亮氨酰胺

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Boc-norvaline (2.0 g, 9.2 mmol) and leucinamide (1.53 g, 9.2 mmol) were dissolved in dry DMF (90 mL). The reaction was cooled to 0° C. and DCC (2.3 g, 11 mmol), HOBt (1.48 g, 11 mmol), and DEA (1.9 mL, 11 mmol) added. The mixture was stirred for 20 min at 0° C. and allowed to slowly warm to room temperature overnight (17 h). The mixture was concentrated to 1/3 its original volume, cooled, and filtered. The filtrate was concentrated, affording a yellow oil which was purified by column chromatography (SiO2, 1:1 hexanes/EtOAc→EtOAc) providing Boc-norvaline-leucinamide as white solid (selected signals 400 MHz, 1H NMR, CDCI3: δ 4.93 (m, 1 H), 4.45 (m, 1 H), 3.99 (m, 1 H), 1.81-1.71 (m, 2 H), 1.68-1.50 (m, 4 H), 1.41 (s, 9 H), 1.4-1.3 (m, 2 H), 0.9 (m, 9 H)). The Boc-protecting group was removed by treatment of Boc-norvaline-leucinamide (1.5 g, 4.6 mmol) with 50% TFA/DCM (60 mL) at room temperature (30 min). The reaction mixture was concentrated in vacuo and the peptide triturated with diethyl ether and dried in vacuo overnight providing norvaline-leucinamide as a foamy white solid (Electrospray MS M+H=230.1). Boc-valine (233 mg, 1.1 mmol) and norvaline-leucinamide (246 mg, 1.1 mmol) were dissolved in DMF (5 mL) and the solution cooled to 0° C. DCC (266 mg, 1.3 mmol), HOBt (174 mg, 1.3 mmol), and DIEA (224 μL, 1.3 mmol) were added and the reaction allowed to slowly warm to RT (overnight, 17 h). The reaction was filtered and the filtrate concentrated in vacuo affording a solid which was purified by column chromatography (SiO2, EtOAc). This provided the desired Boc-valine-norvaline-leucinamide as a white solid. to slowly warm to room temperature overnight (17 h) The mixture was concentrated to 1/3 its original volume cooled filtered The filtrate was concentrated affording a yellow oil which was purified by column chromatography (SiO2, 1:1 hexanes/EtOAc→EtOAc)

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

实验步骤: 0.3 g (0.33 mmol) of N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine was dissolved in 15 ml of dichloromethane. 0.22 ml (1.98mmol) of N-methylmorpholine, 96 mg (0.5 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 45 mg (0.33 mmol) of hydroxybenzotriazole and 217 mg (0.99 mmol) of 3,3-difluoro-1(S)-(dimethoxymethyl)butylamine hydrochloride were added andthe solution was stirred at room temperature for 18hours. The mixture was washed with 2M hydrochloric acid and aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulphate and evaporated. The residuewas triturated with diethyl ether and the resulting solid was filtered off and dried. There were obtained 143 g of N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[3,3-difluoro-1(S)-dimethoxymethyl)butyl]-L-leucinamide; MS: m/e 1106 [M+Na]+. The mixture was washed with 2M hydrochloric acid and aqueous sodium hydrogen carbonate solution dried over anhydrous sodium sulphate evaporated The residuewas triturated with diethyl ether the resulting solid was filtered off dried

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 71 (40 mg) in DCM was added DIEA (45 uL) followed by isobutylchloroformate (26 uL). After stirring at room temperature for 30 min, leucine amide (18 mg) and DIEA (25 uL) was added and stirred for 1 h. The reaction mixture was evaporated and dissolved in MeOH, and purified with a preparative LC-MS to give compound 72. LCMS (+ESI) m/z=537.3 [M+H]+. stirred for 1 h The reaction mixture was evaporated dissolved in MeOH purified with a preparative LC-MS

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 71 (40 mg) in DCM was added DIEA (45 uL) followed by isobutylchloroformate (26 uL). After stirring at room temperature for 30 min, leucine amide (18 mg) and DIEA (25 uL) was added and stirred for 1 h. The reaction mixture was evaporated and dissolved in MeOH, and purified with a preparative LC-MS to give compound 72. LCMS (+ESI) m/z=537.3 [M+H]+. stirred for 1 h The reaction mixture was evaporated dissolved in MeOH purified with a preparative LC-MS

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

实验步骤: Compound 49 was prepared according to the procedure described for the synthesis of compound 37 by replacing intermediate 19 with intermediate 15, and replacing tert-leucine methylamide with L-leucine amide. 1H NMR (CDCl3) δ 7.49-7.58 (m, 2H), 7.34-7.38 (m, 1H), 7.18-7.24 (m, 1H), 4.50 (m, 1H), 3.58 (s, 2H), 3.20 (s, 2H), 2.27 (s, 3H), 2.53 (s, 3H), 1.71-1.82 (m, 3H), 0.88-0.99 (m, 6H). LCMS (+ESI) m/z=406.3 [M+H]+.

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

实验步骤: Compound 49 was prepared according to the procedure described for the synthesis of compound 37 by replacing intermediate 19 with intermediate 15, and replacing tert-leucine methylamide with L-leucine amide. 1H NMR (CDCl3) δ 7.49-7.58 (m, 2H), 7.34-7.38 (m, 1H), 7.18-7.24 (m, 1H), 4.50 (m, 1H), 3.58 (s, 2H), 3.20 (s, 2H), 2.27 (s, 3H), 2.53 (s, 3H), 1.71-1.82 (m, 3H), 0.88-0.99 (m, 6H). LCMS (+ESI) m/z=406.3 [M+H]+.

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

实验步骤: The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e=388.4 [M+H]+.

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

实验步骤: The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(isobutylthio)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e=364.5 [M+H]+.

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

实验步骤: The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(isobutylthio)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e=364.5 [M+H]+.

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

实验步骤: The title compound was synthesized in analogy to Example 1, using 6-(isobutylthio)picolinic acid (CAN 1247607-03-9) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e=324.2 [M+H]+.

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

实验步骤: The title compound was synthesized in analogy to Example 1, using 6-(isobutylthio)picolinic acid (CAN 1247607-03-9) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e=324.2 [M+H]+.

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

实验步骤: The title compound was synthesized in analogy to Example 1, using 6-(isobutylsulfonyl)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e=356.2 [M+H]+.