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With phosphoric acid In methanol; water; acetonitrile at 68℃; for 1 h;
Baricitinib (0.30 g; 0.8 nimol) was dissolved in acetonitrile (7 ml) under boiling and during30 minutes, a solution of phosphoric acid (0.20 g; 2.1 equivalents; 85percent cone. in water) inmethanol (1.2 ml) was added by dripping. The obtained suspension was stirred for 1 hour at the temperature of 68°C, then it was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and dried at 35°C and 200 mbar for 18h. Baricitinib phosphate of form C was obtained as white powder (376 mg; 99.2percent). Stoichiometry 1:1.14.
93%
With phosphoric acid In ethanol; acetonitrile at 70℃; for 2 h;
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 (7, 204 g, 550 mmol) in acetonitrile (5.1 L) and ethanol (1.6 L) was added a solution of phosphoric acid (67.4 g, 688 mmol, 1.25 equiv) in ethanol (800 mL) slowly over 30 min at 70° C. The resulting reaction mixture was stirred at 70° C. for 2 h before being gradually cooled to room temperature with stirring for overnight. The solids were collected by filtration, washed with acetonitrile (160 mL) and dried in vacuum oven at 45° C. for 6 h to afford 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile phosphoric acid salt (240 g, 258.2 g theoretical, 93percent yield) as a white solid.
With phosphoric acid; In methanol; water; acetonitrile; at 68℃; for 1h;
Baricitinib (0.30 g; 0.8 nimol) was dissolved in acetonitrile (7 ml) under boiling and during30 minutes, a solution of phosphoric acid (0.20 g; 2.1 equivalents; 85% cone. in water) inmethanol (1.2 ml) was added by dripping. The obtained suspension was stirred for 1 hour at the temperature of 68C, then it was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and dried at 35C and 200 mbar for 18h. Baricitinib phosphate of form C was obtained as white powder (376 mg; 99.2%). Stoichiometry 1:1.14.
93%
With phosphoric acid; In ethanol; acetonitrile; at 70℃; for 2h;Product distribution / selectivity;
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 (7, 204 g, 550 mmol) in acetonitrile (5.1 L) and ethanol (1.6 L) was added a solution of phosphoric acid (67.4 g, 688 mmol, 1.25 equiv) in ethanol (800 mL) slowly over 30 min at 70 C. The resulting reaction mixture was stirred at 70 C. for 2 h before being gradually cooled to room temperature with stirring for overnight. The solids were collected by filtration, washed with acetonitrile (160 mL) and dried in vacuum oven at 45 C. for 6 h to afford 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile phosphoric acid salt (240 g, 258.2 g theoretical, 93% yield) as a white solid.
With phosphoric acid; In ethanol; acetonitrile; at 70℃; for 2h;
2.2 g of Barrickinib was suspended in a mixed solvent of 54 ml of acetonitrile and 20 ml of ethanol (technical grade), and the suspension was heated to 70 C, and the suspension was completely dissolved, and 0.9 g of phosphoric acid (85%, 1.3 eq) was dissolved. After 7 ml of ethanol, the solution was slowly added dropwise, stirred at 70 C for 2 hours, slowly lowered to room temperature (over 150 minutes), and stirred at room temperature until every other day, filtered, and washed with 10 ml of acetonitrile, 30 Drying under vacuum at C for 5 days gave a white solid which, after detection, was the crystalline form D of Barrickinib and its melting point was 180.1 to 181.5 C.
{1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3,d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3 -yl}acetonitrile phosphate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With phosphoric acid; In ethanol; acetonitrile; at 25℃; for 12h;
10.2mg of phosphate crystalline Form B of compound of Formula (I) was added into a mixed solvent of 0.97 mL of acetonitrile and 0.03 mL of water to obtain a suspension, then it was stirred at 25 C. for 12 hours, centriffiged to obtain a lower layer of solid, placed the solid at a constant temperature of 25 C. for drying overnight, the obtained solid was detected as phosphate crystalline Form C. The XRPD datas of the solid prepared in this example are listed in Table 12. The XRPD pattern is displayed in FIG. 20. The DSC thermogram is displayed in FIG. 21, the TGA thermogram is displayed in FIG. 22.
With phosphoric acid; In water; acetonitrile; at 80℃; for 1h;
The crude barrickinib 1.0g and acetonitrile 33mL,Mixed, 0.36 g of phosphoric acid.Stir and heat to dissolve in a water bath at 80 C.Keep warm for 1 hour.Slowly cool down to 5 ~ 10 C,Stirring,Filter, drain,Drying at 50 C to obtain a crude product of barretinib phosphate 0.79 g.
With phosphoric acid; In propan-1-ol; ethanol; at 68℃; for 1.5h;
<strong>[1187594-09-7]Baricitinib</strong> (0.30 g; 0.8 rnniol) was dissolved in n-propauol (18 ml) under boiling and during30 minutes, a solution of phosphoric acid (0.22 g; 2,4 equivalents; 85% conc.) in ethanol(1,2 ml) was added by dripping. The obtained suspension was stirred for 1.5 hours at the temperature of 68C, then it was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and dried at 35C and 200 mbar for 1 8h. <strong>[1187594-09-7]Baricitinib</strong> hemiphosphate of form II was obtained as white powder (371 mg; 97.9%). Stoichiometry 1:0.5.
Baricitinib phosphate (200 mg) was suspended in an ethanol/water mixture (mixture ratio 3/1).The suspension was stirred at 50C in a shaker for 2 weeks. The precipitate was filtered offand dried in vacuum. Baricitinib hemiphosphate of form I was obtained as white powder(185 mg; 93%). Stoichiometry 1:0.6.
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