Diethyl Malonate → 2-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-malonic acid diethyl ester

HRID 2353843Notes

Reaction equation

HRID 2353843 reaction equation
Br[C:2]1[CH:31]=[CH:30][C:5]2[C:6]3[C:11]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=5)=[C:15]([Cl:28])[CH:14]=4)=[N:10][CH:9]=[N:8][C:7]=3[S:29][C:4]=2[CH:3]=1.[CH2:32]([O:34][C:35](=[O:42])[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:33].[H-].[Na+]>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].C1(C2C=CC=CC=2)C=CC(P(C(C)(C)C)C(C)(C)C)=CC=1>[CH2:32]([O:34][C:35](=[O:42])[CH:36]([C:2]1[CH:31]=[CH:30][C:5]2[C:6]3[C:11]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=5)=[C:15]([Cl:28])[CH:14]=4)=[N:10][CH:9]=[N:8][C:7]=3[S:29][C:4]=2[CH:3]=1)[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:33]

Participants

6

Reactant 3

HCID 7761Diethyl MalonateHCID 24758Sodium hydrideHCID 59380385HCID 59380385, compound

Product 1

HCID 593804662-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-malonic acid diethyl esterYield 75.2%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 12159709HCID 12159709, compoundCatalyst

Conditions

Temperature
137.5 °C

Procedure

To a stirring suspension of (7-bromo-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine (150 mg, 0.291 mmol) in malonic acid diethyl ester (2 mL, 2 g, 12.5 mmol) was added sodium hydride (60%, 35.0 mg, 0.874 mmol). The resulting mixture was bubbled with N2 for 2 min, followed by addition of biphenyl-4-yl-di-tert-butyl-phosphane (4.35 mg, 0.015 mmol), and tris(dibenzylideneacetone)dipalladium (13.3 mg, 0.015 mmol). The mixture was bubbled with N2 for an additional 2 min. The reaction mixture was stirred at 135-140° C. for 20 min. It was cooled to rt, and concentrated in vacuo. The residue was purified by chromatography (hexane/EtOAc=2/1 to 1/1) to give the product (130 mg, 75%). 1H-NMR (CDCl3-d) δ 8.56 (s, 1H), 8.05 (d, 1H), 8.00 (s, 1H), 7.82 (b, 1H), 7.74 (s, 1H), 7.66 (d, 1H), 7.49 (q, 1H), 7.34-7.39 (m, 1H), 7.20-7.26 (m, 2H), 6.99-7.05 (m, 2H), 5.18 (s, 2H), 4.80 (s, 1H), 4.20-4.31 (m, 4H), 1.28-1.34 (m, 6H); LCMS RT=4.23 min, [M+H]+=594.1.

Workup

  1. customThe resulting mixture was bubbled with N2 for 2 min
  2. customThe mixture was bubbled with N2 for an additional 2 min
  3. temperatureIt was cooled to rt
  4. concentrationconcentrated in vacuo
  5. customThe residue was purified by chromatography (hexane/EtOAc=2/1 to 1/1)

Sources & evidence

ORD record
ord-73e76f11ec864f9ba6b24440b2a2d353
Source dataset
uspto-grants-2010_07
Patent number
US07750017B2

Reaction notes

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