Cesium carbonate → 2,4,4-Trimethyl-7-{2-(2-methyl-pyrrolidin-1-yl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-4-yl}-1,2,3,4-tetrahydro-isoquinoline

HRID 230961Notes

Reaction equation

HRID 230961 reaction equation
Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][N:8]([CH3:12])[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.CC([O-])=O.[K+].Cl[C:39]1[CH:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([C:51]3[C:56]([C:57]([F:60])([F:59])[F:58])=[CH:55][CH:54]=[CH:53][N:52]=3)[CH2:47][CH2:46]2)[N:42]=[C:41]([N:61]2[CH2:65][CH2:64][CH2:63][CH:62]2[CH3:66])[N:40]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][N:8]1[CH2:7][C:6]([CH3:14])([CH3:13])[C:5]2[C:10](=[CH:11][C:2]([C:39]3[CH:44]=[C:43]([N:45]4[CH2:50][CH2:49][N:48]([C:51]5[C:56]([C:57]([F:58])([F:59])[F:60])=[CH:55][CH:54]=[CH:53][N:52]=5)[CH2:47][CH2:46]4)[N:42]=[C:41]([N:61]4[CH2:65][CH2:64][CH2:63][CH:62]4[CH3:66])[N:40]=3)=[CH:3][CH:4]=2)[CH2:9]1

Participants

9

Reactant 5

HCID 10796Cesium carbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 57761092HCID 57761092, compoundHCID 577613324-Chloro-2-(2-methyl-pyrrolidin-1-yl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine

Product 1

HCID 577618072,4,4-Trimethyl-7-{2-(2-methyl-pyrrolidin-1-yl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-4-yl}-1,2,3,4-tetrahydro-isoquinoline

Reagents, catalysts & solvents 3

HCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 679Dimethyl SulfoxideSolvent

Procedure

To a mixture of 7-bromo-2,4,4-trimethyl-1,2,3,4-tetrahydro-isoquinoline (140 mg, 0.55 mmol), 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (140 mg, 0.55 mmol), DPPF (9 mg, 0.017 mmol), and KOAc (162 mg, 1.65 mmol) in DMSO, add PdCl2(DPPF)-DCM complex (13 mg, 0.0165 mmol). Purge the reaction mixture for 10 minutes with dry N2. Heat the stirring reaction mixture overnight at 80° C. Cool to room temperature. Add 4-chloro-2-(2-methyl-pyrrolidin-1-yl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine (141 mg, 0.33 mmol), Pd(PPh3)4 (19 mg, 0.017 mmol), and Cs2CO3 (162 mg, 0.50 mmol). Heat the stirring reaction mixture overnight at 80° C., cool to room temperature, and partition between water and EtOAc. Dry the solution (Na2SO4), concentrate under reduced pressure. Purify the residue by flash column chromatography eluting with DCM:MeOH (9:1) to afford 2,4,4-trimethyl-7-{2-(2-methyl-pyrrolidin-1-yl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-4-yl}-1,2,3,4-tetrahydro-isoquinoline. 1H NMR (400 MHz, CDCl3): δ 1.30 (m, 9H, 3×CH3); 1.68 (m, 1H, CH2CH2); 1.91 (m, 1H, CH2CH2); 2.05 (m, 2H, CH2CH2); 2.40 (s, 2H); 2.43 (s, 3H, NCH3); 3.39 (m, 4H); 3.61 (s, 2H); 3.67 (m, 2H); 3.79 (m, 4H); 4.34 (m, 1H); 6.27 (s, 1H, Ar—H); 7.01 (m, 1H); 7.35 (m, 1H); 7.63 (s, 1H); 7.88 (m, 1H); 7.88 (m, 1H); 8.44 (m, 1H).

Workup

  1. additionadd PdCl2(DPPF)-DCM complex (13 mg, 0.0165 mmol)
  2. customPurge the reaction mixture for 10 minutes with dry N2
  3. temperatureHeat
  4. customthe stirring reaction mixture overnight at 80° C
  5. temperatureHeat
  6. customthe stirring reaction mixture overnight at 80° C.
  7. temperaturecool to room temperature
  8. custompartition between water and EtOAc
  9. dry with materialDry the solution (Na2SO4)
  10. concentrationconcentrate under reduced pressure
  11. customPurify the residue by flash column chromatography
  12. washeluting with DCM:MeOH (9:1)

Sources & evidence

ORD record
ord-cb580462258847cdb80bd2a2e332599b
Source dataset
uspto-grants-2009_07
Patent number
US07566712B2

Reaction notes

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