(2S)-2-氨基-3-苯丙酰胺

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

实验步骤: N-(Toluene-4-sulfonyl)-L-proline was reacted with L-phenylalanine amide using the procedure described in Method 12 to yield N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine amide. To a solution of NaH (60% mineral oil—prewashed with THF) in THF at 0° C. was added N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine amide and the reaction was stirred at 0° C. for 45 minutes. Toluene-4-sulfonyl chloride was added and the reaction was stirred for 16 hours at room temperature. The reaction mixture was extracted with EtOAc (3×50 mL) and 0.2 N HCl (50 mL), and the combined organic layers were washed successively with sat. NaHCO3 (50 mL), and sat. NaCl (2×50 mL), dried over MgSO4, filtered, and concentrated to yield the title compound as an oil.

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

实验步骤: N-(Toluene-4-sulfonyl)-L-proline was reacted with L-phenylalanine amide using the procedure described in Method 12 to yield N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine amide. To a solution of NaH (60% mineral oil—prewashed with THF) in THF at 0° C. was added N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine amide and the reaction was stirred at 0° C. for 45 minutes. Toluene-4-sulfonyl chloride was added and the reaction was stirred for 16 hours at room temperature. The reaction mixture was extracted with EtOAc (3×50 mL) and 0.2 N HCl (50 mL), and the combined organic layers were washed successively with sat. NaHCO3 (50 mL), and sat. NaCl (2×50 mL), dried over MgSO4, filtered, and concentrated to yield the title compound as an oil.

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

实验步骤: To a solution of L-Phenylalaninamide (3.93 g, 23.9 mmol) in acetonitrile (25 mL) was added 1,3-propane sultone (2.70 g, 21.8 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was filtered and washed with acetonitrile (2×25 mL). The solid product was suspended in EtOH (100 mL). The suspension was stirred at reflux for 1 hour. The solid material was filtered and dried in vacuo, affording the title compound (5.18 g, 83%). 1H NMR (D2O, 500 MHz) δ ppm 7.24 (m, 3H), 7.16 (m, 2H), 4.02 (m, 1H), 3.15 (m, 1H), 3.01 (m, 3H), 2.83 (m, 2H), 2.02 (m, 2H), 1.98 (m, 2H). 13C (D2O, 125 MHz) δ ppm 170.48, 133.72, 129.58, 129.21, 128.11, 61.55, 47.95, 45.52, 36.21, 21.44. [α]D=+23.1° (c=0.0021 in water), ES-MS 285 (M−1). at reflux for 2 hours The solid was filtered washed with acetonitrile (2×25 mL) The suspension was stirred at reflux for 1 hour The solid material was filtered dried in vacuo

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

实验步骤: To a solution of compound 3 (2.6 g, 12.3 mmol) in DMF was added HOBt.H2O (2.26 g, 14.76 mmol), EDC.HCl (2.80 g, 14.76 mmol), HCl.H-Phe-NH2 (3.16 g, 14.76 mmol), triethylamine (1.72 mL, 12.3 mmol) sequentially at 0° C. and the mixture was stirred for 14 h at room temperature. After the solvent was removed in vacuo, the residue was dissolved in AcOEt and washed with 5% citric acid, 5% NaHCO3 and saturated NaCl for three times, respectively. Then, the organic layer was dried over Na2SO4 and evaporated in vacuo. The resultant crude product was purified by silica-gel column chromatography (CHCl3:MeOH=100:1 to 10:1) to obtain the desired compound 4; yield 1.9 g (43.4%); m.p. 49-53° C.; 1H NMR (300 MHz, CDCl3) δ 11.04 (s, 1H), 7.82 (s, 1H), 7.34-7.22 (m, 5H), 6.24 (s, 1H), 5.96 (br s, 1H), 5.45 (br s, 1H), 4.78-4.71 (m, 1H), 3.24-3.11 (m, 2H), 1.38 (s, 9H); HRMS (EI): m/z 357.1689 (M+) (calced for C19H23N3O4: 357.1688). After the solvent was removed in vacuo the residue was dissolved in AcOEt washed with 5% citric acid, 5% NaHCO3 and saturated NaCl for three times Then, the organic layer was dried over Na2SO4 evaporated in vacuo The resultant crude product was purified by silica-gel column chromatography (CHCl3:MeOH=100:1 to 10:1)

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

实验步骤: Fmoc-Phe-OPfp (0.5 mmol) and HOBt (0.5 mmol) were added to a suspension of resin B (prepared from 185 mg, 0.1 mmol of the Fmoc-derivative) in DMF (5 ml) and the mixture was shaken for 1 hour. The resin was successively washed with DMF (5 ml×5), then treated with 20% piperidine in DMF (5 ml) for 15 min. The treated resin was washed with DMF (5 ml×5) and CH2Cl2 (5 ml×5) and dried in vacuo; yield 179 mg. The dried resin (5 mg) was treated with 1M thioanisole/TFA-m-cresole (100 μl-10 μl) at 28° C. for 60 min. H-Phe-NH2 liberated was determined by TLC scanner. The latter treated resin was subjected to 6N HCl hydrolysis. No Phe was detected by amino acid analyser. This result shows that phenylalanine had been cleaved almost completely from the resin. It was therefore established that resin B is useful as an amide precursor for amino acids and that the thioanisole-containing solution described above is a superior cleavage reagent. The resin was successively washed with DMF (5 ml×5) treated with 20% piperidine in DMF (5 ml) for 15 min The treated resin was washed with DMF (5 ml×5) and CH2Cl2 (5 ml×5) dried in vacuo The dried resin (5 mg) was treated with 1M thioanisole/TFA-m-cresole (100 μl-10 μl) at 28° C. for 60 min The latter treated resin was subjected to 6N HCl hydrolysis containing solution

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

实验步骤: Fmoc-Phe-OPfp (0.5 mmol) and HOBt (0.5 mmol) were added to a suspension of resin B (prepared from 185 mg, 0.1 mmol of the Fmoc-derivative) in DMF (5 ml) and the mixture was shaken for 1 hour. The resin was successively washed with DMF (5 ml×5), then treated with 20% piperidine in DMF (5 ml) for 15 min. The treated resin was washed with DMF (5 ml×5) and CH2Cl2 (5 ml×5) and dried in vacuo; yield 179 mg. The dried resin (5 mg) was treated with 1M thioanisole/TFA-m-cresole (100 μl-10 μl) at 28° C. for 60 min. H-Phe-NH2 liberated was determined by TLC scanner. The latter treated resin was subjected to 6N HCl hydrolysis. No Phe was detected by amino acid analyser. This result shows that phenylalanine had been cleaved almost completely from the resin. It was therefore established that resin B is useful as an amide precursor for amino acids and that the thioanisole-containing solution described above is a superior cleavage reagent. The resin was successively washed with DMF (5 ml×5) treated with 20% piperidine in DMF (5 ml) for 15 min The treated resin was washed with DMF (5 ml×5) and CH2Cl2 (5 ml×5) dried in vacuo The dried resin (5 mg) was treated with 1M thioanisole/TFA-m-cresole (100 μl-10 μl) at 28° C. for 60 min The latter treated resin was subjected to 6N HCl hydrolysis containing solution

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

实验步骤: Bz-Phe-2,4-dimethoxybenzylamide (4.2 mg) was dissolved in trifluoroacetic acid (1.0 ml) containing 10% (v/v) trifluoromethane sulfonic acid (TFMSA) and the reaction mixture was kept in the dark for 1 h at 20° C. TFA/TFMSA was removed by blowing with N2 and the residue was suspended in 95% (v/v) CH3CN (1.0 ml). The reaction mixture was analyzed by HPLC system-7 and the generated Bz-Phe-NH2 (>95%) was determined quantitatively using a Bz-Phe-NH2 standard solution (Bz-Phe-NH2 was purchased from Bachem, Switzerland). dark for 1 h at 20° C TFA/TFMSA was removed

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

实验步骤: The title compound was prepared from L-Phe-NH2 following the procedure for 2,3-Dioxo-2,3-dihydro-1H-indole-5-sulfonic acid propylamide.

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

实验步骤: To a solution of compound 3 (2.6 g, 12.3 mmol) in DMF was added HOBt.H2O (2.26 g, 14.76 mmol), EDC.HCl (2.80 g, 14.76 mmol), HCl.H-Phe-NH2 (3.16 g, 14.76 mmol), triethylamine (1.72 mL, 12.3 mmol) sequentially at 0° C. and the mixture was stirred for 14 h at room temperature. After the solvent was removed in vacuo, the residue was dissolved in AcOEt and washed with 5% citric acid, 5% NaHCO3 and saturated NaCl for three times, respectively. Then, the organic layer was dried over Na2SO4 and evaporated in vacuo. The resultant crude product was purified by silica-gel column chromatography (CHCl3:MeOH=100:1 to 10:1) to obtain the desired compound 4; yield 1.9 g (43.4%); m.p. 49-53° C.; 1H NMR (300 MHz, CDCl3) δ 11.04 (s, 1H), 7.82 (s, 1H), 7.34-7.22 (m, 5H), 6.24 (s, 1H), 5.96 (br s, 1H), 5.45 (br s, 1H), 4.78-4.71 (m, 1H), 3.24-3.11 (m, 2H), 1.38 (s, 9H); HRMS (EI): m/z 357.1689 (M+) (calced for C19H23N3O4: 357.1688). After the solvent was removed in vacuo the residue was dissolved in AcOEt washed with 5% citric acid, 5% NaHCO3 and saturated NaCl for three times Then, the organic layer was dried over Na2SO4 evaporated in vacuo The resultant crude product was purified by silica-gel column chromatography (CHCl3:MeOH=100:1 to 10:1)

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

实验步骤: To a solution of compound 3 (2.6 g, 12.3 mmol) in DMF was added HOBt.H2O (2.26 g, 14.76 mmol), EDC.HCl (2.80 g, 14.76 mmol), HCl.H-Phe-NH2 (3.16 g, 14.76 mmol), triethylamine (1.72 mL, 12.3 mmol) sequentially at 0° C. and the mixture was stirred for 14 h at room temperature. After the solvent was removed in vacuo, the residue was dissolved in AcOEt and washed with 5% citric acid, 5% NaHCO3 and saturated NaCl for three times, respectively. Then, the organic layer was dried over Na2SO4 and evaporated in vacuo. The resultant crude product was purified by silica-gel column chromatography (CHCl3:MeOH=100:1 to 10:1) to obtain the desired compound 4; yield 1.9 g (43.4%); m.p. 49-53° C.; 1H NMR (300 MHz, CDCl3) δ 11.04 (s, 1H), 7.82 (s, 1H), 7.34-7.22 (m, 5H), 6.24 (s, 1H), 5.96 (br s, 1H), 5.45 (br s, 1H), 4.78-4.71 (m, 1H), 3.24-3.11 (m, 2H), 1.38 (s, 9H); HRMS (EI): m/z 357.1689 (M+) (calced for C19H23N3O4: 357.1688). After the solvent was removed in vacuo the residue was dissolved in AcOEt washed with 5% citric acid, 5% NaHCO3 and saturated NaCl for three times Then, the organic layer was dried over Na2SO4 evaporated in vacuo The resultant crude product was purified by silica-gel column chromatography (CHCl3:MeOH=100:1 to 10:1)

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

实验步骤: 7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with phenylalaninamide (38 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 47 mg of the title compound. the organic phase washed sequentially with water, and brine dried over anhydrous magnesium sulfate filtered concentrated under vacuum to provide a residue This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate The product containing band was collected eluted with 5% methanol in ethyl acetate

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

实验步骤: 7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with phenylalaninamide (38 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 47 mg of the title compound. the organic phase washed sequentially with water, and brine dried over anhydrous magnesium sulfate filtered concentrated under vacuum to provide a residue This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate The product containing band was collected eluted with 5% methanol in ethyl acetate