Water → HCID 68516918, compound

HRID 1513082Notes

Reaction equation

HRID 1513082 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH2:16][C:17]3[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]([F:25])[C:18]=3[F:26])[C:12]([O:27][CH3:28])=[CH:11][C:10]=2[Cl:29])[C:5]([C:30]([O:32]C)=[O:31])=[C:4]([CH3:34])[N:3]=1.ClC1N=C(Cl)C(C(OC)=O)=C(C)[N:37]=1.O.[N-]=[N+]=[N-].[Na+]>CN(C)C=O>[NH2:37][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH2:16][C:17]3[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]([F:25])[C:18]=3[F:26])[C:12]([O:27][CH3:28])=[CH:11][C:10]=2[Cl:29])[C:5]([C:30]([OH:32])=[O:31])=[C:4]([CH3:34])[N:3]=1

Participants

6

Reactant 4

HCID 962Water2×HCID 33557Sodium AzideHCID 57531614Methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylateHCID 86641288HCID 86641288, compound

Product 1

HCID 68516918HCID 68516918, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

To a suspension of methyl 2-chloro-4-[2-chloro-5-(2,3-difluoro-6-methoxy-benzyloxy)-4-methoxyphenylamino]-6-methylpyrimidine-5-carboxylate (0.42 g), which was prepared in a similar manner to that described in Example 380 using methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate instead of ethyl 4-chloro-6-methylpyrimidine-5-carboxylate, in N,N-dimethylformamide (12 mL) were added water (2 mL) and sodium azide (0.26 g), and the mixture was stirred at 60° C. for 2 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue were added tetrahydrofuran (12 mL), methanol (12 mL) and 10% platinum-carbon powder (0.1 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. To the mixture were added tetrahydrofuran (12 mL) and 2 mol/L aqueous sodium hydroxide solution (12 mL), and the resulting mixture was stirred at 60° C. for 2 hours. The insoluble material was removed by filtration, and the filtrate was acidified by adding 1 mol/L hydrochloric acid. The precipitated crystals were collected by filtration. The crystals were washed with water, and dried under reduced pressure to give 2-amino-4-[2-chloro-5-(2,3-difluoro-6-methoxy-benzyloxy)-4-methoxyphenylamino]-6-methylpyrimidine-5-carboxylic acid (0.35 g). To this material were added 1,4-dioxane (30 mL), tetrahydrofuran (10 mL), triethylamine (3 mL) and diphenylphosphoryl azide (0.38 mL), and the reaction vessel was equipped with a reflux condenser, and the mixture was stirred at 100° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=10/1) to give the title compound (0.2 g).

Workup

  1. customwas prepared in a similar manner to that
  2. extractionthe resulting mixture was extracted with ethyl acetate
  3. washThe extract was washed with water and brine
  4. dry with materialdried over anhydrous magnesium sulfate
  5. customthe solvent was removed under reduced pressure
  6. additionTo the residue were added tetrahydrofuran (12 mL), methanol (12 mL) and 10% platinum-carbon powder (0.1 g)
  7. stirringthe mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours
  8. additionTo the mixture were added tetrahydrofuran (12 mL) and 2 mol/L aqueous sodium hydroxide solution (12 mL)
  9. stirringthe resulting mixture was stirred at 60° C. for 2 hours
  10. customThe insoluble material was removed by filtration
  11. additionby adding 1 mol/L hydrochloric acid
  12. filtrationThe precipitated crystals were collected by filtration
  13. washThe crystals were washed with water
  14. customdried under reduced pressure

Sources & evidence

ORD record
ord-523670b952e1458a86dc69ff8a1a5087
Source dataset
uspto-grants-2012_07
Patent number
US08217069B2

Reaction notes

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