Ammonium Hydroxide → Baricitinib

HRID 1966176Notes

Reaction equation

HRID 1966176 reaction equation
[CH2:1]([S:3]([N:6]1[CH2:9][C:8]([CH2:32][C:33]#[N:34])([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7]1)(=[O:5])=[O:4])[CH3:2].[OH-].[NH4+]>C(#N)C.O>[N:18]1[C:17]2[NH:21][CH:22]=[CH:23][C:16]=2[C:15]([C:13]2[CH:12]=[N:11][N:10]([C:8]3([CH2:32][C:33]#[N:34])[CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:9]3)[CH:14]=2)=[N:20][CH:19]=1

Participants

5

Reactant 2

HCID 14923Ammonium HydroxideHCID 578688652-(1-(Ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

Product 1

HCID 44205240BaricitinibYield 83.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent3×HCID 6342AcetonitrileSolvent

Conditions

Temperature
75 °C

Procedure

To a solution of 2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (6, 327 g, 655 mmol) in acetonitrile (3 L) and water (300 mL) was added LiBF4 (614 g, 6.55 mol, 10.0 equiv). The resulting reaction mixture was stirred at 75° C. for overnight. The reaction mixture was cooled to 0° C. before a solution of ammonium hydroxide (NH4OH, 570 mL) in water (2.2 L) was added slowly to keep the temperature below 10° C. (pH 9-10). The mixture was stirred at room temperature for overnight. When the reaction was deemed complete, water (10 L) was added and the resulting mixture was vigorously stirred for 3 h at room temperature. The solids were collected by filtration, washed with water (6.7 L) and heptane (6.7 L), and dried in vacuum oven at 45° C. over the weekend. The dried solid was then dissolved in 20% MeOH in dichloromethane (12 L), and was purified by column chromatography on 1.3 Kg of silica gel eluting with a 20% MeOH in dichloromethane solution (18 L) to afford 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (7, 204 g, 243.3 g theoretical, 83.8% yield) as an off-white solid. For 7: 1H NMR (300 MHz, d6-DMSO) 81.25 (t, 3H), 3.25 (q, 2H), 3.75 (s, 2H), 4.25 (d, 2H), 4.65 (d, 2H), 7.10 (d, 1H), 7.65 (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. additionwas added slowly
  3. customthe temperature below 10° C. (pH 9-10)
  4. stirringThe mixture was stirred at room temperature for overnight
  5. stirringthe resulting mixture was vigorously stirred for 3 h at room temperature
  6. filtrationThe solids were collected by filtration
  7. washwashed with water (6.7 L) and heptane (6.7 L)
  8. customdried in vacuum oven at 45° C. over the weekend
  9. dissolutionThe dried solid was then dissolved in 20% MeOH in dichloromethane (12 L)
  10. customwas purified by column chromatography on 1.3 Kg of silica gel eluting with a 20% MeOH in dichloromethane solution (18 L)

Sources & evidence

ORD record
ord-77faaec673014a498264142a125610e6
Source dataset
uspto-grants-2013_04
Patent number
US08420629B2

Reaction notes

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