Selective nr2b antagonist
A kind of technology selected from, compound, applied in the compound field of formula I, can solve problems such as unmet clinical needs
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Embodiment 1
[0147] Example 1 (P1&P2)
[0148]
[0149] To a stirred solution of (R)-4-amino-2-(4-fluorobenzyl)isoxazolidin-3-one (0.092 g, 0.437 mmol) in ACN (2 mL) was added DIPEA (0.381 mL, 2.183 mmol) and 3-(4-methoxyphenyl)pentane-1,5-diester dimethanesulfonate (0.16 g, 0.437 mmol). The reaction mixture was stirred at 90 °C for 12 h in a pressure tube. Mostly desired product quality by LCMS. The reaction mixture was concentrated, water (50ml) was added to the residue, and the product was extracted with ethyl acetate (3*25mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give (R)-2-(4-fluorobenzyl)-4-(4-(4-methoxyphenyl)piperidine-1- base) isoxazolidin-3-one (0.15 g, 0.125 mmol, 28.6% yield), LCMS purity 32%, as a brown gummy substance. This crude product was used in the next step without further purification.
[0150] LCMS: Buffer: 10 mM Ammonium Acetate pH 5 - Adjusted with HCOOH, Mobile Phase A: Buffer: ACN (95:5), Mobil...
Embodiment 2
[0169] Example 2 (P1&P2)
[0170]
[0171] To a stirred solution of 3-(4-methoxyphenyl)pentane-1,5-diester (0.25 g, 0.682 mmol) dimethanesulfonate in ACN (3 mL) was added (R)-4-amino - 2-(4-methylbenzyl)isoxazolidin-3-one hydrochloride (0.166 g, 0.682 mmol) and DIPEA (0.357 mL, 2.047 mmol). The reaction mixture was stirred at 120 °C for 18 h in a pressure tube. 14% expected product mass by LCMS. The reaction mixture was concentrated to remove ACN, 50ml of water was added, the product was extracted with ethyl acetate (3*25mL), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give crude material 0.4g. This crude product was used in the next step without further purification.
[0172] LCMS: Buffer: 10 mM Ammonium Acetate pH 5 - Adjusted with HCOOH, Mobile Phase A: Buffer: ACN (95:5), Mobile Phase B: Buffer: ACN (5:95), Method: %B: Omin - 5%: 1.1min-95%: 1.7min-95% Column name: AcquityBEH C18 (2.1x50mm) 1.7u method: C:\Mass...
Embodiment 3
[0185] Example 3 (racemic mixture):
[0186]
[0187]To a stirred solution of 4-bromo-2-(4-fluorobenzyl)isoxazolidin-3-one (0.031 g, 0.112 mmol) in DMF (2 mL) at RT was added DIPEA (0.059 mL, 0.337 mmol) and 6 -(piperidin-4-yl)pyridin-3-ol (0.02 g, 0.112 mmol). The reaction mixture was stirred at RT for 18h. 32% desired product mass by LCMS. The reaction mixture was purified by HPLC to give 2-(4-fluorobenzyl)-4-(4-(5-hydroxypyridin-2-yl)piperidin-1-yl)isoxazolidin-3-one (2.2 mg , 5.86 μmol, 5.23% yield) as a pale yellow solid.
[0188] LCMS (ammonium acetate method): A: 95% water: 5% acetonitrile; 10mMNH4OAC, B: 5% water: 95% acetonitrile; 10mMNH4OAC, flow rate: 1.1ml / min, temperature: 50 ℃, column: Ascentis Express C18 (50x2 .1) mm, 2.7 μm, time (min): 0---3, %B: 0---100, RT-1.159 min, M(+1)-372.
[0189] LCMS (TFA method): A: 95% water: 5% acetonitrile; 0.1% TFA, B: 5% water: 95% acetonitrile; 0.1% TFA, flow rate: 1.1ml / min, temperature: 50 ° C, column: Ascentis Expr...
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