Cesium carbonate → ethyl (2R)-2-[(2-[(2,3-difluorobenzyl)thio]-6-{[(9-methyl-3,9-diazabicyclo[4.2.1]non-3-yl)sulfonyl]amino}pyrimidin-4-yl)oxy]propanoate

HRID 1024962Notes

Reaction equation

[CH3:1][N:2]1[CH:8]2[CH2:9][CH2:10][CH:3]1[CH2:4][N:5]([S:11]([NH2:14])(=[O:13])=[O:12])[CH2:6][CH2:7]2.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+].[CH2:55]([O:57][C:58](=[O:79])[C@H:59]([O:61][C:62]1[CH:67]=[C:66](Cl)[N:65]=[C:64]([S:69][CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[C:73]([F:77])[C:72]=2[F:78])[N:63]=1)[CH3:60])[CH3:56]>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:78][C:72]1[C:73]([F:77])=[CH:74][CH:75]=[CH:76][C:71]=1[CH2:70][S:69][C:64]1[N:63]=[C:62]([O:61][C@H:59]([CH3:60])[C:58]([O:57][CH2:55][CH3:56])=[O:79])[CH:67]=[C:66]([NH:14][S:11]([N:5]2[CH2:6][CH2:7][CH:8]3[N:2]([CH3:1])[CH:3]([CH2:10][CH2:9]3)[CH2:4]2)(=[O:13])=[O:12])[N:65]=1

Participants

Conditions

Temperature: 100 °C

Procedure

To a solution of 9-methyl-3,9-diazabicyclo[4.2.1]nonane (0.56 g) in 1,4-dioxane (10 ml) was added sulfamide (0.37 g) and the reaction mixture was then heated at reflux in 1,4-dioxane for 72 h. The reaction mixture was purified by loading onto SCX and eluting with 7N NH3/MeOH (200 ml). The eluent was then reduced in vacuo to yield 9-methyl-3,9-diazabicyclo[4.2.1]nonane-3-sulfonamide (0.13 g) as a yellow solid. A mixture of 9-methyl-3,9-diazabicyclo[4.2.1]nonane-3-sulfonamide (0.13 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.31 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), 0.25 g) in 1,4-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 0.35 g

Workup

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

Sources & evidence

ORD record: ord-d3363413df534979b7e60ddb2fee8bd3
Source dataset: uspto-grants-2014_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08722883B2

Reaction notes

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