Phosphoric Acid → Baricitinib phosphate

HRID 1966183Notes

Reaction equation

HRID 1966183 reaction equation
[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

Participants

5

Reactant 2

HCID 1004Phosphoric Acid2×HCID 44205240Baricitinib

Product 1

HCID 44231848Baricitinib phosphateYield 89.8%

Reagents, catalysts & solvents 2

HCID 702EthanolSolvent3×HCID 6342AcetonitrileSolvent

Procedure

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).

Workup

  1. customThe resulting reaction mixture
  2. filtrationThe solids were collected by filtration
  3. washwashed with acetonitrile (500 mL)
  4. temperatureThe resulting mixture was then warmed
  5. temperatureto reflux
  6. stirringstirred
  7. temperatureat reflux for 1 h
  8. temperaturebefore being cooled down to room temperature slowly
  9. stirringstirred at room temperature for overnight
  10. filtrationThe solids were collected by filtration
  11. washwashed with ethanol (2 L) and heptane/ethanol (v/v 2/1, 2.1 L)
  12. customdried in vacuum oven at 40° C. for overnight

Sources & evidence

ORD record
ord-75860c9747c0448ca5c37bd3bf7d4775
Source dataset
uspto-grants-2013_04
Patent number
US08420629B2

Reaction notes

Loading…