Potassium Phosphate, Tribasic → HCID 66990986, compound

HRID 2367316Notes

Reaction equation

HRID 2367316 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[CH:14]([CH3:15])[CH2:13][CH:12]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:11]2)[CH:3]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=1[F:37])#[N:27].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]3[C@H:14]([CH3:15])[CH2:13][C@H:12]([C:16]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[CH2:11]3)[CH:3]=2)=[CH:30][C:29]=1[F:37])#[N:27]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 2783130(4-Cyano-3-fluorophenyl)boronic acidHCID 58504582HCID 58504582, compound

Product 1

HCID 66990986HCID 66990986, compoundYield 114.1%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

Racemic (3S,5R)-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-(phenylmethyl)-3-pyrrolidinecarboxamide (100 mg, 0.28 mmol), (4-cyano-3-fluorophenyl)boronic acid (60 mg, 0.36 mmol, 1.3 equiv), tricyclohexylphosphine (12 mg, 0.043 mmol, 0.15 equiv), Pd2(dba)3 (20 mg, 0.022 mmol, 0.075 equiv) and K3PO4 (101 mg, 0.48 mmol, 1.7 equiv) were charged to a 20 mL microwave vial, followed by addition of 1,4-dioxane (3 mL) and water (1 mL). The mixture was bubbled with argon for 15 minutes, followed by capping and heating to 100° C. for 21 hours. This crude mixture was combined with another run starting with 300 mg of racemic (3S,5R)-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-5-methyl-N-(phenylmethyl)-3-pyrrolidinecarboxamide. The combined mixture was filtered through celite, and the cake was rinsed with EtOAc (100 mL). The filtrate was concentrated in vacuo, and the resulting residue was taken up in 25 mL of water, sonicated briefly, and filtered. The dark colored solids were washed with water, and dried under house vacuum for 1 hour. Attempt was made to dissolve these solids in CHCl3, EtOAc, and CH3OH, but there was always some residue left. The residue was checked by LCMS be the pure desired product. This dark colored residue was collected by filtration, and dissolved in CHCl3 with a small amount of MeOH (2% by volume, total solvent used about 100 mL) to give a dark solution, which was filterd through celite. The filtrate was concentrated in vacuo, and the resulting yellowish residue was dried under vacuum to give 142 mg of the title compound. The above organic filtrate (combined CHCl3, EtOAc and CH3OH wash) was concentrated in vacuo. Trituration in EtOAc (6 mL) and drying under vacuum gave another 220 mg of the title compound.

Workup

  1. customThe mixture was bubbled with argon for 15 minutes
  2. filtrationThe combined mixture was filtered through celite
  3. washthe cake was rinsed with EtOAc (100 mL)
  4. concentrationThe filtrate was concentrated in vacuo
  5. customsonicated briefly
  6. filtrationfiltered
  7. washThe dark colored solids were washed with water
  8. customdried under house vacuum for 1 hour
  9. dissolutionto dissolve these solids in CHCl3
  10. waitleft
  11. filtrationThis dark colored residue was collected by filtration
  12. dissolutiondissolved in CHCl3 with a small amount of MeOH (2% by volume, total solvent used about 100 mL)
  13. customto give a dark solution, which
  14. concentrationThe filtrate was concentrated in vacuo
  15. customthe resulting yellowish residue was dried under vacuum

Sources & evidence

ORD record
ord-cc4efc5c60184164a4243729b1013d54
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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