Water → Povorcitinib

HRID 1049144Notes

Reaction equation

HRID 1049144 reaction equation
[C:1]([CH2:3][C:4]1([N:25]2[CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=[N:26]2)[CH2:7][N:6]([C:8]2[C:22]([F:23])=[CH:21][C:11]([C:12]([NH:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:13])=[C:10]([F:24])[CH:9]=2)[CH2:5]1)#[N:2].Br[C:40]1[C:41]([CH3:46])=[N:42][NH:43][C:44]=1[CH3:45].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([CH2:3][C:4]1([N:25]2[CH:29]=[C:28]([C:40]3[C:41]([CH3:46])=[N:42][NH:43][C:44]=3[CH3:45])[CH:27]=[N:26]2)[CH2:5][N:6]([C:8]2[C:22]([F:23])=[CH:21][C:11]([C:12]([NH:14][C@@H:15]([CH3:20])[C:16]([F:17])([F:18])[F:19])=[O:13])=[C:10]([F:24])[CH:9]=2)[CH2:7]1)#[N:2]

Participants

7

Reactant 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 769374-bromo-3,5-dimethyl-1H-pyrazoleHCID 1317360004-{3-(Cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide

Product 1

HCID 86280672PovorcitinibYield 9.7%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 4-{3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (329 mg, 0.610 mmol, from Example 4, step 5), 4-bromo-3,5-dimethyl-1H-pyrazole (206 mg, 1.18 mmol), tetrakis(triphenylphosphine)palladium(0) (110 mg, 0.098 mmol) and sodium carbonate (320 mg, 3.0 mmol) in 1,4-dioxane (10 mL)/water (5 mL) was purged with nitrogen and stirred at 110° C. for 1 h. The reaction mixture was diluted with EtOAc, washed with water and brine, concentrated. The residue was purified first with silica gel (eluting with 0-100% EtOAc/hexanes followed by 10% methanol/dichloromethane), and then by prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (30 mg, 9.7%). 1H NMR (500 MHz, DMSO-d6) δ 12.17 (1H, s), 8.45 (1H, d, J=8.0 Hz), 8.10 (1H, s), 7.70 (1H, s), 7.34 (1H, m), 6.61 (1H, s), 4.77 (1H, m), 4.62 (2H, d, J=9.0 Hz), 4.39 (1H, d, J=9.0 Hz), 3.64 (2H, s), 2.22 (6H, s), 1.31 (6H, d, J=7.0 Hz) ppm. LCMS calculated for C23H23F5N7O (M+H)+: m/z=508.2. Found: 508.0.

Workup

  1. customwas purged with nitrogen
  2. additionThe reaction mixture was diluted with EtOAc
  3. washwashed with water and brine
  4. concentrationconcentrated
  5. customThe residue was purified first with silica gel (eluting with 0-100% EtOAc/hexanes followed by 10% methanol/dichloromethane)
  6. washby prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min)

Sources & evidence

ORD record
ord-fcc3f77de76d450b9768ff6470a97b12
Source dataset
uspto-grants-2016_07
Patent number
US09382231B2

Reaction notes

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