Process for preparing ERK inhibitors

Abstract

The present disclosure generally relates to methods for preparing Compound (I).

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 209,877, filed June 11, 2021, and U.S. Provisional Application No. 63 / 273,326, filed October 29, 2021, each of which is incorporated by reference in its entirety.

[0002] The present application relates to a process for the synthesis of ERK1 / 2 inhibitors, novel intermediates and methods for synthesizing the same. [Background technology]

[0003] Extracellular signal-regulated kinases (ERK1 / 2) are ubiquitously expressed protein serine / threonine kinases and comprise key components of the mitogen-activated protein kinase (MAPK) signaling pathway. The MAPK pathway is an evolutionarily conserved cell signaling pathway that regulates a variety of cellular processes, including cell cycle progression, cell migration, cell survival, differentiation, metabolism, proliferation, and transcription. ERK1 / 2 activity is commonly upregulated in cancer as a result of activating mutations within upstream components of the MAPK pathway. ERK1 / 2 inhibitors are useful in therapy, particularly in the treatment of cancer.

[0004] Disclosed herein are improved methods for the synthesis of ERK1 / 2 inhibitor compounds. Summary of the Invention

[0005] The present disclosure provides, in one embodiment, a compound of formula (I): [ka] ("Compound (I)"), or a pharma- ceutically acceptable salt, solvate or hydrate thereof, is provided, including the use of intermediates of formula (C), formula (D), formula (G-1), formula (G-3), formula (H-1), formula (J-3), formula (J-4), formula (S), and / or other intermediates described herein. Improved methods for the synthesis of intermediates of formula (J-2), and their use for the synthesis of Compound (I) are also provided. Compound (I) is named (2R)-2-(6-{5-chloro-2-[(tetrahydro-2H-pyran-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide.

[0006] In one embodiment, as described in the Detailed Description and Examples section, a compound of formula (D): [ka] or a salt thereof.

[0007] In one embodiment, as described in the Detailed Description and Examples section, a compound of formula (J): [ka] Provided herein is a process for the preparation of a compound of the formula:

[0008] In one embodiment, the formula (G-1): [ka] (Wherein, R is C 1~5 or a salt thereof.

[0009] In one embodiment, the formula (G-2): [ka] (Wherein, R is C1~5 or a stereoisomer or salt thereof.

[0010] In one embodiment, the formula (G-3): [ka] (Wherein, R is C 1~5 or a salt thereof.

[0011] In one embodiment, the formula (H-1): [ka] or a salt thereof is provided herein.

[0012] In one embodiment, the formula (J-3): [ka] Provided herein are compounds of the formula:

[0013] In one embodiment, the formula (J-4): [ka] Provided herein are compounds of the formula:

[0014] In one embodiment, the formula (M-2): [ka] or a salt thereof is provided herein.

[0015] In one embodiment, a compound of formula (S): [ka] (In the formula, R 2 and R 3 are independently H, C 1~5 alkyl or R2 and R 3 can contain 1, 2, 3 or 4 C together with the atoms to which they are attached. 1~3 Provided herein are compounds of the formula:

[0016] In one embodiment, as described in the Detailed Description and Examples section, a compound of formula (N): [ka] Methods for preparing the compounds of the formula (I) are provided herein. [Brief description of the drawings]

[0017] [Figure 1] FIG. 1 shows the X-ray powder diffraction pattern of Form B of Compound (I) prepared by the methods described herein. [Diagram 2] FIG. 2 shows the single crystal X-ray structure for Form B of Compound (I) as an ORTEP plot. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Compound (I) is described in WO 2017 / 068412 as Example 685, which is incorporated herein by reference in its entirety. Compound (I) is useful for the treatment of cancer and other conditions described in WO 2017 / 068412.

[0019] The method for synthesizing compound (I) described in WO 2017 / 068412 includes the reaction of trichloropyrimidine (X) with a boronic acid compound (M-1) and then with tetrahydropyranylamine (B), as shown in Scheme A below. [ka]

[0020] It was determined that the reaction of (M-1) with (X) to provide (Y) results in undesirable side reactions that are problematic during large-scale manufacture. The Suzuki coupling reaction between compounds (M-1) and (X) leads to the formation of compounds other than (Y) due to the presence of multiple chlorine atoms in compound (X). Typically, the Suzuki coupling between (M-1) and (X) provided approximately 50% yield (35.9% area by HPLC) of the bis-coupled impurity and approximately 33.4% area by HPLC of an additional impurity associated with hydrolysis of (Y) and (X). Furthermore, the reaction of (Z) with (B) requires harsh conditions including the use of N-methylpyrrolidine (NMP) as a solvent, can only be carried out on a small scale, and leads to the telescoping of two impurities that are difficult to separate from the final compound (I), (Z-1) and (Z-2), shown below. [ka]

[0021] Described herein is a method for preparing a compound of formula (D) and the use of compound (D) for the preparation of compound (N). Advantageously, the use of compound (D) improves the process for the preparation of compound (I) by avoiding the production of undesired by-products and increasing the yield of compound (N).

[0022] A further improvement described herein is the preparation of compounds of formula (J-2) with improved purity and improved chiral purity, and their use for the preparation of compound (I), as described herein in Scheme 1 and in the Examples.

[0023] definition The following description sets forth exemplary embodiments of the present technology, however, it should be appreciated that such description is not intended to limit the scope of the disclosure, but is instead intended as an illustration of exemplary embodiments.

[0024] As used herein, the following words, expressions and symbols are generally intended to have the meanings set forth below, except to the extent that the context in which they are used indicates otherwise.

[0025] As used herein, "a compound of formula (XX)" is used interchangeably with "formula XX", "compound (XX)", "compound XX", "XX" or "(XX)".

[0026] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment to a substituent. For example, -C(O)NH2 is attached through a carbon atom. Dashes at the beginning or end of a chemical group are for convenience, and a chemical group may be shown with one or more dashes or without any dashes without loss of ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of the groups. Unless chemically or structurally required, no directionality is indicated or implied by the order of listing or naming chemical groups.

[0027] Prefix “C” u~v " indicates that the following group has u to v carbon atoms. For example, "C 1~6 "Alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0028] As used herein, reference to "about" with respect to a value or parameter includes (and describes) embodiments directed to the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ±10%. In other embodiments, the term "about" includes the indicated amount ±5%. In certain other embodiments, the term "about" includes the indicated amount ±1%. Additionally, the term "about X" includes the description of "X". Additionally, the singular forms "a" and "the" not clearly indicating a plural referent in the context include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0029] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1~20 alkyl), 1 to 8 carbon atoms (i.e. C 1~8 alkyl), 1 to 6 carbon atoms (i.e. C 1~6 alkyl), or 1 to 4 carbon atoms (i.e., C 1~4 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbon atoms is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbon atoms may be included, so that, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0030] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), 2 to 8 carbon atoms (i.e. C 2~8 alkenyl), 2 to 6 carbon atoms (i.e. C 2~6 alkenyl), or 2 to 4 carbon atoms (i.e. C 2~4 Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0031] "Alkoxy" refers to the group --OR, where R is alkyl as defined herein.

[0032] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to an aromatic carbocyclic group having 6 to 20 ring carbon atoms (i.e., C 6~20 aryl), 6 to 12 ring carbon atoms (i.e. C 6~12 aryl), or 6 to 10 ring carbon atoms (i.e., C 6~10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap in any way with heteroaryl, as defined below. When one or more aryl groups are fused to a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused to a heterocyclyl, the resulting ring system is a heterocyclyl.

[0033] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having a single ring or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups with at least one double bond). As used herein, cycloalkyl refers to cyclic alkyl groups having 3 to 20 ring carbon atoms (i.e., C3~20 Cycloalkyl), 3 to 12 ring carbon atoms (i.e. C 3~12 Cycloalkyl), 3 to 10 ring carbon atoms (i.e. C 3~10 cycloalkyl), 3 to 8 ring carbon atoms (i.e. C 3~8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3~6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0034] "Carboxylic acid" refers to an organic acid containing a -COOH group. "Alkali metal salt of a carboxylic acid" refers to a salt of a carboxylic acid containing a Group 1 metal ion, i.e., lithium, sodium, potassium, rubidium, cesium, or francium salt.

[0035] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances when that event or circumstance occurs or does not occur. Also, the term "optionally substituted" refers to any one or more hydrogen atoms on a specified atom or group may or may not be replaced with a non-hydrogen moiety.

[0036] Some of the compounds may exist as stereoisomers. Regardless of which stereoisomer is shown, it is understood by those skilled in the art that the compound includes other stereoisomers and / or racemic mixtures. For example, if the (S) stereoisomer is shown, the (R) stereoisomer and racemic mixtures are also expressly included within the scope of the embodiments presented herein.

[0037] Some of the compounds may exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and the nature of the equilibrium between the tautomers, one skilled in the art would understand the compound to include both the amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0038] Any formula or structure given herein is intended to represent isotopically labeled forms of the compound as well as unlabeled forms. Isotopically labeled compounds have the structure shown in the formula given herein, except that one or more atoms are replaced with an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine. 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I, etc. Various isotopically labeled compounds of the present disclosure include, for example, 3 H and 14 C. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiation treatment of patients.

[0039] The present disclosure also includes "deuterium analogs" of compounds of formula I in which one to n hydrogens attached to a carbon atom are replaced with deuterium, where n is the number of hydrogens in the molecule. Such compounds are highly resistant to metabolism and are therefore useful for increasing the half-life of any compound of formula I when administered to a mammal, particularly a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12): 524-527 (1984). Such compounds are synthesized by means known in the art, for example, using starting materials in which one or more hydrogens have been replaced with deuterium.

[0040] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may confer certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds may be useful for PET or SPECT studies.The isotopically labeled compounds and their prodrugs of the present disclosure can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below, substituting non-isotopically labeled reagents with readily available isotopically labeled reagents.In this context, it is understood that deuterium is considered as a substituent in the compound of formula I.

[0041] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise noted, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen in natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0042] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. "Salts" may be derived from inorganic acids, inorganic bases, organic acids, or organic bases. Salts derived from inorganic acids include salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include salts of acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, mandelic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, tetrahydrofuran carboxylic acid, and the like. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary amines, secondary amines, and tertiary amines.

[0043] Pharmaceutically acceptable salts, hydrates, solvates, and tautomeric forms of Compound (I) described herein are also provided. "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.

[0044] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. Furthermore, when a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, etc. Similarly, pharma-ceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts.Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)), aryl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0045] The salt or pharma- ceutically acceptable salt provided herein may be a "solvate" formed by the interaction of a solvent and a compound. Solvates of the salts of the compounds described herein are also provided. When the solvent is water, the solvate is a hydrate. The salt or pharma- ceutically acceptable salt provided herein may be a hydrate. Also provided are "hydrates" of the compounds described herein.

[0046] The term "substantially crystalline" refers to a form of the compound of formula (I) having 50% to 100% crystallinity. Within this range, the compound of formula (I) may have at least 55% crystallinity, or at least 60% crystallinity, or at least 70% crystallinity, or at least 80% crystallinity, or at least 90% crystallinity, or at least 95% crystallinity, or at least 98% crystallinity, or at least 99% crystallinity, or at least 99.5% crystallinity, or at least 99.9% crystallinity, such as 100% crystallinity.

[0047] The term "transaminase" refers to an amine transaminase (ATA) enzyme reagent capable of transferring an amino group to an appropriate substrate. When the substrate is prochiral, the transminase can selectively form a single stereoisomer. By way of example only, an amine transferase reagent can convert a ketone to either an (R) amine or an (S) amine, as shown below: [ka]

[0048] Examples of ATAs include, but are not limited to, commercially available ATAs such as (R-) selective transaminases ATA-013, ATA-205, ATA-301, ATA-303, and ATA-412. Other ATAs within the scope of the present disclosure are commercially available, for example, from CODEX™ ATA screening kits, Johnson Matthey screening kits, Enzymeworks, Synzozymes, etc., and known to those of skill in the art.

[0049] Abbreviation Abbreviation Meaning ACN or MeCN Acetonitrile BINAP (1,1'-binaphthalene-2,2'-diyl)bis(diphenylphosphine) (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) BuOH n-butanol ℃ Celsius DCM Dichloromethane DMF Dimethylformamide DIBAL-H Diisobutylaluminum hydride DIPEA Diisopropylethylamine aq. Water-based g grams hrs time M Molar concentration Me Methyl (CH3) MeOH Methanol mg milligram MHz Megahertz ml / mL milliliter mM millimolar concentration mmol MTBE Methyl tert-butyl ether nL nanoliter nm nanometer μL / μl microliter μM micromolar Pd(dppf)Cl2 [Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) PPh3 Triphenylphosphine P(o-Tol)3 Tri(o-tolyl)phosphine PCy3HBF4 Tricyclohexylphosphine tetrafluoroborate dppf 1,1'-ferrocenediyl-bis(diphenylphosphine) dppe Ethylenebis(diphenylphosphine) STAB Sodium triacetoxyborohydride TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate t-BuXphos [2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl] TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin Layer Chromatography Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0050] method Formula (D): [ka] or a salt thereof, comprising the steps of: (i) Formula (A): [ka] or a salt thereof, [ka] or a salt thereof, and a compound of formula (C): [ka] or a salt thereof; and (ii) chlorinating said compound of formula (C) or a salt thereof to provide a compound of formula (D) or a salt thereof; A process is provided herein, comprising:

[0051] In some embodiments of the process for preparing compound (D), the compound of formula (A) has the formula (A-1): [ka] It is a compound of the formula:

[0052] In some embodiments of the process for preparing compound (D), step (i) further comprises a base and a solvent. In some of these embodiments, the base is an amine. In some embodiments, the amine is diisopropylethylamine. In some embodiments of the process for preparing compound (D), the solvent is a protic solvent. In some embodiments, the protic solvent is n-butanol. Other protic solvents, such as methanol, ethanol, isopropanol, propanol, etc., are contemplated within the scope of the embodiments presented herein.

[0053] In some embodiments of the process for preparing compound (D), step (ii) is carried out in the presence of phosphoryl chloride. Other suitable chlorinating agents, such as sulfuryl chloride, thionyl chloride, phosgene, and its derivatives (diphosgene and triphosgene), are contemplated within the scope of the embodiments presented herein.

[0054] Formula (J): [ka] or a stereoisomer or a salt thereof, comprising the steps of: (i) Formula (E): [ka] with a compound of formula (F): [ka] or a stereoisomer or a salt thereof, and a compound of formula (G): [ka] wherein R is C1-5 alkyl, or a stereoisomer or salt thereof; (ii) contacting the compound of formula (G) or a stereoisomer or a salt thereof with a reducing agent to obtain a compound of formula (H): [ka] or a stereoisomer or a salt thereof; (iii) contacting the compound of formula (H), or a stereoisomer or salt thereof, with an acid to provide a compound of formula (J), or a stereoisomer or salt thereof; A process is provided herein, comprising:

[0055] In some embodiments of the process for preparing compound (J), the compound of formula (F) has the formula (F-1): [ka] or a salt thereof, The compound of formula (G) is represented by formula (G-1): [ka] (wherein R is C1-5 alkyl) or a salt thereof; The compound of formula (H) is represented by formula (H-1): [ka] The structure is The compound of formula (J) is represented by formula (J-1): [ka] or a salt thereof.

[0056] Formula (J): [ka] or a stereoisomer or a salt thereof, comprising the steps of: (i) Formula (E): [ka] with a compound of formula (F): [ka] or a stereoisomer or a salt thereof, and a compound of formula (G): [ka] wherein R is C1-5 alkyl, or a stereoisomer or salt thereof; (ii) contacting the compound of formula (G) or a stereoisomer or a salt thereof with a reducing agent to obtain a compound of formula (G-2): [ka] (wherein R is C1-5 alkyl) or a salt thereof; (iii) contacting the compound of formula (G-2), or a stereoisomer or a salt thereof, with a reducing agent to obtain a compound of formula (H): [ka] or a stereoisomer or a salt thereof; (iv) contacting the compound of formula (H), or a stereoisomer or salt thereof, with an acid to provide a compound of formula (J), or a stereoisomer or salt thereof; A method is provided herein comprising:

[0057] In some embodiments of the process for preparing compound (J), the compound of formula (F) has the formula (F-1): [ka] or a salt thereof, The compound of formula (G) has the formula (G-1): [ka] (wherein R is C1-5 alkyl) or a salt thereof; The compound of formula (G-2) is represented by formula (G-3): [ka] (wherein R is C1-5 alkyl) or a salt thereof; The compound of formula (H) is represented by formula (H-1): [ka] The structure is The compound of formula (J) is represented by formula (J-1): [ka] or a salt thereof.

[0058] In some embodiments of the process for preparing compound (J), the compound of formula (J) has formula (J-2): [ka] It has the structure:

[0059] In some embodiments of the process for preparing compound (J) described above, step (i) is carried out in the presence of a Lewis acid. In some embodiments, the Lewis acid is selected from the group consisting of MgSO4, CuSO4, Cs2CO3, Yb(OTf)3, ZnCl2, tris-(2,2,2-trifluoroethyl)borate, trialkyl borate, diazabicycloundecene (DBU), KO t Bu, TiCl4, BF3·OEt2, Sc(OTf)3, or formula (K): Ti(OR 1 )4(K) (Formula, R 1 is a C1-5 alkyl) titanium alkoxide.

[0060] In some embodiments, the Lewis acid is Ti(OiPr)4 or Ti(OEt)4.

[0061] In some embodiments of the process for preparing compound (J), the imine bond and the ester group are reduced in a single reduction step, and the reducing agent in step (ii) is borane, NaBH4 / BF3·OEt2, sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al™), diisobutylaluminum hydride (DIBAL), or NaBH4 / I2. In some such embodiments, the reducing agent in step (ii) is borane. In some such embodiments, compound (G-1) may be partially reduced to give a mixture of compounds in which the ester group remains intact and / or is reduced to an alcohol.

[0062] In some embodiments of the process for preparing compound (J), the first reduction step reduces the imine bond and the second reduction step reduces the ester group, and the reducing agent for the first reduction in step (ii) is LiBH4, NaBH4, or ZnBH4. In some of such embodiments, the reducing agent for the second reduction in step (iii) is borane, NaBH4 / BF3·OEt2, sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al™), diisobutylaluminum hydride (DIBAL), or NaBH4 / I2.

[0063] Formula (N): [ka] or a salt thereof, comprising the steps of: Formula (D): [ka] or a salt thereof, [ka] (In the formula, R 2 and R 3 are independently H, C 1~5 alkyl or R 2 and R 3 can contain 1, 2, 3 or 4 C together with the atoms to which they are attached.1~3 Provided herein is a process that includes contacting a compound of formula (N) or a salt thereof with a compound of formula (R) (which forms a 5- or 6-membered ring, optionally substituted with alkyl) under conditions sufficient to provide a compound of formula (N) or a salt thereof.

[0064] In some embodiments of the process for preparing compound (N), the process is carried out in the presence of an aqueous base and a palladium catalyst. In some of such embodiments, the aqueous base is aqueous K2CO3, aqueous Na2CO3, aqueous Cs2CO3, aqueous LiOH, or aqueous K3PO4. In some embodiments, the aqueous base is aqueous K3PO4. In some of these embodiments, the palladium catalyst is Pd(dppf)Cl2 or Pd(OAc)2 with a ligand selected from PPh3, P(o-Tol)3, PCy3HBF4, Dppf, Dppe, Xantphos, Xphos, BINAP (racemic, R or S), and t-BuXphos. In some embodiments, the palladium catalyst is Pd(dppf)Cl2.

[0065] In some embodiments of the process for preparing compound (N), the compound of formula (D) is (i) Formula (A): [ka] or a salt thereof, [ka] or a salt thereof, and a compound of formula (C): [ka] or a salt thereof; and (ii) chlorinating said compound of formula (C) or a salt thereof to provide said compound of formula (D) or a salt thereof; It is prepared by a process comprising:

[0066] In some embodiments of the process for preparing compound (N), the compound of formula (A) has the formula (A-1): [ka] It is a compound of the formula:

[0067] In some embodiments, the process for preparing compound (N) comprises: (iv) Removing the tert-butyl group in the compound of formula (N) or a salt thereof to obtain a compound of formula (O): [ka] or a salt thereof; (v) A compound of the formula (O) and a compound of the formula (J-1): [ka] or a salt thereof to obtain a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate or hydrate thereof; Further includes:

[0068] In such an embodiment of the process for preparing compound (N), step (v) provides a monohydrate of the compound of formula (I).

[0069] In some embodiments, the compound of formula (J-1) or a salt thereof is (i) Formula (E): [ka] The compound of formula (F-1): [ka] or a salt thereof, and a compound of formula (G-1): [ka] wherein R is C1-5 alkyl; and (ii) contacting the compound of formula (G-1) with a reducing agent to obtain a compound of formula (H-1): [ka] or a salt thereof; (iii) contacting the compound of formula (H-1) with an acid to provide the compound of formula (J-1) or a salt thereof; It is prepared by a process comprising:

[0070] In some embodiments, the compound of formula (J-1) or a salt thereof is (i) Formula (E): [ka] The compound of formula (F-1): [ka] or a salt thereof, and a compound of formula (G-1): [ka] wherein R is C1-5 alkyl; and (ii) contacting the compound of formula (G-1) with a reducing agent to obtain a compound of formula (G-3): [ka] or a salt thereof; (iii) contacting the compound of formula (G-3) with a reducing agent to obtain a compound of formula (H-1): [ka] or a salt thereof; (iv) contacting the compound of formula (H-1) with an acid to provide the compound of formula (J-1) or a salt thereof; It is prepared by a process comprising:

[0071] In some embodiments, the compound of formula (AB): [ka] A process for preparing a compound of the formula (i) Formula (AA): [ka] or a salt thereof is contacted with a transaminase to obtain a compound represented by the formula (J-1): [ka] or a salt thereof; (ii) protecting a compound of formula (J-1) to provide a compound of formula (AB), wherein Boc is butyloxycarbonyl; A process is provided that includes:

[0072] In some embodiments, the process includes deprotecting a compound of formula (AB) to form a compound of formula (J-1): [ka] or a salt thereof.

[0073] In some embodiments, the deprotection is carried out in the presence of hydrochloric acid, trifluoroacetic acid, phosphoric acid, sulfuric acid, zinc bromide, catalytic iodine, acetyl chloride in methanol, or oxalyl chloride in methanol. In some embodiments, the deprotection is carried out in the presence of hydrochloric acid, and the compound of formula (J-1) is converted to the compound of formula (J-2): [ka] It is a compound of the formula:

[0074] In some embodiments, the compound of formula (AA) has the formula (AC): [ka] or a salt thereof with an alkali metal salt of a carboxylic acid or a carboxylic acid, or a mixture thereof, in the presence of a solvent and water. In some such embodiments, the reaction is carried out in the presence of sodium formate and formic acid. Other alkali metal salts of carboxylic acids will be known to those of skill in the art and are contemplated within the scope of the disclosure. Other carboxylic acids will be known to those of skill in the art and are contemplated within the scope of the disclosure. In some embodiments, the solvent is an alcohol (e.g., methanol, ethanol, isopropanol), tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetonitrile, or a mixture thereof. In some embodiments, the solvent is a mixture of an alcohol and one or more of tetrahydrofuran, dimethylformamide, dimethylsulfoxide, or acetonitrile.

[0075] In some embodiments, the compound of formula (AC) has the formula (AD): [ka] with a compound of formula (AE): [ka] or a salt thereof under conditions sufficient to provide a compound of formula (AC).

[0076] Formula (J-2): [ka] A process for preparing a compound of the formula (i) Formula (AD): [ka] is contacted with magnesium metal and diethyl oxalate to produce a compound of formula (E): [ka] providing a compound of formula (I) (ii) hydrolyzing the compound of formula (E) to obtain a compound of formula (AF): [ka] or a salt thereof; (iii) contacting the compound of formula (AF) or a salt thereof with a transaminase to obtain a compound of formula (AG): [ka] or a salt thereof; (iv) contacting the compound of formula (AG) with a reducing agent and quenching the reaction with hydrochloric acid to provide the compound of formula (J-2). A process is provided herein, comprising:

[0077] In some embodiments, the reducing agent is sodium borohydride and the reaction is carried out in the presence of a Lewis acid (e.g., boron trifluoride etherate, BF3·OEt2). In some embodiments, the reducing agent is a borane. In some embodiments, the borane is generated in situ. Other suitable reducing agents will be known to those of skill in the art and are contemplated within the scope of the present disclosure.

[0078] In some embodiments, the formula (AH): [ka] (In the formula, R 4 , H, C 2~6 Provided herein are compounds of formula (AH), where AH is an alkyl or aryl. In some embodiments, compound AH is an intermediate formed in the reaction of compound (AC) with sodium formate. In some embodiments, R 4 , H, C 1~6 It is alkyl or aryl.

[0079] Formula (AB): [ka] or a salt thereof.

[0080] Formula (I): [ka] or a pharma- ceutically acceptable salt, solvate or hydrate thereof, comprising the steps of: (i) Formula (A-1): [ka] with a compound of formula (B): [ka] or a salt thereof, and a compound of formula (C): [ka] or a salt thereof; and (ii) Chlorinating the compound of formula (C) or a salt thereof to obtain a compound of formula (D): [ka] or a salt thereof; (iii) reacting the compound of formula (D) or a salt thereof with a compound of formula (M): [ka] (In the formula, R 2 and R 3 are independently H, C 1~5 alkyl or R 2 and R 3 can contain 1, 2, 3 or 4 C together with the atoms to which they are attached. 1~3 forming a 5- or 6-membered ring optionally substituted with alkyl) and a compound of formula (N): [ka] or a salt thereof; and (iv) Removing the tert-butyl group in the compound of formula (N) or a salt thereof to obtain a compound of formula (O): [ka] or a salt thereof; (v) Reacting a compound of formula (O) with a compound of formula (J-2): [ka] to provide a compound of formula (I) or a pharma- ceutically acceptable salt, solvate or hydrate thereof; Including, In some embodiments, the compound of formula (J-2) is (vi) Formula (E): [ka] The compound of formula (F-1): [ka] or a salt thereof, and a compound of formula (G-1): [ka] wherein R is C1-5 alkyl; and (v-ii) contacting the compound of formula (G-1) with a reducing agent to obtain a compound of formula (H-1): [ka] or a salt thereof; (v-iii) contacting the compound of formula (H-1) or a salt thereof with an acid to obtain the compound of formula (J-2); Provided herein is a process for preparing the compound according to the present invention, comprising:

[0081] In some embodiments of the process for preparing a compound of formula (I) described above, a compound of formula (J-2) is prepared as described in Example 19. In some embodiments of the process for preparing a compound of formula (I) described above, a compound of formula (J-2) is prepared as described in Example 20.

[0082] Formula (I): [ka] or a pharma- ceutically acceptable salt, solvate or hydrate thereof, comprising the steps of: (i) Formula (A-1): [ka] with a compound of formula (B): [ka] or a salt thereof, and a compound of formula (C): [ka] or a salt thereof; and (ii) Chlorinating the compound of formula (C) or a salt thereof to obtain a compound of formula (D): [ka] or a salt thereof; (iii) reacting the compound of formula (D) or a salt thereof with a compound of formula (M): [ka] (In the formula, R 2 and R 3 are independently H, C 1~5 alkyl or R 2 and R 3 can contain 1, 2, 3 or 4 C together with the atoms to which they are attached. 1~3forming a 5- or 6-membered ring optionally substituted with alkyl) and a compound of formula (N): [ka] or a salt thereof; and (iv) Removing the tert-butyl group in the compound of formula (N) or a salt thereof to obtain a compound of formula (O): [ka] or a salt thereof; (v) Reacting a compound of formula (O) with a compound of formula (J-2): [ka] to provide a compound of formula (I) or a pharma- ceutically acceptable salt, solvate or hydrate thereof; Including, In some embodiments, the compound of formula (J-2) is (vi) Formula (E): [ka] The compound of formula (F-1): [ka] or a salt thereof, and a compound of formula (G-1): [ka] wherein R is C1-5 alkyl; and (v-ii) contacting the compound of formula (G-1) with a reducing agent to obtain a compound of formula (G-3): [ka] or a salt thereof; (v-iii) contacting the compound of formula (G-3) with a reducing agent to obtain a compound of formula (H-1): [ka] or a salt thereof; (v-iv) contacting the compound of formula (H-1) or a salt thereof with an acid to obtain the compound of formula (J-2); Provided herein is a process for preparing the compound according to the present invention, comprising:

[0083] In some embodiments of the process for preparing a compound of formula (I) described above, a compound of formula (J-2) is prepared as described in Example 19. In some embodiments of the process for preparing a compound of formula (I) described above, a compound of formula (J-2) is prepared as described in Example 20.

[0084] In some embodiments of the process for preparing a compound of formula (I), step (v) provides a monohydrate of the compound of formula (I).

[0085] For any of the processes described herein, in some embodiments, the tert-butyl group is removed in the presence of trifluoroacetic acid (TFA).

[0086] Formula (L): [ka] or a salt thereof, comprising the steps of: Formula (P): [ka] With a compound of formula (Q): [ka] or a salt thereof under conditions sufficient to provide a compound of formula (L) or a salt thereof.

[0087] In some embodiments, the process for preparing compound (L) is carried out in the presence of sodium triacetoxyborohydride (STAB), a base, and a protic solvent. In some embodiments, the base is an amine.

[0088] Formula (N): [ka] or a salt thereof, comprising the steps of: Formula (L): [ka] The compound of formula (S): [ka] (In the formula, R 2 and R 3 are independently H, C 1~5 alkyl or R 2 and R 3 can contain 1, 2, 3 or 4 C together with the atoms to which they are attached. 1~3 Provided herein is a process comprising contacting a compound of formula (N) with a compound of formula (N) (wherein N is an alkyl group, optionally substituted with alkyl), under conditions sufficient to provide a compound of formula (N).

[0089] Formula (I): [ka] or a pharma- ceutically acceptable salt, solvate or hydrate thereof, comprising the steps of: Formula (T): [ka] or a salt thereof, [ka] (In the formula, R 2 and R 3are independently H, C 1~5 alkyl or R 2 and R 3 can contain 1, 2, 3 or 4 C together with the atoms to which they are attached. 1~3 Provided herein is a process comprising contacting a compound of formula (I) or a salt thereof, wherein the compound forms a 5- or 6-membered ring, optionally substituted with alkyl, with a compound of formula (I), or a salt thereof, under conditions sufficient to provide a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or hydrate thereof.

[0090] Formula (I): [ka] or a pharma- ceutically acceptable salt, solvate or hydrate thereof, comprising the steps of: Formula (V): [ka] (In the formula, R 2 and R 3 are independently H, C 1~5 alkyl or R 2 and R 3 can contain 1, 2, 3 or 4 C together with the atoms to which they are attached. 1~3 forming a 5- or 6-membered ring optionally substituted with alkyl) or a salt thereof, [ka] or a salt thereof under conditions sufficient to provide a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or hydrate thereof.

[0091] In some embodiments, the compound of formula (I) is a monohydrate.

[0092] Provided herein is Compound (I) prepared according to any of the processes described herein.

[0093] Provided herein is Compound (I) or a hydrate thereof prepared according to any of the processes described herein. Provided herein is Compound (I) or a monohydrate thereof prepared according to any of the processes described herein.

[0094] In some embodiments, the monohydrate of the compound of formula (I) is a crystalline form (form B). Form B is described in WO 2018 / 193410. In some embodiments, an improved method for preparing form B of the compound of formula (I) is provided herein. In some embodiments, form B of compound (I) can be characterized by an X-ray diffraction pattern exhibiting maximum peak intensities at the diffraction angles set forth in Table A, i.e., 14.0°, 20.6°, 24.0°, and 24.2° (±0.2°).

[0095] TIFF2024524851000116.tif31170

[0096] Data collection and structure refinement were carried out as follows. Diffractometer SuperNova, Dual, Cu at Zero, Atlas Radiation source SuperNoca(Cu) X-ray source, CuKα Data collection method: Scanning Data collection θ range: 3.460°~66.589° Index range -14≦h≦15, -10≦h≦9, -14≦h≦15, Collected Reflections 24752 Independent reflection 4834[R(int)=0.0371] Independent reflection coverage: 97.4% Absorption correction: equivalent to semi-empirical Maximum and minimum transmission rates 1.00000 and 0.80872 Structural analysis method Direct method Structure analysis / refinement program SHELXTL (Sheldrick, 2013) Refinement Technique Full Matrix Least Squares for F2

[0097] Some embodiments provide Form B of Compound (I) having an X-ray powder diffraction pattern characterized by the presence of major peaks at diffraction angles (2θ) of 14.0° and / or 20.6° and / or 24.0° and / or 24.2° (±0.2°).

[0098] In some embodiments, the X-ray diffraction pattern of Form B of Compound (I) is characterized by the presence of at least one peak at a diffraction angle selected from 14.0°, 20.6°, 24.0°, and 24.2° (±0.2°). In some embodiments, provided herein is a substantially crystalline form (Form B) of Compound (I) having an X-ray powder diffraction pattern characterized by the presence of a major peak at a diffraction angle of 14.0° (±0.2°). In some embodiments, provided herein is a substantially crystalline form (Form B) of Compound (I) having an X-ray powder diffraction pattern characterized by the presence of a major peak at a diffraction angle of 20.6° (±0.2°). In some embodiments, provided herein is a substantially crystalline form (Form B) of Compound (I) having an X-ray powder diffraction pattern characterized by the presence of a major peak at a diffraction angle of 24.0° (±0.2°). In some embodiments, provided herein is a substantially crystalline form of Compound (I) (Form B) having an X-ray powder diffraction pattern characterized by the presence of a major peak at a diffraction angle of 24.2° (±0.2°).

[0099] In some embodiments, the substantially crystalline form of Compound (I) (Form B) has an X-ray powder diffraction pattern characterized by the presence of major peaks at two or more, e.g., three or four, diffraction angles selected from 14.0°, 20.6°, 24.0°, and 24.2° (±0.2°).

[0100] The X-ray powder diffraction pattern of Form B of Compound (I) may also have peaks present at diffraction angles selected from 8.8, 13.0, 13.8, 14.4, 17.3, 19.3, 21.3, and 28.7 (±0.2°). Some embodiments provide a substantially crystalline form of Compound (I) (Form B) having an X-ray powder diffraction pattern characterized by the presence of a major peak at diffraction angles 14.0° and / or 20.6° and / or 24.0° and / or 24.2° (±0.2°) as defined above, and optionally one or more additional peaks at diffraction angles selected from 8.8°, 13.0°, 13.8°, 14.4°, 17.3°, 19.3°, 21.3°, and / or 28.7° (±0.2°). In some embodiments, the substantially crystalline form of Compound (I) (Form B) has an X-ray powder diffraction pattern characterized by the presence of major peaks at diffraction angles of 14.0° and / or 20.6° and / or 24.0° and / or 24.2° (±0.2°), and optionally one or more additional peaks at diffraction angles of 13.8° and / or 9.3° and / or 21.3° (±0.2°).

[0101] In some embodiments, the substantially crystalline form of Compound (I) (Form B) has an X-ray powder diffraction pattern characterized by the presence of major peaks at diffraction angles of 14.0°, 20.6°, 24.0°, 24.2°, 13.8°, 19.3°, and 21.3° (±0.2°).

[0102] In some embodiments, the substantially crystalline form of Compound (I) (Form B) has an X-ray powder diffraction pattern characterized by the presence of major peaks at diffraction angles of 14.0°, 20.6°, 24.0°, 24.2°, 8.8°, 13.0°, 13.8°, 14.4°, 17.3°, 19.3°, 21.3°, and 28.7° (±0.2°).

[0103] In some embodiments, the substantially crystalline form (Form B) of Compound (I) exhibits an endothermic event with an onset temperature between 100° C. and 110° C. when subjected to differential scanning calorimetry (DSC). In some embodiments, the substantially crystalline form (Form B) of Compound (I) exhibits an endothermic event with an onset temperature between 101° C. and 108° C. when subjected to DSC. Some embodiments provide a substantially crystalline form (Form B) of Compound (I) that exhibits an endothermic event with a peak between 110° C. and 125° C. Some embodiments provide a substantially crystalline form (Form B) of Compound (I) that exhibits an endothermic event with a peak between 111° C. and 113° C.

[0104] In some embodiments, the substantially crystalline form B of Compound (I) is analyzed by thermogravimetric analysis (TGA) and exhibits a weight loss transition having an onset temperature of between 85° C. and 95° C., e.g., 90.86° C., which is complete at between 110° C. and 130° C., e.g., 120° C.

[0105] Provided herein is a substantially crystalline form of Compound (I) (Form B), prepared according to the methods described herein and having an X-ray powder diffraction pattern substantially as shown in Figure 1. Data collection was performed as follows. Diffractometer Bruker D8 Focus Vertical goniometer θ / 2θ Sample stage rotation Filter Nickel K β Filters X-ray generator Cu, Kα, λ=1.54056Å Tube voltage: 40kV Tube current 40mA Scan Type Lock Couple Scan Mode Continue Scan range: 4° to 40° 2θ using Cu Kα radiation Scan step 0.02° Process time 0.3 seconds Sample rotation speed: 15 rpm Detector LYNXEYE

[0106] In some embodiments, Form B of Compound (I) may be characterized by an X-ray diffraction pattern exhibiting maximum peak intensities at specific diffraction angles, i.e., 14.2°, 14.6°, 20.7°, and 24.3° (±0.2°). In some embodiments, Form B of Compound (I) may be characterized by an X-ray diffraction pattern exhibiting maximum peak intensities at specific diffraction angles, i.e., 8.9°, 14.0°, 14.2°, 14.6°, 20.7°, 24.3°, and 29.0° (±0.2°). In some embodiments, Form B of Compound (I) may be characterized by an X-ray diffraction pattern exhibiting maximum peak intensities at specific diffraction angles, i.e., 8.9°, 13.2°, 14.0°, 14.2°, 14.6°, 17.5°, 19.5°, 20.7°, 21.4°, 21.7°, 23.7°, 24.3°, and 29.0° (±0.2°). In some embodiments, Form B of Compound (I) may be characterized by an X-ray diffraction pattern exhibiting maximum peak intensities at the diffraction angles set forth in Table B.

[0107] TIFF2024524851000117.tif41170

[0108] In some embodiments, provided herein is a substantially crystalline form (Form B) of Compound (I), Form B being a monohydrate of Compound (I). The single crystal X-ray structure of Form B is shown as an ORTEP plot in Figure 2.

[0109] Formula (I): [ka] A composition comprising a compound of the formula: Formula (Z-1) and / or Formula (Z-2) of 0.5% area / area or less: [ka] Provided herein is a composition comprising a compound of the formula:

[0110] In one embodiment, compound (I) prepared according to any process described herein comprises compounds (Z-1) and (z-2) at 0.1% area / area or less. In one embodiment, compound (I) prepared according to any process described herein comprises compound (Z-1) at 0.3% area / area or less. In one embodiment, compound (I) prepared according to any process described herein comprises compound (Z-1) at 0.1% area / area or less. In one embodiment, compound (I) prepared according to any process described herein comprises compound (Z-2) at 0.3% area / area or less. In one embodiment, compound (I) prepared according to any process described herein comprises compound (Z-2) at 0.1% area / area or less. As used herein, "area / area" refers to HPLC or chiral HPLC peak area.

[0111] (S)-2-Amino-2-(3-fluoro-5-methoxyphenyl)ethanol-1-ol hydrochloride (compound (J-2), CAS number: 2095692-22-9) is commercially available from Sigma Aldrich in small quantities at approximately 95% purity, although the chiral purity is unknown. Large quantities of this material of high chiral purity are desirable. Scheme 1 outlines an improved procedure for the preparation of compound (J-2). [ka]

[0112] Lewis acid mediated reaction of compound (E) with compound (F-1) provides imine compound (G-1), which can be reduced to compound (H-1) in a single reduction step (e.g., by use of a reducing agent such as borane, NaBH4 / BF3·OEt2, sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al™), diisobutylaluminum hydride (DIBAL), NaBH4 / I2, or any other suitable reducing agent). Alternatively, the imine compound (G-1) can be reduced to compound (G-3) using a first reducing agent such as LiBH4, NaBH4, ZnBH4, or any other suitable reducing agent, and then further reduced to compound (H-1) using an additional reducing agent such as borane, NaBH4 / BF3·OEt2, sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al™), diisobutylaluminum hydride (DIBAL), NaBH4 / I2, or any other suitable reducing agent. Lewis acids include MgSO4, CuSO4, Cs2CO3, Yb(OTf)3, ZnCl2, tris-(2,2,2-trifluoroethyl)borate, trialkyl borates, diazabicycloundecene (DBU), KO t Bu, TiCl4, BF3·OEt2, Sc(OTf)3, or formula (K): Ti(OR 1 )4(K) (In the formula, R 1 may be a titanium alkoxide of C1-5 alkyl, or any other suitable Lewis acid.

[0113] The initial procedure for the preparation of compound (J-2), as described in Example 10, resulted in a chiral HPLC purity of about 91.5% area for compound (J-2).

[0114] To improve the chiral purity of compound (J-2), compound (J-2) was free-based to compound (J-1) as described in Example 11.

[0115] The free base compound (J-1) was converted to the mandelate salt, i.e., compound (J-3), as described in Example 12. Compound (J-3) was then free-based to provide compound (J-1), as described in Example 14. The chiral purity of the free base, i.e., compound (J-1), was improved to 99.9% area. Compound (J-1) was then converted to the HCl salt, i.e., compound (J-2), as described in Example 15. The chiral HPLC purity of compound (J-2) was improved to about 99.9% area, as described in Example 15.

[0116] Similarly, the free base compound (J-1) was converted to the furoate salt, i.e., compound (J-4), as described in Example 13. Compound (J-4) was then converted to the HCl salt, i.e., compound (J-2), as described in Example 13. The chiral HPLC purity of compound (J-2) was improved to approximately 100% area, as described in Example 13.

[0117] Thus, the methods described herein provide an improved intermediate, namely compound (J-2), with excellent chiral purity.

[0118] Scheme 2 below illustrates an embodiment for synthesizing compound (I) using the methods described above and in the Examples section. [ka]

[0119] In Scheme 2, R 2 and R 3is as defined herein in some or any embodiment. Compound (L) is converted to boronate (M) in the presence of a boronating agent and a catalyst such as Pd(dppf)Cl2, Pd2(dba)3, Pd(PPh3)4, or any other suitable catalyst for metal-mediated coupling reaction. Suitable solvents for the reaction include, but are not limited to, acetonitrile, DMF, or other aprotic solvents. Bases may be used, for example, KOAc, NaOAc, or other suitable bases. The reaction temperature may range from about 70°C to 120°C, about 100°C to 120°C, or about 80°C to 90°C. After formation of boronate (M), compound (D) is added to the reaction mixture at a lower temperature (e.g., by cooling the reaction mixture to about 70°C to 85°C, or about 70°C to 75°C) in the presence of aqueous base. Any suitable aqueous base may be used, including, but not limited to, K2CO3, aqueous Na2CO3, aqueous Cs2CO3, aqueous LiOH, and / or aqueous K3PO4. NaOH and / or NaHCO3 may be used, although it has been found that NaOH may cause racemization. The palladium catalyst from the first step remains in the reaction mixture and also catalyzes the reaction of compound (D) with compound (M) in a single-pot process. It is understood that the reactions may be carried out in separate steps / pots / reactors. Compound (N) formed according to Scheme 2 is then converted to compound (I). Example 3 describes one embodiment for the preparation of compound (N), as shown in Scheme 2. Compound (D) may be used to improve the overall yield of compound (I) using compound (J-2) prepared according to the methods described herein.

[0120] Scheme 3 below illustrates an embodiment for synthesizing compound (I) using the methods described above and in the Examples section. [ka]

[0121] In Scheme 3, R 2 and R 3is as defined herein in some or any embodiment. Compound (T) is converted to boronate (V) in the presence of a boronating agent and a catalyst such as Pd(dppf)Cl2, Pd2(dba)3, Pd(PPh3)4, or any other suitable catalyst for metal-mediated coupling reaction. Suitable solvents for the reaction include, but are not limited to, acetonitrile, DMF, or other aprotic solvents. Bases may be used, for example, KOAc, NaOAc, or other suitable bases. The reaction temperature may range from about 70°C to 120°C, about 100°C to 120°C, or about 80°C to 90°C. After formation of boronate (V), compound (D) is added to the same reaction mixture at a lower temperature (e.g., by cooling the reaction mixture to about 70°C to 85°C, or about 70°C to 75°C) in the presence of aqueous base. Any suitable aqueous base may be used, including, but not limited to, K2CO3, aqueous Na2CO3, aqueous Cs2CO3, aqueous LiOH, and / or aqueous K3PO4. NaOH and / or NaHCO3 may be used, although it has been found that NaOH may cause racemization. Optionally, a catalyst may be added, such as Pd(dppf)Cl2, Pd2(dba)3, Pd(PPh3)4, or any other suitable catalyst for metal-mediated coupling reactions with compound (D). Optionally, the two reactions may be carried out as a one-pot procedure, where the catalyst from the first step also catalyzes the second reaction. Example 18 illustrates one embodiment of preparing compound (I) from compound (T). Compound (D) may be used to improve the overall yield of compound (I) using compound (J-2) prepared according to the methods described herein.

[0122] Scheme 4 below illustrates an embodiment for synthesizing compound (I) using the methods described above and in the Examples section. [ka]

[0123] In Scheme 4, R 2 and R 3is as defined herein in some or any embodiment. Compound (S) may be used instead of compound (D) for coupling with bromo compound (L) using standard coupling procedures described herein or known to one skilled in the art. The use of compound (S) and compound (J-2) prepared according to the methods described herein can improve the overall yield of compound (I). Compound (S) can be prepared starting from compound (D) using suitable boronation conditions known to one skilled in the art.

[0124] Scheme 5 below illustrates an embodiment for synthesizing compound (I) using the methods described above and in the Examples section. [ka]

[0125] In Scheme 5, R 2 and R 3 is as defined herein in some or any embodiment. Compound (S) may be used instead of compound (D) for coupling with bromo compound (T) using standard coupling procedures described herein or known to one of skill in the art. The use of compound (S) and compound (J-2) prepared according to the methods described herein can improve the overall yield of compound (I).

[0126] Combinations of the above processes can be used to prepare the compounds described herein, including any of the procedures described in the Examples section.

[0127] The compounds of the present disclosure can be prepared from readily available starting materials, for example, using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, it is understood that other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0128] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting certain functional groups, are well known in the art. For example, numerous protecting groups are described in TW Greene and GM Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein.

[0129] In addition, compounds of the present disclosure may contain one or more chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures thereof) are within the scope of the present disclosure, unless otherwise specified. Pure stereoisomers (or enriched mixtures thereof) can be prepared, for example, using optically active starting materials or stereoselective reagents known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, and the like.

[0130] The starting materials for the following reactions are either commonly known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemie or Sigma (St. Louis, Missouri, USA). Others are described in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989), organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5 th These compounds can be prepared by procedures or obvious modifications as described in standard reference texts, such as Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). EXAMPLES

[0131] The compounds and intermediates described herein can be prepared using the methods disclosed herein and routine variations thereof, which will become apparent from the disclosures herein and methods well known in the art. In addition to the teachings herein, conventional well-known synthetic methods may also be used. The synthesis of typical compounds described herein can be achieved as described in the following examples. Where available, reagents can be purchased commercially, for example from Sigma Aldrich or other chemical suppliers.

[0132] The following examples are provided to demonstrate specific embodiments of the present disclosure. It should be understood by those skilled in the art that the methods disclosed in the following examples represent methods that work well in implementing the present disclosure, and therefore can be considered as constituting specific modes for its implementation. However, those skilled in the art should understand in light of the present disclosure that many changes can be made in the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the present disclosure.

[0133] Example 1: Preparation of compound of formula (C) 5-chloro-2-[(tetrahydro-2H-pyran-4-yl)amino]pyrimidin-4-ol [ka] A mixture of compound of formula (A-1) (85 Kg, 82.5% assay, 99.9% area purity as free base, 1 eq.), compound of formula (B) (85.2 Kg, 2 eq.), and diisopropylethylamine (219.8 Kg, 4 eq.) in n-butanol (576.6 Kg) was heated to 110°C-115°C for 6 days. After consumption of compound of formula A-1 to 0.80% area by HPLC, the reaction mixture was cooled to 20°C-30°C. The reaction mixture was extracted with 10% aqueous K3PO3 solution (3×386 Kg). The combined aqueous layers were washed with ethyl acetate (282 Kg). After separation of the organic layer, the pH of the aqueous layer was adjusted to 7.0 using concentrated hydrochloric acid (65 Kg). The resulting suspension was stirred at 10°C for 2 hours and filtered. The solid was washed with water (210 Kg) and dried at 70° C. with a nitrogen sweep until the moisture content was less than 0.1%, to give 77 Kg of crude product (compound of formula C). The crude solid was suspended in n-butanol (1656 Kg) and heated to 108° C. to dissolve. The solution was slowly cooled to 0° C.-5° C. over 7-8 hours and stirred at this temperature for 6 hours. The solid was filtered and washed with n-butanol (245 Kg) and acetonitrile (236 Kg). The wet cake was dried at 70° C. with a nitrogen sweep until the residual n-butanol was 2700 ppm and the residual acetonitrile was 500 ppm to give compound of formula C as a white solid (69 Kg, 71% yield, HPLC purity=99.8% area).

[0134] The product was analyzed by LCMS (Cortecs C18+, 90 Å, 2.7 μm, 2.1 mm×30 mm, 3-way split, 0.1% formic acid, 5%→100% MeCN / water): m / z 230.1 (M+H) + (ES + ), 0.84 min, 99% purity at 260nm+ / -80nm.

[0135] 1H NMR (400 MHz, DMSO-d6) δ 11.10 (br s, 1H), 7.81 (s, 1H), 6.66 (br s, 1H), 3.93-3.77 (m, 3H), 3.36 (td, J=11.5, 2.2 Hz, 2H), 1.87-1.77 (m, 2H), 1.51-1.37 (m, 2H).

[0136] 13 C NMR (101 MHz, DMSO) δ 158.04 (C), 153.27 (CH + C), 108.44 (C), 65.72 (2 x CH2), 46.69 (CH), 32.29 (2 x CH2).

[0137] Example 2: Preparation of 4,5-dichloro-N-(oxan-4-yl)pyrimidin-2-amine, a compound of formula (D) [ka] Phosphoryl chloride (185 Kg, 4 equiv.) was added to a mixture of compound of formula C (69 Kg, 1 equiv.) in acetonitrile (550 Kg) and heated at 70°C-75°C for 6 hours. After completion of the reaction, the reaction mixture was cooled to about 35°C and concentrated to 3-4 volumes. Acetonitrile (270 Kg) was charged and subsequently concentrated to 3-4 volumes. The mixture was cooled to room temperature and added to an aqueous solution of K3PO4 (414 Kg) in water (1662 Kg). The resulting suspension was stirred at 20°C-25°C for 2 hours, filtered, and washed with preheated (30°C-40°C) water (345 Kg). The wet cake was dried with nitrogen sweep at 45°C-50°C for 3 days to give compound of formula D as a white solid (68.6 Kg, 90% yield, HPLC purity = 99.9% area).

[0138] The product was analyzed by LCMS (Cortecs C18+, 90 Å, 2.7 μm, 2.1 mm×30 mm, 3-way split, 0.1% formic acid, 5%→100% MeCN / water): m / z 248.0 / 250.0 (M+H). + (ES + ), 1.69 min, 99% purity at 260nm+ / -80nm.

[0139] 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.93 (d, J=7.7 Hz, 1H), 3.95-3.72 (m, 3H), 3.45-3.27 (m, 2H), 1.85-1.71 (m, 2H), 1.56-1.39 (m, 2H).

[0140] 13 C NMR (101 MHz, DMSO) δ159.50 (C), 158.10 (CH), 156.61 (C), 113.70 (C), 65.89 (2 x CH2), 47.19 (CH), 32.05 (2 x CH2).

[0141] Example 3: Preparation of compound of formula (N) tert-butyl (2R)-2-(6-(5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl)-1-oxo-1,3-dihydro-2H-isoindol-2yl)propanoate [ka] A mixture of compound of formula L (91.8 Kg, 1 eq.), bis(pinacolato)diboron (82 Kg, 1.2 eq.), potassium acetate (79 Kg, 2.95 eq.), and Pd(dppf)Cl2 (5 Kg, 0.025 eq.) in acetonitrile (734 Kg) was heated to 80°C-85°C for 2 hours. After conversion of compound of formula L to compound of formula M-1, the reaction mixture was cooled to 70°C-75°C and an aqueous solution of compound of formula D (68 Kg) and K3PO4 (143 Kg) in water (789 Kg) was added. The reaction mixture was heated at 70°C-75°C for 48 hours until compound of formula M-1 was less than 1%, and then cooled to room temperature. The reaction mixture was charged with an aqueous solution of sodium chloride (186 Kg) in water (733 Kg) and ethyl acetate (1656 Kg). The aqueous layer was separated and the organic layer was concentrated to 8-10 volumes. Ethyl acetate (1656 Kg) was added and distilled to about 9 volumes. Fresh ethyl acetate (1656 Kg) was added and the organic layer was washed with an aqueous solution of citric acid (46 Kg) in water (882 Kg) followed by 4 washes with 2% aqueous N-acetylcysteine ​​(10 volumes each wash). The organic layer was washed with 5% aqueous K2HPO4 (10 volumes) and the organic layer was treated with activated charcoal (18 Kg). The organic layer was filtered through a pad of silica gel (18 cm high; 200 Kg) and washed with ethyl acetate (4000 Kg). The filtrate was concentrated to about 5-6 volumes and replaced with acetonitrile (825 Kg; 2 times) and concentrated to 5-6 volumes each time. The acetonitrile solution was heated to 55°C-60°C and water (1560 Kg) was added over 5 hours. The mixture was cooled to room temperature over 5 hours and maintained at this temperature for 6 hours. The resulting suspension was filtered and washed with a mixture of acetonitrile (367 Kg) and water (1100 Kg). The wet cake was dissolved in acetonitrile (1190 Kg) at 58°C-62°C and water (1530 Kg) was added at that temperature over 5 hours. The mixture was cooled to room temperature over 5 hours and stirred at this temperature for 3 hours. The resulting suspension was filtered and washed with a mixture of acetonitrile (367 Kg) and water (1100 Kg). The wet cake was dried under vacuum at 35°C-45°C until the residual water was less than 0.1% to give the compound of formula N as a white solid (90.6 Kg, 71% yield, HPLC purity = 99.5% area).

[0142] The product was analyzed by LCMS (Cortecs C18+, 90 Å, 2.7 μm, 2.1 mm×30 mm, 3-way split, 0.1% formic acid, 5%→100% MeCN / water): m / z 473.2 / 475.2 (M+H). + (ES + ), 2.04 min, 99% purity at 260nm+ / -80nm.

[0143] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.03 (d, J=1.6 Hz, 1H), 7.99 (dd, J=7.9, 1.7 Hz, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.68-7.52 (m, 1H), 4.81 (q, J=7.4 Hz, 1H), 4.63 (d, J=17.7 Hz, 1H), 4.56 (d, J=17.8 Hz, 1H), 3.99-3.80 (m, 3H), 3.44-3.33 (m, 2H), 1.90-1.78 (m, 2H), 1.58-1.47 (m, 5H), 1.40 (s, 9H).

[0144] 13 C NMR (101 MHz, DMSO) δ170.57 (C), 167.06 (C), 160.01 (C), 158.22 (CH), 143.61 (C), 136.10 (C), 132.24 (CH), 131.73 (C), 123.54 (CH), 123.25 (CH), 114.68 (C), 81.31 (C), 66.00 (2 x CH2), 50.00 (CH), 47.07 (CH), 46.99 (CH2), 32.28 (2 x CH2), 27.58 (3 x CH3), 15.33 (CH3).

[0145] Example 4: Preparation of compound of formula (O), (2R)-2-(6-(5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl)-1-oxo-1,3-dihydro-2H-isoindol-2yl)propanoic acid [ka] To a solution of compound of formula N (11.8 Kg, 1 equiv.) in dichloromethane (312 Kg) was added trifluoroacetic acid (36 Kg, 13 equiv.). The reaction mixture was stirred at 20°C-30°C for 35 hours until compound of formula N was consumed to less than 1%. The reaction mixture was distilled to 4 volumes and replaced with toluene (3×123 Kg) and distilled to 4 volumes. Dichloromethane (126 Kg) was added and the organic layer was washed with a 10% aqueous solution of K2HPO4 (2×177 Kg). The combined aqueous layers were washed once with dichloromethane (82 Kg). The aqueous layer was heated to 55°C-62°C and the pH was adjusted to 3.0 using aqueous hydrochloric acid. The mixture was cooled to 20°C-25°C over 3 hours and maintained at this temperature for 2-3 hours. The precipitated solid was filtered, washed with water (2×35 Kg), and dried under nitrogen gas flow at 40° C.-45° C. for 12 hours to give the compound of formula O as a white solid (9.6 Kg, 90% yield, HPLC purity=100% area).

[0146] The product was analyzed by LCMS (Cortecs C18+, 90 Å, 2.7 μm, 2.1 mm×30 mm, 3-way split, 0.1% formic acid, 5%→100% MeCN / water): m / z 473.2 / 475.2 (M+H). + (ES + ), 2.04 min, 99% purity at 260nm+ / -80nm.

[0147] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.03 (d, J=1.6 Hz, 1H), 7.99 (dd, J=7.9, 1.7 Hz, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.68-7.52 (m, 1H), 4.81 (q, J=7.4 Hz, 1H), 4.63 (d, J=17.7 Hz, 1H), 4.56 (d, J=17.8 Hz, 1H), 3.99-3.80 (m, 3H), 3.44-3.33 (m, 2H), 1.90-1.78 (m, 2H), 1.58-1.47 (m, 5H), 1.40 (s, 9H).

[0148] 13 C NMR (101 MHz, DMSO) δ 170.57 (C), 167.06 (C), 161.5 (broad peak), 160.01 (C), 158.22 (CH), 143.61 (C), 136.10 (C), 132.24 (CH), 131.73 (C), 123.54 (CH), 123.25 (CH), 114.68 (C), 81.31 (C), 66.00 (2 x CH2), 50.00 (CH), 47.07 (CH), 46.99 (CH2), 32.28 (2 x CH2), 27.58 (3 x CH3), 15.33 (CH3).

[0149] Example 5: Preparation of compound of formula (I), (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propenamide [ka] A mixture of compound of formula O (9.29 Kg, 98.2% assay, 1 eq.), compound of formula J-2 (6.06 Kg, 1.2 eq.), and N-ethyldiisopropylamine (12 Kg, 4 eq.) in dichloromethane (247 Kg) was cooled to -3°C to 3°C and TBTU (8.79 Kg, 1.2 eq.) was added in five portions at 15 min intervals each time. The reaction mixture was stirred at this temperature for 1 h and HPLC analysis showed consumption of compound of formula O (less than 1%). The reaction mixture was warmed to room temperature and washed twice with 10% aqueous hydrochloric acid (95 Kg) followed by two washes with 10% aqueous K2HPO4 (95 Kg). The organic layer was washed with water (95 Kg) and distilled down to 5 to 6 volumes. The dichloromethane was replaced with absolute ethanol (143 Kg) and distilled down to 6 volumes. The ethanol solution was heated to about 50° C. and water (67 Kg) was added over 2 hours. The mixture was seeded with compound of formula I (80 g) and stirred at this temperature for 10 hours. The resulting suspension was cooled to room temperature over 5 hours and stirred at this temperature for 3 hours, after which it was filtered and washed with a mixture of ethanol (15 Kg) and water (19 Kg). The wet cake was dried with a stream of nitrogen gas at 30° C.-35° C. until the residual water was less than 4% to obtain crude compound of formula I (11.2 Kg). The crude product was dissolved in absolute ethanol (37 Kg) at about 50° C. and water (22 Kg) was added over 1 hour. Seed crystals of compound of formula (40 g) were added and water (22 Kg) was added over 1 hour. The mixture was stirred at about 50° C. for about 2 hours and cooled to about 40° C. over 1 hour. The mixture was stirred at this temperature for 15 hours and cooled to room temperature over 5 hours. After stirring at room temperature for 2 hours, the resulting suspension was filtered and washed with a mixture of ethanol (16 Kg) and water (20 Kg). The wet cake was dried under a stream of nitrogen at about 35° C. for 3 days to a moisture content of less than 3% to give the compound of formula I as a white solid (10.3 Kg, 77% yield, HPLC purity=99.5% area, chiral purity=100% area).

[0150] The product was analyzed by LCMS (Cortecs C18+, 90 Å, 2.7 μm, 2.1 mm×30 mm, 3-way split, 0.1% formic acid, 5%→100% MeCN / water): m / z 186.2 (M+H). + (ES +), 0.10 min, 99% purity at 260 nm + / - 80 nm. The amount of the compound of formula (Z-1) in the product is about 0.03% area by HPLC, and the amount of the compound of formula (Z-2) in the product is less than 0.02% area by HPLC.

[0151] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 3H), 7.03 (t, J=1.9 Hz, 1H), 7.02-6.96 (m, 1H), 6.83 (dt, J=11.0, 2.3 Hz, 1H), 5.54 (t, J=5.1 Hz, 1H), 4.25 (t, J=5.9 Hz, 1H), 3.78 (s, 3H), 3.72 (t, J=5.2 Hz, 2H).

[0152] 13 C NMR (101 MHz, DMSO-d6) δ 162.79 (C, J=242.6 Hz), 160.71 (C, J=11.7 Hz), 139.05 (C, J=9.9 Hz), 110.16 (CH, J=2.6 Hz), 106.65 (CH, J=22.9 Hz), 101.30 (CH, J=25.0 Hz), 62.70 (CH2), 55.83 (CH3), 55.59 (CH, J=2.1 Hz).

[0153] 19 F NMR (376 MHz, DMSO) δ -111.31.

[0154] Example 6: Preparation of compound of formula (L) tert-butyl (2R)-2-(6-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)propanoate [ka] A mixture of tert-butyl D-alaninate, HCl salt (859 mg, 97 wt%, 1.15 equiv, 4.59 mmol), methyl 5-bromo-2-formylbenzoate (1.00 g, 97 wt%, 1 equiv, 3.99 mmol), and DIPEA (1.05 mL, 1.5 equiv, 5.99 mmol) in benzotrifluoride (10 mL) was stirred at room temperature for 1 h, then concentrated in vacuo and azeotroped with MeCN (20 mL). The resulting residue was redissolved in benzotrifluoride (10 mL) and sodium triacetoxyborohydride (2.11 g, 2.5 equiv, 9.98 mmol) was added portionwise over 15 min. The reaction was stirred at room temperature for 2 h and then quenched with water (20 mL). The aqueous layer was further extracted with benzotrifluoride (10 mL) and the combined organic layers were washed with HCl (10 mL, 1 M aqueous solution) and NaHCO3 (10 mL, saturated aqueous solution). The organic phase was concentrated to approximately 2 mL and the temperature was maintained at 70 °C while n-heptane (7 mL) was added. The reaction was slowly cooled to 35 °C to allow crystallization. The reaction was then cooled to 18 °C for 10 min and the precipitate was collected. The precipitate was washed on the filter with n-heptane (2 mL) and then dried in a vacuum desiccator at 45 °C for 2 h to give tert-butyl (R)-2-(6-bromo-1-oxoisoindolin-2-yl)propanoate (0.80 g, 2.3 mmol, 58% yield, HPLC purity = 99% area) as a crystalline white solid.

[0155] The product was analyzed by LCMS (XSelect CSH C18 column, 130 Å, 2.5 μm, 4.6 mm × 30 mm, acidic (0.1% formic acid), 4-way split, 5% → 95% MeCN / water): m / z 284.0 / 286.0 (M-tBu). + (ES + ), 99% purity (diode array) at 2.22 min.

[0156] 1H NMR (400 MHz, DMSO-d6) δ 7.90-7.78 (m, 2H), 7.61 (dd, J=8.0, 0.8 Hz, 1H), 4.77 (q, J=7.4 Hz, 1H), 4.53 (d, J=17.7 Hz, 1H), 4.46 (d, J=17.7 Hz, 1H), 1.48 (d, J=7.5 Hz, 3H), 1.38 (s, 9H).

[0157] Example 7: Preparation of ethyl 2-(3-fluoro-5-methoxyphenyl)-2-oxoacetate, a compound of formula (E) [ka] A slurry of Mg metal (11.9 g, 1.0 equiv) in tetrahydrofuran (200 mL) was heated to 65±5° C. and DIBAL-H (3.6 mL, 0.0073 equiv) and a solution of 3-bromo-5-fluoroanisole in tetrahydrofuran (200 mL) were added. The reaction mixture was stirred at 65±5° C. until the 3-bromo-5-fluoroanisole was consumed by TLC. The resulting solution was cooled to 5±5° C. and added dropwise to a solution of diethyl oxalate (71.7 g, 1.2 equiv) in tetrahydrofuran (1 L) maintained at −25±5° C. The reaction mixture was stirred at this temperature for 1 h, warmed to 25±5° C., and stirred at 25±5° C. for 1 h. The reaction was quenched by the addition of saturated aqueous NH4Cl (500 mL) and then extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (500 mL) and concentrated to dryness to give compound of formula E as a yellow liquid (116.8 g, yield=66%, HPLC purity=55.8% area).

[0158] Example 8: Preparation of ethyl 2-(3-fluoro-5-methoxyphenyl)-2-oxoacetate, a compound of formula (E) [ka] A solution of 3-bromo-5-fluoroanisole (550 g, 1 equiv.) in tetrahydrofuran (5.5 L) was cooled to -10°C and nBuMgCl (0.33 equiv.) and nBuLi (0.67 equiv.) were added slowly. The reaction mixture was stirred at this temperature until the starting material was consumed (by HPLC) and then added dropwise to a solution of diethyl oxalate (3 equiv.) in tetrahydrofuran (2.75 L) maintained at -55°C. The reaction mixture was maintained at this temperature until consumption of the starting material was followed by quenching with saturated aqueous ammonium chloride (2.75 L). The product was extracted into methyl tert-butyl ether (2 x 2.75 L) and the combined organic layers were washed with brine (2.75 L) and concentrated to dryness to give the compound of formula E as an orange oil (610 g, yield = 71%, HPLC purity = 73.79% area).

[0159] Example 9: Preparation of compound of formula (G-1) [ka] To a solution of compound of formula E (600 g, 1 equiv.) in tetrahydrofuran (6 L) was charged R-(+)-2-methyl-2-propanesulfinamide (385 g, 1.2 equiv.) and Ti(OEt)4 (1391 g, 2.3 equiv.). The mixture was heated to about 60° C. until the reaction was complete, then cooled to 50° C. and charged with EDTE (N,N,N',N'-tetrakis(2-hydroxyethyl)ethylenediamine) (1567 g, 2.5 equiv.). The reaction mixture was stirred at 50° C. for 30 minutes and cooled to room temperature. Methyl tert-butyl ether (3 L) and water (3 L) were charged, stirred for 30 minutes, and the phases were separated. The aqueous layer was extracted once with methyl tert-butyl ether (3 L) and the combined organic layers were washed with brine (3 L) and concentrated to dryness to give compound of formula G-1 as a brown oil (1187 g, yield=84%, HPLC purity: ethyl ester=68.75% area, and isopropyl ester=17.83% area).

[0160] Example 10: Preparation of compound of formula (J-2), (S)-2-amino-2-(3-fluoro-5-methoxyphenyl)ethan-1-ol, hydrochloride salt [ka] A solution of the compound of formula G-1 (449 g, 1 eq.) in tetrahydrofuran (4.49 L) was cooled to -35°C and borane solution (1 M in tetrahydrofuran, 3.0 eq.) was added dropwise while maintaining the temperature at -30°C to -40°C. The reaction mixture was stirred at -35°C for 2 hours and after completion of the reaction, the mixture was warmed to room temperature. The reaction mixture was stirred at room temperature for 16 hours until the conversion of the compound of formula G-3 to the compound of formula H-1 was complete. The reaction mixture was then added dropwise to methanol (2.245 L) cooled to 5°C (Caution: Hydrogen gas evolution). At 5°C, hydrochloric acid solution (4 M in methanol, 6 eq.) was added dropwise. The reaction mixture was warmed to room temperature and stirred at this temperature for 16 hours until the conversion of the compound of formula H-1 to the compound of formula J-2 was complete. The reaction mixture was concentrated under vacuum to 5 volumes and the solvent was exchanged with methyl tert-butyl ether (2 x 4.5 L) until residual methanol was less than 1%. The 5 volumes of methyl tert-butyl ether solution was stirred at room temperature for 1 h, and the resulting suspension was filtered and washed with methyl tert-butyl ether (900 mL). The wet was dried under vacuum to give the compound of formula J-2 as a white solid (390.3 g, yield = 75%, HPLC purity = 96.3% area, chiral purity: 91.5% area).

[0161] Example 11: Preparation of (S)-2-amino-2-(3-fluoro-5-methoxyphenyl)ethan-1-ol, a compound of formula (J-1) [ka] To a slurry of crude compound of formula J-2 (748 g, 1 equiv.) in methyl tert-butyl ether (7.48 L) at 5° C. was added aqueous sodium hydroxide (1.7 M, 2.992 L) slowly. After addition, the mixture was allowed to reach room temperature and stirred for 1 h. The phases were separated and the aqueous layer was extracted with methyl tert-butyl ether (2×7.48 L). The combined organic layers were washed with brine (3.74 L) and concentrated to dryness. Drying was performed using azeotropic distillation with methyl tert-butyl ether to remove residual water to less than 3%, affording compound of formula J-1 as a pale yellow solid (563 g, yield=93%, HPLC purity=96.74% area, chiral purity=94.93% area).

[0162] Example 12: Preparation of (S)-2-amino-2-(3-fluoro-5-methoxyphenyl)ethan-1-ol L-mandelate, a compound of formula (J-3) [ka] To a room temperature solution of the compound of formula J-1 (333 g, 1 equiv.) in methyl tert-butyl ether (3.33 L) was charged with (S)-(+)-mandelic acid (274 g, 1 equiv.). The resulting suspension was stirred at room temperature for 1 h and then charged with methanol (500 mL). The reaction mixture was warmed to 45° C. and stirred at this temperature for 16 h. The reaction mixture was cooled to room temperature and stirred for 3 h. The solid was filtered, washed with methyl tert-butyl ether (1.33 L) and dried under vacuum to give the mandelate salt of formula J-3 as a white solid (520 g, yield=86%, HPLC purity=99.1% area, chiral purity=99.8% area).

[0163] Example 13: Preparation of compound of formula (J-4), (S)-2-amino-2-(3-fluoro-5-methoxyphenyl)ethan-1-ol (R)-tetrahydrofuran-2-carboxylic acid [ka] To a solution of compound of formula J-1 (630 mg, 1 equiv, 3.40 mmol, chiral HPLC=96.68% area) in acetonitrile (113 mL) was added (R)-tetrahydrofuran-2-carboxylic acid (395 mg, 324 μL, 1.00 equiv, 3.40 mmol). The resulting white suspension was heated at reflux (ambient temperature 90° C.) for 30 min to give a pale yellow solution. The mixture was stirred at this temperature for 1 h, cooled to room temperature and stirred at this temperature for 12 h. The solid was filtered, washed with acetonitrile (5 mL) and dried under vacuum to give tetrafuran carboxylate of formula (J-4) as a white solid (775 mg, 76% yield, chiral HPLC=100% area).

[0164] Compound of formula (J-4) (775 mg, 1 equiv.) was partitioned between dichloromethane (20 mL) and saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with dichloromethane (2×10 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to approximately 5 mL. A solution of hydrochloric acid (4N in dioxane, 3 equiv., 1.9 mL) was added. The mixture was stirred for 30 min and evaporated to dryness to give compound of formula J-2 as a white solid (523 g, chiral purity=100% area).

[0165] Example 14: Preparation of (S)-2-amino-2-(3-fluoro-5-methoxyphenyl)ethan-1-ol, a compound of formula (J-1) [ka] To a 5° C. solution of compound of formula J-4 (mandalate salt) (515 g, 1 eq.) in methyl tert-butyl ether (5.15 L) was added aqueous sodium hydroxide (0.46 M, 2.575 L, 1.5 eq.). The mixture was warmed to room temperature and stirred for 2 h. The phases were separated and the aqueous layer was extracted with methyl tert-butyl ether (3×2.575 L). The combined organic layers were concentrated under vacuum to 1 volume containing 259 g of compound of formula J-1 (yield=92%, HPLC purity=99.62% area, chiral purity=99.9% area).

[0166] Example 15: Preparation of (S)-2-amino-2-(3-fluoro-5-methoxyphenyl)ethan-1-ol hydrochloride, a compound of formula (J-2) [ka] To a room temperature solution of compound of formula J-1 (259 g, 1 equiv.) in methyl tert-butyl ether (2.5 L) was added hydrochloric acid (4 M in dioxane, 763 mL, 2 equiv.). The mixture was stirred at room temperature for 3 h, and the resulting solid was filtered and washed with methyl tert-butyl ether (1.56 L). The wet cake was dried under vacuum to give compound of formula J-2 as a white solid (306 g, yield=99%, HPLC purity=99.8% area, chiral purity=99.89% area, less than 100 ppm residual L-mandelic acid).

[0167] Example 16: Preparation of compounds of formula (R) [ka] Trifluoroacetic acid (43.5 g, 381.8 mmol, 13 equiv) was added to a solution of compound of formula L (10 g, 29.4 mmol, 1.0 equiv) in dichloromethane (200 mL) over 15 min. The reaction mixture was stirred at 35° C. for 18 h. The reaction mixture was concentrated to 3 volumes at 30° C. and distilled twice with toluene (10 volumes of toluene were added and concentrated to 3 volumes each time). The resulting slurry was concentrated completely to give a white solid, which was triturated with ethyl acetate (200 mL) at 75° C. for 30 min, cooled to 5° C. over 30 min, held for 30 min, and filtered. The white solid was dried under high vacuum for 4 h to give the product as a white solid (7.5 g, yield=90%).

[0168] Example 17: Preparation of compounds of formula (T) [ka] A solution of carboxylic acid compound R (6 g, 21.1 mmol, 1.0 equiv.), compound of formula J-1 (5.6 g, 25.3 mmol, 1.2 equiv.), and N-ethyldiisopropylamine (10.9 g, 84.4 mmol, 4.0 equiv.) in dichloromethane (72 mL) was cooled to 0° C. TBTU (8.4 g, 25.3 mmol, 1.2 equiv.) was added in five portions over a calculated period of 70 min, and the reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was washed successively with 1N HCl (2×60 mL), 10% K2HPO4 solution (2×60 mL), and water (60 mL). The organic layer was filtered over a short pad of anhydrous Na2SO4 and concentrated completely to give an off-white solid. The crude solid was dissolved in ethanol (60 mL) at 75° C. and cooled to 50° C. over 1 h to give a spongy slurry. Water (60 mL) was added over 1 h, cooled to 20° C. over 30 min, and stirred for 1 h. The slurry was then filtered and rinsed with an ethanol / water mixture (1:1, 12 mL×2) to give a white, fluffy solid. The wet solid was dried under vacuum at 35° C. for 20 h to give amide compound T as a white fluffy solid (7.5 g, 79% yield).

[0169] Example 18: Preparation of compounds of formula (I) [ka] A dry flask was charged under nitrogen with DMF (30 mL), compound T (3.0 g, 6.64 mmol, 1.0 equiv), bis-pinacolatodiboron (2.0 g, 7.9 mmol, 1.2 equiv), KOAc (1.92 g, 19.6 mmol, 2.95 equiv), and Pd(dppf)Cl2 (0.122 g, 0.166 mmol, 0.025 equiv). The reaction mixture was degassed (evacuated to 200 mbar and backfilled with nitrogen, 3 times). The reaction mixture was heated to 110° C. over 30 min and stirred for 4 h (TLC in EtOAc showed a very faint spot of amide remaining). The reaction mixture was then diluted with EtOAc (100 mL) and the phases were separated. The aqueous layer was further extracted with EtOAc (50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and filtered through a pad of anhydrous Na2SO4 (2 cm) and Celite (1 cm). The filtrate was concentrated to give a dark oil, which was purified by column chromatography (0%→10% MeOH in DCM) to give crude boronate compound V (3.4 g) as a dark paste. The crude boronate salt (3.4 g, estimated 6.64 mmol, 1.0 equiv) was dissolved in DMF (30 mL) and Pd(dppf)Cl2 (0.122 g, 0.166 mmol, 0.025 equiv) was added, followed by the compound of formula D (1.65 g, 6.64 mmol, 1.0 equiv) and aqueous K3PO4 (3.52 g, 16.6 mmol, 2.5 equiv in 30 mL water). The reaction mixture was then stirred at 80 °C for 12 h (TLC showed consumption of compound D). The reaction mixture was transferred to 20% NaCl solution (30 mL), EtOAc (60 mL) was added to quench the reaction, and the phases were separated. The aqueous layer was extracted with EtOAc (30 mL). The combined organic layers were then washed successively with 5% citric acid solution (30 mL x 2), 5% K2HPO4 solution (30 mL x 2), and water (30 mL). The organic layers were then concentrated and purified by column chromatography to obtain partially pure fractions, which were concentrated to give the compound of formula I as a brown foam (2.9 g, HPLC purity = 84.5%). The crude product was then recrystallized from EtOH / H2O (1:1) to give the compound of formula (I) as a pale yellow solid (2.3 g, yield = 59%, HPLC purity = 97% area).

[0170] Example 19: Preparation of compound of formula (J-2) [ka]

[0171] Step 1: Preparation of Compounds of Formula (AC) To a -10°C solution of 3-fluoro-5-bromoanisole (1.0 Kg, 1.0 equiv.) in tetrahydrofuran (3 L) was slowly added a 1.3 M solution of iPrMgCl·LiCl (5.63 L, 1.5 equiv.) in tetrahydrofuran while maintaining the temperature at -15°C to -5°C. The reaction mixture was warmed to 20°C to 25°C and stirred at this temperature for 4 h. HPLC analysis showed 0.51% unreacted starting material. The reaction mixture was cooled to -55°C to -45°C and a solution of 2-chloro-N-methoxy-N-methylacetamide (compound of formula (AE)) (805 g, 1.2 equiv.) in tetrahydrofuran (4 L) was slowly added while maintaining the temperature at -55°C to -45°C. The reaction mixture was warmed to 15°C to 25°C and stirred at this temperature for 14 h. The reaction mixture was cooled to -10°C to 0°C and quenched with 1M hydrochloric acid (6 L). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (5 L). The combined organic layers were washed with saturated sodium chloride solution (10 L) and concentrated until about 5 L remained in the reactor. Ethyl acetate (2 L x 3) was added and concentrated under vacuum to about 5 L. N-heptane (4 L) was added over 2 hours and the reaction mixture was stirred at 15°C to 25°C for 2 hours. The resulting solid was filtered, washed with n-heptane (2 L) and dried under vacuum at 40°C to obtain the compound of formula (AC) (760 g, yield: 70%, HPLC purity: 98.15% area).

[0172] Step 2: Preparation of Compounds of Formula (AA) To a solution of compound of formula (AC) (1.328 Kg, 1 eq.) in absolute ethanol (6.38 L) was added water (10.63 L), formic acid (1.207 Kg, 4 eq.) and sodium formate (1.471 Kg, 3.3 eq.). The reaction mixture was heated to 85° C.-95° C. and stirred at this temperature for 8 h. HPLC analysis showed 0.61% unreacted starting material (compound of formula (AC)). The reaction mixture was cooled to 20° C.-25° C. and extracted with methyl tert-butyl ether (13.28 L). The aqueous layer was separated and extracted with methyl tert-butyl ether (6.64 L). The combined organic layers were washed with a solution of sodium carbonate (521 g, 0.75 eq.) in water (6.64 L) followed by a wash with saturated sodium chloride solution (6.64 L). The organic layer was concentrated under vacuum at 40° C. until approximately 4000 L remained in the reactor. Absolute ethanol (5.31 L) was charged and concentrated until approximately 4 L remained in the reactor. N-heptane (13.28 L) was added over 5-6 hours and the resulting slurry was stirred at 20-25° C. for 16 hours. The slurry was concentrated until 13.28 L remained in the reactor and n-heptane (6.64 L) was added. The slurry was concentrated until 13.28 L remained in the reactor and n-heptane (6.64 L) was added. The slurry was concentrated until 13.28 L remained in the reactor. GC analysis showed undetectable levels of residual ethanol. The mixture was filtered and dried under a stream of nitrogen to give the product (986 g, yield: 80%, HPLC purity: 96.04%).

[0173] Step 3: Preparation of compound of formula (J-2) To the compound of formula (AA) (10 g) was added EW-TA-184 (2 g, 20% w / w, purchased from Enzyme Works Inc., Zhangjiagang, China), tris(hydroxymethyl)aminomethane (500 mL), isopropylamine (20 eq., 66 mL), dimethyl sulfoxide (750 mL), and a 0.1 M solution of pyridoxal phosphate (2 g). The reaction mixture at pH 9.0 was stirred at 20°C-35°C for 4 h. HPLC analysis showed 98.3% reaction conversion. Solid sodium hydroxide (42 g) was added to adjust the pH to 13.16. The mixture was stirred for 1 h and filtered. The mixture was concentrated under reduced pressure at less than 40°C for about 2 h. Di-tert-butyl dicarbonate (2 eq.) was added and the reaction mixture was stirred at 20°C-25°C for 20 h. The reaction mixture was extracted three times with dichloromethane (200 mL each time). The combined organic layers were washed with water (3×200 mL) and saturated sodium chloride solution (3×200 mL). The organic layers were concentrated under reduced pressure until approximately 15 mL remained in the reactor, and n-heptane (300 mL) was added over 30 min. The slurry was stirred at 20°C-25°C for 1 h, filtered, and washed with n-heptane (2×20 mL). HPLC analysis of the wet cake showed 98.98% area purity of the boc-protected compound of formula (AB). The wet cake was dissolved in dichloromethane (100 mL) and 4 M hydrochloric acid in 1,4-dioxane (4.0 equiv.) was added. The reaction mixture was stirred at 20°C-25°C for 15 h, filtered, washed with dichloromethane (20 mL), and dried under vacuum to give the compound of formula (J-2) (7.16 g, yield: 60%, HPLC purity: 99.5% area, chiral purity: 100% area).

[0174] Example 20: Preparation of compound of formula (J-2) [ka]

[0175] Step 1: Preparation of Compounds of Formula (E) To a mixture of metallic magnesium (15.8 Kg) and iodine (0.8 Kg) in tetrahydrofuran (344.1 Kg) was added 3-fluoro-5-bromoanisole (12.8 Kg) at 10°C-25°C. The mixture was heated to 60°C-65°C and stirred at this temperature for 3-5 hours. A solution of 3-fluoro-5-bromoanisole (115.4 Kg, 1 equiv.) in tetrahydrofuran (342.7 Kg) was added at a rate of 20 Kg / hr-35 Kg / hr while maintaining the temperature at 55°C-65°C. The reaction mixture was stirred at 55°C-65°C for 3 hours and cooled to 10°C-25°C. The reaction mixture was added to a solution of diethyl oxalate (95.8 Kg) in tetrahydrofuran (911 Kg) at -75°C to -65°C at a rate of 60 Kg / hr to 150 Kg / hr. The reaction mixture was stirred at -75°C to -65°C for 6.5 hours until completion of the reaction. The reaction mixture was quenched by adding to a solution of hydrochloric acid (97.4 Kg) in water (172 Kg) at -20°C to 30°C at a standard rate of 100 Kg / hr to 200 Kg / hr. The mixture was stirred at 20°C to 30°C for 1 hour and solid sodium chloride (22.2 Kg) was added. The organic layer was separated and concentrated to 1 to 2 volumes under vacuum at 45°C to obtain compound of formula (E) (256 Kg, Assay: 38.59%, HPLC Purity: 68.11% area).

[0176] Step 2: Preparation of compounds of formula (AF) To a solution of sodium hydroxide (103.2 Kg) in water (1288 Kg) at 20°C-30°C was added a tetrahydrofuran solution of the compound of formula (E) (255.8 Kg, corrected to 98.7 Kg for 38.59% assay). The reaction mixture was stirred at 20°C-30°C for 11 hours until the reaction was complete by HPLC analysis. The mixture was filtered and the cake was washed with water (283 Kg). The filtrate was extracted twice with methyl tert-butyl ether (526.9 Kg) and the aqueous layer was acidified with hydrochloric acid at 15°C-30°C until a pH of 1 was obtained. The mixture was extracted with methyl tert-butyl ether (617 Kg). The aqueous layer was separated and extracted with methyl tert-butyl ether (621 Kg). The combined organic layers were concentrated under reduced pressure at 40°C until approximately 300 L remained. n-Heptane (479.6 Kg) was added and concentrated under vacuum until approximately 300 L remained. n-Heptane (480.8 Kg) was added and concentrated under vacuum until approximately 300 L remained. The mixture was heated to 40°C-45°C, stirred at this temperature for 2 hours, and then cooled to 0°C-5°C. The mixture was stirred at 0°C-5°C for 4 hours, and the resulting solid was filtered, washed with cold n-heptane (96.2 Kg), and dried under vacuum at 45°C to obtain the compound of formula (AF) (80.4 Kg, Assay: 94.58%, HPLC Purity: 97% area).

[0177] Step 3: Preparation of Compounds of Formula (AG) A solution of tris(hydroxymethyl)aminomethane (18.0 Kg) in water (1376 Kg) was stirred at 20°C-25°C for 30 minutes and the pH was adjusted to 8.9 using aqueous hydrochloric acid (1:1) (6.0 Kg). 211 Kg of this solution (Solution A) was stored for later use. Compound of formula (AF) (80.4 Kg, corrected to 76 Kg for assay) was charged and the pH was adjusted to 12.4 using 5 M sodium hydroxide solution (87.4 Kg). The pH was then adjusted to 9.0 using 6 M hydrochloric acid (8.2 Kg). Solution A and ammonium formate (76.4 Kg) were added and the pH was adjusted to 9.1 using 5 M sodium hydroxide solution (24.6 Kg). The reaction mixture was maintained between 28°C-32°C. A solution of FDH enzyme solution (92.2 Kg) and nicotinamide adenine dinucleotide (1.6 Kg) was prepared and added to the reaction mixture at 28°C-32°C. At the same temperature, AADH506035 enzyme solution (33 Kg) from Asymchem was added. The reaction mixture was stirred at 28°C-32°C for 15.5 hours and the temperature was adjusted to 15°C-30°C. 6M hydrochloric acid was added to adjust the pH to 0.82, the mixture was filtered through a centrifugal filter device, and the cake was rinsed twice with water (240 Kg). The filtrate was extracted twice with methyl tert-butyl ether (300 Kg). The aqueous layer was concentrated under vacuum at 60°C until about 700 L remained in the reactor. The mixture was cooled to 15°C-25°C and the pH was adjusted to 5.9 using 50% aqueous potassium carbonate solution. The mixture was cooled to 5°C-10°C and stirred at this temperature for 6 hours. The mixture was filtered, washed with water (240 Kg) and dried under vacuum at 45° C.-65° C. to obtain the compound of formula (AG) (Yield: 58%, Assay: 82.7%, HPLC Purity: 99.4% area).

[0178] Step 4: Preparation of compound of formula (J-2) To a solution of compound of formula (AG) (53.4 Kg, corrected to 44.2 Kg for assay) in tetrahydrofuran (762.6 Kg) cooled to 5°C-15°C, sodium borohydride (25.8 Kg) was added. The reaction mixture was further cooled to -10°C-0°C and 47% boron trifluoride etherate (164 Kg) was added slowly at a standard rate of 40 Kg / hr-70 Kg / hr. The mixture was reacted at -10°C-0°C for 18 hours until compound of formula (AG) was consumed. The reaction mixture was quenched by adding a solution of hydrochloric acid (66 Kg) in water (595 Kg) below 10°C to pH 1.4. The reaction mixture was degassed by bubbling nitrogen to remove residual hydrogen gas. Methyl tert-butyl ether (326 Kg) was added and the pH was adjusted to 10.0 using 5M aqueous sodium hydroxide solution. The mixture was filtered and rinsed with methyl tert-butyl ether (132 Kg). The organic layer in the filtrate was separated and the aqueous layer was extracted twice with methyl tert-butyl ether (326 Kg). The combined organic layers were concentrated under vacuum at 40°C until about 100 L remained in the reactor. Methyl tert-butyl ether (329 Kg) was added and concentrated under vacuum at 40°C until about 100 L remained in the reactor. This process of methyl tert-butyl addition (329 Kg each time) and distillation was repeated 10 times until a final volume of about 450 L remained in the reactor. The mixture was heated to 50°C and L-(+)-mandelic acid (33.6 Kg) was added, followed by methanol (24 Kg). The mixture was stirred at 50°C-60°C for about 10 hours and then cooled to 20°C-30°C. The suspension was filtered and rinsed with methyl tert-butyl ether (238 Kg). The wet cake was charged to the reactor and 1M sodium hydroxide (29.6 Kg in 265 Kg water) was added at 0°C-10°C. The mixture was warmed to 20°C-30°C and the phases were separated. The aqueous layer was extracted three times with methyl tert-butyl ether (133 Kg) and the combined organic layers were washed with a solution of sodium hydroxide (0.2 Kg) and sodium chloride (17.6 Kg) in water (68.4 Kg). The organic phase was concentrated under vacuum at 40°C until approximately 150 L remained in the reactor. Methyl tert-butyl ether (192 Kg) was added and distilled until approximately 150 L remained in the reactor.This process of adding methyl tert-butyl ether (192 Kg each time) and distilling was repeated three times. To the concentrate at 20°C-30°C, 4M hydrochloric acid in 1,4-dioxane (117 Kg) was added at a standard rate of 15 Kg / h-20 Kg / h. The mixture was stirred at 20°C-30°C for 4 hours, filtered, washed with methyl tert-butyl ether (90 Kg), and dried under vacuum at 45°C to obtain the compound of formula (J-2) (39.2 Kg, assay: 99.1%, yield: 79%, HPLC purity: 99.8% area, chiral HPLC purity: 100% area).

[0179] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0180] The invention illustratively described herein may suitably be practiced in the absence of any element(s), limitation(s) not specifically disclosed herein. Thus, for example, terms such as "comprising," "including," "containing," and the like, are to be read expansively and without limitation. Moreover, the terms and expressions employed herein are used as terms of description and not of limitation, and in the use of such terms and expressions, there is no intention to exclude any equivalents of the features shown and described or portions thereof, and it is recognized that various modifications are possible within the scope of the invention as defined by the claims.

[0181] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated herein by reference in their entirety, to the same extent as if each was individually incorporated herein by reference. In the case of conflict, the present specification, including definitions, will control.

[0182] Although the present disclosure has been described in conjunction with the above embodiments, the above description and examples should be understood as illustrative rather than limiting the scope of the present disclosure. Other aspects, advantages and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which the present disclosure pertains.

Claims

1. A composition comprising a compound of formula (I): 【Chemical Formula 1】 and having a compound of formula (Z-1) and / or formula (Z-2) in an area / area of 0.5% or less: 【Chemical Formula 2】 The composition.

2. A process for preparing a compound of formula (D): 【Chemical Formula 3】 or a salt thereof, comprising: (i) contacting a compound of formula (A): 【Chemical Formula 4】 or a salt thereof, such as a compound of formula (A-1): 【Chemical Formula 5】 with a compound of formula (B): 【Chemical Formula 6】 or a salt thereof, and a compound of formula (C): 【Chemical Formula 7】 or a salt thereof under conditions sufficient to provide a compound of formula (D) or a salt thereof (e.g., in the presence of a base (such as an amine like diisopropylethylamine) and a solvent (such as a protic solvent like n-butanol)); and (ii) optionally chlorinating the compound of formula (C) or a salt thereof (in the presence of phosphoryl chloride) to provide a compound of formula (D) or a salt thereof. The process.

3. A process for preparing a compound of formula (J): 【Chemical Formula 8】 or a stereoisomer or a salt thereof, comprising: A. The process comprising: (i) reacting a compound of formula (E): 【Chemical Formula 9】 with a compound of formula (F): 【Chemical Formula 10】 a compound, or a stereoisomer or salt thereof, and a compound of formula (G): [Chemical Formula 11] (wherein R is C １ - ５ alkyl), or a stereoisomer or salt thereof, under conditions sufficient to effect contact; (ii) contacting the compound of formula (G), or a stereoisomer or salt thereof, with a reducing agent to provide a compound of formula (H): [Chemical Formula 12] or a stereoisomer or salt thereof; (iii) contacting the compound of formula (H), or a stereoisomer or salt thereof, with an acid to provide a compound of formula (J), or a stereoisomer or salt thereof; and optionally, the compound of formula (F) has the structure of formula (F - 1): [Chemical Formula 13] or is a salt thereof; the compound of formula (G) has the structure of formula (G - 1): [Chemical Formula 14] (wherein R is C1 - 5 alkyl) or is a salt thereof; the compound of formula (H) has the structure of formula (H - 1): [Chemical Formula 15] and the compound of formula (J) has the structure of formula (J - 1): [Chemical Formula 16] or is a salt thereof, or B. The process is (i) reacting a compound of formula (E): [Chemical Formula 17] with a compound of formula (F): [Chemical Formula 18] a compound, or a stereoisomer or salt thereof, and a compound of formula (G): [Chemical Formula 19] (wherein R is C1-C5 alkyl), or a stereoisomer or salt thereof, under conditions sufficient to provide contact, (ii) contacting the compound of formula (G), or a stereoisomer or salt thereof, with a reducing agent to obtain a compound of formula (G-2): [Chemical Formula 20] (wherein R is C1-C5 alkyl), or a salt thereof, (iii) contacting the compound of formula (G-2), or a stereoisomer or salt thereof, with a reducing agent to obtain a compound of formula (H): [Chemical Formula 21] or a stereoisomer or salt thereof, (iv) contacting the compound of formula (H), or a stereoisomer or salt thereof, with an acid to obtain a compound of formula (J), or a stereoisomer or salt thereof, and optionally, the compound of formula (F) has the structure of formula (F-1): [Chemical Formula 22] or a salt thereof, the compound of formula (G) has the structure of formula (G-1): [Chemical Formula 23] (wherein R is C1-C5 alkyl), or a salt thereof, the compound of formula (G-2) has the structure of formula (G-3): [Chemical Formula 24] (wherein R is C1-C5 alkyl), or a salt thereof, the compound of formula (H) has the structure of formula (H-1): [Chemical Formula 25] and has the structure of, The compound of formula (J) is a compound of formula (J-1): 【Chemical 26】 or a salt thereof, process.

4. The compound of formula (J) is a compound of formula (J-2): 【Chemical 27】 The process according to claim 2, having the structure of.

5. Step (i) is MgSO₄, CuSO₄, Cs₂CO₃, Yb(OTf)₃, ZnCl₂, tris-(2,2,2-trifluoroethyl)borate, trialkyl borate, diazabicycloundecene (DBU), KOtBu, TiCl₄, BF₃·OEt₂, Sc(OTf)₃, or formula (K): Ti(OR₁)₄ (K) (wherein R₁ is C₁-C₅ alkyl) The process according to claim 2 or 3, carried out in the presence of a Lewis acid such as titanium alkoxide (for example, Ti(O iPr)₄ or Ti(OEt)₄).

6. a) In Option A, the reducing agent in step (ii) is borane, NaBH ４ / BF ３ ·OEt ２ , sodium bis(2-methoxyethoxy)aluminum hydride, diisobutylaluminum hydride (DIBAL), or NaBH ４ / I ２ (for example, the reducing agent is borane), b) In Option B, the reducing agent in step (ii) is LiBH₄, NaBH₄, or ZnBH₄, and / or c) In Option B, the reducing agent in step (iii) is borane, NaBH₄ / BF₃·OEt₂, sodium bis(2-methoxyethoxy)aluminum hydride, diisobutylaluminum hydride (DIBAL), or NaBH₄ / I₂, The process according to claim 4.

7. Formula (N): 【Chemical 28】 A process for preparing a compound of formula (N) or a salt thereof, Optionally prepared by the process according to claim 1, a compound of formula (D): 【Chemical 29】 Or a salt thereof, with a compound of formula (M): 【Chemical 30】 (Wherein R ２ And R ３ Are independently H, C １～５ Alkyl, or R ２ And R ３ Together with the atoms to which they are attached, form a 5- or 6-membered ring optionally substituted with 1, 2, 3 or 4 C １～３ Alkyl) and a compound of formula (N) or a salt thereof under conditions sufficient to provide a compound of formula (N) or a salt thereof.

8. The process according to claim 6, carried out in the presence of an aqueous base (such as aqueous K2CO3, aqueous Na2CO3, aqueous Cs2CO3, aqueous LiOH, or aqueous K3PO4) and a palladium catalyst (such as Pd(dppf)Cl2 or Pd(OAc)2 having a ligand selected from PPh3, P(o-Tol)3, PCy3HBF4, Dppf, Dppe, Xantphos, Xphos, BINAP (racemic, R or S), and t-BuXphos).

9. (iv) Removing the tert-butyl group in the compound of formula (N) or a salt thereof to provide a compound of formula (O): 【Chemical 31】 Or a salt thereof, (v) Coupling the compound of formula (O) with a compound of formula (J-1): 【Chemical 32】 Or a salt thereof to couple to a compound of formula (I): 【Chemical Formula 33】 The process according to claim 7 or 8, further comprising providing a compound of or a pharmaceutically acceptable salt, solvate or hydrate (e.g., monohydrate) thereof.

10. The compound of formula (J-1) or a salt thereof is A. (i) A compound of formula (E): 【Chemical Formula 34】 is contacted with a compound of formula (F-1): 【Chemical Formula 35】 or a salt thereof, and a compound of formula (G-1): 【Chemical Formula 36】 (wherein R is C １ ~ ５ alkyl) under conditions sufficient to provide a compound of (ii) The compound of formula (G-1) is contacted with a reducing agent to provide a compound of formula (H-1): 【Chemical Formula 37】 or a salt thereof. (iii) The compound of formula (H-1) is contacted with an acid to provide the compound of formula (J-1) or a salt thereof, and the process comprising, or B. (i) A compound of formula (E): 【Chemical Formula 38】 is contacted with a compound of formula (F-1): 【Chemical Formula 39】 or a salt thereof, and a compound of formula (G-1): 【Chemical Formula 40】 (wherein R is C1-5 alkyl) under conditions sufficient to provide a compound of (ii) The compound of formula (G-1) is contacted with a reducing agent to provide a compound of formula (G-3): 【Chemical Formula 41】 To provide a compound of formula or a salt thereof, (iii) contacting the compound of formula (G-3) with a reducing agent to obtain a compound of formula (H-1): [Chemical formula 42] To provide a compound of formula or a salt thereof, (iv) contacting the compound of formula (H-1) with an acid to obtain a compound of formula (J-1) or a salt thereof, A process comprising The process according to claim 9, prepared by any of the above.

11. Formula (I): [Chemical formula 43] A process for preparing a compound of formula , or a pharmaceutically acceptable salt, solvate or hydrate thereof, A. The process is (i) contacting a compound of formula (A-1): [Chemical formula 44] with a compound of formula (B): [Chemical formula 45] or a salt thereof, and a compound of formula (C): [Chemical formula 46] or a salt thereof, under conditions sufficient to provide (ii) chlorinating the compound of formula (C) or a salt thereof to provide a compound of formula (D): [Chemical formula 47] or a salt thereof, (iii) reacting the compound of formula (D) or a salt thereof with a compound of formula (M): [Chemical formula 48] (wherein R ２ and R ３ are independently H, C １～５ alkyl, or R ２ and R ３ together with the atom to which they are attached, form one, two, three or four C １～３a compound forming an optionally alkyl-substituted 5- or 6-membered ring, and a compound of formula (N): [Chemical Formula 49] contacting under conditions sufficient to provide a compound of or a salt thereof, (iv) removing the tert-butyl group in the compound of formula (N) or a salt thereof to provide a compound of formula (O): [Chemical Formula 50] a compound of or a salt thereof, (v) coupling the compound of formula (O) with a compound of formula (J-2): [Chemical Formula 51] to provide the compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate (e.g., monohydrate) thereof, comprising, wherein the compound of formula (J-2) is (v-i) a compound of formula (E): [Chemical Formula 52] contacting with a compound of formula (F-1): [Chemical Formula 53] a compound of or a salt thereof, and a compound of formula (G-1): [Chemical Formula 54] (wherein R is C １ ~ ５ alkyl) under conditions sufficient to provide a compound of, (v-ii) contacting the compound of formula (G-1) with a reducing agent to provide a compound of formula (H-1): [Chemical Formula 55] a compound of or a salt thereof, (v-iii) contacting the compound of formula (H-1) or a salt thereof with an acid to provide the compound of formula (J-2), prepared by a process comprising, or B. wherein the process is (i) a compound of formula (A-1): [Chemical Formula 56] The compound of formula (B): [Chemical 57] The compound of formula (C): [Chemical 58] are contacted under conditions sufficient to provide the compound of formula (D): (ii) chlorinating the compound of formula (C) or a salt thereof to provide a compound of formula (D): [Chemical 59] or a salt thereof, (iii) the compound of formula (D) or a salt thereof is reacted with a compound of formula (M): [Chemical 60] (wherein R ２ and R ３ are independently H, C １～５ alkyl, or R ２ and R ３ together with the atoms to which they are attached form a 5- or 6-membered ring optionally substituted with one, two, three or four C １～３ alkyl) and a compound of formula (N): [Chemical 61] are contacted under conditions sufficient to provide the compound of formula (O): (iv) removing the tert-butyl group in the compound of formula (N) or a salt thereof to provide a compound of formula (O): [Chemical 62] or a salt thereof, (v) coupling the compound of formula (O) with a compound of formula (J-2): [Chemical 63] to provide the compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate (e.g., monohydrate) thereof, comprising wherein the compound of formula (J-2) is (v-i) formula (E): [Chemical 64] The compound of formula (F-1): [Chemical formula 65] is contacted with a compound of formula (G-1): [Chemical formula 66] (wherein R is C １ ~ ５ alkyl) under conditions sufficient to provide a compound of formula (G-1), (v-ii) The compound of formula (G-1) is contacted with a reducing agent to provide a compound of formula (G-3): [Chemical formula 67] or a salt thereof, (v-iii) The compound of formula (G-3) is contacted with a reducing agent to provide a compound of formula (H-1): [Chemical formula 68] or a salt thereof, (v-iv) The compound of formula (H-1) or a salt thereof is contacted with an acid to provide a compound of formula (J-2), A process prepared by a process comprising:

12. A process for preparing a compound of formula (L): [Chemical formula 69] or a salt thereof, comprising: A compound of formula (P): [Chemical formula 70] is contacted with a compound of formula (Q): [Chemical formula 71] or a salt thereof, under conditions sufficient to provide a compound of formula (L) or a salt thereof, optionally in the presence of sodium triacetoxyborohydride (STAB), an amine, and a protic solvent.

13. A process for preparing a compound of formula (N): [Chemical formula 72] or a salt thereof, comprising: Formula (L): 【Chemical 73】 A compound of the formula (S): 【Chemical 74】 (wherein R ２ and R ３ are independently H, C １～５ alkyl, or R ２ and R ３ together with the atom to which they are attached form a 5- or 6-membered ring optionally substituted with one, two, three or four C １～３ alkyl) is contacted with the compound of the formula (N) under conditions sufficient to provide the compound of the formula (N).

14. Formula (I): 【Chemical 75】 A process for preparing a compound of the formula (I), or a pharmaceutically acceptable salt, solvate or hydrate (e.g., monohydrate) thereof, comprising Formula (T): 【Chemical 76】 A compound of the formula (S) or a salt thereof is contacted with a compound of the formula (S): 【Chemical 77】 (wherein R ２ and R ３ are independently H, C １～５ alkyl, or R ２ and R ３ together with the atom to which they are attached form a 5- or 6-membered ring optionally substituted with one, two, three or four C １～３ alkyl) or a salt thereof and the compound of the formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, under conditions sufficient to provide the compound of the formula (I).

15. Formula (I): 【Chemical 78】 A process for preparing a compound of the formula (I), or a pharmaceutically acceptable salt, solvate or hydrate (e.g., monohydrate) thereof, comprising Formula (V): [Chemical 79] (wherein, R ２ and R ３ are independently H, C １～５ alkyl, or R ２ and R ３ together with the atom to which they are attached form a 5- or 6-membered ring optionally substituted with one, two, three or four C １～３ alkyl) or a salt thereof, with a compound of formula (D): [Chemical 80] of a compound or a salt thereof and the compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, under conditions sufficient to provide them.

16. Formula (AB): [Chemical 81] A process for preparing a compound of (i) contacting a compound of formula (AA): [Chemical 82] with a transaminase to provide a compound of formula (J-1): [Chemical 83] or a salt thereof, (ii) protecting the compound of formula (J-1) to provide a compound of formula (AB) (wherein Boc is tert-butyloxycarbonyl), A process comprising.

17. Deprotecting the compound of formula (AB) to provide a compound of formula (J-1): [Chemical 84] or a salt thereof (such as its hydrochloride salt), and the deprotection is optionally carried out in the presence of hydrochloric acid, trifluoroacetic acid, phosphoric acid, sulfuric acid, zinc bromide, catalytic iodine, acetyl chloride in methanol, or oxalyl chloride in methanol. The method according to claim 16.

18. The compound of the formula (AA) is a compound of the formula (AC): 【Chemical Formula 85】 or a salt thereof, is prepared by contacting with an alkaline earth metal salt of a carboxylic acid, or a carboxylic acid, or a mixture thereof, in the presence of a solvent (such as alcohol, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, acetonitrile, or a mixture thereof) and water, and the compound of the formula (AC) is a compound of the formula (AD): 【Chemical Formula 86】 The compound of the formula (AD) is optionally prepared by contacting with a compound of the formula (AE): 【Chemical Formula 87】 or a salt thereof, under conditions sufficient to provide the compound of the formula (AC), according to the method of claim 16.

19. A process for preparing a compound of the formula (J-2): 【Chemical Formula 88】 comprising: (i) contacting a compound of the formula (AD): 【Chemical Formula 89】 with magnesium metal and diethyl oxalate to provide a compound of the formula (E): 【Chemical Formula 90】 (ii) hydrolyzing the compound of the formula (E) to obtain a compound of the formula (AF): 【Chemical Formula 91】 or a salt thereof; (iii) contacting the compound of the formula (AF) or a salt thereof with a transaminase to provide a compound of the formula (AG): 【Chemical Formula 92】 or a salt thereof; (iv) contacting the compound of the formula (AG) with a reducing agent and quenching the reaction product with hydrochloric acid to provide the compound of the formula (J-2). A process comprising

20. The following: (a) Compound of formula (G-1): 【Chemical formula 93】 (wherein R is C1-C5 alkyl) or a salt thereof; (b) Compound of formula (G-3): 【Chemical formula 94】 (wherein R is C1-C5 alkyl) or a salt thereof; (c) Compound of formula (H-1): 【Chemical formula 95】 or a salt thereof; (d) Compound of formula (J-3): 【Chemical formula 96】 ; (e) Compound of formula (J-4): 【Chemical formula 97】 ; (f) Compound of formula (M-2): 【Chemical formula 98】 or a salt thereof; (g) Compound of formula (S): 【Chemical formula 99】 (wherein R2 and R3 are independently H, C1-C5 alkyl, or R2 and R3 together with the atom to which they are attached form a 5- or 6-membered ring optionally substituted with one, two, three or four C1-C3 alkyls) or a salt thereof; (h) Compound of formula (AH): 【Chemical formula 100】 (wherein R4 is H, C2-C6 alkyl, or aryl); (i) Compound of formula (AB): 【Chemical formula 101】 (wherein Boc is butyloxycarbonyl) or a salt thereof; (j) A compound of formula (I) or a monohydrate thereof prepared by the process according to claim 9 A compound selected from

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