Potassium Phosphate, Tribasic → HCID 178482344, compound

HRID 2367306Notes

Reaction equation

HRID 2367306 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][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]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>[CH:20]1([NH:19][C:17]([C@H:12]2[CH2:13][CH2:14][C@@H:15]([CH3:16])[N:10]([C:4]3[CH:3]=[C:2]([C:32]4[CH:31]=[C:30]5[C:35]([C:27]([CH3:26])=[N:28][NH:29]5)=[CH:34][CH:33]=4)[N:7]=[C:6]([NH:8][CH3:9])[N:5]=3)[CH2:11]2)=[O:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 51357955(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamideHCID 1784342083-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-YL)-1H-indazole

Product 1

HCID 178482344HCID 178482344, compoundYield 35%

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]-N-cyclohexyl-6-methyl-3-piperidinecarboxamide (440 mg, 1.20 mmol), 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (466 mg, 1.80 mmol, 1.5 equiv), tricyclohexylphosphine (50 mg, 0.18 mmol, 0.15 equiv), Pd2(dba)3 (83 mg, 0.09 mmol, 0.075 equiv) and K3PO4 (434 mg, 2.04 mmol, 1.7 equiv) were charged to a 30 mL microwave vial, followed by addition of 1,4-dioxane (4.5 mL) and water (1.5 mL). The mixture was bubbled with argon for 10 minutes, followed by capping and heating at 100° C. for 20 hours. The mixture was filtered through celite, and rinsed with EtOAc (50 mL). The filtrate was concentrated in vacuo, and the residue was partitioned between EtOAc (50 mL) and brine (20 mL). The organic was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient elution with 1% EtOAc in CHCl3 to 100% EtOAc. This purified material was combined with purified product from a duplicate run. The combined residue was triturated in a mixture of CHCl3 (1 mL) and hexane (6 mL). Drying under vacuum at 65° C. for 20 hours afforded the title compound (194 mg) as a beige solid. LC-MS (ES) m/z=462 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.20-1.34 (m, 3H), 1.30 (d, J=6.8 Hz, 3H), 1.35-1.45 (m, 2H), 1.64-1.71 (m, 1H), 1.73-1.83 (m, 5H), 1.85-1.95 (m, 2H), 1.95-2.07 (m, 1H), 2.35-2.45 (m, 1H), 2.59 (s, 3H), 2.98 (s, 3H), 3.07-3.17 (m, 1H), 3.63-3.73 (m, 1H), 4.45-4.65 (bs, 1H), 6.48 (s, 1H), 7.66 (dd, J=8.5, 1.1 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 8.02 (s, 1H).

Workup

  1. customThe mixture was bubbled with argon for 10 minutes
  2. filtrationThe mixture was filtered through celite
  3. washrinsed with EtOAc (50 mL)
  4. concentrationThe filtrate was concentrated in vacuo
  5. customthe residue was partitioned between EtOAc (50 mL) and brine (20 mL)
  6. dry with materialThe organic was dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by silica gel column chromatography
  10. washa gradient elution with 1% EtOAc in CHCl3 to 100% EtOAc
  11. customThe combined residue was triturated in a mixture of CHCl3 (1 mL) and hexane (6 mL)
  12. customDrying under vacuum at 65° C. for 20 hours

Sources & evidence

ORD record
ord-c2f00eda78f74824a75ee55b5a47f1e7
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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