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Phosphoric Acid → Baricitinib phosphate

HRID 1692965
Notes
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Reaction equation

HRID 1692965 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](=[O:28])([OH:31])([OH:30])[OH:29].[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
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 2

HCID 1004Phosphoric AcidHCID 44205240Baricitinib

Product 1

HCID 44231848Baricitinib phosphateYield 93%

Reagents, catalysts & solvents 2

HCID 702EthanolSolvent2×HCID 6342AcetonitrileSolvent

Conditions

Temperature
70 °C

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 (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. For final product: 1H NMR (300 MHz, d6-DMSO) δ 1.25 (t, 3H), 3.25 (q, 2H), 3.75 (s, 2H), 4.20 (d, 2H), 4.61 (d, 2H), 7.10 (d, 1H), 7.60 (dd, 1H),8.50 (s, 1H), 8.70 (s, 1H), 8.95 (s, 1H), 12.2 (bs, 1H); MS: m/z calcd. 372.12; found: 372.0.

Workup

  1. customThe resulting reaction mixture
  2. temperaturebefore being gradually cooled to room temperature
  3. stirringwith stirring for overnight
  4. filtrationThe solids were collected by filtration
  5. washwashed with acetonitrile (160 mL)
  6. customdried in vacuum oven at 45° C. for 6 h

Sources & evidence

ORD record
ord-645bf0ae0c0a4a169802ecdb3a1af6aa
Source dataset
uspto-grants-2012_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08158616B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes