Trifluoroacetic anhydride → 6-{4-[6-(4-Fluoro-phenyl)-2-(2-(R)-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-pyridine-2-carboxylic acid methyl ester

HRID 1444129Notes

Reaction equation

HRID 1444129 reaction equation
[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7](O)[N:6]=1)=[O:4].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[C:37]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][C@H:40]3[CH3:45])[N:36]=[C:35]([N:46]3[CH2:50][CH2:49][CH2:48][C@H:47]3[CH3:51])[N:34]=2)=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl.CC(N(C)C)=O.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N:42]2[CH2:43][CH2:44][N:39]([C:37]3[CH:38]=[C:33]([C:30]4[CH:29]=[CH:28][C:27]([F:26])=[CH:32][CH:31]=4)[N:34]=[C:35]([N:46]4[CH2:50][CH2:49][CH2:48][C@H:47]4[CH3:51])[N:36]=3)[C@H:40]([CH3:45])[CH2:41]2)[N:6]=1)=[O:4]

Participants

8

Reactant 4

HCID 9845Trifluoroacetic anhydrideHCID 81531DiisopropylethylamineHCID 591683354-(4-Fluoro-phenyl)-6-(2-(R)-methyl-piperazin-1-yl)-2-(2-(R)-methyl-pyrrolidin-1-yl)-pyrimidineHCID 178497865HCID 178497865, compound

Product 1

HCID 591683776-{4-[6-(4-Fluoro-phenyl)-2-(2-(R)-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-pyridine-2-carboxylic acid methyl ester

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6212ChloroformSolvent2×HCID 31374DimethylacetamideSolvent

Conditions

Temperature
100 °C

Procedure

To a cold solution (0° C.) of 6-hydroxy-5-methyl-pyridine-2-carboxylic acid methyl ester (Adamczyk et. al. (2002) Tetrahedron 58:6951-6963) (167 mg, 1.0 mmol) in CHCl3 (15 mL), add trifluoroacetic anhydride (423 mg, 1.5 mmol) dropwise followed by TEA (202 mg, 2.0 mmol). Stir the mixture for 1 h. Dilute with CHCl3, wash with sat. NaHCO3, dry the organic layer (Na2SO4) and concentrate under reduced pressure. Mix the residue with 4-(4-fluoro-phenyl)-6-(2-(R)-methyl-piperazin-1-yl)-2-(2-(R)-methyl-pyrrolidin-1-yl)-pyrimidine (426 mg, 1.2 mmol) and DIEA (129 mg, 1.0 mmol) in DMA. Heat the mixture at 100° C. for 16 h. Dilute with water, extract with EtOAc, and wash with brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:5) to afford the title compound.

Workup

  1. washwash with sat. NaHCO3
  2. dry with materialdry the organic layer (Na2SO4)
  3. concentrationconcentrate under reduced pressure
  4. extractionextract with EtOAc
  5. washwash with brine
  6. dry with materialDry the organic layer (Na2SO4)
  7. concentrationconcentrate under reduced pressure
  8. customPurify the residue by flash column
  9. washeluting with EtOAc-Hexanes (1:5)

Sources & evidence

ORD record
ord-1918ba827d874eef9c007cb7136a18cc
Source dataset
uspto-grants-2010_02
Patent number
US07662830B2

Reaction notes

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