Methanesulfonic anhydride → ethyl 4-((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-ylamino)(4-chloro-2-fluorophenyl)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylate

HRID 869078Notes

Reaction equation

HRID 869078 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[C:4]([F:33])[CH:3]=1.CS(OS(C)(=O)=O)(=O)=O.[NH2:43][C:44]1[CH:45]=[C:46]([Cl:52])[C:47](=[O:51])[N:48]([CH3:50])[CH:49]=1>C(Cl)Cl>[Cl:52][C:46]1[C:47](=[O:51])[N:48]([CH3:50])[CH:49]=[C:44]([NH:43][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:33])[C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])[CH:45]=1

Participants

5

Reactant 3

HCID 81560Methanesulfonic anhydrideHCID 717560735-Amino-3-chloro-1-methyl-1,2-dihydropyridin-2-oneHCID 89601495ethyl 4-((4-chloro-2-fluorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylate

Product 1

HCID 89602440ethyl 4-((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-ylamino)(4-chloro-2-fluorophenyl)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylateYield 80.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A solution of 485 mg (0.944 mmol) ethyl 4-((4-chloro-2-fluorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylate (product from step 184.3), 0.658 ml (4.72 mmol) TEA in 19 ml CH2Cl2 was cooled down to 0° C. 411 mg (1.41 mmol) methanesulfonic anhydride was added and the solution was allowed to warm to RT. 229 mg (1.416 mmol) 5-amino-3-chloro-1-methylpyridin-2(1H)-one (intermediate W1) was added and the solution was stirred for 1.5 hour. The mixture was diluted with CH2Cl2 and washed with 1M NaHCO3 solution. The water phase was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and evaporated. The crude product was purified by column chromatography (Silicagel, heptane, EtOAc) to give 474 mg (0.758 mmol, 80% yield) of the title compound as a brown oil. LCMS: (M+H)=619/621; tR=1.13 min (LC-MS 4). HPLC: tR=5.52 min (HPLC 7). TLC: Rf=0.09 (Heptane/EtOAc 1:2).

Workup

  1. washwashed with 1M NaHCO3 solution
  2. extractionThe water phase was extracted with CH2Cl2
  3. dry with materialThe combined organic phases were dried (Na2SO4)
  4. filtrationfiltered
  5. customevaporated
  6. customThe crude product was purified by column chromatography (Silicagel, heptane, EtOAc)

Sources & evidence

ORD record
ord-aa5a1928384e4e149688c5a58c38351f
Source dataset
uspto-grants-2015_03
Patent number
US08969341B2

Reaction notes

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