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       Copyright 2011 Peter Murray-Rust et. al.

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<example id="h0282" title="EXAMPLE 124"><heading id="h0283" title="8-hydroxy-6-methyl-[1,6]naphthyridine-7-carboxylic acid 3,5-dichloro-benzylamide"><p id="p0402" num="0402">
<chemistry id="chem0200" num="0200"><img id="ib0200" file="imgb0200.tif" wi="75" he="33" img-content="chem" img-format="tif" orientation="portrait" inline="no"/></chemistry></p></heading><heading id="h0284" title="Step 1: Preparation of 2-bromo-6-methyl-pyridin-3-ol (124A)"><p id="p0403" num="0403">To a solution of 5-hydroxy-2-methyl pyridine (20 g, 183.2 mmol) in dry pyridine (350 mL) was added a solution of bromine (10.3 mL, 201.5 mmol) in dry pyridine (100 mL) dropwise. After 1.5h, the reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was treated with water (160 mL) and filtered. The resultant pale solid was washed with water (300 mL) and air dried. The crude product was recrystallized in EtOH (200mL) to give the title compound as a solid.</p></heading><heading id="h0285" title="Step 2: Preparation of 2-bromo-3-methoxy-6-methyl-pyridine"><p id="p0404" num="0404">A mixture of 124A (19.9 g, 106 mmol), potassium carbonate (29.3 g, 212 mmol) and iodomethane (9.9 mL, 159 mmol) in acetone (300 mL) was refluxed overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was purified with flush chromatography (hexanes/ethyl acetate) to furnish 124B as a solid.</p></heading><heading id="h0286" title="Step 3: Preparation of 2-bromo-3-methoxy-6-methyl-pyridine N-oxide (124C)"><p id="p0405" num="0405">A mixture of 124B (14.8 g, 73.6 mmol) and urea hydrogen peroxide (14.5 g, 154.6 mmol) in dichloromethane (300 mL) was cooled to 0°C. Trifluoroacetic anhydride (20.7 mL, 147.2 mmol) was added slowly and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was re-cooled to 0°C and saturated aqueous sodium thiosulfate solution was added. After stirring for 30 min, the reaction mixture was acidified with 1N HCl to pH 1, extracted with dichloromethane. The organic phase was concentrated and the residue was purified with a short silica gel pad (eluted with 5% MeOH in chloroform)to give crude product. The crude product was recrystallized (hexanes/dichloromethane) to furnish 124C as a solid.</p></heading><heading id="h0287" title="Step 4: Preparation of 2-bromo-3-methoxy-6-methyl-4-nitro-pyridine N-oxide (124D)"><p id="p0406" num="0406">A solution of 124C (7.0 g, 32.4 mmol) in concentrate H<sub>2</sub>SO<sub>4</sub> (9.5 mL) was added to a solution of concentrate H<sub>2</sub>SO<sub>4</sub> (9.5 mL) and fuming HNO<sub>3</sub> (13 mL) and the mixture was heated at 60°C for 30 min. After cooling to room temperature, the reaction mixture was added to iced 6M solution of NaOH (150 mL) and neutralized to pH 6 with 1N NaOH solution. The reaction mixture was extracted with dichloromethane (4x100 mL). The combined organic phases were dried over Na<sub>2</sub>SO<sub>4</sub>, filtered and concentrated to give 124D as a solid.</p></heading><heading id="h0288" title="Step 5: Preparation of 2-bromo-3-methoxy-6-methyl-pyridin-4-ylamine (124E)"><p id="p0407" num="0407">A mixture of 124D (0.75 g, 2.9 mmol), iron (0.48 g, 8.6 mmol) and ammonium chloride (0.46 g, 8.6 mmol) in EtOH/H<sub>2</sub>O (10 mL/3 mL) was refluxed (bath temperature 90°C) for 4 h. After cooling to room temperature, the reaction mixture was diluted with water, extracted with dichloromethane three times. The combined organic phases were dried over Na<sub>2</sub>SO<sub>4</sub>, filtered and concentrated to give 124E as a oil.</p></heading><heading id="h0289" title="Step 6: Preparation of 2-bromo-3-methoxy-6-methyl-[1,6]naphthyridine (124F)"><p id="p0408" num="0408">To a mixture of 124E (1.97 g, 9.0 mmol) and sodium iodide (0.27 g, 1.8 mmol) in 70% H<sub>2</sub>SO<sub>4</sub> (30 mL) at 110°C under nitrogen was added acrolein (1.1 mL, 13.6 mmol) via syringe pump (1 mL/h). The reaction was stirred for another 30 min at 110°C after complete addition. After cooling to room temperature, the reaction mixture was diluted with ice water (50 mL) then added to an aqueous solution (500 mL) of Na<sub>2</sub>CO<sub>3</sub> (60 g) slowly. This mixture was extracted with chloroform (3x200 mL). The combined organic phases were dried over Na<sub>2</sub>SO<sub>4</sub>, filtered and concentrated. The residue was purified by flush chromatography (hexanes/ethyl acetate) to give 124F as a solid.</p></heading><heading id="h0290" title="Step 7: Preparation of 8-methoxy-6-methyl-[1,6]naphthyridine-7-carboxylic acid methyl ester (124G)"><p id="p0409" num="0409">A glass lined steel bomb was charge with 124F (1.0 g, 3.95 mmol), 1,3-bis(diphenylphosphino)propane (0.33 g, 0.8 mmol), sodium acetate (0.35 g, 4.35 mmol) and MeOH (30 mL). The mixture was purged with nitrogen for 10 min. Palladium acetate (0.19 g, 0.84 mmol) was then added. The vessel was sealed, purged with carbon monoxide (3x 100 psi) then pressurized with carbon monoxide to 300 psi. The bomb was then heated at 100°C overnight. The pressure was relieved and the reaction mixture was filtered through Celite and the filtrate was concentrated. The resultant residue was purified by flush chromatography (hexanes/ethyl acetate) to give 124G as a solid.</p></heading><heading id="h0291" title="Step 8: Preparation of 8-hydroxy-6-methyl-[1,6]naphthyridine-7-carboxylic acid 3,5-dichloro-benzylamide (124H)"><p id="p0410" num="0410">A mixture of 124G (150 mg, 0.64 mmol), 3,5-dichlorobenzylamine (153 mg, 0.87 mmol) and aluminum chloride (27 mg, 0.20 mmol) in toluene (8 mL) was refluxed for 4 h under nitrogen. After cooling to room temperature, the reaction mixture was treated with aqueous saturated NaHCO<sub>3</sub> solution and ethylenediaminetetraacetic acid (1 g, 3.4 mmol) to pH 7. The mixture was extracted with chloroform four times. The combined organic phases were dried over Na<sub>2</sub>SO<sub>4</sub> and concentrated. The residue was purified by preparative reverse-phase HPLC to give 124H.<br/>
<spectrum type="hnmr">1H NMR (<quantity type="frequency"><value><point>400</point></value> <units>MHz</units></quantity>, DMSO) δ <peaks type=".."><peak><quantity type="shift"><value><point>13.2</point></value></quantity> (<quantity type="peaktype">s</quantity>, <quantity type="integral"><value><point>1</point></value><units>H</units></quantity>)</peak>, <peak><quantity type="shift"><value><point>9.73</point></value></quantity> (<quantity type="peaktype">t</quantity>, <quantity type="integral"><value><point>1</point></value><units>H</units></quantity>)</peak>, <peak><quantity type="shift"><value><point>9.15</point></value></quantity> (<quantity type="peaktype">dd</quantity>, <quantity type="integral"><value><point>1</point></value><units>H</units></quantity>)</peak>, <peak><quantity type="shift"><value><point>8.64</point></value></quantity> (<quantity type="peaktype">dd</quantity>, <quantity type="integral"><value><point>1</point></value><units>H</units></quantity>)</peak>, <peak><quantity type="shift"><value><point>7.83</point></value></quantity> (<quantity type="peaktype">dd</quantity>, <quantity type="integral"><value><point>1</point></value><units>H</units></quantity>)</peak>, <peak><quantity type="shift"><value><point>7.52</point></value></quantity> (<quantity type="peaktype">s</quantity>, <quantity type="integral"><value><point>1</point></value><units>H</units></quantity>)</peak>, <peak><quantity type="shift"><value><point>7.44</point></value></quantity> (<quantity type="peaktype">s</quantity>, <quantity type="integral"><value><point>2</point></value><units>H</units></quantity>)</peak>, <peak><quantity type="shift"><value><point>4.57</point></value></quantity> (<quantity type="peaktype">d</quantity>, <quantity type="integral"><value><point>2</point></value><units>H</units></quantity>)</peak>, <peak><quantity type="shift"><value><point>2.85</point></value></quantity> (<quantity type="peaktype">s</quantity>, <quantity type="integral"><value><point>3</point></value><units>H</units></quantity>)</peak></peaks></spectrum>.</p></heading></example>
