(2,5-dioxopyrrolidin-1-yl) (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoate

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

実験手順: 6.97 g (40.5 mmoles) of aminooxy-acetic acid hydrobromide are reacted with 14.68 g (40.5 mmoles) of BOC--Phe--OSu in 100 ml of DMF in the presence of 6.3 ml (45 mmoles) of triethylamine. Next day the reaction mixture is evaporated in vacuo, the oily residue is dissolved in 100 ml of chloroform, and the chloroform solution is washed thrice with 1 n hydrochloric acid. The organic solution is dried, evaporated in vacuo, and the oily residue is solidified with diisopropyl ether. The crude product is purified by precipitation from an ethyl acetate-diisopropyl ether solvent system. 9.70 g (74%) of BOC--Phe--OGly--OH are obtained; m.p.: 136°-137° C., Rf5 : 0.4, [α]D : -17.8° (c: 1.0, in ethanol). Next day the reaction mixture is evaporated in vacuo the oily residue is dissolved in 100 ml of chloroform the chloroform solution is washed thrice with 1 n hydrochloric acid The organic solution is dried evaporated in vacuo The crude product is purified by precipitation from an ethyl acetate-diisopropyl ether solvent system 9.70 g (74%) of BOC--Phe--OGly--OH are obtained

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

実験手順: To a solution of oxycodone-freebase (1.0 eq) in tetrahydrofuran (THF) (10 ml/mmol) was added LiN(TMS)2 (3.5 eq). After 5 minutes, Boc-Phe-OSu (3.5 eq) was added. The reaction was stirred at ambient temperatures for 18 hours, quenched with water and solvents removed. Crude protected product was purified using reverse-phase HPLC. Deprotection occurred with 4N HCl in dioxane (20 ml/mmol) to obtain Phe-Oxycodone. quenched with water and solvents removed was purified

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

実験手順: In a 10 ml solution of DMF containing 500 mg (1.38 mmol) of Boc-Phe-OSu was added 5 ml of an aqueous solution of H-Ser-OH.Et3N [preparation from 290 mg (2.76 mmol) of H-Ser-OH and 384 μl (2.76 mmol) of Et3N] and the mixture was stirred for 14 hr. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate and washed with 1N-HCl and saturated sodium chloride aqueous solution, successively, together with salting out. The resultant solution was dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the resulting residue was purified with a silica gel column chromatography (CHCl3:MeOH). The eluate was mixed with ether and n-hexane to give crystals of 150 mg of the title compound with yield of 31%. The reaction mixture was evaporated the residue was dissolved in ethyl acetate washed with 1N-HCl and saturated sodium chloride aqueous solution The resultant solution was dried over anhydrous sodium sulfate evaporated under reduced pressure the resulting residue was purified with a silica gel column chromatography (CHCl3:MeOH) The eluate was mixed with ether and n-hexane

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

実験手順: 6.97 g (40.5 mmoles) of aminooxy-acetic acid hydrobromide are reacted with 14.68 g (40.5 mmoles) of BOC--Phe--OSu in 100 ml of DMF in the presence of 6.3 ml (45 mmoles) of triethylamine. Next day the reaction mixture is evaporated in vacuo, the oily residue is dissolved in 100 ml of chloroform, and the chloroform solution is washed thrice with 1 n hydrochloric acid. The organic solution is dried, evaporated in vacuo, and the oily residue is solidified with diisopropyl ether. The crude product is purified by precipitation from an ethyl acetate-diisopropyl ether solvent system. 9.70 g (74%) of BOC--Phe--OGly--OH are obtained; m.p.: 136°-137° C., Rf5 : 0.4, [α]D : -17.8° (c: 1.0, in ethanol). Next day the reaction mixture is evaporated in vacuo the oily residue is dissolved in 100 ml of chloroform the chloroform solution is washed thrice with 1 n hydrochloric acid The organic solution is dried evaporated in vacuo The crude product is purified by precipitation from an ethyl acetate-diisopropyl ether solvent system 9.70 g (74%) of BOC--Phe--OGly--OH are obtained

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

実験手順: To a solution of oxycodone-freebase (1.0 eq) in tetrahydrofuran (THF) (10 ml/mmol) was added LiN(TMS)2 (3.5 eq). After 5 minutes, Boc-Phe-OSu (3.5 eq) was added. The reaction was stirred at ambient temperatures for 18 hours, quenched with water and solvents removed. Crude protected product was purified using reverse-phase HPLC. Deprotection occurred with 4N HCl in dioxane (20 ml/mmol) to obtain Phe-Oxycodone. quenched with water and solvents removed was purified

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

実験手順: To a 250 mL round bottom flask equipped with an addition funnel was added a solution of sodium 8-aminocaprylate (14.61 mmol, 32.5 mL, 1.2 equiv). The pH of the solution was adjusted to 8.2 by addition of concentrated HCl. The solution was cooled in an ice-bath. Boc-Phe-OSu (12.42 mmol, 4.50 g, 1.0 equiv) was dissolved in 1,4-dioxane (20 mL) and added dropwise. The mixture was stirred in the ice-bath for 30 min and at ambient temperature for 12 h. The solution was acidified with 1 M sulfuric acid (80 mL) and extracted with ether (100+50 mL). The combined organic layers were washed with water (40 mL), dried and evaporated to give a pale yellow oil. The oil was triturated with hexanes (3×50 mL) to afford (N-tert-butoxycarbonylphenylalanyl)-8-aminocaprylic acid (5) (2.17 g, 43%) as a colorless solid. To a 250 mL round bottom flask equipped with an addition funnel The solution was cooled in an ice-bath added dropwise extracted with ether (100+50 mL) The combined organic layers were washed with water (40 mL) dried evaporated to give a pale yellow oil The oil was triturated with hexanes (3×50 mL)

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

実験手順: To a 250 mL round bottom flask equipped with an addition funnel was added a solution of sodium 8-aminocaprylate (14.61 mmol, 32.5 mL, 1.2 equiv). The pH of the solution was adjusted to 8.2 by addition of concentrated HCl. The solution was cooled in an ice-bath. Boc-Phe-OSu (12.42 mmol, 4.50 g, 1.0 equiv) was dissolved in 1,4-dioxane (20 mL) and added dropwise. The mixture was stirred in the ice-bath for 30 min and at ambient temperature for 12 h. The solution was acidified with 1 M sulfuric acid (80 mL) and extracted with ether (100+50 mL). The combined organic layers were washed with water (40 mL), dried and evaporated to give a pale yellow oil. The oil was triturated with hexanes (3×50 mL) to afford (N-tert-butoxycarbonylphenylalanyl)-8-aminocaprylic acid (5) (2.17 g, 43%) as a colorless solid. To a 250 mL round bottom flask equipped with an addition funnel The solution was cooled in an ice-bath added dropwise extracted with ether (100+50 mL) The combined organic layers were washed with water (40 mL) dried evaporated to give a pale yellow oil The oil was triturated with hexanes (3×50 mL)

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

実験手順: In a 10 ml solution of DMF containing 500 mg (1.38 mmol) of Boc-Phe-OSu was added 5 ml of an aqueous solution of H-Ser-OH.Et3N [preparation from 290 mg (2.76 mmol) of H-Ser-OH and 384 μl (2.76 mmol) of Et3N] and the mixture was stirred for 14 hr. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate and washed with 1N-HCl and saturated sodium chloride aqueous solution, successively, together with salting out. The resultant solution was dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the resulting residue was purified with a silica gel column chromatography (CHCl3:MeOH). The eluate was mixed with ether and n-hexane to give crystals of 150 mg of the title compound with yield of 31%. The reaction mixture was evaporated the residue was dissolved in ethyl acetate washed with 1N-HCl and saturated sodium chloride aqueous solution The resultant solution was dried over anhydrous sodium sulfate evaporated under reduced pressure the resulting residue was purified with a silica gel column chromatography (CHCl3:MeOH) The eluate was mixed with ether and n-hexane

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

実験手順: To a solution of oxycodone-freebase (1.0 eq) in tetrahydrofuran (THF) (10 ml/mmol) was added LiN(TMS)2 (3.5 eq). After 5 minutes, Boc-Phe-OSu (3.5 eq) was added. The reaction was stirred at ambient temperatures for 18 hours, quenched with water and solvents removed. Crude protected product was purified using reverse-phase HPLC. Deprotection occurred with 4N HCl in dioxane (20 ml/mmol) to obtain Phe-Oxycodone. quenched with water and solvents removed was purified

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

実験手順: To a solution of oxycodone-freebase (1.0 eq) in tetrahydrofuran (THF) (10 ml/mmol) was added LiN(TMS)2 (3.5 eq). After 5 minutes, Boc-Phe-OSu (3.5 eq) was added. The reaction was stirred at ambient temperatures for 18 hours, quenched with water and solvents removed. Crude protected product was purified using reverse-phase HPLC. Deprotection occurred with 4N HCl in dioxane (20 ml/mmol) to obtain Phe-Oxycodone. quenched with water and solvents removed was purified

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

実験手順: To a solution of oxycodone-freebase (1.0 eq) in tetrahydrofuran (THF) (10 ml/mmol) was added LiN(TMS)2 (3.5 eq). After 5 minutes, Boc-Phe-OSu (3.5 eq) was added. The reaction was stirred at ambient temperatures for 18 hours, quenched with water and solvents removed. Crude protected product was purified using reverse-phase HPLC. Deprotection occurred with 4N HCl in dioxane (20 ml/mmol) to obtain Phe-Oxycodone. quenched with water and solvents removed was purified

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

実験手順: To a solution of 1-octylamine (0.9 g, 6.9 mmol) and triethylamine (0.7 g, 6.9 mmol) in ethyl acetate (80 ml) was added a solution of BOC-Phe-OSu (2.5 g, 6.9 mmol) in ethyl acetate (50 ml). The mixture was stirred at room temperature for 20 hours. The organic layer was washed with water, 10% sodium carbonate, water and brine and denied on MgSO4. Evaporation of the solvent in vacuo yielded MdL080 as a white powder (2.5 g, 6.6 mmol, 96%). 1H NMR (CDCl3): δ=7.26-7.14 (m, 5H), 5.59 (bp 1H), 5.02 (bp, 1H), 4.20 (m, 1H), 3.07 (m, 4H), 1.57-1.17 (m, 21H), 0.82 (t, 3H, 3J=6.8 Hz); 13C NMR (CDCl3): δ=170.98, 136.68, 129.19, 128.60, 126.76, 65.88, 39.34, 88.71, 31.66, 29.21, 29.07, 28.16, 26.64, 22.52, 13.97. The organic layer was washed with water, 10% sodium carbonate, water and brine Evaporation of the solvent in vacuo