4-Amino-N-1-azabicyclo[2.2.2]oct-3-yl-5-chloro-2-methoxybenzamide hydrochloride

Originator

Zacopride hydrochloride,ZYF Pharm Chemical

Uses

Zacopride is a highly potent SR-3 antagonist and SR-4 agonist. 5-HT3 receptor antagonist. Activates IK1 channel.

Uses

Anti-emetic; stimulant (peristaltic).

Definition

ChEBI: 4-amino-N-(1-azabicyclo[2.2.2]octan-3-yl)-5-chloro-2-methoxybenzamide is a member of benzamides.

Manufacturing Process

4-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide, fumarate [1:1]:
In a closed system equipped with an oil bubbler, 30 ml of tetrahydrofuran were added to a mixture of 4-amino-5-chloro-2-methoxybenzoic acid, 2.02 g (0.010 mole) and 1,1'-carbonyldiimidazole, 1.62 g (0.010 mole) with stirring. When evolution of carbon dioxide ceased, nitrogen was bubbled through the reaction mixture for 1 hr. A solution of 3-aminoquinuclidine, 1.26 g (0.010 mole) in 10 ml tetrahydrofuran was added dropwise to the stirred reaction mixture and stirring at room temperature continued for 3 hrs. TLC analysis (3% conc. ammonium hydroxide solution in methanol) showed some product formation. The mixture was heated at reflux temperature for 18 hours and then concentraded to an oil. TLC analysis showed the presence of the product, imidazole and 3-aminoquinuclidine. The oil was dissolved in methylene chloride (75 ml) and washed twice with 50 ml portions of aqueous sodium bicarbonate solution. The methylene chloride layer was dried over anhydrous magnesium sulfate and concentrated to yield 2.0 g (67%) of a glassy amorphous solid, the free base of the title compound.
In another reaction on a 0.020 mole scale, 5.18 g (83.8%) of the product as the free base was obtained.
The products were combined, dissolved in methanol (20 ml) and the solution and treated with a solution of fumaric acid (2.73 g) in methanol (50 ml). Absolute ether was added to precipitate the salt which was collected by filtration and recrystallized from methanol-water (200:20) with isopropyl ether added to the point of incipient cloudiness. The recrystallized salt (5.38 g) melted at 223°-225°C.
4-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide, hydrochloride, hydrate (1:1:1):
To an isopropyl alcohol solution of the above free base of the title compound is added in equal molar amount of 37% (conc.) hydrochloric acid. A salt is separated by addition of acetone followed by filtration which is recrystallized from acetone-water to give the title compound, MP: 158°-160°C.

Therapeutic Function

Antiemetic, Peristaltic stimulant

Biological Activity

Highly potent 5-HT 3 receptor antagonist (K i = 0.38 nM) and 5-HT 4 receptor agonist (K i = 373 nM). Antiemetic and anxiolytic following systemic administration in vivo .