[1,4′-Bipiperidine]-1′-carbonyl chloride

13, 5, 7-Trihydroxy-2- (4-methoxyphenyl) -8- (3-methylbut-2-en-1-yl) -4H-chromen-4-one (150 mg , 0.41 mmol) was dissolved in drypyridine (10 mL), and then a solution of [1, 4'-bipiperidine] -1'-formyl chloride (235 mg, 1.02 mmol) in dichloromethane (10 mL) was added.Thereaction mixture was stirred at room temperature overnight undernitrogen protection, extracted with dichloromethane (40 mL × 3), combined organic phases, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (dichloromethane: methanol = 15: 1) to give the title compound(55 mg, yield: 18%)as a yellow solid.To a stirred solution of fulvestrant (0.2 g) in chloroform (6 ml) and water (1 ml), sodium hydroxide (0.132 g) and tetra-n-butylammonium bromide (0.128 g) was added at room temperature and vigorously stirred at room temperature for 30 min. 4-Piperidinopiperidine-l -carbonyl chloride (0.097 g) was added to the reaction mixture and stirred at room temperature for 16 h. The reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was evaporated under vacuum to obtain crude material. The crude material was purified by preparative HPLC using mobile phase A) 5 mmol ammonium bicarbonate + 0.1% N in water and B) acetonitrile. Product fraction was lyophilized to afford (7R, 8R, 9S, l3S, l4S, l7S)-l7-hydroxy-l3- methyl-7-(9-((4, 4, 5, 5, 5-pentafluoropentyl)sulfmyl)nonyl)-7, 8, 9, 11, 12, 13, 14, 15, 16, l7-decahydro- 6//-cyclopenta|a|phenanthren-3-yl [l, 4'-bipiperidine]-r-carboxylate (0.019 g, 7.20%) as a white solid. (0376) -NMR (400 MHz, DMSO): d 7.272 (d, 1H), 6.821 (d, 1H), 6.781 (s, 1H), 4.559 (s, 1H), 4.131 (s, 1H), 4.047 (s, 1H), 3.558 (m, 2H), 3.501-3.486 (m, 5H), 2.961 (s, 2H), 2.892-2.623 (m, 10H), 2.446-2.279 (m, 12H), 1.996-1.885 (m, 4H), 1.835-1.746 (m, 5H), 1.771-1.514 (m, 4H), 1.734- 1.601 (m, 8H), 1.525-1.262 (m, 24H), 0.901 (dd, 2H) and 0.684 (s, 3H).(E) To a reaction flask was added 250ml two QH-91 1.1g (3mmol), 4- piperidinyl piperidine chloride 1.4g (6mmol), dry dichloromethane 100ml, stir until dissolved, triethylamine 1.7 ml (12mmol), 4- dimethylaminopyridine 111mg (0.9mmol), heated to reflux (external reflux condenser with a drying tube) overnight, TLC plate point the reaction was complete.To the reaction flask was added ice water to quench the reaction, liquid separation and extraction, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.With acetone: isopropanol, 3: 2, crystallization, recrystallization to give the final product QH-197 (1.6g, 95% yield).100 mg 28 (0.22 mmol) were dissolved in a mixture of CH2CI2 (5 ml) and Pyridine (5 ml). After addition of 86 mg 1, 4?-bipiperidine-l?-carbonyl chloride (0.37 mmol) in 0.5 ml CH2CI2 the solution was stirred at room temperature for 16 h. The mixture was diluted with 40 ml of CH2CI2, washed with water and dried with Na2SO4. The solvent was removed under reducedpressure. The residue was suspended in ether and the beige crystals were filtered off, washed with ether and dried.Yield: 140 mg, 0.21 mmol (95 %). Mp: 261.3 - 262.9 C. IR (KBr): v (cm1) = 3279, 2931, 1711.1H NMR (DMSO-d6) 5 12.15 (d, J = 2.3 Hz, 1H), 9.58 (s, 1H), 9.01 (s, 1H), 8.09 (d, i = 2.2 Hz, 1H), 8.01 (s, 1H), 7.81 - 7.74 (m, 2H), 7.54 - 7.45 (m, 3H), 7.10 (dd, J = 8.9, 2.3 Hz, 1H), 6.53(s, 1H), 4.30 - 3.99 (m, 2H), 3.09 - 2.78 (m, 2H), 2.49 - 2.41 (m, 4H), 1.86 - 1.70 (m, 2H), 1.56- 1.33 (m, 9H), 1.31 (s, 9H). ESI-MS (70 eV) m/z (%): 653.3 (100) [MH+]Add to 100mL dry reaction flask50mL of dichloromethane, 100 mg of reactant 3-hydroxyl-6, 7-dimethoxy-9-methanol (PF403)Soluble in it, Add 60 muL of triethylamine, Then add 90 mg of pivaloyl chloride.After reacting for 2 hours, the reaction solution was washed with saturated ammonium chloride.Dry, evaporate and separate by silica gel column chromatography.Eluent dichloromethane/methanol (50/1), The product was obtained in an amount of 0.12 g, yield 77%.General procedure: To a solution of thiazole (1.0eq.) dissolved in DMF (4mL), K2CO3 (3.0eq.) was added, and the reaction mixture was left for 30min at 60C. Then, KI (1.0eq.) and the alkyl halide (0.9eq.) was added and the reaction was left for an additional 8h. The reaction mixture was taken up in DCM, washed with Na2CO3 (3x) and dried over MgSO4 and concentrated in vacuo. The concentrate was purified by flash chromatography yielding the desired compound.General procedure: To a solution of thiazole (1.0eq.) dissolved in DMF (4mL), K2CO3 (3.0eq.) was added, and the reaction mixture was left for 30min at 60C. Then, KI (1.0eq.) and the alkyl halide (0.9eq.) was added and the reaction was left for an additional 8h. The reaction mixture was taken up in DCM, washed with Na2CO3 (3x) and dried over MgSO4 and concentrated in vacuo. The concentrate was purified by flash chromatography yielding the desired compound.General procedure: To a solution of thiazole (1.0eq.) dissolved in DMF (4mL), K2CO3 (3.0eq.) was added, and the reaction mixture was left for 30min at 60C. Then, KI (1.0eq.) and the alkyl halide (0.9eq.) was added and the reaction was left for an additional 8h. The reaction mixture was taken up in DCM, washed with Na2CO3 (3x) and dried over MgSO4 and concentrated in vacuo. The concentrate was purified by flash chromatography yielding the desired compound.