tert-butyl (2S)-2-carbamoylpiperidine-1-carboxylate

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

Procedure: Triethylamine (14.46 ml) was added to a solution of (2S)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid (18.3 g) [see Preparation 1] in tetrahydrofuran (240 ml) at −20° C. under an atmosphere of nitrogen. Ethyl chloroformate (7.52 ml) was then added to the mixture and the resulting solution was stirred for 40 mins. at −10° C. and then 0.88 aqueous ammonia solution (32 ml) added. The reaction mixture was stirred for 10 mins. after which time the solvent was removed under reduced pressure and the residue diluted with ethyl acetate and water. The organic layer was separated and dried over magnesium sulphate and the solvent was removed under reduced pressure to afford tert-butyl (2S)-2-(aminocarbonyl)-1-piperidinecarboxylate (18.65 g) as a white solid. 1H-NMR (CDCl3) δ: 6.0 (1H, bs), 5.40 (1H, bs), 4.80 (1H, s), 4.00 (1H, m), 2.85 (1H, t), 2.30 (1H, d), 1.80-1.40 (14H, m). The reaction mixture was stirred for 10 mins after which time the solvent was removed under reduced pressure the residue diluted with ethyl acetate and water The organic layer was separated dried over magnesium sulphate the solvent was removed under reduced pressure

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

Procedure: 1.6 g (7 mmoles) of BOC-HPro-NH2 are dissolved in 10 ml of warm ethyl acetate. The solution is cooled to room temperature, and 10 ml of a 6 n hydrochloric acid solution in ethyl acetate are added. The reaction mixture is allowed to stand for one hour, thereafter it is diluted with ether, the separated precipitate is triturated and filtered off. 1.05 g (91%) of H-HPro-NH2.HCl are obtained; m.p.: 178°-180° C., Rf6 =0.32, [α]D25 =+26.2° (c=1%, in methanol). the separated precipitate is triturated filtered off

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

Procedure: 1.6 g (7 mmoles) of BOC-HPro-NH2 are dissolved in 10 ml of warm ethyl acetate. The solution is cooled to room temperature, and 10 ml of a 6 n hydrochloric acid solution in ethyl acetate are added. The reaction mixture is allowed to stand for one hour, thereafter it is diluted with ether, the separated precipitate is triturated and filtered off. 1.05 g (91%) of H-HPro-NH2.HCl are obtained; m.p.: 178°-180° C., Rf6 =0.32, [α]D25 =+26.2° (c=1%, in methanol). the separated precipitate is triturated filtered off

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.29 g (10 mmoles) of BOC-HPro-OH are dissolved in 30 ml of ethyl acetate, 1.4 ml (10 mmoles) of triethylamine are added to the solution, the mixture is cooled to -10° C., and then 1.3 ml (10 mmoles) of isobutyl chloroformate are added dropwise. After 15 minutes of stirring gaseous ammonia is introduced into the reaction mixture for 0.5 hours at -10° C., and then the mixture is allowed to stand at 0°-5° C. for 2 hours. The precipitate is filtered off, the filtrate is evaporated, and the oily residue is dissolved in 30 ml of chloroform. This solution is washed twice with 10 ml of n hydrochloric acid, each, twice with 10 ml of n sodium hydrocarbonate solution, each, and then with 10 ml of water, dried over anhydrous sodium sulfate, and evaporated. The oily residue is crystallized from n-hexane to obtain 1.95 g of a crude product. This crude product is recrystallized from a mixture of ethyl acetate and ether to obtain 1.78 g (78%) of BOC-HPro-NH2 ; m.p.: 138°-140° C., Rf2 =0.43, [α]D25 =-24.85° (c=1%, in acetic acid). The precipitate is filtered off the filtrate is evaporated the oily residue is dissolved in 30 ml of chloroform This solution is washed twice with 10 ml of n hydrochloric acid each, twice with 10 ml of n sodium hydrocarbonate solution, each, and then with 10 ml of water, dried over anhydrous sodium sulfate evaporated The oily residue is crystallized from n-hexane to obtain 1.95 g of a crude product This crude product is recrystallized from a mixture of ethyl acetate and ether

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

Procedure: To a solution of N-Boc-L-pipecolinic acid (200 mg, 0.87 mmol) in DMF (3.5 mL) was added TBTU (336 mg, 1.05 mmol), ammonium chloride (93 mg, 1.74 mmol) then DIPEA (182 μL, 1.05 mmol) and the reaction stirred for 16 h. The mixture was partitioned between ethyl acetate (2×30 mL) and water (30 mL), and the organics combined before being washed with 1M sodium hydroxide (3×30 mL) and brine (3×30 mL). The organic solution was dried (MgSO4) and solvent removed in vacuo to give the title compound as a white solid. δH (d6 DMSO): 7.23 (1H, s), 6.97 (1H, s), 4.56–4.39 (1H, br m), 3.43–3.74 (1H, d), 3.14–2.90 (1H, br m), 2.09–2.00 (1H, d), 1.63–1.47 (3H, m), 1.30–1.17 (2H, m). The mixture was partitioned between ethyl acetate (2×30 mL) and water (30 mL) before being washed with 1M sodium hydroxide (3×30 mL) and brine (3×30 mL) The organic solution was dried (MgSO4) and solvent removed in vacuo

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

Procedure: Triethylamine (14.46 ml) was added to a solution of (2S)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid (18.3 g) [see Preparation 1] in tetrahydrofuran (240 ml) at −20° C. under an atmosphere of nitrogen. Ethyl chloroformate (7.52 ml) was then added to the mixture and the resulting solution was stirred for 40 mins. at −10° C. and then 0.88 aqueous ammonia solution (32 ml) added. The reaction mixture was stirred for 10 mins. after which time the solvent was removed under reduced pressure and the residue diluted with ethyl acetate and water. The organic layer was separated and dried over magnesium sulphate and the solvent was removed under reduced pressure to afford tert-butyl (2S)-2-(aminocarbonyl)-1-piperidinecarboxylate (18.65 g) as a white solid. 1H-NMR (CDCl3) δ: 6.0 (1H, bs), 5.40 (1H, bs), 4.80 (1H, s), 4.00 (1H, m), 2.85 (1H, t), 2.30 (1H, d), 1.80-1.40 (14H, m). The reaction mixture was stirred for 10 mins after which time the solvent was removed under reduced pressure the residue diluted with ethyl acetate and water The organic layer was separated dried over magnesium sulphate the solvent was removed under reduced pressure

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

Procedure: Anhydrous ammonia gas was bubbled through a solution of (S)-(−)-1-(tert-butoxycarbonyl)-2-piperidine carboxylic acid (500 mg, 2.18 mmol) in DMF (50 ml) for 15 minutes. PyBop (1.25 g, 2.40 mmol) was added. After 5 hours, solvent was evaporated under reduced pressure. A solution of the resultant residue in ethyl acetate was washed with 5% citric acid (50 ml×3), 1 N NaOH (50 ml×3), dried with MgSO4, filtered, and concentrated to give 450 mg of (S)-2-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester as a clear oil in 95% yield, which was used without further purification. solvent was evaporated under reduced pressure A solution of the resultant residue in ethyl acetate was washed with 5% citric acid (50 ml×3), 1 N NaOH (50 ml×3) dried with MgSO4 filtered concentrated

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

Procedure: To a solution of N-Boc-L-pipecolinic acid (200 mg, 0.87 mmol) in DMF (3.5 mL) was added TBTU (336 mg, 1.05 mmol), ammonium chloride (93 mg, 1.74 mmol) then DIPEA (182 μL, 1.05 mmol) and the reaction stirred for 16 h. The mixture was partitioned between ethyl acetate (2×30 mL) and water (30 mL), and the organics combined before being washed with 1M sodium hydroxide (3×30 mL) and brine (3×30 mL). The organic solution was dried (MgSO4) and solvent removed in vacuo to give the title compound as a white solid. δH (d6 DMSO): 7.23 (1H, s), 6.97 (1H, s), 4.56-4.39 (1H, br m), 3.43-3.74 (1H, d), 3.14-2.90 (1H, br m), 2.09-2.00 (1H, d), 1.63-1.47 (3H, m), 1.30-1.17 (2H, m). The mixture was partitioned between ethyl acetate (2×30 mL) and water (30 mL) before being washed with 1M sodium hydroxide (3×30 mL) and brine (3×30 mL) The organic solution was dried (MgSO4) and solvent removed in vacuo

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

Procedure: 1.6 g (7 mmoles) of BOC-HPro-NH2 are dissolved in 10 ml of ethyl acetate under heating. The solution is cooled to room temperature, and 10 ml of a 6 n hydrochloric acid solution in ethyl acetate are added. After one hour of standing the mixture is diluted with ether, the separated precipitate is triturated and then filtered off. 1.05 g (91%) of H-HPro-NH2.HCl are obtained; m.p.: 178°-180° C., Rf6 =0.32, [α]D25 =+26.2° (c=1%, in methanol). under heating the separated precipitate is triturated filtered off

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

Procedure: 2.29 g (10 mmoles) of BOC-HPro-OH are dissolved in 30 ml of ethyl acetate, 1.4 ml (10 mmoles) of triethylamine are added to the solution, and then 1.3 ml (10 mmoles) of isobutyl chloroformate are added dropwise at -10° C. After 15 minutes of stirring gaseous ammonia is passed through the mixture at -10° C. for 0.5 hours, and the resulting mixture is allowed to stand at 0°-5° C. for 2 hours. The separated precipitate is filtered off, the filtrate is evaporated, and the oily residue is dissolved in 30 ml of chloroform. The solution is shaken twice with 10 ml of n hydrochloric acid, each, twice with 10 ml of n sodium hydrocarbonate solution, each, and then with 10 ml of water, dried over anhydrous sodium sulfate and evaporated. The oily residue is crystallized from n-hexane, and the resulting 1.96 g of crude product are recrystallized from a mixture of ethyl acetate and ether. 1.78 g (78%) of BOC-HPro-NH2 are obtained; m.p.: 138°-140° C., Rf2 =0.43, [α]D25 =-24.85° (c=1%, in acetic acid). The separated precipitate is filtered off the filtrate is evaporated the oily residue is dissolved in 30 ml of chloroform each, twice with 10 ml of n sodium hydrocarbonate solution, each, and then with 10 ml of water, dried over anhydrous sodium sulfate evaporated The oily residue is crystallized from n-hexane the resulting 1.96 g of crude product are recrystallized from a mixture of ethyl acetate and ether

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

Procedure: 1.6 g (7 mmoles) of BOC-HPro-NH2 are dissolved in 10 ml of warm ethyl acetate. The solution is cooled to room temperature, and 10 ml of a 6 n hydrochloric acid solution in ethyl acetate are added. The reaction mixture is allowed to stand for one hour, thereafter it is diluted with ether, the separated precipitate is triturated and filtered off. 1.05 g (91%) of H-HPro-NH2.HCl are obtained; m.p.: 178°-180° C., Rf6 =0.32, [α]D25 =+26.2° (c=1%, in methanol). the separated precipitate is triturated filtered off

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.29 g (10 mmoles) of BOC-HPro-OH are dissolved in 30 ml of ethyl acetate, 1.4 ml (10 mmoles) of triethylamine are added to the solution, the mixture is cooled to -10° C., and then 1.3 ml (10 mmoles) of isobutyl chloroformate are added dropwise. After 15 minutes of stirring gaseous ammonia is introduced into the reaction mixture for 0.5 hours at -10° C., and then the mixture is allowed to stand at 0°-5° C. for 2 hours. The precipitate is filtered off, the filtrate is evaporated, and the oily residue is dissolved in 30 ml of chloroform. This solution is washed twice with 10 ml of n hydrochloric acid, each, twice with 10 ml of n sodium hydrocarbonate solution, each, and then with 10 ml of water, dried over anhydrous sodium sulfate, and evaporated. The oily residue is crystallized from n-hexane to obtain 1.95 g of a crude product. This crude product is recrystallized from a mixture of ethyl acetate and ether to obtain 1.78 g (78%) of BOC-HPro-NH2 ; m.p.: 138°-140° C., Rf2 =0.43, [α]D25 =-24.85° (c=1%, in acetic acid). The precipitate is filtered off the filtrate is evaporated the oily residue is dissolved in 30 ml of chloroform This solution is washed twice with 10 ml of n hydrochloric acid each, twice with 10 ml of n sodium hydrocarbonate solution, each, and then with 10 ml of water, dried over anhydrous sodium sulfate evaporated The oily residue is crystallized from n-hexane to obtain 1.95 g of a crude product This crude product is recrystallized from a mixture of ethyl acetate and ether