Potassium Phosphate, Tribasic → HCID 178482343, compound

HRID 2367305Notes

Reaction equation

HRID 2367305 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])[CH2:11]2)[CH:3]=1.[CH3:26][C:27]1[C:35]2[C:30](=[CH:31][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:34]=2)[NH:29][N:28]=1.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>[CH3:16][C@H:15]1[N:10]([C:4]2[CH:3]=[C:2]([C:32]3[CH:31]=[C:30]4[C:35]([C:27]([CH3:26])=[N:28][NH:29]4)=[CH:34][CH:33]=3)[N:7]=[C:6]([NH:8][CH3:9])[N:5]=2)[CH2:11][C@@H:12]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[CH2:13][CH2:14]1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 51357695(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-phenyl-3-piperidinecarboxamideHCID 1784342083-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-YL)-1H-indazole

Product 1

HCID 178482343HCID 178482343, compoundYield 39%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-phenyl-3-piperidinecarboxamide (420 mg, 1.17 mmol), 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (452 mg, 1.75 mmol, 1.5 equiv), tricyclohexylphosphine (49 mg, 0.175 mmol, 0.15 equiv), Pd2(dba)3 (80 mg, 0.088 mmol, 0.075 equiv) and K3PO4 (412 mg, 1.98 mmol, 1.7 equiv) were charged to a 30 mL microwave vial, followed by addition of 1,4-dioxane (6 mL) and water (2 mL). The mixture was bubbled with argon for 10 minutes, followed by heating at 100° C. for 20 hours. After cooling to room temperature, the mixture was filtered through celite and rinsed with EtOAc (30 mL). The filtrate was concentrated in vacuo, and the resulting residue was partitioned between EtOAc (30 mL) and brine (10 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using gradient elution of 1% A in CHCl3 to 70% A in CHCl3 (A was a mixture of 800/80/3200 CH3OH/NH4OH/CHCl3). Trituration of the purified material in a mixture of CHCl3 (1 mL), MTBE (2 mL) and hexane (6 mL), and drying under vacuum at 65° C. for 20 hours afforded the title compound (208 mg) as a tan solid. LC-MS (ES) m/z=456 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.33 (d, J=6.8 Hz, 3H), 1.78-1.96 (m, 3H), 2.05-2.16 (m, 1H), 2.58-2.16 (m, 1H), 2.59 (s, 3H), 2.99 (s, 3H), 3.18-3.27 (m, 1H), 6.53 (s, 1H), 7.12 (t, J=7.3 Hz, 1H), 7.34 (t, J=8.0 Hz, 2H), 7.60 (d, J=7.3 Hz, 2H), 7.68 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 8.04 (s, 1H).

Workup

  1. customThe mixture was bubbled with argon for 10 minutes
  2. temperatureAfter cooling to room temperature
  3. filtrationthe mixture was filtered through celite
  4. washrinsed with EtOAc (30 mL)
  5. concentrationThe filtrate was concentrated in vacuo
  6. customthe resulting residue was partitioned between EtOAc (30 mL) and brine (10 mL)
  7. dry with materialThe organic was dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by silica gel column chromatography
  11. washelution of 1% A in CHCl3 to 70% A in CHCl3 (
  12. additiona mixture of 800/80/3200 CH3OH/NH4OH/CHCl3)
  13. additionTrituration of the purified material in a mixture of CHCl3 (1 mL), MTBE (2 mL) and hexane (6 mL)
  14. customdrying under vacuum at 65° C. for 20 hours

Sources & evidence

ORD record
ord-d9bd35aa0bf04a619eda8a9441f2ead7
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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