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

HRID 2367303Notes

Reaction equation

HRID 2367303 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.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[C:42]3[C:38]([CH:39]=[N:40][NH:41]3)=[CH:37][CH:36]=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>[NH:41]1[C:42]2[C:38](=[CH:37][CH:36]=[C:35]([C:2]3[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]4[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[O:18])[CH2:11]4)[CH:3]=3)[CH:43]=2)[CH:39]=[N:40]1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 441192506-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazoleHCID 58504823(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide

Product 1

HCID 58504750(3S,6R)-1-[6-(1H-Indazol-6-yl)-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamideYield 71.7%

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 (600 mg, 1.61 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (509 mg, 2.09 mmol, 1.3 equiv), Pd2(dba)3 (110 mg, 0.12 mmol, 0.075 equiv), tricyclohexylphosphine (68 mg, 0.24 mmol, 0.15 equiv), and K3PO4 (579 mg, 2.73 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 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 gradient elution of 1% A to 70% A in CHCl3 (A was a mixture of 200/80/800 CH3OH/NH4OH/CHCl3). Trituration of the residue collected from the chromatography in a mixture of CHCl3 (2 mL), MTBE (3 mL) hexane (6 mL), followed by drying under vacuum at 65° C. for 20 hours gave the title compound (526 mg) as a pale yellowish solid. LC-MS (ES) m/z=456 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.31 (d, J=7.1 Hz, 3H), 1.75-1.90 (m, 3H), 1.99-2.10 (m, 1H), 2.45-2.55 (m, 1H), 2.97 (s, 3H), 3.10-3.19 (m, 1H), 4.42 (s, 2H), 4.50-4.60 (bs, 1H), 4.75-4.85 (bs, 1H), 6.50 (s, 1H), 7.24-7.38 (m, 5H), 7.69 (dd, J=8.5, 1.1 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 8.09 (s, 1H), 8.10 (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 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. washelution of 1% A to 70% A in CHCl3 (
  11. additiona mixture of 200/80/800 CH3OH/NH4OH/CHCl3)
  12. customTrituration of the residue collected from the chromatography in a mixture of CHCl3 (2 mL), MTBE (3 mL) hexane (6 mL)
  13. customby drying under vacuum at 65° C. for 20 hours

Sources & evidence

ORD record
ord-0ad14146b6644c82ab25dbe82bbdb8dd
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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