Nucleophilic aromatic substitution of 2-chloro-3-nitropyridine (II) with excess piperazine (I) in acetonitrile at room temperature produces 1-(3-nitro-2-pyridyl)piperazine. Protection of the free piperazine nitrogen by treatment with di-tert-butyldicarbonate affords nitropyridine (III). Reduction of the nitro group to the amine is accomplished via hydrogenation (40 psi) over palladium on carbon. Treatment of the aminopyridine with acetaldehyde and sodium cyanoborohydride in methanol affords the (ethylamino)pyridine (IV). Removal of the BOC protecting group with trifluoroacetic acid and coupling of the resulting 1-[3-(ethylamino)pyridyl]piperazine with 5-methoxyindole-2-carboxylic acid using 1-ethyl-3-(dimethylaminopropyl)carbodiimide (EDC) or 1,1'-carbonyldiimidazole (CDI) affords U-87201 (V). Dissolution of (V) in methanol, treatment with 1 eq of methanesulfonic acid, and the addition of diethyl ether results in the precipitation of atevirdine mesylate.
The synthesis of delavirdine mesylate is depicted in Scheme 19654001a: The first three chemical steps are the same as those used for the synthesis of atevirdine mesylate (ATV, U-87201E) (2, 3). Nucleophilic aromatic substitution of 2-chloro-3-nitropyridine (II) with excess piperazine in acetonitrile at room temperature produces 1-(3-nitro-2-pyridyl)piperazine. Protection of the free piperazine nitrogen by treatment with di-tert-butyldicarbonate affords nitropyridine (III). Reduction of the nitro group to the amine is accomplished via hydrogenation (40 psi) over palladium on carbon. Treatment of the aminopyridine with acetone and sodium cyanoborohydride in methanol affords the 3-(1-methylethylamino)pyridine (IV). Removal of the BOC protecting group with trifluoroacetic acid and coupling of the resulting 1-[3-(1-methylethylamino)pyridyl]piperazine with 5-nitroindole-2-carboxylic acid using 1-ethyl-3-(dimethylaminopropyl)carbodiimide (EDC) or 1,1'-carbonyldiimidazole (CDI) affords (V). Catalytic reduction of the nitro group and treatment of the resulting amine with methanesulfonyl chloride provides U-90152. Dissolution of U-90152 in acetonitrile and treatment with 1 eq of methanesulfonic acid results in the precipitation of delavirdine mesylate.
The reaction of 3-amino-2-chloropyridine (I) with triethyl orthoacetate (II) catalyzed by TsOH gives the acetimidate (III), which is reduced to 3-(ethylamino)-2-chloropyridine (IV) by means of DIBAL in toluene. The reaction of (IV) with piperazine (V) by means of Na2CO3 by heating at 144 C affords 3-(ethylamino)-2-(1-piperazinyl)pyridine (VI), which is finally condensed with 5-methoxy-1H-indole-2-carboxylic acid (II) by means of CDI in dichloromethane and treated with CH3SO3H in methanol to provide the target mesylate.