| 404.1 mg |
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 0.333333h; |
77.4 Preparation of (25, 4 ?)-l-[(25)-2-{2-[3-(2-{2-[(95)-7-(4-chlorophenyl)-4,5, 13- trimethyl-3-thia-l,8,l l,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10, 12-pentaen-9- yl]acetamido}ethoxy)propoxy]acetamido}-3,3-dimethylbutanoyl]-4-hydroxy-N-[(i5)-l-[4-(4- methyl-l,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (Example 77).
To a stirred solution of (5)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl) acetic acid (900 mg, 2.32 mmol), ieri-butyl 2-(3-(2- aminoethoxy)propoxy) acetate (650 mg, 2.79 mmol), and DIPEA (1.5 g, 11.61 mmol) in anhydrous N,N-dimethylformamide (6 mL) was added HATU (2.65 mg, 6.97 mmol) at 0°C, the resulting mixture was stirred at rt for 20 min. LC-MS showed the reaction was completed. The mixture was partitioned between ethyl acetate (100 mL) and water (40 mL). The aqueous layer was extracted with ethyl acetate (50 mL x 2). The combined organic layers were collected, washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluted with 2-10% MeOH in DCM) to afford (S)-tert-buty 2-(3-(2-(2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)acetamido)ethoxy)propoxy)acetate (800 mg, yield 58%) as white solid. This solid (800 mg, 1.30 mmol) in formic acid (5 mL) was stirred at 60 °C for 1 h. TLC showed the reaction was completed. The volatiles were evaporated under reduced pressure to afford (5)-2-(3-(2-(2-(4- (4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)acetamido)ethoxy)propoxy)acetic acid as a crude yellow oil without further purification. The oily material (700 mg, Crude) was mixed with (25,4i?)-l-[(5')-2-amino-3,3-dimethylbutanoyl]- 4-hydroxy-N-[(5) -(4-(4-methylthiazol-5-yl)phenyl)ethyl]-pyrrolidine-2-carboxamide hydrochloride (UTM-2, 920 mg,1.91 mmol), DIPEA (1.05 g, 8.11 mmol), HATU (1.85 g, 4.87 mmol) in anhydrous N,N-dimethylformamide (8 mL) at 0°C, the resulting mixture was stirred at room temperature for 20 min. LC-MS showed the reaction was completed. The mixture was partitioned between ethyl acetate (60 mL) and water (30 mL). The aqueous layer was extracted with ethyl acetate (30 mL x 2). The combined organic layers were collected, washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by preparative HPLC to afford the title compound in Example 77 (404.1 mg, yield 32%) as white solid. H NMR (400 MHz, CD3OD): δ 1.06 (s, 9H), 1.51 & 1.59 (d, J = 6.8 Hz, 3H), 1.72 (s, 3H), 1. 93-2.00 (m, 3H), 2.20-2.25 (m, IH), 2.46 (s, 3H), 2.49 (s, 3H), 2.71 (s, 3H), 3.45-3.67 (m, 10H), 3.75-3.78 (m, IH), 3.85-3.88 (m, IH), 3.95-4.05 (m, 2H), 4.45 (br, IH), 4.59-4.71 (m, 3H), 4.99-5.04 (m, IH), 7.40-7.49 (m, 8H), 7.57 (d, J = 9.6 Hz, IH), 8.89 (s, IH); LC-MS (ES+): m/z 986.4/988.4 [M+H+] |
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