1,2-Di-Boc-piperidazine

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of di-tert-butyl hydrazine-1,2-dicarboxylate (10 g, 43.1 mmol) in dry N,N-dimethylformamide (25 ml) was added to a stirred suspension of sodium hydride (3.79 g of a 60% suspension in mineral oil, 95 mmol) in dry N,N-dimethylformamide (175 ml) at 0° C. under nitrogen. The reaction mixture was stirred for 30 minutes and then 1,4-dibromobutane (9.3 g, 43.1 mmol) was added within half a minute. The reaction was stirred at room temperature overnight. Then water (˜20 ml) was added carefully to the reaction mixture at room temperature, and stirring was continued for ca. 5 minutes. Thereafter the quenched reaction mixture was poured into 1 liter of water. The product was extracted twice with diethyl ether (200 ml), and the combined organic layers were washed with three times with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 14 g of crude tetrahydropyridazine-1,2-dicarboxylic acid di-tert-butyl ester. This was dissolved in diethyl ether (200 ml) and 4N hydrochloric acid in dioxane (108 ml, 431 mmol) was added. The resulting mixture was stirred overnight at room temperature. The thus formed white precipitate was isolated by filtration and dried under a flow of nitrogen to yield 4.6 g of crude product. Analysis by 1H NMR indicated that the reaction had not gone to completion. This crude product was combined with the crude product of a similar preparation, dissolved in dichloromethane (200 ml) and treated with 4N hydrochloric acid in dioxane (60 ml, 240 mmol) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and triturated with dry diethyl ether. The resulting precipitate was isolated by filtration and dried and a flow of nitrogen to yield 6.3 g of product, which was used without further purification in the next step. The reaction was stirred at room temperature overnight stirring was continued for ca. 5 minutes Thereafter the quenched reaction mixture The product was extracted twice with diethyl ether (200 ml) the combined organic layers were washed with three times with 10% aqueous sodium chloride solution dried over anhydrous sodium sulfate concentrated in vacuo