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<example id="h0010" title="EXAMPLE 2"><heading id="h0011" title="N-(2,5-dichlorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide"><p id="p0139" num="0139">
<chemistry id="chem0078" num="0078"><img id="ib0078" file="imgb0078.tif" wi="77" he="33" img-content="chem" img-format="tif" orientation="portrait" inline="no"/></chemistry></p></heading><heading id="h0012" title="Step 1: Preparation of 8-hydroxy-1,6-naphthyridine-7-carboxylic acid"><p id="p0140" num="0140">To a slurry of methyl 8-hydroxy-1,6-naphthyridine-7-carboxylate from Example 1 step 2 (1.50g, 7.35 mmol) in methanol. (45ml) was added lithium hydroxide (22.0ml of a 1M aq. solution, 22.0 mmol) and the reaction was heated at 100°C for 7 hrs. Upon cooling to room temperature, hydrochloric acid (22.0ml of a 1M aq. solution, 22.0 mmol) was added and the reaction stirred for 16 hrs. The mixture was concentrated to a volume of 50 ml and neutralized with dilute NaHCO<sub>3</sub> (pH=7) The resulting precipitate was collected by filtration and washed with water and dried <i>in vacuo</i> to afford the title compound.<br/>
FAB MS calcd for C<sub>9</sub>H<sub>6</sub>N<sub>2</sub>O<sub>3</sub> 191 (MH<sup>+</sup>), found 191.<br/>
<spectrum type="hnmr">1H NMR (d6DMSO, <quantity type="frequency"><value><point>400</point></value><units>MHz</units></quantity>) δ <peaks type=".."><peak><quantity type="shift"><value><point>9.20</point></value></quantity> (<quantity type="integral"><value><point>1</point></value><units>H</units></quantity>, <quantity type="peaktype">m</quantity>)</peak>, <peak><quantity type="shift"><value><point>8.72</point></value></quantity> (<quantity type="integral"><value><point>1</point></value><units>H</units></quantity>, <quantity type="peaktype">s</quantity>)</peak>, <peak><quantity type="shift"><value><point>8.58</point></value></quantity> (<quantity type="integral"><value><point>1</point></value><units>H</units></quantity>, <quantity type="peaktype">m</quantity>)</peak>, <peak><quantity type="shift"><value><point>7.80</point></value></quantity> (<quantity type="integral"><value><point>1</point></value><units>H</units></quantity>, <quantity type="peaktype">dd</quantity>, J=<quantity type="coupling"><value><point>8.3</point></value> and <value><point>4.2</point></value> <units>Hz</units></quantity>)</peak> ppm</peaks></spectrum>.</p></heading><heading id="h0013" title="Step 2: Preparation of N-(2,5-dichlorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide"><p id="p0141" num="0141">Triphosgene (0.556g, 1.87 mmol) was added over 20 mins to a solution of the acid from step 1. (0.89g, 4.68 mmol) and diisopropylethylamine 3.26 ml, 18.7 mmol) in DMF (22 ml) at 0°C. The dark solution was allowed to warm to room temperature and stirred a further 1 hr. 2,5-dichlorobenzylamine (0.142 ml, 1.05 mmol) was treated with a portion of the above solution (0.58ml, 0.07 mmol) and the resulting mixture was stirred at room temperature for 16 hrs. The solution was treated with trifluroacetic acid (TFA) (0.025 ml) and purified by preparative HPLC. (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50X20mm I.D., C18, S-5 um, 120A) (available from Waters) eluting with 5 - 95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.<br/>
<sup>1</sup>H NMR (d<sub>6</sub>DMSO, 400MHz) δ 9.90 (1H, br t, <i>J</i>=5.0 Hz)), 9.20 (1H, d, <i>J</i>=4.0 Hz), 8.95 (1H, s), 8.65 (1H, d, <i>J</i>=8.0Hz), 7.85 (1H, dd, <i>J</i>=8.0 and 4.0 Hz), 7.54 (1H, d, <i>J</i>=8.0Hz), 7.50-7.30 (2H, m), 4.64 (2H, d, <i>J</i>=5.0 Hz) ppm.<br/>
FAB MS calcd for C<sub>16</sub>H<sub>11</sub>N<sub>3</sub>O<sub>2</sub>Cl<sub>2</sub> 348 (MH<sup>+</sup>), found 348.<br/>
FAB HRMS exact mass calcd for C<sub>16</sub>H<sub>11</sub>N<sub>3</sub>O<sub>2</sub>Cl<sub>2</sub> 348.0301 (MH<sup>+</sup>), found 348.0294.</p></heading></example>
