Cesium carbonate → 2-{3-[6-(2,2-Difluoro-2-phenyl-ethylamino)-2-methoxy-pyrimidin-4-yl]-phenyl}-2-methyl-propionic acid

HRID 2110730Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 2110730
Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]([F:20])([F:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[C:21]([C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25])([OH:23])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:19][C:12]([F:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:29]2[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:21]([OH:23])=[O:22])[CH:32]=[CH:31][CH:30]=2)[CH:3]=1

Komponenten

7

Edukt 3

HCID 10796Cesium carbonateHCID 442489972-(3-Boronophenyl)-2-methylpropanoic acidHCID 86240121(6-Chloro-2-methoxy-pyrimidin-4-yl)-(2,2-difluoro-2-phenyl-ethyl)-amine

Produkt 1

HCID 533216792-{3-[6-(2,2-Difluoro-2-phenyl-ethylamino)-2-methoxy-pyrimidin-4-yl]-phenyl}-2-methyl-propionic acidAusbeute 105,7 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 178418397HCID 178418397, VerbindungKatalysatorHCID 962WaterLösungsmittel2×HCID 80711,2-DimethoxyethaneLösungsmittel

Versuchsvorschrift

A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-(2,2-difluoro-2-phenyl-ethyl)-amine (0.19 g, 0.62 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid [190 mg, 0.94 mmol, see Example 49(b), step 2], and Cs2CO3 (0.51 g, 1.6 mmol) in ethylene glycol dimethyl ether (10 mL) and water (2 mL) is degassed by bubbling with Argon gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium (0) (36 mg, 0.03 mmol) at room temperature. After 6 h at 85° C., the mixture is diluted with water (15 mL), and extracted with EtOAc (2×20 mL). The extracts are dried (MgSO4), filtered, and concentrated. The residue is chromatographed on SiO2 eluting with 70% EtOAc in heptane to afford 2-{3-[6-(2,2-difluoro-2-phenyl-ethylamino)-2-methoxy-pyrimidin-4-yl]-phenyl}-2-methyl-propionic acid [0.28 g Example 67]. LCMS: RT=2.82 minutes; MS: 428 (M+H); 1H NMR (300 MHz, CDCl3) 9.6 (1H, s), 8 (1H, s), 7.81 (1H, d, J=7.5 Hz), 7.5-7.4 (7H, m), 6.4 (1H, s), 4.2-4 (2H, m), 3.96 (3H, s), 1.65 (6H, s). IC50=38 nM

Aufarbeitung

  1. customis degassed
  2. customby bubbling with Argon gas for 5 minutes
  3. extractionextracted with EtOAc (2×20 mL)
  4. dry with materialThe extracts are dried (MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue is chromatographed on SiO2 eluting with 70% EtOAc in heptane

Quellen und Nachweise

ORD-Eintrag
ord-bd65dcc524404bfa8189bc171ad688a5
Quelldatensatz
uspto-grants-2009_04
Patentnummer
US07517889B2

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