Synthesis of Thiophene-Containing Compound 009

Example 7

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Step 1:

Compound 1 (830 mg, 5 mmol) and cyclopropanecarboxylic acid (430 mg, 5 mmol) were combined in 4M HCl (20 mL). The reaction was refluxed overnight. After completed, the mixture was concentrated and purified by Prep-HPLC. White solid was afforded as Compound 2 (312 mg, 31%).

Step 2:

Compound 2 (100 mg, 0.50 mmol), tert-butyl 2-amino-4-(thiophen-2-yl)phenylcarbamate (144 mg, 0.50 mmol), and EDCI (288 mg, 1.50 mmol) were combined in Py (5 mL). The reaction was stirred at rt overnight. After completed, the mixture was concentrated and purified by column chromatography (DCM/MeOH=10/1). Compound 3 was isolated as a colorless oil (54 mg, 23%).

Step 3:

Compound 3 (54 mg, 0.11 mmol) was dissolved in DCM (2 ml). Then TFA (1 ml) was added. The mixture was stirred at rt for 2 h. The crude material was concentrated and washed with Et₂O. Compound 009 was isolated as a white solid (30 mg, TFA salt). LCMS: m/z=375.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO) δ 9.96 (s, 1H), 8.26 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.50 (s, 1H), 7.35 (dd, J=8.5, 2.5 Hz, 2H), 7.28 (d, J=3.0 Hz, 1H), 7.07 (t, J=3.5 Hz, 1H), 6.88 (s, 1H), 2.42 (t, J=3.0 Hz, 1H), 1.37 (dd, J=2.5 Hz, 4H).