(EXTRACTED FROM WIPO PAGE)
METHODS, PROCESSES AND INTERMEDIATES FOR PREPARING
CHROMAN COMPOUNDS
CROSS REFERENCE TO RELATED APPLICATIONS
[1] This PCT application claims the benefit in 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.
FIELD
[2] The disclsoure relates to the synthesis of substituted chroman compounds and novel intermediates, and the use of novel intermediates. In particular, the disclsoure relates to enantioselective synthesis of the Calcium sensing receptor (CaSR) modulating agent 2- methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, its intermediates and pharmaceutically acceptable salts thereof.
INCORPORATION BY REFERENCE
[3] All U.S. patents, U.S. patent application publications, foreign patents, foreign and PCT published applications, articles and other documents, references and publications noted herein, and all those listed as References Cited in any patent or patents that issue herefrom, are hereby incorporated by reference in their entirety, The information incorporated is as much a part of this application as if all the text and other content was repeated in this application, and will be treated as part of the text and content of this application as filed.
BACKGROUND
[4] The following includes information that may be useful in understanding the invention. It is not an admission that any of the information, publications or documents specifically or implicitly referenced herein is prior art, or essential, to the described or claimed invention. All publications and patents mentioned herein are hereby incorporated by reference in their entirety.
[5] Calcium-sensing receptor is a class C G-protein-coupled receptor (GPCR). It plays a major role in the maintenance of a physiological serum ionized calcium (Ca2+)
concentration by regulating the circulating levels of parathyroid hormone. Extracellular Ca2+ (Ca2+o) is the primary physiological ligand for CaSR.
[6] Small molecules that are positive allosteric modulators called calcimimetics, modulate and improve the receptors sensitivity to the already existing milieu of extracellular ionic calcium and reduces PTH secretion. This has been explored as potential therapy for hyperparathyroidism and diseases associated with decreased CaSR signaling. Cinacalcet was the first CaSR modulating agent to be approved by the U.S. Food and Drug Administration (FDA).
[7] PCT International Patent Application Publication Nos. WO 2012/127388, WO 2012/120476, WO 2012/127385, WO 2012/069421, WO 2012/069419, WO
2012/069402, US 2011/0028452, WO 2010/150837, WO 2010/136037, WO
2010/042642, WO 2010/038895, WO 2009/065406, WO 2008/059854, WO
2006/123725, WO 2004/106280, WO 2004/069793, WO 2002/012181 and US 2003/0199497 refer to compounds related to calcium sensing receptors (CaSR) for the treatment of various diseases mediated by CaSR. Kessler et al., “N1-Benzoyl-N2-[l-(l- 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 CaSR.
[8] WO2013/124828 discloses a series of substituted chroman compounds for CaSR modulation. One specific compound disclosed therein is 2-methyl-5-((2R,4S)-2-((((R)-l- (naphthalen-l-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid. The application also describes a general method of synthesis of these substituted chroman compounds. The process disclosed involves chiral resolution of racemic chroman-2-carboxylic acid used as the starting material to get the desired (R) chroman-2-carboxlic acid in subsequent steps. However, carrying out the chiral resolution of the intermediate is difficult, costly, and not suitable for an industrial scale. Further, carrying out the chiral resolution of the intermediate also affects the overall yield of the manufacturing method.
[9] In view of the above, there is a need for a more efficient method that is less complicated, more cost effective and industrially advantageous 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.
SUMMARY
[10] The invention described and claimed herein has many attributes and aspects including, but not limited to, those set forth or described or referenced in this Summary. It is not intended to be all-inclusive and the invention described and claimed herein are not limited to or by the features or embodiments identified in this Summary, which is included for purposes of illustration only and not restriction.
[11] This disclosure provides for facile, cost-effective and industrially advantageous methods and processes for the synthesis of 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l- yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid and its salts. Particularly, the methods and processes described herein involve an enantioselective method comprising steps wherein the stereochemistry of intermediates or final compounds is controlled. In some aspects, this disclosure provides with 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 aspects, this disclosure provides for a method and process for synthesizing Compound 7 from a route involving Compound 3.
[12] The methods and processes disclosed herein also involve novel intermediates and/or their salts, which are useful for the facile synthesis of Compound A and its salts.
[13] In some aspects, this disclosure provides for the compound (R)-N-( 1 -(naphthalen- 1 - yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (Compound 3) and/or its salts,

[14] In some aspects, this disclosure provides for the compound (R)-N-( (R)- l-(naphthalen- l-yl)ethyl)-4-oxochromane-2-carboxamide (Compound 4) and/or its salts,

[15] In some aspects, this disclosure provides for the compound (R)-N-( (R)- l-(naphthalen- l-yl)ethyl)spiro[chromane-4,2'-[l,3]dioxolane]-2-carboxamide (Compound 5) and/or its salts,

[16] In some aspects, this disclosure provides for the compound (R)- 1 -(naphthalen- 1-yl)- N-(((R)-spiro[chromane-4,2'-[ 1 ,3]dioxolan] -2-yl)methyl)ethan- 1 -amine (Compound 6) and/or its salts,

[17] In some aspects, this disclosure provides for the compound (R)-2-((((R)-l- (naphthalen- 1 -yl)ethyl)amino)methyl)chroman-4-one (Compound 7) and its salts, and (R)-2-((((R)- 1 -(naphthalen- 1 -yl)ethyl) amino)methyl)chroman-4-one (Compound 7”),

[18] In some aspects, this disclosure provides for the (R)-2-((( 1 -(naphthalen- 1 - yl)ethyl)amino)methyl)-4H-chromen-4-one (Compound 16) and its salts,

[19] In some aspects, this disclosure provides for a method and 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),

as depicted in Scheme- 1:
SCHEME-I
which comprises:
a) reacting 4-oxo-4H-chromene-2-carboxylic acid (Compound 1) with (R)-l- (naphthalen- 1 -yl)ethan- 1 -amine (Compound 2) in the presence of one or more coupling catalysts to obtain (R)-N-(l-(naphthalen-l-yl)ethyl)-4-oxo-4H-chromene-2- carboxamide (Compound 3), wherein the one or more coupling catalysts is propylphosphonic anhydride (T3P), l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HC1), Ν,Ν'-Dicyclohexylcarbodiimide (DCC), Ν,Ν'-Diisopropylcarbodiimide (DIC), 1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3 -oxide hexafluorophosphate (HATU), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU), or a combination thereof;
b) enantioselectively reducing the double bond of Compound 3 by asymmetric hydrogenation to obtain the optically active (R)-N-((R)-l-(naphthalen-l-yl) ethyl)-4- oxochromane-2-carboxamide (Compound 4) using one or more optically active diphosphine ligands, wherein the one or more optically active diphosphine ligands is (R)-(+)-4,4'-Bis(diphenylphosphino)-3,3'-bi(l,2-methylenedioxybenzene) [(R)- SEGPHOS® ] , 4,4'-Bis(diphenylphosphino)-3,3'-bi(l ,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-l,l'-(o-phenylene)diphospholane [R,R-Me-DuPhos], or a combination thereof;
c) reacting Compound 4 with glycol (such as, but not limited to, ethylene glycol or propylene glycol) in the presence of one or more catalysts in the presence of one or more nonpolar solvents to obtain (R)-N-((R)-l-(naphthalen-l- yl)ethyl)spiro[chromane-4,2'-[l,3]dioxolane]-2-carboxamide (Compound 5), wherein the one or more catalysts is p-toluenesulfonic acid (PTSA), methanesulfonic acid (MSA), trifluoroacetic acid (TEA), tosylic acid (TsOH), pyridinium p- toluenesulfonate (PPTS), orthophosphoric acid, or a combination thereof, and wherein the one or more nonpolar solvents includes, but not limited to, toluene (methylbenzene), xylene, dioxane, benzene, dichloromethane (CH2C12), carbon tetrachloride (CC14), trichloromethane (CHC13), methyl tert-butyl ether (MTBE), or a combination thereof;
d) reducing the amide group of Compound 5 using a reducing agent to obtain (R)-l- (naphthalen-l-yl)-N-(((R)-spiro[chromane-4,2'-[l,3]dioxolan]-2-yl)methyl)ethan-l- amine (Compound 6), wherein the reducing agent is Vitride, borane -dimethyl sulphide complex, (Zn(OAc)2)/DEMS, or a combination thereof;
e) treating Compound 6 with aqueous acidic media to obtain (R)-2-((((R)-l-(naphthalen- l-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 obtain tert-butyl ((R)-l-(naphthalen-l-yl)ethyl)(((R)- 4-oxochroman-2-yl)methyl) carbamate (Compound 8), wherein the one or more basic catalyst is tripotassium phosphate, triethyl amine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium-bi-carbonate, sodium carbonate, potassium bi-carbonate, potassium carbonate, or combination thereof;
g) reacting Compound 8 with one or more triflating agents to give (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 is N-phenyl-bis(trifluoromethanesulfonimide), trifluoromethanesulfonic anhydride; N- (4-tert-Butylphenyl)bis(trifluoromethanesulfonimide),
Bis(trifluoromethanesulfonyl)aniline, Cornin’ s reagent, N-(5-Chloro-2- pyridyl)bis(trifluoromethanesulfonimide); trifluoromethanesulfonyl chloride, 4- nitrophenyl trifluoromethanesulfonate, l-(trifluoromethanesulfonyl)imidazole)), or a combination thereof;
h) coupling Compound 9 with methyl 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate in the presence of one or more palladium catalysts to give methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-l-(naphthalen-l-yl)ethyl)amino)methyl)- 2H-chromen-4-yl)-2-methylbenzoate (Compound 10), wherein the one or more palladium catalysts is palladium-tetrakis(triphenylphosphine), palladium(n)bis(triphenylphosphine) dichloride, palladium(O)
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)-l-(naphthalen-l- 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 through hydrogenation using palladium charcoal catalyst in methanolic ammonia under optimum hydrogen pressure not more than about 2.0 Kg/cm2, or through treatment with ammonium formate in the presence of palladium charcoal catalyst optionally in the presence of one or more polar solvents, wherein the one or more polar solvents includes, 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)-l-(naphthalen-l- yl)ethyl)amino) methyl) chroman-4-yl)benzoate hydrochloride (Compound 12) through Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid or trimethyl silyl iodide in the presence of one or more polar solvents, wherein the one or more polar solvents includes, 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 is sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, or a combination thereof), followed by aqueous reaction with the resultant carboxylate salt into the carboxylic acid, and isolation of the pure diastereoisomer by using recrystallization technique with a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvents to give 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l- yl)ethyl)amino)methyl) chroman-4-yl)benzoic acid (Compound- A”), wherein the one or more protic polar solvents includes, but not limited to, ethanol, methanol, isopropanol, or a combination thereof, and the one or more aprotic polar solvents includes, but not limited to, dichloromethane, dimethylformamide, tetrahydrofuran, or a combination thereof; and
1) converting Compound- A” to its hydrochloride salt, 2-methyl-5-((2R,4S)-2-((((R)-l- (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 includes, but not limited to, ethanol, methanol, isopropanol, or a combination thereof.
[20] In some aspects, this disclosure provides for a method and 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),

as depicted in Scheme 2:
SCHEME 2
which comprises:
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 is sodium borohydride (NaBH4), lithium borohydride (LiBH4), lithium aluminum hydride (LiAlH4), NaH, sodium cyanoborohydride, diisobutyl aluminum hydride, metal hydrides, tributyl tin, borane complexes (e.g., BH3-THF), or a combination 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 is thionyl chloride, a sulfonyl chloride (such as, but not limited to, mesyl chloride, toluenesulfonyl chloride or trichloromethanesulfonic chloride), or a combination thereof;
c) coupling 2-(chloromethyl)-4H-chromen-4-one (Compound 15) with (R)-l- (naphthalen-2-yl)ethan- 1 -amine (Compound 2) to obtain (R)-2-((( 1 -(naphthalen- 1 - yl)ethyl)amino)methyl)-4H-chromen-4-one (Compound 16) in the presence of potassium carbonate, potassium iodide or combination thereof;
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 to obtain the optically active (R)-2-((((R)-l -(naphthalen- l-yl)ethyl) amino)methyl)chroman-4-one (Compound 7”), using one or more optically active diphosphine ligands, wherein the one or more optically active diphosphine ligands is (R)-(+)-4,4'-Bis(diphenylphosphino)-3,3'-bi(l,2-methylenedioxybenzene) [(R)- SEGPHOS® ] , 4,4'-Bis(diphenylphosphino)-3,3'-bi(l ,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)diphospholane [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 is tripotassium phosphate, triethyl amine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium-bi-carbonate, sodium carbonate, potassium bi-carbonate, potassium carbonate, or combination thereof; and
f) converting Compound 8 to Compound A as described in Scheme- 1.
[21] In some aspects, this disclosure provides for a method and 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),

as depicted in Scheme-3:
SCHEME-3

which comprises:
Step A:
a) converting (R)-chromane-2-carboxylic acid (Compound 17) to (R)-4-oxochromane- 2-carboxylic acid (Compound 18) by treating Compound 17 with one or more oxidizing agents (such as, but not limited to, KMn04, Mn02, tert-butyl hydroperoxide-Chromium(VI)oxide, potassium peroxomonosulfate, sodium bromate, FeC13, TBAB -Copper dichloride, AIBN-Oxygen, NaC102-N-Hydroxyphthalimide, or a combination thereof) in the presence of magnesium sulphate in one or more polar solvents (such as, but not limited to, tetrahydrofuran, dichloromethane (DCM), tedtrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me-THF), toluene (methylbenzene), ethyl acetate, dimethylformamide (DMF), water, acetone or a combination thereof);
Step B:
a) converting methyl 4-oxo-4H-chromene-2-carboxylate (Compound 13) to methyl (R)- 4-oxochromane-2-carboxylate (Compound 19) via asymmetric hydrogenation using one or more optically active diphosphine ligands (such as, but not limited to, (R)-(+)- 4,4'-Bis(diphenylphosphino)-3,3'-bi(l,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-l,l'-(o-phenylene)diphospholane [R,R-Me-DuPhos], or a combination thereof);
b) hydrolyzing methyl (R)-4-oxochromane-2-carboxylate (Compound 19) to give (R)-4- oxochromane-2-carboxylic acid (Compound 18) 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 combination thereof);
c) coupling (R)-4-oxochromane-2-carboxylic acid (Compound 18) with (R)-l- (naphthalen-l-yl)ethan-l -amine (Compound 2) in the presence of one or more coupling catalysts (such as, but not limited to, propylphosphonic anhydride (T3P) 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HC1), Ν,Ν'- Dicyclohexylcarbodiimide (DCC), Ν,Ν'-Diisopropylcarbodiimide (DIC), 1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3 -oxide hexafluorophosphate (HATU), 2-( lH-benzotriazol- 1 -yl)- 1,1,3 ,3-tetramethyluronium hexafluorophosphate (HBTU), or a combination thereof) to obtain (R)-N-(l- (naphthalen-l-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (Compound 4); and d) converting (R)-N-(l-(naphthalen-l-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (Compound 4) to Compound A using method described in Scheme- 1.
[22] In some aspects, the disclosure provides a method or process for the synthesis of 2- methyl-5-((2R,4S)-2-((((R)-l-(naphthalen- 1 -yl)ethyl)amino)methyl) chroman-4- yl)benzoic acid hydrochloride (Compound A),

as depicted in Scheme-4:
SCHEME-4
which comprises:
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 a combination thereof) to give tert-butyl (E)-( 1 -(naphthalen- l-yl)ethyl)((4-(2-tosylhydrazineylidene)chroman-2-yl)methyl)carbamate (Compound 20);
b) coupling tert-butyl (E)-(l -(naphthalen- 1 -yl)ethyl)((4-(2- tosylhydrazineylidene)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 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); and
c) converting Compound 10 to Compound A as described in Scheme- 1.
DETAILED DESCRIPTION OF THE INVENTION
[23] The invention is not limited to particular compositions, methods, uses, compounds, processes, or methodologies described, as these may vary. The terminology used in this Detailed Description section is for the purpose of describing particular versions or embodiments only, and is not intended to limit the scope of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, the preferred methods, devices, and materials described herein.
[24] Definitions
[25] For purposes of interpreting the specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.
[26] 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 qualify the numerical values that it modifies, denoting such a value as variable within a margin of error. When no particular margin of error (such as, for example, standard deviation to a mean value) is recited, the term “about” means plus or minus 10% of the numerical value of the number with which it is being used. For example, “about 50%” means in the 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 a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another
embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
[27] The term “alkyl” as used herein is 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. The alkyl group can also be substituted or unsubstituted. Unless stated otherwise, the term “alkyl” contemplates both substituted and unsubstituted alkyl groups. The alkyl group 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.
[28] The term “alkenyl” as used herein is 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.
[29] The term “alkynyl” as used herein is 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.
[30] The term “cycloalkyl” as used herein is a monovalent saturated monocyclic ring containing three to eight ring carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
[31] The term “heterocyclylalkyl” as used herein is a -(alkylene)-R radical, wherein R is heterocyclyl as defined herein, e.g., pyrrolidinylmethyl, tetrahydrofuranylethyl, pyridinylmethylpiperidinylmethyl, and the like.
[32] The term “aryl” as used herein is a monocyclic or fused bicyclic ring assembly containing 6 to 10 ring carbon atoms wherein each ring is aromatic, e.g., phenyl or naphthyl.
[33] The term “aromatic” as used herein is a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp2 hybridized and the total number of pi electrons is equal to 4n+2.
[34] The term “heteroaryl” as used herein is a group or part of a group denotes 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) is (are) selected from nitrogen, oxygen or sulfur, the remaining ring atoms being carbon. Representative heteroaryl rings include, but 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.
[35] The term “acyl” as used herein is a — COR radical where “R” is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocyclyl as defined herein, e.g., formyl, acetyl, trifluoroacetyl, benzoyl, piperazin-l-ylcarbonyl, and the like. When R is alkyl it is referred to in this application as alkylcarbonyl. When R is aryl it is referred to in this application as arylcarbonyl. When R is heteroaryl it is referred to in this application as heteroarylcarbonyl. When R is heterocyclyl it is referred to in this application as heterocyclylcarbonyl.
[36] The term “alkylamino” as used herein is a radical — NHR, wherein “R” is alkyl as defined herein, e.g., methylamino, ethylamino, n-, iso-propylamino, n-, iso-, tert- butylamino, and the like.
[37] The term “alkylthio” as used herein is a — SR radical, wherein “R” is alkyl as defined herein, e.g., methylthio, ethylthio, propylthio, or butylthio, and the like.
[38] The term “alkylsulfonyl” as used herein is a — S02R radical, wherein “R” is alkyl as defined herein, e.g., methylsulfonyl, ethylsulfonyl, and the like.
[39] The term “alkoxyalkyl” as used herein is a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons 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.
[40] The term “alkoxy carbonyl” as used herein is a — C(O)OR radical, wherein “R” is an alkyl group as defined herein, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.
[41] The term “amino” as used herein is an — Nth radical.
[42] The term “aminoalkyl” as used herein is a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, 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.
[43] The term “carboxy” as used herein is a — C(O)OH radical.
[44] The term “carboxyalkyl” as used herein is a ton alkyl radical, as defined herein, substituted with at least one, preferably one or two, — C(O)OH group(s), e.g., carboxymethyl, carboxyethyl, 1-, 2-, or 3-carboxypropyl, and the like.
[45] The term “halo” as used herein is fluoro, chloro, bromo or iodo.
[46] The term “hydroxy” as used herein is an — OH radical.
[47] Unless otherwise stated, the term "oxo" as used herein is a C(=O) group. Such an oxo group may be a part of either a cycle or a chain in the compounds disclosed in this application.
[48] The term “silyl” as used herein is a silicon radical wherein the silicon is substituted with one to three of hydrogen, halo, alkyl, amino, aryl, or a combination thereof.
[49] The term “pharmaceutically acceptable” as used herein is that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
[50] The term “pharmaceutically acceptable salts” as used herein is salts of compounds of this disclosure that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic 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- hydroxy-ethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4'- methylenebis(3-hydroxy-2-ene-l-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.
[51] Pharmaceutically acceptable salts also include base addition salts that may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include, but 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.
[52] The term “isomers” as used herein is compounds of having 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 termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes “optical isomers.” A carbon atom bonded to four nonidentical substituents is termed a “chiral center.” A compound with one chiral center that has two enantiomeric forms of opposite chirality is termed a “racemic mixture.” A compound that has more than one chiral center has 2n-l enantiomeric pairs, wherein “n” is the number of chiral centers. Compounds with more than one chiral center may exist as either an individual diastereomer or as a mixture of diastereomers, termed a “diastereomeric mixture.” When one chiral center is present a stereoisomer may 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 centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see, e.g., “March’s Advanced Organic Chemistry, ed. Michael B. Smith, 8th ed., John Wiley & Sons, Inc. (2020)).
[53] As used herein, the term “nonpolar aprotic solvent” or “aprotic nonpolar solvent” refers a liquid which can dissolve non-polar organic compounds and which has does not comprise an acidic proton. Nonpolar aprotic solvents can include, but not be limited to, toluene (methylbenzene), xylene, dioxane, benzene, dichloromethane (CH2C12), carbon tetrachloride (CC14), trichloromethane (CHC13), methyl tert-butyl ether (MTBE), or a combination thereof.
[54] As used herein, the term “protic polar solvent” or “polar protic solvent” refers to a liquid which can dissolve polar organic compounds, comprises a strong dipole moment, and further comprises a proton bound to an oxygen atom. Protic polar solvents can include, but not be limited to, ethanol, methanol, isopropanol, or a combination thereof.
[55] As used herein, the term “aprotic polar solvent” refers to a liquid which can dissolve polar organic compounds and comprises a strong dipolar moment but does not comprise a proton bound to an oxygen atom. Aprotic polar solvents can include, but not be limited to, dichloromethane, dimethylformamide, tetrahydrofuran, dioxane, or a combination thereof.
[56] As used herein, the term “nonpolar solvent” refers to an organic liquid which can dissolve organic compounds and does not comprise a strong dipole moment. Nonpolar solvents can include, but not be limited to, toluene (methylbenzene), xylene, dioxane, benzene, dichloromethane (CH2C12), carbon tetrachloride (CC14), trichloromethane (CHC13), methyl tert-butyl ether (MTBE), or a combination thereof.
[57] As used herein, the term “polar solvent” or “organic polar solvent” refers to a liquid which can dissolve compounds, including organic compounds, and comprises a strong dipole moment. Polar solvents can include, but not be 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.
[58] Organic Synthesis
[59] The compounds described herein may be prepared by synthetic organic chemistry processes or methods. Further, in the schemes described herein, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., unless otherwise specified, may also be used and are therefore included within the scope of the invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, are also within the scope of the invention. All the isomers of the compounds described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
[60] The methods and processes provided herein are as depicted in Schemes 1 to 4. In certain embodiments, when a temperature is indicated in a reaction, the temperature may be varied from about plus or minus 0.1°C, 0.5°C., 1°C., 5°C., or 10°C. Depending upon which solvent is employed in a particular reaction, the optimum temperature may vary. In conducting a reaction provided herein, neither the rate, nor the order, of addition of the reactants is critical unless otherwise indicated. Unless otherwise indicated, reactions are conducted at ambient atmospheric pressure. Unless otherwise indicated, the exact amount of reactants is not critical. In some embodiments, the amount of a reactant may be varied by about 10 mole percent or about 10% by weight. Unless otherwise indicated, the solvents used in the processes provided herein may be selected from those commercially available or otherwise known to those skilled in the art. Appropriate solvents for a given reaction are within the knowledge of the skilled person and include mixtures of solvents. The products obtained by any of the processes provided herein may be recovered by evaporation or extraction, and may be purified by standard procedures, such as distillation or recrystallization.
[61] The inventors have developed alternate synthetic routes to prepare Compound A that involves using novel intermediate that is beyond those described in U.S. Patent No.
9,598,391 and PCT International Patent Application Publication No. WO2013/124828.
[62] In one aspect, the invention provides for a method or process for the synthesis of 2- methyl-5-((2R,4S)-2-((((R)-l-(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) following the steps comprising:
a) reacting 4-oxo-4H-chromene-2-carboxylic acid (Compound 1) with (R)-l- (naphthalen- 1 -yl)ethan- 1 -amine (Compound 2) in the presence of one or more coupling catalysts (such as, but not limited to, propylphosphonic anhydride (T3P), 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HC1), Ν,Ν'- Dicyclohexylcarbodiimide (DCC), Ν,Ν'-Diisopropylcarbodiimide (DIC), 1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3 -oxide hexafluorophosphate (HATU), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU), or a combination thereof) to obtain (R)-N-(l- (naphthalen-l-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (Compound 3);
the acid-amine coupling of Compound 1 with Compound 2 to obtain Compound 3 is performed in the presence of propylphosphonic anhydride (T3P). In some aspects, the reaction can be conducted with an acid-amine coupling reagent (such as, but not limited to, propylphosphonic anhydride) with a suitable base (such as, but not limited to, triethyl amine, diisopropylethyl amine, pyridine, 4-dimethylaminopyridine (DMAP), l,8-Diazabicyclo(5.4.0)undec-7-ene (DBU), l,5-Diazabicyclo(4.3.0)non-5- ene (DBN), 2,6-di-tert-butyl pyridine) in one or more suitable solvents (such as, but not limited to, a polar aprotic solvent, a polar protic solvent, a non-polar aprotic solvent, tetrahydrofuran , dichloromethane (DCM), tetrahydrofuran (THE), 2- methyltetrahydrofuran (2-Me-THF), toluene (methylbenzene), ethyl acetate, dimethylformamide (DMF), acetonitrile (ACN), 1,4-dioxane, one or more Ethers (such as, but not limited to, dimethyl ether, diethyl ether, tertbutyl methyl ether, diisopropyl ether, di-n-propylether, methyl ethyl ether, or a combination thereof), water, or a combination thereof). In some aspects, the acid-amine coupling of Compound 1 with Compound 2 can be performed using one or more amide-formation coupling catalysts (such as, but not limited to, l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI), l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HC1), Ν,Ν'- Dicyclohexylcarbodiimide (DCC), N,N'-Diisopropylcarbodiimide (DIC), 1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3 -oxide hexafluorophosphate (HATU), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU), or a combination thereof). In some aspects, the one or more amide-formation coupling catalysts can further comprise one or more acid activators. In some aspects, the one or more acid activators includes, but 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 acid imide (HONB), HODHad, HOCt, HOEt, pyridinium p-toluenesulfonate (PPTS), p-toluenesulfonic acid (TsOH), (7-Azabenzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), (benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate) (PyBOP), AOP, benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), Bis(2-oxo-l,3- oxazolidin-3-yl)phosphinic chloride (BOP-C1), tetramethylfluoroformamidinium hexafluorophosphate (TFFH), BROP, PyBrop, N-ethoxycarbonyl-2-ethoxy-l,2- dihydroquinoline (EEDQ), l-isobutoxycarbonyl-2-isobutoxy-l,2-dihydroquinoline (IIDQ), CIP, Diphenylphosphoryl azide (DPP A), (l-Cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU®), [Ethyl cyano(hydroxyimino)acetato-02]tri-l-pyrrolidinylphosphonium hexafluorophosphate (PyOxim), 1 , 1 '-Carbonyldiimidazole (CDI), 4- Dimethylaminopyridine (DMAP), PTSA-C1, Thionyl chloride, Oxalyl chloride, Diethyl chlorophosphate, 0,0-Diethyl hydrogen phosphorodithioate, Cyanuric chloride, Cyanuric fluoride, diphenylphosphoryl azide (DPPA), Catecholborane (HBcat), or a combination thereof (the abbreviations used in this application refer to their commonly understood meanings in the field of synthetic organic chemistry); b) enantioselectively reducing of the double bond of Compound 3 by asymmetric hydrogenation to obtain the optically active (R)-N-((R)-l-(naphthalen-l-yl) ethyl)-4- oxochromane-2-carboxamide (Compound 4) using one or more optically active diphosphine ligands (such as, but not limited to, (R)-(+)-4,4'-Bis(diphenylphosphino)- 3,3'-bi(l,2-methylenedioxybenzene) [(R)- SEGPHOS® ], 4,4'- Bis(diphenylphosphino)-3,3'-bi(l,2-methylenedioxybenzene) [SEGPHOS®], (R)-(+)- 4,4'-Bis[di(3,5-xylyl)phosphino]-3,3'-bi(l,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-l,l'-(o-phenylene)diphospholane [R,R-Me-DuPhos], or a combination thereof);
the asymmetric hydrogenation to provide an enantioselective reduction of the double bond of Compound 3 to obtain the optically active Compound 4 can be performed using one or more optically active diphosphine ligands. In some aspects, the one or more optically active diphosphine ligands includes, but not limited to, (R)-(+)-4,4*- Bis(diphenylphosphino)-3,3'-bi(l,2-methylenedioxybenzene) [(R)- SEGPHOS® ], 4,4'-Bis(diphenylphosphino)-3,3'-bi(l,2-methylenedioxybenzene) [SEGPHOS®], (R)- (+)-4,4'-Bis[di(3,5-xylyl)phosphino]-3,3'-bi(l,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',6,6'- Tetramethoxy-4,4'-bis(diphenylphosphino)-3,3 '-bipyridine [((R)-P-PHOS™] , (R)- (4,4',6,6'-tetramethoxy-[l,l'-biphenyl]-2,2'-diyl)bis(bis(3,5- dimethylphenyl)phosphane) [(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]-3,5-dimethoxyphenyl]-bis(3,5-ditert-butyl-4-methoxyphenyl)phosphane [(R)-DTBM-GARPHOS™], (R)-(+)-(l,l 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)diphospholane [R,R-Me-DuPhos] , or a combination thereof. In some aspects, the one or more optically active diphosphine ligands is any phosphine ligand listed in Downing, J.H. & Smith, M.B., "Phosphorus Ligands," Comprehensive Coordination Chemistry Π. Section 1.12, pgs. 253-296 (2003), or a combination thereof. In some aspects, the one or more optically active diphosphine ligands is reacted in the presence of one or more metal complexes. In some aspects, the one or more metal complexes includes, but not limited to, Copper(II) acetate (CU(OAC)2), Palladium(II) acetate (Pd(OAc)2), Zinc acetate (Zn(OAc)2), ruthenium, rhodium metal complexes, or a combination thereof. In some aspects, the one or more metal complexes further comprises one or more phosphine ligands. In some aspects, the one or more phosphine ligands includes, but not limited to, triphenyl phosphine (PPh3), tris(2-carboxyethyl)phosphine) (TCEP), APhos, benzyldiphenylphosphine, or a combination thereof. In some aspects, the one or more phosphine ligands is present with one or more reducing agents. In some aspects, the one or more reducing agents includes, but not limited to, diethoxymethylsilane (DEMS), simple alkylsilanes (which includes, but is not limited, triethylsilane (Et3SiH), Et2SiH2)), alkylsiloxanes (which includes, but not limited to, polymethylhydrosiloxane (PMHS), DBMS, or tetramethyldisiloxane (TMDS)), phenylsilanes (which includes, but not limited to, phenylsilane (PhSiH3) or diphenylsilane)), halosilanes (which includes, but not limited to, trichlorosilane), hydrosilanes (which includes, but not limited to, tris(trimethylsilyl)silane), or a combination thereof. In some aspects, the asymmetric hydrogenation can be performed in one or more solvents (such as, but not limited to, one or more polar aprotic solvent that includes, but not limited to, tetrahydrofuran (THF), Ethers, methyl-tert-butylether (MTBE), 2-methyltetrahydrofuran (2-Me-THF), acetonitrile, toluene (methylbenzene), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), N-Methyl-2-Pyrrolidone (NMP), dichloromethane, or a combination thereof).
c) reacting Compound 4 with one or more glycols (such as, but not limited to, ethylene glycol propylene glycol, 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) in the presence of one or more nonpolar solvents (such as, but not limited to, toluene (methylbenzene), xylene, dioxane, benzene, dichloromethane (CH2C12), carbon tetrachloride (CC14), trichloromethane (CHC13), methyl tert-butyl ether (MTBE), or a combination thereof), to obtain (R)-N-((R)-l-(naphthalen-l-yl)ethyl)spiro[chromane- 4,2'-[l,3]dioxolane]-2-carboxamide (Compound 5),

the protection of Compound 4 with one or more glycols (such as, but not limited to, ethylene glycol, propylene glycol, or a combination thereof) to give Compound 5 is performed using one or more glycols (such as, but not limited to, ethylene glycol, propylene glycol, butylene glycol, 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, hydrochloric acid (HC1), sulfuric acid (H2S04), Solid acid (which can include or exclude Zeolite or resin-bound TsOH), or a combination thereof). In some aspects, the protection of Compound 4 is performed in one or more nonpolar solvents (such as, but not limited to, xylene, dioxane, benzene, dichloromethane (CH2C12), carbon tetrachloride (CC14), trichloromethane (CHC13), methyl tert-butyl ether (MTBE), toluene (methylbenzene), or a combination thereof). The inventors have recognized that the synthetic schemes they invented and which are described herein involve glycol,
preferably ethylene glycol, which is a very low-cost aldehyde protecting group which can be easily added and removed using methods. In combination with an acid-amine coupling step that can also be performed using low-cost catalysts, the synthetic schemes described herein are an economic method to obtain intermediates for synthesizing Compound A. In some aspects, variations on the synthetic scheme provided herein for the protection of the carbonyl group of Compound 4 can be performed using any carbonyl protecting group known in the art, such as, but not limited to, ketals (such as, but not limited to, acetal, thioketals (such as, but not limited to, thioacetal), or a combination thereof). Additional protecting groups may be used in accordance with standard practice, including their addition and removal, for examples, see P.G.M. Wuts, Greene’s Protective Groups in Organic Chemistry, 5th ed., John Wiley & Sons, Inc. (2014). In some aspects, 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-dimethyl sulphide complex, (Zn(OAc)2)/DEMS, or a combination thereof) to obtain (R)-l-(naphthalen-l-yl)-N-(((R)-spiro[chromane- 4,2'-[l,3]dioxolan]-2-yl)methyl)ethan-l-amine (Compound 6),

the reduction of Compound 5 to Compound 6 is performed using Vitride™ in toluene and Methyl-THF. In some aspects, reduction of Compound 5 to Compound 6 is performed using borane dimethyl sulfide complex or with (Zn(OAc)2/DEMS in the presence of one or more solvents such as, but not limited to, THF, methyl THF, toluene, ethanol, methanol, isopropyl alcohol, tert-butyl alcohol, dioxane, or a combination thereof;
e) treating Compound 6 with aqueous acidic media to obtain (R)-2-((((R)-l-(naphthalen- l-yl)ethyl)amino)methyl)chroman-4-one hydrochloride (Compound 7),
the Compound 6 is deprotected to Compound 7 using aqueous acidic media with one or more polar aprotics or one or more protic solvents. In some aspects, the aqueous acidic media with polar aprotic solvent is aqueous 6N HCI in acetone. In some aspects, the one or more polar aprotic solvents includes, but not limited to, dioxane. In some aspects, the one or more polar protic solvents includes, but 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, triethyl amine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium-bi- carbonate, sodium carbonate, potassium bi-carbonate, potassium carbonate, or a combination thereof), to obtain tert-butyl ((R)- 1 -(naphthalen- 1 -yl)ethyl)(((R)-4- oxochroman-2-yl)methyl) carbamate (Compound 8),

the free amino group of Compound 7 is protected using Boc anhydride (Di-tert-butyl dicarbonate) to obtain Compound 8 in the presence of one or more basic catalysts. In some aspects, the amino group of Compound 7 (Compound 7” free base) can also be protected with Boc without 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 aspects, the one or more basic catalysts includes, but not limited to, triethyl amine, pyridine, DMAP, DBU, DBN, tripotassium phosphate, sodium carbonate, sodium-bi-carbonate, sodium carbonate, potassium bi-carbonate, potassium carbonate, or a combination thereof. In some aspects, the one or more solvents includes, but not limited to, DCM (also referred to herein as CH2CI2), water, THF, dioxane, acetonitrile, DMF, toluene, or a combination thereof. In some aspects, the free amino group of Compound 7 can be protected using the one or more amine protecting groups (such as, but not limited to, benzyl, p- methoxybenzyl, carboxybenzoyl (cbz), or a combination thereof), in accordance with standard practice, for examples, see P.G.M. Wuts, Greene’s Protective Groups in Organic Chemistry, 5th ed., 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, Cornin’ s reagent, N-(5-Chloro-2- pyridyl)bis(trifluoromethanesulfonimide), trifluoromethanesulfonyl chloride, 4- nitrophenyl trifluoromethanesulfonate, l-(trifluoromethanesulfonyl)imidazole), or a combination thereof) to give (R)-2-(((tert-butoxycarbonyl)((R)- 1 -(naphthalen- 1 - yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate (Compound 9),

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(O) bis(dibenzylideneacetone); palladium(II)bis(triphenylphosphine) diacetate; [1,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(II)); or a combination thereof) to give methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-l-(naphthalen-l- yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound 10),
i) converting methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-l-(naphthalen-l- 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 through hydrogenation using palladium charcoal catalyst in methanolic ammonia under optimum hydrogen pressure not more than about 2.0 Kg/cm2, or through treatment with ammonium formate in the presence of palladium charcoal catalyst optionally in the presence of one or more polar solvents, wherein the one or more polar solvents includes, but not limited to, methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof;

this hydrogenation of Compound 10 to give Compound 11, is carried-out by in a hydrogenation reactor using ammonia in methanolic solution and 5 % Pd/C (SO % wet and 10 % w/w loading), 10 % Pd/C or 2 % Pd/C under heating at about 28 °C to about 34 °C in methanol or ethylacetate-methanol solvent system. This transfer hydrogenation can be performed with Pd-C catalyst using formate (10 eq) as a hydrogen source, for example, ammonium formate or sodium formate in an aqueous or organic solvent. The reduction of the double bond in Compound 10 to give Compound 11 when carried-out by in a hydrogenation reactor using ammonia in
methanolic solution the optimum hydrogen pressure is not more than about 10.0 Kg/cm2, specifically not more than about 5.0 Kg/cm2, more specifically not more than about 2.0 Kg/cm2, wherein optimum hydrogen pressure is between about 0.1 Kg/cm2 to about 2.0 Kg/cm2, preferably optimum hydrogen pressure is between about 1.0 Kg/cm2 to about 2.0 Kg/cm2. 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 at about 30 °C to about 33 °C. The reaction can be conducted in one or more suitable solvents (such as, but limited to, halogenated hydrocarbons, C6 to CM aromatic hydrocarbons, C1 to C5 alcohols, C2 to C7 esters, C4 to C7 ethers, C1 to C5 carboxylic acids, water, or a combination thereof). In some aspects, the one or more reaction solvents includes, but 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) through Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid or trimethyl silyl iodide in the presence of one or more polar solvents, wherein the one or more polar solvents includes, but not limited to, methanol, dichloromethane, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof,

the Boc-deprotection reaction of Compound 11 to give Compound 12 is carried-out by using hydrochloric acid under reflux at about 63 °C in methanol. In some aspects, the concentration of hydrochloric acid is 6 N aqueous HCI. In some aspects, Boc- deprotection can occur using AlCl3, trifluoroacetic acid in dichloromethane, or sequential treatment of trimethyl silyl iodide then methanol. In some aspects, the Boc deprotection can be performed in the presence of one or more cation scavengers. The one or more cation scavengers includes, but 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 resultant carboxylate salt into the carboxylic acid, and isolation of the pure diastereoisomer by using recrystallization technique with a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvents to give 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 includes, but not limited to, ethanol, methanol, isopropanol, or a combination thereof, and the one or more aprotic polar solvents includes, but not limited to, dichloromethane, dimethylformamide, tetrahydrofuran, or a combination thereof;

hydrolysis of Compound 12 is carried out by using sodium hydroxide under heating at about 55 °C in a methanol-tetrahydrofuran solvent system. In some aspects, hydrolysis can occur using one or more hydroxide bases (e.g., lithium hydroxide, potassium hydroxide, cesium hydroxide, or a combination thereof), or lithium chloride followed by aqueous reaction with the resultant lithium carboxylate salt into the carboxylic acid. In some aspects, isolation of diastereomerically pure Compound- A” from the crude hydrolysis product of Compound 12 is carried-out by a recrystallization technique using a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvents. In some aspects, the one or more protic polar solvents includes, but not limited to, ethanol, methanol, isopropanol, or a combination thereof. In some aspects, the one or more aprotic polar solvents
includes, but not limited to, dichloromethane, dimethylformamide, tetrahydrofuran, or a combination thereof. In some aspects, the recrystallization method involves heating the reaction mixture in a solvent, for example, above 55 °C in a mixture of a solvent- nonsolvent, and allowing the solution to slowly cool to room temperature or below whereby seed crystals of the desired compound (e.g., Compound A”) preferentially crystallize while an undesired compound (e.g., Compound 12) essentially remains in solution. Capture of the isolated substantially pure product (e.g., Compound A”), optionally followed by wash with a pre-cooled solution of the solvent-nonsolvent solution, results in substantially purified Compound 12 free of substantially free of impurities. In some aspects, isolation of diastereomerically pure Compound-A” from the crude hydrolysis product of Compound 12 is carried-out by a recrystallization technique using an ethanol:dichloromethane solvent mixture. In some aspects, the (v/v) ratio of ethanol to dichloromethane can range from 1:5 to 5:1; and
1) converting Compound- A” to its hydrochloride salt, 2-methyl-5-((2R,4S)-2-((((R)-l- (naphthalen- 1 -yl)ethyl)amino)methyl) chroman-4-yl)benzoic acid hydrochloride (Compound A) using hydrochloric acid in one or more protic polar solvents (sucn as, but not limited to, ethanol, methanol, isopropanol, or a combination thereof).

converting Compound- A” to Compound-A is carried out by using acid neutralization with hydrochloric acid. In some aspects, the hydrochloric acid is 2 N aqueous HC1.
[63] In another aspect, a method or process for the manufacture of 2-methyl-5-((2R,4S)-2- ((((R)-l-(naphthalen-l-yl)ethyl)amino)methyl) chroman-4-yl)benzoic acid (Compound
A”) from methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-l-(naphthalen-l- yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound 10), wherein the method or process involving the steps of,
a) converting methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-l-(naphthalen-l- 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 through hydrogenation using palladium charcoal catalyst in methanolic ammonia under optimum hydrogen pressure not more than about 2.0 Kg/cm2, or through treatment with ammonium formate in the presence of palladium charcoal catalyst optionally in the presence of one or more polar solvents, wherein the one or more polar solvents includes, but not limited to, methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof;

b) converting Compound 11 to methyl 2-methyl-5-((2R)-2-((((R)-l-(naphthalen-l- yl)ethyl)amino) methyl) chroman-4-yl)benzoate hydrochloride (Compound 12) through Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid or trimethyl silyl iodide in the presence of one or more polar solvents, wherein the one or more polar solvents includes, but not limited to, methanol, dichloromethane, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof;

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 resultant carboxylate salt into the carboxylic acid, and isolation of the pure diastereoisomer by using recrystallization technique with a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvents to give 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 includes, but not limited to, ethanol, methanol, isopropanol, or a combination thereof, and the one or more aprotic polar solvents includes dichloromethane, dimethylformamide, tetrahydrofuran, or a combination thereof;

[64] In another aspect, the invention provides for a method or process for the manufacture of 2-methyl-5-((2R,4S)-2-((((R)- 1 -(naphthalen- 1 -yl)ethyl)amino)methyl) chroman-4- yl)benzoic acid (Compoumd A”), wherein methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-l- (naphthalen- 1 -yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound 10) is manufactured from (R)-2-(((tert-butoxycarbonyl)((R)- 1 -(naphthalen- 1 - yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate (Compound 9), by reaction of Compound 9 with methyl 2-methyl-5-(4,4,5,5-tetramethyl-l,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,

[65] In another aspect, the invention provides for a method or process for the manufacture of 2-methyl-5-((2R,4S)-2-((((R)- 1 -(naphthalen- 1 -yl)ethyl)amino)methyl) chroman-4- yl)benzoic acid (Compoumd A”), wherein (R)-2-(((tert-butoxycarbonyl)((R)- 1 - (naphthalen- 1 -yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate (Compound 9) is manufactured from tert-butyl ((R)- 1 -(naphthalen- 1 -yl)ethyl)(((R)-4- oxochroman-2-yl)methyl) carbamate (Compound 8), by reaction of 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; Cornin’ s reagent; N-(5-Chloro-2-pyridyl)bis(trifluoromethanesulfonimide); trifluoromethanesulfonyl chloride; 4-nitrophenyl trifluoromethanesulfonate; 1- (trifluoromethanesulfonyl)imidazole), or a combination thereof),

[66] In another aspect, the invention provides for a method or process for the manufacture of 2-methyl-5-((2R,4S)-2-((((R)- 1 -(naphthalen- 1 -yl)ethyl)amino)methyl) chroman-4- yl)benzoic acid (Compoumd A”), wherein tert-butyl ((R)-l -(naphthalen- l-yl)ethyl)(((R)- 4-oxochroman-2-yl)methyl) carbamate (Compound 8) is manufactured 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,

[67] In some aspects, the invention provides for a method or process for the manufacture 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 manufactured from (R)- 1 -(naphthalen- 1 -yl)-N -(((R)-spiro[chromane-4,2'- [ 1 ,3]dioxolan] -2- yl)methyl)ethan- 1 -amine (Compound 6), by treatment of Compound 6 with aqueous hydrochloric acid,

[68] In another aspect, the invention provides for a method or process for the manufacture of 2-methyl-5-((2R,4S)-2-((((R)- 1 -(naphthalen- 1 -yl)ethyl)amino)methyl) chroman-4- yl)benzoic acid (Compoumd A”), wherein (R)-l -(naphthalen- l-yl)-N-(((R)- spiro [chromane-4,2'- [1,3] dioxolan] -2-yl)methyl)ethan- 1 -amine (Compound 6) is manufactured from (R)-N-((R)-l-(naphthalen-l-yl)ethyl)spiro[chromane-4,2'- [ 1 ,3]dioxolane]-2-carboxamide (Compound 5), by reducing the amide group of Compound 5 using one or more reducing agents (such as, but not limited to, Vitride, borane-dimethyl sulphide complex, (Zn(0 Ac)2)/DEMS , or a combination thereof);

[69] In another aspect, the invention provides for a method or process for the manufacture of 2-methyl-5-((2R,4S)-2-((((R)- 1 -(naphthalen- l-yl)ethyl)amino)methyl) chroman-4- yl)benzoic acid (Compoimd A”), wherein (R)-N-((R)-l-(naphthalen-l- yl)ethyl)spiro[chromane-4,2'-[l,3]dioxolane]-2-carboxamide (Compound 5) is manufactured from (R)-N-((R)-l-(naphthalen-l-yl) ethyl)-4-oxochromane-2-carboxamide (Compound 4), by reacting Compound 4 with one or more glycols (such as, but not limited to, ethylene glycol or propylene glycol) 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 in the presence of one or more nonpolar solvents (such as, but not limited to, toluene (methylbenzene), xylene, dioxane, benzene, dichloromethane (CH2C12), carbon tetrachloride (CC14), trichloromethane (CHC13), methyl tert-butyl ether (MTBE), or a combination thereof);

[70] In one aspect, the invention provides for a method or process for the manufacture of
2-methyl-5 -((2R,4S)-2-((((R)- 1 -(naphthalen- 1 -yl)ethyl)amino)methyl) chroman-4- yl)benzoic acid (Compound-A”), wherein (R)-N-((R)-l-(naphthalen-l-yl) ethyl)-4- oxochromane-2-carboxamide (Compound 4) is manufactured from (R)-N-(l-(naphthalen- l-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide (Compound 3), by enantioselective reduction of the double bond of Compound 3 via asymmetric hydrogenation using one or more optically active diphosphine ligands (such as (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(l,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)diphospholane [R,R-Me-DuPhos] , or a combination thereof);

[71] In one aspect, the invention provides for a method or process for the manufacture of
2-methyl-5 -((2R,4S)-2-((((R)- 1 -(naphthalen- 1 -yl)ethyl)amino)methyl) chroman-4- yl)benzoic acid (Compound- A”), wherein (R)-N-( 1 -(naphthalen- 1 -yl)ethyl)-4-oxo-4H- chromene-2-carboxamide (Compound 3) is manufactured 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 coupling catalysts (such as, but not limited to, propylphosphonic anhydride (T3P) 1 -Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HC1), Ν,Ν'-Dicyclohexylcarbodiimide (DCC), Ν,Ν'-Diisopropylcarbodiimide (DIC), 1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2-( lH-benzotriazol- 1 -yl)- 1,1,3 ,3-tetramethyluronium hexafluorophosphate (HBTU), or a combination thereof);

[72] In one aspect, the invention provides for a method or process for the converting 2- methyl-5-((2R,4S)-2-((((R)- 1 -(naphthalen- l-yl)ethyl)amino)methyl) chroman-4- yl)benzoic acid (Compound-A”) to 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l- 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),

[73] In one aspect, the invention provides for a method or process for the manufacture of
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 involving 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 (NaBH4), lithium borohydride (LiBH4), lithium aluminum hydride (LiAlH4), sodium cyanoborohydride, NaH, diisobutyl aluminum hydride, metal hydrides, tributyl tin, borane complexes (e.g., BH3-THF), or a combination 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 (such as, but not limited to, thionyl chloride, sulfonyl chlorides (such as, but not limited to, mesyl chloride, toluenesulfonyl chloride, trichloromethanesulfonic chloride, or a combination thereof), or a combination thereof,

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

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 to obtain the optically active (R)-2-((((R)-l -(naphthalen- l-yl)ethyl) amino)methyl)chroman-4-one (Compound 7”), using one more more optically active
diphosphine ligand (such as, but not limited to, (R)-(+)-4,4'-Bis(diphenylphosphino)- 3,3'-bi(l,2-methylenedioxybenzene) [(R)- SEGPHOS® ], 4,4'- Bis(diphenylphosphino)-3,3'-bi(l,2-methylenedioxybenzene) [SEGPHOS®], (R)-(+)- 4,4'-Bis[di(3,5-xylyl)phosphino]-3,3'-bi(l,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-l,l'-(o-phenylene)diphospholane [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 catalyst (such as, but not limited to, tripotassium phosphate, triethyl amine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium-bi- carbonate, sodium carbonate, potassium bi-carbonate, potassium carbonate, or combination thereof), to obtain Compound 8,

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; Cornin’ s reagent; N-(5-Chloro-2- pyridyl)bis(trifluoromethanesulfonimide); trifluoromethanesulfonyl chloride; 4- nitrophenyl trifluoromethanesulfonate; l-(trifluoromethanesulfonyl)imidazole); or a combination thereof) to give (R)-2-(((tert-butoxycarbonyl)((R)- 1 -(naphthalen- 1 - yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate (Compound 9),

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(O) bis(dibenzylideneacetone); palladium(II)bis(triphenylphosphine) diacetate; [1,V- bis(diphenylphosphino)ferrocene]dichloropalladium(II), or a combination thereof) to give methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-l-(naphthalen-l- yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound 1),

h) converting methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-l-(naphthalen-l- 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 through hydrogenation using palladium charcoal catalyst in methanolic ammonia under optimum hydrogen pressure not more than about 2.0 about Kg/cm2, or through treatment with ammonium formate in the presence of palladium charcoal catalyst optionally in the presence of one or more polar solvents, wherein the one or more polar solvents includes, but not limited to, methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof,

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) through Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid or trimethyl silyl iodide in the presence of one or more polar solvents, wherein the one or more polar solvents includes, but not limited to, methanol, dichloromethane, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof,

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 resultant carboxylate salt into the carboxylic acid, and isolation of the pure diastereoisomer by using recrystallization technique with a solvent mixture of one or more protic polar solvents and one or more aptotic polar solvents to give 2-methyl-5-((2R,4S)-2-((((R)- l-(naphthalen- 1- yl)ethyl)amino)methyl) chroman-4-yl)benzoic acid (Compound A”) wherein the one or more protic polar solvents includes, but not limited to, ethanol, methanol, isopropanol, or a combination thereof, and the one or more aprotic polar solvents includes, but not limited to, dichloromethane, dimethylformamide, tetrahydrofuran, or a combination thereof,

k) converting Compound A” to its hydrochloride salt, 2-methyl-5-((2R,4S)-2-((((R)-l- (naphthalen-l-yl)ethyl)amino)methyl) chroman-4-yl)benzoic acid hydrochloride (Compound A) using hydrochloric acid in a protic polar solvent can include or exclude: ethanol, methanol, isopropanol, or a combination thereof,

[74] In one aspect, the invention provides a method or process for the manufacture of 2- methyl-5-((2R,4S)-2-((((R)- l-(naphthalen- l-yl)ethyl)amino)methyl) chroman-4- yl)benzoic acid (Compound A”), wherein tert-butyl ((R)-l-(naphthalen-l-yl)ethyl)(((R)- 4-oxochroman-2-yl)methyl) carbamate (Compound 8) is manufactured from (R)-2-(((l- (naphthalen-l-yl)ethyl)amino)methyl)-4H-chromen-4-one (Compound 16) by following the steps involving
a) enantioselectively reducing the double bond of Compound 16 via asymmetric hydrogenation to obtain the optically active (R)-2-((((R)- 1 -(naphthalen- 1 -yl)ethyl) amino)methyl)chroman-4-one (Compound 7’) using one or more optically active diphosphine ligands (such as, but not limited to, (R)-(+)-4,4'-Bis(diphenylphosphino)- 3,3'-bi( 1 ,2-methylenedioxybenzene) [(R)- SEGPHOS® ], 4,4'- Bis(diphenylphosphino)-3,3'-bi(l,2-methylenedioxybenzene) [SEGPHOS®], (R)-(+)- 4,4'-Bis[di(3,5-xylyl)phosphino]-3,3'-bi(l,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)diphospholane [R,R-Me-DuPhos], or a combination thereof),
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, triethyl amine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium-bi- carbonate, sodium carbonate, potassium bi-carbonate, potassium carbonate, or a combination thereof), to obtain Compound 8,

[75] In one aspect, the invention provides a method or process for the manufacture of 2- methyl-5-((2R,4S)-2-((((R)- l-(naphthalen- l-yl)ethyl)amino)methyl) chroman-4- yl)benzoic acid (Compoumd A”), wherein (R)-2-((( 1 -(naphthalen- 1 - yl)ethyl)amino)methyl)-4H-chromen-4-one (Compound 16) is manufactured from 2- (chloromethyl)-4H-chromen-4-one (Compound 15) by coupling Compound 15 with (R)- l-(naphthalen-2-yl)ethan-l -amine (Compound 2) to obtain (R)-2-((( 1 -(naphthalen- 1 - yl)ethyl)amino)methyl)-4H-chramen-4-one (Compound 16) in the presence of one or more bases (such as, but not limited to, potassium carbonate, cesium carbonate, potassium iodide, or a combination thereof),

[76] In one aspect, the invention provides a method or process for the manufacture of 2- methyl-5-((2R,4S)-2-((((R)- 1 -(naphthalen- l-yl)ethyl)amino)methyl) chroman-4- yl)benzoic acid (Compound A”), wherein converting 2-(hydraxymethyl)-4H-chramen-4- one (Compound 14) to 2-(chloromethyl)-4H-chramen-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, trichloromethanesulfonic chloride, or a combination thereof), or a combination thereof),

[77] In one aspect, the invention provides a method or process for the manufacture of 2- methyl-5-((2R,4S)-2-((((R)- l-(naphthalen- l-yl)ethyl)amino)methyl) chroman-4- yl)benzoic acid (Compound A”), wherein 2-(hydraxymethyl)-4H-chramen-4-one (Compound 14) manufactured 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 (2M THF solution), lithium borohydride (LiBH4), lithium aluminum hydride (LiAlH4), or a combination thereof),

[78] In one aspect, the invention provides for a method or process for the manufacture of
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-oxochromane-2-carboxylic acid (Compound 18), the method or process comprising:
a) coupling (R)-4-oxochromane-2-carboxylic acid (Compound 18) with (R)-l- (naphthalen- 1 -yl)ethan- 1 -amine (Compound 2) in the presence of one or more coupling catalysts (such as, but not limited to, propylphosphonic anhydride (T3P) 1 -Ethyl-3 -(3 -dimethylaminopropyl)carbodiimide (EDCI), l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HC1), Ν,Ν'- Dicyclohexylcarbodiimide (DCC), Ν,Ν'-Diisopropylcarbodiimide (DIC), 1- [Bis(dimethylamino)methylene] -lH-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2-( lH-benzotriazol- 1 -yl)- 1 ,1,3,3- tetramethyluronium hexafluorophosphate (HBTU), or a combination thereof), to obtain (R)-N-(l-(naphthalen-l-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide
(Compound 4),

b) reacting Compound 4 with one or more glycols (such as, but not limited to, ethylene glycol, propylene glycol, or a combination thereof) in the presence of one or more catalysts (such as, but not limited to, p-toluenesulfonic acid (PTS A), methanesulfonic acid (MSA), trifluoroacetic acid (TFA), tosylic acid (TsOH), pyridinium p-toluenesulfonate (PPTS), orthophosphoric acid, or a combination thereof) in the presence of one or more nonpolar solvents (such as, but not limted to, toluene (methylbenzene), xylene, dioxane, benzene, dichloromethane (CH2C12), carbon tetrachloride (CC14), trichloromethane (CHC13), methyl tert- butyl ether (MTBE), or a combination thereof), to obtain (R)-N-((R)-1- (naphthalen-l-yl)ethyl)spiro[chromane-4,2'-[l,3]dioxolane]-2-carboxamide (Compound 5),
c) reducing the amide group of Compound 5 using one or more reducing agents (such as, but not limited to, Vitride, borane-dimethyl sulphide complex, (Zn(0 Ac)2)/DEMS , or a combination thereof) to obtain (R)- 1 -(naphthalen- 1 - yl)-N-(((R)-spiro[chromane-4,2'-[l,3]dioxolan]-2-yl)methyl)ethan-l-amine (Compound 6),
d) treating Compound 6 with aqueous acidic media to obtain (R)-2-((((R)-l- (naphthalen- 1 -yl)ethyl)amino)methyl)chroman-4-one hydrochloride (Compound 7),
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, triethyl amine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium-bi-carbonate, sodium carbonate, potassium bi-carbonate, potassium carbonate, or a combination thereof), to obtain tert-butyl ((R)-l- (naphthalen- 1 -yl)ethyl)(((R)-4-oxochroman-2-yl)methyl) carbamate (Compound 8),

f) reacting Compound 8 with one or more triflating agent (such as, but not limited to, N -phenyl-bis(trifluoromethanesulfonimide) ; trifluoromethanesulfonic anhydride; N-(4-tert- Butylphenyl)bis(trifluoromethanesulfonimide);
Bis(trifluoromethanesulfonyl)aniline; Cornin’ s reagent; N-(5-Chloro-2- pyridyl)bis(trifluoromethanesulfonimide); trifluoromethanesulfonyl chloride;
4-nitrophenyl trifluoromethanesulfonate; 1- (trifluoromethanesulfonyl)imidazole); or a combination thereof) to give (R)-2- (((tert-butoxycarbonyl)((R)- 1 -(naphthalen- 1 -yl)ethyl)amino)methyl)-2H- chromen-4-yl trifluoromethanesulfonate (Compound 9),
g) coupling Compound 9 with methyl 2-methyl-5-(4,4,5,5-tetramethyl-l,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(O) bis(dibenzylideneacetone), palladium(II)bis(triphenylphosphine) diacetate, [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II), or a combination thereof) to give methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-l- (naphthalen- 1 -yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound 10),
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)-l-(naphthalen-l- yl)ethyl)amino)methyl) chroman-4-yl)-2-methylbenzoate (Compound 11), wherein the conversion is carried out through hydrogenation using palladium charcoal catalyst in methanolic ammonia under optimum hydrogen pressure not more than about 2.0 Kg/cm2, or through treatment with ammonium formate in the presence of palladium charcoal catalyst optionally in the presence of one or more polar solvents, wherein the one or more polar solvents includes, but not limited to, methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof,

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) through Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid or trimethyl silyl iodide in the presence of one or more polar solvents, wherein the one or more polar solvents includes, but not limited to, methanol, dichloromethane, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof,
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 resultant carboxylate salt into the carboxylic acid, and isolation of the pure diastereoisomer by using recrystallization technique with a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvents to give 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 includes, but not limited to, ethanol, methanol, isopropanol, or a combination thereof, and the one or more aprotic polar solvents includes, but not limited to, dichloromethane, dimethylformamide, tetrahydrofuran, or a combination thereof,

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 one or more protic polar solvents (such as, but not limited to, ethanol, methanol, isopropanol, or a combination thereof),

[79] In one aspect, the invention provides a method or process for the manufacture of 2- methyl-5-((2R,4S)-2-((((R)- 1 -(naphthalen- l-yl)ethyl)amino)methyl) chroman-4- yl)benzoic acid hydrochloride (Compound A), wherein (R)-4-oxochromane-2-carboxylic acid (Compound 18) is manufactured from methyl (R)-4-oxochromane-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),

[80] In one aspect, the invention provides for a method or process for the manufacture of
2-methyl-5 -((2R,4S)-2-((((R)- 1 -(naphthalen- 1 -yl)ethyl)amino)methyl) chroman-4- yl)benzoic acid hydrochloride (Compound A), wherein methyl (R)-4-oxochromane-2- carboxylate (Compound 19) is manufactured from methyl 4-oxo-4H-chromene-2- carboxylate (Compound 13) via asymmetric hydrogenation using one or more optically active diphosphine ligands (such as, but not limited to, (R)-(+)-4,4'- Bis(diphenylphosphino)-3,3'-bi(l,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(l,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)diphospholane [R,R-Me-DuPhos], or a combination thereof),

[81] In one aspect, the invention provides for a method or process for the manufacture 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-oxochromane-2-carboxylic acid (Compound 18) is manufactured from (R)-chromane-2-carboxylic acid (Compound 17) by treating Compound 17 with, in the presence of one or more oxidizing agents (such as, but not limited to, KMn04, Mn02, tert-butyl hydroperoxide-chromium(VI)oxide, potassium peroxomonosulfate, sodium bromate, FeC13, TBAB -Copper dichloride, AIBN- Oxygen, NaC102-N-Hydroxyphthalimide, or a combination thereof) in the presence of magnesium sulphate in one or more polar solvents (such as, but not limited to, tetrahydrofuran, dichloromethane (DCM), tedtrahydrofuran (THF), 2- methyltetrahydrofuran (2-Me-THF), toluene (methylbenzene), ethyl acetate, dimethylformamide (DMF), water, acetone, or combination thereof),

[82] In one aspect, the invention provides for a method or process for the manufacture of
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-tosylhydrazineylidene) chroman-2-yl)methyl)carbamate (Compound 20), wherein the method or process involving the steps of:
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 obtain methyl 5- ((R)-2-(((tert-butoxycarbonyl)((R)-l-(naphthalen-l-yl)ethyl)amino)methyl)-2H- chromen-4-yl)-2-methylbenzoate (Compound 10),

b) converting methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-l-(naphthalen-l- 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 through hydrogenation using palladium charcoal catalyst in methanolic ammonia under optimum hydrogen pressure not more than 2.0 about Kg/cm2, or through treatment with ammonium formate in the presence of palladium charcoal catalyst optionally in the presence of one or more polar solvents, wherein the one or more polar solvents includes, but not limited to, methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, or a combination thereof,

CLAIMS
What is claimed is:
1. A method for the manufacture of 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l- yl)ethyl)amino)methyl) chroman-4-yl)benzoic acid (Compound A”) from methyl-5- ((R)-2-(((tert-butoxycarbonyl)((R)-l-(naphthalen-l-yl)ethyl)amino)methyl)-2H- chromen-4-yl)-2-methylbenzoate (Compound 10), wherein the method comprising: a. converting methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-l-(naphthalen-l- yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound 10) to methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-l-(naphthalen-l- yl)ethyl)amino)methyl) chroman-4-yl)-2-methylbenzoate (Compound 11), wherein the conversion is carried out through hydrogenation using palladium charcoal catalyst in methanolic ammonia under optimum hydrogen pressure not more than about 2.0 Kg/cm2, or through treatment with ammonium formate in the presence of a palladium charcoal catalyst, in the presence of one or more polar solvents, wherein the one or more polar solvents is selected from methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, and a combination thereof,

b. converting Compound 11 to methyl 2-methyl-5-((2R)-2-((((R)-l-(naphthalen- l-yl)ethyl)amino) methyl) chroman-4-yl)benzoate hydrochloride (Compound 12) through Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid or trimethyl silyl iodide in the presence of one or more polar solvents, wherein the one or more polar solvents is selected from methanol, dichloromethane, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, rand a combination thereof,
and
c. hydrolyzing the ester group of Compound 12 using one or more hydroxide bases followed by aqueous reaction of the resultant carboxylate salt into the carboxylic acid to give 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l- yl)ethyl)amino)methyl) chroman-4-yl)benzoic acid (Compound A”), wherein the one or more hydroxide bases is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, and a combination thereof,

2. The method of claim 1, wherein step (c) further comprises isolating the pure diastereoisomer by using a recrystallization technique with a solvent mixture of one or more protic polar solvents and one or more aptotic polar solvents, wherein the one or more protic polar solvents is selected from ethanol, methanol, isopropanol, and a combination thereof, and the one or more aprotic polar solvents is selected from dichloromethane, dimethylformamide, tetrahydrofuran, and a combination thereof.
3. The method of claim 1, wherein methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-l- (naphthalen- 1 -yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound 10) is manufactured from (R)-2-(((tert-butoxycarbonyl)((R)- 1 - (naphthalen- 1 -yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate
(Compound 9), by reaction of 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, wherein the one or more palladium catalysts is selected from palladium-tetrakis(triphenylphosphine), palladium(n)bis(triphenylphosphine) dichloride; palladium(O) bis(dibenzylideneacetone), palladium (II)bis(triphenylphosphine) diacetate, [1, 1'- bis(diphenylphosphino)ferrocene]dichloropalladium(n)), and a combination thereof,

4. The method of claim 3, wherein (R)-2-(((tert-butoxycarbonyl)((R)- l-(naphthalen- 1- yl)ethyl)amino)methyl)-2H-chromen-4-yl trifluoromethanesulfonate (Compound 9) is manufactured from tert-butyl ((R)-l -(naphthalen- l-yl)ethyl)(((R)-4-oxochroman-2- yl)methyl) carbamate (Compound 8), by reaction of Compound 8 with one or more triflating agents, wherein the one or more triflating agents is selected from N-phenyl- bis(trifluoromethanesulfonimide), trifluoromethanesulfonic anhydride, N-(4-tert- Butylphenyl)bis(trifluoromethanesulfonimide), Bis(trifluoromethanesulfonyl)aniline, Cornin’ s reagent, N-(5-Chloro-2-pyridyl)bis(trifluoromethanesulfonimide), trifluoromethanesulfonyl chloride, 4-nitrophenyl trifluoromethanesulfonate, 1- (trifluoromethanesulfonyl)imidazole)), and a combination thereof,

5. The method of claim 4, wherein tert-butyl ((R)- 1 -(naphthalen- 1 -yl)ethyl)(((R)-4- oxochroman-2-yl)methyl) carbamate (Compound 8) is manufactured 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,

6. The method of claim 5, wherein (R)-2-((((R)-l-(naphthalen-l-yl)ethyl)amino)methyl) chroman-4-one hydrochloride (Compound 7) is manufactured from (R)-l- (naphthalen-l-yl)-N-(((R)-spiro[chromane-4,2'-[l,3]dioxolan]-2-yl)methyl)ethan-l- amine (Compound 6), by treatment of Compound 6 with aqueous hydrochloric acid,

7. The method of claim 6, wherein (R)-l-(naphthalen-l-yl)-N-(((R)-spiro[chromane- 4,2'-[ 1 ,3]dioxolan] -2-yl)methyl)ethan- 1 -amine (Compound 6) is manufactured from (R)-N-((R)-l-(naphthalen-l-yl)ethyl)spiro[chromane-4,2'-[l,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 is selected from Vitride, borane-dimethyl sulphide complex, (Zn(OAc)2)/DEMS, and a combination thereof,

8. The method of claim 7, wherein (R)-N-((R)-l-(naphthalen-l-yl)ethyl)spiro[chromane- 4,2'-[l,3]dioxolane]-2-carboxamide (Compound 5) is manufactured from (R)-N-((R)- l-(naphthalen-l-yl) ethyl)-4-oxochromane-2-carboxamide (Compound 4), by reacting Compound 4 with one or more glycols in the presence of one or more catalysts in the presence of a nonpolar solvent, wherein the one or more glycols is selected from ethylene glycol, propylene glycol, and a combination thereof, and wherein the one or more catalysts is selected from p-toluenesulfonic acid (PTSA), methanesulfonic acid (MSA), trifluoroacetic acid (TFA), tosylic acid (TsOH), pyridinium p- toluenesulfonate (PPTS), orthophosphoric acid, and a combination thereof,

9. The method of claim 8, wherein (R)-N-((R)-l-(naphthalen-l-yl) ethyl)-4- oxochromane-2-carboxamide (Compound 4) is manufactured from (R)-N-(l- (naphthalen-l-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 is selected from (R)-(+)-4,4'- Bis(diphenylphosphino)-3,3'-bi(l,2-methylenedioxybenzene) [(R)- SEGPHOS® ], 4,4'-Bis(diphenylphosphino)-3,3'-bi(l,2-methylenedioxybenzene) [SEGPHOS®], (R)- (+)-4,4'-Bis[di(3,5-xylyl)phosphino]-3,3'-bi(l,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-l,l'-(o-phenylene)diphospholane [R,R-Me-DuPhos], and a combination thereof,

10. The method of claim 9, wherein (R)-N-( 1 -(naphthalen- 1 -yl)ethyl)-4-oxo-4H- chromene-2-carboxamide (Compound 3) is manufactured from 4-oxo-4H-chromene- 2-carboxylic acid (Compound 1) by reaction with (R)-l-(naphthalen-l-yl)ethan-l- amine (Compound 2) in the presence of one or more amide coupling catalysts, wherein the one or more amide coupling catalysts is selected from propylphosphonic anhydride (T3P) l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), l-Ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HC1), Ν,Ν'- Dicyclohexylcarbodiimide (DCC), Ν,Ν'-Diisopropylcarbodiimide (DIC), 1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3 -oxide hexafluorophosphate (HATU), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU), and a combination thereof,

11. The method of any of claims 1 to 10, further comprising converting 2-methyl-5- ((2R,4S)-2-((((R)- 1 -(naphthalen- 1 -yl)ethyl)amino)methyl) chroman-4-yl)benzoic acid (Compoimd A”) to 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l- yl)ethyl)amino)methyl) chroman-4-yl)benzoic acid hydrochloride (Compound A) using aqueous hydrochloric acid in a protic polar solvent,

12. A method for the manufacture of 2-methyl-5-((2R,4S)-2-((((R )-\ -(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)-l- (naphthalen- 1 -yl)ethan- 1 -amine (Compound 2) in the presence of one or more amide coupling catalysts to obtain (R)-N-(l -(naphthalen- l-yl)ethyl)-4-oxo- 4H-chromene-2-carboxamide (Compound 3), wherein the one or more amide coupling catalysts is selected from propylphosphonic anhydride (T3P), 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HC1), Ν,Ν'- Dicyclohexylcarbodiimide (DCC), Ν,Ν'-Diisopropylcarbodiimide (DIC), 1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2-( 1 H-benzotriazol- l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate (HBTU), and a combination thereof,

b. enantioselectively reducing the double bond of Compound 3 by asymmetric hydrogenation to obtain the optically active (R)-N-((R)-l-(naphthalen-l-yl) ethyl)-4-oxochromane-2-carboxamide (Compound 4) using one or more optically active diphosphine ligands, wherein the one or more optically active diphosphine ligands is selected from (R)-(+)-4,4'-Bis(diphenylphosphino)- 3,3'-bi(l,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)-l, 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,5rR)- 2,2',5,5'-Tetramethyl-l, 1 '-(o-phenylene)diphospholane [R,R-Me-DuPhos] , and a combination thereof,
c. reacting Compound 4 with one or more glycols in the presence of one or more acidic catalysts in the presence of a nonpolar solvent to obtain (R)-N-((R)-1- (naphthalen-l-yl)ethyl)spiro[chromane-4,2'-[l,3]dioxolane]-2-carboxamide (Compound 5), wherein the one or more glycols is selected from ethylene glycol, propylene glycol, and a combination thereof, and wherein the one or more acidic catalysts is selected from p-toluenesulfonic acid (PTSA), methanesulfonic acid (MSA), trifluoroacetic acid (TEA), tosylic acid (TsOH), pyridinium p-toluenesulfonate (PPTS), orthophosphoric acid, and a combination thereof,
d. reducing the amide group of Compound 5 using one or more reducing agents to obtain (R)-l-(naphthalen-l-yl)-N-(((R)-spiro[chromane-4,2'-[l,3]dioxolan]- 2-yl)methyl)ethan- 1 -amine (Compound 6), wherein the one or more reducing agents is selected from Vitride, borane -dimethyl sulphide complex, (Zn(0 Ac)2)/DEMS , and a combination thereof,

e. treating Compound 6 with aqueous acidic media to obtain (R)-2-((((R)-l- (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 obtain tert-butyl ((R)-l-(naphthalen- l-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl) carbamate (Compound 8), wherein the one or more basic catalysts is selected from tripotassium phosphate, triethyl amine, pyridine, DMAP, DBU, DBN, sodium carbonate,
sodium-bi-carbonate, sodium carbonate, potassium bi-carbonate, potassium carbonate, and a combination thereof,
g. reacting Compound 8 with one or more triflating agents to give (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 is selected from N -phenyl-bis(trifluoromethanesulfonimide) ; trifluoromethanesulfonic anhydride; N-(4-tert- Butylphenyl)bis(trifluoromethanesulfonimide);
Bis(trifluoromethanesulfonyl)aniline; Cornin’ s reagent; N-(5-Chloro-2- pyridyl)bis(trifluoromethanesulfonimide); trifluoromethanesulfonyl chloride;
4-nitrophenyl trifluoromethanesulfonate, 1- (trifluoromethanesulfonyl)imidazole)), and a combination thereof,
h. coupling Compound 9 with methyl 2-methyl-5-(4,4,5,5-tetramethyl-l,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), wherein the one or more palladium catalysts is selected from palladium- tetrakis(triphenylphosphine), palladium(II)bis(triphenylphosphine) dichloride, palladium(0) bis(dibenzylideneacetone), palladium(II)bis(triphenylphosphine) diacetate, [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and 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)-l-(naphthalen-l- yl)ethyl)amino)methyl) chroman-4-yl)-2-methylbenzoate (Compound 11), using hydrogenation,
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) through Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid or trimethyl silyl iodide in the presence of one or more polar solvents,
k. hydrolyzing the ester group of Compound 12 using one or more hydroxide bases, followed by aqueous reaction with the resultant carboxylate salt into the carboxylic acid to give 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l- yl)ethyl)amino)methyl) chroman-4-yl)benzoic acid (Compound A”), wherein the one or more hydroxide bases is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, and a combination thereof,
; and
1. 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 protic polar solvent,

13. The method of claim 12, wherein in step (i), the hydrogenation is performed with a palladium charcoal catalyst in methanolic ammonia under optimum hydrogen pressure not more than about 2.0 Kg/cm2, or through treatment with ammonium formate in the presence of palladium charcoal catalyst, in the presence of one or more polar solvents.
14. The method of claim 12, wherein step (k) further comprises isolating the pure diastereoisomer by using a recrystallization technique with a solvent mixture of one or more protic polar solvents and one or more aptotic polar solvents.
15. The method of claim 4, wherein tert-butyl ((R)-l-(naphthalen-l-yl)ethyl)(((R)-4- oxochroman-2-yl)methyl) carbamate (Compound 8) is manufactured from (R)-2-(((l- (naphthalen-l-yl)ethyl)amino)methyl)-4H-chromen-4-one (Compound 16) by the method comprising:
a. enantioselectively reducing the double bond of Compound 16 via asymmetric hydrogenation to obtain the optically active (R)-2-((((R)-l-(naphthalen-l- yl)ethyl) amino)methyl)chroman-4-one (Compound T’) using one or more optically active diphosphine ligands, wherein the one or more optically active diphosphine ligands is selected from (R)-(+)-4,4'-Bis(diphenylphosphino)- 3,3'-bi(l,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)-l, 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-l, 1 '-(o-phenylene)diphospholane [R,R-Me-DuPhos], and a combination thereof,
; 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 is selected from tripotassium phosphate, triethyl amine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium-bi-carbonate, sodium carbonate, potassium bi-carbonate, potassium carbonate, and a combination thereof,

16. The method of claim 15, wherein (R)-2-((( 1 -(naphthalen- 1 -yl)ethyl)amino)methyl)- 4H-chromen-4-one (Compound 16) is manufactured from 2-(chloromethyl)-4H- chromen-4-one (Compound 15) by coupling Compound 15 with (R)- 1 -(naphthalen-2- yl)ethan-l -amine (Compound 2) in the presence of potassium carbonate, potassium iodide or a mixture thereof,

17. The method of claim 16, wherein 2-(chloromethyl)-4H-chromen-4-one (Compound 15) is manufactured 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 is selected from mesyl chloride, tosyl chloride, and a combination thereof,

18. The method of claim 17, wherein 2-(hydroxymethyl)-4H-chromen-4-one (Compound 14) is manufactured 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 is selected from sodium borohydride, borane dimethyl sulfide (THF solution), lithium borohydride (LiBH4), lithium aluminum hydride (LiAlH4), and a combination thereof,

19. A method for the manufacture of 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 comprises:
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, the one or more reducing agents is selected from sodium borohydride (NaBH4), lithium borohydride (LiBH4), lithium aluminum hydride (LiAlH4), NaH, diisobutyl aluminum hydride, sodium cyanoborohydride, tributyl tin, BH3-THF, and a combination 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 using one or more chlorinating agents, wherein the one or more chlorinating agents is selected from thionyl chloride, one or more sulfonyl chlorides, and a combination thereof, and wherein the one or more sulfonyl chlorides is selected from mesyl chloride, toluenesulfonyl chloride, trichloromethanesulfonic chloride, and a combination thereof,

c. coupling 2-(chloromethyl)-4H-chromen-4-one (Compound 15) with (R)-l- (naphthalen-2-yl)ethan- 1 -amine (Compound 2) to obtain (R)-2-(((l- (naphthalen- 1 -yl)ethyl)amino)methyl)-4H-chromen-4-one (Compound 16) in the presence of potassium carbonate, potassium iodide or a combination thereof,
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 to obtain the optically active (R)-2-((((R)-l-(naphthalen-l- yl)ethyl) amino)methyl)chroman-4-one (Compound 7’), using one or more
optically active diphosphine ligands, wherein the one or more optically active diphosphine ligands is selected from (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)-l, 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-l, 1 '-(o-phenylene)diphospholane [R,R-Me-DuPhos], and a combination thereof,
e. reacting Compoumd 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 is selected from tripotassium phosphate, triethyl amine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium-bi-carbonate, sodium carbonate, potassium bi-carbonate, potassium carbonate, and a combination thereof,

f. reacting Compound 8 with one or more triflating agents to give (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 is selected from N -phenyl-bis(trifluoromethanesulfonimide) ; trifluoromethanesulfonic anhydride; N-(4-tert- Butylphenyl)bis(trifluoromethanesulfonimide);
Bis(trifluoromethanesulfonyl)aniline; Cornin’ s reagent; N-(5-Chloro-2- pyridyl)bis(trifluoromethanesulfonimide); trifluoromethanesulfonyl chloride;
4-nitrophenyl trifluoromethanesulfonate, 1- (trifluoromethanesulfonyl)imidazole)), and a combination thereof,

g. coupling Compound 9 with methyl 2-methyl-5-(4,4,5,5-tetramethyl-l,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), wherein the one or more palladium catalysts is selected from palladium- tetrakis(triphenylphosphine); palladium(II)bis(triphenylphosphine) dichloride; palladium(0) bis(dibenzylideneacetone); palladium(II)bis(triphenylphosphine) diacetate; [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and a combination thereof,

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)-l-(naphthalen-l- yl)ethyl)amino)methyl) chroman-4-yl)-2-methylbenzoate (Compound 11) using hydrogenation,
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) through Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid or trimethyl silyl iodide in the presence of one or more polar solvents;

j. hydrolyzing the ester group of Compound 12 using one or more hydroxide bases, followed by aqueous reaction with the resultant carboxylate salt into the carboxylic acid to give 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l- yl)ethyl)amino)methyl) chroman-4-yl)benzoic acid (Compound-A”), wherein the one or more hydroxide bases is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, and a combination thereof,

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 protic polar solvent,

20. The method of claim 19, wherein in step (h), hydrogenation is performed with palladium charcoal catalyst in methanolic ammonia under optimum hydrogen pressure not more than about 2.0 Kg/cm2, or through treatment with ammonium formate in the presence of palladium charcoal catalyst, in the presence of one or more polar solvents, wherein the one or more polar solvents is selected from methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, and a combination thereof;
21. The method of claim 19, wherein step (j) further comprises isolating the pure diastereoisomer by using a recrystallization technique with a solvent mixture of one or more protic polar solvents and one or more aptotic polar solvents, wherein the one or more protic polar solvents is selected from ethanol, methanol, isopropanol, and a combination thereof, and the one or more aprotic polar solvent is selected from dichloromethane, dimethylformamide, tetrahydrofuran, and a combination thereof.
22. A method for the manufacture of 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-oxochromane-2-carboxylic acid (Compound 18), the method comprising:
a. coupling (R)-4-oxochromane-2-carboxylic acid (Compound 18) with (R)-l- (naphthalen- 1 -yl)ethan- 1 -amine (Compound 2) in the presence of one or more amide-coupling catalysts to obtain (R)-N-(l-(naphthalen-l-yl)ethyl)-4-oxo- 4H-chromene-2-carboxamide (Compound 4), wherein the one or more amidecoupling catalysts is selected from propylphosphonic anhydride (T3P) 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HC1), Ν,Ν'- Dicyclohexylcarbodiimide (DCC), Ν,Ν'-Diisopropylcarbodiimide (DIC), 1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2-(lH-benzotriazol-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate (HBTU), and a combination thereof,

b. reacting Compound 4 with one or more glycols in the presence of one or more catalysts in the presence of a nonpolar solvent to obtain (R)-N-((R)-1- (naphthalen-l-yl)ethyl)spiro[chromane-4,2'-[l,3]dioxolane]-2-carboxamide (Compound 5), wherein the one or more glycols is selected from ethylene glycol, propylene glycol, and a combination thereof, and wherein the one or more catalysts is p-toluenesulfonic acid (PTSA), methanesulfonic acid (MSA), trifluoroacetic acid (TEA), tosylic acid (TsOH), pyridinium p-toluenesulfonate (PPTS), orthophosphoric acid, and a combination thereof,
c. reducing the amide group of Compound 5 using one or more reducing agent to obtain (R)-l-(naphthalen-l-yl)-N-(((R)-spiro[chromane-4,2'-[l,3]dioxolan]-2- yl)methyl)ethan- 1 -amine (Compound 6), wherein the one or more reducing agent is selected from Vitride, borane-dimethyl sulphide complex, (Zn(0 Ac)2)/DEMS , and a combination thereof,
d. treating Compound 6 with aqueous acidic media to obtain (R)-2-((((R)-l- (naphthalen- 1 -yl)ethyl)amino)methyl)chroman-4-one hydrochloride (Compound 7),

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)-l-(naphthalen- l-yl)ethyl)(((R)-4-oxochroman-2-yl)methyl) carbamate (Compound 8), wherein the one or more basic catalysts is selected from tripotassium phosphate, triethyl amine, pyridine, DMAP, DBU, DBN, sodium carbonate, sodium-bi-carbonate, sodium carbonate, potassium bi-carbonate, potassium carbonate, and a combination thereof,
f. reacting Compound 8 with one or more triflating agents to give (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 is selected from N-phenyl-bis(trifluoromethanesulfonimide), trifluoromethanesulfonic anhydride, N-(4-tert- Butylphenyl)bis(trifluoromethanesulfonimide),
Bis(trifluoromethanesulfonyl)aniline, Cornin’ s reagent, N-(5-Chloro-2- pyridyl)bis(trifluoromethanesulfonimide), trifluoromethanesulfonyl chloride,
4-nitrophenyl trifluoromethanesulfonate, 1- (trifluoromethanesulfonyl)imidazole)), and a combination thereof,

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 give 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 is selected from palladium- tetrakis(triphenylphosphine), palladium(II)bis(triphenylphosphine) dichloride, palladium(0) bis(dibenzylideneacetone), palladium(II)bis(triphenylphosphine) diacetate, [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and a combination thereof,
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)-l-(naphthalen-l- yl)ethyl)amino)methyl) chroman-4-yl)-2-methylbenzoate (Compound 11), wherein, the conversion is carried out through hydrogenation,
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) through Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid or trimethyl silyl iodide in the presence of one or more polar solvents,

j. hydrolyzing the ester group of Compound 12 using one or more hydroxide bases, followed by aqueous reaction with the resultant carboxylate salt into the carboxylic acid to give 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l- yl)ethyl)amino)methyl) chroman-4-yl)benzoic acid (Compound A”), wherein the one or more hydroxide bases is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, and a combination thereof,
; 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 protic polar solvent,

23. The method of claim 22, wherein in step (h), hydrogenation is performed using palladium charcoal catalyst in methanolic ammonia under optimum hydrogen pressure not more than about 2.0 Kg/cm2, or through treatment with ammonium formate in the presence of palladium charcoal catalyst, in the presence of one or more polar solvents, wherein the one or more polar solvents is selected from methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, and a combination thereof.
24. The method of claim 22, wherein step (j) further comprises isolating the pure diastereoisomer by using recrystallization technique with a solvent mixture of one or more protic polar solvents and one or more aprotic polar solvent, wherein the one or more protic polar solvents is selected from ethanol, methanol, isopropanol, and a combination thereof, and the one or more aprotic polar solvent is selected from dichloromethane, dimethylformamide, tetrahydrofuran, and a combination thereof.
25. The method of claim 22, wherein (R)-4-oxochromane-2-carboxylic acid (Compound 18) is manufactured from methyl (R)-4-oxochromane-2-carboxylate (Compound 19) using base hydrolysis in a polar solvent using one or more bases, wherein the one or more bases is selected from sodium hydroxide, potassium hydroxide, cesium hydroxide, and a combination thereof,

26. The method of claim 22, wherein methyl (R)-4-oxochromane-2-carboxylate (Compound 19) is manufactured 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 is selected from (R)-(+)-4,4'-Bis(diphenylphosphino)-3,3'-bi(l,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(l,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-l,l'-(o-phenylene)diphospholane [R,R-Me-DuPhos], and a combination thereof,

27. The method of claim 22, wherein (R)-4-oxochromane-2-carboxylic acid (Compound 18) is manufactured from (R)-chromane-2 -carboxylic acid (Compound 17) by treating Compound 17 with one or more oxidizing agents in the presence of magnesium sulphate in a polar solvent, wherein the one or more oxidizing agents is selected from KMn04, Mn02, tert-butyl hydroperoxide-Chromium(VI)oxide, potassium peroxomonosulfate, sodium bromate, FeC13, TBAB-Copper dichloride, AIBN- Oxygen, NaC102-N-Hydroxyphthalimide, and a combination thereof,

28. A method for the manufacture of 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l- 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-tosylhydrazineylidene) chroman-2-yl)methyl)carbamate (Compound 20), the method comprising:
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 obtain methyl 5-((R)-2-(((tert-butoxycarbonyl)((R)-l-(naphthalen-l- yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound 10),
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)-l-(naphthalen-l- yl)ethyl)amino)methyl) chroman-4-yl)-2-methylbenzoate (Compound- 11), wherein, the conversion is carried out using hydrogenation,
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 Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid or trimethyl silyl iodide in the presence of one or more polar solvents,

d. hydrolyzing the ester group of Compound 12, using one or more hydroxide bases, followed by aqueous reaction with the resultant carboxylate salt into the carboxylic acid to give 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l- yl)ethyl)amino)methyl) chroman-4-yl)benzoic acid (Compound A”), wherein the one or more hydroxide bases is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, and a combination thereof,
; and
e. 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 protic polar solvent,

29. The method of claim 28, wherein in step (b), hydrogen is performed using palladium charcoal catalyst in methanolic ammonia under optimum hydrogen pressure not more than about 2.0 Kg/cm2, or through treatment with ammonium formate in the presence of palladium charcoal catalyst, in the presence of one or more polar solvents, wherein the one or more polar solvents is selected from methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, and a combination thereof.
30. The method of claim 28, wherein step (d) further comprises isolating the pure diastereoisomer by using recrystallization technique with a solvent mixture of one or more protic polar solvent and one or more aprotic polar solvent, wherein the one or more protic polar solvents is selected from ethanol, methanol, isopropanol, and a combination thereof, and the one or more aprotic polar solvents is selected from dichloromethane, dimethylformamide, tetrahydrofuran, and a combination thereof. 31. The method of claim 28, wherein tert-butyl (E)-(l -(naphthalen- l-yl)ethyl)((4-(2- tosylhydrazineylidene)chroman-2-yl)methyl)carbamate (Compound 20) is manufactured from tert-butyl ( 1 -(naphthalen- 1 -yl)ethyl)((4-oxochroman-2- yl)methyl)carbamate (Compound 8) by reacting Compound 8 with one or more sulfonohydrazides, wherein the one or more sulfonohydrazides is selected from 4- methylbenzenesulfonohydrazide 4-ethylbenzenesulfonohydrazide, thiophene-2- sulfonohydrazide, naphthalene-2-sulfonohydrazide, and a combination thereof,

32. A method for the manufacture of 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), the method comprising:
a. reacting 4-oxo-4H-chromene-2-carboxylic acid (Compound 1) with (R)-l- (naphthalen- 1 -yl)ethan- 1 -amine (Compound 2) in the presence of one or more amide coupling catalysts to obtain (R)-N-(l -(naphthalen- l-yl)ethyl)-4-oxo- 4H-chromene-2-carboxamide (Compound 3), wherein the one or more amide coupling catalysts is selected from propylphosphonic anhydride (T3P), 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HC1), Ν,Ν'- Dicyclohexylcarbodiimide (DCC), Ν,Ν'-Diisopropylcarbodiimide (DIC), 1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2-( 1 H-benzotriazol- l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate (HBTU), and a combination thereof, b. enantioselectively reducing the double bond of Compound 3 by asymmetric hydrogenation to obtain the optically active (R)-N-((R)-l-(naphthalen-l-yl) ethyl)-4-oxochromane-2-carboxamide (Compound 4) using one or more optically active diphosphine ligands, wherein the one or more optically active diphosphine ligands is selected from (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)-l, 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-l, 1 '-(o-phenylene)diphospholane [R,R-Me-DuPhos], and a combination thereof,
c. reacting Compound 4 with one or more glycols in the presence of one or more catalysts in the presence of a nonpolar solvent to obtain (R)-N-((R)-1- (naphthalen-l-yl)ethyl)spiro[chromane-4,2'-[l,3]dioxolane]-2-carboxamide
(Compound 5), wherein the one or more glycols is selected from ethylene glycol, propylene glycol, and a combination thereof, and the one or more catalysts is selected from p-toluenesulfonic acid (PTSA), methanesulfonic acid (MSA), trifluoroacetic acid (TFA), tosylic acid (TsOH), pyridinium p- toluenesulfonate (PPTS), orthophosphoric acid, and a combination thereof,
d. reducing the amide group of Compound 5 using one or more reducing agents to obtain (R)-l-(naphthalen-l-yl)-N-(((R)-spiro[chromane-4,2'-[l,3]dioxolan]- 2-yl)methyl)ethan-l -amine (Compound 6), wherein the one or more reducing agents is selected from Vitride, borane -dimethyl sulphide complex, (Zn(OAc)2)/DEMS, and a combination thereof,
e. treating Compound 6 with aqueous hydrochloric acid to obtain (R)-2-((((R)-l- (naphthalen- 1 -yl)ethyl)amino)methyl)chroman-4-one hydrochloride (Compound 7),

f. reacting Compound 7 with Boc anhydride (Di-tert-butyl dicarbonate) and tripotassium phosphate to obtain tert-butyl ((R)- 1 -(naphthalen- 1 - yl)ethyl)(((R)-4-oxochroman-2-yl)methyl) carbamate (Compound 8),
g. reacting (tert-butyl ( 1 -(naphthalen- 1 -yl)ethyl)((4-oxochroman-2- yl)methyl)carbamate (Compound 8) with one or more sulfonohydrazides to give tert-butyl (E)-( 1 -(naphthalen- 1 -yl)ethyl)((4-(2- tosylhydrazineylidene)chroman-2-yl)methyl)carbamate (Compound 20), wherein the one or more sulfonohydrazides is selected from 4- methylbenzenesulfonohydrazide 4-ethylbenzenesulfonohydrazide, thiophene- 2-sulfonohydrazide, naphthalene-2-sulfonohydrazide, and a combination thereof,
h. coupling tert-butyl (E)-( 1 -(naphthalen- 1 -yl)ethyl)((4-(2- tosylhydrazineylidene)chroman-2-yl)methyl)carbamate (Compound 20) with methyl 5-bromo-2-methylbenzoate in the presence of one or more triphosphine ligands to obtain methyl 5-((R)-2-(((tert-butoxycarbonyl)((R)-l- (naphthalen- 1 -yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound 10), wherein the one or more triphosphine ligands is selected from 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 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)-l-(naphthalen-l- yl)ethyl)amino)methyl) chroman-4-yl)-2-methylbenzoate (Compound 11), wherein the conversion is carried out through hydrogenation,
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) through Boc-deprotection reaction using aqueous hydrochloric acid, trifluoroacetic acid or trimethyl silyl iodide in the presence of one or more polar solvents,

k. hydrolyzing the ester group of Compound 12 using one or more hydroxide bases, followed by aqueous reaction with the resultant carboxylate salt into the carboxylic acid to give 2-methyl-5-((2R,4S)-2-((((R)-l-(naphthalen-l- yl)ethyl)amino)methyl) chroman-4-yl)benzoic acid (Compound A”), wherein the one or more hydroxide bases is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium chloride, and a combination thereof,

; and
1. 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 protic polar solvent,

33. The method of claim 32, wherein in step (i), hydrogenation is performed using palladium charcoal catalyst in methanolic ammonia under optimum hydrogen pressure not more than about 2.0 Kg/cm2, or through treatment with ammonium formate in the presence of palladium charcoal catalyst, in the presence of one more polar solvents, wherein the one or more polar solvents is selected from methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, dioxane, and a combination thereof.
34. The method of claim 32, wherein in step (k) further comprises isolating the pure diastereoisomer by using recrystallization technique with 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 is selected from ethanol, methanol, isopropanol, and a combination thereof, and the one or more aprotic polar solvents is selected from dichloromethane, dimethylformamide, tetrahydrofuran, and a combination thereof.
35. A compound selected from (R)-N -(1 -(naphthalen- 1 -yl)ethyl)-4-oxo-4H-chromene-2- carboxamide (Compound 3), (R)-N-((R)-l-(naphthalen-l-yl) ethyl)-4-oxochromane- 2-carboxamide (Compound 4), (R)-N-((R)-l-(naphthalen-l-yl)ethyl)spiro[chromane- 4,2'-[l,3]dioxolane]-2-carboxamide (Compound 5), (R)-l-(naphthalen-l-yl)-N-(((R)- spiro[chromane-4,2'-[l,3]dioxolan]-2-yl)methyl)ethan-l-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-(((l -(naphthalen- l-yl)ethyl)amino)methyl)-4H-chromen- 4-one (Compound 16)