2-MORPHOLINECARBOXYLIC ACID HCL synthesis

Yield:-

Reaction Conditions:

with trifluoroacetic acid in dichloromethane for 1 h;

Steps:

28
Example 28: 4-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-l,2,4- oxadiazol-3-yl)phenyl)ethyl)morpholine-2-carboxylic acid[00278] 4-(tert-Butoxycarbonyl)morpholine-2-carboxylic acid (69.5 mg, 0.301 mmol) was treated with TFA/DCM for 1 hour. Solvents were removed in vacuo and the resulting material was dried. The solids were dissolved in 2-propanol (2 mL) and DMSO (1 mL). 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)- 1,2,4- oxadiazole (30 mg, 0.075 mmol) and cesium carbonate (98 mg, 0.301 mmol) were added. The reaction mixture was heated at 80 ⁰C overnight. LCMS indicated almost complete conversion to desired product and no starting material. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX Luna C18 5 micron column (250 x 30mm); 25-100% CH₃CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 21 mg of 4-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-l,2,4-oxadiazol-3- yl)phenyl)ethyl) morpholine-2-carboxylic acid as a TFA salt. ¹H NMR (400 MHz, MeOH-d₃) δ ppm 8.23 (2 H, d, J=I .91 Hz), 7.69 (4 H, dd, J=12.08, 7.69 Hz), 7.54-7.65 (3 H, m), 5.29 (1 H, td, J=6.81, 4.39 Hz), 4.41-4.65 (1 H, m), 4.08-4.37 (1 H, m), 3.92- 4.05 (2 H, m), 3.56-3.91 (1 H, m), 3.44 (3 H, t, J=6.81 Hz), 3.12-3.38 (1 H, m). MS (m+1) = 531. HPLC Peak RT = 3.24 minutes (Analytical Method A). Purity = 85%.

References:

BRISTOL-MYERS SQUIBB COMPANY;GILMORE, John L.;SHEPPECK, James E. WO2011/17578, 2011, A1 Location in patent:Page/Page column 134