新斯的明杂质23

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: When diethylcarbamylchloride is replaced in the above procedure by carbamyl chloride (prepared in situ from potassium cyanate and anhydrous hydrogen chloride in anhydrous chloroform), ethylcarbamyl chloride or dimethylcarbamyl chloride, then the products prepared are α-carbamylthio2'-chloro-4-biphenylylacetic acid, α-ethylcarbamylthio-2'-chloro-4-biphenylylacetic acid or α-dimethylcarbamylthio-2'-chloro-4-biphenylylacetic acid. the products prepared

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: When diethylcarbamylchloride is replaced in the above procedure by carbamyl chloride (prepared in situ from potassium cyanate and anhydrous hydrogen chloride in anhydrous chloroform), ethylcarbamyl chloride or dimethylcarbamyl chloride, then the products prepared are α-carbamylthio2'-chloro-4-biphenylylacetic acid, α-ethylcarbamylthio-2'-chloro-4-biphenylylacetic acid or α-dimethylcarbamylthio-2'-chloro-4-biphenylylacetic acid. the products prepared

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of carbamoyl chloride in a suitable solvent such as chlorobenzene is introduced by line 1 into reactor 3 and a slight excess of 1,3-dimethylurea in chlorobenzene usually containing some 1,3-dimethylurea hydrochloride in chlorobenzene is added by line 2 to reactor 3 which is operated at 30° to 40° C. A slurry of 1,3-dimethylurea hydrochloride (solid phase) and methyl isocyanate in chlorobenzene (liquid phase) is formed and the slurry is removed by line 4 to filter 5. The liquid phase from the filter is removed by line 6 to distillation column 7 wherein the solution is distilled to remove methyl isocyanate by line 8 after condensation in condensor 9. The chlorobenzene solvent from distillation column 7 is passed by line 10 to wash the filter and obtain a slurry of chlorobenzene and 1,3-dimethylurea hydrochloride. is added by line 2 to reactor 3 which is operated at 30° to 40° C

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of carbamoyl chloride in a suitable solvent such as chlorobenzene is introduced by line 1 into reactor 3 and a slight excess of 1,3-dimethylurea in chlorobenzene usually containing some 1,3-dimethylurea hydrochloride in chlorobenzene is added by line 2 to reactor 3 which is operated at 30° to 40° C. A slurry of 1,3-dimethylurea hydrochloride (solid phase) and methyl isocyanate in chlorobenzene (liquid phase) is formed and the slurry is removed by line 4 to filter 5. The liquid phase from the filter is removed by line 6 to distillation column 7 wherein the solution is distilled to remove methyl isocyanate by line 8 after condensation in condensor 9. The chlorobenzene solvent from distillation column 7 is passed by line 10 to wash the filter and obtain a slurry of chlorobenzene and 1,3-dimethylurea hydrochloride. is added by line 2 to reactor 3 which is operated at 30° to 40° C

反应条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Oxycodone free base (6.5 g, 20.6 mmol) was dissolved in dry, degassed tetrahydrofuran (120 mL), and the mixture was cooled to −10° C. using a dry ice/acetone bath. Potassium bis(trimethylsilyl)amide (KHMDS) (103.0 mL, 51.6 mmol, 0.5 M in toluene) was added via cannula. The mixture was stirred under N2 at below −5° C. for 30 min. N,N-Bis(tert-butyl) N′-2-(chlorocarbonyl(methyl)amino)ethylcarbamate (8.0 g, 23.7 mmol), (Compound C) in THF (30 mL) was then added via cannula over 15 min. The mixture was stirred at −5° C. for 30 min. Another portion of carbamoyl chloride (4.0 g, 11.9 mmol) in THF (10 mL) was added. The reaction was stirred at room temperature for 2 h. Sodium bicarbonate (10 mL, sat. aq.) was added. The mixture was concentrated in vacuo to half of its initial volume. EtOAc (50 mL) was added, and layers were separated. The organic phase was further washed with water (3×20 mL) and brine (40 mL), and then was concentrated. The residue was purified by silica gel chromatography, using DCM/MeOH (gradient 100/1 to 100/15) to afford a white foam in 55% yield (7.0 g, 13.4 mmol). This material was dissolved in a 1:1 mixture of DCM/trifluoroacetic acid (TFA) (20 mL/20 mL) at room temperature and stirred for 1 h. The solution was then concentrated in vacuo to afford a TFA salt of oxycodone 6-(N-methyl-N-(2-amino)ethylcarbamate (Compound KC-19) as a thick oil (7.3 g, 11.4 mmol, 99% purity). MS: (m/z) calc: 415.2, observed (M+H+) 416.5. in dry degassed tetrahydrofuran (120 mL) The mixture was stirred at −5° C. for 30 min The reaction was stirred at room temperature for 2 h The mixture was concentrated in vacuo to half of its initial volume EtOAc (50 mL) was added layers were separated The organic phase was further washed with water (3×20 mL) and brine (40 mL) was concentrated The residue was purified by silica gel chromatography to afford a white foam in 55% yield (7.0 g, 13.4 mmol) stirred for 1 h The solution was then concentrated in vacuo

反应条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Oxycodone free base (6.5 g, 20.6 mmol) was dissolved in dry, degassed tetrahydrofuran (120 mL), and the mixture was cooled to −10° C. using a dry ice/acetone bath. Potassium bis(trimethylsilyl)amide (KHMDS) (103.0 mL, 51.6 mmol, 0.5 M in toluene) was added via cannula. The mixture was stirred under N2 at below −5° C. for 30 min. N,N-Bis(tert-butyl) N′-2-(chlorocarbonyl(methyl)amino)ethylcarbamate (8.0 g, 23.7 mmol), (Compound C) in THF (30 mL) was then added via cannula over 15 min. The mixture was stirred at −5° C. for 30 min. Another portion of carbamoyl chloride (4.0 g, 11.9 mmol) in THF (10 mL) was added. The reaction was stirred at room temperature for 2 h. Sodium bicarbonate (10 mL, sat. aq.) was added. The mixture was concentrated in vacuo to half of its initial volume. EtOAc (50 mL) was added, and layers were separated. The organic phase was further washed with water (3×20 mL) and brine (40 mL), and then was concentrated. The residue was purified by silica gel chromatography, using DCM/MeOH (gradient 100/1 to 100/15) to afford a white foam in 55% yield (7.0 g, 13.4 mmol). This material was dissolved in a 1:1 mixture of DCM/trifluoroacetic acid (TFA) (20 mL/20 mL) at room temperature and stirred for 1 h. The solution was then concentrated in vacuo to afford a TFA salt of oxycodone 6-(N-methyl-N-(2-amino)ethylcarbamate (Compound KC-19) as a thick oil (7.3 g, 11.4 mmol, 99% purity). MS: (m/z) calc: 415.2, observed (M+H+) 416.5. in dry degassed tetrahydrofuran (120 mL) The mixture was stirred at −5° C. for 30 min The reaction was stirred at room temperature for 2 h The mixture was concentrated in vacuo to half of its initial volume EtOAc (50 mL) was added layers were separated The organic phase was further washed with water (3×20 mL) and brine (40 mL) was concentrated The residue was purified by silica gel chromatography to afford a white foam in 55% yield (7.0 g, 13.4 mmol) stirred for 1 h The solution was then concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine nitric acid salt (100 mg, 0.394 mmol) was dissolved CH2Cl2 and triethylamine (119 mg, 166 μL, 1.182 mmol, 3.0 eq) followed by carbamoyl chloride (46.4 mg, 39.7 μL, 0.433 mmol, 1.1 eq) were added. The reaction was stirred at room temperature for 4 hours and then concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-5% MeOH/CH2Cl2 as the eluting solvent to obtain 7-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-carboxylic acid dimethylamide as a light orange oil (88 mg, 85%). LCMS (m/e) 264 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.01-7.95 (m, 2H), 7.26 (d, 1H, J=9.3 Hz), 3.45-3.39 (m, 4H), 3.11-3.04 (m, 4H), 2.84 (s, 3H), 2.83 (s, 3H). were added concentrated under reduced pressure Purification by silica gel chromatography