Phosphoric Acid → Baricitinib phosphate

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[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([C:10]2[CH:11]=[N:12][N:13]([C:15]3([CH2:24][C:25]#[N:26])[CH2:18][N:17]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH2:16]3)[CH:14]=2)=[N:3][CH:2]=1.[P:27](=[O:31])([OH:30])([OH:29])[OH:28]>C(#N)C.C(O)C>[P:27]([OH:31])([OH:30])([OH:29])=[O:28].[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([C:10]2[CH:11]=[N:12][N:13]([C:15]3([CH2:24][C:25]#[N:26])[CH2:16][N:17]([S:19]([CH2:22][CH3:23])(=[O:20])=[O:21])[CH2:18]3)[CH:14]=2)=[N:3][CH:2]=1

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실험 절차

To a solution of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (14, 471.2 g, 1268.6 mmol) in acetonitrile (10.86 L) and ethanol (3.75 L) was added an 85% aqueous solution of phosphoric acid (H3PO4, 191.6 g, 1661.7 mmol, 1.31 equiv) in ethanol (EtOH, 1.68 L) slowly over 50 min at 70° C. The resulting reaction mixture was cooled down to room temperature slowly and stirred at room temperature for overnight. The solids were collected by filtration and washed with acetonitrile (500 mL). The resulting wet cake was then suspended in ethanol (EtOH, 7.0 L) before being treated with an aqueous 85% solution of phosphoric acid (H3PO4, 95.1 g, 824.6 mmol, 0.65 equiv) in ethanol (EtOH, 1.23 L) at room temperature. The resulting mixture was then warmed to reflux and stirred at reflux for 1 h before being cooled down to room temperature slowly and stirred at room temperature for overnight. The solids were collected by filtration, washed with ethanol (2 L) and heptane/ethanol (v/v 2/1, 2.1 L), and dried in vacuum oven at 40° C. for overnight to afford 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile phosphate salt (534.8 g, 595.5 g theoretical, 89.8% yield) as white crystalline solids. For phosphate salt: mp: 187° C.; elemental analysis for C16H20N7O6PS, Calcd: C, 40.94; H, 4.29; N, 20.89; P, 6.60; S, 6.83. Found: C, 40.65; H, 4.22; N, 20.71; P, 6.53; S, 6.95; FTIR (vmax, cm−1): 3123 (—CH—), 2254 (CN), 1627 and 1441 (heteroaromatic C═N), 1600 and 1559 (heteroaromatic C═C), 1312 (—SO2—); 1H NMR (DMSO-d6, 300 MHz) δ 12.19 (s, 1H), 8.94 (s, 1H), 8.71 (s, 1H), 8.48 (s, 1H), 7.62 (dd, 1H, J=3.5, 2.3 Hz), 7.08 (dd, 1H, J=3.6, 1.5 Hz), 4.60 (d, 2H, J=9.3, 9.2 Hz), 4.23 (d, 2H, J=9.3, 9.2 Hz), 3.69 (s, 2H), 3.23 (q, 2H, J=7.2 Hz), 1.23 (t, 3H, J=7.3 Hz) ppm; 13C NMR (DMSO-d6, 75 MHz) δ 152.3, 150.9, 149.4, 140.0, 129.7, 127.1, 122.2, 116.8, 113.1, 100.1, 58.6, 56.1, 43.3, 26.9, 7.5 ppm; C16H17N7O2S (free base, MW, 371.42), LCMS (EI) m/e 372 (M++H).