Naphthyridinone-aniline compounds for treatment of dermal disorders
A technology of compound and mixture, applied in the field of nalidinone aniline compound for treating skin diseases
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Embodiment 1
[0335] Example 1: (R)-2-(2,3-dihydroxypropyl)-8-(2-fluoro-4-iodophenylamino)-2,6-naphthyridin-1(2H)-one
[0336]
[0337] Step 1: Methyl 3-bromo-5-fluoroisonicotinate
[0338]
[0339] To a stirred solution of dry diisopropylamine (8.8 mL, 62.5 mmol) in dry THF (300 mL) at 0 °C was added n-BuLi (2.5M in hexane, 25 mL, 62.5 mmol). The reaction mixture was stirred at room temperature for 30 min, then cooled to -78 °C and a solution of 3-bromo-5-fluoropyridine (10 g, 56.8 mmol) in dry THF (300 mL) was added. The reaction mixture was stirred for 1 h and treated with methyl chloroformate (5.3 mmol, 68.2 mmol). The reaction mixture was stirred for 1.5 h, then washed with saturated NH at 0 °C 4 Quenched with aqueous Cl, extracted with EtOAc (3×100 mL), washed with H 2 O (100 mL) and brine (100 mL), washed with Na 2 SO 4 Dry and vacuum dry. The crude material was purified by flash column chromatography (silica gel, 0-7% EtOAC in hexanes) to give the product as a yellowis...
Embodiment 2
[0360] Example 2: (S)-2-(2,3-dihydroxypropyl)-8-(2-fluoro-4-iodophenylamino)-2,6-naphthyridin-1(2H)-one
[0361]
[0362] Step 1: (S)-2-((2,2-Dimethyl-1,3-dioxol-4-yl)methyl)-8-fluoro-2,6-naphthyridine-1 (2H)-Kone
[0363]
[0364] To a solution of 8-fluoro-1H-pyrano[4,3-c]pyridin-1-one hydrochloride (500 mg, 3.03 mmol) in MeOH (22 mL) was added (S)-(2,2-dimethyl (1,3-dioxolan-4-yl)methanamine (556mg, 4.24mmol) and the reaction mixture was stirred at 80°C for 72h. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc and washed with H 2 O (50mL), brine (50mL), washed with Na 2 SO 4 Dry and concentrate in vacuo. The crude material was purified by flash column chromatography (silica gel, 0-100% EtOAC in hexanes) to give the product as a yellow solid (165 mg, 20%). UPLC-MS (acidic method, 2min): rt 0.76min, m / z 279.1[M+H] + .
[0365] 1 H NMR (400MHz, CDCl 3 ):δ8.74(s,1H),8.46(d,J=3.1Hz,1H),7.37(d,J=7.4Hz,1H),6.55(dd,J=7.4,2.3Hz,...
Embodiment 3
[0373] Example 3: 2-(3-aminopropyl)-8-(2-fluoro-4-iodophenylamino)-2,6-naphthyridin-1(2H)-one hydrochloride
[0374]
[0375] Step 1: tert-butyl 3-(8-fluoro-1-oxo-2,6-naphthyridin-2(1H)-yl)propylcarbamate
[0376]
[0377] 8-Fluoro-1H-pyrano[4,3-c]pyridin-1-one hydrochloride ((0.50g, 2.48mmol) and tert-butyl 3-aminopropylcarbamate (0.74g, 4.24mmol ) in MeOH (22 mL) was heated at 80 °C for 18 h, then concentrated in vacuo. The crude residue was treated with EtOAc and the collected organic phases were washed with brine, washed with Na 2 SO 4 Drying, filtration and concentration in vacuo afforded the crude product (1.02 g, 35% pure) which was used in the next step without further purification. UPLC-MS (acidic method, 2min): rt0.97min, m / z 322.1[M+H] + .
[0378] Step 2: 3-(8-(2-Fluoro-4-iodophenylamino)-1-oxo-2,6-naphthyridin-2(1H)-yl)propylcarbamate tert-butyl ester
[0379]
[0380] will be at -78°C in N 2 A stirred solution of 2-fluoro-4-iodoaniline (680 m...
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