6-Bromo-3,4-dihydro-1H-[1,8]naphthyridin-2-one

Off- White to Yellow Solid

c) Step 5: 6-Bromo-3, 4-dihydro-lW-l, 8-naphthyridin-2-oneA solution of sodium hydroxide (IN, 248 ml_) was added to a suspension of 6- bromo-2-oxo-l, 2, 3, 4-tetrahydro-lH-l, 8-naphthyridine-3-methylcarboxylate (16.6 g, 58.24 mmol; which may be prepared as described in Dl, Step 4) in methanol (620 ml_) at room temperature. The reaction mixture was then refluxed for 4 hours and cooled down to room temperature. A solution of hydrochloric acid (IN, 248 ml_) was then added and the mixture was refluxed overnight. The methanol was removed and the residue filtered. The resulting precipitate was washed with water and dried under high vacuum to afford the title product as a white solid (7.7 g, 58percent).LCMS (ESI-APCI) m/z 227.0-229.0 (M + H)To a solution of methyl 6-bromo-2-oxo-l, 2, 3, 4-tetrahydro-l, 8-naphthyridine-3- carboxylate (6.8 g, 23.9 mmol) in MeOH (250 mL) was added NaOH aqueous solution (105 mL, 1 M). The reaction was heated to reflux and stirred further for 4 hours, then cooled to rt, and neutralized with HCl aqueous solution (100 mL, 1 M). The resulted mixture was re fluxed overnight, and concentrated in vacuo. The residue was suspended in CHCI3/CH3OH (95/5, 25 mL), then filtered, and the filtrate was concentrated in vacuo to give the title compound as an off-white solid (2.5 g, 46percent). MS (ESI, pos. ion) m/z: 227.0 (M+l); The compound 6 - bromo -2 - oxo - 1, 2, 3, 4 - tetrahydro - 1, 8 - naphthyridine -3 - carboxylic acid methyl ester (6.8 g, 23.9 mmol) dissolved in MeOH (250 ml) in, then added to the reaction solution in the NaOH aqueous solution (105 ml, 1 M), heating to reflux, the reaction stirred 4 hours, cooling to room temperature, then adding HCl aqueous solution (100 ml, 1 M) the reaction obtain recipe to neutral, once again heating to reflux, stirring overnight, then concentrated under reduced pressure, the residue suspended in CHClAnhydrous DMA (32 mL, sparged with N2 before using) was added to a flask containing 6- bromo-3, 4-dihydro- l , 8-naphthyridin-2( ///)-onc (1 eq, 10 mmol), palladium(II) acetate (0.05 eq, 0.5 mmol), and tricyclohexylphosphine tetrafluoroborate (0.1 eq, 1.0 mmol) followed by the addition of //77-butyl acrylate (1.5 eq, 15 mmol, sparged with N2 before using), N, N- diisopropylethylamine (2 eq, 20 mmol, distilled and sparged with N2 before using). The reaction mixture was heated to 90-100 C for 24 h. After reaction completion, the reaction mixture was diluted with ethyl acetate and filtered through a pad of celite and the filtrate was washed with saturated sodium bicarbonate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. Purification by flash purification column chromatography (10:90 to 30:70, EtOAc:CH2Cl2) followed by trituration with ether/n-pentane yielded //77-butyl (£?)-3-(7-oxo-5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-3-yl)acrylate (S5, 2.151 g, 7.85 mmol, 78%) as a white solid. *H NMR (500 MHz, Chloroform-//): d 8.94 (s, 1H), 8.32 (d, / = 2.1 Hz, 1H), 7.65 (d, / = 1.5 Hz, 1H), 7.51 (d, / = 16.0 Hz, 1H), 6.33 (d, / = 16.0 Hz, 1H), 2.99 (t, 7 = 7.6 Hz, 2H), 2.71 (dd, / = 8.4, 6.8 Hz, 2H), 1.53 (s, 9H). 13C NMR (126 MHz, Chloroform-//): 170.97, 165.97, 151.95, 147.37, 139.43, 134.05, 126.16, 120.57, 118.84, 80.99, 77.36, 30.40, 28.34, 24.22.Step 6: tert-Butyl (E)-3-(7-Oxo-5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-3-yl)- acrylatei-butyl acrylate, tert-Butyl acrylate (31.2 ml_, 210 mmol), diisopropylethylamine (19.4 ml_, 110 mmol) and P(o-tolyl)3 (3.2 g, 10.5 mmol) were successively added to a suspension of 6-bromo-3, 4-dihydro-lH-l, 8-naphthyridin-2-one (11.9 g, 52.5 mmol; which may be prepared as described in Dl, Step 5) in propionitrile (83 ml_) and dimethylformamide (46 ml_). The resulting mixture was then purged with argon prior to the addition of palladium acetate (1.2 g, 5.2 mmol). The mixture was purged with argon again and refluxed overnight. The reaction mixture was then filtered on Celite. The filtrate was concentrated to dryness and the residue was solubilized in ethyl acetate (200 ml_). The resulting solution was washed with a saturated solution of sodium chloride (3 x 100 ml_), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (98: 2) as eluent. After trituration with Et20/petroleum ether (1/1), the title product was obtained as a yellow solid (4.35 g, 40%).LCMS (ESI-APCI) m/z 275.0 (M + H)+(i) LAH, Dry THF, reflux, 16h; (ii) Br2, HOAc, 20-35C, 3h: (iii) 48% HBr.refhix, dimethyl malonate, CH3OH, 20-35C, 16h; (v) NaOH, CH3OH, reflux, 4h, then HC1, reflux, 16h; (vi) tert-butyl acrylate, Pd(OAc)2, P(o- tolyl)3, DIEA, DMF.Propionitrile, 90C, 16h; (vii) TFA, CH2C12 , 20-35T, 4h, then 4% dioxane. HC1, 20-35C, 2h. (Reference for Step-(i): WO 2005095391 and Step-(ii-vii): J. Med. Chem. 2003, 46, 1627-1635)To a solution of S4. At room temperature, The above 6-bromo-3-carboxylic acid ethyl ester-1, 2, 3, 4-tetrahydro 1, 8-naphthyridin-2-one (69.5 g, 1.0 eq)Sodium hydroxide (55.8 g, 6.0 eq) was added to water and the mixture was warmed to 100 C for 2 h.After the reaction is completed, the temperature is lowered to 20-25 C, 2.5 mol / L hydrochloric acid is slowly added dropwise to pH = 2, and the temperature is raised again to 100 C for 4 h.After the reaction is completed, the temperature is lowered to 20-25 C, and the pH of the system is adjusted to 6 with an aqueous sodium hydroxide solution, and the system is directly filtered by suction.6-Bromo-3, 4-dihydro-1H-[1, 8]naphthyridin-2-one was obtained in a yield of 64%.To a mixture of 0.50 g (2.2 mmol) of 6-bromo-3, 4-dihydro-lH-l, 8-naphthyridin-2-one in 10 mL of DMF is added 0.13 g (3.3 mmol) of 60% NaH in mineral oil. After stirring for 30 min, 0.62 g (4.4 mmol) of Mel is added and the mixture is stirred for 18 h, concentrated, dissolved in EtOAc, washed with water and brine, dried with Na2S04, filtered and concentrated. The residue is purified by flash chromatography (0-50% EtOAc in heptane) to provide 0.50 g (2.1 mmol) of 6- bromo-l-methyl-3, 4-dihydro-l, 8-naphthyridin-2-one. This material combined with 0.62 g (4.1 mmol) of Nal, 40 mg (0.21 mmol) of Cul, 5 mL of 1, 4-dioxane, and 30 mg (0.21 mmol) of trans-N, N'-dimethylcyclohexane-l, 2-diamine, and then stirred at 110 C for 18 hours. The reaction mixture is concentrated, dissolved in EtOAc, washed with water, brine, dried with Na2S04, filtered and concentrated. The residue is purified by flash chromatography (0-50% EtOAc in heptane) to provide 0.57 g (2.0 mmol) of N-005. Compound C-AAD is then prepared from N-005 and I-AAK using the general method described for the synthesis of I- AAA.General procedure: To a stirred solution of 7-fluoroindoline-2, 3-dione (500 mg, 3.03 mmol) in DMF (5 mL) were successively added K2C03 (502 mg, 3.63 mmol) and methyl iodide (0.199 mL, 3.18 mmol). The resulting mixture was stirred at RT for 1 hr. The mixture was quenched with water, diluted with EtOAc and saturated aqueous NaHC03 solution and both phases were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgS04, filtered and concentrated under reduced pressure to afford the title product (497 mg, 2.219 mmol, 73.3% yield) as yellow solid. Rt = 0.69 min (UPLC-MS); ESI-MS = 179.9 [M+1]+ (UPLC-MS).22. 7-Oxo-5, 6, 7, 8-tetrahydro-[1 , 8]naphthyridine-3-boron ic acid In a screw-capped vessel 6-bromo-3, 4-dihydro-I H-[1 , 8]naphthyridin-2-one (100 mg, 0.44 mmol) was dissolved in tetrahydrofurane SeccoSolv(3 mL). Bis(pinacolato)diboron (145 mg, 0.57 mmol), potassium acetate(130 mg, 1.32 mmol) and 1, 1 bis(diphenylphosphino)ferrocenepalladium(ll) dichloride DCM complex (18.0 mg, 0:022 mmol) were added and the red reaction mixture was stirred overnight at 80C. The crudemixture was filtered, the solvent evaporated to dryness and the dark residue was purified by chromatography (DCM/MeOH) to give 100 mg (84 % purity, 99 % yield) of an off-white solid identified as the title compound. LCIMS (Method B): Rt 1.29 mm, (M+H) 193.

Molecular Weight:227.06
XLogP3:1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:225.97418
Monoisotopic Mass:225.97418
Topological Polar Surface Area:42
Heavy Atom Count:12
Complexity:198
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes