Phosphoric Acid → Jakafi

HRID 880562Notes

Reaction equation

HRID 880562 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@@H:15]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:16][C:17]#[N:18])[CH:14]=2)=[N:3][CH:2]=1.[P:24](=[O:28])([OH:27])([OH:26])[OH:25]>ClCCl.CC(O)C>[P:24]([OH:28])([OH:27])([OH:26])=[O:25].[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@@H:15]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:16][C:17]#[N:18])[CH:14]=2)=[N:3][CH:2]=1

Participants

5

Reactant 2

HCID 1004Phosphoric AcidHCID 25126798Ruxolitinib

Product 1

HCID 25127112JakafiYield 85.9%

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolvent2×HCID 6344DichloromethaneSolvent

Procedure

To a solution of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile ((R)-12, 54.2 g, 177 mol) in dichloromethane (782 mL) and 2-propanol (104 mL) at reflux was added a solution of phosphoric acid (19.9 g, 0.173 mol, 1.15 equiv) in 2-propanol (34.0 mL) over a period of 47 minutes. Following the acid addition, the resulting mixture was heated to reflux for an additional 1 hour. The mixture was gradually cooled to ambient temperature and stirred for 3 hours. The solids were collected by filtration and washed with dichloromethane (390 mL), followed by n-heptane (390 mL). The solids were partially dried under vacuum at room temperature and then under vacuum at 62° C. to afford (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate (60.1 g, 84% yield) as white to off-white crystalline solids. Analysis by chiral HPLC (chiralcel OD, 90:10 hexane/ethanol) gave the enantiopurity as 99.2% ee. 1H NMR (DMSO-d6, 400 MHz) δ 12.11 (bs, 1H), 8.79 (d, 1H, J=0.59 Hz), 8.67 (s, 1H), 8.36 (s, 1H), 7.59 (q, 1H, J=2.3 Hz), 6.98 (q, 1H, J=1.6 Hz), 4.53 (td, 1H, J=19.6, 4.4 Hz), 3.22 (dq, 2H, J=9.6, 4.3 Hz), 2.40 (m, 1H), 1.79 (m, 1H), 1.65-1.13 (m, 7H). C17H21N6O4P (MW, 404.36), LCMS (EI) m/e 307 (M++H) and m/e 329 (M++Na).

Workup

  1. additionthe acid addition
  2. temperaturethe resulting mixture was heated
  3. temperatureto reflux for an additional 1 hour
  4. filtrationThe solids were collected by filtration
  5. washwashed with dichloromethane (390 mL)
  6. customThe solids were partially dried under vacuum at room temperature

Sources & evidence

ORD record
ord-3fd040315898434889cda66ed29904bf
Source dataset
uspto-grants-2015_03
Patent number
US08993582B2

Reaction notes

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