Methods, processes and intermediates for preparing chroman compounds

Abstract

The present disclosure describes economical and scalable methods and processes for synthesizing the calcium-sensing receptor (CaSR) modulator 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, its intermediates, and pharmaceutically acceptable salts thereof. Also described herein is the use of said intermediates for the synthesis of compounds that can be intermediates in the synthesis of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid.

Description

Detailed Description of the Invention

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This PCT application claims the benefit of and to Indian Provisional Patent Application No. 202021002110, filed January 17, 2020, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0002] [Field] This disclosure relates to the synthesis of substituted chroman compounds and novel intermediates, and uses of the novel intermediates. In particular, this disclosure relates to the enantioselective synthesis of the calcium-sensing receptor (CaSR) modulator 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, its intermediates, and pharmaceutically acceptable salts thereof.

[0003] [Incorporated by reference] All U.S. patents, U.S. patent application publications, foreign patents, foreign and PCT published applications, articles and other documents, references and publications mentioned herein, and all that are listed as cited references in any patent issued in connection with this application, are incorporated herein by reference in their entirety. The incorporated information is part of this application as if all text and other content were repeated in this application, and will be treated as part of the text and content of this application as filed.

[0004] [background] The following contains information that may be useful in understanding the present invention. No admission is made that any of the information, publications, or documents referenced herein, specifically or implicitly, is prior art to or essential to the invention described or claimed. All publications and patents mentioned herein are incorporated herein by reference in their entirety.

[0005] The calcium-sensing receptor (Ca) is a class C G protein-coupled receptor (GPCR). It regulates the physiological serum ionized calcium (Ca) by regulating blood levels of parathyroid hormone. 2+ ) concentration. 2+ (Ca 2+ o) is the major physiological ligand for CaSR.

[0006] Small molecules, called calcimimetics, which are positive allosteric modulators, modulate and improve receptor sensitivity to the existing environment of extracellular ionic calcium and reduce PTH secretion. This has been explored as a potential treatment for hyperparathyroidism and diseases associated with reduced CaSR signaling. Cinacalcet was the first CaSR modulator approved by the U.S. Food and Drug Administration (FDA).

[0007] PCT International Patent Application Publication Numbers: WO2012 / 127388, WO2012 / 120476, WO2012 / 127385, WO2012 / 069421, WO2012 / 069419, WO2012 / 069402, US2011 / 0028452, WO2010 / 150837, WO2010 / 136037, WO2010 / 042642, WO2010 / 038 895, WO2009 / 065406, WO2008 / 059854, WO2006 / 123725, WO2004 / 106280, WO2004 / 069793, WO2002 / 012181 and US2003 / 0199497 refer to compounds related to the calcium-sensing receptor (CaSR) for the treatment of various diseases mediated by the CaSR. Kessler et al., "N1-Benzoyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes: Development of 4-Chlorophenylcarboxamide (Calhex 231) as a New Calcium Sensing Receptor Ligand Demonstrating Potent Calcilytic Activity," J. Med. Chem. (2006), 49, 5119-5128, also discloses compounds related to the CaSR.

[0008] WO 2013 / 124828 discloses a series of substituted chroman compounds for CaSR modulation. One specific compound disclosed therein is 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid. This application also describes a general method for synthesizing these substituted chroman compounds. The disclosed process involves chiral resolution of a racemic chroman-2-carboxylic acid used as a starting material to obtain the desired (R)chroman-2-carboxylic acid in a subsequent step. However, performing chiral resolution of an intermediate is difficult, expensive, and not suitable for industrial scale. Furthermore, performing chiral resolution of an intermediate also affects the overall yield of the production method.

[0009] In view of the above, there is a need for a less complicated, more cost-effective and industrially advantageous more efficient method for the preparation of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid and its salts.

[0010] [overview] The invention described and claimed herein has many attributes and aspects, including but not limited to those described or illustrated or referenced in this Summary. It is not intended to be all-inclusive, and the invention described and claimed herein is not limited to or by the features or embodiments identified in this Summary, which is included for purposes of illustration only and not limitation.

[0011] The present disclosure provides facile, cost-effective, and industrially advantageous methods and processes for the synthesis of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid and its salts. In particular, the methods and processes described herein involve enantioselective methods, including steps in which the stereochemistry of an intermediate or final compound is controlled. In some embodiments, the present disclosure provides novel intermediates, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7″, Compound 7, and Compound 16 (each described in detail herein), that are useful as precursors in the synthesis of Compound A (described in detail herein). In some embodiments, the present disclosure provides methods and processes for synthesizing Compound 7 from a route involving Compound 3.

[0012] The methods and processes disclosed herein also involve novel intermediates and / or salts thereof that are useful for the facile synthesis of Compound A and its salts.

[0013] In some embodiments, the present disclosure provides the compound (R)—N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (Compound 3) and / or a salt thereof,

[0014] [ka] to provide.

[0015] In some embodiments, the present disclosure provides the compound (R)—N—((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (Compound 4) and / or a salt thereof,

[0016] [ka] to provide.

[0017] In some embodiments, the present disclosure provides the compound (R)—N—((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2′-[1,3]dioxolane]-2-carboxamide (Compound 5) and / or a salt thereof,

[0018] [ka] to provide.

[0019] In some embodiments, the present disclosure provides the compound (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4,2′-[1,3]dioxolan]-2-yl)methyl)ethan-1-amine (Compound 6) and / or a salt thereof,

[0020] [ka] to provide.

[0021] In some embodiments, the present disclosure provides the compound (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one (Compound 7) and salts thereof, as well as (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one (Compound 7″),

[0022] [ka] [ka] to provide.

[0023] In some embodiments, the present disclosure provides (R)-2-(((1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (compound 16) and salts thereof,

[0024] [ka] to provide.

[0025] In some embodiments, the present disclosure provides 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A),

[0026] [ka] Scheme 1:

[0027] [ka] The present invention provides a method and process for the synthesis of the compounds shown in Scheme-1, which comprises: a) Reacting 4-oxo-4H-chromene-2-carboxylic acid (compound 1) with (R)-1-(naphthalen-1-yl)ethan-1-amine (compound 2) in the presence of one or more coupling catalysts to obtain (R)-N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (compound 3). wherein the one or more coupling catalysts are propylphosphonic anhydride (T3P), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HCl), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), or a combination thereof; b) enantioselectively reducing the double bond of compound 3 by asymmetric hydrogenation using one or more optically active diphosphine ligands to obtain optically active (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (compound 4), wherein the one or more optically active diphosphine ligands are (R)-(+)-4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [(R)-SEGPHOS®], 4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [SEGPHOS®], (R)-(+)-4,4'-bis[di( 3,5-xylyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [(R)-DM-SEGPHOS®], (R)-(-)-4,4'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [((R)-DTBM-SEGPHOS®)], (R)-(+)-2,2 '-Bis(diphenylphosphino)-1,1'-binaphthalene [(R)-BINAP], 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl [s-Phos], 5-bis(diphenylphosphino)-9,9-dimethylxanthene [Xantphos], (2R,3R)-(+)-bis(diphenylphosphino)butane [R-Chiraphos], 4,4,4',4',6 ,6'-hexamethyl-2,2'-spirobichroman-8,8'-diylbis(diphenylphosphane) [SPANphos], bis(diphenylphosphinoethyl)phenylphosphine [Triphos], (2R,2'R,5R,5'R)-2,2',5,5'-tetramethyl-1,1'-(o-phenylene)diphosphorane [R,R-Me-DuPhos], or a combination thereof; c) reacting compound 4 in the presence of one or more non-polar solvents with one or more catalysts; ethylene Glico Ru andto obtain (R)-N-((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2'-[1,3]dioxolane]-2-carboxamide (compound 5), wherein the one or more catalysts are p-toluenesulfonic acid (PTSA), methanesulfonic acid (MSA), trifluoroacetic acid (TFA), tosylic acid (TsOH), pyridinium p-toluenesulfonate (PPTS), orthophosphoric acid, or a combination thereof, and the one or more nonpolar solvents include, but are not limited to, toluene (methylbenzene), xylene, dioxane, benzene, dichloromethane (CHCl), carbon tetrachloride (CCl), trichloromethane (CHCl), methyl tert-butyl ether (MTBE), or a combination thereof; d) reducing the amide group of compound 5 using a reducing agent to obtain (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4,2'-[1,3]dioxolan]-2-yl)methyl)ethan-1-amine (compound 6), wherein the reducing agent is Vitride, borane-dimethylsulfide complex, (Zn(OAc)2) / DEMS, or a combination thereof; e) treating compound 6 with an aqueous acidic medium to obtain (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one hydrochloride (compound 7); f) reacting compound 7 with Boc anhydride (di-tert-butyl dicarbonate) in the presence of one or more basic catalysts to give tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate (compound 8), wherein the one or more basic catalysts are tripotassium phosphate, triethyl phosphate, amine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, or combinations thereof; g) reacting compound 8 with one or more triflating agents to obtain (R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate (compound 9), wherein the one or more triflating agents are N-phenyl-bis(trifluoromethanesulfonimide), trifluoromethanesulfonic anhydride; N-(4-tert-butylphenyl)bis(trifluoromethanesulfonimide), bis(trifluoromethanesulfonyl)aniline, Comin's reagent, N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide); trifluoromethanesulfonyl chloride, 4-nitrophenyl trifluoromethanesulfonate, 1-(trifluoromethanesulfonyl)imidazole), or a combination thereof; h) coupling compound 9 with methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate in the presence of one or more palladium catalysts to obtain methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10), wherein the one or more palladium catalysts are palladium tetrakis(triphenylphosphine), palladium(II) bis(triphenylphosphine)dichloride, palladium(0) bis(dibenzylideneacetone), palladium(II) bis(triphenylphosphine)diacetate, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), or a combination thereof; i) converting methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10) to methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2-methylbenzoate (compound 11), wherein the conversion is at a rate of about 2.0 Kg / cm2 or through treatment with ammonium formate in the presence of a palladium-on-charcoal catalyst, optionally in the presence of one or more polar solvents, including, but not limited to, methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof; j) converting compound 11 to methyl 2-methyl-5-((2R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoate hydrochloride (compound 12) via a Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid, or trimethylsilyl iodide in the presence of one or more polar solvents, including, but not limited to, methanol, dichloromethane, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof; k) hydrolyzing the ester group of Compound 12 using one or more hydroxide bases (wherein the one or more hydroxide bases are sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, or a combination thereof), followed by aqueous reaction with the resulting carboxylate salt to the carboxylic acid and isolation of the pure diastereoisomer by using a recrystallization method using a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvents to obtain 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound-A″). wherein the one or more protic polar solvents include, but are not limited to, ethanol, methanol, isopropanol, or a combination thereof. The one or more aprotic polar solvents include, but are not limited to, dichloromethane, dimethylformamide, tetrahydrofuran, or a combination thereof; and l) converting Compound-A″ to its hydrochloride salt, 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A) using hydrochloric acid in one or more protic polar solvents, wherein the one or more protic polar solvents include, but are not limited to, ethanol, methanol, isopropanol, or a combination thereof.

[0028] In some embodiments, the present disclosure provides 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A),

[0029] [ka] Scheme 2:

[0030] [ka] and Scheme 2, which includes: a) converting methyl 4-oxo-4H-chromene-2-carboxylate (compound 13) to 2-(hydroxymethyl)-4H-chromen-4-one (compound 14) by reacting compound 14 with one or more reducing agents, wherein the one or more reducing agents are sodium borohydride (NaBH), lithium borohydride (LiBH), lithium aluminum hydride (LiAlH), NaH, sodium cyanoborohydride, diisobutylaluminum hydride, metal hydrides, tributyltin, borane complexes (e.g., BH-THF), or combinations thereof; b) converting 2-(hydroxymethyl)-4H-chromen-4-one (compound 14) to 2-(chloromethyl)-4H-chromen-4-one (compound 15) by reacting compound 14 with one or more chlorinating agents, wherein the one or more chlorinating agents are thionyl chloride, sulfonyl chlorides (such as, but not limited to, mesyl chloride, toluenesulfonyl chloride, or trichloromethanesulfonyl chloride), or combinations thereof; c) coupling 2-(chloromethyl)-4H-chromen-4-one (compound 15) with (R)-1-(naphthalen-2-yl)ethan-1-amine (compound 2) in the presence of potassium carbonate, potassium iodide or a combination thereof to obtain (R)-2-(((1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (compound 16); d) enantioselectively reducing the double bond of (R)-2-(((1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (compound 16) via asymmetric hydrogenation using one or more optically active diphosphine ligands to obtain optically active (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one (compound 7″). The one or more optically active diphosphine ligands may be (R)-(+)-4,4′-bis(diphenylphosphino)-3,3′-bi(1,2-methylenedioxybenzene) [(R)-SEGPHOS®], 4,4′-bis(diphenylphosphino)-3,3′-bi(1,2-methylenedioxybenzene) [SEGPHOS®], (R)-(+)-4,4′-bis[di( 3,5-xylyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [(R)-DM-SEGPHOS®], (R)-(-)-4,4'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [((R)-DTBM-SEGPHOS®)], (R)-(+)-2,2 '-Bis(diphenylphosphino)-1,1'-binaphthalene [(R)-BINAP], 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl [s-Phos], 5-bis(diphenylphosphino)-9,9-dimethylxanthene [Xantphos], (2R,3R)-(+)-bis(diphenylphosphino)butane [R-Chiraphos], 4,4,4',4',6 ,6'-hexamethyl-2,2'-spirobichroman-8,8'-diylbis(diphenylphosphane) [SPANphos], bis(diphenylphosphinoethyl)phenylphosphine [Triphos], (2R,2'R,5R,5'R)-2,2',5,5'-tetramethyl-1,1'-(o-phenylene)diphosphorane [R,R-Me-DuPhos], or a combination thereof; e) treating compound 7″ with Boc anhydride (di-tert-butyl dicarbonate) in the presence of one or more basic catalysts to obtain compound 8, wherein the one or more basic catalysts are tripotassium phosphate, triethylamine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, or a combination thereof; and f) Converting compound 8 to compound A as described in Scheme-1.

[0031] In some embodiments, the present disclosure provides 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A),

[0032] [ka] Scheme 3:

[0033] [ka] and Scheme-3 includes the following: Step A: a) converting (R)-chroman-2-carboxylic acid (compound 17) to (R)-4-oxochroman-2-carboxylic acid (compound 18) by treating compound 17 with one or more oxidizing agents (such as, but not limited to, KMnO4, MnO2, tert-butylhydroperoxide-chromium(VI) oxide, potassium peroxomonosulfate, sodium bromate, FeCl3, TBAB-copper dichloride, AIBN-oxygen, NaClO2-N-hydroxyphthalimide, or a combination thereof) in the presence of magnesium sulfate in one or more polar solvents (such as, but not limited to, tetrahydrofuran, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me-THF), toluene (methylbenzene), ethyl acetate, dimethylformamide (DMF), water, acetone, or a combination thereof); Step B: a) one or more optically active diphosphine ligands (including but not limited to, (R)-(+)-4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [(R)-SEGPHOS®], 4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [SEGPHOS®], (R)-(+)-4,4'-bis[di(3,5-xylyl)phosphino]-3, 3'-Bi(1,2-methylenedioxybenzene) [(R)-DM-SEGPHOS®], (R)-(-)-4,4'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [((R)-DTBM-SEGPHOS®)], (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [(R)-BINAP], 2-di Cyclohexylphosphino-2',6'-dimethoxybiphenyl [s-Phos], 5-bis(diphenylphosphino)-9,9-dimethylxanthene [Xantphos], (2R,3R)-(+)-bis(diphenylphosphino)butane [R-Chiraphos], 4,4,4',4',6,6'-hexamethyl-2,2'-spirobichroman-8,8'-diylbis(diphenylphosphane) [SPANphos], bis(diphenylphos converting methyl 4-oxo-4H-chromene-2-carboxylate (compound 13) to methyl (R)-4-oxochroman-2-carboxylate (compound 19) via asymmetric hydrogenation using (e.g., (2R,2'R,5R,5'R)-2,2',5,5'-tetramethyl-1,1'-(o-phenylene)diphosphorane [R,R-Me-DuPhos], or a combination thereof; b) hydrolyzing methyl (R)-4-oxochroman-2-carboxylate (compound 19) using base hydrolysis in one or more polar solvents (such as, but not limited to, water, tetrahydrofuran, dichloromethane (DCM), 2-methyltetrahydrofuran (2-Me-THF), toluene (methylbenzene), ethyl acetate, dimethylformamide (DMF), or combinations thereof) using one or more bases (such as, but not limited to, sodium hydroxide, potassium hydroxide, cesium hydroxide, or combinations thereof) to obtain (R)-4-oxochroman-2-carboxylic acid (compound 18); c) one or more coupling catalysts (including but not limited to, propylphosphonic anhydride (T3P), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HCl), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2-(1H- coupling (R)-4-oxochroman-2-carboxylic acid (compound 18) with (R)-1-(naphthalen-1-yl)ethan-1-amine (compound 2) in the presence of (R)-N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (compound 4), such as (R)-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), or a combination thereof; d) Conversion of (R)-N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (compound 4) to compound A using the method described in scheme 1.

[0034] In some embodiments, the present disclosure provides 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A),

[0035] [ka] Scheme 4:

[0036] [ka] Scheme-4 provides a method or process for the synthesis shown in Scheme-4, which includes: a) reacting (tert-butyl(1-(naphthalen-1-yl)ethyl)((4-oxochroman-2-yl)methyl)carbamate (compound 8) with one or more sulfonohydrazides (such as, but not limited to, 4-methylbenzenesulfonohydrazide, 4-ethylbenzenesulfonohydrazide, thiophene-2-sulfonohydrazide, naphthalene-2-sulfonohydrazide, or combinations thereof) to obtain tert-butyl (E)-(1-(naphthalen-1-yl)ethyl)((4-(2-tosylhydrazinylidene)chroman-2-yl)methyl)carbamate (compound 20); b) coupling tert-butyl (E)-(1-(naphthalen-1-yl)ethyl)((4-(2-tosylhydrazinylidene)chroman-2-yl)methyl)carbamate (compound 20) with methyl 5-bromo-2-methylbenzoate in the presence of one or more triphosphine ligands (such as, but not limited to, dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane, azodicarboxylic acid diethyl ester-triphenylphosphine, dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane), or combinations thereof) to obtain methyl 5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10); and c) Converting compound 10 to compound A as described in Scheme-1. DETAILED DESCRIPTION OF THE INVENTION

[0037] [Detailed Description of the Invention] The present invention is not limited to the specific compositions, methods, uses, compounds, processes, or methodologies described herein because they can be varied.The terminology used in this detailed description section is only for describing specific versions or embodiments, and is not intended to limit the scope of the present invention.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art.Any methods and materials similar or equivalent to those described herein can be used in the implementation or testing of the embodiments of the present invention described herein, and preferred methods, devices, and materials.

[0038] definition For the purposes of interpreting this specification, the following definitions will apply and wherever appropriate, terms used in the singular will also include the plural and vice versa.

[0039] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. As used herein, the term "about" is intended to modify the numerical value it modifies to express a value that varies within a margin of error. When a specific margin of error (e.g., standard deviation relative to a mean) is not stated, the term "about" means plus or minus 10% of the numerical value of the number with which it is used. For example, "about 50%" means within a range of 45% to 55%. Ranges may be expressed herein as from "about" one particular value and / or to "about" another particular value. When such ranges are expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, it will be understood that the use of "about" preceding the term forms another embodiment. It will be further understood that each endpoint of a range is significant both in relation to the other endpoint and independently of the other endpoint.

[0040] The term "alkyl" as used herein refers to a branched or unbranched hydrocarbon group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, and the like. Alkyl groups can be substituted or unsubstituted. Unless otherwise specified, the term "alkyl" contemplates both substituted and unsubstituted alkyl groups. Alkyl groups can be substituted with one or more groups, including, but not limited to, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl, amino, alkylamino, aminoalkyl, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxyalkyl, halo, hydroxy, nitro, silyl, alkylthio, alkylsulfonyl, thiol, and the like.

[0041] As used herein, the term "alkenyl" refers to a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing one or two double bonds, e.g., ethenyl, propenyl (including all isomeric forms), 1-methylpropenyl, butenyl (including all isomeric forms), pentenyl (including all isomeric forms), and the like.

[0042] The term "alkynyl" as used herein refers to a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing one or two triple bonds, e.g., ethynyl, propynyl (including all isomeric forms), 1-methylpropynyl, butynyl (including all isomeric forms), pentynyl (including all isomeric forms), and the like.

[0043] The term "cycloalkyl," as used herein, refers to a monovalent saturated monocyclic ring containing from 3 to 8 ring carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0044] As used herein, the term "heterocyclylalkyl" refers to a -(alkylene)-R group where R is heterocyclyl as defined herein, e.g., pyrrolidinylmethyl, tetrahydrofuranylethyl, pyridinylmethylpiperidinylmethyl, and the like.

[0045] The term "aryl" as used herein refers to a monocyclic or fused bicyclic ring assembly containing 6 to 10 ring carbon atoms in which each ring is aromatic, e.g., phenyl or naphthyl.

[0046] As used herein, the term "aromatic" refers to a ring system whose constituent atoms are unsaturated and in which all atoms in the ring system are sp 2 It is a moiety in which the total number of π electrons is equal to 4n+2.

[0047] The term "heteroaryl," as used herein, refers to a group or part of a group representing an aromatic monocyclic or bicyclic moiety of 5 to 10 ring atoms in which one or more, preferably one, two, or three, of the ring atom(s) are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Representative heteroaryl rings include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrazolyl, and the like.

[0048] The term "acyl," as used herein, refers to a -COR group, where "R" is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocyclyl as defined herein, such as formyl, acetyl, trifluoroacetyl, benzoyl, piperazin-1-ylcarbonyl, and the like. When R is alkyl, it is referred to herein as alkylcarbonyl. When R is aryl, it is referred to herein as arylcarbonyl. When R is heteroaryl, it is referred to herein as heteroarylcarbonyl. When R is heterocyclyl, it is referred to herein as heterocyclylcarbonyl.

[0049] The term "alkylamino" as used herein refers to an -NHR group, where "R" is alkyl as defined herein, e.g., methylamino, ethylamino, n-, iso-propylamino, n-, iso-, tert-butylamino, and the like.

[0050] The term "alkylthio" as used herein refers to a -SR group, where "R" is alkyl as defined herein, e.g., methylthio, ethylthio, propylthio, or butylthio, and the like.

[0051] The term "alkylsulfonyl" as used herein refers to a -SO2R group, where "R" is alkyl as defined herein, e.g., methylsulfonyl, ethylsulfonyl, and the like.

[0052] As used herein, the term "alkoxyalkyl" refers to a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms substituted with at least one alkoxy group, preferably one or two alkoxy groups, as defined herein, e.g., 2-methoxy-ethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

[0053] The term "alkoxycarbonyl" as used herein refers to a -C(O)OR group, where "R" is an alkyl group as defined herein, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

[0054] The term "amino" as used herein refers to the group --NH.sub.2.

[0055] The term "aminoalkyl," as used herein, refers to a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms substituted with at least one, and preferably one or two, -NRR', where "R" is hydrogen, alkyl, acyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocyclylalkyl, and R' is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonyl, or aminosulfonyl, as defined herein, e.g., aminomethyl, methylaminoethyl, dimethylaminoethyl, 1,3-diaminopropyl, acetylaminopropyl, and the like.

[0056] The term "carboxy" as used herein refers to the group --C(O)OH.

[0057] As used herein, the term "carboxyalkyl" refers to a ton alkyl radical, as defined herein, substituted with at least one, preferably one or two, -C(O)OH groups, e.g., carboxymethyl, carboxyethyl, 1-, 2-, or 3-carboxypropyl, and the like.

[0058] The term "halo" as used herein means fluoro, chloro, bromo, or iodo.

[0059] The term "hydroxy" as used herein refers to an --OH group.

[0060] Unless otherwise specified, the term "oxo" as used herein refers to a C(=O) group. Such oxo groups may be part of either a ring or a chain within the compounds disclosed in the present application.

[0061] The term "silyl" as used herein is a silicon group in which the silicon is substituted with one to three of hydrogen, halo, alkyl, amino, aryl, or combinations thereof.

[0062] As used herein, the term "pharmaceutically acceptable" refers to substances that are generally safe, non-toxic, and not biologically or otherwise undesirable, useful in the preparation of pharmaceutical compositions, and include those that are acceptable for veterinary use as well as for human pharmaceutical use.

[0063] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure that is pharmaceutically acceptable, as defined herein, and has the desired pharmacological activity. Such salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or salts with acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methylsulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p- Includes acid addition salts formed with organic acids such as chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.

[0064] Pharmaceutically acceptable salts also include base addition salts that can be formed when acidic protons present can react with inorganic or organic bases. Acceptable inorganic bases include, but are not limited to, sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, calcium hydroxide, and the like. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

[0065] As used herein, the term "isomers" refers to compounds that have identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereomers," and stereoisomers that are non-superimposable mirror images are called "enantiomers" or sometimes "optical isomers." A carbon atom bonded to four non-identical substituents is called a "chiral center." A compound with one chiral center, having two enantiomeric forms of opposite chirality, is called a "racemic mixture." A compound with more than one chiral center has 2n-1 enantiomeric pairs, where "n" is the number of chiral centers. A compound with more than one chiral center may exist as individual diastereomers or as a mixture of diastereomers, called a "diastereomeric mixture." When one chiral center is present, a stereoisomer can be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral center and are described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for determining stereochemistry and separation of stereoisomers are well known in the art (see, for example, "March's Advanced Organic Chemistry," edited by Michael B. Smith, 8th Edition, John Wiley & Sons, Inc. (2020)).

[0066] As used herein, the term "non-polar aprotic solvent" or "aprotic non-polar solvent" refers to a liquid that can dissolve non-polar organic compounds and does not contain acidic protons. Non-polar aprotic solvents can include, but are not limited to, toluene (methylbenzene), xylene, dioxane, benzene, dichloromethane (CHCl), carbon tetrachloride (CCl), trichloromethane (CHCl), methyl tert-butyl ether (MTBE), or a combination thereof.

[0067] As used herein, the term "protic polar solvent" or "polar protic solvent" refers to a liquid that can dissolve polar organic compounds, contains a strong dipole moment, and further contains protons attached to oxygen atoms. Protic polar solvents can include, but are not limited to, ethanol, methanol, isopropanol, or combinations thereof.

[0068] As used herein, the term "aprotic polar solvent" refers to a liquid that can dissolve polar organic compounds and contains a strong dipole moment but does not contain a proton attached to an oxygen atom. Aprotic polar solvents can include, but are not limited to, dichloromethane, dimethylformamide, tetrahydrofuran, dioxane, or a combination thereof.

[0069] As used herein, the term "non-polar solvent" refers to an organic liquid that can dissolve organic compounds and does not contain a strong dipole moment. Non-polar solvents can include, but are not limited to, toluene (methylbenzene), xylene, dioxane, benzene, dichloromethane (CHCl), carbon tetrachloride (CCl), trichloromethane (CHCl), methyl tert-butyl ether (MTBE), or a combination thereof.

[0070] As used herein, the term "polar solvent" or "organic polar solvent" refers to a liquid that can dissolve compounds, including organic compounds, and that contains a strong dipole moment. Polar solvents can include, but are not limited to, methanol, dichloromethane, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, water, 2-methyltetrahydrofuran (2-Me-THF), toluene (methylbenzene), ethyl acetate, dimethylformamide (DMF), or a combination thereof.

[0071] organic synthesis The compounds described herein may be prepared by synthetic organic chemical processes or methods. Furthermore, in the schemes described herein where specific bases, acids, reagents, solvents, coupling agents, etc. are referred to, it is understood that other bases, acids, reagents, solvents, coupling agents, etc. may be used and are therefore within the scope of the present invention, unless otherwise specified. Variations in reaction conditions, e.g., reaction temperature and / or duration, are also within the scope of the present invention. All isomers of the compounds described in these schemes are also encompassed within the scope of the present invention, unless otherwise specified.

[0072] The methods and processes provided herein are as shown in Schemes 1-4. In certain embodiments, when temperatures are indicated in reactions, the temperatures may vary from about plus or minus 0.1°C, 0.5°C, 1°C, 5°C, or 10°C. The optimal temperature may vary depending on which solvent is used in a particular reaction. In carrying out the reactions provided herein, neither the rate nor the order of addition of reactants is critical unless otherwise indicated. Unless otherwise indicated, reactions are carried out at ambient atmospheric pressure. Unless otherwise indicated, the exact amount of reactants is not critical. In some embodiments, the amount of reactants may vary by about 10 mole percent or about 10 weight percent. Unless otherwise indicated, solvents used in the processes provided herein may be selected from commercially available or otherwise known to those of skill in the art. Suitable solvents for a given reaction are within the knowledge of those of skill in the art and include mixtures of solvents. Products obtained by any of the processes provided herein may be recovered by evaporation or extraction and purified by standard procedures, such as distillation or recrystallization.

[0073] The present inventors have developed an alternative synthetic route for preparing Compound A which involves the use of novel intermediates beyond those described in U.S. Pat. No. 9,598,391 and PCT International Patent Application Publication No. WO2013 / 124828.

[0074] In one embodiment, the present invention provides a method or process for the synthesis of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A) starting from 4-oxo-4H-chromene-2-carboxylic acid (Compound 1) according to the steps comprising: a) one or more coupling catalysts (including but not limited to, propylphosphonic anhydride (T3P), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HCl), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide, reacting 4-oxo-4H-chromene-2-carboxylic acid (compound 1) with (R)-1-(naphthalen-1-yl)ethan-1-amine (compound 2) in the presence of an amine such as 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), or a combination thereof, to obtain (R)-N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (compound 3);

[0075] [ka] The acid-amine coupling of compound 1 with compound 2 to give compound 3 is carried out in the presence of propylphosphonic anhydride (T3P). In some embodiments, the reaction is carried out in one or more suitable solvents (including but not limited to, polar aprotic solvents, polar protic solvents, non-polar aprotic solvents, tetrahydrofuran, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me-THF), toluene (methylbenzene), ethyl acetate, dimethylformamide (DMF), acetonitrile (ACN), 1,4-dioxane, one or more ethers (including but not limited to, dimethyl ether, diethyl ether, tert butyl methyl ether, diisopropyl ether, di-n The coupling reaction can be carried out using an acid-amine coupling reagent (such as, but not limited to, propylphosphonic anhydride) with a suitable base (such as, but not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 2,6-di-tert-butylpyridine, etc.) in a solvent such as hexane, hexane-1,1-dimethyl-2,2-dimethyl-1,2 ... In some embodiments, the acid-amine coupling of compound 1 with compound 2 can be carried out using one or more amide-forming coupling catalysts, such as, but not limited to, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HCl), N,N′-dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIC), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), or a combination thereof.In some embodiments, the one or more amide-forming coupling catalysts can further comprise one or more acid activators.In some embodiments, the one or more acid activators include, but are not limited to, hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), 2-hydroxy-1,2,3-benzotriazin-4(3H)-one (HODhbt), HODhat, N-hydroxybicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic imide (HONB), HODHad, HOCt, HOEt, pyridinium p-toluenesulfonate (PPTS), p-toluol, methylparaben ... Benzene sulfonic acid (TsOH), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) (PyBOP), AOP, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), bis(2-oxo-1,3-oxazolidin-3-yl)phosphinic chloride (BOP-Cl), tetramethylfluoroformamidine methyl ... rolidinylphosphonium hexafluorophosphate (PyOxim), 1,1'-carbonyldiimidazole (CDI), 4-dimethylaminopyridine (DMAP), PTSA-Cl, thionyl chloride, oxalyl chloride, diethylchlorophosphate, O,O-diethyl hydrogen phosphorodithioate, cyanuric chloride, cyanuric fluoride, diphenylphosphoryl azide (DPPA), catecholborane (HBcat), or combinations thereof (abbreviations used in this application refer to their commonly understood meaning in the art of synthetic organic chemistry); b) one or more optically active diphosphine ligands (including but not limited to, (R)-(+)-4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [(R)-SEGPHOS®], 4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [SEGPHOS®], (R)-(+)-4,4'-bis[di(3,5-xylyl)phosphino]-3,3'- Bi(1,2-methylenedioxybenzene) [(R)-DM-SEGPHOS®], (R)-(-)-4,4'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [((R)-DTBM-SEGPHOS®)], (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [(R)-BINAP], 2-dicyclohexyl bis(diphenylphosphino)-2',6'-dimethoxybiphenyl [s-Phos], 5-bis(diphenylphosphino)-9,9-dimethylxanthene [Xantphos], (2R,3R)-(+)-bis(diphenylphosphino)butane [R-Chiraphos], 4,4,4',4',6,6'-hexamethyl-2,2'-spirobichroman-8,8'-diylbis(diphenylphosphane) [SPANphos], bis(diphenylphosphinoethyl)phenanthroline enantioselectively reducing the double bond of compound 3 by asymmetric hydrogenation using a chiral amine such as (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (compound 4) using an aryl phosphine [Triphos], (2R,2'R,5R,5'R)-2,2',5,5'-tetramethyl-1,1'-(o-phenylene)diphosphorane [R,R-Me-DuPhos], or a combination thereof;

[0076] [ka] Asymmetric hydrogenation to achieve enantioselective reduction of the double bond of compound 3 to give optically active compound 4 can be carried out using one or more optically active diphosphine ligands. In some embodiments, the one or more optically active diphosphine ligands include, but are not limited to, (R)-(+)-4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [(R)-SEGPHOS®], 4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [SEGPHOS®], (R)-(+)-4,4'-bis[di(3,5-xylyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [SEGPHOS®], diphenylphosphino)-3,3'-bipyridine [(R)-DM-SEGPHOS®], (R)-(-)-4,4'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [(R)-DTBM-SEGPHOS®], (R)-(+)-2,2',6,6'-tetramethoxy-4,4'-bis(diphenylphosphino)-3,3'-bipyridine [(R)-P-PHOS®], (R)-(4,4',6,6' -tetramethoxy-[1,1'-biphenyl]-2,2'-diyl)bis(bis(3,5-dimethylphenyl)phosphine) [(R)-GARPHOS™], (R)-(4,4',6,6'-tetramethoxybiphenyl-2,2'-diyl)bis{bis[3,5-bis(trifluoromethyl)phenyl]phosphine} [(R)-BTFM-GARPHOS™], (R)-[2-[2-bis(3,5-ditert-butyl-4-methoxyphenyl)phosphanyl-4,6-dimethoxyphenyl]phosphine] [nyl]-3,5-dimethoxyphenyl]-bis(3,5-ditert-butyl-4-methoxyphenyl)phosphane [(R)-DTBM-GARPHOS™], (R)-(+)-(1,1′-binaphthalene-2,2′-diyl)bis(diphenylphosphine) [(R)-BIPHEP], (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene [(R)-BINAP], 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl [s-Phos],5-bis(diphenylphosphino)-9,9-dimethylxanthene [Xantphos], (2R,3R)-(+)-bis(diphenylphosphino)butane [R-Chiraphos], 4,4,4',4',6,6'-hexamethyl-2,2'-spirobichroman-8,8'-diylbis(diphenylphosphane) [SPANphos], bis(diphenylphosphinoethyl)phenylphosphine [Triphos], (2R,2'R,5R,5'R)-2,2',5,5'-tetramethyl-1,1'-(o-phenylene)diphosphorane [R,R-Me-DuPhos], or combinations thereof. In some embodiments, the one or more optically active diphosphine ligands are any phosphine ligands listed in Downing, JH and Smith, MB, "Phosphorus Ligands," Comprehensive Coordination Chemistry II, Section 1.12, pp. 253-296 (2003), or combinations thereof. In some embodiments, the one or more optically active diphosphine ligands are reacted in the presence of one or more metal complexes. In some embodiments, the one or more metal complexes include, but are not limited to, copper(II) acetate (Cu(OAc)), palladium(II) acetate (Pd(OAc)), zinc acetate (Zn(OAc)), ruthenium, rhodium metal complexes, or combinations thereof. In some embodiments, the one or more metal complexes further comprise one or more phosphine ligands. In some embodiments, the one or more phosphine ligands include, but are not limited to, triphenylphosphine (PPh), tris(2-carboxyethyl)phosphine (TCEP), APhos, benzyldiphenylphosphine, or a combination thereof. In some embodiments, the one or more phosphine ligands are present with one or more reducing agents. In some embodiments, the one or more reducing agents include, but are not limited to, diethoxymethylsilane (DEMS), simple alkylsilanes (including, but not limited to, triethylsilane (EtSiH), EtSiH), alkylsiloxanes (including, but not limited to, polymethylhydrosiloxane (PMHS), DEMS,or tetramethyldisiloxane (TMDS)), phenylsilanes (including, but not limited to, phenylsilane (PhSiH) or diphenylsilane), halosilanes (including, but not limited to, trichlorosilane), hydrosilanes (including, but not limited to, tris(trimethylsilyl)silane), or combinations thereof. In some embodiments, the asymmetric hydrogenation can be carried out in one or more solvents (such as, but not limited to, one or more polar aprotic solvents including, but not limited to, tetrahydrofuran (THF), ether, methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran (2-Me-THF), acetonitrile, toluene (methylbenzene), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dichloromethane, or combinations thereof). c) reacting compound 4 in the presence of one or more non-polar solvents (such as, but not limited to, toluene (methylbenzene), xylene, dioxane, benzene, dichloromethane (CHCl), carbon tetrachloride (CCl), trichloromethane (CHCl), methyl tert-butyl ether (MTBE), or a combination thereof) in the presence of one or more catalysts (such as, but not limited to, p-toluenesulfonic acid (PTSA), methanesulfonic acid (MSA), trifluoroacetic acid (TFA), tosylic acid (TsOH), pyridinium p-toluenesulfonate (PPTS), orthophosphoric acid, or a combination thereof); ethylene Glico Ru and reacting to obtain (R)—N-((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2′-[1,3]dioxolane]-2-carboxamide (compound 5);

[0077] [ka] To obtain compound 5 ethylene Glico ToProtection of compound 4 by HCl in the presence of one or more catalysts (such as, but not limited to, p-toluenesulfonic acid (PTSA), methanesulfonic acid (MSA), trifluoroacetic acid (TFA), tosylic acid (TsOH), pyridinium p-toluenesulfonate (PPTS), orthophosphoric acid, hydrochloric acid (HCl), sulfuric acid (HSO), solid acids (which may include or exclude zeolite or resin-bound TsOH), or combinations thereof). ethylene Glico Lu In some embodiments, protection of compound 4 is carried out in one or more non-polar solvents, such as, but not limited to, xylene, dioxane, benzene, dichloromethane (CHCl), carbon tetrachloride (CCl), trichloromethane (CHCl), methyl tert-butyl ether (MTBE), toluene (methylbenzene), or combinations thereof. The inventors believe that the synthetic schemes invented by the inventors and described herein are ,workmanIt is recognized that the protective group involves ethylene glycol. It is a very low-cost aldehyde protecting group that can be easily added and removed using methods. Combined with an acid-amine coupling step that can also be performed using a low-cost catalyst, the synthetic scheme described herein is an economical way to obtain an intermediate for synthesizing compound A. In some embodiments, a variation of the synthetic scheme provided herein for protecting the carbonyl group of compound 4 can be performed using any carbonyl protecting group known in the art, such as, but not limited to, a ketal (including, but not limited to, an acetal, a thioketal (including, but not limited to, a thioacetal), or a combination thereof). Additional protecting groups, including their addition and removal, can be used according to standard practices, see, for example, P.G.M.Wuts, Greene's Protective Groups in Organic Chemistry, 5th Edition, John Wiley & Sons, Inc. (2014). In some embodiments, compound 4 can be protected using, for example, 2-mercaptoethanol, 1,2-ethanedithiol, 1,3-propanedithiol, trimethyl orthoformate, triethyl orthoformate, or a combination thereof; d) reducing the amide group of compound 5 using one or more reducing agents (such as, but not limited to, Vitride, borane-dimethylsulfide complex, (Zn(OAc)2) / DEMS, or a combination thereof) to provide (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4,2'-[1,3]dioxolan]-2-yl)methyl)ethan-1-amine (compound 6);

[0078] [ka] The reduction of compound 5 to compound 6 is carried out using Vitride™ in toluene and methyl-THF. In some embodiments, the reduction of compound 5 to compound 6 is carried out using borane dimethyl sulfide complex or (Zn(OAc) 2) / Implemented using DEMS; e) treating compound 6 with an aqueous acidic medium to obtain (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one hydrochloride (compound 7);

[0079] [ka] Compound 6 is deprotected to compound 7 using an aqueous acidic medium containing one or more polar aprotic or one or more protic solvents. In some embodiments, the aqueous acidic medium containing a polar aprotic solvent is aqueous 6N HCl in acetone. In some embodiments, the one or more polar aprotic solvents include, but are not limited to, dioxane. In some embodiments, the one or more polar protic solvents include, but are not limited to, isopropanol, ethanol, methanol, or a combination thereof. f) reacting compound 7 with Boc anhydride (di-tert-butyl dicarbonate) in the presence of one or more basic catalysts (such as, but not limited to, tripotassium phosphate, triethylamine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, or combinations thereof) to provide tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate (compound 8);

[0080] [ka] The free amino group of compound 7 is protected using Boc anhydride (di-tert-butyl dicarbonate) in the presence of one or more basic catalysts to give compound 8. In some embodiments, the amino group of compound 7 (compound 7″ free base) can also be protected with Boc without a base in the presence of one or more solvents (such as, but not limited to, water, ethanol, methanol, isopropyl alcohol, tert-butyl alcohol, dioxane, THF, or a combination thereof). In some embodiments, the one or more basic catalysts include, but are not limited to, triethylamine, pyridine, DMAP, DBU, DBN, tripotassium phosphate, sodium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, or a combination thereof. In some embodiments, the one or more solvents include, but are not limited to, DCM (also referred to herein as CHCl), water, THF, dioxane, acetonitrile, DMF, toluene, or a combination thereof. In some embodiments, the free amino group of compound 7 can be protected using one or more amine protecting groups (such as, but not limited to, benzyl, p-methoxybenzyl, carboxybenzoyl (cbz), or combinations thereof) according to standard practices, see, e.g., P.G.M.Wuts, Greene's Protective Groups in Organic Chemistry, 5th Edition, John Wiley & Sons, Inc. (2014). g) reacting Compound-8 with one or more triflating agents (such as, but not limited to, N-phenyl-bis(trifluoromethanesulfonimide), trifluoromethanesulfonic anhydride, N-(4-tert-butylphenyl)bis(trifluoromethanesulfonimide), bis(trifluoromethanesulfonyl)aniline, Comin's reagent, N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide), trifluoromethanesulfonyl chloride, 4-nitrophenyl trifluoromethanesulfonate, 1-(trifluoromethanesulfonyl)imidazole), or combinations thereof) to provide (R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate (Compound-9);

[0081] [ka] h) coupling compound 9 with methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate in the presence of one or more palladium catalysts (such as, but not limited to, palladium-tetrakis(triphenylphosphine); palladium(II) bis(triphenylphosphine) dichloride; palladium(0) bis(dibenzylideneacetone); palladium(II) bis(triphenylphosphine) diacetate; [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)); or combinations thereof) to provide methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10);

[0082] [ka] i) converting methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound-10) to methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2-methylbenzoate (Compound-11), wherein the conversion is at a rate of about 2.0 Kg / cm 2 or through treatment with ammonium formate in the presence of a palladium-on-charcoal catalyst, optionally in the presence of one or more polar solvents, wherein the one or more polar solvents include, but are not limited to, methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof;

[0083] [ka] The hydrogenation of compound 10 to give compound 11 is carried out in a hydrogenation reactor using ammonia in methanolic solution and 5% Pd / C (50% wet and 10% w / w loading), 10% Pd / C, or 2% Pd / C in methanol or an ethyl acetate-methanol solvent system at about 28°C to about 34°C. This transfer hydrogenation can be carried out in aqueous or organic solvents using a formate (10 eq), e.g., ammonium formate or sodium formate, as the hydrogen source, with a Pd-C catalyst. When the reduction of the double bond in compound 10 to give compound 11 is carried out in a hydrogenation reactor using ammonia in methanolic solution, the optimal hydrogen pressure is about 10.0 kg / cm. 2 Not exceeding 5.0 kg / cm 2 not exceeding, more specifically, about 2.0 kg / cm 2 where the optimum hydrogen pressure is about 0.1 kg / cm 2 ~About 2.0Kg / cm 2Preferably, the optimum hydrogen pressure is between about 1.0 Kg / cm 2 ~About 2.0Kg / cm 2 The reduction of the double bond in compound 10 to give compound 11 is carried out at a temperature between about 10°C and about 50°C, more preferably about 30°C to about 33°C. The reaction is carried out in one or more suitable solvents, including but not limited to, halogenated hydrocarbons, C6-C8 14 The reaction can be carried out in a solvent such as an aromatic hydrocarbon, a C1-C5 alcohol, a C2-C7 ester, a C4-C7 ether, a C1-C5 carboxylic acid, water, or a combination thereof. In some embodiments, the one or more reaction solvents include, but are not limited to, water, methanol, isopropyl alcohol, dichloromethane, toluene, ethyl acetate, diethyl ether, or a combination thereof. j) converting compound 11 to methyl 2-methyl-5-((2R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoate hydrochloride (compound 12) via a Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid, or trimethylsilyl iodide in the presence of one or more polar solvents, wherein the one or more polar solvents include, but are not limited to, methanol, dichloromethane, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof;

[0084] [ka] The Boc-deprotection reaction of compound 11 to give compound 12 is carried out using hydrochloric acid in methanol at reflux at about 63° C. In some embodiments, the concentration of hydrochloric acid is 6N aqueous HCl. In some embodiments, Boc-deprotection can occur using AlCl, trifluoroacetic acid in dichloromethane, or sequential treatment with trimethylsilyl iodide and methanol. In some embodiments, Boc-deprotection can be carried out in the presence of one or more cation scavengers. The one or more cation scavengers include, but are not limited to, anisole, thioanisole, or a combination thereof. k) hydrolyzing the ester group of Compound 12 using one or more hydroxide bases (such as sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, or a combination thereof), followed by aqueous reaction with the resulting carboxylate salt to a carboxylic acid and isolation of the pure diastereoisomers by using a recrystallization method using a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvents to obtain 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound-A″), wherein the one or more protic polar solvents include, but are not limited to, ethanol, methanol, isopropanol, or a combination thereof, and the one or more aprotic polar solvents include, but are not limited to, dichloromethane, dimethylformamide, tetrahydrofuran, or a combination thereof;

[0085] [ka] Hydrolysis of compound 12 is carried out using sodium hydroxide in a methanol-tetrahydrofuran solvent system under heating at about 55°C. In some embodiments, hydrolysis can be carried out using one or more hydroxide bases (e.g., lithium hydroxide, potassium hydroxide, cesium hydroxide, or a combination thereof), or can be carried out using lithium chloride followed by aqueous reaction with the resulting carboxylic acid lithium salt to form the carboxylic acid. In some embodiments, isolation of diastereomerically pure compound-A" from the crude hydrolysis product of compound 12 is carried out by a recrystallization method using a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvents. In some embodiments, the one or more protic polar solvents include, but are not limited to, ethanol, methanol, isopropanol, or a combination thereof. In some embodiments, the one or more aprotic polar solvents include, but are not limited to, dichloromethane, dimethylformamide, tetrahydrofuran, or a combination thereof. In some embodiments, the recrystallization method involves heating a reaction mixture in a solvent, e.g., above 55°C in a solvent-nonsolvent mixture, and slowly cooling the solution to room temperature or below, whereby seed crystals of the desired compound (e.g., Compound A″) preferentially crystallize, while the undesired compound (e.g., Compound 12) remains essentially in solution. Recovery of the isolated, substantially pure product (e.g., Compound A″), optionally followed by washing with a pre-cooled solution of the solvent-nonsolvent solution, yields substantially purified Compound 12, substantially free of impurities. In some embodiments, isolation of diastereoisomerically pure Compound-A″ from the crude hydrolysis product of Compound 12 is carried out by a recrystallization method using an ethanol:dichloromethane solvent mixture. In some embodiments, the (v / v) ratio of ethanol to dichloromethane can range from 1:5 to 5:1; and l) converting Compound-A″ into its hydrochloride salt, 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A), using hydrochloric acid in one or more protic polar solvents (such as, but not limited to, ethanol, methanol, isopropanol, or a combination thereof).

[0086] [ka] The step of converting Compound-A″ to Compound-A is carried out by using acid neutralization with hydrochloric acid. In some embodiments, the hydrochloric acid is 2N aqueous HCl.

[0087] In another aspect, there is provided a method or process for producing 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound A″) from methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound 10), comprising the steps of: a) converting methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10) to methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2-methylbenzoate (compound 11), wherein the conversion is at a rate of about 2.0 Kg / cm 2or through treatment with ammonium formate in the presence of a palladium-on-charcoal catalyst, optionally in the presence of one or more polar solvents, wherein the one or more polar solvents include, but are not limited to, methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof;

[0088] [ka] b) converting compound 11 to methyl 2-methyl-5-((2R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoate hydrochloride (compound 12) through a Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid, or trimethylsilyl iodide in the presence of one or more polar solvents, including, but not limited to, methanol, dichloromethane, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof;

[0089] [ka] and c) hydrolyzing the ester group of compound 12 using one or more hydroxide bases (such as, but not limited to, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, or a combination thereof), followed by aqueous reaction with the resulting carboxylate salt to a carboxylic acid and isolation of the pure diastereoisomers by using a recrystallization method using a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvents to obtain 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (compound A″), wherein the one or more protic polar solvents include, but are not limited to, ethanol, methanol, isopropanol, or a combination thereof, and the one or more aprotic polar solvents include dichloromethane, dimethylformamide, tetrahydrofuran, or a combination thereof;

[0090] [ka]

[0091] In another aspect, the present invention provides a method or process for the preparation of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound A″), comprising one or more palladium catalysts (including but not limited to palladium-tetrakis(triphenylphosphine), palladium(II) bis(triphenylphosphine) dichloride; palladium(0) bis(dibenzylideneacetone), palladium(II) bis(triphenylphosphine) diacetate, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)), or any of their derivatives. and a combination thereof, in which methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound 10) is prepared from (R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate (Compound 9) by reacting Compound 9 with methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate in the presence of

[0092] [ka]

[0093] In another aspect, the present invention provides a method or process for the preparation of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound A″), comprising reacting Compound 8 with one or more triflating agents, including but not limited to, N-phenyl-bis(trifluoromethanesulfonimide); trifluoromethanesulfonic anhydride; N-(4-tert-butylphenyl)bis(trifluoromethanesulfonimide); bis(trifluoromethanesulfonyl)aniline; Comin's reagent; N-(5-chloro-2-pyridyl)bis(trifluoromethan) and (R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate (Compound 9) is prepared from tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate (Compound 8) by reacting with a tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate (Compound 8), such as (R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate; trifluoromethanesulfonyl chloride; 4-nitrophenyl trifluoromethanesulfonate; 1-(trifluoromethanesulfonyl)imidazole), or a combination thereof.

[0094] [ka]

[0095] In another aspect, the present invention provides a method or process for the preparation of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound A″), wherein tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate (Compound 8) is prepared from (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one hydrochloride (Compound 7) by reacting Compound 7 with Boc anhydride (di-tert-butyl dicarbonate) and tripotassium phosphate.

[0096] [ka]

[0097] In some embodiments, the present invention provides a method or process for the preparation of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound A″), wherein (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one hydrochloride (Compound 7) is prepared from (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4,2′-[1,3]dioxolan]-2-yl)methyl)ethan-1-amine (Compound 6) by treating Compound 6 with aqueous hydrochloric acid.

[0098] [ka]

[0099] In another aspect, the present invention provides a method or process for the preparation of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound A″), comprising reducing the compound using one or more reducing agents, such as, but not limited to, Vitride, borane-dimethylsulfide complex, (Zn(OAc)2) / DEMS, or a combination thereof. The present invention provides a method or process for preparing (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4,2'-[1,3]dioxolan]-2-yl)methyl)ethan-1-amine (compound 6) from (R)-N-((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2'-[1,3]dioxolane]-2-carboxamide (compound 5) by reducing the amide group of compound 5.

[0100] [ka]

[0101] In another aspect, the present invention provides a method or process for the preparation of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound A″), comprising reacting Compound 4 with one or more non-polar solvents (such as, but not limited to, toluene (methylbenzene), xylene, dioxane, benzene, dichloromethane (CHCl), carbon tetrachloride (CCl), trichloromethane (CHCl), methyl tert-butyl ether (MTBE), or a combination thereof) in the presence of a catalyst selected from p-toluenesulfonic acid (PTSA), methanesulfonic acid (MSA), trifluoroacetic acid (TFA), tosylic acid (TsOH), pyridinium p-toluenesulfonate (PPTS), orthophosphoric acid, or a combination thereof. ethylene Glico Ru andThe present invention provides a method or process for producing (R)-N-((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2'-[1,3]dioxolane]-2-carboxamide (compound 5) from (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (compound 4) by reacting the

[0102] [ka]

[0103] In one aspect, the present invention provides a method or process for the preparation of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound-A″), comprising the step of reacting one or more optically active diphosphine ligands ((R)-(+)-4,4′-bis(diphenylphosphino)-3,3′-bi(1,2-methylenedioxybenzene) [(R)-SEGPHOS®], ... ) [SEGPHOS®], (R)-(+)-4,4'-bis[di(3,5-xylyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [(R)-DM-SEGPHOS®], (R)-(-)-4,4'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [((R)-DTBM-SEGPHOS®)], (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [(R)-B INAP], 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl [s-Phos], 5-bis(diphenylphosphino)-9,9-dimethylxanthene [Xantphos], (2R,3R)-(+)-bis(diphenylphosphino)butane [R-Chiraphos], 4,4,4',4',6,6'-hexamethyl-2,2'-spirobichroman-8,8'-diylbis(diphenylphosphane) [SPANphos], bis(diphenylphosphinoethyl)phenylphosphine [Triphos], (2R,2'R,5 The present invention provides a method or process for preparing (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (compound 4) from (R)-N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (compound 3) by enantioselective reduction of the double bond of compound 3 via asymmetric hydrogenation using, for example, (R,5'R)-2,2',5,5'-tetramethyl-1,1'-(o-phenylene)diphosphorane [R,R-Me-DuPhos], or a combination thereof.

[0104] [ka]

[0105] In one aspect, the present invention provides a method or process for the preparation of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound-A″), comprising one or more coupling catalysts (including but not limited to, propylphosphonic anhydride (T3P), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HCl), N,N′-dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIC), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2-(1H-benzotriazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2-(1H-benzotriazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (2 ... The present invention provides a method or process for producing (R)-N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (Compound 3) from 4-oxo-4H-chromene-2-carboxylic acid (Compound 1) by reaction with (R)-1-(naphthalen-1-yl)ethan-1-amine (Compound 2) in the presence of an amine such as (R)-N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxylic acid, (Compound 1 ...

[0106] [ka]

[0107] In one embodiment, the present invention provides a method or process for converting 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound-A″) to 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A) using hydrochloric acid in one or more protic polar solvents (such as, but not limited to, ethanol, methanol, isopropanol, or combinations thereof).

[0108] [ka]

[0109] In one aspect, the present invention provides a method or process for preparing 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A) from methyl 4-oxo-4H-chromene-2-carboxylate (Compound 13), wherein the method involves the steps of: a) converting methyl 4-oxo-4H-chromene-2-carboxylate (compound 13) to 2-(hydroxymethyl)-4H-chromen-4-one (compound 14) by reacting compound 13 with one or more reducing agents, such as, but not limited to, sodium borohydride (NaBH), lithium borohydride (LiBH), lithium aluminum hydride (LiAlH), sodium cyanoborohydride, NaH, diisobutylaluminum hydride, metal hydrides, tributyltin, borane complexes (e.g., BH-THF), or combinations thereof;

[0110] [ka] b) converting 2-(hydroxymethyl)-4H-chromen-4-one (compound 14) to 2-(chloromethyl)-4H-chromen-4-one (compound 15) by reacting compound 14 with one or more chlorinating agents, such as, but not limited to, thionyl chloride, sulfonyl chloride (such as, but not limited to, mesyl chloride, toluenesulfonyl chloride, trichloromethanesulfonyl chloride, or a combination thereof), or a combination thereof;

[0111] [ka] c) coupling 2-(chloromethyl)-4H-chromen-4-one (compound 15) with (R)-1-(naphthalen-2-yl)ethan-1-amine (compound 2) in the presence of one or more bases (such as, but not limited to, potassium carbonate, potassium iodide, or a combination thereof) to obtain (R)-2-(((1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (compound 16);

[0112] [ka] d) one or more optically active diphosphine ligands, including but not limited to, (R)-(+)-4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [(R)-SEGPHOS®], 4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [SEGPHOS®], (R)-(+)-4,4'-bis[di(3,5-xylyl)phosphino]-3,3'-bi(1,2-methylenedioxy) (R)-DM-SEGPHOS®), (R)-(-)-4,4'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [(R)-DTBM-SEGPHOS®)], (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [(R)-BINAP], 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl [s- Phos], 5-bis(diphenylphosphino)-9,9-dimethylxanthene [Xantphos], (2R,3R)-(+)-bis(diphenylphosphino)butane [R-Chiraphos], 4,4,4',4',6,6'-hexamethyl-2,2'-spirobichroman-8,8'-diylbis(diphenylphosphane) [SPANphos], bis(diphenylphosphinoethyl)phenylphosphine [Triphos], (2R,2'R,5R,5'R)-2,2',5 enantioselectively reducing the double bond of (R)-2-(((1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (compound 16) via asymmetric hydrogenation using, for example, (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (compound 7″),

[0113] [ka] e) treating compound 7″ with Boc anhydride (di-tert-butyl dicarbonate) in the presence of one or more basic catalysts (such as, but not limited to, tripotassium phosphate, triethylamine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, or combinations thereof) to give compound 8;

[0114] [ka] f) reacting compound 8 with one or more triflating agents (such as, but not limited to, N-phenyl-bis(trifluoromethanesulfonimide); trifluoromethanesulfonic anhydride; N-(4-tert-butylphenyl)bis(trifluoromethanesulfonimide); bis(trifluoromethanesulfonyl)aniline; Comin's reagent; N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide); trifluoromethanesulfonyl chloride; 4-nitrophenyl trifluoromethanesulfonate; 1-(trifluoromethanesulfonyl)imidazole; or combinations thereof) to provide (R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate (compound 9);

[0115] [ka] g) coupling compound 9 with methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate in the presence of one or more palladium catalysts (such as, but not limited to, palladium-tetrakis(triphenylphosphine); palladium(II) bis(triphenylphosphine) dichloride; palladium(0) bis(dibenzylideneacetone); palladium(II) bis(triphenylphosphine) diacetate; [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), or a combination thereof) to provide methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 1);

[0116] [ka] h) converting methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10) to methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2-methylbenzoate (compound 11), wherein the conversion is at about 2.0 Kg / cm 2 or through treatment with ammonium formate in the presence of a palladium on charcoal catalyst, optionally in the presence of one or more polar solvents, wherein the one or more polar solvents include, but are not limited to, methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or combinations thereof;

[0117] [ka] i) converting compound 11 to methyl 2-methyl-5-((2R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoate hydrochloride (compound 12) via a Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid, or trimethylsilyl iodide in the presence of one or more polar solvents, including, but not limited to, methanol, dichloromethane, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof;

[0118] [ka] j) hydrolyzing the ester group of compound 12 using one or more hydroxide bases (such as, but not limited to, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, or a combination thereof), followed by aqueous reaction with the resulting carboxylate salt to a carboxylic acid and isolation of the pure diastereoisomers by using a recrystallization method using a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvents to obtain 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (compound A″), wherein the one or more protic polar solvents include, but are not limited to, ethanol, methanol, isopropanol, or a combination thereof, and the one or more aprotic polar solvents include, but are not limited to, dichloromethane, dimethylformamide, tetrahydrofuran, or a combination thereof;

[0119] [ka] and k) converting compound A″ into its hydrochloride salt, 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (compound A), using hydrochloric acid in a protic polar solvent, wherein the protic polar solvent may include or exclude ethanol, methanol, isopropanol, or a combination thereof;

[0120] [ka]

[0121] In one embodiment, the present invention provides a method or process for the preparation of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound A″), wherein tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate (Compound 8) is prepared from (R)-2-(((1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (Compound 16) according to the steps involving: a) one or more optically active diphosphine ligands (including but not limited to, (R)-(+)-4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [(R)-SEGPHOS®], 4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [SEGPHOS®], (R)-(+)-4,4'-bis[di(3,5-xylyl)phosphino]-3,3'- Bi(1,2-methylenedioxybenzene) [(R)-DM-SEGPHOS®], (R)-(-)-4,4'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [((R)-DTBM-SEGPHOS®)], (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [(R)-BINAP], 2-dicyclohexyl Phosphino-2',6'-dimethoxybiphenyl [s-Phos], 5-bis(diphenylphosphino)-9,9-dimethylxanthene [Xantphos], (2R,3R)-(+)-bis(diphenylphosphino)butane [R-Chiraphos], 4,4,4',4',6,6'-hexamethyl-2,2'-spirobichroman-8,8'-diylbis(diphenylphosphane) [SPANphos], bis(diphenylphosphinoethyl)phenyl enantioselectively reducing the double bond of compound 16 via asymmetric hydrogenation using a phosphine (e.g., Triphos), (2R,2'R,5R,5'R)-2,2',5,5'-tetramethyl-1,1'-(o-phenylene)diphosphorane (R,R-Me-DuPhos), or a combination thereof, to obtain optically active (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one (compound 7'');

[0122] [ka] and b) treating compound 7″ with Boc anhydride (di-tert-butyl dicarbonate) in the presence of one or more basic catalysts (such as, but not limited to, tripotassium phosphate, triethylamine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, or combinations thereof) to give compound 8;

[0123] [ka]

[0124] In one embodiment, the present invention provides a method or process for the preparation of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound A″), comprising reacting Compound 15 with (R)-1-(naphthalen-2-yl)ethoxybenzoic acid in the presence of one or more bases, such as, but not limited to, potassium carbonate, cesium carbonate, potassium iodide, or a combination thereof. and (R)-2-(((1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (Compound 16) is prepared from 2-(chloromethyl)-4H-chromen-4-one (Compound 15) by coupling with 2-(chloromethyl)-4H-chromen-1-amine (Compound 2) to obtain (R)-2-(((1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (Compound 16).

[0125] [ka]

[0126] In one embodiment, the present invention provides a method or process for the preparation of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound A″), wherein 2-(hydroxymethyl)-4H-chromen-4-one (Compound 14) is converted to 2-(chloromethyl)-4H-chromen-4-one (Compound 15) by reacting Compound 14 with one or more chlorinating agents, such as, but not limited to, thionyl chloride, one or more sulfonyl chlorides, such as, but not limited to, mesyl chloride, toluenesulfonyl chloride, trichloromethanesulfonyl chloride, or a combination thereof, or a combination thereof.

[0127] [ka]

[0128] In one embodiment, the present invention provides a method or process for the preparation of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound A″), in which 2-(hydroxymethyl)-4H-chromen-4-one (Compound 14) is prepared from methyl 4-oxo-4H-chromene-2-carboxylate (Compound 13) by reacting Compound 13 with one or more reducing agents, such as sodium borohydride, borane dimethyl sulfide (2 M in THF), lithium borohydride (LiBH), lithium aluminum hydride (LiAlH), or a combination thereof.

[0129] [ka]

[0130] In one embodiment, the present invention provides a method or process for producing 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A) from (R)-4-oxochroman-2-carboxylic acid (Compound 18), the method or process comprising: a) one or more coupling catalysts (including but not limited to, propylphosphonic anhydride (T3P), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HCl), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2-(1 coupling of (R)-4-oxochroman-2-carboxylic acid (compound 18) with (R)-1-(naphthalen-1-yl)ethan-1-amine (compound 2) in the presence of (R)-N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (compound 4), such as (R)-N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide;

[0131] [ka] b) reacting compound 4 in the presence of one or more non-polar solvents (such as, but not limited to, toluene (methylbenzene), xylene, dioxane, benzene, dichloromethane (CHCl), carbon tetrachloride (CCl), trichloromethane (CHCl), methyl tert-butyl ether (MTBE), or a combination thereof) in the presence of one or more catalysts (such as, but not limited to, p-toluenesulfonic acid (PTSA), methanesulfonic acid (MSA), trifluoroacetic acid (TFA), tosylic acid (TsOH), pyridinium p-toluenesulfonate (PPTS), orthophosphoric acid, or a combination thereof); ethylene Glico Ru and reacting to obtain (R)-N-((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2'-[1,3]dioxolane]-2-carboxamide (compound 5);

[0132] [ka] c) reducing the amide group of compound 5 using one or more reducing agents (such as, but not limited to, Vitride, borane-dimethylsulfide complex, (Zn(OAc)2) / DEMS, or a combination thereof) to provide (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4,2'-[1,3]dioxolan]-2-yl)methyl)ethan-1-amine (compound 6);

[0133] [ka] d) treating compound 6 with an aqueous acidic medium to obtain (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one hydrochloride (compound 7);

[0134] [ka] e) reacting compound 7 with Boc anhydride (di-tert-butyl dicarbonate) in the presence of one or more basic catalysts (such as, but not limited to, tripotassium phosphate, triethylamine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, or combinations thereof) to obtain tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate (compound 8);

[0135] [ka] f) reacting compound 8 with one or more triflating agents (such as, but not limited to, N-phenyl-bis(trifluoromethanesulfonimide); trifluoromethanesulfonic anhydride; N-(4-tert-butylphenyl)bis(trifluoromethanesulfonimide); bis(trifluoromethanesulfonyl)aniline; Comin's reagent; N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide); trifluoromethanesulfonyl chloride; 4-nitrophenyl trifluoromethanesulfonate; 1-(trifluoromethanesulfonyl)imidazole; or combinations thereof) to provide (R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate (compound 9);

[0136] [ka] g) coupling compound 9 with methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate in the presence of one or more palladium catalysts (such as, but not limited to, palladium-tetrakis(triphenylphosphine), palladium(II) bis(triphenylphosphine) dichloride, palladium(0) bis(dibenzylideneacetone), palladium(II) bis(triphenylphosphine) diacetate, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), or a combination thereof) to obtain methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10);

[0137] [ka] h) converting methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound 10) to methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2-methylbenzoate (Compound 11), wherein the conversion is at a rate of about 2.0 Kg / cm 2 or through treatment with ammonium formate in the presence of a palladium-on-charcoal catalyst, optionally in the presence of one or more polar solvents, including, but not limited to, methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or combinations thereof;

[0138] [ka] i) converting compound 11 to methyl 2-methyl-5-((2R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoate hydrochloride (compound 12) via a Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid, or trimethylsilyl iodide in the presence of one or more polar solvents, including, but not limited to, methanol, dichloromethane, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof;

[0139] [ka] j) hydrolyzing the ester group of Compound 12 using one or more hydroxide bases (such as, but not limited to, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, or a combination thereof), followed by aqueous reaction with the resulting carboxylate salt to a carboxylic acid and isolation of the pure diastereoisomers by using a recrystallization method using a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvents to obtain 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound-A″), wherein the one or more protic polar solvents include, but are not limited to, ethanol, methanol, isopropanol, or a combination thereof, and the one or more aprotic polar solvents include, but are not limited to, dichloromethane, dimethylformamide, tetrahydrofuran, or a combination thereof;

[0140] [ka] and k) converting Compound A″ into its hydrochloride salt, 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A), using hydrochloric acid in one or more protic polar solvents (such as, but not limited to, ethanol, methanol, isopropanol, or a combination thereof);

[0141] [ka]

[0142] In one embodiment, the present invention provides a method or process for the preparation of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A), wherein (R)-4-oxochroman-2-carboxylic acid (Compound 18) is prepared from methyl (R)-4-oxochroman-2-carboxylate (Compound 19) using base hydrolysis in one or more polar solvents (such as, but not limited to, water, tetrahydrofuran, dichloromethane (DCM), 2-methyltetrahydrofuran (2-Me-THF), toluene (methylbenzene), ethyl acetate, dimethylformamide (DMF), or a combination thereof) using one or more bases (such as, but not limited to, sodium hydroxide, potassium hydroxide, cesium hydroxide, or a combination thereof).

[0143] [ka]

[0144] In one aspect, the present invention provides a method or process for the preparation of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A), comprising the step of reacting one or more optically active diphosphine ligands, including but not limited to, (R)-(+)-4,4′-bis(diphenylphosphino)-3,3′-bi(1,2-methylenedioxybenzene) [(R)-SEGPHOS®], 4,4′-bis(diphenylphosphine (R)-(+)-4,4'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [SEGPHOS®], (R)-(+)-4,4'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [(R)-DM-SEGPHOS®], (R)-(-)-4,4'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [(R)-DTBM-SEGPHOS®], (R)-(+ )-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [(R)-BINAP], 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl [s-Phos], 5-bis(diphenylphosphino)-9,9-dimethylxanthene [Xantphos], (2R,3R)-(+)-bis(diphenylphosphino)butane [R-Chiraphos], 4,4,4',4',6,6'-hexamethyl-2,2'-spirobichroman-8,8'-diylbis(diphenylphosphane) [SPA

[0013] The present invention provides a method or process for preparing methyl (R)-4-oxochroman-2-carboxylate (compound 19) from methyl 4-oxo-4H-chromene-2-carboxylate (compound 13) via asymmetric hydrogenation using an asymmetric aryl group such as methyl (R)-4-oxochroman-2-carboxylate (compound 19) or methyl 4-oxo-4H-chromene-2-carboxylate (compound 13) using an asymmetric aryl group such as methyl (R)-4-oxochroman-2-carboxylate (compound 19) or methyl 4-oxo-4H-chromene-2-carboxylate (compound 13) via asymmetric hydrogenation using an asymmetric aryl group such as methyl (R)-4-oxochroman-2-carboxylate (compound 19) or methyl 4-oxochroman ....

[0145] [ka]

[0146] In one aspect, the present invention provides a method or process for the preparation of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A), comprising:

[0013] The present invention provides a method or process for preparing (R)-4-oxochroman-2-carboxylic acid (compound 18) from (R)-chroman-2-carboxylic acid (compound 17) by treating compound 17 with one or more oxidizing agents (such as, but not limited to, KMnO, MnO, tert-butylhydroperoxide-chromium(VI) oxide, potassium peroxomonosulfate, sodium bromate, FeCl, TBAB-copper dichloride, AIBN-oxygen, NaClO-N-hydroxyphthalimide, or combinations thereof) in the presence of magnesium sulfate in a solvent.

[0147] [ka]

[0148] In one embodiment, the present invention provides a method or process for preparing 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A) from tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R,E)-4-(2-tosylhydrazinylidene)chroman-2-yl)methyl)carbamate (Compound 20), the method or process comprising the following steps: a) coupling compound 20 with methyl 5-bromo-2-methylbenzoate in the presence of dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane to give methyl 5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10);

[0149] [ka] b) converting methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10) to methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2-methylbenzoate (compound 11), wherein the conversion is at a rate of about 2.0 Kg / cm 2 or through treatment with ammonium formate in the presence of a palladium on charcoal catalyst, optionally in the presence of one or more polar solvents, wherein the one or more polar solvents include, but are not limited to, methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or combinations thereof;

[0150] [ka] c) converting compound 11 to methyl 2-methyl-5-((2R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoate hydrochloride (compound 12) through a Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid, or trimethylsilyl iodide in the presence of one or more polar solvents, wherein the one or more polar solvents include, but are not limited to, methanol, dichloromethane, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof;

[0151] [ka] d) hydrolyzing the ester group of compound 12 using one or more hydroxide bases (such as, but not limited to, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, or a combination thereof), followed by aqueous reaction with the resulting carboxylate salt to a carboxylic acid and isolation of the pure diastereoisomers by using a recrystallization method using a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvents to obtain 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (compound A″), wherein the one or more protic polar solvents include, but are not limited to, ethanol, methanol, isopropanol, or a combination thereof, and the one or more aprotic polar solvents include, but are not limited to, dichloromethane, dimethylformamide, tetrahydrofuran, or a combination thereof;

[0152] [ka] and e) converting compound A″ into its hydrochloride salt, 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (compound A), using hydrochloric acid in one or more protic polar solvents (such as, but not limited to, ethanol, methanol, isopropanol, or a combination thereof);

[0153] [ka]

[0154] In one aspect, the present invention provides a method or process for the preparation of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A), comprising reacting Compound 8 with one or more sulfonohydrazides, including but not limited to, 4-methylbenzenesulfonohydrazide, 4-ethylbenzenesulfonohydrazide, thiophene-2-sulfonohydrazide, naphthyl benzoate, 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride, and (b) reacting tert-butyl (E)-(1-(naphthalen-1-yl)ethyl)((4-(2-tosylhydrazinylidene)chroman-2-yl)methyl)carbamate (Compound 20) with tert-butyl (1-(naphthalen-1-yl)ethyl)((4-oxochroman-2-yl)methyl)carbamate (Compound 8), such as with 4-(2-tosylhydrazinylidene)chroman-2-yl, 4-(2-tosylhydrazinylidene)chroman-2-yl, or a combination thereof.

[0155] [ka]

[0156] In one embodiment, the present invention provides a method or process for preparing 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A) from 4-oxo-4H-chromene-2-carboxylic acid (Compound 1), wherein the method involves the following steps: a) one or more coupling catalysts (including but not limited to, propylphosphonic anhydride (T3P), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HCl), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2-( reacting 4-oxo-4H-chromene-2-carboxylic acid (compound 1) with (R)-1-(naphthalen-1-yl)ethan-1-amine (compound 2) in the presence of an organic solvent (such as 1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), and combinations thereof) to obtain (R)—N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (compound 3);

[0157] [ka] b) one or more optically active diphosphine ligands (including but not limited to, (R)-(+)-4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [(R)-SEGPHOS®], 4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [SEGPHOS®], (R)-(+)-4,4'-bis[di(3,5-xylyl)phosphino]-3,3'- Bi(1,2-methylenedioxybenzene) [(R)-DM-SEGPHOS®], (R)-(-)-4,4'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [((R)-DTBM-SEGPHOS®)], (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [(R)-BINAP], 2-dicyclohexyl bis(diphenylphosphino)-2',6'-dimethoxybiphenyl [s-Phos], 5-bis(diphenylphosphino)-9,9-dimethylxanthene [Xantphos], (2R,3R)-(+)-bis(diphenylphosphino)butane [R-Chiraphos], 4,4,4',4',6,6'-hexamethyl-2,2'-spirobichroman-8,8'-diylbis(diphenylphosphane) [SPANphos], bis(diphenylphosphinoethyl)phenanthroline enantioselective reduction of the double bond of compound 3 by asymmetric hydrogenation using a chiral amine such as (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (compound 4),

[0158] [ka] c) one or more non-polar solvents (including but not limited to toluene, methylbenzene, In the presence of one or more catalysts (such as, but not limited to, p-toluenesulfonic acid (PTSA), methanesulfonic acid (MSA), trifluoroacetic acid (TFA), tosylic acid (TsOH), pyridinium p-toluenesulfonate (PPTS), orthophosphoric acid, or a combination thereof), compound 4 is reacted with toluene, xylene, dioxane, benzene, dichloromethane (CH2Cl2), carbon tetrachloride (CCl4), trichloromethane (CHCl3), methyl tert-butyl ether (MTBE), or a combination thereof. WoE Chilen Glyco Ru and reacting to obtain (R)—N-((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2′-[1,3]dioxolane]-2-carboxamide (compound 5);

[0159] [ka] d) reducing the amide group of compound 5 using one or more reducing agents (such as, but not limited to, Vitride, borane-dimethylsulfide complex, (Zn(OAc)2) / DEMS, or a combination thereof) to provide (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4,2'-[1,3]dioxolan]-2-yl)methyl)ethan-1-amine (compound 6);

[0160] [ka] e) treating compound 6 with aqueous hydrochloric acid to give (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one hydrochloride (compound 7);

[0161] [ka] f) reacting compound 7 with Boc anhydride (di-tert-butyl dicarbonate) and tripotassium phosphate to give tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate (compound 8);

[0162] [ka] g) reacting (tert-butyl(1-(naphthalen-1-yl)ethyl)((4-oxochroman-2-yl)methyl)carbamate (compound 8) with one or more sulfonohydrazides (such as 4-methylbenzenesulfonohydrazide, 4-ethylbenzenesulfonohydrazide, thiophene-2-sulfonohydrazide, naphthalene-2-sulfonohydrazide, or combinations thereof) to obtain tert-butyl (E)-(1-(naphthalen-1-yl)ethyl)((4-(2-tosylhydrazinylidene)chroman-2-yl)methyl)carbamate (compound 20);

[0163] [ka] h) coupling tert-butyl (E)-(1-(naphthalen-1-yl)ethyl)((4-(2-tosylhydrazinylidene)chroman-2-yl)methyl)carbamate (compound 20) with methyl 5-bromo-2-methylbenzoate in the presence of one or more triphosphine ligands (such as, but not limited to, dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane or azodicarboxylic acid diethyl ester-triphenylphosphine, dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane, or combinations thereof) to obtain methyl 5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10);

[0164] [ka] i) converting methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10) to methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2-methylbenzoate (compound 11), wherein the conversion is at a rate of about 2.0 Kg / cm 2 or through treatment with ammonium formate in the presence of a palladium on charcoal catalyst, optionally in the presence of one or more polar solvents, wherein the one or more polar solvents include, but are not limited to, methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or combinations thereof;

[0165] [ka] j) converting compound 11 to methyl 2-methyl-5-((2R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoate hydrochloride (compound 12) via a Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid, or trimethylsilyl iodide in the presence of one or more polar solvents, wherein the one or more polar solvents include, but are not limited to, methanol, dichloromethane, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof;

[0166] [ka] k) hydrolyzing the ester group of Compound 12 using one or more hydroxide bases (such as, but not limited to, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, or a combination thereof), followed by aqueous reaction with the resulting carboxylate salt to a carboxylic acid and isolation of the pure diastereoisomers by using a recrystallization method using a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvents to obtain 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound-A″), wherein the one or more protic polar solvents include, but are not limited to, ethanol, methanol, isopropanol, or a combination thereof, and the one or more aprotic polar solvents include, but are not limited to, dichloromethane, dimethylformamide, tetrahydrofuran, or a combination thereof;

[0167] [ka] and l) converting compound A″ into its hydrochloride salt, 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (compound A), using hydrochloric acid in one or more protic polar solvents (such as, but not limited to, ethanol, methanol, isopropanol, or a combination thereof);

[0168] [ka]

[0169] In one embodiment, the present invention provides (R)-N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (Compound 3), (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (Compound 4), (R)-N-((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2′-[1,3]dioxolane]-2-carboxamide (Compound 5), (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4,2′-[1,3]dioxolane]-2-carboxamide (Compound 6), (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4,2′-[1,3]dioxolane]-2-carboxamide) and (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (Compound 16).

[0170] [ka]

[0171] The present invention is further illustrated in detail by the experimental methods and processes herein, but the present invention should not be construed as being limited thereto.

[0172] [Example] The present invention is further illustrated, but not limited, by the following examples which describe the preparation of compounds 1-20 according to the invention.

[0173] The compounds of the present invention can be prepared by the processes and methods described in the reaction schemes set forth herein.

[0174] Starting materials and reagents used in the preparation of these compounds are available from suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.), or may be incorporated by reference in books such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-22 (John Wiley & Sons, Inc. (2016)); Rodd's Chemistry of Carbon Compounds, Volumes 1-4 (Elsevier Science Publishers, (2008)); Organic Reactions, Volumes 1-100 (John Wiley & Sons, Inc. (1942-2019)), March's Advanced Organic Chemistry, (John Wiley & Sons, Inc., 8th Edition (2020)), and Comprehensive Organic Transformations, edited by Richard C. Larock, Ph.D. (John Wiley & Sons, Inc., 3rd Edition (2018)) and other references. These schemes are merely illustrative of some of the ways in which the compounds of the invention can be synthesized, and various modifications to these schemes can be made and will be suggested to those skilled in the art upon reading this disclosure.

[0175] The starting materials and the intermediates of the reactions may be isolated and purified, if desired, using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0176] Unless specified to the contrary, the reactions described herein are carried out over a temperature range of about −78° C. to about 150° C., more preferably about 0° C. to about 125° C., and most preferably at about room temperature (or ambient temperature), e.g., about 20° C., at atmospheric pressure.

[0177] In the reactions described below, if a reactive functional group is desired in the final product, it may be necessary to protect the reactive functional group, for example, a hydroxy group, an amino group, an imino group, a thio group, a carboxy group, or a combination thereof, to avoid the undesired participation of the reactive functional group in the reaction. Conventional protecting groups, such as benzyl, p-methoxybenzyl, carboxybenzoyl (cbz), 2-mercaptoethanol, 1,2-ethanedithiol, 1,3-propanedithiol, trimethyl orthoformate, triethyl orthoformate, or any protecting group described in PG M Buts, Greene's Protective Groups in Organic Chemistry, 5th Edition, John Wiley & Sons, Inc. (2014), may be used according to standard practice.

[0178] Synthesis of Representative Compounds of the Invention [Example 1] Step-1: (R)—N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (compound 3):

[0179] [ka]

[0180] To a stirred solution of 4-oxo-4H-chromene-2-carboxylic acid (200 g, 1052 mmol) and TEA (293 mL, 2104 mmol) in THF (6 v, volume: 1200 mL) was added T3P coupling reagent (939 mL, 1578 mmol) at 5-10 °C under a nitrogen atmosphere. To this was added (R)-1-(naphthalen-1-yl)ethan-1-amine (198 g, 1157 mmol) at the same temperature, and the resulting mass was slowly warmed to ambient temperature and stirred for 16 h. The reaction was monitored by TLC and HPLC analysis. Upon completion, it was quenched with ice-cold water (2 L, 10 v) and extracted with ethyl acetate (2 L, 10 v). The organic phase was separated, and the aqueous phase was back-extracted with ethyl acetate (1 L, 5 v). The combined organic phase was washed with water (0.4 L × 2, 4 v) and brine solution (0.4 L, 2 v). It was concentrated to dryness, and then the crude solid was redissolved in ethanol (600 mL, 3 v) at 60–65 °C. It was slowly cooled to ambient temperature and stirred for 16 h. The mass was cooled to 0–5 °C and stirred for 30 min. The solid was filtered, washed with ice-cold ethanol (100 mL, 0.5 v), and dried in a vacuum tray dryer at 50–55 °C for 16 h to give an off-white solid of (R)-N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide. Yield: 91% (327 g). HPLC purity: 100%. Melting point: 122–125 °C. LC-MS: 344.34 (MH+). 1H NMR:(400MHz,DMSO-d6)δ:9.61(d,J=8.0Hz,1H), 8.23~8.17(m,1H), 8.05(dd,J=8.0,1.6Hz,1H), 7.97(dd,J=8.0,1.6Hz,1H), 7.90~7.85(m, 2H), 7.78(dd,J=8.5,1.0Hz,1H), 7.70(dd,J=7.2,1.1Hz,1H), 7.63~7.51(m,4H), 6.89(s,1H), 5.99(p,J=7.1Hz,1H), 1.69(d,J=6.9Hz,3H).

[0181] Step-2: (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (compound 4):

[0182]

change

[0183] To a degassed solution of THF (750 mL, 5 v) at room temperature was added Cu(OAc) (0.238 g, 1.310 mmol, 0.003 eq), PPh (0.378 g, 1.442 mmol, 0.0033 eq), and (R)-DM-SEGPHOS® ligand (1.042 g, 1.442 mmol, 0.0033 eq). The resulting mixture was stirred at ambient temperature for 3 h. (Note: A pale burgundy solution was formed.) Then, diethoxymethylsilane DEMS (280 mL, 1737 mmol, 4 eq) was slowly added, and stirring was continued for 1 h. (Note: An orange solution was formed at this stage.) To the catalyst mixture was added (R)-N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (150 g, 437 mmol, 1.0 eq) in THF (750 mL, 5.0 v) at 25–30 °C, and the resulting mixture was stirred for 16 h. The reaction progress was monitored by HPLC analysis. Upon completion of the reaction, the reaction mass was slowly added to aqueous 10% sodium bicarbonate solution (25 v, 3.75 L) at 10 ± 5 °C, and the resulting mass was stirred at ambient temperature for 12 h. The product was extracted into ethyl acetate (10 v, 1500 mL), and the aqueous phase was back-extracted with additional ethyl acetate (5 v, 750 mL). The combined extracts were washed with water (10 v, 1500 mL), followed by half-saturated brine solution (5 v, 750 mL), and dried over anhydrous Na2SO4. The resulting mixture was filtered and concentrated to give crude (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide as a white solid. The crude product was purified using an ethyl acetate:n-hexane mixture (8:1 ratio, 1200:150 mL, 9 v). It was filtered and dried under vacuum at 40 ± 5 °C to give pure (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (140 g). Yield: 93%. Melting point: 194–197 °C. HPLC purity: 97.19% RR, 0.06% other isomer SR, and 99.88% de. LC-MS: 346.34 (MH+).1H NMR:(400MHz,DMSO-d6)δ:8.86(d,J=7.9Hz,1H), 8.08(dd,J=7.9,1.6Hz,1H), 8. 00~7.92(m,1H), 7.85(d,J=8.1Hz,1H), 7.74(dd,J=7.8,1.8Hz,1H), 7.62~7.49(m ,5H), 7.15(dd,J=8.4,1.0Hz,1H), 7.09(ddd,J=8.0,7.2,1.1Hz,1H), 5.73(p,J=7 .0Hz,1H), 5.18(dd,J=8.7,5.0Hz,1H), 3.03~2.89(m,2H), 1.52(d,J=6.9Hz,3H).

[0184] Step-3: (R)-N-((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2'-[1,3]dioxolane]-2-carboxamide (compound 5):

[0185] [ka]

[0186] To a stirred solution of (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (250 g, 724 mmol, 1 eq) in toluene (5000 mL, ca. 20 v), ethylene glycol (1009 mL, 18.1 mol, 25 eq) was added, followed by p-toluenesulfonic acid monohydrate (13.7 g, 72.4 mmol, 0.1 eq), and the resulting mixture was refluxed for 16 h at 120 ± 10 °C. After 16 h, HPLC showed a starting material content of 2.45%, and additional amounts of PTSA (1.37 g, 72.4 mmol, 0.1 eq) and ethylene glycol (250 mL, 4.52 mol, 6.25 eq) were added, and the reaction was continued for 5 h. The reaction progress was monitored by UPLC, and upon completion, the mass was cooled to 25±5° C., then treated with water (80 mL, 10 v) and stirred for 30 min. The product was extracted into ethyl acetate (80 mL, 10 v), and the aqueous phase was back-extracted with ethyl acetate (40 mL, 5 v). The combined organic phases were dried over Na2SO4, filtered, and concentrated to give (R)-N-((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2′-[1,3]dioxolane]-2-carboxamide as an off-white solid. The impure compound was used in the next step. The purification procedures described herein can be used to obtain the pure compound.

[0187] Purification method: The crude product was slurried in ethyl acetate (3 v) at 65-70 °C for 30 min. It was slowly cooled to ambient temperature and stirred for 16 h. The mass was then cooled between 0-5 °C for 1 h, and the precipitated solid was collected by filtration and washed with ice-cold ethyl acetate (0.5 v). It was further dried in a VTD at 50-55 °C for 16 h to give an off-white solid in 71.5% yield and 98.65% HPLC purity. Yield: 93% (261 g). Melting point: 198-202 °C. LC-MS: 390.16 (MH+). 1H NMR:(400MHz,DMSO-d6)δ8.78(d,J=8.0Hz,1H), 8.15(d,J=8.3Hz,1H), 7.97(dd,J=8.0,1.6Hz,1H), 7. 86(d,J=8.0Hz,1H), 7.64~7.50(m,4H), 7.40(dd,J=7.7,1.7Hz,1H), 7.28(ddd,J=8.7,7.3,1.7Hz,1H) , 7.01~6.91(m,2H), 5.82(p,J=7.1Hz,1H), 4.70(dd,J=12.4,2.4Hz,1H), 4.21(qd,J=5.8,2.3Hz,1H), 4.15~4.00(m,3H), 2.28(dd,J=13.6,2.5Hz,1H), 2.09(dd,J=13.6,12.5Hz,1H), 1.58(d,J=6.9Hz,3H).

[0188] Step-4: (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4,2'-[1,3]dioxolan]-2-yl)methyl)ethan-1-amine (compound 6):

[0189] [ka]

[0190] Under nitrogen, to a solution of (R)-N-((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2′[1,3]dioxolane]-2-carboxamide (260 g, 668 mmol, 1.0 eq) in THF (1040 mL, 4.0 v) and toluene (2600 mL, 10 v) was added a solution of vitride in toluene (562 mL, 70% w / w, 2003 mmol, 3.0 eq) over 1 h at 5±5° C. It was allowed to reach room temperature over 1 h and then heated to 85±5° C. for 6 h. The progress of the reaction was monitored by HPLC until the content of the intermediate (R)-N-((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2′[1,3]dioxolane]-2-carboxamide was 1.0% or less. The reaction mass was cooled to 10±5°C, and excess vitride was quenched by the addition of ethyl acetate (520 mL, 1.0 v), followed by water (520 mL, 1 v). The resulting mixture was stirred for 15 min. To this was added an aqueous solution of NaOH (5N, 1300 mL, 5 v) and stirred for 15 min. The phases were separated, the aqueous phase was extracted once with ethyl acetate (2600 mL, 10 v), and the organic phases were combined. It was washed with water (1300 mL, 5 v) and a saturated solution of brine (1300 mL, 5 v) and concentrated under vacuum at 40±5°C. The material was redissolved in ethyl acetate (1300 mL, 10 v) at ambient temperature and then treated with charcoal (10%, 26 g) and Silia Met S-thiol (10%, 26 g) for 1 h. It was filtered through a bed of freshly prepared Celite and washed with ethyl acetate (1300 mL, 5 v). The combined filtrate was concentrated to dryness, and the mass was redissolved in ethanol (780 mL, 3 v) at 55 ± 5 °C, then cooled to ambient temperature and stirring was continued for 16 h. It was cooled to 0 ± 5 °C, filtered, and the solid was washed with ice-cold ethanol (260 mL, 1 v). The off-white solid was dried in a VTD at 45 ± 50 °C for 12 h to give (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4,2'-[1,3]dioxolan]-2-yl)methyl)ethan-1-amine. Yield: 78% (196.1 g). Melting point: 141-144 °C. LC-MS: 376.2 (MH+). HPLC purity: 97.95%.1H NMR:(400MHz,DMSO-d6)δ8.30(dd,J=7.8,1.8Hz,1H), 7.96~7.90(m,1H), 7.80(d,J=8.1Hz,1H), 7.73(dd,J=7.2,1.3Hz,1H), 7.52(ddt,J= 8.0,6.8,5.3Hz,3H), 7.36(dd,J=7.7,1.7Hz,1H), 7.22(ddd,J=8.7,7.2,1.7Hz,1H), 6.90(td,J=7.5,1.2Hz,1H), 6.79(dd,J=8.3,1.1Hz, 1H), 4.64(dt,J=9.2,4.4Hz,1H), 4.28(dddd,J=12.0,6.8,5.2,1.9Hz,1H), 4.21~4.15(m,1H), 4.10~3.97(m,3H), 2.80(dt,J=12.0,5.7Hz) ,1H), 2.65(ddd,J=12.4,7.8,4.9Hz,1H), 2.42(s,1H), 2.20(dd,J=13.6,2.0Hz,1H), 1.78(dd,J=13.7,12.2Hz,1H), 1.42(d,J=6.5Hz,3H).

[0191] Step-5: (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one hydrochloride (compound 7):

[0192] [ka]

[0193] To a stirred solution of (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4,2'-[1,3]dioxolan]-2-yl)methyl)ethan-1-amine (272 g, 724 mmol, 1.0 eq) in acetone (2.6 L, ca. 4.8 v) was added aqueous 6 N HCl solution (540 mL, ca. 2 v), and the resulting mixture was heated between 70 and 80 °C for 4 h. The reaction was monitored by HPLC (absence of starting material). Upon completion, it was brought to room temperature over 1 h, water (540 mL, ca. 2 v) was added, and the mass was then cooled to 0 ± 5 °C for 1 h. The solid thus precipitated was filtered and washed with water (1090 mL, 4 v), followed by ice-cold acetone (540 mL, 2.0 v, ca. 10 °C). It was dried in a VTD at 45-50°C for 16 hours to give pure (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one hydrochloride as a white solid. Yield: 89% (236.1 g). Melting point: 264-267°C. HPLC: Chemical purity: 99.92%, Chiral purity: 100% de and ee. LC-MS: 332.40 (MH + free base). 1H NMR:(400MHz,DMSO-d6)δ10.50~10.26(m,1H), 10.00(d,J=9.1Hz,1H), 8.33~8.28(m,1H), 8.14(dd,J =7.3,1.1Hz,1H), 8.05~7.98(m,2H), 7.76(dd,J=7.8,1.7Hz,1H), 7.69~7.59(m,4H), 7.14~7.07(m,2H) ), 5.50(p,J=6.6Hz,1H), 5.10(ddt,J=13.6,8.2,3.0Hz,1H), 3.43(dd,J=13.1,5.8Hz,1H), 3.29(tt,J =8.5,3.5Hz,1H), 2.93(dd,J=17.0,13.3Hz,1H), 2.77(dd,J=17.0,3.0Hz,1H), 1.77(d,J=6.6Hz,3H).

[0194] Step-6: tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate (compound 8):

[0195] [ka]

[0196] To a stirred solution of (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one hydrochloride (235 g, 1.0 eq) in DCM (2.35 L, 10 v) at 10-15 °C, triethylamine (267 mL, 1.92 mol, 3.0 eq) was added, followed by di-tert-butyl dicarbonate (153.5 g, 1.92 mol, 1.1 eq), and the resulting mixture was heated between 40 and 45 °C for 6 h. The reaction progress was monitored by HPLC and TLC analysis. Upon completion, the mass was cooled to ambient temperature and diluted with water (1.15 L, 5 v). The phases were separated, and the aqueous phase was back-extracted with DCM (470 mL, 2 v). The organic phases were combined, washed with water (1.15 L, 5 v), brine solution (470 mL, 2 v), dried over Na2SO4, and filtered. The material was passed through a silica bed and concentrated to give tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate as a yellow oily liquid. Yield: 92.5% (255 g). HPLC: Chiral purity 100%. LC-MS: 454.11 (M+Na). 1H NMR:(400MHz,DMSO-d6)δ:8.10~8.00(m,1H), 7.97(dd,J=7.9,1.6Hz,1H), 7.90(d,J=8.1Hz,1 H), 7.69(d,J=7.2Hz,1H), 7.60~7.50(m,4H), 7.37(ddd,J=8.7,7.2,1.8Hz,1H), 6.92(td,J=7 .6,1.0Hz,1H), 6.18(d,J=8.3Hz,1H), 3.66(tt,J=8.1,4.9Hz,1H), 3.40~3.21(m,3H), 2.44(d ,J=14.4Hz,1H), 2.25(dd,J=17.0,3.2Hz,1H), 1.64(d,J=6.8Hz,3H), 1.48(d,J=12.2Hz,9H).

[0197] Step-7: (R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate (compound 9):

[0198] [ka]

[0199] To a solution of tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate (1.0 eq) in THF (7.0 v) was added HMPA (0.0015 v) under nitrogen. Potassium bis(trimethylsilyl)amide (KHMDS) solution (1 M in THF) (1.5 eq) was added dropwise to the solution at −83±5° C. over 1 hour 30 minutes. The reaction mass was stirred at −83±5° C. for 45 minutes. A solution of N-phenyl-bis(trifluoromethanesulfonimide) (PhNTf2) (1.5 eq) in THF (4.0 v) was added dropwise over 3 hours 10 minutes at the same temperature. This was stirred for another 30 minutes. The reaction was quenched using purified water (1.5 v) at −20±10° C. to give (R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate, which was used as such in the next step.

[0200] In some embodiments, HMPA substitutes can be used in place of the HMPA solvent, including, but not limited to, DMPU, DMI, DMSO, DMF, NMP, DMA, or combinations thereof.

[0201] In some embodiments, the isolation procedure may include the following: upon completion of the reaction, the mass was quenched with purified water (1.5 v) at −20±10° C. The THF was concentrated, and then the product was extracted with n-hexane (5 v × 3 times), and the combined extracts were washed with water (5 v) and concentrated to give (R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate. Yield: 84%. Mass: 586.0 [M+Na]. 1H NMR(400MHz,DMSO-d6)δ:8.00(dt,J=6.9,3.5Hz,2H), 7.97~7.88(m,1H), 7. 68(s,1H), 7.57(ddd,J=8.7,6.9,3.0Hz,3H), 7.22(t,J=7.7Hz,1H), 7.05(d d,J=7.7,1.6Hz,1H), 6.96(td,J=7.6,1.1Hz,1H), 6.45(s,1H), 6.09(s,1H) , 5.30(s,1H), 3.95(s,1H), 1.63(d,J=6.9Hz,3H), 1.39(s,9H), 1.24(s,2H).

[0202] Step-8: Methyl 5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound 10):

[0203] [ka]

[0204] (R)-2-(((tert-Butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate in THF (1.0 eq) was added to a reactor under nitrogen. To the solution was added methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.95 eq) and K3PO4 (1.5 eq). Pd(PPh3)4 (1.2 mol %) was added to the solution at ambient temperature under nitrogen. The reaction mixture was heated to reflux for 12–18 h. The reaction mass was cooled to ambient temperature, and to it was added Celite (1 w / w), n-heptane (3.0 v), and water (1.0 v). The reaction mass was filtered, the layers were separated, and the aqueous phase was further extracted with MTBE (2.0 v).

[0205] Activated carbon (0.2 w / w), silica gel (1.0 w / w), and Celite (1.0 w / w) were added to the combined organic phase. The mixture was stirred at ambient temperature for 3 hours. The mixture was then filtered, and the resulting material was evaporated under vacuum to approximately 2 v. Isopropyl alcohol (2.0 v) was added to the reaction mass and evaporated to approximately 2.0 v. This co-distillation process was repeated once more. The material was cooled to 5 ± 5 °C, stirred at the same temperature for 4 to 8 hours, and filtered to obtain methyl 5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate as a wet cake.

[0206] The wet cake was stirred in isopropyl alcohol (2.0 v) and heated to 68 ± 5 °C to obtain a clear solution. It was then cooled to 15 ± 5 °C and stirred at the same temperature for 16 hours. The solid precipitate was filtered and the solid was washed with isopropyl alcohol (0.5 v). The solid was dried under vacuum at 40 ± 5 °C until the LOD was 0.5% or less.

[0207] The solid was added to a reactor containing ethyl acetate (3.15 v). The resulting solution was filtered through a microporous filter. The ethyl acetate layer was washed with purified water (1.5 w / w) for 10 minutes. The organic phase was separated and washed again with purified water (1.5 w / w). The organic layer was separated and evaporated under vacuum at 40 ± 5 °C to approximately 1.5-2 v. The residue was co-distilled twice with isopropyl alcohol (or ethanol) (1.57 v) to approximately 1.5-2 v. Purified water (3.0 w / w) was added to the solution. The isopropyl alcohol was removed by evaporation under vacuum at 40 ± 5 °C to approximately 3.5-4 v. The precipitated solid was filtered and washed with water (0.5 v). The solid thus obtained was dried in a vacuum oven at 45±5° C. until the LOD was 0.5% or less to give methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate. Yield: 56.81%. Mass: 586.44 (M+Na). 1H NMR(400MHz,DMSO-d6)δ:8.08(d,J=8.0Hz,1H), 7.97(dd,J=8.1,1.4Hz,1H), 7.91(d,J=8.2 Hz,1H), 7.68(d,J=7.2Hz,1H), 7.65~7.49(m,4H), 7.35(d,J=7.9Hz,1H), 7.21(s,1H), 7.10 ~7.02(m,1H), 6.81~6.69(m,2H), 6.38(bs,1H), 6.11(bs,1H), 5.19(bs,1H), 3.85(s,3H), 3 .75(bs,1H), 3.31(m,1H), 2.53(s,3H), 1.65(d,J=6.8Hz,3H), 1.50(bs,1H), 1.32(bs,9H).

[0208] In some embodiments, an alternative procedure can include the following: To a solution of (R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate (110 g, 195 mmol) in a mixture of THF (volume: 500 ml, ratio: 2.000) and water (volume: 250 ml, ratio: 1.000) under nitrogen, methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (51.2 g, 185 mmol), tribasic potassium phosphate (91 g, 429 mmol), and tetrakis (1.128 g, 0.976 mmol) were added sequentially. The mixture was heated to reflux for 18 hours. The progress of the reaction was monitored by HPLC. After complete consumption of the starting material, the mass was filtered through a Celite pad and concentrated under reduced pressure. The residue was diluted with water, and the product was extracted with n-hexane (5 v × 3 times). The combined extracts were washed with water (5 v) and concentrated under reduced pressure. The residue was co-distilled with ethanol (2 v), and then fresh ethanol (4 v) was added, and the resulting mixture was warmed to obtain a clear solution. It was cooled to room temperature and stirred for 18 hours. The mass was cooled to 0 ± 5 °C with stirring for 1 hour, and the thus crystallized product was filtered and the solid was washed with ice-cold ethanol (1 v). The solid thus obtained was dried in a vacuum oven at 45 ± 5 °C until the LOD was 0.5% or less to obtain methyl 5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate. Yield: 82%. Mass: 586.44 (M+Na).1H NMR(400MHz,DMSO-d6)δ:8.08(d,J=8.0Hz,1H), 7.97(dd,J=8.1,1.4Hz,1H), 7.91(d,J=8.2 Hz,1H), 7.68(d,J=7.2Hz,1H), 7.65~7.49(m,4H), 7.35(d,J=7.9Hz,1H), 7.21(s,1H), 7.10 ~7.02(m,1H), 6.81~6.69(m,2H), 6.38(bs,1H), 6.11(bs,1H), 5.19(bs,1H), 3.85(s,3H), 3 .75(bs,1H), 3.31(m,1H), 2.53(s,3H), 1.65(d,J=6.8Hz,3H), 1.50(bs,1H), 1.32(bs,9H).

[0209] Step-9: Methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2-methylbenzoate (Compound 11):

[0210] [ka]

[0211] Ammonium formate (10.0 eq) was dissolved in methanol and heated to 33-34°C (6.0 v) to give a clear solution. Methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (1.0 eq) was dissolved in ethyl acetate (3.0 v) and heated to 33-34°C, and 5% Pd / C 50% wet (10% w / wg) was added. The ammonium formate solution was then added to the suspension using an addition funnel over 6 h. The reaction mixture was heated at 33-34°C for 2 h 30 min. The reaction mixture was cooled to 20°C over 4 h and stirred at 20°C for 9 h. The catalyst was filtered off through a GF / F glass microfiber filter and washed with methanol (1.0 v) and then ethyl acetate (2.0 v). The solution was then concentrated at 250 mbar and diluted with ethyl acetate to reach a 25 / 75 methanol / ethyl acetate molar ratio (NMR). Ethyl acetate (4.0 v) was added to the white suspension thus obtained, followed by water (8.0 v), allowing for easy separation of the two homogeneous layers. The organic layer was washed with water (8.0 v) and then subsequently concentrated at 250 mbar and diluted with methanol to remove the ethyl acetate (NMR). The intermediate methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2-methylbenzoate was isolated as a methanol solution (approximately 3.0 v), which was ready for use in the next step of the synthesis. Yield: 100%. Mass: 588.25 [M+Na].1H NMR(400MHz,DMSO-d6)δ:8.05(dd,J=8.1,1.5Hz,2H),7.94(d,J=8.2Hz,1H),7.72(d,J=7.1Hz,1H),7 .69~7.48(m,3H), 7.34(d,J=2.0Hz,1H), 7.24(d,J=7.9Hz,1H), 6.98(dd,J=7.8,2.0Hz,1H), 6.92(t,J =7.3Hz,1H), 6.59(td,J=7.5,1.3Hz,1H), 6.33(s,1H), 6.27(d,J=7.7Hz,1H), 6.14(s,1H), 3.83(s,3 H), 3.21(dd,J=14.4,5.9Hz,2H), 2.48(s,3H), 1.66(s,3H), 1.48(bs,2H), 1.37(bs,9H), 1.24(s,2H).

[0212] In some embodiments, an alternative procedure can include the following: In a hydrogenation reactor, methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (1.0 eq) was dissolved in ethyl acetate (4 v), followed by the addition of methanol (7 v), ammonia 7N in methanol solution (2 v), and the resulting mixture was stirred for 15-30 minutes. 5% Pd / C 50% wet (10% w / w) was then added, and hydrogen gas was supplied to the reaction mass (2.0 Kg / cm). 2(pressure not exceeding 1000 kJ / min). The reaction mixture temperature was maintained between 28 and 34°C for 5 to 7 hours. Once the reaction was complete by HPLC monitoring, the catalyst was filtered off through a GF / F glass microfiber filter and washed with methanol (1.0 v) and then ethyl acetate (2.0 v). The solution was then concentrated under reduced pressure and exchanged with ethyl acetate (5 v). The resulting concentrated mass was dissolved in ethyl acetate (5 v). The intermediate methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2-methylbenzoate was isolated as an ethyl acetate solution (5 v), which was ready for use in the next step of the synthesis. Yield: 100%. Mass: 588.25 [M+Na]. 1H NMR (400 MHz, DMSO-d6) δ: 1H NMR(400MHz,DMSO-d6)δ:8.05(dd,J=8.1,1.5Hz,2H),7.94(d,J=8.2Hz,1H),7.72(d,J=7.1Hz,1H),7 .69~7.48(m,3H), 7.34(d,J=2.0Hz,1H), 7.24(d,J=7.9Hz,1H), 6.98(dd,J=7.8,2.0Hz,1H), 6.92(t,J =7.3Hz,1H), 6.59(td,J=7.5,1.3Hz,1H), 6.33(s,1H), 6.27(d,J=7.7Hz,1H), 6.14(s,1H), 3.83(s,3 H), 3.21(dd,J=14.4,5.9Hz,2H), 2.48(s,3H), 1.66(s,3H), 1.48(bs,2H), 1.37(bs,9H), 1.24(s,2H).

[0213] Step-10: Methyl 2-methyl-5-((2R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoate hydrochloride (Compound 12):

[0214] [ka]

[0215] Methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2-methylbenzoate (300 g, 530 mmol, 1.0 eq) in methanol (1.2 L, 4.0 v) was heated to reflux (63° C.). Aqueous 6 N HCl (approximately 352 mL, 2121 mmol, 4.0 eq) was added to the reaction mixture at 63° C. over 2 hours using an addition funnel. The solution was stirred at 63° C. for an additional hour, cooled to 20° C. at a rate of −10° C. / h, and then stirred at 20° C. for 7 hours. The white suspension was filtered and the solid washed first with methanol (225 mL, 0.75 v) and then with water [2 x 300 mL (1 v)] to give methyl 2-methyl-5-((2R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoate hydrochloride as a wet white hydrochloride salt. The product was ready for use in the next step of the synthesis. Yield: 98%. Mass: 466.12. NMR(400MHz,DMSO-d6)δ8.33~8.26(m,1H), 7.96~7.90(m,1H), 7.79(d,J=8.1Hz,1H), 7.72(dd,J=7.2,1.2Hz,1H), 7.63(d,J= 1.3Hz,1H), 7.56~7.47(m,3H), 7.29(d,J=1.2Hz,2H), 7.07(td,J=7.4,1.4Hz,1H), 6.79(dd,J=8.2,1.2Hz,1H), 6.72(td,J=7. 5,1.3Hz,1H), 6.53(dt,J=7.7,1.3Hz,1H), 4.68(d,J=6.9Hz,1H), 4.27(dt,J=15.3,6.1Hz,2H), 3.79(s,3H), 2.78(s,1H), 2. 70~2.59(m,1H), 2.49(s,3H), 2.42(s,1H), 2.25(ddd,J=13.4,5.8,1.7Hz,1H), 1.77(q,J=12.0Hz,1H), 1.42(d,J=6.5Hz,3H).

[0216] In some embodiments, an alternative procedure can include the following: methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2-methylbenzoate (10 g, 17.66 mmol, 1.0 eq) in ethyl acetate (60 mL, 6 v) was heated to reflux (63 °C). Concentrated HCl (6 mL, 4.0 eq, 0.6 v) was added to the reaction mixture at 63 °C using an addition funnel and continued for 2 h. The reaction progress was monitored by HPLC. The reaction mixture was cooled to 25-30 °C. It was neutralized with saturated aqueous sodium bicarbonate solution (pH adjusted to 7) at 25-30 °C. The organic phase was separated, washed with water (5 v), and concentrated to dryness. It was redissolved in methanol (20 v) at 60-65 °C for 30 min and stirred at 25-3 °C for 16 h. The crystallized chirally pure product was collected by filtration, and the solid was washed with ice-cold methanol (1 v). It was dried in vacuo to give methyl 2-methyl-5-((2R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoate hydrochloride as a wet white solid. Chiral purity: 99.80% (RRS). Yield: 70.5% (5.8 g). Mass: 466.12. NMR(400MHz,DMSO-d6)δ8.33~8.26(m,1H), 7.96~7.90(m,1H), 7.79(d,J=8.1Hz,1H), 7.72(dd,J=7.2,1.2Hz,1H), 7.63(d,J= 1.3Hz,1H), 7.56~7.47(m,3H), 7.29(d,J=1.2Hz,2H), 7.07(td,J=7.4,1.4Hz,1H), 6.79(dd,J=8.2,1.2Hz,1H), 6.72(td,J=7. 5,1.3Hz,1H), 6.53(dt,J=7.7,1.3Hz,1H), 4.68(d,J=6.9Hz,1H), 4.27(dt,J=15.3,6.1Hz,2H), 3.79(s,3H), 2.78(s,1H), 2. 70~2.59(m,1H), 2.49(s,3H), 2.42(s,1H), 2.25(ddd,J=13.4,5.8,1.7Hz,1H), 1.77(q,J=12.0Hz,1H), 1.42(d,J=6.5Hz,3H).

[0217] Step-11: 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A″ and Compound A):

[0218] [ka]

[0219] Methyl-2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoate hydrochloride (260 g, 518 mmol, 1.0 eq) was dissolved in a mixture of methanol (1.48 L, 5.7 v) and tetrahydrofuran (1.48 L, 5.7 v). The solution was heated to 55 °C, and 10 N NaOH (approximately 260 mL, 2589 mmol, 5.0 eq) was added over 20 min. The clear solution was stirred at 55 °C for 2 h (pH 10). The reaction mixture was cooled to 30 °C and diluted with water (1.82 L, 7.0 v). The pH was adjusted to 6-7 by slow addition of aqueous HCl 2N (1062 mL, 2124 mmol, 4.1 eq). The zwitterion was precipitated, and the suspension was cooled to 20°C and stirred at this temperature for 30 min. The sandy solid was easily filtered and washed first with water [2 x 1300 mL (5 v)], then with EtOH (520 mL, 2.0 v), and then with isopropyl alcohol (IPA) (260 mL, 1.0 v). The white solid was dried in vacuo at 40°C for 20 h to give 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (compound A'') (crude, 225 g). Yield: 96.15%. Purity: 83.79:15.57%.

[0220] Purification: Crude 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (225 g, 498 mmol, 1.0 eq) was suspended in a 5:1 ethanol / dichloromethane solvent mixture (5.4 L, 24.0 v). The suspension was heated to vigorous reflux (60 °C) to complete dissolution of the material. Subsequent crystallization began before dissolution was complete. The suspension was stirred at 60 °C for 10 min, then cooled to 20 °C at a rate of -20 °C / h, filtered, and washed first with a 5:1 ethanol / dichloromethane solvent mixture (2 × 675 mL, 3 v) and then with ethanol (225 mL, 1 v). The white solid was dried overnight in vacuo at 40°C to give 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (compound A'') as a white solid. Yield: 64.1% (150g). Purity: 99.70:0.20%

[0221] Hydrochloride Salt Preparation: The diastereomeric pure 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid thus obtained (150 g, 332 mmol, 1.0 eq) was suspended in water (2.55 L, 17 v). After heating the reaction mass to 30 °C, a solution of 2 N aqueous NaOH (approximately 300 mL, 598 mmol, 1.8 eq) was quickly added to complete dissolution of the compound. The solution was filtered through a GF / A glass microfiber filter to remove any solid impurities. Then, 2 N aqueous HCl (665 mL, 1329 mmol, 4 eq) was added at the same temperature, inducing the precipitation of a large amount of white solid that was difficult to stir. The reaction mass was stirred at ambient temperature (22 °C) for 20 h. The resulting slurry was filtered and washed with water [1500 mL (10 v), then 3 x 600 mL (4 v)] until the pH of the filtrate was 6. After 65 h at 40 °C in a drying oven, 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride was obtained as a white solid in quantitative yield. Yield: 89.53%. Purity: 99.63%. Mass: 452.18 [MH+]. 1H NMR(DMSO-d6)δ:12.76(bs,1H), 10.07(bs,1H), 9.64(bs,1H), 8.30(d,J=8.4Hz,1H), 8.14~7.93(m,3H), 7.73 ~7.56(m,4H), 7.33~7.20(m,2H), 7.14(t,J=7.6Hz,1H), 6.87(dd,J=8.2,1.0Hz,1H), 6.79(td,J=7.6,1.1Hz,1 H), 6.57(d,J=7.7Hz,1H), 5.48(bs,1H), 4.68(m,1H), 4.29(dd,J=12.0,5.7Hz,1H), 3.30(d,J=8.6Hz,1H), 3.2 0(d,J=12.8Hz,1H), 2.48(s,3H), 2.24(dd,J=12.7,5.3Hz,1H), 1.92(q,J=12.1Hz,1H), 1.77(d,J=6.6Hz,3H). IR (KBr, cm-1): 3057.55, 2956.04, 2876.08, 2767.21, 2681.29, 2499.80, 2481.85, 2298.48, 2202.11, 1711.42 , 1595.25, 1579.33, 1517.30, 1497.94, 1483.60, 1451.74, 1400.13, 1379.30, 1362.67, 1300.55, 1279.31, 1238 .73, 1217.88, 1187.99, 1175.75, 1118.41, 1089.60, 1072.72, 1020.79, 972.36, 928.79, 913.23, 892.94, 860.86, 797.19, 780.99, 745.77, 704.12, 667.76, 611.33, 571.04, 543.00, 528.59, 470.53, 435.58, 416.04, 401.77.

[0222] [Example 2] Step-1: 2-(hydroxymethyl)-4H-chromen-4-one (compound 14)

[0223] [ka]

[0224] To a stirred solution of methyl 4-oxo-4H-chromene-2-carboxylate (0.5 g, 2.449 mmol) in methanol (10 v) was added sodium borohydride (1.1 eq, 2.69 mmol, 0.102 g) slowly over 30 min at -20 to -25 °C under a nitrogen atmosphere. Upon completion, the reaction mass was diluted with water (10 v), and the product was extracted with ethyl acetate (10 v) and washed with water (5 v) followed by saturated brine solution (5 v). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to give the crude compound. It was purified by column chromatography to give pure 2-(hydroxymethyl)-4H-chromen-4-one (0.26 g, 60.3%). GC-MS: 176.13 (M+). 1H NMR(400MHz,DMSO-d6)δ8.04(dd,J=7.9,1.7Hz,1H), 7.80(ddd,J=8.7,7.1,1.7Hz,1H), 7.62(dd,J=8.4,1.0 Hz,1H), 7.49(ddd,J=8.1,7.1,1.1Hz,1H), 6.35(s,1H), 5.82(t,J=6.1Hz,1H), 4.45(dd,J=6.1,1.0Hz,2H).

[0225] Step-2: 2-(chloromethyl)-4H-chromen-4-one (compound 15)

[0226] [ka]

[0227] To a stirred solution of 2-(hydroxymethyl)-4H-chromen-4-one (0.5 g, 2.84 mmol) in anhydrous dichloromethane (10 v) at room temperature, 0.31 mL of thionyl chloride (4.26 mmol) was added, and the reaction mixture was stirred at room temperature for 18 h. Upon completion of the reaction, it was concentrated and exchanged with dichloromethane (5 v). The concentrated mass was dissolved in anhydrous n-heptane and evaporated again to give 2-(chloromethyl)-4H-chromen-4-one (0.5 g, 91%), which was further reacted without purification. GC-MS: 194.08, 196.08 (M+). H NMR (400 MHz, chloroform-d) δ 8.26–8.17 (m, 1H), 7.72 (ddd, J = 8.8, 7.2, 1.7 Hz, 1H), 7.51 (dd, J = 8.5, 1.1 Hz, 1H), 7.44 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 6.46 (s, 1H), 4.45 (s, 2H).

[0228] Step-3: (R)-2-(((1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (compound 16)

[0229] [ka]

[0230] To a solution of (R)-1-(naphthalen-2-yl)ethan-1-amine (0.458 g, 2.67 mmol), potassium carbonate (0.852 g, 6.17 mmol), and potassium iodide (0.341 g, 2.055 mmol) in anhydrous acetonitrile (4 mL, 10 v) was added 2-(chloromethyl)-4H-chromen-4-one (0.4 g, 2.055 mmol). The resulting mixture was stirred and refluxed for 12 h. It was then cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc (10 v) and water (10 v). The organic phase was separated, and the aqueous phase was back-extracted once with EtOAc (10 v). The organic phases were combined, washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give (R)-2-(((1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (0.5 g, 73.9%). LC-MS: 330.40 (MH+). 1H NMR(400MHz,DMSO-d6)δ8.28~8.19(m,1H), 8.00(dd,J=7.9,1.7Hz,1H), 7.97~7.88(m,1H), 7.83~7.71(m,3H), 7.55~7.41(m,5H), 6.39( s,1H), 4.69(t,J=5.7Hz,1H), 3.68(dd,J=16.4,5.8Hz,1H), 3.57(dd,J=16.4,5.8Hz,1H), 3.15(d,J=6.6Hz,1H), 1.44(d,J=6.6Hz,3H).

[0231] Step-4: (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one (compound 7'')

[0232] [ka]

[0233] To a degassed solution of THF (2 mL, 5 v) was added Cu(OAc)2 (11 mg, 0.061 mmol, 0.03 eq) and (R)-DM-SEGPHOS® ligand (31 mg, 0.043 mmol, 0.035 eq) at room temperature. The resulting mixture was stirred at ambient temperature for 3 h. (Note: A pale burgundy solution was formed.) Then, diethoxymethylsilane (DEMS) (0.785 mL, 4.90 mmol, 4 eq) was slowly added, and stirring was continued for 1 h. (Note: An orange solution was formed at this stage.) To the catalyst mixture was added (R)-2-(((1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (0.4 g, 1.214 mmol, 1.0 eq) in THF (2 mL, 5 v) solution at 25–30 °C, and the resulting mixture was stirred for 16 h. Upon completion of the reaction, the reaction mass was slowly added to aqueous 10% sodium bicarbonate solution (25 v, 10 mL) at 10 ± 5 °C, and the resulting mass was stirred at ambient temperature for 12 h. The product was extracted into ethyl acetate (60 v, 24 mL), and the aqueous phase was back-extracted with additional ethyl acetate (10 v, 4 mL). The combined extracts were washed with water (10 v, 4 mL), followed by half-saturated brine solution (5 v, 2 mL), and dried over anhydrous Na2SO4. It was filtered and concentrated to give crude (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one as a white solid. The crude product was purified using column chromatography to give pure (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one (0.29 g, 71.4%). LC-MS: 332.3 (MH+). 1H NMR(400MHz,DMSO-d6)δ8.32~8.25(m,1H), 7.93(dd,J=7.8,1.8Hz,1H), 7.80(d,J=8.1Hz,1H), 7.72(ddd,J=7.2,3.8,1.4Hz,2H), 7.53( ddddd,J=11.8,10.5,8.2,4.7,1.6Hz,4H), 7.09~6.99(m,2H), 5.77(s,1H), 4.72~4.56(m,2H), 2.90~2.66(m,4H), 1.41(d,J=6.5Hz,3H).

[0234] [Example 3] Step-1: (R)-4-oxochroman-2-carboxylic acid (compound 18)

[0235] [ka]

[0236] A stirred solution of (R)-chroman-2-carboxylic acid (2.0 g, 11.22 mmol, 1.0 eq) in acetone (50 mL, 100 v) and purified water (20 mL, 20 v) was warmed to 42 ± 5 °C. To this was added MgSO (4.05 g, 33.7 mmol) in aliquots over approximately 3 h, followed by KMnO (10.64 g, 67.3 mmol). This was stirred at ambient temperature for at least 18 h. Upon completion, the reaction mass was cooled to 15 ± 5 °C and stirred with saturated aqueous NaSO solution (0.84 w / w) for 30 min. The product was extracted with ethyl acetate (10 v × 2), filtered through a freshly prepared bed of Celite, and concentrated under vacuum to give (R)-4-oxochroman-2-carboxylic acid (1.6 g, 74.2%) as an off-white solid. GC-MS:192.13(M+). 1H NMR(400MHz,DMSO-d6)δ13.36(s,1H), 7.74(dd,J=7.8,1.8Hz,1H), 7.60(ddd,J=8.7,7.2,1.8Hz,1H), 7. 15~7.05(m,2H), 5.33(dd,J=7.5,5.3Hz,1H), 3.11(dd,J=17.0,5.3Hz,1H), 2.98(dd,J=17.0,7.5Hz,1H).

[0237] Step-2: (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (compound 4)

[0238] [ka]

[0239] To a stirred solution of (R)-4-oxochroman-2-carboxylic acid (1 g, 5.025 mmol) and TEA (1.09 mL, 7.807 mmol) in THF (6 mL, 6 v) was added T3P coupling reagent (3.72 mL, 6.246 mmol) at 5-10 °C under a nitrogen atmosphere. To this was added (R)-1-(naphthalen-1-yl)ethan-1-amine (0.891 g, 5.025 mmol) at the same temperature, and the resulting mass was slowly warmed to ambient temperature and stirred for 16 h. Upon completion, it was diluted with ice-cold water (10 mL, 10 v), and the product was extracted with ethyl acetate (20 mL, 20 v). The organic phase was separated, and the aqueous phase was back-extracted once with ethyl acetate (10 mL, 10 v). The combined organic phase was washed with water (8 mL × 2, 16 v) and brine solution (8 mL, 8 v). It was concentrated to dryness, and the crude solid was then redissolved in ethanol (3 mL, 3 v) at 60-65 °C. It was slowly cooled to ambient temperature and stirred for 2 h. The material was cooled to 0-5 °C and then stirred for 30 min. The solid product was filtered, washed with ice-cold ethanol (1 mL, 1 v), and dried in a vacuum tray dryer between 50-55 °C for 3 h to give an off-white solid of (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (1.65 g, 92%). LC-MS: 346.34 (MH+). 1H NMR(400MHz,DMSO-d6)δ8.86(d,J=7.9Hz,1H), 8.16~8.05(m,1H), 7.96(dd,J=7.2,2.3Hz,1H), 7.85(d,J=8.1Hz,1H), 7.73(dd,J=7.8,1.8Hz,1H), 7.67~7.48(m,5H), 7.19~7.01(m,2H), 5.75(dp,J=14.4,7.1Hz,1H), 5.17 (dd,J=8.7,5.1Hz,1H), 3.04~2.87(m,2H), 1.53(dd,J=12.9,6.9Hz,3H).

[0240] [Example 4] Step-1: Methyl (R)-4-oxochroman-2-carboxylate (Compound 19)

[0241] [ka]

[0242] To a stirred mixture of Cu(OAc)2 (4.45 mg, 0.024 mmol) in THF (5 mL) was added R-DM-SEGPHOS (19 mg, 0.027 mmol), and the resulting mixture was stirred at ambient temperature for 30–40 min. To this was added diethoxymethylsilane (1.569 mL, 9.80 mmol) at ambient temperature and stirred for an additional 1 h. A solution of methyl 4-oxo-4H-chromene-2-carboxylate (0.5 g, 2.449 mmol) in THF (5 mL) was then added to the catalyst mixture, and stirring was continued for 24 h. Upon completion, the reaction mass was poured into ice-cold water (10 mL), and the product was extracted with ethyl acetate (20 mL). The crude product was purified by column chromatography to yield methyl (R)-4-oxochroman-2-carboxylate (430 mg, 85%) as a pale yellow liquid. GC-MS:206.11(M+). 1H NMR(400MHz,DMSO-d6)δ7.75(dd,J=7.8,1.7Hz,1H), 7.61(ddd,J=8.4,7.2,1.8Hz,1 H), 7.15~7.08(m,2H), 5.47(dd,J=8.1,5.1Hz,1H), 3.70(s,3H), 3.16~2.98(m,2H).

[0243] Step-2: (R)-4-oxochroman-2-carboxylic acid (compound 18)

[0244] [ka]

[0245] To a stirred solution of methyl (R)-4-oxochroman-2-carboxylate (1 g, 4.85 mmol) in THF (10 ml) was added aqueous sodium hydroxide solution (5.203 mmol, 0.194 g in 2 mL of water), and the resulting mixture was stirred for 2 h. Upon completion, the volatiles were removed by concentration, and the resulting mass was diluted with 5 mL of water and then carefully acidified between 5 and 10 °C. The precipitated product was collected by filtration, washed with water (2 mL), and dried under reduced pressure between 50 and 55 °C for 2 h to give a pure off-white solid of (R)-4-oxochroman-2-carboxylic acid (0.82 g, 88%). GC-MS: 192.13 (M+). 1H NMR(400MHz,DMSO-d6)δ13.36(s,1H), 7.74(dd,J=7.8,1.8Hz,1H), 7.60(ddd,J=8.7,7.2,1.8Hz,1H), 7. 15~7.05(m,2H), 5.33(dd,J=7.5,5.3Hz,1H), 3.11(dd,J=17.0,5.3Hz,1H), 2.98(dd,J=17.0,7.5Hz,1H).

[0246] Step-3: (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (compound 4)

[0247] [ka]

[0248] To a stirred solution of (R)-4-oxochroman-2-carboxylic acid (1 g, 5.025 mmol) and TEA (1.09 mL, 7.807 mmol) in THF (6 mL, 6 v) was added T3P coupling reagent (3.72 mL, 6.246 mmol) at 5-10 °C under a nitrogen atmosphere. To this was added (R)-1-(naphthalen-1-yl)ethan-1-amine (0.891 g, 5.025 mmol) at the same temperature, and the resulting mass was slowly warmed to ambient temperature and stirred for 16 h. Upon completion, it was diluted with ice-cold water (10 mL, 10 v), and the product was extracted with ethyl acetate (20 mL, 20 v). The organic phase was separated, and the aqueous phase was back-extracted with ethyl acetate (10 mL, 10 v). The combined organic phase was washed with water (8 mL × 2, 16 v) and brine solution (8 mL, 8 v). It was concentrated to dryness, and then the crude solid was redissolved in ethanol (3 mL, 3 v) at 60-65 °C. It was slowly cooled to ambient temperature and stirred for 2 h. The mass was cooled to 0-5 °C and stirred for 30 min. The solid product was filtered, washed with ice-cold ethanol (1 mL, 1 v), and dried in a vacuum tray dryer at 50-55 °C for 3 h to give an off-white solid of (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (1.65 g, 92%). LC-MS: 346.34 (MH+). 1H NMR(400MHz,DMSO-d6)δ8.86(d,J=7.9Hz,1H), 8.16~8.05(m,1H), 7.96(dd,J=7.2,2.3Hz,1H), 7.85(d,J=8.1Hz,1H), 7.73(dd,J=7.8,1.8Hz,1H), 7.67~7.48(m,5H), 7.19~7.01(m,2H), 5.75(dp,J=14.4,7.1Hz,1H), 5.17 (dd,J=8.7,5.1Hz,1H), 3.04~2.87(m,2H), 1.53(dd,J=12.9,6.9Hz,3H).

[0249] [Example 5] Step 1: tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R,E)-4-(2-tosylhydrazinylidene)chroman-2-yl)methyl)carbamate (compound 20)

[0250] [ka]

[0251] To a stirred solution of tert-butyl (1-(naphthalen-1-yl)ethyl)((4-oxochroman-2-yl)methyl)carbamate (1.2 g, 2.78 mmol) in ethanol (volume: 15 mL) was added 4-methylbenzenesulfonohydrazide (0.570 g, 3.06 mmol), and the resulting mixture was heated between 85-90 °C for 10 h. Upon completion, the reaction mass was cooled to 0-5 °C, and the precipitated product was collected by filtration. It was sucked dry to give tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R,E)-4-(2-tosylhydrazinylidene)chroman-2-yl)methyl)carbamate (1.3 g, 2.168 mmol, 78% yield). LC-MS: 600.08 (MH+).

[0252] Step 2: Methyl 5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound 10)

[0253] [ka]

[0254] To a degassed solution of tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R,E)-4-(2-tosylhydrazinylidene)chroman-2-yl)methyl)carbamate (0.5 g, 0.834 mmol) in an ethanol-toluene (volume: 10 mL, 1:1) mixture, methyl 5-bromo-2-methylbenzoate (0.191 g, 0.834 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane (0.028 g, 0.058 mmol), and potassium carbonate (0.230 g, 1.667 mmol) were added sequentially between 25 and 30 °C. The resulting mass was degassed with nitrogen gas for another 10 min. To this was added catalyst Pd2(dba)3 (0.038 g, 0.042 mmol) and the mass was heated between 95-100 °C for 4 h. Upon completion, the reaction mass was diluted with water (10 mL) and the product was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated to dryness to give methyl 5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (400 mg, 0.710 mmol, 85% yield). LC-MS: 585.96 (M+Na). 1H NMR(400MHz,DMSO-d6)δ:8.08(d,J=8.0Hz,1H), 7.97(dd,J=8.1,1.4Hz,1H), 7.91(d,J=8.2 Hz,1H), 7.68(d,J=7.2Hz,1H), 7.65~7.49(m,4H), 7.35(d,J=7.9Hz,1H), 7.21(s,1H), 7.10 ~7.02(m,1H), 6.81~6.69(m,2H), 6.38(bs,1H), 6.11(bs,1H), 5.19(bs,1H), 3.85(s,3H), 3 .75(bs,1H), 3.31(m,1H), 2.53(s,3H), 1.65(d,J=6.8Hz,3H), 1.50(bs,1H), 1.32(bs,9H).

[0255] In some embodiments, the present disclosure also provides: A1. (R)-N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (Compound 3), (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (Compound 4), (R)-N-((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2'-[1,3]dioxolane]-2-carboxamide (Compound 5), (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4, A compound selected from 2'-[1,3]dioxolan]-2-yl)methyl)ethan-1-amine (Compound 6), (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one hydrochloride (Compound 7), (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one (Compound 7''), and (R)-2-(((1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (Compound 16).

[0256] [ka] A2. A method for the synthesis of tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate (compound 8) starting from 4-oxo-4H-chromene-2-carboxylic acid (compound 1), said method comprising: a) acid-amine coupling of compound 1 with compound 2 in the presence of propylphosphonic anhydride (T3P) to obtain compound 3;

[0257] [ka] b) enantioselective reduction of the double bond of compound 3 via asymmetric hydrogenation to give optically active compound 4;

[0258] [ka] c) converting compound 4 by reacting with glycol in PTSA and toluene to give compound 5;

[0259] [ka] d) reducing the amide group of compound 5 using Vitride to give compound 6;

[0260] [ka] e) deprotecting compound 6 using aqueous 6N HCl to give compound 7;

[0261] [ka] and f) protecting the free amino group of compound 7 using Boc anhydride (di-tert-butyl dicarbonate) and tripotassium phosphate to give compound 8;

[0262] [ka] A3. The method of A2, wherein the synthesis produces 1 kg, 10 kg, or 100 kg of compound 8. A4. The method of A2, wherein in step (c), the glycol is ethylene glycol.

[0263] The invention described and claimed herein has many attributes and embodiments, including, but not limited to, those described or illustrated or referenced in this detailed disclosure. Not intended to be all-inclusive, the invention described and claimed herein is not limited to or by the features or embodiments identified in this detailed disclosure, which is included for illustrative purposes only and not for purposes of limitation. Those skilled in the art will readily recognize that many of the components and parameters can be changed or modified to a certain extent or substituted with known equivalents without departing from the scope of the invention. It is to be understood that such modifications and equivalents are incorporated herein as if individually described. The invention also includes all of the steps, features, compositions, and compounds referenced or illustrated herein, individually or collectively, as well as any and all combinations of any two or more of said steps or features.

[0264] All patents, publications, scientific papers, websites, and other documents and materials referenced or mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains, and each such referenced document and material is incorporated herein by reference to the same extent as if it were individually incorporated by reference in its entirety or set forth herein in its entirety. Applicants reserve the right to physically incorporate into this specification any and all materials and information from any such patents, publications, scientific papers, and other referenced materials or documents. Reference to any applications, patents, and publications in this specification is not, and should not be, considered an acknowledgment or any form of suggestion that they constitute valid prior art or form part of common general knowledge in any country in the world.

Claims

1. 1. A process for preparing 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (compound A″), comprising: a. tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate (compound 8) is prepared from (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one hydrochloride (compound 7) by reacting compound 7 with Boc anhydride (di-tert-butyl dicarbonate) and tripotassium phosphate; 【Chemistry 1】 b. (R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate (Compound 9) is prepared from tert-butyl((R)-1-(naphthalen-1-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate (Compound 8) by reacting Compound 8 with one or more triflating agents, wherein the one or more triflating agents are N-phenyl-bis(trifluoromethane sulfonimide), trifluoromethanesulfonic anhydride, N-(4-tert-butylphenyl)bis(trifluoromethanesulfonimide), bis(trifluoromethanesulfonyl)aniline, Comin's reagent, N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide), trifluoromethanesulfonyl chloride, 4-nitrophenyl trifluoromethanesulfonate, 1-(trifluoromethanesulfonyl)imidazole), and combinations thereof; 【Chemistry 2】 c. Reacting compound 9 with methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate in the presence of one or more palladium catalysts to give methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10) as (R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl (Chemical Formula 9), wherein the one or more palladium catalysts are selected from palladium-tetrakis(triphenylphosphine), palladium(II) bis(triphenylphosphine) dichloride, palladium(0) bis(dibenzylideneacetone), palladium(II) bis(triphenylphosphine) diacetate, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and combinations thereof; 【Transformation 3】 d. Converting methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10) to methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2-methylbenzoate (compound 11), wherein the conversion is carried out at a rate of 2.0 Kg / cm ２ or through treatment with ammonium formate in the presence of a palladium-on-charcoal catalyst in the presence of one or more polar solvents, wherein the one or more polar solvents are selected from methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, and combinations thereof; 【Chemistry 4】 e. Converting compound 11 to methyl 2-methyl-5-((2R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoate hydrochloride (compound 12) via a Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid, or trimethylsilyl iodide in the presence of one or more polar solvents, wherein the one or more polar solvents are selected from methanol, dichloromethane, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, and combinations thereof; 【Transformation 5】 and f. Hydrolyzing the ester group of compound 12 using one or more hydroxide bases, followed by aqueous reaction of the resulting carboxylate salt to carboxylic acid to obtain 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (compound A″), wherein the one or more hydroxide bases are selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, and combinations thereof; 【Transformation 6】 Including, The method, wherein step (f) further comprises isolating the pure diastereoisomers by using a recrystallization method using a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvents, wherein the one or more protic polar solvents are selected from ethanol, methanol, isopropanol, and combinations thereof, and the one or more aprotic polar solvents are selected from dichloromethane, dimethylformamide, tetrahydrofuran, and combinations thereof.

2. 10. The method of claim 1, wherein (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one hydrochloride (compound 7) is prepared from (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4,2'-[1,3]dioxolan]-2-yl)methyl)ethan-1-amine (compound 6) by treatment of compound 6 with aqueous hydrochloric acid. 【Transformation 7】

3. 3. The method of claim 2, wherein (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4,2′-[1,3]dioxolan]-2-yl)methyl)ethan-1-amine (compound 6) is prepared from (R)—N-((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2′-[1,3]dioxolane]-2-carboxamide (compound 5) by reducing the amide group of compound 5 using one or more reducing agents, wherein the one or more reducing agents are selected from Vitride, borane-dimethyl sulfide complex, (Zn(OAc)2) / DEMS, and combinations thereof. 【Transformation 8】

4. 4. The method of claim 3, wherein (R)—N—((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2′-[1,3]dioxolane]-2-carboxamide (compound 5) is prepared from (R)—N—((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (compound 4) by reacting compound 4 with ethylene glycol in the presence of a non-polar solvent in the presence of one or more catalysts, wherein the one or more catalysts are selected from p-toluenesulfonic acid (PTSA), methanesulfonic acid (MSA), trifluoroacetic acid (TFA), tosylic acid (TsOH), pyridinium p-toluenesulfonate (PPTS), orthophosphoric acid, and combinations thereof. 【Chemistry 9】

5. 5. The method of claim 4, wherein (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (compound 4) is prepared from (R)-N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (compound 3) by enantioselectively reducing the double bond of compound 3 via asymmetric hydrogenation using one or more optically active diphosphine ligands, wherein the one or more optically active diphosphine ligands are (R)-(+)- 4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [(R)-SEGPHOS®], 4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [SEGPHOS®], (R)-(+)-4,4'-bis[di(3,5-xylyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [(R)-DM-SEGPHOS®], (R)-(-)-4,4'-bis[di(3,5 -di-tert-butyl-4-methoxyphenyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [(R)-DTBM-SEGPHOS®)], (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [(R)-BINAP], 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl [s-Phos], 5-bis(diphenylphosphino)-9,9-dimethylxanthene [Xantphos], (2R,3R)-(+)- bis(diphenylphosphino)butane [R-Chiraphos], 4,4,4',4',6,6'-hexamethyl-2,2'-spirobichroman-8,8'-diylbis(diphenylphosphane) [SPANphos], bis(diphenylphosphinoethyl)phenylphosphine [Triphos], (2R,2'R,5R,5'R)-2,2',5,5'-tetramethyl-1,1'-(o-phenylene)diphosphorane [R,R-Me-DuPhos], and combinations thereof. 【Chemistry 10】

6. 6. The method of claim 5, wherein (R)-N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (Compound 3) is prepared from 4-oxo-4H-chromene-2-carboxylic acid (Compound 1) by reaction with (R)-1-(naphthalen-1-yl)ethan-1-amine (Compound 2) in the presence of one or more amide coupling catalysts, the one or more amide coupling catalysts being selected from the group consisting of propylphosphonic anhydride (T3P), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI ...

10. The method of claim 1, wherein the hydroxybenzoate is selected from the group consisting of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HB ... and combinations thereof. 【Chemistry 11】

7. 7. The method of any one of claims 1 to 6, further comprising converting 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound A″) to 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A) using aqueous hydrochloric acid in a polar protic solvent. 【Chemistry 12】

8. 1. A process for preparing 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A) from 4-oxo-4H-chromene-2-carboxylic acid (Compound 1), comprising: a. Reacting 4-oxo-4H-chromene-2-carboxylic acid (Compound 1) with (R)-1-(naphthalen-1-yl)ethan-1-amine (Compound 2) in the presence of one or more amide coupling catalysts to obtain (R)—N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (Compound 3), wherein the one or more amide coupling catalysts are selected from the group consisting of propylphosphonic anhydride (T3P), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1-ethyl-3-(3 N,N'-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HCl), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), and combinations thereof; 【Chemistry 13】 b. Enantioselectively reducing the double bond of compound 3 by asymmetric hydrogenation using one or more optically active diphosphine ligands to obtain optically active (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (compound 4), wherein the one or more optically active diphosphine ligands are (R)-(+)-4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [(R)-SEGP HOS®], 4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [SEGPHOS®], (R)-(+)-4,4'-bis[di(3,5-xylyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [(R)-DM-SEGPHOS®], (R)-(-)-4,4'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-3,3'- Bis(1,2-methylenedioxybenzene) [(R)-DTBM-SEGPHOS®)], (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [(R)-BINAP], 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl [s-Phos], 5-bis(diphenylphosphino)-9,9-dimethylxanthene [Xantphos], (2R,3R)-(+)-bis(diphenylphosphino)butane [R-Chiraphos], 4,4,4',4',6,6'-hexamethyl-2,2'-spirobichroman-8,8'-diylbis(diphenylphosphane) [SPANphos], bis(diphenylphosphinoethyl)phenylphosphine [Triphos], (2R,2'R,5R,5'R)-2,2',5,5'-tetramethyl-1,1'-(o-phenylene)diphosphorane [R,R-Me-DuPhos], and combinations thereof; 【Chemistry 14】 c. Reacting compound 4 with ethylene glycol in the presence of one or more acidic catalysts in the presence of a non-polar solvent to obtain (R)—N—((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2′-[1,3]dioxolane]-2-carboxamide (compound 5), wherein the one or more acidic catalysts are selected from p-toluenesulfonic acid (PTSA), methanesulfonic acid (MSA), trifluoroacetic acid (TFA), tosylic acid (TsOH), pyridinium p-toluenesulfonate (PPTS), orthophosphoric acid, and combinations thereof; 【Chemistry 15】 d. reducing the amide group of compound 5 using one or more reducing agents to obtain (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4,2′-[1,3]dioxolan]-2-yl)methyl)ethan-1-amine (compound 6), wherein the one or more reducing agents are selected from Vitride, borane-dimethylsulfide complex, (Zn(OAc)2) / DEMS, and combinations thereof; 【Chemistry 16】 e. treating compound 6 with an aqueous acidic medium to obtain (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one hydrochloride (compound 7); 【Chemistry 17】 f. reacting compound 7 with Boc anhydride (di-tert-butyl dicarbonate) in the presence of one or more basic catalysts to obtain tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate (compound 8), wherein the one or more basic catalysts are selected from tripotassium phosphate, triethylamine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, and combinations thereof; [Chemistry 18] g. reacting compound 8 with one or more triflating agents to obtain (R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate (compound 9), wherein the one or more triflating agents are selected from N-phenyl-bis(trifluoromethanesulfonimide), trifluoromethanesulfonic anhydride, N-(4-tert-butylphenyl)bis(trifluoromethanesulfonimide), bis(trifluoromethanesulfonyl)aniline, Comin's reagent, N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide), trifluoromethanesulfonyl chloride, 4-nitrophenyl trifluoromethanesulfonate, 1-(trifluoromethanesulfonyl)imidazole), and combinations thereof; 【Chemistry 19】 h. coupling compound 9 with methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate in the presence of one or more palladium catalysts to obtain methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10), wherein the one or more palladium catalysts are selected from palladium tetrakis(triphenylphosphine), palladium(II) bis(triphenylphosphine)dichloride, palladium(0) bis(dibenzylideneacetone), palladium(II) bis(triphenylphosphine)diacetate, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and combinations thereof; 【Chemistry 20】 i. converting methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10) to methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2-methylbenzoate (compound 11) using hydrogenation; 【Chemistry 21】 j. Converting compound 11 to methyl 2-methyl-5-((2R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoate hydrochloride (compound 12) via a Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid, or trimethylsilyl iodide in the presence of one or more polar solvents; 【Chemistry 22】 k. Hydrolyzing the ester group of compound 12 using one or more hydroxide bases, followed by aqueous reaction with the resulting carboxylate salt to a carboxylic acid to obtain 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (compound A″), wherein the one or more hydroxide bases are selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, and combinations thereof; 【Chemistry 23】 and l. Converting Compound A″ to its hydrochloride salt, 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A) using hydrochloric acid in a polar protic solvent; 【Chemistry 24】

9. 9. The method of claim 8, wherein in step (i), the hydrogenation is performed at a rate of 2.0 Kg / cm ２ The process is carried out using a palladium-on-charcoal catalyst in methanolic ammonia under an optimum hydrogen pressure not exceeding 1000 kJ / kg or through treatment with ammonium formate in the presence of a palladium-on-charcoal catalyst in the presence of one or more polar solvents.

10. 9. The method of claim 8, wherein step (k) further comprises isolating the pure diastereoisomers by using a recrystallization method using a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvents.

11. 10. The method of claim 1, wherein tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate (compound 8) is prepared from (R)-2-(((1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (compound 16), the method comprising: a. Enantioselective reduction of the double bond of compound 16 via asymmetric hydrogenation using one or more optically active diphosphine ligands to obtain optically active (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one (compound 7″), wherein the one or more optically active diphosphine ligands are (R)-(+)-4,4′-bis(diphenylphosphino)-3,3′-bi(1,2-methylenedioxybenzene) [(R)-S EGPHOS®], 4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [SEGPHOS®], (R)-(+)-4,4'-bis[di(3,5-xylyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [(R)-DM-SEGPHOS®], (R)-(-)-4,4'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-3,3 '-Bi(1,2-methylenedioxybenzene) [(R)-DTBM-SEGPHOS®)], (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [(R)-BINAP], 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl [s-Phos], 5-bis(diphenylphosphino)-9,9-dimethylxanthene [Xantphos], (2R,3R)-(+)-bis(diphenylphosphino)butanol 4,4,4',4',6,6'-hexamethyl-2,2'-spirobichroman-8,8'-diylbis(diphenylphosphane) [SPANphos], bis(diphenylphosphinoethyl)phenylphosphine [Triphos], (2R,2'R,5R,5'R)-2,2',5,5'-tetramethyl-1,1'-(o-phenylene)diphosphorane [R,R-Me-DuPhos], and combinations thereof; 【Chemistry 25】 and b. Reacting compound 7″ with Boc anhydride (di-tert-butyl dicarbonate) in the presence of one or more basic catalysts to obtain compound 8, wherein the one or more basic catalysts are selected from tripotassium phosphate, triethylamine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, and combinations thereof; 【Chemistry 26】

12. 12. The method of claim 11, wherein (R)-2-(((1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (compound 16) is prepared from 2-(chloromethyl)-4H-chromen-4-one (compound 15) by coupling compound 15 with (R)-1-(naphthalen-2-yl)ethan-1-amine (compound 2) in the presence of potassium carbonate, potassium iodide, or a mixture thereof. 【Chemistry 27】

13. 13. The method of claim 12, wherein 2-(chloromethyl)-4H-chromen-4-one (compound 15) is produced by reacting 2-(hydroxymethyl)-4H-chromen-4-one (compound 14) with thionyl chloride, one or more sulfonyl chlorides, or a combination thereof, wherein the one or more sulfonyl chlorides are selected from mesyl chloride, tosyl chloride, and a combination thereof. 【Chemistry 28】

14. 14. The method of claim 13, wherein 2-(hydroxymethyl)-4H-chromen-4-one (compound 14) is prepared from methyl 4-oxo-4H-chromene-2-carboxylate (compound 13) by reacting compound 13 with one or more reducing agents, wherein the one or more reducing agents are selected from sodium borohydride, borane dimethyl sulfide (in THF), lithium borohydride (LiBH), lithium aluminum hydride (LiAlH), and combinations thereof. 【Chemistry 29】

15. 1. A process for preparing 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A) from methyl 4-oxo-4H-chromene-2-carboxylate (Compound 13), comprising: a. Converting methyl 4-oxo-4H-chromene-2-carboxylate (compound 13) to 2-(hydroxymethyl)-4H-chromen-4-one (compound 14) by reacting compound 13 with one or more reducing agents, wherein the one or more reducing agents are selected from sodium borohydride (NaBH4), lithium borohydride (LiBH4), lithium aluminum hydride (LiAlH4), NaH, diisobutylaluminum hydride, sodium cyanoborohydride, tributyltin, BH3-THF, and combinations thereof; 【Transformation 30】 b. Converting 2-(hydroxymethyl)-4H-chromen-4-one (compound 14) to 2-(chloromethyl)-4H-chromen-4-one (compound 15) by reacting compound 14 with one or more chlorinating agents, wherein the one or more chlorinating agents are selected from thionyl chloride, one or more sulfonyl chlorides, and combinations thereof, and the one or more sulfonyl chlorides are selected from mesyl chloride, toluenesulfonyl chloride, trichloromethanesulfonyl chloride, and combinations thereof; 【Chemistry 31】 c. Coupling 2-(chloromethyl)-4H-chromen-4-one (compound 15) with (R)-1-(naphthalen-2-yl)ethan-1-amine (compound 2) in the presence of potassium carbonate, potassium iodide, or a combination thereof to obtain (R)-2-(((1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (compound 16); 【Chemistry 32】 d. Enantioselective reduction of the double bond of (R)-2-(((1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (compound 16) via asymmetric hydrogenation using one or more optically active diphosphine ligands to obtain optically active (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one (compound 7″), wherein the one or more optically active diphosphine ligands are (R)-(+)-4,4′-bis(diphenyl)-4,4′-diphenyl-2,4′-diphenyl-1,4′-diphenyl-2 ... 4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [(R)-SEGPHOS®], 4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [SEGPHOS®], (R)-(+)-4,4'-bis[di(3,5-xylyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [(R)-DM-SEGPHOS®], (R)-(-)-4,4'-bis[di(3,5-di-tert- butyl-4-methoxyphenyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [(R)-DTBM-SEGPHOS®)], (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [(R)-BINAP], 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl [s-Phos], 5-bis(diphenylphosphino)-9,9-dimethylxanthene [Xantphos], (2R,3R)-(+)-bis( diphenylphosphino)butane [R-Chiraphos], 4,4,4',4',6,6'-hexamethyl-2,2'-spirobichroman-8,8'-diylbis(diphenylphosphane) [SPANphos], bis(diphenylphosphinoethyl)phenylphosphine [Triphos], (2R,2'R,5R,5'R)-2,2',5,5'-tetramethyl-1,1'-(o-phenylene)diphosphorane [R,R-Me-DuPhos], and combinations thereof; 【Transformation 33】 e. reacting compound 7″ with Boc anhydride (di-tert-butyl dicarbonate) in the presence of one or more basic catalysts to obtain compound 8, wherein the one or more basic catalysts are selected from tripotassium phosphate, triethylamine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, and combinations thereof; 【Transformation 34】 f. reacting compound 8 with one or more triflating agents to obtain (R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate (compound 9), wherein the one or more triflating agents are selected from N-phenyl-bis(trifluoromethanesulfonimide), trifluoromethanesulfonic anhydride, N-(4-tert-butylphenyl)bis(trifluoromethanesulfonimide), bis(trifluoromethanesulfonyl)aniline, Comin's reagent, N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide), trifluoromethanesulfonyl chloride, 4-nitrophenyl trifluoromethanesulfonate, 1-(trifluoromethanesulfonyl)imidazole), and combinations thereof; 【Chemistry 35】 g. Coupling compound 9 with methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate in the presence of one or more palladium catalysts to obtain methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10), wherein the one or more palladium catalysts are selected from palladium tetrakis(triphenylphosphine), palladium(II) bis(triphenylphosphine)dichloride, palladium(0) bis(dibenzylideneacetone), palladium(II) bis(triphenylphosphine)diacetate, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and combinations thereof; 【Transformation 36】 h. converting methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10) to methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2-methylbenzoate (compound 11) using hydrogenation; 【Chemistry 37】 i. converting compound 11 to methyl 2-methyl-5-((2R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoate hydrochloride (compound 12) via a Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid, or trimethylsilyl iodide in the presence of one or more polar solvents; 【Transformation 38】 j. hydrolyzing the ester group of Compound 12 using one or more hydroxide bases, followed by aqueous reaction with the resulting carboxylate salt to a carboxylic acid to obtain 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (Compound-A″), wherein the one or more hydroxide bases are selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, and combinations thereof; 【Chemistry 39】 and k. converting Compound-A″ to its hydrochloride salt, 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A) using hydrochloric acid in a polar protic solvent; 【Chemistry 40】

16. 16. The method of claim 15, wherein in step (h), the hydrogenation is at a rate of 2.0 Kg / cm ２ or in the presence of one or more polar solvents, through treatment with ammonium formate in the presence of a palladium-on-charcoal catalyst, wherein the one or more polar solvents are selected from methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, and combinations thereof.

17. 16. The method of claim 15, wherein step (j) further comprises isolating the pure diastereoisomers by using a recrystallization method using a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvents, wherein the one or more protic polar solvents are selected from ethanol, methanol, isopropanol, and combinations thereof, and the one or more aprotic polar solvents are selected from dichloromethane, dimethylformamide, tetrahydrofuran, and combinations thereof.

18. 1. A process for preparing 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A) from (R)-4-oxochroman-2-carboxylic acid (Compound 18), comprising: a. Coupling (R)-4-oxochroman-2-carboxylic acid (Compound 18) with (R)-1-(naphthalen-1-yl)ethan-1-amine (Compound 2) in the presence of one or more amide coupling catalysts to obtain (R)-N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (Compound 4), wherein the one or more amide coupling catalysts are selected from the group consisting of propylphosphonic anhydride (T3P), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1-ethyl-3 -(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HCl), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), and combinations thereof; 【Chemistry 41】 b. Reacting compound 4 with ethylene glycol in the presence of one or more catalysts in the presence of a non-polar solvent to obtain (R)—N—((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2′-[1,3]dioxolane]-2-carboxamide (compound 5), wherein the one or more catalysts are p-toluenesulfonic acid (PTSA), methanesulfonic acid (MSA), trifluoroacetic acid (TFA), tosylic acid (TsOH), pyridinium p-toluenesulfonate (PPTS), orthophosphoric acid, and combinations thereof; 【Chemistry 42】 c. reducing the amide group of compound 5 using one or more reducing agents to obtain (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4,2′-[1,3]dioxolan]-2-yl)methyl)ethan-1-amine (compound 6), wherein the one or more reducing agents are selected from Vitride, borane-dimethylsulfide complex, (Zn(OAc)2) / DEMS, and combinations thereof; 【Chemistry 43】 d. Treating compound 6 with an aqueous acidic medium to obtain (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one hydrochloride (compound 7); 【Chemistry 44】 e. reacting compound 7 with Boc anhydride (di-tert-butyl dicarbonate) in the presence of one or more basic catalysts to obtain tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate (compound 8), wherein the one or more basic catalysts are selected from tripotassium phosphate, triethylamine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, and combinations thereof; 【Chemistry 45】 f. reacting compound 8 with one or more triflating agents to obtain (R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate (compound 9), wherein the one or more triflating agents are selected from N-phenyl-bis(trifluoromethanesulfonimide), trifluoromethanesulfonic anhydride, N-(4-tert-butylphenyl)bis(trifluoromethanesulfonimide), bis(trifluoromethanesulfonyl)aniline, Comin's reagent, N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide), trifluoromethanesulfonyl chloride, 4-nitrophenyl trifluoromethanesulfonate, 1-(trifluoromethanesulfonyl)imidazole), and combinations thereof; 【Chemistry 46】 g. Coupling compound 9 with methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate in the presence of one or more palladium catalysts to obtain methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10), wherein the one or more palladium catalysts are selected from palladium tetrakis(triphenylphosphine), palladium(II) bis(triphenylphosphine)dichloride, palladium(0) bis(dibenzylideneacetone), palladium(II) bis(triphenylphosphine)diacetate, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and combinations thereof; 【Chemistry 47】 h. converting methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10) to methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2-methylbenzoate (compound 11), wherein said conversion is carried out via hydrogenation; 【Chemistry 48】 i. converting compound 11 to methyl 2-methyl-5-((2R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoate hydrochloride (compound 12) via a Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid, or trimethylsilyl iodide in the presence of one or more polar solvents; 【Chemistry 49】 j. hydrolyzing the ester group of compound 12 using one or more hydroxide bases, followed by aqueous reaction with the resulting carboxylate salt to a carboxylic acid to obtain 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (compound A″), wherein the one or more hydroxide bases are selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, and combinations thereof; [Transformation 50] and k. converting Compound A″ to its hydrochloride salt, 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A) using hydrochloric acid in a polar protic solvent; 【Chemistry 51】

19. 19. The method of claim 18, wherein in step (h), the hydrogenation is at a rate of 2.0 kg / cm ２ or through treatment with ammonium formate in the presence of a palladium-on-charcoal catalyst in methanolic ammonia under an optimum hydrogen pressure not exceeding 0.15 g / L, wherein the one or more polar solvents are selected from methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, and combinations thereof.

20. 20. The method of claim 18, wherein step (j) further comprises isolating the pure diastereoisomers by using a recrystallization method using a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvents, wherein the one or more protic polar solvents are selected from ethanol, methanol, isopropanol, and combinations thereof, and the one or more aprotic polar solvents are selected from dichloromethane, dimethylformamide, tetrahydrofuran, and combinations thereof.

21. 19. The method of claim 18, wherein (R)-4-oxochroman-2-carboxylic acid (compound 18) is prepared from methyl (R)-4-oxochroman-2-carboxylate (compound 19) using base hydrolysis in a polar solvent using one or more bases, wherein the one or more bases are selected from sodium hydroxide, potassium hydroxide, cesium hydroxide, and combinations thereof. 【Chemistry 52】

22. 19. The method of claim 18, wherein methyl (R)-4-oxochroman-2-carboxylate (compound 19) is prepared from methyl 4-oxo-4H-chromene-2-carboxylate (compound 13) via asymmetric hydrogenation using one or more optically active diphosphine ligands, wherein the one or more optically active diphosphine ligands are (R)-(+)-4,4′-bis(diphenylphosphino)-3,3′-bi(1,2-methylenedioxybenzene) [(R)-SEGP HOS®], 4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [SEGPHOS®], (R)-(+)-4,4'-bis[di(3,5-xylyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [(R)-DM-SEGPHOS®], (R)-(-)-4,4'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-3,3'- Bis(1,2-methylenedioxybenzene) [(R)-DTBM-SEGPHOS®)], (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [(R)-BINAP], 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl [s-Phos], 5-bis(diphenylphosphino)-9,9-dimethylxanthene [Xantphos], (2R,3R)-(+)-bis(diphenylphosphino)butane [R-Chiraphos], 4,4,4',4',6,6'-hexamethyl-2,2'-spirobichroman-8,8'-diylbis(diphenylphosphane) [SPANphos], bis(diphenylphosphinoethyl)phenylphosphine [Triphos], (2R,2'R,5R,5'R)-2,2',5,5'-tetramethyl-1,1'-(o-phenylene)diphosphorane [R,R-Me-DuPhos], and combinations thereof. 【Chemistry 53】

23. 19. The method of claim 18, wherein (R)-4-oxochroman-2-carboxylic acid (compound 18) is prepared from (R)-chroman-2-carboxylic acid (compound 17) by treating compound 17 with one or more oxidizing agents in the presence of magnesium sulfate in a polar solvent, wherein the one or more oxidizing agents are selected from KMnO4, MnO2, tert-butylhydroperoxide-chromium(VI) oxide, potassium peroxomonosulfate, sodium bromate, FeCl3, TBAB-copper dichloride, AIBN-oxygen, NaClO2-N-hydroxyphthalimide, and combinations thereof. 【Chemistry 54】

24. 1. A process for preparing 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A) from 4-oxo-4H-chromene-2-carboxylic acid (Compound 1), comprising: a. Reacting 4-oxo-4H-chromene-2-carboxylic acid (Compound 1) with (R)-1-(naphthalen-1-yl)ethan-1-amine (Compound 2) in the presence of one or more amide coupling catalysts to obtain (R)—N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (Compound 3), wherein the one or more amide coupling catalysts are selected from the group consisting of propylphosphonic anhydride (T3P), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1-ethyl-3-(3 N,N'-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HCl), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), and combinations thereof; 【Transformation 55】 b. Enantioselectively reducing the double bond of compound 3 by asymmetric hydrogenation using one or more optically active diphosphine ligands to obtain optically active (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (compound 4), wherein the one or more optically active diphosphine ligands are (R)-(+)-4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [(R)-SEGP HOS®], 4,4'-bis(diphenylphosphino)-3,3'-bi(1,2-methylenedioxybenzene) [SEGPHOS®], (R)-(+)-4,4'-bis[di(3,5-xylyl)phosphino]-3,3'-bi(1,2-methylenedioxybenzene) [(R)-DM-SEGPHOS®], (R)-(-)-4,4'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-3,3'- Bis(1,2-methylenedioxybenzene) [(R)-DTBM-SEGPHOS®)], (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [(R)-BINAP], 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl [s-Phos], 5-bis(diphenylphosphino)-9,9-dimethylxanthene [Xantphos], (2R,3R)-(+)-bis(diphenylphosphino)butane [R-Chiraphos], 4,4,4',4',6,6'-hexamethyl-2,2'-spirobichroman-8,8'-diylbis(diphenylphosphane) [SPANphos], bis(diphenylphosphinoethyl)phenylphosphine [Triphos], (2R,2'R,5R,5'R)-2,2',5,5'-tetramethyl-1,1'-(o-phenylene)diphosphorane [R,R-Me-DuPhos], and combinations thereof; 【Transformation 56】 c. Reacting compound 4 with ethylene glycol in the presence of one or more catalysts in the presence of a non-polar solvent to obtain (R)—N—((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2′-[1,3]dioxolane]-2-carboxamide (compound 5), wherein the one or more catalysts are selected from p-toluenesulfonic acid (PTSA), methanesulfonic acid (MSA), trifluoroacetic acid (TFA), tosylic acid (TsOH), pyridinium p-toluenesulfonate (PPTS), orthophosphoric acid, and combinations thereof; 【Chemistry 57】 d. reducing the amide group of compound 5 using one or more reducing agents to obtain (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4,2′-[1,3]dioxolan]-2-yl)methyl)ethan-1-amine (compound 6), wherein the one or more reducing agents are selected from Vitride, borane-dimethylsulfide complex, (Zn(OAc)2) / DEMS, and combinations thereof; 【Transformation 58】 e. treating compound 6 with aqueous hydrochloric acid to give (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one hydrochloride (compound 7); 【Chemistry 59】 f. Reaction of compound 7 with Boc anhydride (di-tert-butyl dicarbonate) and tripotassium phosphate to give tert-butyl ((R)-1-(naphthalen-1-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl)carbamate (compound 8); 【Transformation 60】 g. reacting (tert-butyl(1-(naphthalen-1-yl)ethyl)((4-oxochroman-2-yl)methyl)carbamate (compound 8) with one or more sulfonohydrazides to obtain tert-butyl (E)-(1-(naphthalen-1-yl)ethyl)((4-(2-tosylhydrazinylidene)chroman-2-yl)methyl)carbamate (compound 20), wherein the one or more sulfonohydrazides are selected from 4-methylbenzenesulfonohydrazide, 4-ethylbenzenesulfonohydrazide, thiophene-2-sulfonohydrazide, naphthalene-2-sulfonohydrazide, and combinations thereof; 【Chemistry 61】 h. Coupling of tert-butyl (E)-(1-(naphthalen-1-yl)ethyl)((4-(2-tosylhydrazinylidene)chroman-2-yl)methyl)carbamate (compound 20) with methyl 5-bromo-2-methylbenzoate in the presence of one or more triphosphine ligands to give methyl 5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromene 10) to obtain dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane or azodicarboxylic acid diethyl ester-triphenylphosphine, dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane, and combinations thereof; 【Transformation 62】 i. converting methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (compound 10) to methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2-methylbenzoate (compound 11), wherein said conversion is carried out via hydrogenation; 【Transformation 63】 j. Converting compound 11 to methyl 2-methyl-5-((2R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoate hydrochloride (compound 12) via a Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid, or trimethylsilyl iodide in the presence of one or more polar solvents; 【Chemistry 64】 k. Hydrolyzing the ester group of compound 12 using one or more hydroxide bases, followed by aqueous reaction with the resulting carboxylate salt to a carboxylic acid to obtain 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid (compound A″), wherein the one or more hydroxide bases are selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, and combinations thereof; 【Transformation 65】 and l. Converting Compound A″ to its hydrochloride salt, 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid hydrochloride (Compound A) using hydrochloric acid in a polar protic solvent; 【Chemical Formula 66】

25. 25. The method of claim 24, wherein in step (i), the hydrogenation is at a rate of 2.0 kg / cm ２ or through treatment with ammonium formate in the presence of a palladium-on-charcoal catalyst in methanolic ammonia under an optimum hydrogen pressure not exceeding 0.15 g / L, wherein the one or more polar solvents are selected from methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, and combinations thereof.

26. 25. The method of claim 24, further comprising isolating the pure diastereoisomers in step (k) by using a recrystallization method using a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvents, wherein the one or more protic polar solvents are selected from ethanol, methanol, isopropanol, and combinations thereof, and the one or more aprotic polar solvents are selected from dichloromethane, dimethylformamide, tetrahydrofuran, and combinations thereof.

27. (R)-N-(1-(naphthalen-1-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (Compound 3), (R)-N-((R)-1-(naphthalen-1-yl)ethyl)-4-oxochroman-2-carboxamide (Compound 4), (R)-N-((R)-1-(naphthalen-1-yl)ethyl)spiro[chroman-4,2'-[1,3]dioxolane]-2-carboxamide (Compound 5), (R)-1-(naphthalen-1-yl)-N-(((R)-spiro[chroman-4,2 a compound selected from (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one hydrochloride (Compound 7), (R)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-one (Compound 7″), and (R)-2-(((1-(naphthalen-1-yl)ethyl)amino)methyl)-4H-chromen-4-one (Compound 16). 【Transformation 67】

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