benzyl (2S)-piperidine-2-carboxylate

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

Procedure: The title compound was prepared by a similar method to Preparation 2 from tert-butyl 2-chloro-1H-1,3-benzimidazole-1-carboxylate [see Preparation 46] and benzyl (2S)-2-piperidinecarboxylate [see J.A.C.S. (1 996), 118(7), 1629-1644]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 80:20, by volume, hexane:ethyl acetate, in 5% increments to afford tert-butyl 2-[(2S)-2-[(benzyloxy)carbonyl]-1-piperidinyl]-1H-1,3-benzimidazole-1-carboxylate as an oil. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 80:20, by volume, hexane

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

Procedure: To a solution of 145 mg (0.37 mmol) of (S)-Benzyl pipecolate salt (134) (described in Example 1) in 8.0 mL of methylene chloride was added 102 mg (0.57 mmol) of 4-methoxycinnamic acid, 107 mg (0.55 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 130 μL (0.74 mmol) of diisopropylethylainine, The resulting solution was stirred at ambient temperature for 12 h and was then concentrated under reduced pressure. Flash chromatography (elution with 1:1 ethyl acetate-hexane) gave 91 mg (65%) of the amide (112) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ7.66 (d), 7.50 (d), 7.35 (m), 6.90 (d), 6.82 (d), 6.63 (d), 5.55 (d), 5.20 (br s), 4.86 (br s), 4.67 (br d) 4.03 (br d), 3.83 (s), 3.37 (dt), 2.78 (dt) 2.33 (br d), 1.74 (m), 1.43 (m). Rf 0.40 (1:1 ether-hexane). was then concentrated under reduced pressure Flash chromatography (elution with 1:1 ethyl acetate-hexane)

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

Procedure: To a solution of 145 mg (0.37 mmol) of (S)-Benzyl pipecolate salt (134) (described in Example 1) in 8.0 mL of methylene chloride was added 102 mg (0.57 mmol) of 4-methoxycinnamic acid, 107 mg (0.55 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 130 μL (0.74 mmol) of diisopropylethylainine, The resulting solution was stirred at ambient temperature for 12 h and was then concentrated under reduced pressure. Flash chromatography (elution with 1:1 ethyl acetate-hexane) gave 91 mg (65%) of the amide (112) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ7.66 (d), 7.50 (d), 7.35 (m), 6.90 (d), 6.82 (d), 6.63 (d), 5.55 (d), 5.20 (br s), 4.86 (br s), 4.67 (br d) 4.03 (br d), 3.83 (s), 3.37 (dt), 2.78 (dt) 2.33 (br d), 1.74 (m), 1.43 (m). Rf 0.40 (1:1 ether-hexane). was then concentrated under reduced pressure Flash chromatography (elution with 1:1 ethyl acetate-hexane)

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

Procedure: Benzyl pipecolate was routinely generated by treating an ethyl acetate suspension of this salt with saturated sodium bicarbonate until dissolution of the organic material. The aqueous layer was extracted twice with ethyl acetate and the combined organic extracts were dried with MgSO4 and evaporated to yield (S)-Benzyl pipecolate (133) as a pale yellow oil. by treating until dissolution of the organic material The aqueous layer was extracted twice with ethyl acetate the combined organic extracts were dried with MgSO4 evaporated

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

Procedure: Benzyl pipecolate was routinely generated by treating an ethyl acetate suspension of this salt with saturated sodium bicarbonate until dissolution of the organic material. The aqueous layer was extracted twice with ethyl acetate and the combined organic extracts were dried with MgSO4 and evaporated to yield (S)-Benzyl pipecolate (133) as a pale yellow oil. by treating until dissolution of the organic material The aqueous layer was extracted twice with ethyl acetate the combined organic extracts were dried with MgSO4 evaporated

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

Procedure: The title compound was prepared by a similar method to Preparation 2 from tert-butyl 2-chloro-1H-1,3-benzimidazole-1-carboxylate [see Preparation 46] and benzyl (2S)-2-piperidinecarboxylate [see J.A.C.S. (1 996), 118(7), 1629-1644]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 80:20, by volume, hexane:ethyl acetate, in 5% increments to afford tert-butyl 2-[(2S)-2-[(benzyloxy)carbonyl]-1-piperidinyl]-1H-1,3-benzimidazole-1-carboxylate as an oil. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 80:20, by volume, hexane

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

Procedure: The title compound was prepared by a similar method to Preparation 2 from tert-butyl 2-chloro-1H-1,3-benzimidazole-1-carboxylate [see Preparation 46] and benzyl (2S)-2-piperidinecarboxylate [see J.A.C.S. (1 996), 118(7), 1629-1644]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 80:20, by volume, hexane:ethyl acetate, in 5% increments to afford tert-butyl 2-[(2S)-2-[(benzyloxy)carbonyl]-1-piperidinyl]-1H-1,3-benzimidazole-1-carboxylate as an oil. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 80:20, by volume, hexane

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

Procedure: To a solution of 145 mg (0.37 mmol) of (S)-Benzyl pipecolate salt (14) (described in Example 1) in 8.0 mL of methylene chloride was added 102 mg (0.57 mmol) of 4-methoxycinnamic acid, 107 mg (0.55 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 130 μL (0.74 mmol) of diisopropylethylamine. The resulting solution was stirred at ambient temperature for 12 h and was then concentrated under reduced pressure. Flash chromatography (elution with 1:1 ethyl acetate-hexane) gave 91 mg (65%) of the amide (8) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.66 (d), 7.50 (d), 7.35 (m), 6.90 (d), 6.82 (d), 6.63 (d), 5.55 (d), 5.20 (br s), 4.86 (br s), 4.67 (br d) 4.03 (br d), 3.83 (s), 3.37 (dt), 2.78 (dt) 2.33 (br d), 1.74 (m), 1.43 (m), Rf 0.40 (1:1 ether-hexane). was then concentrated under reduced pressure Flash chromatography (elution with 1:1 ethyl acetate-hexane)

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

Procedure: Benzyl pipecolate was routinely generated by treating an ethyl acetate suspension of this salt with saturated sodium bicarbonate until dissolution of the organic material. The aqueous layer was extracted twice with ethyl acetate and the combined organic extracts were dried with MgSO4 and evaporated to yield (S)-Benzyl pipecolate (15) as a pale yellow oil. by treating until dissolution of the organic material The aqueous layer was extracted twice with ethyl acetate the combined organic extracts were dried with MgSO4 evaporated

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

Procedure: To a solution of 145 mg (0.37 mmol) of (S)-Benzyl pipecolate salt (14) (described in Example 1) in 8.0 mL of methylene chloride was added 102 mg (0.57 mmol) of 4-methoxycinnamic acid, 107 mg (0.55 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 130 μL (0.74 mmol) of diisopropylethylamine. The resulting solution was stirred at ambient temperature for 12 h and was then concentrated under reduced pressure. Flash chromatography (elution with 1:1 ethyl acetate-hexane) gave 91 mg (65%) of the amide (8) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.66 (d), 7.50 (d), 7.35 (m), 6.90 (d), 6.82 (d), 6.63 (d), 5.55 (d), 5.20 (br s), 4.86 (br s), 4.67 (br d) 4.03 (br d), 3.83 (s), 3.37 (dt), 2.78 (dt) 2.33 (br d), 1.74 (m), 1.43 (m), Rf 0.40 (1:1 ether-hexane). was then concentrated under reduced pressure Flash chromatography (elution with 1:1 ethyl acetate-hexane)

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

Procedure: Benzyl pipecolate was routinely generated by treating an ethyl acetate suspension of this salt with saturated sodium bicarbonate until dissolution of the organic material. The aqueous layer was extracted twice with ethyl acetate and the combined organic extracts were dried with MgSO4 and evaporated to yield (S)-Benzyl pipecolate (15) as a pale yellow oil. by treating until dissolution of the organic material The aqueous layer was extracted twice with ethyl acetate the combined organic extracts were dried with MgSO4 evaporated

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

Procedure: To a solution of 145 mg (0.37 mmol) of (S)-Benzyl pipecolate salt (134) (described in Example 1) in 8.0 mL of methylene chloride was added 102 mg (0.57 mmol) of 4-methoxycinnamic acid, 107 mg (0.55 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 130 μL (0.74 mmol) of diisopropylethylamine. The resulting solution was stirred at ambient temperature for 12 h and was then concentrated under reduced pressure. Flash chromatography (slution with 1:1 ethyl acetate-hexane) gave 91 mg (65%) of the amide (112) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.66 (d), 7.50 (d), 7.35 (m), 6.90 (d), 6.82 (d), 6.63 (d), 5.55 (d), 5.20 (br s), 4.86 (br s), 4.67 (brd) 4.03 (br d), 3.83 (s), 3.37 (dr), 2.78 (dt) 2.33 (br d), 1.74 (m), 1.43(m). Rf 0.40 (1:1 ether-hexane). was then concentrated under reduced pressure