Sodium hydride → (S)-((4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl nicotinate

HRID 2200845

Reaction equation

HRID 2200845 reaction equation
[H-].[Na+].[CH3:3][CH2:4][C:5]1[C:14]2[CH2:15][N:16]3[C:21](=[O:22])[C:20]4[CH2:23][O:24][C:25]([C@:27]([OH:30])([CH2:28][CH3:29])[C:19]=4[CH:18]=[C:17]3[C:13]=2[N:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([OH:31])[CH:9]=[CH:10]2)=[O:26].[C:32]([O:40][CH2:41]Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1>CN(C=O)C>[C:32]([O:40][CH2:41][O:31][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]3[C:17]4[N:16]([CH2:15][C:14]3=[C:5]([CH2:4][CH3:3])[C:6]=2[CH:7]=1)[C:21](=[O:22])[C:20]1[CH2:23][O:24][C:25](=[O:26])[C@@:27]([CH2:28][CH3:29])([OH:30])[C:19]=1[CH:18]=4)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 1048427-Ethyl-10-Hydroxycamptothecin2×HCID 14608830Chloromethyl nicotinate

Product 1

HCID 89037103(S)-((4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl nicotinateYield 13%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
0 °C

Procedure

NaH (0.012 g, 0.51 mmol, 1.0 eq) was added portion wise to a solution of SN-38, (S)-4,11-diethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione [4150] (0.20 g, 0.51 mmol, 1.0 eq) in DMF (2 ml) under N2 atmosphere at 0° C. The resulting reaction mixture was stirred at 0° C. for an additional 30 min. To the reaction mixture, chloromethyl nicotinate [259] (0.087 g, 0.51 mmol, 1.0 eq) dissolved in DMF was added dropwise while maintaining the temperature at 0° C. The reaction was then allowed to come to RT and stirred overnight. The reaction mass was quenched with addition of water. The reaction mixture was extracted with DCM (2×100 ml). The organic layers were combined and washed with brine, dried over Na2SO4 and evaporated. The resultant crude product was purified on column chromatography (2% MeOH: DCM, silica gel 100-200 mesh) to yield a pale yellow solid, (S)-column chromatography (2% MeOH: DCM, silica gel 100-200 mesh) to yield a pale yellow solid, (S)-((4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl nicotinate [305] (0.036 g, 13%).

Workup

  1. customThe resulting reaction mixture
  2. additionwas added dropwise
  3. temperaturewhile maintaining the temperature at 0° C
  4. customto come to RT
  5. stirringstirred overnight
  6. customThe reaction mass was quenched with addition of water
  7. extractionThe reaction mixture was extracted with DCM (2×100 ml)
  8. washwashed with brine
  9. dry with materialdried over Na2SO4
  10. customevaporated
  11. customThe resultant crude product was purified on column chromatography (2% MeOH: DCM, silica gel 100-200 mesh)
  12. customto yield a pale yellow solid, (S)-column chromatography (2% MeOH: DCM, silica gel 100-200 mesh)

Sources & evidence

ORD record
ord-d9e28d41441f488d8d08d9d47352435e
Source dataset
uspto-grants-2016_06
Patent number
US09359376B2

Linked notes

Loading…