US 12,421,204 B2
Process for preparing chroman compounds
Rajender Kumar Kamboj, Pune (IN); Shaji George Kochumalayil, Bangalore (IN); Spinvin Venugopal, Kochi (IN); Kamlesh Jyotindra Padiya, Pune (IN); Prabakaran Kamalakannan, Pune (IN); Kumar Ram Naik, Pune (IN); Sachin Subhash Ingawale, Pune (IN); Bhavani Shankar Rajesh, Pune (IN); and Rajendra Ganpati Powar, Pune (IN)
Assigned to LUPIN LIMITED, Mumbai (IN)
Appl. No. 17/778,282
Filed by LUPIN LIMITED, Mumbai (IN)
PCT Filed Nov. 18, 2020, PCT No. PCT/IN2020/050965
§ 371(c)(1), (2) Date May 19, 2022,
PCT Pub. No. WO2021/100059, PCT Pub. Date May 27, 2021.
Claims priority of application No. 201921047127 (IN), filed on Nov. 19, 2019.
Prior Publication US 2023/0025246 A1, Jan. 26, 2023
Int. Cl. C07D 311/58 (2006.01)
CPC C07D 311/58 (2013.01) [C07B 2200/13 (2013.01)] 10 Claims
OG exemplary drawing
 
1. 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),

OG Complex Work Unit Chemistry
wherein the synthesis includes the steps of:
a) reducing methyl 5-((R)-2-(((tert-butoxycarbonyl) ((R)-1-(naphthalen-1-yl) ethyl) amino) methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound-1) using Pd/C and ammonium formate to give methyl 5-((2R)-2-(((tert-butoxycarbonyl) ((R)-1-(naphthalen-1-yl) ethyl) amino) methyl) chroman-4-yl)-2-methylbenzoate (Compound-2)

OG Complex Work Unit Chemistry
b) carrying out a Boc-deprotection reaction of Compound-2 to give the corresponding amino methyl 2-methyl-5-((2R)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino) methyl) chroman-4-yl) benzoate hydrochloride (Compound-3)

OG Complex Work Unit Chemistry
c) hydrolyzing the ester group of Compound-3 and isolating the pure diastereoisomer by using recrystallization to give 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl) ethyl) amino) methyl) chroman-4-yl) benzoic acid (Compound-4)

OG Complex Work Unit Chemistry
and
d) converting Compound-4 to its hydrochloride salt

OG Complex Work Unit Chemistry
and further comprising a method for the manufacture of methyl 5-((R)-2-(((tert-butoxycarbonyl) ((R)-1-(naphthalen-1-yl) ethyl) amino) methyl)-2/-chromen-4-yl)-2-methylbenzoate (Compound-1) which comprises:
A) reducing the amide group of (R)-N-((R)-1-(naphthalen-1-yl) ethyl) chroman-2-carboxamide (Compound-5) using sodium bis(2-methoxyethoxy) aluminium hydride, followed by acid treatment, to give (R)-N-((R)-chroman-2-ylmethyl)-1-(naphthalen-1-yl) ethanamine hydrochloride (Compound-6)

OG Complex Work Unit Chemistry
B) protecting the free amino group of Compound-6 to give tert-butyl ((R)-chroman-2-ylmethyl) ((R)-1-(naphthalen-1-yl) ethyl) carbamate (Compound-7)

OG Complex Work Unit Chemistry
C) oxidizing Compound-7 to give tert-butyl ((R)-1-(naphthalen-1-yl) ethyl) (((R)-4-oxochroman-2-yl) methyl) carbamate (Compound-8)

OG Complex Work Unit Chemistry
D) reacting Compound-8 with a triflating agent to give (R)-2-(((tert-butoxycarbonyl) ((R)-1-(naphthalen-1-yl) ethyl) amino) methyl)-2H-chromen-4-yl trifluoromethanesulfonate (Compound-9)

OG Complex Work Unit Chemistry
and
E) coupling of Compound-9 with methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate to give methyl5-((R)-2-(((tert-butoxycarbonyl) ((R)-1-(naphthalen-1-yl) ethyl) amino) methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound-1)

OG Complex Work Unit Chemistry