Cesium carbonate → 2-(2,6-Dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-4-(3-methoxypropoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

HRID 80818

Reaction equation

HRID 80818 reaction equation
FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[CH3:16])(=O)=O.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[C:27]1[N:28]=[C:29]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:30]2[CH2:36][NH:35][CH2:34][CH2:33][C:31]=2[N:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C.O.[Pd+2]>[CH3:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[C:21]=1[C:27]1[N:28]=[C:29]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:30]2[CH2:36][N:35]([C:7]3[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=3[CH3:16])[CH2:34][CH2:33][C:31]=2[N:32]=1

Participants

8

Reactant 3

HCID 10796Cesium carbonateHCID 130964092-Methyl-5-(propan-2-yl)phenyl trifluoromethanesulfonateHCID 712388462-(2,6-Dimethylphenyl)-4-(3-methoxypropoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

Product 1

HCID 712448102-(2,6-Dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-4-(3-methoxypropoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

Reagents, catalysts & solvents 4

HCID 105144Allyl(1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)chloropalladium(II)CatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
140 °C

Procedure

To 5-isopropyl-2-methylphenyl trifluoromethanesulfonate, prepared as described in Example 15 (153 mg, 0.541 mmol) in a microwave vial was added a solution of 2-(2,6-dimethylphenyl)-4-(3-methoxypropoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine in THF (4 mL). Next, Cs2CO3 (235 mg, 0.721 mmol) was added and the reaction mixture was degassed via a series of argon/vacuum cycles. The reaction mixture was then charged with chloro(2-dicyclohxylphosphino-2′,4′,6%-triisopropyl-1,1′-biphenyl)-[2-(2-aminoethyl)phenyl)]-palladium(II) (CAS#1028206-56-5, 26.6 mg, 0.036 mmol). The vessel was then sealed and heated via microwave irradiation at 140° C. for 90 minutes. The reaction was then cooled to room temperature and diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted once with ethyl acetate. The organic layers were combined, dried over Na2SO4 filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (5-50% ethyl acetate/heptanes) to provide 2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-4-(3-methoxypropoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, CD2Cl2) δ ppm 1.25 (d, J=7.1 Hz, 6 H) 2.08 (quin, J=6.3 Hz, 2 H) 2.28 (s, 6 H) 2.49 (s, 3 H) 2.92 (dt, J=13.8, 6.9 Hz, 1 H) 3.28 (s, 3 H) 3.49 (t, J=5.9 Hz, 2 H) 3.58 (t, J=5.7 Hz, 2 H) 3.81 (t, J=5.6 Hz, 2 H) 4.37 (s, 2 H) 4.71 (t, J=6.4 Hz, 2 H) 7.12 (dd, J=7.7, 1.4 Hz, 1 H) 7.17 (s, 1 H) 7.20-7.27 (m, 3 H) 7.36-7.41 (m, 1 H); MS (ESI+) m/z 460.4 (M+H)+.

Workup

  1. customthe reaction mixture was degassed via a series of argon/vacuum cycles
  2. customThe vessel was then sealed
  3. temperatureThe reaction was then cooled to room temperature
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted once with ethyl acetate
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe resulting residue was purified by silica gel flash chromatography (5-50% ethyl acetate/heptanes)

Sources & evidence

ORD record
ord-eb7f4b021966485db8d11a782f60e82d
Source dataset
uspto-grants-2014_09
Patent number
US08846656B2

Linked notes

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