIII) is 95% by weight or more.

[0284] Embodiment 108 is a method for preparing the compound of formula (XXIII) according to Embodiment 106, wherein the palladium content of the compound of formula (XXIII) is less than 10 ppm.

[0285] Embodiment 109 is a method for preparing the compound of formula (XXIII) according to Embodiment 106, wherein after storage at 5 °C and 60% relative humidity for 12 months, the aldehyde impurity of the compound of formula (XXIII) represented by the area percentage of RRT 1.3 is 0.15 area percentage or less.

[0286] Embodiment 110 is a method for preparing the compound of formula (XXIII) according to Embodiment 106, which further comprises reacting the compound of formula (XXII) with anhydrous L-(+)-lactic acid in the presence of one or more crystallization solvents.

[0287] Embodiment 111 is a method for preparing the compound of formula (XXIII) according to Embodiment 110, wherein the one or more crystallization solvents are methyl isobutyl ketone (MIBK) and n-heptane.

[0288] Embodiment 112 is a method for preparing the compound of formula (XXIII) according to Embodiment 110, wherein the one or more crystallization solvents are isopropyl alcohol and n-heptane.

[0289] Embodiment 113 is a method for preparing a compound of formula (XXIII) according to Embodiment 110, wherein one or more crystallization solvents are methyl ethyl ketone (MEK) and n-heptane.

[0290] Embodiment 114 is a method for preparing a compound of formula (XXIII) according to Embodiment 110, wherein one or more crystallization solvents are tetrahydrofuran (THF) and n-heptane.

[0291] Embodiment 115 is a method for preparing a compound of formula (XXIII) according to Embodiment 110, wherein one or more crystallization solvents are acetonitrile and methyl tert-butyl ether (MTBE).

[0292] Embodiment 116 is a method for preparing a compound of formula (XXIII) according to Embodiment 110, wherein one or more crystallization solvents are methyl acetate and n-heptane.

[0293] Embodiment 117 is a method for preparing a compound of formula (XXIII) according to Embodiment 110, wherein one or more crystallization solvents are ethyl acetate and n-heptane.

[0294] Embodiment 118 is a method for preparing a compound of formula (XXIII) according to Embodiment 110, further comprising seeding the reaction mixture with a lactate crystal compound of formula (XXIII).

[0295] Embodiment 119 is a method for preparing a compound of formula (XXIII) according to Embodiment 118, wherein seeding of the reaction mixture occurs at a temperature of 60 °C or lower.

[0296] Embodiment 120 is a method for preparing a compound of formula (XXIII) according to Embodiment 118, further comprising cooling the reaction mixture at a rate of about 0.01 °C / min to 1 °C / min.

[0297] Embodiment 121 is a method for preparing the compound of formula (XXIII) according to Embodiment 118, further comprising cooling the reactants at a rate of about 0.03 °C / min to 0.3 °C / min.

[0298] The problems of the known preparation processes of the compounds of formula (XXIII) and formula (XXIIIa) are addressed by the present application, as well as the embodiments and examples disclosed herein. Referring to Figure 2, the inventors unexpectedly discovered that the hydroxymethyl group of the compound of formula (XII) can be synthesized by preparing the important ester intermediate compound of formula (X) in a highly crystalline form using palladium-catalyzed carbonylation and then reducing it. Furthermore, the embodiments and examples herein describe new intermediates, chemical substances, and methods for synthesizing new chemical substances and intermediates. For example, the compounds of formula (Ia), formula (I), formula (IX), formula (X), formula (XI), and the oxalate compounds of formula (XVIa) and formula (XX) are new chemical substances that can be used in the preparation and synthesis of the compounds of formula (XXIII) and formula (XXIIIa).

[0299] The syntheses of Figure 2 and other exemplary embodiments also provide new chemical substances in the form of crystalline salts of formula (XVI) and formula (XX) and new methods for synthesizing the crystalline salt compounds of these formulas. The crystalline salts of the compounds of formula (XVI) and formula (XX) have higher purity than the amorphous salt form or the free base form, improving the purity of the synthesis of the final product compounds of formula (XXIII) and formula (XXIIIa). In certain embodiments, the compound of formula (XX) is in the form of an oxalate and is used in the form of an oxalate in the synthesis of the compound of formula (XXIII).

[0300] In the synthesis of the final compounds of formula (XXIII) and other compounds of formula (XXIIIa), certain advantages are provided by using the novel intermediate compounds of formula (Ia), formula (Va), formula (VII), formula (IX), formula (X) and formula (XI). The intermediates of formula (Ia), formula (Va), formula (VII), formula (IX), formula (X) and formula (XI) provide higher efficiency, predictability, separation, purity and stability in the synthesis of the final compounds of formula (XXIII). In the synthesis of the final compounds of formula (XXIII) and other compounds of formula (XXIIIa), further advantages are provided by using the novel intermediate compounds of formula (IX), formula (X), formula (XI), formula (XVI), formula (XVIa) and formula (XX). The intermediates of formula (IX), formula (X), formula (XI), formula (XVI), formula (XVIa) and formula (XX) provide higher efficiency, predictability, separation and purity in the synthesis of the final compounds of formula (XXIII).

[0301] The problems of the known preparation processes of the compounds of formula (XXIII) and other compounds of formula (XXIIIa) are addressed by the embodiments and examples of the present application. The present application discloses unexpected improvements in the synthesis of the compounds of formula (IX), formula (X), formula (XI), formula (XVI), formula (XVIa) and formula (XX), and in the synthesis of the final compounds of formula (XXIII). The hydroxymethyl group in the compound of formula (XII) is disposed using palladium-catalyzed carbonylation of the compound of formula (IX) to prepare an important ester intermediate compound of formula (X) in a highly crystalline form, which is then reduced to give a final product of formula (XXIII) with high purity and stability, which is less sticky and more suitable as a pharmaceutical formulation.

[0302] The following examples illustrate exemplary reaction conditions, parameters, and reagents for performing exemplary steps in the synthesis of compounds of formula (IX), formula (X), formula (XI), formula (XVI), formula (XVIa), formula (XX), the final product compounds of formula (XXIII), and other compounds of formula (XXIIIa). The following examples illustrate some of the embodiments described herein. Those skilled in the art will understand that various changes may exist for the examples without departing from the scope or spirit of the present application or the disclosed exemplary embodiments, including variations regarding the synthetic methods, processes, reactants, reagents, parameters, and conditions described herein. In the following examples, the acronym "NMT" is an abbreviation for "not more than".

[0303] Abbreviations BOC or Boc tert-butyloxycarbonyl tBuXphos 2-di-tert-butylphosphino-2’,4’,6’-triisopropylbiphenyl DCM Dichloromethane DMF Dimethylformamide DMSO Dimethyl sulfoxide DPPB 1,4-bis(diphenylphosphino)butane DPPE 1,2-bis(diphenylphosphino)ethane DPPF 1,1’-ferrocenediyl-bis(diphenylphosphine) DPPP 1,3-bis(diphenylphosphino)propane EtOAc Ethyl acetate EtOH Ethanol HCl Hydrochloric acid HBr Hydrobromic acid IPA Isopropyl alcohol KF Hygroscopic Karl Fischer test Me Methyl MeCN or ACN Acetonitrile MEK Methyl ethyl ketone MeOH Methanol MsOH Methanesulfonic acid MIBK Methyl isobutyl ketone MTBE or TBME Methyl tert-butyl ether NBS N-Bromosuccinimide NMP N-Methylpyrrolidine NMT Below Ph Phenyl Pd(OAc)Palladium(II) acetate 2 Palladium(II) acetate PdPalladium 2 (dba)Tris(dibenzylideneacetone)dipalladium(0) 3 Tris(dibenzylideneacetone)dipalladium(0) PPhTriphenylphosphine 3 Triphenylphosphine ppm Parts per million rac-BINAP (±)-2,2’-Bis(diphenylphosphino)-1,1’-binaphthalene RRT Relative retention time RH Relative humidity RuPhos 2-Dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl TFA Trifluoroacetic acid THF Tetrahydrofuran 2-Me-THF 2-Methyltetrahydrofuran TLC Thin layer chromatography TsOH p-Toluenesulfonic acid Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene XPhos 2-Dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl XPhos-Pd-G2 Chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II)

Example

[0304] Example 1: Preparation and synthesis of the compound of formula (IIIb):

Chemical formula

[0305] 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 the compound of formula (III) (8.0 g, 40.27 mmol, 1.0 eq) were added to a three-necked flask dried under nitrogen. 2-Me-THF (120 mL) was added, and the reaction mixture was heated to a temperature of 75 °C for 5 hours (until the compound of formula (III) disappeared), and the reaction mixture was cooled to a temperature of 60 °C.

Chemical formula

[0306] 4-Fluorobenzyl chloride (17.46 g, 14.47 mL, 120.8 mmol, 3.0 eq) was added to the reaction mixture, and then an aqueous potassium carbonate solution (57 mL, 1.8 M, 102.28 mmol, 2.54 eq) was added dropwise (over 1 hour). The reaction mixture was then stirred at a temperature of 60 °C for an additional 5 hours until the completion of the boronate as measured by thin layer chromatography (TLC). The reaction mixture was then cooled to room temperature and transferred to a separatory funnel. The organic layer was separated, and the aqueous layer was extracted with EtOAc (25 mL × 3). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was then purified by column chromatography (hexane:EtOAc = 20:1 → 15:1 → 10:1) to obtain 9.56 g (35.15 mmol, 87.3 wt%) of the desired product, which was formed as a pale yellow oil. The 1 1H-NMR (CDCl 3 ) 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).

[0307] Example 2: Preparation and synthesis of the compound of formula (IIIc): [Chemical formula]

[0308] NiCl 2 ·6H 2 O (10.90 g, 45.9 mmol, 2.5 equivalents) was added to a solution of the compound of formula (IIIb) (5.0 g, 18.36 mmol, 1.0 equivalent) in MeOH (60 mL). The reaction flask was transferred to an ice bath, and NaBH 4 (1.64 g, 43.5 mmol, 2.37 equivalents) was added portionwise over 15 minutes. The reaction mixture was stirred at 0 °C for 15 minutes and then at room temperature for an additional 3 hours (until the starting material disappeared by TLC). The reaction was then cooled in an ice bath, and 30% ammonia solution (50 mL) was added dropwise to quench it. The reaction mixture was then filtered through Celite™, the filter cake was washed with MeOH (10 mL × 3), and the filtrate was concentrated. Then, 15 mL of 30% ammonia solution was added to the reaction mixture, and it was extracted with dichloromethane (50 mL) and (4 × 20 mL). The combined organic extracts were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude reaction product was then purified by column chromatography (DCM:MeOH = 10:1, 1% Et 3 N) to obtain 3.68 g (73% by weight) of the desired product as a pale yellow viscous oil. The 1 1H-NMR (CDCl 3 ) analysis gave 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).

[0309] Example 3: Preparation and synthesis of the compound of formula (VII): [Chemical formula]

[0310] Solid NaHCO 3(11.2 g, 113.0 mmol, 10.0 equivalents) was added to a solution of the compound of formula (IIIc) (3.68 g, 13.3 mmol, 1.0 equivalent) in DMSO (55 mL). The slurry was then heated at 120 °C for 48 h. TLC showed a small amount of unreacted starting compound of formula (IIIc). NaHCO 3 (2.24 g, 22.5 mmol, 2.0 equivalents) was added and the reaction mixture was stirred at 120 °C for an additional 4 h. 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 h to give 2.61 g (77%) of the crude product as a pale yellow solid. The 1 1H-NMR (CDCl 3 ) 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).

[0311] Example 3A: Preparation and Synthesis of the Compound of Formula (VII):

Chemical formula

[0312] Lithium bromide (71.32 g, 3.0 equivalents), palladium acetate (0.614 g, 0.01 equivalent), and XPhos (3.39 g, 0.026 equivalent) were added to a solution of the compound of formula (V) (50 g, 1 equivalent) in N-methylpyrrolidone (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 equivalents, 0.5 M in THF) was added. The reaction mixture was heated at a temperature of 30 °C to 36 °C for 12 hours. At the end of the reaction, the reaction mixture was cooled to a temperature of 15 °C to 25 °C and quenched with a 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 twice with a 13% aqueous ammonium chloride solution (220 mL) at a temperature of 45 °C to 55 °C. 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 the mixture was stirred at a temperature of 15 °C to 25 °C for 30 minutes, filtered, and washed with heptane (100 mL). This solid was dried under vacuum at a temperature of 40 °C for about 8 to 10 hours to obtain the compound of formula (VII) (68.5 g, yield 81.2%, area HPLC purity 98.5%).

[0313] Example 3B: Preparation and Synthesis of the Compound of Formula (VIII):

Chemical formula

[0314] A solution of N-bromosuccinimide (21.4 Kg, 1.01 equivalents) in dimethylformamide (178 Kg) was added to a solution of the compound of formula (VII) (32.4 Kg, 1 equivalent) 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 water (455 Kg) was added at the end of the reaction. The resulting solid was filtered, washed with a mixture of dimethylformamide (95 Kg) and water (95 Kg), and then washed again with water (196 Kg). This 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, yield 84%, area HPLC purity 98.6%).

[0315] Example 4: Preparation and Synthesis of Compounds of Formula (Va):

Chem.

[0316] BOC anhydride (21.28 ml, 92 mmol) was added portionwise with rapid stirring to a mixture of the compound of formula (V) (6-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine) (10 g, 54.7 mmol) in THF (100 ml) and 8% w / w sodium carbonate in water (150 ml, 143 mmol). The reaction mixture was left stirring overnight. Triethylamine (TEA) (20 ml, 143 mmol) and BOC anhydride (10.64 ml, 45.8 mmol) were added and stirring was continued for a further 24 hours. Approximately 40% conversion occurred. The mixture was partitioned between EtOAc (200 ml) and water (200 ml). The organic layer was separated, dried (MgSO 4 ), filtered and the solvent removed to give a thick oil. Analysis of this oil after 16 hours showed complete conversion to the desired compound. The compound was purified by flash chromatography on silica gel (220 g cartridge, 0%→10% TBME / isohexane) to give the compound of formula (Va) (tert-butyl 6-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate) (13 g, 44.6 mmol, 81% yield) as a colorless oil. CDCl 3 in 1 1H-NMR was consistent with the structure of the product with 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, 1H), 7.54 (d, J = 48.7 Hz, 1H), 3.78 (s, 2H), 1.83 - 1.45 (m, 9H), 1.39 (s, 6H).

[0317] Example 5: Preparation and Synthesis of Compounds of Formula (Vc): [Chemistry]

[0318] Bis(pinacolato)diboron (BPin) 2 (5 g, 19.69 mmol), Pd-170 (XPhos Pd(crotyl)Cl (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 and this was backfilled with nitrogen three times and evacuated. A solution of the compound of formula (Va) (tert-butyl 6-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate) (5 g, 17.68 mmol) in 2-MeTHF (50 ml) was added, backfilled with nitrogen three times to evacuate this mixture and then stirred at 75 °C (internal temperature) for 30 minutes (or until conversion of the starting material by UPLC) under nitrogen. [Chemistry]

[0319] Also, in the present specification, formula (Vbb) is described as follows. [Chemistry]

[0320] 1.8 M potassium carbonate (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 mixture was cooled to ambient temperature and the organics were separated. The aqueous phase was extracted with EtOAc (50 ml). The organics were combined and dried over MgSO 4It was dried, filtered, adsorbed onto silica (10 g) in advance, and purified by chromatography on silica gel (80 g cartridge, 0%→20% EtOAc / isooctane) to obtain the compound of formula (Vc) (tert-butyl 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate) (5.8 g, 15.46 mmol, 87% yield) as a tan gum. The product was analyzed by LCMS (Waters Acquity UPLC, X-Select, Waters X-Select UPLC C18, 1.7 μm, 2.1×30 mm, acidic (0.1% formic acid) ternary gradient, 5%→95% MeCN / water) and the following results were obtained: 2370-69-2A, m / z 357.2 (M+H)+ (ES+); at 1.77 min, purity 95% (diode array). CDCl 3 In 2370-69-2A 1 1H-NMR was consistent with the product structure at a purity of 95% of 4% w / w EtOAc, 1% w / w isooctane. 1 1H-NMR (500 MHz, chloroform-d) gave the following results: δ 8.01 (s, 1H), 7.91&7.21 (2 x s, 1H, rotamer), 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).

[0321] Example 6: Preparation and synthesis of the 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):

Chemical formula

[0322] The 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 an NaCl / 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 mixture was warmed to room temperature and left to stand, and stirred for 60 hours. The reaction mixture was poured into brine (40 mL) and extracted with TBME (2 × 20 mL). The combined organic layers were concentrated directly on silica. The crude product was purified by chromatography on silica gel (12 g cartridge, 0%→20% EtOAc / isohexane) to give the compound of formula (IX) (190 mg, 0.43 mmol, 61.6% yield) as a white solid. 1 H-NMR (500 MHz, DMSO-d 6 ) analysis gave 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+), purity 99% (254 nm).

[0323] Example 6A: Preparation and synthesis of the 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):

Chemical formula

[0324] Di-tert-butyl dicarbonate (68.0 Kg, 2.57 equivalents) was added to a solution of the compound of formula (VIII) (41.6 Kg, assay 97.6%, purity 99.1%, 1 equivalent) in toluene (143.7 Kg) at a temperature of 15°C to 25°C. The mixture was cooled to 0°C to 10°C and stirred at that temperature for 10 to 20 minutes. A solution of sodium carbonate (19.2 Kg) in purified water (164.2 Kg) was added to this mixture, and the mixture was stirred at a temperature of 15°C to 25°C for 22 hours until the reaction was complete. N,N-Dimethylaminopyridine (0.4 Kg, 0.03 equivalent) was added to the mixture, and the resulting mixture was stirred at a temperature of 15°C to 25°C for 12 hours. The organic phase was separated, and the aqueous phase was extracted with toluene (145 Kg). The combined organic phases were concentrated under vacuum (NMT 50°C) to approximately 5 volumes. Toluene was swapped with methanol (4 × 320 Kg) until the residual toluene was NMT 1% with an approximately 5-volume methanol solution. The mixture was cooled to a temperature of 15°C to 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°C to 40°C to obtain the compound of formula (IX) (47.98 Kg, assay 100%, purity 100%) as an off-white solid.

[0325] Example 7: Preparation and Synthesis of the 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)

Chemical formula

[0326] Phenol (33.20 Kg, 3.5 equivalents), palladium(II) acetate (0.7 Kg, 0.03 equivalents), rac-1,1'-binaphthyl-2,2'-diphenylphosphine (1.9 Kg, 0.03 equivalents), and triethylamine (30.0 Kg, 3.0 equivalents) were added to a solution of the compound of formula (IX) (43.0 Kg, assay 99.8%, purity 99.9%, 1 equivalent) in acetonitrile (356 Kg) in a pressure reactor. The pressure reactor was sealed, purged with nitrogen gas, and then exchanged with carbon monoxide gas to a pressure of 0.03 MPa to 0.05 MPa. The reaction mixture was heated to a temperature of 55 °C to 65 °C, and at this temperature and pressure (0.03 MPa to 0.05 MPa), it was stirred for 33 hours until the compound of formula (IX) became NMT 1.0%. The reactor was purged with nitrogen gas, 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 not exceeding 50 °C, and swapped with ethanol (3 × 170 Kg) until the residual acetonitrile became NMT 2.0%. The mixture was heated to 45 °C to 50 °C, and water (26 Kg) was added at this temperature. The mixture was stirred at this temperature for 4 hours, then 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 a crude substance (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 swapped with ethanol (2 × 170 Kg) and distilled to about 5 volumes until the residual methyl tert-butyl ether became NMT 2%. The mixture was heated to a temperature of 70 °C to 80 °C and slowly cooled to 40 °C to 50 °C. Water (25 Kg) was added at this temperature, 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 became NMT 0.50% and KF became NMT 1%. The compound of formula (X) (38.8 Kg, assay 100%, purity 100%) was obtained as an off-white solid.

[0327] Example 8: Preparation and Synthesis of the Compound of Formula (XI) (Phenyl-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carboxylate):

Chem.

[0328] A solution of hydrochloric acid (75.6 Kg, 5.5 M) in isopropanol at a temperature of 50 °C to 55 °C was added to a solution of the compound of formula (X) (31.8 Kg, assay 100%, purity 100%, 1 equivalent) in isopropanol (226 Kg). The reaction mixture was stirred at this temperature for 9 hours until the reaction was complete (NMT 0.5% of the compound of formula (X)). The reaction mixture was concentrated under vacuum at about 45 °C to about 4 volumes and then cooled to a temperature of 15 °C to 25 °C. After adding 2-methyltetrahydrofuran (191 Kg) and water (256 Kg), the pH was adjusted to 8 using an 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 under vacuum at about 45 °C to about 4 volumes. Fresh 2-methyltetrahydrofuran (3 × 240 Kg) was added and distilled until the water content was NMT 0.10% to about 4 volumes, thereby obtaining a 2-methyltetrahydrofuran solution of the compound of formula (XI), which was subsequently used continuously in the next step (telescoped into).

[0329] Example 9: Preparation and Synthesis of the Compound of Formula (XII) ({6-[(4-Fluorophenyl)methyl]-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3.2-b]pyridin-5-yl}methanol):

Chem.

[0330] A solution of lithium borohydride (32.2 Kg, 1.05 equivalents) in THF at a temperature of -10°C 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°C to 0°C. The reaction mixture was stirred at this temperature for 9 hours until the reaction was complete (the unreacted compound of formula (XI) was NMT 1.0%). Then, this reaction mixture was added to a solution of potassium dihydrogen phosphate (38 Kg) in water (340 Kg). The organic phase was washed three times with an aqueous sodium hydroxide solution to obtain a pH of 12.5 to 13.0. The organic phase was washed with an aqueous potassium dihydrogen phosphate solution at pH 6.4 to 7.0. The organic phase was separated, swapped with toluene (2 × 220 Kg), and distilled until the residual 2-methyltetrahydrofuran was NMT 2% to obtain a volume of approximately 3. Then, the mixture was heated to a temperature of 70°C to 75°C and gradually cooled to a temperature of 0°C to 5°C over 4 to 5 hours. N-heptane (55 Kg) was added to the cooled mixture, 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) and dried under vacuum at a temperature of 30°C to 40°C for approximately 15 hours to obtain the compound of formula (XII) (15.5 Kg, yield 81.2%, assay 100%, purity 100%) as an off-white solid.

[0331] 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):

Chemical formula

[0332] 2-Chloroacetyl chloride (3.04 Kg, 1.10 equivalents) was added to a mixture of the compound of formula (XII) (7.0 Kg, assay 100%, purity 100%, 1 equivalent) in acetonitrile (55 Kg) at a temperature of 5 °C to 10 °C. The reaction mixture was warmed to a temperature of 7 °C to 13 °C and stirred at this temperature for 2 hours until the remaining compound of formula (XII) was NMT 0.2%. The reaction mixture was distilled under vacuum to NMT a temperature of 40 °C to 5 volumes, followed by addition of toluene (30.45 Kg) and distillation to 5 volumes. Methanol (66.5 Kg) was added and the mixture was cooled to a temperature of 0 °C to 5 °C. A solution of potassium carbonate (7.56 Kg, 2.24 equivalents) in water (42.8 Kg) was added at this temperature and stirred for approximately 30 minutes. The pH of the reaction mixture was adjusted to 3.5 - 4.5 using 3 M hydrochloric acid (27 liters). Toluene (2 x 30 Kg) was added and the mixture was distilled under vacuum to 10 volumes at NMT a temperature of 20 °C. Fresh toluene (60.9 Kg) was added and the organic layer was separated. The aqueous layer was washed with toluene (30 Kg). The combined organic layers were distilled to approximately 10 volumes, cooled to a temperature of 0 °C to 5 °C, n-heptane (47.6 kg) was added, and stirring was continued at this temperature for approximately 1 hour, followed by filtration. The filter cake was washed with a mixture of toluene (6 Kg) and n-heptane (4.76 Kg) to obtain the compound of formula (XIII) (8.0 Kg, yield 90.8%; assay 99.3%, purity 99.76%).

[0333] Example 11: Preparation and synthesis of the compound of formula (XV) (tert-butyl-(2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate):

Chemical formula

[0334] Triethylamine (135.2 Kg, 3 equivalents) and di-tert-butyl dicarbonate (242.6 Kg, 2.5 equivalents) were added to a solution of the compound of formula (XIV) (98.8 Kg, assay 90.9%, purity 95%, 1 equivalent) in ethanol (287.5 Kg). The mixture was reacted at a temperature of 15 °C to 30 °C for 12 hours until the reaction was complete (the remaining compound of formula (XIV) was NMT 1%). A solution of sodium hydroxide (124.4 Kg, 30 equivalents) in water (362 Kg) was added, and the mixture was heated at a temperature of 40 °C to 45 °C for 30 minutes, at 50 °C to 60 °C for 30 minutes, and at 70 °C to 75 °C for 30 hours until the reaction was complete. The reaction mixture was cooled to a temperature of 15 °C to 30 °C, and the pH was adjusted to 9.0 to 9.5 using aqueous hydrochloric acid (181.4 Kg in 308 Kg of water). The mixture was filtered and washed with dichloromethane (718 Kg). The organic phase was separated from the filtrate, and the aqueous layer was extracted with dichloromethane (3 × 719 Kg). The combined organic layers were washed with brine (157 Kg of sodium chloride in 901 Kg of water) and concentrated under vacuum at NMT 45 °C to about 4 volumes. The solvent was swapped with methyl tert-butyl ether (2 × 336 Kg), and distilled until the residual dichloromethane was NMT 15% to give about 4 volumes. The solvent was swapped with n-heptane (3 × 310 Kg) under vacuum at NMT 45 °C, and distilled until the residual dichloromethane was NMT 0.5%, the residual methyl tert-butyl ether was NMT 3%, and the residual ethanol was NMT 0.5% to give about 6 volumes. The mixture was cooled to a temperature of 10 °C 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 nitrogen stream until the residual n-heptane was NMT 0.5% to obtain the compound of formula (XV) (88.4 Kg, yield 84.8%, assay 97.6%, chemical purity 100% and chiral purity 100%) as a white solid.

[0335] Example 12: Preparation of the compound of formula (XVI) (tert-butyl-(2R,5R)-4-benzyl-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate):

Chemical formula

[0336] Benzaldehyde (46.8 Kg, 1.1 equivalents) was added to a solution of the compound of formula (XV) (92.6 Kg, assay 97.6%, purity 100%, 1 equivalent) 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 equivalents) 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 the content of the compound of formula (XV) reached NMT 0.1%. The reaction mixture was quenched with a solution of sodium bicarbonate (75 Kg in 960 Kg of water). The reaction mixture was degassed by nitrogen gas purge and extracted with dichloromethane (617 Kg). The organic layer was separated and treated with a solution of sodium bisulfite (185 Kg in 730 Kg of water) until the benzaldehyde content reached NMT 1%. The organic layer was washed with brine (300 Kg of sodium chloride in 993 Kg of water) and concentrated under reduced pressure to about 6 volumes at NMT 35°C until the KF reached NMT 0.2%. The obtained colorless and transparent solution of the compound of formula (XVI) in dichloromethane (259 Kg, yield 90%, assay 43.7%, purity 96%) was used in Example 14 to prepare the compound of formula (XVII).

[0337] Example 13: Preparation and Synthesis of the Oxalate Salt of the Compound of Formula (XVIa):

Chemical formula

[0338] Alternatively, the compound of formula (XV) can be converted to the oxalate compound of formula (XVIa) and used in the next step in Example 14. To produce the compound of formula (XVIa), methyl tert-butyl ether (5 volumes) was slowly added to a solution of the compound of formula (XV) in dichloromethane (20 g, assay approximately 27.6%), and concentrated to 3 volumes at a temperature of 30 °C. This process was repeated three more times to obtain a thin slurry in which a white solid was suspended. The slurry was filtered and washed with methyl tert-butyl ether (3 × 5 mL). The combined organic filtrates were washed with saturated sodium bicarbonate (2 × 10 mL), brine (10 mL), and dried over anhydrous sodium sulfate. The suspension was filtered and rinsed with methyl tert-butyl ether (3 × 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 volumes) was slowly added over 15 minutes. The resulting white slurry was stirred at room temperature for an additional 15 minutes, filtered through a Buchner funnel, and washed with methyl tert-butyl ether (2 × 2 volumes). The filter cake was dried under vacuum for 30 minutes to obtain the oxalate compound of formula (XVIa) (4.64 g, 11.3 mmol, 79% yield) as a white solid. This solid was slurried with methyl tert-butyl ether (10 volumes) and stirred for 15 minutes to form a white slurry. The white slurry obtained through a Buchner funnel was filtered and washed with methyl tert-butyl ether (2 × 2 volumes). The white filter cake was dried under vacuum for 30 minutes to produce the oxalate compound of formula (XVIa) (4.43 g, 96% recovery, 100% purity) as a white solid. It is also possible to use the oxalate compound of formula (XVIa) in the next step described in Example 14 to produce the compound of formula (XVII).

[0339] Example 14: Preparation and Synthesis of the Compound of Formula (XVII) (tert-Butyl-(2R,5R)-4-Benzyl-5-(Chloromethyl)-2-Methylpiperazine-1-Carboxylate)

Chemical Structure

[0340] To a solution of the compound of formula (XVI) (or its oxalate compound of formula (XVIa)), additional dichloromethane (761 Kg) and triethylamine (110 Kg, 3 equivalents) were charged and cooled to a temperature of 0 °C to 10 °C. Methanesulfonyl chloride (62.8 Kg, 1.5 equivalents) was added and the reaction mixture was stirred at this temperature for 9.5 hours until the conversion of the compound of formula (XVI) was NMT 10%. The mixture was warmed to a temperature of 15 °C to 30 °C and stirred at this temperature for a further 5.5 hours until the reaction was complete or until the compound of formula (XVI) reached NMT 1%. The reaction was quenched with a solution of ammonium chloride (200 Kg) in water (588 Kg). The organic layer was separated and the aqueous layer was extracted with dichloromethane (1013 Kg). The combined organic layers were washed with brine (312 Kg of sodium chloride in 931 Kg of water) and filtered through a pad of silica gel (93 Kg) using dichloromethane (1850 Kg). The filtrate was swapped with n-heptane (2 × 450 Kg) until the residual dichloromethane was NMT 0.2%. The mixture was cooled to a temperature of 0 °C to 5 °C and stirred at this temperature for 15 hours. The crystallized solid was filtered, washed with cold n-heptane (157 Kg) and dried under reduced pressure at NMT temperature 30 °C until the residual n-heptane was NMT 0.5% and the residual dichloromethane was NMT 0.5% to obtain the compound of formula (XVII) (99.0 Kg, yield 80.2%, assay 96.72%, purity 97.4%) as a pale yellow solid.

[0341] Example 15: Preparation and synthesis of the compound of formula (XIX) (tert-butyl-(2R,5S)-4-benzyl-2-methyl-5-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazine-1-carboxylate):

Chemical formula

[0342] Potassium iodide (64.4 Kg, 1.9 equivalents), potassium carbonate (86 Kg, 3.1 equivalents) and (R)-3-methylmorpholine hydrochloride (31 Kg of the compound of formula XVIII, 1.07 equivalents) were added to a mixture of the compound of formula (XVII) (70.8 Kg, assay 96.7%, purity 97.4%, 1 equivalent) in acetonitrile (536 Kg) at a temperature of 15 °C to 30 °C. The reaction mixture was first heated at 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 completion of the reaction or until the compound of formula (XVII) was NMT 0.5%, and filtered to remove the inorganic residue. The filtrate was swapped with n-heptane (2 × 274 Kg) by distilling at NMT temperature 45 °C under reduced pressure until the residual acetonitrile was NMT 0.2% to about 6 volumes. The mixture was cooled to a temperature of -5 °C to 5 °C, 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 rinse. 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 NMT temperature 40 °C to obtain the compound of formula (XIX) (49.2 Kg, yield 60.6%, assay 100%, purity 99.9%) as a white solid.

[0343] Example 16: Preparation and Synthesis of the Compound of Formula (XX) ((2R,5S)-tert-Butyl-2-methyl-5-{[(R)-3-methylmorpholino]methyl}piperazine-1-carboxylate Oxalate):

Chemical formula

[0344] To a mixture of the compound of formula (XIX) (13 Kg, 1 equivalent) in absolute ethanol (205 Kg), palladium on carbon (0.65 Kg, 10% supported, 50% wet) was added. The reaction mixture was purged with nitrogen gas followed by hydrogen gas. The reaction mixture was pressurized to 2 bar and heated at a temperature of 65 °C to 75 °C for 3 hours. The reaction mixture was cooled to a temperature of 15 °C to 25 °C, degassed with nitrogen gas, filtered, and washed with ethanol (21 Kg). The filtrate was concentrated under reduced pressure at a temperature not exceeding 50 °C to a volume of about 7.8, and cooled to a temperature of 10 °C to 15 °C. Oxalic acid (2.9 Kg, 1 equivalent) was added, the reaction mixture was warmed to a temperature of 15 °C to 25 °C and stirred for 1 hour. Acetonitrile (159 Kg) was charged, stirred at this temperature for 40 minutes, and then cooled to a temperature of 0 °C to 5 °C. The mixture was stirred at a temperature of 0 °C to 5 °C for 1 hour, filtered, washed with cold acetonitrile (2 × 40 Kg), and dried under reduced pressure at a temperature not exceeding 50 °C to obtain the compound of formula (XX) in oxalate form (10.6 Kg, yield 81.5%, purity 99.88%) as a white solid.

[0345] Example 17: Preparation and Synthesis of the 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):

Chemical formula

[0346] A mixture of the compound of formula (XIII) (7.9 Kg, 1 equivalent), the compound of formula (XX) (9.6 Kg, 1.1 equivalents), potassium iodide (7.1 Kg, 1.97 equivalents) and potassium carbonate (18.0 Kg, 5.94 equivalents) in acetonitrile (75 Kg) was stirred at a temperature of 15 °C to 25 °C for 3 hours until the reaction was complete or until the compound of formula (XIII) reached NMT 0.5%. The reaction mixture was distilled under reduced pressure to 4 volumes at NMT a temperature of 40 °C and cooled to a temperature of 15 °C to 25 °C. Ethyl acetate (43 Kg) and water (63 Kg) were added and stirred for 15 minutes. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (21 Kg). The combined organic layers were washed with a solution of potassium carbonate (3.2 Kg, 1.05 equivalents) in water (63 Kg), and subsequently washed three times with a solution of potassium dihydrogen phosphate (3.6 Kg) and sodium chloride (3.6 Kg) in water (30 Kg). The organic layer was treated with Quadrasil MP (trademark) (0.40 Kg) at a temperature of 15 °C to 25 °C for 3 hours, filtered and washed with methanol (25 Kg). The filtrate was swapped with methanol (25 Kg, 63 Kg) by distilling under reduced pressure to 4 volumes at NMT a temperature of 40 °C. Anhydrous methanol (85 Kg) was added to obtain a solution of the compound of formula (XXI) (115.7 Kg, yield 87%, assay 10.5%, purity 98.7%) in methanol, which was used as such in the next step of Example 18 to prepare the compound of formula (XXII).

[0347] Example 18: Preparation and Synthesis of the 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):

Chemical formula

[0348] A solution of the compound of (XXI) in methanol (114.6 Kg, assay 10.5%, purity 98.7%, 1 equivalent) obtained in the previous step of Example 17 was cooled to 0 °C to 10 °C, and 6N hydrochloric acid in methanol (22 Kg, 7.7 equivalents) 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 the compound of formula (XXI) reached NMT 0.5%. The reaction mixture was distilled under reduced pressure to about 5 volumes at a temperature of NMT 40 °C. The solvent was swapped with water (2 × 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). After adjusting the pH of the aqueous phase to 11.5 to 12.0 using an aqueous sodium hydroxide solution (37.6 Kg), it was extracted with ethyl acetate (3 × 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 with ethyl acetate (3 × 108 Kg) under reduced pressure at a temperature of NMT 40 °C until the water content reached NMT 0.7% to a volume of 9, and the compound of formula (XXII) was obtained as a solution in ethyl acetate (100.7 Kg, yield 88.6%, assay 8.9%, purity 98.2%), which was used as it was in the next step of Example 19 to prepare the compound of formula (XXIII).

[0349] Example 19: Preparation and Synthesis of the 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-one, L-(+)-lactate):

Chemical formula

[0350] A solution of the compound of formula (XXII) (from the step before Example 18) in ethyl acetate (98.7 Kg, assay 8.9%, purity 98.2%) was distilled under reduced pressure at a temperature not exceeding 40 °C until the water content reached not more than 0.7% to a volume of 7.5. A solution of anhydrous L-(+)-lactic acid (1.62 Kg, 1.10 equivalents) in ethyl acetate (20 Kg) was clarified with a water content of not more than 0.7% and rinsed with ethyl acetate (4.0 Kg). The solution of the 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 amount of the anhydrous lactic acid solution in ethyl acetate was added. The seed compound of formula (XXIII) (44 g) was seeded into this mixture at this temperature, and the remaining 2 / 3 of the amount of the lactic acid solution in ethyl acetate was slowly added over 2 hours at a temperature of 40 °C to 50 °C. n-Heptane (66 Kg) was added at this temperature and subjected to stirring for approximately 5.5 hours, and then cooled at a cooling rate of 1 °C per 5 minutes to a temperature of 5 °C to 15 °C. 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 not exceeding 45 °C until the residual ethyl acetate was not more than 4500 ppm and the residual n-heptane was not more than 4500 ppm to obtain the compound of formula (XXIII) as a crystalline white solid in the form of a lactate (10.6 Kg, yield 100%, purity 99.58%, palladium content less than 1 ppm, form C).

[0351] Example 20: Experimental data on the crystallization of the compound of formula (XXIII) A batch of the crude lactate of the compound of formula (XXIII) was prepared by reacting the compound of formula (XXIII) (37 g) with anhydrous L-(+)-lactic acid (1.1 equivalents) in ethyl acetate (255 mL). The resulting solution was evaporated to dryness to obtain the crude lactate of the compound of formula (XXIII) (41.7 g, yield 96.5%, area HPLC purity 98.81%). This crude lactate of the compound of formula (XXIII) was used in the following crystallization studies.

[0352] Crystallization Experiment 1: Crystallization from methyl isobutyl ketone (MIBK) and n-heptane: A suspension of the crude lactate 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), cooled to a temperature of 20 °C over 12 hours, and n-heptane (320 mL) was added over 1 hour. The resulting suspension was filtered and dried under vacuum to obtain the crystalline lactate compound of formula (XXIII) (yield 68%, area HPLC purity 99.16%, XRPD: form C).

[0353] Crystallization experiment 2: Crystallization from isopropanol and n-heptane: A suspension of the crude lactate compound of formula (XXIII) (4.0 g) in isopropanol (12 mL) was heated to a temperature of 30 °C to dissolve it, and 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 compound of formula (XXIII) (yield 67%, area HPLC purity 99.18%, XRPD: form C).

[0354] Crystallization experiment 3: Crystallization from methyl ethyl ketone (MEK) and n-heptane: A suspension of the crude lactate 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 compound of formula (XXIII), cooled to a temperature of 20 °C over 3 hours, and n-heptane (12 mL) was added over 6 hours. The resulting suspension was filtered and dried under vacuum to obtain the crystalline lactate compound of formula (XXIII) (yield 86%, area HPLC purity 99.13%, XRPD: form C).

[0355] Crystallization experiment 4: Crystallization from tetrahydrofuran (THF) and n-heptane: A suspension of the crude lactate compound of formula (XXIII) (4.0 g) in tetrahydrofuran (THF) (9 mL) was heated to 50 °C to dissolve. The solution was cooled to 35 °C, seeded with n-heptane (2 mL) and the lactate seed compound of formula (XXIII), and cooled to 20 °C over 6 hours. n-Heptane (8 mL) was added over 6 hours. The resulting suspension was filtered and dried under vacuum to obtain the crystallized lactate compound of formula (XXIII) (yield 81%, area HPLC purity 99.23%, XRPD: form C).

[0356] Crystallization experiment 5: Crystallization from acetonitrile and methyl tert-butyl ether (MTBE): A suspension of the crude lactate compound of formula (XXIII) (4.0 g) in acetonitrile (10 mL) was heated to 57 °C to dissolve. The solution was cooled to 50 °C and seeded with the lactate seed compound of formula (XXIII). Methyl tert-butyl ether (20 mL) was added and the solution was cooled to 20 °C over 6 hours. The resulting suspension was filtered and dried under vacuum to obtain the crystallized lactate compound of formula (XXIII) (yield 69%, area HPLC purity 99.62%, XRPD: form C).

[0357] Crystallization experiment 6: Preparation of the lactate compound of formula (XXIII) from methyl acetate and n-heptane: A solution of the free base compound of formula (XXIII) (17.47 g, assay 28.62%; 5 g of free base) in ethyl acetate was swapped with methyl acetate (50 mL) (3 times). A solution of L-(+)-lactic acid (0.92 g) in methyl acetate (72 mL) was added and the reaction mixture was heated to 50 °C. The solvent was switched with methyl acetate (50 mL) (3 times). The solution was adjusted to 40 °C in 50 minutes and seeded with the lactate compound of formula (XXIII) (25 mg). The suspension was concentrated to 8 volumes, n-heptane (40 mL) was added over 6 hours, and the suspension was cooled to 20 °C over 6 hours. The solid was filtered and dried at 55 °C for 7 hours to obtain the crystallized lactate compound of formula (XXIII) (5.11 g, yield 88%; area HPLC purity 99.67%; form C).

[0358] Crystallization Experiment 7: Preparation of the Lactate Compound of Formula (XXIII) from Ethyl Acetate and n-Heptane: A solution of the free base compound of formula (XXIII) in ethyl acetate (17.47 g, assay 28.62%; 5 g of free base) was swapped with methyl acetate (50 mL) (3 times) to obtain less than 0.5% KF. A solution of L-(+)-lactic acid (0.92 g) in methyl acetate (53 mL) was added and the reaction mixture was heated to a temperature of 78 °C. This solution was adjusted to a temperature of 65 °C in 50 minutes and seeded with the lactate compound of formula (XXIII) (25 mg). The solution was adjusted to a temperature of 40 °C in 90 minutes, n-heptane (73 mL) was added over 6 hours, and this solution was cooled to a temperature of 20 °C in 6 hours. The solid was filtered and dried at a temperature of 55 °C for 7 hours to obtain crystals of the lactate compound of formula (XXIII) (5.4 g, yield 93%; area HPLC purity 99.50%; form C).

[0359] The X-ray powder diffraction results of form C of the crystallized final product compound of formula (XXIII) described in Crystallization Experiment 7 are shown in Figure 5.

[0360] Crystallization Experiment 8: Crystallization of Crude Lactic Acid from Ethyl Acetate and n-Heptane: A suspension of crude lactic acid (11 Kg; area HPLC purity 99.76%) in ethyl acetate (158 Kg) was heated to reflux (at about 78 °C). The resulting solution was cooled to 65 °C, filtered to remove insolubles, and finally rinsed with ethyl acetate (5 Kg). The resulting solution was heated to reflux (at about 78 °C) and cooled from 46 °C to 50 °C at a rate of 0.5 °C / min. After seeding with the lactate compound of formula (XXIII) (55 g) at 48 °C, the mixture was maintained at this temperature for about 30 minutes. The slurry was then cooled to 20 °C in about 140 minutes and n-heptane (62 Kg) was added over 100 minutes. The slurry was then cooled to 10 °C in about 50 minutes and the mixture was stirred at this temperature for about 5 hours. The solid was filtered, washed with a mixture of ethyl acetate (20 Kg) and n-heptane (15 Kg), and dried under vacuum at 40 °C to 50 °C for about 4 hours to obtain the crystallized lactate compound of formula (XXIII) (9.9 Kg, yield 90%; area HPLC purity 99.91%, form C).

[0361] Based on experimental data, there is a correlation between the palladium content in the final end-product and the active ingredient of formula (XXIII), and the oxidative decomposition of aldehyde impurities. This correlation was observed under storage conditions of 25 °C and relative humidity (RH) of 60%. This decomposition is manifested as the aldehyde impurity peak of formula (XXV) that appears at a relative retention time (RRT) of 1.3.

Chemical formula

[0362] It was found that the peak of this impurity is 0.2% a / a or less when stored at 2 °C to 8 °C, but higher levels are observed at higher temperatures. The experimental results for the active ingredient lots corresponding to the formulations shown in Tables 1 to 3 are shown in Figures 6 to 7, and Tables 1, 4, and 5.

[0363] Experimental results were obtained using the lot of the compound of formula (XXIII) shown in Table 1.

[0364]

Table 1

[0365]

Table 2

[0366]

Table 3

[0367] The stability data for aldehyde impurities and the effect of palladium content, expressed as the area percentage at RRT 1.3 under storage conditions of 25 °C and 60% RH, are shown in Table 4 and Figure 6.

[0368]

Table 4

[0369] Provide the effect of temperature on stability and the level of aldehyde impurities represented by the area percentage of RRT1.3 in Table 5 and Figure 7.

[0370] [Table 5]

[0371] The experimental results shown in Figures 6 - 7, and Tables 1, 4 and 5 confirm that there is a correlation between the palladium content in the active ingredient and the oxidative degradation observed at 25 °C / 60% RH, as determined by the percentage of the peak area appearing at RRT1.3. The peak levels of these impurities were found to be 0.2% a / a or less when stored at 2 °C - 8 °C, but higher levels were observed at elevated temperatures. These results suggest that the reduction of palladium and maximization of purity in the final product, the compound of formula (XXIII), leads to more stable pharmaceutical raw materials and drug formulations.

[0372] Novel intermediate compounds of formula (Ia), formula (Va), formula (VII), formula (IX), formula (X) and formula (XI) are disclosed herein and can be used in the synthesis of the final product compound of formula (XXIII) and other compounds of formula (XXIIIa). The intermediates of formula (Ia), formula (Va), formula (VII), formula (IX), formula (X) and formula (XI) provide higher efficiency, predictability, isolation, purity and stability in the final product and during the synthesis of the final product compound of formula (XXIII). The problems of the known preparation processes of the compounds of formula (XXIII) and other compounds of formula (XXIIIa) are addressed by the embodiments and examples of the present application.

[0373] Novel intermediate compounds of formula (IX), formula (X), formula (XI), formula (XVI), formula (XVIa) and formula (XX) are disclosed herein and 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), formula (X), formula (XI), formula (XVI), formula (XVIa) and formula (XX) provide higher efficiency, predictability, isolation, purity and stability in the final product and during the synthesis of the final product compound of formula (XXIII). The problems of the known preparation processes of the compounds of formula (XXIII) and other compounds of formula (XXIIIa) are addressed by the embodiments and examples of the present application.

[0374] The compounds of formula (XXIII) synthesized by the processes and intermediates disclosed herein can be formed into complexes, prodrugs or salt forms as disclosed in U.S. Patent No. 9,783,538.

[0375] The compounds of formula (XXIII) synthesized by the processes and intermediates disclosed herein can be used in the treatment of the diseases and conditions disclosed in U.S. Patent No. 9,783,538.

[0376] The compounds of formula (XXIII) synthesized by the processes and intermediates disclosed herein can be administered according to the medicaments, pharmaceutical preparations, pharmaceutical compositions, dosage forms, excipients, therapeutic agents and dosing regimens disclosed in U.S. Patent No. 9,783,538.

[0377] The compounds of formula (XXIII) synthesized by the processes and intermediates disclosed herein can be used in medicaments for the treatment of 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.

[0378] The disclosed exemplary compounds, intermediates and synthetic methods produce important intermediate compounds of formula (IX), resulting in higher purity and stability in the compounds of formula (XXIII) which are effective IAP antagonists. Also, the exemplary synthetic routes utilize novel chemical substances such as the compounds of formula (Ia) to produce the compounds of formula (IX) and formula (XXIII).

[0379] The disclosed exemplary compounds, intermediates and synthetic methods produce important intermediate compounds of formula (IX), formula (X), (XI), formula (XVI), formula (XVIa) and formula (XX), resulting in higher purity and higher stability in the compounds of formula (XXIII) which are effective IAP antagonists. Also, the exemplary synthetic routes utilize novel chemical substances such as the compounds of formula (IX), formula (X), formula (XI), formula (XVIa) and formula (XX) to produce the compounds of formula (XXIII).

Claims

1. A method for preparing a compound of formula (XXXIII): 【Chemical 1】 comprising: (1-i) contacting a compound of formula (XX): 【Chemical 2】 with a compound of formula (XIII): 【Chemical 3】 and a compound of formula (XXI): 【Chemical Formula 4】 or a salt, solvate or hydrate thereof, under conditions sufficient to provide the compound; (1-ii) deprotecting the compound of formula (XXI), or a salt, solvate or hydrate thereof, to provide a compound of formula (XXII): 【Chemical Formula 5】 or a salt, solvate or hydrate thereof; (1-iii) contacting the compound of formula (XXII) with lactic acid to provide a compound of formula (XXXIII).

2. The compound of formula (XIII) is prepared by: (2-i) reacting a compound of formula (V): [[Chemical Formula 6]] with a compound of formula (VI): [Chemical Formula 7] in the presence of one or more palladium catalysts and ligands to provide a compound of formula (VII): 【Chemical 8】 ; (2-ii) brominating the compound of formula (VII) to obtain a compound of formula (VIII): 【Chemical Formula 9】 ; (2-iii) protecting the compound of formula (VIII) to provide a compound of formula (IX): 【Chemical 10】 ; (2-iv) contacting the compound of formula (IX) with carbon monoxide and a compound of formula (X): 【Chemical 11】 or a salt, solvate or hydrate thereof, under conditions sufficient to provide the compound; (2-v) removing the tert-butyloxycarbonyl (Boc) protecting group from the compound of formula (X), or a salt, solvate or hydrate thereof, to provide a compound of formula (XI): 【Chemical Formula 12】 ; (2-vi) reducing the compound of formula (XI) to provide a compound of formula (XII): 【Chemical 13】 ; (2-vii) contacting the compound of formula (XII) with chloroacetyl chloride to provide a compound of formula (XIII). The method according to claim 1, wherein the compound of formula (XIII) is prepared by the method comprising the above steps.

3. The one or more palladium catalysts in step (2-i) are selected from the group consisting of XPhos-Pd-G2 catalyst, Pd(OAc) ２ and Pd ２ (dba) ３ The method according to claim 2, wherein the one or more palladium catalysts in step (2-i) are selected from the group consisting of XPhos-Pd-G2 catalyst, Pd(OAc), Pd(dba), and Pd.

4. The ligand in step (2-i) is PPh ３ , Xantphos, DPPPE, DPPP, DPPB, DPPF, rac-BINAP, RuPhos, XPhos and tBuXPhos, and the method according to claim 2, which is selected from the group consisting of.

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

6. The method according to claim 5, wherein the reaction of the compound of formula (IX) occurs in solution in the presence of rac-1,1'-binaphthyl-2,2'-diphenylphosphine.

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

8. Reacting the compound of formula (IX) can be carried out in the presence of PPh ３ , Xantphos, DPPPE, DPPP, DPPB, DPPF, rac-BINAP, RuPhos, tBuXphos and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), which is selected from the group consisting of, according to claim 5 Method.

9. A method for preparing a compound of formula (XX): 【Chemical 14】 comprising: (9-i) a compound of formula (XIX): 【Chemical Formula 15】 debenzylating the compound of (9-ii) contacting the debenzylated product with oxalic acid in a solvent to provide a compound of formula (XX); and A method comprising. **Claim 10** The method according to claim 9, wherein the debenzylation in step (9-i) is carried out in the presence of palladium on carbon and hydrogen gas. **Claim 11** Formula (XX): 【Chemical 16】 Compound of. **Claim 12** Formula (XXXIII): 【Chemical 17】 A method for preparing a compound of (12-i) a compound of formula (IX): 【Chemical Formula 18】 or a salt, solvate or hydrate thereof, with carbon monoxide and a compound of formula (X): 【Chemical Formula 19】 contacting a salt, solvate or hydrate thereof under conditions sufficient to provide a compound of (12-ii) 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): 【Chemical 20】 a salt, solvate or hydrate thereof, or (12-iii) reducing the compound of formula (XI) or a salt, solvate or hydrate thereof to provide a compound of formula (XII): 【Chemical 21】 a salt, solvate or hydrate thereof, or (12-iv) contacting the compound of formula (XII) or a salt, solvate or hydrate thereof with chloroacetyl chloride to provide a compound of formula (XIII): 【Chemical 22】 a salt, solvate or hydrate thereof, or (12-v) the compound of formula (XIII) or a salt, solvate or hydrate thereof with a compound of formula (XX): 【Chemical 23】 contacting a compound of formula (XXI): 【Chemical Formula 24】 under conditions sufficient to provide a salt, solvate or hydrate thereof, and (12-vi) deprotecting the compound of formula (XXI) or a salt, solvate or hydrate thereof to provide a compound of formula (XXII): 【Chemical 25】 a salt, solvate or hydrate thereof, or (12-vii) contacting the compound of formula (XXII) with lactic acid to provide a compound of formula (XXXIII); and A method comprising.

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