Synthesis
General procedure: 4-methylbenzene-1-sulfonyl chloride (759 mg, 3.98 mmol), 3-(methylsulfonyl)propan-1-ol (500 mg, 3.62 mmol), and triethylamine (0.555 mL, 3.98 mmol) were dissolved in dry dichloromethane (5 mL), and the reaction mixture was stirred under nitrogen atmosphere for 12 hours. Upon completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by semi-preparative HPLC-UV to afford 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (881 mg, 83% yield) as a white solid.MS (ESI+) m/z: 293.1 [M + H]+.
Tert-butyl (4-hydroxy-2,6-dimethylphenyl)carbamate (269 mg, 1.13 mmol), 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (398 mg, 1.36 mmol), and potassium carbonate (188 mg, 1.36 mmol) were dissolved in dry N,N-dimethylformamide (2.5 mL), and the reaction mixture was stirred for 12 h at 80 °C and under nitrogen atmosphere. The reaction mixture was stirred at 80 °C and under nitrogen for 12 hours. After completion of the reaction, ethyl acetate (20 mL) was added and the mixture was washed with brine (2 x 10 mL). The organic layer was concentrated under reduced pressure and the residue was purified by semi-preparative HPLC-UV to afford tert-butyl (2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)carbamate (375 mg, 93% yield) as a white solid.MS (ESI+) m/z: 380.2 [M + Na]+.
From tert-butyl (2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)carbamate (375 mg, 1.05 mmol), the synthesis of compound 34 was followed to afford 2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)aniline hydrochloride (309 mg, quantitative yield).MS (ESI+) m/z: 258.1 [ M + H]+.
From 2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)aniline hydrochloride (46.1 mg, 0.157 mmol), methyl 7-(3-(N-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)aminosulfonyl)phenyl)heptanoate was obtained as described in Method A (33 mg, 39% yield).MS (ESI+) ) m/z: 562.3 [M + Na]+.
Compound 35 was then obtained by hydrolysis of the ester derivative (20 mg, 0.046 mmol) as a white solid (23 mg, 83% yield) following the synthesis of compound 1. 1H NMR (300 MHz, chloroform-d) δ ppm 1.24-1.43 (m, 4H), 1.51-1.67 (m, 4H), 1.96 (s, 6H). 2.26-2.41 (m, 4H), 2.61 (t, J=7.58 Hz, 2H), 2.97 (s, 3H), 3.22-3.31 (m, 2H), 4.04 (t, J=5.68 Hz, 2H), 6.32 (br s, 1H), 6.52 (s, 2H), 7.33-7.41 (m, 2H), 7.48- 7.58 (m, 2H), 9.36 (br s, 2H).MS (ESI+) m/z: 526.2 [M + H]+.
References
[1] Patent: WO2018/29150, 2018, A1. Location in patent: Page/Page column 37-38
[2] Patent: WO2013/144098, 2013, A1. Location in patent: Page/Page column 96
[3] Patent: WO2015/89809, 2015, A1. Location in patent: Page/Page column 62
[4] Patent: WO2015/95256, 2015, A1. Location in patent: Page/Page column 62; 63
[5] Patent: WO2017/13046, 2017, A1. Location in patent: Page/Page column 34-35
