| 80% |
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A 3 L flask equipped with a mechanical stirrer was charged with a suspension of (2R,2TR)- 1,1T-adipoylbis(pyrrolidine-2-carboxylic acid) (30 g, 88 mmol) in 1,4-dioxane (200 mL). K2C03 (30.5 g, 220 mmol) was added to stirred suspension at RT and the reaction mixture was stirred at RT for10 mm then heated to 80 C. Tetrabutylammonium iodide (6.51 g, 17.63 mmol) was added to a solution of chloromethyl tetrahydro-2H-pyran-4-carboxylate (36.2 g, 203 mmol) dissolved in 1,4- dioxane (100 mL). After 10 mm stirring at RT, the precipitate was flltered and the orange nItrate was added drop wise over 30 mm in the reaction mixture prepared above. After 8 h at 80 C, the reaction mixture was flltered and the nitrate was concentrated under reduced pressure. The residue was taken up in EtOAc (300 mL) and washed with NaHCO3 aq. solution (1 x 100 mL), sodium sulflte aq. solution (1 x 100 mL), 0.5 N HCI (1 x 50 mL), water (1 x 100 mL) and brine. The organic layer was dried over anhydrous Na2SO4, filtered then stirred 15 mm with vegetal charcoal, flltered overcelite bed and concentrated in vacuo to afford the title compound as a pale yellow gum which crystallized. The amorphous solid was taken up in iPr2O and filtered to afford the title compound as off-white powder (28 g, 50.9 %).CrystallisationFinal puriflcationSeveral batches of (2R,2TR)-Bis(((tetrahyd ro-2H-pyran-4-carbonyl)oxy)methyl) 1, 1T adipoylbis(pyrrolidine-2-carboxylate) (106 g, 170 mmol) were gathered and diluted in ethyl acetate (200 mL) and heated to reflux in a 2 L flask with magnetic stirrer. After 20 mm the solid was dissolved and the flask was taken off the heating system, flltered and allowed to cool down naturallyto RT. When the temperature fell to 50 C some crystals began to appear. The product was left to stand overnight at RT without stirring to complete the crystallisation process. The mixture was filtered, washed successively with iPr2O (1 x 150 mL) and pentane (2 x 100 mL). The product was dried at 35 C and 5 mbars for 5 h to afford the product as a white powder (82.5 g, 80 %).LC/MS : m/z 625 [M+H], Rt 2.68 mm.?H NMR (400 MHz, CDCI3) O ppm 5.84 (d, J = 5.5 Hz, 2 H), 5.74 (d, J = 5.5 Hz, 2 H), 4.46 (m, 2 H),4.01-3.91 (m, 4 H), 3.70-3.59 (m, 2 H), 3.58-3.38 (m, 6 H), 2.67-2.55 (m, 2H), 2.43 - 1.54 (m, 24H).Some minor peaks were observed due to the presence of rotamers.?3c NMR (100 MHz, CDCI3) 173.20, 171.41, 171.21, 79.55, 66.33, 58.53, 46.95, 33.68, 29.11,28.53, 24.88, 24.20 , 22.52.HRMS : m/z calculated for C30H45N20,2 [M--H] 625.2972, found 625.3010.XRPD data were acquired on a PANalytical X?Pert Pro powder diffractometer, model PW3040/60 using an X?Celerator detector. The acquisition conditions were: radiation: Cu Ka, generator tension: 40 kV, generator current: 45 mA, start angle: 2.0 20, end angle: 40.0 20, stepsize: 0.0167 20, time per step: 31.75 seconds. The sample was prepared by mounting a few milligrams of sample (compound of Formula (III)) on a silicon wafer (zero background plate), resulting in a thin layer of powder. |
| 80% |
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A 3 L flask equipped with a mechanical stirrer was charged with a suspension of <strong>[224624-80-0](2R,2'R)-1,1'-adipoylbis(pyrrolidine-2-carboxylic acid)</strong> (30 g, 88 mmol) in 1,4-dioxane (200 mL). K2C03 (30.5 g, 220 mmol) was added to stirred suspension at RT and the reaction mixture was stirred at RT for 10 min then heated to 80 C. Tetrabutylammonium iodide (6.51 g, 17.63 mmol) was added to a solution of chloromethyl tetrahydro-2H-pyran-4-carboxylate (36.2 g, 203 mmol) dissolved in 1,4-dioxane (100 mL). After 10 min stirring at RT, the precipitate was filtered and the orange filtrate was added drop wise over 30 min in the reaction mixture prepared above. After 8 h at 80 C, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was taken up in EtOAc (300 mL) and washed with NaHC03 aq. solution (1 x 100 mL), sodium sulfite aq. solution (1 x 100 mL), 0.5 N HCI (1 x 50 mL), water (1 x 100 mL) and brine. The organic layer was dried over anhydrous Na2S04, filtered then stirred 15 min with vegetal charcoal, filtered over celite bed and concentrated in vacuo to afford the title compound as a pale yellow gum which crystallized. The amorphous solid was taken up in iPr20 and filtered to afford the title compound as off-white powder (28 g, 50.9 %).(2R,2'R)-bis(((tetrahydro-2H-pyran-4-carbonyl)oxy)methyl)-1,1'-adipoylbis(pyrrolidine-2-carboxylate) (106 g, 170 mmol) was pooled, diluted with ethyl acetate (200 mL) and heated under reflux in a 2 L flask equipped with a stirring magnet. After 20 minutes, the solids were dissolved, the flask was separated from the heating system, filtered and allowed to cool naturally to room temperature. When the temperature dropped to 50 DEG C, some crystals began to appear. The product was allowed to stand at room temperature overnight without stirring to complete the crystallization process. The mixture was filtered and washed successively with iPr2O (1 x 150 mL) and pentane (2 x 100 mL). The product was dried at 35 & lt; 0 & gt; C and 5 mbar for 5 hours to give the product as a white powder (82.5 g, 80%). |
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