Water → Ethyl 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-2-methoxypyrimidine-5-carboxylate

HRID 1513034Notes

Reaction equation

HRID 1513034 reaction equation
Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([O:13][CH3:14])[N:3]=1.Cl.[Cl:16][C:17]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH2:27][C:28]2[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]([F:36])[C:29]=2[F:37])=[CH:20][C:18]=1[NH2:19].C(N(CC)C(C)C)(C)C.O>C(#N)C.C(OCC)(=O)C>[Cl:16][C:17]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH2:27][C:28]2[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]([F:36])[C:29]=2[F:37])=[CH:20][C:18]=1[NH:19][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([O:13][CH3:14])[N:3]=1

Participants

7

Reactant 4

HCID 962WaterHCID 81531DiisopropylethylamineHCID 22760998Ethyl 4-chloro-2-methoxypyrimidine-5-carboxylateHCID 685094222-Chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline Hydrochloride

Product 1

HCID 68515564Ethyl 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-2-methoxypyrimidine-5-carboxylateYield 17.6%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of ethyl 4-chloro-2-methoxypyrimidine-5-carboxylate (0.22 g), 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline hydrochloride (0.4 g) and N,N-diisopropylethylamine (0.37 mL) in acetonitrile (3 mL) was heated at reflux for 1.5 hours. The reaction mixture was poured into water. To the mixture was added ethyl acetate, and the insoluble material was collected by filtration. The collected solids were washed with water and ethyl acetate, and dried under reduced pressure to give ethyl 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-2-methoxypyrimidine-5-carboxylate (91 mg). To this material were added methanol (2 mL) and 1 mol/L aqueous sodium hydroxide solution (0.9 mL), and the mixture was stirred at 50° C. for 1 hour. To the mixture was added tetrahydrofuran (1 mL), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was cooled to room temperature. To the mixture was added 1 mol/L hydrochloric acid (1.0 mL), and the mixture was stirred for 30 minutes. The precipitated crystals were collected by filtration. The collected crystals were washed with water and diethyl ether, and dried under reduced pressure to give 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-2-methoxypyrimidine-5-carboxylic acid (57 mg). To this material were added 1,4-dioxane (1 mL), triethylamine (0.049 mL) and diphenylphosphoryl azide (0.026 mL), and the mixture was stirred at room temperature for 1 hour, and then heated at reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/5). The product was suspended in a mixed solvent (n-hexane/ethyl acetate=1/1), and collected by filtration. The collected material was washed with the same solvent, and dried under reduced pressure to give the title compound (20 mg).

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 1.5 hours
  3. filtrationthe insoluble material was collected by filtration
  4. washThe collected solids were washed with water and ethyl acetate
  5. customdried under reduced pressure

Sources & evidence

ORD record
ord-c602d31f50164b70940c5190d4b50508
Source dataset
uspto-grants-2012_07
Patent number
US08217069B2

Reaction notes

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