Nitrogen → HCID 58204769, compound

HRID 1629427Notes

Reaction equation

HRID 1629427 reaction equation
C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.CN(C)CCN(C)C.C([Li])(CC)C.N#N.Br[C:29]1[CH:51]=[CH:50][C:32]2[C:33]3[N:37]([CH2:38][CH2:39][O:40][C:31]=2[CH:30]=1)[CH:36]=[C:35]([C:41]1[N:42]([CH:47]([CH3:49])[CH3:48])[N:43]=[C:44]([CH3:46])[N:45]=1)[N:34]=3.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>COC(C)(C)C.ClCCl.[Cl-].[Cl-].[Zn+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.N1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH:47]([N:42]1[C:41]([C:35]2[N:34]=[C:33]3[N:37]([CH2:38][CH2:39][O:40][C:31]4[CH:30]=[C:29]([CH:12]5[CH2:11][CH2:10][CH2:9][NH:8]5)[CH:51]=[CH:50][C:32]=43)[CH:36]=2)=[N:45][C:44]([CH3:46])=[N:43]1)([CH3:49])[CH3:48]

Participants

12

Reactant 6

HCID 947NitrogenHCID 8037N,N,N',N'-TetramethylethylenediamineHCID 643455N-Boc-pyrrolidineHCID 2734635Tri-tert-butylphosphine tetrafluoroborateHCID 582043229-Bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineHCID 178418400CID 53628100

Product 1

HCID 58204769HCID 58204769, compound

Reagents, catalysts & solvents 5

HCID 167845palladium(II) acetateCatalystHCID 3007855ZincchlorideCatalystHCID 20144828HCID 20144828, compoundCatalystHCID 6344DichloromethaneSolventHCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of N-(tert-Butoxycarbonyl)pyrrolidine (1.02 mL, 0.00584 mol) and N,N,N′,N′-Tetramethylethylenediamine (0.881 mL, 0.00584 mol) in anhydrous 2-Methoxy-2-methylpropane (12 mL) at −78° C. was added sec-Butyllithium (0.00584 mol, 1.4M in cyclohexane, 4.17 mL). The reaction was stirred for 3 hours at −78° C. A solution of Zinc dichloride (0.00350 mol, 0.5 M in THF, 7.0 mL) was added dropwise with rapid stirring and was stirred at −78° C. for 30 minutes. The reaction was then warmed to room temperature and stirred an additional 30 mintues. To a N2-filled flask containing 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (0.900 g, 0.00232 mol), Palladium Acetate (0.0260 g, 0.116 mmol) and Tri-t-butylphosphonium tetrafluoroborate (0.0420 g, 0.000145 mol) was added the zinc chloride pyrrolidine solution (1.25 equiv., 0.243M, 11.9 mL). The reaction was heated to 90° C. overnight. An incomplete conversion to product was observed by LC/MS. The mixture was diluted with dichloromethane and filtered through celite. Saturated NH4Cl was added and the mixture was extracted 3 times with dichloromethane. The organic layers were combined, dried with Na2SO4 and concentrated. The crude was redissolved in Methylene chloride (4.5 mL). Trifluoroacetic Acid (5.5 mL) was added and the reaction was stirred at room temperature for 30 minutes, then concentrated. The crude was purified by reverse-phase HPLC and the enantiomers were separated by chiral SFC to obtain 10 mg of each enantiomer of 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-pyrrolidin-2-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as a white solid. MS(ESI+) 379.2

Workup

  1. stirringwith rapid stirring
  2. stirringwas stirred at −78° C. for 30 minutes
  3. temperatureThe reaction was then warmed to room temperature
  4. stirringstirred an additional 30 mintues
  5. temperatureThe reaction was heated to 90° C. overnight
  6. filtrationfiltered through celite
  7. additionSaturated NH4Cl was added
  8. extractionthe mixture was extracted 3 times with dichloromethane
  9. dry with materialdried with Na2SO4
  10. concentrationconcentrated
  11. dissolutionThe crude was redissolved in Methylene chloride (4.5 mL)
  12. additionTrifluoroacetic Acid (5.5 mL) was added
  13. stirringthe reaction was stirred at room temperature for 30 minutes
  14. concentrationconcentrated
  15. customThe crude was purified by reverse-phase HPLC
  16. customthe enantiomers were separated by chiral SFC

Sources & evidence

ORD record
ord-c71b3f9f641d4b4fad94ed84801de56c
Source dataset
uspto-grants-2014_07
Patent number
US08785626B2

Reaction notes

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