US 12,454,512 B2
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
Kevin Paul Cole, Indianapolis, IN (US); Neil John Kallman, Indianapolis, IN (US); and Nicholas Andrew Magnus, Carmel, IN (US)
Assigned to ELI LILLY AND COMPANY, Indianapolis, IN (US)
Appl. No. 17/620,198
Filed by Eli Lilly and Company, Indianapolis, IN (US)
PCT Filed Jun. 11, 2020, PCT No. PCT/US2020/037186
§ 371(c)(1), (2) Date Dec. 17, 2021,
PCT Pub. No. WO2020/257043, PCT Pub. Date Dec. 24, 2020.
Claims priority of provisional application 62/862,805, filed on Jun. 18, 2019.
Prior Publication US 2022/0242826 A1, Aug. 4, 2022
Int. Cl. C07D 217/16 (2006.01)
CPC C07D 217/16 (2013.01) 9 Claims
 
1. A process for preparing a co-crystal of compound of the formula:

OG Complex Work Unit Chemistry
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.