Dichlorobis(triphenylphosphine)palladium → Palladium

HRID 1972310Notes

Reaction equation

HRID 1972310 reaction equation
[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[C:13]4[CH:18]=[C:17]([CH2:19][N:20]5[CH2:25][CH2:24][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]5)[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.ClC1N=C(N2CCOCC2)C2C=C(CN3CCN(S(C)(=O)=O)CC3)SC=2N=1.[O:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH:64]1N1C=C2C(C=CC=C2B2OC(C)(C)C(C)(C)O2)=N1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd:126]Cl>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:29][S:26]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[S:16][C:14]3[N:15]=[C:10]([C:5]4[C:4]5[C:9]([CH:8]=[CH:7][CH:6]=4)=[N:1][N:2]([CH:64]4[CH2:65][CH2:66][CH2:67][CH2:68][O:63]4)[CH:3]=5)[N:11]=[C:12]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[C:13]=3[CH:18]=2)[CH2:21][CH2:22]1)(=[O:27])=[O:28].[Pd:126]

Participants

8

Reactant 4

HCID 6102075Dichlorobis(triphenylphosphine)palladiumHCID 252532304-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholineHCID 252688432-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazoleHCID 568339462-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidine

Product 2

HCID 23938PalladiumHCID 252691944-(6-((4-(Methylsulfonyl)piperazin-1-yl)methyl)-2-(2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl)thieno[2,3-d]pyrimidin-4-yl)morpholine

Reagents, catalysts & solvents 2

HCID 10340Sodium CarbonateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
88 °C

Procedure

Scheme 8 shows the synthesis of 4-(2-(1H-Indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine II sulfate salt starting with Suzuki coupling of 4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine 20 in 1,4-dioxane with 2-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole 10 (1.25 equiv.) and bis(triphenylphosphine)palladium (II) chloride (0.02 equiv.) in aqueous sodium carbonate. The mixture was heated to 88° C. and stirred for 14 hours. The reaction mixture was cooled, filtered, rinsed with water, and stirred with FLORISIL® (60-100 mesh, Sigma-Aldrich Chemical Company, Inc) in methylene chloride at ambient temperature for 5 hours. The mixture was filtered, rinsed with methylene chloride and ethyl acetate, and the filtrate and the rinse were combined and concentrated to give solid 21 with Pd content of 150 ppm. The solid was dissolved in methylene chloride and SILIABOND® Thiourea (Silicycle Inc) was added. The mixture was stirred for 5 hours, filtered, rinsed with methylene chloride and ethyl acetate. All the filtrate and the rinse were combined and concentrated to give 4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-2-(2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl)thieno[2,3-d]pyrimidin-4-yl)morpholine 21 as a solid in 70% yield with Pd content<10 ppm), along with a minor amount of THP regioisomer 21A.

Workup

  1. temperatureThe reaction mixture was cooled
  2. filtrationfiltered
  3. washrinsed with water
  4. stirringstirred with FLORISIL® (60-100 mesh, Sigma-Aldrich Chemical Company, Inc) in methylene chloride at ambient temperature for 5 hours
  5. filtrationThe mixture was filtered
  6. washrinsed with methylene chloride and ethyl acetate
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-36c0f470e6ab468d97035e87b766c204
Source dataset
uspto-grants-2013_04
Patent number
US08431694B1

Reaction notes

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