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<example id="h0181" title="EXAMPLE 81"><heading id="h0182" title="8-Hydroxy-5-(3-piperidin-1-yl-prop-1-ynyl)-[1,6]naphthyridine-7-carboxylic acid 3,5-dichloro-benzylamide"><p id="p0306" num="0306">
<chemistry id="chem0157" num="0157"><img id="ib0157" file="imgb0157.tif" wi="77" he="60" img-content="chem" img-format="tif" orientation="portrait" inline="no"/></chemistry></p></heading><heading id="h0183" title="Step 1: Preparation of 5-(3-methanesulfonyloxy-prop-1-ynyl)-8-(1-phenylmethanoyloxy)-[1,6]naphthyridine-7-carboxylic acid methyl ester"><p id="p0307" num="0307">A solution of 8-hydroxy-5-(3-hydroxy-prop-1-ynyl)-[1,6]naphthyridine-7-carboxylic acid (200 mg, 0.552 mmol, see Example 79 Step 3), mesyl chloride (94 µL, 1.21 mmol), and triethylamine (84 µL, 0.607 mmol) in dry CHCl<sub>3</sub> was stirred for one hour. The reaction was quenched with pH=7 buffer and extracted with CHCl<sub>3</sub>. The combined organic extracts were washed with brine, dried over Na<sub>2</sub>SO<sub>4</sub>, filtered and the solvent was evaporated <i>in vacuo</i> to give the desired product was a light brown oil.<br/>
<spectrum type="hnmr">1H NMR (<quantity type="solvent">CDCl3</quantity>, <quantity type="frequency"><value><point>400</point></value><units>MHz</units></quantity>) δ <peaks type=".."><peak><quantity type="shift"><value><point>9.19</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>8.77</point></value></quantity> (<quantity type="integral"><value><point>1</point></value><units>H</units></quantity>, <quantity type="peaktype">d</quantity>, J=<quantity type="coupling"><value><point>8.51</point></value> <units>Hz</units></quantity>)</peak>, <peak><quantity type="shift"><value><point>8.34</point></value></quantity> (<quantity type="integral"><value><point>2</point></value><units>H</units></quantity>, <quantity type="peaktype">d</quantity>, J=<quantity type="coupling"><value><point>7.87</point></value> <units>Hz</units></quantity>)</peak>, <peak><quantity type="shift"><value><point>7.76</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>4.21</point></value> and <value><point>8.51</point></value> <units>Hz</units></quantity>)</peak>, <peak><quantity type="shift"><value><point>7.71</point></value></quantity> (<quantity type="integral"><value><point>1</point></value><units>H</units></quantity>, <quantity type="peaktype">t</quantity>, J=<quantity type="coupling"><value><point>7.51</point></value> <units>Hz</units></quantity>)</peak>, <peak><quantity type="shift"><value><point>7.58</point></value></quantity> (<quantity type="integral"><value><point>2</point></value><units>H</units></quantity>, <quantity type="peaktype">t</quantity>, J=<quantity type="coupling"><value><point>7.69</point></value> <units>Hz</units></quantity>)</peak>, <peak><quantity type="shift"><value><point>5.23</point></value></quantity> (<quantity type="integral"><value><point>2</point></value><units>H</units></quantity>, <quantity type="peaktype">s</quantity>)</peak>, <peak><quantity type="shift"><value><point>3.95</point></value></quantity> (<quantity type="integral"><value><point>3</point></value><units>H</units></quantity>, <quantity type="peaktype">s</quantity>)</peak>, and <peak><quantity type="shift"><value><point>3.68</point></value></quantity> (<quantity type="integral"><value><point>3</point></value><units>H</units></quantity>, <quantity type="peaktype">s</quantity>)</peak> ppm</peaks></spectrum>.</p></heading><heading id="h0184" title="Step 2: Preparation of 8-(1-phenyl-methanoyloxy)-5-(3-piperidin-1-yl-prop-1-ynyl)-[1,6]naphthyridine-7-carboxylic acid methyl ester"><p id="p0308" num="0308">To a stirred mixture of piperdine (207 µL, 2.09 mmol) and potassium carbonate (296 mg, 2.14 mmol) in dry acetonitrile (10 mL) was pipetted in 5-(3-methanesulfonyloxy-prop-1-ynyl)-8-(1-phenyl-methanoyloxy)-[1,6]naphthyridine-7-carboxylic acid methyl ester (230 mg, 0.522 mmol) in acetonitrile (1 mL) and the mixture was stirred at room temperature for 3 hours. The reaction was concentrated, filtered, and purified on the Gilson auto-prep running a 95-50% H<sub>2</sub>O (0.1% TFA)/CH<sub>3</sub>CN (0.09% TFA) gradient over 30 minutes to obtain the desired compound as a light brown oil.<br/>
<sup>1</sup>H NMR (CDCl<sub>3</sub>, 400MHz) δ□9.27 (1H, d, <i>J</i>=4.30 Hz), 8.73 (1H, d, <i>J</i>=8.50 Hz), 7.83 (1H, dd, <i>J</i>=4.30 and 8.50 Hz), 4.25 (2H, s), 4.11 (3H, s), 3.83 (4H, m), 2.96-2.89 (2H, m), and 1.98 (4H, m) ppm.</p></heading><heading id="h0185" title="Step 3: Preparation of 8-hydroxy-5-(3-piperidin-1-yl-prop-1-ynyl)-[1,6]naphthyridine-7-carboxylic acid 3,5-dichloro-benzylamide"><p id="p0309" num="0309">Following the general procedure for addition of 3,5-dichlorobenzylamine to the ester as in Example 1, Step 3 gave the title compound as a brown solid.<br/>
<sup>1</sup>H NMR (CDCl<sub>3</sub>, 400MHz) δ□9.26 (1H, d, J= 4.21 Hz), 8.66 (1H, d, J=8.61 Hz), 8.44 (1H, s), 7.79 (1H, dd, J=4.21 and 8.61 Hz), 7.32 (1H, s), 7.29 (2H, s), 4.66 (2H, d, J=6.41 Hz), 4.30 (2H, s), 3.70 (4H, m), 2.95 (2H, m), and 2.01 (4H, m) ppm.<br/>
FAB HRMS exact mass calcd for C<sub>24</sub>H<sub>22</sub>Cl<sub>2</sub>N<sub>4</sub>O<sub>2</sub> 469.119258 (MH<sup>+</sup>), found 469.119314.<br/>
Anal. Calcd for C<sub>24</sub>H<sub>22</sub>Cl<sub>2</sub>N<sub>4</sub>O<sub>2</sub>•1.35 MeOH•0.05 TFA: C, 47.39; H, 3.98; N, 7.51. Found: C, 47.40; H, 3.98; N, 7.23.</p></heading></example>
