5-Bromo-1-methyl-1H-pyridin-2-one

To a suspension of NaH (4.8 g, 0.2 mol) in THF (10 mL) was added a solution of 5-bromopyridin-2(1H)-one (8.6 g, 0.05 mol) in THF (120 mL) at 0° C. The resulting mixture was stirred for 1 h and CHTo a suspension of NaH (4.8 g, 0.2 mol) in THF (10 mL) was added a solution of 5-bromopyridin-2(1H)-one (8.6 g, 0.05 mol) in THF (120 mL) at 0 C. The resulting mixture was stirredfor 1 h and CH3I (35.5 g, 0.25 mol) was added. The mixture was stirred for 3 h. The reaction wasquenched with aqueous NH4Cl solution. The organic phase was concentrated to give the crude product, which was purified by column chromatography to give 5-bromo-1-methylpyridin-2(1H)-one (8.9 g, 96.78 percent). 1H NMR (CDCl3): δ= 3.5 (S, 3H), 6.52 (m, 1H), 7.32 (m, 1H), 7.45(m, 1H).General procedure: In a dry Schlenk tube 6-methyl-2(1H)-pyridone (1) (3.43 g, 31.44 mmol) was dissolved in 50 mLof 1, 4-dioxane and KOt-Bu (8.69 g, 62.88 mmol) was added. The mixture was stirred at 100 °C for 2 h, then cooled down to rt, MeI (19.6 mL, 314.41 mmol) was added dropwise and the mixture was stirred at 80 °C for 16 h. The solvent was removed under reduced pressure and the residue was separated between DCM and water. The extraction was performed using DCM (3×) and the combined organic phases were dried over MgSOStep 3: 5-Brom -l-methylpyridin-2(lH)-one To a solution of 5-bromopyridin-2(lH)-one (0.18 g, 1.03 mmol) in DMF (5 niL) was added iodomethane (0.2 niL, 3.1 mmol) and potassium carbonate (0.8 g, 6.2 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure, the residue dissolved in ethyl acetate (200 mL), washed with water (50 mL) and brine solution. The organic layers were combined and dried over sodium sulfate, filtered and concentrated under vacuum to afford 5-bromo-l-methylpyridin-2(lH)-one [Albrecht, US Patent Application Publication No. 2009/0318436] as yellow solid (40Reference General procedure: A Schlenk tube was charged with the 2-pyridone substrate (1.0 mmol) [in the case of a liquid substrate, this was added neat after the solvent], [Ir(cod)(OMe)]2 (6.6 mg, 0.01 equiv), 4, 4′-di-tert-butyl-2, 2′-dipyridyl (5.4 mg, 0.02 equiv) and bis(pinacolato)diboron (178 mg, 0.70 equiv). After purging with nitrogen, deoxygenated and anhydrous THF (1.4 mL) was added and the reaction mixture was heated at reflux for 48 h (in cases where full conversion occurred after 24 h, the reaction was halted at that time). The volatile materials were then removed under reduced pressure and the crude product was dissolved in MeOH (2.5 mL) and a solution of CuBr2 (670 mg, 3.0 mmol) in H2O (2.5 mL) was added. The reaction mixture was heated at 80 °C for 18 h under air, cooled to r.t., diluted with NH4OH (5 mL, 15percent aq) and extracted with CH2Cl2 (5 × 5 mL). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude reaction mixture by flash column chromatography on silica gel afforded the desired product. Table 1 shows the product distributions of 2–5 but no attempt was made to optimise monosubstitution (vs. disubstitution) in the case of 1b or 1c. According to General Procedure 1, analysis of the 1H NMR spectrum ofthe crude reaction mixture showed a conversion of 100percent. Products 5-bromo-1-methylpyridin-2(1H)-one (3b), 4-bromo-1-methylpyridin-2(1H)-one (2b), 4, 6-dibromo-1- methylpyridin-2(1H)-one (4b) and 3, 5-dibromo-1-methylpyridin-2(1H)-one (5b) were generated in a 35:5:39:21 ratio. Purification by flash column chromatography on silica gel (n-hexane–EtOAc, 70:30 to EtOAc, 100percent) gave an inseparable 95:5 mixture of 5-bromo-1-methylpyridin-2(1H)-one (3b) and 4-bromo-1-methylpyridin-2(1H)-one (2b) (71 mg, 38percent) as an orange oil. 2b (minor component) Rf = 0.24 (EtOAc). 1H NMR (400 MHz, CDCl3): δ = 7.11 (d, J = 7.5 Hz, 1 H), 6.79 (d, J = 2.0 Hz, 1 H), 6.28 (dd, J = 2.0, 7.5 Hz, 1 H), 3.50 (s, 3 H). The spectroscopic properties of this compound were consistent with data available in literature. 3b (major component) Rf = 0.24 (EtOAc).1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 2.5 Hz, 1 H), 7.33 (dd, J = 2.5, 9.5 Hz, 1 H), 6.46 (d, J = 9.5 Hz, 1 H), 3.50 (s, 3 H). The spectroscopic properties of this compound were consistent with data availablein literature.19a4, 6-Dibromo-1-methylpyridin-2(1H)-one (4b) Yield: 58 mg (22percent); off-white solid; Rf = 0.59 (EtOAc). IR (neat): 3111, 2922, 2851, 1650, 1566, 1495 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.75 (s, 1 H), 6.66 (s, 1 H), 3.68 (s, 3 H).13C NMR (100 MHz, CDCl3): δ = 161.5, 134.8, 128.3, 120.7, 114.4, 36.4.HRMS-ESI: m/z [M + H]+ calcd for C6H679Br2NO: 265.8811; found:265.8799.3, 5-Dibromo-1-methylpyridin-2(1H)-one (5b)Yield: 28 mg (11percent); white solid; Rf = 0.51 (EtOAc). 1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 2.0 Hz, 1 H), 7.43 (d, J = 2.0 Hz, 1 H), 3.58 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 158.0, 143.8, 137.5, 117.4, 96.5, 39.0. The spectroscopic properties of this compound were consistent withthe data available in literature.A solution of bromine (2.3 mL, 46 mmol) and chloroform (10 mL) was added to a stirring solution of l-methyl-2-pyridone (5.0 mL, 456 mmol) and chloroform (46 mL) at reflux. After 1 h, the reaction mixture was cooled to room temperature. After 72 h, the reaction mixture was filtered and the filter cake was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated, silica gel (1.0 g) was added to the organic material, and the volatiles were removed under a vacuum. The residue was subjected to flash chromatography on silica gel (120 g RediSepGeneral procedure: A mixture of 8-(4-chlorophenyl)-2-((2, 2, 2- trifluoroethyl)amino)pyrido[4, 3-i/]pyrimi-din-7(d7/)-one (100 mg, 0.28 mmol, 1.0 equiv), 5-bromo-2-methyl-2H-indazole (119 mg, 0.56 mmol, 2.0 equiv.), Cul (5.4 mg, 0.028 mmol, 0.1 equiv.), N1, A2-dimethylcy cl ohexane-l, 2-diamine (8.1 mg, 0.056 mmol, 0.2 equiv.), CS2CO3 (276 mg, 0.847 mmol, 3.0 equiv.) and dioxane (2 mL) was stirred at l00C under N2 atmosphere for l6h. The crude mixture was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography on silica gel to yield 8-(4- chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2-((2, 2, 2- tri fl uoroethyl )am i no)py ri do[-/, 3-6/]pyrimidin-7(6//)-one (Example 123).To a stirred solution of 5-bromo-l-methylpyridin-2(lH)-one(A47, 1.0 g, 5.37 mmol) in l, 4-dioxane(10 mL) and tributylditin(2, 4.0 mL, 8.06 mmol). The reaction mixture was purged with N2 gas for 20 min. to the above reaction mixture was added [l, T-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdQ2(dppf)(0.39 g, 0.537 mmol), and the resulting solution was further purged with N2 gas for 10 min then stirred for 16 h at l00C. The reaction mixture was filtered over celite bed and washed with ethylacetate. The filtrate was washed with water, brine solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. The compound was purified by column chromatography using 0-5% methanol/dichlorome thane as the eluent to afford 1 -methyl-5-(tributylstannyl)pyridin-2(lH)-one A48 as colorless liquid. Yield: 0.90 g(42%) LC-MS(ES) m/z : 400.16[M+H]+.A stirred solution of methyl 3-methyl-6-(tributylstannyl)imidazo[l, 2- a]pyrazine-2-carboxylate(2, 0.3 g, 0.62 mmol) and 5-bromo-l-methylpyridin-2(lH)-one(3, 0.141 g, 0.75 mmol) in dioxane 15 mL was degassed with argon for 20 minutes. Then [l, r-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride(0.045 g, 0.062 mmol) was added. The reaction mixture was heated at l00C for 16 h. After completion, reaction mixture quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to offered methyl 3- methyl-6-(l-methyl-6-oxo-l, 6-dihydropyridin-3-yl)imidazo[l, 2-a]pyrazine-2- carboxylate 1-83 as brown solid. Yield: 0.2 g(71%) LC-MS(ES) m/z = 299.01 [M+H]+.To a mixture containing 5-bromo-l -methylpyridin-2(lH)-one (15.05 mg, 0.080 mmol), tert-butyl 4-(3-isopropyl-2-(4, 4, 5, 5-tetramethyl-l , 3, 2-dioxaborolan-2-yl)-lH- indol-5-yl)piperidine-l-carboxylate (25 mg, 0.053 mmol), and Xphos Pd G2 (2.100 mg, 2.67 muetaiotaomicron) in a screw cap vial was added THF (1 mL) followed by an aqueous solution of tripotassium phosphate (100 mu, 0.300 mmol). The vial was fitted with a Teflon lined septum cap. The vial was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and backfilled with nitrogen gas. The evacuation procedure was repeated three times. The needle was removed and the vial was heated at 65 C for 18 h. The reaction mixture was concentrated to dryness and treated with TFA (1 mL) for 30 min to facilitate the removal of the tert-butyloxycarbonyl group. The reaction mixture was re- concentrated to dryness and re-dissolved in DMF (2 mL). The sample was filtered through an Acrodisc, 13 mm, 0.45 micron nylon membrane syringe filter and was purified via preparative LC/MS with using condition Method D2 to afford 5-(3-isopropyl-5- (piperidin-4-yl)-lH-indol-2-yl)-l -methylpyridin-2(lH)-one (12 mg, 0.034 mmol, 64.3% yield). LCMS MH+: 350. HPLC Ret. Time 0.58 min. Method Bl . NMR (500 MHz, DMSO-d6) delta 10.84 (s, IH), 7.81 (d, J=2.1 Hz, IH), 7.53 (dd, J=9.3, 2.3 Hz, IH), 7.47 (s, IH), 7.23 (d, J=8.2 Hz, IH), 6.94 (d, J=8.3 Hz, IH), 6.52 (d, J=9.3 Hz, IH), 3.52 (s, 3H), 3.19-3.09 (m, 2H), 2.77-2.66 (m, 2H), 1.84 (m, 3H), 1.80-1.75 (m, 2H), 1.72-1.59 (m, 2H), 1.39 (d, J=7.0 Hz, 6H).To 5-bromo-l-methylpyridin-2(lH)-one (0.75 g, 3.9 mmol) in dioxane was added 5, 5, 5', 5'-tetramethyl-2, 2'-bi(l, 3, 2-dioxaborinane) (1.0 g, 4.4 mmol), KOAc (1.2 g, 12 mmol). The reaction mixture was degassed with N2, then PdCl2(dppf)-DCM (0.16 g, 0.19mmol) was added and the reaction mixture was heated to 90 C for 18 h. The reaction mixture was allowed to cool, filtered and partitioned with water (20 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (15 mL) and dried (MgS04), filtered and concentrated under reduced pressure to afford 5-(5, 5-dimethyl-l, 3, 2-dioxaborinan-2-yl)-l- methylpyridin-2(lH)-one (0.67 g, 76 % yield) as a dark oil). LCMS m/z = 222 (M+H).+A mixture of 1-benzyl-4-(4, 4, 5, 5-tetramethyl-[1, 3, 2]dioxaborolan-2-yl)-1H-pyrazole (140 mg, 0.495 mmol), 5-bromo-1H-pyridin-2-one (100 mg, 0.495 mmol), Pd(PPh3)4(60 mg, 0.049 mmol), and Na2CO3 (104 mg, 0.990 mmol) in dioxane (5 mL) and H2O (1 mL) was heated to 90 C. for 5 hr under N2. Then, the mixture was diluted with EtOAc (60 mL) and H2O (50 mL). The organic phase was washed with brine (60 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC to give the compound 5-(1-benzyl-1H-pyrazol-4-yl)-1-methylpyridin-2(1H)-one (60 mg, 0.22 mmol) as a yellow oil in 44% yield. 1H NMR (400 MHz, CD3OD): delta 7.96 (s, 1H), 7.38-7.31 (m, 2H), 7.38-7.28 (m, 6H), 6.58 (d, J=9.3 Hz, 1H), 5.22 (s, 2H), 3.59 (s, 3H). LCMS (M+H)+ 266.

Molecular Weight:188.02
XLogP3:0.8
Hydrogen Bond Acceptor Count:1
Exact Mass:186.96328
Monoisotopic Mass:186.96328
Topological Polar Surface Area:20.3
Heavy Atom Count:9
Complexity:195
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes