This compound can be obtained in two different ways: 1) The bromination of 1-(2-ethylindan-2-yl)-1-ethanone (I) with Br2 in ether gives 2-bromo-1-(2-ethylindan-2-yl)-1-ethanone (II), which is then cyclized with formamide by heating at 170-80 C. 2) The cyclization of alpha,alpha'-dibromo-o-xylene (III) with 4-penten-2-one (IV) by means of tetrabutylammonium hydroxide in toluene at 100 C gives 1-(2-vinylindan-2-yl)-1-ethanone (V), which is brominated with Br2 in dichloromethane to yield 2-bromo-1-(2-vinylindan-2-yl)-1-ethanone (VI). The cyclization of (VI) with formamide at 160 C as before affords 4-(2-vinylindan-2-yl)-1H-imidazole (VII), which is finally hydrogenated with H2 over Pd/C in ethanol.
By reaction of 10-(3-chloropropionyl)-2-(ethoxycarbonylamino)phenothiazine (I) with diethylamine in refluxing toluene.
A new synthesis of atipamezole has been described: The cyclization of alpha,alpha'-dibromo-o-xylene (I) with acetylacetone (II) by means of NaOH and tetrabutylammonium bromide in toluene/water at 80 C under phase-transfer conditions gives the unstable diacetyl derivative (III), which presumably undergoes cleavage to afford 2-acetylindane (IV). The alkylation of (IV) with ethyl iodide and potassium tert-butoxide yields 2-acetyl-2-ethylindane (V), which is brominated with Br2 to give 2-(bromoacetyl)-2-ethylindane (VI). Finally, this compound is cyclized with formamide at 160 C [some 2-ethyl-2-(4-oxazolyl)indane is also formed but is easily eliminated]; the cyclization can also be carried out with formamidine in liquid ammonia.
The alkylation of indane-2-carboxylic acid methyl ester (I) with ethyl iodide by means of lithium isopropylcyclohexylamide (LiICA) in THF/DMSO gives the 2-ethyl substituted compound (II), which is hydrolyzed with tBu-OK in DMSO, yielding 2-ethylindane-2-carboxylic acid (III). The reaction of (III) with methanesulfonyl chloride and diazomethane affords the alpha-diazoketone (IV), which is treated with dimethyldioxirane (DMDO) in acetone to provide the ketoaldehyde (V). Finally, this compound is cyclized with 11C-formaldehyde and NH4OH by means of ZnO in THF/water to yield the target labeled imidazole derivative. The intermediate ketoaldehyde (V) has also been obtained in two other ways: a) The alkylation of 2-(diethoxyacetyl)indane (VI) with ethyl iodide by means of tBu-OK in THF gives the corresponding 2-ethyl-substituted compound (VII), which is finally hydrolyzed to the desired ketoaldehyde (V) with HCl in THF/water. b) The oxidation of 2-acetyl-2-ethylindane (VIII) with SeO2 in hot acetic acid/water gives also the desired ketoaldehyde (V).