US 8735390...Glaxosmithkline Intellectual Property Development Limited

 6-Chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole

 US8735390
 http://www.google.com/patents/US8735390
Glaxosmithkline Intellectual Property Development Limited

Intermediate 6
6-Chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole

Method A 4-[5-(Bromomethyl)-1,3-oxazol-2-yl]-6-chloro-1-(phenylsulfonyl)-1H-indazole (0.580 g, 1.28 mmol) was dissolved in dichloromethane (5 ml) and (2R,6S)-2,6-dimethylmorpholine (0.317 ml, 2.56 mmol) added. The reaction mixture was stirred at RT for 3 h then the solvent removed under a stream of nitrogen. The resultant yellow solid was dissolved in dichloromethane (5 ml) and washed with water (2×2.5 ml). The layers were separated (hydrophobic frit) and the organic evaporated in vacuo to give the title compound as a pale yellow solid (0.60 g).
LCMS (Method A): Rt 0.86 mins, MH⁺ 487.
¹H NMR (400 MHz, Chloroform-d) δ (ppm) 8.93 (d, J=1.0 Hz, 1 H), 8.33 (dd, J=1.0, 1.5 Hz, 1H), 8.04-8.00 (m, 2 H), 7.98 (d, J=1.5 Hz, 1 H), 7.62 (tt, J=1.5, 7.5 Hz, 1 H), 7.51 (t, J=7.5 Hz, 2 H), 7.15 (s, 1 H), 3.67 (s, 2 H), 3.75-3.66 (m, 2 H), 2.79-2.72 (m, 2 H), 1.86 (dd, J=10.5, 11.0 Hz, 2 H), 1.16 (d, J=6.5 Hz, 6 H).


Method B
(2R,6S)-2,6-dimethylmorpholine (160 ml) and then triethylamine (180 ml) were added to a suspension of 4-[5-(Bromomethyl)-1,3-oxazol-2-yl]-6-chloro-1-(phenylsulfonyl)-1H-indazole (478.1 g) in acetone (3.8 L) stirred under nitrogen at less than 25° C. The reaction mixture was stirred at 20-25° C. for 2.5 hours and then water (3.8 L) was added. The resultant suspension was stirred at than 25° C. for 35 min and was then filtered, washed with a mixture of 2:1 v/v water:acetone (2×1.0 L) and the solid dried under vacuum at 45±5° C. to give the title compound as an off-white solid (500.5 g). LCMS (Method B): Rt 3.43 min, MH⁺ 487.



Method C
All weights, volumes and equivalents are relative to 5-(bromomethyl)-2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazole (corrected for assay).
To a suspension of 5-(bromomethyl)-2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazole (1 wt, 540 g) in acetone (8.7 vol, 4.7 L) is added 2,6-dimethylmorpholine (0.33 vol, 1.2 eq, 178 ml), followed by triethylamine (0.37 vol, 1.2 eq, 200 ml) at <25° C. under a nitrogen atmosphere. The resulting mixture is stirred at 20-25° C. for at least 0.5 hr, then monitored for completion by HPLC. Water (8.7 vol, 4.7 L) is then added to the mixture over ca 5 minutes. The resulting suspension is aged at <25° C. for at least 0.5 hr, then the solids are collected by vacuum filtration, washed with water/acetone (2:1 v/v, 2×2.2 vol, 2×1.2 L) and dried in vacuo with a nitrogen bleed at 45±5° C.
Recrystallisation—All weights, volumes and equivalents are relative to ((2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methyl)-cis-2,6-dimethylmorpholine. A stirred suspension of ((2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methyl)-cis-2,6-dimethylmorpholine (1 wt, 30 g) in DMSO (9 vol, 270 ml) is heated to 75-80° C. under a nitrogen atmosphere. The resulting clear solution is transferred to a crystallising vessel via a 5 μm Domnick hunter in line filter, then the line is washed with further DMSO (1.0 vol, 30 ml). The hot solution is allowed to cool to 20-25° C. over at least 2 hr, then the resulting suspension is aged at this temperature for at least 1 hr. The resulting solids are filtered, washed with DMSO (1.5 vol, 45 ml), followed by water/acetone (2:1 v/v, 2×2 vol, 2×60 ml) before being sucked dry for 0.5 hr. The batch is dried in vacuo at 45° C. to constant probe temperature to afford ((2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methyl)-cis-2,6-dimethylmorpholine as an off-white solid.

 

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