Potassium Phosphate, Tribasic → Asciminib

HRID 73746Notes

Reaction equation

HRID 73746 reaction equation
O1CCCCC1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:30]1[C:31]([N:50]2[CH2:54][CH2:53][C@@H:52]([OH:55])[CH2:51]2)=[N:32][CH:33]=[C:34]([CH:49]=1)[C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([Cl:48])([F:47])[F:46])=[CH:40][CH:39]=1)=[O:36]>C1(C)C=CC=CC=1.[Cl-].[Na+].O.CO.C(Cl)Cl.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>[Cl:48][C:45]([F:46])([F:47])[O:44][C:41]1[CH:42]=[CH:43][C:38]([NH:37][C:35](=[O:36])[C:34]2[CH:49]=[C:30]([C:11]3[NH:7][N:8]=[CH:9][CH:10]=3)[C:31]([N:50]3[CH2:54][CH2:53][C@@H:52]([OH:55])[CH2:51]3)=[N:32][CH:33]=2)=[CH:39][CH:40]=1

Participants

8

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 115872081-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 72545856(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

Product 1

HCID 72165228Asciminib

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 1140TolueneSolventHCID 21226129Dichloromethane methanolSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
110 °C

Procedure

1-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (29.6 g, 102 mmol), K3PO4 (51.6 g, 236 mmol) and Pd(PPh3)4 (4.55 g, 3.93 mmol) were added to a suspension of (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 9.2, 36.4 g, 79 mmol) in toluene (360 mL) under an argon atmosphere and the mixture was stirred at 110° C. for 4 h. The RM was poured into brine (500 mL) and extracted with EtOAc (2×1 L). The combined extracts were washed with brine (500 mL), dried over Na2SO4, and the solvent was evaporated off under reduced pressure to give a residue which was purified by chromatography (Silica gel column, 1.5 kg, DCM/MeOH 95:5) to afford a dark yellow foam, that was dissolved in MeOH/DCM (1 L of 3:1) and treated with Si-Thiol (Biotage, 35 g, 45.5 mmol) for 17 h at 30° C. The resin was filtered off, and solvent was evaporated off under reduced pressure, until the desired compound crystallized. The product was filtered washed with MeOH and dried to afford the title compound.

Workup

  1. extractionextracted with EtOAc (2×1 L)
  2. washThe combined extracts were washed with brine (500 mL)
  3. dry with materialdried over Na2SO4
  4. customthe solvent was evaporated off under reduced pressure
  5. customto give a residue which
  6. customwas purified by chromatography (Silica gel column, 1.5 kg, DCM/MeOH 95:5)
  7. customto afford a dark yellow foam, that
  8. filtrationThe resin was filtered off
  9. customsolvent was evaporated off under reduced pressure, until the desired compound
  10. customcrystallized
  11. filtrationThe product was filtered
  12. washwashed with MeOH
  13. customdried

Sources & evidence

ORD record
ord-277abdfa1c8645a3b7227a8138bcf48c
Source dataset
uspto-grants-2014_09
Patent number
US08829195B2

Reaction notes

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