Hydrochloric Acid → HCID 59309711, compound

HRID 1513075Notes

Reaction equation

HRID 1513075 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[N:22]1[C:30](=[O:31])[NH:29][C:28]2[C:23]1=[N:24][C:25]([CH:34](C(OCC)=O)[C:35]([O:37]CC)=[O:36])=[N:26][C:27]=2[O:32][CH3:33].O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[C:35]([CH2:34][C:25]1[N:24]=[C:23]2[C:28]([NH:29][C:30](=[O:31])[N:22]2[C:3]2[CH:4]=[C:5]([O:10][CH2:11][C:12]3[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=3[F:21])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[Cl:1])=[C:27]([O:32][CH3:33])[N:26]=1)([OH:37])=[O:36]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 8028TetrahydrofuranHCID 168937Lithium hydroxide, monohydrateHCID 68511226HCID 68511226, compound

Product 1

HCID 59309711HCID 59309711, compoundYield 99.4%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

A mixture of 2,4-dichloro-6-methoxy-5-nitropyrimidine (0.24 g), 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.26 g) and N,N-diisopropylethylamine (0.15 mL) in acetonitrile (4 mL) was stirred at room temperature overnight. To the reaction mixture were added ethyl acetate and water, and the resulting mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the organic layer of the filtrate was separated. The organic layer 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=2/1−1/2) to give 2-chloro-N-(2-chloro-6-methoxy-5-nitropyrimidin-4-yl)-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.4 g). A mixture of 2-chloro-N-(2-chloro-6-methoxy-5-nitropyrimidin-4-yl)-5-(2,3-difluoro-6-methoxy-benzyloxy)-4-methoxyaniline (0.29 g), diethyl malonate (0.1 mL) and cesium carbonate (1.83 g) in 1,2-dimethoxyethane (2 mL) was stirred at 100° C. in a reaction vessel equipped with a reflux condenser for 6 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=2/1−1/1) to give diethyl 2-{-4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-6-methoxy-5-nitropyrimidin-2-yl}malonate (0.27 g). To this material were added tetrahydrofuran (6 mL); methanol (2 mL) and 10% platinum-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 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 tetrahydrofuran (5 mL). To the solution were added triphosgene (50 mg) and sodium hydride (55%, 64 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. 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 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-bis(ethoxycarbonyl)methyl-6-methoxy-7,9-dihydro-8H-purin-8-one (0.2 g). The mixture of the obtained 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-bis(ethoxycarbonyl)methyl-6-methoxy-7,9-dihydro-8H-purin-8-one (80 mg), lithium hydroxide monohydrate (0.11 g), tetrahydrofuran (3 mL), methanol (1.5 mL) and water (1.5 mL) was stirred at room temperature overnight. 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 to give the title compound (67 mg).

Workup

  1. extractionthe resulting mixture was extracted with ethyl acetate
  2. washThe extract was washed with water and brine
  3. dry with materialdried over anhydrous sodium sulfate
  4. customThe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-fc70e905cd8d43e7886e7a1e408c308e
Source dataset
uspto-grants-2012_07
Patent number
US08217069B2

Reaction notes

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