Methyl chloroformate → (6-Chloro-4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-methanone

HRID 1025830Notes

Reaction equation

HRID 1025830 reaction equation
[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=3[Cl:30])=[O:15])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[Cl:31]C1C=CC=C(C(OO)=O)C=1.C[Si](C)(C)N[Si](C)(C)C.ClC(OC)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:31][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[O:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[Cl:30])=[O:15])[CH2:6][CH2:5][N:4]2[CH:1]1[CH2:2][CH2:3]1

Participants

7

Reactant 5

HCID 6586Methyl chloroformateHCID 13838HexamethyldisilazaneHCID 70297m-Chloroperbenzoic acidHCID 516892Sodium BicarbonateHCID 53311869(4-Cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)(4-(2,5-dichloro-phenoxy)-pyridin-3-yl)-methanone

Product 1

HCID 53311952(6-Chloro-4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-methanoneYield 31%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To an ice-cold suspension of 0.61 g (1.39 mmol) (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-methanone (Example 8) in 3 mL dichloromethane were added 0.388 g (1.73 mmol) m-chloroperbenzoic acid (Aldrich, CAS RN 937-14-4). The cooling bath was removed, the reaction stirred at room temperature for 45 min., poured on a saturated solution of aqueous sodium bicarbonate and extracted three times with dichloromethane. The organic layers were washed with a saturated solution of aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate:methanol (100:0:0 to 0:100:0 to 0:0:100). From the resulting light brown foam (0.51 g; MS (ESI): m/z=456.087 [M+H]+), 0.20 g (0.44 mmol) were dissolved in 8 mL tetrahydrofuran and 0.09 mL (0.44 mmol) hexamethyldisilazane and 0.08 mL (1.1 mmol) methyl chloroformate were added. The resulting brown, turbid solution was stirred for 1.5 hours at room temperature, poured on saturated aqueous sodium bicarbonate solution and was extracted three times with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 25:75). The resulting orange solid (0.13 g) was dissolved in acetonitrile and a few drops N,N-dimethylformamide, filtered using a syringe micro filter and purified two times on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give 65 mg (31%) of the title compound as a light brown foam. MS (ESI): m/z=474.054 [M+H]+.

Workup

  1. customThe cooling bath was removed
  2. additionpoured on a saturated solution of aqueous sodium bicarbonate
  3. extractionextracted three times with dichloromethane
  4. washThe organic layers were washed with a saturated solution of aqueous sodium bicarbonate and brine
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. additiontreated with silica gel
  8. customevaporated
  9. customThe resulting powder was purified by silica gel chromatography
  10. dissolutionFrom the resulting light brown foam (0.51 g; MS (ESI): m/z=456.087 [M+H]+), 0.20 g (0.44 mmol) were dissolved in 8 mL tetrahydrofuran
  11. stirringThe resulting brown, turbid solution was stirred for 1.5 hours at room temperature
  12. extractionwas extracted three times with ethyl acetate
  13. washThe organic layers were washed with brine
  14. dry with materialdried over magnesium sulfate
  15. filtrationfiltered
  16. additiontreated with silica gel
  17. customevaporated
  18. customThe resulting powder was purified by silica gel chromatography
  19. washeluting with a gradient of n-heptane:ethyl acetate (100:0 to 25:75)
  20. dissolutionThe resulting orange solid (0.13 g) was dissolved in acetonitrile
  21. filtrationa few drops N,N-dimethylformamide, filtered
  22. filtrationmicro filter
  23. custompurified two times on a preparative HPLC system (Phenomenex Gemini column)

Sources & evidence

ORD record
ord-bf14405c9ac8477db4a562e84689c4cd
Source dataset
uspto-grants-2014_05
Patent number
US08729091B2

Reaction notes

Loading…