Tetrahydrofuran → 1-(2,5-Dimethylbenzyl)-9-(quinoxalin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

HRID 41560

Reaction equation

HRID 41560 reaction equation
[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[N:11]1[CH2:22][CH2:21][C:14]2([NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1.C1COCC1.[CH3:28][C:29]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:30]=1[CH2:31]Cl>[NH4+].[Cl-]>[CH3:28][C:29]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:30]=1[CH2:31][N:19]1[C:14]2([CH2:21][CH2:22][N:11]([C:2]3[CH:3]=[N:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH2:12][CH2:13]2)[CH2:15][CH2:16][CH2:17][C:18]1=[O:20]

Participants

5

Reactant 3

HCID 8028TetrahydrofuranHCID 69987Benzene, 2-(chloromethyl)-1,4-dimethyl-HCID 67251636HCID 67251636, compound

Product 1

HCID 532596341-(2,5-Dimethylbenzyl)-9-(quinoxalin-2-yl)-1,9-diazaspiro[5.5]undecan-2-oneYield 43.8%

Reagents, catalysts & solvents 1

HCID 25517Ammonium ChlorideSolvent

Procedure

To a solution of 9-(quinoxalin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one (80 mg, 0.27 mmol) in THF (5 mL) sodium hydride 95% (32 mg, 0.81 mmol) was added and the mixture was stirred for 10 min at rt. Then 2,5-dimethylbenzylchloride (70 mg, 0.35 mmol) was added and the reaction mixture was heated at 60° C. over 18 h. Saturated aqueous NH4Cl solution (40 mL) was added and the reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by reversed phase preparative HPLC (column Zorbax eclipseXDB C18, flow 20 mL/min, mobile phase 0.1% TFA in water (A): acetonitrile (B) gradient) to yield the title compound (49 mg, 22%). [1H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 7.88 (d, 1H), 7.70-7.55 (m, 2H), 7.48-7.35 (t, 1H), 7.05-6.85 (m, 2H), 6.72 (s, 1H), 4.55 (s, 2H), 4.55-4.39 (m, 2H), 3.12 (t, 2H), 2.65 (t, 2H), 2.30 (s, 3H), 2.15 (s, 3H), 2.20-1.88 (m, 6H), 1.85-1.63 (m, 2H); LCMS RtE=1.64 min, [M+H]+=415.2].

Workup

  1. temperaturethe reaction mixture was heated at 60° C. over 18 h
  2. extractionthe reaction mixture was extracted with ethyl acetate (100 mL)
  3. dry with materialThe organic layer was dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe resulting crude product was purified by reversed phase preparative HPLC (column Zorbax eclipseXDB C18, flow 20 mL/min, mobile phase 0.1% TFA in water (A): acetonitrile (B) gradient)

Sources & evidence

ORD record
ord-4f329e38558046f68f2678bebbf80542
Source dataset
uspto-grants-2013_09
Patent number
US08530648B2

Linked notes

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