Ethyl Acetate → HCID 68515253, compound

HRID 1513060Notes

Reaction equation

HRID 1513060 reaction equation
Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([CH3:13])[N:3]=1.[NH2:14][C:15]1[C:27]([Cl:28])=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([O:29][CH2:30][C:31]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[C:33]([F:39])[C:32]=2[F:40])[CH:16]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>C(#N)C.O>[Cl:28][C:27]1[C:15]([NH:14][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([CH3:13])[N:3]=2)=[CH:16][C:17]([O:29][CH2:30][C:31]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[C:33]([F:39])[C:32]=2[F:40])=[C:18]([CH:26]=1)[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 81531DiisopropylethylamineHCID 156459054-Chloro-6-methoxy-2-methyl-5-nitropyrimidineHCID 59309965HCID 59309965, compound

Product 1

HCID 68515253HCID 68515253, compoundYield 49.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
105 °C

Procedure

A mixture of 4-chloro-6-methoxy-2-methyl-5-nitropyrimidine (0.14 g), ethyl 2-[4-amino-5-chloro-2-(2,3-difluoro-6-methoxybenzyloxy)phenoxy]acetate (0.23 g) and N,N-diisopropylethylamine (0.11 mL) in acetonitrile (3 mL) was stirred at 105° C. in a reaction vessel equipped with a reflux condenser for 17 hours. The reaction mixture was cooled to room temperature. To the reaction mixture were added ethyl acetate and water, and the resulting mixture was stirred at room temperature for 30 minutes. The organic layer was separated, and washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−2/3) to give ethyl 2-[5-chloro-2-(2,3-difluoro-6-methoxybenzyloxy)-4-(6-methoxy-2-methyl-5-nitropyrimidin-4-ylamino)phenoxy]acetate (0.16 g). To this material were added tetrahydrofuran (4 mL), methanol (2 mL) and 10% platinum-carbon powder (30 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (5 mL). To the solution was added 1,1′-carbonyldiimidazole (88 mg) at room temperature. To the mixture was added sodium hydride (55%, 59 mg) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/2−3/7) to give the title compound (70 mg).

Workup

  1. customequipped with a reflux condenser for 17 hours
  2. temperatureThe reaction mixture was cooled to room temperature
  3. stirringthe resulting mixture was stirred at room temperature for 30 minutes
  4. customThe organic layer was separated
  5. washwashed with water and brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. customThe solvent was removed under reduced pressure
  8. customthe residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−2/3)

Sources & evidence

ORD record
ord-020b7ceb6a44458b80d5fddf582356cd
Source dataset
uspto-grants-2012_07
Patent number
US08217069B2

Reaction notes

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