4-Chloro-6-methyl-1,3,5-triazin-2-amine → HCID 49785754, compound

HRID 1621386Notes

Reaction equation

HRID 1621386 reaction equation
O1CCOCC1.Cl[C:8]1[C:9]([NH:25][C:26]2[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=2)=[N:10][CH:11]=[C:12]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]2)[CH:13]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])(=O)C.[K+].Cl[C:91]1[N:96]=[C:95]([CH3:97])[N:94]=[C:93]([NH2:98])[N:92]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:98][C:93]1[N:94]=[C:95]([CH3:97])[N:96]=[C:91]([C:8]2[C:9]([NH:25][C:26]3[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=3)=[N:10][CH:11]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]3)[CH:13]=2)[N:92]=1

Participants

9

Reactant 6

HCID 305914-Chloro-6-methyl-1,3,5-triazin-2-amineHCID 312751,4-DioxaneHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 66599953HCID 66599953, compound

Product 1

HCID 49785754HCID 49785754, compoundYield 1.5%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)Catalyst

Conditions

Temperature
100 °C

Procedure

1,4-Dioxane (4.00 mL, 46762 μmol) was added to a mixture of 3-(3-chloro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-ylamino)phenol (390 mg, 983 μmol), bis(pinacolato)diboron (299 mg, 1179 μmol), X-Phos (46.8 mg, 98.3 μmol), tris(dibenzylideneacteone)dipalladium(0) (45.0 mg, 49.1 μmol) and potassium acetate (0.154 ml, 2457 μmol) and the mixture was stirred at 100° C. for 3 h. After cooling to room temperature, 4-chloro-6-methyl-1,3,5-triazin-2-amine (213 mg, 1474 μmol) and bis(di-tert-butyl (4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Aldrich, St. Louis, Mo.) (61.1 mg, 98.3 μmol) was added and the mixture was resealed and continued heating at 100° C. overnight. The mixture was allowed to cool to room temperature, filtered through a short path of Celite® (diatomaceous earth), and the filter cake was washed with EtOAc (2×20 mL). The combined organic phases were concentrated with SiO2 and purified by flash column chromatography (ISCO CombiFlash® system, Teledyne ISCO, Lincoln, Nebr.), pure DCM to 10% 2 M NH3/MeOH in DCM) to give 3-(3-(4-Amino-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-ylamino)phenol (7 mg, 1.5%) as a yellow solid. LCMS (API-ES) m/z 471 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 11.98 (br. s., 1H) 9.27 (d, J=4.89 Hz, 1H) 8.59-8.78 (m, 1H) 8.26 (d, J=2.93 Hz, 1H) 7.61-7.92 (m, 1H) 7.50 (d, J=1.76 Hz, 1H) 6.81-7.26 (m, 2H) 6.24-6.50 (m, 1H) 3.49 (br. s., 2H) 3.11 (br. s., 4H) 2.87 (d, J=5.87 Hz, 3H) 2.37-2.48 (m, 7H).

Workup

  1. temperatureAfter cooling to room temperature
  2. temperaturecontinued heating at 100° C. overnight
  3. temperatureto cool to room temperature
  4. filtrationfiltered through a short path of Celite® (diatomaceous earth)
  5. washthe filter cake was washed with EtOAc (2×20 mL)
  6. concentrationThe combined organic phases were concentrated with SiO2
  7. custompurified by flash column chromatography (ISCO CombiFlash® system, Teledyne ISCO, Lincoln, Nebr.), pure DCM to 10% 2 M NH3/MeOH in DCM)

Sources & evidence

ORD record
ord-e5c128ba9856444c922985a5da8de5d8
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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