Vatalanib → HCID 22386482, compound

HRID 2119316Notes

Reaction equation

HRID 2119316 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[CH:35]=[CH:34][C:15]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[N:19][N:18]=2)=[CH:14][CH:13]=1.[F:36]N1C(C)(C)C2C=CC=CC=2S1.C([O-])(O)=O.[Na+]>C1COCC1.C(O)(=O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[F:36])=[N:19][N:18]=2)=[CH:34][CH:35]=1

Participants

7

Reactant 4

HCID 151194VatalanibHCID 516892Sodium BicarbonateHCID 3251421Potassium bis(trimethylsilyl)amideHCID 22386450HCID 22386450, compound

Product 1

HCID 22386482HCID 22386482, compound

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 8028TetrahydrofuranSolvent4×

Conditions

Temperature
-78 °C

Procedure

Under N2-atmosphere, 7.02 ml (4.65 mmol; 15% in toluene) of potassium bis(trimethylsilyl)-amide are dissolved in 78 ml THF and then cooled to −78° C. A solution of 537.5 mg (1.55 mmol) of 1-(4-chlor-anilino)-4-(pyridin-4-yl-methyl)-phthalazine (see WO 98/35958) in 30 ml THF is added dropwise. The resulting black solution is stirred for additional 30 min, then 1.00 g (4.65 mmol) of 2-fluoro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole (Fluka; Buchs, Switzerland) in 30 ml THF are added slowly. The reaction solution slowly turns to yellow-orange. After 3 h at −78° C., a solution of 1 ml acetic acid in 5 ml of THF is added. The reaction mixture is poured into a diluted NaHCO3-solution and extracted three times with ethyl acetate. The organic layers are washed with 2 portions of water and brine, dried (Na2SO4) and concentrated. Chromatography (SiO2; EtOAc/dichloromethane 2:1 to EtOAc to EtOAc/EtOH 9:1 to 4:1) and crystallization from acetonitrile/acetone finally gave the title compound: 1H NMR (DMSO-d6) δ9.50 (s, HN), 8.65 (d, 1H), 8.61 (d, 2H), 8.16 (d, 1H), 8.03 (t, 1H), 7.99 (t, 1H), 7.96 (d, 2H), 7.43 (d, 2H), 7.40 (d, 2H), 7.34 (s, 1H); 19F NMR (DMSO-d6) δ−50.7; FAB-MS (M+H)+=365.

Workup

  1. waitAfter 3 h at −78° C.
  2. extractionextracted three times with ethyl acetate
  3. washThe organic layers are washed with 2 portions of water and brine
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated
  6. customChromatography (SiO2; EtOAc/dichloromethane 2:1 to EtOAc to EtOAc/EtOH 9:1 to 4:1) and crystallization from acetonitrile/acetone

Sources & evidence

ORD record
ord-bc6ff02bc5b34da4a1ff9149cfe65ab9
Source dataset
uspto-grants-2004_02
Patent number
US06686347B2

Reaction notes

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