Sodium Bicarbonate → (5-chloropyridin-2-yl)(1H-imidazol-1-yl)methanone

HRID 930289Notes

Reaction equation

HRID 930289 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([F:30])=[C:16]([C@:18]2([CH3:29])[CH2:23][C@@H:22]([C:24]([F:27])([F:26])[F:25])[O:21][C:20]([NH2:28])=[N:19]2)[CH:17]=1.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([N:40]2[CH:44]=[CH:43][N:42]=[CH:41]2)=[O:39])=[N:36][CH:37]=1.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([N:40]2[CH:44]=[CH:43][N:42]=[CH:41]2)=[O:39])=[N:36][CH:37]=1.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([NH:28][C:20]2[O:21][C@H:22]([C:24]([F:26])([F:27])[F:25])[CH2:23][C@:18]([C:16]3[CH:17]=[C:12]([NH:11][C:8](=[O:10])[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)[CH:13]=[CH:14][C:15]=3[F:30])([CH3:29])[N:19]=2)=[O:39])=[N:36][CH:37]=1

Participants

7

Reactant 4

HCID 516892Sodium BicarbonateHCID 27628725-Chloro-2-picolinic acidHCID 71663148(4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amineHCID 86732120(5-chloropyridin-2-yl)(1H-imidazol-1-yl)methanone2×

Product 2

HCID 86732120(5-chloropyridin-2-yl)(1H-imidazol-1-yl)methanoneHCID 867321215-chloro-N-((4S,6S)-4-(5-(5-chloropicolinamido)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)picolinamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A stock solution of (5-chloropyridin-2-yl)(1H-imidazol-1-yl)methanone was prepared by adding N,N′-carbonyldiimidazole (Aldrich; 278 mg, 1.72 mmol) to a solution of 5-chloropicolinic acid (Shao Yuan; 280 mg, 1.78 mmol) in THF (5.0 mL) and heating the reaction mixture to 60° C. for 2 h. (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (4i, 50 mg, 0.172 mmol) was added to a flask containing 0.55 mL (1.1 equiv.) of the (5-chloropyridin-2-yl)(1H-imidazol-1-yl)methanone stock solution. The reaction mixture was allowed to stir for 30 min at ambient temperature, after which a second aliquot of (5-chloropyridin-2-yl)(1H-imidazol-1-yl)methanone solution (0.55 mL, 1.1 equiv.) was added. After 16 hs, saturated aqueous NaHCO3 (50 mL) was added to the reaction mixture and the product was extracted with EtOAc (3×50 mL). The combined organic extracts were dried over MgSO4, concentrated, and purified by flash chromatography on silica gel (Gradient: 0%→50% EtOAc/hexane) to give 5-chloro-N-((4S,6S)-4-(5-(5-chloropicolinamido)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)picolinamide (85.3 mg, 0.150 mmol) as a colorless glass. MS m/z=570 M+. Calculated for C24H17Cl2F4N5O3: 570.3

Workup

  1. additionwas added to a flask
  2. extractionthe product was extracted with EtOAc (3×50 mL)
  3. dry with materialThe combined organic extracts were dried over MgSO4
  4. concentrationconcentrated
  5. custompurified by flash chromatography on silica gel (Gradient: 0%→50% EtOAc/hexane)

Sources & evidence

ORD record
ord-93cb4714410043d3879a8a0f1d6a0876
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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