Cesium carbonate → {1-[2-(6,7-Dihydro-5,8-dioxa-1,3-diaza-cyclopenta[b]naphthalen-1-yl)-quinolin-8-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester

HRID 1745913Notes

Reaction equation

HRID 1745913 reaction equation
Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[C:16]3=[CH:17][C:18]4[O:19][CH2:20][CH2:21][O:22][C:23]=4[CH:24]=[C:15]3[N:14]=[CH:13]1)[CH:8]=[CH:7]2.[C:25]([O:29][C:30](=[O:38])[NH:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26].C([O-])([O-])=O.[Cs+].[Cs+].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>O1CCOCC1.C(O)(C(F)(F)F)=O.C(Cl)Cl.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]>[C:25]([O:29][C:30](=[O:38])[NH:31][CH:32]1[CH2:37][CH2:36][N:35]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([N:12]2[C:16]4=[CH:17][C:18]5[O:19][CH2:20][CH2:21][O:22][C:23]=5[CH:24]=[C:15]4[N:14]=[CH:13]2)[CH:8]=[CH:7]3)[CH2:34][CH2:33]1)([CH3:28])([CH3:26])[CH3:27]

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 7238334-(N-Boc-amino)piperidineHCID 222269031-(8-Bromo-quinolin-2-yl)-6,7-dihydro-1H-5,8-dioxa-1,3-diaza-cyclopenta[b]naphthalene

Product 1

HCID 69559050{1-[2-(6,7-Dihydro-5,8-dioxa-1,3-diaza-cyclopenta[b]naphthalen-1-yl)-quinolin-8-yl]-piperidin-4-yl}-carbamic acid tert-butyl esterYield 54.5%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6344DichloromethaneSolventHCID 6422Trifluoroacetic acidSolventHCID 312751,4-DioxaneSolvent

Procedure

1-(8-Bromo-quinolin-2-yl)-6,7-dihydro-1H-5,8-dioxa-1,3-diaza-cyclopenta[b]naphthalene 81C (700 mg, 1.83 mMol) and piperidin-4-yl-carbamic acid tert-butyl ester (733 mg, 3.66 mMol) were dissolved in 6.0 mL of dioxane under an atmosphere of dry N2. To this solution was added Cs2CO3 (835 mg, 2.56 mMol), racemic-BINAP (68 mg, 0.109 mMol) and tris(dibenzylideneacetone)dipalladium (0) (34 mg, 0.037 mMol) and the reaction mixture was heated to reflux and reacted at this temperature overnight. The mixture was then cooled to ambient temperature, filtered; and concentrated under vacuum to give 1.12 g of an orange film. The film was dissolved in a solution of 5 mL of TFA and 5 mL of DCM under an atmosphere of dry N2. The reaction mixture was stirred at ambient temperature for 30 minutes after which time it was concentrated under vacuum to give a yellow oil. The oil was partitioned between ethyl ether and 0.1 N aqueous HCl. The aqueous layer was then washed with DCM. The aqueous layer was basified to pH˜11 with NaOH. The resulting solution was washed three times with DCM. The DCM extracts were combined, dried over Na2SO4, filtered and concentrated to give 500 mg of a yellow solid. The solid was chromatographed on flash silica gel eluting with MeOH/DCM (1090) to give 127 mg of the title compound 81 as a yellow solid.

Workup

  1. temperatureto reflux
  2. customreacted at this temperature overnight
  3. filtrationfiltered
  4. concentrationand concentrated under vacuum
  5. customto give 1.12 g of an orange film
  6. concentrationwas concentrated under vacuum
  7. customto give a yellow oil
  8. customThe oil was partitioned between ethyl ether and 0.1 N aqueous HCl
  9. washThe aqueous layer was then washed with DCM
  10. washThe resulting solution was washed three times with DCM
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-bd3751ee5cac41bd8ee2151391e89220
Source dataset
uspto-grants-2006_03
Patent number
US07019147B1

Reaction notes

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