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US 7,582,753 B2Granted
Process for the preparation of benzotriazepine derivatives
AssigneeJanssenPharmaceutica, NV
InventorsAhmed F. Abdel-Magid, Luigi Anzalone, Judith Cohen, Steven Mehrman, Frank Villani
Life of this patent
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Abstract
The present invention is directed to a novel process for the preparation of benzo[e][1,2,4]triazepin-2-one derivatives, useful in the preparation of gastrin and cholecystokinin receptor ligands.
Claims3
A process for the preparation of a compound of formula (Is)
- reacting (2-amino-phenyl)-cyclohexyl-methanone with phosgene, diphosgene or triphosgene;
- in the presence of an organic base;
- in an aprotic organic solvent;
- to yield cyclohexyl-(2-isocyanato-phenyl)-methanone;
- reacting the cyclohexyl-(2-isocyanato-phenyl)-methanone with ethyl hydrazine acetate hydrochloride;
- in the presence of an aprotic organic base;
- in an organic solvent;
- to yield [1-[[[2-(cyclohexylcarbonyl)-phenyl]-amino]-carbonyl]-hydrazino]-acetic acid ethyl ester;
- reacting the [1-[[[2-(cyclohexylcarbonyl)-phenyl]-amino]-carbonyl]-hydrazino]-acetic acid ethyl ester with an acid;
- in an organic solvent;
- to yield (5-cyclohexyl-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl)-acetic acid ethyl ester;
- reacting the (5-cyclohexyl-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl)-acetic acid ethyl ester with 2-chloro-1-cyclopentyl-ethanone;
- in the presence of an organic or inorganic base;
- in an organic solvent;
- in the presence of a source of iodide;
- to yield [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetic acid ethyl ester;
- reacting the [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetic acid ethyl ester is reacted with an aqueous base;
- to yield [5-cyclohexyl-1-(2-cyclopentyl -2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetic acid;
- reacting the [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl )-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetic acid with a chlorinating agent;
- in an organic solvent;
- to yield [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetyl chloride;
- reacting the [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl )-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetyl chloride with 3-(3-amino-phenyl)-2H-[1,2,4]oxadiazol-5-one;
- in the presence of an organic base;
- in an aprotic organic solvent;
- to yield the 2-[5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-N-[3-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-acetamide, the compound of formula (Is).
22 more elements
Dependencies are inferred from the claim text.