Phosphoric Acid → HCID 66824296, compound

HRID 1966191Notes

Reaction equation

HRID 1966191 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([CH2:25][C:26]#[N:27])[CH2:18][N:17]([S:19]([CH:22]4[CH2:24][CH2:23]4)(=[O:21])=[O:20])[CH2:16]3)[CH:14]=2)=[N:3][CH:2]=1.C(#N)C.[P:31](=[O:35])([OH:34])([OH:33])[OH:32].C(O)C.P(=O)(O)(O)O>C(O)C>[P:31]([OH:35])([OH:34])([OH:33])=[O:32].[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([CH2:25][C:26]#[N:27])[CH2:16][N:17]([S:19]([CH:22]4[CH2:23][CH2:24]4)(=[O:20])=[O:21])[CH2:18]3)[CH:14]=2)=[N:3][CH:2]=1

Participants

6

Reactant 4

HCID 1004Phosphoric AcidHCID 6342AcetonitrileHCID 93197ETHYL PHOSPHATEHCID 442311341187594-14-4

Product 1

HCID 66824296HCID 66824296, compoundYield 84.5%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Conditions

Temperature
70 °C

Procedure

To a 1 L round bottom flask equipped with a stir bar, an addition funnel, a nitrogen inlet and a condenser was charged 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile (27, 11.3 g, 29.5 mmol) and acetonitrile (275 mL) at room temperature. The resulting mixture was warmed to 70° C. before being charged with ethanol (EtOH, 150 mL) in three portions at 70° C. The resulting homogeneous solution was filtered into a clean 1 L round bottom flask equipped with the overhead stirring, an addition funnel, a nitrogen inlet and a condenser. The mixture was then warmed to 67° C. producing a homogeneous solution again. A solution of phosphoric acid (H3PO4, 3.03 g, 30.9 mmol, 1.05 equiv) in ethanol (EtOH, 30 mL) was then charged drop wise to the solution over ten minutes at 67° C. The solution was still homogeneous after the end of the addition of phosphoric acid ethanol solution. The resulting reaction mixture was stirred at 67° C. for 10 minutes before being gradually cooled down to room temperature and stirred at room temperature for 19 h. The solids were collected by filtration and washed with acetonitrile (2×40 mL). The wet cake was partially dried under high vacuum and then transferred to a 75° C. vacuum oven and dried to constant weight to afford 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile phosphate (12.0 g, 14.2 g theoretical, 84.5% yield) as white solids. For Phosphate: 1H NMR (DMSO-d6, 500 MHz) δ 12.13 (br. s, 1H), 9.20 (br. s, 3H), 8.94 (s, 1H), 8.70 (s, 1H), 8.47 (s, 1H), 7.61 (dd, 1H, J=3.4, 2.3 Hz), 7.07 (dd, 1H, J=3.6, 1.6 Hz), 4.65 (d, 2H, J=9.1 Hz), 4.28 (d, 2H, J=9.7 Hz), 3.68 (s, 2H), 2.82 (m, 1H), 1.01 (m, 4H) ppm; 13C NMR (DMSO-d6, 125 MHz) δ 152.9, 151.6, 150.0, 140.6, 130.3, 127.7, 122.9, 117.3, 113.8, 100.7, 59.7, 57.1, 27.6, 25.4, 4.9 ppm; C17H20N7O6PS (MW, 481.42; C17H17N7O2S for free base, MW, 383.43), LCMS (EI) m/e 384 (M++H).

Workup

  1. customTo a 1 L round bottom flask equipped with a stir bar, an addition funnel, a nitrogen inlet and a condenser
  2. filtrationThe resulting homogeneous solution was filtered into a clean 1 L round bottom flask
  3. customequipped with the overhead
  4. temperatureThe mixture was then warmed to 67° C.
  5. customproducing a homogeneous solution again
  6. customThe resulting reaction mixture
  7. stirringwas stirred at 67° C. for 10 minutes
  8. temperaturebefore being gradually cooled down to room temperature
  9. stirringstirred at room temperature for 19 h
  10. filtrationThe solids were collected by filtration
  11. washwashed with acetonitrile (2×40 mL)
  12. customThe wet cake was partially dried under high vacuum
  13. customtransferred to a 75° C.
  14. customdried to constant weight

Sources & evidence

ORD record
ord-36536216d44849fdaf9156623c8185c2
Source dataset
uspto-grants-2013_04
Patent number
US08420629B2

Reaction notes

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