4-Methoxybenzylamine → 1'-(7-Fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6'-(4-morpholinyl)-1',2,2',3,5,6-hexahydrospiro[pyran-4,3'-pyrrolo[3,2-b]pyridin]-5'-amine

HRID 1618768Notes

Reaction equation

HRID 1618768 reaction equation
Br[C:2]1[N:7]=[C:6]2[C:8]3([CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH2:9][N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH3:28])[C:5]2=[CH:4][C:3]=1[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.COC1C=CC(C[NH2:47])=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1>[F:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([N:10]3[C:5]4[C:6](=[N:7][C:2]([NH2:47])=[C:3]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH:4]=4)[C:8]4([CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH2:9]3)=[C:12]([CH3:28])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:14]2)=[CH:19][CH:18]=1

Participants

5

Reactant 3

HCID 754524-MethoxybenzylamineHCID 23676156Sodium t-butoxideHCID 866642805'-Bromo-1'-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6'-(4-morpholinyl)-1',2,2',3,5,6-hexahydrospiro[pyran-4,3'-pyrrolo[3,2-b]pyridine]

Product 1

HCID 672855841'-(7-Fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6'-(4-morpholinyl)-1',2,2',3,5,6-hexahydrospiro[pyran-4,3'-pyrrolo[3,2-b]pyridin]-5'-amine

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

To a stirred solution of 5′-bromo-1′-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (60 mg, 0.102 mmol) in 1,4-dioxane (1.5 mL) was added 4-methoxybenzylamine (19.78 μL, 0.152 mmol) and sodium tert-butoxide (19.53 mg, 0.203 mmol). The reaction was heated at reflux for 2 h. After this time the reaction was partitioned between EtOAc (50 mL) and water (15 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. The crude mixture was then dissolved in DCM (3 mL) and treated with TFA (0.5 mL) and stirred at rt for 2 h. At this time the reaction was evaporated in vacuo and partitioned between DCM (30 mL) and NaHCO3 (10 mL, sat. aqueous solution). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. The resulting crude product was purified by reverse phase HPLC (10 to 60% acetonitrile water) to give 1′-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-5′-amine. 1H NMR (400 MHz, chloroform-d) δ ppm 8.71-8.78 (1H, m), 7.77-7.94 (4H, m), 7.40 (1H, ddd, J=7.2, 4.9, 1.6 Hz), 7.18-7.26 (1H, m), 6.10-6.15 (1H, m), 4.13 (2H, q, J=7.2 Hz), 3.92-4.02 (2H, m), 3.68-3.86 (4H, m), 3.51-3.60 (2H, m), 2.67-2.82 (4H, m), 2.24-2.41 (5H, m), 1.67-1.84 (2H, m). Mass Spectrum (ESI) m/e=527.2 (M+1).

Workup

  1. temperatureThe reaction was heated
  2. temperatureat reflux for 2 h
  3. customAfter this time the reaction was partitioned between EtOAc (50 mL) and water (15 mL)
  4. dry with materialThe separated organic layer was dried over MgSO4
  5. filtrationfiltered
  6. customevaporated in vacuo
  7. dissolutionThe crude mixture was then dissolved in DCM (3 mL)
  8. additiontreated with TFA (0.5 mL)
  9. customAt this time the reaction was evaporated in vacuo
  10. custompartitioned between DCM (30 mL) and NaHCO3 (10 mL, sat. aqueous solution)
  11. dry with materialThe separated organic layer was dried over MgSO4
  12. filtrationfiltered
  13. customevaporated in vacuo
  14. customThe resulting crude product was purified by reverse phase HPLC (10 to 60% acetonitrile water)

Sources & evidence

ORD record
ord-5508a672a0a64be19dbdfb6e583c84a4
Source dataset
uspto-grants-2014_07
Patent number
US08765940B2

Reaction notes

Loading…