4-Methyl-2'-bromoacetophenone (I) is condensed with 2-amino-5-methyl pyridine (II) to give 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine (III). Compound (III) is condensed with formaldehyde and dimethylamine in a Mannich reaction to give the 3-dimethyl aminomethyl derivative (IV), which is quaternized on the side chain nitrogen to afford the quaternary iodide (V). Displacement of trimethylamine from the quaternary salt (V) with cyanide ion leads to 2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetonitrile (VI). Acid hydrolysis of the nitrile then affords the corresponding acid (VII). Conversion of the acid to its acid chloride followed by condensation with dimethylamine then leads to zolpidem free base, which is converted to its L-(+)- tartrate (2:1) by treatment with L-(+)-tartaric acid.
1) 4-Chloro-2'-bromoacetophenone (I) is condensed with 2-amino 5-chloropyridine (II) to give 6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine (III). 2) The above compound is reacted with formaldehyde and dimethylamine under Mannich conditions affording the 3-dimethylaminomethyl derivative (IV), which is subsequently quaternized with methyl iodide to afford the quaternary iodide (V). 3) Displacement of trimethylamine from salt (V) with cyanide ion leads to formation of the nitrile (VI), which on hydrolysis with hydrochloric acid in acetic acid gives the corresponding acid (VII). 4) In situ conversion of the acid to its acid chloride with phosphorus oxychloride followed by treatment with di-n-propylamine then leads to alpidem.
The oxidation of 3-(benzyloxy)estrone (I) with I2 and KOH in refluxing methanol gives 3-(benzyloxy)-16,17-seco-estra-1,3,5(10)-triene-16,17-dioic acid (II), which is cyclized with urea at 180篊 to yield the cyclic imide (III). The alkylation of (III) with propyl chloride (IV) and NaH in DMF affords the N-propyl derivative (V). Alternatively, the N-propyl derivative (V) can also be obtained by direct cyclization of diacid (II) with propylamine (VI) at 180?C. The debenzylation of (V) to the 3-hydroxy derivative (VII) is performed by hydrogenation with H2 over Pd/C in methanol/THF. Finally, compound (VII) is treated with chlorosulfonamide and NaH in DMF to provide the target sulfamate.
The oxidation of 3-(benzyloxy)estrone (I) with I2 and KOH in refluxing methanol gives 3-(benzyloxy)-16,17-seco-estra-1,3,5(10)-triene-16,17-dioic acid (II), which is cyclized with urea at 180?C to yield the cyclic imide (III). The alkylation of (III) with 3-(chloromethyl)pyridine (IV) and NaH in DMF affords the N-(3-pyridylmethyl) derivative (V). Alternatively, the N-(3-pyridylmethyl) derivative (V) can also be obtained by direct cyclization of diacid (II) with 3-pyridylmethylamine (VI) at 180?C. The debenzylation of (V) to the 3-hydroxy derivative (VII) is performed by hydrogenation with H2 over Pd/C in methanol/THF. Finally, compound (VII) is treated with chlorosulfonamide and NaH in DMF to provide the target sulfamate.