benzyl piperidine-1-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of DEAD (1.61 mL, 10.2 mmol) in 20 mL of THF was added to a solution of triphenylphosphine (2.69 g, 10.3 mmol), the N-Cbz-piperidine prepared in Example 16A (2.36 g, 100 mmol) and phthalimide (1.50 g, 10.2 mmol) in 80 mL of THF. After stirring 10.5 h at R.T. the mixture was quenched with water, extracted with EtOAc (3×) and the combined extracts washed with brine solution, dried over Na2SO4 and concentrated to give the crude product. Purification of this material by chromatography (hexanes/EtOAc; 2:1) gave 1.81 g, (50%) of 1-benzyloxycarbonyl-4-phthalimidylpiperidine. [1H]-NMR(CDCl3) consistent with structure. was quenched with water extracted with EtOAc (3×) the combined extracts washed with brine solution dried over Na2SO4 concentrated to give the crude product Purification of this material by chromatography (hexanes/EtOAc; 2:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Hydroxypiperidine (10.8 g, 107 mmol) and Et3N (17 mL, 123 mmol) in 80 mL of CH2Cl2 was cooled in an ice bath whereupon benzyl chloroformate (16.3 mL, 114 mmol) was added. After stirring 1.5 h at R.T. the mixture was subjected to standard work-up conditions to give 13.9 g (55%) of N-Cbz-piperidine after chromatography (CHCl3 /MeOH; 10:1). [1H]-NMR(CDCl3) consistent with structure. was added

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of DEAD (1.61 mL, 10.2 mmol) in 20 mL of THF was added to a solution of triphenylphosphine (2.69 g, 10.3 mmol), the N-Cbz-piperidine prepared in Example 16A (2.36 g, 100 mmol) and phthalimide (1.50 g, 10.2 mmol) in 80 mL of THF. After stirring 10.5 h at R.T. the mixture was quenched with water, extracted with EtOAc (3×) and the combined extracts washed with brine solution, dried over Na2SO4 and concentrated to give the crude product. Purification of this material by chromatography (hexanes/EtOAc; 2:1) gave 1.81 g, (50%) of 1-benzyloxycarbonyl-4-phthalimidylpiperidine. [1H]-NMR(CDCl3) consistent with structure. was quenched with water extracted with EtOAc (3×) the combined extracts washed with brine solution dried over Na2SO4 concentrated to give the crude product Purification of this material by chromatography (hexanes/EtOAc; 2:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Hydroxypiperidine (10.8 g, 107 mmol) and Et3N (17 mL, 123 mmol) in 80 mL of CH2Cl2 was cooled in an ice bath whereupon benzyl chloroformate (16.3 mL, 114 mmol) was added. After stirring 1.5 h at R.T. the mixture was subjected to standard work-up conditions to give 13.9 g (55%) of N-Cbz-piperidine after chromatography (CHCl3 /MeOH; 10:1). [1H]-NMR(CDCl3) consistent with structure. was added

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 43.0 g (126 mmol) (3R,4R) and (3S,4S)-4-benzyl-3,4-dihydroxy-piperidine-1-carboxylic acid benzyl ester and 23.1 g (189 mmol) DMAP in 600 ml CH2Cl2 were added dropwise under argon 500 ml (340 mmol, 0.70 N) (S)-N-trifluoroacetyl-prolinechloride. The reaction mixture was stirred for 16 hours at r.t. and then sat. NaHCO3 solution was added. The aqueous phase was extracted three times with CH2Cl2 and the combined organic layers were washed with sat. NaHCO3 and 1N HCl, dried over MgSO4 and the solvent was removed under reduced pressure to give the crude product. Purification by chromatography on silica gel (hexane:ethyl acetate 4:1 to 1:1) and crystallization from diethylether yielded 17.9 g (33 mmol, 27%) (3R,4R), 4-benzyl-4-hydroxy-3-(2S)-trifluoroacetyl-cyclopentanecarbonyloxy)-piperidine-1-carboxylic acid benzyl ester. The aqueous phase was extracted three times with CH2Cl2 the combined organic layers were washed with sat. NaHCO3 and 1N HCl dried over MgSO4 the solvent was removed under reduced pressure to give the crude product Purification by chromatography on silica gel (hexane:ethyl acetate 4:1 to 1:1) and crystallization from diethylether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The compound of formula XV is then treated with benzylchloroformate in a polar solvent such as water, water/acetone, chloroform, dichloroethane or ethyl acetate, in the presence of a base such as triethylamine or sodium bicarbonate, to yield the N-carbobenzyloxy piperidine (N--Cbz piperidine) of formula XVI having the same stereochemistry (i.e., wherein R2 and --COOCH3 are in the cis configuration). This reaction may be carried out at temperatures from about 0° C. to about 100° C., preferably about 25° C., for about 5 minutes to 18 hours. Treatment of the compound of formula XVI so formed with about 5 equivalents each of trimethyl aluminum and ammonium chloride in a nonpolar solvent such as benzene or toluene for about 0.5 to about 16 hours yields a compound of the formula XVII having the same stereochemistry. Reaction temperature may range from about room temperature to about 100° C., with about 50° C. being preferred.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of compound 1 (183 mg) in CH2Cl2 (10 mL) was added triphosgene (0.7 eq.) and triethylamine (1.0 eq.) at 0° C. The reaction mixture was stirred for 1 h. at r.t., and N-Cbz-piperidine (1.5 eq.) and Et3N (0.5 mL) were added. The reaction mixture was stirred overnight and washed with 1N HCl and sat NaHCO3 (3×5 mL). The solvents were removed by evaporation under reduced pressure to give the title product 18, which was purified by chromatography (SiO2, CH2Cl2/EtOAc 10:1). Yield: 360 mg. The reaction mixture was stirred overnight washed with 1N HCl The solvents were removed by evaporation under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 4-[(pyridazin-4-ylamino)-methyl]-piperidine (0.20 g, 1.04 mmol), in DMF (3 mL) was added carbonic acid benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester (0.26 g, 1.04 mmol). The resulting reaction solution was stirred at rt for 0.5 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (1-7 (10% NH4OH in MeOH)/99-93 CH2Cl2) to give 4-(pyridazin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. The resulting reaction solution concentrated in vacuo The residue was purified by silica gel chromatography (1-7 (10% NH4OH in MeOH)/99-93 CH2Cl2)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The compound of formula XV is then treated with benzylchloroformate in a polar solvent such as water, water/acetone, chloroform, dichloroethane or ethyl acetate, in the presence of a base such as triethylamine or sodium bicarbonate, to yield the N-carbobenzyloxy piperidine (N-Cbz piperidine) of formula XVI having the same stereochemistry (i.e., wherein R2 and --COOCH3 are in the cis configuration). This reaction may be carried out at temperatures from about 0° C. to about 100° C., preferably about 25° C., for about 5 minutes to 18 hours. Treatment of the compound of formula XVI so formed with about 5 equivalents each of trimethyl aluminum and ammonium chloride in a nonpolar solvent such as benzene or toluene for about 0.5 to about 16 hours yields a compound of the formula XVII having the same stereochemistry. Reaction temperatures may range from about room temperature to about 100° C., with about 50° C. being preferred.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Compound 1-(1-acetyl-6-benzyloxy-3-methyl-1H-indol-5-yl)-2-bromo-ethanone (0.039 g, 0.1 mmol), K2CO3 (0.019 g, 0.14 mmol) and Cbz-piperidine (0.026 ml, 0.1 mmol) was stirred in DMF (2 ml) at room temperature for 5 hours. The solvent was removed in vacuo and the residue redissolved in DCM and washed with water, brine, dried over MgSO4. Purification by column chromatography in hexane/EtOAc (3:2) afforded the product (0.008 g, 17%). LC/MS: RT=2.236 min. 498 (MH+). The solvent was removed in vacuo the residue redissolved in DCM washed with water, brine dried over MgSO4 Purification by column chromatography in hexane/EtOAc (3:2)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of DEAD (1.61 mL, 10.2 mmol) in 20 mL of THF was added to a solution of triphenylphosphine (2.69 g, 10.3 mmol), the N-Cbz-piperidine prepared in Example 16A (2.36 g, 100 mmol) and phthalimide (1.50 g, 10.2 mmol) in 80 mL of THF. After stirring 10.5 h at R.T. the mixture was quenched with water, extracted with EtOAc (3×) and the combined extracts washed with brine solution, dried over Na2SO4 and concentrated to give the crude product. Purification of this material by chromatography (hexanes/EtOAc; 2:1) gave 1.81 g, (50%) of 1-benzyloxycarbonyl-4-phthalimidylpiperidine. [1H]-NMR(CDCl3) consistent with structure. was quenched with water extracted with EtOAc (3×) the combined extracts washed with brine solution dried over Na2SO4 concentrated to give the crude product Purification of this material by chromatography (hexanes/EtOAc; 2:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Hydroxypiperidine (10.8 g, 107 mmol) and Et3N (17 mL, 123 mmol) in 80 mL of CH2Cl2 was cooled in an ice bath whereupon benzyl chloroformate (16.3 mL, 114 mmol) was added. After stirring 1.5 h at R.T. the mixture was subjected to standard work-up conditions to give 13.9 g (55%) of N-Cbz-piperidine after chromatography (CHCl3 /MeOH; 10:1). [1H]-NMR(CDCl3) consistent with structure. was added