Process for preparing histone demethylation inhibitors

Abstract

Provided herein are methods for preparing 3-({[(4R)-7-{methyl[4-(propan-2-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid and novel intermediate compounds for use in the preparation of histone demethylation inhibitors.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 234,344, filed August 18, 2021, which is incorporated herein by reference in its entirety for all purposes.

[0002] The present disclosure generally relates to methods for preparing 3-({[(4R)-7-{methyl[4-(propan-2-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid and novel intermediate compounds. [Background technology]

[0003] The compound 3-({[(4R)-7-{methyl[4-(propan-2-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid (referred to herein as Compound 8) is a selective inhibitor of the KDM4 family of histone demethylation (see, e.g., U.S. Pat. No. 9,242,968). The chemical structure of Compound 8 is shown below.

[0004] [ka] This groundbreaking epigenetic-modifying compound shows promise in the treatment of various types of cancer.

[0005] Large quantities of highly purified compound are needed to further establish the clinical efficacy of compound 8. Accordingly, in one aspect, provided herein is a method for preparing 3-({[(4R)-7-{methyl[4-(propan-2-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid and salts thereof. Intermediate compounds for use in preparing this compound are also provided herein. Summary of the Invention

[0006] In certain embodiments, described herein are methods for preparing 3-({[(4R)-7-{methyl[4-(propan-2-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid and its salts as histone demethylation inhibitors. Also described herein are intermediate compounds for use in preparing the histone demethylation inhibitors.

[0007] The present embodiments can be more fully understood by reference to the detailed description and examples that are intended to exemplify non-limiting embodiments.

[0008] In one embodiment, compound 8

[0009] [ka] or a salt thereof.

[0010] In certain embodiments, compound 8

[0011] [ka] or a salt thereof, comprising the steps of: (a) Compound 14

[0012] [ka] or its salt is hydrolyzed to give compound 15

[0013] [ka] or a solvate thereof; (b) reacting compound 15, or a solvate thereof, with an acid to form compound 8; (c) optionally converting compound 8 into a pharmaceutically acceptable salt thereof; Including, In the formula, M + is selected from alkali cations and protonated amine bases; Methods are provided herein.

[0014] In one aspect, provided herein are novel compounds that are useful as intermediates in the synthesis of compound 8, or a salt thereof.

[0015] [ka] Provided herein is a compound selected from: [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 shows the results of a pressure screening study evaluating the effect of pressure on the conversion of compound 2 to compound 3 in Alternative Synthesis 1.

[0017] [Figure 2] FIG. 2 shows the results of solubility testing of compound 12 from Alternative Synthesis 1 in different solvent systems.

[0018] Detailed Description of the Invention definition 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 disclosure belongs. In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments of the present disclosure. It is to be understood that the foregoing summary and the following detailed description are exemplary and explanatory only and are not intended to limit any claimed subject matter. In the event that any material incorporated herein by reference contradicts the express content of the present disclosure, the express content shall control. In this application, the use of the singular includes the plural unless specifically stated otherwise. It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless stated otherwise. Furthermore, the use of the terms "including," as well as other forms such as "include," "includes," and "included," is not limiting.

[0019] Unless the context requires otherwise, throughout the specification and claims, the term "comprise" and variations thereof, such as "comprises" and "comprising," are to be interpreted in the inclusive sense, i.e., "including, but not limited to."

[0020] Any concentration range, percentage range, ratio range, or integer range herein should be understood to include any integer value within the recited range, and, where appropriate, fractions thereof (such as tenths and hundredths of integers), unless otherwise indicated. Also, any numerical range recited herein for any physical characteristic, such as polymer subunits, size, or thickness, should be understood to include any integer within the recited range, unless otherwise indicated. As used herein, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the indicated range, value, or structure, unless otherwise indicated.

[0021] Throughout this specification, a reference to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0022] As used herein, the term "salt" refers to an acid or base salt of a compound disclosed herein. It is understood that a "pharmaceutically acceptable salt" is non-toxic. Non-limiting examples of pharmaceutically acceptable salts include acid addition salts and base addition salts.

[0023] Pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and those derived from, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, It is formed using organic acids such as glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-l,5-disulfonic acid, naphthalene-2-sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, -toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid.

[0024] Pharmaceutically acceptable base addition salts are prepared from the addition of inorganic or organic bases to free acids. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Non-limiting examples of inorganic salts include ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, non-limiting examples of which include ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, V-ethylpiperidine, polyamine resins, and the like.

[0025] "Optional" or "optionally" means that the event described after the circumstance may or may not occur, and that the description includes cases where this event or circumstance occurs and cases where it does not occur. For example, "optionally converting compound X to its salt" means that compound X may or may not be converted to a salt. In some embodiments, compound X is converted to a salt, while in other embodiments, compound X is not converted to a salt.

[0026] While various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein for clarity in the context of separate embodiments, the invention may also be implemented in a single embodiment.

[0027] Discovery Synthesis The discovery synthesis described in U.S. Patent No. 9,242,968 for preparing compound 8 involves several steps that make compound 8 unsuitable for large-scale synthesis, including a C-N coupling reaction that generates harmful reaction steps and polymeric impurities. Therefore, there is a need to develop an alternative synthesis for producing compound 8. Furthermore, compound 8 has low solubility in water and most common organic solvents and tends to precipitate as an amorphous paste, making large-scale filtration difficult. Therefore, there is also a need to provide compound 8 in an alternative form, such as a salt.

[0028] The discovery synthesis described in US Pat. No. 9,242,968 for preparing compound 8 is outlined in Scheme 1.

[0029] [ka]

[0030] The discovery pathway begins with the reaction of 7-bromochromanone (compound 1) with trimethylsilyl cyanide to give the corresponding cyanohydrin, which is then heated with acid to give 2,3,3-unsaturated amide 2. The required chirality is introduced via highly selective (~95% ee) ruthenium-catalyzed asymmetric hydrogenation of the double bond, yielding compound 3. Reduction of the amide with BH3 in THF gives the corresponding amine 4. Two successive palladium-catalyzed C—N couplings with compounds 9 and 10 each afford compound 6. Hydrolysis of compound 6 gives the free form of compound 8.

[0031] The discovery synthesis outlined in Scheme 1 produces compound 8 in six linear steps with an overall yield of approximately 16%. However, as noted above, the discovery synthesis is not suitable for large-scale production due to several adverse reaction steps and the C-N coupling reaction, which generates polymeric impurities. For example, step 2 involves high-pressure hydrogenation, step 3 involves the risk of explosion in the BH3·THF reaction, and step 4 has selectivity issues. Furthermore, compound 8 has poor solubility in most common solvents and tends to precipitate as an amorphous resin, making large-scale isolation by filtration impossible. Therefore, further development of compound 8 requires (i) alternative synthetic routes involving elimination of adverse reactions and more selective C-N coupling strategies, and (ii) alternative forms of compound 8 with more favorable morphologies, such as its salts (e.g., pharmaceutically acceptable salts).

[0032] Thus, in one aspect, provided herein is an alternative synthetic route that provides 3-({[(4R)-7-{methyl[4-(propan-2-yl)phenyl]amino}-3,4-dihydro-2H-l-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid (compound 8) as a salt.

[0033] Alternative synthesis 1 In one aspect, provided herein is a method for preparing compound 8, or a salt thereof, according to the synthetic route outlined in Scheme 2 (“Alternative Synthesis 1”).

[0034] [ka]

[0035] The synthetic strategy of Alternative Synthesis 1 for preparing the lysine salt of compound 8, shown in Scheme 2, centers on the Buchwald coupling reaction between protected amine 11 and compound 10a. Other salts can also be made using Alternative Synthesis 1. This reaction is highly selective, affording the desired coupling product 12 as the sole product in good yield. Alternative Synthesis 1 offers an advantage over the discovery route because it requires only a single CN coupling step rather than two sequential CN coupling steps (Scheme 1, Steps 4 and 5), thus providing a more cost-efficient synthesis (reducing costs associated with noble metal catalysts and extra processing associated with heavy metal removal). A significant limitation of the first CN coupling step of the discovery route (Scheme 1, Step 4) is the formation of polymeric impurities resulting from the reaction of the desired product of the reaction, aryl bromide 5, with another molecule of amine 4, etc. (see Scheme 3 below).

[0036] [ka] Polymer impurities are notoriously difficult to remove because they tend to be less soluble than the desired monomer. Additionally, as the polymer grows larger, detection becomes extremely difficult. These challenges represent a significant risk to product purity. A solution to this observed problem is provided in Alternative Synthesis 1.

[0037] Another significant drawback of the discovery route for large-scale production is the high-pressure hydrogenation step (Step 2 in Scheme 1, approximately 725 psi or 5 MPa). Many manufacturing facilities do not have the capability to perform chemical reactions on a large scale at such extreme pressures. Pressure screening showed little or no effect of pressure or temperature on the selectivity of the hydrogenation. In all cases, good selectivity was obtained. In addition, screening showed that lower hydrogen pressures were sufficient for conversion to product. Thus, Alternative Synthesis 1 eliminates the high-pressure hydrogenation step of the discovery route.

[0038] Furthermore, isolation of a high-purity product (compound 3) with reduced residual metals from the hydrogenation reaction in step 2 has proven useful for downstream processing. Activated carbon (e.g., Ecosorb C941) has been found to effectively remove residual Ru.

[0039] Another drawback of the discovery route is the explosion hazard associated with the use of BH3·THF in the amide reduction in Step 3 of Scheme 1. BH3·THF has a self-accelerating decomposition temperature (SADT) of 40 °C. If this reagent is exposed to adiabatic conditions above 40 °C, a self-sustaining exothermic reaction can cause a temperature increase, and exposure of BH3·THF to temperatures above 60 °C can lead to an explosion. The discovery route uses excess BH3·THF at 50–60 °C. To avoid this hazard, the thermally stable BH3·DMS complex was used in the amide reduction reaction (Step 3) of Alternative Synthesis 1 (Scheme 2). This complex can be heated at higher temperatures with significantly less risk of a runaway reaction. The BH3·DMS reaction cleanly produces compound 4, which can be directly used in the next step. Therefore, Alternative Synthesis 1 eliminates the explosion hazard associated with the discovery route.

[0040] Overall, alternative synthesis 1 provides a more efficient route to compound 8 and its salts with superior purity and chiral purity compared to the discovery route.

[0041] Thus, in certain embodiments, compound 8

[0042] [ka] or a salt thereof, comprising the steps of: (a) Compound 14

[0043] [ka] or its salt by hydrolysis, compound 15

[0044] [ka] or a solvate thereof; (b) reacting compound 15, or a solvate thereof, with an acid to form compound 8; (c) optionally converting compound 8 into a pharmaceutically acceptable salt thereof; Including, In the formula, M + is selected from alkali cations and protonated amine bases; A method is disclosed herein.

[0045] In certain embodiments, M of compound 15 + Na + , K. + and protonated dicyclohexylamine. In some embodiments, M + Na + is.

[0046] In certain embodiments, step (a) is carried out on a salt of compound 14. In some embodiments, the salt is selected from HCl, HBr, HI, HSO, HPO, methanesulfonate, p-toluenesulfonate, camphorsulfonate, oxalate, and benzenesulfonate. In certain embodiments, the salt is an HCl salt. In some embodiments, the salt of compound 14 is compound 14a.

[0047] [ka] is.

[0048] In certain embodiments, step (a) is carried out using at least one base. In some embodiments, the at least one base is selected from an alkaline hydroxide and dicyclohexylamine. In other embodiments, the alkaline hydroxide is selected from NaOH and KOH. In some embodiments, the alkaline hydroxide is NaOH.

[0049] In certain embodiments, step (a) is carried out using an alcohol as a solvent. In some embodiments, the alcohol is selected from ethanol and methanol. In certain embodiments, the alcohol is ethanol.

[0050] In certain embodiments, compound 15 is formed as a solvate. In some embodiments, compound 15 is formed as an ethanol solvate or a methanol solvate. In certain embodiments, compound 15 is formed as an ethanol solvate. In some embodiments, the ethanol solvate is compound 15a.

[0051] [ka] is.

[0052] In certain embodiments, the acid in step (b) is selected from HCl, HBr, HI, HSO, HPO, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, oxalic acid, and benzenesulfonic acid. In some embodiments, the acid in step (b) is HCl.

[0053] In certain embodiments, step (b) is carried out using an aqueous alcohol as a solvent. In some embodiments, the aqueous alcohol is selected from ethanol and methanol. In certain embodiments, the aqueous alcohol is methanol.

[0054] In certain embodiments, compound 8 is a lysine salt (compound 8a)

[0055] [ka] is reacted with lysine in step (c) to form

[0056] In certain embodiments, compound 14 or a salt thereof in step (a) is (i) Compound 13

[0057] [ka] or a salt and / or solvate thereof, compound 16

[0058] [ka] to form compound 14, and (ii) optionally converting compound 14 to a salt thereof It is prepared by

[0059] In certain embodiments, step (i) is carried out using at least one polar aprotic solvent. In some embodiments, the at least one polar aprotic solvent is selected from N-methyl-2-pyrrolidone (NMP), 2-methyltetrahydrofuran (2-MeTHF), DMF, DMSO, THF, DMAc, N-methylimidazole, acetonitrile, dimethoxyethane, and 1,4-dioxane. In certain embodiments, the at least one polar aprotic solvent is selected from N-methyl-2-pyrrolidone (NMP) and 2-methyltetrahydrofuran (2-MeTHF). In some embodiments, the at least one polar aprotic solvent is N-methyl-2-pyrrolidone (NMP).

[0060] In certain embodiments, step (i) is carried out using a base. In some embodiments, the base is selected from t-amylamine, CsCO, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylimidazole (NMI), EtN, 1,4-diazabicyclo[2.2.2]octane (Dabco), borate buffer, DBU, TMG, NaOTMS, and KHMDS. In some embodiments, the base is selected from t-amylamine, diisopropylethylamine, tert-butylamine, DBU, and TMG. In certain embodiments, the base is t-amylamine.

[0061] In certain embodiments, step (i) is carried out at a temperature of about 60°C to 100°C. In some embodiments, the temperature is about 70°C to 90°C. In certain embodiments, the temperature is about 70°C to 80°C.

[0062] In certain embodiments, compound 14 is reacted with an acid in step (ii) to form a salt. In some embodiments, the acid in step (ii) is selected from HCl, HBr, HI, HSO, HPO, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, oxalic acid, and benzenesulfonic acid. In certain embodiments, the acid in step (ii) is HCl.

[0063] In certain embodiments, compound 13 or a salt and / or solvate thereof is compound 12.

[0064] [ka] is prepared by deprotecting under acidic conditions to form compound 13 or a salt and / or solvate thereof.

[0065] In certain embodiments, the acidic conditions include H2SO4, HCl, HBr, and / or benzenesulfonic acid. In certain embodiments, the acidic conditions include H2SO4. In certain embodiments, the acidic conditions include H2SO4 in an aqueous alcohol. In some embodiments, the aqueous alcohol is methanol or ethanol. In certain embodiments, the aqueous alcohol is methanol.

[0066] In certain embodiments, deprotecting compound 12 to form compound 13, or a salt and / or solvate thereof, is carried out at a temperature of about 35° C. to 55° C. In some embodiments, deprotection is carried out at a temperature of about 35° C. to 45° C.

[0067] In certain embodiments, compound 12 is a compound similar to compound 11.

[0068] [ka] to compound 10a using a palladium catalyst and phenol.

[0069] [ka] to form compound 12.

[0070] In certain embodiments, the palladium catalyst is selected from Xphos Pd(crotyl)Cl, RuPhos Pd G2, XPhos Pd G2, BrettPhos Pd G3, CPhos Pd G3, DavePhos Pd G3, P(tBu)3 Pd G2, JosiPhos Pd G3, MorDalPhos Pd G3, BINAP Pd G3, SPhos Pd G2, SPhos Pd G2, tBuXPhos Pd G3, XantPhos Pd G3, and XPhos Pd G3. In some embodiments, the palladium catalyst is selected from:

[0071] [ka] Selected from.

[0072] In certain embodiments, the palladium catalyst is

[0073] [ka] is.

[0074] In certain embodiments, the palladium catalyst is used in an amount of about 1 mol % to 3 mol %. In some embodiments, the palladium catalyst is used in an amount of about 2 mol %.

[0075] In certain embodiments, the reaction of compound 11 with compound 10a is carried out using a solvent selected from THF and 2-methyltetrahydrofuran. In some embodiments, the solvent is 2-methyltetrahydrofuran.

[0076] In certain embodiments, the reaction of compound 11 with compound 10a is carried out at a temperature of about 70° C. to 90° C. In some embodiments, the temperature is about 80° C. In certain embodiments, the temperature is about 75° C.

[0077] In certain embodiments, the reaction of compound 11 with compound 10a is carried out in the presence of a base. In some embodiments, the base is selected from NaOPh and Cs2CO3. In certain embodiments, the base is Cs2CO3. In some embodiments, the Cs2CO3 is milled.

[0078] In certain embodiments, compound 11 is a compound selected from the group consisting of compound 4

[0079] [ka] is prepared by reacting with Boc2O to form compound 11.

[0080] In certain embodiments, compound 4 is compound 3

[0081] [ka] is prepared by reacting with BH3·DMS to form compound 4.

[0082] In certain embodiments, the reaction of compound 3 with BH3·DMS is carried out using a solvent selected from toluene, tetrahydrofuran, and 2-methyltetrahydrofuran. In some embodiments, the solvent is 2-methyltetrahydrofuran.

[0083] In certain embodiments, the reaction of compound 3 with BH3·DMS is carried out at a temperature of about 55° C. to 65° C. In certain embodiments, the temperature is about 70° C.

[0084] In certain embodiments, compound 3 is compound 2

[0085] [ka] to form compound 3. In some embodiments, the ruthenium catalyst is selected from (s)-RuCl[(p-cymene)(DM-SEGPHOS®)]Cl, (s)-RuCl[(p-cymene)(DTBM-SEGPHOS®)]Cl, (s)-RuCl[(p-cymene)(BINAP)]Cl, (s)-RuCl[(p-cymene)(T-BINAP)]Cl, (s)-RuCl[p-cymene)(H-BINAP)]Cl, (s)-RuCl[(p-cymene)(SEGPHOS®)]Cl, and Ru(OAc)[(s)-BINAP]. In some embodiments, the ruthenium catalyst is Ru(OAc)[(s)-BINAP].

[0086] In certain embodiments, the hydrogenation is carried out using methanol, tetrahydrofuran, or a combination thereof as a solvent. In some embodiments, the hydrogenation is carried out using a combination of methanol and tetrahydrofuran as a solvent.

[0087] In certain embodiments, the hydrogenation is carried out at a temperature of about 30° C. to 50° C. In some embodiments, the temperature is about 30° C. to 45° C. In certain embodiments, the temperature is about 35° C.

[0088] In certain embodiments, the hydrogenation is carried out under high pressure. In some embodiments, the hydrogenation is carried out using a pressure of about 60 psi to 200 psi. In certain embodiments, the pressure is about 75 psi to 200 psi. In some embodiments, the pressure is about 100 psi to 150 psi. In certain embodiments, the pressure is about 150 psi.

[0089] In certain embodiments, compound 2 is a compound 1

[0090] [ka] with (i) trimethylsilyl cyanide and (ii) an acid to form compound 2. In certain embodiments, the reaction of compound 1 with (i) trimethylsilyl cyanide is carried out using ZnI or ZnCl. In some embodiments, the reaction of compound 1 with (i) trimethylsilyl cyanide is carried out using ZnCl. In certain embodiments, the reaction of compound 1 with (i) trimethylsilyl cyanide is carried out using ZnI.

[0091] In certain embodiments, the reaction of compound 1 with (i) trimethylsilyl cyanide is carried out using a solvent selected from toluene, dichloromethane, and dichloromethane. In some embodiments, the solvent is dichloromethane.

[0092] In certain embodiments, in preparing compound 2, the (ii) acid is sulfuric acid, acetic acid, or a combination thereof. In some embodiments, the (ii) acid is sulfuric acid. In certain embodiments, the (ii) acid is acetic acid. In some embodiments, the (ii) acid is a combination of sulfuric acid and acetic acid.

[0093] In certain embodiments, in preparing compound 2, the reaction of (ii) with the acid is carried out at a temperature of about 50°C to 100°C. In some embodiments, the temperature is about 50°C to 90°C. In some embodiments, the temperature is about 50°C to 80°C. In certain embodiments, the temperature is about 70°C to 80°C.

[0094] Alternative synthesis 2 In another aspect, provided herein is a method for preparing compound 8, or a salt thereof, according to the synthetic route outlined in Scheme 4 ("Alternative Synthesis 2").

[0095] [ka]

[0096] The synthetic strategy for preparing the lysine salt of compound 8 shown in Scheme 4 is a variation of the discovery route (Scheme 1) using the same bond-forming sequence. Other salts can also be made using Alternative Synthesis 2, which replaces the non-selective Buchwald coupling (Scheme 1, Step 4) with the selective S-coupling of compound 4a with 4-cyano-3-fluoropyridine (compound 16). N Substitution with Ar reaction gives compound 17. Coupling of compound 17 with compound 10a gives compound 14, which is also an intermediate in Alternative Synthesis 1.

[0097] Alternative Synthesis 2 requires only a single CN coupling step, as opposed to the two sequential CN coupling steps required by the discovery pathway (Scheme 1, steps 4 and 5). Therefore, Alternative Synthesis 2 is a more cost-effective synthesis due to the reduced costs associated with precious metal catalysts and the extra processing associated with heavy metal removal. Additionally, as noted above for Alternative Synthesis 1, a significant limitation of the first CN coupling step of the discovery pathway (step 4, Scheme 1) is the formation of polymeric impurities resulting from the reaction of the desired product of the reaction (compound 5) with another molecule of amine 4, for example (Scheme 3). The difficulties associated with identifying and removing the polymeric impurities impact the product purity provided by the discovery pathway. This problem can be resolved by using Alternative Synthesis 2.

[0098] Alternative Synthesis 2 also eliminates the high-pressure hydrogenation step of the discovered route (Step 2 of Scheme 1, approximately 725 psi or 5 MPa). A hydrogen pressure of 150 psi was found to be sufficient for hydrogenation.

[0099] Alternative Synthesis 2 utilizes the thermally stable BH3·DMS complex in the amide reduction reaction (Scheme 4, Step 3) in contrast to the potentially explosive BH3·THF reagent used in the discovery route (Scheme 1, Step 3). As noted above, BH3·DMS can be heated at higher temperatures with significantly less risk of runaway reactions. Therefore, Alternative Synthesis 2 eliminates the explosion hazard associated with the discovery route.

[0100] Overall, alternative synthesis 2 provides a more efficient route to compound 8 and its salts with superior purity and chiral purity compared to the discovery route.

[0101] Thus, in certain embodiments, compound 8

[0102] [ka] or a salt thereof, comprising the steps of: (a) Compound 14

[0103] [ka] or its salt by hydrolysis, compound 15

[0104] [ka] or a solvate thereof; (b) reacting compound 15, or a solvate thereof, with an acid to form compound 8; (c) optionally converting compound 8 into a pharmaceutically acceptable salt thereof; Including, In the formula, M + is selected from alkali cations and protonated amine bases; method.

[0105] In certain embodiments, M of compound 15 + Na + , K. + and protonated dicyclohexylamine. In some embodiments, M + Na + is.

[0106] In certain embodiments, step (a) is carried out on a salt of compound 14. In some embodiments, the salt is selected from HCl, HBr, HI, HSO, HPO, methanesulfonate, p-toluenesulfonate, camphorsulfonate, oxalate, and benzenesulfonate. In certain embodiments, the salt is an HCl salt. In some embodiments, the salt of compound 14 is compound 14a.

[0107] [ka] is.

[0108] In certain embodiments, step (a) is carried out using at least one base. In some embodiments, the at least one base is selected from an alkaline hydroxide and dicyclohexylamine. In other embodiments, the alkaline hydroxide is selected from NaOH and KOH. In some embodiments, the alkaline hydroxide is NaOH.

[0109] In certain embodiments, step (a) is carried out using an alcohol as a solvent. In some embodiments, the alcohol is selected from ethanol and methanol. In certain embodiments, the alcohol is ethanol.

[0110] In certain embodiments, compound 15 is formed as a solvate. In some embodiments, compound 15 is formed as an ethanol solvate or a methanol solvate. In certain embodiments, compound 15 is formed as an ethanol solvate. In some embodiments, the ethanol solvate is compound 15a.

[0111] [ka] is.

[0112] In certain embodiments, the acid in step (b) is selected from HCl, HBr, HI, HSO, HPO, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, oxalic acid, and benzenesulfonic acid. In some embodiments, the acid in step (b) is HCl.

[0113] In certain embodiments, step (b) is carried out using an aqueous alcohol as a solvent. In some embodiments, the aqueous alcohol is selected from ethanol and methanol. In certain embodiments, the aqueous alcohol is methanol.

[0114] In certain embodiments, compound 8 is a lysine salt (compound 8a)

[0115] [ka] is reacted with lysine in step (c) to form

[0116] In certain embodiments, compound 14 or a salt thereof is

[0117] [ka] to compound 10a using a palladium catalyst and phenol.

[0118] [ka] to form compound 14 or a salt thereof.

[0119] In certain embodiments, the palladium catalyst is selected from Xphos Pd(crotyl)Cl, RuPhos Pd G2, XPhos Pd G2, BrettPhos Pd G3, CPhos Pd G3, DavePhos Pd G3, P(tBu)3 Pd G2, JosiPhos Pd G3, MorDalPhos Pd G3, BINAP Pd G3, SPhos Pd G2, SPhos Pd G2, tBuXPhos Pd G3, XantPhos Pd G3, and XPhos Pd G3. In some embodiments, the palladium catalyst is selected from:

[0120] [ka] Selected from.

[0121] In certain embodiments, the palladium catalyst is

[0122] [ka] is.

[0123] In certain embodiments, the palladium catalyst is used in an amount of at least about 2 mole %. In some embodiments, the palladium catalyst is used in an amount of about 3 mole %.

[0124] In certain embodiments, the reaction of compound 17 with compound 10a is carried out with and without water using a solvent selected from THF, toluene, dioxane, and 2-methyltetrahydrofuran. In some embodiments, the solvent is 2-methyltetrahydrofuran.

[0125] In certain embodiments, the reaction of compound 17 with compound 10a is carried out at a temperature of about 70° C. to 90° C. In some embodiments, the temperature is about 75° C. to 80° C. In certain embodiments, the temperature is about 80° C.

[0126] In certain embodiments, the reaction of compound 17 with compound 10a is carried out in the presence of a base. In some embodiments, the base is selected from EtN, DIPEA, DBU, and CsCO. In certain embodiments, the base is CsCO. In some embodiments, the CsCO is milled.

[0127] In certain embodiments, compound 17 is a compound 4a

[0128] [ka] Compound 16

[0129] [ka] to form compound 17.

[0130] In certain embodiments, the reaction of compound 4a with compound 16 is carried out using a catalyst selected from TMG, t-butylamine, tert-amylamine, and DBU. In some embodiments, the catalyst is DBU.

[0131] In certain embodiments, the reaction of compound 4a with compound 16 is carried out using a solvent selected from DMSO, DMF, DMAc, NMP, N-methylimidazole, acetonitrile, dimethoxyethane, 1,4-dioxane, and 2-methyltetrahydrofuran. In some embodiments, the solvent is 2-methyltetrahydrofuran.

[0132] In certain embodiments, the reaction of compound 4a with compound 16 is carried out at a temperature of about 30° C. to 70° C. In some embodiments, the temperature is about 40° C. to 60° C. In certain embodiments, the temperature is about 50° C.

[0133] In certain embodiments, compound 4a is a compound 3

[0134] [ka] is prepared by reacting with BH3·DMS and HCl to form compound 4a.

[0135] In certain embodiments, the reaction of compound 3 with BH·DMS and HCl is carried out using a solvent selected from toluene, tetrahydrofuran, and 2-methyltetrahydrofuran. In some embodiments, the solvent is 2-methyltetrahydrofuran.

[0136] In certain embodiments, the reaction of compound 3 with BH3·DMS and HCl is carried out at a temperature of about 40° C. to 90° C. In some embodiments, the temperature is about 50° C. to 80° C. In some embodiments, the temperature is about 60° C. to 70° C. In certain embodiments, the temperature is about 70° C.

[0137] In certain embodiments, compound 3 is compound 2

[0138] [ka] to form compound 3 using a ruthenium catalyst. In certain embodiments, the ruthenium catalyst is selected from (s)-RuCl[(p-cymene)(DM-SEGPHOS®)]Cl, (s)-RuCl[(p-cymene)(DTBM-SEGPHOS®)]Cl, (s)-RuCl[(p-cymene)(BINAP)]Cl, (s)-RuCl[(p-cymene)(T-BINAP)]Cl, (s)-RuCl[p-cymene)(H-BINAP)]Cl, (s)-RuCl[(p-cymene)(SEGPHOS®)]Cl, and Ru(OAc)[(s)-BINAP]. In some embodiments, the ruthenium catalyst is Ru(OAc)[(s)-BINAP].

[0139] In certain embodiments, the hydrogenation is carried out using methanol, tetrahydrofuran, or a combination thereof as a solvent, hi some embodiments, the hydrogenation is carried out using a combination of methanol and tetrahydrofuran.

[0140] In certain embodiments, the hydrogenation is carried out at a temperature of about 30° C. to 50° C. In some embodiments, the temperature is about 30° C. to 40° C. In certain embodiments, the temperature is about 35° C.

[0141] In certain embodiments, the hydrogenation is carried out under high pressure. In some embodiments, the hydrogenation is carried out using a pressure of about 60 psi to 200 psi. In certain embodiments, the pressure is about 75 psi to 200 psi. In some embodiments, the pressure is about 100 psi to 150 psi. In certain embodiments, the pressure is about 150 psi.

[0142] In certain embodiments, compound 2 is a compound 1

[0143] [ka] with (i) trimethylsilyl cyanide and (ii) an acid to form compound 2. In certain embodiments, the reaction of compound 1 with (i) trimethylsilyl cyanide is carried out using ZnI or ZnCl. In some embodiments, the reaction of compound 1 with (i) trimethylsilyl cyanide is carried out using ZnCl. In certain embodiments, the reaction of compound 1 with (i) trimethylsilyl cyanide is carried out using ZnI.

[0144] In certain embodiments, the reaction of compound 1 with (i) trimethylsilyl cyanide is carried out using a solvent selected from toluene, dichloromethane, and dichloromethane. In some embodiments, the solvent is dichloromethane.

[0145] In certain embodiments, in preparing compound 2, the (ii) acid is sulfuric acid, acetic acid, or a combination thereof. In some embodiments, the (ii) acid is sulfuric acid. In certain embodiments, the (ii) acid is acetic acid. In some embodiments, the (ii) acid is a combination of sulfuric acid and acetic acid.

[0146] In certain embodiments, in preparing compound 2, the reaction of (ii) with the acid is carried out at a temperature of about 50°C to 100°C. In some embodiments, the temperature is about 50°C to 90°C. In some embodiments, the temperature is about 50°C to 80°C. In certain embodiments, the temperature is about 70°C to 80°C.

[0147] intermediate compound In one aspect, provided herein are novel compounds that are useful as intermediates in the synthesis of compound 8, or a salt thereof. In certain embodiments, the compound is

[0148] [ka] or a salt and / or solvate thereof.

[0149] In certain embodiments, the compound is Compound 13 or a salt and / or solvate thereof. In some embodiments, the compound is a salt of Compound 13. In certain embodiments, the compound is a solvate of Compound 13. In some embodiments, the compound is a solvate-salt of Compound 13. In certain embodiments, the compound is

[0150] [ka] is.

[0151] In certain embodiments, the compound is Compound 14 or a salt and / or solvate thereof. In some embodiments, the compound is a salt of Compound 14. In certain embodiments, the compound is

[0152] [ka] is.

[0153] In certain embodiments, the compound is Compound 17 or a salt and / or solvate thereof. In some embodiments, the compound is a salt of Compound 17. In certain embodiments, the compound is a solvate thereof. [Example]

[0154] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided.

[0155] On a Bruker 300MHz, 400MHz, or 500MHz spectrometer 1 H and 13 C nuclear magnetic resonance (NMR) spectra were obtained and are reported in ppm (δ) referenced to residual CHCl, CDSO-CD, etc. Spin-spin coupling constants were reported as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint), broad (br), or multiplet (m) using the coupling constant (J) in Hz. Mass spectra were obtained using an Agilent 6230B time-of-flight (ToF) mass spectrometer. Accurate mass analysis was performed in ESI positive and negative ion modes using CAPSO as the internal calibrant.

[0156] The abbreviations used are as follows:

[0157] [Table 1-1]

[0158] [Table 1-2]

[0159] [Table 1-3]

[0160] [Table 1-4]

[0161] [Table 1-5]

[0162] Example 1. Alternative synthesis of the lysine salt of compound 8 The synthetic route for Alternative Synthesis 1 is outlined above in Scheme 2 and described in more detail below.

[0163] [ka]

[0164] Compound 2 was prepared from compound 1 using trimethylsilyl cyanide and ZnCl. More specifically, a 500 L glass-lined, jacketed reactor was charged with 7-bromochroman-4-one (1) (7.7 kg), ZnI (260 g), and dichloromethane (141 kg) under N. TMSCN (5.1 kg) was then charged to the reactor, and the solution was heated to reflux and aged for approximately 3 to 5 hours before being evaluated for conversion. The reaction mixture was then concentrated to 1 to 2 volumes using a stream of N at an internal temperature below 30 °C. Glacial acetic acid (50.6 kg) was charged to the reaction mixture, and the mixture was cooled to 15 to 25 °C. Water (5.0 kg) was charged to the mixture between 15 and 25 °C, and concentrated HSO (38.2 kg) was then added dropwise to the mixture while maintaining the internal temperature between 15 and 70 °C (actually ~45 °C). The solution was then heated to 60-70°C and aged for 7-9 hours. The internal temperature of the mixture was adjusted to 50-60°C, and water (331 kg) was added dropwise to the reactor at the same temperature range. The resulting suspension was stirred and aged for 1-2 hours, then cooled to 5-15°C at 10°C / hour, and the slurry was then filtered. The resulting wet cake was washed with water (144 kg) until the pH was 6-7 and no CN was detected, and then dried. A yellow solid crude product (18.3 kg) was obtained. The resulting crude solid and ethyl acetate (302 kg) were then placed in a 500 L glass-lined, jacketed reactor and aged for approximately 1 hour. Ecosorb-941 activated carbon (800 g) was then added to the mixture, which was then heated to 35-45°C and aged for 1-2 hours. The resulting slurry was cooled to 20-30°C and filtered through Celite (6.0 kg). The Celite cake was washed twice with ethyl acetate (16 kg). The combined organic filtrate was concentrated to approximately 1-3 volumes under vacuum at below 50°C. The resulting solution was solvent-exchanged with dichloromethane (138 kg) to produce a slurry by distillation crystallization at below 50°C. The resulting slurry was filtered, and the wet cake was washed with dichloromethane (5.0 kg) and subsequently dried at 45°C for 8 hours to give compound 2 (6.08 kg) in 70% yield. 1H NMR(500MHz, CDCl3)δ(ppm)=7.46(d, J=8.2Hz, 1H), 7.09(dd, J=2.0Hz, 8.2Hz, 1H), 7.04(d, J=2.0Hz, 1H), 6.31(t, J=3.9Hz, 1H), 5.72(br s, 2H), 4.81(d, J=4.0Hz, 2H). 13 C NMR (126MHz, CDCl3)δ(ppm)=167.8, 154.9, 131.5, 126.8, 124.9, 124.5, 123.2, 119.8, 118.5, 77.2, 76.9, 76.7, 64.7. C 10 HRMS (ESI) m / z calculated for H9BrNO2 (M+H): 253.9811, found: 253.9817.

[0165] [ka]

[0166] One issue with the hydrogenation of compound 2 in the discovery pathway (Scheme 1 above) was the lack of high pressure (approximately 725 psi) and a scalable isolation procedure. Therefore, a pressure / temperature screen was performed to evaluate the reaction. Results indicated that there was little to no effect of pressure or temperature on the selectivity of the hydrogenation. Results further indicated that hydrogen pressures as low as 60 psi were sufficient to observe conversion to product (see Figure 1). The final reaction conditions were selected to balance equipment capacity, reaction rate, and product quality.

[0167] Another problem with the hydrogenation step in the discovery route (Scheme 1 above) was the isolation of compound 3. Therefore, an activated carbon screen was performed to identify an effective medium for removing residual Ru. Based on these results, a scaled-up synthesis of compound 3 was performed as follows.

[0168] A 500 L stainless steel reactor was charged with compound 2 (5.35 kg), Ru(OAc)2[(S)-BINAP] (0.23 kg), THF (49 kg), and MeOH (44 kg) under N2. The contents were stirred and aged between 15 and 25 °C (~0.5 h). The reactor was then purged three times with N2 and then three times with H2, and finally adjusted to 150 psi, heated (35 to 45 °C), and aged the mixture (10 to 20 h). After completion of the conversion, the temperature was adjusted (20 to 30 °C), and activated carbon Excosorb C-941 (3.0 kg) was charged to the reactor and aged (16 to 24 h). The resulting slurry was filtered through Celite (5.0 kg), and the pad was washed with THF (11.0 kg). The combined organic filtrate was concentrated under vacuum to below 50°C (6-7 vol). This material was solvent-switched to IPAc (114 kg) under vacuum below 50°C and assayed to reach <2% THF. The resulting IPAc solution was then heated (60-70°C) and heptane (42.0 kg) was added dropwise (NLT 6 h). The reaction was then aged (1-2 h). The resulting slurry was cooled to 15-25°C (6-10°C / h) and aged (5-10 h). The resulting slurry was filtered and the cake washed with (1:2) IPAc / n-heptane (14.0 kg). The resulting wet cake was dried (40-50°C for 24-36 h) to give the desired compound 3 (4.8 kg, 89% yield, 95% ee). 1 H NMR(500MHz, CD3SOCD3)δ(ppm)=7.61(br s, 1H), 7.12-6.96(m, 4H), 4.35-4.29(m, 1H), 4.13(ddd, J=3.5Hz, 6.4Hz, 10.5Hz, 1H), 3.60(t, J=5.8Hz, 1H), 2.09-1.95(m, 2H). 13 C NMR (126MHz, CD3SOCD3, 300K) δ(ppm)=174.5, 155.5, 131.2, 122.8, 120.6, 119.7, 119.1, 63.7, 39.4, 25.0. C 10 H 11 HRMS (ESI) m / z calculated for BrNO2 (M+H): 255.9968, found: 255.9966.

[0169] [ka]

[0170] One problem with the amide reduction of compound 3 in the discovery route (Scheme 1 above) was that the procedure used excess BH3·THF at 50-60 °C. As mentioned above, these conditions represent an explosion hazard. To circumvent this hazard, we developed the amide reduction reaction (discussed below) using the thermally stable BH3·DMS complex. The complex can be heated at higher temperatures while significantly reducing the risk of a runaway reaction.

[0171] Therefore, the amide reduction of compound 3 was carried out using the BH3·DMS complex. Compound 4 was not isolated but instead inserted into step 4 as shown in the scheme above.

[0172] Although it was feasible to inject the crude reaction mixture containing compound 4 into protection step 4, the subsequent crystallization of compound 11 presented significant challenges. Compound 11 has a tendency to oil before forming a solid, resulting in lower product quality and significant caking on the reactor walls. This behavior stems from a combination of several factors. Compound 11 has high solubility in several common organic solvents, including heptane, limiting crystallization to alcohol / water mixtures (the DMSO / water solubility curve is too steep). Compound 11 has a melting point of 65-70 °C, which decreases to 30 °C in n-PrOH / water mixtures (a solvent system chosen based on solubility). Additionally, because the process was injectable from step 3, all impurities from the amide reduction were carried over into the crystallization.

[0173] The problem of compound 11 oiling was resolved by filtering the crude reaction mixture after workup through a silica plug. This step likely removes polar impurities that contribute to the tendency of compound 11 to oil. It was also discovered that the gradual addition of water and crystallization at temperatures below 20 °C were important to avoid compound 11 oiling. Crystallization based on this protocol proved robust to scale-up and was successfully implemented at a scale of approximately 4 kg, as shown in Table 1.

[0174] Therefore, compound 11 was prepared on a large scale as follows. Compound 3 (4.25 kg) and 2-MeTHF (57.0 kg) were charged to a 250 L glass-lined vessel under N2, and the solution was heated to 55-65°C. After reaching this temperature, neat BH3-DMS (5.7 kg) was charged to the reaction mixture at 55-65°C over approximately 1 h. After the addition was complete, the mixture was heated (70-80°C) and aged (16-18 h) and subsequently evaluated by HPLC analysis. The mixture was then cooled (-10-0°C), followed by the dropwise addition of 6N HCl (6.6 kg, charged over 3-4 h) and water (7.0 kg, charged over 1-2 h) to obtain a quench solution (pH ≈1). A 5N NaOH solution (25.0 kg) was charged dropwise, maintaining the temperature below 10 °C, and the pH was adjusted to 13–14. The temperature was then adjusted to 20–30 °C, the layers were separated, the aqueous layer was washed with 2-MeTHF (6 kg), and the resulting organic layers were combined. A solution of BocO (4.35 kg, 1.05× wt.) in 2-MeTHF (4 kg), prepared in a separate reactor, was charged to the resulting organic layer. The reactor train was rinsed with 2-MeTHF (3 kg), which was added to the reaction mixture. The resulting mixture was aged (14–16 h). The reaction was then quenched, washed twice with 5 wt.% NaCl solution (26 kg, 5.0× wt.), filtered through a silica gel pad (3.0 kg, 0.5× wt.), and rinsed with 2-MeTHF (9 kg). The resulting solution was concentrated to 1-3 volumes under vacuum at an internal temperature below 45°C. The solution was then solvent exchanged with n-propyl alcohol (75.8 kg, 17.8 wt) at or below 50°C and then cooled to an internal temperature of 20-30°C. The reaction mixture was then charged dropwise (over 1.5 hours) with water (12.75 kg, 3.0× wt) and seeded (130 g, 0.03× wt). The temperature was adjusted to 0-15°C (targeting 5°C at a rate of 0.2°C / min) and the slurry was aged (16-18 hours). Additional water (17.1 kg, 3.7× wt) was charged dropwise (over approximately 1.5 hours) to the slurry at 0-15°C.The mixture was then filtered at 0°C-10°C, and the resulting wet cake was washed with cold (1:4) n-propyl alcohol:water (15.0 kg, 3.5×wt) to give compound 11 (4.65 kg, 92% ee). 1 H NMR (500MHz, CD3SOCD3)δ(ppm)=7.11-7.00(m, 3H), 6.95(d, J=2.0Hz, 1H), 4.17(td, J=4.1Hz, 11.0Hz, 1H), 4.07(dt, J=2.7, 10.6Hz, 1H) , 3.23 (td, J=5.4, 13.5Hz, 1H), 3.03 (ddd, J=6.4Hz, 9.5Hz, 13.7Hz, 1H), 2.81 (qd, J=4.7Hz, 9.4Hz, 1H), 1.94-1.75 (m, 2H), 1.38 (s, 9H). 13 C NMR (126MHz, CD3SOCD3)δ(ppm)=156.3, 156.0, 131.8, 123.6, 123.3, 119.9, 119.5, 78.2, 63.1, 45.2, 33.8, 28.7, 24.1. C 15 H 19 HRMS (ESI) m / z calculated for BrNO3 (MH): 340.0554, found: 340.0538.

[0175] [Table 2]

[0176] [ka]

[0177] Compound 12 was synthesized from compound 11 (prepared from steps 3 and 4 above) and compound 10a.

[0178] Compound 10a can be prepared from commercially available 4-isopropylaniline as follows: A reactor is charged with 4-isopropylaniline (500 g, 3.70 mol, 1.0 eq) and MeOH (2.5 L, 5×vol) under N2. Paraformaldehyde (156 g, 5.20 mol, 1.4 eq) is added. The resulting slurry is stirred at 20°C and charged with a 25 wt% solution of NaOMe (2.54 L, 3.0 eq), maintaining the internal temperature below 32°C. The resulting solution is allowed to stir at room temperature overnight (16 hours). NaBH4 (182 g, 4.81 mol, 1.3 eq) is then charged in portions. The resulting solution is then heated to 60°C for 2 hours. The reaction mixture is then cooled to room temperature and quenched with 1 M KOH (2 L, 4×vol). Methanol is removed under reduced pressure. Water (2.5 L, 5× vol) and DCM (1.5 L, 3× vol) are added, and the resulting emulsion is broken by filtration through a Celite pad. The layers are separated, and the aqueous layer is further extracted with DCM (1 L, 2× vol). The organic layer is dried over MgSO4, filtered, and concentrated to a low volume under reduced pressure (approximately 2× vol). The mixture is placed in a reactor, cooled to −40°C, and 5 M HCl in Et2O (2.5 equiv.) is added over 30 min and stirred for 1 h. Petroleum ether (3 L, 6× vol) is then added and stirred for an additional 1 h. The precipitated solid is isolated by filtration and washed with petroleum ether (2× 1 L, 2× vol). The material is dried under vacuum to afford crude compound 10a in 95%–110% yields and 80%–88% purity. The crude product (400 g) is placed in a reactor, heptane (6 L, 15 vol) is added, and the mixture is heated to 90 °C. 1-Butanol (0.6 L, 1.5 vol) is added to the slurry over 25-30 min until dissolution is achieved. The reaction is then heated for an additional 60 min. The solution is allowed to cool to room temperature over 3 h. Once at 30 °C, the material is isolated by filtration, washed with heptane (2 x 1 L, 2.5 vol), and dried under vacuum to give a recovery of 77%-81% with a purity of approximately 97%-98% by HPLC. A second recrystallization is performed. Compound 10a (500 g) is placed in the reactor.Heptane (6.5 L, 13 vol) was added and heated to 90°C. 1-butanol (1.56 vol-1.95 vol) was added to the slurry over 25-30 min until dissolution was achieved, then heated for an additional 60 min. The solution was allowed to cool to room temperature over 3 h, filtered, and washed with heptane (2 x 1 L, 2.0 vol) to give compound 10a (432 g). 1 H NMR(500MHz, CD3SOCD3)δ(ppm)=7.16(d, J=7.6Hz, 2H), 7.09-6.93(m, 3H), 6.40(dd, J=2.4Hz, 8.4Hz, 1H), 6.23(d, J=2.4Hz, 1H), 4.13-3.9 7(m, 2H), 3.36-3.27(m, 1H), 3.24-3.12(m, 3H), 3.07-2.93(m, 1H), 2.88-2.70(m, 2H), 1.95-1.75(m, 2H), 1.39(s, 9H), 1.19-1.18(d, 6H). 13 C NMR (126MHz, CD3SOCD3)δ(ppm)=155.8, 154.9, 148.5, 146.3, 142.3, 129.6, 127.0, 122.1, 115.1, 110.8, 105.4, 77.6, 62.2, 45.0, 33.0, 32.7, 28.2, 28.1, 24.2, 24.0. C 25 H 35 HRMS (ESI) m / z calculated for N2O3 (M+H): 411.2642, found: 411.2631.

[0179] The conversion of compound 11 to compound 12 via a C-N coupling reaction with compound 10a was another challenge in the development of alternative synthesis 1. A series of tests were performed to screen over 48 different conditions to identify the optimal catalyst, solvent, and base (see, for example, Tables 2–4).

[0180] [Table 3]

[0181] [Table 4]

[0182] [Table 5]

[0183] Table 2 shows the results of catalyst screening using different solvents. DP:IS (desired product area vs. internal standard area) is a ratio term used to measure relative solution yields between multiwell plates. The results give a relative ranking of solution yields. Toluene gave good results under these conditions, but was ultimately not chosen due to its low solubility of the desired product.

[0184] The results in Table 3 show that hydrous phenol bases are not acceptable. The results also show the effect of added phenol compared to the addition of water. Phenol has been used in the past to replace anhydrous KOPh and / or CsOPh (see Hartwig et al., J. Am. Chem. Soc. 2015, 137, 8460-8468), but has been used as a base rather than an additive. Therefore, previous reactions using phenol could not be carried out on a large scale.

[0185] Finally, Table 4 shows the acceptable catalyst loading range. Screening tests led to the discovery of significant catalyst activation with 1.3 equivalents of phenol. The reaction using phenol proved robust, with complete conversion observed at batch scale. The increased catalyst activity under these conditions also allowed for a reduction in catalyst loading to 1 mol% or 2 mol%, as shown in Table 4.

[0186] Workup and isolation of compound 12 also presented challenges. Workup was hindered by an emulsion, which resulted in incomplete resolution with significant product loss. Black rag (presumably spent catalyst) was observed to be the source of the emulsion. The emulsion issue was addressed by performing an in-process filtration through Celite prior to aqueous workup, followed by a NaOH (aq) wash, followed by a water wash to remove all inorganics and phenol.

[0187] The crystallization of compound 12 also required optimization. Compound 12 has low solubility in several common solvents, as shown in Table 5 below. Tests were conducted to find the optimal solvent system of iPrOH / MeTHF. Figure 2 shows the temperature-dependent solubility curve of compound 12 in 0 to 4% by volume 2-MeTHF in 1-propanol, measured on a Technobis Crystal-16 instrument.

[0188] [Table 6]

[0189] To optimize chiral purity, an analysis of the filtrate from the final crystallization from compound 12 was performed (see Table 6). As can be seen in Table 6, the ee% of the filtrate increases as the wet cake is washed, demonstrating that washing the cake is useful for obtaining high quality, high ee material. After the second wash and through the third wash, the ee% of the filtrate can be observed to increase significantly from the second wash.

[0190] [Table 7]

[0191] Based on the results of various screening tests, the process for producing compound 12 from compound 11 was scaled up as follows. Compound 11 (3.00 kg, 1.0× wt), phenol (1.073 kg, 0.358× wt, 1.3 eq), Cs2CO3 (9.416 kg, 3.139× wt, 3.3 eq), compound 10a (1.790 kg, 0.597× wt, 1.1 eq), and palladium catalyst (0.118 kg, 0.039× wt, 0.02 eq) were placed in an appropriately sized reactor. The reactor contents were sparged with N2 and then charged with anhydrous 2-MeTHF (45 L, 15× vol). The resulting mixture was heated (75°C + / - 5°C) and aged until conversion was complete (6-16 h). The mixture was cooled (25°C) and quenched by the addition of water (0.3 L, 0.1×vol) over 30 min. A suspension of Celite (0.3 kg, 0.1×wt) in 2-MeTHF (1.35 L, 0.45×vol) was charged to the mixture, aged (approximately 10 min), and filtered. The reactor train and wet cake were rinsed with 2-MeTHF (3 L, 1.0×vol). The organic filtrate and washes were combined and then heated to 30–35°C. The organic layer was extracted twice with 5 M NaOH (12 L, 4×vol) and twice with water (12 L, 4×vol), and the resulting organic layer was filtered through a polish filter. Extraction can alternatively be achieved using less concentrated NaOH (e.g., 1 M). The reaction mixture was dried by successive distillations (<1 wt% Karl Fischer) with 2-MeTHF, and the reaction volume was reduced (approximately 15 L, 5×vol). The mixture was heated (50-60°C) and 1-propanol (6 L, 2x vol) was added. The mixture was aged (approximately 1 h), then cooled (35-45°C), where it was seeded (0.03x) and aged (2 h). Additional 1-propanol (6 L, 2x vol) was slowly charged to the slurry, and the mixture was continuously distilled with additional 1-propanol (5x vol at 50-60°C) (until the 2-MeTHF content was less than 1% by volume). The mixture was aged after distillation (NLT 60 min), then cooled (15-20°C) and aged (NLT 6 h).The resulting slurry was filtered and the wet cake was washed twice with 1-propanol (3 L, 1×vol), 1-propanol (6 L, 2×vol), and dried (40° C.) to give compound 12 (2.90 kg, >99.5%).

[0192] The results from three different batches are shown in Table 7 below.

[0193] [Table 8]

[0194] [ka]

[0195] Compound 13a was prepared as follows: Compound 12 (2.90 kg, 1.0× wt), methanol (20 L, 7× vol), and H2SO4 (1.90 kg, 0.655× wt, 2.75 equiv) were pumped into an appropriately sized reactor under N2. Additional methanol (1 L, 0.345× vol) was used to rinse the lines and wash the train. The mixture was heated (35°C-40°C) and aged until the reaction was complete (~6 h). The reaction mixture was polish filtered, the train was washed with methanol (2.9 L, 1× vol), and the filtrate and wash were combined. The resulting solution was heated (35°C-40°C), and water (11.6 L, 4× vol) was added to the reaction mixture, the internal temperature was maintained (~30 min), and the mixture was aged (~1 h). A 6 wt% aqueous sulfuric acid solution (11.6 L, 4× volume) was added to the reactor at a rate that maintained the temperature (1-2 h). The mixture was then cooled (20-30°C) over 1 h and aged (1 h). The resulting slurry was filtered, and the wet cake and reactor train were rinsed twice with 50% (v / v) aqueous methanol (5.8 L, 2× volume). The resulting wet cake was washed with water (5.8 L, 2× volume). The resulting wet cake was dried (40-50°C) to yield Compound 13a (2.36 kg). 1H NMR (500MHz, CD3SOCD3, 300K) δ(ppm)=7.17(br d, J=8.4Hz, 2H), 7.10-6.88(m, 3H), 6.40(br dd, J=2.4Hz, 8.5Hz, 1H), 6.23(br d, J=2.3Hz, 1H), 4.14-3.97(m, 2H), 3.21-3.09(m, 3H), 3.00(br d, J=8.7Hz, 1H), 2.92-2.72(m, 3H), 1.93(br d, J=4.3Hz, 2H), 1.19(d, J=7.0Hz, 6H). 13 C NMR (126MHz, CD3SOCD3)δ(ppm)=147.4, 141.9, 135.9, 120.7, 118.8, 118.6, 115.3, 114.4, 103.5, 102.2, 96.6, 54.1, 35.6, 31.2, 25.3, 23.5, 16.4, 15.0. C 20 H 27 HRMS (ESI) m / z calculated for N2O (M+H): 311.2118, found: 311.2112.

[0196] [ka]

[0197] The next challenge in developing Alternative Synthesis 1 was coupling to introduce the required pyridine moiety. Screening tests were performed using several starting materials and metal catalysts. For example, a catalyst screen was performed on 25 mg of racemic compound A (see Table 9 below) using 12 different catalysts. ∼10 mol% of the catalyst was added along with an excess of bromide substrate. After approximately 14 h at 70–75 °C, 3 catalysts (Pd-173, Pd-174, and Pd-175) afforded 20–25 area% of racemic compound C.

[0198] [Table 9]

[0199] Further testing was performed and is summarized in Table 10 below. Preliminary data suggested that Pd-175 provided the highest conversion to the desired product (entries 1–3). The free base of the amine substrate showed higher conversion than the amine salt (entries 3, 6, and 10). Toluene as a solvent provided better conversion than MeTHF and DMA (entries 3, 4, and 11). Addition of phenol did not improve the reaction (entries 5 and 6). The reaction stopped after 1 hour, and additional catalyst loading provided slightly higher conversion (entry 6). Conversion decreased with less catalyst (entries 6 and 8). The iodide substrate provided lower conversion than the bromide substrate (entries 6 and 9), and the ester substrate using Cs2CO3 base did not work well (entry 7).

[0200] [Table 10]

[0201] In addition to these screening tests, nucleophilic aromatic substitution (S N The possibility of using X = F and DBU as the base was investigated. Another screening test was performed to identify an initial base and coupling partner (compound 16a) with a suitable leaving group (Cl or F) (see Table 11 below). A previous screen (not shown) identified the best coupling partner as compound 16a with X = F and DBU as the base.

[0202] [Table 11]

[0203] Further screening was used to optimize both the solvent and base using compound 16 (see Table 12 below). NThe goal was to define the optimal solvent and base for promoting the Ar reaction. Tert-amylamine provided the highest DP:IS ratio (desired product area vs. internal standard area), but the SM Pyr:IS ratio (starting material pyridine vs. internal standard) indicated that the starting fluoropyridine remained at the end of these reaction conditions. DBU and TMG provided similar results, although secondary to tert-amylamine, considering that the starting material present in 50% excess could not tolerate the reaction conditions. The addition of NMP as a cosolvent was also observed in the reaction.

[0204] [Table 12-1]

[0205] [Table 12-2]

[0206] Therefore, a large-scale synthesis of compound 14a was carried out as follows. A suitably sized reactor was charged with compound 13a (2.30 kg, 1.0× wt), compound 16 (0.850 kg, 0.370× wt, 1.14 eq), and tert-amylamine (0.81 kg, 0.35× wt, 1.5 eq) under N2. The reactor and contents were purged with N2 and charged with NMP (12.4 L, 5× vol). The mixture was heated (70°C-75°C) and aged until the reaction was complete (approximately 24 h). The reaction was then cooled (20°C-25°C) and charged with MTBE (23 L, 10× vol). The reaction mixture was then extracted with 5 wt% aqueous NaHCO3 (11.5, 5x vol), 5 wt% aqueous LiCl (11.5, 5x vol), and three times with water (11.5, 5x vol). Additional MTBE was added to adjust the total volume (23 L, 10x). Isopropanol (11.5 L, 5x vol) was added to the reactor, followed by freshly prepared 2 M HCl in IPA (0.610 L, 0.265x vol). The solution was then seeded (0.03x) to facilitate the isolation of compound 14a while maintaining the temperature (20-25 °C), although seeding is not required. The mixture was then aged (approximately 1 h), and then freshly prepared 2 M HCl in IPA (3.048 L, 1.325 L x vol) was added over 5 h while maintaining the temperature (20-25 °C). The resulting orange suspension was aged (NLT 1 h) and then filtered. The resulting wet cake was slurry washed twice with (2:1 v:v) MTBE / IPA (2.3 L, 1×vol), followed by displacement washing twice with 2:1 v:v MTBE / IPA (2.3 L, 1×vol) and dried (40° C.) to give compound 14a (2.60 kg). 1H NMR (500MHz, CD3SOCD3)δ(ppm)=8.49(s, 1H), 7.97(d, J=5.3Hz, 1H), 7.78(br d, J=5.0Hz, 1H), 7.27-7.09(m, 4H), 6.97(d, J=7.4Hz, 2H), 6.40(dd, J=2.4Hz, 8.4Hz, 1H), 6.26(d, J=2.4Hz, 1H), 4.18-4.08(m, 2H), 3.65(br dd, J=5.2Hz, 13.7Hz, 1H), 3.41(br dd, J=10.2Hz, 13.4Hz, 1H), 3.25-3.03(m, 4H), 2.85(spt, J=6.9Hz, 1H), 1.96-1.84(m, 2H), 1.32-1.09(m, 6H). 13 C NMR (126MHz, CD3SOCD3)δ(ppm)=155.0, 148.6, 146.2, 145.8, 142.4, 132.1, 131.5, 130.0, 12 8.0, 127.0, 122.1, 115.4, 114.5, 110.7, 105.4, 102.9, 62.2, 47.2, 32.7, 31.2, 24.2, 23.9, C 26 H 29 HRMS (ESI) m / z calculated for NO (M+H): 413.2336, found: 413.2330.

[0207] Results from three different batches are reported in Table 13 below.

[0208] [Table 13]

[0209] [ka]

[0210] The next reaction in Alternative Synthesis 1 involved hydrolysis of the cyano group. The challenge was to develop a process that avoided the isolation of the free acid (compound 8). The free acid tends to precipitate as an amorphous resin, making filtration at scale impossible, and its solubility is undetectable in water (low to neutral pH) and most common organic solvents. This was achieved by developing a process that yields the sodium salt EtOH solvate (compound 15a). Compound 15a readily crystallizes from hydrolysis conditions as a free-flowing solid that is easy to filter and dry. Compound 15a also provides a soluble intermediate for the synthesis of lysine salts.

[0211] Compound 15a was prepared as follows: A suitably sized reactor was charged with compound 14a (500 g, 1.0×wt) and 200 proof EtOH (2.5 L, 5×vol). The reaction mixture was purged with N and heated (50°C). In a separate vessel, a solution consisting of 10 M NaOH (550 mL, 1.1×vol, 5.0 equiv.), water (250 mL, 0.5×vol), and EtOH (500 mL, 1×) was prepared and then charged to the reaction mixture via a twin funnel (over 2.5 hours). After the addition was complete, the temperature was increased (70°C) and the mixture was aged (approximately 16 hours). After conversion was complete, EtOH (4.25 L, 8.5×vol) was slowly charged to the reaction mixture (2 hours) while maintaining the temperature (70°C). After the addition was complete, the resulting slurry was cooled to ambient temperature (15-25°C) (3 h) and filtered. The wet cake was washed three times with EtOH (0.75 L, 1.5x volume) and the material was dried in a vacuum oven (40°C) to give compound 15a (514 g). 1H NMR(500MHz, CDCl3)δ(ppm)=7.99(br dd, J=5.0Hz, 12.1Hz, 1H), 7.69(br s, 1H), 7.38(br s, 1H), 7.25-7.11(m, 1H), 7.08-6.93(m, 2H), 6.91-6.78(m, J=7.5Hz, 2H), 6.72(br s, 1H), 6.25(br s, 1H), 6.20(br s, 1H), 3.71(ddd, J=2.6Hz, 6.9Hz, 14.0Hz, 2H), 3.11(br s, 1H), 3.01(br s, 3H), 2.93-2.81(m, 1H), 2.75(td, J=6.6Hz, 13.4Hz, 4H), 1.78-1.49(m, 2H), 1.28-1.17(m, 1H), 1.13(br d, J=6.7Hz, 6H). 13 C NMR (126MHz, CD3SOCD3)δ(ppm)=164.6, 147.2, 141.2, 138.9, 137.1, 135.0, 126.6, 124.7, 1 21.1, 118.6, 117.8, 116.7, 114.3, 106.9, 102.9, 97.5, 54.6, 31.2, 25.3, 24.6, 17.3, 15.0. C 26 H 30 HRMS (ESI) m / z calculated for N3O3 (M+H): 432.2282, found: 432.2273.

[0212] [ka]

[0213] The final product (compound 8a) was produced by the reaction of compound 15a with (L)-lysine under acidic conditions. More specifically, compound 15a (559 g, 1.0 wt) and L-lysine (540 g, 0.966 wt) were added to a suitable sized reactor. The reactor was then purged with N2, and water (6.99 L, 12.5 vol) was added. The resulting mixture was then heated (50 °C) and aged (approximately 1 h). Methanol (2.52 L, 4.5 vol) was added in one portion, and the reaction was then aged (10 min). An aqueous solution of 2.12 M HCl (671 mL, 1.2 vol) was then added via an addition funnel (over 45 min), the mixture was cooled (40 °C), and compound 8a seeds (16 g, 0.03 wt) were added. The resulting slurry was aged (16 h) and cooled to ambient temperature (15°C-25°C). The solid was then isolated by filtration, and the wet cake was washed by recycling the filtrate, which was then washed three times with MeOH (1.12 L, 2x volume). The resulting wet cake was dried in a vacuum oven (40°C-50°C) to give compound 8a (417 g).

[0214] Example 2. Alternative synthesis of the lysine salt of compound 8. The synthetic route for Alternative Synthesis 2 is outlined in Scheme 4 above and described in more detail below.

[0215] [ka]

[0216] Compound 3 was prepared according to steps 1 and 2 in Example 1 above.

[0217] [ka]

[0218] Compound 4a was prepared as follows: Compound 3 (1.0 g, 1.0× wt) and MeTHF (16 mL) were charged to a suitable sized reactor at 15°C to 25°C, followed by slow addition of borane-dimethyl sulfide (1.8 mL, 5.0 equiv.). The mixture was then heated at 60°C to 65°C for at least 22 hours. After completion of the reaction, the mixture was cooled and slowly quenched with 6N aqueous HCl (1.5 mL, 1.5× vol) followed by 10 mL of water, maintaining the temperature below 20°C. The organic phase was separated and concentrated. 3N HCl in CPME was introduced to the concentrate, followed by the addition of isopropyl acetate (8 mL), to precipitate the product as an off-white solid. The solid was isolated by filtration and washed with isopropyl acetate. Drying under vacuum gave compound 4a (0.611 g, 61.2% yield, 99.4 area % purity) as an off-white solid.

[0219] [ka]

[0220] Compound 17 was prepared as follows. A 10 mL reactor equipped with an N2 inlet and pitched-blade impeller was charged with compound 4a (5.62 g), compound 16 (3.68 g), and 2-MeTHF (33 mL), and the mixture was inerted with N2. DBU (7.52 mL) was added to the mixture, and the mixture was heated (50 °C) and then aged (14.5 h). Additional compound 16 (1.41 g) was added to the mixture, which was further aged (24 h), and then cooled. The resulting slurry was filtered, and the filtrate and wet cake were washed with additional 2-MeTHF (20 mL) and then DCM (20 mL). The organic filtrates were combined and concentrated on a rotary evaporator to give a brown liquid. The resulting crude product was purified by silica gel chromatography (a 120 g ISCO column on a Teledyne ISCO loaded with DCM and eluted with 10–70% EtOAc / hexanes). The resulting fractions were collected, concentrated, and dried (40° C.) to give compound 17 as a pale yellow solid (4.79 g, 69% yield).

[0221] [ka]

[0222] Compound 14 can be prepared from Compound 17 and Compound 10a according to the following method, which was performed on a racemic mixture of Compound 17 (referred to herein as Compound 17b) to yield a racemic mixture of Compound 14 (referred to herein as Compound 14b).

[0223] To a 1000 mL three-necked round-bottom flask equipped with an overhead stirrer were added 17b (28.1 g), 10a (16.74 g), CsCO (88.23 g), phenol (10.12 g), and palladium catalyst (1.65 g). The reactor was flushed with N for 25 minutes. Anhydrous, degassed 2-MeTHF (300 mL) was added via cannula, and the mixture was stirred, heated (75-80 °C), and aged (approximately 53 h). The mixture was then cooled to room temperature and charged with 2-MeTHF (50 mL). The mixture was then filtered. The reactor train and wet cake were washed with acetone (150 mL). The resulting organic layer was concentrated under reduced pressure to give a black oil. Ethanol (35 mL) was seeded with 14b (50 mg) to facilitate isolation, and the mixture was stirred at room temperature overnight. The resulting slurry was filtered, washed with MTBE (20 mL), and then dried to give compound 14b (26.5 g, 78% yield) as a yellow solid.

[0224] [ka]

[0225] Compound 15a was prepared according to step 8 of Example 1 above.

[0226] [ka]

[0227] Compound 8a was prepared according to step 9 of Example 1 above.

[0228] The present disclosure has been described in some detail by way of illustration and example, for purposes of clarity of understanding, but the illustrations and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated herein by reference in their entireties.

Claims

1. Compound 8 【Chemical 1】 or a salt thereof, comprising the steps of: (a) Compound 14 【Chemistry 2】 or its salt by hydrolysis, Compound 15 【Chemistry 3】 or a solvate thereof; (b) reacting said compound 15 or a solvate thereof with an acid to form said compound 8; (c) optionally converting said compound 8 into a pharmaceutically acceptable salt thereof; Including, In the formula, M ＋ is selected from alkali cations and protonated amine bases; Optionally, step (a) is carried out using at least one base selected from an alkaline hydroxide and dicyclohexylamine; Further optionally, the alkaline hydroxide is selected from NaOH and KOH; Further optionally, step (a) is carried out using an alcohol as a solvent; Further optionally, the alcohol is selected from ethanol and methanol; Further optionally, compound 15 is formed as an ethanol solvate. method.

2. The method of claim 1, wherein the acid in step (b) is HCl; Optionally, step (b) is carried out using aqueous alcohol as a solvent; Further optionally, the aqueous alcohol is selected from ethanol and methanol. The method of claim 1.

3. The compound 8 is a lysine salt 8a 【Chemistry 4】 2. The method of claim 1, wherein in step (c) the lysine is reacted with the lysine to form

4. The compound 8 is a lysine salt 8a 【Chemistry 5】 3. The method of claim 2, wherein in step (c) the lysine is reacted with the lysine to form

5. The compound 14 or a salt thereof in step (a) is (i) Compound 13 【Chemistry 6】 or a salt and / or solvate thereof, Compound 16 【Chemistry 7】 to form compound 14, and (ii) optionally converting said compound 14 into a salt thereof Prepared by Optionally, step (i) is carried out using at least one polar aprotic solvent; Further optionally, the at least one polar aprotic solvent is N-methyl-2-pyrrolidone (NMP); Further optionally, step (i) is carried out using a base; Further optionally, the base is t-amylamine; Further optionally, step (i) is carried out at a temperature of about 60-100°C; Further optionally, step (i) is carried out at a temperature of about 70-80°C; Further optionally, said compound 14 is reacted with HCl in step (ii) to form a hydrochloride salt; The method of claim 1.

6. The compound 13 or a salt and / or solvate thereof is compound 12 【Chemistry 8】 under acidic conditions to form compound 13 or a salt and / or solvate thereof; Optionally, the acidic conditions include H2SO4 in aqueous alcohol; Further optionally, the aqueous alcohol is methanol or ethanol; and further optionally, deprotecting said compound 12 to form said compound 13, or a salt and / or solvate thereof, is carried out at a temperature of about 35-55° C.; Further optionally, deprotecting said compound 12 to form said compound 13, or a salt and / or solvate thereof, is carried out at a temperature of about 35-45°C. The method of claim 5.

7. The method of claim 1, wherein compound 12 is prepared by the reaction of compound 11 with a palladium catalyst and phenol. 【Chemistry 9】 to compound 10a 【Chemistry 10】 to form compound 12, Optionally, the palladium catalyst is 【Chemistry 11】 Selected from Further optionally, the palladium catalyst is 【Chemistry 12】 and Further optionally, the palladium catalyst is used in an amount of about 2 mol %; Further optionally, reacting said compound 11 with said compound 10a is carried out using 2-methyltetrahydrofuran as a solvent; Further optionally, reacting said compound 11 with said compound 10a is carried out at a temperature of about 80° C.; Further optionally, reacting said compound 11 with said compound 10a is carried out in the presence of a base; Further optionally, the base is Cs2CO3; The method of claim 6.

8. The compound 11 is compound 4 【Chemistry 13】 with Boc 2 O to form said compound 11.

9. The compound 4 is compound 3 【Chemistry 14】 with BH 3 .DMS to form compound 4, Optionally, reacting said compound 3 with said BH 3 .DMS is carried out using 2-methyltetrahydrofuran as a solvent; Further optionally, reacting said compound 3 with said BH 3 .DMS is carried out at a temperature of about 70° C. The method of claim 8.

10. The compound 14 or a salt thereof is prepared by the reaction of compound 17 with a palladium catalyst and phenol. 【Chemistry 15】 Compound 10a 【Chemistry 16】 to form compound 14 or a salt thereof, Optionally, the palladium catalyst is 【Chemistry 17】 Selected from Further optionally, the palladium catalyst is 【Chemistry 18】 and Further optionally, the palladium catalyst is used in an amount of at least about 2 mol %; Further optionally, the palladium catalyst is used in an amount of about 3 mol %; Further optionally, reacting said compound 17 with said compound 10a is carried out using 2-methyltetrahydrofuran as a solvent; Further optionally, reacting said compound 17 with said compound 10a is carried out at a temperature of about 80° C.; Further optionally, reacting said compound 17 with said compound 10a is carried out in the presence of a base; Further optionally, the base is Cs2CO3; The method of claim 1. Claim 11: The compound 17 is a compound 4a 【Chemistry 19】 Compound 16 【Chemistry 20】 to form compound 17, Optionally, reacting said compound 4a with said compound 16 is carried out using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a catalyst; Further optionally, reacting said compound 4a with said compound 16 is carried out using 2-methyltetrahydrofuran as a solvent; Further optionally, reacting said compound 4a with said compound 16 is carried out at a temperature of about 30° C. to 70° C.; Further optionally, reacting said compound 4a with said compound 16 is carried out at a temperature of about 50° C. The method of claim 10. Claim 12: The compound 4a is compound 3 【Chemical 21】 with BH 3 .DMS and HCl to form compound 4a; Optionally, reacting said compound 3 with said BH 3 .DMS and said HCl is carried out using 2-methyltetrahydrofuran as a solvent; Further optionally, reacting said compound 3 with said BH 3 .DMS and said HCl is carried out at a temperature of about 40-90° C.; Further optionally, reacting said compound 3 with said BH 3 .DMS and said HCl is carried out at a temperature of about 70° C.; The method of claim 11.

13. The method of claim 1, wherein compound 3 is prepared by converting compound 2 using a ruthenium catalyst. 【Chemical 22】 to form compound 3, Optionally, the ruthenium catalyst is Ru(OAc) 2 [(s)-BINAP]; Further optionally, said hydrogenation is carried out using methanol, tetrahydrofuran, or a combination thereof as a solvent; Further optionally, said hydrogenation is carried out at a temperature of about 30-50°C; Further optionally, the hydrogenation is carried out at a temperature of about 35° C.; Further optionally, said hydrogenation is carried out under high pressure; Further optionally, the hydrogenation is carried out using a pressure of about 150 psi.

10. The method of claim 9.

14. The method of claim 1, wherein compound 3 is prepared by the reaction of compound 2 with a ruthenium catalyst. 【Chemical 23】 to form compound 3, Optionally, the ruthenium catalyst is Ru(OAc) 2 [(s)-BINAP]; Further optionally, said hydrogenation is carried out using methanol, tetrahydrofuran, or a combination thereof as a solvent; Further optionally, said hydrogenation is carried out at a temperature of about 30-50°C; Further optionally, the hydrogenation is carried out at a temperature of about 35° C.; Further optionally, said hydrogenation is carried out under high pressure; Further optionally, the hydrogenation is carried out using a pressure of about 150 psi. The method of claim 12. Claim 15: Compound 2 is compound 1 【Chemistry 24】 with (i) trimethylsilyl cyanide and (ii) an acid to form compound 2; Optionally, reacting compound 1 with trimethylsilyl cyanide in (i) is carried out using ZnI 2 ; Further optionally, reacting compound 1 with trimethylsilyl cyanide in (i) is carried out using dichloromethane as a solvent; Further optionally, the acid in (ii) is sulfuric acid, acetic acid, or a combination thereof; Further optionally, the reaction of (ii) with the acid is carried out at a temperature of about 70-80°C. The method of claim 13. Claim 16: Compound 2 is compound 1 【Chemistry 25】 with (i) trimethylsilyl cyanide and (ii) an acid to form compound 2; Optionally, reacting compound 1 with trimethylsilyl cyanide in (i) is carried out using ZnI 2 ; Further optionally, reacting compound 1 with trimethylsilyl cyanide in (i) is carried out using dichloromethane as a solvent; Further optionally, the acid in (ii) is sulfuric acid, acetic acid, or a combination thereof; Further optionally, the reaction of (ii) with the acid is carried out at a temperature of about 70-80°C.

15. The method of claim 14.

17.

26. or a salt and / or solvate thereof, Or optionally, 【Chemical 27】 a compound which is Or optionally, 【Chemical Formula 28】 A compound which is

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