Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related thereto
AssigneeArena Phamaceuticals, Inc.
InventorsUlrich Weigl, Frank Porstmann, Christoph Straessler, Lars Ulmer, Ulf Koetz
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Abstract
The present invention provides processes, methods and intermediates for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, salts, hydrates and crystal forms thereof which are useful as serotonin (5-HT) receptor agonists for the treatment of, for example, central nervous system disorders such as obesity.
Claims29
A method of resolving a mixture of compounds of Formula (Ia) and (Ib):
- comprising:
- contacting said mixture of compounds with L-(+)-tartaric acid in the presence of a solvent comprising acetone to form L-(+)-tartaric acid salts of said compounds;
- precipitating the L-(+)-tartaric acid salt of said compound of Formula (Ia), wherein the L-(+)-tartaric acid salt of said compound of Formula (Ia) has an enantiomeric excess of about 90% or greater.
A method of resolving a mixture of compounds of Formula (Ia) and (Ib):
- comprising:
- dissolving a mixture of the L-(+)-tartaric acid salts of said compounds of Formula (Ia) and (Ib), wherein the mixture is enriched with the L-(+)-tartaric acid salt of said compound of Formula (Ia), in a solution comprising acetone and water at a temperature of about 45° C. to about 60° C. to form a solution;
- cooling said solution to a temperature of about −5° C. to about 10° C.;
- and
- precipitating the L-(+)-tartaric acid salt of said compound of Formula (Ia), wherein the L-(+)-tartaric acid salt of said compound of Formula (Ia) has an enantiomeric excess of about 90% or greater.
A method for preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl hemihydrate of Formula (II):
- comprising the steps:
- neutralizing 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzoazepinium hemi tartrate of the formula:
- with potassium carbonate in the presence of water and ethyl acetate to form a biphasic liquid mixture consisting essentially of an aqueous phase and an ethyl acetate phase comprising (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine of Formula (Ia):
- separating said ethyl acetate phase of said biphasic liquid mixture from the aqueous phase of said biphasic liquid mixture;
- and
- contacting said ethyl acetate phase with HCl in the presence of water to form (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl hemihydrate.
A method for preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl hemihydrate of Formula (II):
- comprising the steps:
- forming a liquid mixture consisting essentially of ethyl acetate phase and (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine of Formula (Ia):
- contacting said liquid mixture with HCl in the presence of water to form an HCl salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, wherein the ratio of water to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is at least 1 to 2;
- and
- crystallizing said HCl salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine to form (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl hemihydrate.
Dependencies are inferred from the claim text.