Ethyl 4-methyl-2-piperidinecarboxylate

To a stirred solution of 28.3 g of NG-nitro-N2-(tert-butoxycarbonyl)-L-arginine in 450 ml of dry tetrahydrofuran were added in turn 9.0 g of triethylamine and 12.2 g of isobutyl chloroformate while keeping the temperature at -20°C. After 10 minutes, to this was added 15.2 g of ethyl 4-methyl-2-piperidinecarboxylate and the mixture was stirred for 10 minutes at -20°C. At the end of this period, the reaction mixture was warmed to room temperature. The solvent was evaporated and the residue taken up in 400 ml of ethyl acetate, and washed successively with 200 ml of water, 100 ml of 5% sodium bicarbonate solution, 100 ml of 10% citric acid solution and 200 ml of water. The ethyl acetate solution was dried over anhydrous sodium sulfate. The solution was evaporated to give 31.5 g (75 %) of ethyl l-[NG-nitro-N2-(tert-butoxycarbonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate in the form of a syrup. 

Chemical Name 1-methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride... 

To a stirred solution of 30 g of ethyl l-[NG-nitro-N2-(tert-butoxycarbonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate in 50 ml of ethyl acetate was added 80 ml of 10% dry HCI-ethyl acetate at 0°C. After 3 hours, to this solution was added 200 ml of dry ethyl ether to precipitate a viscous oily product. This was filtered and washed with dry ethyl ether to give ethyl l-[NG-nitro-L-arginyl]-4-methyl-2-piperidinecarboxylate hydrochloride as an amorphous solid. 

A solution of 30 g the above product in 100 ml of ethanol and 100 ml of 1 N sodium hydroxide solution was stirred for 24 hrs at room temperature. At the end of this period, the solution was neutralized with 1 N hydrochloric acid and then concentrated to 70 ml. The solution was adjusted to pH=ll with 1 N sodium hydroxide solution, washed three times with 100 ml of ethyl acetate, acidified with 1 N hydrochloric acid and then extracted three times with 100 ml of chloroform. The combined chloroform solution was dried over anhydrous sodium sulfate and evaporated to give 28.0 g (97%) of l-[NG-nitro-N2-(3-methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid as an amorphous solid. IR (KBr) 3,300, 1,720, 1,630 cm-1. 

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