Aza-Indolyl Derivatives for Treating Obesity

Bentley etal, US Patent 6,583,134 (June 24, 2003) Assignee Hoffman-LaRoche Inc and Vemnalis Research Limited Utility Treatment of Gastrointestinal Disorders 

To 3-aniino-4-iodopyridine (10.00 mmol) dissolved in 25 ml acetonitrile was added 1.67 ml trifluoroacetic anhydride at 0°C and KjCOj (30 mmol) and the mixture stirred 10 minutes at ambient temperature. To this was added bis(triphenylphosphine)-palladium(n)chloride (0.25 mmol), copper(I)iodide (0.50 mmol), and 5-chloro-l-pentyne (12.00 mmol) and the mixture refluxed 3 hours. Thereafter, the mixture was cooled, partitioned between water and EtOAc, and the organic phase extracted with water at pH 1.00. The aqueous phase was mixed with CH2CI2 and the pH raised to 10 by the addition of 2M NaOH. The organic phases were combined, dried, concentrated, and the residue dissolved in 20 ml acetonitrile. To this brownish solution was added Nal (20 mmol) and NaH (ca 55%, 20 mmol), the mixture stirred 2 hours, poured onto ice, partitioned between 100 ml apiece of water and EtOAc, and the phases separated. The organic phase was extracted 5 times with 50 ml water at pH 1.00, mixed with 100 ml CH2CI2, and the pH raised to 10 using 2M NaOH. The phases were separated, the organic phase dried, concentrated and the product isolated in 51% yield, mp = 95-96 °C after re-crystallization in t-butyl-methylether. Elemental analysis data supplied. 

3 ml DMF was added 0.33 ml phosphorus oxychloride at 0 °C and the mixture stirred 10 minutes at ambient temperature. A solution of the product from Step 1 (0.63 mmol) dissolved in 0.1ml DMF was added and the mixture stirred 3 hours. Thereafter, the reaction was quenched with ice (5 g), the pH raised to 9 by addition of 28% NaOH, the mixture refluxed 10 minutes, cooled, and extracted 3 times with 5 ml EtOAc. The extracts were dried, concentrated, and the product isolated in 97% yield, mp = 150-151 °C after re-crystallization from EtOAc. Elemental analysis data supplied. 

8-(2-Nitro-propenyl)-2,3-dihydro-lH-3a,6-diaza-cyclopenta[a]indene 

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