克霉唑EP杂质C

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

实验步骤: A mixture of 2-ethyl-4-formylimidazole attached to 2-chlorotrityl resin (4, 78 mg, 0.052 mmol based on 0.67 mmol/g loading), DMF (0.9 ml) and piperidine (0.1 ml) was gently stirred for 45 min. at ambient temperature, afterwhich was added 2-indolinone (5, 70 mg, 0.523 mmol). The resultant mixture was gently stirred and heated at 80° C. for 20 h. The resin was filtered and washed with 30 ml each of acetone, water, dichloromethane, methanol, and another portion of acetone. Finally, the resin was air dried for 20 min. heated at 80° C. for 20 h The resin was filtered washed with 30 ml each of acetone, water, dichloromethane, methanol dried for 20 min.

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

实验步骤: Following the procedure outlined in Example 4, 5.00 g (17.1 mmol) of (2-chlorophenyl) diphenyl methanol, designated as T-3 on Appendix A, was treated with 2.5 ml thionyl chloride (34 mmol) according to general method B to give 4.39 g (82%) of (2-Chlorophenyl) diphenyl chloromethane, mp: 131° C.

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

实验步骤: To 3 g of 2-chlorotrityl chloride resin with 1.3 mmol/g substitution (Novabiochem, 01-64-0114) in 30 ml of dry DCM in 30 ml reaction vessel for solid phase synthesis, 2.577 g (5.85 mmol, 1.5 eq) of Fmoc-Dab(diBoc)-OH (Mw=440.5, (Fmoc-(N-γ-Boc)-L-α,γ-diaminobutyric acid, AnaSpec, 28246) and 2.23 ml (12.87 mmol, 3.3 eq) of DIPEA (Aldrich, Mw=129.2, d=0.74) were added. were added

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

实验步骤: Chlorotrityl chloride resin (2.3 g, 3.0 mmol) was swelled in DCM for 20 mins and filtered. Dimethylmalonic acid (2 eq; 6.0 mmol; 793 mg) was dissolved i DCM:NMP 1:1 (10 mL) and added to the resin followed by DIPEA (6 eq; 18.0 mmol; 3.14 mL) and DCM (10 mL). The resin was shaken overnight at RT. The resin was filtered and washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each). The resin was swelled in NMP for 20 mins and filtered. HOAt (3 eq; 9.0 mmol; 1.23 g), DIC (3 eq; 9.0 mmol; 1.40 mL) and NMP (25 mL) was added and the resin was shaken for 90 min at RT. The resin was filtrered and 2-(Aminomethyl)pyridine (2 eq; 6 mmol; 659 mg), DIPEA (4 eq; 6.0 mmol; 2.09 mL), and NMP (10 mL) was added. The resin was shaken for overnigth. The resin was filtered and washed with NMP (5×20 mL) and DCM (10×20 mL). TFA/TIS/water (95:2.5:2.5; 30 mL) was added to the resin and it was shaked for 1 hr, filtered and concentrated in vacuo to yield the title compound. filtered added to the resin The resin was filtered washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each) The resin was swelled in NMP for 20 mins filtered the resin was shaken for 90 min at RT The resin was shaken for overnigth The resin was filtered washed with NMP (5×20 mL) and DCM (10×20 mL) TFA/TIS/water (95:2.5:2.5; 30 mL) was added to the resin and it was shaked for 1 hr filtered concentrated in vacuo

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

实验步骤: 2-Chlorotrityl chloride resin (2.3 g, 3.0 mmol) was swelled in DCM for 20 mins and filtered. Dimethylmalonic acid (2 eq; 6.0 mmol; 793 mg) was dissolved i DCM:DMF 1:1 (10 mL) and added to the resin followed by DIPEA (6 eq; 18.0 mmol; 3.14 mL) and DCM (10 mL). The resin was shaken overnight at RT. The resin was filtered and washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each). The resin was swelled in DMF for 20 mins and filtered. HOAt (3 eq; 9.0 mmol; 1.23 g), DIC (3 eq; 9.0 mmol; 1.40 mL) and DMF (25 mL) was added and the resin was shaken for 90 min at RT. The resin was filtrered and 3-(1-Trityl-1H-imidazol-4-yl)-propyl amine (1.8 eq; 5.40 mmol; 1.84 g), DIPEA (4 eq; 6.0 mmol; 2.09 mL), and DMF (10 mL) was added. The resin was shaken for 2 days. The resin was filtered and washed with NMP (5×20 mL) and DCM (10×20 mL). 2,2,2-Trifluoroethanol/dichlormethan 1:1 (20 mL) was added to the resin and it was shaked for 2 hrs. The resin was washed with 2,2,2-Trifluoroethanol/dichlormethan 1:1 (10 mL) and the combined filtrates were collected and concentrated in vacuo to yield the title compound. filtered added to the resin The resin was filtered washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each) The resin was swelled in DMF for 20 mins filtered the resin was shaken for 90 min at RT The resin was shaken for 2 days The resin was filtered washed with NMP (5×20 mL) and DCM (10×20 mL) 2,2,2-Trifluoroethanol/dichlormethan 1:1 (20 mL) was added to the resin and it was shaked for 2 hrs The resin was washed with 2,2,2-Trifluoroethanol/dichlormethan 1:1 (10 mL) the combined filtrates were collected concentrated in vacuo

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

实验步骤: 2-Chlorotrityl resin (0.536 g, 0.75 mmol/g) was placed in a dry glass fritted shaker flask. To the resin was added CH2Cl2 (10 mL), diisopropylethylamine (0.522 mL) and Fmoc-L-asparagine (0.265 g, 0.75 mmol) and the reaction was agitated on an orbital shaker for 14 h. The reaction solution was drained and the resin washed with CH2Cl2/MeOH/DIEA (17:2:1; 3×10 mL), CH2Cl2 (3×10 mL), DMF (3×10 mL), and CH2Cl2 (3×10 mL). The resin was swelled with DMF (2 mL) and the solvent drained. A solution of 50% piperidine in DMF (10 mL) was added to the resin and the reaction was agitated on an orbital shaker for 90 min. The reaction solution was drained and the resin washed with DMF (2×10 mL), CH2Cl2 (2×10 mL), DMF (2×10 mL), CH2Cl2 (2×10 mL), and DMA (1×2 mL). (R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (0.132 g, 0.30 mmol) and HATU (0.285 g, 0.75 mmol) were dissolved in DMA (2 mL), and the resulting solution added to the resin. Diisopropylethylamine (0.130 mL, 0.75 mmol) was added and the reaction agitated on an orbital shaker for 48 h. The reaction solution was drained and washed as described above. The resin was treated with 10% TFA in CH2Cl2 and agitated on an orbital shaker for 90 min. The reaction solution was collected and the resin washed with CH2Cl2 (4×3 mL). The filtrates were combined with the supernatant and the volatiles removed in vacuo at 40° C. The residue was dissolved in CH2Cl2 (5 mL) and washed with water (2×5 mL) and brine (5 mL). The organic layer was dried over anhydrous Na2SO4, the solution decanted, and the solvent removed in vacuo to afford 0.122 g (73%) of (R)-2-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-succinamic acid as an orange foam. the resin washed with CH2Cl2/MeOH/DIEA (17:2:1; 3×10 mL), CH2Cl2 (3×10 mL), DMF (3×10 mL), and CH2Cl2 (3×10 mL) A solution of 50% piperidine in DMF (10 mL) was added to the resin the reaction was agitated on an orbital shaker for 90 min the resin washed with DMF (2×10 mL), CH2Cl2 (2×10 mL), DMF (2×10 mL), CH2Cl2 (2×10 mL), and DMA (1×2 mL) the resulting solution added to the resin the reaction agitated on an orbital shaker for 48 h washed The resin was treated with 10% TFA in CH2Cl2 agitated on an orbital shaker for 90 min The reaction solution was collected the resin washed with CH2Cl2 (4×3 mL) the volatiles removed in vacuo at 40° C The residue was dissolved in CH2Cl2 (5 mL) washed with water (2×5 mL) and brine (5 mL) The organic layer was dried over anhydrous Na2SO4 the solution decanted the solvent removed in vacuo

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

实验步骤: Following the procedure outlined in Example 4, 5.00 g (17.1 mmol) of (2-chlorophenyl) diphenyl methanol, designated as T-3 on Appendix A, was treated with 2.5 ml thionyl chloride (34 mmol) according to general method B to give 4.39 g (82%) of (2-Chlorophenyl) diphenyl chloromethane, mp: 131° C.

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

实验步骤: Add a solution of pyridine-3,5-dicarboxylic acid (220 mg, 1.32 mmol), diisopropylethylamine (918 μL, 5.28 mmol), and DMF (1.5 mL) in dichloromethane (10 mL) to 2-chlorotritylchloride resin (11.0 g, 1.1 mmol) in a peptide synthesis vessel and mix for 3 h. Filter and wash the resin with a 17:2:1 mixture of dichloromethane:methanol:diisopropylethylamine, followed by dichloromethane. Add a solution of methylpropylamine (225 μL, 2.2 mmol), and benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (1.14 g, 2.2 mmol) in dichloromethane (10 mL) to the resin and mix for 1 h. Filter and wash the resin with dichloromethane (2×10 mL). Add a solution of 5% trifluoroacetic acid in dichloromethane (10 mL) to the resin and let stand for 10 min. Filter the resin and wash with dichloromethane (2×10 mL). Combine the filtrates and concentrate to give the title compound (110 mg, 50%). mix for 3 h Filter wash the resin with a 17:2:1 mixture of dichloromethane mix for 1 h Filter wash the resin with dichloromethane (2×10 mL) Add a solution of 5% trifluoroacetic acid in dichloromethane (10 mL) to the resin Filter the resin wash with dichloromethane (2×10 mL) Combine the filtrates and concentrate

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

实验步骤: To 3 g of 2-chlorotrityl chloride resin with 1.3 mmol/g substitution (Novabiochem, 01-64-0114) in 30 ml of dry DCM in 30 ml reaction vessel for solid phase synthesis, 2.577 g (5.85 mmol, 1.5 eq) of Fmoc-Dab(diBoc)-OH (Mw=440.5, (Fmoc-(N-γ-Boc)-L-α,γ-diaminobutyric acid, AnaSpec, 28246) and 2.23 ml (12.87 mmol, 3.3 eq) of DIPEA (Aldrich, Mw=129.2, d=0.74) were added. were added

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

实验步骤: To 3 g of 2-chlorotrityl chloride resin with 1.3 mmol/g substitution (Novabiochem, 01-64-0114) in 30 ml of dry DCM in 30 ml reaction vessel for solid phase synthesis, 2.577 g (5.85 mmol, 1.5 eq) of Fmoc-Dab(diBoc)-OH (Mw=440.5, (Fmoc-(N-γ-Boc)-L-α,γ-diaminobutyric acid, AnaSpec, 28246) and 2.23 ml (12.87 mmol, 3.3 eq) of DIPEA (Aldrich, Mw=129.2, d=0.74) were added. were added

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

实验步骤: To 3 g of 2-chlorotrityl chloride resin with 1.3 mmol/g substitution (Novabiochem, 01-64-0114) in 30 ml of dry DCM in 30 ml reaction vessel for solid phase synthesis, 2.577 g (5.85 mmol, 1.5 eq) of Fmoc-Dab(diBoc)-OH (Mw=440.5, (Fmoc-(N-γ-Boc)-L-α,γ-diaminobutyric acid, AnaSpec, 28246) and 2.23 ml (12.87 mmol, 3.3 eq) of DIPEA (Aldrich, Mw=129.2, d=0.74) were added. were added

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

实验步骤: A mixture of 2-ethyl-4-formylimidazole attached to 2-chlorotrityl resin (4, 78 mg, 0.052 mmol based on 0.67 mmol/g loading), DMF (0.9 ml) and piperidine (0.1 ml) was gently stirred for 45 min. at ambient temperature, afterwhich was added 2-indolinone (5, 70 mg, 0.523 mmol). The resultant mixture was gently stirred and heated at 80° C. for 20 h. The resin was filtered and washed with 30 ml each of acetone, water, dichloromethane, methanol, and another portion of acetone. Finally, the resin was air dried for 20 min. heated at 80° C. for 20 h The resin was filtered washed with 30 ml each of acetone, water, dichloromethane, methanol dried for 20 min.