Sodium hydride → [2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(2-phenoxy-ethyl)-amine

HRID 885694Notes

Reaction equation

HRID 885694 reaction equation
C(OC(=O)[N:7]([CH:17]1[CH2:25][CH2:24][C:23]2[C:19](=[CH:20][N:21]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[N:34]=4)[N:29]=[CH:28][CH:27]=3)[N:22]=2)[CH2:18]1)[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.C(OC(=O)NC1CCC2C(=CN(C3C4C(=CC=C(OC)N=4)N=CC=3)N=2)C1)(C)(C)C.[H-].[Na+].BrCCOC1C=CC=CC=1>CN(C=O)C.CCOC(C)=O.O>[CH3:37][O:36][C:33]1[N:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[C:26]2[N:21]1[CH:20]=[C:19]2[C:23]([CH2:24][CH2:25][CH:17]([NH:7][CH2:8][CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:18]2)=[N:22]1

Participants

8

Reactant 4

HCID 24758Sodium hydride2×HCID 68526Benzene, (2-bromoethoxy)-2×HCID 59560627[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]carbamic acid tert-butyl esterHCID 68497153[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(2-phenoxy-ethyl)-carbamic acid tert-butyl ester

Product 1

HCID 11948461[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(2-phenoxy-ethyl)-amineYield 48%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

[2-(6-Methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-(2-phenoxy-ethyl)-carbamic acid tert-butyl ester. To a solution of [2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]carbamic acid tert-butyl ester (104 mg, 0.260 mmol) in DMF (2.6 mL) was added NaH (60% in mineral oil, 27 mg, 0.66 mmol) at 0° C. The reaction mixture was warmed to RT and stirred for 30 min. Upon cooling the reaction mixture to 0° C., β-bromophenetole (78 mg, 0.39 mmol) was added. The mixture was warmed to RT, and treated with additional NaH (31 mg, 1.3 mmol) and β-bromophenetole (261 mg, 1.30 mmol). After 30 h, H2O (30 mL) and EtOAc (40 mL) were added to the reaction mixture. The organic layer was separated, washed with brine (20 mL), dried (MgSO4), filtered, and concentrated. The crude was purified on SiO2 (0-100% EtOAc/hexanes) to give 65 mg (48%) of the title compound as a white solid. MS (ESI): exact mass calculated for C29H33N5O4, 515.25; m/z found, 516.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.09 (br s, 1H), 8.77 (d, J=5.0, 1H), 8.26 (d, J=9.1, 1H), 8.15 (d, J=5.0, 1H), 7.30-7.27 (m, 2H), 7.18 (d, J=9.1, 1H), 6.97-6.92 (m, 1H), 6.90 (d, J=7.8, 2H), 4.16-4.04 (m, 6H), 3.65-3.59 (m, 2H), 3.09-3.05 (m, 1H), 2.92 (br s, 3H), 2.11 (br s, 2H), 1.49 (s, 9H).

Workup

  1. temperatureUpon cooling the reaction mixture to 0° C.
  2. temperatureThe mixture was warmed to RT
  3. waitAfter 30 h
  4. customThe organic layer was separated
  5. washwashed with brine (20 mL)
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude was purified on SiO2 (0-100% EtOAc/hexanes)

Sources & evidence

ORD record
ord-1d3fb751bcc4405aae00ca21cc1d4b13
Source dataset
uspto-grants-2012_08
Patent number
US08242275B2

Reaction notes

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