Potassium Phosphate, Tribasic → HCID 178482345, compound

HRID 2367307Notes

Reaction equation

HRID 2367307 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][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:11]2)[CH:3]=1.[CH3:27][C:28]1[C:36]2[C:31](=[CH:32][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:35]=2)[NH:30][N:29]=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:33]3[CH:32]=[C:31]4[C:36]([C:28]([CH3:27])=[N:29][NH:30]4)=[CH:35][CH:34]=3)[N:7]=[C:6]([NH:8][CH3:9])[N:5]=2)[CH2:11][C@@H:12]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:14]1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 58504823(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamideHCID 1784342083-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-YL)-1H-indazole

Product 1

HCID 178482345HCID 178482345, compoundYield 67.1%

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-(phenylmethyl)-3-piperidinecarboxamide (370 mg, 0.99 mmol), 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (383 mg, 1.48 mmol, 1.5 equiv), tricyclohexylphosphine (42 mg, 0.5 mmol, 0.15 equiv), Pd2(dba)3 (68 mg, 0.07 mmol, 0.075 equiv) and K3PO4 (357 mg, 1.68 mmol, 1.7 equiv) were charged to a 30 mL microwave vial, followed by addition of 1,4-dioxane (4 mL) and water (1.33 mL). The mixture was bubbled with argon for 10 minutes, followed by capping and heating at 100° C. for 20 hours. This mixture was combined with another run starting with 200 mg of (3S,6R)-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide. The combined mixture was filtered through celite, and rinsed with EtOAc (50 mL). The filtrate was concentrated in vacuo, and the resulting residue was partitioned between EtOAc (75 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 gradient elution of 1% A in CHCl3 to 50% A in CHCl3 (where A was a mixture of 800/80/3200 CH3OH/NH4OH/CHCl3). Trituration of the purified material in a mixture of CHCl3 (1 mL) and hexane (6 mL), and drying under vacuum at 65° C. afforded the title compound (312 mg) as a tan solid. LC-MS (ES) m/z=470 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.30 (d, J=6.8 Hz, 3H), 1.75-1.90 (m, 3H), 1.97-2.10 (m, 1H), 2.42-2.54 (m, 1H), 2.59 (s, 3H), 2.97 (s, 3H), 3.10-3.20 (m, 1H), 4.42 (s, 2H), 4.60-4.70 (bs, 1H), 4.75-4.85 (bs, 1H), 6.49 (s, 1H), 7.25-7.37 (m, 5H), 7.65 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 8.02 (s, 1H).

Workup

  1. customThe mixture was bubbled with argon for 10 minutes
  2. filtrationThe combined mixture was filtered through celite
  3. washrinsed with EtOAc (50 mL)
  4. concentrationThe filtrate was concentrated in vacuo
  5. customthe resulting residue was partitioned between EtOAc (75 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. washelution of 1% A in CHCl3 to 50% A in CHCl3 (where
  11. additiona mixture of 800/80/3200 CH3OH/NH4OH/CHCl3)
  12. additionTrituration of the purified material in a mixture of CHCl3 (1 mL) and hexane (6 mL)
  13. customdrying under vacuum at 65° C.

Sources & evidence

ORD record
ord-a3e98a6c0d324443a76fc25b1f7d2c85
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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