Processes and intermediates for the preparation of 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethenone

A process for preparing a co-crystal of compound of the formula:

• comprising the steps of:
• i.) Sequential treatment of (R)-2-bromophenylalanine with a reducing agent and iodine;
• and subsequent treatment with a mild mineral base and an alkyl carbonate to obtain (4R)-4-[(2-bromophenyl)methyl] oxazolidin-2-one;
• ii.) Treatment of (4R)-4-[(2-bromophenyl)methyl] oxazolidin-2-one with a sodium arylsulfinate and acetaldehyde to obtain (4R)-3-[(1S)-1-(arylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl] oxazolidin-2-one;
• iii.) Optionally crystallizing the (4R)-3-[(1S)-1-(arylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl] oxazolidin-2-one;
• iv.) Optionally verifying the stereochemistry of (4R)-3-[(1S)-1-(arylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl] oxazolidin-2-one by single crystal X-ray analysis;
• v.) Pictet-Spengler cyclization of (4R)-3-[(1S)-1-(arylsulfonyl)ethyl]-4-[(2-bromophenyl)methyl] oxazolidin-2-one with a transition metal halide, to obtain (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo [3,4-b] isoquinolin-3-one;
• vi.) Optionally crystallizing the (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo [3,4-b] isoquinolin-3-one;
• vii.) Optionally verifying the stereochemistry of (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo [3,4-b] isoquinolin-3-one by single crystal X-ray analysis;
• viii.) Heck coupling of (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydro-3H-oxazolo [3,4-b] isoquinolin-3-one with 2-methyl-3-buten-2-ol to obtain (E)-4-((1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbut-3-en-2-ol;
• ix.) Optionally crystallizing the (E)-4-((1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbut-3-en-2-ol;
• x.) Reduction of (E)-4-((1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methylbut-3-en-2-ol under hydrogenation conditions to obtain 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol;
• xi.) Optionally crystallizing 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol;
• xii.) Coupling of 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methylbutan-2-ol with 2,6-dichlorophenylacetic acid in the presence of a coupling agent for amide synthesis and a non-nucleophilic organic base to obtain 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone;
• xiii.) Optionally crystallizing 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone;
• and
• xiv.) Treating 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone with 4-hydroxybenzoic acid to obtain a co-crystal of 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone with 4-hydroxybenzoic acid.