Cesium carbonate → N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-[(1R)-2-hydroxy-1-methylethoxy]-4-pyrimidinyl]-(3R,5S)-3,5-dimethylpiperazine-1-sulfonamide

HRID 2388833Notes

Reaction equation

HRID 2388833 reaction equation
[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH2:3]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+].C([O:55][C:56](=O)[C@H:57]([O:59][C:60]1[CH:65]=[C:64](Cl)[N:63]=[C:62]([S:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[C:70]=2[F:76])[N:61]=1)[CH3:58])C>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:76][C:70]1[C:71]([F:75])=[CH:72][CH:73]=[CH:74][C:69]=1[CH2:68][S:67][C:62]1[N:63]=[C:64]([NH:12][S:9]([N:4]2[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]2)(=[O:10])=[O:11])[CH:65]=[C:60]([O:59][C@H:57]([CH3:58])[CH2:56][OH:55])[N:61]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 53628381(3R,5S)-3,5-dimethylpiperazine-1-sulfonamideHCID 866198702-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy](2R)-propanoic acid ethyl ester

Product 1

HCID 59558840N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-[(1R)-2-hydroxy-1-methylethoxy]-4-pyrimidinyl]-(3R,5S)-3,5-dimethylpiperazine-1-sulfonamide

Reagents, catalysts & solvents 2

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

Conditions

Temperature
100 °C

Procedure

To a solution of (2R,6S)-2,6-dimethylpiperazine (1 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 partitioned between EtOAc (150 ml) and H2O (150 ml) and the aqueous re-extracted with EtOAc (2×150 ml). Organics were collected dried and reduced in vacuo to yield (3R,5S)-3,5-dimethylpiperazine-1-sulfonamide as a white solid (0.29 g). A mixture of (3R,5S)-3,5-dimethylpiperazine-1-sulfonamide (0.29 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.628 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), 0.5 g) in dioxane (10 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 30 min. 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: 0.940 g

Workup

  1. temperaturewas heated
  2. temperature300 W, open vessel with cooling for 30 min
  3. customthe residue was partitioned between EtOAc (150 ml) and H2O (100 ml)
  4. customThe organics were separated
  5. extractionthe aqueous layer was re-extracted with EtOAc (2×150 ml)
  6. dry with materialdried (MgSO4)

Sources & evidence

ORD record
ord-a1c73f82f45049b58d343cdfe023a00b
Source dataset
uspto-grants-2012_09
Patent number
US08269002B2

Reaction notes

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