Cesium carbonate → Ethyl (2R)-2-[(2-[(2,3-difluorobenzyl)thio]-6-{[(4-pyridin-4-ylpiperazin-1-yl)sulfonyl]amino}pyrimidin-4-yl)oxy]propanoate

HRID 1959014Notes

Reaction equation

HRID 1959014 reaction equation
[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([S:13]([NH2:16])(=[O:15])=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:57]([O:59][C:60](=[O:81])[C@H:61]([O:63][C:64]1[CH:69]=[C:68](Cl)[N:67]=[C:66]([S:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([F:79])[C:74]=2[F:80])[N:65]=1)[CH3:62])[CH3:58]>O1CCOCC1.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]>[F:80][C:74]1[C:75]([F:79])=[CH:76][CH:77]=[CH:78][C:73]=1[CH2:72][S:71][C:66]1[N:65]=[C:64]([O:63][C@H:61]([CH3:62])[C:60]([O:59][CH2:57][CH3:58])=[O:81])[CH:69]=[C:68]([NH:16][S:13]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)(=[O:15])=[O:14])[N:67]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 115867864-Pyridin-4-ylpiperazine-1-sulfonamideHCID 866198702-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy](2R)-propanoic acid ethyl ester

Product 1

HCID 53628379Ethyl (2R)-2-[(2-[(2,3-difluorobenzyl)thio]-6-{[(4-pyridin-4-ylpiperazin-1-yl)sulfonyl]amino}pyrimidin-4-yl)oxy]propanoate

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

To a solution of 1-pyridin-4-ylpiperazine (1.23 g) in dioxane (10 ml) was added sulfamide (0.746 g) and the reaction mixture was then heated at reflux in dioxane for 72 h. The reaction mixture was purified by loading onto SCX and eluting with (200 ml) MeOH/NH3. The eluent was then reduced in vacuo to yield 4-pyridin-4-ylpiperazine-1-sulfonamide as a white solid. A mixture of 4-pyridin-4-ylpiperazine-1-sulfonamide (0.260 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.438 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester ((the product of example 5 step i), 0.350 g) in dioxane (10 ml) was heated at reflux in a microwave at 100 C, 300 W, open vessel with cooling for 30 mins. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield: 0.720 g

Workup

  1. temperaturewas heated
  2. temperatureat reflux in a microwave at 100 C, 300 W, open vessel
  3. temperaturewith cooling for 30 mins
  4. customthe residue was partitioned between EtOAc (150 ml) and H2O (100 ml)
  5. customThe organics were separated
  6. extractionthe aqueous layer was re-extracted with EtOAc (2×150 ml)
  7. dry with materialdried (MgSO4)

Sources & evidence

ORD record
ord-6989085a8be341469876594d7fe402fc
Source dataset
uspto-grants-2013_04
Patent number
US08410123B2

Reaction notes

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