Processes for preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates thereof
AssigneeArena Pharmaceuticals, Inc.
InventorsTawfik Gharbaoui, Sagun K. Tandel, You-An Ma, Marlon Carlos, John Robert Fritch
Life of this patent
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Abstract
The present invention provides processes and intermediates for the preparation of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and salts thereof which are useful as serotonin-2C (5-HT2C) receptor agonists for the treatment of, for example, obesity.
Claims66
A process for preparing an amide compound of Formula 1-3:
- comprising reacting a phenylacetic acid derivative compound of Formula 1-1:
- or salt thereof, wherein Lg is a leaving group,
- with an amine compound of Formula 1-2:
- or salt thereof, in the presence of a coupling reagent to afford said amide compound of Formula 1-3.
A process for preparing an amide compound of Formula 1-3:
- comprising reacting, in a solvent comprising toluene and at elevated temperature, a phenylacetic acid derivative compound of Formula 1-1:
- or salt thereof, wherein Lg is OH, with an amine compound of Formula 1-2:
- or salt thereof, in the presence of at least one boron-containing acid to afford said amide compound of Formula 1-3.
A process for preparing an amide compound of Formula 1-3:
- comprising reacting, in a solvent comprising isopropyl alcohol and at about room temperature, a phenylacetic acid derivative compound of Formula 1-1:
- or salt thereof, wherein Lg is OH, with an amine compound of Formula 1-2:
- or salt thereof, in the presence of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride to afford said amide compound of Formula 1-3.
A process for preparing an amide compound of Formula 1-3:
- comprising reacting, in an alcohol solvent and optionally in the presence of an acid catalyst, a phenylacetic acid derivative compound of Formula 1-1:
- or salt thereof, wherein Lg is OH, with an amine compound of Formula 1-2:
- or salt thereof, in the presence of 2,2-dimethoxypropane to afford said amide compound of Formula 1-3.
A process for preparing an amino alcohol compound of Formula 2-1:
- or salt thereof, comprising reacting an amide compound of Formula 1-3:
- with a reducing agent to afford said amino alcohol compound of Formula 2-1, or salt thereof.
A process for preparing an amino alcohol compound of Formula 2-1:
- or salt thereof, comprising:
- a) reacting a phenylacetic acid derivative compound of Formula 1-1:
- or salt thereof, wherein Lg is a leaving group, with an amine compound of Formula 1-2:
- or salt thereof, in the presence of a coupling reagent to afford an amide compound of Formula 1-3 and optionally a dihydrooxazole compound of Formula 1-4, or salt thereof:
- and
- b) reacting said amide compound of Formula 1-3 and optionally said dihydrooxazole compound of Formula 1-4, or salt thereof, with a reducing agent to afford said amino alcohol compound of Formula 2-1, or salt thereof.
A compound of Formula 1-3:
A compound of Formula 1-4:
- or salt thereof.
A composition comprising a compound of Formula 1-3 and a compound of Formula 1-4, or salt thereof:
A process for preparing a compound of Formula 3-5:
- comprising:
- a) reacting a phenylacetic acid derivative compound of Formula 1-1:
- or salt thereof, wherein Lg is a leaving group, with an amine compound of Formula 1-2:
- or salt thereof, in the presence of a coupling reagent to afford an amide compound of Formula 1-3 and optionally a dihydrooxazole compound of Formula 1-4, or salt thereof:
- b) reacting said amide compound of Formula 1-3 and optionally said dihydrooxazole compound of Formula 1-4, or salt thereof, with a reducing agent to afford an amino alcohol compound of Formula 2-1:
- or salt thereof;
- c) reacting said amino alcohol compound of Formula 2-1, or salt thereof, with a chlorinating reagent to afford a dichloro compound of Formula 3-1:
- or salt thereof;
- d) reacting said dichloro compound of Formula 3-1 with a cyclizing reagent to afford a 3-benzazepine compound of Formula 3-2:
- e) contacting said 3-benzazepine compound of Formula 3-2 with L-(+)-tartaric acid to afford a tartrate salt of Formula 3-3:
- f) reacting said tartrate salt of Formula 3-3 with a base to afford the optically active compound of Formula 3-4:
- and
- g) reacting said optically active compound of Formula 3-4 with HCl to afford said compound of Formula 3-5.
Dependencies are inferred from the claim text.