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 2388836ノート

反応式

HRID 2388836 の反応式
[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

参加物

7

反応物 4

HCID 10796Cesium carbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 536283849-Methyl-3,9-diazabicyclo[4.2.1]nonane-3-sulfonamideHCID 866198702-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy](2R)-propanoic acid ethyl ester

生成物 1

HCID 53628383ethyl (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

試薬・触媒・溶媒 2

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 312751,4-Dioxane溶媒

反応条件

温度
100 °C

実験手順

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

後処理

  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)

出典と根拠

ORDレコード
ord-ecd258e18bfe464c800978a87228fafb
出典データセット
uspto-grants-2012_09
特許番号
US08269002B2

反応ノート

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