Methods, processes and intermediates for preparing chroman compounds

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 (Compound A″) from methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound 10), wherein the method comprising:

• a. converting methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound 10) to methyl 5-((2R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)-2-methylbenzoate (Compound 11), wherein the conversion is 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)-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 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)-1-(naphthalen-1-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,