A kind of 1,4-dihydro-1,6-naphthyridine derivative, pharmaceutical composition and use thereof
A technology of derivatives and compositions, applied in drug combinations, antipyretics, pharmaceutical formulations, etc., can solve problems such as limiting the use of MR antagonists
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Embodiment 1
[0059] Example 1: (S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6- The preparation of naphthyridine-4-deuterium-3-carboxamide (compound 1):
[0060]
[0061] Preparation of Intermediate 1-3: To a solution of methyl 3-oxobutyrate (10.0 g) in toluene (100 mL) were added 3-hydroxypropionitrile (16.4 g), NBS (5.0 g). The resulting suspension was stirred overnight at 120°C under nitrogen protection. TLC (petroleum ether:ethyl acetate=3:1) showed that the reaction was complete. Then water was added to quench the reaction, extracted with ethyl acetate, the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 3:1 elution) gave Intermediate 1-3 (5.0 g, 37.4% yield) as a yellow oily liquid. MS(ESI):m / z 156.06[M+1] + ; 1 H NMR (400MHz, CDCl3) δ 2.30 (s, 3H), 2.74-2.76 (m, 2H), 3.54 (s, 2H), 4.34-4.38 (m, 2H). Preparation of ...
Embodiment 2
[0069] Example 2: (S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-8-trideuteromethyl-1,4-dihydro The preparation of -1,6-naphthyridine-4-hydrogen-3-carboxamide (compound 2):
[0070]
[0071] Preparation of Intermediate 2-1: Pyridine (16 g, 200 mmol) was added to lithium hexamethyldisilazide (1M THF solution, 205 mL), cooled to 0°C, and stirred for 40 min. Trideuteriodomethane (30g, 405mmol) was added dropwise. After the dropwise addition, the temperature was increased to 30°C, reacted for 5h, cooled to 0°C, and saturated ammonium chloride solution was used to quench the reaction. The aqueous phase was extracted three times with ethyl acetate, acetic acid The ethyl ester phase was combined with the organic phase, dried over anhydrous sodium sulfate, and the filtrate was concentrated in vacuo. Intermediate 2-1 was obtained as a white solid (14.4 g, yield 75%) by silica gel chromatography (PE:ethyl acetate=1:2). LCMS:m / z 97.02[M+H] + .
[0072] Preparation of Intermedia...
Embodiment 3
[0080] The preparation of compound 2: compound 2-11 (150mg), is resolved by following method with SFC: operating system: WatersUPCC (CA-119) supercritical fluid chromatography; Chromatographic column: AS-3 (100*3mm 3μm); mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (0.1% diethylamine); flow rate: 1.5mL / min. SFC resolution showed that there were two peaks, peak 1 corresponding to 3.488min (R) body compound white solid (70mg, 99% purity), peak 2 corresponding to 4.915min (S) body (76mg, 99.4% purity) The white solid is compound 2. LCMS:m / z 382.2[M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ1.03-1.07 (m, 3H), 2.19 (s, 3H), 3.82 (s, 3H), 4.00-4.02 (m, 2H), 5.57 (s, 3H), 6.67-6.74 (m, 2H), 7.15 (d, J=8Hz, 1H), 7.26-7.29 (m, 1H), 7.37 (s, 1H), 7.55 (s, 1H), 7.69 (s, 1H). Example 3: (S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-8-trideuteromethyl-1,4-dihydro Preparation of -1,6-naphthyridine-4-deuterium-3-carboxamide (compound 3):
[0081]
[0082] Prep...
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