2-Ethoxy-1-(ethoxycarbonyl)-1,2-dihydroquinoline → (S)-tert-Butyl 5-bromo-3-(1-(tert-butoxycarbonyl)-pyrrolidine-2-carboxamido)-1H-indazole-1-carboxylate

HRID 1510834Notes

Reaction equation

HRID 1510834 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[NH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([Br:44])[CH:42]=2)[N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:36]=1>ClCCCl>[Br:44][C:41]1[CH:42]=[C:43]2[C:38](=[CH:39][CH:40]=1)[N:37]([C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])[N:36]=[C:35]2[NH:34][C:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15]

Participants

5

Reactant 3

HCID 278332-Ethoxy-1-(ethoxycarbonyl)-1,2-dihydroquinolineHCID 850831,2-Pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, (2S)-HCID 58287777tert-butyl 3-amino-5-bromo-1H-indazole-1-carboxylate

Product 1

HCID 58287783(S)-tert-Butyl 5-bromo-3-(1-(tert-butoxycarbonyl)-pyrrolidine-2-carboxamido)-1H-indazole-1-carboxylate

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent2×

Procedure

A solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (8.41 g, 39.1 mmol) and ethyl 2-ethoxyquinoline-1(2H)-carboxylate (EEDQ, 9.66 g, 39.1 mmol) in DCE (50 mL) was allowed to stir at rt for 10 min. To this solution was added a solution of tert-butyl 3-amino-5-bromo-1H-indazole-1-carboxylate (6.1 g, 19.54 mmol) in DCE (50 mL) in one portion and the resulting mixture was heated at 70° C. overnight. The mixture was partitioned between sat NaHCO3 and EtOAc and the phases were separated. The aqueous layer was extracted (×2) with EtOAc and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified on flash chromatography (BIOTAGE® eluting with a gradient of 0 to 100% Ether/Hexanes) to afford the title compound as yellow solid contaminated with quinoline. The material was dissolved in ether and washed several times with HCl (1M). The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound (4.8 g, 48% yield) as yellow solid. The material was used as is in subsequent steps. 1H NMR (500 MHz, CD3OD) δ 8.19 (app d, J=11.3 Hz, 1H), 8.03 (unresolved dd, J=8.9, 11.0 Hz, 1H), 7.67-7.70 (m, 1H), 4.40-4.44 (m, 1H), 3.57-3.61 (m, 1H), 3.47-3.52 (m, 1H), 2.33-2.42 (m, 1H), 2.01-2.13 (m, 2H), 1.91-1.98 (m, 1H), 1.68 (s, 9H), 1.50, 1.42 (s, 9H, rotamers, 2:1 ratio). LCMS: Anal. Calcd. for C22H29BrN4O5: 508, 510; found: 509, 511 (M+H)+.

Workup

  1. temperaturethe resulting mixture was heated at 70° C. overnight
  2. customThe mixture was partitioned
  3. customthe phases were separated
  4. extractionThe aqueous layer was extracted (×2) with EtOAc
  5. dry with materialthe combined organic layers were dried (Na2SO4)
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified on flash chromatography (BIOTAGE®
  8. washeluting with a gradient of 0 to 100% Ether/Hexanes)

Sources & evidence

ORD record
ord-ee69e834ae90483ea53794dedb2bde8f
Source dataset
uspto-grants-2012_07
Patent number
US08211928B2

Reaction notes

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