1,1-Dichloroethane → HCID 11692406, compound

HRID 351307Notes

Reaction equation

HRID 351307 reaction equation
[CH3:1][C:2]1([CH2:6][O:7][C:8]2[CH:34]=[CH:33][C:11]3[N:12]([C:15]4[CH:24]=[CH:23][C:22]5[C:17](=[C:18](OS(C(F)(F)F)(=O)=O)[CH:19]=[CH:20][CH:21]=5)[N:16]=4)[CH:13]=[N:14][C:10]=3[CH:9]=2)[CH2:5][O:4][CH2:3]1.[C:35]([O:39][C:40](=[O:48])[NH:41][CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)([CH3:38])([CH3:37])[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].ClC(Cl)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:35]([O:39][C:40](=[O:48])[NH:41][CH:42]1[CH2:47][CH2:46][N:45]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[N:16]=[C:15]([N:12]2[C:11]4[CH:33]=[CH:34][C:8]([O:7][CH2:6][C:2]5([CH3:1])[CH2:3][O:4][CH2:5]5)=[CH:9][C:10]=4[N:14]=[CH:13]2)[CH:24]=[CH:23]3)[CH2:44][CH2:43]1)([CH3:38])([CH3:36])[CH3:37]

Participants

8

Reactant 4

HCID 63651,1-DichloroethaneHCID 10796Cesium carbonateHCID 7238334-(N-Boc-amino)piperidineHCID 58807286HCID 58807286, compound

Product 1

HCID 11692406HCID 11692406, compoundYield 79%

Reagents, catalysts & solvents 3

HCID 634876Binap, (A+-)-CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
85 °C

Procedure

BINAP (379 mg, 608 μmol, 0.06 equivalents), tris(dibenzylideneacetone)dipalladium (186 mg, 203 μmol, 0.02 equivalents) and toluene (35 mL, 7 volumes) were added to a 100 mL round bottom flask. The solution was deoxygenated and stirred at 20–25° C. for ˜30 minutes. Next, trifluoro-methanesulfonic acid 2-[5-(3-methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl ester (5 g, 10.1 mmol, 1 equivalent), piperidin-4-yl-carbamic acid tert-butyl ester (4.06 g, 20.3 mmol, 2.0 equivalents), and cesium carbonate (4.62 g, 14.2 mmol, 1.3 equivalents) were charged. The reaction was again deoxygenated and then heated to 85° C. for 24–32 hours. At reaction completion, the reaction was cooled to 30° C. and dichloroethane (5 volumes) and Celite (0.5 wt. equivalent) were added. The slurry was filtered through a pad of Celite and rinsed with dichloroethane (5 volumes). The mother liquor was then concentrated to low volume and ethyl acetate (75 mL, 15 volumes) was charged. The thin slurry was granulated at 20–25° C. for 8–15 h and then filtered. The mother liquor was collected and washed with a 2.5% NaH2PO4 solution (3×9 volumes). The organics were again concentrated to low volume and acetonitrile (25 mL, 5 volumes) was charged. The slurry was granulated for 10–20 hours, and then the solids were filtered and dried under vacuum at 40° C. with a slight nitrogen bleed to yield 4.33 g (1-{2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-yl)-carbamic acid tert-butyl ester as a yellow solid. (79% yield).

Workup

  1. customThe solution was deoxygenated
  2. customThe reaction was again deoxygenated
  3. customAt reaction completion
  4. temperaturethe reaction was cooled to 30° C.
  5. filtrationThe slurry was filtered through a pad of Celite
  6. washrinsed with dichloroethane (5 volumes)
  7. concentrationThe mother liquor was then concentrated to low volume and ethyl acetate (75 mL, 15 volumes)
  8. additionwas charged
  9. waitThe thin slurry was granulated at 20–25° C. for 8–15 h
  10. filtrationfiltered
  11. customThe mother liquor was collected
  12. washwashed with a 2.5% NaH2PO4 solution (3×9 volumes)
  13. concentrationThe organics were again concentrated to low volume and acetonitrile (25 mL, 5 volumes)
  14. additionwas charged
  15. waitThe slurry was granulated for 10–20 hours
  16. filtrationthe solids were filtered
  17. customdried under vacuum at 40° C. with a slight nitrogen

Sources & evidence

ORD record
ord-363d52142be2483d8fd30063af76c303
Source dataset
uspto-grants-2007_02
Patent number
US07183414B2

Reaction notes

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