Potassium Phosphate, Tribasic → (3S,6R)-N-Cyclohexyl-1-[6-(1H-indazol-6-yl)-2-(methylamino)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxamide

HRID 2367300Notes

Reaction equation

HRID 2367300 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.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[C:41]3[C:37]([CH:38]=[N:39][NH:40]3)=[CH:36][CH:35]=2)O1.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:34]4[CH:42]=[C:41]5[C:37]([CH:38]=[N:39][NH:40]5)=[CH:36][CH:35]=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 441192506-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazoleHCID 51357955(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamide

Product 1

HCID 58504558(3S,6R)-N-Cyclohexyl-1-[6-(1H-indazol-6-yl)-2-(methylamino)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxamideYield 58%

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 (700 mg, 1.91 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (607 mg, 2.50 mmol, 1.3 equiv), Pd2(dba)3 (131 mg, 0.14 mmol, 0.075 equiv), tricyclohexylphosphine (80 mg, 0.287 mmol, 0.15 equiv), and K3PO4 (690 mg, 3.25 mmol, 1.7 equiv) were charged to a 30 mL microwave vial, followed by addition of 1,4-dioxane (12 mL) and water (4 mL). The mixture was bubbled with argon for 10 minutes, and heated at 100° C. for 20 hours. After cooling to room temperature, the mixture was filtered through celite, and the filtrate was concentrated in vacuo. The resulting residue was partitioned between EtOAc (50 mL) and brine (15 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo. Purification was performed by silica gel column chromatography using a gradient elution of 1% A in CHCl3 to 75% A in CHCl3 (A was a mixture of 200/80/800 CH3OH/NH4OH/CHCl3). Trituration of the residue obtained from the chromatography in a mixture of MTBE (3 mL) and hexane (3 mL), followed by drying under vacuum at 65° C. for 24 hours afforded the title compound (496 mg) as solids. LC-MS (ES) m/z=448 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.20-1.30 (m, 3H), 1.30 (d, J=6.8 Hz, 3H), 1.35-1.48 (m, 2H), 1.64-1.74 (m, 1H), 1.75-1.84 (m, 5H), 1.86-1.94 (m, 2H), 1.96-2.08 (m, 1H), 2.34-2.45 (m, 1H), 2.98 (s, 3H), 3.08-3.18 (m, 1H), 3.64-3.71 (m, 1H), 4.50-4.70 (bs, 1H), 4.75-4.95 (bs, 1H), 6.50 (s, 1H), 7.69 (dd, J=8.5, 1.1 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H), 8.09 (s, 1H), 8.11 (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. concentrationthe filtrate was concentrated in vacuo
  5. customThe resulting residue was partitioned between EtOAc (50 mL) and brine (15 mL)
  6. dry with materialThe organic was dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customPurification
  10. washa gradient elution of 1% A in CHCl3 to 75% A in CHCl3 (
  11. additiona mixture of 200/80/800 CH3OH/NH4OH/CHCl3)
  12. customTrituration of the residue obtained from the chromatography in a mixture of MTBE (3 mL) and hexane (3 mL)
  13. customby drying under vacuum at 65° C. for 24 hours

Sources & evidence

ORD record
ord-448ce0e0de074366aa439ce5f88e8cf2
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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